Question: Does Vitamin D impact COVID-19 prevention and treatment?

Title: Does vitamin D deficiency increase the severity of COVID-19? Content: The severity of coronavirus 2019 infection (COVID-19) is determined by the presence of pneumonia, severe acute respiratory distress syndrome (SARS-CoV-2), myocarditis, microvascular thrombosis and/or cytokine storms, all of which involve underlying inflammation. A principal defence against uncontrolled inflammation, and against viral infection in general, is provided by T regulatory lymphocytes (Tregs). Treg levels have been reported to be low in many COVID-19 patients and can be increased by vitamin D supplementation. Low vitamin D levels have been associated with an increase in inflammatory cytokines and a significantly increased risk of pneumonia and viral upper respiratory tract infections. Vitamin D deficiency is associated with an increase in thrombotic episodes, which are frequently observed in COVID-19. Vitamin D deficiency has been found to occur more frequently in patients with obesity and diabetes. These conditions are reported to carry a higher mortality in COVID-19. If vitamin D does in fact reduce the severity of COVID-19 in regard to pneumonia/ARDS, inflammation, inflammatory cytokines and thrombosis, it is our opinion that supplements would offer a relatively easy option to decrease the impact of the pandemic.

Title: Does Vitamin D play a role in the management of Covid-19 in Brazil? Content: The study discusses the possible role of adequate vitamin D status in plasma or serum for preventing acute respiratory infections during the Covid-19 pandemic. Our arguments respond to an article, published in Italy, that describes the high prevalence of hypovitaminosis D in older Italian women and raises the possible preventive and therapeutic role of optimal vitamin D levels. Based on literature review, we highlight the findings regarding the protective role of vitamin D for infectious diseases of the respiratory system. However, randomized controlled trials are currently lacking. Adequate vitamin D status is obtained from sun exposure and foods rich in vitamin D. Studies in Brazil have shown that hypovitaminosis D is quite common in spite of high insolation. Authors recommend ecological, epidemiological and randomized controlled trials studies to verify this hypothesis.

Title: The Role of Vitamin D in The Age of COVID-19: A Systematic Review and Meta-Analysis Along with an Ecological Approach Content: Background: Following emerge of a novel coronavirus from Wuhan, China, in December 2019, it has affected the whole world and after months of efforts by the medical communities, there is still no specific approach for prevention and treatment against the Coronavirus Disease 2019 (COVID-19). Evidence recommends that vitamin D might be an important supportive agent for the immune system, mainly in cytokine response regulation against COVID-19. Hence, we carried out a rapid systematic review and meta-analysis along with an ecological investigation in order to maximize the use of everything that exists about the role of vitamin D in the COVID-19. Methods: A systematic search was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science and Google Scholar (intitle) as well as preprint database of medRxiv, bioRxiv, Research Square, preprints.org, search engine of ScienceDirect and a rapid search through famous journals up to May 26, 2020. Studies focused on the role of vitamin D in confirmed COVID-19 patients were entered into the systematic review. Along with our main aim, to find the second objective: correlation of global vitamin D status and COVID-19 recovery and mortality we carried out a literature search in PubMed database to identify the national or regional studies reported the vitamin D status globally. CMA v. 2.2.064 and SPSS v.16 were used for data analysis. Results: Out of nine studies entered into our systematic review, six studies containing 3,822 participants entered into the meta-analysis. The meta-analysis indicated that 46.5% of COVID-19 patients were suffering from vitamin D deficiency (95% CI, 28.2%-65.8%) and in 43.3% of patients, levels of vitamin D were insufficient (95% CI, 27.4%-60.8%). In regard to our ecological investigation on 51 countries including 408,748 participants, analyses indicated no correlation between vitamin D levels and recovery rate (r= 0.041) as well as mortality rate (r=-0.073) globally. However, given latitude, a small reverse correlation between mortality rate and vitamin D status was observed throughout the globe (r= -0.177). In Asia, a medium direct correlation was observed for recovery rate (r= 0.317) and a significant reveres correlation for mortality rate (r= -0.700) with vitamin D status in such patients. In Europe, there were no correlations for both recovery (r= 0.040) and mortality rate (r= -0.035). In Middle East, the recovery rate (r= 0.267) and mortality rate (r= -0.217) showed a medium correlation. In North and Sought America, surprisingly, both recovery and mortality rate demonstrated a direct correlation respectively (r= 1.000, r=0.500). In Oceania, unexpectedly, recovery (r= -1.000) and mortality (r= -1.000) rates were in considerable reverse correlation with vitamin D levels. Conclusion: In this systematic review and meta-analysis with an ecological approach, we found a high percentage of COVID-19 patients who suffer from vitamin D deficiency or insufficiency. Much more important, our ecological investigation resulted in substantial direct and reverse correlations between recovery and mortality rates of COVID-19 patients with vitamin D status in different countries. Considering latitudes, a small reverse correlation between vitamin D status and mortality rate was found globally. It seems that populations with lower levels of vitamin D might be more susceptible to the novel coronavirus infection. Nevertheless, due to multiple limitations, if this study does not allow to quantify a value of the Vitamin D with full confidence, it allows at least to know what the Vitamin D might be and that it would be prudent to invest in this direction through comprehensive large randomized clinical trials.

Title: Association of Vitamin D Deficiency and Treatment with COVID-19 Incidence Content: Importance: Vitamin D treatment has been found to decrease incidence of viral respiratory tract infection, especially in vitamin D deficiency. It is unknown whether COVID-19 incidence is associated with vitamin D deficiency and treatment. Objective: To examine whether vitamin D deficiency and treatment are associated with testing positive for COVID-19. Design: Retrospective cohort study Setting: University of Chicago Medicine Participants: Patients tested for COVID-19 from 3/3/2020-4/10/2020. Vitamin D deficiency was defined by the most recent 25-hydroxycholecalciferol <20ng/ml or 1,25-dihydroxycholecalciferol <18pg/ml within 1 year before COVID-19 testing. Treatment was defined by the most recent vitamin D type and dose, and treatment changes between the time of the most recent vitamin D level and time of COVID-19 testing. Vitamin D deficiency and treatment changes were combined to categorize vitamin D status at the time of COVID-19 testing as likely deficient(last-level-deficient/treatment-not-increased), likely sufficient(last-level-not-deficient/treatment-not-decreased), or uncertain deficiency(last-level-deficient/treatment-increased or last-level-not-deficient/treatment-decreased). Main Outcomes and Measures: The main outcome was testing positive for COVID-19. Multivariable analysis tested whether the most recent vitamin D level and treatment changes after that level were associated with testing positive for COVID-19 controlling for demographic and comorbidity indicators. Bivariate analyses of associations of treatment with vitamin D deficiency and COVID-19 were performed. Results: Among 4,314 patients tested for COVID-19, 499 had a vitamin D level in the year before testing. Vitamin D status at the time of COVID-19 testing was categorized as likely deficient for 127(25%) patients, likely sufficient for 291(58%) patients, and uncertain for 81(16%) patients. In multivariate analysis, testing positive for COVID-19 was associated with increasing age(RR(age<50)=1.05,p<0.021;RR(age[≥]50)=1.02,p<0.064)), non-white race(RR=2.54,p<0.01) and being likely vitamin D deficient (deficient/treatment-not-increased:RR=1.77,p<0.02) as compared to likely vitamin D sufficient(not-deficient/treatment-not-decreased), with predicted COVID-19 rates in the vitamin D deficient group of 21.6%(95%CI[14.0%-29.2%] ) versus 12.2%(95%CI[8.9%-15.4%]) in the vitamin D sufficient group. Vitamin D deficiency declined with increasing vitamin D dose, especially of vitamin D3. Vitamin D dose was not significantly associated with testing positive for COVID-19. Conclusions and Relevance: Vitamin D deficiency that is not sufficiently treated is associated with COVID-19 risk. Testing and treatment for vitamin D deficiency to address COVID-19 warrant aggressive pursuit and study.

Title: Letter: does vitamin D have a potential role against COVID‐19? Authors' reply Content: We thank Kumar et al for their comments on our review article and the letter connected with that by Panarese and Shahini.(1,2) We agree that there is a complicated effect of vitamin D in preventing the severity of COVID‐19, while this mechanism is not exactly the same as that of influenza.

Title: What is the role of supplementation with ascorbic acid, zinc, vitamin D, or N-acetylcysteine for prevention or treatment of COVID-19? Content: Several agents intended to supplement dietary intake or endogenous molecules may have a theoretical role in preventing or treating COVID-19. Because of their potential to influence immune response, ascorbic acid (vitamin C), zinc, vitamin D, and N-acetylcysteine have been hypothesized to be useful for prevention or treatment of COVID-19. The authors outline the biologic plausibility, applicable clinical data, and potential role of each of these agents.

Title: Strong Correlation Between Prevalence of Severe Vitamin D Deficiency and Population Mortality Rate from COVID-19 in Europe Content: Background: SARS-CoV-2 virus causes a very wide range of COVID-19 disease severity in humans: from completely asymptomatic to fatal, and the reasons behind it are often not understood. There is some data that Vitamin D may have protective effect, so authors decided to analyze European country-wide data to determine if Vitamin D levels are associated with COVID-19 population death rate. Methods: To retrieve the Vitamin D levels data, authors analyzed the Vitamin D European population data compiled by 2019 ECTS Statement on Vitamin D Status published in the European Journal of Endocrinology. For the data set to used for analysis, only recently published data, that included general adult population of both genders ages 40-65 or wider, and must have included the prevalence of Vitamin D deficiency. Results: There were 10 countries data sets that fit the criteria and were analyzed. Severe Vitamin D deficiency was defined as 25(OH)D less than 25 nmol/L (10 ng/dL). Pearson correlation analysis between death rate per million from COVID-19 and prevalence of severe Vitamin D deficiency shows a strong correlation with r = 0.76, p = 0.01, indicating significant correlation. Correlation remained significant, even after adjusting for age structure of the population. Additionally, over time, correlation strengthened, and r coefficient asymptoticaly increased. Conclusions: Authors recommend universal screening for Vitamin D deficiency, and further investigation of Vitamin D supplementation in randomized control studies, which may lead to possible treatment or prevention of COVID-19.

Title: Vitamin D Levels and COVID-19 Susceptibility: Is there any Correlation? Content: Coronavirus disease (COVID-19) is a major pandemic and now a leading cause of death worldwide. Currently, no drugs/vaccine is available for the treatment of this disease. Future preventions and social distancing are the only ways to prevent this disease from community transmission. Vitamin D is an important micronutrient and has been reported to improve immunity and protect against respiratory illness. This short review highlights the important scientific link between Vit D levels and susceptibility to COVID-19 in patients. This review also discusses recommendations for Vit D dose required for healthy as well as COVID-19 susceptible patients for protection and prevention.

Title: Targeting Vitamin D Deficiency to Limit Exacerbations in Respiratory Diseases: Utopia or Strategy With Potential? Content: Patients with respiratory diseases such as cystic fibrosis, chronic obstructive pulmonary disease, or asthma often experience an acute worsening of respiratory symptoms, termed exacerbations. Although the course of exacerbations is disease specific, they are mostly triggered by a respiratory infection. Exacerbations often require hospitalization and are an important cause of mortality. Treatments of exacerbations aim to minimize the negative impact and to prevent subsequent events. Despite many existing therapy options, many patients do not benefit from therapy and suffer from recurrent events. Vitamin D deficiency is a worldwide problem and is extremely prevalent in these patients. Vitamin D, known for its calcemic effects, also has immunomodulatory and anti-infectious actions and can therefore be a possible agent to treat or prevent exacerbations. This review will focus on vitamin D as a potential candidate to treat or prevent exacerbations in CF, COPD, and asthma.

Title: Role of vitamin D in preventing of COVID-19 infection, progression and severity Content: The outbreak of COVID-19 has created a global public health crisis. Little is known about the protective factors of this infection. Therefore, preventive health measures that can reduce the risk of infection, progression and severity are desperately needed. This review discussed the possible roles of vitamin D in reducing the risk of COVID-19 and other acute respiratory tract infections and severity. Moreover, this study determined the correlation of vitamin D levels with COVID-19 cases and deaths in 20 European countries as of 20 May 2020. A significant negative correlation (p=0.033) has been observed between mean vitamin D levels and COVID-19 cases per one million population in European countries. However, the correlation of vitamin D with COVID-19 deaths of these countries was not significant. Some retrospective studies demonstrated a correlation between vitamin D status and COVID-19 severity and mortality, while other studies did not find the correlation when confounding variables are adjusted. Several studies demonstrated the role of vitamin D in reducing the risk of acute viral respiratory tract infections and pneumonia. These include direct inhibition with viral replication or with anti-inflammatory or immunomodulatory ways. In the meta-analysis, vitamin D supplementation has been shown as safe and effective against acute respiratory tract infections. Thus, people who are at higher risk of vitamin D deficiency during this global pandemic should consider taking vitamin D supplements to maintain the circulating 25(OH)D in the optimal levels (75-125nmol/L). In conclusion, there is not enough evidence on the association between vitamin D levels and COVID-19 severity and mortality. Therefore, randomized control trials and cohort studies are necessary to test this hypothesis.

Title: Role of vitamin D in preventing of COVID-19 infection, progression and severity Content: The outbreak of COVID-19 has created a global public health crisis. Little is known about the protective factors of this infection. Therefore, preventive health measures that can reduce the risk of infection, progression and severity are desperately needed. This review discussed the possible roles of vitamin D in reducing the risk of COVID-19 and other acute respiratory tract infections and severity. Moreover, this study determined the correlation of vitamin D levels with COVID-19 cases and deaths in 20 European countries as of 20 May 2020. A significant negative correlation (p = 0.033) has been observed between mean vitamin D levels and COVID-19 cases per one million population in European countries. However, the correlation of vitamin D with COVID-19 deaths of these countries was not significant. Some retrospective studies demonstrated a correlation between vitamin D status and COVID-19 severity and mortality, while other studies did not find the correlation when confounding variables are adjusted. Several studies demonstrated the role of vitamin D in reducing the risk of acute viral respiratory tract infections and pneumonia. These include direct inhibition with viral replication or with anti-inflammatory or immunomodulatory ways. In the meta-analysis, vitamin D supplementation has been shown as safe and effective against acute respiratory tract infections. Thus, people who are at higher risk of vitamin D deficiency during this global pandemic should consider taking vitamin D supplements to maintain the circulating 25(OH)D in the optimal levels 75-125 nmol/L. In conclusion, there not enough evidence on the association between vitamin D levels and COVID-19 severity and mortality. Therefore, randomized control trials and cohort studies are necessary to test this hypothesis.

Title: Nutrients in prevention, treatment, and management of viral infections; special focus on Coronavirus. Content: BACKGROUND The coronavirus disease 2019 (COVID-19) is a pandemic caused by coronavirus with mild to severe respiratory symptoms. This paper aimed to investigate the effect of nutrients on the immune system and their possible roles in the prevention, treatment, and management of COVID-19 in adults. METHODS This Systematic review was designed based on the guideline of the Preferred Reporting for Systematic Reviews (PRISMA). The articles that focussed on nutrition, immune system, viral infection, and coronaviruses were collected by searching databases for both published papers and accepted manuscripts from 1990 to 2020. Irrelevant papers and articles without English abstract were excluded from the review process. RESULTS Some nutrients are actively involved in the proper functioning and strengthening of the human immune system against viral infections including dietary protein, omega-3 fatty acids, vitamin A, vitamin D, vitamin E, vitamin B1, vitamin B6, vitamin B12, vitamin C, iron, zinc, and selenium. Few studies were done on the effect of dietary components on prevention of COVID-19, but supplementation with these nutrients may be effective in improving the health status of patients with viral infections. CONCLUSION Following a balanced diet and supplementation with proper nutrients may play a vital role in prevention, treatment, and management of COVID-19. However, further clinical trials are needed to confirm these findings and presenting the strong recommendations against this pandemic.

Title: Nutrients in prevention, treatment, and management of viral infections; special focus on Coronavirus Content: BACKGROUND: The coronavirus disease 2019 (COVID-19) is a pandemic caused by coronavirus with mild to severe respiratory symptoms. This paper aimed to investigate the effect of nutrients on the immune system and their possible roles in the prevention, treatment, and management of COVID-19 in adults. METHODS: This Systematic review was designed based on the guideline of the Preferred Reporting for Systematic Reviews (PRISMA). The articles that focussed on nutrition, immune system, viral infection, and coronaviruses were collected by searching databases for both published papers and accepted manuscripts from 1990 to 2020. Irrelevant papers and articles without English abstract were excluded from the review process. RESULTS: Some nutrients are actively involved in the proper functioning and strengthening of the human immune system against viral infections including dietary protein, omega-3 fatty acids, vitamin A, vitamin D, vitamin E, vitamin B1, vitamin B6, vitamin B12, vitamin C, iron, zinc, and selenium. Few studies were done on the effect of dietary components on prevention of COVID-19, but supplementation with these nutrients may be effective in improving the health status of patients with viral infections. CONCLUSION: Following a balanced diet and supplementation with proper nutrients may play a vital role in prevention, treatment, and management of COVID-19. However, further clinical trials are needed to confirm these findings and presenting the strong recommendations against this pandemic.

