Explore the Timeless Appeal and Health Benefits of Tomatoes, the Quintessential Taste of Summer. An average tomato contains a gram each of protein and fiber, no fat, and only a small amount of carbohydrate, most of which is sugar. Tomatoes are a reliable source of vitamin C, vitamin A, folate, vitamin K, and potassium.  They are also high in carotenoid phytochemicals including beta-carotene, lycopene, and lutein. Culinary Medicine by Lori A Smolin, PhD and Mary B Grosvenor, MS, RD Nothing says summer like ripe, juicy home-grown tomatoes. With 10,000 varieties to choose from, they are among America’s top vegetable choices. [1,2] They come in a rainbow of colors from golden to purple and range in size from tiny ones the size of a marble to giant ones bigger than your fist. Tomatoes are technically fruit – an edible berry – but we generally eat them as a vegetable in salads and on sandwiches. We also eat them canned and processed; 60 percent of the tomatoes we eat are consumed in foods such as sauces, beverages, soups, ketchup, pizza, and spaghetti sauce. Whether fresh or cooked, they provide flavor, nutrition, and health benefits. How Tomatoes Went Global Tomatoes were grown in South America as early as 700 BCE. [3] The plant eventually made it north into Mexico and then to Europe in the 1500s. Along their journey, tomatoes were known by many different names ranging from golden apple and love apple to wolf peach and poison apple. [2] Although tomatoes were eaten by indigenous peoples in the Americas, in Europe they were initially grown as an ornamental plant because people thought the fruit was poisonous. Tomatoes are a member of the nightshade family of plants, which contain potentially harmful chemicals called alkaloids. Belladonna, for example, is a nightshade that was used by the ancients as a poison, and by fortune tellers and witches to cause hallucinations. [4]  Tomatoes, however, do not contain enough of these alkaloids to be harmful. [5,6] Nonetheless, the myth of poison tomatoes was perpetuated into the 18th century, in part because some European aristocrats died after consuming them. These deaths were not actually due to the tomatoes, but rather to the pewter plates they were served on. Pewter is high in lead and the acidity of the tomatoes leached lead from the dinnerware, causing lead poisoning among the diners. [1,2]   The consumption of tomatoes was eventually bolstered in Europe by the invention of pizza in Naples, Italy in 1880. [3] Tomatoes made their way back to the Americas with colonists in the early 1700s, but popularity there did not become widespread until the early 1900s. [1,2] Today, tomatoes are the most popular homegrown vegetable; annual consumption in the United States is over thirty-one pounds per person. [1,7]  Nutrients and Phytochemicals Tomatoes have been called a superfood because of their nutritional benefits. They are low in calories; an entire large tomato has only about 20 Calories. An average tomato (2.6 inches) contains a gram each of protein and fiber, no fat, and a small amount of carbohydrate, most of which is sugar. Tomatoes are a reliable source of vitamin C, vitamin A, folate, vitamin K, and potassium.  They are also high in carotenoid phytochemicals including beta-carotene, lycopene, and lutein. Beta-carotene is a red-orange pigment that functions as an antioxidant and can be converted into vitamin A in the body. Lycopene is a red pigment that is an even more potent antioxidant than beta-carotene and has anti-inflammatory effects. [8] Lutein is best known for its ability to protect the eye from light-induced damage. Lutein also provides color to food ranging from yellow to red depending on its concentration. Tomatoes and Health Many of the health benefits of tomatoes and tomato products are attributed to their antioxidant content. Antioxidants protect us from conditions associated with oxidative stress and chronic inflammation such as macular degeneration, neurological and skin disorders, diabetes, cardiovascular disease, and cancer. A diet high in antioxidants can help reduce the risks of these conditions.  Age-related macular degeneration and cataracts are ophthalmic disorders associated with oxidative stress. [7,9]  Lutein, a dietary antioxidant in tomatoes, has been shown to protect against the development of both. The neurodegenerative diseases Alzheimer’s and Parkinson’s are also associated with oxidative stress. Although animal and laboratory studies studies have shown that the pathological changes seen in these are ameliorated with lycopene and tomato extract, few human studies have shown a protective role. [7] The nutrients and phytochemicals in tomatoes may contribute to skin health both by reducing the symptoms of inflammatory skin disorders and by protecting the skin from UV radiation. While tomatoes are a healthy food choice for people with diabetes, there is little evidence supporting a protective effect in diabetes. [7]  The antioxidants in tomatoes have been most extensively studied for their ability to protect against cardiovascular disease and cancer. [7] Lycopene has been shown to reduce the risk of atherosclerosis by inhibiting the oxidation of LDL cholesterol as well as by reducing inflammation, platelet aggregation, and blood pressure. [7,8] High intake and high blood levels of lycopene are associated with a lower risk of cardiovascular disease. [10] One study found that even a single serving of tomatoes, consumed raw, as sauce, or as sauce with olive oil, reduced total cholesterol and triglyceride levels and increased HDL cholesterol levels; the greatest effect occurred when the tomatoes were consumed as sauce with olive oil. [11] Lycopene and other antioxidants in tomatoes have been suggested to guard against cancer by protecting DNA and proteins from oxidative damage. High intakes of tomatoes and lycopene are associated with a lower cancer mortality. [7,12] While lycopene has been studied in a variety of cancers, the greatest benefit was found with prostate cancer. Human observational studies have found lycopene intake to be correlated with a reduced risk of prostate cancer, but more study is needed to recommend a specific amount. [13]  Despite all these benefits, for some individuals tomato consumption can cause significant side effects. The acidic nature of tomatoes may worsen acid reflux or gastroesophageal reflux disease (GERD). The insoluble fiber in tomato skin may be difficult to digest resulting in abdominal pain or diarrhea. Individuals with a sensitivity to nightshades may develop skin irritation, joint pain, and increased inflammation with tomato consumption. Tomatoes can also cause allergic reactions. The most common reaction is irritation of the lips, tongue, pharynx; symptoms can also include irritation of the lower gastrointestinal tract and, in rare cases, anaphylactic reactions. [14] Some individuals with an intolerance to tomatoes only react to fresh tomatoes and can consume processed tomato products. Those allergic to tomatoes should avoid them altogether. Maximizing Tomato Flavor and Nutrition Not all tomatoes are the same. Different varieties have different gastronomic traits and nutritional properties. How they are grown and stored also affects their flavor. Tomatoes you buy in the grocery store typically look beautiful but often do not have the juicy sweet flavor of those plucked from a garden. This is because commercial tomatoes have been bred to ripen to a homogeneous color; the unintended consequence of this genetic variant is that they have less sugar and less flavor. [15] Another reason grocery store tomatoes do not taste as good as home grown is they are picked green and ripened artificially with ethylene gas. Tomatoes naturally produce ethylene gas, which causes them to slowly redden and ripen. Gassing green tomatoes forces them to turn red quickly, but not to develop flavor. If you grow them in your garden, you can leave them on the vine until they are completely ripe or harvest them just when they are starting to color – they will ripen on the kitchen counter. For the best flavor, store ripe tomatoes at room temperature. You can refrigerate the unripe ones until you want them to ripen; the refrigeration puts ethylene gas on hold. [16] The type of tomato also affects its nutrient and phytochemical content. Most tomatoes have similar amounts of potassium and vitamin C; green tomatoes are lower in vitamin A. Because the carotenoids in tomatoes are pigments, different colored tomatoes provide different amounts of certain phytochemicals. Yellow tomatoes, often sought for their sweeter and less acidic flavor, do not contain much lycopene. Orange tomatoes are also sweeter and less acidic but do contain lycopene in a form that is better absorbed than the lycopene in red tomatoes. [17]  Purple and black varieties are the best sources of lycopene, lutein, and beta-carotene but are often rejected because consumers are put off by the color. [18]   How tomatoes are prepared affects their nutritional value. The tomato skin is the most concentrated source of lycopene, so you can maximize lycopene by keeping the skin on when eating or cooking tomatoes. Cooking increases the bioavailability of lycopene and concentrates it by cooking off the water. What you eat with your tomatoes also affects how much lycopene you absorb. Like other carotenoids, lycopene is fat soluble, so it is absorbed better when fat is included in the meal. So, drizzle some olive oil on your fresh tomatoes and add it to cooked sauces.  Bottom Line  A diet rich in tomatoes, whether from fresh, cooked, or processed, boosts your vitamin, mineral, and phytochemical intake, and may even reduce your risk of a variety of chronic diseases. Add your favorites to salads, sandwiches, and casseroles. Whether cherry, plum, Campari, Brandywine, beefsteak, Roma, or any of the thousands of varieties, tomatoes will add a sweet tart taste, complexity, color, and a lot of nutrition to your diet, along with the flavor of summer. Try our Fresh, Flavorful, and Healthy: Marinated Cucumber and Tomato Salad Recipe - A Perfect Summer Salad References [1] USDA Economic Research Service. Potatoes and Tomatoes are the Most Commonly Consumed Vegetables. US per capita loss-adjusted vegetable availability, 2019. https://www.ers.usda.gov/data-products/chart-gallery/gallery/chart-detail/?chartId=58340 . Accessed May 10, 2024. [2]  Benoit DJ. A History of Tomatoes, The University of Vermont. February 8, 2023: https://www.uvm.edu/news/extension/history-tomatoes#:~:text=Tomato%20seeds%20were%20brought%20from,primarily%20as%20an%20 ornamental%20 plant. Accessed May 10, 2024. [3] K. Annabelle Smith. Why the Tomato Was Feared in Europe for More Than 200 Years. Smithsonian. Published June 18, 2013. https://www.smithsonianmag.com/arts-culture/why-the-tomato-was-feared-in-europe-for-more-than-200-years-863735/ [4]  The Supernatural Side of Plants – CornellBotanicGardens. cornellbotanicgardens.org . https://cornellbotanicgardens.org/the-supernatural-side-of-plants-2/ ‌ [5] Zelman K What to Know About Nightshade Vegetables. WebMD. Published April 8, 2021. https://www.webmd.com/diet/what-to-know-about-nightshade-vegetables ‌ [6]  Dolan LC, Matulka RA, Burdock GA. Naturally Occurring Food Toxins.  Toxins . 2010;2(9):2289-2332. doi: https://doi.org/10.3390/toxins2092289 ‌ [7] Collins EJ, Bowyer C, Tsouza A, Chopra M. Tomatoes: An Extensive Review of the Associated Health Impacts of Tomatoes and Factors That Can Affect Their Cultivation. Biology. 2022; 11(2):239. https://doi.org/10.3390/biology11020239 [8]  Khan UM, Sevindik M, Zarrabi A, et al. Lycopene: Food Sources, Biological Activities, and Human Health Benefits.  Oxidative Medicine and Cellular Longevity . 2021;2021:2713511. doi: https://doi.org/10.1155/2021/2713511 ‌ [9]  Johra FT, Bepari AK, Bristy AT, Reza HM. A Mechanistic Review of β-Carotene, Lutein, and Zeaxanthin in Eye Health and Disease. Antioxidants. 2020; 9(11):1046. https://doi.org/10.3390/antiox9111046 [10] Cheng HM, Koutsidis G, Lodge JK, Ashor AW, Siervo M, Lara J. Lycopene and tomato and risk of cardiovascular diseases: A systematic review and meta-analysis of epidemiological evidence.  Critical Reviews in Food Science and Nutrition . 2017;59(1):141-158. doi: https://doi.org/10.1080/10408398.2017.1362630 ‌ [11]  Valderas-Martinez P, Chiva-Blanch G, Casas R, et al. Tomato Sauce Enriched with Olive Oil Exerts Greater Effects on Cardiovascular Disease Risk Factors than Raw Tomato and Tomato Sauce: A Randomized Trial.  Nutrients . 2016;8(3):170. doi: https://doi.org/10.3390/nu8030170 ‌ [12]  Mazidi M, Ferns GA, Banach M. A high consumption of tomato and lycopene is associated with a lower risk of cancer mortality: results from a multi-ethnic cohort.  Public Health Nutrition . 2020;23(9):1569-1575. doi: https://doi.org/10.1017/S1368980019003227 ‌ [13]  Kapała A, Szlendak M, Motacka E. The Anti-Cancer Activity of Lycopene: A Systematic Review of Human and Animal Studies.  Nutrients . 2022;14(23):5152. doi: https://doi.org/10.3390/nu14235152 [14] Włodarczyk K, Smolińska B, Majak I. Tomato Allergy: The Characterization of the Selected Allergens and Antioxidants of Tomato (Solanum lycopersicum)—A Review.  Antioxidants . 2022;11(4):644. doi: https://doi.org/10.3390/antiox11040644 ‌ [15]  Powell ALT, Nguyen CV, Hill T, et al. Uniform ripening encodes a Golden 2-like transcription factor regulating tomato fruit chloroplast development.  Science (New York, NY) . 2012;336(6089):1711-1715. doi: https://doi.org/10.1126/science.1222218 [16] Russell A. Pick tomatoes at color break. AgriLife Today. Published June 10, 2022. Accessed June 3, 2024. https://agrilifetoday.tamu.edu/2022/06/10/pick-tomatoes-at-color-break ‌ [17]  Robinson J. Lycopene in Orange Tomatoes – Mother Earth News. www.motherearthnews.com . https://www.motherearthnews.com/natural-health/lycopene-in-tomatoes-zmgz16fmzsto/#:~:text=Orange%20tomatoes%20contain%20a%20different [18]  Woodstream W. Which Tomatoes Are the Healthiest to Grow? www.saferbrand.com .  https://www.saferbrand.com/articles/which-tomatoes-are-the-healthiest-to-grow ‌

