The Pharmacology, Medical Uses, and Adverse Effects of Cannabis By Stuart M. Caplen, MD Cannabis Cannabis has been used for thousands of years for its medicinal and psychotropic qualities.[1] In the United States, cannabis was widely available in over-the-counter medicines during the 19th and early 20th centuries. Federal restriction of cannabis usage and sale first occurred in 1937, with the passage of the Marihuana (sic) Tax Act. Legal penalties for its use increased in the 1950’s.[2] Many states have now legalized medical cannabis, and an increasing number of states have legalized recreational use as well.[1] This article will discuss the pharmacology, medical uses, and adverse effects of cannabis. The term cannabis will be used preferentially unless the reference source specifically reported on marijuana usage. Cannabis Pharmacology and Cannabinoid Receptors Cannabis is a term for a genus of plants in the Cannabaceae family. Both marijuana and hemp are cannabis plants. The three strains of cannabis most frequently used are Cannabis sativa, Cannabis indica, and Cannabis ruderalis. C. Sativa contains a high amount of tetrahydrocannabinol (THC). C. Indica is a mixed THC-cannabidiol (CBD) plant, and C. ruderalis contains high amounts of CBD.[1] Hemp refers to cannabis that contains minimal THC levels with similar CBD levels to C. ruderalis. To qualify as hemp in the U.S. cannabis needs to contain less than 0.3% THC.[3] Cannabinoid Receptors The endocannabinoid system is thought to regulate body homeostasis.[1] There are two cannabinoid receptors present in humans, CB1 and CB2 which act by inhibiting adenyl cyclase. CB1 receptors are located primarily in the central nervous system in brain and spinal cord presynaptic neurons, as well as within the peripheral nervous system.[1,4] CB1 receptors are also found in the gastrointestinal system, spleen, heart, liver, uterus, bladder, and vas deferens.[1,4] CB1 receptors mediate many of the psychoactive effects of cannabinoids.[5] CB1 receptor activation in the hypothalamus and pituitary gland results in modulation of the hypothalamic-pituitary system. Receptor activation leads to inhibitory effects on the release of growth hormone, thyroid hormone, prolactin, and luteinizing hormone.[4,6] Activation of CB1 receptors can result in decreased gastric acid secretion, lower esophageal sphincter relaxation, altered intestinal motility, visceral pain, and inflammation.[4] CB2 receptors are concentrated mainly in immune cells and tissues. CB2 receptors appear to inhibit inflammation, visceral pain, and intestinal motility.[4] There is some suggestive early research that activation of CB2 receptors might be useful in treating some inflammatory conditions.[7] Cannabinoids There are a number of cannabinoids in cannabis with delta 9-tetrahydrocannabinol (THC) being principally active.[4] THCa found in cannabis plants is the inactive precursor compound of delta 9-THC. It requires heat to convert THCa to the psychoactive delta 9-THC. The required heating can occur when smoking cannabis or heating it for edibles, such as baking cannabis brownies.[8] Delta-8 THC, a relative of delta-9 THC, has a similar molecular structure and is also sold in cannabis stores. Delta-8 THC has less psychoactive effect than delta 9-THC, and is found in lower quantities in cannabis plants than THCa.[9] THC acts as an agonist at both CB1 and CB2 receptors.[10] Delta 9-Tetrahydrocannabivarin (THCV) is a naturally occurring analogue of THC and has an opposite effect to THC. It is an inverse agonist/selective antagonist of the CB1 receptor. (It not only blocks the receptor from other agonists, it actually reverses the effects of receptor stimulation.) It lacks psychoactive effects, and in animal studies THCV decreased appetite, increased energy metabolism, and had positive effects on reducing glucose levels, and increasing insulin sensitivity. It is being investigated for use in the management of obesity and treatment of type 2 diabetes.[11,12] Cannabidiol (CBD) and cannabigerol (CBG) are two additional cannabinoids found in cannabis. CBD is not psychotropic and has many opposite effects on the body to THC, acting to reduce the effects of THC on the CB1 receptor,[10] as well as having anti-inflammatory properties. In low doses CBD has an anti-emetic effect, but higher doses may cause vomiting. It is also an agonist of other receptors in the body including the 5-HT1A receptor. 5-HT1A is a serotonin receptor that is one of the targets of antianxiety, antidepressant and antipsychotic medications.[13] CBG is a non-psychotropic cannabinoid with anti-inflammatory properties, but it acts as an antagonist at the CB1 and 5-HT1A receptors, and can reverse the anti-emetic actions of low-dose CBD at the 5-HT1A receptor.[4,14,15] Nearly 100 metabolites of THC have been identified, many of which also have pharmacologic actions. Some are psychotropic, others have anti-emetic, anti-inflammatory, ocular pressure lowering, or analgesic effects.[4] There are a number of endogenous cannabinoids produced in the body that bind to cannabinoid receptors, the most well-known being anandamide and 2-arachidonylglycerol (2-AG). These are released by neurons and thought to be neurotransmitters or neuromodulators.[4] THC is stored in body fat which becomes a long-term storage site, and contributes to the long length of time THC is able to be detected on urine drug screens, and may contribute to symptoms in the cannabis hyperemesis syndrome.[4,16] Effects of Cannabinoids Many people experience a pleasant euphoria and sense of relaxation with cannabis use. Other common effects, which may vary dramatically among users, include heightened sensory perception such as colors being brighter, laughing fits, altered perception of time, and increased appetite.[17] Cannabis may also cause blurred vision, altered judgment, dysphoria, anxiety, paranoia, impaired motor coordination, or with use of higher doses, psychosis.[17] These negative effects are seen more often when a person uses too much, the cannabis has an unexpectedly high potency, or the user is inexperienced.[17] Because of the increased systemic absorption and longer time of onset of edible cannabis compared with smoked cannabis, edible cannabis is more likely to result in adverse psychiatric and cardiovascular effects needing medical attention.[1] The effects of smoked cannabis typically lasts from one to three hours, and those of edible cannabis, such as ingesting cannabis brownies or gummies, may last much longer.[17] THC stimulates the sympathetic nervous system while inhibiting the parasympathetic nervous system which causes an increase in heart rate, myocardial oxygen demand, supine blood pressure, and platelet activation. It has also been associated with endothelial dysfunction and oxidative stress. CBD has many opposite effects to THC and may cause a reduction in heart rate and blood pressure. CBD also has an anti-inflammatory effect. CBD has been shown to cause an improvement in vasodilation in models of endothelial dysfunction, and has been shown to reduce inflammation and vascular hyperpermeability in diabetic animal models.[1] The cannabinoid system also helps regulate the endocrine system.[18] Note on Cannabis Literature Interpretation of the current scientific data on both positive and adverse effects of cannabis is difficult, as much of it is observational or retrospective with a lack of blinded, randomized, prospective studies.[1] Positive Effects of Cannabis[1] Medical Indications for Use Improvements in neuropathic and fibromyalgic pain There are a number of studies that demonstrate a reduction in symptoms in neuropathic pain with cannabis use.[19,21] A retrospective case series of 38 patients with fibromyalgia found a significant improvement in pain, severity, and disability symptoms with medical cannabis. However, almost half of the patients stopped therapy due to nonserious adverse side effects of the medication.[22] Appetite stimulation and anti-emetic after chemotherapy THC increases appetite by stimulating CB1 feeding centers in the hypothalamus.[18] Dronabinol (synthetic THC) and nabilone (a CB1 receptor agonist) are two commercially available cannabinoids for the treatment of chemotherapy-induced nausea and vomiting.[4,19,21] Decreased pain, decreased bladder dysfunction, and decreased spasticity in multiple sclerosis (MS)[21] Although the results were mixed, a metanalysis found limited efficacy of cannabinoids for the treatment of spasticity, pain, and bladder dysfunction in patients with MS.[23] There is limited evidence that dronabinol (synthetic THC), and other studied THC/CBD medications decrease pain, bladder dysfunction, and spasticity in multiple sclerosis.[21] Nabiximols, an oromucosal spray absorbed by the buccal mucosa, which contains equal parts CBD and THC, has been approved as a treatment for MS patients with moderate to severe spasticity in a number of countries, but is not currently available in the U.S.[24] Reduction of attacks of drug-resistant epilepsy in both adults and children The CB1 receptor provides protection against epilepsy by inhibition of both glutamate release as well as the harmful cascade of changes that can lead to seizures after an initial insult.[25] CBD appears to have anti-convulsant properties, whereas CB1 agonists such as THC have been found to have either pro- or anti-epileptic properties.[21] Cannabidiol (oral CBD) has been found to be an effective treatment of childhood drug-resistant seizures in Dravet syndrome* and Lennox-Gastaut syndrome**, and has FDA approval for those indications.[21] [*Severe Myoclonic Epilepsy of Infancy] [**A childhood onset seizure disorder that induces several different types of seizures in those that suffer from it.] Observational studies have suggested CBD may cause a possible reduction in seizure frequency and an improved quality of life in adolescents with drug-resistant epilepsy.[21] Possible Medical Uses, with Limited or Inconclusive Evidence THC May help alleviate opioid withdrawal effects Pre-clinical studies suggest THC may alleviate some opioid withdrawal symptoms. Observational studies suggest that cannabis use could help alleviate opioid withdrawal symptoms, but as of yet the evidence is insufficient to draw firm conclusions.[21] Improvement of dystonia Preclinical studies suggest cannabinoids may help with dystonia symptoms. Dystonia is a movement disorder that includes involuntary body movement or involuntary muscle contraction or spasm. There are mixed results from case studies and small trials with respect to use of cannabinoids for dystonia symptoms. One small trial found CBD had some efficacy.[21,26] THC reduces intraocular pressure (IOP), but CBD raises it. One small study of six patients found a sublingual dose of THC reduced the IOP temporarily, and was well tolerated. Sublingual low doses of CBD did not reduce IOP, whereas higher doses produced a transient increase IOP rise.[27] THC is currently not an FDA recommended therapy for glaucoma. Issues with the use of THC for glaucoma treatment include the short length of time it works if the cannabis is smoked, development of tolerance, and unwanted side effects. Scientists are looking to try to create a long-acting THC eyedrop.[28,29] Treatment of Alzheimer’s disease and Parkinson’s disease Pre-clinical studies suggest that THC and CBD may protect against oxidative stress and inflammation in animal models of Alzheimer's disease.[21] Limited case and observational studies suggest that oral THC and nabilone are associated with improvement in a number of symptoms associated with Alzheimer's disease, such as nocturnal motor activity, disturbed behavior, sleep, agitation, and resistiveness.[21] The evidence from a limited number of studies of the use of cannabinoids for symptoms of Parkinson's disease is mixed.[21] Treatment of anxiety disorders[21] Evidence from pre-clinical and clinical studies suggests that THC exhibits biphasic effects on mood, with low doses of THC reducing anxiety and having mood-elevating effects, but high doses of THC potentially increasing anxiety and having mood-lowering effects. Limited evidence from a small number of clinical studies indicate that THC may improve symptoms of anxiety and depression in patients suffering from some chronic diseases such as HIV/AIDS, MS, and chronic neuropathic pain. Limited evidence from some observational studies suggests that medical cannabis with equal proportions of CBD and THC may cause less anxiety and depression than cannabis that is mostly THC. Improvement of symptoms of inflammatory bowel disease According to a Cochrane database review, the effects of cannabis on Crohn’s disease and ulcerative colitis is uncertain.[30] Improved glycemic control in diabetics Observational studies suggest chronic cannabis use may lead to an improved metabolic profile. There is limited clinical evidence suggesting a potential beneficial effect of THCV on glycemic control in patients with type II diabetes.[21] Treatment of sleep disorders Low doses of cannabis may improve sleep disorders, while high doses may worsen sleep patterns.[21,31] Reducing the incidence of death in heart failure There is some limited observational, retrospective data showing decreased mortality in cannabis users versus non-users in patients with congestive heart failure.[1] Protection against ischemia/reperfusion injury after ischemia Preclinical studies suggest that CBD and very low doses of THC may have some protective effects against ischemia/reperfusion injury due to CB2 receptor anti-inflammatory properties.[1] Topical CBD Although topical CBD is widely available, there is currently a dearth of scientific research on its effectiveness. The most common study cited as a positive result is one where topical CBD gel was found to reduce swelling, pain and synovial thickening in rats with induced osteoarthritis.[32] Adverse Effects of Cannabis[1] It is thought that most of the adverse effects of cannabis use arise from the THC component rather than CBD. However, CBD may cause diarrhea, decreased appetite, drowsiness, or mood irritability. CBD in very high doses has been found to cause hepatotoxicity in mice, although paradoxically it has also been found to improve symptoms of hepatic encephalopathy in mice.[33,34] CBD has also been found to cause reproductive system toxicity in animal studies including impairment of sexual behavior, reduced testosterone levels, testicular cell degeneration, and decreased fertilization rates.[35] Whether these animal studies of hepatic injury and sexual function are reflective of possible human toxicity is not known. Cardiac Adverse Effects Cannabinoid receptors are present in myocytes and platelets.[36] Cannabis use has been linked by case reports and observational studies to negative cardiovascular effects such as tachycardia, premature ventricular contractions, atrial fibrillation, and ventricular arrhythmias.[1] In states where cannabis has been legalized, there has been an observed increase in hospitalizations and emergency department visits for acute myocardial infarction (AMI).[1,37] Marijuana use in one study was associated with 3-fold higher mortality rate after AMI, and mortality was higher in subjects that used marijuana more frequently.[38] In the same study, the risk of triggering an AMI was elevated almost 5-fold within one hour after smoking marijuana.[39] Recent data suggest that marijuana use is present in 6% of patients ≤50 years of age who presented with their first AMI and is associated with worse all-cause and cardiovascular mortality. Marijuana use in that study was associated with a two times higher death rate among these patients, even after adjusting for tobacco use.[40] A small study of ten patients with coronary artery disease found that exercise time until angina onset was reduced after smoking one marijuana cigarette, as compared with a placebo.[41] A systematic analysis found an increased risk of both acute coronary syndrome and chronic cardiovascular disease associated with cannabis use.[42] The possible reasons smoking cannabis may increase cardiac risk include increased blood pressure, heart rate, myocardial oxygen demand, and carboxyhemoglobin levels.