Vitamin D, the sunlight vitamin. How do we get it, what does it do, and what happens if we get too much or too little? Nutrition InBrief FibonacciCOMPENDIUM By Stefanie Schwartz, MS, RD, CDN , and Richard Strongwater, MD , and Stuart M. Caplen MD Cholecalciferol (Vitamin D3) is produced in the body when ultraviolet rays from the sun hit the skin and trigger vitamin D synthesis from 7-dehydrocholesterol. This is the primary source of vitamin D in humans. Ergocalciferol (Vitamin D2) is produced from the UV irradiation of ergosterol, which the body obtains from yeast and other ingested fungi/mushrooms. Vitamin D (prohormones) is actually a group of fat-soluble vitamins but only two, vitamin D2 and vitamin D3 are present in humans. Vitamin D4 is present in certain mushrooms and the benefits of it in humans is uncertain. Sources of Vitamin D (in route to the active hormones) Cholecalciferol (Vitamin D3) is produced in the body when ultraviolet rays from the sun hit the skin and trigger vitamin-D synthesis from cholesterol. The liver then converts vitamin D3 to calcidiol (25-hydroxy vitamin D3) , and then the kidneys convert calcidiol to the active form, calcitriol (1,25-dihydroxy vitamin D3). In food, Vitamin D2 (ergocalciferol) is generally plant and fungus based. Vitamin D2, (produced from the UV irradiation of ergosterol) is then converted in the liver to ercalcidiol (prehormone), and then to ercalcitriol (hormone), the active metabolite of Vitamin D2 . Ercalcitriol may have less efficacy than calcitriol in reducing human health risks. Most of our Vitamin D3 and Vitamin D2 comes from the precursors as mentioned above. These precursor molecules in our skin are then irradiated by the sun and form Vitamin D3 and Vitamin D2. Some of our Vitamin D3 (cholecalciferol) is found naturally in fish and fish oils such as salmon, sardines, tuna, mackerel, trout, and cod liver oil. There is a smaller amount of D3 in eggs and beef liver. Some mushrooms and yeast contain D2 (ergocalciferol). Other sources of vitamin D2 and D3 include vitamin fortified cereals and either dairy or non-dairy milk products. Risk Factors for Vitamin D Deficiency Vitamin D deficiency is common, with one study reporting that vitamin D inadequacy occurred in approximately 36% of healthy young adults and up to 57% of general medicine inpatients in the United States. People with very dark skin may be more susceptible to vitamin D deficiency due to decreased skin absorption of ultraviolet sunlight due to the pigment melanin blocking the UV absorption. Sunscreen with a sun protection factor of 30 reduces vitamin D skin synthesis by more than 95%. Wintertime in cold climate regions may increase the risk of vitamin D deficiency due to less body sun and ultraviolet light exposure. There are also a number of medical conditions and medications that can increase the chance of developing vitamin D deficiency. Why Vitamin D? Vitamin D promotes calcium absorption in the gut and maintains serum calcium and phosphate levels to enable bone mineralization. It is also needed for osteoblast (bone producing cells) and osteoclast (bone degrading cells) formation. Osteoblasts and osteoclasts are needed for bone remodeling which is an ongoing process in the body. Vitamin D deficiency may cause a softening and weakening of bones, which in children is called rickets and in adults osteomalacia. Low vitamin D levels can also worsen osteoporosis (porous bones that are thin, weakened and susceptible to fracture) by reducing calcium absorption. Calcium and vitamin D supplementation may result in some increase in bone mineral density, and reduce fracture risk, but vitamin D alone appears to have no effect on fracture risk. Vitamin D also plays a role in cell growth, neuromuscular and immune function, and reduction of inflammation. A study of vitamin D levels and COVID-19 found that vitamin D levels less than 20 ng/ml were more common in patients with severe COVID-19 infections than in patients with mild or moderate disease. They also found that patients with vitamin D levels less than 20 ng/ml were 14 times more likely to have severe or critical disease than patients with Vitamin D levels equal to or greater than 40 ng/ml. A review of 25 studies concluded that vitamin D supplementation reduced the chances of getting an upper respiratory infection by 12%. Sufficient vitamin D status may help to prevent colon, prostate, and breast cancer. Vitamin D Deficiency Defined The total 25-hydroxy vitamin D level of both vitamin D2 and vitamin D3, ( AKA the prehormones) is the most accurate way to measure your vitamin D level. These prehormones, the storage/circulating forms of vitamin D, are the molecular compounds that are currently used to measure your vitamin D status. Vitamin D3 (cholecalciferol) is the form of vitamin D that your body has either synthesized or that you have absorbed from an animal source (such as fatty fish or liver) or from a cholecalciferol vitamin supplement. The storage form, 25-hydroxy vitamin D3 (calcidiol), is synthesized in the liver from cholecalciferol. Vitamin D2 (ergocalciferol) is the other form of vitamin D that you have either absorbed from some mushrooms or from foods fortified with plant vitamin D or from an ergocalciferol supplement. The storage form, 25-hydroxy vitamin D2 (ercalcidiol), is synthesized in the liver from ergocalciferol. Ergo- and cholecalciferol work similarly in the body. The important value is the total serum 25 hydroxy vitamin D. This level measures both D2 and D3 together and is reported as a total 25-hydroxy vitamin D level. Vitamin D deficiency is defined as a blood level below 20 ng/ml (nanograms per milliliter), and vitamin D insufficiency when blood levels are between 21–29 ng/ml, although some sources feel that in normal individuals 20 ng/ml or greater is an adequate vitamin D level. Serious effects from vitamin D deficiency are seen when the level is below 12 ng/ml. Current guidelines put adequate vitamin D levels at between 20ng/ml (or 30ng/ml depending on the source) to 40 ng/mL, but up to 50 ng/mL might be warranted in cancer patients or other populations. Over 50 ng/ml can be toxic. Too Much Vitamin D ? Too much vitamin D may be a health hazard and may lead to elevated blood calcium levels which can cause nausea, vomiting, muscle weakness, bone fractures, heart arrhythmias, high blood pressure, abnormal calcium deposition in places like the kidneys, blood vessels or eyes, and possibly an increased risk of pancreatic cancer. Current Vitamin D Recommendations Recommendations of supplement dosage vary in the literature. The Endocrine Society Clinical Practice Guidelines suggests that adults aged 19–70 years old require at least 600 IU/day (international units per day) of vitamin D to maximize bone health and muscle function. The guidelines also suggest that adults over 70 years of age may need 800 IU/day of vitamin D. However, in all adult age groups they note that to raise the blood vitamin D level above 30 ng/ml may require at least 1500–2000 IU/day of supplemental vitamin D. Anyone with a medical issue should consult with their physician before adding any new medication including vitamin D. Conclusion Supplementation with vitamin D prohormones, cholecalciferol and/or ergocalciferol may be required to enable the maintenance of a normal vitamin D level. This supplementation should be given in appropriate doses over a treatment period as determined by the patient and their clinician. ADDITIONAL VITAMIN D INFORMATION : Vitamin D Simplified is an article written for the curious public, it may be suitable as a patient handout. References LeFevre, M and LeFevre, N. Vitamin D screening and supplementation in community-dwelling adults: Common questions and answers. American Family Physician. 2018;97:254-260. Institute of Medicine, Food and Nutrition Board: Dietary Reference Intake for calcium and D. Washington DC: National Academy Press. 2010. Davis CD. Vitamin D and cancer: current dilemmas and future research needs. Am J Clin Nutr. 2008;88:565S-569S. Stolzenberg-Solomon RZ, Vieth R, Azad A, et al. A prospective nested case controlled study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Res. 2006;66:10213-10219. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr. 2008;88:582S-586S. Horlick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab . 2011;96:1911-1930. Ensrud KE, Ewing SK, Friedman L, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab. 2010;95:5266-5273. Initial brief published 9/14/2021

If arthritis pain hasn't responded to other treatments, CBD may be the answer for pain and inflammation InBrief by Madeleine Beckman and Lynn Parodneck, M.D. Cannabidiol (CBD) is a chemical found in cannabis. CBD and tetrahydrocannabinol (THC), the psychoactive component of cannabis, are among many constituents in cannabis plants being studied for potentially therapeutic effects. CBD alone does not cause psychoactivity. CBD derived from cannabis plants remains classified as a Schedule 1 illegal substance by the DEA, but CBD derived from industrial hemp (cannabis sativa plants tested to contain less than 0.3% THC), is now federally legal on a national scale after the passage of the 2018 Hemp Farming Act. [1] Hemp-derived CBD products can currently be purchased online and over-the-counter (OTC) throughout the country. In contrast, marijuana-derived CBD products can only be purchased by qualifying patients in states with medical marijuana programs (30 states, and the District of Columbia as of this writing) or by consumers in states with adult-use/recreational laws (9 states and the District of Columbia as of this writing). In 2018 the FDA also approved the prescription drug Epidiolex,® an isolated form of CBD, as a treatment for certain forms of epilepsy. [2] Ongoing research shows the potential benefit of CBD for reducing arthritis pain and inflammation. [3] CBD acts on the body’s own endocannabinoid system, a network of receptors in the central nervous system that modulate inflammation, pain, and immune response, among other functions that are still being actively studied. The body produces its own cannabinoids (endocannabinoids), but receptors can also respond to cannabinoids found from cannabis plants (phytocannabinoids). Animal studies show that CBD relieves arthritis pain and inflammation in dogs. In one study, canines receiving 2 mg/kg of CBD twice daily showed decreased pain from osteoarthritis and increased activity levels. [4] In another study, cannabinoids were shown to affect the expression of TRPV1-4 channels ( aka : capsaicin receptor) with potential therapeutic applications, including reduction of inflammation. [5] The European Journal of Pain notes that transdermal administration of CBD has long-lasting therapeutic effects of symptomatic arthritis.[6] The study’s data indicate that transdermal CBD is a promising treatment for developing new and improved therapies for arthritis. CBD has also been shown to have a preventative effect on inflammation and arthritis symptoms; a study published in the journal Pain in December 2017 analyzed whether CBD could prevent osteoarthritis pain and joint neuropathy. Based on the study’s findings, researchers affirmed that it did both, because it decreased joint inflammation and served as a protectant to nerve function. [7] Other support for CBD oil comes from Daniel Clauw, MD, a pain specialist at the University of Michigan in Ann Arbor, whose clinical experience shows the potential benefits of CBD. Dr. Cluaw recommends OTC CBD oil to some patients in his practice and cites one recent trial showing that CBD alone was effective in the treatment of osteoarthritis of the knee. [8] Oil-based preparations of CBD can be administered orally in pills, by mixing into food, by vaporization, or transdermally via topical creams or patches. All legal OTC CBD products contain less than 0.3% THC, and many contain pure CBD. There is no risk of psychoactivity in pure-CBD oils, so they can be safely used during the day and on a long-term basis. CBD oil is generally well-tolerated, with mild side effects reported including dry mouth, drowsiness, and appetite changes. [9] For patients interested in trying OTC CBD oils, Dr. Clauw recommends starting with a CBD-only product, 5-10mg twice daily, and slowly increasing to a dose of 50-100mg per day. A great deal of confusion exists among both consumers and healthcare professionals about the way CBD is sourced, processed, and employed medicinally. Many OTC CBD products contain chemically-isolated CBD from industrial hemp, which is then suspended in a carrier oil (typically coconut oil). Other products are “whole plant” extracts made by heating hemp flowers within the carrier oil to extract the full spectrum of cannabinoids, including small amounts of THC. (To qualify as legal under the Hemp Farming Act, concentrations must not exceed 0.3%). Consumers should be cautious of hemp products that are not tested for pesticides or other contaminants. Some research also suggests that isolated CBD may not be as effective as CBD administered in combination with the other terpenes and flavinoids present in cannabis, many of which have their own demonstrated therapeutic effects. [10] One theory about the way that cannabis modulates the endocannabinoid system is through the synergy of these various phytocannabinoids, but this remains disputed among researchers, and studies employing pure CBD have also produced positive results for a wide range of ailments. [11] Patients with significant pain who live in states where medical marijuana is legalized may wish to seek the care of a certified doctor to obtain cannabis products containing greater concentrations of THC. Finally, there is some risk of CBD interacting with certain prescription medications, particularly those metabolized in the liver, due to the potential of CBD to increase liver enzymes at higher doses. [12] When considering CBD oil as an herbal alternative or adjunct therapy to NSAID’s for the treatment of arthralgias, patients should always speak with a physician before trying new supplements, herbs, or products not fully FDA-approved. RESOURCES Hemp Farming Act of 2018 FDA approval of Epidiolex. 