Diagnosis and Treatment of Mosquito-Borne Dengue Illness Infectious Disease by Stuart M Caplen, MD On March 26, 2024 Puerto Rico declared a dengue epidemic after having 549 cases, including 341 hospitalizations and 29 severe cases year to date through March 10th.[2] No other animal infects and causes disease as effectively as mosquitos, which are the deadliest animals in the world to humans.  Infections caused by mosquitos kill over 700,000 people a year.[3]  In this article we will look at mosquito borne dengue virus illness. Dengue Dengue viruses are Flaviviruses, transmitted through the bite of infected Aedes aegypti or Aedes albopictus mosquitos.  Dengue is caused by one of four related viruses: Dengue virus 1, 2, 3, and 4.  For this reason, a person can be infected as many as four times with the different dengue viruses.[6] The history of dengue is not well known, but a dengue-like outbreak in humans was recorded in a Chinese medical encyclopedia in 992.  In the 1700s dengue was known as breakbone fever.  Queen Luisa of Spain used the word dengue while writing about her recovery from it in 1801.  No one is sure about dengue’s etymology, but the word dengue in Spanish means affectation, or careful, and may have described the stiff, painful movements of people with dengue fever.  Another theory is that the name came from a Swahili phrase “Ka dinga pepo”, or “disease caused by an evil spirit”.[7] Dengue is common in more than 100 countries around the world.  About three billion people live in endemic areas, and every year up to 400 million people get infected with dengue, approximately 100 million people get symptomatic illness, and 22,000 die from severe dengue.[7] Dengue is common in the U.S. territories of Puerto Rico, the U.S. Virgin Islands, and American Samoa.  Nearly all dengue cases reported in the U.S. mainland are from travelers infected elsewhere.  In 2023, there were 2,890  cases of dengue reported in the U.S. including Puerto Rico.[8]  Dengue is a frequent cause of infection in Central and South America, East Africa, Southeast Asia and the Pacific Islands.[9]  World Health Organization(WHO) Clinical Dengue Definitions [10] Dengue is defined by a combination of ≥2 clinical findings in a febrile person who traveled to, or lives in a dengue-endemic area.  Clinical findings include nausea, vomiting, rash, aches and pains, a positive tourniquet test, leukopenia, or the following warning signs which may predict severe dengue: abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, restlessness, and liver enlargement.   Severe dengue is defined as dengue with any of the following symptoms: severe plasma leakage leading to shock or fluid accumulation with respiratory distress; severe bleeding; or severe organ impairment such as elevated liver transaminases ≥1,000 IU/L, impaired consciousness, or heart impairment.  Dengue Clinical Disease and Treatment[10] Most dengue infections are asymptomatic, with only 25% of dengue virus infections estimated to be symptomatic.  It commonly presents as a mild to moderate, nonspecific, acute febrile illness.  Approximately 5% of patients with dengue progress to severe dengue, a life-threatening disease.  The early clinical findings of severe dengue are nonspecific, but recognizing early signs of shock, and promptly initiating intensive care unit therapy can reduce the risk of death to <0.5%. A study of antibody dependent enhancement of dengue in children, found that the level of serum antibodies from a first infection determined the risk of severe dengue disease on reinfection.  The presence of high dengue antibody titers in an individual are protective, but people with intermediate antibody titers had a much higher likelihood of developing severe dengue, even greater than those with low antibody titers.  In that study the chances of getting severe dengue during a second infection was 1.6% in the high antibody titer group, 11.4% in the intermediate antibody titer group, and 6.6% in low antibody titer group.  It is thought that particularly with intermediate dengue antibody titers, some binding of antibodies to the dengue virus occurs, but the antibody does not necessarily neutralize the virus.  This creates a virus-antibody complex that appears to facilitate viral entry into host cells, and can trigger an immune cascade that leads to severe dengue.  This is felt to be the reason why a dengue re-infection with a different strain, or first infection after dengue vaccination, may increase the risk of contracting severe dengue.[11] Dengue begins abruptly after a typical incubation period of five to seven days, and has three phases: febrile, critical, and convalescent or recovery. Febrile Phase The febrile phase lasts two to seven days and can be biphasic.  Other signs and symptoms may include severe headache, retro-orbital eye pain, muscle, joint, bone pain, and/or a macular (reddened and flat) or maculopapular ( reddened flat with some raised areas) rash.  Some patients have an injected oropharynx and facial erythema (redness) the first 24–48 hours after onset.  Bleeding may occur from thrombocytopenia (low platelets), or in more ill patients from a coagulopathy (blood clotting disorder).  Thrombocytopenia results from transient bone marrow suppression, and increased peripheral destruction of platelets in dengue.[13]  In this phase, patients may have minor hemorrhagic manifestations such as ecchymosis(blood vessel leakage under the skin over 1 centimeter ), purpura (blood vessel leakage between 4 and 10 millimeters), epistaxis (nosebleeds), bleeding gums, or hematuria (bloody urine).  Petechiae (blood vessel leakage less than 4mm) may occur, and a positive tourniquet test may aid in the diagnosis of dengue.  A positive tourniquet test result is ten or more petechiae per one square inch in the arm, after inflating a blood pressure cuff halfway between the systolic and diastolic pressures for two minutes.[14]   Critical Phase The critical phase of dengue begins at defervescence, and typically lasts 24–48 hours.  Most patients clinically improve during this phase, but there can be substantial plasma leakage due to a marked increase in vascular permeability.  Patients with severe plasma leakage and third spacing may have pleural effusions, ascites, hypoproteinemia, or hemoconcentration.  Liver enlargement may occur.[13]  Once hypotension develops, irreversible shock and death may ensue despite resuscitation.  Patients can also develop severe hemorrhagic manifestations such as hematemesis (vomiting blood), bloody stools, or menorrhagia (heavy menstrual bleeding).  Increased activated partial thromboplastin time (APTT), and a reduction in fibrinogen levels may be seen in severe dengue.[13]  Uncommon complications include myocarditis, pancreatitis, and encephalitis. Convalescent/Recovery Phase [10] In severe dengue, as plasma leakage and third spacing subsides, the patient enters the convalescent or recovery phase, and begins to reabsorb extravasated intravenous fluids, pleural effusions and ascites.  As a patient’s hemodynamic status stabilizes there is a significant diuresis of the excess extracellular fluid.  The patient’s hematocrit stabilizes, or may fall because of the dilutional effect of the reabsorbed fluid, and the white cell count usually starts to rise, followed by a recovery of platelet count.  In the convalescent-phase rashes may desquamate (flake off) and become pruritic (itchy). Dengue and Pregnancy [6] There is limited data about dengue during pregnancy.  Perinatal transmission can occur, and maternal infection may increase the likelihood of symptomatic infection in the newborn.  In 41 perinatal transmission cases to fetuses described in the literature, all developed thrombocytopenia, most had evidence of plasma leakage typically with ascites or pleural effusions, and 39 were febrile.  Nearly 40% had a hemorrhagic manifestation, and 25% were hypotensive at some point.  Perinatally infected neonates typically become ill during the first week of life.  Placental transfer of maternal dengue IgG antibodies from a previous infection does occur, but when the protective effect of these antibodies wanes, infants 6–12 months of age are at risk for severe dengue. Laboratory Findings and Testing [15] Laboratory findings commonly include leukopenia, thrombocytopenia, hyponatremia (low blood white cells, platelets and sodium respectively), elevated aspartate aminotransferase and alanine aminotransferase (liver enzymes), and in the majority of cases, a normal erythrocyte sedimentation rate (marker of inflammation).[17] During days one to seven after symptom onset, dengue virus RNA can be detected with molecular tests, such as an RT-PCR(reverse transcriptase polymerase chain reaction).  NS1 is a dengue virus protein that also can be detected by some commercial tests.  An IgM antibody level should also be drawn.  A negative result from a molecular, NS1, or IgM antibody test is not conclusive.  After seven days post symptom onset, patients with initially negative RT-PCR, NS1,and IgM (immunoglobulin M) antibody tests from the first seven days of illness should have a convalescent sample tested for IgM antibodies.  During the convalescent phase, IgM antibodies are usually present and can be reliably detected.  IgM antibodies against dengue virus can remain detectable for 3 months or longer after infection. If a PCR or NS1 test is positive for dengue, a current dengue diagnosis is confirmed.  If the PCR result is negative and the IgM antibody test is positive, the laboratory diagnosis is presumptive dengue virus infection. Cross reactivity with other flaviviruses such West Nile, yellow fever, and Zika, is a limitation of dengue IgM antibody tests.  Therefore, a patient with past flavivirus infection(s) may be falsely test positive for dengue virus IgM antibodies.  To determine if dengue is causing the infection, IgM positive specimens should be tested for specific neutralizing antibodies by a plaque reduction neutralization test (PRNT).   Whenever a pregnant woman is tested for dengue, it is recommended Zika also be tested for using an RT-PCR test, as they may present similarly.  Treatment[18] No specific antiviral agents or treatments exist for dengue.  Supportive care is recommended and patients should try to stay well hydrated, and avoid aspirin and other NSAIDS because of their anticoagulant properties.  Fever can be controlled with acetaminophen and possibly tepid sponge baths.  Febrile patients should avoid mosquito bites to reduce risk of further transmission to other people. In severe dengue, ICU care may be required.  Prophylactic platelet transfusions in dengue patients are not beneficial, and may contribute to fluid overload.  Administration of corticosteroids has not demonstrated any benefit, except in the case of autoimmune-related complication such as immune thrombocytopenia purpura. A vaccine to prevent dengue, Dengvaxia, administered in three doses six months apart, is licensed and available in some countries for people aged 9-45 years old.  The WHO recommends that the vaccine only be given to people with confirmed prior dengue virus infection, as previously uninfected people who are vaccinated and then get dengue have a higher chance of developing severe dengue.  In 2019, Dengvaxia was FDA approved for use in children 9-16 years old, with laboratory confirmed prior dengue virus infection, living in an endemic area such as the U.S. territories of American Samoa, Guam, Puerto Rico or the U.S. Virgin Islands.[19] #InfectiousDisease #mosquito #DengueFever CME article on 4 Mosquito-Borne Virus: Zika, Dengue, Chikungunya, and West Niles References [1]Dengue Virus and Dengue, Clinical Case Management E-learning, Transmission of DENV.  CDC  Version1.3, July 2018.  Retrieved from: https://www.cdc.gov/dengue/training/cme/ccm/page45901.html   [2] Malhi S. Puerto Rico declares an epidemic after dengue cases spike. What you need to know. The Washington Post. March 27, 2024. Retrieved from: https://www.washingtonpost.com/health/2024/03/27/puerto-rico-dengue-fever-epidemic/ [3] Nuwer R.  Mosquitoes Kill More Humans Than Human Murderers Do.  SMITHSONIANMAG.COM .  April 30, 2014.  Retrieved from: https://www.smithsonianmag.com/smart-news/mosquitoes-kill-more-humans-human-murderers-do-180951272/ [4] Dengue Clinical Case Management E-learning, Immunity.  CDC  Version1.3, July 2018.  Retrieved from: https://www.cdc.gov/dengue/training/cme/ccm/page45893.html [5] Photo by Frederick Murphy.  CDC.  2012.  Retrieved from: https://phil.cdc.gov/Details.aspx?pid=12493 [6] About Dengue: What You Need to Know. CDC. Last reviewed: May 3, 2019.  Retrieved from: https://www.cdc.gov/dengue/about/index.html [7] Lobo IA.  What Is Dengue Fever?  Sciable by Nature Education.  January 17, 2014. Retrieved from: https://www.nature.com/scitable/whatisscitable/ [8]Statistics and Maps – 2019, Dengue cases in the US.  CDC.  Last reviewed: March 13, 2020.  Retrieved from: https://www.cdc.gov/dengue/statistics-maps/2019.html [9] Dengue Around the World. CDC. Last reviewed: September 21, 2023.  Retrieved from: https://www.cdc.gov/dengue/areaswithrisk/around-the-world.html [10] Dengue, Clinical Presentation. CDC. Last reviewed: May 3, 2019. Retrieved from: https://www.cdc.gov/dengue/healthcare-providers/clinical-presentation.html [11] Katzelnick LC et al. Antibody-dependent enhancement of severe dengue disease in humans.  Science Vol. 358, Issue 6365, pp. 929-932.  Nov 17, 2017. Retrieved from: https://science.sciencemag.org/content/358/6365/929 [12] Dengue Virus and Dengue, Clinical Case Management E-learning, Transmission of DENV.  CDC  Version1.3, July 2018.  Retrieved from: https://www.cdc.gov/dengue/training/cme/ccm/page47443.html [13]Guzman M et al.  Dengue Infection.  Nature reviews disease primers.   August 18, 2016.  Retrieved from: https://www.nature.com/articles/nrdp201656 [14] Dengue Virus and Dengue, Clinical Case Management E-learning, Tourniquet Test.  CDC  Version1.3, July 2018.  Retrieved from: https://www.cdc.gov/dengue/training/cme/ccm/page73112.html [15]Dengue, Testing Guidance. CDC. Last reviewed: January 24, 2020.  Retrieved from: https://www.cdc.gov/dengue/healthcare-providers/testing/testing-guidance.html [16]Dengue Virus and Dengue, Clinical Case Management E-learning, Laboratory Findings — Critical Phase.  CDC  Version1.3, July 2018.  Retrieved from: https://www.cdc.gov/dengue/training/cme/ccm/page55886.html [17]de Souza LJ et al. Alteration in the erythrocyte sedimentation rate in dengue patients: analysis of 1,398 cases.  Braz J Infect Dis 12 (6).   Dec 2008.  Retrieved from: https://www.scielo.br/j/bjid/a/ChvxMq6g3JtMBdKdBSGPTwH/?lang=en [18]Dengue, Treatment. CDC. Last reviewed: May 3, 2019. Retrieved from: https://www.cdc.gov/dengue/healthcare-providers/treatment.html [19]Dengue, Prevention.  CDC. Last reviewed: May 20, 2022. Retrieved from: https://www.cdc.gov/dengue/healthcare-providers/hc-providers-prevention.html initially posted July 2023