[40,41] Case reports have suggested associations of cannabis with stress cardiomyopathy[43] and myocarditis[44]. Arteritis Delta-9 THC and delta-8 THC can induce peripheral vasoconstriction.[45-48] Cannabis arteritis resembling thromboangiitis obliterans (Buerger’s disease) has been reported in male patients who developed distal ischemia leading to necrosis of fingers or toes.[45-48] While cigarette smoking is a confounding factor in many of these reported cases, it appears cannabis may be an aggravating factor in the development of arteritis.[48] It has also been found that rats exposed to secondhand marijuana smoke for one minute developed impaired femoral artery flow-mediated dilatation for at least 90 minutes, which was longer than the impairment by secondhand tobacco smoke. Femoral artery flow-mediated dilatation is a measure of vascular endothelial dysfunction.[49] Stroke A population survey found that weekly marijuana smokers experienced a 3.3 times higher rate of stroke or transient ischemic attacks than both non-users and infrequent users.[50]. In a case series of 17 patients who presented with ischemic stroke after or during cannabis use, three patients had stroke symptoms within 30 minutes after using cannabis, and five out of 14 had a recurrent stroke upon reuse of cannabis[51]. In contrast, a retrospective review and a systematic review found no correlation between marijuana smoking and stroke, but both of these reviews cited issues with the quality of the data.[52,53] Pulmonary Effects Chronic cannabis smoking can produce symptoms similar to those of tobacco smoking such as cough, sputum production, shortness of breath, and wheezing. The association between long-term cannabis smoking (without tobacco) and chronic obstructive pulmonary disease is unclear, but chronic bronchitis has been reported.[21,54] Cannabis smoking has been shown to worsen symptoms of chronic bronchitis, but if stopped does not increase the risk of later developing chronic bronchitis. Chronic marijuana smokers may develop an increase in FVC (forced vital capacity) as opposed to the decrease in FEV1 (forced expiratory volume in 1 second) seen in cigarette smokers.[55] Acutely, marijuana smoking causes a 5-fold increase in the blood carboxyhemoglobin level compared with tobacco, which may play a part in cannabis’ negative cardiac effects.[53,54,56] There is no evidence for a link between cannabis smoking and lung cancer.[21] Pregnancy While there is a lack of definitive evidence on the adverse effects of cannabis on pregnancy, the American College of Obstetricians and Gynecologists recommends that women who are pregnant or contemplating pregnancy should discontinue marijuana use. THC crosses the placenta and has been found in breast milk up to six days after cannabis use. Cannabis may potentially affect the newborn’s brain development resulting in hyperactivity, poor cognitive function, or other possible long-term consequences.[1,54,57] A recent study found that maternal cannabis use during pregnancy was associated with greater anxiety, aggression, and hyperactivity in children three to six years old. They also found dampened activity in genes that make key immune-related proteins in the placentas of mothers using cannabis.[58,59] Cannabis Hyperemesis Syndrome [4] Cannabis hyperemesis syndrome (CHS) was first described in 2004, and is characterized by chronic cannabis use, cyclic episodes of nausea and vomiting, and use of hot showers to relieve symptomatology. The typical patient is a young adult with a history of daily cannabis use for a number of years. After cannabis was legalized in Colorado, there was a 29% increase in vomiting-related emergency department visits suggesting a possible connection.[60] CHS is typically a recurrent problem, with initial symptoms of early morning nausea and abdominal discomfort. In the active phase there is persistent nausea and vomiting, leading to dehydration. Patients frequently learn that hot showers relieve some of their symptoms and may shower many times a day.[61] After an acute episode, the patient may go back to normal for days to months until the next episode occurs. The hyperemetic phase of CHS typically lasts for one to two days, and relapse is possible if the patient restarts cannabis use. Treatment is supportive with intravenous rehydration if needed. Antiemetics may be tried, but are frequently unsuccessful in controlling the vomiting. As a number of these patients develop gastritis and esophagitis, a proton pump inhibitor is recommended. Hot showers may improve symptoms of nausea and vomiting, abdominal pain, and decreased appetite during the acute phase. Topical capsaicin cream applied to the abdomen also seems to relieve symptoms. The precise mechanism by which they reduce the symptoms of CHS is unknown. Transient receptor potential vanilloid subtype 1 (TRPV1) receptor is centrally involved in control of gastric motility and is activated by cannabinoids, high temperatures, and capsaicin. Chronic exposure to cannabinoids may downregulate or desensitize TRPV1 signaling, explaining how prolonged exposure to cannabinoids might lead to decreased TRPV1 signaling, altered gastric motility, and emesis.[62] This theory may explain why both hot showers and capsaicin work to relieve symptoms. Another theory to try to explain the efficacy of hot bathing suggests that heat may act to partially correct cannabis-induced thermoregulatory and digestive system disequilibrium in the hypothalamus.[4,61] Cannabis and Psychiatric Disorders There have been some studies that linked cannabis use to increased risk for psychiatric disorders, including psychosis, depression, anxiety, and substance use disorders.[63] To what extent cannabis actually precipitates these conditions is not always able to be determined, as people with psychiatric disorders may also use cannabis to self-medicate.[64] Psychotic Disorders Although there are variations depending on the study, the baseline median lifetime risk of a psychotic disorder in the general public is thought to be about 0.72%[65] In one study, daily users of low potency cannabis (< 10% THC) had 2.2 times the risk of psychosis over non-users. Daily users of high potency cannabis (>10% THC) were found to have 4.8 times the risk of psychotic disorder over non-users. The increased risk of psychosis varied across the three European cities in the study with the highest number of subjects using high-potency cannabis daily; there was a four times greater risk of psychosis in Paris, five times greater risk in London, and more than nine times greater risk in Amsterdam over non-users.[66] A 10-year longitudinal study of subjects 14 to 24 years old at baseline found cannabis use was a risk factor for the development of psychotic symptoms.[67] One study found that daily cannabis users carrying a variant of the AKT1 gene, (which codes for an enzyme that affects dopamine signaling in the corpus striatum), had a seven times increased risk of psychosis over daily cannabis users without the genetic variant.[66,68] There is also increased risk of psychosis in people who use cannabis and carry a variant of the gene for catechol-O-methyltransferase which is responsible for degrading neurotransmitters such as dopamine and norepinephrine.[66] Anxiety Disorders The National Epidemiological Survey on Alcohol and Related Conditions found no increase in mood and anxiety disorders with cannabis use, but there was a correlation to other substance use disorders.[66,69] However, another meta-analysis of 112,000 people found a positive correlation between cannabis use and an anxiety disorder.[70] Suicidality There is some suggestive evidence from epidemiologic studies that there is a relationship between the heavy use of cannabis and suicidality, especially in men.[21,71] In addition, rimonabant, a synthetic CB1 receptor antagonist was found to increase the risk of suicidality and was taken off the market.[21,72] Cannabis Use Disorder and Cannabis Withdrawal Symptoms It is estimated that about 10% of cannabis users will develop cannabis use disorder. The percentage is even higher in users that start before age 18, up to 16%.[73] Cannabis use disorder is defined as a problematic pattern of cannabis use leading to clinically significant psychological impairment or distress, that has negative effects on the person’s ability to function at work, school, home, and/or causes social or interpersonal problems.[74] Cannabis withdrawal may be a part of cannabis use disorder. Symptoms may begin within a day after cessation, peak by the third day, and can last up to two weeks. It is most commonly seen after heavy, prolonged cannabis usage. Withdrawal symptoms occur only in some individuals on stopping cannabis, and may consist of irritability, anger, nervousness, anxiety, insomnia, nightmares, decreased appetite, weight loss, depressed mood, and possibly abdominal pain, shakiness/tremors, sweating, fever, chills, or headache. Cannabis Overdose Acute overdoses of cannabis almost all have a good prognosis. In a review of 985 pediatric accidental ingestions, the most common symptoms were drowsiness or lethargy, ataxia, agitation, and nausea or vomiting. There were a few patients that had respiratory depression, bradycardia, or hypotension, but there were no deaths.[75] There is one atypical case report in the literature of an 11-month-old child thought to have an acute cannabis ingestion, who developed lethargy, had a seizure and died from non-infectious myocarditis, There was no history of an ingestion, but screening tests for THC were positive.[76] Other Adverse Effects During cannabis intoxication, the user may for a short time experience impaired short-term memory, attention, judgment, and other cognitive functions as well as anxiety, paranoia, and, uncommonly, psychosis. Persistent longer lasting, but not permanent symptoms include impaired learning, impaired coordination, and sleep disturbances. Long-term cumulative effects of repeated use may include impairments in learning and memory with a potential small loss of IQ in heavy adolescent users,[77,78] increased risk of other drug and alcohol use disorders, and increased risk of psychosis in people with genetic vulnerability, or daily use of high potency cannabis.[66] Driving Performance While Under the Influence of Cannabis A study of subjects given vaporized THC, THC/CBD or CBD compared to placebo measured the standard deviation of lateral position(SDLP), which is a measure of lane weaving, swerving, and overcorrecting. It was found that there was no difference between the performance of the CBD group versus the placebo at 100 minutes after taking the medication. There was some worsening of SDLP performance of the THC and THC/CBD groups at 40 to 100 minutes after cannabis use, which returned to normal by four to five hours. The impairment with cannabis in the THC group was modest and comparable to a blood alcohol level of 0.05%.[79] A number of studies have looked at the rate of motor vehicle deaths after cannabis legalization versus pre-legalization, or compared to other states. While the issue is not resolved, there is no evidence of widespread motor vehicular fatalities after cannabis legalization. Some studies found no significant difference and some others minimal increases in motor vehicle fatalities, such as one study which reported an increase of 2.1 fatalities per billion miles driven in states where cannabis was legalized.[80-83] Medical Cannabis Prescription Formulations[84] Rimonabant was approved for use in Europe in 2006 for the treatment of anorectic obesity. It is a synthetic inverse agonist/selective antagonist of the CB1 receptor. It was withdrawn from the market due to the high incidence of serious psychiatric side effects. The FDA has approved epidiolex (cannabidiol) for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older. Marinol and syndros are two synthetic cannabinoids containing dronabinol, a synthetic THC, that are FDA approved for the treatment of nausea associated with cancer chemotherapy, and for the treatment of anorexia and weight loss in AIDS patients. Cesamet (nabilone), a synthetic cannabinoid similar to THC, is FDA approved for treatment of the nausea associated with cancer chemotherapy. Sativex (nabixmols) is a 1:1 mixture of 9-delta-tetrahydocannabinol (THC) and cannabidiol (CBD) in a spray absorbed by the buccal mucosa, which is available in many countries, but not the U.S. It is approved as a treatment for multiple sclerosis patients with moderate to severe spasticity who do not adequately respond to first-line antispasticity therapy.[24] Cannabis Drug Interactions Cannabinoids can interfere with the action of multiple classes of cardiovascular medications by inhibiting cytochrome P450. This can lead to increased blood levels of some medications including calcium channel blockers, statins, warfarin, NSAIDS, beta-blockers, and anti-arrhythmics such as flecainide, mexiletine, propafenone, amiodarone, quinidine, and lidocaine.[1] A recent study found that both THC and CBD in vitro inhibited some UDP-glucuronosyltransferase (UGT) enzymes. UGT enzymes are found in both the liver and the kidney and have an important role in the metabolism and detoxification of a wide range of substances including acetaminophen, furosemide, carbamazepine, codeine, gemfibrozil, morphine, and NSAIDS. The concern is that by inhibiting the metabolization of these medications, especially in individuals with decreased hepatic or renal function, cannabis may possibly increase the chance of an adverse reaction, but further clinical study is needed.[85] Conclusion Cannabis has some proven medical benefit for conditions such as refractory epilepsy, nausea in cancer patients, and attenuating neuropathic pain. It is used by many people for anxiety reduction, although the evidence for that effect is far from conclusive. Most people can use cannabis without a problem, however a small percentage of people, especially frequent users of high potency cannabis, may experience adverse effects such as hyperemesis, psychosis, or negative cardiovascular effects. There is also the possibility of some adverse drug interactions. It appears THC is responsible for the majority of the negative effects due to its stimulatory properties, while CBD has fewer negative issues with its use. Knowledge of the full extent of both positive and negative effects of cannabis smoking or ingestion has been limited by a lack of well controlled scientific studies. As an estimated 48 million people in the U.S used cannabis in 2019,[86] clinicians should be aware of both the diseases that can be treated by cannabis, and the clinical problems it may cause. References [1] Page II RL et al. Medical Marijuana, Recreational Cannabis, and Cardiovascular Health: A Scientific Statement From the American Heart Association. 