2018, Jun. Rheumatology (Oxford) . 2006 Jan;45(1):50-2. Epub 2005 Nov 9. Front Vet Sc i. “Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs.” 2018 Jul. Acta Physiol (Oxf) . “Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation.” 2012 Feb. European Journal of Pain . “Transdermal cannabidiol reduces inflammation and pain-related behaviors in a rat model of arthritis.” 2015. Pain . 2017 Dec. www.arthritis.org Cannabis and Cannabinoid Research . “An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.” 2017 Jun 1. \ British Journal of Pharmacology . “Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. 2011 Aug. Scientific American . “Some of the Parts: Is the ‘Entourage Effect’ Scientifically Valid?” 2017 Apr. MedicinePlus: Cannabidiol Initial posting June 27, 2019

The Salter or Salter-Harris classification of fractures refers to a specific group of fractures limited to children. These fractures involve an injury to the open physis or growth plate. Radiographs may be sufficient to make the diagnosis. In some instances, a CT scan or MRI may aid diagnosis. See below for further discussion and examples. Pediatric Orthopedics InBrief Distal Femoral Physeal Fracture by Allan Strongwater, M.D. A distal femoral physeal fracture is a fracture that requires an open growth plate and hence is limited to children. The fracture is classified according to the Salter-Harris classification as grades I-V (see below). This fracture may be difficult to diagnose and may have very serious sequela including distal femoral growth abnormality. Signs and Symptoms This fracture is due to trauma. Pain and swelling, especially a large knee effusion is not uncommon as the physis is intra-articular to the knee. Radiographs are not always sufficient to make the diagnosis, especially in types I (physeal distraction fracture) and V (physeal compression fracture), in which case MRI can be very helpful. Causes and Risk Factors Trauma is the causative agent in this injury. This fracture is not uncommonly seen during aggressive sports such as football, hockey, basketball and the like. Juvenile osteoporosis and other childhood illness resulting in osteoporosis or osteomalacia (osteogenesis imperfecta) are predisposing factors to this injury. Diagnostic Evaluation and Differential Diagnosis If there is a question of a distal femoral physeal fracture radiographs of the distal femur should be obtained. Due to the proximity of the distal femoral physis to the collateral ligaments and other intra-articular structures the differential diagnosis includes ligamentous sprains, meniscal injury, and distal metaphyseal femur fracture. Pearl The distal femoral physis is responsible for approximately 0.6 cm. of longitudinal growth annually. Injury to the physis may result in slowed growth or growth arrest leading to shortening of the affected femur. Angular deformity is also possible and not uncommonly seen following Salter-Harris type IV or V fracture. The physis or growth plate is the thin cartilage plate at the end of each of the developing long bones. The physis is found in children and adolescents and is generally weaker than the surrounding ligaments. Treatment and Recommended Follow-Up Treatment of this potentially serious problem is best left to a pediatric orthopaedic surgeon. Immediate treatment should consist of immobilization of the affected extremity and neurovascular examination of the limb. Once the patient is stable, imaging studies of the distal femur should be obtained. Closed reduction and cast application may be sufficient for Salter-Harris types I and V. However accurate reduction of the joint surface in type III and IV fractures is essential. Salter-Harris Classification of Fractures The Salter or Salter-Harris classification of fractures refers to a specific group of fractures limited to children. These fractures involve an injury to the open physis or growth plate. Radiographs are usually sufficient to make the diagnosis. In some instances, a CT scan or MRI may aid diagnosis. Salter 1 Fracture A Salter 1 fracture involves an injury to the open physis or growth plate. It is a pure distraction injury with force separating the epiphysis of a bone from the metaphysis. Patients with a Salter 1 fracture present with local pain and refuse to use the injured body part. Local swelling and tenderness on examination may be apparent. Causes and Risk Factors A Salter 1 fracture is the result of trauma to a child and should raise suspicion of child abuse. Diagnostic Evaluation Plain radiograph is usually sufficient for diagnosis of a Salter 1 fracture. Magnetic resonance imaging may be necessary when a history of trauma is unclear, and the possibility of infection exists. Treatment and Recommended Follow-up Casting or splinting of the affected area is usually sufficient to treat a Salter 1 fracture. Immobilization for 4-6 weeks is required. These fractures usually have an excellent prognosis, and the physis usually heals with no growth disturbance. However, the child should be followed for at least 1 year for early detection of growth plate problems. Salter 2 Fracture A Salter 2 fracture involves a fracture line that passes from the metaphysis into the physis and traverses the physis but does not pass into the epiphysis or joint. Signs and Symptoms Presents with local pain, refusal to use the injured body part, local swelling and tenderness on examination. Diagnostic Evaluation Plain radiograph is usually sufficient for diagnosis. MRI may be necessary in some rare instances in which a history of trauma is unclear, and the possibility of type 3 or 4 fracture exists. Pearl to Know Salter 2 fracture is a fracture across the physis (growth plate), and into the metaphysis. This fracture usually has a good prognosis, but growth disturbance is possible resulting in shortening or more commonly angulation. This fracture is usually evident on plain xray. MRI may be helpful in confirming the diagnosis in rare cases. Physical examination usually demonstrates mild swelling and tenderness with the child refusing to use the affected body part. Treatment and Recommended Follow-Up Cast or splint is usually sufficient. Immobilization for 4 to 6 weeks is required. In some cases surgical reduction with fixation may be necessary. Salter Harris type 2 fractures usually have an excellent prognosis. The physis usually heals with no growth disturbance. However, the child should be followed for at least one year for early detection of growth plate problems including shortening and angulation of growth. Salter 3 Fracture The Salter 3 fracture demonstrates a fracture line that passes from the physis into the epiphysis and usually exits into the joint. Accurate reduction is required to avoid growth and joint problems. It typically presents with local pain, refusal to use the injured body part, local swelling and point tenderness on examination. Diagnostic Evaluation Plain radiograph is usually sufficient for diagnosis, however, CT scan may be necessary in some instances in which a history of trauma is unclear or the fracture cannot be visualized. Treatment and Recommended Follow-Up Accurate anatomic reduction is essential to avoid joint dysfunction and or growth abnormality. Referral to a pediatric orthopaedic surgeon is necessary. Salter Harris type 3 fractures usually have a guarded prognosis due to the potential growth plate abnormality and intra-articular injury. The child should be followed for at least one year for early detection of growth plate problems. Pearl to Know Salter 3 fracture is an intra-articular fracture. The fracture line passes through the physis and into the epiphysis, often entering the articular surface of the joint. This fracture may not be evident on plain Xray. CT scan may be helpful in confirming the diagnosis. Physical examination usually demonstrates mild swelling and tenderness with the child refusing to use the affected body part. Careful follow up for at least one year is necessary to make an early diagnosis and intervene if growth injury becomes evident. Salter 4 Fracture The Salter 4 fracture line passes from the metaphysis across the physis into the epiphysis and exits into the joint, disrupting the articular cartilage. This fracture has a poorer prognosis that types 1-3 because of the more frequent occurrence of a physeal growth arrest resulting in shortening and or angulation of growth. Signs and Symptoms Presents with local pain, refusal to use the injured body part, local swelling and tenderness on examination. Diagnostic Evaluation Plain radiograph is usually sufficient for diagnosis. CT scan may be necessary in some instances in which the extent of the fracture is unclear. Pearl to Know Salter 4 fracture has a poorer prognosis as the fracture passes from the metaphysis, across the physis into the epiphysis and exits into the joint, damaging the physis and articular cartilage. This fracture may not be evident on plain Xray. CT scan may be helpful in confirming the extent of the fracture and the diagnosis. Physical examination usually demonstrates mild swelling and tenderness with the child refusing to use the affected body part. Treatment and Recommended Follow-Up Because this fracture crosses the physis and the joint surface, accurate anatomic reduction is necessary to avoid growth problems including shortening and angulation of growth. Reduction is necessary to avoid premature arthritis of the joint. Salter Harris type 4 fractures have a poorer prognosis compared to Salter types 1,2,3. The physis injury may result in growth irregularity resulting in shortening or angulation and the joint injury may predispose to early mechanical arthritis of the joint. Following orthopaedic treatment the child should be followed for at least one year to detect early growth plate irregularities. Salter 5 Fracture The Salter 5 fracture is relatively rare; it is a severe injury to the physis due to axial compression, crushing the physis. Growth plate problems are relatively frequent after this injury. Careful follow-up is necessary. Radiographs are often insufficient to make a conclusive diagnosis, a CT scan or MRI may aid diagnosis (see diagnostic evaluation). Signs and Symptoms This fracture usually presents with relatively little swelling. It presents with local pain, refusal to use the injured body part despite minimal radiographic signs, and tenderness on examination. Diagnostic Evaluation Plain radiograph may not be sufficient for diagnosis. CT scan may be necessary in some instances to confirm the diagnosis. Pearl to Know Salter 5 fracture is a pure compression injury with force compressing the epiphysis of a bone. This fracture may not be evident on plain Xray. MRI may be helpful in confirming the diagnosis. Physical examination usually demonstrates mild swelling and tenderness with the child refusing to use the affected body part. Treatment and Recommended Follow-Up Cast or splint is usually sufficient. Immobilization for 4 to 6 weeks is required. Careful follow-up for not less than one year is necessary so that early intervention can be initiated if a growth arrest occurs. Salter Harris type 5 fractures usually have a poor prognosis resulting in early growth plate arrest with limb length shortening. The child should be followed for at least one year for early detection of growth plate problems.