In a study published May, 2024 a French infertility clinic measured glyphosate levels in the blood and semen of males who presented for infertility testing. Glyphosate (GLY) is the active component of glyphosate-based herbicides, which are some of the most commonly used herbicides in the world.  Glyphosate-based herbicides were approved in the U.S. in 1974 by the EPA and in 2002 by the European Commission for use in Europe. GLY was detected in 56% of the subjects and the levels in semen were four times that found in blood.  The authors reported that they could not find any adverse effects on sperm motility, concentration, or morphology.  However, they did find markers of increased oxidative stress in both blood and semen in subjects who had elevated GLY levels compared to controls.  Oxidative stress is postulated to impair sperm quality and results from the accumulation of reactive oxygen species, such as oxygen free radicals, which can cause cellular damage to tissues.  Oxidative stress, in other research, has been implicated in the development of some cancers. GLY blood and semen levels did not significantly differ in subjects living in the city versus those living in the countryside.  There was also no significant difference in GLY levels in those that ate organic food compared to those that didn’t.  Smokers were found to have higher GLY levels than nonsmokers. The authors suggested that it might be interesting for future research to see if lifestyle changes or antioxidant therapy might be of help to reduce oxidative stress in infertile males. Comments: This is the first published study specifically looking for glyphosate in semen, and documented it in 56% of the men tested.  Even more concerning was that that the levels were four times higher in semen than in blood.  There has been a global decline in fertility rates and semen quality over the last few decades.  It is thought chemical exposures such as pesticides and herbicides may be part of the problem. This study, although it did not report specific negative effects on sperm motility, morphology, or concentration, did find evidence of increased oxidative stress in the blood and semen of subjects with elevated GLY levels.  In animal studies, GLY has been found to reduce sperm quality and also can create changes in gene expression (called epimutations) that can be passed on to descendants. This study is a stark reminder that chemicals used routinely in the environment eventually may end up in our bodies with potentially negative health effects. Resources Vasseur C, Serra L, El Balkhi S, et al. Glyphosate presence in human sperm: First report and positive correlation with oxidative stress in an infertile French population. Ecotoxicol Environ Saf. Published online May 1, 2024. Retrieved from: https://www.sciencedirect.com/science/article/pii/S014765132400486X?via%3Dihub Chang VC, Andreotti G, Ospina M, et al. Glyphosate exposure and urinary oxidative stress biomarkers in the Agricultural Health Study. J Natl Cancer Inst. 2023;115(4):394-404. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086635/ Kubsad, D., Nilsson, E.E., King, S.E. et al. Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology. Sci Rep 9, 6372 (2019). Retrieved from: https://www.nature.com/articles/s41598-019-42860-0#citeas

How much and what should I drink to stay hydrated? by Mary B Grosvenor, MS, RD and Lori A Smolin, PhD As our climate continues to change, we are experiencing more and more sweltering days each summer. When temperatures rise, we sweat. The evaporation of sweat is cooling but also causes water to be lost from our body. If we do not replace what we lose, we become dehydrated; blood volume decreases and with it the body’s ability to function. Dehydration symptoms can occur with a water loss of as little as one percent of body weight and a loss of ten percent of water can be deadly. [1]  As heat waves become hotter and more frequent more people are affected, both in terms of comfort and health. To stay healthy in the summer heat, stay hydrated by knowing how much and what to drink. Why Is Staying Hydrated So Important? Water is vital for life. All the chemical reactions that occur in our bodies take place in water. Water delivers oxygen and nutrients to cells and removes waste products. It is needed to regulate acid-base balance, provide lubrication and protection, and regulate body temperature. Normal body temperature is around 98.6°F (37°C). If it rises above 108°F, death is likely. Water helps maintain a normal body temperature in a number of ways. It holds heat and changes temperature slowly, helping to keep body temperature constant when the outside temperature fluctuates. The water in blood affects the amount of heat lost from the surface of the body. When body temperature rises, the blood vessels in the skin dilate, causing blood to flow close to the surface where it can release heat to the environment. The water lost in sweat helps to cool the body by evaporation; excess body heat is used to convert beads of sweat into vapor. Water Ins and Outs The human body is about 60% water, but this fluctuates as we gain and lose water throughout the day. We take in water from water and other fluids we drink as well as from foods we eat. Juices, sports drinks, broth, soup, and milk contribute to fluid needs; even coffee, tea, and other caffeinated beverages contribute to your daily water intake. [2] Although it is often suggested that caffeinated beverages have a negative impact on hydration status, the diuretic effects are minimal in individuals who regularly consume caffeine, so the net amount of water that caffeinated beverages contribute is similar to noncaffeinated beverages. [3] Alcohol is also a diuretic so alcoholic beverages are not recommended for hydration, but the overall effect of alcohol consumption on fluid balance depends on the relative amounts of water and alcohol consumed. So, on a hot day, enjoying beer with less than 4% alcohol and alternating your beer with water is unlikely to negatively impact your hydration. [4,5] Whole fruits and vegetables also contribute a significant amount of water; watermelon, lettuce, and tomatoes are over 90% water, apples and pears are about 85% water. We lose water from the body in urine, about 4 to 8 cups per day, and feces, about ½ cup per day. We also lose about four cups of water daily through evaporation from our lungs and skin. When we are active, or the temperature is high, we lose water in sweat. An average adult doing light work at an ambient temperature of 84°F loses about ten cups of water per day in sweat. Strenuous activity in a hot environment can dramatically increase these sweat losses to more than six cups per hour. [6] Dehydration Early symptoms of dehydration include fatigue, dry mouth, thirst, and headache. As the kidneys work to conserve water, urination becomes less frequent, and the urine becomes darker in color. The fatigue and discomfort of dehydration can lead to irritability and difficulty with cognition, memory, and concentration. [7] Chronic mild dehydration can impair health by increasing the risk of kidney stones, urinary tract infections, high blood pressure, and stroke. [8]  If dehydration becomes severe confusion, fainting, an inability to urinate, rapid breathing, and increased heart rate occur. These symptoms signal a potentially life-threatening condition, and oral fluids may not be enough to restore hydration; medical attention and intravenous fluids are needed. The risk of dehydration increases as the environmental temperature rises. Risks are particularly high in infants, older adults, and in those who are active in the heat. Infants are at risk because their kidneys cannot concentrate urine efficiently and, due to their small body size, they lose proportionately more water through evaporation. In older adults, thirst sensation and kidney function decrease, potentially reducing water intake and increasing urinary losses. The risk is further increased in those with conditions such as diabetes and kidney disease that can increase urinary water losses and in those taking diuretics or other medications that increase urination. Individuals who exercise or work outdoors in the heat are at risk because they may lose large amounts of water in sweat. How Much and What Should You Drink? The recommended fluid intake for adults is about eleven cups per day for women and sixteen cups per day for men. (This represents overall fluid intake per day, including anything you eat or drink that contains water, such as fruits or vegetables.) [9] But this amount can vary greatly depending on body size, environmental temperature, and activity level. Larger individuals need more water than smaller ones. Men typically have higher water needs than women because they have larger bodies and more muscle, which requires more water to maintain than fat. Temperature has a significant impact on water needs. When it is hot we need more water to replace the water we lose in sweat and through evaporation. Activity further increases sweat losses; water needs can triple with activity in very hot weather. [9] To stay hydrated when working or exercising in a hot environment, you need to drink about one cup every 15 to 20 minutes  (3-4 cups per hour) for the duration of the work or exercise. The sensation of thirst helps motivate us to drink but relying on thirst alone may not be enough to maintain a healthy body water level in all situations. You can assess your hydration by checking the color of your urine. If you are consuming enough, your urine will be a pale-yellow color; darker urine can indicate dehydration.  Another indicator of hydration is weight loss. The goal is to drink enough to prevent more than a 2% loss of total body weight as water; this would be about three pounds for a 150 lb. person. While most of us do not weigh ourselves over the course of the day, this method is often used by athletes exercising in the heat. [10,11] The best fluid to keep you hydrated on a hot day is water. It is absorbed quickly and contains no calories or added sugars. When exercising or working in the heat for longer than 45 minutes, sports drinks may be helpful. They contain carbohydrates to fuel your activity and electrolytes to replace losses that may occur in sweat. While salt tablets were once promoted to maintain hydration, these are no longer recommended in most cases. Small snacks consumed with plenty of water can provide energy and replace lost electrolytes. It is uncommon for a healthy adult to drink too much water, but this can occur usually following extensive intense physical activity, such as military training or marathon running. Fluid intake should be limited to no more than 1.5 quarts per hour; excess fluid can cause a life-threatening electrolyte imbalance. [11] The Bottom Line When it is hot, we need to drink more to prevent dehydration, sometimes two to three times as much. This fluid can come from plain water and other fluids such as juice, sports drinks, milk, and even coffee or tea. However, in most situations water is the best hydration drink. [11] It is inexpensive and free of calories, sugar, and other additives. If you are exercising for a long period, working out in the heat, or tend to sweat a lot during physical activity, consider sports drinks to replenish electrolytes along with fluids. Editor’s Note- For adults, the Institute of Medicine recommends men drink thirteen cups of water or other beverage every day and for women nine cups of water or beverage daily. References [1]  Institute of Medicine (US) Committee on Military Nutrition Research; Marriott BM, editor. Nutritional Needs in Hot Environments: Applications for Military Personnel in Field Operations. Washington (DC): National Academies Press (US); 1993. 5, Water Requirements During Exercise in the Heat. Available from https://www.ncbi.nlm.nih.gov/books/NBK236237/# [2] Maughan RJ, Watson P, Cordery PA, et al. A randomized trial to assess the potential of different beverages to affect hydration status: development of a beverage hydration index. The American Journal of Clinical Nutrition. 2015;103(3):717-723. doi:https://doi.org/10.3945/ajcn.115.114769 [3] Maughan RJ, Griffin J. Caffeine ingestion and fluid balance: a review. Journal of Human Nutrition and Dietetics. 2003;16(6):411-420. doi:https://doi.org/10.1046/j.1365-277x.2003.00477.x [4] Shirreffs SM, Maughan RJ. Restoration of fluid balance after exercise-induced dehydration: effects of alcohol consumption. Journal of Applied Physiology. 1997;83(4):1152-1158. doi:https://doi.org/10.1152/jappl.1997.83.4.1152 [5] Wynne JL, Wilson PB. Got Beer? A Systematic Review of Beer and Exercise. International Journal of Sport Nutrition and Exercise Metabolism. 2021;31(5):438-450. doi:https://doi.org/10.1123/ijsnem.2021-0064 [6] Bates GP, Miller VS. Sweat rate and sodium loss during work in the heat. Journal of Occupational Medicine and Toxicology. 2008;3(1):4. doi:https://doi.org/10.1186/1745-6673-3-4 [7 Karim M, Alamgir H. High temperatures on mental health: Recognizing the association and the need for proactive strategies—A perspective. Health science reports. 2023;6(12). doi:https://doi.org/10.1002/hsr2.1729 [8] Hasegawa Y, Kato K, Kazuhiro Ogai, Konya C, Takeo Minematsu. Need for a consensus definition of chronic dehydration: A scoping review. Drug discoveries & therapeutics. Published online January 1, 2024. doi:https://doi.org/10.5582/ddt.2024.01014 [9]  Institute of Medicine. 2005. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: The National Academies Press. https://doi.org/10.17226/10925. [10] Thomas DT, Erdman KA, Burke LM. American College of Sports Medicine Joint Position Statement. Nutrition and Athletic Performance [published correction appears in Med Sci Sports Exerc. 2017 Jan;49(1):222. doi: 10.1249/MSS.0000000000001162]. Med Sci Sports Exerc. 2016;48(3):543-568. doi:10.1249/MSS.0000000000000852 [11] Heat stress: Hydration. Accessed July 12, 2024. https://www.cdc.gov/niosh/mining/userfiles/works/pdfs/2017-126.pdf.