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AKA Beaver Fever InBrief By Cheng-Hung Tai, M.D. and Rich Strongwater, M.D. Giardiasis is a disease caused by the parasite Giardia (Giardia duodenalis, lamblia, and intestinalis). Common symptoms include greasy loose stools or diarrhea, abdominal cramping, weight loss, nausea/vomiting, and fever. Symptoms typically start 1 to 3 weeks after infection and may last up to 2 to 6 weeks in immune-competent patients. It is caused by the spread of Giardia cysts found within contaminated food or water, where the host (humans) would ingest. It is the most common human parasitic disease worldwide, and most commonly seen in the developing world, with prevalence reported as high as 40%. It is important to note that there are two morphologic forms of Giardia: cysts and trophozoites. The cysts are the infectious form, whereas the trophozoites are the active, flagellated parasitic form that attaches to small bowel mucosal surfaces. This attachment ultimately causes malabsorption by breaking down digestive enzymes at the brush border of the small intestine. Diagnostic Evaluation Diagnosis for giardiasis includes a detailed history and physical. For example, a recent traveler to a resource-poor country, given a history of consuming poorly-prepared foods, would place the individual at a higher risk for Giardiasis. Common lab tests include: microscopy stool studies for ova and parasites (demonstration of microscopic cysts or trophozoites in stool samples) and stool antigen/nucleic acid detection assays including immunoassay antigen detection (ELISA) and PCR-based molecular methods. The stool assays are the most sensitive tests. Nucleic acid amplication assays for Giardia are often utilized for rapid panel detection on stool samples. Prevention Maintain proper hand hygiene Avoid drinking untreated water from rivers or lakes Boil untreated water for at least 1 minute or filter water “Cook it, boil it, peel it, or forget it” (with respect to food, fruits and vegetables and water) Treatment Options The treatment for giardiasis involves symptom management with supportive care and antimicrobial therapy. Oral rehydration is imperative, as patients that are symptomatic may have significant volume loss due to diarrhea. Hand hygiene is important to prevent the spread of infection as well. Those that are asymptomatic (incidental finding of giardiasis) without high risk of transmission (e.g. food-handlers), not initiating antimicrobial treatment could be considered. Although they would continue to shed cysts until resolution (self-limiting disease). Most patients treated with antimicrobial therapy will experience symptom resolution within 5-7 days. The preferred agents include nitazoxanide, tinidazole, and metronidazole (e.g. Flagyl 3 times a day for 5-10 days). Other agents with efficacy include albendazole, mebendazole, and paromomycin. In patients with recurrent symptoms despite treatment, it is important to consider treatment failure (due to drug resistance), immunosuppression, or possibly treatment non-adherence. Repeat stool testing should be considered, and if immunodeficiencies are suspected, appropriate studies should be sent (IgA deficiency, HIV, etc.). #InBrief #InfectiousDisease Sources and further reading: Schlagenhauf P, Weld L, Goorhuis A, et al. Travel-associated infection presenting in Europe (2008-12): an analysis of EuroTravNet longitudinal, surveillance data, and evaluation of the effect of the pre-travel consultation. Lancet Infect Dis. 2015;15(1):55-64. Shane AL, Mody RK, Crump JA, et al. 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clin Infect Dis. 2017;65(12):e45-e80. Ross AG, Olds GR, Cripps AW, Farrar JJ, Mcmanus DP. Enteropathogens and chronic illness in returning travelers. N Engl J Med. 2013;368(19):1817-25. Desai, A. Giardiasis. JAMA. 2021;325(13):1356. doi:10.1001/jama.2020.10289 Hooshyar H, Rostamkhani P, Arbabi M, Delavari M. Giardia lamblia infection: review of current diagnostic strategies. Gastroenterol Hepatol Bed Bench. 2019; 12(1): 3–12. PMCID: PMC6441489 PMID: 30949313

Ebola: AKA Ebola Virus Disease (EVD) or Ebola Haemorrhagic Fever Medical InBrief by Rich Strongwater, MD and Harish Moorjani, MD Ebola virus is named after the Ebola River in the Democratic Republic of Congo (formerly Zaire), where one of the first outbreaks of the infection occurred in 1976. Ebola virus disease is highly contagious; it is spread by direct contact with body fluids (eg, blood, saliva, mucous, vomit, feces, urine, semen, sweat, breast milk) and has a fatality rate as high as 50%. It is not spread by respiratory droplets or through the air by other means. Human-to-human transmission via semen may occur up to 2 months after initial infection. The second most recent ebola virus outbreak 2014-2016 (28,000 people infected and 11,300 reported deaths) was larger than all of the previous epidemics combined. This epidemic started in Guinea in December 2013, and most of the cases originated from five West-African countries (ie, Guinea, Liberia, Nigeria, Senegal, and Sierra Leone). During this outbreak, 11 patients with EVD were treated in the United States. Nine were patients brought back to the United States from West Africa. Two of these patients died. The two other patients were healthcare providers that had treated that first patient in the United States (who had contracted Ebola while traveling to West Africa). Thankfully both healthcare workers survived. The most recent “Kivu” Ebola epidemic occurred in the Democratic Republic of the Congo (DRC) occurring between 2018 and 2020 resulted in 2299 deaths out of a total of 3481 reported cases Causes and Risk Factors Ebola virus disease in humans is caused by four of five viruses in the genus Ebolavirus--Bundibugyo virus, Sudan virus, Taï Forest virus, and Ebola virus (formerly Zaire Ebola virus). Ebola virus is the most dangerous and is responsible for the largest number of outbreaks. The fifth virus of this genus, Reston virus, most likely does not cause disease in humans, but has caused disease in other primates. These five viruses are closely related to Marburg viruses. Ebola virus disease (ebola hemorrhagic fever, ebola) affects humans and other primates. Fruit bats are the natural reservoir for ebola and may directly infect a human or indirectly by contact with a living or dead animal. Regarding fruit bats, conventional wisdom recommends the following: Avoid touching dead fruit bats Avoid eating the meat of a fruit bat already found dead Avoid hunting a fruit bat that appears sick or is behaving strangely Diagnostic Evaluation and Differential Diagnosis Isolating the ebola virus by cell culture, detecting the viral RNA by polymerase chain reaction (PCR), and detecting proteins by enzyme-linked immunosorbent assay (ELISA) works best early and in those who have died from the disease. Detecting antibodies against the virus works best late in the disease and in those who recover. During an outbreak, virus isolation is often not feasible. The most common diagnostic methods are real-time PCR and ELISA detection of proteins, which can be performed in field or mobile hospitals. Routine blood testing in a patient with ebola virus disease may reveal a low platelet count, an initially decreased and then increased white blood cell count, elevated liver transaminase levels, and abnormal clotting often consistent with disseminated intravascular coagulation (eg, prolonged prothrombin time, partial thromboplastin time, bleeding time). Differential diagnoses include malaria, cholera, and other viral hemorrhagic fevers. Signs and Symptoms Signs and symptoms of ebola virus infection start between 2 days to 3 weeks after exposure and include fever, sore throat, myalgias, and headache followed by abdominal pain, vomiting, diarrhea, rash, and decreased liver and renal function. Both internal and external hemorrhage occur. During the 2014-2016 outbreak the incubation period proved to be ~11 days, and 95% of the cases had symptom onset within 21 days after exposure. Death may occur 6-16 days after symptoms appear and is often due to shock from fluid loss or hemorrhage. Treatment As of February 2021 there are two drug treatments approved by the U.S. FDA to treat EVD caused by the Zaire ebolavirus. Inmazeb, approved in October 2020, is a combination of three monoclonal antibodies. The second drug, Ebanga, is a single monoclonal antibody and was approved in December 2020. Monoclonal antibodies (mAbs) are synthetic proteins that perform like natural human antibodies and inhibit viral replication after infection. Inmazeb and Ebanga bind to a glycoprotein on the surface of the ebola virus. This prevents the virus from entering the human host’s cells. Both of these treatments were evaluated in a randomized controlled trial during the 2018-2020 Ebola outbreak in the Democratic Republic of the Congo. Overall survival was much higher for patients receiving either of the two treatments. Neither Inmazeb™ nor Ebanga™ has been evaluated for efficacy against species other than Zaire ebolavirus. Adapted from Ebola Virus Disease. Therapeutics. Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of High-Consequence Pathogens and Pathology (DHCPP), Viral Special Pathogens Branch (VSPB). February 26, 2021 Survival is also improved by early supportive care with rehydration and symptomatic supportive treatment. These measures may include management of pain, nausea, fever, and anxiety, as well as rehydration via the oral or intravenous route. Blood products such as packed red blood cells, platelets, or fresh frozen plasma may also be used. Other regulators of coagulation have also been tried; these include heparin to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding. Antimalarial medications and antibiotics are often used before the diagnosis is confirmed, although there is no evidence to suggest such treatment is helpful. Prevention Ebola Vaccine ERVEBO® (Ebola Zaire Vaccine, Live also known as V920, rVSVΔG-ZEBOV-GP or rVSV-ZEBOV) is approved by the U.S. Food and Drug Administration (FDA) for the prevention of disease caused by Ebola virus (formerlyZaire ebolavirus) in individuals 18 years of age and older as a single dose administration. ERVEBO is a replication-competent, live, attenuated recombinant vesicular stomatitis virus (rVSV) vaccine. It is not possible to become infected with EBOV from the vaccine because the vaccine only contains a gene from the Ebola virus, not the whole virus. Specifically, it contains a gene for the EBOV glycoprotein that replaces the gene for the native VSV glycoprotein. ERVEBO does not provide protection against other species of Ebolavirus or Marburgvirus. Clinical efficacy of the vaccine was supported by a vaccination study during the 2014–2016 outbreak in Guinea. In this study, 3,775 people in close contact with diagnosed EVD cases (contacts) and their close contacts (contacts of contacts) received immediate vaccination. No one who was vaccinated developed EVD 10 or more days after vaccination. The duration of protection conferred by an initial dose of ERVEBO is also unknown. A booster dose for people who have been previously vaccinated may extend the duration of protection for ERVEBO. Adapted from Ebola Vaccine: Information about ERVEBO® Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of High-Consequence Pathogens and Pathology (DHCPP), Viral Special Pathogens Branch (VSPB). March 8, 2022 Clinical prevention trials in combined phase II and phase III using a recombinant inactivated vaccine are under way. More medical information in our FibonacciCOMPENDIUM on FibonacciMD.app #InBrief #InfectiousDisease Sources Vossler, H., Akilimali, P., Pan, Y. et al. Analysis of individual-level data from 2018–2020 Ebola outbreak in Democratic Republic of the Congo. Sci Rep 12, 5534 (2022). https://doi.org/10.1038/s41598-022-09564-4 Ebola: What you need to know. Scientific American Web site. https://www.scientificamerican.com/report/ebola-what-you-need-to-know1/. Accessed March 4, 2018. Sierra Leone trial to introduce a vaccine against ebola (STRIVE). Centers for Disease Control and Prevention Web site. https://www.cdc.gov/vhf/ebola/strive/qa.html. April 20, 2016. Accessed March 4, 2018. Ebola hemorrhagic fever. Centers for Disease Control and Prevention Web site. https://www.cdc.gov/vhf/ebola/symptoms/index.html. November 2, 2014. Accessed March 4, 2018. Ebola virus disease WHO fact sheet on Ebola: key facts, definition, transmission, symptoms, diagnosis, treatment, prevention, WHO response. World Health Organization Web site. www.who.int/mediacentre/factsheets/fs103/en/ Accessed March 4, 2018. Ebola virus and Marburg virus. Symptoms and causes. Mayo Clinic Web site. https://www.mayoclinic.org/diseases-conditions/ebola-virus/symptoms-causes/syc-20356258. November 7, 2017. Accessed March 4, 2018. Choi MJ, Cossaboom CM, Whitesell AN, et al. Use of Ebola Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020. MMWR Recomm Rep 2021;70(No. RR-1):1–12. DOI: http://dx.doi.org/10.15585/mmwr.rr7001a1external iconexternal icon. Malenfant JH, Joyce A, Choi MJ, et al. Use of Ebola Vaccine: Expansion of Recommendations of the Advisory Committee on Immunization Practices to Include Two Additional Populations—United States, 2021. MMWR Morb Mortal Wkly Rep 2022;71:290–292. DOI: http://dx.doi.org/10.15585/mmwr.mm7108a2external icon Ebola Vaccine: Information about ERVEBO® Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of High-Consequence Pathogens and Pathology (DHCPP), Viral Special Pathogens Branch (VSPB). Page last reviewed: March 8, 2022 Ebola Virus Disease. Therapeutics. Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of High-Consequence Pathogens and Pathology (DHCPP), Viral Special Pathogens Branch (VSPB). Page last reviewed: February 26, 2021 Chakraborty C. Therapeutics development for Ebola virus disease: A recent scenario. Epub Oct 2021; 60:208-215. PMID: 34464933 DOI: 10.1016/j.coph.2021.07.020

AKA IGRAs Interferon-gamma release assay QuantiFERON-TB gold in-tube assay Tuberculosis assay InBrief by Jay A. Zaslow, MD, MPH and Rich Strongwater, MD The QuantiFERON-TB gold assay is a blood test used to detect latent tuberculosis (TB) infection (LTBI). It is the most commonly used interferon-gamma release assay (IGRA) used to diagnose infection with Mycobacterium tuberculosis. In patients infected with M tuberculosis, white blood cells release interferon-gamma when exposed to M tuberculosis antigens. Results can be available to the patient within 24 hours. The QuantiFERON-TB gold blood test has a sensitivity of 80%-90% and a specificity of 95% for LTBI. It is not designed to diagnose active tuberculosis, which requires microbiologic testing (ie, sputum acid-fast bacilli and culture). Advantages of IGRAs One practical advantage of IGRAs over the TB skin test (TST) is that the patient does not need to return for a second visit for test interpretation. Unlike the TST, the IGRA is not affected by Bacillus Calmette-Guerin (BCG) vaccination status. The PPD has a specificity as low as 60% in individuals from countries where BCG vaccination is used. Algorithms are available to confirm a positive PPD using the QuantiFERON-TB gold test in low-risk individuals suspected of having a false-positive PPD (eg, those having BCG vaccination, serial testing, or cross-reactivity from other nontuberculous mycobacterium strains). Disadvantages and Limitations of IGRAs Blood samples must be processed within 8-30 hours after collection while white blood cells are still viable. Errors in collecting or transporting blood specimens or in running and interpreting the assay can decrease the accuracy of IGRAs. There is limited data on the use of IGRAs to predict who will progress to TB disease in the future. There is limited data on the use of IGRAs for: Children younger than 5 years of age; Persons recently exposed to M. tuberculosis; Immunocompromised persons; and Serial testing. Tests may be expensive. Pearl to Know As with TST, live virus vaccines might affect IGRA test results. However, the effect of live virus vaccination on IGRAs has not been studied. Until additional information is available, IGRA testing in the context of live virus vaccine administration should be done as follows: Either on the same day as vaccination with live-virus vaccine or 4-6 weeks after the administration of the live-virus vaccine At least one month after smallpox vaccination References: CDC: MMWR 12/16/05 54(RR15) 49-55 IGRAs– Blood Tests for TB Infection Fact Sheet. Interferon-Gamma Release Assays (IGRAs) – Blood Tests for TB Infection. Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention. Page last reviewed: May 4, 2016. https://www.cdc.gov/tb/publications/factsheets/testing/igra.htm TB and Children. Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention. Page last reviewed: October 19, 2021

