Merge branch 'master' into simina_edits

content/21.nutraceuticals.md

@@ -90,7 +90,7 @@ Indeed, protectin D1 has been shown to increase survival from H1N1 viral infecti
 Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages [@doi:10.1038/nature13479].
 In influenza, SPM promote antiviral B lymphocytic activities [@doi:10.4049/jimmunol.1302795], and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [@doi:10.1016/j.cell.2013.02.027].
 It is hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 [@doi:10.1007/s10555-020-09889-4; @doi:10.1016/j.mehy.2020.110340].
-Another theory is that some comorbidities such as obesity could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 [@doi:10.3389%2Ffimmu.2020.01997]. 
+Another theory is that some comorbidities such as obesity could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 [@doi:10.3389/fimmu.2020.01997]. 
 However, not all studies are in agreement that n-3 PUFA or their resulting SPM are effective against infections [@doi:10.3945/jn.109.108027].
 At a minimum, the effectiveness of n-3 PUFA against infections would be dependent on the dosage, timing, and the specific pathogens responsible [@doi:10.1016/j.jinf.2016.10.001].
 On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans [@doi:10.1194/jlr.M060392].
@@ -144,9 +144,10 @@ Vitamin C plays a significant role in promoting immune function due to its effec
 It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species amongst other effects related to COVID-19 pathology [@doi:10.1155/2014/426740; @doi:10.1007/s00210-013-0880-1; @doi:10.3390/nu9111211].
 Vitamin C is utilized by the body during viral infections, as evinced by lower concentrations in leukocytes and lower concentrations of urinary vitamin C.
 Post-infection, these levels return to baseline ranges [@doi:10.1177/003693307301800102; @doi:10.1111/j.1749-6632.1975.tb29312.x; @doi:10/fd22sv; @doi:10.3390/nu9040339; @doi:10.1079/bjn19920004].
+It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs [@doi:10.3390/nu11040708].
 Indeed, COVID-19 patients appear to be deficient in vitamin C [@doi:10.1016/j.medidd.2020.100064; @doi:10.1186/s13054-020-03249-y]. 
 COVID-19 is also associated with the formation of microthrombi and coagulopathy [@doi:10.1172/JCI140183] that contributes to the observed lung pathology [@doi:10.1183/16000617.0240-2020], which can be ameliorated by early infusions of vitamin C by inhibiting endothelial surface P-selectin expression and platelet-endothelial adhesion [@doi:10.3390/antiox6030049].
-Indeed, intravenous vitamin C also reduced D-dimer levels in a case study of 17 COVID-19 patients [@doi:10.1080/14787210.2020.1794819], which are notably elevated in COVID-19 patients [@doi:10.1186/s13054-020-03060-9; @doi:10.1016/s2665-9913(20)30121-1].
+Indeed, intravenous vitamin C also reduced D-dimer levels in a case study of 17 COVID-19 patients [@doi:10.1080/14787210.2020.1794819], which are notably elevated in COVID-19 patients [@doi:10.1186/s13054-020-03060-9; @doi:10/ggvd74].
 
 A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (> 200 mg) failed to reduce the incidence of colds [@doi:10.1002/14651858.CD000980.pub4].
 Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections such as pneumonia [@doi:10.1097/00006454-199709000-00003].
@@ -161,11 +162,13 @@ The first trial established in Wuhan, China [@doi:10.1136/bmjopen-2020-039519] h
 Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (_p_ = 0.04) [@doi:10.21203/rs.3.rs-52778/v1].
 
 Even though evidence supporting the use of vitamin C is beginning to emerge, we will not know how effective vitamin C is as a therapeutic for quite some time.
-Currently (as of December 2020) over fifteen trials are registered with clinicaltrials.gov that are either recruiting, active or are currently in preparation.
+Currently (as of January 2021) over fifteen trials are registered with clinicaltrials.gov that are either recruiting, active or are currently in preparation.
 When completed, these trials will provide crucial evidence on the efficacy of vitamin C as a therapeutic for COVID-19 infection.
 However, the majority of supplementation studies investigate the intravenous infusion of vitamin C in severe patients. 
 Therefore, there is a lack of studies investigating the potential prophylactic administration of vitamin C via oral supplementation for healthy individuals or potentially asymptomatic SARS-CoV-2 positive patients.
 Once again, vitamin C intake is part of a healthy diet and the vitamin likely presents minimal risk, but its potential prophylactic or therapeutic effects against COVID-19 are yet to be determined.
+To maintain vitamin C status, it would be prudent for individuals to ensure that they consume the recommended dietary allowance (RDA) of vitamin C to maintain a healthy immune system [@doi:10.3390/nu12051466]. 
+The RDA recommended by the FDA is 75-90 mg/d, and EFSA recommends 110 mg/d [@doi:10.17226/9810].
 
