The Benefits and Risks of Creatine Supplement Creatine is one of the most popular ergogenic supplements on the market.[1] W hen taken at doses in the range 3-5 g/day, creatine supplements are considered safe and can be beneficial for healthy adults as suggested by several scientific reviews. Culinary Medicine by Lori A Smolin, PhD and Mary B Grosvenor, MS, RD    It was widely introduced in the early 1990s after athletes competing in sprint and power events at the Barcelona Olympic Games suggested that it enhanced their performance.[2] Since that time, its benefits have been studied in many other sports as well as in conditions as diverse as neurological disorders, depression, memory loss, and the chronic diseases and muscle loss common with aging. Over the years, questions have been raised about its potential side effects. However, currently creatine supplementation is considered safe for healthy adults.[1,3]  Creatine is an amino acid naturally found in the body; about 95% of creatine is stored in muscle with the remaining amount found in other tissues including the brain. About two thirds of the creatine in the body is converted to phosphocreatine (PCr). PCr can be used to regenerate ATP, which provides energy to fuel cellular processes. Having more creatine increases the amount of PCr, which enhances the availability of ATP.[4]  The body requires approximately 2 g of creatine to replenish what is used daily. About half of this amount is produced in the body, primarily in the liver and kidneys.[1,4] The rest is obtained from animal products in the diet, mainly meat, poultry, and fish. The average creatine intake in the US is estimated to be 1.38 g/day, however almost 43% of individuals surveyed consumed less than 1 g/day.[5] Vegetarians, for example, consume almost no creatine and have lower muscle levels than meat eaters. Use and Safety of Creatine Supplements  Creatine supplements have a global market of over $500 million.[5] Supplements are available over the counter in several forms, the most common and most studied of which is creatine monohydrate.  Creatine, when sold as a dietary supplement, is not regulated by the US Food and Drug Administration (FDA) and therefore may contain contaminants and may not provide the exact amount of creatine listed on the label. The creatine monohydrate used to fortify foods such as energy drinks and protein bars is considered a food additive. The FDA, which does regulate ingredients added to food, has categorized this use of creatine as “generally recognized as safe” (GRAS), supporting the view that it is safe for consumption.[6] Nonetheless, misconceptions still exist about the safety and side effects of creatine, particularly with regard to kidney function, weight gain, and muscle cramping. Perhaps the greatest concern about creatine supplementation is that it could harm the kidneys. Both creatine and PCr are degraded to creatinine, which is excreted by the kidneys. There has been speculation that increasing the load of creatine and creatinine that needs to be excreted by the kidneys could result in renal damage. Blood creatinine levels do increase when kidney function is poor. However, blood creatinine levels are also dependent on muscle mass and the amount of dietary creatine consumed, so transient high serum creatinine may reflect the increased creatine intake rather than failing kidneys.  A meta-analysis of creatine supplements and renal function found that supplementation did not cause renal damage.[7] This and many other studies provide evidence that 3 to 5 grams/day of supplemental creatine does not negatively affect renal function.[3,4] The concern that creatine supplementation leads to unhealthy weight gain or muscle cramps is also unfounded. Creatine supplementation may cause weight gain but does not increase fat mass.  Some weight gain occurs due to an increase in muscle. This is because over time creatine supplementation allows for greater training intensity, resulting in an increase in muscle mass.[4] There also may be a transitory increase in body weight from fluid retention over the first few days of supplementation.[3]  Shifts in fluid distribution due to creatine supplementation have also been speculated to cause dehydration and muscle cramping in hot environments. However, a study that compared creatine use to a placebo found that creatine users had a lower incidence of muscle cramps and dehydration than the control group.[3] Ergogenic Benefits of Creatine Supplements? Increasing creatine consumption increases muscle creatine and PCr levels. More PCr means a larger supply of ATP, the primary energy source for short intense bouts of exercise. The increased availability of ATP delays fatigue, enhancing training, and leading to stronger muscles and ultimately improved exercise performance. Creatine has been shown to improve muscle mass and performance in athletes engaged in most sports as well as to help with post-exercise recovery and injury prevention. While it can increase muscle mass, it is not an anabolic steroid or a controlled substance; it is not screened for, or banned by, the World Anti-Doping Agency (WADA) or any other sports agency.[3]   The most effective way to increase muscle creatine stores is to consume 3–5 g/day of supplemental creatine monohydrate.[1] A loading dose of 5 grams four times a day for 5 to 7 days can be used to rapidly increase muscle stores of creatine.[4] However, the loading phase is not necessary to get the benefits of creatine – it just takes longer for muscle creatine levels to rise without loading. Creatine is a popular supplement among adolescent athletes and theoretically the ergogenic benefit should be similar to that seen in adults.[3] But, the lack of randomized controlled trials and acute and long-term safety data has limited widespread support for creatine use in children and adolescents.[8]   Creatine and the Brain The brain requires a constant supply of ATP. As in muscle, brain PCr is important for resynthesizing ATP from ADP. Creatine supplementation appears to increase brain creatine content; however, studies have used a wide range of creatine doses, so the amount needed to raise brain levels is not as well established as that for increasing muscle creatine.[9] An increase in brain creatine is thought be beneficial in conditions that affect mood, cognition, and motor tasks. Creatine supplementation has therefore been suggested as a treatment for a variety of neurological and mental health conditions and to have a neuroprotective effect following traumatic brain injury and concussions.  Supplementation has been found to have limited, if any, benefits for the treatment of multiple sclerosis, Parkinson’s, and Huntington’s disease.[9] Research does suggest a possible role for creatine supplementation in the treatment of depression, anxiety, and post-traumatic stress disorder (PTSD). For example, there is a link between low dietary intake of creatine and the risk of depression in adults. A number of case studies and small clinical trials of creatine supplementation alone as well as with traditional pharmacological interventions have observed improvements in the symptoms of depression, but additional larger-scale randomized trials are needed. Individuals with generalized anxiety and PTSD have been found to have reduced levels of brain creatine; small studies have shown improvement with creatine supplementation. Based on limited evidence creatine supplementation for the management of concussion and traumatic brain injury appears promising.[9]  Creatine supplementation has also been studied for its effect on memory, which is an energy demanding function. Studies have gotten mixed results, with some showing creatine to benefit cognitive function and memory and others showing no effect. A meta-analysis found that creatine supplements have a beneficial effect on memory in healthy individuals and the benefits were greater in older adults.[10]  Potential Benefits of Creatine in Aging  Creatine supplementation has been studied for its effect on a number of health concerns that increase with age, such as osteoporosis, heart disease, and insulin resistance.[1,11]   While there is some evidence supporting a benefit in these conditions, more research is needed. Creatine can help older adults prevent sarcopenia, the loss of muscle mass and strength that occurs with aging. Although creatine supplements alone do not benefit muscle function or mass, when taken in conjunction with resistance exercise, creatine supplements have been found to enhance gains in muscle mass and strength in older adults. Maintaining muscle lessens the risk of falls, fractures, and physical disability, which reduce independence in older adults.[12,13]  Potential Benefits for Vegetarians Vegetarians consume almost no creatine. And although creatine synthesis is augmented in vegetarians, they still have lower blood and muscle levels.[14] Creatine supplementation has been shown to increase lean tissue mass as well as muscle strength and endurance in vegetarians.[15] However, it is unclear whether creatine supplements improve exercise performance to a greater extent in vegetarians than in non-vegetarians.  Despite their low creatine intake, brain creatine concentrations in vegetarians appears to be similar to that in omnivores. Nonetheless, creatine supplementation was found to improve memory in vegetarians but not in omnivores.[15]  The lower creatine stores in vegetarians, and improvements in muscle strength and memory with supplementation, has led to the suggestion that supplemental creatine may be necessary to optimize health in vegetarians.[1,14] Although risks are low, more study is needed before a general recommendation can be made.  Summary  When taken at doses in the range 3-5 g/day, creatine supplements are safe and can be beneficial for healthy adults.[3] Over 1000 short and long-term studies of creatine supplements at various doses in healthy and diseased populations in different life-stage groups have consistently shown that creatine poses no adverse health risks.[4]  The International Society of Sports Nutrition, the Academy of Nutrition and Dietetics, and the American College of Sports Medicine all concur that creatine is the most effective ergogenic nutritional supplement currently available for increasing high-intensity exercise capacity and lean body mass in response to training.[4]  Supplemental creatine, when combined with resistance exercise, helps maintain muscle mass in older adults.[12]  Many clinical applications of supplemental creatine have been studied. A potential benefit has been demonstrated for improving depression and memory,[9,10] but the benefits in other conditions are not well established.[1,3] Vegetarians, whose diets contain almost no dietary creatine and have low creatine levels, may benefit from supplementation.[15]  Editor’s comment:  Further studies are needed to determine if it is safe or even beneficial for patients with renal insufficiency to take supplemental creatine. [16]  #CulinaryMedicine References [1] Kreider RB, Stout JR. Creatine in Health and Disease. Nutrients. 2021;13(2):447. doi: https://doi.org/10.3390/nu13020447 [2] Bird SP. Creatine supplementation and exercise performance: a brief review. Journal of sports science & medicine. 2003;2(4):123-132. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963244/#:~:text=Introduced%20to%20the%20general%20public [3] Antonio J, Candow DG, Forbes SC, et al. Common Questions and Misconceptions about Creatine supplementation: What Does the Scientific Evidence Really show? Journal of the International Society of Sports Nutrition. 2021;18(1). doi: https://doi.org/10.1186/s12970-021-00412-w [4] Kreider RB, Kalman DS, Antonio J, et al. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. Journal of the International Society of Sports Nutrition. 2017;14(1). doi: https://doi.org/10.1186/s12970-017-0173-z [5] Ostojic SM. Creatine as a food supplement for the general population. Journal of Functional Foods. 2021;83:104568. doi: https://doi.org/10.1016/j.jff.2021.104568 [6] GRAS Notice 931 | FDA. www.fda.gov . https://www.fda.gov/media/143525 [7] de Souza E, Silva A, Pertille A, Reis Barbosa CG, et al. Effects of Creatine Supplementation on Renal Function: A Systematic Review and Meta-Analysis. Journal of Renal Nutrition. 2019;29(6):480-489. doi: https://doi.org/10.1053/j.jrn.2019.05.004 [8] Jagim AR, Kerksick CM. Creatine Supplementation in Children and Adolescents. Nutrients. 2021;13(2):664. doi: https://doi.org/10.3390/nu13020664 [9] Forbes SC, Cordingley DM, Cornish SM, et al. Effects of Creatine Supplementation on Brain Function and Health. Nutrients. 2022;14(5):921. doi: https://doi.org/10.3390/nu14050921 [10] Prokopidis K, Giannos P, Triantafyllidis KK, Kechagias KS, Forbes SC, Candow DG. Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials. Nutrition Reviews. 2022;81(4). doi.org/10.1093/nutrit/nuac064 [11] Sales LP, Pinto AJ, Rodrigues SF, et al. Creatine Supplementation (3 g/d) and Bone Health in Older Women: A 2-Year, Randomized, Placebo-Controlled Trial. Newman A, ed. The Journals of Gerontology: Series A. 2019;75(5):931-938. doi: https://doi.org/10.1093/gerona/glz162 [12] Dolan E, Artioli GG, Pereira RMR, Gualano B. Muscular Atrophy and Sarcopenia in the Elderly: Is There a Role for Creatine Supplementation? Biomolecules. 2019;9(11):E642. doi: https://doi.org/10.3390/biom9110642 [13] Smith-Ryan AE, Cabre HE, Eckerson JM, Candow DG. Creatine Supplementation in Women’s Health: A Lifespan Perspective. Nutrients. 2021;13(3):877. doi: https://doi.org/10.3390/nu13030877 [14] Ostojic SM, Forbes SC. Perspective: Creatine, a Conditionally Essential Nutrient: Building the Case. Advances in Nutrition. 2021;13(1):34-37. doi: https://doi.org/10.1093/advances/nmab111 [15] Kaviani M, Shaw K, Chilibeck PD. Benefits of Creatine Supplementation for Vegetarians Compared to Omnivorous Athletes: A Systematic Review. International Journal of Environmental Research and Public Health. 2020;17(9):3041. doi: https://doi.org/10.3390/ijerph17093041 [16] Post A, Tsikas D, Bakker S. Creatine is a Conditionally Essential Nutrient in Chronic Kidney Disease: A Hypothesis and Narrative Literature Review.  Nutrients.  2019 May; 11(5): 1044. Published online 2019 May 10. doi:  10.3390/nu11051044