AKA Malignant Mesothelioma Oncology InBrief by Kruti Vora, MS-3 Edited by: Charles L. Fishman, MD Mesothelioma is a cancer of the mesothelium, which includes the pleura, peritoneum, pericardium, and tunica vaginalis. The pleura is the most common site of disease, and this is usually due to exposure to asbestos fibers. This cancer is aggressive in nature, and prognosis post diagnosis is poor. This is an uncommon cancer, with only 2,500 - 3,000 mesotheliomas diagnosed in the U.S. each year. 80% or more are related to asbestos exposure, with exposure occurring 10 - 40 years earlier. There are 3 cell types- epithelial 50%, sarcomatous (spindle-shaped mesenchymal cells) 16%, and biphasic 34%. The epithelial cell type has a better prognosis. Signs and Symptoms Pleural involvement of mesothelioma often has a slow onset of nonspecific pulmonary symptoms, which usually occur several decades after initial exposure to asbestos. Patients may have chest pain, dyspnea, cough, night sweats, or vocal hoarseness. As the disease progresses, patients may have systemic symptoms such as fatigue, fever, weakness, and weight loss, and symptoms of metastasis to the bone, liver, CNS, or invasion of local structures such as the brachial plexus or superior vena cava (causing SVC syndrome). Diagnostic Evaluation and Differential Diagnosis A history of asbestos exposure indicates risk for mesothelioma, however it is important to note that patients exposed to asbestos are still at higher risk of developing a bronchogenic carcinoma than mesothelioma. Initial evaluation will include a chest x-ray and chest CT scan to look for pleural thickening, plaques, or effusions, which are characteristic of mesothelioma. For definitive diagnosis, patients undergo a video-assisted thoracoscopic (VATS) biopsy or open thoracotomy. Bronchoscopy is also performed with endobronchial ultrasound biopsies to evaluate for lymph node involvement. The VATS biopsy method has a higher diagnostic yield than pleural fluid cytology evaluation or closed pleural biopsy. The diagnostic biopsy in mesothelioma is associated with positive staining for calretinin, vimentin and cytokerotin. The disease is staged based on extent of local progression, whether or not the tumor can be resected, regional lymph nodes involvement, and the presence of distant metastasis. Treatment and Recommended Follow-Up Surgery remains the mainstay of treatment for localized mesothelioma. In more advanced disease, surgery remains controversial. Some patients who are good surgical candidates may undergo procedures as limited as partial pleurectomy or as invasive as extrapleural pneumonectomy (removal of pleura, ipsilateral lung, pericardium, and diaphragm). It is unclear which of these procedures provides the optimal survival benefit. Post procedure, chemotherapy and radiotherapy are generally required. Patients who are not surgical candidates are offered palliative radiation and chemotherapy, and symptomatic treatment of pleural effusions via pleurodesis, catheters, or pleurectomy. Immunotherapy is being investigated as a potential new treatment for mesothelioma. Unfortunately, despite advances in treatment of mesothelioma, prognosis is still poor with life expectancy of 22.2 months for stage 1 patients with surgery, and 14.9 months for stage 4 patients with surgery. Without treatment, pleural mesothelioma patients live an average of 6-9 months. Patients must have close follow-up during and after treatment to monitor for disease recurrence. Additional Reading about Mesothelioma: https://www.asbestos.com/mesothelioma/• https://www.ncbi.nlm.nih.gov/pubmed/30410726• https://www.sciencedirect.com/science/article/pii/S0140673605670250 • https://www.nejm.org/doi/full/10.1056/NEJMra050152

Dive into the complexities of anaplasmosis, a tickborne illness caused by Anaplasma phagocytophilum. Explore its symptoms, diagnostic methods, and treatment options. Learn how to recognize early signs, navigate laboratory findings, and understand the importance of prompt medical attention in combating this emerging health concern. 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” . ANAPLASMOSIS (Part 3) by Stuart M. Caplen, MD Anaplasmosis, also known as human granulocytic anaplasmosis, is a tickborne disease caused by the bacterium Anaplasma phagocytophilum. Blacklegged ticks, Ixodes scapularis, in the eastern United States, and western blacklegged ticks, Ixodes pacificus, on the West Coast are the main causes of infection. Coinfections with other tickborne illness such as Lyme disease have been reported. Infections have occasionally been reported through blood transfusion and organ donation.[32] Peak transmission is during June to November. Two peaks of increased case reporting usually occur, with the first peak during June–July and a smaller peak during October-November. There are about 4,000 to 5,700 cases reported per year to the CDC.[33] Signs and Symptoms of Early Illness of Anaplasmosis [34] Signs and symptoms typically begin within 5-14 days after the bite of an infected tick, and are non-specific. They may include: Fever, chills, rigors Severe headache Malaise Myalgia Gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia) in about 20% of cases A non-specific rash occurs in less than 10% of patients with anaplasmosis. As rash is a rare finding in anaplasmosis, if a rash is present, consider a coinfection with Lyme disease, or another tickborne disease. Rarely: Nervous system involvement (e.g., meningoencephalitis, focal paralysis) Late Illness Symptoms of Anaplasmosis [34] If treatment is delayed severe illness can occur but is rare. Symptoms may include: Renal or respiratory failure Peripheral neuropathies Disseminated intravascular coagulation (DIC)-like coagulopathies Rhabdomyolysis Hemorrhage The clinical course of anaplasmosis varies from person to person, and may depend on patient age, co-morbid conditions, immune status and time of treatment. Laboratory Findings in Anaplasmosis [34] Laboratory findings can include mild anemia, thrombocytopenia, leukopenia and mild to moderate elevations in hepatic transaminases. However, normal laboratory findings do not rule out possible infection. Testing for Anaplasmosis [35] Laboratory testing for anaplasmosis is similar to ehrlichiosis. Indirect immunofluorescence antibody (IFA) assay for IgG using Anaplasma phagocytophilum antigen, is the standard diagnostic test for anaplasmosis. IgG IFA assays should be performed on paired acute and convalescent serum samples collected 2–4 weeks apart to demonstrate evidence of a fourfold rise. Antibody titers are frequently negative in the first week of illness. Anaplasmosis cannot be confirmed using a single acute antibody test. Between 5–10% of healthy people in some areas might have elevated antibody titers due to past exposure to A. phagocytophilum or similar organisms, which is why comparison of paired, serologic assays provides the best evidence of recent infection. Some reference laboratories offer IgM IFA assays which are not necessarily indicators of acute infection, and might be less specific than IgG antibodies. Therefore, IgM antibody titers alone should not be used for laboratory diagnosis. Polymerase chain reaction (PCR) amplification can be performed on DNA extracted from whole blood specimens. PCR is most sensitive in the first week of illness, and decreases in sensitivity following the administration of appropriate antibiotics. Unfortunately, a negative result does not rule out the diagnosis. PCR can also be used to amplify DNA in solid tissue and bone marrow specimens for testing. During the first week of illness a peripheral blood smear might reveal morulae (microcolonies of anaplasmae) in the cytoplasm of granulocytes and is highly suggestive of a diagnosis. However, blood smear examination is relatively insensitive, and should not be relied upon solely to diagnose anaplasmosis. The observance of morulae in a particular cell type cannot reliably differentiate between Anaplasma and Ehrlichia species. If a bone marrow biopsy is performed as part of the investigation of cytopenias, immunostaining of the bone marrow biopsy specimen looking for morulae can diagnose anaplasmosis. They may also be seen in organ biopsies taken for other purposes. Culture of A. phagocytophilum is only available at specialized laboratories, and routine hospital blood cultures cannot detect the organism Treatment of Anaplasmosis [36] Post-tick bite antibiotic prophylaxis is not currently recommended to prevent anaplasmosis. Doxycycline is recommended as the first-line treatment for anaplasmosis in adults and children of all ages. The dosage in adults is 100 mg every 12 hours, in children under 45 kg (100 lbs.)the dose is 2.2 mg/kg body weight given twice a day. Patients with suspected anaplasmosis should be treated with doxycycline for 10–14 days to provide appropriate length of therapy for possible concurrent Lyme disease infection. Lack of a clinical response to doxycycline suggests that the patient’s condition might not be due to anaplasmosis, or might be a due to a coinfection. Resistance to doxycycline or relapses in anaplasmosis symptoms after the completion of the recommended course have not been documented. In cases of life-threatening allergies to doxycycline, severe doxycycline intolerance, and in some pregnant patients for whom the clinical course of anaplasmosis appears mild, rifampin might be considered. Rifampin has been used successfully in several pregnant women with anaplasmosis, and small numbers of children <8 years for a 7–10-day course. However, rifampin is not effective in treating Rocky mountain spotted fever, a disease that might be confused with anaplasmosis, nor is it an effective treatment for a potential Lyme disease coinfection. An infectious disease consult is recommended when treating the pregnant patient. #InfectiousDisease More TICK-BORNE Disease articles: Lyme | Ehrlichiosis | Babesia The CME version of this article is available for the medical community with an online CME test in the APP. REFERENCES [3] Tickborne Diseases of the United States, CDC, last reviewed September 22, 2020. Retrieved from: https://www.cdc.gov/ticks/tickbornediseases/overview.html [15] Tickborne Diseases of the United States, CDC, 5th edition 2018. Retrieved from: https://www.cdc.gov/ticks/tickbornediseases/TickborneDiseases-P.pdf [15A] Signs and Symptoms of Untreated Lyme Disease, CDC, last reviewed: January 15, 2021. Retrieved from: https://www.cdc.gov/lyme/signs_symptoms/index.html [16] Photo credits: Alison Young, Taryn Holman, Yevgeniy Balagula/Dermatlas.org, Lyme Disease Rashes and Look-alikes, CDC, last reviewed: October 9, 2020. Retrieved from: https://www.cdc.gov/lyme/signs_symptoms/rashes.html [17] Photo Credit: Bernard Cohen/Dermatlas.org, Lyme Disease Rashes and Look-alikes, CDC, last reviewed: October 9, 2020. Retrieved from: https://www.cdc.gov/lyme/signs_symptoms/rashes.html [18] Moniuszko-Malinowska A, Czupryna P, Dunaj J, et al. Acrodermatitis chronica atrophicans: various faces of the late form of Lyme borreliosis. Postepy Dermatol Alergol. 2018;35(5):490-494. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232541/ [19] Photo credit, Glatz M et al., Clinical Spectrum of Skin Manifestations of Lyme Borreliosis in 204 Children in Austria, Advances in Dermatology and Venereology, Vol 95, Issue 5, Nov 4, 2014. Retrieved from: https://www.medicaljournals.se/acta/content/html/10.2340/00015555-2000 [20] Warshafsky S et al., Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis, Journal of Antimicrobial Chemotherapy, Volume 65, Issue 6, June 2010, Pages 1137–1144. Retrieved from: https://academic.oup.com/jac/article-pdf/65/6/1137/2086677/dkq097.pdf [21] Nadelman R et al., Prophylaxis with Single-Dose Doxycycline for the Prevention of Lyme Disease after an Ixodes scapularis Tick Bite, N Engl J Med 2001; 345:79-84. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJM200107123450201 [22] Photo Credit- Ticks Image Gallery, CDC, last reviewed: December 18, 2020. Retrieved from: https://www.cdc.gov/ticks/gallery/index.html [23] Smith G et al., Management of Tick Bites and Lyme Disease During Pregnancy, J Obstet Gynaecol Can 2012;34(11):1087–1091. Retrieved from: https://www.jogc.com/article/S1701-2163(16)35439-1/pdf [24] Treatment for erythema migrans, CDC, last reviewed: November 3, 2020. Retrieved from: https://www.cdc.gov/lyme/treatment/index.html [25] Post-Treatment Lyme Disease Syndrome, CDC, last reviewed: November 8, 2019. Retrieved from: https://www.cdc.gov/lyme/postlds/index.html [26] Ehrlichiosis Transmission, CDC,last reviewed: January 17, 2019. Retrieved from:https://www.cdc.gov/ehrlichiosis/transmission/index.html [27] Ehrlichiosis Epidemiology and Statistics, CDC, last reviewed: March 26, 2020. Retrieved from: https://www.cdc.gov/ehrlichiosis/stats/index.html [28] Ehrlichiosis Clinical and Laboratory Diagnosis, CDC, last reviewed: January 17, 2019. Retrieved from: https://www.cdc.gov/ehrlichiosis/healthcare-providers/diagnosis.html [29] Ehrlichiosis Signs and Symptoms, CDC, last reviewed: January 17, 2019. Retrieved from: https://www.cdc.gov/ehrlichiosis/healthcare-providers/diagnosis.html [30] Ehrlichiosis Treatment, CDC, last reviewed: January 17, 2019.Retrieved from: https://www.cdc.gov/ehrlichiosis/healthcare-providers/treatment.html [31] Todd S et al., No Visible Dental Staining in Children Treated with Doxycycline for Suspected Rocky Mountain Spotted Fever, J Pediatrics 2015;166:1246-51. Retrieved from: http://www.jpeds.com/article/S0022-3476(15)00135-3/pdf?ext=.pdf [32] Anaplasmosis Transmission, CDC, last reviewed: January 11, 2019. Retrieved from:https://www.cdc.gov/anaplasmosis/transmission/index.html [33] Anaplasmosis Epidemiology and Statistics, CDC, last reviewed: March 26, 2020. Retrieved from: https://www.cdc.gov/anaplasmosis/stats/index.html [34] Anaplasmosis Signs and Symptoms, CDC, last reviewed: January 11, 2019. Retrieved from: https://www.cdc.gov/anaplasmosis/symptoms/index.html [35] Anaplasmosis Clinical and Laboratory Diagnosis, CDC, last reviewed: January 11, 2019. Retrieved from: https://www.cdc.gov/anaplasmosis/healthcare-providers/clinical-lab-diagnosis.html [36] Anaplasmosis Treatment, CDC, last reviewed: January 11, 2019. Retrieved from: https://www.cdc.gov/anaplasmosis/healthcare-providers/treatment.html

Small-Cell Lung Cancer represents 15% of all lung cancers and tends to be responsive to chemo therapy and radiation Small Cell Lung Cancer aka SCLC Oncology Terms FibonacciMD Compendium InShort By Anurag Saraf , MD and Nancy Mills MD Definition of Small Cell Lung Cancer Small Cell Lung Cancer (SCLC) is a poorly differentiated neuroendocrine tumor of the lung that represents 15% of all lung cancers. It is distinguished from other lung cancers in its rapid growth pattern and its typically disseminated presentation. It tends to be very responsive to chemotherapy and radiation, more so than non-small cell lung cancer (NSCLC), and prophylactic treatment for brain metastases is commonly considered. The cancer is staged into two categories: limited-stage (disease confined to a potential radiation portal in the thorax) with median survival of 15-20 months and 5-year survival of 10-13%, and extensive-stage with median survival of 8-10 months and 5-year survival of 1-2%. Causes and Risk Factors of SCLC SCLC is almost exclusively seen in smokers, and most common in heavy smokers. Incidence of SCLC has decreased in recent decades, most attributed to a decrease in smoking in men. Second hand smoke exposure can also be a risk factor. Age is a common risk factor, as most patients are seen between the ages of 60-80 years old. Signs and Symptoms of SCLC Patients may commonly present in later stage, with symptoms of cough and hemoptysis as well as weight loss, fatigue, and/or fevers. Metastasis is common at presentation and patients may present with cholestatic findings or neurologic findings associated with liver or brain metastasis, respectively. Paraneoplastic syndromes are also common. SIADH is one of the most common syndromes associated with SCLC, and patients may present with findings of hyponatremia before any pulmonary symptoms. Other common paraneoplastic syndromes include neurologic syndromes, with symptoms ranging from ataxia, opsoclonus, myoclonus, and psychosis. Read more about the Diagnostic Evaluation of Small Cell Lung Cancer Staging and Further Stratifications Treatment and Recommended Follow-up and Pearl to Know and more about SCLC in our FibonacciCOMPENDIUM #O ncology Small-Cell Lung Cancer in our FibonacciCOMPENDIUM Further Reading: 1. Small-cell lung cancer: what we know, what we need to know and the path forward. Nature Cancer Reviews 2017 (https://www.nature.com/articles/nrc.2017.87) 2. Treatment for small cell lung cancer, where are we now?-a review. Translational Lung Cancer Review 2016 (https://www.ncbi.nlm.nih.gov/pubmed/26958491) IMIT takes pride in its work, and the information published on the IMIT Platform is believed to be accurate and reliable. The IMIT Platform is provided strictly for informational purposes, and IMIT recommends that any medical, diagnostic, or other advice be obtained from a medical professional. Read full disclaimer.