click on the 3-dots to share or print A review of the diagnosis and treatment of envenomations of scorpions. By Stuart M. Caplen, MD Introduction This article will review the diagnosis and treatment of envenomations of scorpions. Whether an individual clinician will commonly treat scorpion envenomations depends on where they are practicing. In the United States, anti-venom for scorpion envenomations has helped reduce morbidity and mortality. Scorpions Poison control centers in the United States receive close to 17,000 reports of scorpion envenomations per year.[28] There are over 1,700 scorpion species around the world but only 25 are lethal to humans. In the United States there are a number of different species but there are two that cause most significant envenomations. The most common is Centruroides sculpturatus, followed by Centruroides vittatus.[29] There has been some taxonomic confusion in the past with Centruroides sculpturatus and Centruroides exilicauda being considered the same species and the names used interchangeably in the literature. However, research has concluded they are two separate species.[30] The Centruroides sculpturatus is also known as a bark scorpion for its ability to climb and can be found in trees, rock walls or house walls as well as under rocks or in crevices. The Centruroides vittatus is also known as the striped bark scorpion due to the marking on its back. Both species are found in Arizona, New Mexico, Texas, California, Utah, Nevada, and in adjacent areas of Mexico.[31.32] The Centruroides exilicauda is found in Mexico and is also known as the Baja California scorpion. Its venom is much less toxic to humans than the other two species.[30] Scorpion Venom[29,31] An adult scorpion is typically two to three inches long,[31] with a stinger on its tail which it uses to paralyze prey to make it easier to eat. It also will sting predators(and humans) when threatened. Infants and children are more sensitive to the neurotoxin than adults. Adults are stung more often than children, however children more frequently suffer from severe illness. Scorpion's venom is composed of multiple neurotoxins, an ACE inhibitor, and a component that inhibits platelet aggregation. The neurotoxins inhibit sodium channels of the peripheral nervous system, causing a prolonged membrane action potential and allowing repetitive axonal firing.[32] Symptom onset is typically within a few minutes after the sting and progresses to its maximal effect within five hours. Patients with only localized symptoms can be safely discharged home if there is no progression of the disease after observation for those five hours. There have been no reported deaths from scorpion envenomation in Arizona since 2013.[28] Scorpion Envenomation[29,32] A grading system has been developed to categorize and assist in the treatment of scorpion stings. Grade I envenomation causes local pain and paresthesias at the sting site. The puncture wound may not be visible. The sting does not usually produce a local inflammatory reaction, making diagnosis in young children and infants difficult. The "tap test" may confirm a provider's suspicion of a sting by sculpturatus by tapping on the area of the sting, causing increased pain. This may not occur with other scorpion species. Supportive care and analgesia are all that is typically required. Grade II envenomation causes local pain and paresthesias at the site of the sting as well as proximal to the sting site. Occasionally there may be radiation to contralateral extremities. Care includes analgesia and possibly anxiolytics if needed. Grade III includes Grade II symptoms with added cranial nerve and bulbar dysfunction (increased oral secretions, blurry vision, rapid tongue movement, nystagmus), or skeletal neuromuscular dysfunction with flailing of the extremities, opisthotonos (tetanus-like hyperextension of the head with arching of the back), or emprosthotonus (forward flexion of the head and feet toward each other) being possible. Autonomic dysfunction may also occur and most commonly symptoms include salivation, vomiting, bronchoconstriction, diaphoresis, and tachycardia. Grade III envenomations can sometimes adversely affect a patient’s airway. In pediatric patients common findings are restlessness, writhing, opsoclonus (uncontrolled chaotic rapid eye movements), tachycardia, and hypersalivation. Patients with Grade III stings generally require analgesia and anxiolytics as well as antivenom. Grade IV envenomations includes both cranial nerve and skeletal muscle dysfunction, which can lead to hyperthermia, rhabdomyolysis, pulmonary edema, and multiple organ failure. Antivenom will be required. Treatment Grades I and II envenomations generally just require supportive care, ice packs, tetanus immunization if needed, analgesia and possibly anxiolytics.[29,32] For Grades III or IV envenomation antivenom and hospital admission may be required. In 2011 Anascorp Centruroides (scorpion) immune F(AB)2 was approved by the FDA, which contains purified fragments of immunoglobulin G that bind and neutralize venom. A typical dose is three to five vials. It is made from horse serum so serum sickness, allergic reactions, and anaphylaxis may occur.[33] Without antivenom, the average time to resolution of symptoms is approximately 30 hours. In one small study of 15 critically ill children, 100% of the antivenom treated patients had resolution of symptoms within four hours versus 14% in the placebo group.[34] Typically, about 2% of all scorpion envenomated patients will require antivenom.[28] Conclusion Fortunately, most of the envenomations from scorpions are not severe. However, severe systemic toxicity can occur. Deaths are rare, especially with the availability of anti-venom for scorpion envenomations. Antihistamines may help with itching and there is one anecdotal case series, not confirmed by other studies, where the author suggested that antihistamines may help with wound healing. References [28] Kang, A Min, and Daniel E Brooks. “Nationwide Scorpion Exposures Reported to US Poison Control Centers from 2005 to 2015.” Journal of medical toxicology : official journal of the American College of Medical Toxicology vol. 13,2 (2017): 158-165. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440315/ [29] Shamoon Z, Peterfy RJ, Hammoud S, et al. Scorpion Toxicity. [Updated 2021 Aug 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK430928/ [30] Norma A. Valdez-Cruz NA et al. Biochemical, genetic and physiological characterization of venom components from two species of scorpions: Centruroides exilicauda Wood and Centruroides sculpturatus Ewing. Biochimie, Volume 86, Issue 6, Pages 387-396. 2004. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/S0300908404000641?via%3Dihub [31] Animal Fact Sheet: Bark Scorpion Arizona-Sonora Desert Museum. 2008. Retrieved from: https://www.desertmuseum.org/kids/oz/long-fact-sheets/Bark%20Scorp.php [32] Huang C. Scorpion's Sting. EMResident. 8/14/2014. Retrieved from: https://www.emra.org/emresident/article/scorpions-sting/ [33] Anascorp® Centruroides (Scorpion) Immune F(ab’)2 (Equine) Package insert. July 2011. Retrieved from: https://www.fda.gov/media/81093/download [34] Boyer LV et al. Antivenom for Critically Ill Children with Neurotoxicity from Scorpion Stings. N Engl J Med 2009; 360:2090-2098. Retrieved from: https://www.nejm.org/doi/full/10.1056/nejmoa0808455 Originally published October 2021

InBrief by Stuart M Caplen, MD In the United States (US), there are approximately 104,000 people on the organ transplant list with a new person added to that list every 10 minutes. Each day, 17 people in the US die waiting for an organ transplant, and about a million people worldwide are in need of a kidney.[1,2] Thus the idea of being able to produce replacement organs is highly desirable. The cost of initiating renal dialysis treatment in US patients is estimated to be around $80,000 for each Medicare patient and $238,000 for a privately insured patient.[3] Medicare costs for continuing renal dialysis treatment are about $40,000 per patient per year.[4] In 2020, according to research published by the American Society of Nephrology, the average cost of a kidney transplant was $442,500.[5] When 3D kidneys become available, costs of removing the kidney from a donor and transporting it to the recipient would be eliminated, but there would be other expenses such as maintaining cell banks that can grow cells for bioinks.[1] However, it is possible that implanting 3D printed organs will be less expensive than traditional transplants[5], and depending on life expectancy, less expensive than renal dialysis. History In 2006 Anthony Atala and his colleagues performed one of the first partial replacement of organs grown from a patient’s own tissue. Seven children with myelomeningocele* who had high-pressure or poorly compliant bladders were determined to be candidates for cystoplasty**. A biopsy was performed and bladder and muscle cells were taken from the patients and those cells were allowed to proliferate in the laboratory. They spread a layer of the cells on the outside of a bladder-shaped, biodegradable mold of synthetic polymer and collagen, with muscle on the outside and bladder urothelial cells on the inside. The organ part was bathed in nutrients for about seven weeks, at which time they were then successfully surgically attached to the patient's bladder. Subjects that had omentum wrapped around the implant had the most improvement in bladder function.[6,7] (* A condition where the spine does not fuse properly and the infant is born with a sac containing part of the spinal cord.) (** Surgery to enlarge the urinary bladder.) More recently the idea of using 3D printers to produce organs has been explored. The term “3D printing” was first coined by Charles W. Hull in 1986. He named the method “stereolithography,” and used a thin layer of materials sequentially printed layer by layer with UV light to form a 3D structure [8]. This method was later modified using biomaterials to form 3D printed scaffolds of cells. Biomaterials are natural or synthetic substances containing living stem cells, which are also called bioinks and are the key components of bioprinting.[8] The 3D Bioprinting Process To begin the process of bioprinting an organ, doctors typically start with a patient’s own cells. The process involves taking a small needle biopsy of an organ or performing a minimally invasive surgical procedure that removes a small piece of tissue. This tissue is processed and put inside a sterile incubator or bioreactor, which is a pressurized stainless-steel vessel that duplicates the body’s oxygen and temperature levels and supplies the cells with individualized nutrients that vary by cell type. Those cells are then combined with a gel, to produce a bioink, which is a printable mixture of living cells, water-rich molecules called hydrogels, and the media and growth factors that help the cells continue to proliferate and differentiate. The hydrogels mimic the human body’s extracellular matrix, which contains substances including proteins, collagen and hyaluronic acid. Collagen and gelatin are two of the most common biomaterials used for bioprinting tissues or organs. Biomaterials typically are nontoxic, biodegradable and biocompatible to avoid a negative immune response. The bioink is then loaded into a printing chamber in a 3D printer. A printhead and nozzle are used to extrude the bioink and build the material up layer by layer. Similar to a color printer where you have several different cartridges, where each cartridge prints a different color, bioprinting uses different type cells instead of ink. The length of the printing process depends on the organ or tissue being printed, the fineness of the resolution and the number of printheads needed. Depending on the organ’s complexity, there is sometimes a need to mature the tissue further in a bioreactor. While organs or partial organs can be produced by 3D printing now, the issue of connecting it to the patient’s vascular and nervous system and have it actually function has not been solved, and it is estimated by some experts that it may take at least another decade to do so.[1] In the 3D bioprinting process a computer-generated model first needs to be produced as a template for the 3D printer to follow. Computer-aided design in the future will allow patient individualization of a 3D printed organ by the printers being programmed with data from a patient’s imaging scans. 3D printing of organs is technically very difficult. Just a few of the issues involved in reproducing a lung are requirements to produce very small individual alveoli and their surrounding vascular structures, duplicating a dual vascular system, and creating ciliated cells in the mucosa.[8] The Future of 3D Organ Printing In 2014, a California-based company called Organovo was the first to successfully engineer commercially available 3D bioprinted human liver and kidney tissue. Although the tissue is actual liver and kidney tissue, it is not usable at the present time for transplants, but can be used for research purposes. One published example is using 3D printed liver tissue for drug testing, to determine if there are any toxic effects on liver cells from the drug being tested.[5,10] There is now animal experimentation using rat omental tissue or progenitor cells from bone marrow to create cardiac tissue which is then grafted onto their hearts.[11,12] In one study, after implanting a patch of cardiac cells in rats who had induced myocardial infarctions, the implants improved cardiac function.[11] Researchers are also attempting to use spider web silk as the framework for cardiac bioprinting, as spider silk is felt to be an excellent source to produce hydrogels needed for 3D printing.[13,14] Ureters, the esophagus, bile ducts, urethras, intestines, skeletal muscle and bone are all areas of current interest in organ bioprinting, and it is possible in the future that almost any body part might be able to be reproduced.[8] With respect to the time frame of 3D printing being used clinically, it is felt that organs such as skin may be the first tissue to be successfully bioprinted. It is predicted the next stage will be production of hollow tubes such as blood vessels, followed by hollow organs such as urinary bladders and finally, much further in the future, solid organs.