CRISPR - What Is It, and How Can It Be Used In Medicine? On December 8th, 2023, the FDA approved two new gene therapies for sickle cell disease.  Exagamglogene Autotemcel (Casgevy), is the first CRISPR based theory to gain FDA approval. Using CRISPR/Cas9 technology the patient’s stem cells are modified and then reinfused back into the patient where they engraft (attach and multiply) in the patient’s bone marrow to increase the production of hemoglobin F. By Stuart M. Caplen, MD Updated December 19, 2023 The discovery of CRISPR, a gene editing technology, may turn out to be one of the most significant scientific advances in human history. We now have the ability to manipulate DNA relatively easily in ourselves and other animals, plants, and microscopic organisms. For the first time, humans can control their own genetic destiny. This article will delve into what CRISPR actually is, how it works, and what the ramifications are for disease treatment and society as a whole. Jennifer Doudna, PhD and Emmanuelle Charpentier, PhD received the Nobel Prize in Chemistry in 2020 for their 2012 discovery of how to use CRISPR to edit the genome. Their work was truly groundbreaking and stood on the shoulders of other discoveries such as the structure of DNA by Watson and Crick, the Human Genomic Project which mapped out the complete human DNA, and previous researchers who discovered the CRISPR system and the nuclease enzyme Cas9 it uses to make cuts in genetic material.[1] Before CRISPR it was possible to make changes to DNA, but it was cumbersome, time consuming, and expensive. CRISPR made redesigning genetic material a much faster and easier process. What is CRISPR in Nature? CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeats.[2] CRISPR is the process in nature by which a bacterial cell can identify, cut, and inactivate DNA sequences in viruses to protect itself from viral attacks. It was discovered by Francisco Mojica, PhD in 1993[1], who when sequencing bacterial DNA noticed that there were short segments of DNA that appeared to have no functionality, and were found at regular intervals. The segments were palindromic, meaning each side of the segment was a mirror image of the other side. It was later discovered that these DNA segments were duplicates of short segments of the genetic code of DNA viruses (bacteriophages) that had previously attacked the bacteria. When a bacterium is attacked, it is able to cut off a segment of the viral DNA called a protospacer and then incorporate that section into its own DNA, at which time the new segment is called a spacer. The bacterium is then able to make inverse RNA copies of that DNA spacer which matches the viral DNA. Those inverse RNA copies can be transported and attached to the viral DNA by guide RNA(gRNA) where a nuclease enzyme called Cas9(CRISPR-associated protein 9) unzips the double stranded viral DNA exposing the base pairs. After attachment, Cas9 acts like a DNA scissors cutting both strands of the viral DNA, preventing the virus from replicating and protecting the bacterium from further attack.[2,3,4] The CRISPR process requires guide RNA(gRNA), a specific RNA sequence that identifies the target DNA region of interest (such as in an invading virus). gRNA consists of two components: 1) CRISPR RNA (crRNA), a 17-20 nucleotide sequence copied from the bacterial DNA spacer that is complementary to the target viral DNA protospacer and 2) transport RNA (tracrRNA), which carriers the Cas9 nuclease enzyme to the target viral DNA.[4] CRISPR Needs a PAM Sequence to Work The Cas9 nuclease is carried by the gRNA to a specified portion of the target viral DNA. For CRISPR to work, there must be a Protospacer Adjacent Motif (PAM) sequence located near the targeted section of viral DNA. The PAM sequence is most typically two to six nucleotides in length, but can be longer. It serves as a signal or keyhole for Cas9 and is required for Cas9 activation that results in the cutting and inactivation of the viral DNA. The PAM sequence is generally found three to four nucleotides away from the cut site on the viral DNA.[3] As the bacterial spacer contains the same gene base sequences as the virus, it is theoretically possible for the gRNA to mistakenly attach to the bacteria’s own DNA, and if activated result in its own destruction. The PAM sequence protects the bacteria from doing that, as the correct PAM sequence found on the virus is needed for the CRISPR-Cas9 system to activate.[3] Once the Cas9 is attached to the correct viral DNA segment and has identified the proper PAM sequence, it makes a double-stranded break in the target DNA.[2,3,4] At that point, the DNA strand may reattach with some mutations that adversely affect it, or become nonfunctional, providing the bacteria protection against that viral DNA strand forming new viruses.[2] CRISPR In the Laboratory In the laboratory CRISPR can be used for gene editing. A specific gRNA is used and combined with a nuclease such as Cas9 with the needed PAM sequence. This is mixed with cells targeted for editing and after attachment of the gRNA, the Cas9 cleaves the target DNA. A new DNA gene or segment is can then be inserted into the cleaved DNA with reclosure of the cut DNA segments. CRISPR can be used to either induce or correct a mutation or remove a gene or set of genes from the targeted DNA. One technical limitation is that CRISPR, while much more accurate than other gene editors, can still at times cut in the wrong place, resulting in undesirable or unexpected effects.[2] CRISPR Modifications Single Guide RNA Doudna and Charpentier were able to create a new type of RNA not found in nature, called single guide RNA (sgRNA), which is a single RNA molecule that contains both the crRNA and tracrRNA sequences. sgRNA being one molecule rather than the two separate ones found in nature made genetic manipulation in the laboratory much easier. Doudna and Charpentier received the Nobel prize for figuring out the specific mechanics of the CRISPR system, understanding that this method could be used to manipulate DNA in any living creature or plant, and creating sgRNA.[5] CRISPR Improvements The CRISPR concept, although groundbreaking, is now considered somewhat of a blunt instrument by scientists. CRISPR only works on DNA, and mutational errors are possible as both strands of the DNA try to repair themselves. In nature, once the viral DNA has been cleaved, the process is completed and the virus can no longer replicate. However, laboratory gene editing is different as when the Cas9-cleaved DNA tries to repair itself, the cell will try to repair the break using any available DNA it can find. Scientists can inject large amounts of the new gene they want to insert into the target cell in the hope that it will be inserted at the site of the DNA cut.[6] The CRISPR system has been modified and improved for gene editing, so rather than just cutting the DNA it can also add activators or depressors of gene function to specified areas, or edit a specific gene by changing one nucleotide for another.[2,6] Scientists have created modified CRISPR-Cas9 to cut only one strand of DNA, not both, to allow more pinpoint gene editing.[2] A newer technique is called prime editing, which is able to pinpoint and make small nucleotide base changes. It uses a modified Cas9 enzyme that initially just cuts one strand of DNA and replaces the targeted nucleotides with the new ones. Then the Cas9 nicks the complementary DNA strand and replaces the corresponding part, correcting both strands of DNA with much less chance of a mutation. This method could also allow changing genes in multiple locations for diseases such as Tay-Sachs.[7] Scientists have also adapted CRISPR to edit RNA using a recently discovered different nuclease Cas13(CRISPR-associated protein 13) enzyme. This could expand CRISPR’s usefulness to modify RNA viruses, such as SARS-CoV-2 that causes COVID-19.[8] Improved PAM Sequence Activation In genetic editing the most commonly used Cas9 nuclease is derived from Streptococcus pyogenes.[3] PAM sequences for S. pyogenes that activate Cas9 are spread throughout the human genome (an estimated 161 million times or every 42 nucleotides[9]), but they are not always positioned in the correct location to activate gRNA to target a particular gene. If a PAM sequence is not located near a nucleotide that is the target to be modified or removed, CRISPR may not work. Also, if the PAM sequence is located multiple times in the target DNA, there may be attachment of the gRNA to untargeted areas, and unwanted mutations may occur. Genetic targeting in the laboratory can be improved by the use of a differently coded PAM sequence that may solely be located in the area of the targeted gene. This may be achieved by the use of S. pyogenes Cas9 variants that have different PAM sequences, using Cas9 nucleases derived from other bacterial species, or the use of more recently discovered non-Cas9 enzymes that have different PAM sequences and can also be used for genetic manipulation.[10] The specific PAM sequence that activates Cas9 to cut the viral DNA for S. pyogenes is NGG where N is any nucleotide.* Just by chance this sequence is randomly found frequently in human DNA. S. pyogenes Cas9 variants have different PAM sequences such as NGAN, NGNG, NGAG, or NGCG which can be used to target different areas on the DNA chain. The PAM sequence for Staphylococcus aureus Cas9 is NGRRT, Neisseria meningitidis Cas9 has a NNNNGATT PAM sequence code. One can appreciate how by using different nucleases with different PAM codes, a Cas9 or non-Cas9 enzyme can be selected that will only activate near the specific target area you wish to modify.[10] *(G= guanine, A=adenine, C=cytosine, N=any nucleotide, R= any purine(A or G) CRISPR Ethical Considerations Given that CRISPR has the potential to change a species forever, international meetings of geneticists were held on the ethics of how to use it for human gene editing. It was agreed that somatic cell manipulation was allowed in individual humans to help cure a disease, but more research was needed before germ cell manipulation was to be attempted which would be passed on to progeny.[5] However, in 2018 a Chinese geneticist He Jiankui, PhD modified embryos which were then implanted and led to the birth of twin girls. He disabled a gene called CCR5, which encodes a protein that allows HIV to enter cells, in an attempt to mimic a mutation that exists in about 10% of Europeans and protects them from HIV infection. However, as CRISPR gene editing had never been done before in human germ cells that were used for conception, there was no way of knowing if he also induced other mutations in the girls’ genomes that might affect them adversely. Ironically, CCR5 is thought to actually help people fight off the effects of various other infections, such as West Nile virus and the girls might then be more susceptible to other diseases as well.[11] In December 2019, Dr. Jiankui was sentenced to three years' imprisonment and a three-million-yuan fine(approximately $450,000) for this banned human research.[12] Medical Uses of CRISPR Sickle Cell Disease and Thalassemia The initial uses of CRISPR to fight disease involved attempts to cure patients with genetic diseases through simple gene substitutions. Sickle cell anemia and beta thalassemia are some examples. It has been found that inducing sickle cell and thalassemia patients to produce higher levels of fetal hemoglobin (hemoglobin F) instead of hemoglobin S will reduce their symptoms. After birth, fetal hemoglobin production is normally reduced by the BCL11A locus on chromosome 2, which is the target gene scientists were attempting to manipulate using CRISPR technology.[13] In one study of two patients, one with sickle cell anemia and one with beta-thalassemia, CD34+ hematopoietic stem and progenitor cells were harvested from the patients by apheresis. (Separation of withdrawn blood into blood components followed by the retransfusion of only some of the blood components back into the patient.) The cells were then edited by CRISPR-Cas9 technology to reduce the BCL11A inhibition which would have the desirable effect of increasing hemoglobin F production. Myeloablative conditioning was performed on the patients to allow these new cells to graft into the bone marrow, and then the cells were reinfused. The patient with sickle cell disease had averaged seven severe vaso-occlusive episodes per year prior to therapy, and at 16 months after therapy had not had another one. The thalassemia patient, who had averaged 34 units of packed red cells per year prior to therapy, received only one transfusion of packed red cells 30 days after the infusion and after that did not require any more as of 18 months of follow-up. Both patients had serious infections soon after the myeloablative conditioning/infusions which were treated successfully.[14] Another method recently demonstrated experimentally in mice is using a direct gene edit. Sickle cell disease is the result of a one base pair mutation in the gene that controls hemoglobin production. The sickle hemoglobin allele was converted to a normal allele in stem cells taken from mice using CRISPR and then transfused back into the mice after they had been irradiated to destroy their existing bone marrow cells. It was found that after exposure to hypoxic conditions only 29.8% of the RBCs in the genetically treated mice sickled, compared to 86.3% in the control group. Spleen size was also noted to be smaller in the treated mice.[15] It should be noted that there are other non-CRISPR methods being tested and used to try to cure thalassemia and sickle cell disease. One promising method, lentiglobin gene therapy uses a virus vector to seed the bone marrow with RNA that increases expression of the hemoglobin F gene.[16] However, some scientists are wary of using lentiviruses for gene therapy as integration into the genome is random, and because of their potential to cause unintended disruptions in other genes.[13] Update (December 19, 2023) On December 8th, 2023, the FDA approved two new gene therapies for sickle cell disease.  Exagamglogene Autotemcel (Casgevy), is the first CRISPR based theory to gain FDA approval. Using CRISPR/Cas9 technology the patient’s stem cells are modified and then reinfused back into the patient where they engraft (attach and multiply) in the patient’s bone marrow to increase the production of hemoglobin F.  In a study of 44 patients, in which 31 made inclusion criteria, it was reported that 93.5% had been free of severe vaso-occlusive crises for at least one 12 consecutive month period over 2 years.[U1] The second approval was for lovotibeglogene autotemcel (Lyfgenia),  a cell-based gene therapy. Lovotibeglogene autotemcel does not use CRISPR technology, but uses a lentiviral vector to seed the bone marrow.  With lovotibeglogene autotemcel, the patient’s stem cells are genetically modified to produce HbA-T87Q, a gene-therapy derived hemoglobin which functions similarly to hemoglobin A.[U1]  In a study of 47 patients, in which 34 made inclusion criteria, 88% were vaso-occlusion event free and 94% were severe vaso-occlusion event free for a median of 35.8 months.[U2] In addition to the typical hematological adverse events associated with myeloablation required for stem cell therapy, several patients in clinical trials getting lovotibeglogene autotemcel, developed a hematological malignancy.  There is a black box warning that recommends life-long monitoring of patients who receive lovotibeglogene autotemcel for malignancy.[U3] The number of patients getting these new therapies may be limited by the ability of patients to withstand myeloablation that is needed before the therapy can be given, the need for a month-long hospitalization, a limited number of medical centers approved to administer the therapies and a cost of 2.2 to 3.1 million dollars per patient.  In addition, the long-term effects of these therapies are not known yet.[U4] As of August 17, 2022, there is also an FDA approved cell-based gene therapy for beta thalassemia called betibeglogene autotemcel (Zynteglo). It is similar to lovotibeglogene autotemcel and engrafts in the patient’s bone marrow to cause production of beta A-T87Q-globin (a modified beta-globin protein) to replace the patient’s damaged beta-globin. The new beta-globin combines with alpha-globin to produce functional adult hemoglobin. There is no black box cancer warning for betibeglogene autotemcel, but cancer screening for at least 15 years is recommended.[U5,U6] Leber’s Congenital Amaurosis 10 Another recent use of CRISPR is treating Leber’s congenital amaurosis 10 (LCA 10). No treatment is currently available for the disease, which is a cause of blindness in childhood. Mutations in the CEP290 gene disable photoreceptors in the retina, although the cells are still present and potentially functional in people with LCA10. CRISPR edited genes were experimentally injected into one eye near the retina of some subjects in hopes that the mutations in CEP290 could be replaced locally with a normal CEP290 gene and the photoreceptors turned back on.[17] Although results are not published yet, two of the patients said in an interview that their vision has not been fully restored, but they are able to see colors and make out shapes of objects much better than before the therapy. For one patient the therapy improved his ability to feed himself as he was able to see both eating utensils and his food better. However, for as yet unclear reasons, the therapy has not worked for all the patients in the study.