A brief review of chronic Hepatitis B. An analysis of cause and risk factors, staging and diagnosis, treatment and prevention. Infectious Disease Term InBrief by Rich Strongwater, M.D. Hepatitis B virus (HBV), a DNA virus, is the most common cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide, leading to 0.5- to 1.2-million deaths/year. Approximately 70% of patients infected with HBV have subclinical or anicteric (without jaundice) hepatitis; some 30% develop acute icteric (with jaundice) hepatitis. After symptomatic acute infection, about 90% of infected neonates, 30%-50% of children 1-4 years of age, and 1%-10% (generally < 5%) of adults develop persistent infection. Approximately 15%-40% of patients with persistent infection develop advanced liver disease, cirrhosis, and/or HCC. Overall, > 2-billion persons worldwide have serologic evidence of HBV infection; of these, 300 million are chronic carriers with some form of chronic infection. In the U.S. there are an estimated 1.6 million residents with chronic hepatitis B infections. Foreign born U.S. residents (especially non-Hispanic Asians) have the highest prevalence. HBV infection is most prevalent in China, sub-Saharan Africa, and parts of the Middle East and Southeast Asia. Causes and Risk Factors HBV is transmitted via percutaneous or mucosal exposure to infected blood or bodily fluids (e.g., saliva, semen). Activities that increase risk of HBV transmission include sexual activity, intravenous drug use, and activities such as tattooing, piercings, acupuncture, medical and dental procedures, medical tourism. Risk of infection increases in unsafe settings or during travel to endemic regions. Other high-risk activity includes working in healthcare, living with any household contacts with HBV, and receiving chronic hemodialysis or blood transfusions. Coinfection with hepatitis-C virus or a history of alcohol abuse worsens the prognosis. Diagnostic Evaluation The incubation period for HBV infection generally lasts 1-4 months, but may last as long as 6 months. The hallmark of HBV infection is the presence of hepatitis-B surface antigen (HBsAg), the first serologic marker that typically appears 1-10 weeks after an acute exposure. Persistently elevated HBsAg levels after 6 months indicates a chronic infection. Total Hepatitis-B core antibody (HBcAb or anti-HBc) and hepatitis-B IgM core antibody(IgM anti-HBc) b both appear shortly after the appearance of HBsAg. Anti-HBc may be the only marker of a hepatitis B infection after HBsAg disappears and before hepatitis-B surface antibody (HBsAb or anti-HBs) appears in an improving patient. A positive total anti-HBc on its own is a nonspecific finding and can indicate an acute, chronic, or past resolved HBV infection. If total anti-HBc is the only positive marker, a IgM anti-HBc level should be checked and a negative result most commonly indicates a resolved HBV infection, A positive IgM anti-HBc indicates a recent infection of less than six months, as typically IgM anti-HBc disappears at that time. In chronic hepatitis-B both the late phase marker hepatitis-B IgG core antibody (IgG anti-HBc), and HBsAg are typically present with no anti-ABs detectable. In occult infections, low levels of antigen can result in a positive IgG anti-HBc with negative HBsAg levels. PCR for serum HBV DNA may be helpful in diagnosing an occult HBV infection. HBV DNA measures viral load and is detectable usually at one month after infection and disappears at disease resolution. It is detectable in chronic infection at varying levels. Disappearance of HBsAg and the appearance of anti-HBs and IgG anti-HBc usually indicates recovery from an acute hepatitis B infection. In patients who have acquired immunity from vaccination, only anti-HBs levels will be present. Table 1 - Interpretation of Hepatitis B Serologic Test Results Most patients with chronic HBV infection have mild-to-moderate elevation in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. A progression to cirrhosis is suspected when there is evidence of hypersplenism with decreased white blood cell and platelet counts and impaired hepatic function indicated by hypoalbuminemia, prolonged prothrombin time, and hyperbilirubinemia). Staging There are four phases of chronic HBV infection: The immune tolerant high replication phase is characterized by the findings of high HBV DNA serum levels, positive hepatitis B e antigen (HBeAg), and normal ALT levels. In this initial stage there is no evidence of active liver disease. The presence of HBeAg indicates active replication of virus and is associated with a more virulent HBV infection. In the immune clearance phase, persistence of HBeAg would be associated with chronic liver disease. In the inactive carrier state, patients are HBeAg-negative and hepatitis B e antibody-postive(HBeAb) and have normal ALT and low serum HBV DNA levels. In some cases, patients have a reactivation phase, in which they are still HBeAg-negative but have elevated ALT and HBV serum DNA levels, with continued HBV replication and active liver disease. Some patients do eventually go on to become HBsAg-negative with undetectable HBV DNA levels, indicating complete recovery after chronic infection. Treatment of Hepatitis B Medications approved by the FDA for the treatment of chronic hepatitis B include two formulations of interferon (interferon alpha and pegylated interferon) and five nucleoside or nucleotide analogs (lamuvidine, telbivudine, abacavir, entecavir, and tenofovir). Prevention of Hepatitis B For prevention of HBV infection, recombinant HBV vaccine (thimerosal-free Engerix-B and Recombivax-HB) is usually given at 0, 1, and 6 months. One dose may be given just before a short travel; the second dose may be given at 1 month upon return. Alternatively, an accelerated schedule involving immunization on days 0, 7, and 21 (with a booster at 12 months) is recommended for higher risk travel necessitating more rapid and confident protection. Some 5%-10% of people do not respond to currently available vaccines. In 2008, the estimated global coverage rate of HBV vaccination in infants was 69%. In 2020, the estimated global coverage with three doses of hepatitis B vaccine was 83%, but only 42% of infants received their first dose at birth. Infectious Disease definitions in the FibonacciCOMPENDIUM #InBrief #FibonacciCOMPENDIUM References: Johnson DF, Leder K, Torresi J. Hepatitis B and C infection in international travelers. J Travel Med. 2013;20:194-202. Williamson MA, Snyder LA, eds. Wallach's Interpretation of Diagnostic Tests. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. Fauci A, Braunwald E, Kasper D, et al. Harrison's Manual of Medicine. 17th ed. New York: McGraw-Hill Medical; 2009. Lim JK, Nguyen M, Kim W, Gish R, Perumalswami P, Jacobson I. Prevalence of Chronic Hepatitis B Virus Infection in the United States. The American Journal of Gastroenterology. 2020; 115,9:1429-1438. doi: 10.14309/ajg.0000000000000651 Heiberg IL, Hoegh M, Ladelund S, Niesters H, Hogh B. Hepatitis B Virus DNA in Saliva from Children with Chronic Hepatitis B Infection. Implications for Saliva as a Potential Mode of Horizontal Transmission. The Pediatric Infectious Disease Journal. 2010; 29,5:465-467. doi: 10.1097/INF.0b013e3181d8e009 Song JE, Kim DY. Diagnosis of Hepatitis B. Ann. Transl. Med. 2016;4(18):338. Doi. 10.21037/atm.2016.09.11 Global Viral Hepatitis: Millions of People are Affected | CDC Page last reviewed: July 19, 2021 Content source: Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD, and TB Prevention https://www.cdc.gov › hepatitis › global Pockros P, Mulgaonkar A. Cessation of Nucleoside/Nucleotide Analogue Therapy in Chronic Hepatitis B HBeAg-Negative Patients. Gastroenterology & Hepatology. 2022;18,(6). Updated CDC Recommendations for the Management of Hepatitis B Virus–Infected Health-Care Providers and Students. MMWR Morbidity and Mortality Weekly Report. July 6, 2012. Retrieved from: https://www.cdc.gov/mmwr/pdf/rr/rr6103.pdf [Table 1] Interpretation of Hepatitis B Serologic Test Results, CDC, 2005. Retrieved from: https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf

What do female babies, left hips, and breech presentations all have in common? Congenital Hip Dysplasia, aka CHD, CDH, DDH Orthopaedic InBrief by Allan Strongwater, M.D . CHD Congenital Dislocation of the hip CDH Developmental Dysplasia of the hip Developmental Dislocation of the hip DDH Physiology The hip joint is a spherical ball in socket joint comprised of bone from the pelvis, contributed to by the Ilium, Ischium and Pubic bones forming the socket, called the acetabulum. The ball portion of the hip joint is the head of the proximal femur. The acetabulum and femoral head are, in large part, covered by articular cartilage forming the weight bearing, gliding surface of the joint. The skeletally immature pediatric hip contains a number of growth plates (physes), absent in the adult, that allow for increases in size and changes in shape of the joint during the growth period. The physis is located between the metaphysis and the epiphysis of the bone. The physis is comprised primarily of special growth cartilage cells carefully aligned in vertical columns like stacks of coins. During growth, the bone elongates by adding cells to each of the columns. If the columnar alignment of the cartilage is disrupted, growth in the affected physis may stop, slow or grow in a deformed manner. The delicate structure of the physis can be injured in a number of ways, including by direct (fracture through the physis) and indirect trauma (due to excessive compressive loads), and from various infective organisms, particularly staphylococcus aureus and streptococcus. Several neoplastic processes of both the benign and malignant type can be identified targeting the pediatric hip. Several, rare inborn genetic disorders like Gaucher’s disease and fibrous dysplasia can affect hip development. When observing a radiograph of the pediatric hip, multiple growth plates, physes, may be visible in and around the hip, depending upon the projected view of the image. In addition to the visual differences between bone and cartilage, cartilage of the physis is mechanically much less strong, especially resisting shear force. The physis is therefore susceptible to injury of both acute and chronic forms of trauma resulting in types of injury not seen in adults, such as slipped capital femoral epiphysis, transphyseal fracture or avulsion fractures of the lesser trochanter, greater trochanter and ischial apophysis. As we review some of the specific common congenital and acquired afflictions of the immature hip it is important to keep the structural differences between skeletally immature and mature hip in focus as it will help clarify the etiology of the pathology discussed. This InReview will limit discussion to Congenital Hip Dysplasia. A broader discussion, “A Summary of some Common Congenital and Acquired Afflictions of the Immature Hip” will be presented in FibonacciMD in the near future. Pathological afflictions In the newborn and peri-natal period, the greatest concern regarding the hip is the presence or absence of congenital dislocation of the hip (CDH). This serious problem has been referred to by several names: developmental dislocation of the hip (DDH) or congenital hip dysplasia (CHD). In all cases the pathology refers to abnormal seating of the femoral head within the acetabulum and spans the gamut from the femoral head being completely out of the acetabulum (no or minimal contact between the articular surfaces of the femoral head and acetabulum) to merely not being concentrically located in the acetabulum (referred to as subluxated or non-concentric). The unstable hip also falls into the category of CDH. The unstable hip is initially located within the acetabulum but can be dislocated out of the acetabulum with little force by the examiner performing a Barlow maneuver. The optimal time to identify CDH is shortly after birth. If detected early in life and appropriately treated, complete cure with no disability is possible in most cases. Delay in diagnosis may result in less satisfactory outcome with more complicated treatment. In many cases, if the dislocated hip is not diagnosed in the first few months of life, it may remain undiscovered until the child starts to walk at which time the toddler will demonstrate a notable limp on the affected lower extremity. Causes and Risk Factors CDH tends to be more common in female babies, in the left hip, with breech presentation, and with a positive family history of CDH. The precise cause of congenital hip dislocation is unknown however there are clearly defined risk factors including: oligohydramnios, multiple fetuses, previous pregnancy resulting in a baby with hip dislocation, female baby, first born, and breech presentation. Signs and Symptoms In the perinatal period, before 6 weeks of age, the most reliable finding on examination is a positive Ortolani sign. This is a palpable clunk as the dislocated hip pops back into the acetabulum when the hips are flexed and abducted. The Barlow is the pop of the hip moving out of the acetabulum when the hip is moved from a position of flexion and abduction to adduction. If either of these maneuvers are positive, the baby requires treatment. Careful history and examination are indicated. Several physical findings may be apparent on careful examination of the infant including: A limb length inequality with the affected dislocated hip on the short side as the femoral head usually migrates proximal, lateral and posteriorly. Shortening of the thigh segment on the affected side is referred to as a positive Galeazzi sign. Thigh skin fold asymmetry with extra skin folds on the affected side, due to shortening. Positive Ortolani or Barlow signs, a low frequency palpable clunk as the femoral head moves in and out of the acetabulum (this is not an audible click) as the hip is moved from flexion adduction to flexion abduction when axial compression is applied. These signs are often associated with either hip dislocation or instability of the joint. Sometimes a sense of telescoping can be palpated on gentle push pull of the affected limb especially if the femoral head is completely out of the acetabulum. Finally, an important sensitive indicator of CDH is the presence of asymmetric range of hip abduction. When dislocated or subluxated, the center of rotation of the hip joint moves out of the acetabulum resulting in tightening of medial musculotendinous structures which restrict the range of abduction motion of the affected joint. In cases of bilateral CDH symmetric reduced range of hip abduction may obscure proper diagnosis. Uncommonly, the femoral head represented as a hard mass can be palpated in the buttock of the affected hip. Certain neuromuscular afflictions that result in abnormal muscle tone in the womb predispose to the development of CDH most commonly myelomeningocele. Later in childhood, myelomeningocele, cerebral and other neuromuscular afflictions may lead to late dislocation or subluxation of the developing hip, even as late as the adolescent years. Children with neuromuscular afflictions require more careful and frequent evaluation of hip development. Diagnostic Evaluation and Differential Diagnosis Diagnostically there are several tools available to objectively evaluate the immature hip. In the peri-natal period and up to approximately six months of age, real-time high-resolution ultrasound is the most accurate non-invasive means to evaluate the anatomy and stability of the hip as the Ortolani and Barlow maneuvers can be performed under direct visualization of the joint to ensure concentric reduction and stability of the femoral head in the acetabulum. Additionally, the anatomy and configuration of the hip can be measured. In the age group between birth and six months of age radiographs of the hip are relatively contraindicated for the routine workup of CDH. Beyond six months of age the capital femoral epiphysis is sufficiently ossified to make ultrasonic imaging more difficult and therefore less reliable. Once the ossific nucleus of the capital femoral epiphysis is well formed radiographs or CT scan may prove more useful. The most definitive tool to evaluate hip joint stability, congruence of reduction, and intra-articular anatomy is the contrast enhanced arthrogram. Hip joint arthrography should not be undertaken without consideration of all other modalities as the study requires infant sedation and although is of low risk, it is not without complications. In uncommon cases MRI has been used to evaluate the infant hip and surrounding structures. Although MRI is a non-invasive modality it usually requires sedation of the infant and young child. DDH should be differentiated from congenital or developmental coxa vara, perinatal fracture, and proximal focal femoral deficiency. Staging and Further Stratifications A variety of systems have been described to classify the degree of DDH, most are based on the degree of displacement of the femoral head from the true acetabulum and or the degree of deformity of the acetabulum, or both. Pearl to Know Restriction of hip abduction is strongly suspicious for DDH. Asymmetric thigh skin folds is suspicious but not diagnostic of DDH. Treatment and Recommended Follow-Up The precise treatment algorithm for CDH is very complex and highly branched depending on such factors as age of the child, degree of dislocation, duration of dislocation, anatomy of the proximal femur and acetabulum, including any deformity due to previous unsuccessful treatment, any underlying affliction which may be driving the hip dislocation, and integrated with results of various tests that may have been performed. For these reasons, the precise treatment of any specific case is beyond the scope of the current text. The text is intended to provide a general outline of potential treatment strategies. Suffice it to say CDH diagnosed early in life that demonstrates a positive Ortolani and/or Barlow can usually be treated with some form of brace or cast that holds the hip in a position of stable reduction such that the femoral head is contained in the acetabulum. A commonly used brace for the treatment of CDH is the Pavlik harness. Other devices include: Frejka pillow, Von Rosen splint, or universal hip abduction orthosis. The harness is considered a dynamic brace in that range of motion of the lower extremities is allowed but constrained to certain arcs thereby thought to allow the infant to “kick” the hip into reduction. The Pavlik harness requires precise application as potentially serious complications can arise from its use. Periodic adjustment of the Pavlik harness is necessary to accommodate infant growth. CDH in the peri-natal age group can usually be treated for a period of four to six weeks of bracing. The hip must be stable to discontinue immobilization treatment. Rehabilitation of the afflicted hip may be necessary to obtain normal range of motion. Careful follow up to beyond one year of age is recommended. Individuals in which the Ortolani and/or Barlow signs are absent, or the femoral head cannot be reduced into the acetabulum with brace treatment alone require further evaluation of the anatomy of the joint, beyond ultrasonography. Most commonly an arthrogram of the hip, under sedation or anesthesia, is performed and immediately followed by whatever treatment modality is best indicated by the information gleaned from the arthrogram. Hips in this category have usually failed simple closed reduction treatment and may require traction and/or surgical intervention to obtain a concentric reduction of the femoral head into the acetabulum. Traction is applied to the affected lower extremity with the hip and knee in some degree of flexion. The goal is to manually pull, over time, the femoral head distally to the level of the true acetabulum to facilitate closed or open joint reduction followed by brace or cast to hold the hip in a concentrically reduced position. Children who demonstrate anatomic anomalies of the hip, usually seen beyond six months of age may require surgical correction. Anatomic anomalies in and around the hip that require open reduction may include an “hourglass” constriction of the hip joint capsule which prevents reduction of the femoral head through the constricted capsule into the true acetabulum. Capsular contracture may occur with or without iliopsoas tendon contracture which further obstructs movement of the femoral head medially into the true acetabulum. In those individuals in which the femoral head has been dislocated for a substantial period of time, the acetabulum often becomes deformed, or the hip adductor muscles become contracted and need to be corrected. Finally, the femur itself may have malrotation, excessive femoral anteversion leading to hip instability requiring surgical derotation osteotomy. Each child with CDH requires followup care and monitoring until the hip joint development is deemed normal or growth has ceased. Children who at the time of skeletal maturity do not have normal hip development will generally develop hip pain in their fourth or fifth decade of life and require additional hip surgery up to and including total hip replacement surgery. initial post 1/24/2022

