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Neonatal hemochromatosis Neonatal Hemochromatosis is a rare and severe liver disease. Its characteristics are similar to hereditary hemochromatosis, where iron deposition causes damage to the liver and other organs and tissues. # Causes The causes of neonatal hemochromatosis are still unknown, however recent research has led to the hypothesis that it is an alloimmune disease (see alloimmunity). Evidence supporting this hypothesis includes the high recurrence rate within sibships (>80%). This evidence along with other research indicates that Neonatal Hemochromatosis could be classified as a Congenital Alloimmune Hepatitis. # Treatment Effective treatment of the disease has been confined to liver transplants. An antioxidant chelation cocktail has also been reported as having some success though its effectiveness cannot be confirmed. Based on the alloimmune cause hypothesis, a new treatment involving high-dose immunoglobulin to pregnant mothers who have had a previous pregnancy with a confirmed neonatal hemochromatosis outcome, has provided very encouraging results. # Related conditions Neonatal hemochromatosis is sometimes confused with Juvenile Hemochromatosis, which is a hereditary hemochromatosis, caused by mutations of a gene called hemojuvelin. While the symptoms and outcomes from these two diseases are similar, the causes appear to be different.

Methylphenidate (transdermal) # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Methylphenidate (transdermal) is a amphetamine that is FDA approved for the treatment of attention deficit hyperactivity disorder (ADHD). There is a Black Box Warning for this drug as shown here. Common adverse reactions include erythema, weight decreased, decrease in appetite, loss of appetite, nausea, headache, insomnia, Labile affect, nasal congestion, nasopharyngitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Methylphenidate (methylphenidate transdermal system) is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). - The efficacy of methylphenidate in patients diagnosed with ADHD was established in two 7-week controlled clinical trials in children (ages 6-12) and one 7-week, controlled clinical trial in adolescents (ages 13-17). - A diagnosis of ADHD (DSM-IV-TR®) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; "on the go;" excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met. - Special Diagnostic Considerations - The specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV-TR® characteristics. - Need for Comprehensive Treatment Program - Methylphenidate is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Stimulants are not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms. - It is recommended that methylphenidate be applied to the hip area 2 hours before an effect is needed and should be removed 9 hours after application. Dosage should be titrated to effect. The recommended dose titration schedule is shown in the table below. Dose titration, final dosage, and wear time should be individualized according to the needs and response of the patient. - Patients converting from another formulation of methylphenidate should follow the above titration schedule due to differences in bioavailability of methylphenidate compared to other products. - Application - The parent or caregiver should be encouraged to use the administration chart included with each carton of methylphenidate to monitor application and removal time, and method of disposal. It is recommended that parents or caregivers apply and remove the patch for children; responsible adolescents may apply or remove the patch themselves if appropriate. The Medication Guide included at the end of this insert also includes a timetable to calculate when to remove methylphenidate, based on the 9-hour application time. - The adhesive side of methylphenidate should be placed on a clean, dry area of the hip. The area selected should not be oily, damaged, or irritated. Apply patch to the hip area avoiding the waistline, since clothing may cause the patch to rub off. When applying the patch the next morning, place on the opposite hip at a new site if possible. - If patients or caregivers experience difficulty separating the patch from the release liner or observe transfer of adhesive to the liner, tearing and/or other damage to the patch during removal from the liner, the patch should be discarded according to the directions provided below, and a new patch should be applied. Patients or caregivers should inspect the release liner to ensure that no adhesive containing medication has transferred to the liner. If adhesive transfer has occurred, the patch should be discarded. - Methylphenidate should be applied immediately after opening the individual pouch and removing the protective liner. Do not use if the individual pouch seal is broken or if the patch appears to be damaged. Do not cut patches. Only intact patches should be applied. The patch should then be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure that there is good contact of the patch with the skin, especially around the edges. Exposure to water during bathing, swimming, or showering can affect patch adherence. Patches should not be applied or re-applied with dressings, tape, or other common adhesives. In the event that a patch does not fully adhere to the skin upon application, or becomes partially or fully detached during wear time, the patch should be discarded according to the directions provided in this label and a new patch may be applied at a different site. The total recommended wear time for that day should remain 9 hours regardless of the number of patches used - All patients should be advised to avoid exposing the methylphenidate application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the patch . When heat is applied to methylphenidate after patch application, both the rate and the extent of absorption are significantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold . This increased absorption can be clinically significant and result in overdose of methylphenidate. - Patches should not be stored in refrigerators or freezers. - Removal of methylphenidate - methylphenidate patches should be peeled off slowly. If necessary, patch removal may be facilitated by gently applying an oil-based product (i.e., petroleum jelly, olive oil, or mineral oil) to the patch edges, gently working the oil underneath the patch edges. If any adhesive remains on the skin following patch removal, an oil-based product may be applied to patch sites in an effort to gently loosen and remove any residual adhesive that remains following patch removal. - In the unlikely event that a patch remains tightly adhered despite these measures, the patient or caregiver should contact the physician or pharmacist. Nonmedical adhesive removers and acetone-based products (i.e., nail polish remover) should not be used to remove methylphenidate patches or adhesive. - Disposal of methylphenidate - Upon removal of methylphenidate, used patches should be folded so that the adhesive side of the patch adheres to itself and should be flushed down the toilet or disposed of in an appropriate lidded container. If the patient stops using the prescription, each unused patch should be removed from its individual pouch, separated from the protective liner, folded onto itself, and disposed of in the same manner as used patches. - The parent or caregiver should be encouraged to record on the administration chart included with each carton the time that each patch was applied and removed. If a patch was removed without the parent or caregiver's knowledge, or if a patch is missing from the tray or outer pouch, the parent or caregiver should be encouraged to ask the child when and how the patch was removed. - Maintenance/Extended Treatment - There is no body of evidence available from controlled clinical trials to indicate how long the patient with ADHD should be treated with methylphenidate. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. The effectiveness of methylphenidate for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use methylphenidate for extended periods should periodically re-evaluate the long-term usefulness of methylphenidate for the individual patient with periods off medication to assess the patient's functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued. - Dose/Wear Time Reduction and Discontinuation - methylphenidate may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. Plasma concentrations of d-methylphenidate generally begin declining when the patch is removed, although absorption may continue for several hours. Individualization of wear time may help manage some of the side effects caused by methylphenidate. If aggravation of symptoms or other adverse events occur, the dosage or wear time should be reduced, or, if necessary, the drug should be discontinued. Residual methylphenidate remains in used patches when worn as recommended. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methylphenidate (transdermal) in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Methylphenidate (transdermal) in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Methylphenidate (transdermal) in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methylphenidate (transdermal) in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Methylphenidate (transdermal) in pediatric patients. # Contraindications - Hypersensitivity to Methylphenidate - Methylphenidate is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product (polyester/ethylene vinyl acetate laminate film backing, acrylic adhesive, silicone adhesive, and fluoropolymer-coated polyester) - Agitation - methylphenidate is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. - Glaucoma - methylphenidate is contraindicated in patients with glaucoma. - Tics - methylphenidate is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette's syndrome - Monoamine Oxidase Inhibitors - methylphenidate is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result). # Warnings - Serious Cardiovascular Events - Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems - Children and Adolescents - Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. - Adults - Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs. - Hypertension and Other Cardiovascular Conditions - Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. - Assessing Cardiovascular Status in Patients Being Treated With Stimulant Medications - Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation. - Pre-Existing Psychosis - Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. - Bipolar Illness - Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. - Emergence of New Psychotic or Manic Symptoms - Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to none in placebo-treated patients. - Aggression - Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility. - Seizures - There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. - Priapism - Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. - Peripheral Vasculopathy, including Raynaud’s phenomenon - Stimulants, including methylphenidate, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients - Long-Term Suppression of Growth - Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. - Visual Disturbance - Difficulties with accommodation and blurring of vision have been reported with stimulant treatment. - Contact Sensitization - In an open-label study of 305 subjects conducted to characterize dermal reactions in children with ADHD treated with methylphenidate using a 9-hour wear time, one subject (0.3%) was confirmed by patch testing to be sensitized to methylphenidate (allergic contact dermatitis). This subject experienced erythema and edema at methylphenidate application sites with concurrent urticarial lesions on the abdomen and legs resulting in treatment discontinuation. This subject was not transitioned to oral methylphenidate. - Use of methylphenidate may lead to contact sensitization. Methylphenidate should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of methylphenidate and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the patch site. Confirmation of a diagnosis of contact sensitization (allergic contact dermatitis) may require further diagnostic testing. - Patients sensitized from use of methylphenidate, as evidenced by development of an allergic contact dermatitis, may develop systemic sensitization or other systemic reactions if methylphenidate-containing products are taken via other routes, e.g., orally. Manifestations of systemic sensitization may include a flare-up of previous dermatitis or of prior positive patch-test sites, or generalized skin eruptions in previously unaffected skin. Other systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting. No cases of systemic sensitization have been observed in clinical trials of methylphenidate. - Patients who develop contact sensitization to methylphenidate and require oral treatment with methylphenidate should be initiated on oral medication under close medical supervision. It is possible that some patients sensitized to methylphenidate by exposure to methylphenidate may not be able to take methylphenidate in any form. - Patients Using External Heat - Patients should be advised to avoid exposing the methylphenidate application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the patch. When heat is applied to methylphenidate after patch application, both the rate and extent of absorption are significantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold. This increased absorption can be clinically significant and can result in overdose of methylphenidate - Hematologic Monitoring - Periodic CBC, differential, and platelet counts are advised during prolonged therapy. # Adverse Reactions ## Clinical Trials Experience - Detailed information on serious and adverse reactions of particular importance is provided in theBoxed Warning - Drug dependence - Hypersensitivity to Methylphenidate - Marked anxiety, tension, or agitation - Glaucoma - Tics or a family history of Tourette's syndrome - Monoamine Oxidase Inhibitors - Serious Cardiovascular Events - Increase in Blood Pressure - Psychiatric Adverse Events - Seizures - Priapism - Peripheral Vasculopathy - Long-Term Suppression of Growth - Visual Disturbance - Contact Sensitization - External Heat - Hematologic Monitoring - The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in children aged 6-12 included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affect lability, and anorexia. The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in adolescents aged 13-17 were appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain, and anorexia . - The most common (≥ 2% of subjects) adverse reaction associated with discontinuations in double-blind clinical trials in children or adolescents was application site reactions - The overall methylphenidate development program included exposure to methylphenidate in a total of 2,152 participants in clinical trials, including 1,529 children aged 6-12, 223 adolescents aged 13-17, and 400 adults. The 1,752 child and adolescent subjects aged 6-17 years were evaluated in 10 controlled clinical studies, 7 open-label clinical studies, and 5 clinical pharmacology studies. In a combined studies pool of children using methylphenidate with a wear time of 9 hours, 212 subjects were exposed for ≥ 6 months and 115 were exposed for ≥ 1 year; 85 adolescents have been exposed for ≥ 6 months. Most patients studied were exposed to methylphenidate patch sizes of 12.5 cm2, 18.75 cm2, 25 cm2 or 37.5 cm2, with a wear time of 9 hours. - In the data presented below, the adverse reactions reported during exposure were obtained primarily by general inquiry at each visit, and were recorded by the clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of events into a smaller number of standardized event categories. - Throughout this section adverse reactions reported are events that were considered to be reasonably associated with the use of methylphenidate based on comprehensive assessment of the available adverse event information. A causal association for methylphenidate often cannot be reliably established in individual cases. Further, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. - Clinical Trials Experience - Adverse Reactions Associated With Discontinuation of Treatment - In a 7-week double-blind, parallel-group, placebo-controlled study in children with ADHD conducted in the outpatient setting, 7.1% (7/98) of patients treated with methylphenidate discontinued due to adverse events compared with 1.2% (1/85) receiving placebo. The most commonly reported (≥ 1% and twice the rate of placebo) adverse reactions leading to discontinuation in the methylphenidate group were application site reaction (2%), tics (1%), headache (1%), and irritability (1%). - In a 7-week double-blind, parallel-group, placebo-controlled study in adolescents with ADHD conducted in the outpatient setting, 5.5% (8/145) of patients treated with methylphenidate discontinued due to adverse reactions compared with 2.8% (2/72) receiving placebo. The most commonly reported adverse reactions leading to discontinuation in the methylphenidate group were application site reaction (2%) and decreased appetite/anorexia (1.4%). - Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Trials - Skin Irritation and Application Site Reactions - methylphenidate is a dermal irritant. In addition to the most commonly reported adverse reactions presented in Table 2, the majority of subjects in those studies had minimal to definite skin erythema at the patch application site. This erythema generally caused no or minimal discomfort and did not usually interfere with therapy or result in discontinuation from treatment. Erythema is not by itself a manifestation of contact sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the patch site . - Most Commonly Reported Adverse Reactions - Table 2 lists treatment-emergent adverse reactions reported in ≥ 1% methylphenidate-treated children or adolescents with ADHD in two 7 week double-blind, parallel-group, placebo-controlled studies conducted in the outpatient setting. Overall, in these studies, 75.5% of children and 78.6% of adolescents experienced at least 1 adverse event. - Adverse Reactions With the Long-Term Use of methylphenidate - In a long-term open-label study of up to 12 months duration in 326 children wearing methylphenidate 9 hours daily, the most common (≥ 10%) adverse reactions were decreased appetite, headache, and weight decreased. A total of 30 subjects (9.2%) were withdrawn from the study due to adverse events and 22 additional subjects (6.7%) discontinued treatment as the result of an application site reaction. Other than application site reactions, affect lability (5 subjects, 1.5%) was the only additional adverse reaction leading to discontinuation reported with a frequency of greater than 1%. - In a long-term open-label study of up to 6 months duration in 162 adolescents wearing methylphenidate 9 hours daily, the most common (≥ 10%) adverse reactions were decreased appetite and headache. A total of 9 subjects (5.5%) were withdrawn from the study due to adverse events and 3 additional subjects (1.9%) discontinued treatment as the result of an application site reaction. Other adverse reactions leading to discontinuation that occurred with a frequency of greater than 1% included affect lability and irritability (2 subjects each, 1.2%). ## Postmarketing Experience - In addition, the following adverse reactions have been identified during the postapproval use of methylphenidate. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to methylphenidate exposure. - Cardiac Disorders: palpitations - Eye Disorders: visual disturbances, blurred vision, mydriasis, accommodation disorder - General Disorders and Administration Site Disorders: application site reactions such as bleeding, bruising, burn, burning, dermatitis, discharge, discoloration, discomfort, dryness, eczema, edema, erosion, erythema, excoriation, exfoliation, fissure, hyperpigmentation, hypopigmentation/vitiligo, induration, infection, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, scab, swelling, ulcer, urticaria, vesicles, and warmth. - Immune System Disorders: hypersensitivity reactions including generalized erythematous and urticarial rashes, allergic contact dermatitis, angioedema, and anaphylaxis - Investigations: blood pressure increased - Nervous System Disorders: convulsion, dyskinesia - Psychiatric Disorders: transient depressed mood, hallucination, nervousness, libido changes - Skin and Subcutaneous Tissue Disorders: alopecia - Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur. - Other reactions include: - Cardiac: angina, arrhythmia, pulse increased or decreased - Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura - Metabolism/Nutrition: anorexia, weight loss during prolonged therapy - Nervous System: drowsiness, rare reports of Tourette's syndrome, toxic psychosis - Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion - Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate: - Blood/lymphatic: leukopenia and/or anemia - Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma - Psychiatric: transient depressed mood - Skin/Subcutaneous: scalp hair loss - Neuroleptic Malignant Syndrome: Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. - Musculoskeletal: rhabdomyolysis # Drug Interactions - MAO Inhibitors - Methylphenidate should not be used in patients being treated (currently or within the preceding two weeks) with monoamine oxidase inhibitors . - Vasopressor Agents - Because of a possible effect on blood pressure, methylphenidate should be used cautiously with pressor agents. - Hypotension Agents - Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. - Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors - Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and some tricyclic drugs (e.g., imipramine, clomipramine, desipramine) and selective serotonin reuptake inhibitors. Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing methylphenidate. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category C - Animal reproduction studies with transdermal methylphenidate have not been performed. In a study in which oral methylphenidate was given to pregnant rabbits during the period of organogenesis at doses up to 200 mg/kg/day no teratogenic effects were seen, although an increase in the incidence of a variation, dilation of the lateral ventricles, was seen at 200 mg/kg/day; this dose also produced maternal toxicity. A previously conducted study in rabbits showed teratogenic effects of methylphenidate at an oral dose of 200 mg/kg/day. In a study in which oral methylphenidate was given to pregnant rats during the period of organogenesis at doses up to 100 mg/kg/day, no teratogenic effects were seen although a slight delay in fetal skeletal ossification was seen at doses of 60 mg/kg/day and above; these doses caused some maternal toxicity. - In a study in which oral methylphenidate was given to rats throughout pregnancy and lactation at doses up to 60 mg/kg/day, offspring weights and survival were decreased at 40 mg/kg/day and above; these doses caused some maternal toxicity. - Adequate and well-controlled studies in pregnant women have not been conducted. methylphenidate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methylphenidate (transdermal) in women who are pregnant. ### Labor and Delivery - The effect of methylphenidate on labor and delivery in humans is unknown. ### Nursing Mothers - It is not known whether methylphenidate is excreted in human milk. methylphenidate should be administered to a nursing woman only if the potential benefit justifies the potential risk to the child. ### Pediatric Use - Methylphenidate should not be used in children under six years of age, since safety and efficacy in this age group have not been established. Long-term effects of methylphenidate in children have not been well established. - Studies with transdermal methylphenidate have not been performed in juvenile animals. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose. The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day. The clinical significance of the long-term behavioral effects observed in rats is unknown ### Geriatic Use - Methylphenidate has not been studied in patients greater than 65 years of age. ### Gender There is no FDA guidance on the use of Methylphenidate (transdermal) with respect to specific gender populations. ### Race There is no FDA guidance on the use of Methylphenidate (transdermal) with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Methylphenidate (transdermal) in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Methylphenidate (transdermal) in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Methylphenidate (transdermal) in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Methylphenidate (transdermal) in patients who are immunocompromised. # Administration and Monitoring ### Administration - Transdermal ### Monitoring There is limited information regarding Monitoring of Methylphenidate (transdermal) in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Methylphenidate (transdermal) in the drug label. # Overdosage - Signs and symptoms of acute methylphenidate overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, dryness of mucous membranes, and rhabdomyolysis. - Remove all patches immediately and cleanse the area(s) to remove any remaining adhesive. The continuing absorption of methylphenidate from the skin, even after removal of the patch, should be considered when treating patients with overdose. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. - Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate overdosage has not been established. - As with the management of all overdosages, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of overdosage with methylphenidate. # Pharmacology There is limited information regarding Methylphenidate (transdermal) Pharmacology in the drug label. ## Mechanism of Action - Methylphenidate is a CNS stimulant. Its mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known, but methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and to increase the release of these monoamines into the extraneuronal space. ## Structure - Methylphenidate is an adhesive-based matrix transdermal system (patch) that is applied to intact skin. The chemical name for methylphenidate is α-phenyl-2-piperidineacetic acid methyl ester. It is a white to off-white powder and is soluble in alcohol, ethyl acetate, and ether. Methylphenidate is practically insoluble in water and petrol ether. Its molecular weight is 233.31. Its empirical formula is C14H19NO2. The structural formula of methylphenidate is: - Patch Components - methylphenidate contains methylphenidate in a multipolymeric adhesive. The methylphenidate is dispersed in acrylic adhesive that is dispersed in a silicone adhesive. The composition per unit area of all dosage strengths is identical, and the total dose delivered is dependent on the patch size and wear time. - The patch consists of three layers, as seen in the figure below (cross-section of the patch). - Proceeding from the outer surface toward the surface adhering to the skin, the layers are (1) a polyester/ethylene vinyl acetate laminate film backing, (2) a proprietary adhesive formulation incorporating Noven Pharmaceuticals, Inc.'s DOT Matrix™ transdermal technology consisting of an acrylic adhesive, a silicone adhesive, and methylphenidate, and (3) a fluoropolymer-coated polyester protective liner which is attached to the adhesive surface and must be removed before the patch can be used. - The active component of the patch is methylphenidate. The remaining components are pharmacologically inactive. ## Pharmacodynamics - Methylphenidate is a racemic mixture comprised of the d-and l-enantiomers. The d-enantiomer is more pharmacologically active than the l-enantiomer. ## Pharmacokinetics - The pharmacokinetics of methylphenidate when applied to the hip for 9 hours have been studied in ADHD patients 6 to 17 years old. - Absorption - The amount of methylphenidate absorbed systemically is a function of both wear time and patch size. In patients with ADHD, peak plasma levels of methylphenidate are reached at about 10 hours after single application and 8 hours after repeat patch applications (12.5cm2 to 37.5cm2) when worn up to 9 hours. - On single dosing with methylphenidate to children or adolescents, there was a delay of, on average, 2 hours before d-methylphenidate was detectable in the circulation. On repeat dosing, low concentrations (1.2-3.0 ng/mL in children and 0.5-1.7ng/mL in adolescents, on average across the dose range) were observed earlier in the profile, due to carry-over effect. Following the application of methylphenidate once daily with a 9 hour wear time, the mean pharmacokinetic parameters of d-methylphenidate in children and adolescents with ADHD after 4 weeks of therapy are summarized in Table 3. - Following administration of methylphenidate 12.5cm2 to pediatric and adolescent ADHD patients daily for 7 days, there were 13% and 14% increases, respectively, in steady state area under the plasma concentration-time curve (AUCss) relative to that anticipated on the basis of single dose pharmacokinetics (AUC0-∞); after 28 days administration, these increments increased to 64% and 76%, respectively. Cmax increased by nearly 69% and 100% within 4 weeks of daily administration of the starting dose in children and adolescents, respectively. - The observed exposures with methylphenidate could not be explained by drug accumulation predicted from observed single dose pharmacokinetics and there was no evidence that clearance or rate of elimination changed between single and repeat dosing. Neither were they explainable by differences in dosing patterns between treatments, age, race, or gender. This suggests that transdermal absorption of methylphenidate may increase with repeat dosing with methylphenidate; on average, steady-state is likely to have been achieved by approximately 14 days of dosing. - In the single and multiple dose study described above, exposure to l-methylphenidate was 46% of the exposure to d-methylphenidate in children and 40% in adolescents. l-methylphenidate is less pharmacologically active than d-methylphenidate - In a phase 2 PK/PD study in children aged 6-12 years, 2/3 of patients had 2-hour d-MPH concentrations < 5 ng/mL on chronic dosing, and at 3 hours 40% of patients had d-MPH concentrations < 5 ng/mL - When methylphenidate is applied to inflamed skin both the rate and extent of absorption are increased as compared with intact skin. When applied to inflamed skin, lag time is no greater than 1 hour, Tmax is 4 hours, and both Cmax and AUC are approximately 3-fold higher. - When heat is applied to methylphenidate after patch application, both the rate and the extent of absorption are significantly increased. Median Tlag occurs 1 hour earlier, Tmax occurs 0.5 hours earlier, and median Cmax and AUC are 2-fold and 2.5-fold higher, respectively. - Application sites other than the hip can have different absorption characteristics and have not been adequately studied in safety or efficacy studies. - Dose Proportionality - Following a single 9-hour application of methylphenidate patch doses of 10 mg / 9 hours to 30 mg / 9 hours patches to 34 children with ADHD, Cmax and AUC0-t of d-methylphenidate were proportional to the patch dose. Mean plasma concentration-time plots are shown in Figure 1. Cmax of l-methylphenidate was also proportional to the patch dose. AUC0-t of l-methylphenidate was only slightly greater than proportional to patch dose. - Distribution - Upon removal of methylphenidate, methylphenidate plasma concentrations in children with ADHD decline in a biexponential manner. This may be due to continued distribution of MPH from the skin after patch removal. - Metabolism and Excretion - Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. - Transdermal administration of methylphenidate exhibits much less first pass effect than oral administration. Consequently, a much lower dose of methylphenidate on a mg/kg basis compared to oral dosages may still produce higher exposures of d-MPH with transdermal administration compared to oral administration. In addition, very little, if any, l-methylphenidate is systemically available after oral administration due to first pass metabolism, whereas after transdermal administration of racemic methylphenidate exposure to l-methylphenidate is nearly as high as to d-methylphenidate. - The mean elimination t1/2 from plasma of d-methylphenidate after removal of methylphenidate in children aged 6 to 12 years and adolescents aged 13-17 years was approximately 4 to 5 hours. The t1/2 of l-methylphenidate was shorter than for d-methylphenidate and ranged from 1.4 to 2.9 hours, on average. - The Cmax and AUC of d-methylphenidate were approximately 50% lower in adolescents, compared to children, following either a 1-day or 7-day administration of methylphenidate (10mg/9hr). Multiple-dose administration of methylphenidate did not result in significant accumulation of methylphenidate; following 7 days of methylphenidate administration (10mg/9hr) in children and adolescents, the accumulation index of methylphenidate was 1.1, based on the mean steady state area under the plasma concentration-time curve (AUCss) relative to that anticipated on the basis of single dose pharmacokinetics (AUC0-∞). - Food Effects - The pharmacokinetics or the pharmacodynamic food effect performance after application of methylphenidate has not been studied, but because of the transdermal route of administration, no food effect is expected. - Special Populations - Special Populations - Gender - The pharmacokinetics of methylphenidate after single and repeated doses of methylphenidate were similar between boys and girls with ADHD, after allowance for differences in body weight. - Race - The influence of race on the pharmacokinetics of methylphenidate after administration of methylphenidate has not been defined. - Age - The pharmacokinetics of methylphenidate after administration of methylphenidate have not been studied in children less than 6 years of age. - Renal Impairment - There is no experience with the use of methylphenidate in patients with renal insufficiency. - Hepatic Impairment - There is no experience with the use of methylphenidate in patients with hepatic insufficiency. ## Nonclinical Toxicology - Carcinogenesis - Carcinogenicity studies of transdermal methylphenidate have not been performed. In a lifetime carcinogenicity study of oral methylphenidate carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. - Orally administered methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day. - In a 24-week oral carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. In this study, male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. - Mutagenesis - Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitromouse lymphoma cell forward mutation assay, and was negative in vivo in the mouse bone marrow micronucleus assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese hamster ovary cells. - Impairment of Fertility - Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day. # Clinical Studies - Methylphenidate was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in two (2) randomized double-blind, placebo-controlled studies in children aged 6 to 12 years and one (1) randomized, double-blind, placebo-controlled study in adolescents aged 13 to 17 years who met Diagnostic and Statistical Manual (DSM-IV-TR®) criteria for ADHD. The patch wear time was 9 hours in all three (3) studies. - In Study 1, conducted in a classroom setting, symptoms of ADHD were evaluated by school teachers and observers using the Deportment Subscale from the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale which assesses behavior symptoms in the classroom setting. methylphenidate was applied for 9 hours before removal. There was a 5-week open-label methylphenidate dose optimization phase using dosages of 10, 15, 20, and 30 mg / 9 hours, followed by a 2-week randomized, double-blind, placebo-controlled crossover treatment phase using the optimal patch dose for each patient or placebo. The mean differences between methylphenidate and placebo in change from baseline in SKAMP Deportment Scores were statistically significant in favor of methylphenidate beginning at 2 hours and remained statistically significant at all subsequent measured time points through 12 hours after application of the methylphenidate patch. - In Study 2, conducted in the outpatient setting, methylphenidate or placebo was blindly administered in a flexible-dose design using doses of 10, 15, 20, and 30 mg / 9 hours to achieve an optimal regimen over 5 weeks, followed by a 2-week maintenance period using the optimal patch dose for each patient. Symptoms of ADHD were evaluated by the ADHD-Rating Scale (RS)-IV. methylphenidate was statistically significantly superior to placebo as measured by the mean change from baseline for the ADHD-RS-IV total score. Although this study was not designed specifically to evaluate dose response, in general there did not appear to be any additional effectiveness accomplished by increasing the patch dose from 20 mg / 9 hours to 30 mg / 9 hours. - In Study 3, conducted in the outpatient setting, methylphenidate or placebo was blindly administered in a flexible-dose design using doses of 10, 15, 20, and 30 mg / 9 hours during a 5-week dose-optimization phase, followed by a 2-week maintenance period using the optimal patch dose for each patient. Symptoms of ADHD were evaluated using the ADHD-Rating Scale (RS)-IV. methylphenidate was statistically significantly superior to placebo as measured by the mean change from baseline in the ADHD-RS-IV total score. # How Supplied - methylphenidate is supplied in a sealed tray or outer pouch containing 30 individually pouched patches. See the chart below for information regarding available strengths. ## Storage - Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F) . Do not store patches unpouched. Do not store patches in refrigerators or freezers. - Once the sealed tray or outer pouch is opened, use contents within 2 months. Apply the patch immediately upon removal from the individual protective pouch. For transdermal use only. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Priapism - Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism - Circulation problems in fingers and toes ], including Raynaud’s phenomenon] - Instruct patients beginning treatment with methylphenidate about the risk of peripheral vasculopathy, including Raynaud’s Phenomenon, and in associated signs and symptoms: fingers or toes may - feel numb, cool, painful, and/or may change color from pale, to blue, to red - Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. - Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate - Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. - Parents and patients should be informed to apply methylphenidate to a clean, dry site on the hip, which is not oily, damaged, or irritated. The site of application must be alternated daily. The patch should not be applied to the waistline, or where tight clothing may rub it. - If patients or caregivers experience difficulty separating the patch from the release liner or observe tearing and/or other damage to the patch during removal from the liner, the patch should be discarded according to the directions provided in this label, and a new patch should be applied . Patients or caregivers should inspect the release liner to ensure that no adhesive containing medication has transferred to the liner. If adhesive transfer has occurred, the patch should be discarded. - Methylphenidate should be applied 2 hours before the desired effect. methylphenidate should be removed approximately 9 hours after it is applied, although the effects from the patch will last for several more hours. methylphenidate may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. - The parent or caregiver should be encouraged to use the administration chart included with each carton of methylphenidate to monitor application and removal time, and method of disposal. The Medication Guide included at the end of this insert also includes a timetable to calculate when to remove methylphenidate, based on the 9 hour application time. - Patients or caregivers should avoid touching the adhesive side of the patch during application, in order to avoid absorption of methylphenidate. If they do touch the adhesive side of the patch, they should immediately wash their hands after application. - In the event that a patch does not fully adhere to the skin upon application, or is partially or fully detached during wear time, the patch should be discarded according to the directions provided in this label, and a new patch should be applied . If a patch is replaced, the total recommended wear time for that day should remain 9 hours, regardless of the number of patches used. - Patches should not be applied or re-applied with dressings, tape, or other common adhesives. - Exposure to water during bathing, swimming, or showering can affect patch adherence. - Do not cut patches. Only intact patches should be applied. - If there is an unacceptable duration of appetite loss or insomnia in the evening, taking the patch off earlier may be attempted before decreasing the patch dose. - Skin redness or itching is common with methylphenidate and small bumps on the skin may also occur in some patients. If any swelling or blistering occurs the patch should not be worn and the patient should be seen by the prescriber. Patients or caregivers should not apply hydrocortisone or other solutions, creams, ointments, or emollients immediately prior to patch application, since the effect on patch adhesion and methylphenidate absorption has not been established. The potential adverse effects of topical corticosteroid use during treatment with methylphenidate are unknown. - Stimulants may impair the ability of the patient to operate potentially hazardous machinery or vehicles. Patients should be cautioned accordingly until they are reasonably certain that methylphenidate does not adversely affect their ability to engage in such activities. - Patches should be stored at 25 degrees Celsius (77 degrees Fahrenheit) with excursions permitted that do not exceed 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit) . Patients or caregivers should be advised not to store methylphenidate in the refrigerator or freezer. - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for methylphenidate. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. # Precautions with Alcohol - Alcohol-Methylphenidate (transdermal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Daytrana # Look-Alike Drug Names There is limited information regarding Methylphenidate (transdermal) Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Topiramate nonclinical toxicology For patient information about topiramate, click here. # Nonclinical Toxicology ## Carcinogenesis An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m2 basis). ## Mutagenesis Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo. ## Impairment of Fertility No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m2 basis).

Romanowsky stain Romanowsky staining was a prototypical staining technique that was the forerunner of several distinct but similar methods, including Giemsa, Jenner, Wright, and Leishman stains, which are used to differentiate cells in pathologic specimens. Ehrlich had used mixtures of acidic and basic dyes for this purpose in 1879: in 1891 Romanowsky and Malakowsky independently developed a technique using a mixture of Eosin Y and oxidated Methylene Blue that was also useful for this purpose. Because the aqueous dye solutions were unstable, methanol was introduced as a solvent, and Leishman (in 1901) and Wright (in 1902) advocated use of methanol as a fixative prior to staining. Giemsa in 1902 improved this technique by standardizing the dye solutions and adding glycerol to increase solubility and stability. The oxidation of Methylene Blue in aqueous solution using heat and alkali produces a mixture of Azure A, Azure B, Methylene Violet and Methylene Blue. Eosin Y is then added to produce a "neutral" dye. The precipitate is then dissolved in a mixture of methanol and glycerol to form a stock solution: this is diluted with water or an aqueous buffer to form a working solution that is used in the preparation of pathology specimens.

List of antioxidants in food # Vitamins - Vitamin A (Retinol), also synthesized by the body from beta-carotene, protects dark green, yellow and orange vegetables and fruits from solar radiation damage, and is thought to play a similar role in the human body. Carrots, squash, broccoli, sweet potatoes, tomatoes (which gain their color from the compound lycopene), kale, seabuckthorn, collards, cantaloupe, peaches and apricots are particularly rich sources of beta-carotene. - Vitamin C (Ascorbic acid) is a water-soluble compound that fulfills several roles in living systems. Important sources include citrus fruits (such as oranges, sweet lime, etc.), green peppers, broccoli, green leafy vegetables, black currants, strawberries, blueberries, seabuckthorn, raw cabbage and tomatoes. Linus Pauling was a major advocate for its use. - Vitamin E, including Tocotrienol and Tocopherol, is fat soluble and protects lipids. Sources include wheat germ, seabuckthorn, nuts, seeds, whole grains, green leafy vegetables, vegetable oil, and fish-liver oil. Recent studies showed that some tocotrienol isomers have significant anti-oxidant properties. # Vitamin cofactors and minerals - Coenzyme Q10 - Manganese, particularly when in its +2 valence state as part of the enzyme called superoxide dismutase (SOD). # Hormones - Melatonin # Carotenoid terpenoids - Lycopene - found in high concentration in ripe red tomatoes. - Lutein - found in high concentration in spinach and red peppers. - Alpha-carotene - Beta-carotene - found in high concentrations in butternut squash, carrots, orange bell peppers, pumpkins, and sweet potatoes. - Zeaxanthin - the main pigment found in yellow corn. - Astaxanthin - found naturally in red algae and animals higher in the marine food chain. It is a red pigment familiarly recognized in crustacean shells and salmon flesh/roe. - Canthaxanthin # Flavonoid polyphenolics Flavonoids, a subset of polyphenol antioxidants, are present in many berries, as well as in coffee and tea. - Flavones: Luteolin Apigenin Tangeritin - Luteolin - Apigenin - Tangeritin - Flavonols: Quercetin and related, such as rutin Kaempferol Myricetin - walnuts are a rich source Isorhamnetin Proanthocyanidins, or condensed tannins - Quercetin and related, such as rutin - Kaempferol - Myricetin - walnuts are a rich source - Isorhamnetin - Proanthocyanidins, or condensed tannins - Flavanones: Hesperetin (metabolizes to hesperidin) Naringenin (metabolized from naringin) Eriodictyol - Hesperetin (metabolizes to hesperidin) - Naringenin (metabolized from naringin) - Eriodictyol - Flavanols and their polymers: Catechin, Gallocatechin and their coresponding gallate esters Epicatechin, Epigallocatechin and their coresponding gallate esters Theaflavin its gallate esters Thearubigins - Catechin, Gallocatechin and their coresponding gallate esters - Epicatechin, Epigallocatechin and their coresponding gallate esters - Theaflavin its gallate esters - Thearubigins - Isoflavone phytoestrogens - found primarily in soy, peanuts, and other members of the Fabaceae family. Genistein Daidzein Glycitein - Genistein - Daidzein - Glycitein - Stilbenoids: Resveratrol - found in the skins of dark-colored grapes, and concentrated in red wine. Pterostilbene - methoxylated analogue of resveratrol, abundant in Vaccinium berries - Resveratrol - found in the skins of dark-colored grapes, and concentrated in red wine. - Pterostilbene - methoxylated analogue of resveratrol, abundant in Vaccinium berries - Anthocyanins Cyanidin Delphinidin Malvidin Pelargonidin Peonidin Petunidin - Cyanidin - Delphinidin - Malvidin - Pelargonidin - Peonidin - Petunidin # Phenolic acids and their esters - Ellagic acid - found in high concentration in raspberry and strawberry, and in ester form in red wine tannins. - Gallic acid - found in gallnuts, sumac, witch hazel, tea leaves, oak bark, and many other plants. - Salicylic acid - found in most vegetables, fruits, and herbs; but most abundantly in the bark of willow trees, from where it was extracted for use in the early manufacture of aspirin. - Rosmarinic acid - found in high concentration in rosemary, oregano, lemon balm, sage, and marjoram. - Cinnamic acid and its derivatives, such as ferulic acid - found in seeds of plants such as in brown rice, forskin, whole wheat and oats, as well as in coffee, apple, artichoke, peanut, orange and pineapple. - Chlorogenic acid - found in high concentration in coffee (more concentrated in robusta than arabica beans), blueberries and tomatoes. Produced from esterification of caffeic acid. - Chicoric acid - another caffeic acid derivative, is found only in the popular medicinal herb Echinacea purpurea. - Gallotannins - hydrolyzable tannin polymer formed when gallic acid, a polyphenol monomer, esterifies and binds with the hydroxyl group of a polyol carbohydrate such as glucose. - Ellagitannins - hydrolyzable tannin polymer formed when ellagic acid, a polyphenol monomer, esterifies and binds with the hydroxyl group of a polyol carbohydrate such as glucose. - Emblicanin-antioxidant - tannin from Emblica Officinalis # Other nonflavonoid phenolics - Curcumin - Xanthones - Silymarin - mixture of flavonolignans extracted from milk thistle. - Eugenol # Other organic antioxidants - Citric acid, oxalic acid, and phytic acid - Lignan - antioxidant and phytoestrogen found in oats, flax seeds, pumpkin seeds, sesame seeds, rye, soybeans, broccoli, beans, vaginal fluid, urin, and some berries. - Bilirubin, a breakdown product of blood, has been identified as a possibly significant antioxidant. - Uric acid In humans accounts for roughly half the antioxidant ability of plasme. - R-α-Lipoic acid - fat and water soluble - N-Acetylcysteine - water soluble

Brugia malayi # Overview Brugia malayi is a filarial roundworm which causes filariasis in humans. Identified by Lichtenstein and named by Brug in 1927 as distinct from Wuchereria bancrofti, they called it Filaria malayi. In 1958 the separate genus Brugia was proposed by Buckley, and Filaria malayi became known as Brugia malayi. B. malayi is limited to tropical regions of Asia. # Life cycle Infective larvae are transmitted by infected biting arthropods during a blood meal. The larvae migrate to the appropriate site of the host's body, where they develop into microfilariae-producing adults. The adults dwell in various human tissues where they can live for several years. The agents of lymphatic filariasis reside in lymphatic vessels and lymph nodes. B. malayi dwells particularly in the lymphatics, as with Wuchereria bancrofti. The female worms produce microfilariae which circulate in the blood. The microfilariae infect mosquitoes. Inside the mosquito, the microfilariae develop in 1 to 2 weeks into infective filariform (third-stage) larvae. During a subsequent blood meal by the insect, the larvae infect the vertebrate host. They migrate to the lymphatics, where they develop into adults, a slow process that can require up to 18 months. Recently B. malayi was found to contain an endosymbiotic bacterium, Wolbachia, in all life stages. The genome sequence of this bacterium was determined at New England Biolabs. Experimental results indicate that the Wolbachia can be killed by treatment of the human host with doxycycline. Nematodes cured of the Wolbachia are sterile and have increased morbidity. # Laboratory diagnosis Identification of microfilariae by microscopic examination is the most practical diagnostic procedure. Examination of blood samples will allow identification of microfilariae of Brugia malayi. It is important to time the blood collection with the known periodicity of the microfilariae. The blood sample can be a thick smear, stained with Giemsa or hematoxylin and eosin. For increased sensitivity, concentration techniques can be used. These include centrifugation of the blood sample lyzed in 2% formalin (Knott's technique), or filtration through a Nucleopore membrane. Antigen detection using an immunoassay for circulating filarial antigens constitutes a useful diagnostic approach, because microfilaremia can be low and variable. Molecular diagnosis using polymerase chain reaction is also possible. Identification of adult worms is possible from tissue samples collected during nodulectomies (onchocerciasis), or during subcutaneous biopsies or worm removal from the eye (loiasis). ## Genome deciphered On September 20, 2007, scientists mapped the genome or genetic content of Brugia malayi, worm which cause elephantiasis (lymphatic filariasis). Figuring out the content of the genes might lead to development of new drugs and vaccines.