[18] Other Potential Medical Uses CRISPR is also being studied for targeted cancer therapy[19], but in the future, people or embryos with genetic mutations that increase cancer risk might be able to have those genes modified. There are probably many other diseases that could eventually be treated using CRISPR technology, such as targeting an infecting organism’s ability to replicate or the body’s response to it. Non-Medical Uses of CRISPR for Disease Control[20,21] Gene drives are genetic modifications in the germ cells designed to spread through a population at higher-than-normal rates of inheritance. Since 2014, scientists have engineered CRISPR-based gene drive systems in mosquitoes, fruit flies, and fungi, and are currently developing them in mice. Scientists use CRISPR to insert the selected gene drive in both strands of DNA in an animal. After that, all the offspring of a mating between a modified and unmodified animal will have the gene drive on one chromosome while the other chromosome will be normal. During early development of the offspring, the CRISPR portion of the gene drive activates and cuts the normal gene. The gene drive then inserts a copy of itself into the normal chromosome making the progeny homozygous for the gene drive and ensuring nearly 100% transmittal of the gene drive to the next generation. One problem with gene drives is that genetic variation may confer resistance to the gene drive, which has occurred frequently in fruit fly experiments. Mutations may also occur that alter the genetic sequence CRISPR is set to recognize, preventing the gene from being edited. To counteract this problem, scientists are focusing on certain genes that seem to be more protected against mutation. One such gene in mosquitoes is called doublesex, and controls differentiation of the sexes. With a gene drive targeting the doublesex gene, modified female mosquitoes were unable to bite or lay eggs. In the laboratory it was found that in 8 to 12 generations the mosquito population was effectively terminated. There is currently interest in gene drive research to have mosquitoes produce an antibody that inactivates an infectious agent, such as the dengue virus, so the mosquito cannot pass the disease on to humans. Another gene drive is being investigated that causes an internal toxin to be released that will kill a mosquito if it gets infected with a pathogen dangerous to humans. An issue with using gene drive genetic manipulation is that you can potentially change a species forever. One way of preventing that is to develop gene drives that are self-extinguishing. Scientists can engineer a gene drive to gradually lose the ability to propagate, until it runs out over several generations and is unable to spread beyond a target population of mosquitoes or flies. Another method is to use a gene drive that requires continual release of genetically modified mosquitoes or flies for many generations. When those releases stop, the modification becomes diluted with wild-type versions of the gene and is extinguished within a few years. Unfortunately, the future effects of genetic modification are unknown. In trying to eliminate a disease the organism may mutate and become more virulent or find another host. Eliminating or modifying a species may also have unintentional negative effects on the ecology of an area. Ecological Uses of CRISPR Non-medical uses of CRISPR are being tested in many ecological areas. CRISPR is being tested to improve outputs of yeast, bacteria, or algae created biofuels.[22,23] Attempts are being made to modify bacteria and fungi that can degrade plastic, in an attempt to eliminate the significant ecological problem of plastic waste. Current projects are underway using CRISPR to engineer plants or bacteria to improve nitrogen fixation to reduce nitrogen runoff from the soil in farms, which can contaminate water sources. It also can be used to modify crops or animals to intensify or diminish certain traits, such as modifying crops to be resistant to insects, which could potentially reduce pesticide use.[23] The Future The future in this new era of genetic manipulation is uncertain. CRISPR derived technology is very powerful and may do enormous good, potentially ending the suffering that comes with some genetic diseases, cancer, and infectious diseases. Just ending mosquito borne malaria could potentially prevent over 400,000 deaths and close to 229 million infections each year.[24] On the other hand, CRISPR technology may lead to increasing wealth and societal disparity as some sectors of society may be able to genetically enhance their offspring, while those with less access to the technology may not have that opportunity. Problematic issues include the possibility of a well-intentioned genetic manipulation in an insect leading to ecological disaster, or rogue scientists or nations creating entirely new animal species or novel types of humans. At the start of this age of advanced genetic manipulation, we are all living in a huge experimental laboratory. Only time will tell how it works out. “It is not in the stars to hold our destiny but in ourselves.” -William Shakespeare References [1] CRISPR Timeline. Broad Institute. 2021. Retrieved from: www.broadinstitute.org/what-broad/areas-focus/project-spotlight/crispr-timeline [2] CRISPR Explained. Novateinbio. 2019. www.novateinbio.com/content/96-crispr-explained [3] Importance of the PAM Sequence in CRISPR Experiments. Synthego. 2021. Retrieved from: www.synthego.com/guide/how-to-use-crispr/pam-sequence [4] The Complete Guide to Understanding CRISPR sgRNA. Synthego. 2021 Retrieved from: www.synthego.com/guide/how-to-use-crispr/sgrna [5] Isaacson W, The Codebreaker. Simon & Schuster. March 9, 2021. [6] Crossley M. What is CRISPR gene editing, and how does it work? The conversation. January 31, 2018. Retrieved from: www.theconversation.com/what-is-crispr-gene-editing-and-how-does-it-work-84591 [7] Super-precise new CRISPR tool could tackle a plethora of genetic diseases. Nature. 21 October 2019. Retrieved from: www.nature.com/articles/d41586-019-03164-5 [8] New kind of CRISPR technology to target RNA, including RNA viruses like coronavirus. Science Daily. March 16, 2020. Retrieved from: www.sciencedaily.com/releases/2020/03/200316141514.htm [9] Integrated DNA Technologies. 2021. Retrieved from: www.idtdna.com/pages/support/faqs/how-often-are-the-pam-sequences-presented-in-the-mammalian-genome-in-average [10] McDade J. The PAM Requirement and Expanding CRISPR Beyond SpCas9. Addgene. Updated Aug 20, 2020. Retrieved from: www.blog.addgene.org/the-pam-requirement-and-expanding-crispr-beyond-spcas9 [11] Cyranoski D. The CRISPR-baby scandal: what’s next for human gene-editing. Nature. 26 February 2019. Retrieved from: www.nature.com/articles/d41586-019-00673-1 [12] Wee SL. Chinese Scientist Who Genetically Edited Babies Gets 3 Years in Prison. The New York Times. Dec. 30, 2019. Retrieved from: www.nytimes.com/2019/12/30/business/china-scientist-genetic-baby-prison.html [13] Michael Eisenstein. Gene therapies close in on a cure for sickle-cell disease. Nature. 25 August 2021. Retrieved from: www.nature.com/articles/d41586-021-02138-w [14] Frangoul H et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med 2021; 384:252-260. January 21, 2021. Retrieved from: www.nejm.org/doi/full/10.1056/NEJMoa2031054 [15] Newby, G.A., Yen, J.S., Woodard, K.J. et al. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature 595, 295–302 (2021). Retrieved from: www.nature.com/articles/s41586-021-03609-w' [16] Thompson AA et al. Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia: Update from the Northstar Hgb-204 Phase 1/2 Clinical Study. Blood, volume 128, Issue 22. December 2, 2016. Retrieved from: www.ashpublications.org/blood/article/128/22/1175/96014/Lentiglobin-Gene-Therapy-for-Transfusion-Dependent [17] Ledford H. CRISPR treatment inserted directly into the body for first time. Nature. 05 March 2020. Retrieved from: www.nature.com/articles/d41586-020-00655-8 [18] Stein R. A Gene-Editing Experiment Let These Patients With Vision Loss See Color Again. NPR-WNYC. September 29, 2021. Retrieved from: www.npr.org/sections/health-shots/2021/09/29/1040879179/vision-loss-crispr-treatment?t=1633005081997 [19] How CRISPR Is Changing Cancer Research and Treatment. National Cancer Institute. July 27, 2020. Retrieved from: www.cancer.gov/news-events/cancer-currents-blog/2020/crispr-cancer-research-treatment [20] Scudellari M. Self-destructing mosquitoes and sterilized rodents: the promise of gene drives. Nature. 09 July 2019. Retrieved from: www.nature.com/articles/d41586-019-02087-5 [21] Kyrou, K. et al. A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes. Nat Biotechnol 36, 1062–1066 (2018). Retrieved from: www.nature.com/articles/nbt.4245.pdf [22] Javed MR et al. Current situation of biofuel production and its enhancement by CRISPR/Cas9-mediated genome engineering of microbial cells. Microbiological Research, Volume 219, Pages 1-1. 2019. Retrieved from: www.sciencedirect.com/science/article/pii/S0944501318308346?via%3Dihub [23] Gallegos J, 10 ways CRISPR will revolutionize environmental science. Alliance for Science. July 17, 2018. Retrieved from: www.allianceforscience.cornell.edu/blog/2018/07/10-ways-crispr-will-revolutionize-environmental-science/ [24] World Malaria Report 2020-20 years of global progress & challenges. World Health Organization. 30 November 2020. Retrieved from: www.who.int/publications/i/item/9789240015791 [U1] FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. FDA website.  December 8th, 2023. Retrieved from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease [U2] Long-term Follow-up Data From bluebird’s Gene Therapy Program in Sickle Cell Disease Support Durable, Potentially Curative Benefits Through Stable Production of Anti-Sickling Adult Hemoglobin and Resolution of Vaso-Occlusive Events. Bluebird Bio. Retrieved from: https://investor.bluebirdbio.com/news-releases/news-release-details/long-term-follow-data-bluebirds-gene-therapy-program-sickle-cell [U3] LYFGENIA (lovotibeglogene autotemcel) prescribing information. FDA website. Revised 12/23. Retrieved from: https://www.fda.gov/media/174610/download [U4] Kolata g. F.D.A. Approves Sickle Cell Treatments, Including One That Uses CRISPR. The New York Times. December 8, 2023. Retrieved from: https://www.nytimes.com/2023/12/08/health/fda-sickle-cell-crispr.html [U5] ZYNTEGLO (betibeglogene autotemcel) prescribing information. Bluebird Bio.com. August 2022. Retrieved from: https://www.bluebirdbio.com/-/media/bluebirdbio/Corporate%20COM/Files/Zynteglo/ZYNTEGLO_prescribing_information.pdf [U6] FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions. FDA website. August 17, 2022.  Retrieved from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-who initially published: 11/19/2021

Dive into the steaming bowl of history and nutrition as we unravel the story behind ramen, exploring its culinary evolution and delving into potential nutritional benefits that make this iconic dish a fusion of culture, art, and well-being. Culinary Medicine by Lori A Smolin, PhD  and Mary B Grosvenor, MS, Registered Dietitian Ramen is both a cheap easy meal and a global culinary sensation - depending on how it is processed, prepared, and served. This Japanese-rooted dish has become almost an obsession in the United States, the largest consumer of ramen outside of Asia. [1,2,3]. The traditional noodle  dish was brought to Japan by Chinese immigrants in the 1800s. When the Great Kanto Earthquake of 1923 caused serious damage in Tokyo and Yokohama, where ramen shops were concentrated, many ramen chefs were forced to move, spreading the availability of ramen, and creating unique regional ramens throughout Japan. The popularity soared in Japan after World War II when rice was in short supply and the US brought in wheat flour to address the food shortages, much of which ended up in ramen.[4] The instant ramen we make today by just adding boiling water emerged in Japan in 1958 providing an alternative to the long lunchtime lines at street food stalls. Since then, demand has ballooned with global consumption exceeding 100 billion servings of instant noodles annually.[4] One hundred years after ramen chefs ventured out of Tokyo and Yokohama, this bowl of salty, slippery, chewy noodles in a flavorful broth is both a quintessential low-budget meal and competition for sushi, tempura, and sashimi as the most popular item in Japanese restaurants.[2] Traditional Ramen A traditional ramen consists of five main ingredients: men (noodles), dashi (soup stock), tare (sauce), fat or oil, and toppings.[5] The noodles are made from wheat flour, water, salt, and an alkaline solution called kansui that gives the noodles elasticity and chewiness. They vary in shape and thickness depending on the type of wheat used and how much water is added when making the noodle. The soup stock is made from different blends of meat, seafood, and vegetables. The tare, or sauce, added to flavor the soup, is made from a combination of condensed extracts from meat or fish and spices. Animal fat, vegetable oil, and seasoning oil are also used to flavor the soup. The oil forms a layer on top that prevents the ramen from cooling. Toppings ranging from eggs, tofu and cubed meats to wontons, menma (fermented bamboo shoots), nori, bean sprouts, and microgreens are carefully chosen to make each bowl of ramen unique. Instant Ramen Instant ramen is another story.  For many Americans, ramen is the ultimate convenience food - an inexpensive source of calories that is quick and easy to prepare even with limited kitchen facilities. When combined with hot water, the ramen brick expands into chewy noodles with a few dried vegetables that can be flavored with the salty seasoning packet. Instant ramen is ubiquitous in grocery stores and convenience marts. It is a mainstay in college dorms for hungry students who have little money and few cooking skills. This microwavable meal is far from the gourmet treat made by Japanese chefs who simmer fresh noodles in their signature broth and add meat, fish, soy, and vegetable toppings. Traditional Benefits? How does ramen fit into a healthy eating pattern? The cellophane wrapped block of noodles you can buy for 30 cents does not contribute much nutritionally. This version of ramen is low in protein, fiber, and vitamins including vitamins A, C, and B12, and the minerals calcium, magnesium, and potassium.[6] The noodles are high in refined carbohydrate and often saturated fat, which is used in processing to allow the noodles to cook quickly by just adding water. Perhaps the biggest nutritional downside of packaged ramen is its high sodium content; one serving can provide well over half of the maximum amount of sodium recommended for the entire day (2300 mg). On the other hand,  the fresh bowl of ramen you pay $20 for in a Japanese eatery can be a nutritious meal. The broth in restaurant ramen is usually made by boiling bones and vegetables making it lower in sodium than the instant version. The noodles are prepared fresh and slowly simmered so do not contain the extra fat found in the instant variety. And the toppings contribute protein, fiber, vitamins and minerals to the bowl. While the restaurant version is more nutritious, you don’t have to give up the packaged convenience food. An occasional bowl will not significantly decrease the quality of your overall diet, especially if you bolster the nutritional clout of your instant ramen. Use only half of the seasoning packet to reduce the sodium. Toss in some carrots, broccoli, mushrooms, bamboo shoots, and peppers to increase the fiber, vitamins, and minerals (see Figure). Up the protein content by adding an egg, tofu, edamame, fish, seafood, chicken, beef, or pork. Enjoy some ramen, just not everyday. Interested in a healthier way to make ramen? Check out this Healthier Ramen Recipe References [1]  What Caused the Ramen Boom in the U.S. - Myojo USA. Published March 15, 2022. Available online at https://www.myojousa.com/blog/ramen-boom/ Accessed November 15, 2023. [2] World instant noodles association. (2023) 世界ラーメン協会. Available online at: https://instantnoodles.org/en/. Accessed: 25 November 2023). [3] Asia T of. Japanese Ramen: From Street Food to Global Sensation. Taste of Asia. Available online  at https://tasteofasialv.com/blog/f/japanese-ramen-from-street-food-to-global-sensation. Accessed November 25, 2023. [4]Ramen Museum New York (2021) History of ramen, Ramen Museum New York. Available online at: https://ramenmuseum.nyc/history-of-ramen/. Accessed: 25 November 2023. [5] Roots of Ramen (2023) Available online at https://instantnoodles.org/en/  Accessed: November 18, 2023. [6] Are Ramen Noodles Bad for You? Here’s What a Dietitian Has to Say. EatingWell. Available online  at https://www.eatingwell.com/article/8050018/are-ramen-noodles-bad-for-you/#:~:text=Ramen%20noodles%20are%20not%20inherently Accessed November 20, 2023.