In July of 2023 the World Health Organization (WHO) classified it as a possible carcinogen. Does this mean we should avoid aspartame-containing foods? Culinary Medicine by Lori A. Smolin, PhD and Mary B. Grosvenor, MS, RD Nothing like an ice-cold Diet Coke on a hot summer day! It tastes sweet and refreshing but doesn’t contribute calories or added sugars to your diet. The sweet taste of Diet Coke comes from aspartame. This low-calorie, sugar-free sweetener has been on the market for almost 50 years and is among the most studied food additives in the human food supply.[1] Nonetheless, in July of 2023 the World Health Organization (WHO) classified it as a possible carcinogen. [2] Does this mean we should avoid aspartame-containing foods? Chemically, aspartame consists of two amino acids: phenylalanine and aspartic acid. It was inadvertently discovered in the 1960s when James M. Schlatter, a researcher working on antiulcer drugs, licked his finger to turn a page and tasted a sweet flavor. Its use as a sweetener was first approved by the FDA in the 1970s and is now used in beverages, chewing gums, yogurts, and the tabletop sweetener Equal. In 1983 the FDA established an acceptable daily intake (ADI) for aspartame of 50 mg /kg body weight. [1] The ADI is the maximum amount considered safe for an adult to consume daily over a lifetime. The FDA continues to evaluate the safety of aspartame as new data becomes available. [1,2] The WHO International Agency for Research on Cancer (IARC) has been monitoring aspartame as well and recently classified it as a Group 2B carcinogen, “possibly carcinogenic to humans” (see Table). This designation was based on evaluation of three studies that found limited evidence of a positive association between artificially sweetened beverage consumption and the risk of liver cancer. The proposed mechanism is related to the release of methanol from the breakdown of aspartame in the gastrointestinal tract. Methanol is oxidized in the liver to formaldehyde; formaldehyde is directly toxic to liver cells and associated with cancer development.[3] Based on the IARC designation, one would think that aspartame should no longer be approved for use. However, according to the WHO Joint Expert Committee on Food Additives (JECFA), there is no reason to change current guidance on the use of aspartame. [2] This apparent disparity is because these two WHO agencies are tasked with different responsibilities. The IARC reviews scientific evidence to determine whether an agent can cause cancer in humans, but they do not specify the risk of developing cancer at a given exposure level. The JECFA performs risk assessments to determine the probability that a food additive, such as aspartame, will cause harm at a particular level of exposure. The FDA agrees with the JECFA’s assessment that the current recommended limits for aspartame consumption are safe.[1] So, is it OK to enjoy that refreshing beverage? The ADI suggests that the equivalent of about 200 fluid ounces (17 cans) of aspartame-containing soda per day is safe for a healthy adult, but this does not mean it is safe for everyone. Individuals with the genetic disease phenylketonuria (PKU) should not consume aspartame because they cannot metabolize the amino acid phenylalanine normally. When they ingest phenylalanine, it builds up in the blood, potentially resulting in brain damage and other health and developmental problems. Other concerns with aspartame relate to its possible effect on body weight and metabolism. While aspartame is commonly used to improve health by reducing the intake of added sugars, helping to manage blood glucose, and lowering calorie intake, the use of artificial sweeteners has ironically been suggested to stimulate appetite, cause weight gain, increase the risk of hypertension and cardiovascular events, and disrupt the gut microbiota leading to glucose intolerance and an increased risk of type 2 diabetes.[4,5] Currently the data supporting these adverse effects is primarily observational or from animal studies so further research is needed to characterize the health impact of aspartame.[3] Conclusion Recommendations for a healthy diet tell us to limit our intake of added sugars, particularly from sugar-sweetened beverages. However, there are growing concerns that excessive consumption of aspartame and other artificial sweeteners may adversely impact health in the long term. The best advice may be found in the words of Dr. Francesco Branca, director of WHO’s Department of Nutrition and Food Safety: “If consumers are faced with a decision on whether to take cola with sweeteners or one with sugar, I think there should be a third option considered, which is to drink water instead.”[6] References [1] U.S. Food and Drug Administration. Timeline of selected FDA activities and significant events addressing aspartame. May 30, 2023. https://www.fda.gov/food/food-additives-petitions/timeline-selected-fda-activities-and-significant-events-addressing-aspartame. Accessed August 20, 2023. [2] World Health Organization. Aspartame hazard and risk assessment results released. https://www.iarc.who.int/featured-news/aspartame-hazard-and-risk-assessment-results-released. Accessed September 2, 2023. [3] Czarnecka K, Pilarz A, Rogut A, Maj P, etal Aspartame-True or False? Narrative Review of Safety Analysis of General Use in Products. Nutrients. 2021 Jun 7;13(6):1957. doi:10.3390/nu13061957. [4] Azad MB, Abou-Setta AM, Chauhan BF, et al. Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. CMAJ. 2017;189(28):E929-E939. doi:10.1503/cmaj.161390. [5] Nettleton JE, Reimer RA, Shearer J. Reshaping the gut microbiota: Impact of low-calorie sweeteners and the link to insulin resistance. Physiol Behav. 2016;164(Pt B):488-493. doi:10.1016/j.physbeh.2016.04.029. [6] Christensen J. WHO declares widely used sweetener aspartame a possible cancer cause, but intake guidelines stay the same. CNN. July 14, 2023. https://www.cnn.com/2023/07/13/health/aspartame-who-possible-cancer-cause/index.html#:~:text=Aspartame%20is%20one%20of%20the,in%20about%206%2C000%20products%20globally. Accessed August 20, 2023.