Methylene blue # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Methylene blue is a heterocyclic aromatic chemical compound that is FDA approved for the treatment of drug induced methemoglobinemia. Common adverse reactions include Hypertension, hypotension, sweating symptom, abdominal pain, diarrhea, nausea, vomiting, dizziness, headache and confusion. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Indications - Drug induced methemoglobinemia ## Dosage - 0.1 to 0.2 mL per kilogram of body weight (0.045 to 0.09 mL per pound of body weight). Inject Methylene Blue intravenously very slowly over a period of several minutes. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Methylene blue in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Methylene blue in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Methylene blue in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Methylene blue in pediatric patients. # Contraindications - Methylene blue can cause fetal harm when administered to a pregnant woman. An association exists between the use of methylene blue in amniocentesis and atresia of the ileum and jejunum, ileal occlusions and other adverse effects in the neonate. Methylene blue is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. - Intraspinal injection is contraindicated. - Methylene blue is contraindicated in patients with a known hypersensitivity to the drug. # Warnings - Methylene Blue should not be given by subcutaneous or intrathecal injection. - Methylene blue is a potent monoamine oxidase inhibitor: Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reputake inhibitors (SRIs). Serotonin toxicity is characterized by development of neuromuscular hyperactivity (tremor, clonus, myoclonus and hyperreflexia, and, in the advanced stage, pyramidal rigidity); autonomic hyperactivity (diaphoresis, fever, tachycardia, tachypnoea, and mydraisis); and altered mental status (agitation, excitement, and in the advanced stage, confusion). If methylene blue is judged to be indicated, SRIs must be ceased, prior to treatment/procedure/surgery. ## Precautions - Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD): Methylene blue should be avoided in patients with G6PD deficiency due to the risk of paradoxical methemoglobinemia and hemolysis. # Adverse Reactions ## Clinical Trials Experience - Large intravenous doses of Methylene Blue produce nausea, abdominal and precordial pain, dizziness, headache, profuse sweating, mental confusion and the formation of methemoglobin. ## Postmarketing Experience - There is limited information regarding postmarketing experience # Drug Interactions - Methylene blue may interact with any drug that acts as a serotonin reuptake inhibitor (SRI) including, amongst others, selective serotonin reuptake inhbitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans and ergot alkaloids; such combinations may have the consequence of potentially fatal serotonin toxicity (serotonin syndrome). Methylene blue should not be co-administered with any drug that acts as an SRI. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Epidemiologic evidence exists that Methylene blue is a teratogen. An association exists between the use of methylene blue in amniocentesis and atresia of the ileum and jejunum, ileal occlusions and other adverse effects in the neonate. Methylene blue Injection should not be administered to pregnant women during amniocentesis due to the risk of teratogenicity and other newborn adverse effects Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Methylene blue in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Methylene blue during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Methylene blue in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Methylene blue in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Methylene blue in geriatric settings. ### Gender There is no FDA guidance on the use of Methylene blue with respect to specific gender populations. ### Race There is no FDA guidance on the use of Methylene blue with respect to specific racial populations. ### Renal Impairment - Renal Failure: Methylene blue should be used with caution in patients with severe renal impairment . ### Hepatic Impairment There is no FDA guidance on the use of Methylene blue in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Methylene blue in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Methylene blue in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous. ### Monitoring - There is limited information regarding drug monitoring. # IV Compatibility - There is limited information regarding IV compatibility. # Overdosage There is limited information regarding Methylene blue overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Methylene blue is Phenothiazin-5-ium, 3,7-bis (dimethylamino)-, chloride, trihydrate. It will produce two opposite actions on hemoglobin. Low concentrations will convert methemoglobin to hemoglobin. High concentrations convert the ferrous iron of reduced hemoglobin to ferric iron which results in the formation of methemoglobin. ## Structure - Methylene Blue Injection, USP is a sterile solution of methylene blue in water for injection suitable for parenteral administration. - Each mL of solution contains 10 mg of methylene blue and water for injection q.s. pH adjusted with hydrochloric acid and/or sodium hydroxide when necessary. ## Pharmacodynamics - There is limited information regarding pharmacodynamics. ## Pharmacokinetics - There is limited information regarding pharmacokinetics. ## Nonclinical Toxicology - There is limited information regarding nonclinical toxicology. # Clinical Studies - There is limited information regarding clinical studies. # How Supplied Methylene Blue Injection, USP, 1% is supplied as follows: NDC 17478-504-01 1 mL in 2 cc (partially filled) vials in packages of 10. NDC 17478-504-10 10 mL vials in packages of 10. The vials are packaged with a Flip Tear-Off Seal. The seal can either be flipped normally to reveal the rubber stopper or be totally removed so the rubber stopper can be taken out of the vial. The plastic button is attached to the metal seal, which when pulled, tears the seal at the score line allowing the metal portion to be removed. ## Storage STORAGE: Store at 20° to 25°C (68° to 77°F) . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - There is limited information regarding Patient Counseling Information. # Precautions with Alcohol Alcohol-Methylene blue interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - METHYLENE BLUE® # Look-Alike Drug Names - There is limited information regarding Look-Alike Drug Names. # Drug Shortage Status # Price

Deep brain stimulation for Parkinson's disease # Guidance Current evidence on the safety and efficacy of deep brain stimulation for Parkinson's disease appears adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance. The clinical and cost effectiveness of deep brain stimulation for Parkinson's disease is being evaluated by the PD Surg trial, which is expected to complete randomisation in 2005/6. The results of this trial are likely to provide evidence on the most appropriate use of the procedure and clinicians are encouraged to consider randomising patients in the trial. It is recommended that patient selection should be made with the involvement of a multidisciplinary team, and that patients should be offered the procedure only when their disease has become refractory to best medical treatment.# The procedure # Indications Parkinson's disease is a chronic disease of the brain characterised by gradually worsening tremor, muscle rigidity and difficulties with starting and stopping movements. The condition is usually treated with drugs. Surgery may be considered in people who have responded poorly to drugs, who have severe side effects from medication or who have severe fluctuations in response to drugs (on–off syndrome). Parkinson's disease is common, affecting about 0.5% of people aged 65 to 74 years and 1–2% of people aged 75 years and older. Experts believe that 1–10% of people with Parkinson's disease might be suitable for brain surgery. Surgery for Parkinson's disease is carried out on structures within the brain that are responsible for the modification of movements, such as the thalamus, the globus pallidus and the subthalamic nucleus. Each of these structures consists of two parts: one on the left hand side of the brain and one on the right. Surgery may be carried out on one or both sides. Surgical treatment aims to correct the imbalance created by diminished function of the substantia nigra, the underlying abnormality in Parkinson's disease. Surgery alters, through either destruction or electrical stimulation, the function of brain nuclei – such as the thalamus, globus pallidus or subthalamus – that interact functionally with the substantia nigra. Deep brain stimulation is one form of surgery for Parkinson's disease. # Outline of the procedure This procedure involves inserting very fine needles into the brain through small holes made in the skull to determine the exact position of the nucleus to be stimulated, which may be different in each patient. This part of the procedure is usually carried out under local anaesthetic. Once the nucleus is identified, a permanent electrode is placed into it. Under general anaesthetic, this electrode is then connected to a pulse generator, which is implanted subcutaneously on the anterior chest wall. # Efficacy The evidence suggested that deep brain stimulation results in improved motor skills, function and movement in patients with Parkinson's disease. For more details refer to 'Sources of evidence'. The Specialist Advisors considered the procedure to be established practice within specialised units. They did not question short-term efficacy, but commented that long-term efficacy was unknown. One Specialist Advisor commented that careful selection of patients was crucial to maximise the chances of success of the procedure. # Safety The complications associated with deep brain stimulation include risk of stroke, confusion, speech disorders and visual problems. In the two largest studies, involving 102 and 111 patients, the incidence of stroke was approximately 3%. For more details refer to 'Sources of evidence'. The Specialist Advisors noted that all procedures involving deep brain stimulation carried similar risks. They considered the procedure to be safe if performed by a multidisciplinary team in a neuroscience unit. The team should include a neurologist and a neurosurgeon, and the unit should have facilities for psychological assessment and, ideally, neurophysiology. # Other comments The Interventional Procedures Advisory Committee noted that current evidence relates to relatively young patients. Andrew DillonChief ExecutiveNovember 2003# Further information # Sources of evidence The evidence considered by the Interventional Procedures Advisory Committee is described in the following document. 'Interventional procedure overview of deep brain stimulation in Parkinson's disease', April 2003. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on deep brain stimulation Further recommendations have been made as part of the clinical guideline on Parkinson's disease published in June 2006. Clinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. The IP guidance on deep brain stimulation for Parkinson's disease remains current, and should be read in conjunction with the clinical guideline.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2003. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk

Atom Used as a slang or street name for heroin and marijuana combination. # Overview An atom is the smallest particle that comprises a chemical element. An atom consists of an electron cloud that surrounds a dense nucleus. This nucleus contains positively charged protons and electrically neutral neutrons, whereas the surrounding cloud is made up of negatively charged electrons. When the number of protons in the nucleus equals the number of electrons, the atom is electrically neutral; otherwise it is an ion and has a net positive or negative charge. An atom is classified according to its number of protons and neutrons: the number of protons determines the chemical element and the number of neutrons determines the isotope of that element. The concept of the atom as an indivisible component of matter was first proposed by early Indian and Greek philosophers. In the 17th and 18th centuries, chemists provided a physical basis for this idea by showing that certain substances could not be further broken down by chemical methods. During the late 19th and the early 20th centuries, physicists discovered subatomic components and structure inside the atom, thereby demonstrating that the 'atom' was not indivisible. The principles of quantum mechanics were used to successfully model the atom. Relative to everyday experience, atoms are minuscule objects with proportionately tiny masses that can only be observed individually using special instruments such as the scanning tunneling microscope. More than 99.9% of an atom's mass is concentrated in the nucleus, with protons and neutrons having about equal mass. In atoms with too many or too few neutrons relative to the number of protons, the nucleus is unstable and subject to radioactive decay. The electrons surrounding the nucleus occupy a set of stable energy levels, or orbitals, and they can transition between these states by the absorption or emission of photons that match the energy differences between the levels. The electrons determine the chemical properties of an element, and strongly influence an atom's magnetic properties. # History The concept that matter is composed of discrete units and cannot be divided into arbitrarily tiny quantities has been around for millennia, but these ideas were founded in abstract, philosophical reasoning rather than experimentation and empirical observation. The nature of atoms in philosophy varied considerably over time and between cultures and schools, and often had spiritual elements. Nevertheless, the basic idea of the atom was adopted by scientists thousands of years later because it elegantly explained new discoveries in the field of chemistry. The earliest references to the concept of atoms date back to ancient India in the 6th century BCE. The Nyaya and Vaisheshika schools developed elaborate theories of how atoms combined into more complex objects (first in pairs, then trios of pairs). The references to atoms in the West emerged a century later from Leucippus whose student, Democritus, systemized his views. In approximately 450 BCE, Democritus coined the term átomos (Greek ἄτομος), which means "uncuttable" or "the smallest indivisible particle of matter", i.e., something that cannot be divided. Although the Indian and Greek concepts of the atom were based purely on philosophy, modern science has retained the name coined by Democritus. Further progress in the understanding of atoms did not occur until the science of chemistry began to develop. In 1661, the natural philosopher Robert Boyle published The Sceptical Chymist in which he argued that matter was composed of various combinations of different "corpuscules" or atoms, rather than the classical elements of air, earth, fire and water. In 1789 the term element was defined by the French nobleman and scientific researcher Antoine Lavoisier to mean basic substances that could not be further broken down by the methods of chemistry. In 1803, the Englishman John Dalton, an instructor and natural philosopher, used the concept of atoms to explain why elements always reacted in a ratio of small whole numbers—the law of multiple proportions—and why certain gases dissolved better in water than others. He proposed that each element consists of atoms of a single, unique type, and that these atoms could join to each other, to form chemical compounds. Additional validation of particle theory (and by extension atomic theory) occurred in 1827 when botanist Robert Brown used a microscope to look at dust grains floating in water and discovered that they moved about erratically—a phenomenon that became known as "Brownian motion". J. Desaulx suggested in 1877 that the phenomenon was caused by the thermal motion of water molecules, and in 1905 Albert Einstein produced the first mathematical analysis of the motion, thus confirming the hypothesis. The physicist J. J. Thomson, through his work on cathode rays in 1897, discovered the electron and its subatomic nature, which destroyed the concept of atoms as being indivisible units. Thomson believed that the electrons were distributed throughout the atom, with their charge balanced by the presence of a uniform sea of positive charge (the plum pudding model). However, in 1909, researchers under the direction of physicist Ernest Rutherford bombarded a sheet of gold foil with helium ions and discovered that a small percentage were deflected through much larger angles than was predicted using Thomson's proposal. Rutherford interpreted the gold foil experiment as suggesting that the positive charge of an atom and most of its mass was concentrated in a nucleus at the center of the atom (the Rutherford model), with the electrons orbiting it like planets around a sun. Positively charged helium ions passing close to this dense nucleus would then be deflected away at much sharper angles. While experimenting with the products of radioactive decay, in 1913 radiochemist Frederick Soddy discovered that there appeared to be more than one type of atom at each position on the periodic table. The term isotope was coined by Margaret Todd as a suitable name for different atoms that belong to the same element. J.J. Thomson created a technique for separating atom types through his work on ionized gases, which subsequently led to the discovery of stable isotopes. Meanwhile, in 1913, physicist Niels Bohr revised Rutherford's model by suggesting that the electrons were confined into clearly defined orbits, and could jump between these, but could not freely spiral inward or outward in intermediate states. An electron must absorb or emit specific amounts of energy to transition between these fixed orbits. When the light from a heated material is passed through a prism, it produced a multi-colored spectrum. The appearance of fixed lines in this spectrum was successfully explained by the orbital transitions. In 1926, Erwin Schrödinger, using Louis de Broglie's 1924 proposal that particles behave to an extent like waves, developed a mathematical model of the atom that described the electrons as three-dimensional waveforms, rather than point particles. A consequence of using waveforms to describe electrons is that it is mathematically impossible to obtain precise values for both the position and momentum of a particle at the same time; this became known as the uncertainty principle. In this concept, for each measurement of a position one could only obtain a range of probable values for momentum, and vice versa. Although this model was difficult to visually conceptualize, it was able to explain observations of atomic behavior that previous models could not, such as certain structural and spectral patterns of atoms larger than hydrogen. Thus, the planetary model of the atom was discarded in favor of one that described orbital zones around the nucleus where a given electron is most likely to exist. The development of the mass spectrometer allowed the exact mass of atoms to be measured. The device uses a magnet to bend the trajectory of a beam of ions, and the amount of deflection is determined by the ratio of an atom's mass to its charge. The chemist Francis William Aston used this instrument to demonstrate that isotopes had different masses. The mass of these isotopes varied by integer amounts, called the whole number rule. The explanation for these different atomic isotopes awaited the discovery of the neutron, a neutral-charged particle with a mass similar to the proton, by the physicist James Chadwick in 1932. Isotopes were then explained as elements with the same number of protons, but different numbers of neutrons within the nucleus. In the 1950s, the development of improved particle accelerator and particle detectors allowed scientists to study the impacts of atoms moving at high energies. Neutrons and protons were found to be hadrons, or composites of smaller particles called quarks. Standard models of nuclear physics were developed that successfully explained the properties of the nucleus in terms of these sub-atomic particles and the forces that govern their interactions. Around 1985, Steven Chu and co-workers at Bell Labs developed a technique for lowering the temperatures of atoms using lasers. In the same year, a team led by William D. Phillips managed to contain atoms of sodium in a magnetic trap. The combination of these two techniques and a method based on the Doppler effect, developed by Claude Cohen-Tannoudji and his group, allows small numbers of atoms to be cooled to several microkelvin. This allows the atoms to be studied with great precision, and later led to the discovery of Bose-Einstein condensation. Historically, single atoms have been prohibitively small for scientific applications. Recently, devices have been constructed that use a single metal atom connected through organic ligands to construct a single electron transistor. Experiments have been carried out by trapping and slowing single atoms using laser cooling in a cavity to gain a better physical understanding of matter. # Components ## Subatomic particles Though the word atom originally denoted a particle that cannot be cut into smaller particles, in modern scientific usage the atom is composed of various subatomic particles. The constituent particles of an atom consist of the electron, the proton and, for atoms other than hydrogen-1, the neutron. The electron is by far the least massive of these particles at 9.11Template:E g, with a negative electrical charge and a size that is too small to be measured using available techniques. Protons have a positive charge and a mass 1,836 times that of the electron, at 1.6726Template:E g, although this can be reduced by changes to the atomic binding energy. Neutrons have no electrical charge and have a free mass of 1,839 times the mass of electrons, or 1.6929Template:E g. Neutrons and protons have comparable dimensions—on the order of 2.5Template:E m—although the 'surface' of these particles is not sharply defined. In the Standard Model of physics, both protons and neutrons are composed of elementary particles called quarks. The quark is a type of fermion, one of the two basic constituents of matter—the other being the lepton, of which the electron is an example. There are six types of quarks, and each has a fractional electric charge of either +2/3 or −1/3. Protons are composed of two up quarks and one down quark, while a neutron consists of one up quark and two down quarks. This distinction accounts for the difference in mass and charge between the two particles. The quarks are held together by the strong nuclear force, which is mediated by gluons. The gluon is a member of the family of bosons, which are elementary particles that mediate physical forces. ## Nucleus All of the bound protons and neutrons in an atom make up a tiny atomic nucleus, and are collectively called nucleons. The radius of a nucleus is approximately equal to \begin{smallmatrix}1.07 \cdot \sqrt{A}\end{smallmatrix} fm, where A is the total number of nucleons. This is much smaller than the radius of the atom, which is on the order of 105 fm. The nucleons are bound together by a short-ranged attractive potential called the residual strong force. At distances smaller than 2.5 fm, this force is much more powerful than the electrostatic force that causes positively charged protons to repel each other. Atoms of the same element have the same number of protons, called the atomic number. Within a single element, the number of neutrons may vary, determining the isotope of that element. The total number of protons and neutrons determine the nuclide. The number of neutrons relative to the protons determines the stability of the nucleus, with certain isotopes undergoing radioactive decay. The neutron and the proton are different types of fermions. The Pauli exclusion principle is a quantum mechanical effect that prohibits identical fermions (such as multiple protons) from occupying the same quantum physical state at the same time. Thus every proton in the nucleus must occupy a different state, with its own energy level, and the same rule applies to all of the neutrons. (This prohibition does not apply to a proton and neutron occupying the same quantum state.) A nucleus that has a different number of protons than neutrons can potentially drop to a lower energy state through a radioactive decay that causes the number of protons and neutrons to more closely match. As a result, atoms with matching numbers of protons and neutrons are more stable against decay. However, with increasing atomic number, the mutual repulsion of the protons requires an increasing proportion of neutrons to maintain the stability of the nucleus, which slightly modifies this trend of equal numbers of protons to neutrons. The number of protons and neutrons in the atomic nucleus can be modified, although this can require very high energies because of the strong force. Nuclear fusion occurs when multiple atomic particles join to form a heavier nucleus, such as through the energetic collision of two nuclei. At the core of the Sun, protons require energies of 3–10 KeV to overcome their mutual repulsion—the coulomb barrier—and fuse together into a single nucleus. Nuclear fission is the opposite process, causing a nucleus to split into two smaller nuclei—usually through radioactive decay. The nucleus can also be modified through bombardment by high energy subatomic particles or photons. In such processes that change the number of protons in a nucleus, the atom becomes an atom of a different chemical element. The mass of the nucleus following a fusion reaction is less than the sum of the masses of the separate particles. The difference between these two values is emitted as energy, as described by Albert Einstein's mass–energy equivalence formula, E = mc², where m is the mass loss and c is the speed of light. This deficit is the binding energy of the nucleus. The fusion of two nuclei that have lower atomic numbers than iron and nickel is an exothermic process that releases more energy than is required to bring them together. It is this energy-releasing process that makes nuclear fusion in stars a self-sustaining reaction. For heavier nuclei, the total binding energy begins to decrease. That means fusion processes with nuclei that have higher atomic numbers is an endothermic process. These more massive nuclei can not undergo an energy-producing fusion reaction that can sustain the hydrostatic equilibrium of a star. ## Electron cloud The electrons in an atom are attracted to the protons in the nucleus by the electromagnetic force. This force binds the electrons inside an electrostatic potential well surrounding the smaller nucleus, which means that an external source of energy is needed in order for the electron to escape. The closer an electron is to the nucleus, the greater the attractive force. Hence electrons bound near the center of the potential well require more energy to escape than those at the exterior. Electrons, like other particles, have properties of both a particle and a wave. The electron cloud is a region inside the potential well where each electron forms a type of three-dimensional standing wave—a wave form that does not move relative to the nucleus. This behavior is defined by an atomic orbital, a mathematical function that characterises the probability that an electron will appear to be at a particular location when its position is measured. Only a discrete (or quantized) set of these orbitals exist around the nucleus, as other possible wave patterns will rapidly decay into a more stable form. Orbitals can have one or more ring or node structures, and they differ from each other in size, shape and orientation. Each atomic orbital corresponds to a particular energy level of the electron. The electron can change its state to a higher energy level by absorbing a photon with sufficient energy to boost it into the new quantum state. Likewise, through spontaneous emission, an electron in a higher energy state can drop to a lower energy state while radiating the excess energy as a photon. These characteristic energy values, defined by the differences in the energies of the quantum states, are responsible for atomic spectral lines. The amount of energy needed to remove or add an electron (the electron binding energy) is far less than the binding energy of nucleons. For example, it requires only 13.6 eV to strip a ground-state electron from a hydrogen atom. Atoms are electrically neutral if they have an equal number of protons and electrons. Atoms that have either a deficit or a surplus of electrons are called ions. Electrons that are farthest from the nucleus may be transferred to other nearby atoms or shared between atoms. By this mechanism, atoms are able to bond into molecules and other types of chemical compounds like ionic and covalent network crystals. # Properties ## Nuclear properties By definition, any two atoms with an identical number of protons in their nuclei belong to the same chemical element. Atoms with the same number of protons but a different number of neutrons are different isotopes of the same element. Hydrogen atoms, for example, always have only a single proton, but isotopes exist with no neutrons (hydrogen-1, sometimes called protium, by far the most common form), one neutron (deuterium) and two neutrons (tritium). The known elements form a continuous range of atomic numbers from hydrogen with a single proton up to the 118-proton element ununoctium. All known isotopes of elements with atomic numbers greater than 82 are radioactive. About 339 nuclides occur naturally on Earth, of which 269 (about 79%) are stable. Of the chemical elements, 80 have one or more stable isotopes. Elements 43, 61, and all elements numbered 83 or higher have no stable isotopes. As a rule, there is, for each atomic number (each element) only a handful of stable isotopes, the average being 3.4 stable isotopes per element which has any stable isotopes. Sixteen elements have only a single stable isotope, while the largest number of stable isotopes observed for any element is ten (for the element tin). Stability of isotopes is affected by the ratio of protons to neutrons, and also by presence of certain "magic numbers" of neutrons or protons which represent closed and filled quantum shells. These quantum shells correspond to a set of energy levels within the shell model of the nucleus. Of the 269 known stable nuclides, only four have both an odd number of protons and odd number of neutrons: 2H, 6Li, 10B and 14N. Also, only four naturally-occurring, radioactive odd-odd nuclides have a half-life over a billion years: 40K, 50V, 138La and 180mTa. Most odd-odd nuclei are highly unstable with respect to beta decay, because the decay products are even-even, and are therefore more strongly bound, due to nuclear pairing effects. ## Mass Because the large majority of an atom's mass comes from the protons and neutrons, the total number of these particles in an atom is called the mass number. The mass of an atom at rest is often expressed using the unified atomic mass unit (u), which is also called a Dalton (Da). This unit is defined as a twelfth of the mass of a free neutral atom of carbon-12, which is approximately 1.66×10−24 g. hydrogen-1, the lightest isotope of hydrogen and the atom with the lowest mass, has an atomic weight of 1.007825 u. An atom has a mass approximately equal to the mass number times the atomic mass unit. The heaviest stable atom is lead-208, with a mass of 207.9766521 u. As even the most massive atoms are far too light to work with directly, chemists instead use the unit of moles. The mole is defined such that one mole of any element will always have the same number of atoms (about 6.022×1023). This number was chosen so that if an element has an atomic mass of 1 u, a mole of atoms of that element will have a mass of 1 g. Carbon, for example, has an atomic mass of 12 u, so a mole of carbon atoms weighs 12 g. ## Size Atoms lack a well-defined outer boundary, so the dimensions are usually described in terms of the distances between two nuclei when the two atoms are joined in a chemical bond. The radius varies with the location of an atom on the atomic chart, the type of chemical bond, the number of neighboring atoms (coordination number) and a quantum mechanical property known as spin. On the periodic table of the elements, atom size tends to increase when moving down columns, but decrease when moving across rows (left to right). Consequently, the smallest atom is helium with a radius of 32 pm, while one of the largest is caesium at 225 pm. These dimensions are thousands of times smaller than the wavelengths of light (400–700 nm) so they can not be viewed using an optical microscope. However, individual atoms can be observed using a scanning tunneling microscope. Some examples will demonstrate the minuteness of the atom. A typical human hair is about 1 million carbon atoms in width. A single drop of water contains about 2 sextillion (2Template:E) atoms of oxygen, and twice the number of hydrogen atoms. A single carat diamond with a mass of 0.2 g contains about 10 sextillion atoms of carbon. If an apple was magnified to the size of the Earth, then the atoms in the apple would be approximately the size of the original apple. ## Radioactive decay Every element has one or more isotopes that have unstable nuclei that are subject to radioactive decay, causing the nucleus to emit particles or electromagnetic radiation. Radioactivity can occur when the radius of a nucleus is large compared with the radius of the strong force, which only acts over distances on the order of 1 fm. There are three primary forms of radioactive decay: - Alpha decay is caused when the nucleus emits an alpha particle, which is a helium nucleus consisting of two protons and two neutrons. The result of the emission is a new element with a lower atomic number. - Beta decay is regulated by the weak force, and results from a transformation of a neutron into a proton, or a proton into a neutron. The first is accompanied by the emission of an electron and an antineutrino, while the second causes the emission of a positron and a neutrino. The electron or positron emissions are called beta particles. Beta decay either increases or decreases the atomic number of the nucleus by one. - Gamma decay results from a change in the energy level of the nucleus to a lower state, resulting in the emission of electromagnetic radiation. This can occur following the emission of an alpha or a beta particle from radioactive decay. Each radioactive isotope has a characteristic decay time period—the half-life—that is determined by the amount of time needed for half of a sample to decay. This is an exponential decay process that steadily decreases the proportion of the remaining isotope by 50% every half life. Hence after two half-lives have passed only 25% of the isotope will be present, and so forth. ## Magnetic moment Elementary particles possess an intrinsic quantum mechanical property known as spin. This is analogous to the angular momentum of an object that is spinning around its center of mass, although strictly speaking these particles are believed to be point-like and cannot be said to be rotating. Spin is measured in units of the reduced Planck constant (\hbar), with electrons, protons and neutrons all having spin ½ \hbar, or "spin-½". In an atom, electrons in motion around the nucleus possess orbital angular momentum in addition to their spin, while the nucleus itself possesses angular momentum due to its nuclear spin. The magnetic field produced by an atom—its magnetic moment—is determined by these various forms of angular momentum, just as a rotating charged object classically produces a magnetic field. However, the most dominant contribution comes from spin. Due to the nature of electrons to obey the Pauli exclusion principle, in which no two electrons may be found in the same quantum state, bound electrons pair up with each other, with one member of each pair in a spin up state and the other in the opposite, spin down state. Thus these spins cancel each other out, reducing the total magnetic dipole moment to zero in some atoms with even number of electrons. In ferromagnetic elements such as iron, an odd number of electrons leads to an unpaired electron and a net overall magnetic moment. The orbitals of neighboring atoms overlap and a lower energy state is achieved when the spins of unpaired electrons are aligned with each other, a process is known as an exchange interaction. When the magnetic moments of ferromagnetic atoms are lined up, the material can produce a measurable macroscopic field. Paramagnetic materials have atoms with magnetic moments that line up in random directions when no magnetic field is present, but the magnetic moments of the individual atoms line up in the presence of a field. The nucleus of an atom can also have a net spin. Normally these nuclei are aligned in random directions because of thermal equilibrium. However, for certain elements (such as xenon-129) it is possible to polarize a significant proportion of the nuclear spin states so that they are aligned in the same direction—a condition called hyperpolarization. This has important applications in magnetic resonance imaging. ## Energy levels When an electron is bound to an atom, it has a potential energy that is inversely proportional to its distance from the nucleus. This is measured by the amount of energy needed to unbind the electron from the atom, and is usually given in units of electronvolts (eV). In the quantum mechanical model, a bound electron can only occupy a set of states centered on the nucleus, and each state corresponds to a specific energy level. The lowest energy state of a bound electron is called the ground state, while an electron at a higher energy level is in an excited state. In order for an electron to transition between two different states, it must absorb or emit a photon at an energy matching the difference in the potential energy of those levels. The energy of an emitted photon is proportional to its frequency, so these specific energy levels appear as distinct bands in the electromagnetic spectrum. Each element has a characteristic spectrum that can depend on the nuclear charge, subshells filled by electrons, the electromagnetic interactions between the electrons and other factors. When a continuous spectrum of energy is passed through a gas or plasma, some of the photons are absorbed by atoms, causing electrons to change their energy level. Those excited electrons that remain bound to their atom will spontaneously emit this energy as a photon, traveling in a random direction, and so drop back to lower energy levels. Thus the atoms behave like a filter that forms a series of dark absorption bands in the energy output. (An observer viewing the atoms from a different direction, which does not include the continuous spectrum in the background, will instead see a series of emission lines from the photons emitted by the atoms.) Spectroscopic measurements of the strength and width of spectral lines allow the composition and physical properties of a substance to be determined. Close examination of the spectral lines reveals that some display a fine structure splitting. This occurs because of spin-orbit coupling, which is an interaction between the spin and motion of the outermost electron. When an atom is in an external magnetic field, spectral lines become split into three or more components; a phenomenon called the Zeeman effect. This is caused by the interaction of the magnetic field with the magnetic moment of the atom and its electrons. Some atoms can have multiple electron configurations with the same energy level, which thus appear as a single spectral line. The interaction of the magnetic field with the atom shifts these electron configurations to slightly different energy levels, resulting in multiple spectral lines. The presence of an external electric field can cause a comparable splitting and shifting of spectral lines by modifying the electron energy levels, a phenomenon called the Stark effect. If a bound electron is in an excited state, an interacting photon with the proper energy can cause stimulated emission of a photon with a matching energy level. For this to occur, the electron must drop to a lower energy state that has an energy difference matching the energy of the interacting photon. The emitted photon and the interacting photon will then move off in parallel and with matching phases. That is, the wave patterns of the two photons will be synchronized. This physical property is used to make lasers, which can emit a coherent beam of light energy in a narrow frequency band. ## Valence The outermost electron shell of an atom in its uncombined state is known as the valence shell, and the electrons in that shell are called valence electrons. The number of valence electrons determines the bonding behavior with other atoms. Atoms tend to chemically react with each other in a manner that will fill (or empty) their outer valence shells. The chemical elements are often displayed in a periodic table that is laid out to display recurring chemical properties, and elements with the same number of valence electrons form a group that is aligned in the same column of the table. (The horizontal rows correspond to the filling of a quantum shell of electrons.) The elements at the far right of the table have their outer shell completely filled with electrons, which results in chemically inert elements known as the noble gases. ## States Quantities of atoms are found in different states of matter that depend on the physical conditions, such as temperature and pressure. By varying the conditions, materials can transition between solids, liquids, gases and plasmas. Within a state, a material can also exist in different phases. An example of this is solid carbon, which can exist as graphite or diamond. At temperatures close to absolute zero, atoms can form a Bose–Einstein condensate, at which point quantum mechanical effects, which are normally only observed at the atomic scale, become apparent on a macroscopic scale. This super-cooled collection of atoms then behaves as a single Super Atom, which may allow fundamental checks of quantum mechanical behavior. # Identification The scanning tunneling microscope is a device for viewing surfaces at the atomic level. It uses the quantum tunneling phenomenon, which allows particles to pass through a barrier that would normally be insurmountable. Electrons tunnel through the vacuum between two planar metal electrodes, on each of which is an adsorbed atom, providing a tunneling-current density that can be measured. Scanning one atom (taken as the tip) as it moves past the other (the sample) permits plotting of tip displacement versus lateral separation for a constant current. The calculation shows the extent to which scanning-tunneling-microscope images of an individual atom are visible. It confirms that for low bias, the microscope images the space-averaged dimensions of the electron orbitals across closely packed energy levels—the Fermi level local density of states. An atom can be ionized by removing one of its electrons. The electric charge causes the trajectory of an atom to bend when it passes through a magnetic field. The radius by which the trajectory of a moving ion is turned by the magnetic field is determined by the mass of the atom. The mass spectrometer uses this principle to measure the mass-to-charge ratio of ions. If a sample contains multiple isotopes, the mass spectrometer can determine the proportion of each isotope in the sample by measuring the intensity of the different beams of ions. Techniques to vaporize atoms include inductively coupled plasma atomic emission spectroscopy and inductively coupled plasma mass spectrometry, both of which use a plasma to vaporize samples for analysis. A more area-selective method is electron energy loss spectroscopy, which measures the energy loss of an electron beam within a transmission electron microscope when it interacts with a portion of a sample. The atom-probe tomograph has sub-nanometer resolution in 3-D and can chemically identify individual atoms using time-of-flight mass spectrometry. Spectra of excited states can be used to analyze the atomic composition of distant stars. Specific light wavelengths contained in the observed light from stars can be separated out and related to the quantized transitions in free gas atoms. These colors can be replicated using a gas-discharge lamp containing the same element. Helium was discovered in this way in the spectrum of the Sun 23 years before it was found on Earth. # Origin and current state Atoms form about 4% of the total mass density of the observable universe, with an average density of about 0.25 atoms/m3. Within a galaxy such as the Milky Way, atoms have a much higher concentration, with the density of matter in the interstellar medium (ISM) ranging from 105 to 109 atoms/m3. The Sun is believed to be inside the Local Bubble, a region of highly ionized gas, so the density in the solar neighborhood is only about 103 atoms/m3. Stars form from dense clouds in the ISM, and the evolutionary processes of stars result in the steady enrichment of the ISM with elements more massive than hydrogen and helium. Up to 95% of the Milky Way's atoms are concentrated inside stars and the total mass of atoms forms about 10% of the mass of the galaxy. (The remainder of the mass is an unknown dark matter.) ## Nucleosynthesis Stable protons and electrons appeared one second after the Big Bang. During the following three minutes, Big Bang nucleosynthesis produced most of the helium, lithium, and deuterium atoms in the universe, and perhaps some of the beryllium and boron. The first atoms (complete with bound electrons) were theoretically created 380,000 years after the Big Bang—an epoch called recombination, when the expanding universe cooled enough to allow electrons to become attached to nuclei. Since then, atomic nuclei have been combined in stars through the process of nuclear fusion to produce elements up to iron. Isotopes such as lithium-6 are generated in space through cosmic ray spallation. This occurs when a high-energy proton strikes an atomic nucleus, causing large numbers of nucleons to be ejected. Elements heavier than iron were produced in supernovae through the r-process and in AGB stars through the s-process, both of which involve the capture of neutrons by atomic nuclei. Elements such as lead formed largely through the radioactive decay of heavier elements. ## Earth Most of the atoms that make up the Earth and its inhabitants were present in their current form in the nebula that collapsed out of a molecular cloud to form the solar system. The rest are the result of radioactive decay, and their relative proportion can be used to determine the age of the Earth through radiometric dating. Most of the helium in the crust of the Earth (about 99% of the helium from gas wells, as shown by its lower abundance of helium-3) is a product of alpha decay. There are a few trace atoms on Earth that were not present at the beginning (i.e., not "primordial"), nor are results of radioactive decay. Carbon-14 is continuously generated by cosmic rays in the atmosphere. Some atoms on Earth have been artificially generated either deliberately or as by-products of nuclear reactors or explosions. Of the transuranic elements—those with atomic numbers greater than 92—only plutonium and neptunium occur naturally on Earth. Transuranic elements have radioactive lifetimes shorter than the current age of the Earth and thus identifiable quantities of these elements have long since decayed, with the exception of traces of plutonium-244 possibly deposited by cosmic dust. Natural deposits of plutonium and neptunium are produced by neutron capture in uranium ore. The Earth contains approximately 1.33Template:E atoms. In the planet's atmosphere, small numbers of independent atoms exist for the noble gases, such as argon and neon. The remaining 99% of the atmosphere is bound in the form of molecules, including carbon dioxide and diatomic oxygen and nitrogen. At the surface of the Earth, atoms combine to form various compounds, including water, salt, silicates and oxides. Atoms can also combine to create materials that do not consist of discrete molecules, including crystals and liquid or solid metals. This atomic matter forms networked arrangements that lack the particular type of small-scale interrupted order associated with molecular matter. ## Rare and theoretical forms While isotopes with atomic numbers higher than lead (82) are known to be radioactive, an "island of stability" has been proposed for some elements with atomic numbers above 103. These superheavy elements may have a nucleus that is relatively stable against radioactive decay. The most likely candidate for a stable superheavy atom, unbihexium, has 126 protons and 184 neutrons. Each particle of matter has a corresponding antimatter particle with the opposite electrical charge. Thus, the positron is a positively charged antielectron and the antiproton is a negatively charged equivalent of a proton. For unknown reasons, antimatter particles are rare in the universe, hence, no antimatter atoms have been discovered. Antihydrogen, the antimatter counterpart of hydrogen, was first produced at the CERN laboratory in Geneva in 1996. Other exotic atoms have been created by replacing one of the protons, neutrons or electrons with other particles that have the same charge. For example, an electron can be replaced by a more massive muon, forming a muonic atom. These types of atoms can be used to test the fundamental predictions of physics.

Amoxicillin adverse reactions # Adverse Reactions As with other penicillins, it may be expected that untoward reactions will be essentially limited to sensitivity phenomena. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma, hay fever, or urticaria. The following adverse reactions have been reported as associated with the use of penicillins: - Infections and Infestations: Mucocutaneous candidiasis. - Gastrointestinal: Nausea, vomiting, diarrhea, black hairy tongue, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS.) - Hypersensitivity Reactions: Anaphylaxis (See WARNING) Serum sickness-like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis and urticaria have been reported. NOTE: These hypersensitivity reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, amoxicillin should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to amoxicillin therapy. - Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported. - Renal: Crystalluria has also been reported (see OVERDOSAGE). - Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. - Central Nervous System: Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness have been reported rarely. - Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases. - Combination Therapy with Clarithromycin and Lansoprazole: In clinical trials using combination therapy with amoxicillin plus clarithromycin and lansoprazole, and amoxicillin plus lansoprazole, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with amoxicillin, clarithromycin, or lansoprazole. - Triple Therapy: Amoxicillin/Clarithromycin/Lansoprazole:The most frequently reported adverse events for patients who received triple therapy were diarrhea (7%), headache (6%), and taste perversion (5%). No treatment-emergent adverse events were observed at significantly higher rates with triple therapy than with any dual therapy regimen. - Dual Therapy: Amoxicillin/Lansoprazole: The most frequently reported adverse events for patients who received amoxicillin three times daily plus lansoprazole three times daily dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse events were observed at significantly higher rates with amoxicillin three times daily plus lansoprazole three times daily dual therapy than with lansoprazole alone. For more information on adverse reactions with clarithromycin or lansoprazole, refer to their package inserts, ADVERSE REACTIONS.

Sigma-2 receptor The sigma-2 receptor (σ2R) is a sigma receptor subtype that has been found highly expressed in malignant cancer cells, and is currently under investigation for its potential diagnostic and therapeutic uses. The receptor has recently been identified with TMEM97, a protein for which gene and protein sequence is available that had been known to be involved in cholesterol homeostasis. Originally, it was thought that the sigma receptors were a type of opiate receptor, due to its ability to bind ligands such as benzomorphans and PCP. Difficulties were found in distinguishing between the sigma-2 receptor and the NMDA receptors, though it is now known they are not the same entities, and have different distributions throughout the brain. The sigma-2 receptor in particular is more densely located in parts of the brain that are responsible for motor function and emotional response. It has been found to play a role in both hormone signaling and calcium signaling, in neuronal signaling, in cell proliferation and death, and in binding of antipsychotics. The position of the sigma-2 receptor had not previously been located on the human chromosome. # Classification The sigma-2 receptor is a cytochrome related protein located in the lipid raft that is most commonly associated with P450 proteins, and is coupled with the PGRMC1 complex, EGFR, mTOR, caspases, and various ion channels. The sigma-2 receptor is found in several areas of the brain, including high densities in the cerebellum, motor cortex, hippocampus, and substantia nigra, though it shows no homology with other proteins present in brain tissue. It is also highly expressed in the lungs, liver, and kidneys. # Function The sigma-2 receptor takes part in a number of normal-function roles, including cell proliferation, non-neuronal, and neuronal signaling. Much of sigma-2 receptor function relies on signaling cascades. The receptor's interaction with EGFR and PGRMC1 proteins allow for sigma-2 receptors to play diverse roles within cell through Ras, PLC, and PI3K singaling. ## Non-neuronal signaling Binding of a number of hormones and steroids, including testosterone, progesterone, and cholesterol, has been found to occur with sigma-2 receptors, though in some cases with lower affinity than to the sigma-1 receptor. Signaling caused by this binding is thought to occur via a calcium secondary messenger and calcium-dependent phosphorylation, and in association with sphingolipids following endoplasmic reticulum release of calcium. Known effects include decrease of expression of effectors in the mTOR pathway, and suppression of cyclin D1 and PARP-1. ## Neuronal signaling Signaling action in neurons by sigma-2 receptors and their associated ligands results in modulation of action potential firing by regulation of calcium and potassium channels. They also are involved in synaptic vesicular release and modulation of dopamine, serotonin, and glutamate, with activation and increase of the dopaminergic, serotonergic, and noradrenergic activity of neurons. ## Cell proliferation Sigma-2 receptors have been found to be highly expressed in proliferating cells, including tumor cells, and to play a role in the differentiation, morphology, and survival of those cells. By interacting with EGFR membrane proteins sigma-2 receptors play a role in the regulation of signals further downstream such as PKC and RAF. Both PKC and Raf kinase up regulate transcription and cell proliferation. # Ligands Ligands of the sigma-2 receptor are exogenous and internalized by endocytosis, and can act as either agonists or antagonists. They can typically be classified into four groups, which are structurally related. It is not entirely understood how binding to the sigma-2 receptor occurs. Proposed models commonly include one small and one bulky hydrophobic pocket, electrostatic hydrogen interactions, and less commonly a third hydrophobic pocket. A study of the four groups has revealed that a basic nitrogen and at least one hydrophobic moiety is needed to bind a sigma-2 receptor. In addition, there are molecular characteristics that increase the selectivity for sigma-2 receptors, which include bulky hydrophobic regions, nitrogen-carboxylic interaction, and additional basic nitrogens. # Diagnostic use Sigma-2 receptors are highly expressed breast, ovarian, lung cancers, brain, bladder, colon cancers, and melanoma. This novelty makes them a valuable biomarker for identifying cancerous tissues. Furthermore, studies have shown that they are more highly expressed in malignant tumors than dormant tumors. Exogenous sigma-2 receptor ligands have been altered to be neuronal-tracers, used to map cells and their connections. These tracers have high selectivity and affinity for sigma-2 receptors, and high lipophilicity, making them ideal for usage in the brain. Because sigma-2 receptors are highly expressed in tumor cells and are part of the cell proliferation mechanism, PET scans using sigma-2 targeted tracers can reveal if a tumor is proliferating and what its growth rate is. # Therapeutic use ## Neuropsychiatric Due to the binding capabilities of antipsychotic drugs and various neurotransmitters associated with mood, the sigma-2 receptor is a viable target for therapies related to neuropsychiatric disorders and modulation of emotional response. It is thought to be involved in the pathophysiology of schizophrenia, and sigma-2 receptors have been shown to be less abundant in schizophrenic patients. Additionally, PCP, which is an NMDA antagonist, can induce schizophrenia, while sigma-2 receptor activation has been shown to antagonize effects of PCP, implying antipsychotic capabilities. Sigma receptors are a potential target for treatment of dystonia, given high densities in affected regions of the brain. Anti-ischemics ifenprodil and eliprodil, the binding of which increases blood flow, have also shown affinity to sigma receptors. In experimental trials in mice and rats, the sigma-2 receptor ligand siramensine caused reduced anxiety and displayed antidepressant capabilities, while other studies have shown inhibition of selective sigma receptor radioligands by antidepressants, in the mouse and rat brain. ## Cancer Sigma-2 receptors have been associated with pancreatic cancer, lung cancer, breast cancer, melanoma, prostate cancer, and ovarian cancer. Tumor cells are shown to over-express sigma-2 receptors, allowing for potential cancer therapies as many sigma-2 receptor mediated cell responses happen only in tumor cells. Tumor cell responses are modulated via ligand binding. Sigma receptor ligands can act as agonists or antagonists, generating different cellular responses. Agonists inhibit tumor cell proliferation and induce apoptosis, which is thought to be triggered by caspase-3 activity. Antagonists promote tumor cell proliferation, but this mechanism is less understood. Sigma receptor ligands have been conjugated to nanoparticles and peptides to deliver cancer treatment to tumor cells without targeting other tissues. The success with these methods have been limited to in vitro trials. Additionally, using sigma-2 receptors to target tumor cells allows for synergizing anti-cancer drug therapies. Some studies have shown that certain sigma receptor inhibitors increase cancer cells' susceptibility to chemotherapy. Other types of binding to sigma-2 receptors increases cytotoxicity of doxorubicin, antinomyocin, and other cancer cell killing drugs.