In a world where abundance often coexists with overlooked waste, the startling reality of food disposal emerges as a pressing concern. Did you know that the average American discards approximately 20 pounds of food each month?  Up to 40% of food in the United States and a third of food produced globally is never eaten. The implications of this avoidable food waste extend beyond the confines of your kitchen, rippling through environmental landscapes, impacting your grocery budget, and even influencing the nutritional quality of your meals. Culinary Medicine by Lori A Smolin, PhD and Mary B Grosvenor, MS, RD Have you ever made the resolution to eat healthier? You fill the kitchen with fresh fruits and vegetables and whip up a couple of stir-fry dishes and fancy salads. But then life gets busy and by the end of the week, you find yourself with a vegetable drawer full of wilting produce that will likely end up in a landfill. You are not alone. The average American discards about 20 pounds of food each month. This food waste has an impact on the environment as well as your grocery bill and your nutrient intake. The Scope of Food Waste Food waste is an American and a global problem. Up to 40% of food in the US and a third of food produced around the world is never eaten.[1] When food is wasted, the land, water, energy, and labor used to produce it and get it to our homes is also wasted. The food we discard makes up the largest component of solid waste in landfills in the US.  As this waste decomposes, it generates methane, a potent greenhouse gas; food waste is responsible for 58% of landfill emissions.[2] Food waste also contributes to air pollution, water scarcity, biodiversity loss, and soil and water degradation.[3] The food we waste at home and in retail establishments along with what is lost on the farm or during storage or transport, accounts for about 7% of global greenhouse gas emissions.[4] Nearly 30% of agricultural land is used to produce food that is never consumed. This wasted food could feed 2 billion people, more than double the number of undernourished people around the world.[5] In the United States, food is wasted at all stages of production, from how it is grown, packaged, and transported to what is discarded in grocery stores and restaurants. Surprisingly though, individual consumers are the largest single source of wasted food.[2] Food waste costs an average American family of four about $1500 per year. There is also a nutritional cost to this waste. One study found that 66% of the food wasted in homes consisted of fruits and vegetables. These losses accounted for only 29% of calories, but 62% of the fiber, 37% of the calcium, 96% of the vitamin C, and 85% of the vitamin A that was purchased.[6] Simple steps such as buying only what you will use, storing food properly, understanding “use-by” and “sell-by” dates on food labels, freezing or repurposing leftovers, and composting anything that can’t be eaten can reduce your food budget and your environmental impact while increasing your nutrient intake. Buy Only What You Will Use and Use What You Buy The first step in avoiding waste is to plan your meals so you don’t buy more than you need. To do this, review your schedule for the week and decide on recipes that you will have time to prepare and eat. Don’t forget to check your kitchen for foods that need to be used up. Then create a shopping list and bring it with you to the store. It can be tricky to buy only what you need. For example, your recipe may call for a few green beans, but the store sells them in one-pound packages. If you buy the package, come up with a way to use the rest before they spoil. Or you may want to choose frozen rather than fresh; they last for months and are often higher in nutrients than fresh, especially if the fresh ones sit in your fridge for a week.[7] Once you get the food home, put away frozen and refrigerated items first. Then follow your meal plan. Don’t Let the Dates Confuse You The “use-by”, “sell-by”, and “best if used by" dates on food labels are thought of by consumers as a measure of safety. When a food passes the date on the label, consumers often discard the food. However, with the exception of “use-by”, dates on infant formula, these dates are only suggestions by the manufacturer for when the food is at its peak quality, not when it is unsafe to eat (see Table).[8] Misinterpretation of these dates by consumers and retailers leads them to discard perfectly safe food and is a major cause of unnecessary food waste.[9] Foods not exhibiting signs of spoilage may be sold, purchased, donated, and consumed beyond the labeled "best if used by" or “use-by” date. [10]. Use or Freeze Food that is Losing its Freshness Planning and shopping from a list are important but keeping track of what you already have is key in limiting waste. Eat the most perishable foods first - raspberries don’t last as long as oranges. Check your refrigerator throughout the week to see what you need to use up. Is there half of casserole that you didn’t eat earlier in the week? Make a plan to use or freeze what’s left. Find ways to use foods that are aging. Leftover meats and veggies can be turned into taco bowls and stir fries. Softening fruit, such as apples or blueberries, can be baked into muffins or added to cooked oatmeal. Aging bananas can be blended into smoothies or frozen to be used in baking at a later date. Slightly wilted vegetables can be added to smoothies or cooked in soups and casseroles and then these soups and casseroles can be frozen for future meals. Compost What You Can’t Save. No matter how diligent you are at planning, freezing, and repurposing the food in your fridge, some things can’t be saved. But that doesn’t mean you have to throw them in the trash.  If you have a yard, you can set up a compost heap or bin in which to toss food that has spoiled as well as peels and cores. When food waste is composted, it is broken down in the presence of oxygen. This generates some carbon dioxide, but not methane, which is a far more potent greenhouse gas. If you don’t have a yard there are ways of composting inside.[10] Many communities also offer communal compost heaps, and more and more communities and private companies are offering curbside compost pickup. So, if you are not inclined or able to compost yourself see what options are available in your area. Conclusion Don’t give up on the resolution to eat healthier. All the suggestions for reducing food waste, from planning meals to repurposing leftovers and freezing extras can help you to eat the nutritious foods you purchased and improve your diet while saving your food budget and reducing your environmental impact. Next time your vegetable drawer is overflowing, instead of tossing it, freeze it, bake it, stir fry it, or blend it into something delicious. Click here for a great recipe for leftovers, it's called Leftover Bowl Recipe References [1] UN Climate Report Underscores Need to Eat Food We Grow. www.nrdc.org. Published August 8, 2019. Accessed December 15, 2023. https://www.nrdc.org/bio/joanne-berkenkamp/climate-report-underscores-need-eat-food-we-grow [2] Food Waste Management:Quantifying Methane Emissions from Landfilled Food Waste. EPA.gov; 2023. Available online at https://www.epa.gov/land-research/quantifying-methane-emissions-landfilled-food-waste. Accessed November 26, 2023. [3] U.S. Environmental Protection Agency. Estimates of Generation and Management of Wasted Food in the United States in 2019. April 2023. https://www.epa.gov/system/files/documents/2023-03/2019%20Wasted%20Food%20Report_508_opt_ec.pdf. Accessed November 26, 2023 [4] United Nations. (2022). International Day of Awareness on Food Loss and Waste Reduction- Background. https://www.un.org/en/observances/end-food-waste-day/background Accessed December 10, 2023. [5] Hiç C, Pradhan P, Rybski D, Kropp JP. Food Surplus and Its Climate Burdens. Environmental Science & Technology. 2016;50(8):4269-4277. doi:https://doi.org/10.1021/acs.est.5b05088 [6] von Massow M, Parizeau K, Gallant M, et al. Valuing the Multiple Impacts of Household Food Waste. Frontiers in Nutrition. 2019;6. doi:https://doi.org/10.3389/fnut.2019.00143 [7] Healthy Eating on a Budget | MyPlate. www.myplate.gov. https://www.myplate.gov/eat-healthy/healthy-eating-budgetAccessed November 26. 2023. [8] USDA. Food Safety and Inspection Service. Food Product Dating. https://www.fsis.usda.gov/food-safety/safe-food-handling-and-preparation/food-safety-basics/food-product-dating. Accessed November 26, 2023. [9] The Dating Game: How Confusing Food Date Labels Lead to Food Waste in America. www.nrdc.org. Published October 22, 2013. Accessed December 16, 2023. https://www.nrdc.org/resources/dating-game-how-confusing-food-date-labels-lead-food-waste-america#:~:text=Report- Accessed November 30,2023. [10] Composting Is Way Easier Than You Think. www.nrdc.org. Published June 16, 2016. Accessed December 16, 2023. https://www.nrdc.org/stories/composting-way-easier-you-think?gad_source=1&gclid=Cj0KCQiAgqGrBhDtARIsAM5s0_nfBVtNX-BV-9zfrDLAY0tEatEnGTQ65tQlz8do-S3JjC4sSTXb0YgaAgdrEALw_wcB. Accessed November 30, 2023.