Title: Can Vitamin D and L-Cysteine Co-Supplementation Reduce 25(OH)-Vitamin D Deficiency and the Mortality Associated with COVID-19 in African Americans? Content: Early reports indicate an association between the severity of the COVID-19 infection and the widespread 25-hydroxy vitamin D deficiency known to exist in populations around the world. Vitamin D deficiency is extremely common among African American (AA) communities, where the COVID-19 infection rate is three-fold higher, and the mortality rate nearly six-fold higher, compared with rates in predominantly white communities. COVID-19 infection primarily affects the lungs and airways. Previous reports have linked 25-hydroxy vitamin D deficiency with subclinical interstitial lung disease. AA are at risk for lower cellular glutathione (GSH) levels, and GSH deficiency epigenetically impairs VD biosynthesis pathway genes. Compared with vitamin D alone, co-supplementation of vitamin D and L-cysteine (a GSH precursor) showed a better efficacy in improving levels of GSH and VD-regulatory genes at the cellular/tissue level, increasing 25(OH) vitamin D levels, and reducing inflammation biomarkers in the blood in mice studies. We propose that randomized clinical trials are needed to examine the potential of co-supplementation with anti-inflammatory antioxidants, vitamin D and L-cysteine in correcting the 25(OH)VD deficiency and preventing the 'cytokine storm,' one of the most severe consequences of infection with COVID-19, thereby preventing the adverse clinical effects of COVID-19 infection in the vulnerable AA population.

Title: Possible role of vitamin D in Covid-19 infection in pediatric population Content: PURPOSE: Covid-19 is a pandemic of unprecedented proportion, whose understanding and management is still under way. In the emergency setting new or available therapies to contrast the spread of COVID-19 are urgently needed. Elderly males, especially those affected by previous diseases or with comorbidities, are more prone to develop interstitial pneumonia that can deteriorate evolving to ARDS (acute respiratory distress syndrome) that require hospitalization in Intensive Care Units (ICUs). Even children and young patients are not spared by SARS-CoV 2 infection, yet they seem to develop a milder form of disease. In this setting the immunomodulatory role of Vitamin D, should be further investigated. METHODS: We reviewed the literature about the immunomodulatory role of Vitamin D collecting data from the databases Medline and Embase. RESULTS: Vitamin D proved to interact both with the innate immune system, by activating Toll-like receptors (TLRs) or increasing the levels of cathelicidins and ß-defensins, and adaptive immune system, by reducing immunoglobulin secretion by plasma cells and pro-inflammatory cytokines production, thus modulating T cells function. Promising results have been extensively described as regards the supplementation of vitamin D in respiratory tract infections, autoimmune diseases and even pulmonary fibrosis. CONCLUSIONS: In this review, we suggest that vitamin D supplementation might play a role in the prevention and/or treatment to SARS-CoV-2 infection disease, by modulating the immune response to the virus both in the adult and pediatric population.

Title: Possible role of vitamin D in Covid-19 infection in pediatric population Content: PURPOSE: Covid-19 is a pandemic of unprecedented proportion, whose understanding and management is still under way. In the emergency setting new or available therapies to contrast the spread of COVID-19 are urgently needed. Elderly males, especially those affected by previous diseases or with comorbidities, are more prone to develop interstitial pneumonia that can deteriorate evolving to ARDS (acute respiratory distress syndrome) that require hospitalization in Intensive Care Units (ICUs). Even children and young patients are not spared by SARS-CoV 2 infection, yet they seem to develop a milder form of disease. In this setting the immunomodulatory role of Vitamin D, should be further investigated. Methods: We reviewed the literature about the immunomodulatory role of Vitamin D collecting data from the databases Medline and Embase. RESULTS: Vitamin D proved to interact both with the innate immune system, by activating Toll-like receptors (TLRs) or increasing the levels of cathelicidins and β-defensins, and adaptive immune system, by reducing immunoglobulin secretion by plasma cells and pro-inflammatory cytokines production, thus modulating T cells function. Promising results have been extensively described as regards the supplementation of vitamin D in respiratory tract infections, autoimmune diseases and even pulmonary fibrosis. CONCLUSIONS: In this review, we suggest that vitamin D supplementation might play a role in the prevention and/or treatment to SARS-CoV-2 infection disease, by modulating the immune response to the virus both in the adult and pediatric population.

Title: Tripartite Combination of Candidate Pandemic Mitigation Agents: Vitamin D, Quercetin, and Estradiol Manifest Properties of Medicinal Agents for Targeted Mitigation of the COVID-19 Pandemic Defined by Genomics-Guided Tracing of SARS-CoV-2 Targets in Human Cells Content: Genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomic-guided molecular maps of upstream regulatory elements, their expression and functions in the human body, and pathophysiologically relevant cell types. Repressors and activators of the ACE2 and FURIN genes were identified based on the analyses of gene silencing and overexpression experiments as well as relevant transgenic mouse models. Panels of repressors (VDR; GATA5; SFTPC; HIF1a) and activators (HMGA2; INSIG1; RUNX1; HNF4a; JNK1/c-FOS) were then employed to identify existing drugs manifesting in their effects on gene expression signatures of potential coronavirus infection mitigation agents. Using this strategy, vitamin D and quercetin have been identified as putative 2019 coronavirus disease (COVID-19) mitigation agents. Quercetin has been identified as one of top-scoring candidate therapeutics in the supercomputer SUMMIT drug-docking screen and Gene Set Enrichment Analyses (GSEA) of expression profiling experiments (EPEs), indicating that highly structurally similar quercetin, luteolin, and eriodictyol could serve as scaffolds for the development of efficient inhibitors of SARS-CoV-2 infection. In agreement with this notion, quercetin alters the expression of 98 of 332 (30%) of human genes encoding protein targets of SARS-CoV-2, thus potentially interfering with functions of 23 of 27 (85%) of the SARS-CoV-2 viral proteins in human cells. Similarly, Vitamin D may interfere with functions of 19 of 27 (70%) of the SARS-CoV-2 proteins by altering expression of 84 of 332 (25%) of human genes encoding protein targets of SARS-CoV-2. Considering the potential effects of both quercetin and vitamin D, the inference could be made that functions of 25 of 27 (93%) of SARS-CoV-2 proteins in human cells may be altered. GSEA and EPEs identify multiple drugs, smoking, and many disease conditions that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of testosterone versus estradiol impacts on SARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during the coronavirus pandemic. Estradiol, in contrast with testosterone, affects the expression of the majority of human genes (203 of 332; 61%) encoding SARS-CoV-2 targets, thus potentially interfering with functions of 26 of 27 SARS-CoV-2 viral proteins. A hypothetical tripartite combination consisting of quercetin/vitamin D/estradiol may affect expression of 244 of 332 (73%) human genes encoding SARS-CoV-2 targets. Of major concern is the ACE2 and FURIN expression in many human cells and tissues, including immune cells, suggesting that SARS-CoV-2 may infect a broad range of cellular targets in the human body. Infection of immune cells may cause immunosuppression, long-term persistence of the virus, and spread of the virus to secondary targets. Present analyses and numerous observational studies indicate that age-associated vitamin D deficiency may contribute to the high mortality of older adults and the elderly. Immediate availability for targeted experimental and clinical interrogations of potential COVID-19 pandemic mitigation agents, namely vitamin D and quercetin, as well as of the highly selective (Ki, 600 pm) intrinsically specific FURIN inhibitor (a1-antitrypsin Portland (a1-PDX), is considered an encouraging factor. Observations reported in this contribution are intended to facilitate follow-up targeted experimental studies and, if warranted, randomized clinical trials to identify and validate therapeutically viable interventions to combat the COVID-19 pandemic. Specifically, gene expression profiles of vitamin D and quercetin activities and their established safety records as over-the-counter medicinal substances strongly argue that they may represent viable candidates for further considerations of their potential utility as COVID-19 pandemic mitigation agents. In line with the results of present analyses, a randomized interventional clinical trial evaluating effects of estradiol on severity of the coronavirus infection in COVID19+ and presumptive COVID19+ patients and two interventional randomized clinical trials evaluating effects of vitamin D on prevention and treatment of COVID-19 were listed on the ClinicalTrials.gov website.

Title: Perspective: Vitamin D deficiency and COVID-19 severity - plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2, and thrombosis (R1) Content: BACKGROUND: SARS-CoV-2 coronavirus infection ranges from asymptomatic through to fatal COVID-19 characterised by a "cytokine storm" and lung failure. Vitamin D deficiency has been postulated as a determinant of severity. OBJECTIVES: To review the evidence relevant to vitamin D and COVID-19 METHODS: Narrative review RESULTS: Regression modelling shows that more northerly countries in the Northern Hemisphere are currently (May 2020) showing relatively high COVID-19 mortality, with an estimated 4.4% increase in mortality for each 1 degree latitude north of 28 degrees North (P=0.031) after adjustment for age of population. This supports a role for ultraviolet B acting via vitamin D synthesis. Factors associated with worse COVID-19 prognosis include old age, ethnicity, male sex, obesity, diabetes and hypertension and these also associate with deficiency of vitamin D or its response. Vitamin D deficiency is also linked to severity of childhood respiratory illness. Experimentally, vitamin D increases the ratio of angiotensin converting enzyme 2 (ACE2) to ACE, thus increasing angiotensin II hydrolysis and reducing subsequent inflammatory cytokine response to pathogens and lung injury. CONCLUSIONS: Substantial evidence supports a link between vitamin D deficiency and COVID-19 severity but it is all indirect. Community-based placebo-controlled trials of vitamin D supplementation may be difficult. Further evidence could come from study of COVID-19 outcomes in large cohorts with information on prescribing data for vitamin D supplementation or assay of serum unbound 25(OH) vitamin D levels. Meanwhile vitamin D supplementation should be strongly advised for people likely to be deficient.

Title: Perspective: Vitamin D deficiency and COVID‐19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2, and thrombosis (R1) Content: BACKGROUND: SARS‐CoV‐2 coronavirus infection ranges from asymptomatic through to fatal COVID‐19 characterised by a “cytokine storm” and lung failure. Vitamin D deficiency has been postulated as a determinant of severity. OBJECTIVES: To review the evidence relevant to vitamin D and COVID‐19 METHODS: Narrative review RESULTS: Regression modelling shows that more northerly countries in the Northern Hemisphere are currently (May 2020) showing relatively high COVID‐19 mortality, with an estimated 4.4% increase in mortality for each 1 degree latitude north of 28 degrees North (P=0.031) after adjustment for age of population. This supports a role for ultraviolet B acting via vitamin D synthesis. Factors associated with worse COVID‐19 prognosis include old age, ethnicity, male sex, obesity, diabetes and hypertension and these also associate with deficiency of vitamin D or its response. Vitamin D deficiency is also linked to severity of childhood respiratory illness. Experimentally, vitamin D increases the ratio of angiotensin converting enzyme 2 (ACE2) to ACE, thus increasing angiotensin II hydrolysis and reducing subsequent inflammatory cytokine response to pathogens and lung injury. CONCLUSIONS: Substantial evidence supports a link between vitamin D deficiency and COVID‐19 severity but it is all indirect. Community‐based placebo‐controlled trials of vitamin D supplementation may be difficult. Further evidence could come from study of COVID‐19 outcomes in large cohorts with information on prescribing data for vitamin D supplementation or assay of serum unbound 25(OH) vitamin D levels. Meanwhile vitamin D supplementation should be strongly advised for people likely to be deficient.

Title: Evidence Supports a Causal Model for Vitamin D in COVID-19 Outcomes Content: We analyse global data for COVID-19 deaths and recoveries and show that outbreak severity displays a striking latitude relationship with a northern hemisphere bias. Transmission rates can be explained by seasonal weather conditions, but this does not account for observed variations in fatality rates. Many factors point to Vitamin D as a candidate explanation but historical controversy surrounding Vitamin D studies and the lack of a coherent framework for causal inference has hampered acceptance of this explanation despite a wealth of evidence in its favour. We analyse global COVID-19 data using Causal Inference, constructing two contrasting directed acyclic graph (DAG) models, one causal and one acausal, and set out clearly multiple predictions made by each model. We show that observed data strongly match predictions made by the causal model but largely contradict those of the acausal model. We explore historic evidence further supporting the causal model. We review biochemical mechanisms that may explain the various ways in which vitamin D acts. We detail the mechanisms by which the SARS-Cov-2 virus causes the disease and known pathways that involve Vitamin D and show how these both protect against viral infection, as well as ameliorating disease symptoms in COVID-19 and other respiratory diseases. We examine the factors that govern confidence in causal inference models and conclude that a high level of confidence in a causal beneficial role for Vitamin D is justified.

Title: Vitamin D can prevent COVID-19 infection-induced multiple organ damage Content: Vitamin D is an immunomodulator hormone with an anti-inflammatory and antimicrobial effect with a high safety profile. A lot of COVID-19 infected patients develop acute respiratory distress syndrome (ARDS), which may lead to multiple organ damage. These symptoms are associated with a cytokine storm syndrome. The aim of this letter is to note the 5 crucial points that vitamin D could have protective and therapeutic effects against COVID-19. For that reason, COVID-19 infection-induced multiple organ damage might be prevented by vitamin D.

Title: Vitamin D and respiratory infections in infants and toddlers: a nutri-shine perspective Content: There is compelling evidence of a global problem of poor vitamin D status in expecting mothers and postnatal life; and even more critical, is the evidence showing the association of vitamin D deficiency with increased morbidity and mortality risks from respiratory infections. Viral and bacterial pneumonia kills more children than any other illness, accounting for 19 % of all deaths in children less than five years of age worldwide; and under-nutrition, which includes vitamin D insufficiency/deficiency, has been implicated in 53 % of all these deaths. Poor vitamin D status is a result of insufficient sunlight exposure and/or poor dietary intake. Greater understanding of the role of vitamin D deficiency in precipitating lung infections grew from the use of rodent models and observational and intervention studies in infants and toddlers. Vitamin D adequacy is important to maintaining the key protective mechanism of developing lungs since it mediates the synthesis of antimicrobial peptides, the lungs strongest defense against viral and bacterial pathogens. If vitamin D intervention currently under study in several clinical trials is proven successful, then implementation of new fortification practices, revised guidelines for healthy sun exposure and public health programs for vitamin D supplementation of pregnant/lactating women and their infants may be effective strategies to aide in preventing neonates and children under five from developing pneumonia. Globally, there is potential to save more than a million young lives with preventive treatment, a compelling reason why the efficacy of optimizing vitamin D mediated defense against respiratory pathogens in infants and children merits further study.

Title: Can Composite Nutritional Supplement Based on the Current Guidelines Prevent Vitamin and Mineral Deficiency After Weight Loss Surgery? Content: BACKGROUND Nutritional deficiencies occur after weight loss surgery. Despite knowledge of nutritional risk, there is little uniformity of postoperative vitamin and mineral supplementation. The objective of this study was to evaluate a composite supplement based on the clinical practice guidelines proposed in 2008 regarding vitamin and mineral supplementation after Roux-en-Y gastric bypass. The composite included iron (Fe) and calcium as well. METHODS A retrospective chart review of 309 patients undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB) was evaluated for the development of deficiencies in iron and vitamins A, B1, B12, and D. Patients were instructed to take a custom vitamin and mineral supplement that was based on society-approved guidelines. The clinical practice guidelines were modified to include 1600 international units (IU) of vitamin D3 instead of the recommended 800 IU. RESULTS The compliant patients' deficiency rates were significantly lower than those of the noncompliant patients for iron (p = 0.001), vitamin A (p = 0.01), vitamin B12 (p ≈ 0.02), and vitamin D (p < 0.0001). Women's menstrual status did not significantly influence the development of iron deficiency. CONCLUSIONS Use of a composite based on guidelines proposed by the AACE, TOS, and the ASMBS appears to be effective for preventing iron and vitamins A, B1, B12, and D deficiencies in the LRYGB patients during the first postoperative year. Separation of calcium and Fe does not need to be mandatory. Even with simplification, compliance is far from universal.