Explore effective cold remedies from honey to Ma Huang, including traditional herbs and scientifically proven treatments. InBrief by Madeleine Beckman Edited by Richard Strongwater, MD The cold, also known as the “acute upper respiratory tract infection,” commonly occurs among adults and, in particular, young children. This viral infection, often caused by rhinoviruses, is related to sore throat, congested nasal passages, low-grade fever, and fatigue that can last up to 3 weeks; on the other hand, the flu caused by the influenza virus, usually manifests similarly, but with more severe symptoms, muscle aches, and higher fever. Infected patients with the common cold want medicine from their doctors, even though the American Academy of Family Physicians recommends that health professionals limit prescriptions of antibiotics and cautions patients not to overuse expensive, often ineffective over-the-counter(OTC) medications. How to feel better from the common cold? Scientifically proven treatments may help relieve symptoms of colds in adults. These include nasal decongestants, zinc lozenges, OTC analgesics, asthma-relief inhalers, and nebulizers, intranasal ipratropium (Atrovent), and nasal saline solution that may help clear nasal passages. Use of oral nasal decongestants (eg, pseudoephedrine, phenylephrine) may not be a safe option for patients > 50 years of age or persons with cardiovascular disease. The side effects of decongestant use may be worsened by caffeine consumption. Use of probiotics may help prevent colds, but results found in clinical studies have not been significant. Antihistamines used alone show no benefit in shortening the duration or weakening the severity of upper respiratory infections. Use of zinc lozenges shortens the duration of cold symptoms, although it may not affect symptom severity. In children, acetylcysteine prescribed to treat a self-limiting illness such as an upper respiratory infection may help reduce cough and is safe for use in children > 2 years of age. Honey consumption (for children > 2 years of age) and use of intranasal ipratropium (for children > 5 years of age) and saline spray/irrigation (for small children>1 year of age) all may significantly reduce symptoms in young patients. Nonprescription cold medications should not be used in children<4 years of age. Further use of OTC antitussives and antihistamines plus decongestants do not significantly relieve cough symptoms. For both children and adults, use of echinacea, intranasal steroids, and steam treatments have not significantly helped to reduce the duration or severity of cold symptoms. How to avoid catching a cold? According to Rong-Bao Lu, MD, a general practitioner and acupuncturist in New York City, “Acupuncture can be used as a preventive to boost the immune system to help prevent colds or to help cure a cold.” According to a recent report in Medicine,“...traditional Chinese acupuncture was shown to be effective and safe with strong operability, low cost, and environmentally friendly, especially suitable for children with fever...” Although fever may indicate other pathology or more significant disease. Exercise is another scientifically proven method to help avoid these viral infections. David C. Nieman, DrPH, Director of the Appalachian State University Human Performance Laboratory at the North Carolina Research Campus, led a study indicating that moderate exercise (30 minutes/day on most days) lowers the risk for acquiring are respiratory tract infection by 50%. Stress management, regular sleep patterns, healthy eating, high intake of fruit, and proper hygiene (including frequent hand-washing) are all lifestyle factors that influence the risk of contracting the common cold. Do home remedies help? Some home remedies and cures have been passed down over generations. As the saying goes: Choose your medicine. Hot cocoa. Research from the United Kingdom has shown that cocoa (which contains theobromine) helps suppress a cough. Theobromine acts on the vagus nerve, which spurs coughing. Cocoa also offers antioxidant benefits. Further, warmed milk used to make the hot cocoa can induce sleep. Mustard. This herb has been used as a cure for the common cold since ancient Roman times. Many people still spread a mustard paste between two pieces of cloth and lay it on their chests to ward off the flu. Chicken soup. As far back as 60 AD, the Roman surgeon Pedacius Dioscorides praised chicken soup as a cure for the common cold. Researchers have since learned that the amino acid cysteine found in chicken acts as a decongestant. Ma huang. For 3,000 years, the Chinese have been drinking ma-huang tea, which is said to clear even the most congested nasal passages and throats. The traditional ma-huang plant contains pseudoephedrine, a common modern decongestant. Onions and garlic. The jury’s still out, but some research indicates that the antimicrobial and antiviral properties of these bulbs may help prevent a cold and speed recovery if symptoms develop. Onion and garlic may be chopped or minced and then eaten 15 minutes later to give the enzymes in garlic time to react and increase its healthy effects. What is the bottom line? Unfortunately, there is no vaccine to ward off the common cold. Until such a biologic is tested and marketed, avoiding contact with people who already are infected with cold viruses, frequent hand-washing, and not touching the eyes, lips, and nose with unwashed hands are good initial steps to avoiding the discomfort and annoyance of the common cold. #InBrief #IntegrativeMedicine References Cheng Y, Gao B, Jin Y, Xu N, Guo T. Acupuncture for the common cold: a systematic review and meta-analyze protocol. Medicine (Baltimore). 2018;97:e0061. DeGeorge KC, Ring DJ, Dalrymple SN. Treatment of the common cold . Am Fam Physician. 2019;100:281-289. Duijvestijn YC, Mourdi N , Smucny J , Pons G , Chalumeau M. Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease. Cochrane Database Syst Rev. 2009;(1):CD003124. 5 tips: natural products for the flu and colds: what does the science say. National Institutes of Health National Center for Complementary and Integrative Health Web site. https://nccih.nih.gov/health/tips/flucold.htm . December 1, 2017. Accessed November 14, 2019. Hilarious historical cures for the common cold. CBC Kids Web site. https://www.cbc.ca/kidscbc2/the-feed/hilarious-historical-cures-for-the-common-cold . Accessed November 14, 2019. Kang E-J. Kim S Y, Hwang I-H, Ji Y-J. The effects of probiotics on prevention of common cold: a meta-analysis of randomized controlled trial studies. Korean J Fam Med. 2013;34:2-10. Lissiman E, Bhasale AL , Cohen M . Garlic for the common cold. Cochrane Database Syst Rev. 2014;(11):CD006206. Tano L , Tano K. A daily nasal spray with saline prevents symptoms of rhinitis. Acta Otolaryngol. 2004;124:1059-1062. Usmani OS, Belvisi MG , Patel HJ , et al. Theobromine inhibits sensory nerve activation and cough. FASEB J. 2005;29:231-233. Zielinski S. Mythical cures for the common cold. Smithsonian Magazine Web site. https://www.smithsonianmag.com/science-nature/mythical-cures-for-the-common-cold-41990430/ . January 13, 2011. Accessed November 14, 2019. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006206.pub4/full

InBrief by Adele Shenoy MD and Charles L. Fishman, MD Large-cell carcinomas are a diagnosis of exclusion when a lung malignancy does not meet the criteria of small-cell lung cancer (SCLC), adenocarcinoma, or squamous-cell carcinoma based on light microscopy and immunohistochemical-marker expression. Large-cell carcinomas are aggressive and represent about 5%-10% of lung cancers. Histologically, they are malignant epithelial neoplasms (poorly differentiated) without glandular or squamous differentiation or small-cell features. Causes and Risk Factors Smoking is the primary risk factor for all lung cancers, including large-cell carcinoma. The median age of presentation is 61 years; men are three times more likely than women to develop these cancers. Signs and Symptoms Large-cell carcinoma can present with signs and symptoms similar to those of other types of lung cancer, including cough, chest pain, dyspnea, and hemoptysis. Diagnostic Evaluation and Differential Diagnosis On imaging, large-cell carcinoma typically presents as a peripheral mass with or without necrosis. Diagnosis requires a biopsy with histologic confirmation that rules out glandular, squamous, and neuroendocrine differentiation. Electron microscopy plus immunohistochemistry can sometimes better classify tumors and may be required before a diagnosis of large-cell carcinoma can be made. Differential diagnoses include other types of lung carcinoma, including small-cell, adenocarcinoma, and neuroendocrine carcinomas; metastatic lesions of the lung; and benign lesions (eg, hamartomas, fibromas). Treatment Options Treatment of large-cell carcinoma varies based on the patient’s comorbidities and tumor stage. It may be treated with combinations of surgery, chemotherapy, immunotherapy, and radiation therapy. Summary of Lung Cancer Classification Small-cell lung cancers (SCLCs) include small-cell carcinoma (oat-cell cancer), combined small-cell carcinoma, and neuroendocrine lung cancer (NET). Nonsmall-cell lung cancers (NSCLCs) include adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma. Other large-cell carcinomas include neuroendocrine large-cell lung cancers, which tend to be more aggressive than other neuroendocrine tumors. Summary of Lung Cancer Classification Pulmonary Neuroendocrine Tumors (NET) Pulmonary Carcinoid Tumors Typical Carcinoid Tumors Atypical Carcinoid Tumors Large Cell Neuroendocrine Carcinomas Small Cell Lung Carcinomas Carcinoid tumors is also a type of neuroendocrine lung cancer NET's) but represents only a small percentage of primary lung cancer (less than 1%). Carcinoid lung tumors typically present as a low grade, well-differentiated, slow-growing tumor. Less commonly they may present as atypical high-grade, poorly differentiated carcinomas. All NETs may produce circulating neuropeptides. References: Travis WD, Brambilla EW, Burke AP, Marx A, Nicholson AG, eds. WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart. Lyon, France: IARC Press; 2015. Clinical Lung Cancer Genome Project; Network Genomic Medicine. A genomics-based classification of human lung tumors. Sci Transl Med. 2013;5(209):209ra153. Rajdev K, Hasan Siddiqui A, Ibrahim U, Patibandla P, Khan T, El-Sayegh D. An unusually aggressive large cell carcinoma of the lung: undiagnosed until autopsy. Cureus. 2018;10:e2202. Derks J, Hendriks L, Buikhuisen W, Groen H, Thunnissen E, Van Suylen RJ, Houben R, Damhuis R, Speel E, Dingemans AM. Clinical features of large cell neuroendocrine carcinoma: a population-based overview. European Respiratory Journal 2016 47: 615-624; DOI: 10.1183/13993003.00618-2015. Limaiem F, Tariq M, Wallen J. Lung Carcinoid Tumors. StatPearls. Last Update: October 16, 2020. Pulmonary Neuroendocrine Tumors. Memorial Sloan Kettering Cancer Center. https://www.mskcc.org/cancer-care/types/lung/types/pulmonary-neuroendocrine-tumors. #InBrief

In Brief by Justin Cole, MD , Michael Bergstein, MD , and Adele Shenoy, MD Zenker’s diverticulum (ZD) is an outpouching of the hypopharyngeal mucosa through weakened inferior pharyngeal constrictor muscles in the posterior hypopharynx; typically, the cricopharyngeal muscle is involved. This condition appears as a stretching of the lining of the lower part of the pharynx, just above the cricopharyngeal muscle and near the upper esophageal sphincter in an area known as the “triangle of Killian.” It is a false diverticulum, because it does not involve all layers of the esophageal wall. ZD is quite rare (prevalence, 0.11%) and is most commonly seen in men in their 70s and 80s. Signs and Symptoms When the diverticulum is large enough to retain food and mucus, patients have foul-smelling breath, gurgling, regurgitation of food into the mouth, and a mass-like appearance in the neck. Progressive dysphagia (initially with liquids, then with solids)may occur, eventually leading to weight loss and malnourishment. Other symptoms ofZD include hoarseness, dysphonia, cough, hemoptysis, and hematemesis. Dysphagia may be caused by the incomplete opening of the upper esophageal phincter or by extrinsic compression of the cervical esophagus by the diverticulum. Aspiration of necrotic food content or just necrotic mucous poses a real concern and risk for hospitalization. Cause ZD is typically secondary to age-related changes in swallowing resulting from repetitive dyscoordination between relaxation of the upper esophageal sphincter and contraction of the pharynx. Diagnostic Evaluation and Differential Diagnosis Initial diagnosis of ZD is clinical and confirmed by the results of a barium swallow esophagram. An ultrasound can be used in patients who have difficulty swallowing the chalky white barium liquid. Cervical borborygmus (gurgling or rumbling) and a palpable mass in the neck might be considered pathognomonic of ZD.The differential diagnosis of ZD includes strictures and esophageal carcinoma, which can also cause progressive dysphagia. Endoscopy can be used to distinguish ZD from esophageal carcinoma. Treatment If the patient is symptomatic and/or the diverticulum is larger than 1 cm in size, surgical treatment is recommended. Every effort should be made to pursue endoscopic treatment. Open surgery may be needed in the presence of retrognathia, prominent teeth, cervical kyphosis, or temporomandibular joint disease that occlude endoscopy. Prognosis Prognosis for endoscopic repair of ZD is excellent, with success rates of ~ 95%.Recurrence is reported in ~ 5% of patients treated endoscopically. Complications Although most diverticula are repaired endoscopically, surgical diverticulectomy carries a low risk of mediastinitis, recurrent laryngeal nerve injury, pneumonia, hematoma, and infection Pearl The incidence of squamous-cell carcinoma located within the ZD may be as high as1.5% References: Costantini M, Zaninotto G, Rizzetto C, Narne S, Ancona E. Oesophageal diverticula. Best Pract Res Clin Gastroeneterol . 2004;18:3-17. Law R, Katzka DA, Baron TH. Zenker’s diverticulum. Clin Gastroenterol Hepatol. 2014;12:1773-1782. Little RE, Bock JM. Pharyngoesophageal diverticuli:­­­ diagnosis, incidence and management. Curr Opin Otolaryngol Head Neck Surg. 2016; 24:500-504. Prisman E, Genden EM. Zenker diverticulum. Otolaryngol Clin N Am . 2012;46:1101-1111.