RSV (respiratory syncytial virus) has long been known as a children’s disease and is thought to be the leading cause of infant pneumonia in the world. RSV can also be a serious disease in elderly adults due to waning immunity. Infectious Disease InBrief by Stuart M. Caplen MD RSV (respiratory syncytial virus) has long been known as a children’s disease, causing runny nose, coughing, sneezing, fever, and/or wheezing and is thought to be the leading cause of infant pneumonia in the world.[1] Most patients recover in a week or two. RSV can also be a serious disease in elderly adults due to waning immunity, and can cause dyspnea (shortness of breath), hypoxia (low blood oxygen) and pneumonia.[2] RSV in Adults In one study, RSV illness developed annually in approximately 3% to 7% of healthy older adults and 4% to 10% of high-risk adult subjects.[3] It is estimated that yearly in the United States between 60,000-160,000 older adults are hospitalized and 6,000-10,000 die due to RSV infection.[4] In one study of older adults who were hospitalized with RSV disease, 18% were admitted to an intensive care unit and 5.6% died.[5] Adults at highest risk for severe RSV infection include: Older adults Adults with chronic heart or lung disease such as asthma, chronic obstructive pulmonary disease or congestive heart failure Adults with weakened immune systems Adults living in nursing homes or long-term care facilities[4] CDC Vaccination Recommendations On June 29th, 2023 the CDC Advisory Committee on Immunization Practices’ (ACIP) published recommendations for use of new Respiratory Syncytial Virus (RSV) vaccines for people ages 60 years and older, using shared clinical decision-making. This means these individuals may receive a single dose of the vaccine based on discussions with their healthcare provider about whether RSV vaccination is right for them.[6] How the Vaccine Works An RSV protein called RSV prefusion F protein (RSVpreF) provides potent stimulation to the immune system. The RSV vaccines, (which are not mRNA vaccines) work by introducing two RSV subtypes of inactivated RSVpreF into the body. If the person becomes infected, the vaccine stimulated immune system allows rapid recognition of the RSV virus which can help prevent acute or severe disease.[7,8] Abrysvo, manufactured by Pfizer and Arexvy, manufactured by GSK, both are FDA approved as RSV vaccines in adults. (Vaccinating pregnant women to give passive RSV antibodies to neonates is being investigated, and an mRNA vaccine is in phase three testing).[7,9,10] Vaccine Studies In a manufacture sponsored study, the Pfizer vaccine Abrysvo had an efficacy of 66.7% in preventing pneumonia, and a 62.1% efficacy for preventing RSV acute respiratory illness compared to placebo. (In actual numbers, out of a total of 34,284 participants there were 11 participants in the vaccine group and 33 participants in the placebo group who got pneumonia and 22 participants in the vaccine group who developed an acute RSV respiratory illness compared to 58 participants in the placebo group) There were 2 cases of Guillain-Barré variants* in the vaccine group of 17,215 subjects, which works out to 1.16 cases per 10,000 doses.[11] * (A condition where a person's immune system attacks peripheral nerves.) In Arexvy manufacture sponsored trials, vaccine efficacy compared to a placebo group against confirmed RSV-related lower respiratory tract disease (pneumonia) was 82.6%, and was 71.7% against RSV-related acute respiratory infection.[8] Most adverse reactions to Arexvy were typical for vaccines and included local pain, fatigue, myalgias, headache, arthralgias and fever. In the phase three 24,966 subject trial, atrial fibrillation developing within 30 days was reported in 10 participants who received Arexvy and 4 participants who received placebo (of which 7 events in Arexvy arm and 1 event in placebo arm were serious). However, at 6 months atrial fibrillation was reported in 13 participants who received Arexvy and 15 participants in the placebo group. The manufacturer states that currently available information is insufficient to determine a causal relationship of atrial fibrillation to the vaccine. Although no Guillain-Barré syndrome cases were reported in the phase three trial, in one other trial a case of Guillain-Barré syndrome was reported nine days after an Arexvy vaccination. In another trial there were two reported cases of acute disseminated encephalomyelitis** 7 and 22 days after an Arexvy vaccination in subjects who had also concomitantly received the Fluarix Quadrivalent influenza vaccine.[12] ** (A neurological disorder characterized by widespread inflammation of the brain and spinal cord.) Need for Revaccination Data presented to the FDA indicated that Arexvy vaccination could be protective for at least two years, but there is no recommendation as of yet if the vaccination needs to be repeated or how frequently it may need be repeated.[7,13] Conclusion The FDA has approved bivalent RSV vaccines for those over 60 years of age using shared clinical decision making to decide if it is appropriate for that person. There is a considerable amount of serious disease in the elderly from RSV and there is some data indicating that vaccination can reduce the chance of contracting RSV pneumonia 67% to 83% compared to placebo. The chance of a placebo group subject in the Abrysvo study getting an acute RSV infection was 0.19% (33/17,069) and was 0.76% (95/12,494) in the Arexvy placebo group.[8,10] This was much lower than one earlier study which found that 3% to 7% of healthy older adults and 4% to 10% of high-risk elderly subjects got infected with RSV each year.[3] It is possible that the lower numbers of RSV infections found in studies done during the COVID-19 era were due to precautions taken by some subjects during that time. There is a small chance of a serious adverse event from vaccination. The amount of time until revaccination has not been determined, although there is some evidence of continued protection at two years. Considering the potential seriousness of an RSV infection in the elderly, there are patients that might benefit from vaccination, especially those with underlying high-risk medical conditions. The FDA has indicated this should be a decision made by physicians in conjunction with their patients to decide if the benefits versus risks of vaccination against RSV infection warrant vaccination for that patient. Download the PDF References [1] Karron , RA. RSV Illness in the Young and the Old — The Beginning of the End? N Engl J Med 388:1522-1524. April 20, 2023. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMe2302646?query=recirc_curatedRelated_article [2] Respiratory Syncytial Virus (RSV) VIS. CDC. Last Reviewed: July 24, 2023. Retrieved from: https://www.cdc.gov/vaccines/hcp/vis/vis-statements/rsv.html#:~:text=CDC%20recommends%20adults%2060%20years,same%20time%20as%20other%20vaccines. [3] Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 2005;352:1749-1759. Retrieved from: https://www.nejm.org/doi/full/10.1056/nejmoa043951 [4] RSV in Older Adults and Adults with Chronic Medical Conditions. CDC. Last Reviewed: July 14, 2023. Retrieved from: https://www.cdc.gov/rsv/high-risk/older-adults.html [5] Bradley Ackerson and others, Severe Morbidity and Mortality Associated With Respiratory Syncytial Virus Versus Influenza Infection in Hospitalized Older Adults, Clinical Infectious Diseases, Volume 69, Issue 2, 15 July 2019, Pages 197–203. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603263/ [6] CDC Recommends RSV Vaccine For Older Adults. CDC. June 29, 2023. Retrieved from: https://www.cdc.gov/media/releases/2023/s0629-rsv.html [7] Katella K. Should You Get the New RSV Vaccine? Yale Medicine. originally published: July 24, 2023. Updated: August 28, 2023. Retrieved from: https://www.yalemedicine.org/news/should-you-get-the-new-rsv-vaccine [8]Papi a et al. Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults. N Engl J Med 2023; 388:595-608. February 16, 2023. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMoa2209604 [9]Kampmann B. et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med 2023; 388:1451-1464. April 20, 2023. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMoa2216480 [10] Moderna Announces mRNA-1345, an Investigational Respiratory Syncytial Virus (RSV) Vaccine, Has Met Primary Efficacy Endpoints in Phase 3 Trial in Older Adults. Moderna News Details. January 17, 2023. Retrieved from: https://investors.modernatx.com/news/news-details/2023/Moderna-Announces-mRNA-1345-an-Investigational-Respiratory-Syncytial-Virus-RSV-Vaccine-Has-Met-Primary-Efficacy-Endpoints-in-Phase-3-Trial-in-Older-Adults/default.aspx [11] Walsh EE et al. Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults. N Engl J Med 2023; 388:1465-1477. April 20, 2023. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMoa2213836?query=featured_home [12] AREXVY prescribing information. GlaxoSmithKline. Revised: 5/2023. Retrieved from: https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Arexvy/pdf/AREXVY.PDF [13] GSK shares positive data for Arexvy, its respiratory syncytial virus (RSV) older adult vaccine, indicating protection over two RSV seasons. GSK. 21 June 2023. Retrieved from: https://www.gsk.com/en-gb/media/press-releases/gsk-shares-positive-data-for-arexvy-its-respiratory-syncytial-virus-older-adult-vaccine-indicating-protection-over-two-rsv-seasons/

The V/Q ratio quantifies the relationship of lung ventilation to perfusion and in ideal physiology, the ratio is 1. V/Q mismatch on the other hand... Pulmonology Terms FibonacciCOMPENDIUM In Short by Adele Shenoy, MD Edited by Charles L Fishman, MD V/Q mismatch is an imbalance in the relationship between ventilation (V) and perfusion (Q) of the respiratory units within the lung. The V/Q ratio quantifies the relationship of ventilation to perfusion and in ideal physiology, the ratio is 1. V/Q mismatch with a high ratio describes areas of the lung that are well-ventilated and poorly perfused. V/Q mismatch with a low ratio is seen when there are areas of the lung that are poorly ventilated and well-perfused. V/Q mismatch is a common cause of hypoxemia. Interruptions of blood flow within the pulmonary circulation, such as seen with a pulmonary embolism, will lead to impaired gas exchange and an increase in respiratory dead space. This will lead to high ratio V/Q mismatch. Airways disease leading to obstruction and poor ventilation, such as observed in pneumonia, COPD, or atelectasis, will lead to perfusion of unventilated lung, also known as intrapulmonary shunt. This will cause low ratio V/Q mismatch. Both situations will decrease the delivery of oxygen from the lungs. #Pulmonolohy V/Q Mismatch in our FibonacciCOMPENDIUM References: Petersson, J., Glenny, R. Gas exchange and ventilation-perfusion relationships in the lung. European Respiratory Journal. 2014; 44: 1023-1041. Fernandes CJ, Luppino Assad AP, Alves-Jr JL, Jardim C, de Souza R. Pulmonary Embolism and Gas Exchange. Respiration. 2019;98(3):253-262 Sarkar M, Niranjan N, Banyal PK. Mechanisms of hypoxemia. Lung India. 2017 Jan-Feb;34(1):47-60

Adenocarcinoma of the lung is the most common type of lung cancer. Pulmonology Term FibonacciMD Compendium In Short By Adele Shenoy, MD Edited by Charles L. Fishman, MD Adenocarcinoma of the lung is the most common type of lung cancer. It is a malignancy arising from the bronchial glands. It is associated with tobacco use. Synonyms ( AKA ): bronchogenic adenocarcinoma adenocarcinoma of lung NSCLC (see summary table below) Pathology: There are different subtypes of bronchogenic adenocarcinoma that have been shown to be associated with prognosis. Atypical adenomatous hyperplasia is a focal lesion of atypical type II pneumocytes and is thought to be premalignant. Adenocarcinoma in situ (formerly known as Bronchoalveolar Carcinoma) demonstrates lepidic growth (meaning along the lining) of atypical type II pneumocytes or Clara cells along septae and does not invade stroma, vasculature, or pleura. Minimally invasive adenocarcinoma also demonstrates lepidic growth, but is distinguished from adenocarcinoma in situ by invasion into the stroma, vasculature, or pleura of less than 5 mm. Invasive adenocarcinomas invade the stroma by greater than 5 mm. Prognosis The most important determinant of prognosis is stage of disease at diagnosis. Early-stage disease may be resected for cure. Disease invading the lymph nodes, pleura and distant sites is rarely curable. Many studies have examined the relationship between histological subtypes of adenocarcinoma and prognosis. The less aggressive histologic sub types are less likely to spread, and confer a better prognosis Symptoms The severity of symptoms depends on the progression of the disease. Early onset disease may be asymptomatic and only detected incidentally by imaging of the chest. Symptoms may include cough, hemoptysis, and general constitutional symptoms including weight loss and night sweats. Patients may have pleural effusions contributing to shortness of breath and decreased lung sounds. Diagnosis Lung cancer screening with low dose chest CT may allow for early detection of lung nodules. Biopsy provides the definitive diagnosis. Image guided or bronchoscopic biopsies may be done, depending on the location of the lesions present. For staging purposes, the most distant site of disease should be sampled. The differential diagnosis includes other types of lung cancer, such as small cell lung cancer and squamous cell lung cancer. Granulomas and hamartomas are also included on the differential. The histology of the sample determines the definitive diagnosis. Treatment Options If localized, bronchogenic adenocarcinoma is typically treated with surgical resection. If the disease is not amenable to resection, radiotherapy and chemotherapy are effective but rarely curative. A full immunodiagnostic panel is also done to look for molecular targets for immunotherapy. Recent studies have shown improved survival using immunotherapy in combination with chemotherapy as compared to chemotherapy alone. Improvement in survival was seen in both early-stage lung cancer and in metastatic cancer although the benefits of combination therapy seem to be better in early-stage cancer. Additionally, for patients with PDL-1 positive tumors, immunotherapy has been shown to be superior to chemotherapy, both in adverse events and in improving survival. Recent studies have demonstrated that chemotherapy can be avoided for some patients with metastatic NSCLC. Survival and duration of response increases as PDL-1 expression increases. Although even for patients that are PDL-1 negative (<1%) or have PDL-1 (1–49%) tumors, immunotherapy/chemotherapy combination strategies appear to be the new standard of care as first line treatment. In one study, the combination of chemotherapy and immunotherapy yielded an overall survival of 22 months in metastatic NSCLC and reduced the risk of death by 44% compared to chemotherapy alone. Lung Carcinoma (summary table) SCLC small cell carcinoma (oat cell cancer) combined small cell carcinoma neuroendocrine lung cancer NSCLC adenocarcinoma squamous cell carcinoma large cell carcinoma Other neuroendocrine large cell lung cancer (a more aggressive form of neuroendocrine tumors) #Pulmonology Bronchogenic Adenocarcinoma in FibonacciCOMPENDIUM References: Latimer, K., Mott, T. Lung cancer: diagnosis, treatment principles, and screening. Am Fam Physician. 2015 Feb 15;91(4):250-256. Hutchinson, B., Shroff, G., Truong, M., et al. Spectrum of Lung Adenocarcinoma. Seminars in Ultrasound, CT, and MRI. 2019; 40 (3): 255-264. Travis, W., Brambilla, E., Nicholson, A., et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical, and Radiologic Advances Since the 2004 Classification. Journal of Thoracic Oncology. 2015; 10(9): 1243-1260. Wang, Y., Li, C., Wang, Z. et al. Comparison between immunotherapy efficacy in early non-small cell lung cancer and advanced non-small cell lung cancer: a systematic review. BMC Med 20 , 426 (2022). https://doi.org/10.1186/s12916-022-02580-1 Mithoowani, H., Febbraro, M. Non-Small-Cell Lung Cancer in 2022: A Review for General Practitioners in Oncology. Curr Oncol. 2022 Mar; 29(3): 1828–1839. Published online 2022 Mar 9. doi: 10.3390/curroncol29030150 Gadgeel S., Rodríguez-Abreu D., Speranza G., Esteban E., Felip E., Dómine M., Hui R., Hochmair M.J., Clingan P., Powell S.F., et al. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J. Clin. Oncol. 2020;38:1505–1517. doi: 10.1200/JCO.19.03136.