Use of Highly Sensitive Troponin and other Cardiac Biomarkers in Suspected Myocardial Infarction/Acute Coronary Syndromes and Heart Failure by David B. Grossberg MD FACC and Stuart M Caplen MD FACEP Diagnosing a classically presenting myocardial infarction(MI) or acute coronary syndrome(ACS) is relatively straightforward, but a dilemma for emergency department physicians and cardiologists has been how to avoid sending home an atypical MI/ACS. Patients may present with fatigue, shortness of breath, atypical chest pain or abdominal pain, and EKGs may be non-diagnostic in a non-ST segment elevation MI(NSTEMI), making a correct diagnosis difficult. In 2000 a study from ten U.S. emergency departments, and in 2006 one from all the hospitals in Ontario, Canada both reported exactly the same finding; that the missed MI rate in emergency departments averaged 2.1%.[1,2] According to the CDC there are an estimated 805,000 MIs per year in the U.S.[3] A 2.1% miss rate would mean almost 17,000 people in the U.S. who seek care in emergency departments would be mistakenly sent home with a missed MI, which is both an issue of patient morbidity, and a significant malpractice issue. In this article we will look at ways to decrease that MI miss rate, using highly sensitive troponins (also known as high sensitivity troponins), and rapid MI/ACS rule out protocols/algorithms. In addition, a more rapid MI/ACS rule in or out decreases length of stay, frees up beds, is better for patients, and can lead to cost savings.[4] We will also discuss troponin as a prognostic tool, new cardiac markers that may have some utility, and look at B-type natriuretic peptide (BNP); what can it tell you, and how accurate it is. Troponin In the past, cardiac markers such as LDH(lactate dehydrogenase), CKMB(creatine kinase-MB), and myoglobin were used to try to determine whether a chest pain patient had an MI/ACS.[5] Those markers are no longer in use, either due to the length of time it took for the marker to rise, not being sensitive enough to pick up mild disease, or they lacked specificity for cardiac disease, with many false positives requiring more testing and admissions.[6] CKMB may still be in use in some centers, due to physicians still ordering it, but the American College of Cardiology guidelines recommend that it no longer be used.[7] The currently recommended cardiac marker is troponin, and more recently, highly sensitive troponins. Consensus guidelines from both the European Society of Cardiology and the American College of Cardiology state that cardiac troponin is the only biomarker recommended for the diagnosis of an acute MI, due to its superior sensitivity and accuracy.[8,9] Highly sensitive troponins also may be mildly elevated in myocardial ischemia without infarction, allowing identification of those patients. Troponins are released after myocardial injury, no matter what the etiology. Higher troponin levels generally correlate with more cardiac myocyte injury. The reason troponin rises quickly after a cardiac injury is that 5–8% is free in the cardiac myocyte cytoplasm, which is called the early releasable troponin pool. Bound troponin releases more gradually over several days.[10] Troponin levels typically start to rise within two to three hours after the onset of chest pain, and typically peak 12 and 48 hours later. The troponin level will begin to fall over the next four to ten days to a normal level. This typical rise and fall of troponin can potentially distinguish a MI/ACS from other causes of elevated troponin.[11] Troponins are found in skeletal and cardiac muscle cells, but not in smooth muscle cells. There are three subtypes: troponin I, troponin T, and troponin C. Skeletal and cardiac subunits of troponin C are identical, and the two types cannot be differentiated by standard laboratory testing, making troponin C measurement unhelpful in diagnosing MI/ACS. The skeletal and cardiac subunits for both troponin I and troponin T are different, and current serum immunoassays can measure solely the cardiac component.[12] Troponin T in muscle cells binds with calcium, freeing myosin binding sites on actin filaments which allow myosin and actin fibers to contract.[13,14] Troponin T binds to the myosin blocker tropomyosin, which opens up myosin binding sites on actin fibers. Troponin I inhibits the interaction of myosin with actin in conjunction with tropomyosin helping end muscle contraction.[14] Troponin I assays are available from a number of manufacturers and have different reference ranges. The troponin T test is sold only by one manufacturer in the U.S. Highly sensitive troponin testing has been used in Europe since 2010 and was introduced in the U.S. in 2017.[10] Normal values for a high sensitivity troponin test are defined as anything below the 99th percentile of values found when testing at least 300 normal individuals. An abnormal troponin level is defined as a value above the 99th percentile.[15,16] As testing has improved, highly sensitive tests are able to detect troponin at concentrations that are lower than 50% of the level of the 99th percentile.[16] The term high sensitivity with respect to troponin refers to analytical sensitivity, not to clinical sensitivity. In the past troponin tests were less analytically sensitive, and almost any detectable troponin level was abnormal, while today highly sensitive troponin assays can measure detectable troponin levels in many people without cardiac disease.[16] When a test is more clinically sensitive, it typically means that the test is less specific, with more false positives, and this is true of highly sensitive troponins.[12] Another issue in setting normal and elevated troponin levels is that the troponin 99th percentile level in females is lower than in males, and it is recommended that different norms be used depending on gender. Typical normal levels of troponin T are < 15ng/L in men, and < 10ng/L in women.[17] If a blended male and female 99th percentile level is used to define a normal test, MI/ACS may be underdiagnosed in women, because some elevated troponin levels for them will then be considered normal. A blended male-female normal range may possibly also over diagnose MI/ACS in some men.[18] It should be noted that not all authorities agree that using separate values for men and women is the correct option.[19] Non-ACS Causes of Troponin Elevation[20,21] Myocardial ischemia or infarction are the most clinically relevant etiologies for a rise in serum troponin levels, but there are many other conditions that can also lead to an elevation in the serum troponin level, as listed below. Given the wide variety of causes of an elevated troponin level, clinicians should always consider the clinical situation before reflexively diagnosing MI or ACS in a patient. Causes of Elevated Troponin Aortic valvular disease, aortic dissection Cardiac contusion, ablation, pacing, implantable cardioverter-defibrillator firings, cardioversion, endomyocardial biopsy, cardiac surgery Chemotherapeutic agents such as adriamycin, 5-fluorouracil, Herceptin Congestive heart failure Critically ill patients Drug overdose Dysrhythmias Strenuous exercise Heterophile antibodies Hypothyroidism Infiltrative diseases such as amyloidosis, hemochromatosis, sarcoidosis, and scleroderma Extensive skin burns Markedly elevated alkaline phosphatase levels Myocarditis, pericarditis, endocarditis Pulmonary embolism Renal Failure Sepsis Snake venom Stroke, subarachnoid hemorrhage Takotsubo cardiomyopathy, hypertrophic obstructive cardiomyopathy Transplant vasculopathy Renal Failure Troponin tends to rise in renal failure and presents a diagnostic challenge in the chest pain patient. Troponin elevations in renal failure patients may reflect subclinical myocardial injury, an inflammatory response to chronic renal failure, or a chronically volume overloaded state.[22] One study of 171 patients with renal insufficiency found almost all patients had at least one highly sensitive cardiac troponin T(hs-cTnT) measurement elevated above the 99th percentile. On average, hs‐cTnT increased by 16% per year in renal failure patients. Lower baseline glomerular filtration rates resulted in higher hs‐cTnT levels.[23] Some authors have suggested using adjusted troponin levels in renal failure patients might help accuracy.[24] A metanalysis of 13 studies using troponin to diagnose MI in renal failure patients found that the pooled sensitivity for hs-cTnT was only 94%, and the specificity was 56%. Serial troponin sampling seemed to improve diagnostic accuracy.[25] For unknown reasons, troponin I levels are less commonly elevated in renal failure compared to troponin T,[26,27,28] and troponin I may be a more sensitive cardiac marker for MI/ACS in this group of patients.[28] Considering the issues of using troponin measurements in renal failure patients, the best strategy appears to be understanding that this group may have both a higher incidence of heart disease and also more false positive troponin results than people with normal renal function. Clinical presentation, combined with serial EKGs, observing for changing troponin levels over time, and use of additional diagnostic cardiac testing, may be required to confirm or rule out an MI/ACS diagnosis in a renal failure patient. Rapid Rule out MI/ACS Algorithms Chest pain is one of the most common chief complaints seen in the Emergency Department(ED). Visits for acute chest pain and possible acute coronary syndromes(ACS) amount for an estimated 6 million patient-visits per year. The estimated total cost to the U.S. economy for these events is as high as $10-$12 billion.[29] Rapid rule out MI/ACS algorithms decrease emergency department length of stay, which opens beds up for new patients, and by discharging patients who might have been admitted in the past reduces hospital admissions, which can lead to significant cost savings. A European study of a 1-hour MI/ACS rule out protocol compared to longer ones found that the1-hour protocol would reduce bed space hours by an average of 2.1 hours per patient resulting in a savings of approximately 50,000 days of emergency department bed space per year in the United Kingdom.[30] Missed MI is the number one diagnosis in terms of dollars paid out in malpractice litigation, and the third most common claim in malpractice against emergency physicians.[31] The search for algorithms that allow more rapid diagnosis of patients who present to the ED with chest pain has to overcome the difficulty of determining which patients have an atypical MI/ACS presentation, limitations of laboratory testing, and the lack of 100% sensitivity of EKGs for MI/ACS. As emergent cardiac catherization decisions in MI/ACS are made on the basis of either elevated ST segments on EKG consistent with an MI(STEMI), or a clinical condition such as cardiogenic shock in a non-ST segment elevation MI(NSTEMI), rapid rule out algorithms/protocols do not change that aspect of care and are used mainly to decide who can be safely discharged from the emergency department. Some of these algorithms in the past also added cardiac stress testing, echo stress testing, nuclear stress testing or CT coronary angiograms prior to discharge to further narrow down who had an ACS. Although there is some variance depending on the study, most rapid protocols using highly sensitive troponins have demonstrated negative predictive values(NPV) of MI/ACS of between 99 to 100%, which represents a major reduction in in the missed MI rate.[10] European Society of Cardiology Algorithm[8] The European Society of Cardiology (ESC), in its 2020 guidelines, recommends a hs-troponin drawn on arrival and 1 or 2 hours later, known as either a 0/1 or 0/2-hour algorithm, the choice of which is dependent on institutional comfort. They also have 0-hour and 0/3-hour pathways as offshoots of the basic algorithm. There are seven different troponin I assays, but only one troponin T assay used in Europe. Each test has different normal and elevated values, as well as different measures of what is considered an abnormal delta(Δ) or change between the first and second blood tests that would be considered positive for MI/ACS. In the ESC algorithm, these are the cutoff values they used for highly sensitive troponin T for the 0/1 and 0/2-hour algorithms: Low Risk In a low-risk patient, if the EKG is stable, troponin is negative and remains unchanged on repeat testing, and the chest pain started three or more hours prior to arrival, then the patient may go home if clinically indicated. The ESC algorithm makes a further recommendation that if the arrival troponin is very low in a low-risk patient, and the EKG and other clinical factors are favorable, the patient may then be considered for discharge. If a low-risk patient arrives at the ED not having had three hours of prior chest pain, a 3-hour algorithm is recommended. Options for the low-risk patient include sending them home for outpatient follow-up, or if felt to be necessary, doing additional cardiac stress testing or imaging prior to discharge depending on the clinical scenario. According to their data review, low-risk patients have less than a 0.3% of having a missed MI, and less than a 0.5 % chance of having a 30-day major adverse cardiovascular event(MACE). Intermediate Risk For patients who have intermediate risk such as continuing pain, other clinical concerns or risk factors, non-diagnostic troponin testing, or do not clearly fit into a rule-in or rule out algorithm, a 3-hour algorithm is recommended along with echocardiography to try to identify other diagnoses that can cause chest pain before a discharge or admit decision is made. As late increases in cardiac troponin have been described in a small group of patients, continued serial cardiac troponin testing should be performed if clinical suspicion remains high, or if the patient develops recurrent chest pain. Stress cardiac imaging for the intermediate risk patient before discharge if hospitalized, or shortly after discharge if sent home may pick up additional positive ACS cases. Intermediate risk patients put into the 0/3-hour algorithm plus echocardiography have about a 10% chance of having an MI, and a 15-20% chance of a 30-day MACE. High Risk Any patient not needing an acute cardiac catheterization lab intervention, who has an elevated troponin, NSTEMI(non-ST segment elevation myocardial infarction) EKG changes, a significant change in troponin values over time, or clinical factors that increase cardiac risk, is admitted to the hospital under this algorithm for further observation and diagnostic testing. In the high-risk group in the ESC protocol, about 2/3s were found to have an MI. Other Algorithm Studies There are multiple studies that have tested a 0/1-hour MI/ACS rule out algorithm or compared a 0/1-hour to a 0/3-hour one or even longer protocols.[32,33,34,35,36] All these algorithms use both the absolute highly sensitive troponin value, as well as the delta, or change in value from the first to second blood draw. Repeat EKGs and reassessment of the patient’s clinical situation are also important components. Many of the studies found the sensitivity of the 0/1 and 0/3-hour algorithms to rule out MI/ACS in emergency department patients was between 99.6% to 100%. Length of stay was also shown to decrease as the time frame of the algorithm decreased. 30-day survival for the 0/1-hour algorithm was 99.8% in one study,[36] and 99.6% in another that also included new onset MI within 30 days of discharge in that figure.[34] Even with highly sensitive troponins and strict protocols there will be some missed MIs. However, the miss rate is approximately two in a thousand rather than two in a hundred as in the past, a ten-fold reduction. Troponin as a Prognostic Tool Studies have revealed that an elevated troponin T level at baseline on hospital arrival, was an independent predictor of mortality in ACS patients. In the ARTEMIS study, which attempted to test the hypothesis that cardiac biomarkers might predict future cardiac events in diabetic patients, it was found that high levels of highly sensitive troponin T were an independent strong predictor of cardiac death or hospitalization for heart failure.[37] Data from GUSTO-IIa, a trial of antithrombotic agents in ACS, found that troponin T levels were significantly predictive of 30-day mortality.[38] In acute decompensated heart failure, an elevated troponin T level has been shown to correlate with both increased short and long-term mortality, and to a lesser extent hospital readmission rates.[39] Elevated cardiac troponins in renal failure patients who do not have an MI/ACS appears to have negative prognostic value with respect to 6-month mortality.[22] Other Cardiac Markers Myeloperoxidase (MPO) is an enzyme released by activated neutrophils, which has pro-oxidative and proinflammatory properties. It is abundant in ruptured arterial plaque, but neutrophil activation can occur in any infectious, inflammatory, or infiltrative process, so an elevated result may not be specific for cardiac disease.[40] However, elevated levels of MPO are associated with the presence of angiographically proven coronary atherosclerosis, and may identify patients with CAD who might otherwise not be identified.[40,41] High levels of MPO are associated with increased cardiovascular events and mortality.[42] However, an emergency department study did not find MPO useful as an MI/ACS screening tool.[43] Ischemia modified albumin (IMA) is another acute marker of possible myocardial ischemia that is generated when serum circulating albumin is in contact with ischemic myocardium. Ischemia changes the albumin’s configuration making it less able to bind metals like cobalt, which allows for differentiation from normal albumin.[44] IMA also rises in conditions without myocardial ischemia, such as: cerebral infarct, MI, pulmonary infarct, mesenteric infarct, skeletal muscle ischemia, cirrhosis, bacterial infections and certain cancers.[44,45,46] IMA has a high sensitivity for an ACS but low specificity. One study of hs-troponin and IMA found that use of an IMA level right after the onset of chest pain, before troponin has had a chance to rise, may be of help diagnostically. In that study IMA sensitivity for an ACS was 91.3%, specificity was 81.1%, positive predictive value (PPV) was 74.4%, and negative predictive value (NPV) was 93.9%.[47] However, other authors feel that in the era of highly sensitive troponins, IMA adds little due to its low specificity.