[15] Conclusion In the future, 3D bioprinting of tissue and organs may become the preferred way of treating patients who require organ or tissue transplants. The technology is in its infancy, and while tissue from organs can be produced now, and used for research purposes, the tissue is not functional due to the complexity and multiple functions of real human organs. It is estimated it might take at least a decade to be able to solve some of these problems and actually use 3D printed organs clinically. References [1] Rogers K. When we’ll be able to 3D-print organs and who will be able to afford them CNN Health. Updated March 10, 2023. Retrieved from: https://www.cnn.com/2022/06/10/health/3d-printed-organs-bioprinting-life-itself- wellness-scn/index.html [2] Organ Donation Statistics. Department of Health & Human Services Health Resources & Services Administration. Last Reviewed: March 2023. Retrieved from: https://www.organdonor.gov/learn/organ-donation- statistics#:~:text=Who%20is%20on%20the%20Transplant,the%20national%20transplant %20waiting%20list. [3] League RJ et al. Assessment of Spending for Patients Initiating Dialysis Care. JAMA Network Open. October 28, 2022. Retrieved from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797907 [4] Pockros BM, Finch DJ, Weiner DE. Dialysis and Total Health Care Costs in the United States and Worldwide: The Financial Impact of a Single-Payer Dominant System in the US. J Am Soc Nephrol. 2021;32(9):2137-2139. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729831/ [5] 3D-printed organs and their affordability. Global data. June 15, 2022. Retrieved from: https://www.medicaldevice-network.com/comment/3d-printed-organs-affordability/ [6] Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006;367(9518):1241-1246. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/16631879/ [7] Pearson H. Scientists grow bladder replacement in lab. Nature. 4 April 2006. Retrieved from: https://www.nature.com/news/2006/060403/full/news060403-3.html#B1 [8] Panja N, Maji S, Choudhuri S, Ali KA, Hossain CM. 3D Bioprinting of Human Hollow Organs. AAPS PharmSciTech. 2022;23(5):139. Published 2022 May 10. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9088731/ [9] Ramadan Q and Zourob M (2021) 3D Bioprinting at the Frontier of Regenerative Medicine, Pharmaceutical, and Food Industries. Front. Med. Technol. 2:607648. Retrieved from: https://www.frontiersin.org/articles/10.3389/fmedt.2020.607648/full [10] Nguyen DG, Funk J, Robbins JB, et al. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro. PLoS One. 2016;11(7):e0158674. Published 2016 Jul 7. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936711/ [11] Atluri P, Trubelja A, Fairman AS, et al. Normalization of postinfarct biomechanics using a novel tissue-engineered angiogenic construct. Circulation. 2013;128(11 Suppl 1):S95-S104. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111241/ [12] Dvir T, Kedem A, Ruvinov E, et al. Prevascularization of cardiac patch on the omentum improves its therapeutic outcome. Proc Natl Acad Sci U S A. 2009;106(35):14990-14995. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2736451/ [13] Crawford M. 3D-printed spider silk can grow heart muscle cells. The Alliance of Advanced Biomedical Engineering. October 23, 2017. Retrieved from: https://aabme.asme.org/posts/3d-printed-spider-silk-can-grow-heart-muscle-cells [14] Petzold, J., Aigner, T. B., Touska, F., Zimmermann, K., Scheibel, T., Engel, F. B., Adv. Funct. Mater. 2017, 27, 1701427. Retrieved from: https://onlinelibrary.wiley.com/doi/10.1002/adfm.201701427 [15] Murphy, S., Atala, A. 3D bioprinting of tissues and organs. Nat Biotechnol 32, 773– 785 (2014). Retrieved from: https://www.nature.com/articles/nbt.2958

Babesiosis is a potentially fatal tick-borne illness. Exploring the life and feeding cycle of Babesia and the symptoms, testing, and treatments of Babesiosis. Diagnosis of Babesiosis can be challenging, as the tick bite may not have been noticed, clinical symptoms may be non-specific, and laboratory confirmation of infection can be problematic, especially early in the course of these diseases. At times clinicians may need to treat on clinical suspicion alone especially if you live in the Northeast or the upper Midwest. 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” . BABESIOSIS (Part 4) by Stuart M. Caplen, MD Babesiosis is typically caused by a microscopic parasite Babesia microti that infects red blood cells. There are other species of Babesia that can cause infection, but B. microti is the most common. It is transmitted by bites from infected Ixodes scapularis ticks (also called blacklegged ticks or deer ticks), but occasionally can be transmitted by blood transfusion, or congenitally from mother to infant.[37] It is typically seen in the Northeast and upper Midwest. In 2018, 2,161 cases of babesiosis were reported to the CDC.[38] Babesia Life Cycle The Babesia microti life cycle involves two hosts, most commonly the white-footed mouse, Peromyscus leucopus, and a tick in the genus Ixodes. During a blood meal, a Babesia-infected tick introduces sporozoites into the mouse host. Sporozoites enter erythrocytes and undergo asexual reproduction (budding). In the mouse’s blood, some of the spores differentiate into male and female gametes. These gametes can be ingested by another tick, unite and form more sporozoites. The Babesia-infected tick then can introduce the sporozoites into a human host during a blood meal. The sporozoites enter erythrocytes and undergo asexual replication, (budding) which then is responsible for the clinical manifestations of the disease.[39] Symptoms of Babesiosis [40] Many people who are infected with Babesia microti feel fine, and do not have any symptoms. Others develop nonspecific flu-like symptoms, such as fever, chills, sweats, headache, body aches, loss of appetite, nausea, or fatigue. As Babesia parasites infect and destroy red blood cells, a hemolytic anemia leading to jaundice(skin turning yellow from destruction of red blood cells) may occur. Some patients may have an enlarged spleen or liver. 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, concurrent B. microti infection is an important consideration. Laboratory Findings in Babesiosis [41] For acutely ill patients, the findings on routine laboratory testing frequently include hemolytic anemia(destruction of red blood cells) and thrombocytopenia(low platelet count). Additional findings may include kidney dysfunction and elevated levels of liver enzymes. Testing for Babesiosis [42] Diagnosis can be made by microscopic examination of thick and thin blood smears which are Giemsa stained. Repeated smears may be needed sometimes to detect parasites. Babesia microti in Giemsa-stained blood smears [42] Antibody testing may be useful in asymptomatic patients who are donating blood, or if the diagnosis is uncertain after a blood smear is checked. An antibody test using B. microti parasites as antigen detects antibodies in88-96% of patients with a B. microti infection.The extent of cross-reactivity between Babesia species is variable. A negative result with B. microti antigen for a patient exposed on the West Coast of the U.S. may be a false-negative, and the patient should be specifically be tested for antibodies to Babesia duncani. PCR testing can be used to confirm the diagnosis after a positive blood smear to identify the species and also differentiate it from malarial species, such as Plasmodium falciparum, which can look similar microscopically. Treatment of Babesiosis [43] Most asymptomatic persons do not require treatment. Treatment decisions should be individualized, especially for patients who are at risk for severe disease such as patients without a spleen or immunosuppressed individuals. For ill patients, babesiosis usually is treated for at least 7-10 days with a combination oftwo medications — typically either: Atovaquone PLUS azithromycin; OR Clindamycin PLUS quinine (this combination is the standard of care for severelyill patients). Atovaquone is pregnancy category C and the risk to the fetus is unknown. Because there is data about the safe administration of quinine plus clindamycin during pregnancy, this drug combination is generally recommended for treatment of symptomatic babesiosis during pregnancy. An infectious disease consult is recommended when treating a pregnant patient. Initiation of antibiotic therapy, especially in children, should be determined only after careful discussion with your physician/provider. Conclusion Given that diagnostic testing for these tickborne diseases is not 100% sensitive, and symptoms initially may be non-specific, a clinician in an endemic area should keep tickborne infections in mind when considering diagnoses in an ill patient without a clear cause. Unexplained fever, anemia, thrombocytopenia, leukopenia, new onset heart block, myocarditis, pericarditis, cranial nerve palsies, or arthritis can be seen as potential clues to a tickborne infection. A specific history of tick bites may be helpful, although the patient might not even know they have been bitten. Antibiotic prophylaxisfor Lyme disease, when appropriate, will help reduce the incidence of symptomatic disease. While this article is just about four tickborne infections, keep in mind that ticks can transmit many different infections including: Borrelia miyamotoi disease, Colorado tick fever, Heartland and Bourbon virus diseases, Pacific Coast tick fever, Powassan virus disease, Rocky Mountain spotted fever, Rickettsia parkeri rickettsiosis, Rickettsialpox, Tickborne relapsing fever, and Tularemia.[44,45] Author’s Note: Recommended medications are based on current recommendations, and are correct to the best of my knowledge. However, treatment recommendations may change, and readers are advised to review the most current dosages, medications and contraindications with their physician/provider prior to treatment. #InfectiousDisease More TICK-BORNE Disease articles: Lyme | Ehrlichiosis | Anaplasmosis 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 [37] Parasites- Babesiosis, General Information, CDC, last reviewed: April 11, 2018. Retrieved from:https://www.cdc.gov/parasites/babesiosis/gen_info/index.html [38] Swanson M, Gray EB, Surveillance for Babesiosis — United States, 2018, Annual Summary, CDC, Data current as of: April 22, 2019. Retrieved from: https://www.cdc.gov/parasites/babesiosis/resources/babesiosis_surveillance_summary_2018.pdf [39] Babesiosis, DPDx - Laboratory Identification of Parasites of Public Health Concern, CDC, last reviewed: October 30, 2017. Retrieved from: https://www.cdc.gov/dpdx/babesiosis/index.html [40] Parasites – Babesiosis Resources for Health Professionals, CDC, last reviewed: October 30, 2019. Retrieved from: https://www.cdc.gov/parasites/babesiosis/health_professionals/index.html [41] Babesiosis, Laboratory diagnosis, DPDx - Laboratory Identification of Parasites of Public Health Concern, CDC, last reviewed: October 30, 2017. Retrieved from: https://www.cdc.gov/dpdx/babesiosis/index.html [42] Photo credit- Babesiosis Image Gallery, DPDx - Laboratory Identification of Parasites of Public Health Concern, CDC, last reviewed: October 30, 2017. Retrieved from: https://www.cdc.gov/dpdx/babesiosis/index.html [43] Parasites – Babesiosis, Resources for Health Professionals- Treatment, CDC, last reviewed: October 30, 2019. Retrieved from: https://www.cdc.gov/parasites/babesiosis/health_professionals/index.html#tx [44] Diseases Transmitted by Ticks, CDC, last reviewed: April 2, 2020. Retrieved from: https://www.cdc.gov/ticks/diseases/index.html [45] Other Spotted Fever Group Rickettsioses, CDC, last reviewed: January 18, 2019. Retrieved from:https://www.cdc.gov/otherspottedfever/ initially posted: September 28, 2021

A review of the diagnosis and treatment of envenomations of brown recluse spiders. By Stuart M. Caplen, MD Introduction This article will review the diagnosis and treatment of envenomations of brown recluse spiders. Whether an individual clinician will commonly treat these envenomations depends on where in the country they are practicing. Brown Recluse Spiders The brown recluse spider or Loxosceles reclusa, is found mainly in the Midwest and Southcentral regions of the U.S.[5] It is also called the violin or fiddleback spider because of a violin-shaped marking on its back. An adult brown recluse spider with its legs extended is about 1 to 1.5 inches long.[6] They prefer dark areas such as under tree bark and rocks. Indoors they may be found in attics, closets, drawers or under bed sheets. These spiders generally only bite as a defense mechanism when they are crushed or pressed on.[5] Brown Recluse Venom The spider venom is cytotoxic and hemolytic and can cause a syndrome called dermonecrotic arachnidism.[5] Sphingomyelinase D is a major component of the venom that can cause hemolysis and activate the complement system. There are other proteases in the venom that degrade collagen, fibronectin, fibrinogen, gelatin, and elastin basement membranes that have a synergistic effect with sphingomyelinase D leading to many of the skin findings detailed below. Hyaluronidase, alkaline phosphatase, esterase, and ATPase are also involved with the skin manifestations.[5] Brown Recluse Spider Envenomation The initial bite is usually painless until three to eight hours later when the bite may become red, swollen and tender. The majority of brown recluse spider bites remain localized, healing within three weeks without serious complication or need of medical intervention. In more severe envenomations, the victim may develop a necrotic lesion appearing as a dry sinking bluish patch with irregular edges, peripheral erythema and frequently central pallor or a blister. An elevated lesion is not typical of a brown recluse bite. As the venom continues to destroy tissue, the wound may expand up to several inches over a period of days or weeks. The necrotic ulcer can persist for several months leaving a deep scar.[6] Systemic symptoms such as chills, malaise, nausea, headache, dizziness and myalgias may also occur. In children, the elderly, or people with existing medical problems, the systemic reaction may be more severe and may include weakness, fever, joint pain, hemolytic anemia, thrombocytopenia, organ failure, disseminated intravascular coagulation, seizures, and death.