The perfect fruit? Aren’t avocados a vegetable? AKA The Alligator Pear Culinary Medicine InBrief by Stefanie Schwartz, MS, RD, CDN and and Mary Grosvenor, MS, RD Avocados, along with tomatoes, squash, and eggplant, are technically fruit according to botanists because they are the edible seed-bearing part of a flowering plant. However, nutritionists place them in the vegetable food group because of their nutrient content, taste, and culinary use. Regardless of how you categorize avocados, they offer a wide variety of nutritional, health, and culinary benefits. Avocado consumption is associated with improved overall diet quality and nutrient intake. [1] This fruit/vegetable is low in carbohydrate and high in heart-healthy monosaturated fat and fiber, both soluble and insoluble. Avocados are nutrient dense; a quarter of one has only about 60 calories and is a good source of vitamin K, folate, and vitamin E. Avocados have more potassium than bananas and are low in sodium. In addition to nutrients, they provide a variety of phytochemicals, including carotenoids and the plant sterol, beta-sitosterol. The nutritional benefits of avocados carry over into health benefits. The high fat content of avocados increases the bioavailability of carotenoids such as lutein and zeaxanthin, which have antioxidant and anti-inflammatory properties that help prevent age-related macular degeneration and cataracts. Because of their high fat and low carbohydrate content avocados have a very low glycemic index. Low glycemic index foods help manage blood glucose levels and hunger, reducing the risk of metabolic syndrome, obesity, and diabetes [2]. Diets high in avocados are associated with a reduction in cardiovascular disease risk. Some of this cardioprotective effect is due to their monounsaturated fat content. [3] Replacing other fats, particularly those from high fat animal products like whole mike, cheese, and processed meats, with avocados has been shown to reduce LDL cholesterol levels. [4] The plant sterols in avocados help lower total and LDL cholesterol because they compete with cholesterol for absorption. The fiber in avocados not only helps lower blood cholesterol but also promotes a healthy microbiota. This perfect fruit can be sliced, diced, whipped, and blended to provide a variety of textures to a meal. Avocado oil is useful in frying. It has a neutral flavor and does not burn even at high temperatures. They are widely used in vegetarian diets providing a creamy texture and interesting flavor to sandwiches, sauces, and smoothies. Next time you top your burrito with guacamole you can rest assured that you are adding nutrients as well as flavor to your meal. Discover the benefits of avocados! Click for more topics on nutrition, bariatric, integrative medicine, and our health-conscious recipes. #CulinaryMedicine Check out FibonacciRECIPES for healthy recipes In our APP we have recipes with avocados ex: Avocado club egg rolls recipe Avocado dip Chicken tortilla soup Sources [1] Fulgoni VL 3rd, Dreher M, Davenport AJ. Avocado consumption is associated with better diet quality and nutrient intake, and lower metabolic syndrome risk in US adults: results from the National Health and Nutrition Examination Survey (NHANES) 2001-2008. Nutr J. 2013; 12:1. doi: 10.1186/1475-2891-12-1. [2] Dreher ML, Cheng FW, Ford NA. A Comprehensive Review of Hass Avocado Clinical Trials, Observational Studies, and Biological Mechanisms. Nutrients. 2021;13(12):4376. doi: 10.3390/nu13124376. [3] Dreher ML, Davenport AJ. Hass avocado composition and potential health effects. Crit Rev Food Sci Nutr. 2013;53(7):738-750. doi: 10.1080/10408398.2011.556759. [4] Schoeneck M, Iggman D. The effects of foods on LDL cholesterol levels: A systematic review of the accumulated evidence from systematic reviews and meta-analyses of randomized controlled trials. Nutr Metab Cardiovas Dis. 2021;31(5):1325-1338. Initially posted March 2022.

1) Second Bivalent Covid Vaccine Booster Recommendations 2) Is the Bivalent a Better Vaccine? 3) How Much Protection Does a Previous Covid Infection Confer? In Brief By Stuart M Caplen, MD The FDA has authorized a second dose of the bivalent (original and omicron BA.4/BA.5 strains) COVID booster for individuals 65 years of age and older at least four months following their initial bivalent dose. Most immunocompromised individuals who have received a bivalent COVID-19 vaccine may receive a single additional dose of a bivalent COVID-19 vaccine at least 2 months following a dose of a bivalent COVID-19 vaccine, and additional doses may be administered at the discretion of, and at intervals determined by, their healthcare provider. There are different eligibility requirements for immunocompromised individuals 6 months through 4 years of age based on initial vaccine. However, a more complete recommendation had not yet been released when this article was written.[1,2] A second bivalent booster vaccination is not recommended for any other age group at this time.[1] The FDA states that a second bivalent dose for individuals 65 years of age and older is supported by data showing the waning of immunity in this population over time and its restoration by an additional dose. Based on evidence from studies conducted previously, immunocompromised individuals may also require additional doses to maintain immunity.[1] How long does protection from the bivalent vaccine last? A study published in January 2023 found that protection against symptomatic infection lasted at least 3 months after bivalent vaccination in non-immunocompromised individuals who had received at least one dose of monovalent vaccine previously. Vaccine efficacy (VE) against symptomatic omicron BA.5-related infection after 3 months was 52% in persons aged 18–49 years, 43% in persons aged 50–64, and 37% among those aged ≥65 years. VE against symptomatic XBB/XBB.1.5-related infection was 49% among persons aged 18–49, 40% among persons aged 50–64 years, and 43% among those aged ≥65 years. Evidence of waning VE by 2–3 months after receiving a bivalent dose was minimal. The study did not look at the rate of serious infection prevention. [3] Is the bivalent vaccine better than the older monovalent vaccine? There is data that the efficacy of the bivalent vaccine which contains both spike protein antigens used in the original vaccine and the BA.4/BA.5 strains, is no better at preventing disease than the original monovalent RNA vaccine (which is no longer available).[4,5] One study tested subjects who never had a covid infection with a different bivalent mixture of B.1 omicron virus and original virus and found a 1.9% infection rate in the monovalent vaccine group compared to 3.2% in the bivalent vaccine group.[6] This vaccine was not the one chosen to be manufactured and distributed. However, this information, which was available at the time, was not disclosed to the FDA’s advisory committee before they initially approved the emergency authorization for the bivalent vaccine. Although this information might not have had any effect on the final decision, this lack of disclosure, according to a news report, made some of the advisors on the committee angry and disappointed when they found out.[7] It is felt that the lack of improved efficacy of the bivalent vaccine over the older monovalent vaccine might be due to immune imprinting.[8,9] Immune imprinting is where initial exposure to one virus strain primes B cell memory and limits the development of new memory B cells and neutralizing antibodies against variant strains of the virus. Thus, antibodies that work against both the newer and ancestral viral strains are produced without producing specific antibodies unique to the newer strains.[9] It has been theorized that the protection from COVID infection might have been improved if the newer vaccine was monovalent, with only the newer strains included, or had been formulated with larger amounts of the newer strains rather than the current bivalent vaccine formulation.[8] How much protection does a previous COVID infection confer? A systematic review and meta-analysis of how long antibody protection remains after a COVID infection found that protection from re-infection from the original virus, alpha, and delta variants declined over time but remained at 78.6% at 40 weeks and 55.5% at 80 weeks. Protection against re-infection by the omicron BA.1 variant declined more rapidly and was estimated at 36.1% at 40 weeks. Two studies in the meta-analysis looked at protection from re-infection after omicron BA.2 infection and found it was 85.4% at 4 weeks and 37% at 40 weeks. Protection against severe disease was high for all variants, with 90.2% for original virus , alpha, and delta variants, and 88.9% for omicron BA.1 at 40 weeks. The authors concluded that protection from past infection wanes over time, but the level of protection against re-infection, symptomatic disease, and severe disease appears to be at least as durable, if not more so, than that provided by two-dose vaccination with the mRNA vaccines for the original virus, alpha, delta, and omicron BA.1 variants. [10] Conclusion The FDA has recommended that a Spring 2023 COVID bivalent booster may be given to individuals over 65 years of age at least 4 months after their last vaccination or those who are immunocompromised at least 2 months after their last vaccine after consultation with their providers. The bivalent COVID vaccine, while boosting immunity, does not appear to be any more effective than the original monovalent vaccines at preventing illness. This may be due to immune imprinting. A previous COVID infection does induce some long-term immunity from severe disease, the length of which may vary by the COVID strain causing the infection. References [1] Coronavirus (COVID-19) Update: FDA Authorizes Changes to Simplify Use of Bivalent mRNA COVID-19 Vaccines. FDA. 04/18/2023. Retrieved from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update- fda-authorizes-changes-simplify-use-bivalent-mrna-covid-19-vaccines [2] Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. CDC. last updated April 22, 2023. Retrieved from: https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations- us.html [3] Link-Gelles R, Ciesla AA, Roper LE, et al. Early Estimates of Bivalent mRNA Booster Dose Vaccine Effectiveness in Preventing Symptomatic SARS-CoV-2 Infection Attributable to Omicron BA.5– and XBB/XBB.1.5–Related Sublineages Among Immunocompetent Adults — Increasing Community Access to Testing Program, United www.FibonacciMD.app 3 www.FibonacciMD.com States, December 2022–January 2023. MMWR Morb Mortal Wkly Rep 2023;72:119–124. Retrieved from: http://dx.doi.org/10.15585/mmwr.mm7205e1 [4] Wang Q et al. Antibody responses to Omicron BA.4/BA.5 bivalent mRNA vaccine booster shot. bioRxiv 2022. October 24,2022. Retrieved from: https://doi.org/10.1101/2022.10.22.513349 [5] Collier AY et al. Immunogenicity of BA.5 Bivalent mRNA Vaccine Boosters. N Engl J Med 2023; 388:565-567. February 9, 2023. Retrieved from: https://www.nejm.org/doi/10.1056/NEJMc2213948 [6] Chalkias S et al. A Bivalent Omicron-Containing Booster Vaccine against Covid-19. N Engl J Med 2022; 387:1279-1291. Retrieved from: https://www.nejm.org/doi/10.1056/NEJMoa2208343 [7] Cohen E, Thomas N. FDA vaccine advisers ‘disappointed’ and ‘angry’ that early data about new Covid-19 booster shot wasn’t presented for review last year. CNN. https://www.cnn.com/2023/01/11/health/moderna-bivalent-transparency/index.html. Retrieved from: https://www.cnn.com/2023/01/11/health/moderna-bivalent- transparency/index.html [8] Offit PA. Bivalent Covid-19 Vaccines — A Cautionary Tale. NEJM. February 9, 2023. 388:481-483. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMp2215780 [10] Wheatley AK, Fox A, Tan HX, et al. Immune imprinting and SARS-CoV-2 vaccine design. Trends Immunol. 2021;42(11):956-959. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440232/ [9] COVID-19 Forecasting Team. Past SARS-CoV-2 infection protection against re-infection: a systematic review and meta-analysis. Volume 401, ISSUE 10379, P833-842, March 11, 2023, Retrieved from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02465-5/fulltext

Health-conscious eating can begin with how we cook our food - a look at oil frying vs air frying. Culinary Medicine Nutrition and Integrative Medicine In Short By Zachary A. Knecht, PhD Crispy French fries, fried chicken, churros, fritters and fish fillets…we all know fried food is not the healthiest, but we can’t deny that there really is something about it that makes the mouths of even the most calorie-conscious among us water. When we fry food, all that hot flavorful oil penetrates the food and replaces part of its water content; tenderizing, moistening, and giving it an enhanced savory flavor and adding that unique sensorial quality that comes with the crisp-outside against soft-inside textural balance (source). Of course, as we’d prefer to forget, fried food is high in calories and can contain saturated fats, cholesterol, and potentially dangerous compounds such as acrylamide, which form during high-temperature frying (source). That’s not to mention that fried food consumption is associated with an increased risk of type 2 diabetes and coronary artery disease (source). Air frying, and the preponderance of kitchen gadgets that make it possible, have recently emerged as an alternative to traditional deep fat frying. Air fryers are essentially miniaturized convection ovens that circulate very hot air to quickly cook and crisp food. Since only a small amount of oil is needed to coat the food before cooking, air fryers claim to offer the same flavor and desirable sensory experience of deep fat frying without the nutritional detriment. Several studies have made direct comparisons between these cooking techniques so we can get a better idea of whether this is true, and the good news seems to be that, yes! Air-fried foods are at least nominally better nutritionally than deep-fried. One study found that air-fried potatoes contained an average of 70% less fat than deep-fried (source), while another found about 50% higher levels of slowly digestible starches, which help reduce rapid rises in blood sugar after eating (source). A comparison of air versus oil-fried fish also found a higher content of essential amino acids in the air-fried version (source). In addition to these benefits, air fryers are also compact, cook food quickly, and produce less mess (or potentially danger) than the large vat of hot oil needed for traditional deep-fat frying. Air-fryers thus offer convenience in addition to producing lower-calorie, more nutrient-rich fried foods. However, it should hopefully be obvious that air-fried food still contains calories from the oil and small amounts of acrylamides. Thus, ‘healthier’ is not necessarily synonymous with ‘healthy.’ You shouldn’t feel licensed to eat French fries and fried chicken 3 meals-a-day just because they were cooked in an air-fryer. Air-fried foods, just like deep-fried foods, should be consumed in moderation as part of a diet that is plentiful in fresh fruits, vegetables, and whole grains. Of course, the question that lingers as you decide whether or not to ditch the deep fryer completely: ‘does it taste as good?’ The bad news here is that less fat means less flavor, so you’ll probably be able to distinguish your greasy KFC takeout chicken from its air-fried cousin. User experiences with air fryers seem to support this (source, source). However, for someone looking to cut calories, or just wanting to be a bit more health-conscious while still enjoying some crispy fries every once and a while, an air fryer may make a great addition to your kitchen gadget repertoire. #CulinaryMedicine