Title: The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality Content: WHO declared SARS-CoV-2 a global pandemic. The present aim was to propose an hypothesis that there is a potential association between mean levels of vitamin D in various countries with cases and mortality caused by COVID-19. The mean levels of vitamin D for 20 European countries and morbidity and mortality caused by COVID-19 were acquired. Negative correlations between mean levels of vitamin D (average 56 mmol/L, STDEV 10.61) in each country and the number of COVID-19 cases/1 M (mean 295.95, STDEV 298.7, and mortality/1 M (mean 5.96, STDEV 15.13) were observed. Vitamin D levels are severely low in the aging population especially in Spain, Italy and Switzerland. This is also the most vulnerable group of the population in relation to COVID-19. It should be advisable to perform dedicated studies about vitamin D levels in COVID-19 patients with different degrees of disease severity.

Title: Avoidance of vitamin D deficiency to slow the COVID-19 pandemic Content: Vitamin D deficiency, which impedes good immune function, is common during winter and spring in regions of high latitude. There is good evidence that vitamin D deficiency contributes to the seasonal increase of virus infections of the respiratory tract, from the common cold to influenza, and now possibly also COVID-19. This communication explores key factors that make it more likely, particularly in combination, that individuals are vitamin D deficient. These factors include old age, obesity, dark skin tone and common genetic variants that impede vitamin D status. Precision nutrition is an approach that aims to consider known personal risk factors and health circumstances to provide more effective nutrition guidance in health and disease. In regard to avoiding vitamin D deficiency, people with excess body fat, a dark skin tone or older age usually need to use a moderately dosed daily vitamin D supplement, particularly those living in a high-latitude region, getting little ultraviolet B exposure due to air pollution or staying mostly indoors. Carriers of the GC (group-specific component) rs4588 AA genotype also are more likely to become deficient. Very high-dosed supplements with more than 4000 IU vitamin D are rarely needed or justified. A state-by-state Mendelian randomisation analysis of excess COVID-19 mortality of African-Americans in the USA shows a greater disparity in northern states than in southern states. It is conceivable that vitamin D adequacy denies the virus easy footholds and thereby slows spreading of the contagion. This finding should drive home the message that vitamin D supplementation is particularly important for individuals with dark skin tones. Vitamin D deficiency, even for a few months during the winter and spring season, must be rigorously remedied because of its many adverse health impacts that include decreased life expectancy and increased mortality. Slowing the spread of COVID-19 would be an added bonus.

Title: Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths Content: The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D(3) for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/mL (100–150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D(3) doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.

Title: Myth Busters: Dietary Supplements and COVID-19 Content: News and social media platforms have implicated dietary supplements in the treatment and prevention of coronavirus disease 2019 (COVID-19). During this pandemic when information quickly evolves in the presence of contradicting messages and misinformation, the role of the pharmacist is essential. Here, we review theoretical mechanisms and evidence related to efficacy and safety of select supplements in the setting of COVID-19, including vitamin C, vitamin D, zinc, elderberry, and silver. Evidence evaluating these supplements in COVID-19 patients is lacking, and providers and patients should not rely on dietary supplements to prevent or treat COVID-19. Rather, reference to evidence-based guidelines should guide treatment decisions.

Title: Myth Busters: Dietary Supplements and COVID-19. Content: News and social media platforms have implicated dietary supplements in the treatment and prevention of coronavirus disease 2019 (COVID-19). During this pandemic when information quickly evolves in the presence of contradicting messages and misinformation, the role of the pharmacist is essential. Here, we review theoretical mechanisms and evidence related to efficacy and safety of select supplements in the setting of COVID-19, including vitamin C, vitamin D, zinc, elderberry, and silver. Evidence evaluating these supplements in COVID-19 patients is lacking, and providers and patients should not rely on dietary supplements to prevent or treat COVID-19. Rather, reference to evidence-based guidelines should guide treatment decisions.

Title: The angiotensin-converting enzyme 2 (ACE2) receptor in the prevention and treatment of COVID-19 are distinctly different paradigms Content: There is current debate concerning the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs), for hypertension management, during COVID-19 infection. Specifically, the suggestion has been made that ACE inhibitors or ARBs could theoretically contribute to infection via increasing ACE2 receptor expression and hence increase viral load. The ACE2 receptor is responsible for binding the SAR-CoV2 viral spike and causing COVID-19 infection. What makes the argument somewhat obtuse for ACE inhibitors or ARBs is that ACE2 receptor expression can be increased by compounds that activate or increase the expression of SIRT1. Henceforth common dietary interventions, vitamins and nutrients may directly or indirectly influence the cellular expression of the ACE2 receptor. There are many common compounds that can increase the expression of the ACE2 receptor including Vitamin C, Metformin, Resveratrol, Vitamin B3 and Vitamin D. It is important to acknowledge that down-regulation or blocking the cellular ACE2 receptor will likely be pro-inflammatory and may contribute to end organ pathology and mortality in COVID-19. In conclusion from the perspective of the ACE2 receptor, COVID-19 prevention and treatment are distinctly different. This letter reflects on this current debate and suggests angiotensin-converting enzyme inhibitors and ARBs are likely beneficial during COVID-19 infection for hypertensive and normotensive patients.

Title: Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths Content: The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40-60 ng/mL (100-150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.

Title: Vitamin D Deficiency and Air Pollution Exacerbate COVID-19 Through Suppression of Antiviral Peptide LL37 Content: Vitamin D deficiency and insufficiency (VDD) are widely recognized as risk factors for respiratory tract infections. Vitamin D influences expression of many genes with well-established relevance to airway infections and relevant to immune system function. Recently, VDD has been shown to be a risk factor for acquisition and severity of COVID-19. Thus, treating VDD presents a safe and inexpensive opportunity for modulating the severity of the disease. VDD is common in those over 60 years of age, many with co-morbid conditions and in people with skin pigmentation sufficient to reduce synthesis of vitamin D. Exposure to fine particulate air pollution is also associated with worse outcomes from COVID19. Vitamin D stimulates transcription of cathelicidin which is cleaved to generate LL37. LL37 is an innate antimicrobial with demonstrated activity against a wide range of microbes including envelope viruses. LL37 also modulates cytokine signaling at the site of infections. Fine particles in air pollution can interfere with LL37 destruction of viruses and may reduce effective immune signaling modulation by LL37. While vitamin D influences transcription of many immune related genes, the weakened antimicrobial response of those with VDD against SARS-CoV-2 may be in part due to reduced LL37. Conclusion: Vitamin D plays an important role reducing the impact of viral lung disease processes. VDD is an acknowledged public health threat that warrants population-wide action to reduce COVID-19 morbidity and mortality. While vitamin D influences transcription of many immune related genes, the weakened antimicrobial response of those with VDD against SARS-CoV-2 may be in part due to reduced LL37. Action is needed to address COVID-19 associated risks of air pollution from industry, transportation, domestic sources and from primary and second hand tobacco smoke.

Title: Influence of Colostrum and Vitamins A, D(3), and E on Early Intestinal Colonization of Neonatal Holstein Calves Infected with Mycobacterium avium subsp. paratuberculosis Content: Exposure of neonates to Mycobacterium avium subsp. paratuberculosis (MAP) via infected dams is the primary mode of transmission of Johne’s disease. Little is known about the impacts of feeding colostrum and supplemental vitamins on the gut microbiome in calves exposed to MAP. In the present study, calves were assigned at birth to one of six treatment groups: (1) Colostrum deprived (CD), no vitamins; (2) colostrum replacer (CR), no vitamins; (3) CR, vitamin A; (4) CR, vitamin D(3); (5) CR, vitamin E; (6) CR, vitamins A, D(3), E, with five calves per treatment in a 14-day study. All calves were orally inoculated with MAP on days 1 and 3 of the study. Differences due to vitamin supplementation were not significant but treatment groups CR-A, CR-E, and CR-ADE had higher numbers of MAP-positive tissues overall. Shannon diversity indices demonstrated regional differences in microbial communities, primarily Proteobacteria, Bacteroidetes, and Firmicutes, between the ileum, cecum, and spiral colon of all calves. CD calves exhibited increased richness compared with CR calves in the cecum and spiral colon and harbored increased Proteobacteria and decreased Bacteroidetes in the mucosa compared with the lumen for all three tissues. Overall, supplementation with vitamins did not appear to influence gut microbiome or impact MAP infection. Feeding of colostrum influenced gut microbiome and resulted in fewer incidences of dysbiosis.

Title: The D-side of COVID-19: musculoskeletal benefits of vitamin D and beyond Content: Coronavirus 2019 disease (COVID-19) mostly adversely affects the elderly, a population at higher risk for low serum 25-hydroxyvitamin D (25(OH)D) levels. In this viewpoint, we highlight the well-known musculoskeletal properties of vitamin D, which are particularly relevant in the context of COVID-19, suggesting further potential benefits through extra-skeletal effects. Maintaining optimal 25(OH)D is crucial to prevent falls, frailty and fractures in elderly patients, with low activity levels due to lockdown, or who are relatively immobilized during hospitalization and after discharge for prolonged periods of time. Hypovitaminosis D is also associated with susceptibility to respiratory infections, admissions to the intensive care unit, and mortality. We underscore the importance of achieving desirable serum 25(OH)D in COVID-19 elderly patients, to ensure beneficial musculoskeletal effects and possibly respiratory effects of vitamin D, in the context of COVID-19.

Title: Vitamin D(3) and gargling for the prevention of upper respiratory tract infections: a randomized controlled trial Content: BACKGROUND: We undertook a 2X2 factorial, randomized controlled trial (RCT) to assess whether vitamin D(3) supplementation (10,000 international units per week) versus placebo and gargling versus no gargling could prevent viral, clinical upper respiratory tract infection (URTI) in university students. METHODS: We randomized 600 students into 4 treatment arms: 1) vitamin D(3) and gargling, 2) placebo and gargling, 3) vitamin D(3) and no gargling, and 4) placebo and no gargling. Students completed weekly electronic surveys and submitted self-collected mid-turbinate nasal flocked swabs during September and October in 2010 or 2011. Symptomatic students also completed an electronic symptom diary. The primary and secondary outcomes were the occurrence of symptomatic clinical URTI and laboratory confirmed URTI respectively. RESULTS: Of 600 participants, 471 (78.5%) completed all surveys while 43 (7.2%) completed none; 150 (25.0%) reported clinical URTI. Seventy participants (23.3%) randomized to vitamin D(3) reported clinical URTI compared to 80 (26.7%) randomized to placebo (RR:0.79, CI(95):0.61-1.03, p = 0.09). Eighty-five participants (28.3%) randomized to gargling reported clinical URTI compared to 65 participants (21.7%) randomized to the no gargling arm (RR:1.3, CI(95):0.92-1.57, p = 0.19). Laboratory testing identified 70 infections (46.7 per 100 URTIs). Vitamin D(3) treatment was associated with a significantly lower risk for laboratory confirmed URTI (RR: 0.54, CI(95):0.34-0.84, p = 0.007) and with a significantly lower mean viral load measured as log(10) viral copies/mL (mean difference: -0.89, CI(95:) -1.7, -0.06, p = 0.04). Fewer students assigned to gargling experienced laboratory confirmed URTI, however this was not statistically significant (RR:0.82, CI(95):0.53-1.26, p = 0.36). CONCLUSIONS: These results suggest that vitamin D(3) is a promising intervention for the prevention of URTI. Vitamin D(3) significantly reduced the risk of laboratory confirmed URTI and may reduce the risk of clinical infections. TRIAL REGISTRATION: Clinical Trials Registration: NCT01158560.

Title: The Use of IV vitamin C for patients with COVID-19: a single center observational study. Content: BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic has affected almost 2.5 million people worldwide with almost 170 000 deaths reported to date. So far, there is scarce evidence for the current treatment options available for COVID-19. Vitamin C has previously been used for treatment of severe sepsis and septic shock. We reviewed the feasibility of using vitamin C in the setting of COVID-19 in a series of patients. METHODS We sequentially identified a series of patients who were requiring at least 30% of FiO2 or more who received IV vitamin C as part of the COVID-19 treatment and analyzed their demographic and clinical characteristics. We compared inflammatory markers pre and post treatment including D-dimer and ferritin. RESULTS We identified a total of 17 patients who received IV vitamin C for COVID-19. The inpatient mortality rate in this series was 12% with 17.6% rates of intubation and mechanical ventilation. We noted a significant decrease in inflammatory markers, including ferritin and D-dimer, and a trend to decreasing FiO2 requirements, after vitamin C administration. CONCLUSION The use of IV vitamin C in patients with moderate to severe COVID-19 disease may be feasible.

Title: Effects of an Omega-3 and Vitamin D Supplement on Fatty Acids and Vitamin D Serum Levels in Double-Blinded, Randomized, Controlled Trials in Healthy and Crohn’s Disease Populations Content: Two trials separately measured the bioavailability and impact on inflammation of a supplement taken daily containing 510 mg Docosahexaenoic acid (DHA), 344 mg Eicosapentaenoic acid (EPA), and 1000 IU of vitamin D (25-hydroxyvitamin D; 25(OH)D), for healthy and Crohn’s disease (CD) populations. Both trials were double blinded, randomized, placebo-controlled with cross-over. Participants were randomly allocated to groups A (placebo then supplement) or B (supplement then placebo). Both included a washout. Fatty acid (N-3 PUFAs) and vitamin D serum levels, plasma C-reactive protein (CRP), and stool calprotectin were measured before and after each treatment period. Outcome measures were analyzed using generalized linear mixed models, including terms for treatment, period, and a treatment-by-period interaction. The supplement significantly increased serum levels in healthy and CD groups for EPA (p < 0.001 and p < 0.001, respectively), Docosapentaenoic acid (p < 0.001 and 0.005), DHA (p < 0.001 and 0.006), the omega-3 index (p < 0.001 and 0.001), and (vitamin D (p < 0.001 and 0.027). CRP and calprotectin measures showed no evidence of a treatment effect on inflammation; however, model estimation was imprecise for both outcomes, hence further research is required to elucidate potential inflammation effects. The nutrient supplement increased serum levels of key N-3 PUFAs and vitamin D in both populations, showing the preparation was readily bioavailable.

Title: El suplemento con altas dosis de vitamina D podría representar una alternativa promisoria para prevenir o tratar la infección por COVID-19 Content: Resumen Si bien carecemos de suficiente evidencia que justifique suplementar con vitamina D en la prevención y/o tratamiento de la infección por COVID-19, a la fecha resulta cada vez más factible que esta hipótesis sea válida. Dos mecanismos básicos generales deberían ser considerados. Uno sería la acción anti-infecciosa e inmuno-moduladora que ejerce mejorando las barreras intercelulares por estímulo de la inmunidad innata, así también por modulación de la inmunidad adaptativa. También, la vitamina D reduce la producción de citoquinas inflamatorias como IL-2 e interferón gamma (INFγ). Más recientemente se han demostrado múltiples efectos pleiotrópicos sobre las acciones de vitamina D a nivel anti-inflamatorio e inmuno-modulador. Esto explica resultados positivos en estudios con influenza, coronavirus y otras infecciones respiratorias. Se ha descripto relación inversa entre niveles séricos de vitamina D y prevalencia de patología infecciosa respiratoria. De interés, otro abordaje mecanístico responde a considerar la inhibición del sistema renina-angiotensina-aldosterona, que se exacerba en la infección por COVID-19 debido a que el virus se une a la enzima ECA2, quedando disponible más angiotensina II para causar daño. La vitamina D inhibe mediadores del SRAA -presente en todas las células del organismo-, y por inhibir la actividad ECA y aumentar la ECA2, disminuye los niveles de angiotensina II. Presentamos estudios con propuestas de dosis recomendadas de vitamina D y aunque no quede concretada una única guía, los posibles beneficios son promisorios. Finalmente, el propósito de la presente revisión es compartir esta idea con profesionales de la salud para encender el debate y llamar a la reflexión crítica, de modo tal que se pueda contribuir con el emprendimiento de diseños clínicos adecuados para validar los beneficios de utilizar altas dosis de vitamina D en beneficio de la salud pública y sobre todo en tiempos de esta emergencia por COVID-19. Abstract Although we lack enough evidence to justify supplementing with vitamin D in the prevention and treatment of COVID-19 infection, it is increasingly feasible that this hypothesis is valid. Two general underlying mechanisms should be considered. One would be the anti-infectious and immunomodulatory action that it exerts by improving intercellular barriers by stimulating innate immunity, as well as by modulating adaptive immunity. Also, vitamin D reduces the production of inflammatory cytokines, such as IL-2 and interferon-gamma (INFγ). More recently, multiple pleiotropic effects have been demonstrated on the actions of vitamin D at the anti-inflammatory and immunomodulatory level with positive results in studies with influenza, coronavirus, and other respiratory infections. An inverse relationship between serum vitamin D levels and the prevalence of the respiratory infectious disease has been described. Of interest, another mechanistic approach responds to considering the inhibition of the renin-angiotensin-aldosterone system (RAAS), which is exacerbated in COVID-19 infection because the virus binds to the enzyme ACE2, making more angiotensin II available to cause damage. Vitamin D inhibits mediators of RAAS -present in all cells of the body- and by inhibiting ACE activity and increasing ACE2, it lowers angiotensin II levels. We present studies with proposals for recommended doses of vitamin D, and although a single guideline is not specified, the possible benefits are promising. Finally, the purpose of this review is to share this idea with health professionals to ignite the debate and call for critical reflection, so that it can contribute to the undertaking of more and better clinical designs to validate the benefits of using high doses of vitamin D for the benefit of public health and especially in times of crisis for COVID-19.