[5,6] In children, systemic symptoms may occasionally occur without skin findings and should be considered in the differential of acute hemolytic anemia in regions known to have the brown recluse spiders. Hemolysis has been reported up to seven days after a bite so follow up instructions should be given to parents of children even if there are no systemic findings during the initial visit.[5] Diagnosis of Brown Recluse Spider Bites Misdiagnosis of brown recluse spider bites is common. Frequently methicillin resistant staphylococcus aureus(MRSA) abscesses are misidentified as a brown recluse spider bite. Unlike a brown recluse bite, MRSA abscesses may be crusted, purulent, and elevated. A mnemonic NOT RECLUSE has been created to help physicians determine if a skin lesion is or is not from a brown recluse spider. The authors suggest that if 2 or more NOT RECLUSE signs are present, a brown recluse spider bite is a less likely cause of the lesion(s).[7] N – Numerous - A typical recluse bite is a single lesion, but occasionally can be two bites. Multiple lesions indicate some other rash or insect bite O – Occurrence - Most commonly a recuse spider bite involves disturbance of the spider, in bed or hiding in a closet, attic or garage. If no such disturbance is noted, another diagnosis should be considered. T – Timing - Recluse bites are most commonly seen from April to October, although occasionally they can be seen in the winter if the spider is disturbed. If the skin lesion occurs outside of this time frame, another diagnosis should be considered. R – Red Center - A lesion with a red center is generally not a recluse spider bite. Due to tissue ischemia near the bite, the central part of the lesion will be pale, blue-white, or purple. There may be erythema around the lesion due to cytokine release. E – Elevated - Recluse bites are generally flat or sunken. If the lesion is elevated another diagnosis should be considered. C – Chronic - Most recluse bites, except those with a large amount of tissue destruction, heal within three months and it may be as little as three weeks for smaller lesions. Incomplete healing of the lesion suggests another diagnosis. L – Large - The largest brown recluse bite injury generally does not exceed ten centimeters, although there may be a larger area of erythema around the wound. Very large lesions suggest another diagnosis, possible pyoderma gangrenosum. U – Ulcerates Too Early - Recluse bites do not typically ulcerate until seven to 14 days after envenomation. S – Swollen - Recluse bites typically do not cause massive swelling below the neck or above the feet. There may be significant swelling in recluse bites to the feet or eyelids. Swelling of lesions on the body suggests another diagnosis. E – Exudative - With the exceptions of eyes and toes, recluse bites are not initially exudative, moist, or purulent. If pus is seen, another diagnosis hold be considered. Treatment Ice packs and arm elevation are initial first aid for brown recluse bites. Sphingomyelinase D has been shown to have less activity in colder temperatures.[8] Tetanus immunization should be updated if necessary.[5] Antihistamines may be used for itching. There is one article in the literature by a physician who initially in his career did many surgical excisions for brown recluse bites and then he started prescribing antihistamines for seven to ten days. He reported that by using antihistamines in a series of 100 brown recluse bites, he did not need to perform any more surgical excisions. However, there does not appear to be any other clinical studies in the medical literature supporting this claim.[9] Prophylactic antibiotics are not recommended.[10] While most brown recluse spider bites do not require any specific therapy, suggested therapies in the literature for more severe envenomations include dapsone, corticosteroids, antivenom, and surgical excision. Unfortunately, there is a dearth of randomized studies of treatment modalities and some conflicting results. Antivenom is not currently available in the U. S., although there is one available in South America.[11] Use of dapsone for brown recluse spider bites is controversial with conflicting animal studies, but is considered a therapeutic option. Its use is based on its ability to inhibit polymorphic leukocytes which ameliorates some of the venom’s effects.[12,13,14] There may be serious side effects associated with the use of dapsone such as dose-related hemolysis, agranulocytosis, aplastic anemias, and methemoglobinemia.[15] Because of these potential serious side effects, dapsone should be reserved for adult patients who have rapidly progressing necrotic lesions. It is not recommended for children. Adults who are selected to receive dapsone should first be screened for glucose-6-phosphate dehydrogenase deficiency, to prevent hemolysis.[15] One study found no difference in wound healing between dapsone and brown recluse antivenom each alone or combined, although it was felt that dapsone had eliminated the need for surgical excision in some patients.[13] Another animal study compared early surgical excision to delayed surgical excision after dapsone and found use of dapsone prior to surgery decreased scarring, complications and in one case the need for surgical excision.[14] They also found the use of corticosteroids or early surgical excision in an animal model were not effective therapies. If needed, surgical excision of a brown recluse lesion should be delayed until the wound edges are clearly demarcated. Skin grafting may be required for large lesions.[15] Hyperbaric oxygen has been found in one animal study to reduce necrosis from brown recluse envenomation when administered within 48 hours, although other animal studies found no beneficial effect or histologic improvement without obvious clinical benefit from hyperbaric therapy. [16,17,18] Hyperbaric oxygen has also been postulated to decrease wound damage secondary to brown recluse envenomation in at least two ways. It is thought that wound damage is decreased in part because hyperbaric oxygen inactivates sphingomyelinase D by the disruption of sulfhydryl groups. Hyperbaric oxygen therapy also increases the production of collagen by fibroblasts, thereby facilitating wound healing.[15] There are someanimal studies and case reports that have demonstrated some improvement of brown recluse skin lesions with hyperbaric therapy acutely, as well as in patients with non-healing wounds.[16,17,18,19] Conclusion Fortunately, most of the envenomations from brown recluse spiders are not severe. However, severe systemic toxicity can occur. Disfiguring scars with deep tissue penetration are possible with brown recluse spider bites. Treatment protocols for severe brown recluse spider bites are hampered by a lack of good scientific evidence, although ice packs, dapsone in adults, hyperbaric therapy and delayed surgical excision, if needed, are most frequently recommended. Antihistamines may help with itching and there is one anecdotal case series, not confirmed by other studies, where the author suggested that antihistamines may help with wound healing. References [5] Anoka IA, Robb EL, Baker MB. Brown Recluse Spider Toxicity. [Updated 2020 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Last Update: August 10, 2020. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK537045/ [6] Potter MF. Brown Recluse Spider. University of Kentucky College of Agriculture, Food and Environment. Last revised 7/12/18. Retrieved from: https://entomology.ca.uky.edu/ef631 [7] Stoecker WV, Vetter RS, Dyer JA. NOT RECLUSE—A Mnemonic Device to Avoid False Diagnoses of Brown Recluse Spider Bites. JAMA Dermatol. 2017;153(5):377–378. Retrieved from: https://jamanetwork.com/journals/jamadermatology/article-abstract/2603498 [8] Merchant ML, Hinton JF, Geren CR. Sphingomyelinase D activity of brown recluse spider (Loxosceles reclusa) venom as studied by 31P-NMR: effects on the time-course of sphingomyelin hydrolysis. Toxicon. 1998 Mar;36(3):537-45. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/9637373/ [9] Wilson JR et al. Brown Recluse Spider Bites: A Complex Problem Wound. A Brief Review and Case Study. Wound Care Learning Network. March 2005. Retrieved from: http://www.o-wm.com/content/brown-recluse-spider-bites-a-complex-problem-wound-a-brief-review-and-case-study [10] Carlton Jr. PK. Brown recluse spider bite? Consider this uniquely conservative treatment -An antihistamine and observation work as well—and often better—than more intensive therapies. The Journal of Family Practice. Vol 58, No. 2. February 2009. Retrieved from: https://cdn.mdedge.com/files/s3fs-public/Document/September-2017/5802JFP_Article7.pdf [11] Tavener B. Biting back: Taking the sting out of spider venom. BBCNews. 3 August 2013. Retrieved from: https://www.bbc.com/news/health-23408949 [12] Ree R et al. Annals of emergency Medicine. The Diagnosis and Treatment of Brown Recluse Spider Bites. 16:9 September 1987. Retrieved from: https://www.annemergmed.com/article/S0196-0644(87)80738-2/fulltext [13] Rees, R S et al. “Brown recluse spider bites. A comparison of early surgical excision versus dapsone and delayed surgical excision.” Annals of surgery vol. 202,5 (1985): 659-63. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1250983/?page=1 [14] King LE, Rees RS. Dapsone Treatment of a Brown Recluse Bite. JAMA. 1983;250(5):648. Retrieved from: https://jamanetwork.com/journals/jama/article-abstract/387593 [15] Forks TP. Brown Recluse Spider Bites. J Am Board Fam Pract 2000;13:415-23. Retrieved from: https://www.jabfm.org/content/jabfp/13/6/415.full-text.pdf [16] Maynor ML, Moon RE, Klitzman B, Fracica PJ, Canada A. Brown recluse spider envenomation: a prospective trial of hyperbaric oxygen therapy. Acad Emerg Med. 1997 Mar;4(3):184-92. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/9063544/ [17] Phillips S, Kohn M, Baker D, et al. Therapy of brown spider envenomation: a controlled trial of hyperbaric oxygen, dapsone, and cyproheptadine. Ann Emerg Med 1995;25:363-8. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/7864478/ [18] Strain GM, Snider TG, Tedford BL, Cohn GH. Hyperbaric oxygen effects on brown recluse spider (Loxosceles reclusa) envenomation in rabbits. Toxicon. 1991;29(8):989-96. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/1949069/ [19] Hadanny A, Fishlev G, Bechor Y, Meir O, Efrati S. Nonhealing Wounds Caused by Brown Spider Bites: Application of Hyperbaric Oxygen Therapy. Adv Skin Wound Care. 2016 Dec;29(12):560-566. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/27846029/ Originally published October 2021

If untreated, otosclerosis can lead to a combined conductive and sensorineural hearing loss as damage impinges on the cochlea and other inner-ear structures. Otolaryngology In Brief by Justin Cole, MD and Michael Bergstein, MD Otosclerosis is a pathological remodeling of the bones within the otic capsule that occurs at a faster rate than normal, resulting in bony deposits that damage ossicles and other conducting structures. If untreated, it can lead to a combined conductive and sensorineural hearing loss as damage impinges on the cochlea and other inner-ear structures. Signs and Symptoms Otosclerosis presents as progressive loss of hearing that is worse at lower frequencies. Patients report hearing deeper voices and vowel sounds during normal conversation. Some 50% of patients have tinnitus, and 10% complain of vertigo.If otosclerosis is present, there is about an 80% chance that it exists bilaterally. Progression is directly proportional to the degree of hearing loss. Otoscopic exam is typically normal. Some patients exhibit Schwartz sign, which is a pink-red spot on the promontory of the tympanic membrane. Results of the Hearing Handicap Inventory for the Elderly Screening Version (HHIE-S) questionnaire correlateswith hearing loss verified on audiometric findings. Results of the Whisper test and audioscope also correlate with audiometric findings. Use of the tuning fork, including theRinne and Weber tests, are not recommended in assessing otosclerosis. NOTE: Hearing screening may be a useful diagnostic aid, although it is not a substitute for formal audiometry, which should be conducted in all cases of suspected otosclerosis. Causes and Risk Factors Otosclerosis may be autosomal-dominant with incomplete penetrance; ~ 60% of patients report a family history of otosclerosis. Measles exposure may predispose for the condition, but the mechanism behind this process has not been elucidated. Pearl to Know Suspect otosclerosis if there is a family history of hearing loss or if hearing loss becomes worse during times of increased hormone production (eg, puberty, pregnancy, menopause). The disease is histologically present in 12% of Caucasians; only 0.2%-0.3% exhibit signs and symptoms. It is much less common in all other ethnic groups. It affects females more frequently than it does males. Treatment Options Stapes surgery corrects otosclerosis-associated conductive hearing loss, but it will not restore sensorineural hearing loss from extension of disease into the inner ear. In a stapedectomy, the stapes footplate and crura are removed and replaced with a prosthesis. In a stapedotomy, a small hole is created in the stapes footplate through which a prosthesis is placed, without removal of the stapes. A cochlear implant is an option for patients with sensorineural hearing loss, although it may be difficult to implant in otosclerotic patients. Furthermore, there is increased risk of cochlear ossification. Thebone conduction implant is an option for patients with conductive or combined conductive/sensorineural hearing loss. This device is implanted in the temporal bone behind the ear and transmits sound waves directly to the cochlea. It typically requires only unilateral implantation; it is strong enough to stimulate the contralateral cochlea. A middle-ear implant requires the presence of, and amplified conduction through, the ossicular chain and are only implanted concurrently or shortly following stapes surgery. There is limited evidence supporting the use of pharmacologic therapy in otosclerosis. #ENT REFERENCES Batson L, Rizzolo D. Otosclerosis: An update on diagnosis and treatment. JAAPA. 2017;30:17-22. Michels T, Duffy M, Rogers D. Hearing Loss in Adults: Differential Diagnosis and Treatment. Am Fam Physician. 2019Jul15;100(2):98-108. Toscano M, Shermetaro C. Stapedectomy. StatPearls [Internet]. Last Update:January 12, 2021. Initially published June 21, 2021