[48] In an acute setting, IMA may have some value in a patient where EKG and troponin levels are nondiagnostic, but it currently is not a routine part of MI/ACS rule out algorithms.[49,50]. Heart-type fatty acid-binding protein (H-FABP) is involved in the metabolism of fatty acids in cardiac myocytes, and has been investigated as a marker for the early diagnosis of acute MI/ACS,[51] as it is released early to the bloodstream within two to three hours after an MI.[52] In one study of emergency department patients, an arrival H-FABP level was 40% more sensitive than hs-troponin in ruling out an acute MI in patients with non-ischemic EKGs.[53] However, a metanalysis of studies comparing H-FABP to hs-troponin found H-FABP used alone or with hs-troponin did not improve diagnostic accuracy over use of hs-troponin alone for acute MI. The authors reported that the data did not support the routine use of H-FABP as an early risk stratification strategy for suspected MI.[54] H-FABP has not as of yet been approved for use in the U.S. High sensitivity C-reactive protein (hsCRP) is a pattern recognition protein produced in the liver.[55] Pattern recognition proteins are capable of recognizing molecules found in pathogens or released by damaged cells.[56] There has been much literature with regard to the relationship between arteriosclerotic disease, inflammation and prognosis. Inflammatory cells are frequently activated in unstable angina and are especially abundant in coronary plaques where they can play a key role in plaque disruption and acute thrombosis.[57] With respect to levels of hsCRP and cardiac risk, <1 mg/L = low risk; 1–3 mg/L = intermediate risk; 3–10 mg/L = high risk. Over 10 mg/L is a nonspecific elevation and may be from an acute infection or inflammatory process.[55] There are a number of other inflammatory and infectious diseases that can also raise hsCRP. In the JUPITER trial of 17,802 subjects, an elevated CRP above 2.0 was associated with increased ischemic events, even in apparently healthy individuals. Rosuvastatin decreased the hsCRP level by 37%, and the incidence of death, stroke, MI, and unstable angina by 44% compared to placebo.[58] hsCRP appears not to be useful in acute care settings as a biomarker for AMI/ACS but is a fairly reliable prognostic and diagnostic tool to guide cardioprotective therapy in patients with hsCRP elevations.[59] Brain natriuretic peptide (BNP) In patients presenting with dyspnea, clinical diagnosis of whether that patient has heart failure or not may prove difficult. Clinical findings have variable specificities for heart failure; orthopnea (89%), edema (72%), elevated jugular venous pressure (70%), cardiomegaly (85%), added heart sounds (99%), lung crepitations (81%) and hepatomegaly (97%). However, the sensitivity of these features was low, ranging from 11% for additional heart sounds to 53% for peripheral edema. CXR was moderately specific at 76–83%, but insensitive at 67–68%.[60] In addition, there is no clinical way to determine if diastolic heart failure(also called heart failure with preserved ejection fraction-HFpEF) is present.[61] Thus, the search for a marker that could be helpful in distinguishing heart failure from other causes of dyspnea led to the use of BNP. In one large study BNP was more accurate in diagnosing heart failure than any physical finding. [62,63] Brain natriuretic peptide (BNP), originally discovered in brain tissue,[64] is a hormone secreted from cardiac myocytes in response to stretching of its fibers due to volume overload, and plasma levels increase in both systolic(heart failure with reduced ejection fraction-HFrEF), and diastolic heart failure(heart failure with preserved ejection fraction-HFpEF). Small amounts of a precursor protein, pro-BNP, are continuously produced by the heart. Pro-BNP is then split by an enzyme into active hormone BNP and an inactive fragment, amino-terminal pro-BNP(NT-proBNP). Both BNP and NT-proBNP testing are used to measure heart failure but have differing positive and negative cutoff ranges. Levels tend to increase with age, renal disease, and women tend to have higher levels than men. Levels may be lower in obese patients. Pulmonary embolism, pulmonary hypertension, and chronic hypoxia may also raise BNP levels.[61] A literature review found that studies using recommended cutoff points for BNP in emergency department patients had pooled sensitivities of 86 to 100% and specificities of 31 to 97%. For NT-proBNP, sensitivity and specificity for heart failure was found to be 91% and 67% respectively.[65] A systematic review of the use of BNP and NT-proBNP in the primary care patient setting found the pooled sensitivity of BNP was 82% and the specificity was 64%. For NT-proBNP, the pooled sensitivity was 88% and the pooled specificity was 58%.[66] There was no significant advantage of using one test over the other. The authors of both studies concluded that both BNP and NT-proBNP are useful diagnostic tools to identify patients with heart failure. However, the tests have better utility to rule out heart failure than to diagnose it.[65,67] Sensitivities of BNP or NT-proBNP vary with the serum level. In one study of acute dyspnea in the emergency department, if the BNP was below 100pg/ml there was an 89% negative predictive value to exclude heart failure. If the level was less than 50pg/ml the negative predictive value was 96%.[68] Typically between 100 and 400 pg/ml is considered a grey area.[65] If the level was > 400pg/ml there is an estimated 63% sensitivity to diagnose heart failure according to one source.[69] There are also issues with age differences and normal values. In one study NT-proBNP was 100% sensitive in diagnosing ejection fractions below 40% in men 45 to 64 years of age, and women 55 to 74 years old. Sensitivity dropped with age and was 91% in men aged 65-74, 89% in men over 75 years, and only 75% in women over 75 years.[70] In another study of emergency department patients, age differential cutoff points of NT-proBNP were suggested. They found an NT-proBNP at cutpoints of >450 pg/ml for patients <50 years of age and >900 pg/ml for patients ≥50 years of age were highly sensitive and specific for the diagnosis of acute heart failure with sensitivities of 93% and 91% and specificities of 95% and 80% respectively. A NT-proBNP level of <300 pg/ml in that study had a negative predictive value of 99% for heart failure.[71] Use of age adjusted NT-proBNP values is now the norm in most labs.[72] Reference values of BNP and NT-proBNP recommended for use in renal failure patients were found to be inconsistent in one literature review, and their use in these patients to diagnose heart failure is problematic.[65] However, low BNP levels in renal insufficiency may help exclude heart failure.[67] Use of BNP testing may help decrease length of stay and hospital costs by allowing a more rapid diagnosis of the cause of the dyspnea. A Swiss emergency department study of dyspnea patients, comparing BNP testing versus a control group, found the length of stay was 3 days shorter in the BNP group(8 vs 11 days) and the cost of care was $1,854 less in the BNP group than the controls($5,410 vs. $7,264). The BNP test was most helpful when a low value made heart failure unlikely and other potential causes of dyspnea were searched for.[62] There are many studies in the literature that have found that elevated BNP levels are associated with an increased risk of death or cardiovascular events. One pooled review of five studies showed that each BNP increase of 100 pg/mL resulted in a 35% increase in the risk of death.[73] An emergency department study found that BNP levels drawn at admission were highly predictive of 1-year mortality with median BNP values of 3,277 pg/ml in those that died vs. 299 pg/mL in survivors.[74] BNP and NT-proBNP are far from perfect tests, but when very high or low, may assist the clinician in ruling in or ruling out heart failure in a patient with dyspnea. However, one must keep in mind there will be a significant number of false positives and negatives. Its use in renal failure is problematic. It can be used for long term follow-up of heart failure patients and has some value as a prognostic tool. Conclusion The arrival of highly sensitive troponins has revolutionized cardiac care in emergency departments, allowing 0/3-hour, 0/1-hour, or even 0-hour MI/ACS rule out algorithms to safely decrease the missed MI rate. While troponin levels can be used as a prognostic tool, the greatest benefit of the highly sensitive troponins is to allow more accurate and rapid admit or discharge decisions of chest pain patients seen in the emergency department. Given that emergent cardiac catherization in MI/ACS has been found beneficial only in patients with STEMIs, and in NSTEMI patients in cardiogenic shock, the newer highly sensitive troponins haven’t affected the immediate care of MI/ACS patients, other than to identify them more quickly, admit them more expeditiously, and not send them home in error. Unfortunately, the MI/ACS rule-out testing algorithms are not perfect, and while significantly improved at about a 10-fold improvement, a small number of missed MIs will still be sent home. However, if institutionally approved validated algorithms are scrupulously followed, malpractice risk may be mitigated.[75] These rapid algorithms can free up beds, and potentially reduce costs. The wide variety of conditions that can cause increased troponin levels means that clinicians still need to consider the whole clinical picture, and not just rely on a positive lab test to automatically mean that the etiology is an MI/ACS. Other cardiac markers such as hsCRP and MPO appear to be useful as prognostic tools for cardiovascular disease. Acute phase MI/ACS markers such as HT-FAPB and IMA do not appear to add much to a hs-troponin only strategy in an AMI/ACS algorithm. BNP and NT-proBNP tests are most accurate in ruling out heart failure in a patient with dyspnea, due to the relatively high negative predictive value of the tests. If values are very high they have utility in diagnosing heart failure. These tests may be helpful in diagnosing subtle presentations of heart failure, including both heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction, and do have prognostic significance. 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A review of the diagnosis and treatment of envenomations of fire ants. By Stuart M. Caplen, MD Introduction This article will review the diagnosis and treatment of envenomations of venomous creatures - fire ants. Whether an individual clinician will commonly treat these envenomations depends on where in the country they are practicing. Fire Ants Fire ants first were found in the United States in the 1930s. Now there are five times more fire ants per acre in the U.S. than in South America, as they escaped their natural enemies and thrived in the southern U.S.[1] There are two types of fire ants; the red fire ant named Solenopsis invicta and the black named Solenopsis richteri.[2] Red fire ants are typically found in the southeast from Texas to North Carolina. There are areas of New Mexico, Arizona and California that are also infested.[1] The black fire ant is found in northern Alabama, northern Mississippi, and southern Tennessee.[2] Fire ants are remarkably hardy and can even form floating life rafts made of thousands of ants in times of flooding.[3] Fire ants floating in flood water Fire ant bites usually occur when their nest is disturbed, and occur mostly in the summer months.They can swarm with multiple fire ants stinging the victim, and if a fire ant mound is disturbed hundreds to thousands of fire ants may respond.[4] In addition, each ant can sting repeatedly within a very short time. When a fire ant stings its mandible locks onto its prey and venom is injected through a stinger located on the abdomen. It typically stings an average of seven to eight times while rotating its body in a circular pattern repeatedly stinging. Since fire ants hold on to the skin with their mandibles, they are not easily brushed off and often have to be pulled off individually.[4] Fire Ant Venom Fire ant venom is normally used to immobilize or kill prey the ants want to eat. The venom is a 95% water-insoluble alkaloid, with the rest being an aqueous protein solution. The alkaloid part of the venom has cytotoxic and hemolytic properties, while the protein portion may contain allergens. Fire Ant Envenomation In humans the initial response to the venom is a severe burning sensation. In a few minutes, after that subsides, a dermal flare and wheal occur and then within two hours papules form. Vesicles develop within four hours and by 24 hours these become sterile pustules. One way of identifying a fire ant envenomation is by these pustules that form after the sting. There is also a local reaction, which is characterized by erythema and edema which can be larger than ten centimeters in diameter, and can be very painful and pruritic, lasting from 24 to 72 hours. The skin reactions are IgE-mediated, and contain a dense fibrin gel that contains eosinophils, neutrophils, and lymphocytes. Anaphylaxis, may occur due to the allergens in the aqueous protein solution, more frequently in persons sensitized by a previous sting.[2] Treatment Most patients stung by fire ants just require supportive care. Hydrocortisone cream, antihistamines and over the counter analgesics are typically all that is required initially. Ice packs may be helpful to relieve pain and swelling. The sterile pustules should not be opened. However, if they do open up they should be cleaned with soap and water and an antibiotic ointment may be used to prevent secondary infection. If a secondary infection does occur oral antibiotics may be needed. Occasionally, if there is a large local reaction a one-time dose of prednisone may be helpful. Anaphylactic reactions are treated in standard fashion.[2] People who are severely allergic to fire ant stings can receive whole body extract immunotherapy, which contains the entire body of the ant, not just the venom as is typical treatment for other venomous insects. In whole body extract immunotherapy gradually increasing doses are administered which can reduce the risk of a future allergic reaction to fire ant venom.[4] References [1] Fire Ants. CDC. Last reviewed: May 31, 2018. Retrieved from: https://www.cdc.gov/niosh/topics/insects/fireants.html [2] Kruse B, Anderson J, Simon LV. Fire Ant Bites. [Updated 2020 Aug 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK470576/ [3] Zhang S. Yes, That's a Huge Floating Mass of Live Fire Ants in Texas. The Atlantic. August 29, 2017. Retrieved from: https://www.theatlantic.com/science/archive/2017/08/fire-ants-flooding-hurricane-harvey/538365/ [4] Insect Sting Allergy. American College of Allergy, Asthma, and Immunology. Last updated 2/5/2018. Retrieved from: https://acaai.org/allergies/types/insect-sting-allergy Originally published October 2021

Platelet rich plasma is derived from blood drawn from an individual, which is then used in treating that same individual. The blood is specially processed to produce plasma, containing a large number of platelets. by Stuart M. Caplen, MD Platelet Rich Plasma: How Does It Work, and Does It Work? What Is the Evidence? In an effort to improve healing, injection of platelet rich plasma (PRP) is currently being utilized for many different medical conditions. In 2018 it was estimated that the global PRP market was expected to grow to between $380 million and $4.5 billion in the next ten years. The cost of a single treatment, which is not covered by most insurance, was estimated at approximately $500–$2,500, with patients often needing multiple treatments.[1] This article will discuss how PRP works and look at the current evidence as to whether it does improve healing for assorted conditions. What Is Platelet Rich Plasma? Platelet rich plasma is derived from blood drawn from an individual, which is then used in treating that same individual. The blood is specially processed to produce plasma, containing a large number of platelets. The theory behind PRP therapy is that an injection or deposition of concentrated platelets at sites of injury may aid tissue repair by releasing biologically active factors.[2] Platelets contain seven growth factors required for wound healing. They also contain the proteins fibrin, fibronectin, and vitronectin that are used for cell adhesion in bone, connective tissue, and epithelial tissue. Platelet growth factors are stored in platelet alpha granules, and are released after an injury. These growth factors are secreted through the platelet cell membrane after the initiation of the blood clotting cascade. The growth factors next bind to the external surface of cells in the area where they were deposited or injected. The platelets continue to synthesize and secrete more growth factors for the approximately seven days of their life span.[3] PRP theoretically can stimulate the supraphysiological release of growth factors to jump-start healing in chronic injuries, and accelerate the acute injury repair process.[2] After the platelets die, macrophages take over wound healing regulation by secreting their own growth factors. There are many different methods of preparing PRP. Variations in PRP include: the type of anticoagulant used, the number of platelets in the concentrate, the amount of growth factors, the numbers of leukocytes or red blood cells (RBCs), whether to add a procoagulant to activate the clotting cascade in PRP, the speed of the centrifuge, which manufacture’s device is used in the PRP process, and what additional additives the PRP contains. Some authors define PRP as consisting only of platelets, whereas others noted the PRP they used contained increased concentrations of leukocytes, fibrin, or bioactive proteins. This variation in PRP products may be responsible for some of the mixed results seen in the literature.[2,3] There are also differences in the ability of marketed PRP centrifugation devices to separate out the platelets without lysing them, which may affect results, as damaged platelets will not secrete growth factors, and may not assist in wound healing.[2] The reporting of PRP preparation protocols in clinical studies has been inconsistent, and a clear consensus of the best formulation has not been agreed on, making it difficult to compare outcomes from different studies.[2] Clinical use of PRP is not an FDA approved procedure, but the FDA does allow off-label use of PRP. The FDA requires the blood be collected by a single venipuncture, centrifuged, and contain at least 250,000 platelets per microliter,[1] but general consensus is that the platelet concentration in platelet-rich plasma should be around 1 million cells per microliter.[5] When PRP contains RBCs, a local response called eryptosis may occur, which triggers the release of the cytokine macrophage migration inhibitory factor (MMIF), which inhibits the migration of monocytes and macrophages. MMIF increases pro-inflammatory signals that inhibit migration of stem cells and fibroblast proliferation and can cause significant local cellular dysfunction. It is for this reason that removing the majority of RBCs from PRP preparations is considered an important step.[2] Whether to include leukocytes in the PRP is controversial, and the issue is far from settled. Some authors have used leukocyte-rich PRP, also called buffy coat PRP, and others have not. It is hypothesized that PRP high in leukocyte concentration provides protection from infections, contributes to angiogenesis, and increases growth factor release.[5] Study results have been mixed. One study showed leukocyte-rich PRP led to improved outcomes in rabbits with induced tendinopathies over leukocyte-poor PRP.[6] In another rabbit study, the use of leukocyte-poor PRP produced better cartilage repair than leukocyte-rich PRP.[6A] A third study found using leukocyte-poor PRP did not change the in vitro healing effects versus leukocyte-rich PRP.