InBrief by Arno Housman, MD Renal-cell carcinoma (RCC) refers specifically to primary, generally solid tumors arising from the renal cortex (as opposed to those arising from the urothelium of the collecting system). These tumors actually reflect a diverse collection of lesions of varying histologic origin and different biologic potential and represent 80%–85% of primary renal tumors. The most common solid tumor of the kidney is clear-cell carcinoma, representing ~75% of all RCCs. This type of tumor arises from proximal tubular cells and is most commonly associated with a chromosome-3p deletion. Other histological cell types of RCC include papillary tumors (~15%–20%) that may arise from the epithelium of the proximal tubule, and chromophobe tumors (~5%) that may arise from the distal nephron. Further differentiation of cell types is determined by morphology and, possibly, immunohistochemical markers and cytogenetic and molecular genetic analysis. Some 3%–5% of RCCs may remain unclassified. Staging The American Joint Committee on Cancer (AJCC) TNM system is based on three important aspects of cancer assessment: size and extent of the main tumor (T); metastasis of cancer cells to adjacent lymph nodes (N), and metastasis of cancer to other organs (M). Higher numbers appearing after these letters refer to more advanced disease. Zeroes after these numbers refer to absence of involvement; N1 refers to regional node involvement, and M1 refers to distant metastasis. Signs and Symptoms of Renal-cell Carcinoma The classic triad of hematuria, palpable mass, and flank pain associated with renal-cell carcinoma is now only rarely encountered. Currently, the tumor often is found on radiographic imaging (computer tomography [CT], magnetic resonance imaging [MRI]) performed for other reasons. Despite earlier detection of the disease, the cancer still is confined to the kidney only 65% of the time when discovered. Causes and Risk Factors RCC is twice as common among men than women. The median age at diagnosis is 64 years, yet this cancer most commonly is seen among people 60–90 years of age. Risk factors for RCC include smoking, hypertension, obesity, acquired cystic disease of the kidney as seen in chronic renal disease (especially that requiring dialysis), Von-Hippel Lindau disease, chronic hepatitis C, cytotoxic chemotherapy, and other genetic predispositions. Genetic counseling is advised for individuals whose family history suggests a risk of RCC, all diagnosed persons < 46 years of age, and those with multifocal or bilateral disease. At this time, inherited genetics appears to play a role in 2%–4% of RCCs. Treatment Options Solid enhancing renal masses and complex cystic renal lesions (Bosniak 3 and 4) are considered cancers until proven otherwise. Cure requires surgical removal before cancer spread occurs. Controversies regarding evaluation and management of RCC reflect increasingly early detection and diagnosis, advances in surgical technique, development of biological therapies, and genetic testing. Long considered the "gold standard" to treat RCC, radical nephrectomy is now joined by partial nephrectomy and thermal ablation, when appropriate. Neither classic chemotherapeutic regimens nor radiation are effective against RCC. Immunotherapy, novel targeted agents (vascular endothelial growth factor [ VEGF] -receptor inhibitors and tyrosine-kinase inhibitors), and combination regimens offer optimism for the future. One combination regimen includes antiangiogenic VEGF-receptor/tyrosine-kinase inhibitors (sunitinib [Sutent], pazopanib [Votrient], or bevacizumab [Avastin]) with interferon-alpha. Another regimen includes a VEGF-receptor/tyrosine-kinase inhibitor, immunotherapy with nivolumab [Opdivo], and the immunosuppressant everolimus. The US Food and Drug Administration has recently approved the combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) for advanced RCC. Other agents being studied include pembrolizumab (Keytruda), axitinib (Inlyta), ipilimumab (Yervoy), and atezolizumab (Tecentriq). Large tumors (> 10 cm) warrant radical nephrectomy and local lymphadenectomy. Survival rates for smaller lesions seem to be the same whether radical or partial nephrectomy is performed, as long as there is no residual tumor. Current trends support nephron-sparing partial nephrectomy, when appropriate. Partial nephrectomy is used for primary lesions limited to the kidney and < 4 cm in size (T1a). It may also be used for bilateral tumors or other conditions (eg, solitary kidney or primary renal disease) that require nephron-sparing surgery. Use of thermal ablation (eg, cryoablation, radiofrequency ablation) is limited to elderly patients and those with small lesions who require intervention but have significant comorbidities. Long-term survival data is not yet available; short-term data supports use in appropriate candidates but requires long-term follow-up. Prognosis Following definitive surgery for RCC, overall 5-year survival is ~75%, mostly resulting from early, serendipitous tumor discovery. The 15-year, cancer-specific survival rates for kidney-confined RCC are 70% for clear-cell carcinoma, 90% for papillary carcinoma, and 88% for chromophobe carcinoma. In addition to histology, survival depends upon tumor size and tumor location within the kidney (with a subset involving tumor invasion into the renal collecting system) or extension beyond the kidney (eg, involving lymph nodes, major vascular structures, Gerota's fascia, or the ipsilateral adrenal gland). The prognosis for locally advanced or metastatic RCC remains poor. Pearl to Know Renal-cell carcinoma is now the seventh most common cancer type detected in men. The increasing incidence of RCC cannot be fully explained by the increase in incidental detection. #InBrief #Oncology #Urology Sources: American Society of Clinical Oncology. Kidney cancer: stages. Cancer.net Web site. https://www.cancer.net/cancer-types/kidney-cancer/stages. October 2020. Accessed March 15, 2021. Broderick JM. Where are we at in 2020 with non-clear cell RCC? Urology Times Web site. https://www.urologytimes.com/view/where-are-we-at-with-non-clear-cell-renal-cell-carcinoma-in-2020. November 17, 2020. Accessed March 15, 2021. Cairns P. Renal cell carcinoma. Cancer Biomark . 2011;9:461-473. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010;7:245-257. Escudier B, Porta C, Schmidinger M, et al.  Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30:706-720. Gray R, Harris G. Renal carcinoma: diagnosis and management. Am Fam Physician . 2019;99:179-184. Presti JC Jr, Rao PH, Chen Q, et al. Histopathological, cytogenetic, and molecular characterization of renal cortical tumors. Cancer Res. 1991;51:1544-1552. Störkel S, van den Berg E. Morphological classification of renal cancer. World J Urol. 1995;13:153-158. Thoenes W, Störkel S, Rumpelt HJ. Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cytological and histopathological elements and their use for diagnostics. Pathol Res Pract. 1986;181:125-143. #InBrief

Explore the widespread prevalence of Lyme disease beyond reported cases, delve into the tick life cycle, and learn about transmission risks and prevention strategies in endemic areas across the United States. This article explores is part one of a four part CME series “ Diagnosis and Treatment of Four Tickborne Diseases: Lyme Disease, Ehrlichiosis, Anaplasmosis and Babesiosis ” . LYME DISEASE (Part 1) by Stuart M. Caplen, MD Although there are only about 30,000 cases of Lyme disease reported to the CDC per year, the CDC estimates the actual total is about 476,000 cases per year in the United States.[2] As can be seen on the map below, most cases of Lyme disease occur in the Mid-Atlantic states, New England and the Midwest, although there is significant distribution around the country. The geographic distribution of the three other tickborne infections under discussion can also be seen below. Tick Life Cycle and Infection Transmission Lyme disease is a tick transmitted disease, with protean manifestations, usually caused by the spirochete, Borrelia burgdorferi, although it can rarely be caused by Borrelia mayonii. Ticks go through four life stages: egg, six-legged larva, eight-legged nymph, and adult. After hatching from the eggs, ticks must eat blood to survive. Ticks can take up to 3 years to complete their full life cycle, although the Ixodes scapularis tick, also known as the blacklegged or deer tick, that typically spreads Lyme disease has a 2-year life cycle. Most nymph infections occur in the spring and summer, with adult tick caused infections typically occurring during the cooler months. Nymph ticks are much harder to detect, as they are typically less than 2 mm in size, and may be more likely to feed unnoticed, as opposed to an adult tick.[4] For Lyme disease to occur, the tick needs to be attached for a significant time, typically 36-48 hours before an infection can be transmitted.[5] The more engorged the tick the higher the likelihood of an infection being transmitted. Most tick bites do not result in Lyme disease infections. In some studies, only 2% to 3% of people bitten by ticks in endemic areas actually contract Lyme disease.[6,7] Ticks can detect an animal’s breath and sense body odors, heat, moisture, and vibrations. Ticks can’t fly or jump, but many tick species wait in a position known as “questing” on well walked paths. When questing, ticks hold onto leaves and grass by their third and fourth pair of legs and keep their first pair of legs outstretched. When a host brushes by the tick, it climbs aboard, and either attaches quickly or goes looking for places where the skin is thinner. Ticks transmit pathogens that cause disease through the process of feeding. When the tick finds a feeding spot, it grasps the skin and cuts into the surface. The tick then inserts its feeding tube, which may have barbs to help keep the tick in place. Many species also secrete a substance that keeps them firmly attached to the host during the meal. Tick saliva contains an anesthetic like substance, to prevent the host from feeling the attached tick. A tick will then suck the host’s blood slowly for several days. If the host animal has a bloodborne infection, the tick can ingest the pathogens and become infective. If the tick’s saliva contains a pathogen, it may enter the host animal during feeding causing an infection. After feeding, most ticks will drop off the host and move on to the next life stage.[4] How to Remove a Tick Never crush a tick with your fingers. Use fine-tipped tweezers to grasp the tick as close to the skin’s surface as possible. Pull upward with steady, even pressure. Don’t twist or jerk the tick, as this can cause the mouth-parts to break off and remain in the skin. If this happens, remove the mouth-parts with tweezers if they are easily removable. If a significant debridement is necessary, most sources recommend leaving the mouth parts in place. After removing the tick, thoroughly clean the bite area with rubbing alcohol or soap and water. Dispose of a live tick by putting it in alcohol, placing it in a sealed bag or container, wrapping it tightly in tape, or flushing it down the toilet. Methods for tick removal that have been tried, but are not recommended include; applying a hot match or nail to the tick, covering the tick with petroleum jelly, nail polish, alcohol or gasoline, using injected or topical lidocaine, or passing a suture needle through the tick.[8,9] Should You Send the Removed Tick for Laboratory Testing? It may be helpful diagnostically to identify which tick a patient has been bitten by, either with identification by the clinician, or sending the tick to a laboratory for identification.[10,11] Testing if a tick is carrying B. burgdorferi is not recommended, for the following reasons: Positive results showing that the tick contains a disease-causing organism do not necessarily mean that it caused an infection. Negative results can lead to false assurance, as the patient may have unknowingly been bitten by another infected tick as well. Clinical symptoms will typically occur prior to the test results returning. Laboratories that conduct tick testing are not required to have the same standards of quality control used by clinical diagnostic laboratories, potentially leading to misdiagnosis.[10] Lyme Disease Testing Testing for Lyme disease is both complicated, and potentially inaccurate. Currently a 2-tier antibody assay method is the recommended testing method. This has a sensitivity of only 30%–40% during the typical 30-day window period of early infection, while the antibody response is developing. The 2-tier method does have a 70%–100% sensitivity for disseminated disease. Specificity of 2-tier testing is >95% during all stages of Lyme disease.[12] In 2-tier Lyme disease antibody testing, a screening test is done either using an enzyme immunoassay or immunofluorescence assay. If the screening test is negative another diagnosis should be considered, or the test may have been done during the 30-day antibody window period, before enough antibody has been produced to be detected, and repeat testing may be needed later on. If the screening test is positive or equivocal, immunoglobulin G(IgG) and or immunoglobulin M(IgM) western blot tests are confirmative. If symptoms are less than 30 days both IgG and IgM western blot tests are recommended, with IgM being the acute phase antibody first produced, and IgG the later phase and longer lasting antibody. Theoretically, if symptoms have been present for over 30 days only the IgG western blot is needed, but most labs routinely test for both.[14] The western blot is an immunoassay that allows visualization of Borrelia antibodies in specific bands. The IgM western blot is considered positive if two of three antibody bands measured are positive. An IgG western blot is positive if five of the ten antibody bands measured are positive. It is important to avoid interpreting fewer bands as evidence of infection because some of the antibodies tested for are cross-reactive with non-Borrelial antigens. Therefore, presence of one IgM band or less than five IgG bands does not indicate an overall positive result. Overinterpreting a small number of antibody bands leads to reduced specificity and potential misdiagnosis.