Empty sella syndrome # Overview Empty sella syndrome (ESS) is defined as herniation of subarachnoid space into the sella turcica (arachnoidocele) in which there is a characteristic radiological finding of "empty sellar space" on magnetic resonance imaging (MRI) and computerized tomography (CT) with a flattened pituitary and elongated stalk. It can be partial if less than 50% of sellar space is filled with cerebro-spinal fluid (CSF), or complete if CSF fills more than 50% of space in the sella and gland thickness is less than 2mm. # Historical Perspective - The term ‘empty sella’ was first used by Bush in 1951 to describe a peculiar anatomical condition, observed in 40 of 788 human cadavers, particularly females, characterized by a sella turcica with an incomplete diaphragm sellae that forms only a small peripheral rim, with a pituitary gland not absent, but flattened in such a manner as to form a thin layer of tissue at the bottom of the sella turcica. - In , mutations were first identified in the pathogenesis of . - In , the first was developed by to treat/diagnose . # Classification - may be classified according to into subtypes/groups: - Other variants of include , , and . There are two types of ESS: primary and secondary. - Primary ESS happens when a small anatomical defect above the pituitary gland increases pressure in the sella turica and causes the gland to flatten out along the interior walls of the sella turica cavity. Primary ESS is associated with obesity and high blood pressure in women. The disorder sometimes results in a build-up of fluid pressure inside the skull and the pituitary gland may be smaller than usual. - Secondary ESS is the result of the pituitary gland regressing within the cavity after an injury, surgery, or radiation therapy. Individuals with secondary ESS due to destruction of the pituitary gland have symptoms that reflect the loss of pituitary functions, such as the ceasing of menstrual periods, infertility, fatigue, and intolerance to stress and infection. # Pathophysiology - The pathogenesis of is characterized by , , and . - The gene/Mutation in has been associated with the development of , involving the pathway. - On gross pathology, , , and are characteristic findings of . - On microscopic histopathological analysis, , , and are characteristic findings of . In children, ESS may be associated with early onset of puberty, growth hormone deficiency, pituitary tumors, or pituitary gland dysfunction. MRI scans are useful in evaluating ESS and differentiating it from other disorders that produce an enlarged sella. # Clinical Features # Differentiating from other Diseases - must be differentiated from other diseases that cause , , and , such as: - Autoimmune factors - Cavernous sinus thrombosis - Communicating hydrocephalus - Congenital absence of the diaphragma sellae - Diabetes Mellitus - Familial - Head trauma - Increased intracranial pressure - Radiation therapy complication - Meningitis - Pituitary adenoma - Primary in middle-aged obese women - Rupture of intrasellar or parasellar cyst - Sheehan's Syndrome - Surgery - Vascular diseases # Differentiating Empty sella syndrome from other diseases: Empty sella syndrome needs to be differentiated from other diseases causing hypopituitarism. # Epidemiology and Demographics - The prevalence of is approximately per 100,000 individuals worldwide. - In , the incidence of was estimated to be cases per 100,000 individuals in . ## Age - Patients of all age groups may develop . - is more commonly observed among patients aged years old. - is more commonly observed among . ## Gender - affects men and women equally. - are more commonly affected with than . - The to ratio is approximately to 1. ## Race - There is no racial predilection for . - usually affects individuals of the race. - individuals are less likely to develop . # Risk Factors - Common risk factors in the development of are , , , and . # Natural History, Complications and Prognosis - The majority of patients with remain asymptomatic for . - Early clinical features include , , and . - If left untreated, of patients with may progress to develop , , and . - Common complications of include , , and . - Prognosis is generally , and the of patients with is approximately . # Diagnosis Patient #1: MR images demonstrate an expanded and empty sella ## Diagnostic Criteria - The diagnosis of is made when at least of the following diagnostic criteria are met: ## Symptoms - is usually asymptomatic. - Symptoms of may include the following: ## Physical Examination - Patients with usually appear . - Physical examination may be remarkable for: ## Laboratory Findings - There are no specific laboratory findings associated with . - A is diagnostic of . - An concentration of is diagnostic of . - Other laboratory findings consistent with the diagnosis of include , , and . ## Imaging Findings - There are no findings associated with . - is the imaging modality of choice for . - On , is characterized by , , and . - may demonstrate , , and . ## Other Diagnostic Studies - may also be diagnosed using . - Findings on include , , and . # Treatment ## Medical Therapy - There is no treatment for ; the mainstay of therapy is supportive care. - The mainstay of therapy for is and . - acts by . - Response to can be monitored with every . ## Surgery - Surgery is the mainstay of therapy for . - in conjunction with is the most common approach to the treatment of . - can only be performed for patients with . ## Prevention - There are no primary preventive measures available for . - Effective measures for the primary prevention of include , , and . - Once diagnosed and successfully treated, patients with are followed-up every . Follow-up testing includes , , and .

Crowdiagnosis checklist # Crowdiagnosis checklist The following is a checklist to help you improve the quality of the causes page that you are editing. The aim of having a checklist is to ensure consistency among all pages. ## General Items - Confirm that every page starts with __NOTOC__ - Confirm that there is no separate line for Associate Editor in Chief. - Confirm that multiple editor’s title should be separated by a semicolon. - Make sure to remove the following statements when you finish adding content to the page: Please help WikiDoc by adding content here. It's easy! Click here to learn about editing. Please help WikiDoc by adding more content here. It's easy! Click here to learn about editing. - Please help WikiDoc by adding content here. It's easy! Click here to learn about editing. - Please help WikiDoc by adding more content here. It's easy! Click here to learn about editing. - Confirm that every chapter has three headings: ==Overview== ==Causes== ==References== - Confirm that the headings are capitalized correctly. - Make sure that no reference is put next to the headings. ### Overview - Confirm that the overview statement is in a text format and does not contain bullet points. - Confirm that periods, commas and spaces are appropriately placed. - Confirm that no text is bolded or italicized randomly in between the text. - Make sure to check for spellings and grammatical errors thoroughly.Confirm that there are no floating periods and comas. - Confirm that periods and comas are present before the start of references instead at the end to avoid floating periods and comas. - Confirm that all the internal links work and there are no black links in between texts. - Confirm that no links are created to same page. - Make sure to create maximum internal links and for complete words, e.g, Ventricular tachycardia – ] ] – not recommended Ventricular tachycardia- ] – recommended - Ventricular tachycardia – ] ] – not recommended - Ventricular tachycardia- ] – recommended ### Causes - Confirm the presence of the following subcategories in the following order: Life Threatening Causes Common Causes Causes by Organ System Causes in Alphabetical Order - Life Threatening Causes - Common Causes - Causes by Organ System - Causes in Alphabetical Order - Make sure to capitalize the first letter of every word of the subcategories. - Make sure to have subcategories under “===”. - Make sure that no references are put next to the subcategory heading. - Make sure that each cause is a true cause of the symptom and double check in case of doubt. - Confirm that all the causes are linked and appropriate references are cited. - In case the cause does not link to a page on wikidoc but might fall under another page create an internal link as follows: ] infection- not recommended ]- recommended - ] infection- not recommended - ]- recommended - Confirm that all the internal links work and there are no black links in between texts. - Make sure to create maximum internal links and for complete words, e.g, Ventricular tachycardia – ] ] – not recommended Ventricular tachycardia- ] – recommended - Ventricular tachycardia – ] ] – not recommended - Ventricular tachycardia- ] – recommended - Under the subheading "Life Threatening Causes": Confirm the presence of the following definition underneath the subheading of every life threatening causes section: Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. Make sure that the causes do not include chronic conditions. Make sure that the causes are listed in alphabetical order. If the page's disease is itself life-threatening, do not add causes in the life-threatening causes section. Instead, confirm the presence of the following sentence under the subheading:Disease name is a life-threatening condition and must be treated as such irrespective of the causes. Life-threatening conditions may result in death or permanent disability within 24 hours if left untreated. - Confirm the presence of the following definition underneath the subheading of every life threatening causes section: Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. - Make sure that the causes do not include chronic conditions. - Make sure that the causes are listed in alphabetical order. - If the page's disease is itself life-threatening, do not add causes in the life-threatening causes section. Instead, confirm the presence of the following sentence under the subheading:Disease name is a life-threatening condition and must be treated as such irrespective of the causes. Life-threatening conditions may result in death or permanent disability within 24 hours if left untreated. - Under the subheading “Common Causes” make sure that the causes are listed in alphabetical order. - Under the subheading “Causes by Organ system”: Confirm the presence of the differential diagnosis table. Make sure that the causes listed in each row are separated by a coma followed by a space. Make sure that the causes are listed in alphabetical order. Make sure that only the first letter of the first word listed in each row is capitalized, the other causes should not be capitalized unless they refer to a proper noun, e.g “Hodgkin lymphoma” and not “hodgkin lymphoma”. Make sure that each cause fits in the appropriate organ system. - Confirm the presence of the differential diagnosis table. - Make sure that the causes listed in each row are separated by a coma followed by a space. - Make sure that the causes are listed in alphabetical order. - Make sure that only the first letter of the first word listed in each row is capitalized, the other causes should not be capitalized unless they refer to a proper noun, e.g “Hodgkin lymphoma” and not “hodgkin lymphoma”. - Make sure that each cause fits in the appropriate organ system. - Under the subheading “Causes in Alphabetical order”, make sure the list of causes is arranged in multiple columns.

Glycocalyx Glycocalyx is a general term referring to extracellular polymeric material produced by some bacteria, epithelia and other cells. The slime on the outside of a fish is considered a glycocalyx. The term was initially applied to the polysaccharide matrix excreted by epithelial cells forming a coating on the surface of epithelial tissue. # Definition A glycocalyx, otherwise known as the "sweet husk of the cell", is a network of polysaccharides that project from cellular surfaces, e.g. those of bacteria. It serves to protect the bacterium or allows the bacterium to attach itself to inert surfaces (like teeth or rocks), eukaryotes (e.g. streptococcus pneumoniae attaches itself to lung cells), or other bacteria (their glycocalyxes can fuse to envelop the colony). Its presence on inert materials (such as metal hardware implanted for fracture fixation or total joint replacement) make it difficult to eradicate deep infections as the bacteria will 'cling' on to the material via the glycocalyx. It is therefore often necessary to completely remove the hardware device in order to fully eradicate a wound infection. The glycocalyx can be found just outside the cell wall of a bacterium. A distinct, gelatinous glycocalyx is called a capsule, while an irregular, diffuse layer is called a slime layer. Glycocalyx can help protect bacteria from phagocytes. It also helps in the formation of biofilms such as a coating on inert surfaces such as teeth or rocks. The glycocalyx is also the name given to a specific structure of a mature platelet. The glycocalyx is unique among the cellular components of the blood. It is similar to the bacterial glycocalyx above in that it is made up of glycoproteins and allows the platelet to adhere to surfaces such as collagen of damaged vessels. The glycocalyx appears as a fluffy coat to the outer membrane of platelets and contains many of the receptor proteins that allow cell adhesion. Glycocalyx also appears on the cells lining blood vessels (endothelial cells). Among its established roles are reducing friction to the flow of blood and serving as a barrier for loss of fluid through the vessel wall. In times of inflammation, the endothelial cell glycocalyx is sheared off, to permit attachment of leukocytes and movement of water from microvessels. The glycocalyx is chemically unique in everyone but identical twins, and acts like an identification tag that enables the body to distinguish its own healthy cells from transplanted tissues, invading organisms and diseased cells. Human blood types and transfusion compatibility are determined by glycoproteins. A glycocalyx can also be found on the apical portion of microvilli within the digestive tract, especially within the small intestine. It consists of glycoproteins that project from the apical plasma membrane of epithelial absorptive cells. It provides additional surface for adsorption and includes enzymes secreted by the absorptive cells that are essential for the final steps of digestion of proteins and sugars. # Functions - Protection: Cushions the plasma membrane and protects it from physical and chemical injury - Immunity to infection: Enables the immune system to recognize and selectively attack foreign organisms - Defense against cancer: Changes in the glycocalyx of cancerous cells enable the immune system to recognize and destroy them - Transplant compatibility: Forms the basis for compatibility of blood transfusions, tissue grafts, and organ transplants - Cell adhesion: Binds cells together so that tissues do not fall apart - Fertilization: Enables sperm to recognize and bind to eggs - Embryonic development: Guides embryonic cells to their destinations in the body

Metoprolol succinate (tablet) # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Metoprolol succinate (tablet) is a beta-adrenergic blocker that is FDA approved for the treatment of hypertension, angina pectoris, heart failure. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bradyarrhythmia, heart failure, hypotension, diarrhea, nausea, dizziness, fatigue, headache, depression, dyspnea, wheezing. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The initial dosage is 25 to 100 mg daily in a single dose. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. - Dosages above 400 mg per day have not been studied. - Dosing Information - Individualize the dosage of metoprolol succinate. The usual initial dosage is 100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. - Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually over a period of 1 - 2 weeks - Dosing information - Dosage must be individualized and closely monitored during up-titration. Prior to initiation of metoprolol succinate, stabilize the dose of other heart failure drug therapy. - The recommended starting dose of metoprolol succinate is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of metoprolol succinate. - Initial difficulty with titration should not preclude later attempts to introduce metoprolol succinate. If patients experience symptomatic bradycardia, reduce the dose of metoprolol succinate. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of metoprolol succinate or temporarily discontinuing it. - The dose of metoprolol succinate should not be increased until symptoms of worsening heart failure have been stabilized. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: AHA/ACC - Dosing Information/Recommendation - 25 to 50 mg orally every 6 hours for 48 hours 15 minutes after the last IV dose (5 mg over 1 to 2 minutes, increase 5mg every 5 minutes to a total of 15 mg. - The maintenance dose: Up to a total of 100 mg twice daily. ### Non–Guideline-Supported Use - Dosing Information - Administer to a maximum of 200 mg/day prior to cardioversion. - Atrial tachycardia - 25 to 50 mg. - Supraventricular Arrhythmias - 50 to 200 mg daily. - Dosing Information - 100 mg daily. - Dosing information - 100 mg daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - A pediatric clinical hypertension study in patients 6 to 16 years of age did not meet its primary endpoint (dose response for reduction in SBP); however some other endpoints demonstrated effectiveness. - If selected for treatment, the recommended starting dose of metoprolol succinate is 1 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Dosage should be adjusted according to blood pressure response. - Doses above 2 mg/kg (or in excess of 200 mg) once daily have not been studied in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Metoprolol succinate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Metoprolol succinate in pediatric patients. # Contraindications Metoprolol succinate is contraindicated in severe bradycardia, second degree heart block and third degree heart block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product. # Warnings Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered metoprolol succinate, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 - 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate metoprolol succinate, and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing metoprolol succinate in patients treated only for hypertension. Worsening cardiac failure may occur during up-titration of metoprolol succinate. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of metoprolol succinate. It may be necessary to lower the dose of metoprolol succinate or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of metoprolol succinate. PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however, metoprolol succinate may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute, use the lowest possible dose of metoprolol succinate. Bronchodilators, including beta2-agonists, should be readily available or administered concomitantly. If metoprolol succinate is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle. Avoid initiation of a high-dose regimen of extended-release metoprolol in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death. Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. Consider initiating metoprolol succinate therapy at doses lower than those recommended for a given indication; gradually increase dosage to optimize therapy, while monitoring closely for adverse events. Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm. While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction. Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are described elsewhere in labeling: - Worsening angina or myocardial infarction. - Worsening heart failure. - Worsening AV block. ### Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Hypertension and Angina: Most adverse reactions have been mild and transient. The most common (>2%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash. Heart Failure In the MERIT-HF study comparing metoprolol succinate in daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of metoprolol succinate patients discontinued for adverse reactions vs. 12.2% of placebo patients. The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of ≥ 1% in the metoprolol succinate group and greater than placebo by more than 0.5%, regardless of the assessment of causality. In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta–blocker therapy, metoprolol succinate 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. metoprolol succinate use was associated with a higher incidence of bradycardia (6.6% vs. 2.4%; HR, 2.74; 95% CI 2.19, 3.43), hypotension (15% vs. 9.7%; HR 1.55; 95% CI 1.37, 1.74), stroke (1.0% vs. 0.5%; HR 2.17; 95% CI 1.26, 3.74) and death (3.1% vs. 2.3%; HR 1.33; 95% CI 1.03, 1.74) compared to placebo. Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of metoprolol succinate or immediate-release metoprolol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain and hypotension. - Respiratory: Wheezing (bronchospasm), dyspnea. - Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia. - Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting. - Hypersensitive Reactions: Pruritus. - Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, taste disturbance. - In addition, there are adverse reactions not listed above that have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol succinate. - Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics. - Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. - Hypersensitive Reactions: Laryngospasm, respiratory distress. # Drug Interactions Catecholamine depleting drugs (eg, reserpine, monoamine oxidase inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with metoprolol succinate plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or orthostatic hypotension. Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg and immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. resulted in two- to five-fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol. Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia. If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metoprolol succinate (tablet) in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Metoprolol succinate (tablet) during labor and delivery. ### Nursing Mothers - Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Consider possible infant exposure when metorpolol succinate is administered to a nursing woman. ### Pediatric Use - One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo or to one of three dose levels of metorpolol succinate (0.2, 1.0 or 2.0 mg/kg once daily) and followed for 4 weeks. The study did not meet its primary endpoint (dose response for reduction in SBP). Some pre-specified secondary endpoints demonstrated effectiveness including: - Dose-response for reduction in DBP, - 1 mg/kg vs. placebo for change in SBP, and - 2 mg/kg vs. placebo for change in SBP and DBP. - The mean placebo corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to 5 mmHg. Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater reductions were seen in some individuals. - No clinically relevant differences in the adverse event profile were observed for pediatric patients aged 6 to 16 years as compared with adult patients. - Safety and effectiveness of metorpolol succinate have not been established in patients < 6 years of age. ### Geriatic Use - Clinical studies of metorpolol succinate in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients. - Of the 1,990 patients with heart failure randomized to metorpolol succinate in the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older. There were no notable differences in efficacy or the rate of adverse reactions between older and younger patients. - In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Metoprolol succinate (tablet) with respect to specific gender populations. ### Race There is no FDA guidance on the use of Metoprolol succinate (tablet) with respect to specific racial populations. ### Renal Impairment The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. No reduction in dosage is needed in patients with chronic renal failure. ### Hepatic Impairment No studies have been performed with metorpolol succinate in patients with hepatic impairment. Because metorpolol succinate is metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower than those recommended for a given indication; and increase doses gradually in patients with impaired hepatic function. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Metoprolol succinate (tablet) in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Metoprolol succinate (tablet) in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - Dosage must be individualized and closely monitored during up-titration - When discontinuing chronically administered metoprolol succinate, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 - 2 weeks and monitor the patient. - Closely monitor for adverse events while increasing the dosage to optimize therapy. # IV Compatibility There is limited information regarding the compatibility of Metoprolol succinate (tablet) and IV administrations. # Overdosage Overdosage of metoprolol succinate may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting. - Consider treating the patient with intensive care. Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Seek consultation with a regional poison control center and a medical toxicologist as needed. - Beta-blocker overdose may result in significant resistance to resuscitation with adrenergic agents, including beta-agonists. - On the basis of the pharmacologic actions of metoprolol, employ the following measures: - There is very limited experience with the use of hemodialysis to remove metoprolol, however metoprolol is not highly protein bound. - Bradycardia: Evaluate the need for atropine, adrenergic-stimulating drugs or pacemaker to treat bradycardia and conduction disorders. - Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such as dopamine or norepinephrine. - Heart failure and shock: May be treated when appropriate with suitable volume expansion, injection of glucagon (if necessary, followed by an intravenous infusion of glucagon), intravenous administration of adrenergic drugs such as dobutamine, with Alpha1 agonist drugs added in presence of vasodilation. - Bronchospasm: Can usually be reversed by bronchodilators. # Pharmacology ## Mechanism of Action The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity. The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated. ## Structure Metoprolol succinate, is a beta1-selective (cardioselective) adrenoceptor blocking agent, for oral administration, available as extended-release tablets. metoprolol succinate has been formulated to provide a controlled and predictable release of metoprolol for once-daily administration. The tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. The tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of metoprolol tartrate, USP, respectively. Its chemical name is (±)1- (isopropylamino)-3--2-propanol succinate (2:1) (salt). Its structural formula is: Metoprolol succinate is a white crystalline powder with a molecular weight of 652.8. It is freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethyl-acetate, acetone, diethylether and heptane. Inactive ingredients: silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, paraffin. ## Pharmacodynamics Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia. Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction. The relative beta1-selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta1-receptor blocking doses. The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Using an Emax model, the maximum effect is a 30% reduction in exercise heart rate, which is attributed to beta1-blockade. Beta1-blocking effects in the range of 30-80% of the maximal effect (approximately 8-23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30-540 nmol/L. The relative beta1-selectivity of metoprolol diminishes and blockade of beta2-adrenoceptors increases at plasma concentration above 300 nmol/L. Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension, and heart failure there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients. In other studies, treatment with metoprolol succinate produced an improvement in left ventricular ejection fraction. Metoprolol succinate was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes after 6 months of treatment. ## Pharmacokinetics In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S- enantiomers, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity. Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in metoprolol succinate dosage is usually needed in patients with chronic renal failure. Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by a number of drugs. Poor metabolizers and extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity. In comparison to conventional metoprolol, the plasma metoprolol levels following administration of metoprolol succinate are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation. The peak plasma levels following once-daily administration of metoprolol succinate average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of conventional metoprolol, administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of metoprolol succinate, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of conventional metoprolol. Nevertheless, over the 24-hour dosing interval, β1-blockade is comparable and dose-related. The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following metoprolol succinate administration. The pharmacokinetic profile of metoprolol succinate was studied in 120 pediatric hypertensive patients (6-17 years of age) receiving doses ranging from 12.5 to 200 mg once daily. The pharmacokinetics of metoprolol were similar to those described previously in adults. Age, gender, race, and ideal body weight had no significant effects on metoprolol pharmacokinetics. Metoprolol apparent oral clearance (CL/F) increased linearly with body weight. Metoprolol pharmacokinetics have not been investigated in patients < 6 years of age. ## Nonclinical Toxicology Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor. All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonell/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (a Salmonella/mammalian-microsome mutagenicity test) were negative. No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60- kg patient. # Clinical Studies In five controlled studies in normal healthy subjects, the same daily doses of metoprolol succinate and immediate-release metoprolol were compared in terms of the extent and duration of beta1- blockade produced. Both formulations were given in a dose range equivalent to 100-400 mg of immediate-release metoprolol per day. In these studies, metoprolol succinate was administered once a day and immediate-release metoprolol was administered once to four times a day. A sixth controlled study compared the beta1-blocking effects of a 50 mg daily dose of the two formulations. In each study, beta1-blockade was expressed as the percent change from baseline in exercise heart rate following standardized submaximal exercise tolerance tests at steady state. Metoprolol succinate administered once a day, and immediate-release metoprolol administered once to four times a day, provided comparable total beta1-blockade over 24 hours (area under the beta1-blockade versus time curve) in the dose range 100-400 mg. At a dosage of 50 mg once daily, metoprolol succinate produced significantly higher total beta1-blockade over 24 hours than immediate-release metoprolol. For metoprolol succinate, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta1-blockade increased with increasing doses from 50 to 300 mg daily. The effects at peak/trough (ie, at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20% reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg metoprolol succinate once a day, respectively. In contrast to metoprolol succinate, immediate-release metoprolol given at a dose of 50-100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with metoprolol succinate over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen was required for immediate-release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta1-blocking effects of 50 mg immediate-release metoprolol administered t.i.d., 100 mg and 200 mg metoprolol succinate once daily. A 50 mg dose of immediate-release metoprolol t.i.d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of metoprolol succinate. A 200 mg dose of metoprolol succinate produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate-release metoprolol. In a double-blind study, 1092 patients with mild-to-moderate hypertension were randomized to once daily metoprolol succinate (25, 100, or 400 mg), felodipine extended-release tablets, the combination, or placebo. After 9 weeks, metoprolol succinate alone decreased sitting blood pressure by 6-8/4-7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of metoprolol succinate with felodipine extended-release tablets has greater effects on blood pressure. In controlled clinical studies, an immediate-release dosage form of metoprolol was an effective antihypertensive agent when used alone or as concomitant therapy with thiazide diuretics at dosages of 100-450 mg daily. Metoprolol succinate, in dosages of 100 to 400 mg once daily, produces similar β1-blockade as conventional metoprolol tablets administered two to four times daily. In addition, metoprolol succinate administered at a dose of 50 mg once daily lowered blood pressure 24-hours post-dosing in placebo-controlled studies. In controlled, comparative, clinical studies, immediate-release metoprolol appeared comparable as an antihypertensive agent to propranolol, methyldopa, and thiazide diuretics, and affected both supine and standing blood pressure. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration. By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris. In controlled clinical trials, an immediate-release formulation of metoprolol has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. Metoprolol succinate, in dosages of 100 to 400 mg once daily, has been shown to possess beta-blockade similar to conventional metoprolol tablets administered two to four times daily. MERIT-HF was a double-blind, placebo-controlled study of metoprolol succinate conducted in 14 countries including the US. It randomized 3991 patients (1990 to metoprolol succinate) with ejection fraction ≤0.40 and NYHA Class II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to beta-blocker use, those expected to undergo heart surgery, and those within 28 days of myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics, ACE inhibitors, digital glycosides, and nitrates. At randomization, 41% of patients were NYHA Class II; 55% NYHA Class III; 65% of patients had heart failure attributed to ischemic heart disease; 44% had a history of hypertension; 25% had diabetes mellitus; 48% had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics, 89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent, 37% were on an oral anticoagulant, and the mean ejection fraction was 0.28. The mean duration of follow-up was one year. At the end of the study, the mean daily dose of metoprolol succinate was 159 mg. The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p= 0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p= 0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class. The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup (n=1071) and women (n=898), overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects. # How Supplied Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol tartrate, USP, are white, biconvex, film-coated, and scored. ## Storage Store at 25°C (77°F). Excursions permitted to 15-30°C (59- 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise patients to take metoprolol succinate regularly and continuously, as directed, preferably with or immediately following meals. If a dose is missed, the patient should take only the next scheduled dose (without doubling it). Patients should not interrupt or discontinue metoprolol succinate without consulting the physician. Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with metoprolol succinate has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking metoprolol succinate. Heart failure patients should be advised to consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath. # Precautions with Alcohol Alcohol-Metoprolol succinate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Toprol XL # Look-Alike Drug Names - Metoprolol succinate - Metoprolol tartrate - Toprol XL - Topamax # Drug Shortage Status Drug Shortage # Price

User:Navneet # Navneet Kaur, M.B.,B.S. Contact: Email: mann.navneet94@gmail.com # Medical Education August 2012 – Jan 2020 - Bachelor of Medicine and Bachelor of Surgery (M.B.B.S.) from Sri Guru Ram Das Institute of Medical Sciences and Research (SGRDIMSR), Baba Farid University of Health Sciences (BFUHS), Amritsar, Punjab, India. # Professional Affiliations - ECFMG Certified – March 2020. - Registered General practitioner, India. - Member of Medical Student Association of India. # US Clinical Experience June 2021- present - RESEARCH SCHOLAR, at WikiDoc Scholar Program, under Dr. Michael Gibson, Professor of Medicine at Harvard Medical School and Researcher at Baim Institute for Clinical Research June 2021- July 2021 - CLINICAL TELE-ROTATION, with Dr. Charles L. Lawler, MD, Board Certified Internist, Former Program Director, Associate Professor University of Illinois, Elmhurst Health Care, Elmhurst, IL July 2020 -August 2020 - EXTERNSHIP, at SUNY Downstate under Dr. Rattanjit Kohli, MD (Internal Medicine) Brooklyn, New York. April 2019 - OBSERVERSHIP, under Dr. Gurkaramjit S Khaira, MD, Hospitalist (Clinical Medicine) at Geisinger Health System, GCMC hospital, Scranton, PA # Publications ## Peer Reviewed Journal Articles/Abstract - BITEMPORAL HEMIANOPIA- AN INDICATION OF ETHAMBUTOL TOXICITY. Dinesh Kumar, Navneet Kaur, Snimer Kaur Sidhu, Zoya Gurpreet Paul, Rahul VC Tiwari. JCR. 2020; 7(11): 2730-2732. doi:10.31838/jcr.07.19.398 - Case report on Morvan syndrome. Arveen Kaur, Navneet Kaur. Published in International Journal of Basic and Applied Medical Sciences, CIBTech - Syndrome.pdf ## Oral presentation - Anti microbial Resistance and COVID-19, an awareness campaign, Navneet Kaur, Ravneet Kaur, Yashjot Kaur. Presented at: MSAI with support from WORLD HEALTH ORGANISATION (WHO-INDIA Office); - HerChoice- Pro women, Pro Choice, an awareness session followed by group discussion about Safe Abortion, abortion care , abortion as a human right, and the stigma attached.Navneet Kaur, Yashjot Kaur, Ravneet Kaur, Jasleen Kaur. Oral Presentation presented at: Medical Student Association of India; Amritsar, IND; - Case presentation of Morvan syndrome, a rare neurological disorder, from North India, in a young male. Navneet Kaur Oral Presentation presented at: MSAI Online MedFest 2020; IND # Communication Languages - English - Hindi - Punjabi - Urdu

Organ-limited amyloidosis Organ-limited amyloidosis is a category of amyloidosis where the distribution can be associated primarily with a single organ. It is contrasted to systemic amyloidosis, and it can be caused by several different types of amyloid. In almost all of the organ-specific pathologies, there is significant debate as to whether the amyloid plaques are the causal agent of the disease or instead a downstream consequence of a common idiopathic agent. The associated proteins are indicated in parentheses. # Neurological amyloid - Alzheimer's disease (Aβ 39-43) - Parkinson's disease (alpha-synuclein) - Huntington's disease (huntingtin protein) - Transmissible spongiform encephalopathies caused by prion protein (PrP) were sometimes classed as amyloidoses, as one of the four pathological features in diseased tissue is the presence of amyloid plaques. These diseases include; Creutzfeldt-Jakob disease (PrP in cerebrum) Kuru (diffuse PrP deposits in brain) Fatal Familial Insomnia (PrP in thalamus) Bovine spongiform encephalopathy (PrP in cerebrum of cows) - Creutzfeldt-Jakob disease (PrP in cerebrum) - Kuru (diffuse PrP deposits in brain) - Fatal Familial Insomnia (PrP in thalamus) - Bovine spongiform encephalopathy (PrP in cerebrum of cows) # Cardiovascular amyloid - Cardiac amyloidosis Senile cardiac amyloidosis-may cause heart failure - Senile cardiac amyloidosis-may cause heart failure - Congophilic angiopathy # Other - Amylin deposition can occur in the pancreas in some cases of type 2 diabetes mellitus

Positive behavior support Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview Positive behavior support strives to use a system to understand what maintains an individual’s challenging behavior. Students’ inappropriate behaviors are difficult to change because they are functional; they serve a purpose for the child. These behaviors are supported by reinforcement in the environment. Functional assessment clearly describes a behavior; identifies the contexts (events, times, and situation) that predict when behavior will and will not occur, and identifies consequences that maintain the behavior. It also summarizes and creates a hypothesis about the behavior, and directly observes the behavior and takes data to get a baseline. The positive behavior support process involves goal identification, information gathering, hypothesis development, support plan design, implementation and monitoring. The criteria for treatment methods that work include: feasibility, desirability, and effectiveness. Treatment strategies are needed that teachers and parents are able and willing to use and that make an impact on the child’s ability to participate in community and school activities. Positive behavior support has increasingly been recognized as a strategy that meets these criteria. By changing stimulus and reinforcement in the environment and teaching the child in their deficit skill set areas the student's behavior changes in ways that allow him/her to be included in the general education setting. The three areas of deficit skills identified in the article were communication skills, social skills, and self management skills. Re-directive therapy as positive behavior support is especially effective in the parent child relationship. Where other treatment plans have failed re-directive therapy allows for a positive interaction between parents and children. Positive behavior support is successful in the school setting because it is primarily a teaching method (Swartz ,1999). # PBS in Schools Schools are required to conduct FBA and use positive behavior support with students who are identified as disabled and are at risk for expulsion, alternative school placement, or more than 10 days of suspension. Even though FBA is required under limited circumstances it is good professional practice to use a problem solving approach to managing problem behaviors in the school setting (Crone & Horner 2003). The use of Positive Behavior Intervention Supports (PBIS) in schools is widespread (Sugai & Horner, 2002). A basic tenet of the PBIS approach includes identifying students in one of three categories based on risk for behavior problems. Once identified, students receive services in one of three categories: primary, secondary, or tertiary. To help practitioners with differences in interventions used at each of the levels the professional literature refers to a three-tiered (levels) model (Stewart, Martella, Marchand-Martella, & Benner, 2005; Sugai, Sprague, Horner & Walker, 2000; Tobin & Sugai, 2005; Walker et al., 1996). Interventions are specifically developed for each of these levels with the goal of reducing the risk for academic or social failure. The interventions become more focused and complex as one examines the strategies used at each level. Primary prevention strategies focus on interventions used on a school-wide basis for all students (Sugai & Horner, 2002). This level of prevention is considered “primary” because all students are exposed in the same way, and at the same level, to the intervention. The primary prevention level is the largest by number. Approximately 80% to 85% of students who are not at risk for behavior problems respond in a positive manner to this prevention level (Sugai et al, 2000). Primary prevention strategies include, but are not in limited to, using effective teaching practices and curricula, explicitly teaching behavior that is acceptable within the school environment, focusing on ecological arrangement and systems within the school, consistent use of precorrection procedures, using active supervision of common areas, and creating reinforcement systems that are used on a school-wide basis (Lewis, Sugai, & Colvin,1998; Martella & Nelson, 2003; Nelson, Crabtree, Marchand-Martella, & Martella,1998; Nelson, Martella, & Marchand-Martella, 2002). Secondary prevention strategies involve students (i.e., 10% to 15% of the school population) who do not respond to the primary prevention strategies and are at risk for academic failure or behavior problems but are not in need of individual supports (Nelson, et al., 2002). Interventions at the secondary level often are delivered in small groups to maximize time and effort and should be developed with the unique needs of the students within the group. Examples of these interventions include social support such as social skills training (e.g., explicit instruction in skill deficit areas, friendship clubs, check in/ check out, role playing) or academic support (i.e., use of scientifically-validated intervention programs and tutoring). Additionally, secondary programs could include behavioral support approaches (e.g., simple Functional Behavioral Assessments , precorrection, self-management training). Even with the heightened support within secondary level interventions, some students (1% to 7%) will need the additional assistance at the tertiary level (Walker et al., 1996). Tertiary prevention programs focus on students who display persistent patterns of disciplinary problems (Nelson, Benner, Reid, Epstein, & Currin, 2002). Tertiary-level programs are also called intensive or individualized interventions and are the most comprehensive and complex. The interventions within this level are strength based in that the complexity and intensity of the intervention plans directly reflect the complexity and intensity of the behaviors. Students within the tertiary level continue involvement in primary and secondary intervention programs and receive additional supports as well. These supports could include use of full FBA, de-escalation training for the student, heightened use of natural supports (e.g., family member, friends of the student), and development of a Behavior Intervention Plan (BIP). Although comprehensive services are important for all students, a critical aspect of the three-tiered model is the identification of students at one of the three levels. One method of identifying students in need of interventions is to analyze office disciplinary referrals (ODR) taken at the school (Irvin et al., 2006). ODRs may be a means of both identifying students risk level for antisocial behavior and school failure (Walker et al., 1996). Researchers have advocated analyzing this naturally occurring data source as a relatively cheap, effective, and ongoing measurement device for PBS programs (Irvin et al., 2006; Putnam, Luiselli, Handler, & Jefferson, 2003; Sprague et al., 2001; Sugai et al., 2000; Tidwell, Flannery, & Lewis-Palmer, 2003; Walker, Cheney, Stage, & Blum, 2005). ODRs have also been shown to be effective in determining where students fall within a three-leveled model (Sugai et al., 2000), developing professional development as well as help coordinating school efforts with other community agencies (Tobin & Sugai, 1997; Tobin, Sugai, & Colvin, 2000), predicting school failure in older grades as well as delinquency (Sprague et al., 2001), indicating types of behavior resulting in referrals (Putnam et al., 2003), and determination of the effectiveness of precorrection techniques (Oswald, Safran, & Johanson, 2005). Analyzing discipline referral data can also help school personnel identify where to improve ecological arrangements within a school and to recognize how to increase active supervision in common areas (Nelson, Martella, & Galand, 1998; Nelson et al., 2002) # Functional Behavioral Assessment Functional behavior assessment (FBA) emerged from applied behavior analysis. It is the first step in individual and cornerstone of a Positive Behavior Support plan (see ). The assessment seeks to describe the behavior and environmental factors and setting events that predict the behavior in order to guide the development of effective support plans. Assessment lays the foundation of PBS. The assessment includes: - a description of the problem behavior and its general setting of occurrence - identification of events, times and situations that predict problem behavior - identification of consequences that maintain behavior - identification of the motivating function of behavior - collection of direct observational data. Identification of alternative behavior that could replace the child's problem behavior (i.e., what the normal child does). Often this is measured through direct observation or standardized behavioral assessment instruments. In some cases, the problem behavior identified in the functional behavior assessment is further analyzed by conducting a behavior chain analysis- in which the sequences of behavior that build up to the problem behavior become the focus. The results of the assessment help in developing the individualized behavior support plan. This outlines procedures for teaching alternatives to the behavior problems, and redesign of the environment to make the problem behavior irrelevant, inefficient, and ineffective. Another avenue of functional behavior assessment is growing in popularity- it is called Behavior Chain Analysis. In behavior chain analysis, one looks at the progessive changes of behavior as they lead to problem behavior and then attempts to disrupt this sequence. Where as FBA is concerned mostly with Setting-Antecedent-Behavior-Consequence relations, the behavior chain analysis looks at the progression of behavior. Such as first the child may fidget, then he might begin to tease others, then he might start to throw things, and then finally hit another student. # Behavioral strategies available There are many different behavioral strategies that PBS can use to encourage individuals to change their behavior. The strong part of functional behavior assessement is that it allows interventions to directly address the function (purpose) of a problem behavior. For example, a child who acts out for attention could receive attention for alternative behavior (contingency management) or the teacher could make an effort to increase the amount of attention throughout the day (satiation). Changes in setting events or antecedents are often preferred by PBS because contingency management often takes more effort. Another tactic especially when dealing with disruptive behavior is to use information from a Behavior chain analysis to disrupts the behavioral problem early in the sequence to prevent disruption ]. Some of the most commonly used approaches are: - Modifying the environment, antecedents (such as curriculum) to behavior, or routine - Tactical ignoring of the behavior - Distracting the child - Positive reinforcement for an appropriate behavior - Changing expectations and demands placed upon the child - Teaching the child new skills and behaviors - Modification techniques such as desensitization and graded extinction - Changing how people around the child react - Time out (Child) - Medication. # Behavior management program The main keys to developing a behavior management program include: - Identifying the specific behaviors to address - Establishing the goal for change and the steps required to achieve it - Procedures for recognizing and monitoring changed behavior - Choosing the appropriate behavioral strategies that will be most effective. # Consequential management Consequential management is a positive response to challenging behavior. It serves to give the person informed choice and an opportunity to learn. Consequences must be clearly related to the challenging behavior For example, if a glass of water was thrown and the glass smashed, the consequence (restitution) would be for the person to clean up the mess and replace the glass. These sorts of consequences are consistent with normal social reinforcement contingencies. Providing choices is very important and staff can set limits by giving alternatives that are related to a behavior they are seeking. It is important that the alternative is stated in a positive way and that words are used which convey that the person has a choice. For example: Coercive approach “If you don't cut that out you'll have to leave the room.” Positive approach “You can watch TV quietly or leave the room.”