Recently, the K2 form of vitamin K has been suggested to have a role in reducing the risk of bone loss, cardiovascular disease, and potentially, other chronic diseases. These roles in disease prevention have inspired supplement manufacturers to bottle and market supplements of vitamin K2. Should we be taking them? NutritionCulinary Medicine by Lori A Smolin, PhD and Mary B Grosvenor, MS, RD The function of vitamin K was first recognized in 1936 when chickens fed a fat-free diet developed severe bleeding. This essential fat-soluble vitamin is needed for the coagulation, or clotting, of blood. The chickens were not able to absorb the vitamin without adequate fat in their diets and hence their blood did not clot normally. Likewise in humans, when vitamin K is deficient, blood clotting is delayed. Other health problems have also been attributed to reduced levels of this vitamin. There are two forms of vitamin K: K1 (phylloquinone) and K2 (a series of menaquinones). [1] Recently, the K2 form of the vitamin has been suggested to have a role in reducing the risk of bone loss, cardiovascular disease, and potentially, other chronic diseases. [2-5] These roles in disease prevention have inspired supplement manufacturers to bottle and market supplements of vitamin K2. Should we be taking them? Sources of Vitamin K Vitamin K1 is found in plants, primarily leafy green vegetables, such as spinach, kale, broccoli, and collard greens; soybeans, vegetable oils, and some fruits are also good sources (see Table). Vitamin K2 is found in small amounts in animal-based foods including fish, meat, eggs, and dairy. Most K2 is synthesized by bacteria, so it is found in fermented foods like cheese and pickled vegetables. One of the best sources is natto, a traditional Japanese dish made from fermented soybeans. Vitamin K2 is also synthesized both in the body from K1 and by the intestinal microbiota. [6] Some of the K2 synthesized in the gut is absorbed and can satisfy part of our requirement for vitamin K. [1] Vitamin K in the Body Both forms of vitamin K act as cofactors for an enzyme that activates vitamin K-dependent proteins, but vitamins K1 and K2 differ in their absorption rates, tissue distribution, and target activity. [2] Vitamin K1 is absorbed more quickly but is also eliminated faster than K2. Once absorbed, K1 is concentrated in the liver, where it activates proteins needed for coagulation. Vitamin K2 is distributed throughout the body where it activates proteins involved in a wide range of biological functions including those needed to calcify bone and to prevent calcification of blood vessels. [4] These extra-hepatic functions of vitamin K2 are linked to reducing the risk of osteoporosis, cardiovascular disease, and other chronic diseases. [2,7] The recommended intake for vitamin K is based on the amount of K1 consumed by healthy individuals who do not show signs of delayed blood clotting. [8] Hence, vitamin K status has historically been evaluated by assessing dietary intake or blood clotting time. While deficiency is rare, young infants are at risk because little vitamin K is obtained in utero or from breast milk and their gut microbiota has not yet been established. [1,2] Deficiencies may also occur in conditions that disrupt the intestinal microbiota or severely limit intake and/or absorption of fat such as bariatric surgery and malabsorption syndromes, like celiac disease and ulcerative colitis. [1] Medications that increase the risk of deficiency include those that interfere with fat absorption, such as bile sequestrants, and long-term antibiotic use, which kills the gut bacteria that produce vitamin K. The blood thinner warfarin (coumadin) reduces blood clotting by blocking vitamin K activity. Those taking warfarin need to consume adequate and consistent amounts of vitamin K to meet needs without interfering with coagulation; large variations in vitamin K intake can increase or decrease warfarin’s anticoagulant effect. Looking beyond the coagulation function of vitamin K, it is now recognized that deficiencies of the K2 form of the vitamin can lead to conditions that reflect the other roles of this form of the vitamin. Vitamin K2 and Bone Health Vitamin K is important for bone health because it is needed to activate osteocalcin, a protein that facilitates the deposition of calcium into bone, as well as several other proteins important for healthy bones. Observational and interventional studies have investigated the effect of vitamin K on bone mineral density and fracture risk in healthy and osteoporotic individuals. Many studies link higher vitamin K intakes with higher bone mineral density and/or lower hip fracture incidence. [1,6,9] Some studies support the use of vitamin K2 supplements for the prevention of osteoporosis. For example, a meta-analysis of randomized controlled trials of K2 supplementation in postmenopausal women found a positive association between supplements and bone mineral density and reduced fracture incidence. [10] However, small study sample sizes and differences in the population studied and the type of supplement used have made it difficult to draw definitive conclusions about whether to recommend vitamin K2 supplements to prevent and treat osteoporosis. [5,6] Vitamin K2 and Heart Health Vitamin K2 appears to play a pivotal role in two important chronic health problems that involve calcium – bone loss and calcification of soft tissue. [11] Several vitamin K-dependent proteins are involved in preventing calcification of the arteries, which can lead to atherosclerosis and high blood pressure. Some studies have found an association between high vitamin K2 intake and reduced vascular calcification and cardiovascular disease risk, but supplements have not consistently been found to prevent the progression of these conditions. [12,13] Available studies are small and heterogeneous in terms of the type and dose of vitamin K administered, the population studied, and the outcomes measured. [14] More well controlled long-term studies are needed to confirm a role for K2 supplements in preventing vascular calcification and consequently atherosclerosis and hypertension. Vitamin K2 and Other Chronic Diseases The relationship between vitamin K and other chronic diseases is less clear than its roles in osteoporosis or cardiovascular disease. While no large long-term clinical trial results are available, there are many small studies showing interrelationships between vitamin K2 status, intake, and/or supplementation and various chronic diseases. The potential roles of vitamin K2 in kidney disease, diabetes, arthritis, and cancer are hypothesized to be related to the activation of extrahepatic vitamin K-dependent proteins as well as its function in cell proliferation, inflammation, and as an antioxidant. [2,5,7] The role of vitamin K in chronic kidney disease (CKD) is multifactorial. Vitamin K status is often poor in patients with CKD due to dietary restrictions as well as to medications, such as phosphate binders, that reduce bioavailability of the vitamin. Poor vitamin K status has been associated with increased proteinuria and renal function decline. In addition, vitamin K plays a role in both vascular calcification and decreased bone density, complications that increase as CKD progresses. Supplemental K2 has been shown to slow the progression of the disease and reduce these complications. [15] In diabetes, vitamin K2 supplementation has been shown to promote the proliferation of insulin-producing beta cells and to increase insulin sensitivity. [4,7] The antioxidant and anti-inflammatory properties of K2 have been suggested to play a role in reducing the symptoms of rheumatoid arthritis. [3] Supplemental vitamin K2 has also been studied in the treatment of several cancers with promising results. [2] While some studies have found vitamin K2 supplements to improve disease outcomes, more research is needed to elucidate mechanisms and confirm the effectiveness of vitamin K2 for these conditions. Do We Get Enough K2? Although reduced blood clotting due to vitamin K deficiency is rare, low vitamin K2 status has been documented in older adults and in people with age-related diseases, including osteoporosis, cardiovascular disease, and CKD. [2,12] As discussed above, there are many small studies that show supplemental K2 may help prevent or slow the progression of these ailments. [9,12,15] Despite these data, it is not possible to definitively conclude that we get don’t get enough vitamin K2. This is due in part to the fact that studies of vitamin K intake consider primarily K1 because food composition data for K2 are limited. [1,16] In addition, we don’t know how much K2 we get from synthesis by the microbiota or from conversion of K1 to K2 in the body. The recognition that current recommendations may be insufficient to provide for all of the functions of the vitamin has led to the suggestion there be a separate recommendation for vitamin K2. [16] Should You Take a K2 Supplement? There is increasing evidence that our intake of vitamin K2 is too low to support optimal health. And no adverse effects of vitamin K2 from food or supplements have been reported in healthy adults. [8,16] Therefore, it seems logical that we should increase our vitamin K2 intake. While ideally, we should obtain our nutrients from food, it is difficult to significantly increase dietary K2 without supplements. Other than natto, there are few foods that are naturally high in vitamin K2, and not many that are fortified with this vitamin. Although there is not sufficient information to make a specific recommendation, the risk of taking a vitamin K2 supplement is minimal for healthy individuals. If you decide to supplement vitamin K2, make sure the product you choose contains vitamin K2. Multivitamin supplements typically provide vitamin K1, shown on the label ingredient list as phylloquinone (natural vitamin K1) or phytonadione (synthetic vitamin K1). Vitamin K2, listed on the label as menaquinone-4 and/or menaquinone-7, is more often found in individual supplements or those advertised for bone health. Download the Vitamin K PDF References [1] U.S. Department of Health and Human Services. National institutes of Health. Office of Dietary Supplements. Vitamin K. https://ods.od.nih.gov/factsheets/vitaminK-HealthProfessional/#h3. Accessed September 13, 2023. [2]Simes DC, Viegas CSB, Araújo N, Marreiros C. Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases. Nutrients. 2020; 12(1):138. https://doi.org/10.3390/nu12010138 [3]Schwalfenberg GK. Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human Health. J Nutr Metab. 2017;2017:6254836. doi: 10.1155/2017/6254836. Epub 2017 Jun 18. [4]Halder M, Petsophonsakul P, Akbulut AC, et al. Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease. Int J Mol Sci. 2019;20(4):896. Published 2019 Feb 19. doi:10.3390/ijms20040896 5]Harshman SG, Shea MK. The Role of Vitamin K in Chronic Aging Diseases: Inflammation, Cardiovascular Disease, and Osteoarthritis. Curr Nutr Rep. 2016 Jun;5(2):90-98. doi: 10.1007/s13668-016-0162-x. Epub 2016 Mar 31. [6]Palermo A, Tuccinardi D, D'Onofrio L, et al. Vitamin K and osteoporosis: Myth or reality? Metabolism. 2017;70:57-71. doi:10.1016/j.metabol.2017.01.032 [7] Popa DS, Bigman G, Rusu ME. The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases. Antioxidants (Basel). 2021 Apr 6;10(4):566. doi: 10.3390/antiox10040566. [8]Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Institute of Medicine (US) Panel on Micronutrients. Washington (DC): National Academies Press (US); 2001. https://www.ncbi.nlm.nih.gov/books/NBK222299/ [9]Rodríguez-Olleros Rodríguez C, Díaz Curiel M. Vitamin K and Bone Health: A Review on the Effects of Vitamin K Deficiency and Supplementation and the Effect of Non-Vitamin K Antagonist Oral Anticoagulants on Different Bone Parameters. J Osteoporos. 2019 Dec 31;2019:2069176. doi: 10.1155/2019/2069176. [10]Ma ML, Ma ZJ, He YL, et al. Efficacy of vitamin K2 in the prevention and treatment of postmenopausal osteoporosis: A systematic review and meta-analysis of randomized controlled trials. Front Public Health. 2022;10:979649. Published 2022 Aug 11. doi:10.3389/fpubh.2022.979649 [11]Mandatori D, Pelusi L, Schiavone V, Pipino C, Di Pietro N, Pandolfi A. The Dual Role of Vitamin K2 in "Bone-Vascular Crosstalk": Opposite Effects on Bone Loss and Vascular Calcification. Nutrients. 2021;13(4):1222. Published 2021 Apr 7. doi:10.3390/nu13041222 [12] Hariri E, Kassis N, Iskandar J-P, et al. Vitamin K2 —a neglected player in cardiovascular health: a narrative review. Open Heart 2021;8:e001715. doi:10.1136/ openhrt-2021-001715 [13]Shioi A, Morioka T, Shoji T, Emoto M. The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification. Nutrients. 2020;12(2):583. Published 2020 Feb 23. doi:10.3390/nu12020583 [14]Vlasschaert C, Goss CJ, Pilkey NG, McKeown S, Holden RM. Vitamin K Supplementation for the Prevention of Cardiovascular Disease: Where Is the Evidence? A Systematic Review of Controlled Trials. Nutrients. 2020;12(10):2909. Published 2020 Sep 23. doi:10.3390/nu12102909 [15] ]Bellone F, Cinquegrani M, Nicotera R, Carullo N, Casarella A, et al. Role of Vitamin K in Chronic Kidney Disease: A Focus on Bone and Cardiovascular Health. Int J Mol Sci. 2022 May 9;23(9):5282. doi: 10.3390/ijms23095282. [16]Akbulut AC, Pavlic A, Petsophonsakul P, Halder M, Maresz K, et al. Vitamin K2 Needs an RDI Separate from Vitamin K1. Nutrients. 2020; 12(6):1852. doi.org/10.3390/nu12061852 Download the Vitamin K PDF