Title: Beneficial role of vitamin D3 in the prevention of certain respiratory diseases. Content: There is evidence of aberrations in the vitamin D-endocrine system in subjects with respiratory diseases. Vitamin D deficiency is highly prevalent in patients with respiratory diseases, and patients who receive vitamin D have significantly larger improvements in inspiratory muscle strength and maximal oxygen uptake. Studies have provided an opportunity to determine which proteins link vitamin D to respiratory pathology, including the major histocompatibility complex class II molecules, vitamin D receptor, vitamin D-binding protein, chromosome P450, Toll-like receptors, poly(ADP-ribose) polymerase-1, and the reduced form of nicotinamide adenine dinucleotide phosphate. Vitamin D also exerts its effect on respiratory diseases through cell signaling mechanisms, including matrix metalloproteinases, mitogen-activated protein kinase pathways, the Wnt/β-catenin signaling pathway, prostaglandins, reactive oxygen species, and nitric oxide synthase. In conclusion, vitamin D plays a significant role in respiratory diseases. The best form of vitamin D for use in the treatment of respiratory diseases is calcitriol because it is the active metabolite of vitamin D3 and modulates inflammatory cytokine expression. Further investigation of calcitriol in respiratory diseases is needed.

Title: Vitamin D Deficiency and Acute Lower Respiratory Infections in Children Younger Than 5 Years: Identification and Treatment Content: Abstract Introduction Acute lower respiratory infection (ALRI) is a leading cause of childhood mortality. Research suggests that vitamin D deficiency (VDD) puts children at risk for ALRI. The purpose of this review is to examine ALRI and VDD in children 5 years and younger. Common etiologies, diagnosis, prevention, treatment of ALRI, and recommendations for vitamin D supplementation are summarized. Method Databases were searched for studies investigating VDD and ALRI in children. Independent reviewers assessed the internal validity of the studies. Results Of 18 studies examined, VDD was found to be associated with increased risk or severity of ALRI in 13 studies; associations were not found in 4 studies. In one study it was found that high maternal vitamin D levels was associated with ALRI in infants. Discussion Vitamin D supplementation is a low-cost, low-risk intervention that providers should consider for children, especially those at high risk for ALRI. Practitioners should follow current recommendations when prescribing vitamin D supplementation for infants and children.

Title: Vitamin D deficiency 2.0: an update on the current status worldwide Content: Vitamin D testing and the use of vitamin D supplements have increased substantially in recent years. Currently, the role of vitamin D supplementation, and the optimal vitamin D dose and status, is a subject of debate, because large interventional studies have been unable to show a clear benefit (in mostly vitamin D replete populations). This may be attributed to limitations in trial design, as most studies did not meet the basic requirements of a nutrient intervention study, including vitamin D-replete populations, too small sample sizes, and inconsistent intervention methods regarding dose and metabolites. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] < 50 nmol/L or 20 ng/ml) is associated with unfavorable skeletal outcomes, including fractures and bone loss. A 25(OH)D level of >50 nmol/L or 20 ng/ml is, therefore, the primary treatment goal, although some data suggest a benefit for a higher threshold. Severe vitamin D deficiency with a 25(OH)D concentration below <30 nmol/L (or 12 ng/ml) dramatically increases the risk of excess mortality, infections, and many other diseases, and should be avoided whenever possible. The data on a benefit for mortality and prevention of infections, at least in severely deficient individuals, appear convincing. Vitamin D is clearly not a panacea, and is most likely efficient only in deficiency. Given its rare side effects and its relatively wide safety margin, it may be an important, inexpensive, and safe adjuvant therapy for many diseases, but future large and well-designed studies should evaluate this further. A worldwide public health intervention that includes vitamin D supplementation in certain risk groups, and systematic vitamin D food fortification to avoid severe vitamin D deficiency, would appear to be important. In this narrative review, the current international literature on vitamin D deficiency, its relevance, and therapeutic options is discussed.

Title: Natural History of COVID-19 and Current Knowledge on Treatment Therapeutic Options Content: Despite intense research there is currently no effective vaccine available against the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in the later 2019 and responsible for the COVID-19 pandemic. This infectious and communicable disease has become one of the major public health challenges in the world. The clinical management of COVID-19 has been limited to infection prevention and control measures associated with supportive care such as supplemental oxygen and mechanical ventilation. Meanwhile efforts to find an effective treatment to inhibit virus replication, mitigate the symptoms, increase survival and decrease mortality rate are ongoing. Several classes of drugs, many of them already in use for other diseases, are being evaluated based on the body of clinical knowledge obtained from infected patients regarding to the natural history and evolution of the infection. Herein we will provide an updated overview of the natural history and current knowledge on drugs and therapeutic agents being tested for the prevention and treatment of COVID-19. These include different classes of drugs such as antiviral agents (chloroquine, ivermectin, nitazoxanide, hydroxychloroquine, lopinavir, remdesivir, tocilizumab), supporting agents (Vitamin C, Vitamin D, azithromycin, corticosteroids) and promising investigational vaccines. Considering the controversies and excessive number of compounds being tested and reported in the literature we hope that this review can provide useful and updated consolidated information on potential drugs used to prevent, control and treat COVID-19 patients worldwide.

Title: Covid-19, cocooning and vitamin d intake requirements Content: The purpose of this report is to clarify what constitutes best practice on vitamin D supplement use, particularly among older adults, who are at highest risk of Covid-19 On Friday 3rd April, three reports were published on how vitamin D may protect against Covid-19 Two reports are aligned with national and international guidelines on vitamin intake requirements for health: one looked at the importance of vitamin D adequacy in protecting children from respiratory illness but included important advice cautioning against high dose vitamin D;the other is from The Irish Longitudinal Study on Ageing (TILDA) that looked at specific ’at risk’ groups for vitamin D deficiency in those over 50 years in a representative sample from the 26 counties TILDA provides a strong evidence base for intervening in older adults with supplemental vitamin D (10 µg to 20 µg daily) A third report advises that every adult should take high doses of vitamin D (20 µg to 50 µg daily) in order to protect against Covid-19 The authors make no mention about other sources of vitamin D in adults This creates confusion at a time when there is widespread fear and anxiety about the Covid-19 pandemic The following provides a review of the evidence and summarises best practice regarding vitamin D nutrition to protect against Covid-19

Title: Examining the evidence for the use of vitamin C in the prophylaxis and treatment of the common cold Content: Purpose: To present a critical evaluation of the current evidence concerning the therapeutic value of vitamin C for the prophylaxis and treatment of the common cold. Data sources: Cochrane, PubMed, Natural Standard, and the National Center for Complementary and Alternative Medicine databases were searched to identify and acquire primary research reports, literature reviews, and secondary analyses related to the clinical objective. Published clinical trials, literature reviews, meta‐analyses, and systematic reviews were evaluated for evidence‐based practice implications. Conclusions: Vitamin C is frequently used for the treatment and prophylaxis of the common cold; however, no published recommendations were found in a review of the nurse practitioner literature that specifically address the efficacy of vitamin C for the common cold. Our literature review revealed that vitamin C is not effective at preventing the common cold in the general adult population; however, it is effective at preventing colds when consumed regularly by athletes training in subarctic conditions. We also found that regular vitamin C consumption may reduce the duration of cold symptoms in both adults and children, but it does not decrease the severity of cold symptoms. Implications for practice: NPs should counsel their patients that regular vitamin C consumption may decrease the duration of cold symptoms, but does not affect symptom severity or act as a prophylaxis.

Title: Vitamin D Supplementation in Influenza and COVID-19 Infections Comment on: "Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths" Nutrients 2020, 12(4), 988 Content: There is an ongoing debate on the use of vitamin D supplementation in reducing the risk of influenza and COVID-19 infections and deaths. A recently published article highlights a relationship between vitamin D supplementation and reduced risk of COVID-19 and influenza. This comment aims to discuss the evidence on the use of Vitamin D in people who are at risk of developing COVID-19, focusing on safety issues of the Vitamin D supplementation.

Title: Vitamin D Supplementation in Influenza and COVID-19 Infections Comment on: “Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths” Nutrients 2020, 12(4), 988 Content: There is an ongoing debate on the use of vitamin D supplementation in reducing the risk of influenza and COVID-19 infections and deaths. A recently published article highlights a relationship between vitamin D supplementation and reduced risk of COVID-19 and influenza. This comment aims to discuss the evidence on the use of Vitamin D in people who are at risk of developing COVID-19, focusing on safety issues of the Vitamin D supplementation.

Title: A brief review of interplay between vitamin D and angiotensin‐converting enzyme 2: Implications for a potential treatment for COVID‐19 Content: The novel coronavirus disease 2019 (COVID‐19) is rapidly expanding and causing many deaths all over the world with the World Health Organization (WHO) declaring a pandemic in March 2020. Current therapeutic options are limited and there is no registered and/or definite treatment or vaccine for this disease or the causative infection, severe acute respiratory coronavirus 2 syndrome (SARS‐CoV‐2). Angiotensin‐converting enzyme 2 (ACE2), a part of the renin‐angiotensin system (RAS), serves as the major entry point into cells for SARS‐CoV‐2 which attaches to human ACE2, thereby reducing the expression of ACE2 and causing lung injury and pneumonia. Vitamin D, a fat‐soluble‐vitamin, is a negative endocrine RAS modulator and inhibits renin expression and generation. It can induce ACE2/Ang‐(1‐7)/MasR axis activity and inhibits renin and the ACE/Ang II/AT1R axis, thereby increasing expression and concentration of ACE2, MasR and Ang‐(1‐7) and having a potential protective role against acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Therefore, targeting the unbalanced RAS and ACE2 down‐regulation with vitamin D in SARS‐CoV‐2 infection is a potential therapeutic approach to combat COVID‐19 and induced ARDS.

Title: A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19 Content: The novel coronavirus disease 2019 (COVID-19) is rapidly expanding and causing many deaths all over the world with the World Health Organization (WHO) declaring a pandemic in March 2020. Current therapeutic options are limited and there is no registered and/or definite treatment or vaccine for this disease or the causative infection, severe acute respiratory coronavirus 2 syndrome (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2), a part of the renin-angiotensin system (RAS), serves as the major entry point into cells for SARS-CoV-2 which attaches to human ACE2, thereby reducing the expression of ACE2 and causing lung injury and pneumonia. Vitamin D, a fat-soluble-vitamin, is a negative endocrine RAS modulator and inhibits renin expression and generation. It can induce ACE2/Ang-(1-7)/MasR axis activity and inhibits renin and the ACE/Ang II/AT1R axis, thereby increasing expression and concentration of ACE2, MasR and Ang-(1-7) and having a potential protective role against acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Therefore, targeting the unbalanced RAS and ACE2 down-regulation with vitamin D in SARS-CoV-2 infection is a potential therapeutic approach to combat COVID-19 and induced ARDS.

Title: Impact of vitamins A, B, C, D, and E supplementation on improvement and mortality rate in ICU patients with coronavirus-19: a structured summary of a study protocol for a randomized controlled trial Content: OBJECTIVES: This study will evaluate the main hypothesis that supplementation with vitamins A, B, C, D, and E significantly improves the severity and mortality rate in ICU patients with COVID-19. TRIAL DESIGN: This study is a randomized, single-blinded, two-arm (1:1 ratio) parallel group clinical trial. PARTICIPANTS: We are conducting this study in patients with COVID-19 admitted to intensive care units at the Imam Khomeini Hospital Complex in Tehran, Iran. The inclusion criteria are as follows: (1) aged between 20 and 60 years, (2) both male and female patients with COVID-19, (3) clinical or definitive diagnosis (using polymerase chain reaction (PCR) test), (4) patients have not participated in other clinical trials, and (5) no renal or hepatic abnormalities. The exclusion criteria are as follows: (1) patients with specific and rare viral diseases such as HIV and (2) patients who have been undergoing chemotherapy for the past month. INTERVENTION AND COMPARATOR: Duration of intervention: 7 days from randomization Vitamin A 25,000 IU daily. Vitamin D 600,000 IU once during study. Vitamin E 300 IU twice daily. Vitamin C is taken four times per day. B vitamins are taken as a daily Soluvit [which included thiamine nitrate 3.1 mg, sodium riboflavin phosphate 4.9 mg (corresponding to vitamin B(2) 3.6 mg), nicotinamide 40 mg, pyridoxine hydrochloride 4.9 mg (corresponding to vitamin B(6) 4.0 mg), sodium pantothenate 16.5 mg (corresponding to pantothenic acid 15 mg), sodium ascorbate 113 mg (corresponding to vitamin C 100 mg), biotin 60 μg, folic acid 400 μg, and cyanocobalamin 5 μg]. The control group will not receive any supplements or placebo. All supplements are made in Iran except for Soluvit (from Fresenius Kabi, New Zealand). MAIN OUTCOMES: 1. Weight, height, and BMI. 2. Severity of pulmonary involvement according to CT scan. 3. Respiratory support (invasive or non-invasive). 4. Percentage of oxygen saturation (SpO2 level). 5. Serum levels of WBC, CRP, ESR, IL6, IFN-G, and TNF-α. 6. The patient’s body temperature. 7. The presence or absence of involvement of organs other than the lungs (e.g., heart, liver, kidneys). 8. Duration of hospitalization. 9. Mortality rate. RANDOMIZATION: At baseline, eligible patients were randomly assigned to a 1:1 ratio to one of two groups: intervention and control. Block randomization is used based on the gender of patients. BLINDING (MASKING): Patients are unaware of being placed in the intervention or control groups after signing consent. All treatment staff will be aware of which group each of the patients is in due to the specific conditions of the ICU and the absence of placebo for the control group. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The researchers plan to include 60 patients in total, with 30 patients in each group. TRIAL STATUS: This is the first version of the protocol which started on April 2, 2020. Recruitment began April 2, 2020, and is expected to be complete by July 4, 2020. TRIAL REGISTRATION: The Iranian Registry of Clinical Trials IRCT20200319046819N1. Registered on April 4, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol (Fig. 1, Table 1).

Title: Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics Content: Importance: Vitamin D deficiency increases the incidence of respiratory virus infections. More than 1 billion people worldwide are vitamin D deficient. If vitamin D deficiency is associated to incidence or severity of SARS-CoV-2 infection, a global call could be made for vitamin D supplementation to mitigate the pandemic. Objective: to determine if lower serum 25-hydroxyvitamin D (25(OH)D) levels are correlated to the risk for COVID-19 and its severity as measured by CT Design: single-center observational study Setting: AZ Delta general hospital Participants: 186 consecutive patients with PCR-confirmed SARS-CoV-2 infection hospitalized for COVID-19 from March 1, 2020 to April 7, 2020 Main outcome and measures: comparative analysis of 25(OH)D levels in patients hospitalized for COVID-19 at various radiological stages and a season/age/sex-matched diseased control population Results: we report on 186 SARS-CoV-2 infected patients requiring hospitalization for severe COVID-19: 109 males (median age 68 years, IQR 53-79 years) and 77 females (median age 71 years, IQR 65-74 years). At admission patients were screened by CT to determine temporal changes of COVID-19 lung disease and classified as stage 1 (ground glass opacities), 2 (crazy paving pattern) and 3 (consolidation). At intake, 25(OH)D levels were measured and compared to a season-matched population of 2717 diseased controls, consisting of 999 males (median age 69 years, IQR 53-81 years) and 1718 females (median age 68 years, IQR 43-83 years). Male and female COVID-19 patients combined showed lower median 25(OH)D than controls (18.6 ng/mL, IQR 12.6-25.3, versus 21.5 ng/mL, IQR 13.9-30.8; P=0.0016) and a higher fraction of vitamin D deficiency (58.6% versus 45.2%, P=0.0005). A strong sexual dimorphism was found: female patients had comparable vitamin D status as control females. Male COVID-19 patients, however, showed markedly higher percentage of vitamin D deficiency than controls (67.0% versus 49.2%, P=0.0006) and this effect was more pronounced with advanced radiological stage ranging from 55.2% in stage 1 to 74% in stage 3. Conclusions and relevance: vitamin D deficiency is a possible risk factor for severe SARS-CoV-2 infection in males. Vitamin D supplementation might be an inexpensive, accessible and safe mitigation for the SARS-CoV-2 pandemic.