Nutrition and Integrative Medicine summary article on Omega Fatty Acids. Nutrition and Integrative Medicine InReview by Madeleine Beckman Contributors- Rich Strongwater, MD and Stuart M Caplen, MD According to the 2012 National Health Interview and Nutrition Examination Survey, fish oil is one of the most commonly used nonvitamin/nonmineral dietary supplements in the United States. In 2012, 7.8 % of adults reported using fish oil supplements.[1] There are multiple reasons for people taking fish oil supplementation which include improving heart health and reducing symptoms of rheumatoid arthritis. However, definitive evidence supporting its use is lacking for some of the indications it is taken for. This article will discuss the effectiveness or lack of efficacy of both adequate omega fatty acid dietary intake as well as prescription omega fatty acid supplements. Omega Fatty acids The human body does not produce any omega-3 or omega-6 fatty acids which are considered essential polyunsaturated fats and must be obtained from dietary sources. There are three types of omega-3 fatty acids (also called n-3 fatty acids): eicosapentaenoic acid ( EPA ), docosahexaenoic acid ( DHA ), and alpha-linolenic acid ( ALA ). EPA and DHA are found in fatty fish such as wild salmon, lake trout, sardines, anchovies, striped bass, and Arctic char. ALA is the plant form of omega-3 fatty acids found in foods such as flax meal, chia seeds, walnuts, and flax seed oil. There is only limited conversion of ALA to EPA or DHA in the body. The omega fatty acids are an important part of cell membranes and affect the function of the cell receptors in these membranes. They provide the starting point for making hormones that regulate blood clotting, contraction and relaxation of artery walls, and reduce inflammation. They also bind to receptors in cells that regulate gene expression.[2,3] DHA is one of the key nutrients in the development and the maturity of the brain and eyes in utero and infancy.[4] Sources of omega-6 include vegetable oils used in cooking such as corn, safflower, sunflower, or soybean oils, as well as hydrogenated oils found in margarine and vegetable shortening, and meat from livestock animals and poultry raised on grain rather than pasture greens.[5] While some omega-6 is needed for health and normal cell membranes, it is felt that too much omega-6 can lead to a pro-inflammatory condition which may actually worsen health.[5] Omega-6 fatty acids include linoleic (LA) and arachnologic acid. LA helps with structural integrity of the skin and is a part of the lipid skin barrier. LA intake, when substituted for saturated fatty acids, reduces blood cholesterol and low-density lipoprotein (LDL)-cholesterol concentrations partially due to its inhibition of proprotein convertase subtilisin kexin type 9 (PCSK9).[6] A systematic review and meta-analysis found that the replacement of 5% of saturated fatty acids by LA was associated with a 9% reduction in coronary heart disease.[6,7] In another meta-analysis, higher levels of LA were associated with a lower risk of major cardiovascular events [6,8]. Omega-6 to Omega-3 Ratio The ratio of omega-6 to omega-3 fats in our ancestor’s diet was about 1:1 and presently in industrialized countries with the rise of the use of vegetable oils high in omega-6, the ratio of omega-6 to omega-3 is typically around 15:1 or higher, which is thought to be proinflammatory with negative effects on health.[9,10] It has been suggested that a 4:1 ratio of omega-6 to omega-3 intake may be optimal. The actual optimal ratio to target may differ depending on what condition is being treated, but there is evidence that lowering the omega-6 to omega-3 ratio can reduce cardiac mortality, decrease rectal cell proliferation in colorectal cancer patients, and lessen inflammation in patients with rheumatoid arthritis.[10] Health Benefits A multitude of possible health benefits of omega-3 fatty acids have been found in research studies. The most impressive benefits have been the findings for reducing triglyceride levels and preventing heart disease. Many disease entities have been studied to see if omega-3 fatty acid treatment will help. These include cancer prevention, Alzheimer’s disease and dementia, macular degeneration, dry eye disease, rheumatoid arthritis, infant health and development, depression, inflammatory bowel disease, childhood allergies, attention-deficit/hyperactivity disorder, and cystic fibrosis.[11,12] Heart disease There are some Cochrane Database meta-analyses on the use of fatty acids for heart disease. In 2018 one review concluded that increased use of polyunsaturated fatty acids such as omega-3 and omega-6 “probably slightly reduces risk of coronary heart disease and cardiovascular disease events, may slightly reduce risk of coronary heart disease mortality and stroke, but has little or no effect on all‐cause or cardiovascular disease mortality. The mechanism may be via triglyceride reduction.”[13] Another Cochrane review on the use of omega-3 fats concluded that while having no effect on overall mortality, increasing EPA and DHA intake slightly reduced the risk of coronary artery heart disease events and mortality, and reduces serum triglycerides. They also reported that increasing ALA may slightly reduce the risk of cardiovascular events and arrhythmias. The authors calculated the number needed to treat, based on the data, and found that 167 people would need to increase their EPA and DHA intake to prevent one coronary event and 334 people would need to increase their EPA and DHA intake to prevent one death from coronary disease. 500 people would need to increase their ALA intake to prevent one coronary event and 91 people would need to increase their ALA intake to prevent one person from having an arrhythmia.[14] Academic Performance in Children Research has also been conducted with omega-3 fatty acids and childhood- academic performance. In a trial in the European Journal of Clinical Nutrition, 239 children were randomized to receive tuna fish oil (high in omega-3 fatty acids or sunola oil (low in omega-3 fatty acids ) daily from age six months to five years. The authors concluded that their findings did not support administering fatty acids to children to improve academic performance.[15] NIH Conclusions The National Institutes of Health (NIH) has researched some of the uses of omega-3 supplementation as treatment, which are copied or summarized below.[11] Infant Health and Neurodevelopment Observational studies of maternal DHA consumption during pregnancy and breastfeeding found that eating 8 ounces per week of seafood that contains DHA is associated with better infant health outcomes. The 2015–2020 Dietary Guidelines for Americans states that women who are pregnant or breastfeeding should consume 8–12 ounces of seafood per week, choosing from varieties that are higher in EPA and DHA and lower in methyl mercury, such as salmon, herring, sardines, and trout. They should not consume king mackerel, shark, swordfish, and tilefish that are high in methyl mercury, and limit the amount of tuna they consume to 6 ounces a week. Most infant formulas in the U.S. contain DHA and arachidonic acid, however, there is currently insufficient definitive evidence supporting the positive benefits of use in infant formulas. Cancer Breast Cancer - Evidence from several observational studies suggests that higher intakes of omega-3s are associated with a lower risk of breast cancer, but more clinical trials are needed to confirm this finding. Colorectal cancer : Limited evidence from observational studies suggests that greater consumption of fish and omega-3s is associated with a reduced risk of colorectal cancer. Prostate cancer : Several prospective and case-control studies have investigated associations between either blood levels or intakes of omega-3s and risk of low-grade or high-grade prostate cancer. Results from these studies have been inconsistent, with some showing benefit and others no benefit. With respect to cancers in general, the NIH concludes that data from observational studies show no consistent relationship between omega-3s and overall cancer risk, but more studies are needed. Although some evidence suggests that higher omega-3 intake reduces the risk of breast and possibly colorectal cancers, a large clinical trial found that omega-3 supplements did not reduce the overall risk of cancer or the risk of breast, prostate, or colorectal cancers.[16] Cognitive function Omega-3 supplementation does not affect cognitive function in healthy older adults or in people with Alzheimer’s disease compared to placebo. For people with mild cognitive impairment, it may improve certain aspects of cognitive function, including attention, processing speed, and immediate recall. Age-related Macular Degeneration (AMD) Although there is some evidence dietary DHA decreased the incidence of AMD, a Cochrane review concluded that omega-3 supplementation in people with AMD does not reduce the risk of progression to advanced AMD or moderate to severe vision loss.[17] Dry Eye Disease Evidence to date shows no consistent relationship between omega-3s and dry eye disease. Rheumatoid Arthritis Findings suggest that omega-3s may be helpful as an adjunctive treatment to pharmacotherapy for ameliorating the symptoms of rheumatoid arthritis. However, more research is needed to confirm this finding. Depression A Cochrane review found insufficient evidence to determine whether omega-3s are beneficial for major depressive disorders. The authors did find a small-to-modest beneficial effect on depressive symptoms but concluded that the effect was not clinically significant.[18] Inflammatory Bowel Disease Available evidence does not support the use of omega-3 supplements to treat active or inactive inflammatory bowel disease. Childhood allergies (Including Asthma) A Cochrane review concluded that there is limited evidence to support the use of omega-3 supplements by women during pregnancy and/or lactation for reducing the risk of allergic disease in their children. Another meta-analysis concluded that the results were suggestive of a protective association between higher maternal intakes of omega-3s or fish and incidence of allergic disease symptoms in the offspring.[19] Cystic fibrosis A Cochrane review found that omega-3s might improve lung function and increase blood levels of essential fatty acids in people with cystic fibrosis, but there is not enough evidence to recommend routine use to treat cystic fibrosis patients.[20] Premature Labor One meta-analysis concluded that DHA supplementation did not decrease premature births, but resulted in a slight increase gestational latency (Time from rupture of membranes until delivery.) and birth weight.[21] Omega-3 Prescription Supplements In 2019, the FDA announced it would allow certain qualified health claims on products stating that consuming EPA and DHA omega-3 fatty acids in food or dietary supplements may reduce the risk of hypertension and coronary heart disease. However, the FDA stated that the evidence is inconsistent and inconclusive.[22] Omega 3 fatty acids (OM3FA) prescription brands made from fish oils[23] Icosapent ethyl and omega-3-acid ethyl esters are approved for adults with very high triglyceride levels (≥ 500 mg/dl) as an adjunct to diet to decrease triglyceride levels and reduce cardiovascular events. Lovaza or Omtryg (omega-3-acid ethyl esters). These contain a combination of ethyl esters of omega-3 fatty acids, principally EPA and DHA. Typical daily dose is 4 grams/day either as 4 capsules once a day with meals or two capsules twice a day with meals. Vascepa (icosapent ethyl) contains only EPA. The typical daily dose is 4 grams/day taken as two, 2-gram capsules twice a day with meals All OM3FA supplements should be taken whole without being crushed, chewed, or dissolved in the mouth. Adverse Effects [23] The FDA-approved fatty acid prescriptions are generally safe with benign side effects such as fishy taste, eructation, dyspepsia, diarrhea, gas, nausea, and arthralgia. There is a warning in the prescribing information of the omega-3-acid ethyl esters Lovaza and Omtryg of a possible association with more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first months of initiating therapy.[24,25] Contraindications [23] While omega-3 fatty acid supplements are not considered allergenic, the FDA recommends caution in patients allergic to seafood. Monitoring [23] Omega-3 fatty acids may reduce platelet activity and periodic monitoring is recommended for patients on anticoagulants or anti-platelet medications. It is recommended that the LDL cholesterol be monitored for patients taking the DHA-containing products omega-3-acid ethyl esters, due to DHA’s association with an increase in LDL cholesterol. [8] In patients with dyslipidemia, icosapent ethyl may be a better option as it has no association with increased LDL cholesterol. For patients with hepatic impairment, monitoring of the AST and ALT should be performed. In patients with paroxysmal or persistent atrial fibrillation, the prescription products containing omega-3-acid ethyl esters have a possible association with increased recurrences of symptomatic atrial fibrillation or flutter. Physicians should inquire about patients' diets to ensure proper DHA and EPA levels are achieved and fish high in methyl mercury are avoided. Toxicity [23] The FDA-approved omega-3 fatty acid prescriptions are pregnancy category C drugs, and it is unknown if the drug can cause fetal harm or can affect reproductive capacity. Methylmercury, which can be toxic, is found in some fish. Individuals who use fish as their primary source of omega-3 or pregnant and nursing women should limit their intake to two to four servings of fish a week and replace fish that are high in methyl mercury, such as swordfish, albacore tuna, dolphinfish, kingfish, and shark with fish that contain a lower amount of methylmercury, such as salmon, herring, sardines, and trout. DHA and EPA prescription supplements do not contain methylmercury. Dietary Intake Versus Prescription Supplementation of Omega Fatty Acids. It is generally recommended to get omega-3 and omega-6 from dietary sources. Supplementation in the form of medication may be beneficial for certain groups in treating specific disease entities, such as cardiac patients or those with elevated triglycerides. Supplementation may also be considered if dietary intake is inadequate, such as in pregnant or breast-feeding vegans or vegetarians, after consultation with a health care provider and a review of omega-3 dietary intake.