An overview of the roots and types of Multiple Sclerosis and the 5 key principles to confirm an MS diagnosis. Neurology InBrief by Frasat Chaudhry, MD Multiple sclerosis (MS) is a complex chronic disease that causes inflammation and demyelination of the central nervous system (CNS). It is an immune-mediated disorder associated with inflammation and disruption of the blood-brain barrier. Patients experience axonal and neuronal damage as the disease progresses. The Roots of MS Genetic and environmental factors may be related to the etiology and pathogenesis of MS. However, no evidence implicates one particular causative factor. No autoantigen, antibody, or infectious agent has been directly associated with MS. On the other hand, autoreactive lymphocytes apparently gain access to the CNS and trigger a pathologic series of events leading to demyelination, neuroaxonal degeneration, synaptic loss, oligodendrogliopathy, and, finally, tissue loss and astrogliosis. Demyelination, the hallmark of MS, involves the white matter and the cortical and deep gray matter. Further, T and B lymphocytes are involved in disease pathogenesis. Axonal injury, noted from the earliest disease stage, has a significant role in physical and cognitive disability related to this progressive condition. In addition, numerous environmental factors have a suspected relationship with the development and progression of MS. No clear association with any particular entity has been established, although low sunlight exposure, vitamin-D deficiency, obesity, and smoking have shown the strongest evidence for a relationship to the disease. Types of MS MS typically is divided into four phenotypes: a clinically isolated syndrome, relapsing-remitting disease, secondary progressive MS, and primary progressive MS. A clinically isolated syndrome (CIS), the first episode that suggests the disease, occurs in a patient not known to have MS. It typically is a monophasic episode that can develop acutely or subacutely and that must last > 24 hours with or without recovery. Unilateral optic neuritis, painless diplopia, cerebellar syndromes, and myelitis are common presentations. Approximately 85%-90% of MS cases have a relapsing-remitting phenotype, which is characterized by clear neurologic exacerbations or relapses with full or incomplete recovery. Neurologic symptoms and deficits peak over days to weeks. Relapsing-remitting MS can evolve to secondary progressive MS. This condition involves gradual worsening with or without occasional relapses, minor remission, and plateaus over 10-20 years after initial presentation. Primary progressive MS affects 10% of the MS cohort. Affected patients experience progressive disability from time of onset with temporary minor improvement. This diagnosis is made from patient history. Diagnosing MS Neurologists rely on five key principles to help confirm the MS diagnosis. First, the syndrome must be consistent with MS-related demyelination. Second, objective evidence of CNS involvement must be distinguished. Third, dissemination in space (magnetic resonance imaging [MRI] criteria) must be present, as should dissemination in time. Finally, there should be "no better explanation" for the presenting symptoms. In other words, no other rheumatologic, immunologic, or neurologic disease that could mimic MS should be present. Most non-neurologists must be comfortable with identifying the typical syndromes and ordering an appropriate first diagnostic study based on symptoms. Common presentations include optic neuritis, brainstem syndromes, cerebellar syndromes, and transverse myelitis. Brainstem syndromes include internuclear ophthalmoplegia and trigeminal neuralgia. Detailed history and physical examination are key to evaluation and appropriate testing. The best diagnostic test is MRI of the brain with and without gadolinium contrast. Additional testing includes imaging of spinal cord, cerebrospinal fluid (CSF) analysis, and evoked potentials. MRI lesions typical of MS are noted in the periventricular region, corpus callous, centrum semiovale, and deep white-matter structures. They are ovoid in appearance and are arranged at right angles to the corpus callous (Dawson fingers). Gadolinium enhancement on T1-weighted images indicate an active lesion. Approximately 95% of patients with clinically definite MS have oligoclonal bands in the CSF. Conclusion MS diagnosis is based on clinical and objective criteria. Careful history and physical examination findings are a cornerstone to establishing this diagnosis. Download the Multiple Sclerosis PDF #InBrief #Neurology initially published 4/10/2020

By Stuart M Caplen, MD Reading medical literature requires an understanding of statistics, which are used in every experimental trial. Unfortunately, the mathematical underpinning of statistical analysis involves rather complicated equations and theories. This article will discuss some of the definitions and concepts needed to understand the statistics used in the medical literature without delving into the more complicated mathematics, essentially medical statistics for the non-mathematician. Statistical Terms Used in the Medical Literature Normal Distributions The graph above represents a normal bell-shaped curve distribution. It represents average measurements from a sample with most of the values being near the center of the curve. This type of data curve is seen very frequently when performing statistical measurements and is very useful in statistical analysis. A normal distribution could represent diverse data sets such as the intelligent quotients (IQ) in a population or the average number of times asthmatics use their inhaler when they have an asthma attack. The center line labelled µ is the mean or average. The standard deviation (σ) is a measure of how dispersed the data is in relation to the mean. A low standard deviation means the data are clustered around the mean, and a large standard deviation indicates the data points are more spread out. The curve represents how frequently a data value is measured with most results near the mean and fewer results occurring further out from the mean. 95% of the measured values fall within two standard deviations above or below the mean. A result that is outside of two standard deviations from the mean has a much higher chance of being significantly different from the general population or sample being studied. In the graph below representing IQ, 100 is the average or mean in the population with most samples of people centered around that number. A sample of people with an average IQ over 145 would be much more likely to have a statistically significant different IQ score from the 100 IQ mean than a sample of people with an average IQ of 105. There are a number of different statistical tests that can be used for analyzing data in both normal distributions and distributions of data not in the normal bell-shaped curve, which are beyond the scope of this article. Central Tendencies of Data There are 3 ways of describing a central tendency of data; mean, median, and mode. Mean is the average of all the data, median is the number in the middle of the data, and mode is the number that occurs most frequently in the data. As can be seen in the figure above, when the data map forms a symmetric bell-shaped curve all three measures of central tendency are the same, but if the data curve is skewed the three values will be different. The median has the advantage of not being affected as much by outlier values as the mean. The mode is not used very much in the medical literature. In the number series 1, 3, 5, 7, 49, the mean is 13 and the median is 5, which is less affected by the outlier value of 49 than the mean. Experimental results can be affected by which measure is chosen by the author(s). Statistical Definitions and Measurements A population is the total group of interest, and a sample is a smaller subset of the population that will be examined to try to make conclusions about the larger population. There are formulas that can be used to determine how big the sample size must be to accurately represent the whole population. Prevalence is the proportion of a population that have a condition during a specific time frame. Incidence is the proportion of a population who newly develop the condition during that time frame. If in a town of 100 people, 40 in total had contracted a disease and 10 had become newly ill in the last year, the prevalence would be 40% and the incidence 10%. In randomized trials, participants are randomly assigned to receive or not receive treatment. These are generally better designed trials with potentially less bias than non-randomized ones. They avoid much of the selection bias that would come from participants with certain characteristics being chosen preferentially to be in one group that might affect the results, and also the volunteer or self-selection bias that can occur when individuals who volunteer for a trial differ in clinical characteristics from those who do not. However, even in randomized trials there should be an analysis of the characteristics of the different groups or people being tested as one group by chance be sicker or older than the other and the outcomes may be due to that difference rather than from the therapy being tested. [1] Prospective studies designed before data collection or treatment will generally have less sources of bias and confounding factors than retrospective studies, which typically rely on chart review of previously collected results.[2] Accuracy is how close a measurement is to an accepted value or gold standard. Precision is how reproducible a result or measurement is, even if it the result is incorrect or not accurate. Having high precision and accuracy together produces the best results. If a man weighing 150 pounds weighs himself on a scale and the scale indicates 150 pounds and when repeated reads 150 pounds again, the scale is both accurate and precise. If instead the scale read 165 pounds and repeated weighing attempts also read 165 pounds, the scale would have precision but be inaccurate. Sensitivity (true positive rate) is the ability of a test to correctly identify subjects with a specific condition (true positives) out of all people with the condition (true positives + false negatives). Specificity (true negative rate) is the ability of a test to correctly identify all the subjects without the condition (true negatives) out of all people without the condition (true negatives + false positives).[3] In a meta-analysis of CT scanning to diagnose appendicitis the overall sensitivity was 95% and the specificity was 94%. This means that in this analysis CT scanning correctly diagnosed 95% of the patients with appendicitis, but missed 5%. CT scan correctly diagnosed 94% of those who did not have appendicitis and diagnosed 6% incorrectly as having appendicitis when they did not.[4] Positive predictive value is the probability that patients with a positive test result truly have the disease (true positives/(true positives + false positives)). Negative predictive value is the probability that subjects with a negative test result do not have the condition (true negatives/(true negatives + false negatives)). Prevalence of disease plays a significant role in predictive values. The lower the prevalence of a disease the more false positives there will be in testing which can be important clinically. If a test is studied in a high prevalence of disease sample, there may only be a few false positives. If the test is then used as a screening test in a general population with a low prevalence of disease there may be a much higher percentage of false positives that may require additional testing to rule out the disease.[3] This was one of the issues when HIV screening tests were used to test the general population; there were more false positives which required confirmatory testing compared to using the test in a targeted high-risk high prevalence segment of the population.[5] When trials are repeated it is not uncommon to get slightly different results. A 95% confidence interval (CI) is a set of values that if an experiment is repeated the new result would have a 95% chance of being found between those two values.[6] It also represents the set of values from the sample being tested between which there is a 95% chance the true population mean lies. Larger sample sizes (larger trials) and bigger differences between the two groups being compared will generally have smaller confidence intervals and a higher confidence that the result is precise. An example of a CI would be a mean trial result of 78 with a 95% CI of 45 to 82. The Odds ratio (OR) is a measure of association or correlation between a variable and an outcome. It tells you how much the presence or absence of a variable has an effect on the presence or absence of an outcome. The OR is used to figure out if a particular exposure (such as asbestos or sun exposure ) is a risk factor for a particular outcome (such as mesothelioma or melanoma). An odds ratio of more than 1 means that there are higher odds of an outcome happening with exposure to the variable. The larger number the odds ratio is, the stronger the association between the two events. An odds ratio of less than 1 means that there are lower odds of an outcome occurring with exposure to the variable. An odds ratio of exactly 1 means that presence of the variable does not affect the odds of the outcome occurring.[7,8] Odd ratios are typically calculated with 95% confidence intervals. If the spread of values of an OR confidence interval includes the number 1 as a possible result, such as the 95% CI = 0.8-1.3, the calculated OR is not likely to be statistically significant.[7,9] An example of a positive OR is that asbestos exposure has an odds ratio of 3.7 (95% CI = 1.7 to 7.8) for the development of mesothelioma, meaning those exposed to asbestos in one study had an average 3.7 times the risk of developing mesothelioma than those unexposed, although the true value based on the CI could be anywhere from 1.7 to 7.8 times the mesothelioma risk with 95% certainty.[10] One needs to be careful in interpreting odds ratios as the correlation or association of two events does not necessarily mean that one actually caused the other. A Hazard ratio (HR) is a measure of the effect of an intervention over time and is most commonly used for analysis of survival. It is calculated by dividing the hazard in the treatment group by the hazard in the control group. Hazard is defined as the probability that an individual would experience an event such as death or relapse after receiving the treatment being studied. A HR of 0.5 means that at any particular time, half as many patients in the treatment group are experiencing an event compared to the control group. A HR of 1 indicates event rates are the same in both groups. A HR of 2 means that at any particular time twice as many patients in the treatment group are experiencing an event compared to the control group. A hazard ratio is also reported with a 95% CI.[11] In a real-life example, a recent study compared mortality rates in subjects who received four doses of COVID vaccine versus those who received three doses. The reported hazard ratio was 0.22 (95% CI = 0.17-0.28) meaning that patients in the four-dose group were 78% less likely to die over the course of the 40-day period of the study than those who received three doses. The actual value at a 95% confidence level would lie between 72% to 83% less likely to die in the four-dose group.