[10,12] Polymerase chain reaction(PCR) testing can provide highly specific evidence of B. burgdorferi nucleic acid in synovial fluid, skin biopsy tissue, blood, and cerebral spinal fluid(CSF). However, its clinical utility is limited by low sensitivity, particularly for blood and CSF samples. Studies of PCR on blood have found that its high specificity is outweighed by its lack of clinical sensitivity and potential for contamination, and as a result, PCR testing of blood or CSF for Lyme disease is not recommended . [12] For CSF infections, obtaining simultaneous samples of CSF and serum for determination of anti-Borrelia antibodies allows for calculation of the CSF:serum antibody index. This test can differentiate between intrathecal synthesis versus passive diffusion of specific anti-Borrelia antibodies into the CSF.[10,13] Because B.burgdorferi is a slow-growing organism and current culturing methods are labor-intensive and have poor sensitivity, culture is generally not recommended. Routine hospital blood cultures will not grow B.burgdorferi.[10] It is not recommended to perform Lyme disease testing in asymptomatic patients after a tick bite, as an infection may be too early to detect, and even if delayed testing is done 4-6 weeks later there is insufficient evidence that patients with asymptomatic seropositivity should receive antibiotic therapy.[10] Symptoms of Early Lyme Disease [15] Possible symptoms of early Lyme disease include fever, chills, headache, fatigue, muscle and joint aches, and swollen lymph nodes. A small bump or redness at the site of a tick bite that occurs immediately and resembles a mosquito bite is common. This generally goes away in 1-2 days and is not a sign of Lyme disease. The erythema migrans rash occurs in approximately 70 to 80 percent of infected persons. It begins at the site of a tick bite after an average delay of 7 days but onset can range from 3 to 30 days. It typically has a bullseye appearance, but may present with central sparing or complete central involvement.[15A] Possible Signs and Symptoms of Disseminated Lyme Disease [15] Musculoskeletal/Rheumatological Intermittent pain in tendons, muscles, joints, and bones Arthritis with severe joint pain and swelling, particularly the knees and other large joints. Baker’s cyst Neurologic Bell’s palsy or other cranial neuropathies Headache, meningitis, or rarely encephalitis Motor and sensory radiculoneuropathy, mononeuritis multiplex Problems with short-term memory and cognitive problems Cardiac Lyme carditis- leading to heart block, myocarditis, or pericarditis Dermatologic Multiple erythema migrans lesions Acrodermatitis chronica atrophicans A rash that can potentially be seen in chronic Lyme disease, especially on the dorsal surfaces of the hands, feet, knees, and elbows. Initially the rash is erythematous, followed by discoloration, inflammation and potentially skin atrophy. Borrelial lymphocytoma Borrelial lymphocytoma is an uncommon manifestation of early disseminated Lyme disease reported only in Europe, possibly due to infection by other Borrelia strains more common there. It is a bluish-red nodular swelling that typically occurs on the ear lobe in children, or on the breast in adults. Recommended Treatment for Lyme Disease Antibiotic Prophylaxis Prophylactic antibiotic therapy is recommended for adults and children within 72 hours of removal of an identified high-risk tick bite, but not for bites that are equivocal or low risk. One meta-analysis concluded that there was a 2.2% chance of getting Lyme disease in untreated patients, compared to 0.2% infection rate in the antibiotic prophylaxis group.[21] A prospective study of prophylactic antibiotics after tick bites found a 3.2% infection rate in the placebo group and a 0.4% infection rate in the antibiotic prophylaxis group.[22] A tick bite is considered to be high-risk only if it meets these three criteria: The tick bite was from an identified Ixodes vector species. The tick bite occurred in a highly endemic area The tick was attached for ≥36 hours. The duration of tick attachment is an important predictor of subsequent Lyme disease. Unfed or flat recently attached ticks do not pose a significant risk for Lyme disease. The likelihood of transmission increases with the duration of attachment and the majority of transmission occurs after 36–48 hours of attachment.[10] For high-risk tick bites in all age groups, a single dose of oral doxycycline within 72 hours of tick removal is recommended. Doxycycline is given as a single oral dose, 200 mg for adults and 4.4 mg/kg (up to a maximum dose of 200 mg) for children. There is no study of the efficacy of doxycycline in children under 12 years of age and the parents should understand that monitoring for symptoms and signs is important.    Doxycycline is contraindicated in pregnancy, and the recommendation for tick bites during pregnancy most commonly is watchful waiting and treating if Lyme disease occurs, rather than using prophylaxis. Amoxicillin in a 10-day course might work for prophylaxis in the pregnant patient, but is not recommended because the frequency of adverse reactions is higher than the Lyme disease cases it prevents.[23] The latest Lyme disease prophylaxis during pregnancy recommendation of 3 different professional societies, which includes the Infectious Diseases Society of America is this: “Because of uncertainty about the safety of doxycycline in pregnancy, we advise pregnant women to have an informed discussion with their physicians about the risks, benefits, and uncertainties of antibiotic treatment versus observation.”[10] Please note that while amoxicillin and cefuroxime are not recommended currently for prophylaxis, due to a lack of data, they can be used for treatment of early Lyme disease. Recommended Treatment of Erythema Migrans Rash/Early Lyme Disease Doxycycline, amoxicillin, or cefuroxime are recommended as treatment for erythema migrans rash/early Lyme disease. The dosage and duration are listed in the table below. Additional considerations for treating erythema migrans rash/early Lyme disease include: In the pregnant patient or woman who wants to continue breast feeding, amoxicillin would be the first drug of choice. In infants and children, amoxicillin or cefuroxime can be used to avoid the use of doxycycline.[10] If azithromycin is used, the indicated duration is 5–10 days, with a 7-day course being the most common one prescribed most commonly [10]. In patients with acrodermatitis chronica atrophicans, oral antibiotic therapy for 21–28 days is recommended.[12] In patients with borrelial lymphocytoma, oral antibiotic therapy for 14 days is recommended.[10] Coinfection should be investigated in patients who have a persistent fever while on antibiotic treatment for Lyme disease. If fever persists despite treatment with doxycycline, Babesia microti infection is an important consideration.[10] For more information on the CDC recommended antibiotic regimes for Lyme carditis/heart block, arthritis or neurologic Lyme disease, some of which may require intravenous antibiotics as initial therapy, go to this link; https://www.cdc.gov/lyme/treatment/index.html  . For more information on the specific treatment of Lyme disease complications, such as heart block, go to this link; https://www.idsociety.org/practice-guideline/lyme-disease/  . Post-Treatment Lyme Disease Although most cases of Lyme disease can be cured with a 10-day to 4-week course of oral antibiotics, patients can sometimes have symptoms of pain, fatigue, or difficulty thinking that lasts for more than 6 months after they finish treatment, called Post-Treatment Lyme Disease Syndrome (PTLDS). It has been hypothesized that the syndrome is caused by an autoantibody response. There is no proven treatment for PTLDS, and studies have found that prolonged antibiotic treatment works no better than patients who received placebo. Patients with PTLDS usually get better over time, but it can take many months to feel completely well.[10,25] #InfectiousDisease #ticks More TICK-BORNE Disease articles:   Ehrlichiosis  | Anaplasmosis  | Babesia   The CME version of this article" Diagnosis and Treatment of Four Tickborne Diseases Lyme disease, Ehrlichiosis, Anaplasmosis and Babesiosis " is available for the medical community with an online CME test in the APP. REFERENCES [1] Lyme Disease, CDC, last reviewed: February 24, 2021. Retrieved from: https://www.cdc.gov/lyme/index.html [2] Lyme Disease, Data and Surveillance, CDC, last reviewed January 14, 2021. Retrieved from: https://www.cdc.gov/lyme/datasurveillance/index.html [3] Tickborne Diseases of the United States, CDC, last reviewed September 22, 2020. Retrieved from: https://www.cdc.gov/ticks/tickbornediseases/overview.html [4] How ticks spread disease, CDC, last reviewed: September 21, 2020. Retrieved from: https://www.cdc.gov/ticks/life_cycle_and_hosts.html [5] Lyme Disease Transmission. CDC, last reviewed January 29, 2020. Retrieved from: https://www.cdc.gov/lyme/transmission/index.html#:~:text=Ticks%20can%20attach%20to%20any,disease%20bacterium%20can%20be%20transmitted [6] Hofhuis, A et al., Predicting the risk of Lyme borreliosis after a tick bite, using a structural equation model. PloS one vol. 12,7 e0181807. 24 Jul. 2017. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524385/ [7] Nadelman RB et al. Prophylaxis with Single-Dose Doxycycline for the Prevention of Lyme Disease after an Ixodes scapularis Tick Bite, N Engl J Med 2001; 345:79-84, July 12, 2001. Retrieved from: https://www.nejm.org/doi/full/10.1056/nejm200107123450201 [8] Tick removal and testing, CDC, last reviewed April 22, 2019. Retrieved from: https://www.cdc.gov/lyme/removal/index.html [9] Gammons M, Salam G, Tick Removal, Am Fam Physician. 2002 Aug 15;66(4):643-646. Retrieved from: https://www.aafp.org/afp/2002/0815/p643.html#afp20020815p643-b7 [10] Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease, Clinical Infectious Diseases, November 30, 2020. Retrieved from: https://www.idsociety.org/practice-guideline/lyme-disease/ [11] Tick removal and testing, CDC, last reviewed: April 22, 2019. Retrieved from: https://www.cdc.gov/lyme/removal/index.html [12] Moore, Andrew et al. “Current Guidelines, Common Clinical Pitfalls, and Future Directions for Laboratory Diagnosis of Lyme Disease, United States.” Emerging infectious diseases vol. 22,7 (2016): 1169–1177. Retrieved from https://wwwnc.cdc.gov/eid/article/22/7/15-1694_article [13] Theel, Elitza S et al., “Limitations and Confusing Aspects of Diagnostic Testing for Neurologic Lyme Disease in the United States.” Journal of clinical microbiology vol. 57,1 e01406-18. 2 Jan. 2019. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322465/ [14] Two-tiered Testing Decision Tree, CDC, last updated: November 15, 2011. Retrieved from: https://www.cdc.gov/lyme/healthcare/clinician_twotier.html [15] Tickborne Diseases of the United States, CDC, 5th edition 2018. Retrieved from: https://www.cdc.gov/ticks/tickbornediseases/TickborneDiseases-P.pdf [15A]Signs and Symptoms of Untreated Lyme Disease, CDC, last reviewed: January 15, 2021. Retrieved from: https://www.cdc.gov/lyme/signs_symptoms/index.html [16] Photo credits: Alison Young, Taryn Holman, Yevgeniy Balagula/Dermatlas.org, Lyme Disease Rashes and Look-alikes, CDC, last reviewed: October 9, 2020. Retrieved from: https://www.cdc.gov/lyme/signs_symptoms/rashes.html [17] Photo Credit: Bernard Cohen/Dermatlas.org, Lyme Disease Rashes and Look-alikes, CDC, last reviewed: October 9, 2020. Retrieved from: https://www.cdc.gov/lyme/signs_symptoms/rashes.html [18] Moniuszko-Malinowska A, Czupryna P, Dunaj J, et al. Acrodermatitis chronica atrophicans: various faces of the late form of Lyme borreliosis. Postepy Dermatol Alergol. 2018;35(5):490-494. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232541/ [19] Photo credit, Glatz M et al., Clinical Spectrum of Skin Manifestations of Lyme Borreliosis in 204 Children in Austria, Advances in Dermatology and Venereology, Vol 95, Issue 5, Nov 4, 2014. 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Gentle Quadriceps Strengthening Exercises Four exercises to develop your quadriceps to support health concerns such as Chrondromalacia patella and other mild to moderate knee arthritis. Orthopaedics Patient Handouts PDF by Richard Strongwater, MD There are four gentle exercises to help strengthen your quadriceps. These exercises can help develop your quadriceps to support health concerns such as Chrondromalacia patella and other mild to moderate knee arthritis. For full benefit keep stomach engaged and back straight during these exercises. QUADRICEPS, aka the “four-headed” muscle, includes the vastus lateralis obliquus (VLO) , vastus medialis obliquus (VMO), vastus intermedius (VI), and the rectus femoris (RF) Consult your physician before exercise and stop exercise if you experience pain. #1 The Pillow Squeeze Exercise Strengthens the VMO Squeeze Pillow and Hold for 10 seconds 5 – 10 reps #2 The Plank Strengthens all 4 muscles Work up to holding for 30 - 60 seconds # Up and Down Exercise You may do this exercise lying supine or standing while holding support Up and Down with foot straight strengthens VI and RF Work up to 10 reps each side - straight foot and then foot turned in. #4 The Horse Stance Exercise The horse stance exercise strengthens all four Quadricep muscles. If you experience ANY pain, do NOT perform! a) Partial Squat and hold for 20 - 60 seconds b) Come up favoring on e leg as shown c) Exercise completed. One or two reps only Get the Patient Handout PDF of all four Quad exercises. # Orthopaedics #PatientHandouts For more information regarding recommended Chrondromalacia patella check out our FibonacciCOMPENDIUM on FibonacciMD.app