# TABLE OF CONTENTS Executive # Executive Summary The Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007 updates and expands the 1996 Guideline for Isolation Precautions in Hospitals. The following developments led to revision of the 1996 guideline: 1. The transition of healthcare delivery from primarily acute care hospitals to other healthcare settings (e.g., home care, ambulatory care, free-standing specialty care sites, long-term care) created a need for recommendations that can be applied in all healthcare settings using common principles of infection control practice, yet can be modified to reflect setting-specific needs. Accordingly, the revised guideline addresses the spectrum of healthcare delivery settings. Furthermore, the term "nosocomial infections" is replaced by "healthcare-associated infections" (HAIs) to reflect the changing patterns in healthcare delivery and difficulty in determining the geographic site of exposure to an infectious agent and/or acquisition of infection. 2. The emergence of new pathogens (e.g., SARS-CoV associated with the severe acute respiratory syndrome , Avian influenza in humans), renewed concern for evolving known pathogens (e.g., C. difficile, noroviruses, community-associated MRSA ), development of new therapies (e.g., gene therapy), and increasing concern for the threat of bioweapons attacks, established a need to address a broader scope of issues than in previous isolation guidelines. 3. The successful experience with Standard Precautions, first recommended in the 1996 guideline, has led to a reaffirmation of this approach as the foundation for preventing transmission of infectious agents in all healthcare settings. New additions to the recommendations for Standard Precautions are Respiratory Hygiene/Cough Etiquette and safe injection practices, including the use of a mask when performing certain high-risk, prolonged procedures involving spinal canal punctures (e.g., myelography, epidural anesthesia). The need for a recommendation for Respiratory Hygiene/Cough Etiquette grew out of observations during the SARS outbreaks where failure to implement simple source control measures with patients, visitors, and healthcare personnel with respiratory symptoms may have contributed to SARS coronavirus (SARS-CoV) transmission. The recommended practices have a strong evidence base. The continued occurrence of outbreaks of hepatitis B and hepatitis C viruses in ambulatory settings indicated a need to re-iterate safe injection practice recommendations as part of Standard Precautions. The addition of a mask for certain spinal injections grew from recent evidence of an associated risk for developing meningitis caused by respiratory flora. 4. The accumulated evidence that environmental controls decrease the risk of lifethreatening fungal infections in the most severely immunocompromised patients (allogeneic hematopoietic stem-cell transplant patients) led to the update on the components of the Protective Environment (PE). 5. Evidence that organizational characteristics (e.g., nurse staffing levels and composition, establishment of a safety culture) influence healthcare personnel adherence to recommended infection control practices, and therefore are important factors in preventing transmission of infectious agents, led to a new emphasis and recommendations for administrative involvement in the development and support of infection control programs. 6. Continued increase in the incidence of HAIs caused by multidrug-resistant organisms (MDROs) in all healthcare settings and the expanded body of knowledge concerning prevention of transmission of MDROs created a need for more specific recommendations for surveillance and control of these pathogens that would be practical and effective in various types of healthcare settings. This document is intended for use by infection control staff, healthcare epidemiologists, healthcare administrators, nurses, other healthcare providers, and persons responsible for developing, implementing, and evaluating infection control programs for healthcare settings across the continuum of care. The reader is referred to other guidelines and websites for more detailed information and for recommendations concerning specialized infection control problems. # Parts I -III: Review of the Scientific Data Regarding Transmission of Infectious Agents in Healthcare Settings Part I reviews the relevant scientific literature that supports the recommended prevention and control practices. As with the 1996 guideline, the modes and factors that influence transmission risks are described in detail. New to the section on transmission are discussions of bioaerosols and of how droplet and airborne transmission may contribute to infection transmission. This became a concern during the SARS outbreaks of 2003, when transmission associated with aerosol-generating procedures was observed. Also new is a definition of "epidemiologically important organisms" that was developed to assist in the identification of clusters of infections that require investigation (i.e. multidrug-resistant organisms, C. difficile). Several other pathogens that hold special infection control interest (i.e., norovirus, SARS, Category A bioterrorist agents, prions, monkeypox, and the hemorrhagic fever viruses) also are discussed to present new information and infection control lessons learned from experience with these agents. This section of the guideline also presents information on infection risks associated with specific healthcare settings and patient populations. Part II updates information on the basic principles of hand hygiene, barrier precautions, safe work practices and isolation practices that were included in previous guidelines. However, new to this guideline, is important information on healthcare system components that influence transmission risks, including those under the influence of healthcare administrators. An important administrative priority that is described is the need for appropriate infection control staffing to meet the ever-expanding role of infection control professionals in the modern, complex healthcare system. Evidence presented also demonstrates another administrative concern, the importance of nurse staffing levels, including numbers of appropriately trained nurses in ICUs for preventing HAIs. The role of the clinical microbiology laboratory in supporting infection control is described to emphasize the need for this service in healthcare facilites. Other factors that influence transmission risks are discussed i.e., healthcare worker adherence to recommended infection control practices, organizational safety culture or climate, education and training. Discussed for the first time in an isolation guideline is surveillance of healthcareassociated infections. The information presented will be useful to new infection control professionals as well as persons involved in designing or responding to state programs for public reporting of HAI rates. Part III describes each of the categories of precautions developed by the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Centers for Disease Control and Prevention (CDC) and provides guidance for their application in various healthcare settings. The categories of Transmission-Based Precautions are unchanged from those in the 1996 guideline: Contact, Droplet, and Airborne. One important change is the recommendation to don the indicated personal protective equipment (gowns, gloves, mask) upon entry into the patient's room for patients who are on Contact and/or Droplet Precautions since the nature of the interaction with the patient cannot be predicted with certainty and contaminated environmental surfaces are important sources for transmission of pathogens. In addition, the Protective Environment (PE) for allogeneic hematopoietic stem cell transplant patients, described in previous guidelines, has been updated. # Tables, Appendices, and Other Information There are several tables that summarize important information: 1. a summary of the evolution of this document; 2. guidance on using empiric isolation precautions according to a clinical syndrome; 3. a summary of infection control recommendations for category A agents of bioterrorism; 4. components of Standard Precautions and recommendations for their application; 5. components of the Protective Environment; and 6. a glossary of definitions used in this guideline. New in this guideline is a figure that shows a recommended sequence for donning and removing personal protective equipment used for isolation precautions to optimize safety and prevent self-contamination during removal. # Appendix A: Type and Duration of Precautions Recommended for Selected Infections and Conditions Appendix A consists of an updated alphabetical list of most infectious agents and clinical conditions for which isolation precautions are recommended. A preamble to the Appendix provides a rationale for recommending the use of one or more Transmission-Based Precautions, in addition to Standard Precautions, based on a review of the literature and evidence demonstrating a real or potential risk for person-to-person transmission in healthcare settings.The type and duration of recommended precautions are presented with additional comments concerning the use of adjunctive measures or other relevant considerations to prevent transmission of the specific agent. Relevant citations are included. # Pre-Publication of the Guideline on Preventing Transmission of MDROs New to this guideline is a comprehensive review and detailed recommendations for prevention of transmission of MDROs. This portion of the guideline was published electronically in October 2006 and updated in November, 2006 (Siegel JD, Rhinehart E, Jackson M, Chiarello L and HICPAC. Management of Multidrug-Resistant Organisms in Healthcare Settings (2006) (/ accessed May 2016)), and is considered a part of the Guideline for Isolation Precautions. This section provides a detailed review of the complex topic of MDRO control in healthcare settings and is intended to provide a context for evaluation of MDRO at individual healthcare settings. A rationale and institutional requirements for developing an effective MDRO control program are summarized. Although the focus of this guideline is on measures to prevent transmission of MDROs in healthcare settings, information concerning the judicious use of antimicrobial agents is presented since such practices are intricately related to the size of the reservoir of MDROs which in turn influences transmission (e.g., colonization pressure). There are two tables that summarize recommended prevention and control practices using the following seven categories of interventions to control MDROs: administrative measures, education of healthcare personnel, judicious antimicrobial use, surveillance, infection control precautions, environmental measures, and decolonization. Recommendations for each category apply to and are adapted for the various healthcare settings. With the increasing incidence and prevalence of MDROs, all healthcare facilities must prioritize effective control of MDRO transmission. Facilities should identify prevalent MDROs at the facility, implement control measures, assess the effectiveness of control programs, and demonstrate decreasing MDRO rates. A set of intensified MDRO prevention interventions is presented to be added 1. if the incidence of transmission of a target MDRO is NOT decreasing despite implementation of basic MDRO infection control measures, and 2. when the first case(s) of an epidemiologically important MDRO is identified within a healthcare facility. # Summary This updated guideline responds to changes in healthcare delivery and addresses new concerns about transmission of infectious agents to patients and healthcare workers in the United States and infection control. The primary objective of the guideline is to improve the safety of the nation's healthcare delivery system by reducing the rates of HAIs. Abbreviations Used in the Guideline # I.A. Evolution of the 2007 Document The Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007 builds upon a series of isolation and infection prevention documents promulgated since 1970. These previous documents are summarized and referenced in Table 1 and in Part I of the 1996 Guideline for Isolation Precautions in Hospitals 1 . # Objectives and methods The objectives of this guideline are to 1. provide infection control recommendations for all components of the healthcare delivery system, including hospitals, long-term care facilities, ambulatory care, home care and hospice; 2. reaffirm Standard Precautions as the foundation for preventing transmission during patient care in all healthcare settings; 3. reaffirm the importance of implementing Transmission-Based Precautions based on the clinical presentation or syndrome and likely pathogens until the infectious etiology has been determined (Table 2); and 4. provide epidemiologically sound and, whenever possible, evidence-based recommendations. This guideline is designed for use by individuals who are charged with administering infection control programs in hospitals and other healthcare settings. The information also will be useful for other healthcare personnel, healthcare administrators, and anyone needing information about infection control measures to prevent transmission of infectious agents. Commonly used abbreviations are provided on page 11 and terms used in the guideline are defined in the Glossary (page 126). Med-line and Pub Med were used to search for relevant studies published in English, focusing on those published since 1996. Much of the evidence cited for preventing transmission of infectious agents in healthcare settings is derived from studies that used "quasi-experimental designs", also referred to as nonrandomized, pre-post-intervention study designs 2 . Although these types of studies can provide valuable information regarding the effectiveness of various interventions, several factors decrease the certainty of attributing improved outcome to a specific intervention. These include: difficulties in controlling for important confounding variables; the use of multiple interventions during an outbreak; and results that are explained by the statistical principle of regression to the mean, (e.g., improvement over time without any intervention) 3 . Observational studies remain relevant and have been used to evaluate infection control interventions 4,5 . The quality of studies, consistency of results and correlation with results from randomized, controlled trials when available were considered during the literature review and assignment of evidence-based categories (See Part IV: Recommendations) to the recommendations in this guideline. Several authors have summarized properties to consider when evaluating studies for the purpose of determining if the results should change practice or in designing new studies 2,6,7 . Last update: September, 2018 Page 13 of 204 Changes or clarifications in terminology. This guideline contains four changes in terminology from the 1996 guideline: - The term nosocomial infection is retained to refer only to infections acquired in hospitals. The term healthcare-associated infection (HAI) is used to refer to infections associated with healthcare delivery in any setting (e.g., hospitals, longterm care facilities, ambulatory settings, home care). This term reflects the inability to determine with certainty where the pathogen is acquired since patients may be colonized with or exposed to potential pathogens outside of the healthcare setting, before receiving health care, or may develop infections caused by those pathogens when exposed to the conditions associated with delivery of healthcare. Additionally, patients frequently move among the various settings within a healthcare system 8 . - A new addition to the practice recommendations for Standard Precautions is Respiratory Hygiene/Cough Etiquette. While Standard Precautions generally apply to the recommended practices of healthcare personnel during patient care, Respiratory Hygiene/Cough Etiquette applies broadly to all persons who enter a healthcare setting, including healthcare personnel, patients and visitors. These recommendations evolved from observations during the SARS epidemic that failure to implement basic source control measures with patients, visitors, and healthcare personnel with signs and symptoms of respiratory tract infection may have contributed to SARS coronavirus (SARS-CoV) transmission. This concept has been incorporated into CDC planning documents for SARS and pandemic influenza 9,10 . - The term "Airborne Precautions" has been supplemented with the term "Airborne Infection Isolation Room (AIIR)" for consistency with the Guidelines for Environmental Infection Control in Healthcare Facilities 11 , the Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings 2005 12 and the American Institute of Architects (AIA) guidelines for design and construction of hospitals, 2006 13 - A set of prevention measures termed Protective Environment has been added to the precautions used to prevent HAIs. These measures, which have been defined in other guidelines , consist of engineering and design interventions that decrease the risk of exposure to environmental fungi for severely immunocompromised allogeneic hematiopoietic stem cell transplant (HSCT) patients during their highest risk phase, usually the first 100 days post transplant, or longer in the presence of graft-versushost disease 11, . Recommendations for a Protective Environment apply only to acute care hospitals that provide care to HSCT patients. 11,14,16,17 . In combination, these provide comprehensive guidance on the primary infection control measures for ensuring a safe environment for patients and healthcare personnel. # Scope This guideline does not discuss in detail specialized infection control issues in defined populations that are addressed elsewhere, (e.g. # I.B. Rationale for Standard and Transmission-Based Precautions in healthcare settings Transmission of infectious agents within a healthcare setting requires three elements: a source (or reservoir) of infectious agents, a susceptible host with a portal of entry receptive to the agent, and a mode of transmission for the agent. This section describes the interrelationship of these elements in the epidemiology of HAIs. # I.B.1. Sources of infectious agents. Infectious agents transmitted during healthcare derive primarily from human sources but inanimate environmental sources also are implicated in transmission. Human reservoirs include patients , healthcare personnel 29-35 17, 36-39 , and household members and other visitors . Such source individuals may have active infections, may be in the asymptomatic and/or incubation period of an infectious disease, or may be transiently or chronically colonized with pathogenic microorganisms, particularly in the respiratory and gastrointestinal tracts. The endogenous flora of patients (e.g., bacteria residing in the respiratory or gastrointestinal tract) also are the source of HAIs . # I.B.2. Susceptible hosts. Infection is the result of a complex interrelationship between a potential host and an infectious agent. Most of the factors that influence infection and the occurrence and severity of disease are related to the host. However, characteristics of the host-agent interaction as it relates to pathogenicity, virulence and antigenicity are also important, as are the infectious dose, mechanisms of disease production and route of exposure 55 . There is a spectrum of possible outcomes following exposure to an infectious agent. Some persons exposed to pathogenic microorganisms never develop symptomatic disease while others become severely ill and even die. Some individuals are prone to becoming transiently or permanently colonized but remain asymptomatic. Still others progress from colonization to symptomatic disease either immediately following exposure, or after a period of asymptomatic colonization. The immune state at the time of exposure to an infectious agent, interaction between pathogens, and virulence factors intrinsic to the agent are important predictors of an individuals' outcome. Host factors such as extremes of age and underlying disease (e.g., diabetes 56,57 ), human immunodeficiency virus/acquired immune deficiency syndrome 58,59 , malignancy, and transplants 18,60,61 can increase susceptibility to infection as do a variety of medications that alter the normal flora (e.g., antimicrobial agents, gastric acid suppressants, corticosteroids, antirejection drugs, antineoplastic agents, and immunosuppressive drugs). Surgical procedures and radiation therapy impair defenses of the skin and other involved organ systems. Indwelling devices such as urinary catheters, endotracheal tubes, central venous and arterial catheters and synthetic implants facilitate development of HAIs by allowing potential pathogens to bypass local defenses that would ordinarily impede their invasion and by providing surfaces for development of bioflms that may facilitate adherence of microorganisms and protect from antimicrobial activity 65 . Some infections associated with invasive procedures result from transmission within the healthcare facility; others arise from the patient's endogenous flora . High-risk patient populations with noteworthy risk factors for infection are discussed further in Sections I.D, I.E., and I.F. # I.B.3. Modes of transmission. Several classes of pathogens can cause infection, including bacteria, viruses, fungi, parasites, and prions. The modes of transmission vary by type of organism and some infectious agents may be transmitted by more than one route: some are transmitted primarily by direct or indirect contact, (e.g., Herpes simplex virus , respiratory syncytial virus, Staphylococcus aureus), others by the droplet, (e.g., influenza virus, B. pertussis) or airborne routes (e.g., M. tuberculosis). Other infectious agents, such as bloodborne viruses (e.g., hepatitis B and C viruses and HIV are transmitted rarely in healthcare settings, via percutaneous or mucous membrane exposure. Importantly, not all infectious agents are transmitted from person to person. These are distinguished in Appendix A. The three principal routes of transmission are summarized below. # I.B.3.a. Contact transmission. The most common mode of transmission, contact transmission is divided into two subgroups: direct contact and indirect contact. # I.B.3.a.i. Direct contact transmission. Direct transmission occurs when microorganisms are transferred from one infected person to another person without a contaminated intermediate object or person. Opportunities for direct contact transmission between patients and healthcare personnel have been summarized in the Guideline for Infection Control in Healthcare Personnel, 1998 17 and include: - blood or other blood-containing body fluids from a patient directly enters a caregiver's body through contact with a mucous membrane 66 or breaks (i.e., cuts, abrasions) in the skin 67 . - mites from a scabies-infested patient are transferred to the skin of a caregiver while he/she is having direct ungloved contact with the patient's skin 68,69 . - a healthcare provider develops herpetic whitlow on a finger after contact with HSV when providing oral care to a patient without using gloves or HSV is transmitted to a patient from a herpetic whitlow on an ungloved hand of a healthcare worker (HCW) 70,71 . # I.B.3.a.ii. Indirect contact transmission. Indirect transmission involves the transfer of an infectious agent through a contaminated intermediate object or person. In the absence of a point-source outbreak, it is difficult to determine how indirect transmission occurs. However, extensive evidence cited in the Guideline for Hand Hygiene in Health-Care Settings suggests that the contaminated hands of healthcare personnel are important contributors to indirect contact transmission 16 . Examples of opportunities for indirect contact transmission include: - Hands of healthcare personnel may transmit pathogens after touching an infected or colonized body site on one patient or a contaminated inanimate object, if hand hygiene is not performed before touching another patient. 72,73 . - Patient-care devices (e.g., electronic thermometers, glucose monitoring devices) may transmit pathogens if devices contaminated with blood or body fluids are shared between patients without cleaning and disinfecting between patients 74 75-77 . - Shared toys may become a vehicle for transmitting respiratory viruses (e.g., respiratory syncytial virus 24,78,79 or pathogenic bacteria (e.g., Pseudomonas aeruginosa 80 ) among pediatric patients. - Instruments that are inadequately cleaned between patients before disinfection or sterilization (e.g., endoscopes or surgical instruments) or that have manufacturing defects that interfere with the effectiveness of reprocessing 86,87 may transmit bacterial and viral pathogens. Clothing, uniforms, laboratory coats, or isolation gowns used as personal protective equipment (PPE), may become contaminated with potential pathogens after care of a patient colonized or infected with an infectious agent, (e.g., MRSA 88 , VRE 89 , and C. difficile 90 . Although contaminated clothing has not been implicated directly in transmission, the potential exists for soiled garments to transfer infectious agents to successive patients. # I.B.3.b. Droplet transmission. Droplet transmission is, technically, a form of contact transmission, and some infectious agents transmitted by the droplet route also may be transmitted by the direct and indirect contact routes. However, in contrast to contact transmission, respiratory droplets carrying infectious pathogens transmit infection when they travel directly from the respiratory tract of the infectious individual to susceptible mucosal surfaces of the recipient, generally over short distances, necessitating facial protection. Respiratory droplets are generated when an infected person coughs, sneezes, or talks 91,92 or during procedures such as suctioning, endotracheal intubation , cough induction by chest physiotherapy 97 and cardiopulmonary resuscitation 98,99 . Evidence for droplet transmission comes from epidemiological studies of disease outbreaks , experimental studies 104 and from information on aerosol dynamics 91,105 . Studies have shown that the nasal mucosa, conjunctivae and less frequently the mouth, are susceptible portals of entry for respiratory viruses 106 . The maximum distance for droplet transmission is currently unresolved, although pathogens transmitted by the droplet route have not been transmitted through the air over long distances, in contrast to the airborne pathogens discussed below. Historically, the area of defined risk has been a distance of ≤3 feet around the patient and is based on epidemiologic and simulated studies of selected infections 103,104 . Using this distance for donning masks has been effective in preventing transmission of infectious agents via the droplet route. However, experimental studies with smallpox 107,108 and investigations during the global SARS outbreaks of 2003 101 suggest that droplets from patients with these two infections could reach persons located 6 feet or more from their source. It is likely that the distance droplets travel depends on the velocity and mechanism by which respiratory droplets are propelled from the source, the density of respiratory secretions, environmental factors such as temperature and humidity, and the ability of the pathogen to maintain infectivity over that distance 105 . Thus, a distance of ≤3 feet around the patient is best viewed as an example of what is meant by "a short distance from a patient" and should not be used as the sole criterion for deciding when a mask should be donned to protect from droplet exposure. Based on these considerations, it may be prudent to don a mask when within 6 to 10 feet of the patient or upon entry into the patient's room, especially when exposure to emerging or highly virulent pathogens is likely. More studies are needed to improve understanding of droplet transmission under various circumstances. Droplet size is another variable under discussion. Droplets traditionally have been defined as being >5 µm in size. Droplet nuclei, particles arising from desiccation of suspended droplets, have been associated with airborne transmission and defined as ≤5 µm in size 105 , a reflection of the pathogenesis of pulmonary tuberculosis which is not generalizeable to other organisms. Observations of particle dynamics have demonstrated that a range of droplet sizes, including those with diameters of 30µm or greater, can remain suspended in the air 109 . The behavior of droplets and droplet nuclei affect recommendations for preventing transmission. Whereas fine airborne particles containing pathogens that are able to remain infective may transmit infections over long distances, requiring AIIR to prevent its dissemination within a facility; organisms transmitted by the droplet route do not remain infective over long distances, and therefore do not require special air handling and ventilation. Examples of infectious agents that are transmitted via the droplet route include Bordetella pertussis 110 , influenza virus 23 , adenovirus 111 , rhinovirus 104 , Mycoplasma pneumoniae 112 , SARSassociated coronavirus (SARS-CoV) 21,96,113 , group A streptococcus 114 , and Neisseria meningitidis 95,103,115 . Although respiratory syncytial virus may be transmitted by the droplet route, direct contact with infected respiratory secretions is the most important determinant of transmission and consistent adherence to Standard plus Contact Precautions prevents transmission in healthcare settings 24,116,117 . Rarely, pathogens that are not transmitted routinely by the droplet route are dispersed into the air over short distances. For example, although S. aureus is transmitted most frequently by the contact route, viral upper respiratory tract infection has been associated with increased dispersal of S. aureus from the nose into the air for a distance of 4 feet under both outbreak and experimental conditions and is known as the "cloud baby" and "cloud adult" phenomenon . # I.B.3.c. Airborne transmission. Airborne transmission occurs by dissemination of either airborne droplet nuclei or small particles in the respirable size range containing infectious agents that remain infective over time and distance (e.g., spores of Aspergillus spp, and Mycobacterium tuberculosis). Microorganisms carried in this manner may be dispersed over long distances by air currents and may be inhaled by susceptible individuals who have not had face-to-face contact with (or been in the same room with) the infectious individual . Preventing the spread of pathogens that are transmitted by the airborne route requires the use of special air handling and ventilation systems (e.g., AIIRs) to contain and then safely remove the infectious agent 11,12 . Infectious agents to which this applies include Mycobacterium tuberculosis , rubeola virus (measles) 122 , and varicella-zoster virus (chickenpox) 123 . In addition, published data suggest the possibility that variola virus (smallpox) may be transmitted over long distances through the air under unusual circumstances and AIIRs are recommended for this agent as well; however, droplet and contact routes are the more frequent routes of transmission for smallpox 108,128,129 . In addition to AIIRs, respiratory protection with NIOSH certified N95 or higher level respirator is recommended for healthcare personnel entering the AIIR to prevent acquisition of airborne infectious agents such as M. tuberculosis 12 . For certain other respiratory infectious agents, such as influenza 130,131 and rhinovirus 104 , and even some gastrointestinal viruses (e.g., norovirus 132 and rotavirus 133 ) there is some evidence that the pathogen may be transmitted via small-particle aerosols, under natural and experimental conditions. Such transmission has occurred over distances longer than 3 feet but within a defined airspace (e.g., patient room), suggesting that it is unlikely that these agents remain viable on air currents that travel long distances. AIIRs are not required routinely to prevent transmission of these agents. Additional issues concerning examples of small particle aerosol transmission of agents that are most frequently transmitted by the droplet route are discussed below. # I.B.3.d. Emerging issues concerning airborne transmission of infectious agents. # I.B.3.d.i. Transmission from patients. The emergence of SARS in 2002, the importation of monkeypox into the United States in 2003, and the emergence of avian influenza present challenges to the assignment of isolation categories because of conflicting information and uncertainty about possible routes of transmission. Although SARS-CoV is transmitted primarily by contact and/or droplet routes, airborne transmission over a limited distance (e.g., within a room), has been suggested, though not proven . This is true of other infectious agents such as influenza virus 130 and noroviruses 132,142,143 . Influenza viruses are transmitted primarily by close contact with respiratory droplets 23,102 and acquisition by healthcare personnel has been prevented by Droplet Precautions, even when positive pressure rooms were used in one center 144 However, inhalational transmission could not be excluded in an outbreak of influenza in the passengers and crew of a single aircraft 130 . Observations of a protective effect of UV lights in preventing influenza among patients with tuberculosis during the influenza pandemic of 1957-'58 have been used to suggest airborne transmission 145,146 . In contrast to the strict interpretation of an airborne route for transmission (i.e., long distances beyond the patient room environment), short distance transmission by small particle aerosols generated under specific circumstances (e.g., during endotracheal intubation) to persons in the immediate area near the patient has been demonstrated. Also, aerosolized particles <100 µm can remain suspended in air when room air current velocities exceed the terminal settling velocities of the particles 109 . SARS-CoV transmission has been associated with endotracheal intubation, noninvasive positive pressure ventilation, and cardio-pulmonary resuscitation 93,94,96,98,141 . Although the most frequent routes of transmission of noroviruses are contact and food and waterborne routes, several reports suggest that noroviruses may be transmitted through aerosolization of infectious particles from vomitus or fecal material 142,143,147,148 . It is hypothesized that the aerosolized particles are inhaled and subsequently swallowed. Roy and Milton proposed a new classification for aerosol transmission when evaluating routes of SARS transmission: 1. obligate: under natural conditions, disease occurs following transmission of the agent only through inhalation of small particle aerosols (e.g., tuberculosis); 2. preferential: natural infection results from transmission through multiple routes, but small particle aerosols are the predominant route (e.g., measles, varicella); and 3. opportunistic: agents that naturally cause disease through other routes, but under special circumstances may be transmitted via fine particle aerosols 149 . This conceptual framework can explain rare occurrences of airborne transmission of agents that are transmitted most frequently by other routes (e.g., smallpox, SARS, influenza, noroviruses). Concerns about unknown or possible routes of transmission of agents associated with severe disease and no known treatment often result in more extreme prevention strategies than may be necessary; therefore, recommended precautions could change as the epidemiology of an emerging infection is defined and controversial issues are resolved. # I.B.3.d.ii. Transmission from the environment. Some airborne infectious agents are derived from the environment and do not usually involve person-to-person transmission. For example, anthrax spores present in a finely milled powdered preparation can be aerosolized from contaminated environmental surfaces and inhaled into the respiratory tract 150,151 . Spores of environmental fungi (e.g., Aspergillus spp.) are ubiquitous in the environment and may cause disease in immunocompromised patients who inhale aerosolized (e.g., via construction dust) spores 152,153 . As a rule, neither of these organisms is subsequently transmitted from infected patients. However, there is one well-documented report of person-to-person transmission of Aspergillus sp. in the ICU setting that was most likey due to the aerosolization of spores during wound debridement 154 . A Protective Environment refers to isolation practices designed to decrease the risk of exposure to environmental fungal agents in allogeneic HSCT patients 11,14,15, . Environmental sources of respiratory pathogens (eg. Legionella) transmitted to humans through a common aerosol source is distinct from direct patient-to-patient transmission. # I.B.3.e. Other sources of infection. Transmission of infection from sources other than infectious individuals include those associated with common environmental sources or vehicles (e.g., contaminated food, water, or medications (e.g., intravenous fluids). Although Aspergillus spp. have been recovered from hospital water systems 159 , the role of water as a reservoir for immunosuppressed patients remains uncertain. Vectorborne transmission of infectious agents from mosquitoes, flies, rats, and other vermin also can occur in healthcare settings. Prevention of vector borne transmission is not addressed in this document. # I.C. Infectious Agents of Special Infection Control Interest for Healthcare Settings Several infectious agents with important infection control implications that either were not discussed extensively in previous isolation guidelines or have emerged recently are discussed below. These are epidemiologically important organisms (e.g., C. difficile), agents of bioterrorism, prions, SARS-CoV, monkeypox, noroviruses, and the hemorrhagic fever viruses. Experience with these agents has broadened the understanding of modes of transmission and effective preventive measures. These agents are included for purposes of information and, for some (i.e., SARS-CoV, monkeypox), because of the lessons that have been learned about preparedness planning and responding effectively to new infectious agents. # I.C.1. Epidemiologically important organisms. Any infectious agents transmitted in healthcare settings may, under defined conditions, become targeted for control because they are epidemiologically important. C. difficile is specifically discussed below because of wide recognition of its current importance in U.S. healthcare facilities. In determining what constitutes an "epidemiologically important organism", the following characteristics apply: - A propensity for transmission within healthcare facilities based on published reports and the occurrence of temporal or geographic clusters of > 2 patients, (e.g., C..difficile, norovirus, respiratory syncytial virus (RSV), influenza, rotavirus, Enterobacter spp; Serratia spp., group A streptococcus). A single case of healthcare-associated invasive disease caused by certain pathogens (e.g., group A streptococcus post-operatively 160 , in burn units 161 , or in a LTCF 162 ; Legionella sp. 14,163 , Aspergillus sp. 164 ) is generally considered a trigger for investigation and enhanced control measures because of the risk of additional cases and severity of illness associated with these infections. Antimicrobial resistance - Resistance to first-line therapies (e.g., MRSA, VISA, VRSA, VRE, ESBL-producing organisms). - Common and uncommon microorganisms with unusual patterns of resistance within a facility (e.g., the first isolate of Burkholderia cepacia complex or Ralstonia spp. in non-CF patients or a quinolone-resistant strain of Pseudomonas aeruginosa in a facility). - Difficult to treat because of innate or acquired resistance to multiple classes of antimicrobial agents (e.g., Stenotrophomonas maltophilia, Acinetobacter spp.). - Association with serious clinical disease, increased morbidity and mortality (e.g., MRSA and MSSA, group A streptococcus) - A newly discovered or reemerging pathogen I.C.1.a. C.difficile. C. difficile is a spore-forming gram positive anaerobic bacillus that was first isolated from stools of neonates in 1935 165 and identified as the most commonly identified causative agent of antibiotic-associated diarrhea and pseudomembranous colitis in 1977 166 . This pathogen is a major cause of healthcareassociated diarrhea and has been responsible for many large outbreaks in healthcare settings that were extremely difficult to control. Important factors that contribute to healthcare-associated outbreaks include environmental contamination, persistence of spores for prolonged periods of time, resistance of spores to routinely used disinfectants and antiseptics, hand carriage by healthcare personnel to other patients, and exposure of patients to frequent courses of antimicrobial agents 167 . Antimicrobials most frequently associated with increased risk of C. difficile include third generation cephalosporins, clindamycin, vancomycin, and fluoroquinolones. Since 2001, outbreaks and sporadic cases of C. difficile with increased morbidity and mortality have been observed in several U.S. states, Canada, England and the Netherlands . The same strain of C. difficile has been implicated in these outbreaks 173 . This strain, toxinotype III, North American PFGE type 1, and PCR-ribotype 027 (NAP1/027) has been found to hyperproduce toxin A (16 fold increase) and toxin B (23 fold increase) compared with isolates from 12 different pulsed-field gel electrophoresisPFGE types. A recent survey of U.S. infectious disease physicians found that 40% perceived recent increases in the incidence and severity of C. difficile disease 174 . Standardization of testing methodology and surveillance definitions is needed for accurate comparisons of trends in rates among hospitals 175 . It is hypothesized that the incidence of disease and apparent heightened transmissibility of this new strain may be due, at least in part, to the greater production of toxins A and B, increasing the severity of diarrhea and resulting in more environmental contamination. Considering the greater morbidity, mortality, length of stay, and costs associated with C. difficile disease in both acute care and long term care facilities, control of this pathogen is now even more important than previously. Prevention of transmission focuses on syndromic application of Contact Precautions for patients with diarrhea, accurate identification of patients, environmental measures (e.g., rigorous cleaning of patient rooms) and consistent hand hygiene. Use of soap and water, rather than alcohol based handrubs, for mechanical removal of spores from hands, and a bleach-containing disinfectant (5000 ppm) for environmental disinfection, may be valuable when there is transmission in a healthcare facility. See Appendix A for specific recommendations. # I.C.1. b. Multidrug-resistant organisms (MDROs). In general, MDROs are defined as microorganisms -predominantly bacteria -that are resistant to one or more classes of antimicrobial agents 176 . Although the names of certain MDROs suggest resistance to only one agent (e.g., methicillin-resistant Staphylococcus aureus , vancomycin resistant enterococcus ), these pathogens are usually resistant to all but a few commercially available antimicrobial agents. This latter feature defines MDROs that are considered to be epidemiologically important and deserve special attention in healthcare facilities 177 . Other MDROs of current concern include multidrug-resistant Streptococcus pneumoniae (MDRSP) which is resistant to penicillin and other broadspectrum agents such as macrolides and fluroquinolones, multidrug-resistant gramnegative bacilli (MDR-GNB), especially those producing extended spectrum betalactamases (ESBLs); and strains of S. aureus that are intermediate or resistant to vancomycin (i.e., VISA and VRSA) 178-197 198 . MDROs are transmitted by the same routes as antimicrobial susceptible infectious agents. Patient-to-patient transmission in healthcare settings, usually via hands of HCWs, has been a major factor accounting for the increase in MDRO incidence and prevalence, especially for MRSA and VRE in acute care facilities . Preventing the emergence and transmission of these pathogens requires a comprehensive approach that includes administrative involvement and measures (e.g., nurse staffing, communication systems, performance improvement processes to ensure adherence to recommended infection control measures), education and training of medical and other healthcare personnel, judicious antibiotic use, comprehensive surveillance for targeted MDROs, application of infection control precautions during patient care, environmental measures (e.g., cleaning and disinfection of the patient care environment and equipment, dedicated single-patient-use of non-critical equipment), and decolonization therapy when appropriate. The prevention and control of MDROs is a national priority -one that requires that all healthcare facilities and agencies assume responsibility and participate in communitywide control programs 176,177 . A detailed discussion of this topic and recommendations for prevention was published in 2006 may be found at Management of Multidrug-Resistant Organisms in Healthcare Settings (2006) (/ accessed May 2016). # I.C.2. Agents of bioterrorism. CDC has designated the agents that cause anthrax, smallpox, plague, tularemia, viral hemorrhagic fevers, and botulism as Category A (high priority) because these agents can be easily disseminated environmentally and/or transmitted from person to person; can cause high mortality and have the potential for major public health impact; might cause public panic and social disruption; and require special action for public health preparedness 202 . General information relevant to infection control in healthcare settings for Category A agents of bioterrorism is summarized in Table 3. Consult for additional, updated Category A agent information as well as information concerning Category B and C agents of bioterrorism and updates. Category B and C agents are important but are not as readily disseminated and cause less morbidity and mortality than Category A agents. Healthcare facilities confront a different set of issues when dealing with a suspected bioterrorism event as compared with other communicable diseases. An understanding of the epidemiology, modes of transmission, and clinical course of each disease, as well as carefully drafted plans that provide an approach and relevant websites and other resources for disease-specific guidance to healthcare, administrative, and support personnel, are essential for responding to and managing a bioterrorism event. Infection control issues to be addressed include: 1. identifying persons who may be exposed or infected; 2. preventing transmission among patients, healthcare personnel, and visitors; 3. providing treatment, chemoprophylaxis or vaccine to potentially large numbers of people; 4. protecting the environment including the logistical aspects of securing sufficient numbers of AIIRs or designating areas for patient cohorts when there are an insufficient number of AIIRs available; 5. providing adequate quantities of appropriate personal protective equipment; and 6. identifying appropriate staff to care for potentially infectious patients (e.g., vaccinated healthcare personnel for care of patients with smallpox). The response is likely to differ for exposures resulting from an intentional release compared with naturally occurring disease because of the large number persons that can be exposed at the same time and possible differences in pathogenicity. and state and county health department web sites should be consulted for the most upto-date information. Sources of information on specific agents include: anthrax 203 ; smallpox ; plague 207,208 ; botulinum toxin 209 ; tularemia 210 ; and hemorrhagic fever viruses. 211,212 . # I.C.2.a. Pre-event administration of smallpox (vaccinia) vaccine to healthcare personnel. Vaccination of personnel in preparation for a possible smallpox exposure has important infection control implications . These include the need for meticulous screening for vaccine contraindications in persons who are at increased risk for adverse vaccinia events; containment and monitoring of the vaccination site to prevent transmission in the healthcare setting and at home; and the management of patients with vaccinia-related adverse events 216,217 218,219 . Outside the healthcare setting, there were 53 cases of contact transfer from military vaccinees to close personal contacts (e.g., bed partners or contacts during participation in sports such as wrestling 220 ). All contact transfers were from individuals who were not following recommendations to cover their vaccination sites. Vaccinia virus was confirmed by culture or PCR in 30 cases, and two of the confirmed cases resulted from tertiary transfer. All recipients, including one breast-fed infant, recovered without complication. Subsequent studies using viral culture and PCR techniques have confirmed the effectiveness of semipermeable dressings to contain vaccinia . This experience emphasizes the importance of ensuring that newly vaccinated healthcare personnel adhere to recommended vaccination-site care, especially if they are to care for high-risk patients. Recommendations for pre-event smallpox vaccination of healthcare personnel and vaccinia-related infection control recommendations are published in the MMWR 216,225 with updates posted on the CDC bioterrorism web site 205 . # I.C.3. Prions. Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, degenerative, neurologic disorder of humans with an incidence in the United States of approximately 1 person/million population/year 226,227 228,229 , from implantation of contaminated human dura mater grafts 230 or from corneal transplants 231 ). Transmission has been linked to the use of contaminated neurosurgical instruments or stereotactic electroencephalogram electrodes 232,233,234,235 . Prion diseases in animals include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE, or "mad cow disease") in cattle, and chronic wasting disease in deer and elk 236 . BSE, first recognized in the United Kingdom (UK) in 1986, was associated with a major epidemic among cattle that had consumed contaminated meat and bone meal. The possible transmission of BSE to humans causing variant CJD (vCJD) was first described in 1996 and subsequently found to be associated with consumption of BSEcontaminated cattle products primarily in the United Kingdom. There is strong epidemiologic and laboratory evidence for a causal association between the causative agent of BSE and vCJD 237 240 . Similar to sporadic CJD, there have been no reported cases of direct human-to-human transmission of vCJD by casual or environmental contact, droplet, or airborne routes. Ongoing blood safety surveillance in the U.S. has not detected sporadic CJD transmission through blood transfusion . However, bloodborne transmission of vCJD is believed to have occurred in two UK patients 244,245 # I.C.4. Severe Acute Respiratory Syndrome (SARS). SARS is a newly discovered respiratory disease that emerged in China late in 2002 and spread to several countries 135,140 ; Mainland China, Hong Kong, Hanoi, Singapore, and Toronto were affected significantly. SARS is caused by SARS CoV, a previously unrecognized member of the coronavirus family 247,248 . The incubation period from exposure to the onset of symptoms is 2 to 7 days but can be as long as 10 days and uncommonly even longer 249 . The illness is initially difficult to distinguish from other common respiratory infections. Signs and symptoms usually include fever >38.0°C and chills and rigors, sometimes accompanied by headache, myalgia, and mild to severe respiratory symptoms. Outbreaks in healthcare settings, with transmission to large numbers of healthcare personnel and patients have been a striking feature of SARS; undiagnosed, infectious patients and visitors were important initiators of these outbreaks 21, . The relative contribution of potential modes of transmission is not precisely known. There is ample evidence for droplet and contact transmission 96,101,113 ; however, opportunistic airborne transmission cannot be excluded 101, 135-139, 149, 255 . For example, exposure to aerosolgenerating procedures (e.g., endotracheal intubation, suctioning) was associated with transmission of infection to large numbers of healthcare personnel outside of the United States 93,94,96,98,253 .Therefore, aerosolization of small infectious particles generated during these and other similar procedures could be a risk factor for transmission to others within a multi-bed room or shared airspace. A review of the infection control literature generated from the SARS outbreaks of 2003 concluded that the greatest risk of transmission is to those who have close contact, are not properly trained in use of protective infection control procedures, do not consistently use PPE; and that N95 or higher respirators may offer additional protection to those exposed to aerosol-generating procedures and high risk activities 256,257 . Organizational and individual factors that affected adherence to infection control practices for SARS also were identified 257 . Control of SARS requires a coordinated, dynamic response by multiple disciplines in a healthcare setting 9 . Early detection of cases is accomplished by screening persons with symptoms of a respiratory infection for history of travel to areas experiencing community transmission or contact with SARS patients, followed by implementation of Respiratory Hygiene/Cough Etiquette (i.e., placing a mask over the patient's nose and mouth) and physical separation from other patients in common waiting areas.The precise combination of precautions to protect healthcare personnel has not been determined. At the time of this publication, CDC recommends Standard Precautions, with emphasis on the use of hand hygiene, Contact Precautions with emphasis on environmental cleaning due to the detection of SARS CoV RNA by PCR on surfaces in rooms occupied by SARS patients 138,254,258 , Airborne Precautions, including use of fit-tested NIOSHapproved N95 or higher level respirators, and eye protection 259 . In Hong Kong, the use of Droplet and Contact Precautions, which included use of a mask but not a respirator, was effective in protecting healthcare personnel 113 . However, in Toronto, consistent use of an N95 respirator was slightly more protective than a mask 93 . It is noteworthy that there was no transmission of SARS-CoV to public hospital workers in Vietnam despite inconsistent use of infection control measures, including use of PPE, which suggests other factors (e.g., severity of disease, frequency of high risk procedures or events, environmental features) may influence opportunities for transmission 260 . SARS-CoV also has been transmitted in the laboratory setting through breaches in recommended laboratory practices. Research laboratories where SARS-CoV was under investigation were the source of most cases reported after the first series of outbreaks in the winter and spring of 2003 261,262 . Studies of the SARS outbreaks of 2003 and transmissions that occurred in the laboratory re-affirm the effectiveness of recommended infection control precautions and highlight the importance of consistent adherence to these measures. Lessons from the SARS outbreaks are useful for planning to respond to future public health crises, such as pandemic influenza and bioterrorism events. Surveillance for cases among patients and healthcare personnel, ensuring availability of adequate supplies and staffing, and limiting access to healthcare facilities were important factors in the response to SARS that have been summarized 9 . Guidance for infection control precautions in various settings is available at . # I.C.5. Monkeypox. Monkeypox is a rare viral disease found mostly in the rain forest countries of Central and West Africa. The disease is caused by an orthopoxvirus that is similar in appearance to smallpox but causes a milder disease. The only recognized outbreak of human monkeypox in the United States was detected in June 2003 after several people became ill following contact with sick pet prairie dogs. Infection in the prairie dogs was subsequently traced to their contact with a shipment of animals from Africa, including giant Gambian rats 263 . This outbreak demonstrates the importance of recognition and prompt reporting of unusual disease presentations by clinicians to enable prompt identification of the etiology; and the potential of epizootic diseases to spread from animal reservoirs to humans through personal and occupational exposure 264 . Limited data on transmission of monkeypox are available. Transmission from infected animals and humans is believed to occur primarily through direct contact with lesions and respiratory secretions; airborne transmission from animals to humans is unlikely but cannot be excluded, and may have occurred in veterinary practices (e.g., during administration of nebulized medications to ill prairie dogs 265 ). Among humans, four instances of monkeypox transmission within hospitals have been reported in Africa among children, usually related to sharing the same ward or bed 266,267 . Additional recent literature documents transmission of Congo Basin monkeypox in a hospital compound for an extended number of generations 268 . There has been no evidence of airborne or any other person-to-person transmission of monkeypox in the United States, and no new cases of monkeypox have been identified since the outbreak in June 2003 269 . The outbreak strain is a clade of monkeypox distinct from the Congo Basin clade and may have different epidemiologic properties (including human-to-human transmission potential) from monkeypox strains of the Congo Basin 270 ; this awaits further study. Smallpox vaccine is 85% protective against Congo Basin monkeypox 271 . Since there is an associated case fatality rate of ≤10%, administration of smallpox vaccine within 4 days to individuals who have had direct exposure to patients or animals with monkeypox is a reasonable consideration 272 . For the most current information, see CDC Monkeypox ( accessed September 2018). I.C.6. Noroviruses. Noroviruses, formerly referred to as Norwalk-like viruses, are members of the Caliciviridae family. These agents are transmitted via contaminated food or water and from person-to-person, causing explosive outbreaks of gastrointestinal disease 273 . Environmental contamination also has been documented as a contributing factor in ongoing transmission during outbreaks 274,275 . Although noroviruses cannot be propagated in cell culture, DNA detection by molecular diagnostic techniques has facilitated a greater appreciation of their role in outbreaks of gastrointestinal disease 276 . Reported outbreaks in hospitals 132,142,277 , nursing homes 275, , cruise ships 284,285 , hotels 143,147 , schools 148 , and large crowded shelters established for hurricane evacuees 286 , demonstrate their highly contagious nature, the disruptive impact they have in healthcare facilities and the community, and the difficulty of controlling outbreaks in settings where people share common facilites and space. Of note, there is nearly a 5 fold increase in the risk to patients in outbreaks where a patient is the index case compared with exposure of patients during outbreaks where a staff member is the index case 287 . The average incubation period for gastroenteritis caused by noroviruses is 12-48 hours and the clinical course lasts 12-60 hours 273 . Illness is characterized by acute onset of nausea, vomiting, abdominal cramps, and/or diarrhea. The disease is largely selflimited; rarely, death caused by severe dehydration can occur, particularly among the elderly with debilitating health conditions. The epidemiology of norovirus outbreaks shows that even though primary cases may result from exposure to a fecally-contaminated food or water, secondary and tertiary cases often result from person-to-person transmission that is facilitated by contamination of fomites 273,288 and dissemination of infectious particles, especially during the process of vomiting 132,142,143,147,148,273,279,280 . Widespread, persistent and inapparent contamination of the environment and fomites can make outbreaks extremely difficult to control 147,275,284 .These clinical observations and the detection of norovirus DNA on horizontal surfaces 5 feet above the level that might be touched normally suggest that, under certain circumstances, aerosolized particles may travel distances beyond 3 feet 147 . It is hypothesized that infectious particles may be aerosolized from vomitus, inhaled, and swallowed. In addition, individuals who are responsible for cleaning the environment may be at increased risk of infection. Development of disease and transmission may be facilitated by the low infectious dose (i.e., <100 viral particles) 289 and the resistance of these viruses to the usual cleaning and disinfection agents (i.e., may survive ≤10 ppm chlorine) . An alternate phenolic agent that was shown to be effective against feline calicivirus was used for environmental cleaning in one outbreak 275,293 . There are insufficient data to determine the efficacy of alcohol-based hand rubs against noroviruses when the hands are not visibly soiled 294 . Absence of disease in certain individuals during an outbreak may be explained by protection from infection conferred by the B histo-blood group antigen 295 . Consultation on outbreaks of gastroenteritis is available through CDC's Division of Viral and Rickettsial Diseases 296 . # I.C.7. Hemorrhagic fever viruses (HFV). The hemorrhagic fever viruses are a mixed group of viruses that cause serious disease with high fever, skin rash, bleeding diathesis, and in some cases, high mortality; the disease caused is referred to as viral hemorrhagic fever (VHF). Among the more commonly known HFVs are Ebola and Marburg viruses (Filoviridae), Lassa virus (Arenaviridae), Crimean-Congo hemorrhagic fever and Rift Valley Fever virus (Bunyaviridae), and Dengue and Yellow fever viruses (Flaviviridae) 212,297 . These viruses are transmitted to humans via contact with infected animals or via arthropod vectors. While none of these viruses is endemic in the United States, outbreaks in affected countries provide potential opportunities for importation by infected humans and animals. Furthermore, there are concerns that some of these agents could be used as bioweapons 212 . Person-to-person transmission is documented for Ebola, Marburg, Lassa and Crimean-Congo hemorrhagic fever viruses. In resourcelimited healthcare settings, transmission of these agents to healthcare personnel, patients and visitors has been described and in some outbreaks has accounted for a large proportion of cases . Transmissions within households also have occurred among individuals who had direct contact with ill persons or their body fluids, but not to those who did not have such contact 301 . Evidence concerning the transmission of HFVs has been summarized 212,302 . Person-toperson transmission is associated primarily with direct blood and body fluid contact. Percutaneous exposure to contaminated blood carries a particularly high risk for transmission and increased mortality 303,304 . The finding of large numbers of Ebola viral particles in the skin and the lumina of sweat glands has raised concern that transmission could occur from direct contact with intact skin though epidemiologic evidence to support this is lacking 305 . Postmortem handling of infected bodies is an important risk for transmission 301,306,307 . In rare situations, cases in which the mode of transmission was unexplained among individuals with no known direct contact , have led to speculation that airborne transmission could have occurred 298 . However, airborne transmission of naturally occurring HFVs in humans has not been seen. In one study of airplane passengers exposed to an in-flight index case of Lassa fever, there was no transmission to any passengers 308 . In the laboratory setting, animals have been infected experimentally with Marburg or Ebola viruses via direct inoculation of the nose, mouth and/or conjunctiva 309,310 and by using mechanically generated virus-containing aerosols 311,312 . Transmission of Ebola virus among laboratory primates in an animal facility has been described 313 . Secondarily infected animals were in individual cages and separated by approximately 3 meters. Although the possibility of airborne transmission was suggested, the authors were not able to exclude droplet or indirect contact transmission in this incidental observation. Guidance on infection control precautions for HVFs that are transmitted person-toperson have been published by CDC 1,211 and by the Johns Hopkins Center for Civilian Biodefense Strategies 212 . The most recent recommendations at the time of publication of this document were posted on the CDC website on 5/19/05 314 . Inconsistencies among the various recommendations have raised questions about the appropriate precautions to use in U.S. hospitals. In less developed countries, outbreaks of HFVs have been controlled with basic hygiene, barrier precautions, safe injection practices, and safe burial practices 299,306 . The preponderance of evidence on HFV transmission indicates that Standard, Contact and Droplet Precautions with eye protection are effective in protecting healthcare personnel and visitors who may attend an infected patient. Single gloves are adequate for routine patient care; double-gloving is advised during invasive procedures (e.g., surgery) that pose an increased risk for blood exposure. Routine eye protection (i.e. goggles or face shield) is particularly important. Fluid-resistant gowns should be worn for all patient contact. Airborne Precautions are not required for routine patient care; however, use of AIIRs is prudent when procedures that could generate infectious aerosols are performed (e.g., endotracheal intubation, bronchoscopy, suctioning, autopsy procedures involving oscillating saws). N95 or higher level respirators may provide added protection for individuals in a room during aerosolgenerating procedures (Table 3, Appendix A). When a patient with a syndrome consistent with hemorrhagic fever also has a history of travel to an endemic area, precautions are initiated upon presentation and then modified as more information is obtained (Table 2). Patients with hemorrhagic fever syndrome in the setting of a suspected bioweapon attack should be managed using Airborne Precautions, including AIIRs, since the epidemiology of a potentially weaponized hemorrhagic fever virus is unpredictable. # I.D. Transmission Risks Associated with Specific Types of Healthcare Settings Numerous factors influence differences in transmission risks among the various healthcare settings. These include the population characteristics (e.g., increased susceptibility to infections, type and prevalence of indwelling devices), intensity of care, exposure to environmental sources, length of stay, and frequency of interaction between patients/residents with each other and with HCWs. These factors, as well as organizational priorities, goals, and resources, influence how different healthcare settings adapt transmission prevention guidelines to meet their specific needs 315,316 . Infection control management decisions are informed by data regarding institutional experience/epidemiology, trends in community and institutional HAIs, local, regional, and national epidemiology, and emerging infectious disease threats. # I.D.1. Hospitals. Infection transmission risks are present in all hospital settings. However, certain hospital settings and patient populations have unique conditions that predispose patients to infection and merit special mention. These are often sentinel sites for the emergence of new transmission risks that may be unique to that setting or present opportunities for transmission to other settings in the hospital. 318,319 , because of underlying diseases and conditions, the invasive medical devices and technology used in their care (e.g., central venous catheters and other intravascular devices, mechanical ventilators, extracorporeal membrane oxygenation (ECMO), hemodialysis/-filtration, pacemakers, implantable left ventricular assist devices), the frequency of contact with healthcare personnel, prolonged length of stay, and prolonged exposure to antimicrobial agents . Furthermore, adverse patient outcomes in this setting are more severe and are associated with a higher mortality 332 . Outbreaks associated with a variety of bacterial, fungal and viral pathogens due to common-source and person-to-person transmissions are frequent in adult and pediatric ICUs 31, 333-336, 337, 338 . # I.D.1.b. Burn units. Burn wounds can provide optimal conditions for colonization, infection, and transmission of pathogens; infection acquired by burn patients is a frequent cause of morbidity and mortality 320,339,340 . In patients with a burn injury involving ≥30% of the total body surface area (TBSA), the risk of invasive burn wound infection is particularly high 341,342 . Infections that occur in patients with burn injury involving <30% TBSA are usually associated with the use of invasive devices. Methicillin-susceptible Staphylococcus aureus, MRSA, enterococci, including VRE, gram-negative bacteria, and candida are prevalent pathogens in burn infections 53,340, and outbreaks of these organisms have been reported . Shifts over time in the predominance of pathogens causing infections among burn patients often lead to changes in burn care practices 343, . Burn wound infections caused by Aspergillus sp. or other environmental molds may result from exposure to supplies contaminated during construction 359 or to dust generated during construction or other environmental disruption 360 . Hydrotherapy equipment is an important environmental reservoir of gram-negative organisms. Its use for burn care is discouraged based on demonstrated associations between use of contaminated hydrotherapy equipment and infections. Burn wound infections and colonization, as well as bloodstream infections, caused by multidrugresistant P. aeruginosa 361 , A. baumannii 362 , and MRSA 352 have been associated with hydrotherapy; excision of burn wounds in operating rooms is preferred. Advances in burn care, specifically early excision and grafting of the burn wound, use of topical antimicrobial agents, and institution of early enteral feeding, have led to decreased infectious complications. Other advances have included prophylactic antimicrobial usage, selective digestive decontamination (SDD), and use of antimicrobial-coated catheters (ACC), but few epidemiologic studies and no efficacy studies have been performed to show the relative benefit of these measures 357 . There is no consensus on the most effective infection control practices to prevent transmission of infections to and from patients with serious burns (e.g., single-bed rooms 358 , laminar flow 363 and high efficiency particulate air filtration 360 or maintaining burn patients in a separate unit without exposure to patients or equipment from other units 364 ). There also is controversy regarding the need for and type of barrier precautions for routine care of burn patients. One retrospective study demonstrated efficacy and cost effectiveness of a simplified barrier isolation protocol for wound colonization, emphasizing handwashing and use of gloves, caps, masks and plastic impermeable aprons (rather than isolation gowns) for direct patient contact 365 . However, there have been no studies that define the most effective combination of infection control precautions for use in burn settings. Prospective studies in this area are needed. # I.D.1.c. Pediatrics. Studies of the epidemiology of HAIs in children have identified unique infection control issues in this population 63,64, . Pediatric intensive care unit (PICU) patients and the lowest birthweight babies in the high-risk nursery (HRN) monitored in the NNIS system have had high rates of central venous catheter-associated bloodstream infections 64,320, . Additionally, there is a high prevalence of communityacquired infections among hospitalized infants and young children who have not yet become immune either by vaccination or by natural infection. The result is more patients and their sibling visitors with transmissible infections present in pediatric healthcare settings, especially during seasonal epidemics (e.g., pertussis 36,40,41 , respiratory viral infections including those caused by RSV 24 , influenza viruses 373 , parainfluenza virus 374 , human metapneumovirus 375 , and adenoviruses 376 ; rubeola 34 , varicella 377 , and rotavirus 38,378 ). Close physical contact between healthcare personnel and infants and young children (eg. cuddling, feeding, playing, changing soiled diapers, and cleaning copious uncontrolled respiratory secretions) provides abundant opportunities for transmission of infectious material. Practices and behaviors such as congregation of children in play areas where toys and bodily secretions are easily shared and family members rooming-in with pediatric patients can further increase the risk of transmission. Pathogenic bacteria have been recovered from toys used by hospitalized patients 379 ; contaminated bath toys were implicated in an outbreak of multidrug-resistant P. aeruginosa on a pediatric oncology unit 80 . In addition, several patient factors increase the likelihood that infection will result from exposure to pathogens in healthcare settings (e.g., immaturity of the neonatal immune system, lack of previous natural infection and resulting immunity, prevalence of patients with congenital or acquired immune deficiencies, congenital anatomic anomalies, and use of life-saving invasive devices in neontal and pediatric intensive care units) 63 . There are theoretical concerns that infection risk will increase in association with innovative practices used in the NICU for the purpose of improving developmental outcomes, Such factors include co-bedding 380 and kangaroo care 381 that may increase opportunity for skin-to-skin exposure of multiple gestation infants to each other and to their mothers, respectively; although infection risk smay actually be reduced among infants receiving kangaroo care 382 . Children who attend child care centers 383,384 and pediatric rehabilitation units 385 may increase the overall burden of antimicrobial resistance (eg. by contributing to the reservoir of communityassociated MRSA ) . Patients in chronic care facilities may have increased rates of colonization with resistant GNBs and may be sources of introduction of resistant organisms to acute care settings 50 . # I.D.2. Non-acute healthcare settings. Healthcare is provided in various settings outside of hospitals including facilities, such as long-term care facilities (LTCF) (e.g., nursing homes), homes for the developmentally disabled, settings where behavioral health services are provided, rehabilitation centers and hospices 392 . In addition, healthcare may be provided in nonhealthcare settings such as workplaces with occupational health clinics, adult day care centers, assisted living facilities, homeless shelters, jails and prisons, school clinics and infirmaries. Each of these settings has unique circumstances and population risks to consider when designing and implementing an infection control program. Several of the most common settings and their particular challenges are discussed below. While this Guideline does not address each setting, the principles and strategies provided may be adapted and applied as appropriate. # I.D.2.a. Long-term care. The designation LTCF applies to a diverse group of residential settings, ranging from institutions for the developmentally disabled to nursing homes for the elderly and pediatric chronic-care facilities . Nursing homes for the elderly predominate numerically and frequently represent long-term care as a group of facilities. Approximately 1.8 million Americans reside in the nation's 16,500 nursing homes. 