[12] Notably, the hazard ratio takes into account the timing of death (or other events) and not just the overall survival by the end of the study period. Relative risk reduction (RRR) is the percent reduction in a measured outcome between the experimental and control groups. This measure is used in medical literature, but is not a very good way to compare outcomes as it can amplify small differences and make insignificant findings appear more significant. The RRR doesn’t reflect the actual risk of a measured outcome, but can be used by authors to make weak results look better. For example, if 2% of the placebo group die and only 1% of the treatment group die the RRR would be ((2-1)/2)=0.5 or 50%. In the above example, if the numbers were instead a 40% death rate in the placebo group and 20% in the treatment group, the RRR will still remain 50% ((40-20)/40) even though 20% more people will be saved by the treatment compared to only 1% in the first example.[13,14] Absolute Risk Reduction (ARR) is a better measure than RRR and is the arithmetic difference between the event rates in the two groups. In the 2%/1% example above, the ARR is 0.01 (1%). In the 40%/20% example above the ARR is 0.20 (20%) and better reflects the difference in incidence rates than the RRR.[13,14] Number needed to treat (NNT) is the number of patients needed to treat to prevent one additional bad outcome. As an example, for people with known heart disease who took statins for 5 years, 83 patients would have to be treated to save one life and 125 treated to prevent one stroke.[14] NNT is calculated by the equation 1/ARR.[13,14] Number needed to harm (NNH) is the number of people needed when treated for one to develop a harmful side effect. As an example, for every 50 patients who take statins for five years, one patient would be expected to develop diabetes, so the NNH would be 50.[15] Statistically Significant Differences Most experiments start with the null hypothesis which is the baseline assumption that there is no significant difference between the two populations or samples being tested, such as subjects in a treatment group compared to a placebo group. Only if the data demonstrates a significant difference between the two groups is the null hypothesis rejected and a difference between the groups acknowledged, such as the tested drug successfully treating the disease compared to a placebo. Although p values or probability values are used in just about every scientific trial, there are some confusing issues in understanding their significance. P values represent the likelihood that the difference in results of two groups is by random chance. P values range from 0 to 1. The lower the p value, the more statistically significant the difference in results are and the more likely that the two groups are different (treatment versus placebo for example). The larger the p value, the less likely any differences found between the two groups are statistically significant and the more likely that the two groups are similar and any differences found are due to chance. Results of two groups that are separated by two standard deviations or more are typically going to be found to be statistically different by p value and not the result of random chance. Picture it as two bell-shaped curves of data superimposed on each other. The further apart the means of those curves are, the more likely the two groups will be found to be significantly different, as seen in the figure below. The actual calculations used to determine statistical significance are fairly complicated. T- or Z-tests and tables can be used to decide if results are statistically significant but the use of them is beyond the scope of this article. The p value represents the likelihood of getting the given results if the null hypothesis was correct, and there is no difference between the two groups being testing. By convention, for most trials, a p value greater than 0.05 supports the null hypothesis and there was at least a 5% probability of getting the difference in results simply by chance. A p value less than 0.05 indicates that there is likely a significant difference in the populations or samples, such as a drug that significantly improves mortality over placebo and there was a less than 5% probability of getting the results simply by chance. There is an inherent error rate in conclusions of statistical significance using p values as the standard determination of statistical significance. Choice of the 0.05 p value level for significance is an arbitrary choice, and some investigators may decide to use a lower number as the point of significance to reject the null hypothesis. In genetics research, for example, reduction of false-positive risk is sometimes achieved by setting p values at 0.00000001 or lower.[16] Trials with a large number of participants or with large differences between the groups being compared may also decide to use a lower point of significance than 0.05 as the standard. One of the caveats to remember is that just because a result has been shown to have statistical significance or a p value of less than 0.05 does not mean that it is true. By itself, the p value is not necessarily a good test of a hypothesis or evaluation of a clinical model and is not a substitute for scientific reasoning. Scientific conclusions and decision-making should be based on more than whether a p value falls below an arbitrary threshold.[16,17] One should also understand that statistical significance is different than clinical significance or importance. A positive finding in a trial may be statistically significant but have no real clinical effect. An example might be a cancer drug that extends survival by three days that is found to be statistically significant compared to placebo but might not really represent a significant clinical improvement. Statistical Errors It is rare to have a result that is 100% certain and there are errors that may occur because of this. Using a p value of .05 means that there is still up to a 5% chance that the conclusions of statistical significance may be incorrect. A type I error results in a false positive leading to finding a significant difference between two populations or samples when one does not truly exist. A type I error occurs when a null hypothesis is rejected, or a significant difference between the groups is found, when there was really no difference between the groups and they were statistically equivalent. Type I errors increase as p values used to define significance increase, so there is more chance of a type I error when 0.05 is used as the point of significance than when 0.01 is used. A type II error is when there was a significant difference between the tested samples but it was not recognized. The null hypothesis was accepted when it should have been rejected creating a false negative. Type II errors tend to increase as the p value set for significance decreases, so there is more chance of a type II error when 0.01 is used as the point of significance than when 0.05 is used. Non-Inferiority Trials As opposed to standard experimental trials, there are also non-inferiority trials where a new treatment is compared to a known standard one. Non-inferiority trials may be used in cases where a treatment for a disease already exists and it would not be ethical to compare a new drug to a placebo. In those trials, the null hypothesis is reversed from normal and states that the two treatments are different and the new treatment is inferior to the old one. If the the two treatments are found to be in equivalence, the null hypothesis of inferiority is rejected and non-inferiority of the new treatment compared to the old one is supported.[18] Conclusion Medical statistics help make sense out of data, and an understanding of commonly used statistical terms will help a reader better interpret medical literature results. However, clinical and scientific judgment is still required as a result that has statistical significance may not actually be true or have clinical significance. Statistical analysis has allowed medical science to move forward, but it is not perfect and the medical community as a whole needs to both understand and strive to improve the use of statistical analysis in the medical literature. “There are three kinds of lies: lies, damned lies and statistics." Mark Twain attribution to Benjamin Disraeli.[19] Author’s note: If you wish to learn about biases and statistical problems in the medical literature leading to incorrect conclusions, the topic is discussed in a FibonacciMD blog article at this link; Potential Bias and Incorrect Results In the Medical Literature, and Why You Shouldn’t Believe Everything You Read, for which AMA PRA Category 1 Credit™ is available. Dowload the Medical Statistics for the Non-Mathematician PDF References [1] Tripepi G et al. Selection Bias and Information Bias in Clinical Research. Nephron Clin Pract 2010. Retrieved from: https://www.karger.com/Article/Fulltext/312871# [2] Prospective vs. Retrospective Studies. Statsdirect. 2021. Retrieved from: https://www.statsdirect.com/help/Default.htm#basics/prospective.htm [3] Understanding medical tests: sensitivity, specificity, and positive predictive value. HealthNewsReview.org. 2022. Retrieved from: https://www.healthnewsreview.org/toolkit/tips-for-understanding-studies/understanding-medical-tests-sensitivity-specificity-and-positive-predictive-value/ [4] Rud B et al. Computed tomography for diagnosis of acute appendicitis in adults. Cochrane Database Syst Rev. 2019 Nov 19;2019(11). Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953397/ [5] False-Positive HIV Test Results. CDC. May 2018. Retrieved from: https://www.cdc.gov/hiv/pdf/testing/cdc-hiv-factsheet-false-positive-test-results.pdf [6] McLeod S, What are Confidence Intervals in Statistics? Simply Psychology. June 10, 2019, updated 2021. Retrieved from: https://www.simplypsychology.org/confidence-interval.html [7] Szumilas M. Explaining Odds Ratios. J Can Acad Child Adolesc Psychiatry. 2015 Winter; 24(1): 58. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938757/# [8] Stephanie Glen. "Odds Ratio Calculation and Interpretation". StatisticsHowTo.com: Elementary Statistics for the rest of us! https://www.statisticshowto.com/probability-and-statistics/probability-main-index/odds-ratio/ [9] Tenny S, Hoffman MR. Odds Ratio. [Updated 2021 May 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK431098/ [10] Pintos J et al. Risk of mesothelioma and occupational exposure to asbestos and man-made vitreous fibers: evidence from two case-control studies in Montreal, Canada. J Occup Environ Med. 2009 Oct;51(10):1177-84. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/19749604/ [11] Albarqouni L. Tutorial about Hazard Ratios. Students 4 Best Evidence. 5th April 2016. Retrieved from: https://s4be.cochrane.org/blog/2016/04/05/tutorial-hazard-ratios/ [12] Arbel R et al. Second Booster Vaccine and Covid-19 Mortality in Adults 60 to 100 Years Old. A pre-publication study. Research Square. March 24th, 2022. Retrieved from: https://assets.researchsquare.com/files/rs-1478439/v1/24514bba-2c9d-4add-9d8f-321f610ed199.pdf?c=1648141784 [13] Flaherty RJ. A Simple Method for Evaluating the Clinical Literature. Fam Pract Manag. 2004 May;11(5):47-52. Retrieved from: https://www.aafp.org/fpm/2004/0500/p47.html [14] Understanding absolute and relative risk reduction. The University of Western Australia. https://www.meddent.uwa.edu.au/__data/assets/pdf_file/0005/2670593/Risk_reduction_guide0.2.pdf [15] Statins Given for 5 Years for Heart Disease Prevention (With Known Heart Disease). The NNT. Updated: November 2, 2013. Retrieved from: https://www.thennt.com/nnt/statins-for-heart-disease-prevention-with-known-heart-disease/ [16] Andrade C. The P Value and Statistical Significance: Misunderstandings, Explanations, Challenges, and Alternatives. Indian J Psychol Med. 2019;41(3):210-215. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532382/#ref8 [17] The ASA Statement on p-Values: Context, Process, and Purpose. The American Statistician. 09 Jun 2016. Retrieved from: https://www.tandfonline.com/doi/pdf/10.1080/00031305.2016.1154108?needAccess=true [18] Hahn S. Understanding noninferiority trials. Korean J Pediatr. 2012;55(11):403-407. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510268/ [19] Twainquotes.com, Directory of Mark Twain's maxims, quotations, and various opinions, Retrieved from: http://www.twainquotes.com/Statistics.html initial post May 24, 2022

Scientists have made a groundbreaking discovery of a new, virus-like organism in the human gut and oral microbiome. Medical News In a preprint publication posted January, 2024 scientists reported discovering a new organism in the human gut biome.  After studying stool and oral samples and reviewing other databases, the researchers reported they found virions in about 6.6% of stool samples and about 53% of oral samples.  They calculated that about 10% of donors were positive for these virions around the world.  A virion is a strand of RNA similar to a virus but without a protein coat.  These virions are circular and form rod like structures the researchers named obelisks.  They also found obelisks inside Streptococcus sanguinis, a common mouth flora bacteria.  There were multiple distinct variants of the obelisks, oral ones being different than ones found in the gut. Comments: Scientists have just discovered virions, called obelisks, that are present in the human gut and mouth and also found inside some oral bacteria.  What purpose these obelisks serve and whether they cause disease or are helpful in some way is not yet known. The human body is incredibly complex and as this discovery indicates, there is much we still don’t understand about it.  This new finding of obelisks inhabiting the gastrointestinal tract may possibly lead to a better understanding of the effects of the human gut biome on health. Resources Zheludev IN et al. Viroid-like colonists of human microbiomes. bioRxiv. Jan. 20, 2024. Retrieved from:  https://www.biorxiv.org/content/10.1101/2024.01.20.576352v1 Bonk L. Yahoo Finance. Jan 30, 2024. Retrieved from: https://finance.yahoo.com/news/scientists-discover-weird-virus-like-obelisks-in-the-human-gut-and-mouth-162644669.html