Title: Vitamin D and Inflammation: Potential Implications for Severity of Covid-19. Content: Background Recent research has indicated that vitamin D may have immune supporting properties through modulation of both the adaptive and innate immune system through cytokines and regulation of cell signalling pathways. We hypothesize that vitamin D status may influence the severity of responses to Covid-19 and that the prevalence of vitamin D deficiency in Europe will be closely aligned to Covid-19 mortality. Methods We conducted a literature search on PubMed (no language restriction) of vitamin D status (for older adults) in countries/areas of Europe affected by Covid-19 infection. Countries were selected by severity of infection (high and low) and were limited to national surveys or where not available, to geographic areas within the country affected by infection. Covid-19 infection and mortality data was gathered from the World Health Organisation. Results Counter-intuitively, lower latitude and typically 'sunny' countries such as Spain and Italy (particularly Northern Italy), had low mean concentrations of 25(OH)D and high rates of vitamin D deficiency. These countries have also been experiencing the highest infection and death rates in Europe. The northern latitude countries (Norway, Finland, Sweden) which receive less UVB sunlight than Southern Europe, actually had much higher mean 25(OH)D concentrations, low levels of deficiency and for Norway and Finland, lower infection and death rates. The correlation between 25(OH)D concentration and mortality rate reached conventional significance (P=0.046) by Spearman's Rank Correlation. Conclusions Optimising vitamin D status to recommendations by national and international public health agencies will certainly have benefits for bone health and potential benefits for Covid-19. There is a strong plausible biological hypothesis and evolving epidemiological data supporting a role for vitamin D in Covid-19.

Title: Vitamin D and inflammation: Potential implications for severity of Covid-19 Content: Background Recent research has indicated that vitamin D may have immune supporting properties through modulation of both the adaptive and innate immune system through cytokines and regulation of cell signalling pathways We hypothesize that vitamin D status may influence the severity of responses to Covid-19 and that the prevalence of vitamin D deficiency in Europe will be closely aligned to Covid-19 mortality Methods We conducted a literature search on PubMed (no language restriction) of vitamin D status (for older adults) in countries/areas of Europe affected by Covid-19 infection Countries were selected by severity of infection (high and low) and were limited to national surveys or where not available, to geographic areas within the country affected by infection Covid-19 infection and mortality data was gathered from the World Health Organisation Results Counter-intuitively, lower latitude and typically ‘sunny’ countries such as Spain and Italy (particularly Northern Italy), had low mean concentrations of 25(OH)D and high rates of vitamin D deficiency These countries have also been experiencing the highest infection and death rates in Europe The northern latitude countries (Norway, Finland, Sweden) which receive less UVB sunlight than Southern Europe, actually had much higher mean 25(OH)D concentrations, low levels of deficiency and for Norway and Finland, lower infection and death rates The correlation between 25(OH)D concentration and mortality rate reached conventional significance (P=0 046) by Spearman's Rank Correlation Conclusions Optimising vitamin D status to recommendations by national and international public health agencies will certainly have benefits for bone health and potential benefits for Covid-19 There is a strong plausible biological hypothesis and evolving epidemiological data supporting a role for vitamin D in Covid-19

Title: Effects of fractionated colostrum replacer and vitamins A, D, and E on haptoglobin and clinical health in neonatal Holstein calves challenged with Mycobacterium avium ssp. paratuberculosis Content: Abstract Thirty Holstein calves were obtained from 2 dairy farms in central Iowa at birth and randomly assigned to 1 of 6 treatment groups: (1) colostrum deprived (CD), no vitamins; (2) colostrum replacer (CR), no vitamins; (3) CR, vitamin A; (4) CR, vitamin D3; (5) CR, vitamin E; and (6) CR, vitamins A, D3, E, with 5 calves per treatment in a 14-d study. Calves were fed pasteurized whole milk (CD) or fractionated colostrum replacer (CR) at birth (d 0) and injected with vitamins according to treatment group. From d 1 through d 14 of the study, all calves were fed pasteurized whole milk (PWM) supplemented with vitamins as assigned. All calves were inoculated with Mycobacterium avium ssp. paratuberculosis on d 1 and 3 of age. Calves fed CR acquired IgG1 and haptoglobin in serum within 24 h of birth, whereas CD calves did not. The CR-fed calves were 2.5 times less likely to develop scours, and CR calves supplemented with vitamins D3 and E also demonstrated a decreased incidence of scours. Serum vitamin levels of A, D, and E increased within treatment group by d 7 and 14 of the study. Interestingly, synergistic effects of supplemental vitamins A, D3, and E on serum 25-(OH)-vitamin D were observed at d 7, resulting in higher levels than in calves administered vitamin D only. Further, vitamin D3 deficiency was observed in CD and CR calves fed a basal diet of pasteurized whole milk and no supplemental vitamins. Colonization of tissues with Mycobacterium avium ssp. paratuberculosis was negligible and was not affected by colostrum feeding or vitamin supplementation. Results demonstrated passive transfer of haptoglobin to neonatal calves, and potential health benefits of supplemental vitamins D3 and E to calves fed pasteurized whole milk.

Title: 'Scientific Strabismus' or two related pandemics: coronavirus disease and vitamin D deficiency Content: The WHO has announced the novel coronavirus disease (COVID-19) outbreak to be a global pandemic. The distribution of community outbreaks shows seasonal patterns along certain latitude, temperature and humidity, that is, similar to the behaviour of seasonal viral respiratory tract infections. COVID-19 displays significant spread in northern mid-latitude countries with an average temperature of 511°C and low humidity. Vitamin D deficiency has also been described as pandemic, especially in Europe. Regardless of age, ethnicity and latitude, recent data showed that 40 % of Europeans are vitamin D deficient (25-hydroxyvitamin D (25(OH)D) levels <50 nmol/l), and 13 % are severely deficient (25(OH)D < 30 nmol/l). A quadratic relationship was found between the prevalences of vitamin D deficiency in most commonly affected countries by COVID-19 and the latitudes. Vitamin D deficiency is more common in the subtropical and mid-latitude countries than the tropical and high-latitude countries. The most commonly affected countries with severe vitamin D deficiency are from the subtropical (Saudi Arabia 46 %; Qatar 46 %; Iran 33·4 %; Chile 26·4 %) and mid-latitude (France 27·3 %; Portugal 21·2 %; Austria 19·3 %) regions. Severe vitamin D deficiency was found to be nearly 0 % in some high-latitude countries (e.g. Norway, Finland, Sweden, Denmark and Netherlands). Accordingly, we would like to call attention to the possible association between severe vitamin D deficiency and mortality pertaining to COVID-19. Given its rare side effects and relatively wide safety, prophylactic vitamin D supplementation and/or food fortification might reasonably serve as a very convenient adjuvant therapy for these two worldwide public health problems alike.

Title: Vitamin D deficiency in patients with diabetes and COVID- 19 infection Content: BACKGROUND AND AIMS: Data show that vitamin D deficiency may play a role in patients with diabetes mellitus and COVID-19 infection. In this article, we review evidence of vitamin D deficiency and COVID-19 infection in context of diabetes mellitus. METHODS: A literature search was carried out by using the key term 'COVID 19' combined with 'Diabetes', 'Vitamin D', 'Extra skeletal effects', 'immunity', 'infection', 'India' from Pub Med (National Library of Medicine, Bethesda, MD and Google Scholar from December 2019 to May 2020. A manual search of the references was also carried out. RESULTS: Vitamin D deficiency has been linked to increased morbidity and mortality in COVID -19 infections but convincing data on diabetic subgroup of patients in particular is still awaited. CONCLUSION: Robust studies are required to ascertain if Vitamin D supplementation could be beneficial in patients with diabetes and COVID-19.

Title: Vitamin D deficiency in patients with diabetes and COVID- 19 infection Content: BACKGROUND AND AIMS: Data show that vitamin D deficiency may play a role in patients with diabetes mellitus and COVID-19 infection. In this article, we review evidence of vitamin D deficiency and COVID-19 infection in context of diabetes mellitus. METHODS: A literature search was carried out by using the key term ‘COVID 19’ combined with ‘Diabetes’, ‘Vitamin D’, ‘Extra skeletal effects’, ‘immunity’, ‘infection’, ‘India’ from Pub Med (National Library of Medicine, Bethesda, MD and Google Scholar from December 2019 to May 2020. A manual search of the references was also carried out. RESULTS: Vitamin D deficiency has been linked to increased morbidity and mortality in COVID -19 infections but convincing data on diabetic subgroup of patients in particular is still awaited. CONCLUSION: Robust studies are required to ascertain if Vitamin D supplementation could be beneficial in patients with diabetes and COVID-19.

Title: Short Communication: Vitamin D and COVID-19 infection and mortality in UK Biobank Content: Purpose Vitamin D has been proposed as a potential causal factor in COVID-19 risk. We aimed to establish whether blood 25-hydroxyvitamin D (25(OH)D) concentration was associated with COVID-19 mortality, and inpatient confirmed COVID-19 infection, in UK Biobank participants. Methods UK Biobank recruited 502,624 participants aged 37-73 years between 2006 and 2010. Baseline exposure data, including 25(OH)D concentration, were linked to COVID-19 mortality. Univariable and multivariable Cox proportional hazards regression analyses were performed for the association between 25(OH)D and COVID-19 death, and poisson regression analyses for the association between 25(OH)D and severe COVID-19 infection. Results Complete data were available for 341,484 UK Biobank participants, of which 656 had inpatient confirmed COVID-19 infection and 203 died of COVID-19 infection. Vitamin D was associated with severe COVID-19 infection and mortality univariably (mortality HR=0.99; 95% CI 0.98-0.998; p=0.016), but not after adjustment for confounders (mortality HR=0.998; 95% CI=0.99-1.01; p=0.696). Conclusions Our findings do not support a potential link between vitamin D concentrations and risk of severe COVID-19 infection and mortality. Recommendations for vitamin D supplementation to lessen COVID-19 risks may provide false reassurance.

Title: Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment Content: COVID-19 pandemic has a high mortality rate and is affecting practically the entire world population. The leading cause of death is severe acute respiratory syndrome as a consequence of exacerbated inflammatory response accompanied by uncontrolled oxidative stress as well as the inflammatory reaction at the lung level. Until now, there is not a specific and definitive treatment for this pathology that worries the world population, especially the older adults who constitute the main risk group. In this context, it results in a particular interest in the evaluation of the efficacy of existing pharmacological agents that may be used for overcoming or attenuating the severity of this pulmonary complication that has ended the lives of many people worldwide. Vitamin D and melatonin could be good options for achieving this aim, taking into account that they have many shared underlying mechanisms that are able to modulate and control the immune adequately and oxidative response against COVID-19 infection, possibly even through a synergistic interaction. The renin-angiotensin system exaltation with consequent inflammatory response has a leading role in the physiopathology of COVID-19 infection; and it may be down-regulated by vitamin D and melatonin in many organs. Therefore, it is also essential to analyze this potential therapeutic association and their relation with RAS as part of this new approach.

Title: Potential Role of Vitamin D in the Elderly to Resist COVID-19 and to Slow Progression of Parkinson’s Disease Content: While we are still learning more about COVID-19, caused by the novel SARS-CoV-2 virus, finding alternative and already available methods to reduce the risk and severity of the disease is paramount. One such option is vitamin D, in the form of vitamin D(3) (cholecalciferol) supplementation, due to its potential antiviral properties. It has become apparent that older individuals have a greater risk of developing severe COVID-19, and compared to younger adults, the elderly have lower levels of vitamin D due to a variety of biological and behavioral factors. Older adults are also more likely to be diagnosed with Parkinson’s disease (PD), with advanced age being the single greatest risk factor. In addition to its immune-system-modulating effects, it has been suggested that vitamin D supplementation plays a role in slowing PD progression and improving PD-related quality of life. We completed a review of the literature to determine the relationship between vitamin D, PD, and COVID-19. We concluded that the daily supplementation of 2000–5000 IU/day of vitamin D(3) in older adults with PD has the potential to slow the progression of PD while also potentially offering additional protection against COVID-19.

Title: Vitamin D deficiency and COVID-19 pandemic Content: • Vitamin D deficiency is very frequent. • Controlled trials showed that vitamin D decreases acute respiratory infections. • Despite a lack of direct evidence of an effect of vitamin D on COVID-19 infection. • Daily vitamin D supplementation with moderate doses is safe and cheap. • Even a small decrease in COVID-19 infections would easily justify this intervention.

Title: Dietary recommendations during the COVID-19 pandemic Content: Optimal nutrition can improve well-being and might mitigate the risk and morbidity associated with coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review summarizes nutritional guidelines to support dietary counseling provided by dietitians and health-related professionals. The majority of documents encouraged the consumption of fruits, vegetables, and whole grain foods. Thirty-one percent of the guidelines highlighted the importance of minerals and vitamins such as zinc and vitamins C, A, and D to maintain a well-functioning immune system. Dietary supplementation has not been linked to COVID-19 prevention. However, supplementation with vitamins C and D, as well as with zinc and selenium, was highlighted as potentially beneficial for individuals with, or at risk of, respiratory viral infections or for those in whom nutrient deficiency is detected. There was no convincing evidence that food or food packaging is associated with the transmission of COVID-19, but good hygiene practices for handling and preparing foods were recommended. No changes to breastfeeding recommendations have been made, even in women diagnosed with COVID-19.

Title: Dietary recommendations during the COVID-19 pandemic. Content: Optimal nutrition can improve well-being and might mitigate the risk and morbidity associated with coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review summarizes nutritional guidelines to support dietary counseling provided by dietitians and health-related professionals. The majority of documents encouraged the consumption of fruits, vegetables, and whole grain foods. Thirty-one percent of the guidelines highlighted the importance of minerals and vitamins such as zinc and vitamins C, A, and D to maintain a well-functioning immune system. Dietary supplementation has not been linked to COVID-19 prevention. However, supplementation with vitamins C and D, as well as with zinc and selenium, was highlighted as potentially beneficial for individuals with, or at risk of, respiratory viral infections or for those in whom nutrient deficiency is detected. There was no convincing evidence that food or food packaging is associated with the transmission of COVID-19, but good hygiene practices for handling and preparing foods were recommended. No changes to breastfeeding recommendations have been made, even in women diagnosed with COVID-19.

Title: Medications in COVID-19 patients: summarizing the current literature from an orthopaedic perspective Content: PURPOSE: The review aims to provide a summary of the current literature regarding common medications prescribed in orthopaedic surgery and their potential implications in COVID-19 patients. METHODS: A systematic review was performed using the PRISMA guidelines. All clinical studies, reviews, consensus and guidelines related to the above medications and COVID-19 were included. RESULTS: A total of 18 articles were included. The use of analgesia, anti-inflammatories, steroids, anticoagulants, antibiotics, vitamin B, vitamin C and vitamin D and their potential impact on COVID-19 patients were reported. CONCLUSION: Eight main recommendations were derived from the review. Firstly, paracetamol remains the first line of analgesia and antipyretic. Secondly, there is no need to avoid NSAIDs for COVID-19 patients. Thirdly, opioids have the potential for immunosuppression in addition to respiratory depression and, therefore, should be prescribed with care in COVID-19 patients. Fourthly, patients with conditions where steroids are proven to be efficacious can continue to receive their steroids; otherwise, systemic steroids are not recommended for COVID-19 patients. Fifthly, orthopaedic surgeons following up on COVID-19 patients who are using steroids should continue to follow them up for possible avascular necrosis. Sixthly, whenever possible, oral anticoagulation should be converted to parental heparin. Seventhly, common orthopaedic antibiotics including penicillin and clindamycin are safe to continue for COVID-19 patients. However, for COVID-19 patients, the antibiotics can potentially be switched to macrolides and tetracyclines if the organisms are sensitive. Lastly, prescription for vitamins B, C and D should continue as per usual clinical practice.