Hyperkalemia, elevated serum potassium and the current approach to the diagnosis and treatment of potassium disorders. by Kruti Vora, MD, M.C.A. Butman and M.P. Butman, MD “Hyperkalemia” refers to an elevated serum potassium level. In most cases, this occurs when the kidneys are unable to excrete potassium and is usually due to diseases that damage the kidneys, disorders that affect their ability to excrete potassium, diseases that raise potassium levels independent of any problem with the kidneys, or a combination of the aforementioned. The most common causes of chronic kidney damage is diabetes and hypertension. Kidney damage may also occur acutely from dehydration, hypotension, kidney stones, iodinated contrast used in imaging, and the adverse effects of a myriad of medications including antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors, angiotensin II blockers, immunotherapeutic agents, chemotherapy, IVIG, and antiretroviral therapy. Disorders that raise potassium levels in a setting of normal kidney function include abnormalities of the adrenal glands (e.g. Addison’s disease/adrenal insufficiency,acquired hyporeninemic hypoaldosteronism, congenital adrenal hyperplasia), hemolysis, tumor lysis, constipation, and metabolic acidosis. Factitious Hyperkalemia A serum potassium level that is falsely elevated is known as factitious hyperkalemia or pseudohyperkalemia. This may occur when red blood cells within a sample of blood are damaged (hemolysis). The hemolyzed cells release potassium and artifactually elevate the serum potassium concentration in a sample, even though total body potassium may be normal or low. Hemolysis may occur at any point during the collection, transportation, handling, storage, or processing of a blood sample. If hemolysis occurs, the lab should be able to detect and report it, and the blood sample may need to be repeated. Pseudohyperkalemia also may occur in patients with high platelet counts (thrombocytosis), leukocytosis or cancers of the white blood cells due to the fragility of the cellular membrane. or the genetic condition familial pseudohyperkalemia (no hemolysis, but a genetically leaky cell membrane). It also is seen in individuals who have had splenectomies, which can cause a secondary thrombocytosis. If factitious hyperkalemia is suspected it is recommended to repeat the serum potassium level and also perform a plasma potassium level (drawn into a tube that contains either heparin, EDTA or citrate). Serum potassium is usually drawn into a tube that does not contain an anticoagulant. If factitious hyperkalemia (other than leukocytosis or fragile white blood cells) is suspected, the plasma potassium should be normal or significantly lower than the serum level. If specimen hemolysis is suspected, make sure that the patient avoids squeezing their fist during the repeat blood draw. Drawing blood through a larger caliber needle or using a needle to draw the blood specimen rather than drawing through a catheter may also reduce the risk of specimen hemolysis. Note that heparin may actually increase the fragility of white blood cells, making it difficult to confirm “pseudohyperkalemia” in the presence of leukocytosis. Factitious hyperkalemia or pseudohyperkalemia in the absence of EKG changes or other symptoms related to hyperkalemia, may not require treatment but each case should be evaluated on a case-by-case basis. Signs and Symptoms of Significant Hyperkalemia Signs and symptoms of hyperkalemia may include muscle fatigue, weakness, nausea, arrhythmias, and even paralysis. Hyperkalemia is difficult to diagnose without an understanding of the patient’s medical history and any presenting signs or symptoms. Hyperkalemia is defined as a blood potassium level higher than the normal range of 3.6 to 5.2(mmol/L). Other factors, as discussed previously, can result in factitious hyperkalemia, such as hemolysis of blood cells in the blood sample. Misdiagnosis may be prevented by repeating the assay, especially if it seems unlikely for the particular patient to have developed hyperkalemia based on their medical history.Besides treating hyperkalemia, it is of the utmost importance to diagnose and treat the underlying process that the elevated potassium level. Treatment of Hyperkalemia Hyperkalemia can cause fatal cardiac arrhythmias. A rapid rise or a very elevated potassium level alters the resting membrane potential of the cardiac myocyte inactivating fast sodium channels thus blocking conduction which can result in cardiac arrest. Treatment of hyperkalemia is aimed at reducing serum potassium levels to either prevent cardiac dysrhythmias from occurring or if cardiac manifestations are present, reducing potassium levels to restore a normal cardiac rhythm while stabilizing the cardiac membrane. The management varies depending on how urgent the situation is. The urgency depends on the potassium level, how rapidly it rose, the presence of clinical manifestations (e.g., cardiac dysrhythmias, ECG changes, or paralysis), and the underlying cause. The latter will influence treatment and long-term management. The level required for an elevated potassium level to result in a cardiac arrhythmia is variable. However, the higher the serum potassium and the more rapid the rise, the more likely a dysrhythmia will occur. A potassium of 6.5 or greater warrants immediate treatment as does a potassium level of 5.5 in a patient with ECG changes or neuromuscular weakness and a potassium level greater than 5.5 mEq/L in a patient who is at risk of the potassium level rising further (e.g. acute kidney injury). Treatment in such cases requires stabilization of the myocardium while lowering the potassium level. The former entails the administration of intravenous (IV) Calcium Chloride or Calcium Gluconate. Although IV calcium chloride and calcium gluconate do not reduce potassium levels, they stabilize the membrane of the cardiac myocytes, preventing the likelihood of developing an arrhythmia. Reducing potassium can be achieved by either (a) shifting the potassium from the extracellular space (ECF) to the intracellular space (ICF), or (b) by eliminating the potassium from the body. Shifting potassium from the ECF to the ICF is a temporizing measure that does not remove potassium from the body, but does reduce the serum levels by transiently moving it from one compartment to another. With time, potassium will eventually leak back out of the ICF into the ECF. Until that time, other measures may be implemented to remove the potassium remaining in the ECF from the body, so that when the potassium shifts back from the ICF to the ECF, the serum level will not be elevated. One common approach is to administer dextrose in the form of D50W IV followed by 10 units of short-acting insulin IV. The movement of glucose into the cells is accompanied by an intracellular potassium shift. Another technique is to use aerosolized Albuterol, a beta agonist which is known to transiently reduce potassium levels. A third option is to use IV sodium bicarbonate. IV sodium bicarbonate increases extracellular bicarbonate leading to a shift of hydrogen ions from the ICF to the ECF which in turn drives potassium from the ECF to the ICF. As with Dextrose and insulin, this too only transiently lowers serum potassium levels. Removal of potassium from the body can only be achieved in three ways; either (a) excreted by the kidneys (b) by the gastrointestinal tract or (c) with renal dialysis. The intestines account for approximately 10% of daily potassium losses and so serve as a possible location to help remove potassium from the body. Several medications are available including patiromer (Veltassa), sodium zirconium cyclosilicate (Lokelma), and sodium polystyrene sulfonate (Kayexalate). For decades sodium polystyrene sulfonate (aka Kayexalate or Kionex) has been used with great success to remove potassium. It can be given orally or rectally but may take several hours before it has its desired effect, so until then, it may be necessary to administer D50 and insulin to temporarily lower the serum potassium level. The same is true of patiromer and sodium zirconium cyclosilicate. It should be noted that sodium polystyrene sulfonate has been associated with bowel necrosis and is contraindicated in patients who are post op or have an ileus. While bowel necrosis has not been seen thus far with patiromer and sodium zirconium cyclosilicate, neither have been studied in patients who have severe constipation, bowel obstruction or who have postoperative bowel motility disorders and their use in such cases is warned against. Finally, both peritoneal (PD) and hemodialysis dialysis (HD) are effective methods for lowering serum potassium levels if more conservative measures are not possible or if the patient’s condition deteriorates despite conservative management. While PD may be administered acutely, some hospitals may not have the ability to place a PD catheter or have the infrastructure to do the procedure, so hemodialysis has been the default modality. Once a hemodialysis catheter has been inserted dialysis can be provided and the potassium normalized within an hour. Other Causes of Hyperkalemia Metabolic acidosis also affects potassium levels by causing a shift of potassium ions from the intracellular space to the extracellular space. As in factitious hyperkalemia, treatment of the hyperkalemia may or may not be necessary. If treatment is deemed necessary it will be in the form of reducing total body potassium unless there is life threatening signs and symptoms. In DKA, both acidosis and hyperglycemia will cause a shift of potassium to the extracellular space, but total body potassium is frequently depleted yet serum potassium may be initially elevated. Treating the “hyperkalemia” in DKA unless there are life threatening effects may be lethal. Other diseases that should be mentioned that cause the shift of potassium out of the cells into the extracellular space and blood and cause hyperkalemia. These include rhabdomyolysis, burns, hyperosmolar states, tumor lysis syndrome and familial periodic paralysis. Treatment of the hyperkalemia depends on the level of hyperkalemia, speed of onset, the projected duration of the underlying pathology and the presence of EKG changes or severe symptoms. In severe leukocytosis or thrombocytosis hyperkalemia may be due to the fragility of the cells but may be due to the abnormal increase in cell mass. The management of less threatening levels of hyperkalemia is based on the suspected cause of the hyperkalemia and whether it is a transient problem or a chronic problem. For example, if due to a medication, then the dose of the medication may need to be adjusted or discontinued altogether. If from dehydration, then increased fluid is indicated. If the patient is constipated, then review of diet and medications that may cause or be contributing to the constipation should be reviewed and a softener or motility agent may be necessary. In some cases permanent dietary modification may be necessary. See below. FibonacciMD Patient Handout for chronic Hyperkalemia For normokalemic patients the recommended AI (adequate intake) for potassium is 3,500 mg(milligrams) to 4,700 mg per day. Patients with impaired kidney function may require a low potassium diet of less than 3,000 mg per day. Consult with your physician or healthcare clinician to see what your daily intake of potassium should be. High potassium foods (Foods to Avoid) Fruits: Tomato puree, tomato paste & sauce (canned) Banana (1 banana 422 mg) Currants Dried fruit (raisins, sultanas, prunes, apricots, peaches, dates, sundried tomatoes) Avocados Oranges Plantains Pomegranate (1 cup 666 mg) Cantaloupe Watermelon Vegetables: Amaranth leaves Baked potato (skin on) Beans, black (1 cup 611 mg) Beans, white (navy, cannellini) (1 cup 829 mg) Beets (1 cup 518 mg) Brussel sprouts Butternut squash (1 cup 582 mg) Edamame (1 cup 676 mg) Lentils Mushrooms (dried and fresh) Spinach (1 cup cooked 540 mg) Sweet potato ((1 medium 541 mg) Swiss chard (1 cup cooked, 961 mg) Meats: Salmon Clams Mackerel Chili (canned with beans) Halibut Tuna Snapper Rainbow trout Dairy: Chocolate milk Yogurt, low fat (6 oz 398 mg) Skim milk Starch: Cereal or granola that is bran-based or with dried fruits, nuts, or chocolate Snacks: Manufactured potato products like chips, hash browns, potato wedges, french fries, etc. Drinks: Coffee Wine Canned juice such as prune, carrot, tomato, and vegetable juice (1 cup coconut water 600 mg) Low potassium foods (Foods to Include in your Diet) Fruit: (limit to 2 portions a day) Small apple or pear (1 medium apple 150 mg) Only a Handful of grapes Drain any canned fruits Blueberries (1/2 cup 60 mg) Raspberries (1/2 cup 90 mg) Mandarin oranges (1/2 cup 99 mg) Strawberries (1/2 cup 125 mg) Vegetables: Peas (1/2 cup 90 mg) Boiled potatoes (max 1 small portion per day) Cauliflower (1/2 cup 150 mg) Green beans (1/2 cup 90 mg) Cucumber (1/2 cup 80 mg) Eggplant (1 cup cooked 60 mg) Other Low Potassium Vegetables: Carrots, Broccoli, Cabbage Dairy: Cheese Rice or oat milk Eggs Meats: Chicken Turkey Starch: Pasta, rice, noodles, couscous, bread Snacks: Popcorn Marshmallows Mints Sponge cake Corn, rice, wheat-based snacks Unsalted peanut butter Nutless, non-chocolate cookies Drinks: Water Tea Fizzy drinks ABOUT THE AUTHORS Kruti Vora, M.D. Dr. Vora attended Harvard Medical School and has started her internship in the Department of Medicine at Massachusetts General Hospital in Boston, Massachusetts. Her interests are in medical oncology, advocating for health equity, mentorship, and medical education. M.C.A. Butman and M.P. Butman, MD References: High potassium (hyperkalemia) When to see a doctor. (2018, January 11). Retrieved from https://www.mayoclinic.org/symptoms/hyperkalemia/basics/when-to-see-doctor/sym-20050776 Low potassium (hypokalemia). (2020, July 11). Retrieved from https://www.mayoclinic.org/symptoms/low-potassium/basics/definition/sym-20050632 Lewis, J. L., By, Lewis, J. L., & Last full review/revision Apr 2020| Content last modified Apr 2020. (n.d.). Overview of Potassium's Role in the Body - Hormonal and Metabolic Disorders. Retrieved from https://www.merckmanuals.com/home/hormonal-and-metabolic-disorders/electrolyte-balance/overview-of-potassium-s-role-in-the-body Potassium Test. (2020, August 19). Retrieved from https://www.ucsfhealth.org/medical-tests/003484 Office of Dietary Supplements - Potassium. (n.d.). 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