396 Estimates of HAI rates of 1.8 to 13.5 per 1000 resident-care days have been reported with a range of 3 to 7 per 1000 resident-care days in the more rigorous studies . The infrastructure described in the Department of Veterans Affairs nursing home care units is a promising example for the development of a nationwide HAI surveillance system for LTCFs 402 . LCTFs are different from other healthcare settings in that elderly patients at increased risk for infection are brought together in one setting and remain in the facility for extended periods of time; for most residents, it is their home. An atmosphere of community is fostered and residents share common eating and living areas, and participate in various facility-sponsored activities 403,404 . Since able residents interact freely with each other, controlling transmission of infection in this setting is challenging 405 . Residents who are colonized or infected with certain microorganisms are, in some cases, restricted to their room. However, because of the psychosocial risks associated with such restriction, it has been recommended that psychosocial needs be balanced with infection control needs in the LTCF setting . Documented LTCF outbreaks have been caused by various viruses (e.g., influenza virus 35, , rhinovirus 413 , adenovirus 414 , norovirus 278, 279 275, 281 ) and bacteria (e.g., group A streptococcus 162 , B. pertussis 415 , non-susceptible S. pneumoniae 197,198 , other MDROs, and Clostridium difficile 416 ) These pathogens can lead to substantial morbidity and mortality, and increased medical costs; prompt detection and implementation of effective control measures are required. Risk factors for infection are prevalent among LTCF residents 395,417,418 . Age-related declines in immunity may affect responses to immunizations for influenza and other infectious agents, and increase susceptibility to tuberculosis. Immobility, incontinence, dysphagia, underlying chronic diseases, poor functional status, and age-related skin changes increase susceptibility to urinary, respiratory and cutaneous and soft tissue infections, while malnutrition can impair wound healing . Medications (e.g., drugs that affect level of consciousness, immune function, gastric acid secretions, and normal flora, including antimicrobial therapy) and invasive devices (e.g., urinary catheters and feeding tubes) heighten susceptibility to infection and colonization in LTCF residents . Finally, limited functional status and total dependence on healthcare personnel for activities of daily living have been identified as independent risk factors for infection 401,417,427 and for colonization with MRSA 428,429 and ESBL-producing K. pneumoniae 430 . Several position papers and review articles have been published that provide guidance on various aspects of infection control and antimicrobial resistance in LTCFs . The Centers for Medicare and Medicaid Services (CMS) have established regulations for the prevention of infection in LTCFs 437 . Because residents of LTCFs are hospitalized frequently, they can transfer pathogens between LTCFs and healthcare facilities in which they receive care 8, . This is also true for pediatric long-term care populations. Pediatric chronic care facilities have been associated with importing extended-spectrum cephalosporin-resistant, gram-negative bacilli into one PICU 50 . Children from pediatric rehabilitation units may contribute to the reservoir of community-associated MRSA 385, . # I.D.2.b. Ambulatory care. In the past decade, healthcare delivery in the United States has shifted from the acute, inpatient hospital to a variety of ambulatory and community-based settings, including the home. Ambulatory care is provided in hospital-based outpatient clinics, nonhospital-based clinics and physician offices, public health clinics, free-standing dialysis centers, ambulatory surgical centers, urgent care centers, and many others. In 2000, there were 83 million visits to hospital outpatient clinics and more than 823 million visits to physician offices 442 ; ambulatory care now accounts for most patient encounters with the health care system 443 . In these settings, adapting transmission prevention guidelines is challenging because patients remain in common areas for prolonged periods waiting to be seen by a healthcare provider or awaiting admission to the hospital, examination or treatment rooms are turned around quickly with limited cleaning, and infectious patients may not be recognized immediately. Furthermore, immunocompromised patients often receive chemotherapy in infusion rooms where they stay for extended periods of time along with other types of patients. There are few data on the risk of HAIs in ambulatory care settings, with the exception of hemodialysis centers 18,444,445 . Transmission of infections in outpatient settings has been reviewed in three publications . Goodman and Solomon summarized 53 clusters of infections associated with the outpatient setting from 1961-1990 446 . Overall, 29 clusters were associated with common source transmission from contaminated solutions or equipment, 14 with person-to-person transmission from or involving healthcare personnel and ten associated with airborne or droplet transmission among patients and healthcare workers. Transmission of bloodborne pathogens (i.e., hepatitis B and C viruses and, rarely, HIV) in outbreaks, sometimes involving hundreds of patients, continues to occur in ambulatory settings. These outbreaks often are related to common source exposures, usually a contaminated medical device, multi-dose vial, or intravenous solution 82, . In all cases, transmission has been attributed to failure to adhere to fundamental infection control principles, including safe injection practices and aseptic technique.This subject has been reviewed and recommended infection control and safe injection practices summarized 454 . Airborne transmission of M.tuberculosis and measles in ambulatory settings, most frequently emergency departments, has been reported 34,127,446,448, . Measles virus was transmitted in physician offices and other outpatient settings during an era when immunization rates were low and measles outbreaks in the community were occurring regularly 34,122,458 . Rubella has been transmitted in the outpatient obstetric setting 33 ; there are no published reports of varicella transmission in the outpatient setting. In the ophthalmology setting, adenovirus type 8 epidemic keratoconjunctivitis has been transmitted via incompletely disinfected ophthalmology equipment and/or from healthcare workers to patients, presumably by contaminated hands 17,446,448, . If transmission in outpatient settings is to be prevented, screening for potentially infectious symptomatic and asymptomatic individuals, especially those who may be at risk for transmitting airborne infectious agents (e.g., M. tuberculosis, varicella-zoster virus, rubeola ), is necessary at the start of the initial patient encounter. Upon identification of a potentially infectious patient, implementation of prevention measures, including prompt separation of potentially infectious patients and implementation of appropriate control measures (e.g., Respiratory Hygiene/Cough Etiquette and Transmission-Based Precautions) can decrease transmission risks 9,12 . Transmission of MRSA and VRE in outpatient settings has not been reported, but the association of CA-MRSA in healthcare personnel working in an outpatient HIV clinic with environmental CA-MRSA contamination in that clinic, suggests the possibility of transmission in that setting 463 . Patient-to-patient transmission of Burkholderia species and Pseudomonas aeruginosa in outpatient clinics for adults and children with cystic fibrosis has been confirmed 464,465 . # I.D.2.c. Home care. Home care in the United States is delivered by over 20,000 provider agencies that include home health agencies, hospices, durable medical equipment providers, home infusion therapy services, and personal care and support services providers. Home care is provided to patients of all ages with both acute and chronic conditions. The scope of services ranges from assistance with activities of daily living and physical and occupational therapy to the care of wounds, infusion therapy, and chronic ambulatory peritoneal dialysis (CAPD). The incidence of infection in home care patients, other than those associated with infusion therapy is not well studied . However, data collection and calculation of infection rates have been accomplished for central venous catheter-associated bloodstream infections in patients receiving home infusion therapy and for the risk of blood contact through percutaneous or mucosal exposures, demonstrating that surveillance can be performed in this setting 475 . Draft definitions for home care associated infections have been developed 476 . Transmission risks during home care are presumed to be minimal. The main transmission risks to home care patients are from an infectious healthcare provider or contaminated equipment; providers also can be exposed to an infectious patient during home visits. Since home care involves patient care by a limited number of personnel in settings without multiple patients or shared equipment, the potential reservoir of pathogens is reduced. Infections of home care providers, that could pose a risk to home care patients include infections transmitted by the airborne or droplet routes (e.g., chickenpox, tuberculosis, influenza), and skin infestations (e.g., scabies 69 and lice) and infections (e.g.,impetigo) transmitted by direct or indirect contact. There are no published data on indirect transmission of MDROs from one home care patient to another, although this is theoretically possible if contaminated equipment is transported from an infected or colonized patient and used on another patient. Of note, investigation of the first case of VISA in homecare 186 and the first 2 reported cases of VRSA 178,180,181,183 found no evidence of transmission of VISA or VRSA to other home care recipients. Home health care also may contribute to antimicrobial resistance; a review of outpatient vancomycin use found 39% of recipients did not receive the antibiotic according to recommended guidelines 477 . Although most home care agencies implement policies and procedures to prevent transmission of organisms, the current approach is based on the adaptation of the 1996 Guideline for Isolation Precautions in Hospitals 1 as well as other professional guidance 478,479 . This issue has been very challenging in the home care industry and practice has been inconsistent and frequently not evidence-based. For example, many home health agencies continue to observe "nursing bag technique," a practice that prescribes the use of barriers between the nursing bag and environmental surfaces in the home 480. While the home environment may not always appear clean, the use of barriers between two non-critical surfaces has been questioned 481,482 . Opportunites exist to conduct research in home care related to infection transmission risks 483 . # I.D.2.d. Other sites of healthcare delivery. Facilities that are not primarily healthcare settings but in which healthcare is delivered include clinics in correctional facilities and shelters. Both settings can have suboptimal features, such as crowded conditions and poor ventilation. Economically disadvantaged individuals who may have chronic illnesses and healthcare problems related to alcoholism, injection drug use, poor nutrition, and/or inadequate shelter often receive their primary healthcare at sites such as these 484 . Infectious diseases of special concern for transmission include tuberculosis, scabies, respiratory infections (e.g., N. meningitides, S. pneumoniae), sexually transmitted and bloodborne diseases (e.g.,HIV, HBV, HCV, syphilis, gonorrhea), hepatitis A virus (HAV), diarrheal agents such as norovirus, and foodborne diseases 286, . A high index of suspicion for tuberculosis and CA-MRSA in these populations is needed as outbreaks in these settings or among the populations they serve have been reported . Patient encounters in these types of facilities provide an opportunity to deliver recommended immunizations and screen for M. tuberculosis infection in addition to diagnosing and treating acute illnesses 498 . Recommended infection control measures in these non-traditional areas designated for healthcare delivery are the same as for other ambulatory care settings. Therefore, these settings must be equipped to observe Standard Precautions and, when indicated, Transmission-based Precautions. # I.E. Transmission Risks Associated with Special Patient Populations As new treatments emerge for complex diseases, unique infection control challenges associated with special patient populations need to be addressed. # I.E.1. Immunocompromised patients. Patients who have congenital primary immune deficiencies or acquired disease (eg. treatment-induced immune deficiencies) are at increased risk for numerous types of infections while receiving healthcare and may be located throughout the healthcare facility. The specific defects of the immune system determine the types of infections that are most likely to be acquired (e.g., viral infections are associated with T-cell defects and fungal and bacterial infections occur in patients who are neutropenic). As a general group, immunocompromised patients can be cared for in the same environment as other patients; however, it is always advisable to minimize exposure to other patients with transmissible infections such as influenza and other respiratory viruses 499,500 . The use of more intense chemotherapy regimens for treatment of childhood leukemia may be associated with prolonged periods of neutropenia and suppression of other components of the immune system, extending the period of infection risk and raising the concern that additional precautions may be indicated for select groups 501,502 . With the application of newer and more intense immunosuppressive therapies for a variety of medical conditions (e.g., rheumatologic disease 503,504 , inflammatory bowel disease 505 ), immunosuppressed patients are likely to be more widely distributed throughout a healthcare facility rather than localized to single patient units (e.g., hematology-oncology). Guidelines for preventing infections in certain groups of immunocompromised patients have been published 15,506,507 . Published data provide evidence to support placing allogeneic HSCT patients in a Protective Environment 15,157,158 . Also, three guidelines have been developed that address the special requirements of these immunocompromised patients, including use of antimicrobial prophylaxis and engineering controls to create a Protective Environment for the prevention of infections caused by Aspergillus spp. and other environmental fungi 11,14,15 . As more intense chemotherapy regimens associated with prolonged periods of neutropenia or graft-versus-host disease are implemented, the period of risk and duration of environmental protection may need to be prolonged beyond the traditional 100 days 508 . # I.E.2. Cystic fibrosis patients. Patients with cystic fibrosis (CF) require special consideration when developing infection control guidelines. Compared to other patients, CF patients require additional protection to prevent transmission from contaminated respiratory therapy equipment . Infectious agents such as Burkholderia cepacia complex and P. aeruginosa 464,465,514,515 have unique clinical and prognostic significance. In CF patients, B. cepacia infection has been associated with increased morbidity and mortality , while delayed acquisition of chronic P.aeruginosa infection may be associated with an improved long-term clinical outcome 519,520 . Person-to-person transmission of B. cepacia complex has been demonstrated among children 517 and adults 521 with CF in healthcare settings 464,522 , during various social contacts 523 , most notably attendance at camps for patients with CF 524 , and among siblings with CF 525 . Successful infection control measures used to prevent transmission of respiratory secretions include segregation of CF patients from each other in ambulatory and hospital settings (including use of private rooms with separate showers), environmental decontamination of surfaces and equipment contaminated with respiratory secretions, elimination of group chest physiotherapy sessions, and disbanding of CF camps 97,526 . The Cystic Fibrosis Foundation published a consensus document with evidence-based recommendations for infection control practices for CF patients 20 . # I.F. New Therapies Associated with Potentially Transmissible Infectious Agents I.F.1. Gene therapy. Gene therapy has has been attempted using a number of different viral vectors, including nonreplicating retroviruses, adenoviruses, adeno-associated viruses, and replication-competent strains of poxviruses. Unexpected adverse events have restricted the prevalence of gene therapy protocols. The infectious hazards of gene therapy are theoretical at this time, but require meticulous surveillance due to the possible occurrence of in vivo recombination and the subsequent emergence of a transmissible genetically altered pathogen. Greatest concern attends the use of replication-competent viruses, especially vaccinia. As of the time of publication, no reports have described transmission of a vector virus from a gene therapy recipient to another individual, but surveillance is ongoing. Recommendations for monitoring infection control issues throughout the course of gene therapy trials have been published . # I.F.2. Infections transmitted through blood, organs and other tissues. The potential hazard of transmitting infectious pathogens through biologic products is a small but ever present risk, despite donor screening. Reported infections transmitted by transfusion or transplantation include West Nile Virus infection 530 cytomegalovirus infection 531 , Creutzfeldt-Jacob disease 230 , hepatitis C 532 , infections with Clostridium spp. 533 and group A streptococcus 534 , malaria 535 , babesiosis 536 , Chagas disease 537 , lymphocytic choriomeningitis 538 , and rabies 539,540 . Therefore, it is important to consider receipt of biologic products when evaluating patients for potential sources of infection. # I.F.3. Xenotransplantation. The transplantation of nonhuman cells, tissues, and organs into humans potentially exposes patients to zoonotic pathogens. Transmission of known zoonotic infections (e.g., trichinosis from porcine tissue), constitutes one concern, but also of concern is the possibility that transplantation of nonhuman cells, tissues, or organs may transmit previously unknown zoonotic infections (xenozoonoses) to immunosuppressed human recipients. Potential infections that might accompany transplantation of porcine organs have been described 541 . Guidelines from the U.S. Public Health Service address many infectious diseases and infection control issues that surround the developing field of xenotransplantation, 542 work in this area is ongoing. # Part II: Fundamental Elements Needed to Prevent Transmission of Infectious Agents in Healthcare Settings # II.A. Healthcare System Components that Influence the Effectiveness of Precautions to Prevent Transmission # II.A.1. Administrative measures. Healthcare organizations can demonstrate a commitment to preventing transmission of infectious agents by incorporating infection control into the objectives of the organization's patient and occupational safety programs . An infrastructure to guide, support, and monitor adherence to Standard and Transmission-Based Precautions 434,548,549 will facilitate fulfillment of the organization's mission and achievement of the Joint Commission on Accreditation of Healthcare Organization's patient safety goal to decrease HAIs 550 . Policies and procedures that explain how Standard and Transmission-Based Precautions are applied, including systems used to identify and communicate information about patients with potentially transmissible infectious agents, are essential to ensure the success of these measures and may vary according to the characteristics of the organization. A key administrative measure is provision of fiscal and human resources for maintaining infection control and occupational health programs that are responsive to emerging needs. Specific components include bedside nurse 551 and infection prevention and control professional (ICP) staffing levels 552 , inclusion of ICPs in facility construction and design decisions 11 , clinical microbiology laboratory support 553,554 , adequate supplies and equipment including facility ventilation systems 11 , adherence monitoring 555 , assessment and correction of system failures that contribute to transmission 556,557 , and provision of feedback to healthcare personnel and senior administrators 434,548,549,558 . The positive influence of institutional leadership has been demonstrated repeatedly in studies of HCW adherence to recommended hand hygiene practices 176,177,434,548,549, . Healthcare administrator involvement in infection control processes can improve administrators' awareness of the rationale and resource requirements for following recommended infection control practices. Several administrative factors may affect the transmission of infectious agents in healthcare settings: institutional culture, individual worker behavior, and the work environment. Each of these areas is suitable for performance improvement monitoring and incorporation into the organization's patient safety goals 543,544,546,565 . # II.A.1.a.Scope of work and staffing needs for infection control professionals. The effectiveness of infection surveillance and control programs in preventing nosocomial infections in United States hospitals was assessed by the CDC through the Study on the Efficacy of Nosocomial Infection Control (SENIC Project) conducted 1970-76 566 . In a representative sample of US general hospitals, those with a trained infection control physician or microbiologist involved in an infection control program, and at least one infection control nurse per 250 beds, were associated with a 32% lower rate of four infections studied (CVC-associated bloodstream infections, ventilator-associated pneumonias, catheter-related urinary tract infections, and surgical site infections). Since that landmark study was published, responsibilities of ICPs have expanded commensurate with the growing complexity of the healthcare system, the patient populations served, and the increasing numbers of medical procedures and devices used in all types of healthcare settings. The scope of work of ICPs was first assessed in 1982 by the Certification Board of Infection Control (CBIC), and has been reassessed every five years since that time 558, . The findings of these task analyses have been used to develop and update the Infection Control Certification Examination, offered for the first time in 1983. With each survey, it is apparent that the role of the ICP is growing in complexity and scope, beyond traditional infection control activities in acute care hospitals. Activities currently assigned to ICPs in response to emerging challenges include: 1. surveillance and infection prevention at facilities other than acute care hospitals e.g., ambulatory clinics, day surgery centers, long term care facilities, rehabilitation centers, home care; 2. oversight of employee health services related to infection prevention, e.g., assessment of risk and administration of recommended treatment following exposure to infectious agents, tuberculosis screening, influenza vaccination, respiratory protection fit testing, and administration of other vaccines as indicated, such as smallpox vaccine in 2003; 3. preparedness planning for annual influenza outbreaks, pandemic influenza, SARS, bioweapons attacks; 4. adherence monitoring for selected infection control practices; 5. oversight of risk assessment and implementation of prevention measures associated with construction and renovation; 6. prevention of transmission of MDROs; 7. evaluation of new medical products that could be associated with increased infection risk. e.g.,intravenous infusion materials; 8. communication with the public, facility staff, and state and local health departments concerning infection control-related issues; and 9. participation in local and multi-center research projects 434,549,552,558,573,574 . None of the CBIC job analyses addressed specific staffing requirements for the identified tasks, although the surveys did include information about hours worked; the 2001 survey included the number of ICPs assigned to the responding facilities 558 . There is agreement in the literature that 1 ICP per 250 acute care beds is no longer adequate to meet current infection control needs; a Delphi project that assessed staffing needs of infection control programs in the 21st century concluded that a ratio of 0.8 to 1.0 ICP per 100 occupied acute care beds is an appropriate level of staffing 552 . A survey of participants in the National Nosocomial Infections Surveillance (NNIS) system found the average daily census per ICP was 115 316 . Results of other studies have been similar: 3 per 500 beds for large acute care hospitals, 1 per 150-250 beds in long term care facilities, and 1.56 per 250 in small rural hospitals 573,575 . The foregoing demonstrates that infection control staffing can no longer be based on patient census alone, but rather must be determined by the scope of the program, characteristics of the patient population, complexity of the healthcare system, tools available to assist personnel to perform essential tasks (e.g., electronic tracking and laboratory support for surveillance), and unique or urgent needs of the institution and community 552 . Furthermore, appropriate training is required to optimize the quality of work performed 558,572,576 . # II.A.1.a.i. Infection control nurse liaison. Designating a bedside nurse on a patient care unit as an infection control liaison or "link nurse" is reported to be an effective adjunct to enhance infection control at the unit level 577-58 2. Such individuals receive training in basic infection control and have frequent communication with the ICPs, but maintain their primary role as bedside caregiver on their units. The infection control nurse liaison increases the awareness of infection control at the unit level. He or she is especially effective in implementation of new policies or control interventions because of the rapport with individuals on the unit, an understanding of unit-specific challenges, and ability to promote strategies that are most likely to be successful in that unit. This position is an adjunct to, not a replacement for, fully trained ICPs. Furthermore, the infection control liaison nurses should not be counted when considering ICP staffing. # II.A.1.b. Bedside nurse staffing. There is increasing evidence that the level of bedside nurse-staffing influences the quality of patient care 583,584 . If there are adequate nursing staff, it is more likely that infection control practices, including hand hygiene and Standard and Transmission-Based Precautions, will be given appropriate attention and applied correctly and consistently 552 . A national multicenter study reported strong and consistent inverse relationships between nurse staffing and five adverse outcomes in medical patients, two of which were HAIs: urinary tract infections and pneumonia 583 . The association of nursing staff shortages with increased rates of HAIs has been demonstrated in several outbreaks in hospitals and long term care settings, and with increased transmission of hepatitis C virus in dialysis units 22,418,551, . In most cases, when staffing improved as part of a comprehensive control intervention, the outbreak ended or the HAI rate declined. In two studies 590,596 , the composition of the nursing staff ("pool" or "float" vs. regular staff nurses) influenced the rate of primary bloodstream infections, with an increased infection rate occurring when the proportion of regular nurses decreased and pool nurses increased. # II.A.1.c. Clinical microbiology laboratory support. The critical role of the clinical microbiology laboratory in infection control and healthcare epidemiology is described well 553,554, and is supported by the Infectious Disease Society of America policy statement on consolidation of clinical microbiology laboratories published in 2001 553 . The clinical microbiology laboratory contributes to preventing transmission of infectious diseases in healthcare settings by promptly detecting and reporting epidemiologically important organisms, identifying emerging patterns of antimicrobial resistance, and assisting in assessment of the effectiveness of recommended precautions to limit transmission during outbreaks 598 . Outbreaks of infections may be recognized first by laboratorians 162 . Healthcare organizations need to ensure the availability of the recommended scope and quality of laboratory services, a sufficient number of appropriately trained laboratory staff members, and systems to promptly communicate epidemiologically important results to those who will take action (e.g., providers of clinical care, infection control staff, healthcare epidemiologists, and infectious disease consultants) 601 . As concerns about emerging pathogens and bioterrorism grow, the role of the clinical microbiology laboratory takes on even greater importance. For healthcare organizations that outsource microbiology laboratory services (e.g., ambulatory care, home care, LTCFs, smaller acute care hospitals), it is important to specify by contract the types of services (e.g., periodic institution-specific aggregate susceptibility reports) required to support infection control. Several key functions of the clinical microbiology laboratory are relevant to this guideline: - Antimicrobial susceptibility by testing and interpretation in accordance with current guidelines developed by the National Committee for Clinical Laboratory Standards (NCCLS), known as the Clinical and Laboratory Standards Institute (CLSI) since 2005 602 , for the detection of emerging resistance patterns 603,604 , and for the preparation, analysis, and distribution of periodic cumulative antimicrobial susceptibility summary reports . While not required, clinical laboratories ideally should have access to rapid genotypic identification of bacteria and their antibiotic resistance genes 608 . - Performance of surveillance cultures when appropriate (including retention of isolates for analysis) to assess patterns of infection transmission and effectiveness of infection control interventions at the facility or organization. Microbiologists assist in decisions concerning the indications for initiating and discontinuing active surveillance programs and optimize the use of laboratory resources. - Molecular typing, on-site or outsourced, in order to investigate and control healthcare-associated outbreaks 609 . - Application of rapid diagnostic tests to support clinical decisions involving patient treatment, room selection, and implementation of control measures including barrier precautions and use of vaccine or chemoprophylaxis agents (e.g., influenza , B. pertussis 613 , RSV 614,615 , and enteroviruses 616 ). The microbiologist provides guidance to limit rapid testing to clinical situations in which rapid results influence patient management decisions, as well as providing oversight of point-of-care testing performed by non-laboratory healthcare workers 617 . - Detection and rapid reporting of epidemiologically important organisms, including those that are reportable to public health agencies. - Implementation of a quality control program that ensures testing services are appropriate for the population served, and stringently evaluated for sensitivity, specificity, applicability, and feasibility. - Participation in a multidisciplinary team to develop and maintain an effective institutional program for the judicious use of antimicrobial agents 618,619 . # II.A.2. Institutional safety culture and organizational characteristics. Safety culture (or safety climate) refers to a work environment where a shared commitment to safety on the part of management and the workforce is understood and followed 557,620,621 . The authors of the Institute of Medicine Report, To Err is Human 543 , acknowledge that causes of medical error are multifaceted but emphasize repeatedly the pivotal role of system failures and the benefits of a safety culture. A safety culture is created through 1. the actions management takes to improve patient and worker safety; 2. worker participation in safety planning; 3. the availability of appropriate protective equipment; 4. influence of group norms regarding acceptable safety practices; and 5. the organization's socialization process for new personnel. Safety and patient outcomes can be enhanced by improving or creating organizational characteristics within patient care units as demonstrated by studies of surgical ICUs 622,623 . Each of these factors has a direct bearing on adherence to transmission prevention recommendations 257 . Measurement of an institutional culture of safety is useful for designing improvements in healthcare 624,625 . Several hospital-based studies have linked measures of safety culture with both employee adherence to safe practices and reduced exposures to blood and body fluids . One study of hand hygiene practices concluded that improved adherence requires integration of infection control into the organization's safety culture 561 . Several hospitals that are part of the Veterans Administration Healthcare System have taken specific steps toward improving the safety culture, including error reporting mechanisms, performing root cause analysis on problems identified, providing safety incentives, and employee education. . # II.A.3. Adherence of healthcare personnel to recommended guidelines. Adherence to recommended infection control practices decreases transmission of infectious agents in healthcare settings 116,562, . However, several observational studies have shown limited adherence to recommended practices by healthcare personnel 559, . Observed adherence to universal precautions ranged from 43% to 89% 641,642,649,651,652 . However, the degree of adherence depended frequently on the practice that was assessed and, for glove use, the circumstance in which they were used. Appropriate glove use has ranged from a low of 15% 645 to a high of 82% 650 . However, 92% and 98% adherence with glove use have been reported during arterial blood gas collection and resuscitation, respectively, procedures where there may be considerable blood contact 643,656 . Differences in observed adherence have been reported among occupational groups in the same healthcare facility 641 and between experienced and nonexperienced professionals 645 . In surveys of healthcare personnel, self-reported adherence was generally higher than that reported in observational studies. Furthermore, where an observational component was included with a self-reported survey, self-perceived adherence was often greater than observed adherence 657 . Among nurses and physicians, increasing years of experience is a negative predictor of adherence 645,651 . Education to improve adherence is the primary intervention that has been studied. While positive changes in knowledge and attitude have been demonstrated 640,658 , there often has been limited or no accompanying change in behavior 642,644 . Self-reported adherence is higher in groups that have received an educational intervention 630,659 . Educational interventions that incorporated videotaping and performance feedback were successful in improving adherence during the period of study; the long-term effect of these interventions is not known 654 .The use of videotape also served to identify system problems (e.g., communication and access to personal protective equipment) that otherwise may not have been recognized. Use of engineering controls and facility design concepts for improving adherence is gaining interest. While introduction of automated sinks had a negative impact on consistent adherence to hand washing 660 , use of electronic monitoring and voice prompts to remind healthcare workers to perform hand hygiene, and improving accessibility to hand hygiene products, increased adherence and contributed to a decrease in HAIs in one study 661 . More information is needed regarding how technology might improve adherence. Improving adherence to infection control practices requires a multifaceted approach that incorporates continuous assessment of both the individual and the work environment 559,561 . Using several behavioral theories, Kretzer and Larson concluded that a single intervention (e.g., a handwashing campaign or putting up new posters about transmission precautions) would likely be ineffective in improving healthcare personnel adherence 662 . Improvement requires that the organizational leadership make prevention an institutional priority and integrate infection control practices into the organization's safety culture 561 . A recent review of the literature concluded that variations in organizational factors (e.g., safety climate, policies and procedures, education and training) and individual factors (e.g., knowledge, perceptions of risk, past experience) were determinants of adherence to infection control guidelines for protection against SARS and other respiratory pathogens 257 . # II.B. Surveillance for Healthcare-Associated Infections (HAIs) Surveillance is an essential tool for case-finding of single patients or clusters of patients who are infected or colonized with epidemiologically important organisms (e.g., susceptible bacteria such as S. aureus, S. pyogenes or Enterobacter-Klebsiella spp; MRSA, VRE, and other MDROs; C. difficile; RSV; influenza virus) for which transmission-based precautions may be required. Surveillance is defined as the ongoing, systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health 663 . The work of Ignaz Semmelweis that described the role of person-to-person transmission in puerperal sepsis is the earliest example of the use of surveillance data to reduce transmission of infectious agents 664 . Surveillance of both process measures and the infection rates to which they are linked are important for evaluating the effectiveness of infection prevention efforts and identifying indications for change 555, . The Study on the Efficacy of Nosocomial Infection Control (SENIC) found that different combinations of infection control practices resulted in reduced rates of nosocomial surgical site infections, pneumonia, urinary tract infections, and bacteremia in acute care hospitals 566 ; however, surveillance was the only component essential for reducing all four types of HAIs. Although a similar study has not been conducted in other healthcare settings, a role for surveillance and the need for novel strategies have been described in LTCFs 398,434,669,670 and in home care . The essential elements of a surveillance system are: 1. standardized definitions; 2. identification of patient populations at risk for infection; 3. statistical analysis (e.g., risk-adjustment, calculation of rates using appropriate denominators, trend analysis using methods such as statistical process control charts); and 4. feedback of results to the primary caregivers . Data gathered through surveillance of high-risk populations, device use, procedures, and/or facility locations (e.g., ICUs) are useful for detecting transmission trends . Identification of clusters of infections should be followed by a systematic epidemiologic investigation to determine commonalities in persons, places, and time; and guide implementation of interventions and evaluation of the effectiveness of those interventions. Targeted surveillance based on the highest risk areas or patients has been preferred over facility-wide surveillance for the most effective use of resources 673,676 . However, surveillance for certain epidemiologically important organisms may need to be facilitywide. Surveillance methods will continue to evolve as healthcare delivery systems change 392,677 and user-friendly electronic tools become more widely available for electronic tracking and trend analysis 674,678,679 . Individuals with experience in healthcare epidemiology and infection control should be involved in selecting software packages for data aggregation and analysis to assure that the need for efficient and accurate HAI surveillance will be met. Effective surveillance is increasingly important as legislation requiring public reporting of HAI rates is passed and states work to develop effective systems to support such legislation 680 . # II.C. Education of HCWs, Patients, and Families Education and training of healthcare personnel are a prerequisite for ensuring that policies and procedures for Standard and Transmission-Based Precautions are understood and practiced. Understanding the scientific rationale for the precautions will allow HCWs to apply procedures correctly, as well as safely modify precautions based on changing requirements, resources, or healthcare settings 14,655, . In one study, the likelihood of HCWs developing SARS was strongly associated with less than 2 hours of infection control training and lack of understanding of infection control procedures 689 . Education about the important role of vaccines (e.g., influenza, measles, varicella, pertussis, pneumococcal) in protecting healthcare personnel, their patients, and family members can help improve vaccination rates . Education on the principles and practices for preventing transmission of infectious agents should begin during training in the health professions and be provided to anyone who has an opportunity for contact with patients or medical equipment (e.g., nursing and medical staff; therapists and technicians, including respiratory, physical, occupational, radiology, and cardiology personnel; phlebotomists; housekeeping and maintenance staff; and students). In healthcare facilities, education and training on Standard and Transmission-Based Precautions are typically provided at the time of orientation and should be repeated as necessary to maintain competency; updated education and training are necessary when policies and procedures are revised or when there is a special circumstance, such as an outbreak that requires modification of current practice or adoption of new recommendations. Education and training materials and methods appropriate to the HCW's level of responsibility, individual learning habits, and language needs, can improve the learning experience 658, . Education programs for healthcare personnel have been associated with sustained improvement in adherence to best practices and a related decrease in deviceassociated HAIs in teaching and non-teaching settings 639,703 Several studies have shown that, in addition to targeted education to improve specific practices, periodic assessment and feedback of the HCWs knowledge,and adherence to recommended practices are necessary to achieve the desired changes and to identify continuing education needs 562, . Effectiveness of this approach for isolation practices has been demonstrated for control of RSV 116,684 . Patients, family members, and visitors can be partners in preventing transmission of infections in healthcare settings 9,42, . Information about Standard Precautions, especially hand hygiene, Respiratory Hygiene/Cough Etiquette, vaccination (especially against influenza) and other routine infection prevention strategies may be incorporated into patient information materials that are provided upon admission to the healthcare facility. Additional information about Transmission-Based Precautions is best provided at the time they are initiated. Fact sheets, pamphlets, and other printed material may include information on the rationale for the additional precautions, risks to household members, room assignment for Transmission-Based Precautions purposes, explanation about the use of personal protective equipment by HCWs, and directions for use of such equipment by family members and visitors. Such information may be particularly helpful in the home environment where household members often have primary responsibility for adherence to recommended infection control practices. Healthcare personnel must be available and prepared to explain this material and answer questions as needed. # II.D. Hand Hygiene Hand hygiene has been cited frequently as the single most important practice to reduce the transmission of infectious agents in healthcare settings 559,712,713 and is an essential element of Standard Precautions. The term "hand hygiene" includes both handwashing with either plain or antiseptic-containing soap and water, and use of alcohol-based products (gels, rinses, foams) that do not require the use of water. In the absence of visible soiling of hands, approved alcohol-based products for hand disinfection are preferred over antimicrobial or plain soap and water because of their superior microbiocidal activity, reduced drying of the skin, and convenience 559 . Improved hand hygiene practices have been associated with a sustained decrease in the incidence of MRSA and VRE infections primarily in the ICU 561,562, . The scientific rationale, indications, methods, and products for hand hygiene are summarized in other publications 559,717 . The effectiveness of hand hygiene can be reduced by the type and length of fingernails 559,718,719 . Individuals wearing artifical nails have been shown to harbor more pathogenic organisms, especially gram negative bacilli and yeasts, on the nails and in the subungual area than those with native nails 720,721 . In 2002, CDC/HICPAC recommended (Category IA) that artificial fingernails and extenders not be worn by healthcare personnel who have contact with high-risk patients (e.g., those in ICUs, ORs) due to the association with outbreaks of gram-negative bacillus and candidal infections as confirmed by molecular typing of isolates 30,31,559, .The need to restrict the wearing of artificial fingernails by all healthcare personnel who provide direct patient care or by healthcare personnel who have contact with other high risk groups (e.g., oncology, cystic fibrosis patients), has not been studied, but has been recommended by some experts 20 . At this time such decisions are at the discretion of an individual facility's infection control program. There is less evidence that jewelry affects the quality of hand hygiene. Although hand contamination with potential pathogens is increased with ringwearing 559,726 , no studies have related this practice to HCW-to-patient transmission of pathogens. # II.E. Personal Protective Equipment (PPE) for Healthcare Personnel PPE refers to a variety of barriers and respirators used alone or in combination to protect mucous membranes, airways, skin, and clothing from contact with infectious agents. The selection of PPE is based on the nature of the patient interaction and/or the likely mode(s) of transmission. Guidance on the use of PPE is discussed in Part III. A suggested procedure for donning and removing PPE that will prevent skin or clothing contamination is presented in the Figure . Designated containers for used disposable or reusable PPE should be placed in a location that is convenient to the site of removal to facilitate disposal and containment of contaminated materials. Hand hygiene is always the final step after removing and disposing of PPE. The following sections highlight the primary uses and methods for selecting this equipment. # II.E.1. Gloves. Gloves are used to prevent contamination of healthcare personnel hands when 1. anticipating direct contact with blood or body fluids, mucous membranes, nonintact skin and other potentially infectious material; 2. having direct contact with patients who are colonized or infected with pathogens transmitted by the contact route e.g., VRE, MRSA, RSV 559,727,728 ; or 3. handling or touching visibly or potentially contaminated patient care equipment and environmental surfaces 72,73,559 . Gloves can protect both patients and healthcare personnel from exposure to infectious material that may be carried on hands 73 . The extent to which gloves will protect healthcare personnel from transmission of bloodborne pathogens (e.g., HIV, HBV, HCV) following a needlestick or other pucture that penetrates the glove barrier has not been determined. Although gloves may reduce the volume of blood on the external surface of a sharp by 46-86% 729 , the residual blood in the lumen of a hollowbore needle would not be affected; therefore, the effect on transmission risk is unknown. Gloves manufactured for healthcare purposes are subject to FDA evaluation and clearance 730 . Nonsterile disposable medical gloves made of a variety of materials (e.g., latex, vinyl, nitrile) are available for routine patient care 731 . The selection of glove type for non-surgical use is based on a number of factors, including the task that is to be performed, anticipated contact with chemicals and chemotherapeutic agents, latex sensitivity, sizing, and facility policies for creating a latex-free environment 17, . For contact with blood and body fluids during non-surgical patient care, a single pair of gloves generally provides adequate barrier protection 734 . However, there is considerable variability among gloves; both the quality of the manufacturing process and type of material influence their barrier effectiveness 735 . While there is little difference in the barrier properties of unused intact gloves 736 , studies have shown repeatedly that vinyl gloves have higher failure rates than latex or nitrile gloves when tested under simulated and actual clinical conditions 731, . For this reason either latex or nitrile gloves are preferable for clinical procedures that require manual dexterity and/or will involve more than brief patient contact. It may be necessary to stock gloves in several sizes. Heavier, reusable utility gloves are indicated for non-patient care activities, such as handling or cleaning contaminated equipment or surfaces 11,14,739 . During patient care, transmission of infectious organisms can be reduced by adhering to the principles of working from "clean" to "dirty", and confining or limiting contamination to surfaces that are directly needed for patient care. It may be necessary to change gloves during the care of a single patient to prevent cross-contamination of body sites 559,740 . It also may be necessary to change gloves if the patient interaction also involves touching portable computer keyboards or other mobile equipment that is transported from room to room. Discarding gloves between patients is necessary to prevent transmission of infectious material. Gloves must not be washed for subsequent reuse because microorganisms cannot be removed reliably from glove surfaces and continued glove integrity cannot be ensured. Furthermore, glove reuse has been associated with transmission of MRSA and gram-negative bacilli . When gloves are worn in combination with other PPE, they are put on last. Gloves that fit snugly around the wrist are preferred for use with an isolation gown because they will cover the gown cuff and provide a more reliable continuous barrier for the arms, wrists, and hands. Gloves that are removed properly will prevent hand contamination (Figure ). Hand hygiene following glove removal further ensures that the hands will not carry potentially infectious material that might have penetrated through unrecognized tears or that could contaminate the hands during glove removal 559,728,741 . # II.E.2. Isolation gowns. Isolation gowns are used as specified by Standard and Transmission-Based Precautions, to protect the HCW's arms and exposed body areas and prevent contamination of clothing with blood, body fluids, and other potentially infectious material 24,88,262, . The need for and type of isolation gown selected is based on the nature of the patient interaction, including the anticipated degree of contact with infectious material and potential for blood and body fluid penetration of the barrier. The wearing of isolation gowns and other protective apparel is mandated by the OSHA Bloodborne Pathogens Standard 739 . Clinical and laboratory coats or jackets worn over personal clothing for comfort and/or purposes of identity are not considered PPE. When applying Standard Precautions, an isolation gown is worn only if contact with blood or body fluid is anticipated. However, when Contact Precautions are used (i.e., to prevent transmission of an infectious agent that is not interrupted by Standard Precautions alone and that is associated with environmental contamination), donning of both gown and gloves upon room entry is indicated to address unintentional contact with contaminated environmental surfaces 54,72,73,88 . The routine donning of isolation gowns upon entry into an intensive care unit or other high-risk area does not prevent or influence potential colonization or infection of patients in those areas 365, . Isolation gowns are always worn in combination with gloves, and with other PPE when indicated. Gowns are usually the first piece of PPE to be donned. Full coverage of the arms and body front, from neck to the mid-thigh or below will ensure that clothing and exposed upper body areas are protected. Several gown sizes should be available in a healthcare facility to ensure appropriate coverage for staff members. Isolation gowns should be removed before leaving the patient care area to prevent possible contamination of the environment outside the patient's room. Isolation gowns should be removed in a manner that prevents contamination of clothing or skin (Figure). The outer, "contaminated", side of the gown is turned inward and rolled into a bundle, and then discarded into a designated container for waste or linen to contain contamination. # II.E.3. Face protection: masks, goggles, face shields. II.E.3.a. Masks. Masks are used for three primary purposes in healthcare settings: 1. placed on healthcare personnel to protect them from contact with infectious material from patients e.g., respiratory secretions and sprays of blood or body fluids, consistent with Standard Precautions and Droplet Precautions; 2. placed on healthcare personnel when engaged in procedures requiring sterile technique to protect patients from exposure to infectious agents carried in a healthcare worker's mouth or nose, and 3. placed on coughing patients to limit potential dissemination of infectious respiratory secretions from the patient to others (i.e., Respiratory Hygiene/Cough Etiquette). Masks may be used in combination with goggles to protect the mouth, nose and eyes, or a face shield may be used instead of a mask and goggles, to provide more complete protection for the face, as discussed below. Masks should not be confused with particulate respirators that are used to prevent inhalation of small particles that may contain infectious agents transmitted via the airborne route as described below. The mucous membranes of the mouth, nose, and eyes are susceptible portals of entry for infectious agents, as can be other skin surfaces if skin integrity is compromised (e.g., by acne, dermatitis) 66, . Therefore, use of PPE to protect these body sites is an important component of Standard Precautions. The protective effect of masks for exposed healthcare personnel has been demonstrated 93,113,755,756 . Procedures that generate splashes or sprays of blood, body fluids, secretions, or excretions (e.g., endotracheal suctioning, bronchoscopy, invasive vascular procedures) require either a face shield (disposable or reusable) or mask and goggles 93-95, 96, 113, 115, 262, 739, 757 .The wearing of masks, eye protection, and face shields in specified circumstances when blood or body fluid exposures are likely to occur is mandated by the OSHA Bloodborne Pathogens Standard 739 . Appropriate PPE should be selected based on the anticipated level of exposure. Two mask types are available for use in healthcare settings: surgical masks that are cleared by the FDA and required to have fluid-resistant properties, and procedure or isolation masks 758 #2688 . No studies have been published that compare mask types to determine whether one mask type provides better protection than another. Since procedure/isolation masks are not regulated by the FDA, there may be more variability in quality and performance than with surgical masks. Masks come in various shapes (e.g., molded and non-molded), sizes, filtration efficiency, and method of attachment (e.g., ties, elastic, ear loops). Healthcare facilities may find that different types of masks are needed to meet individual healthcare personnel needs. ). NIOSH states that, eye protection must be comfortable, allow for sufficient peripheral vision, and must be adjustable to ensure a secure fit. It may be necessary to provide several different types, styles, and sizes of protective equipment. Indirectly-vented goggles with a manufacturer's anti-fog coating may provide the most reliable practical eye protection from splashes, sprays, and respiratory droplets from multiple angles. Newer styles of goggles may provide better indirect airflow properties to reduce fogging, as well as better peripheral vision and more size options for fitting goggles to different workers. Many styles of goggles fit adequately over prescription glasses with minimal gaps. While effective as eye protection, goggles do not provide splash or spray protection to other parts of the face. # II.E.3.b. Goggles The role of goggles, in addition to a mask, in preventing exposure to infectious agents transmitted via respiratory droplets has been studied only for RSV. Reports published in the mid-1980s demonstrated that eye protection reduced occupational transmission of RSV 760,761 . Whether this was due to preventing hand-eye contact or respiratory dropleteye contact has not been determined. However, subsequent studies demonstrated that RSV transmission is effectively prevented by adherence to Standard plus Contact Precations and that for this virus routine use of goggles is not necessary 24,116,117,684,762 . It is important to remind healthcare personnel that even if Droplet Precautions are not recommended for a specific respiratory tract pathogen, protection for the eyes, nose and mouth by using a mask and goggles, or face shield alone, is necessary when it is likely that there will be a splash or spray of any respiratory secretions or other body fluids as defined in Standard Precautions. Disposable or non-disposable face shields may be used as an alternative to goggles 759 . As compared with goggles, a face shield can provide protection to other facial areas in addition to the eyes. Face shields extending from chin to crown provide better face and eye protection from splashes and sprays; face shields that wrap around the sides may reduce splashes around the edge of the shield. Removal of a face shield, goggles and mask can be performed safely after gloves have been removed, and hand hygiene performed. The ties, ear pieces and/or headband used to secure the equipment to the head are considered "clean" and therefore safe to touch with bare hands. The front of a mask, goggles and face shield are considered contaminated (Figure ). # II.E.4. Respiratory protection. The subject of respiratory protection as it applies to preventing transmission of airborne infectious agents, including the need for and frequency of fit-testing is under scientific review and was the subject of a CDC workshop in 2004 763 . Respiratory protection currently requires the use of a respirator with N95 or higher filtration to prevent inhalation of infectious particles. Information about respirators and respiratory protection programs is summarized in the Guideline for Preventing Transmission of Mycobacterium tuberculosis in Health-care Settings, 2005 (CDC.MMWR 2005; 54: RR-17 12 ). Respiratory protection is broadly regulated by OSHA under the general industry standard for respiratory protection (29CFR1910.134) 764 which requires that U.S. employers in all employment settings implement a program to protect employees from inhalation of toxic materials. OSHA program components include medical clearance to wear a respirator; provision and use of appropriate respirators, including fit-tested NIOSH-certified N95 and higher particulate filtering respirators; education on respirator use and periodic re-evaluation of the respiratory protection program. When selecting particulate respirators, models with inherently good fit characteristics (i.e., those expected to provide protection factors of 10 or more to 95% of wearers) are preferred and could theoretically relieve the need for fit testing 765,766 . Issues pertaining to respiratory protection remain the subject of ongoing debate. Information on various types of respirators may be found at and in published studies 765,767,768 . A user-seal check (formerly called a "fit check") should be performed by the wearer of a respirator each time a respirator is donned to minimize air leakage around the facepiece 769 . The optimal frequency of fittestng has not been determined; re-testing may be indicated if there is a change in facial features of the wearer, onset of a medical condition that would affect respiratory function in the wearer, or a change in the model or size of the initially assigned respirator 12 . Respiratory protection was first recommended for protection of preventing U.S. healthcare personnel from exposure to M. tuberculosis in 1989. That recommendation has been maintained in two successive revisions of the Guidelines for Prevention of Transmission of Tuberculosis in Hospitals and other Healthcare Settings 12,126 . The incremental benefit from respirator use, in addition to administrative and engineering controls (i.e., AIIRs, early recognition of patients likely to have tuberculosis and prompt placement in an AIIR, and maintenance of a patient with suspected tuberculosis in an AIIR until no longer infectious), for preventing transmission of airborne infectious agents (e.g., M. tuberculosis) is undetermined. Although some studies have demonstrated effective prevention of M. tuberculosis transmission in hospitals where surgical masks, instead of respirators, were used in conjunction with other administrative and engineering controls 637,770,771 , CDC currently recommends N95 or higher level respirators for personnel exposed to patients with suspected or confirmed tuberculosis. Currently this is also true for other diseases that could be transmitted through the airborne route, including SARS 262 and smallpox 108,129,772 hhhhhhhh, until inhalational transmission is better defined or healthcare-specific protective equipment more suitable for for preventing infection are developed. Respirators are also currently recommended to be worn during the performance of aerosol-generating procedures (e.g., intubation, bronchoscopy, suctioning) on patients withSARS Co-V infection, avian influenza and pandemic influenza (See Appendix A). Although Airborne Precautions are recommended for preventing airborne transmission of measles and varicella-zoster viruses, there are no data upon which to base a recommendation for respiratory protection to protect susceptible personnel against these two infections; transmission of varicella-zoster virus has been prevented among pediatric patients using negative pressure isolation alone 773 . Whether respiratory protection (i.e., wearing a particulate respirator) would enhance protection from these viruses has not been studied. Since the majority of healthcare personnel have natural or acquired immunity to these viruses, only immune personnel generally care for patients with these infections . Although there is no evidence to suggest that masks are not adequate to protect healthcare personnel in these settings, for purposes of consistency and simplicity, or because of difficulties in ascertaining immunity, some facilities may require the use of respirators for entry into all AIIRs, regardless of the specific infectious agent. Procedures for safe removal of respirators are provided (Figure). In some healthcare settings, particulate respirators used to provide care for patients with M. tuberculosis are reused by the same HCW. This is an acceptable practice providing the respirator is not damaged or soiled, the fit is not compromised by change in shape, and the respirator has not been contaminated with blood or body fluids. There are no data on which to base a recommendation for the length of time a respirator may be reused. # II.F. Safe Work Practices to Prevent HCW Exposure to Bloodborne Pathogens # II.F.1. Prevention of needlesticks and other sharps-related injuries. Injuries due to needles and other sharps have been associated with transmission of HBV, HCV and HIV to healthcare personnel 778,779 . The prevention of sharps injuries has always been an essential element of Universal and now Standard Precautions 1,780 . These include measures to handle needles and other sharp devices in a manner that will prevent injury to the user and to others who may encounter the device during or after a procedure. These measures apply to routine patient care and do not address the prevention of sharps injuries and other blood exposures during surgical and other invasive procedures that are addressed elsewhere . Since 1991, when OSHA first issued its Bloodborne Pathogens Standard to protect healthcare personnel from blood exposure, the focus of regulatory and legislative activity has been on implementing a hierarchy of control measures. This has included focusing attention on removing sharps hazards through the development and use of engineering controls. The federal Needlestick Safety and Prevention Act signed into law in November, 2000 authorized OSHA's revision of its Bloodborne Pathogens Standard to more explicitly require the use of safety-engineered sharp devices 786 . CDC has provided guidance on sharps injury prevention 787,788 , including for the design, implementation and evaluation of a comprehensive sharps injury prevention program 789 . # II.F.2. Prevention of mucous membrane contact. Exposure of mucous membranes of the eyes, nose and mouth to blood and body fluids has been associated with the transmission of bloodborne viruses and other infectious agents to healthcare personnel 66,752,754,779 . The prevention of mucous membrane exposures has always been an element of Universal and now Standard Precautions for routine patient care 1,753 and is subject to OSHA bloodborne pathogen regulations. Safe work practices, in addition to wearing PPE, are used to protect mucous membranes and non-intact skin from contact with potentially infectious material. These include keeping gloved and ungloved hands that are contaminated from touching the mouth, nose, eyes, or face; and positioning patients to direct sprays and splatter away from the face of the caregiver. Careful placement of PPE before patient contact will help avoid the need to make PPE adjustments and possible face or mucous membrane contamination during use. In areas where the need for resuscitation is unpredictable, mouthpieces, pocket resuscitation masks with one-way valves, and other ventilation devices provide an alternative to mouth-to-mouth resuscitation, preventing exposure of the caregiver's nose and mouth to oral and respiratory fluids during the procedure. # II.F.2.a. Precautions during aerosol-generating procedures. The performance of procedures that can generate small particle aerosols (aerosol-generating procedures), such as bronchoscopy, endotracheal intubation, and open suctioning of the respiratory tract, have been associated with transmission of infectious agents to healthcare personnel, including M. tuberculosis 790 , SARS-CoV 93,94,98 and N. meningitidis 95 . Protection of the eyes, nose and mouth, in addition to gown and gloves, is recommended during performance of these procedures in accordance with Standard Precautions. Use of a particulate respirator is recommended during aerosol-generating procedures when the aerosol is likely to contain M. tuberculosis, SARS-CoV, or avian or pandemic influenza viruses. # II.G. Patient Placement II.G.1. Hospitals and long-term care settings. Options for patient placement include single patient rooms, two patient rooms, and multi-bed wards. Of these, single patient rooms are prefered when there is a concern about transmission of an infectious agent. Although some studies have failed to demonstrate the efficacy of single patient rooms to prevent HAIs 791 , other published studies, including one commissioned by the American Institute of Architects and the Facility Guidelines Institute, have documented a beneficial relationship between private rooms and reduction in infectious and noninfectious adverse patient outcomes 792,793 . The AIA notes that private rooms are the trend in hospital planning and design. However, most hospitals and long-term care facilities have multi-bed rooms and must consider many competing priorities when determining the appropriate room placement for patients (e.g., reason for admission; patient characteristics, such as age, gender, mental status; staffing needs; family requests; psychosocial factors; reimbursement concerns). In the absence of obvious infectious diseases that require specified airborne infection isolation rooms (e.g., tuberculosis, SARS, chickenpox), the risk of transmission of infectious agents is not always considered when making placement decisions. When there are only a limited number of single-patient rooms, it is prudent to prioritize them for those patients who have conditions that facilitate transmission of infectious material to other patients (e.g., draining wounds, stool incontinence, uncontained secretions) and for those who are at increased risk of acquisition and adverse outcomes resulting from HAI (e.g., immunosuppression, open wounds, indwelling catheters, anticipated prolonged length of stay, total dependence on HCWs for activities of daily living) 15,24,43,430,794,795 . Single-patient rooms are always indicated for patients placed on Airborne Precautions and in a Protective Environment and are preferred for patients who require Contact or Droplet Precautions 23,24,410,435,796,797 . During a suspected or proven outbreak caused by a pathogen whose reservoir is the gastrointestinal tract, use of single patient rooms with private bathrooms limits opportunities for transmission, especially when the colonized or infected patient has poor personal hygiene habits, fecal incontinence, or cannot be expected to assist in maintaining procedures that prevent transmission of microorganisms (e.g., infants, children, and patients with altered mental status or developmental delay). In the absence of continued transmission, it is not necessary to provide a private bathroom for patients colonized or infected with enteric pathogens as long as personal hygiene practices and Standard Precautions, especially hand hygiene and appropriate environmental cleaning, are maintained. Assignment of a dedicated commode to a patient,and cleaning and disinfecting fixtures and equipment that may have fecal contamination (e.g., bathrooms, commodes 798 , scales used for weighing diapers) and the adjacent surfaces with appropriate agents may be especially important when a single-patient room can not be used since environmental contamination with intestinal tract pathogens is likely from both continent and incontinent patients 54,799 . Results of several studies to determine the benefit of a single-patient room to prevent transmission of Clostridium difficile are inconclusive 167, . Some studies have shown that being in the same room with a colonized or infected patient is not necessarily a risk factor for transmission 791, . However, for children, the risk of healthcare-associated diarrhea is increased with the increased number of patients per room 806 . Thus, patient factors are important determinants of infection transmission risks, and the need for a single-patient room and/or private bathroom for any patient is best determined on a case-by-case basis. Cohorting is the practice of grouping together patients who are colonized or infected with the same organism to confine their care to one area and prevent contact with other patients. Cohorts are created based on clinical diagnosis, microbiologic confirmation when available, epidemiology, and mode of transmission of the infectious agent. It is generally preferred not to place severely immunosuppressed patients in rooms with other patients. Cohorting has been used extensively for managing outbreaks of MDROs including MRSA 22,807 , VRE 638,808,809 , MDR-ESBLs 810 ; Pseudomonas aeruginosa 29 ; methicillin-susceptible Staphylococcus aureus 811 ; RSV 812,813 ; adenovirus keratoconjunctivitis 814 ; rotavirus 815 ; and SARS 816 . Modeling studies provide additional support for cohorting patients to control outbreaks Talon . However, cohorting often is implemented only after routine infection control measures have failed to control an outbreak. Assigning or cohorting healthcare personnel to care only for patients infected or colonized with a single target pathogen limits further transmission of the target pathogen to uninfected patients 740,819 but is difficult to achieve in the face of current staffing shortages in hospitals 583 and residential healthcare sites . However, when continued transmission is occurring after implementing routine infection control measures and creating patient cohorts, cohorting of healthcare personnel may be beneficial. During the seasons when RSV, human metapneumovirus 823 , parainfluenza, influenza, other respiratory viruses 824 , and rotavirus are circulating in the community, cohorting based on the presenting clinical syndrome is often a priority in facilities that care for infants and young children 825 . For example, during the respiratory virus season, infants may be cohorted based soley on the clinical diagnosis of bronchiolitis due to the logistical difficulties and costs associated with requiring microbiologic confirmation prior to room placement, and the predominance of RSV during most of the season. However, when available, single patient rooms are always preferred since a common clinical presentation (e.g., bronchiolitis), can be caused by more than one infectious agent 823,824,826 . Furthermore, the inability of infants and children to contain body fluids, and the close physical contact that occurs during their care, increases infection transmission risks for patients and personnel in this setting 24,795 . # II.G.2. Ambulatory settings. Patients actively infected with or incubating transmissible infectious diseases are seen frequently in ambulatory settings (e.g., outpatient clinics, physicians' offices, emergency departments) and potentially expose healthcare personnel and other patients, family members and visitors 21,34,127,135,142,827 . In response to the global outbreak of SARS in 2003 and in preparation for pandemic influenza, healthcare providers working in outpatient settings are urged to implement source containment measures (e.g., asking couging patients to wear a surgical mask or cover their coughs with tissues) to prevent transmission of respiratory infections, beginning at the point of initial patient encounter 9, 262, 828 as described below in section III.A.1.a. Signs can be posted at the entrance to facilities or at the reception or registration desk requesting that the patient or individuals accompanying the patient promptly inform the receptionist if there are symptoms of a respiratory infection (e.g., cough, flu-like illness, increased production of respiratory secretions). The presence of diarrhea, skin rash, or known or suspected exposure to a transmissible disease (e.g., measles, pertussis, chickenpox, tuberculosis) also could be added. Placement of potentially infectious patients without delay in an examination room limits the number of exposed individuals, e.g., in the common waiting area. In waiting areas, maintaining a distance between symptomatic and non-symptomatic patients (e.g., >3 feet), in addition to source control measures, may limit exposures. However, infections transmitted via the airborne route (e.g., M tuberculosis, measles, chickenpox) require additional precautions 12,125,829 . Patients suspected of having such an infection can wear a surgical mask for source containment, if tolerated, and should be placed in an examination room, preferably an AIIR, as soon as possible. If this is not possible, having the patient wear a mask and segregate him/herself from other patients in the waiting area will reduce opportunities to expose others. Since the person(s) accompanying the patient also may be infectious, application of the same infection control precautions may need to be extended to these persons if they are symptomatic 21,252,830 . For example, family members accompanying children admitted with suspected M. tuberculosis have been found to have unsuspected pulmonary tuberculosis with cavitary lesions, even when asymptomatic 42,831 . Patients with underlying conditions that increase their susceptibility to infection (e.g., those who are immunocompromised 43,44 or have cystic fibrosis 20 ) require special efforts to protect them from exposures to infected patients in common waiting areas. By informing the receptionist of their infection risk upon arrival, appropriate steps may be taken to further protect them from infection. In some cystic fibrosis clinics, in order to avoid exposure to other patients who could be colonized with B. cepacia, patients have been given beepers upon registration so that they may leave the area and receive notification to return when an examination room becomes available 832 . # II.G.3. Home care. In home care, the patient placement concerns focus on protecting others in the home from exposure to an infectious household member. For individuals who are especially vulnerable to adverse outcomes associated with certain infections, it may be beneficial to either remove them from the home or segregate them within the home. Persons who are not part of the household may need to be prohibited from visiting during the period of infectivity. For example, if a patient with pulmonary tuberculosis is contagious and being cared for at home, very young children (<4 years of age) 833 and immunocompromised persons who have not yet been infected should be removed or excluded from the household. During the SARS outbreak of 2003, segregation of infected persons during the communicable phase of the illness was beneficial in preventing household transmission 249,834 . # II.H. Transport of Patients Several principles are used to guide transport of patients requiring Transmission-Based Precautions. In the inpatient and residential settings these include 1. limiting transport of such patients to essential purposes, such as diagnostic and therapeutic procedures that cannot be performed in the patient's room; 2. when transport is necessary, using appropriate barriers on the patient (e.g., mask, gown, wrapping in sheets or use of impervious dressings to cover the affected area(s) when infectious skin lesions or drainage are present, consistent with the route and risk of transmission; 3. notifying healthcare personnel in the receiving area of the impending arrival of the patient and of the precautions necessary to prevent transmission; and 4. for patients being transported outside the facility, informing the receiving facility and the medi-van or emergency vehicle personnel in advance about the type of Transmission-Based Precautions being used. For tuberculosis, additional precautions may be needed in a small shared air space such as in an ambulance 12 . # II.I. Environmental Measures Cleaning and disinfecting non-critical surfaces in patient-care areas are part of Standard Precautions. In general, these procedures do not need to be changed for patients on Transmission-Based Precautions. The cleaning and disinfection of all patient-care areas is important for frequently touched surfaces, especially those closest to the patient, that are most likely to be contaminated (e.g., bedrails, bedside tables, commodes, doorknobs, sinks, surfaces and equipment in close proximity to the patient) 11,72,73,835 . The frequency or intensity of cleaning may need to change based on the patient's level of hygiene and the degree of environmental contamination and for certain for infectious agents whose reservoir is the intestinal tract 54 . This may be especially true in LTCFs and pediatric facilities where patients with stool and urine incontinence are encountered more frequently. Also, increased frequency of cleaning may be needed in a Protective Environment to minimize dust accumulation 11 . Special recommendations for cleaning and disinfecting environmental surfaces in dialysis centers have been published 18 . In all healthcare settings, administrative, staffing and scheduling activities should prioritize the proper cleaning and disinfection of surfaces that could be implicated in transmission. During a suspected or proven outbreak where an environmental reservoir is suspected, routine cleaning procedures should be reviewed, and the need for additional trained cleaning staff should be assessed. Adherence should be monitored and reinforced to promote consistent and correct cleaning is performed. EPA-registered disinfectants or detergents/disinfectants that best meet the overall needs of the healthcare facility for routine cleaning and disinfection should be selected 11,836 . In general, use of the existing facility detergent/disinfectant according to the manufacturer's recommendations for amount, dilution, and contact time is sufficient to remove pathogens from surfaces of rooms where colonized or infected individuals were housed. This includes those pathogens that are resistant to multiple classes of antimicrobial agents (e.g., C. difficile, VRE, MRSA, MDR-GNB 11,24,88,435,746,796,837 ). Most often, environmental reservoirs of pathogens during outbreaks are related to a failure to follow recommended procedures for cleaning and disinfection rather than the specific cleaning and disinfectant agents used . Certain pathogens (e.g., rotavirus, noroviruses, C. difficile) may be resistant to some routinely used hospital disinfectants 275,292, .The role of specific disinfectants in limiting transmission of rotavirus has been demonstrated experimentally 842 . Also, since C. difficile may display increased levels of spore production when exposed to nonchlorine-based cleaning agents, and the spores are more resistant than vegetative cells to commonly used surface disinfectants, some investigators have recommended the use of a 1:10 dilution of 5.25% sodium hypochlorite (household bleach) and water for routine environmental disinfection of rooms of patients with C. difficile when there is continued transmission 844,848 . In one study, the use of a hypochlorite solution was associated with a decrease in rates of C. difficile infections 847 . The need to change disinfectants based on the presence of these organisms can be determined in consultation with the infection control committee 11,847,848 . Detailed recommendations for disinfection and sterilization of surfaces and medical equipment that have been in contact with prion-containing tissue or high