Title: Does vitamin D status impact mortality from SARS-CoV-2 infection? Content:

Title: Vitamin D concentrations and COVID-19 infection in UK Biobank Content: Abstract Background and aims COVID-19 and low levels of vitamin D appear to disproportionately affect black and minority ethnic individuals. We aimed to establish whether blood 25-hydroxyvitamin D (25(OH)D) concentration was associated with COVID-19 risk, and whether it explained the higher incidence of COVID-19 in black and South Asian people. Methods UK Biobank recruited 502,624 participants aged 37–73 years between 2006 and 2010. Baseline exposure data, including 25(OH)D concentration and ethnicity, were linked to COVID-19 test results. Univariable and multivariable logistic regression analyses were performed for the association between 25(OH)D and confirmed COVID-19, and the association between ethnicity and both 25(OH)D and COVID-19. Results Complete data were available for 348,598 UK Biobank participants. Of these, 449 had confirmed COVID-19 infection. Vitamin D was associated with COVID-19 infection univariably (OR = 0.99; 95% CI 0.99–0.999; p = 0.013), but not after adjustment for confounders (OR = 1.00; 95% CI = 0.998–1.01; p = 0.208). Ethnicity was associated with COVID-19 infection univariably (blacks versus whites OR = 5.32, 95% CI = 3.68–7.70, p-value<0.001; South Asians versus whites OR = 2.65, 95% CI = 1.65–4.25, p-value<0.001). Adjustment for 25(OH)D concentration made little difference to the magnitude of the association. Conclusions Our findings do not support a potential link between vitamin D concentrations and risk of COVID-19 infection, nor that vitamin D concentration may explain ethnic differences in COVID-19 infection.

Title: Vitamin D concentrations and COVID-19 infection in UK Biobank Content: BACKGROUND AND AIMS: COVID-19 and low levels of vitamin D appear to disproportionately affect black and minority ethnic individuals. We aimed to establish whether blood 25-hydroxyvitamin D (25(OH)D) concentration was associated with COVID-19 risk, and whether it explained the higher incidence of COVID-19 in black and South Asian people. METHODS: UK Biobank recruited 502,624 participants aged 37-73 years between 2006 and 2010. Baseline exposure data, including 25(OH)D concentration and ethnicity, were linked to COVID-19 test results. Univariable and multivariable logistic regression analyses were performed for the association between 25(OH)D and confirmed COVID-19, and the association between ethnicity and both 25(OH)D and COVID-19. RESULTS: Complete data were available for 348,598 UK Biobank participants. Of these, 449 had confirmed COVID-19 infection. Vitamin D was associated with COVID-19 infection univariably (OR = 0.99; 95% CI 0.99-0.999; p = 0.013), but not after adjustment for confounders (OR = 1.00; 95% CI = 0.998-1.01; p = 0.208). Ethnicity was associated with COVID-19 infection univariably (blacks versus whites OR = 5.32, 95% CI = 3.68-7.70, p-value<0.001; South Asians versus whites OR = 2.65, 95% CI = 1.65-4.25, p-value<0.001). Adjustment for 25(OH)D concentration made little difference to the magnitude of the association. CONCLUSIONS: Our findings do not support a potential link between vitamin D concentrations and risk of COVID-19 infection, nor that vitamin D concentration may explain ethnic differences in COVID-19 infection.

Title: Vitamin D Receptor stimulation to reduce Acute Respiratory Distress Syndrome (ARDS) in patients with Coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166 Content: Coronavirus infection is a serious health problem awaiting an effective vaccine and/or antiviral treatment. The major complication of coronavirus disease 2019 (COVID-19), the Acute Respiratory Distress syndrome (ARDS), is due to a variety of mechanisms including cytokine storm, dysregulation of the renin-angiotensin system, neutrophil activation and increased (micro)coagulation. Based on many preclinical studies and observational data in humans, ARDS may be aggravated by vitamin D deficiency and tapered down by activation of the vitamin D receptor. Several randomized clinical trials using either oral vitamin D or oral Calcifediol (25OHD) are ongoing. Based on a pilot study, oral calcifediol may be the most promising approach. These studies are expected to provide guidelines within a few months.

Title: Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166 Content: Coronavirus infection is a serious health problem awaiting an effective vaccine and/or antiviral treatment. The major complication of coronavirus disease 2019 (COVID-19), the Acute Respiratory Distress syndrome (ARDS), is due to a variety of mechanisms including cytokine storm, dysregulation of the renin-angiotensin system, neutrophil activation and increased (micro)coagulation. Based on many preclinical studies and observational data in humans, ARDS may be aggravated by vitamin D deficiency and tapered down by activation of the vitamin D receptor. Several randomized clinical trials using either oral vitamin D or oral Calcifediol (25OHD) are ongoing. Based on a pilot study, oral calcifediol may be the most promising approach. These studies are expected to provide guidelines within a few months.

Title: Double COVID-19 Confirmed Case Fatality Rate in Countries with High Elderly Female Vitamin D Deficiency Prevalence Content: A number of clues point to a possible role of vitamin D in fighting COVID-19: a reduction in case growth speed with solar zenith angle, higher fatality rate in black people, lower fatality rate in populations that spend more time outdoors. Yet a direct demonstration that vitamin D deficiency is associated with COVID-19 fatalities has remained elusive. We show here in a comparison of 32 countries that countries with high prevalence of vitamin D deficiency among elderly females show a confirmed case fatality rate twice as high as those with low prevalence. We then show that this effect cannot be explained by differences in life expectancy between countries. A mechanistic role for vitamin D in the severity of COVID-19 is proposed.

Title: COVID-19 Fatalities, Latitude, Sunlight, and Vitamin D Content: BACKGROUND: Since Vitamin D is known to be vital in regulating the immune system, and sunlight UV radiation exposure on the skin produces Vitamin D and UV intensity is highest nearest the equator, a study was done to examine the correlation between the latitude and COVID-19 fatality rates for countries. METHODS: Eighty-eight countries were selected based on their likelihood of providing reliable data. Using death rates/million for each country from the "worldometer" web site, a correlation analysis was done between death rates and a country's latitude. RESULTS: A highly significant, positive correlation was found between lower death rates and a country's proximity to the equator (Pearson râ¯=â¯.40 p<.0001, two-tailed t-test). The R squared of .16 means that 16% of the variation in death rates among nations is accounted for by the latitude of the country. Evidence is presented suggesting a direct correlation between sunlight exposure and reduced mortality. DISCUSSION: This study is the first to document a statistically significant correlation between a country's latitude and its COVID-19 mortality and is consistent with other research regarding latitude, Vitamin D deficiency, and COVID-19 fatalities. Limitations of this study are noted. CONCLUSION: Further research is needed to confirm the correlation between latitude and COVID-19 fatalities, and to determine the optimum amounts of safe sunlight exposure and/or vitamin D oral supplementation to reduce COVID-19 fatalities in populations that are at high risk for vitamin D deficiency.

Title: COVID-19 Fatalities, Latitude, Sunlight, and Vitamin D Content: BACKGROUND: Since Vitamin D is known to be vital in regulating the immune system, and sunlight UV radiation exposure on the skin produces Vitamin D and UV intensity is highest nearest the equator, a study was done to examine the correlation between the latitude and COVID-19 fatality rates for countries. METHODS: Eighty-eight countries were selected based on their likelihood of providing reliable data. Using death rates/million for each country from the “worldometer” web site, a correlation analysis was done between death rates and a country's latitude. RESULTS: A highly significant, positive correlation was found between lower death rates and a country's proximity to the equator (Pearson r = .40 p<.0001, two-tailed t-test). The R squared of .16 means that 16% of the variation in death rates among nations is accounted for by the latitude of the country. Evidence is presented suggesting a direct correlation between sunlight exposure and reduced mortality. DISCUSSION: This study is the first to document a statistically significant correlation between a country's latitude and its COVID-19 mortality and is consistent with other research regarding latitude, Vitamin D deficiency, and COVID-19 fatalities. Limitations of this study are noted. CONCLUSION: Further research is needed to confirm the correlation between latitude and COVID-19 fatalities, and to determine the optimum amounts of safe sunlight exposure and/or vitamin D oral supplementation to reduce COVID-19 fatalities in populations that are at high risk for vitamin D deficiency.

Title: Letter: does vitamin D have a potential role against COVID-19? Content:

Title: Letter: does vitamin D have a potential role against COVID‐19? Content:

Title: Vitamin D and Immunity in Infants and Children Content: The last couple of decades have seen an explosion in our interest and understanding of the role of vitamin D in the regulation of immunity. At the molecular level, the hormonal form of vitamin D signals through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor. The VDR and vitamin D metabolic enzymes are expressed throughout the innate and adaptive arms of the immune system. The advent of genome-wide approaches to gene expression profiling have led to the identification of numerous VDR-regulated genes implicated in the regulation of innate and adaptive immunity. The molecular data infer that vitamin D signaling should boost innate immunity against pathogens of bacterial or viral origin. Vitamin D signaling also suppresses inflammatory immune responses that underlie autoimmunity and regulate allergic responses. These findings have been bolstered by clinical studies linking vitamin D deficiency to increased rates of infections, autoimmunity, and allergies. Our goals here are to provide an overview of the molecular basis for immune system regulation and to survey the clinical data from pediatric populations, using randomized placebo-controlled trials and meta-analyses where possible, linking vitamin D deficiency to increased rates of infections, autoimmune conditions, and allergies, and addressing the impact of supplementation on these conditions.

Title: Letter: does vitamin D have a potential role against COVID-19? Authors' reply Content:

Title: 1,25-Dihydroxyvitamin D3 acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis. Content: Multiple sclerosis (MS) is an incurable autoimmune neurodegenerative disease. Environmental factors may be key to MS prevention and treatment. MS prevalence and severity decrease with increasing sunlight exposure and vitamin D(3) supplies, supporting our hypothesis that the sunlight-dependent hormone, 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2) D(3) ), inhibits autoimmune T-cell responses in MS. Moreover, 1,25-(OH)(2) D(3) inhibits and reverses experimental autoimmune encephalomyelitis (EAE), an MS model. Here, we investigated whether 1,25-(OH)(2) D(3) inhibits EAE via the vitamin D receptor (VDR) in T lymphocytes. Using bone marrow chimeric mice with a disrupted VDR only in radio-sensitive hematopoietic cells or radio-resistant non-hematopoietic cells, we found that hematopoietic cell VDR function was necessary for 1,25-(OH)(2) D(3) to inhibit EAE. Furthermore, conditional targeting experiments showed that VDR function in T cells was necessary. Neither 1,25-(OH)(2) D(3) nor T-cell-specific VDR targeting influenced CD4(+) Foxp3(+) T-cell proportions in the periphery or the CNS in these studies. These data support a model wherein 1,25-(OH)(2) D(3) acts directly on pathogenic CD4(+) T cells to inhibit EAE.

Title: Responsibility for vitamin D supplementation of elderly care home residents in England: falling through the gap between medicine and food Content: Abstract Introduction: Vitamin D supplements are recommended for elderly care home residents with little sunlight exposure. However, their use in care homes is limited and vitamin D deficiency in residents is widespread. This study aimed to understand perceived responsibility for the vitamin D status of residents and the determinants of current practice around supplementation. Methods: Thirteen semi-structured interviews were conducted with key informants in two areas of Southern England including care home managers, general practitioners (GPs) and public health professionals. Interviews were audio recorded and transcribed verbatim. Results: Inductive thematic analysis identified four themes: medical framing; professional and sector boundaries; awareness of national guidance; and ethical and practical issues. Vitamin D supplements were not routinely given to residents, and most participants, including the GPs, believed the vitamin D status of residents was the responsibility of the GP. Care home managers felt unable to make decisions about vitamin D and vulnerable to suggestions of wrongdoing in administering over-the-counter vitamin tablets. This results in vitamin D requiring prescription by medical professionals and few care home residents receiving vitamin D supplements. Conclusion: The medical framing of vitamin D supplements in care homes is a practical barrier to residents receiving them and is out of step with public health recommendations. Vitamin D levels in care home residents could be improved through universal supplementation. This requires a paradigm shift so that vitamin D is understood as a protective nutrient as well as a medicine, and a public health as well as a medical responsibility. The failure to ensure vitamin D adequacy of residents may emerge as a factor in the spread and severity of COVID-19 in care homes and gives increased urgency to addressing this issue.

Title: Local expression profiles of vitamin D-related genes in airways of COPD patients. Content: Treatment of Chronic Obstructive Pulmonary Disease (COPD) is based on bronchodilation, with inhaled corticosteroids or azithromycin associated when frequent exacerbations occur. Despite the proven benefits of current treatment regimens, the need for new interventions in delineated subgroups remains. There is convincing evidence for oral vitamin D supplementation in reducing exacerbations in COPD patients severely deficient for circulating vitamin D. However, little is known about local vitamin D metabolism in the airways and studies examining expression of the vitamin D receptor (VDR), the activating enzyme (CYP27B1) and inactivating enzyme (CYP24A1) of vitamin D in lung tissue of COPD patients are lacking. Therefore, the expression and localization of key enzymes and the receptor of the vitamin D pathway were examined in tissue of 10 unused donor lungs and 10 COPD explant lungs. No differences in the expression of CYP27B1 and CYP24A1 were found. Although protein expression of VDR was significantly lower in COPD explant tissue, there was no difference in downstream expression of the antimicrobial peptide cathelicidin. Whereas CYP27B1 and CYP24A1 were present in all layers of the bronchial epithelium, VDR was only expressed at the apical layer of a fully differentiated bronchial epithelium with no expression in vascular endothelial cells. By contrast, CYP24A1 expression was highly present in lung endothelial cells suggesting that systemic vitamin D can be inactivated before reaching the epithelial compartment and the tissue immune cells. These data support the idea of exploring the role of vitamin D inhalation in patients with COPD.

Title: Spurious Correlation? A review of the relationship between Vitamin D and Covid-19 infection and mortality Content: The study reviews the evidence presented in a recent study linking vitamin D levels and Covid-19 infection and mortality. It was argued that correlation alone may not be useful in establishing a relationship between vitamin D levels and Covid-19 infections and mortality. Appropriate controls need to be included for improved understanding of the relationship. We proposed life expectancy as a potential control. Including this control in a regression model, we find that vitamin D levels are not a statistically significant predictor of Covid-19 infections or mortality. Life expectancy, on the other hand, was found to be statistically significant predictor of infections and mortality at country level.

Title: Prevention of exacerbations in patients with COPD and vitamin D deficiency through vitamin D supplementation (PRECOVID): a study protocol. Content: BACKGROUND Vitamin D is well known for its function in calcium homeostasis and bone mineralisation, but is increasingly studied for its potential immunomodulatory properties. Vitamin D deficiency is a common problem in patients with COPD. Previous studies have not demonstrated a beneficial effect of vitamin D on exacerbation rate in COPD patients. However, subgroup analyses suggested protective effects in vitamin D deficient patients. Our objective is to assess the effect of vitamin D supplementation on exacerbation rate specifically in vitamin D deficient COPD patients. METHODS/DESIGN We will perform a randomised, multi-center, double-blind, placebo-controlled intervention study. The study population consists of 240 COPD patients aged 40 years and older with vitamin D deficiency (25-hydroxyvitamin D concentration < 50 nmol/L). Participants will be recruited after an exacerbation and will be randomly allocated in a 1:1 ratio to receive vitamin D3 16800 IU or placebo orally once a week during 1 year. Participants will receive a diary card to register the incidence of exacerbations and changes in medication during the study period. Visits will be performed at baseline, at 6 months and at 12 months after randomisation. Participants will undergo spirometry, measurement of total lung capacity and assessment of maximal respiratory mouth pressure. Several physical performance and hand grip strength tests will be performed, questionnaires on quality of life and physical activity will be filled in, a nasal secretion sample and swab will be obtained and blood samples will be taken. The primary outcome will be exacerbation rate. DISCUSSION This study will be the first RCT aimed at the effects of vitamin D supplementation on exacerbation rate in vitamin D deficient COPD patients. Also, in contrast to earlier studies that used infrequent dosing regimens, our trial will study effects of a weekly dose of vitamin D supplementation. Secondly, the immunomodulatory effects of vitamin D on host immune response of COPD patients and underlying mechanisms will be studied. Finally, the effects on physical functioning will be examined. TRIAL REGISTRATION This trial is registered in ClinicalTrials.gov, ID number NCT02122627 . Date of Registration April 2014.

Title: Letter: low population mortality from COVID‐19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity Content: The recent editorial by Rhodes et al considered latitude and mentioned one mechanism that vitamin D is important in regulating and suppressing the inflammatory response of cytokines of respiratory epithelial cells and macrophages to various pathogens, including respiratory viruses and preventing cytokine storm and the subsequent acute respiratory distress syndrome (RDS) (1).