 ### Vitamin D
 
@@ -231,9 +234,10 @@ Indeed, African Americans may have up to a 6-fold higher COVID-19 mortality rate
 However, other UK scientific bodies including the NICE recommends that individuals supplement for vitamin D as per usual UK government advice, but they warn that people should not supplement for vitamin D solely to prevent COVID-19. 
 However, the NICE have provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 [@url:https://www.nice.org.uk/guidance/ng187/resources/covid19-rapid-guideline-vitamin-d-pdf-66142026720709]. 
 In Slovenia, doctors have been advised to provide nursing home patients with vitamin D [@doi:10.1136/bmj.m1820].
-Despite vitamin D deficiency being a widespread issue in the United States [@doi:10.7759/cureus.2741] the National Institutes of Health have stated that there is "insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19" [@url:https://www.covid19treatmentguidelines.nih.gov/adjunctive-therapy/vitamin-d/].
+Despite vitamin D deficiency being a widespread issue in the United States [@doi:10.7759/cureus.2741], the National Institutes of Health have stated that there is "insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19" [@url:https://www.covid19treatmentguidelines.nih.gov/adjunctive-therapy/vitamin-d/].
 These are just some examples of how public health guidance has responded to the emerging evidence with regards to vitamin D and COVID-19.
-In contrast, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products, due to a lack of clinical data to support their claims [@url:https://www.justice.gov/opa/pr/court-orders-georgia-defendants-stop-selling-vitamin-d-products-treatments-covid-19-and-other]
+There is also evidence that individuals may be paying attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic [@doi:10.3390/nu13010054].  
+However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims [@url:https://www.justice.gov/opa/pr/court-orders-georgia-defendants-stop-selling-vitamin-d-products-treatments-covid-19-and-other]
 It it clear that further studies and clinical trials are required to conclusively determine the prophylactic and therapeutic potential of vitamin D supplementation against COVID-19.
 Until such time that sufficient evidence emerges, individuals should follow their national guidelines surrounding vitamin D intake to achieve vitamin D sufficiency.
 
@@ -245,7 +249,7 @@ Probiotics and next-generation probiotics, which are more akin to pharmacologica
 However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present [@doi:10.1093/advances/nmy063].
 Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting toll-like receptors (TLR) 2 and 4, direct competition with pathogens, the synthesis of antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis [@doi:10.1016/j.earlhumdev.2019.05.010; @doi:10.1093/advances/nmy063; @doi:10.1159/000342079].
 It is also thought that lactobacilli such as _Lactobacillus paracasei, Lactobacillus plantarum_ and _Lactobacillus rhamnosus_ have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms [@doi:10.1016/j.ijfoodmicro.2006.10.044].
-Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms  [@doi:10.1111/lam.12160; @doi:10.1016/j.anaerobe.2011.04.022; @doi:10.4049/jimmunol.1800927; @doi:10.1016/j.ijfoodmicro.2006.10.044; @doi:10.3390/medicina55090519; @doi:10.1038/s41598-019-39602-7; @doi:10.3920/bm2016.0160; @doi:10.3389%2Ffimmu.2020.00015; @doi:10.1016/j.intimp.2013.12.020; @doi:10.1016/j.intimp.2019.106115].
+Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms  [@doi:10.1111/lam.12160; @doi:10.1016/j.anaerobe.2011.04.022; @doi:10.4049/jimmunol.1800927; @doi:10.1016/j.ijfoodmicro.2006.10.044; @doi:10.3390/medicina55090519; @doi:10.1038/s41598-019-39602-7; @doi:10.3920/bm2016.0160; @doi:10.1016/j.intimp.2013.12.020; @doi:10.1016/j.intimp.2019.106115].
 These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere [@doi:10.3390/nu12061718; @doi:10.1038/s41538-020-00078-9; @doi:10.3389/fpubh.2020.00186]. 
 However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis [@doi:10.1038/mi.2011.55], whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut [@doi:10.1111/cmi.12966].
 Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments [@doi:10.1016/j.virusres.2020.198018].
@@ -289,7 +293,10 @@ These include polyphenols, lipid extracts, and tomato-based nutraceuticals among
 Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods [@doi:10.1038/s41421-020-0153-3], and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects [@doi:10.3389/fnut.2020.583080; @doi:10.3390/antiox10010047; @doi:10.3390/nu13010047].
 Notably, melatonin, vitamin D and zinc were included in the treatment plan of the Former President of the United States upon hospitalization due to COVID-19 [@doi:10.1126/science.abf0974].
 These are just some of the many substances and supplements under investigation that currently have limited evidence to support their use or supplementation with the aim to prevent or treat COVID-19.
-While there is plenty speculation surrounding the use of supplements, a survey of 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders [@doi:10.1101/2020.11.27.20239087].
+While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic [@doi:10.3390/nu13010054].
+Additionally, supplement usage increased between the first and second wave of the pandemic. 
+Participants reported various reasons for their use of supplements, including to improve immunity (60%), to improve overall health (57%), and to fill nutrient gaps in their diet (53%). 
+Another survey of 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders [@doi:10.1101/2020.11.27.20239087].
 According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes [@doi:10.1101/2020.11.27.20239087].
 Certainly, randomized controlled trials are required to investigate these findings further.