risk body fluids, and for cleaning of blood and body substance spills, are available in the Guidelines for Environmental Infection Control in Health-Care Facilities 11 and in the Guideline for Disinfection and Sterilization 848 . # II.J. Patient Care Equipment and Instruments/Devices Medical equipment and instruments/devices must be cleaned and maintained according to the manufacturers' instructions to prevent patient-to-patient transmission of infectious agents 86,87,325,849 . Cleaning to remove organic material must always precede high level disinfection and sterilization of critical and semi-critical instruments and devices because residual proteinacous material reduces the effectiveness of the disinfection and sterilization processes 836,848 . Noncritical equipment, such as commodes, intravenous pumps, and ventilators, must be thoroughly cleaned and disinfected before use on another patient. All such equipment and devices should be handled in a manner that will prevent HCW and environmental contact with potentially infectious material. It is important to include computers and personal digital assistants (PDAs) used in patient care in policies for cleaning and disinfection of non-critical items. The literature on contamination of computers with pathogens has been summarized 850 and two reports have linked computer contamination to colonization and infections in patients 851,852 . Although keyboard covers and washable keyboards that can be easily disinfected are in use, the infection control benefit of those items and optimal management have not been determined. In all healthcare settings, providing patients who are on Transmission-Based Precautions with dedicated noncritical medical equipment (e.g., stethoscope, blood pressure cuff, electronic thermometer) has been beneficial for preventing transmission 74,89,740,853,854 . When this is not possible, disinfection after use is recommended. Consult other guidelines for detailed guidance in developing specific protocols for cleaning and reprocessing medical equipment and patient care items in both routine and special circumstances 11,14,18,20,740,836,848 . In home care, it is preferable to remove visible blood or body fluids from durable medical equipment before it leaves the home. Equipment can be cleaned on-site using a detergent/disinfectant and, when possible, should be placed in a single plastic bag for transport to the reprocessing location 20,739 . # II.K. Textiles and Laundry Soiled textiles, including bedding, towels, and patient or resident clothing may be contaminated with pathogenic microorganisms. However, the risk of disease transmission is negligible if they are handled, transported, and laundered in a safe manner 11,855,856 . Key principles for handling soiled laundry are 1. not shaking the items or handling them in any way that may aerosolize infectious agents; 2. avoiding contact of one's body and personal clothing with the soiled items being handled; and 3. containing soiled items in a laundry bag or designated bin. When laundry chutes are used, they must be maintained to minimize dispersion of aerosols from contaminated items 11 . The methods for handling, transporting, and laundering soiled textiles are determined by organizational policy and any applicable regulations 739 ; guidance is provided in the Guidelines for Environmental Infection Control 11 . Rather than rigid rules and regulations, hygienic and common sense storage and processing of clean textiles is recommended 11,857 . When laundering occurs outside of a healthcare facility, the clean items must be packaged or completely covered and placed in an enclosed space during transport to prevent contamination with outside air or construction dust that could contain infectious fungal spores that are a risk for immunocompromised patients 11 . Institutions are required to launder garments used as personal protective equipment and uniforms visibly soiled with blood or infective material 739 . There are few data to determine the safety of home laundering of HCW uniforms, but no increase in infection rates was observed in the one published study 858 and no pathogens were recovered from home-or hospital-laundered scrubs in another study 859 . In the home, textiles and laundry from patients with potentially transmissible infectious pathogens do not require special handling or separate laundering, and may be washed with warm water and detergent 11,858,859 . # II.L. Solid Waste The management of solid waste emanating from the healthcare environment is subject to federal and state regulations for medical and non-medical waste 860,861 . No additional precautions are needed for non-medical solid waste that is being removed from rooms of patients on Transmission-Based Precautions. Solid waste may be contained in a single bag (as compared to using two bags) of sufficient strength 862 . # II.M. Dishware and Eating Utensils The combination of hot water and detergents used in dishwashers is sufficient to decontaminate dishware and eating utensils. Therefore, no special precautions are needed for dishware (e.g., dishes, glasses, cups) or eating utensils; reusable dishware and utensils may be used for patients requiring Transmission-Based Precautions. In the home and other communal settings, eating utensils and drinking vessels that are being used should not be shared, consistent with principles of good personal hygiene and for the purpose of preventing transmission of respiratory viruses, Herpes simplex virus, and infectious agents that infect the gastrointestinal tract and are transmitted by the fecal/oral route (e.g., hepatitis A virus, noroviruses). If adequate resources for cleaning utensils and dishes are not available, disposable products may be used. # II.N. Adjunctive Measures Important adjunctive measures that are not considered primary components of programs to prevent transmission of infectious agents, but improve the effectiveness of such programs, include 1. antimicrobial management programs; 2. postexposure chemoprophylaxis with antiviral or antibacterial agents; 3. vaccines used both for pre and postexposure prevention; and 4. screening and restricting visitors with signs of transmissible infections. # II.N.1. Chemoprophylaxis. Antimicrobial agents and topical antiseptics may be used to prevent infection and potential outbreaks of selected agents. Infections for which postexposure chemoprophylaxis is recommended under defined conditions include B. pertussis 17,863 , N. meningitidi 864 , B. anthracis after environmental exposure to aeosolizable material 865 , influenza virus 611 , HIV 866 , and group A streptococcus 160 . Orally administered antimicrobials may also be used under defined circumstances for MRSA decolonization of patients or healthcare personnel 867 . Another form of chemoprophylaxis is the use of topical antiseptic agents. For example, triple dye is used routinely on the umbilical cords of term newborns to reduce the risk of colonization, skin infections, and omphalitis caused by S. aureus, including MRSA, and group A streptococcus 868,869 . Extension of the use of triple dye to low birth weight infants in the NICU was one component of a program that controlled one longstanding MRSA outbreak 22 . Topical antiseptics are also used for decolonization of healthcare personnel or selected patients colonized with MRSA, using mupirocin as discussed in the MDRO guideline 870 867, 871-873 . # II.N.2. Immunoprophylaxis. Certain immunizations recommended for susceptible healthcare personnel have decreased the risk of infection and the potential for transmission in healthcare facilities 17,874 . The OSHA mandate that requires employers to offer hepatitis B vaccination to HCWs played a substantial role in the sharp decline in incidence of occupational HBV infection 778,875 . The use of varicella vaccine in healthcare personnel has decreased the need to place susceptible HCWs on administrative leave following exposure to patients with varicella 775 . Also, reports of healthcare-associated transmission of rubella in obstetrical clinics 33,876 and measles in acute care settings 34 demonstrate the importance of immunization of susceptible healthcare personnel against childhood diseases. Many states have requirements for HCW vaccination for measles and rubella in the absence of evidence of immunity. Annual influenza vaccine campaigns targeted to patients and healthcare personnel in LTCFs and acute-care settings have been instrumental in preventing or limiting institutional outbreaks and increasing attention is being directed toward improving influenza vaccination rates in healthcare personnel 35,611,690,877,878,879 . Transmission of B. pertussis in healthcare facilities has been associated with large and costly outbreaks that include both healthcare personnel and patients 17, 36, 41, 100, 683, 827, 880, 881 . HCWs who have close contact with infants with pertussis are at particularly high risk because of waning immunity and, until 2005, the absence of a vaccine that could be used in adults. However, two acellular pertussis vaccines were licensed in the United States in 2005, one for use in individuals aged 11-18 and one for use in ages 10-64 years 882 . Provisional ACIP recommendations at the time of publication of this document include adolescents and adults, especially those with contact with infants < 12 months of age and healthcare personnel with direct patient contact 883 884 . Immunization of children and adults will help prevent the introduction of vaccinepreventable diseases into healthcare settings. The recommended immunization schedule for children is published annually in the January issues of the Morbidity Mortality Weekly Report with interim updates as needed 885,886 . An adult immunization schedule also is available for healthy adults and those with special immunization needs due to high risk medical conditions 887 . Some vaccines are also used for postexposure prophylaxis of susceptible individuals, including varicella 888 , influenza 611 , hepatitis B 778 , and smallpox 225 vaccines 17,874 . In the future, administration of a newly developed S. aureus conjugate vaccine (still under investigation) to selected patients may provide a novel method of preventing healthcareassociated S. aureus, including MRSA, infections in high-risk groups (e.g., hemodialysis patients and candidates for selected surgical procedures) 889,890 . Immune globulin preparations also are used for postexposure prophylaxis of certain infectious agents under specified circumstances (e.g., varicella-zoster virus , hepatitis B virus , rabies , measles and hepatitis A virus 17,833,874 ). The RSV monoclonal antibody preparation, Palivizumab, may have contributed to controlling a nosocomial outbreak of RSV in one NICU , but there is insufficient evidence to support a routine recommendation for its use in this setting 891 . # II.N. 3. Management of visitors. # II.N.3.a. Visitors as sources of infection. Visitors have been identified as the source of several types of HAIs (e.g., pertussis 40,41 , M. tuberculosis 42,892 , influenza, and other respiratory viruses 24,43,44,373 and SARS 21, ). However, effective methods for visitor screening in healthcare settings have not been studied. Visitor screening is especially important during community outbreaks of infectious diseases and for high risk patient units. Sibling visits are often encouraged in birthing centers, post partum rooms and in pediatric inpatient units, ICUs, and in residential settings for children; in hospital settings, a child visitor should visit only his or her own sibling. Screening of visiting siblings and other children before they are allowed into clinical areas is necessary to prevent the introduction of childhood illnesses and common respiratory infections. Screening may be passive through the use of signs to alert family members and visitors with signs and symptoms of communicable diseases not to enter clinical areas. More active screening may include the completion of a screening tool or questionnaire which elicits information related to recent exposures or current symptoms. That information is reviewed by the facility staff and the visitor is either permitted to visit or is excluded 833 . Family and household members visiting pediatric patients with pertussis and tuberculosis may need to be screened for a history of exposure as well as signs and symptoms of current infection. Potentially infectious visitors are excluded until they receive appropriate medical screening, diagnosis, or treatment. If exclusion is not considered to be in the best interest of the patient or family (i.e., primary family members of critically or terminally ill patients), then the symptomatic visitor must wear a mask while in the healthcare facility and remain in the patient's room, avoiding exposure to others, especially in public waiting areas and the cafeteria. Visitor screening is used consistently on HSCT units 15,43 . However, considering the experience during the 2003 SARS outbreaks and the potential for pandemic influenza, developing effective visitor screening systems will be beneficial 9 . Education concerning Respiratory Hygiene/Cough Etiquette is a useful adjunct to visitor screening. # II.N.3.b. Use of barrier precautions by visitors. The use of gowns, gloves, or masks by visitors in healthcare settings has not been addressed specifically in the scientific literature. Some studies included the use of gowns and gloves by visitors in the control of MDRO's, but did not perform a separate analysis to determine whether their use by visitors had a measurable impact . Family members or visitors who are providing care or having very close patient contact (e.g., feeding, holding) may have contact with other patients and could contribute to transmission if barrier precautions are not used correctly. Specific recommendations may vary by facility or by unit and should be determined by the level of interaction. # Part III: Precautions to Prevent Transmission of Infectious Agents There are two tiers of HICPAC/CDC precautions to prevent transmission of infectious agents, Standard Precautions and Transmission-Based Precautions. Standard Precautions are intended to be applied to the care of all patients in all healthcare settings, regardless of the suspected or confirmed presence of an infectious agent. Implementation of Standard Precautions constitutes the primary strategy for the prevention of healthcare-associated transmission of infectious agents among patients and healthcare personnel. Transmission-Based Precautions are for patients who are known or suspected to be infected or colonized with infectious agents, including certain epidemiologically important pathogens, which require additional control measures to effectively prevent transmission. Since the infecting agent often is not known at the time of admission to a healthcare facility, Transmission-Based Precautions are used empirically, according to the clinical syndrome and the likely etiologic agents at the time, and then modified when the pathogen is identified or a transmissible infectious etiology is ruled out. Examples of this syndromic approach are presented in Table 2. The HICPAC/CDC Guidelines also include recommendations for creating a Protective Environment for allogeneic HSCT patients. 4 and 5 for summaries of the key elements of these sets of precautions. # III.A. Standard Precautions Standard Precautions combine the major features of Universal Precautions (UP) 780,896 and Body Substance Isolation (BSI) 640 and are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. Standard Precautions include a group of infection prevention practices that apply to all patients, regardless of suspected or confirmed infection status, in any setting in which healthcare is delivered (Table 4). These include: hand hygiene; use of gloves, gown, mask, eye protection, or face shield, depending on the anticipated exposure; and safe injection practices. Also, equipment or items in the patient environment likely to have been contaminated with infectious body fluids must be handled in a manner to prevent transmission of infectious agents (e.g., wear gloves for direct contact, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). The application of Standard Precautions during patient care is determined by the nature of the HCW-patient interaction and the extent of anticipated blood, body fluid, or pathogen exposure. For some interactions (e.g., performing venipuncture), only gloves may be needed; during other interactions (e.g., intubation), use of gloves, gown, and face shield or mask and goggles is necessary. Education and training on the principles and rationale for recommended practices are critical elements of Standard Precautions because they facilitate appropriate decision-making and promote adherence when HCWs are faced with new circumstances 655, . An example of the importance of the use of Standard Precautions is intubation, especially under emergency circumstances when infectious agents may not be suspected, but later are identified (e.g., SARS-CoV, N. meningitides). The application of Standard Precautions is described below and summarized in Table 4. Guidance on donning and removing gloves, gowns and other PPE is presented in the Figure. Standard Precautions are also intended to protect patients by ensuring that healthcare personnel do not carry infectious agents to patients on their hands or via equipment used during patient care. 21,254,897 . The strategy proposed has been termed Respiratory Hygiene/Cough Etiquette 9,828 and is intended to be incorporated into infection control practices as a new component of Standard Precautions. The strategy is targeted at patients and accompanying family members and friends with undiagnosed transmissible respiratory infections, and applies to any person with signs of illness including cough, congestion, rhinorrhea, or increased production of respiratory secretions when entering a healthcare facility 40,41,43 . The term cough etiquette is derived from recommended source control measures for M. tuberculosis 12,126 . # III. The elements of Respiratory Hygiene/Cough Etiquette include 1. education of healthcare facility staff, patients, and visitors; 2. posted signs, in language(s) appropriate to the population served, with instructions to patients and accompanying family members or friends; 3. source control measures (e.g., covering the mouth/nose with a tissue when coughing and prompt disposal of used tissues, using surgical masks on the coughing person when tolerated and appropriate); 4. hand hygiene after contact with respiratory secretions; and 5. spatial separation, ideally >3 feet, of persons with respiratory infections in common waiting areas when possible. Covering sneezes and coughs and placing masks on coughing patients are proven means of source containment that prevent infected persons from dispersing respiratory secretions into the air 107,145,898,899 . Masking may be difficult in some settings, (e.g., pediatrics, in which case, the emphasis by necessity may be on cough etiquette 900 . Physical proximity of <3 feet has been associated with an increased risk for transmission of infections via the droplet route (e.g., N. meningitidis 103 and group A streptococcus 114 and therefore supports the practice of distancing infected persons from others who are not infected. The effectiveness of good hygiene practices, especially hand hygiene, in preventing transmission of viruses and reducing the incidence of respiratory infections both within and outside healthcare settings is summarized in several reviews 559,717,904 . These measures should be effective in decreasing the risk of transmission of pathogens contained in large respiratory droplets (e.g., influenza virus 23 , adenovirus 111 , B. pertussis 827 and Mycoplasma pneumoniae 112 . Although fever will be present in many respiratory infections, patients with pertussis and mild upper respiratory tract infections are often afebrile. Therefore, the absence of fever does not always exclude a respiratory infection. Patients who have asthma, allergic rhinitis, or chronic obstructive lung disease also may be coughing and sneezing. While these patients often are not infectious, cough etiquette measures are prudent. Healthcare personnel are advised to observe Droplet Precautions (i.e., wear a mask) and hand hygiene when examining and caring for patients with signs and symptoms of a respiratory infection. Healthcare personnel who have a respiratory infection are advised to avoid direct patient contact, especially with high risk patients. If this is not possible, then a mask should be worn while providing patient care. # III.A.1.b. Safe injection practices. The investigation of four large outbreaks of HBV and HCV among patients in ambulatory care facilities in the United States identified a need to define and reinforce safe injection practices 453 . The four outbreaks occurred in a private medical practice, a pain clinic, an endoscopy clinic, and a hematology/oncology clinic. The primary breaches in infection control practice that contributed to these outbreaks were 1. reinsertion of used needles into a multiple-dose vial or solution container (e.g., saline bag) and 2. use of a single needle/syringe to administer intravenous medication to multiple patients. In one of these outbreaks, preparation of medications in the same workspace where used needle/syringes were dismantled also may have been a contributing factor. These and other outbreaks of viral hepatitis could have been prevented by adherence to basic principles of aseptic technique for the preparation and administration of parenteral medications 453,454 . These include the use of a sterile, single-use, disposable needle and syringe for each injection given and prevention of contamination of injection equipment and medication. Whenever possible, use of single-dose vials is preferred over multiple-dose vials, especially when medications will be administered to multiple patients. Outbreaks related to unsafe injection practices indicate that some healthcare personnel are unaware of, do not understand, or do not adhere to basic principles of infection control and aseptic technique. A survey of US healthcare workers who provide medication through injection found that 1% to 3% reused the same needle and/or syringe on multiple patients 905 . Among the deficiencies identified in recent outbreaks were a lack of oversight of personnel and failure to follow-up on reported breaches in infection control practices in ambulatory settings. Therefore, to ensure that all healthcare workers understand and adhere to recommended practices, principles of infection control and aseptic technique need to be reinforced in training programs and incorporated into institutional polices that are monitored for adherence 454 . Equipment and products used during these procedures (e.g., contrast media) were excluded as probable sources of contamination. Procedural details available for seven cases determined that antiseptic skin preparations and sterile gloves had been used. However, none of the clinicians wore a face mask, giving rise to the speculation that droplet transmission of oralpharyngeal flora was the most likely explanation for these infections. Bacterial meningitis following myelogram and other spinal procedures (e.g., lumbar puncture, spinal and epidural anesthesia, intrathecal chemotherapy) has been reported previously . As a result, the question of whether face masks should be worn to prevent droplet spread of oral flora during spinal procedures (e.g., myelogram, lumbar puncture, spinal anesthesia) has been debated 916,917 . Face masks are effective in limiting the dispersal of oropharyngeal droplets 918 and are recommended for the placement of central venous catheters 919 . In October 2005, the Healthcare Infection Control Practices Advisory Committee (HICPAC) reviewed the evidence and concluded that there is sufficient experience to warrant the additional protection of a face mask for the individual placing a catheter or injecting material into the spinal or epidural space. # III.A.1.c. Infection Control Practices for Special # III.B. Transmission-Based Precautions There are three categories of Transmission-Based Precautions: Contact Precautions, Droplet Precautions, and Airborne Precautions. Transmission-Based Precautions are used when the route(s) of transmission is (are) not completely interrupted using Standard Precautions alone. For some diseases that have multiple routes of transmission (e.g., SARS), more than one Transmission-Based Precautions category may be used. When used either singly or in combination, they are always used in addition to Standard Precautions. See Appendix A for recommended precautions for specific infections. When Transmission-Based Precautions are indicated, efforts must be made to counteract possible adverse effects on patients (i.e., anxiety, depression and other mood disturbances , perceptions of stigma 923 , reduced contact with clinical staff , and increases in preventable adverse events 565 in order to improve acceptance by the patients and adherence by HCWs. 12,13 . Some states require the availability of such rooms in hospitals, emergency departments, and nursing homes that care for patients with M. tuberculosis. A respiratory protection program that includes education about use of respirators, fit-testing, and user seal checks is required in any facility with AIIRs. In settings where Airborne Precautions cannot be implemented due to limited engineering resources (e.g., physician offices), masking the patient, placing the patient in a private room (e.g., office examination room) with the door closed, and providing N95 or higher level respirators or masks if respirators are not available for healthcare personnel will reduce the likelihood of airborne transmission until the patient is either transferred to a facility with an AIIR or returned to the home environment, as deemed medically appropriate. Healthcare personnel caring for patients on Airborne Precautions wear a mask or respirator, depending on the disease-specific recommendations (Respiratory Protection II.E.4, Table 2, and Appendix A), that is donned prior to room entry. Whenever possible, non-immune HCWs should not care for patients with vaccine-preventable airborne diseases (e.g., measles, chickenpox, and smallpox). # III.B.1. Contact precautions. Contact # III.C. Syndromic and Empiric Applications of Transmission-Based Precautions Diagnosis of many infections requires laboratory confirmation. Since laboratory tests, especially those that depend on culture techniques, often require two or more days for completion, Transmission-Based Precautions must be implemented while test results are pending based on the clinical presentation and likely pathogens. Use of appropriate Transmission-Based Precautions at the time a patient develops symptoms or signs of transmissible infection, or arrives at a healthcare facility for care, reduces transmission opportunities. While it is not possible to identify prospectively all patients needing Transmission-Based Precautions, certain clinical syndromes and conditions carry a sufficiently high risk to warrant their use empirically while confirmatory tests are pending (Table 2). Infection control professionals are encouraged to modify or adapt this table according to local conditions. # III.D. Discontinuation of Transmission-Based Precautions Transmission-Based Precautions remain in effect for limited periods of time (i.e., while the risk for transmission of the infectious agent persists or for the duration of the illness (Appendix A). For most infectious diseases, this duration reflects known patterns of persistence and shedding of infectious agents associated with the natural history of the infectious process and its treatment. For some diseases (e.g., pharyngeal or cutaneous diphtheria, RSV), Transmission-Based Precautions remain in effect until culture or antigen-detection test results document eradication of the pathogen and, for RSV, symptomatic disease is resolved. For other diseases, (e.g., M. tuberculosis) state laws and regulations, and healthcare facility policies, may dictate the duration of precautions 12 ). In immunocompromised patients, viral shedding can persist for prolonged periods of time (many weeks to months) and transmission to others may occur during that time; therefore, the duration of contact and/or droplet precautions may be prolonged for many weeks 500, . The duration of Contact Precautions for patients who are colonized or infected with MDROs remains undefined. MRSA is the only MDRO for which effective decolonization regimens are available 867 . However, carriers of MRSA who have negative nasal cultures after a course of systemic or topical therapy may resume shedding MRSA in the weeks that follow therapy 934,935 . Although early guidelines for VRE suggested discontinuation of Contact Precautions after three stool cultures obtained at weekly intervals proved negative 740 , subsequent experiences have indicated that such screening may fail to detect colonization that can persist for >1 year 27, . Likewise, available data indicate that colonization with VRE, MRSA 939 , and possibly MDR-GNB, can persist for many months, especially in the presence of severe underlying disease, invasive devices, and recurrent courses of antimicrobial agents. It may be prudent to assume that MDRO carriers are colonized permanently and manage them accordingly. Alternatively, an interval free of hospitalizations, antimicrobial therapy, and invasive devices (e.g., 6 or 12 months) before reculturing patients to document clearance of carriage may be used. Determination of the best strategy awaits the results of additional studies. See the 2006 HICPAC/CDC MDRO guideline 927 for discussion of possible criteria to discontinue Contact Precautions for patients colonized or infected with MDROs. # III.E. Application of Transmission-Based Precautions in Ambulatory and Home Care Settings Although Transmission-Based Precautions generally apply in all healthcare settings, exceptions exist. For example, in home care, AIIRs are not available. Furthermore, family members already exposed to diseases such as varicella and tuberculosis would not use masks or respiratory protection, but visiting HCWs would need to use such protection. Similarly, management of patients colonized or infected with MDROs may necessitate Contact Precautions in acute care hospitals and in some LTCFs when there is continued transmission, but the risk of transmission in ambulatory care and home care, has not been defined. Consistent use of Standard Precautions may suffice in these settings, but more information is needed. # III.F. Protective Environment A Protective Environment is designed for allogeneic HSCT patients to minimize fungal spore counts in the air and reduce the risk of invasive environmental fungal infections (see Table 5 for specifications) 11, . The need for such controls has been demonstrated in studies of aspergillus outbreaks associated with construction 11,14,15,157,158 . As defined by the American Insitute of Architecture 13 and presented in detail in the Guideline for Environmental Infection Control 2003 11,861 , air quality for HSCT patients is improved through a combination of environmental controls that include 1. HEPA filtration of incoming air; 2. directed room air flow; 3. positive room air pressure relative to the corridor; 4. well-sealed rooms (including sealed walls, floors, ceilings, windows, electrical outlets) to prevent flow of air from the outside; 5. ventilation to provide >12 air changes per hour; 6. strategies to minimize dust (e.g., scrubbable surfaces rather than upholstery 940 and carpet 941 , and routinely cleaning crevices and sprinkler heads); and 7. prohibiting dried and fresh flowers and potted plants in the rooms of HSCT patients. The latter is based on molecular typing studies that have found indistinguishable strains of Aspergillus terreus in patients with hematologic malignancies and in potted plants in the vicinity of the patients . The desired quality of air may be achieved without incurring the inconvenience or expense of laminar airflow 15,157 . To prevent inhalation of fungal spores during periods when construction, renovation, or other dust-generating activities that may be ongoing in and around the health-care facility, it has been advised that severely immunocompromised patients wear a high-efficiency respiratory-protection device (e.g., an N95 respirator) when they leave the Protective Environment 11,14,945 ). The use of masks or respirators by HSCT patients when they are outside of the Protective Environment for prevention of environmental fungal infections in the absence of construction has not been evaluated. A Protective Environment does not include the use of barrier precautions beyond those indicated for Standard and Transmission-Based Precautions. No published reports support the benefit of placing solid organ transplants or other immunocompromised patients in a Protective Environment. # Part IV: Recommendations These recommendations are designed to prevent transmission of infectious agents among patients and healthcare personnel in all settings where healthcare is delivered. As in other CDC/HICPAC guidelines, each recommendation is categorized on the basis of existing scientific data, theoretical rationale, applicability, and when possible, economic impact. The CDC/HICPAC system for categorizing recommendations is as follows: Category IA Strongly recommended for implementation and strongly supported by welldesigned experimental, clinical, or epidemiologic studies. Category IB Strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale. Category IC Required for implementation, as mandated by federal and/or state regulation or standard. Category II Suggested for implementation and supported by suggestive clinical or epidemiologic studies or a theoretical rationale. No recommendation; unresolved issue. Practices for which insufficient evidence or no consensus regarding efficacy exists. # I. Administrative Responsibilities Healthcare organization administrators should ensure the implementation of recommendations in this section. # I.A. Incorporate preventing transmission of infectious agents into the objectives of the organization's patient and occupational safety programs 543-546, 561, 620, 626, 946 . 739 12, 17, 879-881, 955, 134, 690 . Category IB/IC I.B.8. In all areas where healthcare is delivered, provide supplies and equipment necessary for the consistent observance of Standard Precautions, including hand hygiene products and personal protective equipment (e.g., gloves, gowns, face and eye protection) 739,559,946 . Category IB/IC I.B.9. Develop and implement policies and procedures to ensure that reusable patient care equipment is cleaned and reprocessed appropriately before use on another patient 11,956,957,958,959,836,87,11,960,961 . Category IA/IC I.C. Develop and implement processes to ensure oversight of infection control activities appropriate to the healthcare setting and assign responsibility for oversight of infection control activities to an individual or group within the healthcare organization that is knowledgeable about infection control 434,549,566 . Category # Category II # I.D. Develop and implement systems for early detection and management (e.g., use of appropriate infection control measures, including isolation precautions, PPE) of potentially infectious persons at initial points of patient encounter in outpatient settings (e.g., triage areas, emergency departments, outpatient clinics, physician offices) and at the time of admission to hospitals and long-term care facilities (LTCF) 9,122,134,253,827 . Category IB I.E. Develop and implement policies and procedures to limit patient visitation by persons with signs or symptoms of a communicable infection. Screen visitors to high-risk patient care areas (e.g., oncology units, hematopoietic stem cell transplant units, intensive care units, other severely immunocompromised patients) for possible infection 43 24, 41, 962, 963 566 247 687 . Category IB III.E. Review periodically information on community or regional trends in the incidence and prevalence of epidemiologically-important organisms (e.g., influenza, RSV, pertussis, invasive group A streptococcal disease, MRSA, VRE) (including in other healthcare facilities) that may impact transmission of organisms within the facility 398, 687, 972, 973 974 . Category II # IV. Standard Precautions Assume that every person is potentially infected or colonized with an organism that could be transmitted in the healthcare setting and apply the following infection control practices during the delivery of health care. 956 IV.E.1. Establish policies and procedures for containing, transporting, and handling patient-care equipment and instruments/devices that may be contaminated with blood or body fluids 18,739,975 . Category IB/IC # IV.A. Hand Hygiene IV.E.2. Remove organic material from critical and semi-critical instrument/devices, using recommended cleaning agents before high level disinfection and sterilization to enable effective disinfection and sterilization processes 836 991, 992 . Category IA IV.E.3. Wear PPE (e.g., gloves, gown), according to the level of anticipated contamination, when handling patient-care equipment and instruments/devices that is visibly soiled or may have been in contact with blood or body fluids 18,739,975 . Category IB/IC # IV.F. Care of the Environment 11 Edit : An - indicates recommendations that were renumbered for clarity. The renumbering does not constitute change to the intent of the recommendations. IV.F.1. Establish policies and procedures for routine and targeted cleaning of environmental surfaces as indicated by the level of patient contact and degree of soiling 11 . Category II IV.F.2. Clean and disinfect surfaces that are likely to be contaminated with pathogens, including those that are in close proximity to the patient (e.g., bed rails, over bed tables) and frequently-touched surfaces in the patient care environment (e.g., door knobs, surfaces in and surrounding toilets in patients' rooms) on a more frequent schedule compared to that for other surfaces (e.g., horizontal surfaces in waiting rooms) 11 73, 740, 746, 993, 994 72, 800, 835 995 . Category IB IV.F.3. Use EPA-registered disinfectants that have microbiocidal (i.e., killing) activity against the pathogens most likely to contaminate the patient-care environment. Use in accordance with manufacturer's instructions 842-844, 956, 996 . Category IB/IC IV.F.3.a. Review the efficacy of in-use disinfectants when evidence of continuing transmission of an infectious agent (e.g., rotavirus, C. difficile, norovirus) may indicate resistance to the in-use product and change to a more effective disinfectant as indicated 275,842,847 . Category II # Edit : An - indicates recommendations that were renumbered for clarity. The renumbering does not constitute change to the intent of the recommendations. IV.F.4. In facilities that provide health care to pediatric patients or have waiting areas with child play toys (e.g., obstetric/gynecology offices and clinics), establish policies and procedures for cleaning and disinfecting toys at regular intervals 379,80 . Category IB IV.F.4.a. - Use the following principles in developing this policy and procedures: Category II h Select play toys that can be easily cleaned and disinfected h Do not permit use of stuffed furry toys if they will be shared h Clean and disinfect large stationary toys (e.g., climbing quipment) at least weekly and whenever visibly soiled h If toys are likely to be mouthed, rinse with water after disinfection; alternatively wash in a dishwasher h When a toy requires cleaning and disinfection, do so immediately or store in a designated labeled container separate from toys that are clean and ready for use IV.F.5. Include multi-use electronic equipment in policies and procedures for preventing contamination and for cleaning and disinfection, especially those items that are used by patients, those used during delivery of patient care, and mobile devices that are moved in and out of patient rooms frequently (e.g., daily) 850 851, 852, 997 . Category IB IV.F.5.a. No recommendation for use of removable protective covers or washable keyboards. Unresolved issue # IV.G. Textiles and Laundry IV.G.1. Handle used textiles and fabrics with minimum agitation to avoid contamination of air, surfaces and persons 739,998,999 . Category IB/IC IV.G.2. If laundry chutes are used, ensure that they are properly designed, maintained, and used in a manner to minimize dispersion of aerosols from contaminated laundry 11,13,1000,1001 . Category IB/IC # IV.H. Safe Injection Practices The following recommendations apply to the use of needles, cannulas that replace needles, and, where applicable, intravenous delivery systems 454 IV.H.1. Use aseptic technique to avoid contamination of sterile injection equipment 1002,1003 . Category IA IV.H.2. Do not administer medications from a syringe to multiple patients, even if the needle or cannula on the syringe is changed. Needles, cannulae and syringes are sterile, single-use items; they should not be reused for another patient nor to access a medication or solution that might be used for a subsequent patient 453,919,1004,1005 . Category IA IV.H.3. Use fluid infusion and administration sets (i.e., intravenous bags, tubing and connectors) for one patient only and dispose appropriately after use. Consider a syringe or needle/cannula contaminated once it has been used to enter or connect to a patient's intravenous infusion bag or administration set 453 . Category IB IV.H.4. Use single-dose vials for parenteral medications whenever possible 453 . # Category IA IV.H.5. Do not administer medications from single-dose vials or ampules to multiple patients or combine leftover contents for later use 369 453, 1005 . Category IA IV.H.6. If multidose vials must be used, both the needle or cannula and syringe used to access the multidose vial must be sterile 453,1002 . Category IA IV.H.7. Do not keep multidose vials in the immediate patient treatment area and store in accordance with the manufacturer's recommendations; discard if sterility is compromised or questionable 453,1003 . Category IA IV.H.8. Do not use bags or bottles of intravenous solution as a common source of supply for multiple patients 453,1006 . Category IB IV.I. Infection control practices for special lumbar puncture procedures Wear a surgical mask when placing a catheter or injecting material into the spinal canal or subdural space (i.e., during myelograms, lumbar puncture and spinal or epidural anesthesia). 906 V.D.2.a.ii. Direct exhaust of air to the outside. If it is not possible to exhaust air from an AIIR directly to the outside, the air may be returned to the air-handling system or adjacent spaces if all air is directed through HEPA filters. V.D.2.a.iii. Whenever an AIIR is in use for a patient on Airborne Precautions, monitor air pressure daily with visual indicators (e.g., smoke tubes, flutter strips), regardless of the presence of differential pressure sensing devices (e.g., manometers) 11,12,1023,1024 . V.D.2.a.iv. Keep the AIIR door closed when not required for entry and exit. V.D.2.b. When an AIIR is not available, transfer the patient to a facility that has an available AIIR 12 . Category II V.D.2.c. In the event of an outbreak or exposure involving large numbers of patients who require Airborne Precautions:  Consult infection control professionals before patient placement to determine the safety of alternative room that do not meet engineering requirements for an AIIR.  Place together (cohort) patients who are presumed to have the same infection( based on clinical presentation and diagnosis when known) in areas of the facility that are away from other patients, especially patients who are at increased risk for infection (e.g., immunocompromised patients).  Use temporary portable solutions (e.g., exhaust fan) to create a negative pressure environment in the converted area of the facility. Discharge air directly to the outside,away from people and air intakes, or direct all the air through HEPA filters before it is introduced to other air spaces 12 Category II V.D.2.d. In ambulatory settings: V.D.2.d.i. Develop systems (e.g., triage, signage) to identify patients with known or suspected infections that require Airborne Precautions upon entry into ambulatory settings 9,12,34,127,134 . Category IA V.D.2.d.ii. Place the patient in an AIIR as soon as possible. If an AIIR is not available, place a surgical mask on the patient and place him/her in an examination room. Once the patient leaves, the room should remain vacant for the appropriate time, generally one hour, to allow for a full exchange of air 11,12,122 . Category IB/IC V.D.2.d.iii. Instruct patients with a known or suspected airborne infection to wear a surgical mask and observe Respiratory Hygiene/Cough Etiquette. Once in an AIIR, the mask may be removed; the mask should remain on if the patient is not in an AIIR 12,107,145,899 . Category IB/IC V.D.3. Personnel restrictions Restrict susceptible healthcare personnel from entering the rooms of patients known or suspected to have measles (rubeola), varicella (chickenpox), disseminated zoster, or smallpox if other immune healthcare personnel are available 17,775 . Category IB V.D.4.a. Wear a fit-tested NIOSH-approved N95 or higher level respirator for respiratory protection when entering the room or home of a patient when the following diseases are suspected or confirmed:  - V.D.4.a.i. Infectious pulmonary or laryngeal tuberculosis or when infectious tuberculosis skin lesions are present and procedures that would aerosolize viable organisms (e.g., irrigation, incision and drainage, whirlpool treatments) are performed 12,1025,1026 . Category IB  - V.D.4.a.ii. Smallpox (vaccinated and unvaccinated). Respiratory protection is recommended for all healthcare personnel, including those with a documented "take" after smallpox vaccination due to the risk of a genetically engineered virus against which the vaccine may not provide protection, or of exposure to a very large viral load (e.g., from high-risk aerosol-generating procedures, immunocompromised patients, hemorrhagic or flat smallpox 108,129 . Category II V.D.4.b. § Suspected measles, chickenpox or disseminated zoster. No recommendation is made regarding the use of PPE by healthcare personnel who are presumed to be immune to measles (rubeola) or varicella-zoster based on history of disease, vaccine, or serologic testing when caring for an individual with known or suspected measles, chickenpox or disseminated zoster, due to difficulties in establishing definite immunity 1027,1028 . Unresolved issue V.D.4.c. § Suspected measles, chickenpox or disseminated zoster. No recommendation is made regarding the type of personal protective equipment (i.e., surgical mask or respiratory protection with a N95 or higher respirator) to be worn by susceptible healthcare personnel who must have contact with patients with known or suspected measles, chickenpox or disseminated herpes zoster. Unresolved issue V.D. 11 for additional guidance on environment strategies for preventing transmission of tuberculosis in healthcare settings. The environmental recommendations in these guidelines may be applied to patients with other infections that require Airborne Precautions. 13 . Category IB VI.C.2. Lower dust levels by using smooth, nonporous surfaces and finishes that can be scrubbed, rather than textured material (e.g., upholstery). Wet dust horizontal surfaces whenever dust detected and routinely clean crevices and sprinkler heads where dust may accumulate 940,941 . Category II VI.C.3. Avoid carpeting in hallways and patient rooms in areas 941 . Category IB VI.C.4. Prohibit dried and fresh flowers and potted plants . Category II VI.D. Minimize the length of time that patients who require a Protective Environment are outside their rooms for diagnostic procedures and other activities 11,158,945 . # VI. Protective Environment ( # Category IB VI.E. During periods of construction, to prevent inhalation of respirable particles that could contain infectious spores, provide respiratory protection (e.g., N95 respirator) to patients who are medically fit to tolerate a respirator when they are required to leave the Protective Environment 945,158 13 . Category IB VI.F.4.b. Use an anteroom to further support the appropriate air-balance relative to the corridor and the Protective Environment; provide independent exhaust of contaminated air to the outside or place a HEPA filter in the exhaust duct if the return air must be recirculated 13,1041 . Category IB VI.F.4.c. If an anteroom is not available, place the patient in an AIIR and use portable, industrial-grade HEPA filters in the room to enhance filtration of spores 1042 . Category II Available from: / Preamble The mode(s) and risk of transmission for each specific disease agent included in Appendix A were reviewed. Principle sources consulted for the development of disease-specific recommendations for Appendix A included infectious disease manuals and textbooks . The published literature was searched for evidence of person-to-person transmission in healthcare and non-healthcare settings with a focus on reported outbreaks that would assist in developing recommendations for all settings where healthcare is delivered. Criteria used to assign Transmission-Based Precautions categories follow: - A Transmission-Based Precautions category was assigned if there was strong evidence for person-to-person transmission via droplet, contact, or airborne routes in healthcare or nonhealthcare settings and/or if patient factors (e.g., diapered infants, diarrhea, draining wounds) increased the risk of transmission - Transmission-Based Precautions category assignments reflect the predominant mode(s) of transmission - If there was no evidence for person-to-person transmission by droplet, contact or airborne routes, Standard Precautions were assigned - If there was a low risk for person-to-person transmission and no evidence of healthcareassociated transmission, Standard Precautions were assigned - Standard Precautions were assigned for bloodborne pathogens (e.g., hepatitis B and C viruses, human immunodeficiency virus) as per CDC recommendations for Universal Precautions issued in 1988 . Subsequent experience has confirmed the efficacy of Standard Precautions to prevent exposure to infected blood and body fluid . Additional information relevant to use of precautions was added in the comments column to assist the caregiver in decision-making. Citations were added as needed to support a change in or provide additional evidence for recommendations for a specific disease and for new infectious agents (e.g., SARS-CoV, avian influenza) that have been added to Appendix A. # Clostridium perfringens Gas gangrene Standard n/a Transmission from person to person rare; 1 outbreak in a surgical setting reported . Use Contact Precautions if wound drainage is extensive. # Infection/Condition # Type of Precaution # Duration of Precaution Precautions/Comments Coccidioidomycosis (valley fever) Draining lesions Standard n/a Not transmitted from person to person except under extraordinary circumstances, because the infectious arthroconidial form of Coccidioides immitis is not produced in humans . # Coccidioidomycosis (valley fever) Pneumonia Standard n/a Not transmitted from person to person except under extraordinary circumstances, (e.g., inhalation of aerosolized tissue phase endospores during necropsy, transplantation of infected lung) because the infectious arthroconidial form of Coccidioides immitis is not produced in humans . Colorado # Gastroenteritis # Giardia lamblia Standard n/a Use Contact Precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. # Infection/Condition # Type of Precaution # Duration of Precaution Precautions/Comments Gastroenteritis Noroviruses Standard n/a Use Contact Precautions for a minimum of 48 hours after the resolution of symptoms or to control institutional outbreaks. Persons who clean areas heavily contaminated with feces or vomitus may benefit from wearing masks since virus can be aerosolized from these body substances ; ensure consistent environmental cleaning and disinfection with focus on restrooms even when apparently unsoiled . Hypochlorite solutions may be required when there is continued transmission . Alcohol is less active, but there is no evidence that alcohol antiseptic handrubs are not effective for hand decontamination . Susceptible HCWs should not enter room if immune care providers are available; no recommendation for face protection for immune HCW; no recommendation for type of face protection for susceptible HCWs, i.e., mask or respirator . For exposed susceptibles, postexposure vaccine within 72 hours or immune globulin within 6 days when available The below note has been superseded by the above recommendation update Note: (Recent assessment of outbreaks in healthy 18-24 year olds has indicated that salivary viral shedding occurred early in the course of illness and that 5 days of isolation after onset of parotitis may be appropriate in community settings; however the implications for healthcare personnel and highrisk patient populations remain to be clarified.) # Infection/Condition # Type of Precaution # Table 3C. Ebola Hemorrhagic Fever # Characteristics Additional Information Site(s) of Infection; Transmission Mode As a rule infection develops after exposure of mucous membranes or respiratory tract, or through broken skin or percutaneous injury. Incubation Period 2-19 days, usually 5-10 days # Clinical Features Febrile illnesses with malaise, myalgias, headache, vomiting and diarrhea that are rapidly complicated by hypotension, shock, and hemorrhagic features. Massive hemorrhage in < 50% pts. # Diagnosis Etiologic diagnosis can be made using respiratory tract-polymerase chain reaction, serologic detection of antibody and antigen, pathologic assessment with immunohistochemistry and viral culture with EM confirmation of morphology, # Infectivity Person-to-person transmission primarily occurs through unprotected contact with blood and body fluids; percutaneous injuries (e.g., needlestick) associated with a high rate of transmission; transmission in healthcare settings has been reported but is prevented by use of barrier precautions. # Characteristics Additional Information Recommended Precautions Hemorrhagic fever specific barrier precautions: If disease is believed to be related to intentional release of a bioweapon, epidemiology of transmission is unpredictable pending observation of disease transmission. Until the nature of the pathogen is understood and its transmission pattern confirmed, Standard, Contact and Airborne Precautions should be used. Once the pathogen is characterized, if the epidemiology of transmission is consistent with natural disease, Droplet Precautions can be substituted for Airborne Precautions. Emphasize: 1. use of sharps safety devices and safe work practices, 2. hand hygiene; 3. barrier protection against blood and body fluids upon entry into room (single gloves and fluid-resistant or impermeable gown, face/eye protection with masks, goggles or face shields); and 4. appropriate waste handling. Use N95 or higher respirators when performing aerosol-generating procedures. In settings where AIIRs are unavailable or the large numbers of patients cannot be accommodated by existing AIIRs, observe Droplet Precautions (plus Standard Precautions and Contact Precautions) and segregate patients from those not suspected of VHF infection. Limit blooddraws to those essential to care. See text for discussion and Appendix A for recommendations for naturally occurring VHFs. # Plague Pneumonic plague is not as contagious as is often thought. Historical accounts and contemporary evidence indicate that persons with plague usually transmit the infection only when the disease is in the end stage. These persons cough copious amounts of bloody sputum that contains many plague bacteria. Patients in the early stage of primary pneumonic plague (approximately the first 20-24 h) apparently pose little risk . Antibiotic medication rapidly clears the sputum of plague bacilli, so that a patient generally is not infective within hours after initiation of effective antibiotic treatment . This means that in modern times many patients will never reach a stage where they pose a significant risk to others. Even in the end stage of disease, transmission only occurs after close contact. Simple protective measures, such as wearing masks, good hygiene, and avoiding close contact, have been effective to interrupt transmission during many pneumonic plague outbreaks . In the United States, the last known cases of person to person transmission of pneumonic plague occurred in 1925 . # Table 3D. Plague # Characteristics Additional Information Site(s) of Infection; Transmission Mode Respiratory Tract: Inhalation of respiratory droplets. Comment: Pneumonic plague most likely to occur if used as a biological weapon, but some cases of bubonic and primary septicemia may also occur. Infective dose 100 to 500 bacteria Incubation Period 1 to 6, usually 2 to 3 days. Fever, malaise, backache, headache, and often vomiting for 2-3 days; then generalized papular or maculopapular rash (more on face and extremities), which becomes vesicular (on day 4 or 5) and then pustular; lesions all in same stage. Clinical # Diagnosis Electron microscopy of vesicular fluid or culture of vesicular fluid by WHO approved laboratory (CDC); detection by polymerase chain reaction available only in select LRN labs, CDC and USAMRID Infectivity Secondary attack rates up to 50% in unvaccinated persons; infected persons may transmit disease from time rash appears until all lesions have crusted over (about 3 weeks); greatest infectivity during first 10 days of rash. Recommended Precautions Combined use of Standard, Contact, and Airborne Precautions until all scabs have separated (3-4 weeks). Transmission by the airborne route is a rare event; Airborne Precautions is recommended when possible, but in the event of mass exposures, barrier precautions and containment within a designated area are most important. 204,212 Only immune HCWs to care for pts; Postexposure vaccine within 4 days. Vaccinia: HCWs cover vaccination site with gauze and semi-permeable dressing until scab separates (≥21 days). Observe hand hygiene. Adverse events with virus-containing lesions: Standard plus Contact Precautions until all lesions crusted. Vaccinia adverse events with lesions containing infectious virus include inadvertent autoinoculation, ocular lesions (blepharitis, conjunctivitis), generalized vaccinia, progressive vaccinia, eczema vaccinatum; bacterial superinfection also requires addition of contact precautions if exudates cannot be contained. 216,217 # Table 3F. Tularemia # Characteristics Additional Information Site(s) of Infection; Transmission Mode Respiratory Tract: Inhalation of aerosolized bacteria. Gastrointestinal Tract: Ingestion of food or drink contaminated with aerosolized bacteria. Comment: Pneumonic or typhoidal disease likely to occur after bioterrorist event using aerosol delivery. Infective dose 10-50 bacteria Incubation Period 2 to 10 days, usually 3 to 5 days # Clinical Features Pneumonic: malaise, cough, sputum production, dyspnea; Typhoidal: fever, prostration, weight loss and frequently an associated pneumonia. # Diagnosis Diagnosis usually made with serology on acute and convalescent serum specimens; bacterium can be detected by polymerase chain reaction (LRN) or isolated from blood and other body fluids on cysteine-enriched media or mouse inoculation. # Infectivity Person-to-person spread is rare. Laboratory workers who encounter/handle cultures of this organism are at high risk for disease if exposed. # Recommended Precautions Standard Precautions # I. Patients: allogeneic hematopoeitic stem cell transplant (HSCT) only - Maintain in PE room except for required diagnostic or therapeutic procedures that cannot be performed in the room, e.g., radiology, operating room - Respiratory protection e.g., N95 respirator, for the patient when leaving PE during periods of construction # II. Standard and Expanded Precautions - Hand hygiene observed before and after patient contact - Gown, gloves, mask NOT required for HCWs or visitors for routine entry into the room flutter strips, smoke tubes) or a hand held pressure gauge - Self-closing door on all room exits - Maintain back-up ventilation equipment (e.g., portable units for fans or filters) for emergency provision of ventilation requirements for PE areas and take immediate steps to restore the fixed ventilation system - For patients who require both a PE and Airborne Infection Isolation, use an anteroom to ensure proper air balance relationships and provide independent exhaust of contaminated air to the outside or place a HEPA filter in the exhaust duct. If an anteroom is not available, place patient in an AIIR and use portable ventilation units, industrial-grade HEPA filters to enhance filtration of spores. # IV. Surfaces - Daily wet-dusting of horizontal surfaces using cloths moistened with EPA-registered hospital disinfectant/detergent - Avoid dusting methods that disperse dust During outbreaks, healthcare personnel may be assigned to a cohort of patients to further limit opportunities for transmission (cohorting staff). Colonization. Proliferation of microorganisms on or within body sites without detectable host immune response, cellular damage, or clinical expression. The presence of a microorganism within a host may occur with varying duration, but may become a source of potential transmission. In many instances, colonization and carriage are synonymous. Droplet nuclei. Microscopic particles < 5 µm in size that are the residue of evaporated droplets and are produced when a person coughs, sneezes, shouts, or sings. These particles can remain suspended in the air for prolonged periods of time and can be carried on normal air currents in a room or beyond, to adjacent spaces or areas receiving exhaust air. # Hand hygiene. A general term that applies to any one of the following: 1. handwashing with plain (nonantimicrobial) soap and water); 2. antiseptic handwash (soap containing antiseptic agents and water); 3. antiseptic handrub (waterless antiseptic product, most often alcohol-based, rubbed on all surfaces of hands); or 4. surgical hand antisepsis (antiseptic handwash or antiseptic handrub performed preoperatively by surgical personnel to eliminate transient hand flora and reduce resident hand flora) 559 . # Healthcare-associated infection (HAI). An infection that develops in a patient who is cared for in any setting where healthcare is delivered (e.g., acute care hospital, chronic care facility, ambulatory clinic, dialysis center, surgicenter, home) and is related to receiving health care (i.e., was not incubating or present at the time healthcare was provided). In ambulatory and home settings, HAI would apply to any infection that is associated with a medical or surgical intervention. Since the geographic location of infection acquisition is often uncertain, the preferred term is considered to be healthcare-associated rather than healthcare-acquired. Healthcare epidemiologist. A person whose primary training is medical (M.D., D.O.) and/or masters or doctorate-level epidemiology who has received advanced training in healthcare epidemiology. Typically these professionals direct or provide consultation to an infection control program in a hospital, long term care facility (LTCF), or healthcare delivery system (also see infection control professional). Healthcare personnel, healthcare worker (HCW). All paid and unpaid persons who work in a healthcare setting (e.g., any person who has professional or technical training in a healthcare-related field and provides patient care in a healthcare setting or any person who provides services that support the delivery of healthcare such as dietary, housekeeping, engineering, maintenance personnel). # Hematopoietic stem cell transplantation (HSCT). Any transplantation of blood-or bone marrow-derived hematopoietic stem cells, regardless of donor type (e.g., allogeneic or autologous) or cell source (e.g., bone marrow, peripheral blood, or placental/umbilical cord blood); associated with periods of severe immunosuppression that vary with the source of the cells, the intensity of chemotherapy required, and the presence of graft versus host disease (MMWR 2000; 49: RR-10). High-efficiency particulate air (HEPA) filter. An air filter that removes >99.97% of particles ≥ 0.3µm (the most penetrating particle size) at a specified flow rate of air. HEPA filters may be integrated into the central air handling systems, installed at the point of use above the ceiling of a room, or used as portable units (MMWR 2003; 52: RR-10). Home care. A wide-range of medical, nursing, rehabilitation, hospice and social services delivered to patients in their place of residence (e.g., private residence, senior living center, assisted living facility). Home health-care services include care provided by home health aides and skilled nurses, respiratory therapists, dieticians, physicians, chaplains, and volunteers; provision of durable medical equipment; home infusion therapy; and physical, speech, and occupational therapy. # Immunocompromised patients. Those patients whose immune mechanisms are deficient because of congenital or acquired immunologic disorders (e.g., human immunodeficiency virus infection, congenital immune deficiency syndromes), chronic diseases such as diabetes mellitus, cancer, emphysema, or cardiac failure, ICU care, malnutrition, and immunosuppressive therapy of another disease process ). The type of infections for which an immunocompromised patient has increased susceptibility is determined by the severity of immunosuppression and the specific component(s) of the immune system that is affected. Patients undergoing allogeneic HSCT and those with chronic graft versus host disease are considered the most vulnerable to HAIs. Immunocompromised states also make it more difficult to diagnose certain infections (e.g., tuberculosis) and are associated with more severe clinical disease states than persons with the same infection and a normal immune system. Infection. The transmission of microorganisms into a host after evading or overcoming defense mechanisms, resulting in the organism's proliferation and invasion within host tissue(s). Host responses to infection may include clinical symptoms or may be subclinical, with manifestations of disease mediated by direct organisms pathogenesis and/or a function of cell-mediated or antibody responses that result in the destruction of host tissues. # Infection control and prevention professional (ICP). A person whose primary training is in either nursing, medical technology, microbiology, or epidemiology and who has acquired specialized training in infection control. Responsibilities may include collection, analysis, and feedback of infection data and trends to healthcare providers; consultation on infection risk assessment, prevention and control strategies; performance of education and training activities; implementation of evidence-based infection control practices or those mandated by regulatory and licensing agencies; application of epidemiologic principles to improve patient outcomes; participation in planning renovation and construction projects (e.g., to ensure appropriate containment of construction dust); evaluation of new products or procedures on patient outcomes; oversight of employee health services related to infection prevention; implementation of preparedness plans; communication within the healthcare setting, with local and state health departments, and with the community at large concerning infection control issues; and participation in research. Certification in infection control (CIC) is available through the Certification Board of Infection Control and Epidemiology. # Infection control and prevention program. A multidisciplinary program that includes a group of activities to ensure that recommended practices for the prevention of healthcare-associated infections are implemented and followed by HCWs, making the healthcare setting safe from infection for patients and healthcare personnel. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requires the following five components of an infection control program for accreditation: 1. surveillance: monitoring patients and healthcare personnel for acquisition of infection and/or colonization; 2. investigation: identification and analysis of infection problems or undesirable trends; 3. prevention: implementation of measures to prevent transmission of infectious agents and to reduce risks for device-and procedure-related infections; 4) control: evaluation and management of outbreaks; and 4. reporting: provision of information to external agencies as required by state and federal law and regulation (The Joint Commission (/ accessed May 2016) ). The infection control program staff has the ultimate authority to determine infection control policies for a healthcare organization with the approval of the organization's governing body. Long-term care facilities (LTCFs). An array of residential and outpatient facilities designed to meet the bio-psychosocial needs of persons with sustained self-care deficits. These include skilled nursing facilities, chronic disease hospitals, nursing homes, foster and group homes, institutions for the developmentally disabled, residential care facilities, assisted living facilities, retirement homes, adult day health care facilities, rehabilitation centers, and long-term psychiatric hospitals. # Mask. A term that applies collectively to items used to cover the nose and mouth and includes both procedure masks and surgical masks ([This link is no longer active: www.fda.gov/cdrh/ode/guidance/094.html#4. Similar information may be found at FDA: Masks and N95 Respirators ( evicesandSupplies/PersonalProtectiveEquipment/ucm055977.htm accessed May 2016)]). # Multidrug-resistant organisms (MDROs). In general, bacteria (excluding M. tuberculosis) that are resistant to one or more classes of antimicrobial agents and usually are resistant to all but one or two commercially available antimicrobial agents (e.g., MRSA, VRE, extended spectrum beta-lactamase -producing or intrinsically resistant gram-negative bacilli) 176 . # Nosocomial infection. Derived from two Greek words "nosos" (disease) and "komeion" (to take care of). Refers to any infection that develops during or as a result of an admission to an acute care facility (hospital) and was not incubating at the time of admission. # Personal protective equipment (PPE). A variety of barriers used alone or in combination to protect mucous membranes, skin, and clothing from contact with infectious agents. PPE includes gloves, masks, respirators, goggles, face shields, and gowns. Procedure Mask. A covering for the nose and mouth that is intended for use in general patient care situations. These masks generally attach to the face with ear loops rather than ties or elastic. Unlike surgical masks, procedure masks are not regulated by the Food and Drug Administration. Protective Environment. A specialized patient-care area, usually in a hospital, with a positive air flow relative to the corridor (i.e., air flows from the room to the outside adjacent space). The combination of high-efficiency particulate air (HEPA) filtration, high numbers (≥12) of air changes per hour (ACH), and minimal leakage of air into the room creates an environment that can safely accommodate patients with a severely compromised immune system (e.g., those who have received allogeneic hemopoietic stem-cell transplant ) and decrease the risk of exposure to spores produced by environmental fungi. Other components include use of scrubbable surfaces instead of materials such as upholstery or carpeting, cleaning to prevent dust accumulation, and prohibition of fresh flowers or potted plants. Quasi-experimental studies. Studies to evaluate interventions but do not use randomization as part of the study design. These studies are also referred to as nonrandomized, pre-post-intervention study designs. These studies aim to demonstrate causality between an intervention and an outcome but cannot achieve the level of confidence concerning attributable benefit obtained through a randomized, controlled trial. In hospitals and public health settings, randomized control trials often cannot be implemented due to ethical, practical and urgency reasons; therefore, quasiexperimental design studies are used commonly. However, even if an intervention appears to be effective statistically, the question can be raised as to the possibility of alternative explanations for the result. Such study design is used when it is not logistically feasible or ethically possible to conduct a randomized, controlled trial, (e.g., during outbreaks). Within the classification of quasi-experimental study designs, there is 1. senior management support for safety programs; 2. absence of workplace barriers to safe work practices; 3. cleanliness and orderliness of the worksite; 4. minimal conflict and good communication among staff members; 5. frequent safety-related feedback/training by supervisors; and 6. availability of PPE and engineering controls 620 . Source Control. The process of containing an infectious agent either at the portal of exit from the body or within a confined space. The term is applied most frequently to containment of infectious agents transmitted by the respiratory route but could apply to other routes of transmission, (e.g., a draining wound, vesicular or bullous skin lesions). Respiratory Hygiene/Cough Etiquette that encourages individuals to "cover your cough" and/or wear a mask is a source control measure. The use of enclosing devices for local exhaust ventilation (e.g., booths for sputum induction or administration of aerosolized medication) is another example of source control. Standard Precautions. A group of infection prevention practices that apply to all patients, regardless of suspected or confirmed diagnosis or presumed infection status. Standard Precautions is a combination and expansion of Universal Precautions 780 and Body Substance Isolation 1102 . Standard Precautions is based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. Standard Precautions includes hand hygiene, and depending on the anticipated exposure, use of gloves, gown, mask, eye protection, or face shield. Also, equipment or items in the patient environment likely to have been contaminated with infectious fluids must be handled in a manner to prevent transmission of infectious agents, (e.g., wear gloves for handling, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). # Surgical mask. A device worn over the mouth and nose by operating room personnel during surgical procedures to protect both surgical patients and operating room personnel from transfer of microorganisms and body fluids. Surgical masks also are used to protect healthcare personnel from contact with large infectious droplets (>5 μm in size). According to draft guidance issued by the Food and Drug Administration on May 15, 2003, surgical masks are evaluated using standardized testing procedures for fluid resistance, bacterial filtration efficiency, differential pressure (air exchange), and flammability in order to mitigate the risks to health associated with the use of surgical masks. These specifications apply to any masks that are labeled surgical, laser, isolation, or dental or medical procedure (). Surgical masks do not protect against inhalation of small particles or droplet nuclei and should not be confused with particulate respirators that are recommended for protection against selected airborne infectious agents, (e.g., Mycobacterium tuberculosis). # Glossary Airborne infection isolation room (AIIR). Formerly, negative pressure isolation room, an AIIR is a single-occupancy patient-care room used to isolate persons with a suspected or confirmed airborne infectious disease. Environmental factors are controlled in AIIRs to minimize the transmission of infectious agents that are usually transmitted from person to person by droplet nuclei associated with coughing or aerosolization of contaminated fluids. AIIRs should provide negative pressure in the room (so that air flows under the door gap into the room); and an air flow rate of 6-12 ACH (6 ACH for existing structures, 12 ACH for new construction or renovation); and direct exhaust of air from the room to the outside of the building or recirculation of air through a HEPA filter before retruning to circulation (MMWR 2003; 52 ; MMWR 1994; 43 ). Bioaerosols. An airborne dispersion of particles containing whole or parts of biological entities, such as bacteria, viruses, dust mites, fungal hyphae, or fungal spores. Such aerosols usually consist of a mixture of mono-dispersed and aggregate cells, spores or viruses, carried by other materials, such as respiratory secretions and/or inert particles. Infectious bioaerosols (i.e., those that contain biological agents capable of causing an infectious disease) can be generated from human sources (e.g., expulsion from the respiratory tract during coughing, sneezing, talking or singing; during suctioning or wound irrigation), wet environmental sources (e.g., HVAC and cooling tower water with Legionella) or dry sources (e.g., construction dust with spores produced by Aspergillus spp.). Bioaerosols include large respiratory droplets and small droplet nuclei (Cole EC. AJIC 1998;26: 453-64). # American Institute of Architects (AIA). Caregivers. All persons who are not employees of an organization, are not paid, and provide or assist in providing healthcare to a patient (e.g., family member, friend) and acquire technical training as needed based on the tasks that must be performed. # Cohorting. In the context of this guideline, this term applies to the practice of grouping patients infected or colonized with the same infectious agent together to confine their care to one area and prevent contact with susceptible patients (cohorting patients). a hierarchy of design features that may contribute to validity of results (Harris et al. CID 2004:38: 1586). # Residential care setting. A facility in which people live, minimal medical care is delivered, and the psychosocial needs of the residents are provided for. # Respirator. A personal protective device worn by healthcare personnel over the nose and mouth to protect them from acquiring airborne infectious diseases due to inhalation of infectious airborne particles that are < 5 μm in size. These include infectious droplet nuclei from patients with M. tuberculosis, variola virus , SARS-CoV), and dust particles that contain infectious particles, such as spores of environmental fungi (e.g., Aspergillus sp. # Respiratory Hygiene/ Cough Etiquette. A combination of measures designed to minimize the transmission of respiratory pathogens via droplet or airborne routes in healthcare settings. The components of respiratory hygiene/cough etiquette are 1. covering the mouth and nose during coughing and sneezing, 2. using tissues to contain respiratory secretions with prompt disposal into a no-touch receptacle, 3. offering a surgical mask to persons who are coughing to decrease contamination of the surrounding environment, and 4. turning the head away from others and maintaining spatial separation, ideally >3 feet, when coughing. These measures are targeted to all patients with symptoms of respiratory infection and their accompanying family members or friends beginning at the point of initial encounter with a healthcare setting (e.g., reception/triage in emergency departments, ambulatory clinics, healthcare provider offices) 126