Title: Counter-regulatory 'Renin-Angiotensin' System-based Candidate Drugs to Treat COVID-19 Diseases in SARS-CoV-2-infected patients Content: SARS-CoV-2 / COVID-19 and the 'Renin-Angiotensin' System The ubiquitous 'Renin-Angiotensin' system (RAS), also referred to as 'Renin-Angiotensin-Aldosterone' system, plays a crucial physiological role in humans as being a key regulator of renal, cardiovascular and innate immune functions [1, 2]. It appears to work in tandem with vitamin D, a secosteroid pro-hormone which reportedly acts as a negative regulatory factor of the RAS [3-6]. A dysfunction (e.g. over-reactivity) of RAS, together with hypovitaminosis D, is likely associated with some of the various renal, cardiac, vascular and immune outcomes that might be observed in COVID-19 patients, including the cytokine storm (i.e. unopposed hyperactive immune reaction generating both pro-inflammatory and anti-inflammatory cytokines) and consequent lethal acute respiratory distress syndrome [1, 7]. Recently, SARS-CoV-2 [8, 9], the causative agent of COVID-19, has been described to interfere with the RAS [2] by interacting -via its spike (S) glycoprotein- with the metallopeptidase Angiotensin-Converting Enzyme 2 (ACE2) receptor [9, 10] that is expressed at the surface of epithelial cells from blood vessels, lung, kidney (renal tubules), intestine, and heart, as well as on cerebral neurons and immune monocytes/macrophages [11-13]. The main SARS-CoV-2-related COVID-19 symptoms/diseases reported hitherto are hypertension, atherosclerosis, thrombosis (coagulopathy), diarrhea, glaucoma, anosmia, ageusia, skin lesions (dermatitis), autoimmune inflammation of the central nervous system, and damages to various organs such as the lung, heart, kidney, and testicle [1, 2, 14]. All these diffuse COVID-19 disorders are likely linked to an over-reaction of RAS in SARS-CoV-2-infected persons. Such a RAS imbalance would be also favored by hypovitaminosis D [2-7, 11]. Since RAS appears to be central in COVID-19 symptoms/diseases, selective targeting of key component(s) of this system might be appropriate to treat RAS-dependent disorders. COVID-19 Disorders: 'Renin-Angiotensin' System (RAS) & Counter-regulatory RAS In the RAS pathway [1, 15], Renin (kidney) cleaves Angiotensinogen (liver) to give Angiotensin I (i.e. peptide DRVYIHPFHL). The latter is cleaved by the Angiotensin-Converting Enzyme (ACE) to produce Angiotensin II (i.e. peptide DRVYIHPF), which is the substrate of ACE2 (SARS-CoV-2 receptor) and key player of the RAS. The cellular targets of Angiotensin II are the vasoconstrictor type 1 (AT1R) and vasodilatator type 2 (AT2R) Angiotensin II receptors (AT1R is expressed at the surface of monocytes/macrophages and T-cells indicating that RAS acts on innate immunity in host). When cleaved by ACE2, Angiotensin II gives Angiotensin 1-7 (i.e. peptide DRVYIHP), targeting the vasodilatator proto-oncogene Mas receptor (MasR). Angiotensin 1-7 can be further transformed to Alamandine (i.e. peptide ARVYIHP) by an aspartate decarboxylase. Alamandine would bind to the vasodilatator Mas-related G protein-coupled receptor member D (MRGD) thus promoting most of the Angiotensin 1-7-like effects. Angiotensin II can produce Angiotensin A (i.e. peptide ARVYIHPF) via an aspartate decarboxylase, and Alamandine via an additional ACE2 cleavage. ACE2 can also cleave Angiotensin I to form Angiotensin 1-9 (i.e. peptide DRVYIHPFH), which targets AT2R. In the RAS pathway were finally evidenced the related Angiotensin III (i.e. peptide RVYIHPF) and Angiotensin IV (i.e. peptide VYIHPF) variants targeting the AT1R and vasodilatator AT4R, respectively. From the known molecular functioning of the RAS, Angiotensins I and II (aside Angiotensin III) are playing central roles in the activity of RAS and associated pathologies, including COVID-19 [2, 10]. Interestingly, it appears that a 'counter-regulatory' RAS does exist to modulate system homeostasis; it relies on Angiotensin 1-7, Angiotensin 1-9, Alamandine, Angiotensin A, and Angiotensin IV, which are targeting the MasR, AT2R, MRGD, ACE2 and AT4R vasodilatator receptors, respectively. These peptides were found to exhibit cardioprotective, vasoactive (anti-hypertensive), anti-hypertrophic and/or anti-inflammatory potentials [15]. Such naturally-produced molecules of the RAS are expected to counteract the SARS-CoV-2-induced over-activation of RAS and reverse, to some extent, the associated COVID-19 diseases. CONCLUDING REMARKS A recent report suggests that RAS inhibitors may act on the severity of viral infection and mortality of COVID-19 patients [14]. Whether or not RAS blockers would be beneficial to COVID-19 cases is still controversial. The RAS inhibitors likely prevent the cytokine storm as RAS is reported to control the release of pro-inflammatory cytokines [1, 7]. It appears that COVID-19 disorders of SARS-CoV-2-infected humans depend on the RAS over-reacted by the (ACE2-dependent) viral infection and vitamin D deficiency. The track for a possible COVID-19 treatment would be to target RAS using specific candidate chemotherapeutic drugs. The proposed molecules are (so far) ACE inhibitors (to prevent the production of Angiotensin II from Angiotensin I), and blockers/antagonists of AT1R such as Losartan and derivatives. Recombinant ACE2 (under clinical trials) is also considered as a decoy for the recognition and competitive binding to the spike (S) glycoprotein of SARS-CoV-2 [9, 10]. We support the use of natural candidate peptide drugs that belong to the 'counter-regulatory' RAS, i.e. Angiotensin 1-7, Angiotensin 1-9, Alamandine, Angiotensin A and/or Angiotensin IV to treat COVID-19 disorders. The targeted receptors would thus be MasR, AT2R, MRGD, ACE2 and AT4R. The authors wish to thank Bonabes De Rougé MD for fruitful discussions.

Title: Counter-regulatory 'Renin-Angiotensin' System-based Candidate Drugs to Treat COVID-19 Diseases in SARS-CoV-2-infected patients. Content: SARS-CoV-2 / COVID-19 and the 'Renin-Angiotensin' System The ubiquitous 'Renin-Angiotensin' system (RAS), also referred to as 'Renin-Angiotensin-Aldosterone' system, plays a crucial physiological role in humans as being a key regulator of renal, cardiovascular and innate immune functions [1, 2]. It appears to work in tandem with vitamin D, a secosteroid pro-hormone which reportedly acts as a negative regulatory factor of the RAS [3-6]. A dysfunction (e.g. over-reactivity) of RAS, together with hypovitaminosis D, is likely associated with some of the various renal, cardiac, vascular and immune outcomes that might be observed in COVID-19 patients, including the cytokine storm (i.e. unopposed hyperactive immune reaction generating both pro-inflammatory and anti-inflammatory cytokines) and consequent lethal acute respiratory distress syndrome [1, 7]. Recently, SARS-CoV-2 [8, 9], the causative agent of COVID-19, has been described to interfere with the RAS [2] by interacting -via its spike (S) glycoprotein- with the metallopeptidase Angiotensin-Converting Enzyme 2 (ACE2) receptor [9, 10] that is expressed at the surface of epithelial cells from blood vessels, lung, kidney (renal tubules), intestine, and heart, as well as on cerebral neurons and immune monocytes/macrophages [11-13]. The main SARS-CoV-2-related COVID-19 symptoms/diseases reported hitherto are hypertension, atherosclerosis, thrombosis (coagulopathy), diarrhea, glaucoma, anosmia, ageusia, skin lesions (dermatitis), autoimmune inflammation of the central nervous system, and damages to various organs such as the lung, heart, kidney, and testicle [1, 2, 14]. All these diffuse COVID-19 disorders are likely linked to an over-reaction of RAS in SARS-CoV-2-infected persons. Such a RAS imbalance would be also favored by hypovitaminosis D [2-7, 11]. Since RAS appears to be central in COVID-19 symptoms/diseases, selective targeting of key component(s) of this system might be appropriate to treat RAS-dependent disorders. COVID-19 Disorders: 'Renin-Angiotensin' System (RAS) & Counter-regulatory RAS In the RAS pathway [1, 15], Renin (kidney) cleaves Angiotensinogen (liver) to give Angiotensin I (i.e. peptide DRVYIHPFHL). The latter is cleaved by the Angiotensin-Converting Enzyme (ACE) to produce Angiotensin II (i.e. peptide DRVYIHPF), which is the substrate of ACE2 (SARS-CoV-2 receptor) and key player of the RAS. The cellular targets of Angiotensin II are the vasoconstrictor type 1 (AT1R) and vasodilatator type 2 (AT2R) Angiotensin II receptors (AT1R is expressed at the surface of monocytes/macrophages and T-cells indicating that RAS acts on innate immunity in host). When cleaved by ACE2, Angiotensin II gives Angiotensin 1-7 (i.e. peptide DRVYIHP), targeting the vasodilatator proto-oncogene Mas receptor (MasR). Angiotensin 1-7 can be further transformed to Alamandine (i.e. peptide ARVYIHP) by an aspartate decarboxylase. Alamandine would bind to the vasodilatator Mas-related G protein-coupled receptor member D (MRGD) thus promoting most of the Angiotensin 1-7-like effects. Angiotensin II can produce Angiotensin A (i.e. peptide ARVYIHPF) via an aspartate decarboxylase, and Alamandine via an additional ACE2 cleavage. ACE2 can also cleave Angiotensin I to form Angiotensin 1-9 (i.e. peptide DRVYIHPFH), which targets AT2R. In the RAS pathway were finally evidenced the related Angiotensin III (i.e. peptide RVYIHPF) and Angiotensin IV (i.e. peptide VYIHPF) variants targeting the AT1R and vasodilatator AT4R, respectively. From the known molecular functioning of the RAS, Angiotensins I and II (aside Angiotensin III) are playing central roles in the activity of RAS and associated pathologies, including COVID-19 [2, 10]. Interestingly, it appears that a 'counter-regulatory' RAS does exist to modulate system homeostasis; it relies on Angiotensin 1-7, Angiotensin 1-9, Alamandine, Angiotensin A, and Angiotensin IV, which are targeting the MasR, AT2R, MRGD, ACE2 and AT4R vasodilatator receptors, respectively. These peptides were found to exhibit cardioprotective, vasoactive (anti-hypertensive), anti-hypertrophic and/or anti-inflammatory potentials [15]. Such naturally-produced molecules of the RAS are expected to counteract the SARS-CoV-2-induced over-activation of RAS and reverse, to some extent, the associated COVID-19 diseases. CONCLUDING REMARKS A recent report suggests that RAS inhibitors may act on the severity of viral infection and mortality of COVID-19 patients [14]. Whether or not RAS blockers would be beneficial to COVID-19 cases is still controversial. The RAS inhibitors likely prevent the cytokine storm as RAS is reported to control the release of pro-inflammatory cytokines [1, 7]. It appears that COVID-19 disorders of SARS-CoV-2-infected humans depend on the RAS over-reacted by the (ACE2-dependent) viral infection and vitamin D deficiency. The track for a possible COVID-19 treatment would be to target RAS using specific candidate chemotherapeutic drugs. The proposed molecules are (so far) ACE inhibitors (to prevent the production of Angiotensin II from Angiotensin I), and blockers/antagonists of AT1R such as Losartan and derivatives. Recombinant ACE2 (under clinical trials) is also considered as a decoy for the recognition and competitive binding to the spike (S) glycoprotein of SARS-CoV-2 [9, 10]. We support the use of natural candidate peptide drugs that belong to the 'counter-regulatory' RAS, i.e. Angiotensin 1-7, Angiotensin 1-9, Alamandine, Angiotensin A and/or Angiotensin IV to treat COVID-19 disorders. The targeted receptors would thus be MasR, AT2R, MRGD, ACE2 and AT4R. The authors wish to thank Bonabes De Rougé MD for fruitful discussions.

Title: Modulation of the Immune Response to Respiratory Viruses by Vitamin D Content: Background: Vitamin D deficiency has been shown to be independently associated with increased risk of viral acute respiratory infection (ARI) in a number of observational studies, and meta-analysis of clinical trials of vitamin D supplementation for prevention of ARI has demonstrated protective effects. Several cellular studies have investigated the effects of vitamin D metabolites on immune responses to respiratory viruses, but syntheses of these reports are lacking. Scope: In this article, we review the literature reporting results of in vitro experiments investigating immunomodulatory actions of vitamin D metabolites in human respiratory epithelial cells infected with respiratory viruses. Key findings: Vitamin D metabolites do not consistently influence replication or clearance of rhinovirus, respiratory syncytial virus (RSV) or influenza A virus in human respiratory epithelial cell culture, although they do modulate expression and secretion of type 1 interferon, chemokines including CXCL8 and CXCL10 and pro-inflammatory cytokines, such as TNF and IL-6. Future research: More studies are needed to clarify the effects of vitamin D metabolites on respiratory virus-induced expression of cell surface markers mediating viral entry and bacterial adhesion to respiratory epithelial cells.

Title: Vitamin D: A simpler alternative to tocilizumab for trial in COVID-19? Content: There is anecdotal evidence that tocilizumab, an immunosuppressant drug, may be a potential therapeutic option for patients with severe manifestations of coronavirus disease 2019 (COVID-19). Like tocilizumab, Vitamin D appears to modulate the activity of an interleukin (IL-6), which may explain the seasonal variation in prevalence of influenza. While most cases of COVID-19 have, thus far, occurred in the Northern Hemisphere winter, limiting the ability to assess seasonal variation, there remains substantial variation in the severity of this condition that has yet to be explained. A retrospective comparison of Vitamin D levels in previously obtained blood samples between survivors and confirmed fatalities could establish a rationale for implementation of widespread Vitamin D supplementation. This would be far cheaper and simpler than tocilizumab as a therapeutic option to trial.

Title: Letter: low population mortality from COVID‐19 in countries south of latitude 35° North supports vitamin D as a factor determining severity—authors’ reply Content: We thank Dr Mansur for his interest in our editorial in which we highlighted the association between northern latitude and increased COVID-19 mortality1 and for his helpful comments about the potential importance of vitamin D effects on cathelicidin and on the renin-angiotensin system, which could be important in protecting against severe COVID-19.2 Vitamin D is a secosteroid hormone, derived like cortisol and sex hormones from cholesterol, so not surprisingly it has a broad range of actions reflecting the several hundred or more genes that are vitamin D-responsive.3,4.

Title: Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease. Content: In sickle cell disease, respiratory infection and asthma may lead to respiratory complications that are a leading cause of morbidity and mortality. Vitamin D has anti-infective and immunomodulatory effects that may decrease the risk for respiratory infections, asthma, and acute chest syndrome. We conducted a randomized double-blind active-controlled clinical trial to determine whether monthly oral vitamin D3 can reduce the rate of respiratory events in children with sickle cell disease. Seventy sickle cell subjects, ages 3-20 years, with baseline records of respiratory events over 1 year before randomization, underwent screening. Sixty-two subjects with 25-hydroxyvitamin D levels of 5-60 ng/mL were randomly assigned to oral vitamin D3 (100 000 IU or 12 000 IU, n = 31 each) under observed administration once monthly for 2 years. The primary outcome was the annual rate of respiratory events (respiratory infection, asthma exacerbation, or acute chest syndrome) ascertained by the use of a validated questionnaire administered biweekly. Analysis included 62 children (mean age of 9.9 years, 52% female, and predominantly with homozygous HbS disease [87%]) with mean baseline 25-hydroxyvitamin D of 14.3 ng/mL. The annual rates of respiratory events at baseline and intervention years 1 and 2 were 4.34 ± 0.35, 4.28 ± 0.36, and 1.49 ± 0.37 (high dose) and 3.91 ± 0.35, 3.34 ± 0.37, and 1.54 ± 0.37 (standard dose), respectively. In pediatric patients with sickle cell disease, 2-year monthly oral vitamin D3 was associated with a >50% reduction in the rate of respiratory illness during the second year (P = .0005), with similar decreases associated with high- and standard-dose treatment. This trial was registered at www.clinicaltrials.gov as #NCT01443728.

Title: Reviews of Science for Science Librarians: Vitamins and Trace Elements that May Be Preventive or Ameliorating in This Age of Contagion Content: Prompted by COVID-19, many laypersons now seek information on nutritional support to ward off or help shorten the effects of serious infectious diseases, and are attracted to practices and substances that lack a serious scientific basis. This paper scanned peer-reviewed medical literature to prove a concept: That diets or supplements rich in some vitamins or minerals may indeed be important in managing threats to health caused by a variety of infectious diseases in the past and compares these findings to the current recommendations of the Academy of Nutrition and Dietetics and to research by Zhang and Liu, two China-based pioneers in countering COVID-19. Vitamins A, D, and zinc, are common to both groups and are well supported in the literature. Vitamin C is also a common denominator but has a mixed record of efficacy in dealing with prior infectious outbreaks. Iron has support and do some other vitamins and trace elements. Health science librarians should emphasize that while experts can disagree on particular micronutrients they tend to agree that decisions on protective or curative supplements or diets or should have some basis in fact.