[26] It is recommended that nursing mothers require 200 to 300 mg DHA intake per day from dietary sources with consumption of 1 to 2 portions of fish per week (such as herring, canned light tuna, or salmon) to guarantee a sufficient concentration of DHA in the breast milk and may only need to take DHA supplements if they are malnourished or on a vegan diet.[27] Adequate Intake Levels There are no recommended dietary allowances for omega-3 and omega-6 due to insufficient data. There are adequate intake (AI) levels set by the Food and Nutrition Board of the Institute of Medicine (IOM) (now called the National Academy of Medicine). There are no specific recommendations for DHA or EPA by the IOM, [11,27] Omega-3 AI levels (ALA in adults, total omega-3s under one year of age) Age Male Female Pregnancy Lactation Birth to 6 months* 0.5 g 0.5 g ​ ​ 7–12 months* 0.5 g 0.5 g ​ ​ 1–3 years** 0.7 g 0.7 g ​ ​ 4–8 years** 0.9 g 0.9 g ​ ​ 9–13 years** 1.2 g 1.0 g ​ ​ 14–18 years** 1.6 g 1.1 g 1.4 g 1.3 g ​19-50 years** 1.6 g 1.1 g 1.4 g 1.3 g 51+ years** 1.6 g 1.1 g ​ ​ *As total omega-3s **As ALA(over 1year of age) [10] Omega-6 AI levels[28] For Infants 0-6 months Omega-6 FA* Male 4.4 g Female 4.4 g Infants 7-12 months Omega-6 FA* 4.6 g 4.6 g Children 1-3 years LA** 7 g 7 g Children 4-8 years LA 10 g 10 g Children 9-13 years LA 12 g 10 g Adolescents 14-18 years LA 16 g 11 g Adults 19-50 years LA 17 g 12 g Adults 51 years and older LA 14 g 11 g Pregnancy all ages LA ----- 13 g Breast-feeding all ages LA ----- 13 g *Omega-6 fatty acids present in human milk can contribute to the AI for infants. ** LA = linoleic acid Dietary Sources of Omega-3 and Omega-6 Sources of omega-3 include: ● Fish and other seafood (salmon, mackerel, tuna, seabass, herring, sardines) ● Soybeans and edamame ● Kidney beans ● Nuts and seeds (flaxseed, chia seeds, hemp seeds, walnuts) ● Seaweed and algae ● Wheat germ ● Fortified foods (eggs, yogurt, juices, milk, soy beverages) Omega-3 Levels in Selected Foods [11] Sources of omega-6 include: ● Eggs ● Meat, Poultry ● Whole grain breads ● Cereals ● Oils, such as sunflower, safflower, sesame, grapeseed, soybean, corn ● Seeds, such as: pumpkin, sunflower ● Chickpeas and legumes ● Nuts, including pignolia (pine), almonds and pistachios Estimates of Amounts and Ratios of Omega-6 and Omega-3 in Selected Foods in gms/100gms, Unless Otherwise Indicated. ​ Omega-6 Omega-3 Omega-6:3 ratio Corn oil 49.83 0.6 83.05 Sunflower Oil ​ 49.89 0.33 151 Soybean Oil 51.36 7.6 6.76 Canola Oil 18.65 9.15 2.03 Olive Oil *see below ​ ​ ​ Salmon 0.2 2.17 0.09 Trout 0.42 .75 0.56 Broccoli 0.03 0.11 0.27 Kale (g/1 cup) 0.02 0.03 0.67 Corn (g/1 cup) 0.51 0.01 51 Walnuts 34.02 6.64 5.12 Almonds 10.54 0.3 35.13 Flax seed (g/1TBS) 0.41 1.6 0.26 Chia seed 5.84 17.83 0.32 Peanuts 17.2 .01 1,720 Chicken breast (g/4oz) 0.93 0.11 8.45 Sirloin steak (g/4oz) .23 0.04 5.75 Potato chips (g/1oz) 6.53 0.01 653 Chickpeas (g/1 cup) 1.53 0.06 25.5 Oatmeal (g/1 cup) 0.92 0.04 23 2 Eggs 1.18 0.07 16.86 2 Eggs, omega-3-enriched 1.13 0.23 4.91 [29,30] *Olive oil - The omega-6:3 ratio varies by olive species used. Most typically the ratio quoted is about 10:1 in multiple sources, but it depends on the olives used and how ripe the olives are when they are picked. (The omega-6:3 ratio ranged from about 3:1 to 21:1 in one study of Italian olives depending on the olive species.)[31,32,33] Conclusion Omega-3 and omega-6 fatty acids both appear to have some health benefits. However, when intake of omega-6 far exceeds omega-3, this may be pro-inflammatory and may reverse some of the benefits of the omega-3 anti-inflammatory effects. Pending further research some recommendations include: Obtaining omega-3 and omega-6 from food sources rather than from supplementation as much as possible, unless being treated for a specific disease process or unable to get enough from diet alone. Replacing saturated fats with omega-3 and omega-6 fatty oils, and limiting intake of very high omega-6 to omega-3 ratio oils such as corn oil and sunflower oil. Trying to decrease some omega-6 intake and maintaining a more favorable ratio of omega-6 to omega-3 intake, such as the 4:1 ratio. More information in our FibonacciCOMPENDIUM Omega-3 Fish Oil in Integrative Medicine Omega-3 Fatty Acids in Nutrition Omega-6 Fatty Acids in Nutrition References [1] Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2002–2012. National health statistics reports; no 79. Hyattsville, MD: National Center for Health Statistics. 2015. Retrieved from: https://www.cdc.gov/nchs/data/nhsr/nhsr079.pdf [2] Omega-3 Fatty Acids: An Essential Contribution. The Nutrition Source. Harvard T. H. Chan School of Public Health. 2022. Retrieved from: https://www.hsph.harvard.edu/nutritionsource/what-should-you-eat/fats-and-cholesterol/types-of-fat/omega-3-fats/ [3] Hussey B, Lindley MR, Mastana SS. Omega 3 fatty acids, inflammation and DNA methylation: an overview, Clinical Lipidology, 12:1, 24-32. 2017. Retrieved from: https://www.tandfonline.com/doi/full/10.1080/17584299.2017.1319454 [4] Li J, Pora BLR, Dong K, Hasjim J. Health benefits of docosahexaenoic acid and its bioavailability: A review. Food Sci Nutr. 2021;9(9):5229-5243. Published 2021 Jul 23. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441440/ [5] Mariamenatu AH, Abdu EM. Overconsumption of Omega-6 Polyunsaturated Fatty Acids (PUFAs) versus Deficiency of Omega-3 PUFAs in Modern-Day Diets: The Disturbing Factor for Their "Balanced Antagonistic Metabolic Functions" in the Human Body. J Lipids. 2021;2021:8848161. Published 2021 Mar 17. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990530/ [6] Djuricic I, Calder PC. Beneficial Outcomes of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on Human Health: An Update for 2021. Nutrients. 2021;13(7):2421. Published 2021 Jul 15. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308533/ [7] Farvid MS, Ding M, Pan A, et al. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation. 2014;130(18):1568-1578. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334131/ [8] Marklund M, Wu JHY, Imamura F, et al. Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality. Circulation. 2019;139(21):2422-2436. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582360/ [9] Simopoulos AP. Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases, Biomedicine & Pharmacotherapy, Volume 60, Issue 9, 2006, Pages 502-507. https://www.sciencedirect.com/science/article/abs/pii/S0753332206002435?via%3Dihub [10] Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002;56(8):365-379. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/12442909/ [11] Omega-3 Fatty Acids Fact Sheet for Health Professionals. NIH. Updated: July 18, 2022. Retrieved from: https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/ [12] Omega-3 Fatty Acids Fact Sheet for Consumers. NIH. Updated: July 18, 2022. Retrieved from: https://ods.od.nih.gov/factsheets/Omega3FattyAcids-Consumer/ [13] Abdelhamid AS et al. Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018 Nov 27;11(11):CD012345. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517012/ [14] Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020;3(3):CD003177. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049091/ [15] Brew, B., Toelle, B., Webb, K. et al. Omega-3 supplementation during the first 5 years of life and later academic performance: a randomised controlled trial. Eur J Clin Nutr 69, 419–424 (2015). Retrieved from: https://www.nature.com/articles/ejcn2014155 [16] Manson JE, Cook NR, Lee IM, et al. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 2019;380(1):23-32. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392053/ [17] John G Lawrenson, JG, Evans JR. Omega 3 fatty acids for preventing or slowing the progression of age‐related macular degeneration. Cochrane Database of Systematic Reviews. 09 April 2015. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087473/ [18]Appleton KA et al. Omega‐3 fatty acids for depression in adults. Cochrane Database of Systematic Reviews. 24 November 2021. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321518/ [19] Gunaratne AW, Makrides M. Collins CT. Maternal prenatal and/or postnatal n‐3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood. Cochrane Database of Systematic Reviews. 22 July 2015. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783748/ [20] Watson H, Stackhouse C. Omega‐3 fatty acid supplementation for cystic fibrosis. Cochrane Database of Systematic Reviews. 10 April 2020. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147930/ [21] Saccone G, Berghella V. Omega-3 supplementation to prevent recurrent preterm birth: a systematic review and metaanalysis of randomized controlled trials. American Journal of Obstetrics and Gynecology. Volume 213, Issue 2, 2015, Pages 135-140. Retrieved from: https://www.ajog.org/article/S0002-9378(15)00208-2/fulltext [22] FDA Announces New Qualified Health Claims for EPA and DHA Omega-3 Consumption and the Risk of Hypertension and Coronary Heart Disease. FDA. 06/19/2019. Retrieved from: https://www.fda.gov/food/cfsan-constituent-updates/fda-announces-new-qualified-health-claims-epa-and-dha-omega-3-consumption-and-risk-hypertension-and [23] Krupa K, Fritz K, Parmar M. Omega-3 Fatty Acids. National Library of Medicine. National Center for Biotechnology Information. StatPearls. Last Updated: September 26, 2022. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK564314/ . http://creativecommons.org/licenses/by/4.0/ [24] LOVAZA- omega-3-acid ethyl esters capsule, liquid filled. Daily Med, NIH. Updated February 24, 2021. Retrieved from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c1920576-1b04-4b20-bb00-061f09032574#LINK_c7c5c809-977a-411d-8b59-8bb779c73288 [25] OMTRYG- omega-3-acid ethyl esters capsule. Daily Med, NIH. Updated March 31, 2016. Retrieved from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5fe15bdb-f59f-4b87-8e5d-8a3d5683eb3d [26] SECTION ON BREASTFEEDING, Arthur I. Eidelman, Richard J. Schanler, Margreete Johnston, Susan Landers, Larry Noble, Kinga Szucs, Laura Viehmann; Breastfeeding and the Use of Human Milk. Pediatrics March 2012; 129 (3): e827–e841. Retrieved from: https://publications.aap.org/pediatrics/article/129/3/e827/31785/Breastfeeding-and-the-Use-of-Human-Milk?autologincheck=redirected?nfToken=00000000-0000-0000-0000-000000000000 [27] Dietary Guidelines for Americans 2020 – 2025. USDA. December 2020. https://www.dietaryguidelines.gov/sites/default/files/2021-03/Dietary_Guidelines_for_Americans-2020-2025.pdf [28] Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D. C.: National Academies Press; 2002. Retrieved from: https://nap.nationalacademies.org/read/10490/chapter/10#463 [29] Balić A et al. Omega-3 Versus Omega-6 Polyunsaturated Fatty Acids in the Prevention and Treatment of Inflammatory Skin Diseases. Int J Mol Sci. 2020;21(3):741. Published 2020 Jan 23. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037798/ [30] Omega-3 and Omega-6 Content of Commonly Eaten Foods. Algae.com. Retrieved from: https://blog.algaecal.com/wp-content/uploads/PDFCommonOmega3Foods.pdf [31] Caravita MA et al. Omega-3 / omega-6 fatty acids ratio in olive oils from Italian olive varieties. Agro Food Industry Hi Tech18(6):17-18. November 2007. https://www.researchgate.net/publication/298546476_Omega-3omega-6_fatty_acids_ratio_in_olive_oils_from_Italian_olive_varieties [32] Hernández ML, Sicardo MD, Belaj A, Martínez-Rivas JM. The Oleic/Linoleic Acid Ratio in Olive (Olea europaea L.) Fruit Mesocarp Is Mainly Controlled by OeFAD2-2 and OeFAD2-5 Genes Together With the Different Specificity of Extraplastidial Acyltransferase Enzymes. Front Plant Sci. 2021;12:653997. Published 2021 Mar 8. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982730/ [33] Kafkaletou M, Ouzounidou G, Tsantili E. 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Fruit and Vegetable Supplements InShort by Mary B Grosvenor, MS, RD and Lori A Smolin, PhD AKA Greens powder Fruit and vegetable pills and capsules Fruit and vegetable supplements are whole fruits and vegetables that have been processed to remove water; in some cases, nutrients and components are added or lost. They are sold as pills, purees, and powders. Indications Fruit and vegetable supplements are marketed to increase fruit and/or vegetable intake. Only 1 in 10 Americans eat the recommended daily amounts of fruits and vegetables. A diet high in fruits and vegetables is associated with lower risks of chronic disease including CVD, cancer, diabetes, and obesity. The Dietary Guidelines for Americans recommends adults consume 2.5 cup-equivalents of vegetables and 2 cup-equivalents of fruits per day. Contraindications May contain 300–600 mg of potassium per serving so should be avoided in those with severe renal disease or a history of hyperkalemia. Some brands may contain soy or other common food allergens. Pearls to Know These products are not a substitute for a diet high in fruits and vegetables. Because of losses that occur during processing, many do not contain all the fiber, vitamin, and minerals that were contained in the original food. They are not calorie free; the calories they provide must be considered in weight management plans. These products are sold as dietary supplements, which are not regulated by the FDA. Many are marketed as “superfoods” but there is no legal definition of this term. The serving size on the label (2 to 6 capsules) is not equivalent to a serving of fruits or vegetables. They can cost up to $100 per month, which is more than the cost of eating the recommended servings of actual fruits and vegetables. While some studies have shown specific supplements may influence cardiovascular disease predictors, such as blood pressure or body weight, and others show an increase in serum level of specific vitamins and phytochemicals, the overall effects on individual or public health are not known.. References Lee SH, Moore LV, Park S, Harris DM, Blanck HM. Adults meeting fruit and vegetable intake recommendations — United States, 2019. MMWR Morbidity and Mortality Weekly Report. 2022;71(1):1-9. doi:10.15585/mmwr.mm7101a1 U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2020-2025. 9th Edition. December 2020. https://www.dietaryguidelines.gov/resources/2020-2025-dietary-guidelines-online-materials. Accessed April 7, 2023. Stewart H, Hymen J. USDA ERS - Americans Still Can Meet Fruit and Vegetable Dietary Guidelines for $2.10-$2.60 per Day. https://www.ers.usda.gov/amber-waves/2019/june/americans-still-can-meet-fruit-and-vegetable-dietary-guidelines-for-210-260-per-day/. Published June 3, 2019. Accessed April 19, 2023. Dams S, Holasek S, Tsiountsioura M, Dams S, Holasek S, Tsiountsioura M, et al. An encapsulated fruit, vegetable and berry juice powder concentrate increases plasma values of specific carotenoids and vitamins. International Journal for Vitamin and Nutrition Research. 2021;91(1-2):77-86. doi:10.1024/0300-9831/a000609 Lorenzoni G, Minto C, Vecchio MG, et al. Fruit and vegetable concentrate supplementation and Cardiovascular Health: A systematic review from a public health perspective. Journal of Clinical Medicine. 2019;8(11):1914. doi:10.3390/jcm8111914