[7] It is thought that leukocyte-rich PRP causes more inflammation than leukocyte-poor PRP,[8] so it might be more appropriate to use leukocyte poor PRP for joint injections, where one would not want to cause more inflammation.[9] It is not clear if the clotting cascade needs to be artificially activated for platelets to release their growth factors for PRP to work effectively, or whether just putting the PRP into tissues is enough to start the clotting process that allows release of the growth factors. To activate platelets in PRP injections, a procoagulant such as thrombin or calcium chloride needs to be added to start the clotting cascade.[10] Some authors have used activated platelet PRP, while other authors have not. There is one animal study that found nonactivated platelets promoted better healing than thrombin activated platelets.[11] A small study that used PRP for hair regrowth found that the PRP did not need to be activated to work, and nonactivated PRP promoted greater hair growth.[12] A third study found that just preparing the platelets for PRP activated them, and additional activation was unnecessary.[13] While some medical conditions may possibly benefit from a quick release of growth factors that can be achieved from platelet activation, such as surgical wounds, other conditions may have worse results because the growth factors may degrade before tissue receptors become available for them to bind to.[14] A mouse study found that excessive levels of platelet growth factor may paradoxically inhibit osteochondral regeneration.[15] How Is PRP Prepared?[16] Blood is drawn by venipuncture from the patient in anticoagulated tubes.ACD-A is a common anticoagulant used (yellow-top blood collection tube), but a number of other anticoagulants canbe used. The blood is first centrifuged at a relatively slow speed. The platelet rich plasma is then transferred to tubes that don’t contain an anticoagulant. The platelet rich plasma is then recent rifuged at a higher speed and a platelet pellet collects at the bottom of the tube. Most of the plasma is then removed, leaving about two to four milliliters that is gently swirled to resuspend the platelets in the plasma. The PRP is then ready for use. A pro-coagulant may be added before injection if platelet activation is desired. PRP producing machines are also available, that simplify and automate the production process. A) whole blood in tube with anticoagulant, B) after first centrifugation, C) removing platelet rich plasma, D) plasma inserted into a tube with no anticoagulant, E and F) platelet pellet and a small amount of RBCsafter second centrifugation, G) some plasma removed and platelets gently swirled to reliquefy PRP, H) PRP ready for injection[17] Leukocyte Rich PRP Preparation To make leukocyte-rich PRP, also known as a buffy coat PRP, the blood must first be cooled to 20 to 45 degrees Celsius, followed by a high-speed centrifugation. After some plasma is removed, a low-speed centrifugation is performed. After again removing some supernatant plasma, the mixture of leukocytes and platelets are gently mixed creating the leukocyte-rich or buffy coat PRP. Uses of PRP PRP is being used for multiple indications in many different specialties including; orthopedics, podiatry, oral surgery, sports medicine, and dermatology. This section will explore the current knowledge for some of the possible uses of PRP for medical treatments. Chronic Wound Healing The U.S. Department of Health and Human Services commissioned an expert panel to review the literature on Platelet-Rich Plasma for Wound Care in the Medicare Population. Some of their conclusions were: There was moderate confidence that PRP increased complete wound closure or healing for lower extremity diabetic ulcers, but there was insufficient evidence to make conclusions about hospitalization, amputations and wound recurrence. The evidence was insufficient to make conclusions about the effect of PRP on wound healing in individuals with lower extremity venous ulcers or pressure ulcers. The available literature suffered from important limitations such as: inadequate description of wound care procedures, wound characteristics, PRP formulation techniques, concentration and volume, and inadequate length of follow-up.[18] One systemic review and metanalysis of a PRP gel formulation used for cutaneous wounds found wound healing was improved, compared to wound care control treatment.[19] However, a Cochrane review of PRP for chronic wounds concluded that PRP may improve the healing of foot ulcers associated with diabetes, but this was based on low quality evidence from two small randomized controlled trials. The authors felt that it was unclear whether PRP improved healing of other chronic wounds. The quality of evidence for PRP improving wound healing in chronic wounds was described as low in the Cochrane review, and the studies were either underpowered, or had a significant risk of bias. It was recommended that better designed and adequately powered clinical trials are needed to evaluate the therapy further.[20] Soft Tissue Injuries In a Cochrane review of PRP for soft tissue injuries, looking at studies of rotator cuff tears, shoulder impingement syndrome surgery, elbow epicondylitis, anterior cruciate ligament reconstruction, patellar tendinopathy, Achilles tendinopathy, and acute Achilles tendon rupture surgical repair, the authors’ conclusion was that there was insufficient evidence to support the use of PRP for treating musculoskeletal soft tissue injuries. They found the methods of preparing PRP varied and lacked standardization, and suggested that for the future clarity of research in this area, PRP preparation methods needed to be standardized.[21] Lateral Epicondylitis (Tennis Elbow) A systematic review and metanalysis of corticosteroids versus autologous blood (blood obtained and then injected into the same individual) versus PRP injections for lateral epicondylitis found in the short-term, corticosteroids were associated with the most improvement, but in the long-term patients PRP had better outcomes than the steroid or autologous blood groups.[22] However, a Cochrane review of the literature, found no benefit for the use of autologous blood or PRP injection for treatment of lateral epicondylitis. The authors concluded that it was uncertain whether they improve treatment success and pain relief, and that they probably provided little or no clinically important benefit for pain or function.[23] An interesting study on whether genetics plays a roll in the effectiveness of PRP found that certain genetic variants of the platelet-derived growth factor beta polypeptidegene resulted in better results in the treatment of lateral epicondylitis. People with certain variants were found to have a higher concentration of platelets in whole blood, and higher levels of some platelet growth factors in their PRP than patients with other genetic variants.[24] Plantar Fasciitis A metanalysis of PRP for plantar fasciitis found no significant differences between injected steroids versus PRP for short and intermediate pain relief. However, limited evidence supported the conclusion that PRP is superior to steroid treatments for long-term pain relief. The sample sizes were small with limited high-quality studies, so it was recommended additional larger studies be performed.[25] Another review of the literature found some positive effect of PRP over placebo in two studies for plantar fasciitis, but superiority of PRP over steroid injection was not found in any well-designed study reviewed.[26] Knee Osteoarthritis A double-blinded placebo study found PRP was not superior to placebo for pain and function improvement in knee osteoarthritis over placebo.[27] Several studies found no difference in effect between PRP and hyaluronic acid injection for knee osteoarthritis.[28,29] Back Pain and Disc Disease There are a small number of animal studies and case reports of successful use of PRP for discogenic disease.[30,31] A randomized blinded study of PRP for spinal discogenic pain in 47 patients found a significant improvement in pain, function, and patient satisfaction over the control group.[32] One metanalysis found that intradiscal PRP injections are effective in relieving pain and improving disabilities caused by discogenic lower back pain. However, the pain-reducing effect of PRP was not evident at one-month post-injection and only achieved statistical significance two to six months after the injections.[33] Another systematic review and metanalysis of PRP for low back pain found that compared with a control intervention, PRP injection was found to improve pain relief and patient satisfaction significantly, with no increase in adverse events.[34] Larger randomized, controlled trials are needed to confirm these findings. Carpal Tunnel Syndrome A small study of 60 patients comparing PRP to night splints for carpal tunnel syndrome found statistically significant symptom improvement as well as decreased size of the medial nerve (cross-sectional area is measured by ultrasound and is a reflection of nerve swelling) in the PRP group.[35] A systematic review and meta-analysis of nine randomized controlled trials with 434 total subjects, which compared PRP to corticosteroids, saline or splinting, found that PRP could be effective for mild to moderate carpal tunnel syndrome, and superior to traditional conservative treatments in improving pain and function. At one month there was a significant reduction in the cross-sectional area of the median nerve, and at three to six months other measures of patient perceived improvement occurred. At three months in a subgroup analysis, sensory nerve conduction velocity was significantly improved in the PRP group over the corticosteroid group. The authors noted with the limited number of randomized trials in the literature on PRP for carpal tunnel syndrome, the results needed confirmation with larger trials.[36] Androgenic Alopecia A systemic review of subcutaneous PRP injections for male pattern hair loss (androgenic alopecia) concluded that most studies reported that subcutaneous injection of PRP is likely to reduce hair loss, increase hair diameter and density in patients with androgenic alopecia, but larger and better designed studies were needed to confirm that finding.[37] Facial Rejuvenation There are some small studies that have looked at facial rejuvenation, where PRP is injected into the face to reduce wrinkles and sagging. There are a few small positive studies, but confirmative studies are needed.[38] Scars There is some suggestive evidence thatPRP injections may help reduce acne scars. PRP is also being investigated for use in keloids, traumatic and post-surgical scarring. As with almost all PRP indications, more confirmatory studies are needed to assess the true efficacy of PRP for these indications [39] Conclusion While the theory behind PRP seems sound, unfortunately the efficacy of the procedure has not been definitively proven for many of the conditions which it is currently being used. Contributing to the problem is a lack of standardization of the makeup of PRP being used, the equipment used for preparation, underpowered studies and a lack of non-biased, blinded, randomized controlled trials.[1] It may be that genetic makeup also plays a role in the varying effectiveness of PRP in clinical trials.[24] It appears PRP may be of benefit of in some conditions such as diabetic ulcers and discogenic back pain. It may also be useful in many other conditions, but definitive proof is still lacking. Despite the many mixed or negative results of PRP in the current literature for certain indications, it has become a widely used procedure, and created a new healthcare industry. Fortunately, it has a low possibility of adverse effects. In reviewing PRP studies on lateral epicondylitis there are both positive and negative studies, and depending on which articles were chosen, one could take either side of the argument as to whether PRP is effective. Almost all reviews of PRP usage in the medical literature suggest that better data, and larger randomized controlled trials are needed to determine which medical conditions will actually benefit from PRP therapy. References [1] Jones IA, Togashi RC, Thomas Vangsness C Jr. The Economics and Regulation of PRP in the Evolving Field of Orthopedic Biologics. Curr Rev Musculoskelet Med. 2018;11(4):558-565. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220002/ [2] Everts P, Onishi K, Jayaram P, Lana JF, Mautner K. Platelet-Rich Plasma: New Performance Understandings and Therapeutic Considerations in 2020. Int J Mol Sci. 2020;21(20):7794. Published 2020 Oct 21. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589810/ [3] Marx RE. Platelet-Rich Plasma: Evidence to Support Its Use. J Oral Maxillofac Surg 62:489-496, 2004. Retrieved from: http://www.drkoprp.com/pdfs/prp/PRPbyDr.Marx.pdf [4] Jones IA, Togashi RC, Thomas Vangsness C Jr. The Economics and Regulation of PRP in the Evolving Field of Orthopedic Biologics. Curr Rev Musculoskelet Med. 2018;11(4):558-565. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220002/ [5] Muthuprabakaran K. et al. A cross-sectional analysis of the effects of various centrifugation speeds and inclusion of the buffy coat in platelet-rich plasma preparation. Indian Journal of Dermatology, Venereology and Leprology. 87 (6); 792-799. October 2021. Retrieved from: https://ijdvl.com/a-cross-sectional-analysis-of-the-effects-of-various-centrifugation-speeds-and-inclusion-of-the-buffy-coat-in-platelet-rich-plasma-preparation/#ref6\ [6] Jiang G et al. Comparison of leukocyte-rich platelet-rich plasma and leukocyte-poor platelet-rich plasma on achilles tendinopathy at an early stage in a rabbit model. Am J Sports Med. 2020;48:1189-99. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/32134682/ [6A] Xu Z et al. Comparative evaluation of leukocyte- and platelet-rich plasma and pure platelet-rich plasma for cartilage regeneration. Sci Rep 7, 43301 (2017). https://doi.org/10.1038/srep43301 [7] Giusti I et al. Leukocyte depletion does not affect the in vitro healing ability of platelet rich plasma. Exp Ther Med. 2018;15:4029-38. Retrieved from: https://ijdvl.com/a-cross-sectional-analysis-of-the-effects-of-various-centrifugation-speeds-and-inclusion-of-the-buffy-coat-in-platelet-rich-plasma-preparation/#ref27 [8] Dragoo JL et al. Comparison of the acute inflammatory response of two commercial platelet-rich plasma systems in healthy rabbit tendons. Am J Sports Med. 2012 Jun;40(6):1274-81. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/22495144/ [9] Kim J-H et al. Adverse Reactions and Clinical Outcomes for Leukocyte-Poor Versus Leukocyte-Rich Platelet-Rich Plasma in Knee Osteoarthritis: A Systematic Review and Meta-analysis. Orthopaedic Journal of Sports Medicine. June 2021. Retrieved from: 10.1177/23259671211011948 [10] PRP Labs Editorial Team. How to Activate Platelet Rich Plasma (PRP). PRP Labs. May 6th, 2018. Retrieved from: https://prplabs.com/blog/how-to-activate-platelet-rich-plasma-prp/ [11]Scherer SS et al. Non-activated versus thrombin-activated platelets on wound healing and fibroblast-to-myofibroblast differentiation in vivo and in vitro. Plast Reconstr Surg. 2012;129:46e–54e. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/22186584/ [12] Gentile P et al. Evaluation of Not-Activated and Activated PRP in Hair Loss Treatment: Role of Growth Factor and Cytokine Concentrations Obtained by Different Collection Systems. Int J Mol Sci. 2017;18(2):408. Published 2017 Feb 14. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343942/ [13] Queiroz da Silva L et al. Platelet Activation Is Not Crucial for Platelet-Rich Plasma (PRP), When Used As Autologous Therapeutic Product, and Could be Lyophilized without Any Growth Factor Loss. Blood (2016) 128 (22). Retrieved from: https://ashpublications.org/blood/article/128/22/2639/98543/Platelet-Activation-Is-Not-Crucial-for-Platelet [14] Cavallo C et al. “Platelet-Rich Plasma: The Choice of Activation Method Affects the Release of Bioactive Molecules,” BioMed Research International, vol. 2016, Article ID 6591717, 7 pages, 2016. Retrieved from: https://www.hindawi.com/journals/bmri/2016/6591717/ [15] Ranly DM et al. Platelet-derived growth factor inhibits demineralized bone matrix-induced intramuscular cartilage and bone formation. A study of immunocompromised mice. J Bone Joint Surg Am. 2005;87(9):2052-64. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/16140821/ [16] Dhurat R, Sukesh M. Principles and Methods of Preparation of Platelet-Rich Plasma: A Review and Author's Perspective. J Cutan Aesthet Surg. 2014;7(4):189-197. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338460/#ref15 [17] Dório, M et al. Efficacy of platelet-rich plasma and plasma for symptomatic treatment of knee osteoarthritis: a double-blinded placebo-controlled randomized clinical trial. BMC Musculoskelet Disord 22, 822 (2021). Retrieved from: https://bmcmusculoskeletdisord.biomedcentral.com/track/pdf/10.1186/s12891-021-04706-7.pdf [18] Platelet-Rich Plasma for Wound Care in the Medicare Population. Agency for Healthcare Research and Quality U.S. Department of Health and Human Services. Technology Assessment Project ID: MYOE59 September 17, 2020. Retrieved from: https://www.ahrq.gov/sites/default/files/wysiwyg/research/findings/ta/prp/prp-wound-care.pdf [19] Carter MJ, Fylling CP, Parnell LK. Use of platelet rich plasma gel on wound healing: a systematic review and meta-analysis. Eplasty. 2011;11:e38.Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174862/ [20] Martinez‐Zapata MJ et al. Autologous platelet‐rich plasma for treating chronic wounds. Cochrane Database of Systematic Reviews. 25 May 2016. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/27223580/ [21] Moraes VY et al. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database Syst Rev. 2013 Dec 23;(12):CD010071. Update in: Cochrane Database Syst Rev. 2014;(4):CD010071. PMID: 24363098. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/24363098/ [22] Tang S et al. Platelet-Rich Plasma Vs Autologous Blood Vs Corticosteroid Injections in the Treatment of Lateral Epicondylitis: A Systematic Review, Pairwise and Network Meta-Analysis of Randomized Controlled Trials. PM R. 2020;12(4):397-409. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187193/ [23] Karjalainen TV et al. Autologous blood and platelet-rich plasma injection therapy for lateral elbow pain. Cochrane Database of Systematic Reviews 2021, Issue 9. Art. No.: CD010951. Retrieved from: https://www.cochrane.org/CD010951/MUSKEL_autologous-blood-or-prp-injection-lateral-elbow-pain [24] Niemiec P et al. Why PRP works only on certain patients with tennis elbow? Is PDGFB gene a key for PRP therapy effectiveness? A prospective cohort study. BMC Musculoskelet Disord. 2021;22(1):710. Published 2021 Aug 18. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375168/ [25] Yang WY et al. Platelet-rich plasma as a treatment for plantar fasciitis: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2017;96(44):e8475. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682822/ [26] Yu, T et al. Outcomes of platelet-rich plasma for plantar fasciopathy: a best-evidence synthesis. J Orthop Surg Res 15, 432 (2020). https://doi.org/10.1186/s13018-020-01783-7 [27] Dório, M et al. Efficacy of platelet-rich plasma and plasma for symptomatic treatment of knee osteoarthritis: a double-blinded placebo-controlled randomized clinical trial. BMC Musculoskelet Disord 22, 822 (2021). Retrieved from: https://bmcmusculoskeletdisord.biomedcentral.com/track/pdf/10.1186/s12891-021-04706-7.pdf [28] Filardo G et al. (2012b) Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med 43:1575–1582. https://pubmed.ncbi.nlm.nih.gov/25952818/ [29] Cole BJ et al. 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