Title: The impact of vitamin D food fortification and health outcomes in children: a systematic review and meta-regression. Content: OBJECTIVE Vitamin D (vitD) deficiency is a global childhood health problem. Food fortification is a promising strategy to curb vitD deficiency. We aimed to assess the effectiveness of utilizing vitD fortification in staple foods to improve 25hydroxyvitamin D (25(OH)D) concentration and to reduce the prevalence of vitD deficiency among healthy children. METHODS We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating the use of vitD fortified food products compared to no fortification among healthy children aged 1-18 years old. We searched Medline, Embase, Global Health, and Cochrane (CENTRAL) databases from database inception until May 2019. Independently, six reviewers in pairs screened titles and abstracts, assessed the full text for eligibility, and performed data extraction and quality assessment. The primary outcome is the impact of fortification on 25(OH)D concentration. The secondary outcomes included the impact of fortification on the prevalence of vitD deficiency, school performance, cognitive function, school absences, infection rate, hospital admission length, and compliance with fortified food product consumption. RESULTS We identified 2229 articles. After assessing eligibility, 20 RCTs met the inclusion criteria. The eligible RCTs assessed the fortification of milk, cereal, juice, bread, yogurt, and cheese compared with no fortification. All RCTs, except for three, had a low risk of bias. Food fortification improved 25(OH)D concentration by a mean difference (MD) of 15.51 nmol/L (95% confidence interval (CI) 6.28, 24.74; I2 = 99%), which resulted in a mean increase of 3 nmol/l for every 100 IU of vitD, when adjusted for baseline 25(OH)D concentration and country latitude. Additionally, the prevalence of vitD deficiency decreased by a risk ratio of 0.53 (95% CI 0.41, 0.69; I2 = 95%), and cognitive function improved by a MD of 1.22 intelligence quotient (IQ) points (95% CI 0.65, 1.79; I2 = 0%). The overall evidence quality was high. CONCLUSION VitD food fortification is an effective way to improve 25(OH)D concentration, prevent vitD deficiency, and improve IQ levels. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42017057631.

Title: Vitamin D3 in High-Quality Cow Milk: An Italian Case Study Content: The quality-labeling category of high-quality (HQ) milk defined by the Italian legislation must comply with specific requirements concerning rigorous breeder management, hygienic controls, fat and protein content, bacterial load, somatic cells, lactic acid content, and non-denatured soluble serum proteins. However, there is no specification for the vitamin D content of HQ milk. Moreover, the data on the vitamin D content of this milk category are very scarce. In the present study, the content of vitamin D3 was evaluated in HQ raw and pasteurized cow milk obtained from Italian cowsheds and supermarkets. The vitamin D3 content varied from not detected (less than 1 µg L(−1)) to 17.0 ± 2.0 µg L(−1) milk and was not related to the milk fat content. These results represent a case study including a significant although not exhaustive part of the contemporary Italian market of HQ milk. It was shown for the first time that HQ raw milk does not necessarily contain more vitamin D3, even though non-expert consumers likely to buy milk labeled as HQ could expect it. The vitamin D3 content in HQ pasteurized whole milk should be reported on the label of the milk package as a best practice of consumer information policy.

Title: The link between Vitamin D and Covid-19: distinguishing facts from fiction. Content: Vitamin D is produced in the skin under the influence of UVB-light from the sun or obtained via the diet by eating fatty fish, enriched dairy products or supplements. Vitamin D is known to support a healthy bone and severe deficiency may lead to osteomalacia or the rickets, which still occur in poor areas of the world. In addition, vitamin D support key functions in many organs, including the brain, muscle and the immune systems (Holick, 2007). In fact, the vitamin D receptor (VDR) is expressed in most cell types and may activate somewhere between 200-500 genes, many related to the immune system.

Title: The link between Vitamin D and Covid-19: distinguishing facts from fiction Content: Vitamin D is produced in the skin under the influence of UVB-light from the sun or obtained via the diet by eating fatty fish, enriched dairy products or supplements. Vitamin D is known to support a healthy bone and severe deficiency may lead to osteomalacia or the rickets, which still occur in poor areas of the world. In addition, vitamin D support key functions in many organs, including the brain, muscle and the immune systems (Holick, 2007). In fact, the vitamin D receptor (VDR) is expressed in most cell types and may activate somewhere between 200-500 genes, many related to the immune system.

Title: Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Content: BACKGROUND Randomised controlled trials (RCTs) of vitamin D to prevent COPD exacerbations have yielded conflicting results.Individual participant data meta-analysis could identify factors that explain this variation. METHODS PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched from inception up to and including 5 October 2017 to identify RCTs of vitamin D supplementation in patients with COPD that reported incidence of acute exacerbations. Individual participant data meta-analysis was performed using fixed effects models adjusting for age, sex, Global Initiative for Chronic Obstructive Lung Disease spirometric grade and trial. RESULTS Four eligible RCTs (total 560 participants) were identified; individual participant data were obtained for 469/472 (99.4%) participants in three RCTs. Supplementation did not influence overall rate of moderate/severe COPD exacerbations (adjusted incidence rate ratio (aIRR) 0.94, 95% CI 0.78 to 1.13). Prespecified subgroup analysis revealed that protective effects were seen in participants with baseline 25-hydroxyvitamin D levels <25 nmol/L (aIRR 0.55, 95% CI 0.36 to 0.84) but not in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (aIRR 1.04, 95% CI 0.85 to 1.27; p for interaction=0.015). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted OR 1.16, 95% CI 0.76 to 1.75). CONCLUSIONS Vitamin D supplementation safely and substantially reduced the rate of moderate/severe COPD exacerbations in patients with baseline 25-hydroxyvitamin D levels <25 nmol/L but not in those with higher levels. TRIAL REGISTRATION NUMBER CRD42014013953.

Title: Effect of vitamin D supplementation on pain and physical function in patients with knee osteoarthritis (OA): an OA Trial Bank protocol for a systematic review and individual patient data (IPD) meta-analysis. Content: INTRODUCTION Observational data suggest that vitamin D deficiency is associated with the onset and progression of knee osteoarthritis (OA). However, randomised controlled trials (RCTs) to date investigating the efficacy of vitamin D supplementation in knee OA have reported conflicting results. Further research is needed to clarify the effects of vitamin D on patient-reported outcomes and determine whether there are patient subgroups who may benefit from the supplementation. The aim of this individual patient data (IPD) meta-analysis is to identify patient-level predictors of treatment response to vitamin D supplementation on pain and physical function. METHODS AND ANALYSIS A systematic literature search will be conducted for RCTs of vitamin D supplementation on knee OA. Authors of original RCTs will be contacted to obtain the IPD. The primary outcomes will include long-term (≥12 months) pain and physical function. Secondary outcomes will include medium-term (≥6 months and <12 months) and short-term (<6 months) pain and physical function, as well as patient global assessment, quality of life and adverse events. Potential treatment effect modifiers to be examined in the subgroup analyses include age, gender, body mass index, baseline knee pain severity and physical function, baseline vitamin D level, radiographic stage, presence of bone marrow lesions on MRI, presence of clinical signs of local inflammation and concomitant depressive symptoms. Both one-step and two-step modelling methods will be used to determine the possible modifiable effect of each subgroup of interest. ETHICS AND DISSEMINATION Research ethical or governance approval is exempt for this study as no new data are being collected. This study will be the first IPD meta-analysis to clarify the effect of vitamin D supplementation on clinical symptoms in different subgroups of patients with knee OA. The findings will be disseminated through peer-review publications and conference presentations. PROSPERO REGISTRATION NUMBER CRD42018107740.

Title: Enhancing immunity in viral infections, with special emphasis on COVID-19: A review Content: BACKGROUND AND AIMS: Balanced nutrition which can help in maintaining immunity is essential for prevention and management of viral infections. While data regarding nutrition in coronavirus infection (COVID-19) are not available, in this review, we aimed to evaluate evidence from previous clinical trials that studied nutrition-based interventions for viral diseases (with special emphasis on respiratory infections), and summarise our observations. METHODS: A systematic search strategy was employed using keywords to search the literature in 3 key medical databases: PubMed®, Web of Science® and SciVerse Scopus®. Studies were considered eligible if they were controlled trials in humans, measuring immunological parameters, on viral and respiratory infections. Clinical trials on vitamins, minerals, nutraceuticals and probiotics were included. RESULTS: A total of 640 records were identified initially and 22 studies were included from other sources. After excluding duplicates and articles that did not meet the inclusion criteria, 43 studies were obtained (vitamins: 13; minerals: 8; nutraceuticals: 18 and probiotics: 4). Among vitamins, A and D showed a potential benefit, especially in deficient populations. Among trace elements, selenium and zinc have also shown favourable immune-modulatory effects in viral respiratory infections. Several nutraceuticals and probiotics may also have some role in enhancing immune functions. Micronutrients may be beneficial in nutritionally depleted elderly population. CONCLUSIONS: We summaries possible benefits of some vitamins, trace elements, nutraceuticals and probiotics in viral infections. Nutrition principles based on these data could be useful in possible prevention and management of COVID-19.

Title: Enhancing immunity in viral infections, with special emphasis on COVID-19: A review Content: Abstract Background and aims Balanced nutrition which can help in maintaining immunity is essential for prevention and management of viral infections. While data regarding nutrition in coronavirus infection (COVID-19) are not available, in this review, we aimed to evaluated evidence from previous clinical trials that evaluated nutrition-based interventions for viral diseases (with special emphasis on respiratory infections), and summaries our observations. Methods A systematic search strategy was employed using keywords to search the literature in 3 key medical databases: PubMed®, Web of Science® and SciVerse Scopus®. Studies were considered eligible if they were controlled trials in humans, measuring immunological parameters, on viral and respiratory infections. Clinical trials on vitamins, minerals, nutraceuticals and probiotics were included. Results total of 640 records were identified initially and 22 studies were included from other sources. After excluding duplicates and articles that did not meet the inclusion criteria, 43 studies were obtained (vitamins: 13; minerals: 8; nutraceuticals: 18 and probiotics: 4). Among vitamins, A and D showed a potential benefit, especially in deficient populations. Among trace elements, selenium and zinc have also shown favourable immune-modulatory effects in viral respiratory infections. Several nutraceuticals and probiotics may have some role in enhancing immune functions. Micronutrients may be beneficial in nutritionally depleted elderly population. Conclusions We summaries possible benefits of some vitamins, trace elements, nutraceuticals and and probiotics. Nutrition principles based on these data could be useful in possible prevention and management of COVID-19

Title: Vitamin D in Triple-Negative and BRCA1-Deficient Breast Cancer—Implications for Pathogenesis and Therapy Content: Several studies show that triple-negative breast cancer (TNBC) patients have the lowest vitamin D concentration among all breast cancer types, suggesting that this vitamin may induce a protective effect against TNBC. This effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D), can be attributed to its potential to modulate proliferation, differentiation, apoptosis, inflammation, angiogenesis, invasion and metastasis and is supported by many in vitro and animal studies, but its exact mechanism is poorly known. In a fraction of TNBCs that harbor mutations that cause the loss of function of the DNA repair-associated breast cancer type 1 susceptibility (BRCA1) gene, 1,25(OH)2D may induce protective effects by activating its receptor and inactivating cathepsin L-mediated degradation of tumor protein P53 binding protein 1 (TP53BP1), preventing deficiency in DNA double-strand break repair and contributing to genome stability. Similar effects can be induced by the interaction of 1,25(OH)2D with proteins of the growth arrest and DNA damage-inducible 45 (GADD45) family. Further studies on TNBC cell lines with exact molecular characteristics and clinical trials with well-defined cases are needed to determine the mechanism of action of vitamin D in TNBC to assess its preventive and therapeutic potential.

Title: Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19) Content: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) represents an emergent global threat which is straining worldwide healthcare capacity. As of May 27th, the disease caused by SARS-CoV-2 (COVID-19) has resulted in more than 340,000 deaths worldwide, with 100,000 deaths in the US alone. It is imperative to study and develop pharmacological treatments suitable for the prevention and treatment of COVID-19. Ascorbic acid is a crucial vitamin necessary for the correct functioning of the immune system. It plays a role in stress response and has shown promising results when administered to the critically ill. Quercetin is a well-known flavonoid whose antiviral properties have been investigated in numerous studies. There is evidence that vitamin C and quercetin co-administration exerts a synergistic antiviral action due to overlapping antiviral and immunomodulatory properties and the capacity of ascorbate to recycle quercetin, increasing its efficacy. Safe, cheap interventions which have a sound biological rationale should be prioritized for experimental use in the current context of a global health pandemic. We present the current evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients as an adjunct to promising pharmacological agents such as Remdesivir or convalescent plasma.

Title: Increased brain vitamin D receptor expression and decreased expression of cathelicidin antimicrobial peptide in individuals who died by suicide. Content: Vitamin D deficiency is associated with immune dysregulation, increased vulnerability to infections, depression, and suicidal behavior. One mediator of vitamin D-dependent immune regulation and antimicrobial defense is the cathelicidin antimicrobial peptide (LL-37), encoded by the cathelicidin-related antimicrobial peptide (CRAMP) gene. We compared the mRNA expression of the CRAMP gene, the vitamin D receptor (VDR) gene, as well as the CYP27B1 and CYP24A1 genes (involved in vitamin D metabolism) in the dorsolateral prefrontal cortex (dlPFC) and anterior cingulate cortex (ACC) between depressed individuals who died by suicide (n = 15) and matched (age, gender, and post-mortem interval) non-psychiatric controls (n = 15). Gene expression was measured through qRT-PCR with TaqMan® primers and probes, with GAPDH and β-actin genes as endogenous controls. Statistical analyses included t-tests and Pearson correlations. CRAMP mRNA expression was downregulated and VDR mRNA expression was upregulated in both dlPFC and ACC in suicides relative to controls, with no significant differences in expression of CYP24A1 and CYP27B1. To our knowledge, this is the first study on brain cathelicidin expression in the human brain in relationship to suicide. Increased VDR and decreased CRAMP expression are consistent with previously reported associations between vitamin D deficiency, immune dysregulation, and suicidal behavior, and should lead to future studies uncovering novel interactive targets for suicide prevention.

Title: Greater risk of severe COVID-19 in non-White ethnicities is not explained by cardiometabolic, socioeconomic, or behavioural factors, or by 25(OH)-vitamin D status: study of 1,326 cases from the UK Biobank Content: Background We examined whether the greater severity of coronavirus disease 2019 (COVID-19) amongst men and non-White ethnicities is explained by cardiometabolic, socio-economic, or behavioural factors. Methods We studied 4,510 UK Biobank participants tested for COVID-19 (positive, n=1,326). Multivariate logistic regression models including age, sex, and ethnicity were used to test whether addition of: 1)cardiometabolic factors (diabetes, hypertension, high cholesterol, prior myocardial infarction, smoking, BMI); 2)25(OH)-vitamin D; 3)poor diet; 4)Townsend deprivation score; 5)housing (home type, overcrowding); or 6)behavioural factors (sociability, risk taking) attenuated sex/ethnicity associations with COVID-19 status. Results There was over-representation of men and non-White ethnicities in the COVID-19 positive group. Non-Whites had, on average, poorer cardiometabolic profile, lower 25(OH)-vitamin D, greater material deprivation, and were more likely to live in larger households and flats/apartments. Male sex, non-White ethnicity, higher BMI, Townsend deprivation score, and household overcrowding were independently associated with significantly greater odds of COVID-19. The pattern of association was consistent for men and women; cardiometabolic, socio-demographic and behavioural factors did not attenuate sex/ethnicity associations. Conclusions Sex and ethnicity differential pattern of COVID-19 is not adequately explained by variations in cardiometabolic factors, 25(OH)-vitamin D levels, or socio-economic factors. Investigation of alternative biological pathways and different genetic susceptibilities is warranted.

Title: COVID-19: is there a role for immunonutrition, particularly in the over 65s? Content: In late December 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged in Wuhan, Hubei, China, resulting in the potentially fatal COVID-19. It went on to be officially recognised as a pandemic by the World Health Organisation on 11 March 2020. While many public health strategies have evolved, there has been little mention of the immune system and how this could be strengthened to help protect against viral infections such as SARS-CoV-2. The present paper evaluates the current evidence base relating to immunonutrition, with a particular focus on respiratory viruses. Within the nutrition sector a promising body of evidence studying inter-relationships between certain nutrients and immune competence already exists. This could potentially be an important player in helping the body to deal with the coronavirus, especially among elders. Evidence for vitamins C, D and zinc and their roles in preventing pneumonia and respiratory infections (vitamins C and D) and reinforcing immunity (zinc) appears to look particularly promising. Ongoing research within this important field is urgently needed.