Cladribine for treating relapsing–remitting multiple sclerosis Evidence-based recommendations on cladribine (Mavenclad) for relapsing–remitting multiple sclerosis in adults. # Recommendations Cladribine is recommended as an option for treating highly active multiple sclerosis in adults, only if the person has: rapidly evolving severe relapsing–remitting multiple sclerosis, that is with at least: relapses in the previous year and T1 gadolinium-enhancing lesion at baseline MRI or a significant increase in T2‑lesion load compared with a previous MRI, or relapsing–remitting multiple sclerosis that has responded inadequately to treatment with disease-modifying therapy, defined as 1 relapse in the previous year and MRI evidence of disease activity. This recommendation is not intended to affect treatment with cladribine that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. Why the committee made these recommendations Highly active relapsing–remitting multiple sclerosis is currently treated with alemtuzumab, fingolimod or natalizumab. This appraisal focuses on 2 subgroups of people with highly active relapsing–remitting multiple sclerosis, that is, those with rapidly evolving severe disease and those with suboptimally treated relapsing–remitting multiple sclerosis (disease that has responded inadequately to disease-modifying therapy). Clinical trial results show that cladribine tablets (hereafter referred to as cladribine) reduce relapses and slow the progression of disability compared with placebo for people with relapsing–remitting multiple sclerosis. The effectiveness of cladribine for treating rapidly evolving severe or suboptimally treated relapsing–remitting multiple sclerosis is not proven, but it is likely to be more effective than placebo. Based on indirect analyses, there is not enough evidence to determine whether cladribine is more or less effective than other treatments for people with rapidly evolving severe and suboptimally treated multiple sclerosis. Because of this, cladribine and alternative treatments are considered equally effective for this appraisal. The MRI criteria used by clinicians to define rapidly evolving severe relapsing–remitting multiple sclerosis have changed over time. In addition to the presence of T1 gadolinium-enhancing lesions at baseline, clinicians may now identify patients with rapidly evolving severe relapsing–remitting multiple sclerosis by a significant increase in T2‑lesion load compared with a previous MRI. Cladribine is less costly than other treatments and needs less frequent dosing and monitoring. It is cost effective compared with all other treatments, so can be recommended for rapidly evolving severe and suboptimally treated relapsing–remitting multiple sclerosis.# Information about cladribine # Marketing authorisation indication Cladribine tablets (Mavenclad, Merck Serono) are 'indicated for the treatment of adult patients with highly active relapsing multiple sclerosis as defined by clinical or imaging features'. # Dosage in the marketing authorisation In the summary of product characteristics, the recommended cumulative dose is 3.5 mg/kg body weight over 2 years, taken as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, 1 at the beginning of the first month and 1 at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 days or 5 days on which a patient takes 10 mg or 20 mg (1 or 2 tablets) as a single daily dose, depending on body weight. After completing the 2 treatment courses, no further cladribine treatment is needed in years 3 and 4. # Price The list price is £2,047.24 per 10 mg tablet (excluding VAT, BNF online, November 2019). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion The appraisal committee (section 5) considered evidence submitted by Merck Serono and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence. # Clinical need and patient perspective ## Clinicians and patients would value an oral treatment with less frequent dosing and monitoring Relapsing–remitting multiple sclerosis is a chronic, disabling neurological condition. The patient experts explained that relapses and residual disability between relapses can substantially reduce quality of life. The committee was aware that relapsing–remitting multiple sclerosis can limit people's ability to work, and to engage in social and family life. The patient experts also explained that many of the available treatments need frequent hospital appointments for treatment and monitoring and that this causes significant disruption to patients' lives and careers. The committee heard that an oral treatment taken in 2 short courses over 2 years would be less disruptive. # Treatment pathway and comparators ## The definitions of multiple sclerosis subgroups are not meaningful in NHS clinical practice In the NHS, disease-modifying therapy is used to treat relapsing–remitting multiple sclerosis. The choice of therapy partly depends on the number of relapses and MRI evidence of disease activity, as defined in each treatment's marketing authorisation. Previous NICE technology appraisal guidance has usually defined active disease as at least 2 clinically significant relapses in the previous 2 years. The committee understood that some people with relapsing–remitting multiple sclerosis have highly active disease but that there is no universally accepted definition of highly active disease. The company defined a group of people with 'high disease activity' as having either 1 relapse in the previous year while the person was on disease-modifying therapy and at least 1 T1 gadolinium-enhancing lesion on MRI, or at least 2 relapses (with or without lesions) in the previous year regardless of treatment. The clinical experts explained that this definition was not used in clinical practice and considered it to be very broad. The committee noted that, in previous appraisals, 'highly active disease' has been used to describe a population broadly similar to the population the company referred to as having suboptimally treated multiple sclerosis (see section 3.3). It also heard that, in practice, increases in T2‑lesion numbers compared with a previous MRI are an important indicator of disease activity, and may be more important than the absolute number. The committee concluded that the group referred to by the company as having 'high disease activity' may not be meaningful in NHS clinical practice. ## The subgroups in the company submission are appropriate for decision making People with 'high disease activity' relapsing–remitting multiple sclerosis were divided into 2 subgroups: Rapidly evolving severe relapsing–remitting multiple sclerosis: 2 or more relapses in the previous year whether the person was on treatment or not, and at least 1 T1 gadolinium-enhancing lesion. Suboptimally treated relapsing–remitting multiple sclerosis: at least 1 relapse in the previous year while the person was on disease-modifying therapy, and at least 1 T1 gadolinium-enhancing lesion or 9 T2 lesions.In addition to these subgroups, the 'high disease activity' subgroup also included an undefined group of people, who the committee understood to be those with 2 or more relapses in the previous year without a T1 gadolinium-enhancing lesion. The clinical experts explained that this group was clinically identifiable, but that suboptimal treatment was more difficult to define. The committee considered that the suboptimal treatment subgroup represented people who have highly active disease that had responded inadequately to previous treatment. However, it noted that the criteria used for MRI evidence of disease activity in this group may not be relevant for clinical practice, particularly given the concerns of the clinical experts about using the absolute number of T2 lesions as a criterion (see section 3.2). The clinical experts explained that the categorisations in marketing authorisations are difficult to use in clinical practice because there is a spectrum of disease activity rather than rigidly defined stages. However, they explained that the rapidly evolving severe and suboptimal treatment groups were broadly representative of patients at the more active end of the disease spectrum. The committee concluded that the subgroups broadly represent the population who would have cladribine tablets (hereafter referred to as cladribine) in clinical practice, and are appropriate for decision making. However, it also concluded that it would not use the company's definition of suboptimal treatment as the basis of any recommendation. # Comparators ## The choice of comparator varies by subgroup The clinical experts explained that many people with multiple sclerosis do not take disease-modifying therapies, but that people with highly active disease would. The committee understood that, for people with more active disease, clinicians follow NICE guidance, which recommends that people with rapidly evolving severe multiple sclerosis have alemtuzumab or natalizumab. Similarly, in line with NICE guidance, people with suboptimally treated multiple sclerosis (as defined in the company submission) could have alemtuzumab or fingolimod. The committee concluded that it was appropriate to consider the following comparators for cladribine: alemtuzumab and natalizumab for people with rapidly evolving severe disease alemtuzumab and fingolimod for people with suboptimally treated disease. # Direct clinical evidence ## The main clinical evidence for cladribine comes from the CLARITY trial The CLARITY trial was a randomised double-blind study of 1,326 people with active relapsing–remitting multiple sclerosis, which compared 2 different doses of cladribine with placebo. In the study, 433 people had the licensed dose (3.5 mg/kg body weight) of cladribine and 437 people had placebo. The primary outcome was annualised relapse rate. An important post-hoc outcome was time to 6‑month confirmed disability progression. ## The relevant subgroups are defined post hoc in CLARITY The company provided clinical evidence for the whole (intention-to-treat) population and for a post-hoc high disease activity subgroup from CLARITY. However, it did not provide cost-effectiveness estimates for these groups. The company's main evidence in its cost-effectiveness analysis was based on smaller post-hoc subgroups of the post-hoc high disease activity subgroup. These smaller subgroups were people with rapidly evolving severe and suboptimally treated relapsing–remitting multiple sclerosis. The company explained that it considered the rapidly evolving severe and suboptimal treatment post-hoc groups to broadly reflect the groups in previous NICE appraisals. The committee was concerned that the number of patients who had cladribine in these subgroups was small (50 and 19 patients respectively) meaning that the data based on these subgroups are uncertain. The committee agreed that evidence based on a larger pre-specified subgroup is preferable but appreciated that CLARITY had been planned before the current disease categorisations had emerged. ## Definitions of outcomes in CLARITY differ from other clinical trials and previous appraisals To determine disability progression above the Expanded Disability Status Scale (EDSS) state 5, a 0.5‑point change in EDSS state was used in CLARITY, whereas other clinical trials used a 1.0‑point change. A clinical expert explained that the difference between EDSS state 5 and EDSS state 5.5 is more subjective, and that it is less clinically significant than a change from EDSS state 5 to EDSS state 6, which requires the use of a walking aid. The committee noted that there were also differences in how a relapse was defined, with relapse-related disability specifically based on EDSS state in CLARITY but not in other trials. On balance, the committee considered that the differences in outcomes were unlikely to have a large effect on the comparative effectiveness, and concluded that the outcomes were broadly comparable across trials. ## Cladribine reduces relapses and delays disability compared with placebo in the whole population and the high disease activity subgroup In the intention-to-treat analysis and in the high disease activity subgroup, cladribine reduced the annualised relapse rate and delayed disability progression sustained for 6 months compared with placebo (see table 1). The committee concluded that, for the overall population of people with relapsing–remitting multiple sclerosis and for the overall high disease activity subgroup, cladribine was more effective than placebo. Outcome Intention to treat (433 people having cladribine) Overall high disease activity (140 people having cladribine) Annualised relapse rate (rate ratio ) (0.33 to 0.53) (0.24 to 0.50) Time to confirmed 6‑month disability progression (hazard ratio ) (0.36 to 0.78) (0.08 to 0.44) ## Results for the rapidly evolving severe and suboptimal treatment subgroups are uncertain In the rapidly evolving severe subgroup, cladribine reduced relapses and delayed disability progression compared with placebo. However, the effect on disability progression was not statistically significant. In the suboptimal treatment subgroup, the annualised relapse rate was lower with cladribine than with placebo, but the effect was not statistically significant. The effect on disability progression could not be estimated in this group because of small patient numbers. The exact results for the rapidly evolving severe and suboptimal treatment subgroups are commercial in confidence. The committee considered that the lack of statistical significance was partly because of the small patient numbers. It noted that, in the overall high disease activity group, which included both of the smaller subgroups, cladribine was highly effective and the results were statistically significant (see section 3.8). The committee concluded that, despite some uncertainty over the effect size, cladribine was likely to be more effective than placebo in both the rapidly evolving severe and suboptimal treatment groups. # Indirect clinical evidence ## The company network meta-analysis is appropriate The company's network meta-analysis compared cladribine with other treatments (including the comparators for this appraisal and other disease-modifying therapies such as beta interferon), in the overall population, and in the high disease activity, rapidly evolving severe and suboptimal treatment subgroups. The committee discussed the company's assumptions in the network meta-analysis: The company assumed that the relevant outcomes were comparable between trials, despite the differences in outcome measures in CLARITY compared with clinical trials for other treatments (see section 3.7). The ERG explained that it considered this to be a major limitation, but the company suggested that these subtle differences should not have a major impact. The committee agreed that the outcome measures used were broadly similar across trials. The company assumed that the subgroups in CLARITY were comparable to those used in other clinical trials. The committee was aware that the definitions of high disease activity, rapidly evolving severe disease and suboptimally treated disease despite previous treatment differed from those used in previous NICE guidance for relapsing–remitting multiple sclerosis (see section 3.2 and section 3.3). However, the committee considered that the subgroups were defined based on similar radiological and clinical criteria. It accepted that the subgroup populations were comparable between this appraisal and previously published appraisals.The committee concluded that the network meta-analysis was appropriate for this appraisal. ## The network meta-analysis does not provide conclusive evidence for the effectiveness of cladribine compared with current NHS treatments For each subgroup, the company used separate evidence networks to estimate the relative effectiveness of cladribine on annualised relapse rate, disability progression sustained for 3 months, and disability progression sustained for 6 months. Comparisons with cladribine were not possible for some of the comparators in each of the subgroups. Notably, results were not available for disability progression in the suboptimal treatment subgroup. Among the comparisons presented, cladribine did not have a statistically significant effect relative to its comparators (that is, alemtuzumab, fingolimod and natalizumab) on any of the outcomes in any of the subgroups. The committee also noted that the confidence intervals were wide and overlapped between treatments. It concluded that there was insufficient evidence from the network meta-analysis to show that cladribine had substantially different effectiveness to alemtuzumab, fingolimod or natalizumab. ## The meta-regression provides a full set of comparisons but may use invalid methods The company did a meta-regression for the outcome of disability progression sustained for 6 months for cladribine, alemtuzumab, fingolimod and natalizumab compared with placebo to address the weaknesses of the network meta-analysis, particularly for the suboptimal treatment group. In the absence of data in the network meta-analysis (see section 3.11), the meta-regression estimated effectiveness based on differences in the baseline risk of disability progression. The committee noted that, although confidence intervals for cladribine, alemtuzumab, fingolimod and natalizumab compared with placebo were narrower than those for estimates in the network meta-analysis, they overlapped for all treatments in both the rapidly evolving severe and suboptimal treatment subgroups. It also noted that, for the rapidly evolving severe subgroup, the estimated effectiveness of cladribine compared with placebo from the meta-regression was similar to the estimate from the network meta-analysis. However, it was concerned that alemtuzumab compared with placebo appeared substantially less effective in the meta-regression than in the network meta-analysis. The company suggested this could be explained by the differences in baseline risk between trials. The company validated the methodology by comparing the effect sizes predicted by the meta-regression with the effect sizes seen in the relevant trials. The committee agreed with the ERG's concerns that there were differences in effect size not explained by differences in baseline risk, which would make the company's approach invalid. In addition, the committee was aware that the assumptions and issues which the network meta-analysis relied on (see section 3.10) also applied to the meta-regression. The committee acknowledged the company's attempts to address the data limitations, but on balance agreed that the meta-regression approach may be invalid. The committee concluded that, although the meta-regression did provide estimates for effect sizes adjusted for baseline risk, the evidence from the meta-regression was insufficient to show that cladribine had substantially different effectiveness to alemtuzumab, fingolimod and natalizumab. # Company's economic model ## The model is appropriate for decision making The committee noted that the company's model was similar to models used in previous NICE technology appraisal guidance, but that the company had removed progression to secondary progressive multiple sclerosis. The company explained that it was difficult to identify the transition to secondary progressive multiple sclerosis in clinical practice, and noted that health-related quality of life is more closely related to EDSS state than to the clinical form of multiple sclerosis. The company suggested that this meant that separating the 2 forms of the disease was unnecessary for economic modelling because all health-related benefits of treatment would be captured by changes in EDSS state. The committee concluded that the company's model was appropriate for decision making. # Natural history of the disease in subgroup analyses ## Calculating different rates of disability progression in the subgroups is simplistic and potentially inaccurate The natural history of multiple sclerosis in the company's economic model was based on the British Columbia multiple sclerosis dataset, which was used in previous NICE technology appraisal guidance. The company explained that the British Columbia dataset included a mixture of people with active and highly active multiple sclerosis. The company stated that rapidly evolving severe or suboptimally treated multiple sclerosis is expected to progress faster than active relapsing–remitting multiple sclerosis. Therefore, it adjusted the disease progression rates to allow for a higher probability of progression for EDSS states 0 to 6. This adjustment was based on the difference in 6‑month confirmed disability progression in CLARITY in each subgroup compared with its complement (that is, people not included in that subgroup). The clinical experts and the ERG explained that, although assuming different rates of disease progression for each subgroup was reasonable, the company's approach was simplistic and potentially inaccurate. The committee appreciated that there was no clear alternative data source or method, and was aware that such adjustment had not been used in previous technology appraisals. However, because the adjustment would have a limited effect on the cost effectiveness of cladribine, the committee did not pursue this point any further. # Treatment effect ## A scenario exploring equal clinical effectiveness should be considered in the economic analysis Because there was insufficient clinical evidence to show that cladribine had substantially different effectiveness to its comparators (see section 3.12), the ERG provided a scenario assuming that cladribine and its comparators were equally effective in reducing relapses and delaying disability progression. The committee concluded that, based on the evidence, it would take into account this ERG scenario in its decision making. # Waning of treatment effect ## The waning of the treatment effect should be the same for all comparators In previous NICE technology appraisal guidance for multiple sclerosis (such as for alemtuzumab and dimethyl fumarate), the committee agreed that most treatments for multiple sclerosis become less effective over time. Therefore, the economic modelling included the assumption that the treatment effect declines by 25% after 2 years and by 50% after 5 years for all therapies. The committee heard that the company had attempted to assess whether there was a declining effect of cladribine by analysing data from the extension of the CLARITY trial. The company used a treatment switching analysis to estimate a hazard ratio for disability progression for cladribine compared with placebo over 4 years. It showed that this hazard ratio was similar to the hazard ratio estimated over 2 years. Therefore, the company suggested that there was no evidence of the treatment effect waning within the first 4 years. The company assumed that the waning effect for cladribine began after 4 years (that is, a 25% decline in treatment effect after 4 years and a 50% decline after 5 years). However, for the comparators, the company used the waning assumptions used in previous appraisals (that is, a 25% decline in treatment effect after 2 years and a 50% decline after 5 years). The committee noted that there was no statistically significant evidence to support different waning effects and that patient numbers used for the analysis in the subgroups were very small. It concluded that the company's evidence was insufficient to justify using a different treatment waning assumption for cladribine. # Treatment stopping rates ## Applying annualised rates based on clinical trials is likely to overestimate treatment stopping rates The company used the rates at which patients stop treatment with cladribine or its comparators from the respective clinical trials. The committee understood that, given the method of administration of both cladribine and alemtuzumab (that is, both involve 2 short courses of treatment a year apart), annual discontinuation rates did not apply, and the rate of stopping treatment refers to stopping between the first and second courses. The committee noted that fingolimod and natalizumab were all taken more frequently and for longer, so annual discontinuation rates were relevant. The ERG explained that people are more likely to stop treatment during the first year of treatment than in a subsequent year. Therefore, the company's approach of applying trial-based discontinuation rates to subsequent years would overestimate the number of people stopping treatment. In its exploratory analyses, the ERG assumed that, after the first 2 years of treatment, people only stopped treatment with fingolimod and natalizumab when there was no further clinical benefit (in the company model, until EDSS state 7, which would indicate secondary progressive multiple sclerosis). The committee concluded that the company had likely overestimated treatment stopping rates, but noted that this did not have a substantial effect on the cost-effectiveness analysis. # Restarting treatment after relapse ## Restarting cladribine treatment should not be included in the economic model The company included restarting treatment with cladribine and alemtuzumab following relapse in the economic model, which increased the costs but not the clinical effects of each treatment in the model. The ERG explained that there was no published effectiveness evidence on restarting treatment, and that it had removed this from the model in its exploratory analyses. The committee noted that cladribine's marketing authorisation does not refer to restarting treatment, and concluded that it should not be included in the economic model. # Health-state costs ## Informal care costs should not be included in the model The committee discussed the annual costs associated with each EDSS health state in the economic model. It noted that the company had used medical costs from Hawton and Green (2016) and non-medical costs from Karampampa et al. (2012), and that these were large compared with the health-state costs accepted in previous NICE technology appraisals. The committee noted that the company had included informal care costs. The ERG argued that these should be excluded to reflect the perspective of the NHS or personal social services on costs, as per the NICE reference case. In its exploratory analyses, the ERG used the UK MS Survey (using 2015/16 unit costs) as its source for EDSS state costs, which had been used in previous appraisals (including for dimethyl fumarate, fingolimod and natalizumab). The committee concluded that it was appropriate to exclude informal care costs and that the UK MS Survey values should be used for decision making. # Caregiver quality of life ## The effect on the quality of life of carers should be taken into account The ERG removed the quality-of-life decrement for carers of people with multiple sclerosis from the company's economic modelling because it considered this inconsistent with the NICE reference case. The committee was aware that previous NICE guidance for relapsing–remitting multiple sclerosis included utility values for caregivers. The committee agreed that it was important to recognise the impact that caring for people with multiple sclerosis has on caregivers, and concluded that caregiver quality-of-life decrements should be included in the cost-effectiveness analysis. # Other factors ## There is no evidence of any additional benefits of cladribine Cladribine is an oral treatment given in 2 short treatment periods over 2 years. The committee understood that this is significantly less disruptive to daily routines than existing treatments for multiple sclerosis, which need to be given more frequently or by injection. The committee agreed that these benefits would be welcomed by patients, and noted that existing oral treatments are all taken daily. However, the committee was not presented with evidence for the extent of these benefits in practice compared with other treatments. The committee concluded that it had not been presented with any additional evidence of benefits that were not captured in the measurement of quality-adjusted life years (QALYs). # Cost-effectiveness results and conclusion ## The ERG's changes to the model are appropriate and are considered with the company's results The committee had concluded that cladribine was clinically effective compared with placebo in the rapidly evolving severe and suboptimal treatment subgroups, but that there was insufficient evidence to determine whether cladribine was any more or less effective than its comparators (see section 3.12). The ERG had provided a scenario in which cladribine and its comparators (that is, alemtuzumab, fingolimod and natalizumab) were equally effective. The committee did not agree with the ERG's change excluding caregiver quality of life from the cost-effectiveness analysis (see section 3.20). The ERG also made other adjustments to the company's model: assuming equal waning of treatment effectiveness for cladribine and all comparators (see section 3.16) assuming that after 2 years, trial discontinuation rates for fingolimod and natalizumab did not apply (see section 3.17) removing restarting treatment with cladribine and alemtuzumab from the model (see section 3.18) using EDSS health-state costs based on UK MS Survey data (see section 3.19).The committee agreed that these changes were appropriate. It noted that the ERG had not explored the effect of some company assumptions, such as adjusting the natural history of disease progression (see section 3.14). However, it recognised that this was not likely to have a significant effect on cost effectiveness. The committee concluded that, although it did not fully reflect committee preferences, it would consider the ERG's exploratory scenario that assumes equal effectiveness of cladribine and its comparators in addition to the company base-case cost-effectiveness results. ## Cladribine is cost effective for rapidly evolving severe and suboptimally treated relapsing–remitting multiple sclerosis In the company's base-case cost-effectiveness analysis, cladribine dominated (that is, was more effective and cheaper than) all other treatments. The committee noted that these results were based on effectiveness estimates from the company's meta-regression, which it had concluded was insufficient to show that cladribine had substantially different effectiveness from its comparators (see section 3.12). The committee therefore considered the effect of the ERG's exploratory analyses incorporating most of the committee's preferred assumptions and assuming equal effectiveness of cladribine, and the relevant comparators in both the rapidly evolving severe and suboptimal treatment subgroups. It noted that, in isolation, none of the ERG's changes to the company model changed the company's base-case results, and cladribine continued to dominate all other treatments in both subgroups. After combining the ERG's assumptions, cladribine remained more effective and cheaper than fingolimod and natalizumab in the relevant subgroups. Cladribine was less effective and cheaper than alemtuzumab in the combined scenario analysis in both the rapidly evolving severe and suboptimal treatment subgroups. This resulted in incremental cost-effectiveness ratios (ICERs) of £219,549 gained per QALY lost and £372,802 gained per QALY lost respectively. For interventions that are less costly and less effective than a comparator, an intervention is considered cost effective if the ICER generated is above the level considered acceptable rather than below it. The committee concluded that cladribine was a cost-effective use of NHS resources for rapidly evolving severe relapsing–remitting multiple sclerosis and suboptimally treated relapsing–remitting multiple sclerosis (that is, disease that has responded inadequately to disease-modifying therapy). However, the committee understood from the experts that it was not the number of, but the increase in, MRI lesions that is important to measure response to treatment (see section 3.2). It therefore agreed to refer to MRI evidence of disease activity rather than using the company's definition of suboptimal treatment.

Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. # Introduction ## Puberty normal physiology Puberty is the physiological process during which secondary sexual characteristics develop. The physical changes, driven by marked hormonal alterations, are not only limited to the development of secondary sexual characteristics but also include changes in body composition, brain, cardiovascular and skeletal development. In parallel, the adolescent matures psychosocially and emotionally. The onset of puberty depends on genetic, nutritional and environmental factors [bib_ref] The timing of normal puberty and the age limits of sexual precocity:..., Parent [/bib_ref]. Oestrogen and testosterone are produced and secreted in response to pituitary gonadotropins (luteinising hormone (LH) and folliclestimulating hormone (FSH)), which are under the control of hypothalamic gonadotropin-releasing hormone (GnRH). There is a broad range for the age at pubertal onset. In girls, the earliest visible sign of central puberty is usually breast budding, described as breast stage 2 (B2) on the Tanner scale [bib_ref] Variations in pattern of pubertal changes in girls, Marshall [/bib_ref]. The average attainment age for breast stage 2 is less than 10 years and should appear before the age of 13 years [bib_ref] Mogensen SS & Juul A. Recent secular trends in pubertal timing: implications..., Sørensen [/bib_ref]. Menarche usually occurs 2-3 years after the onset of puberty, after peak height velocity, which usually occurs between B3 and B4 [bib_ref] Somatic pubertal development, Taranger [/bib_ref] [bib_ref] Pubertal correlates in black and white girls, Biro [/bib_ref]. However, individual variation is large. In boys, the first sign of pubertal development is an increase in testis volume, ≥4 mL assessed by orchidometer, which occurs at an average age of 11 years, and should appear before the age of 14 years. This is typically followed by the development of pubic and axillary hair [bib_ref] Variations in the pattern of pubertal changes in boys, Marshall [/bib_ref]. Peak height velocity usually coincides with a testis volume of about 10-12 mL [bib_ref] Variations in the pattern of pubertal changes in boys, Marshall [/bib_ref]. After this, voice breaking occurs [bib_ref] Voice break in boys-temporal relations with other pubertal milestones and likely causal..., Busch [/bib_ref]. ## Mini-puberty Mini-puberty is a period which describes the activation of the hypothalamic-pituitary-gonadal hormone axis (HPG axis) in the first months of life. The gonadotropin levels show a postnatal LH surge during the first 24 h followed by an increase at around 1 week and a peak between 1 and 3 months of age [bib_ref] Up-to-date review about minipuberty and overview on hypothalamic-pituitarygonadal axis activation in fetal..., Lanciotti [/bib_ref]. Compared to full-term infants, those born preterm or small for gestational age show an exaggerated postnatal HPG axis activity. In boys, HPG activation coincides with a testosterone peak, with penile and testicular growth and with final testicular descent if not already in the scrotum at birth. In girls, it coincides with an increase in oestradiol, infant breast development, uterine growth and maturation of ovarian follicles. The complete biological significance of mini-puberty is still to be elucidated, but it affects brain development, may be responsible for differences in body composition and have long-term consequences for gonadal function [bib_ref] The early postnatal period, mini-puberty, provides a window on the role of..., Hines [/bib_ref] [bib_ref] Replacement of male mini-puberty, Papadimitriou [/bib_ref]. After the age of 3 months, gonadotropins decrease towards the age of 6 months, although FSH levels in girls can remain elevated until 3-4 years of age. The infant activation of the HPG hormone axis is silenced from the age of 3-6 months until reactivation at the onset of puberty. Therefore, these first months of life provide a window of opportunity for investigating the HPG hormone axis [bib_ref] Distinguishing between hidden testes and anorchia: the role of endocrine evaluation in..., Jespersen [/bib_ref] [bib_ref] Minipuberty in Klinefelter syndrome: current status and future directions, Aksglaede [/bib_ref] [bib_ref] Andersson AM & Juul A. Sex differences in reproductive hormones during mini-puberty..., Johannsen [/bib_ref]. The analysis of basal gonadotropin and gonadal hormones at the age of 1-3 months of life is helpful when investigating infants with suspected central or primary hypogonadism. as 45,X/46,XY mosaicism are brought up either as boys or girls, depending on several factors including the degree of prenatal masculinisation. In 46,XY DSD, there may be a problem in gonadal development, testosterone/DHT synthesis or action. It includes patients with complete gonadal dysgenesis, typically with a female phenotype at birth, no pubertal development and a uterus. It also includes patients with partial gonadal dysgenesis with varying degrees of masculinisation at birth as well as during puberty; some of their physical features overlap with those of patients with 46,XY partial androgen insensitivity (PAIS). [bib_ref] Aromatase inhibitors in puberty, Hero [/bib_ref] ,XY complete androgen insensitivity (CAIS) is associated with a female phenotype but without a uterus due to the production of anti-Müllerian hormone (AMH) by the testis during fetal development. [bib_ref] Aromatase inhibitors in puberty, Hero [/bib_ref] ,XY disorders of androgen synthesis are also associated with reduced masculinisation at birth, and, in some conditions such as 17β-hydroxysteroid dehydrogenase deficiency and 5α-reductase deficiency, the activation of isoenzymes in parallel to the increase of testosterone levels during puberty can result in spontaneous virilisation. The 46,XX DSD category includes the relatively frequent occurrence of patients with androgen excess due to congenital adrenal hyperplasia caused by 21-hydroxylase deficiency and also patients with 46,XX DSD with testis development due to, for example, the presence of sexdetermining factor of Y (SRY) on one of the X chromosomes or on other chromosomes. Ovotesticular DSD is characterised by the presence of both testicular and ovarian tissue, with a karyotype that can be 46,XX, 46,XY or mosaic. Individuals with DSD may be identified in the neonatal period because of atypical external genitalia, lack of neonatal minipuberty or may be diagnosed in puberty/adolescence when pubertal development is delayed, incomplete, absent or atypical [bib_ref] Society for Endocrinology UK guidance on the initial evaluation of an infant..., Ahmed [/bib_ref]. Girls may seek medical attention because of the absence of breast development and/or primary amenorrhoea or with increasing virilisation during puberty. Boys may present with short height, slow or non-progressing pubertal development and/or gynaecomastia. There is an increased risk of malignancy in patients with 46,XY DSD, especially if gonads are intra-abdominal, and patients may present with gonadal tumour-secreting steroid hormones, complicating the diagnosis and may even be the presenting symptom. In some cases, early gonadectomy may have been performed due to a high malignancy risk of the presence of a Y chromosome together with undermasculinisation [bib_ref] Gonadectomy in conditions affecting sex development: a registry-based cohort study, Lucas-Herald [/bib_ref]. Finally, deficiencies of sexual development requiring treatment also include patients with impaired gonadal function due to gonadotropin deficiency and congenital hypogonadotropic hypogonadism (CHH), which can be divided into normosmic CHH and Kallmann syndrome (CHH and deficient sense of smell). CHH can also be a part of multiple pituitary hormone deficiencies or part of a syndrome such as CHARGE or Waardenburg syndrome. Phenotypes associated with CHH apparently shortly after birth or during childhood are midline defects such as cleft lip and/or palate, dental anomaly, anomaly of digits, congenital hearing impairment, anosmia/hyposmia, microphallus/cryptorchisism and family history of CHH. ## The role of hormonal replacement therapy during puberty It is not uncommon that testosterone or oestrogen replacement therapy (ERT) is required in adolescents with DSD or pituitary deficiency (see [fig_ref] Table 2: Spontaneous puberty, sex hormone replacement and possibility of fertility in subjects with... [/fig_ref] [bib_ref] Puberty in individuals with a disorder of sex development, Nordenström [/bib_ref]. The overall aim of the therapy is to ensure that secondary sexual characteristics and maturation of the body and the brain occur at a similar pace to peers. This may also be the case even if puberty has started spontaneously but ceases to progress appropriately. Regardless of the cause of hypogonadism, appropriate oestrogen or testosterone replacement will be required for puberty induction and puberty progression. This should mimic the physiological process inducing the secondary sexual characteristics, growth plate maturation and psychological functioning. In those with no identified cause of hypogonadism, the lack of pubertal features at the age of 13 years in girls and 14 years in boys should prompt investigations and may indicate the need for pharmacological puberty induction. In those with an identified cause of hypogonadism, puberty should be induced over a period of 2-4 years until a satisfactory outcome, usually when an adult dose has been reached. Sex steroid hormones are imperative for somatic and psychological wellbeing, also in the longer perspective, due to their effects on bone mineral density (BMD), haematopoiesis and cardiovascular, sexual and metabolic health. ## Aromatase inhibitors in puberty Aromatase inhibitors inhibit the formation of oestrogens from androgens, leading to oestrogen depletion. Given that oestrogens mediate the growth spurt in both sexes and contribute to epiphyseal closure, it was hypothesised that oestrogen depletion would improve adult height in boys [bib_ref] A specific aromatase inhibitor and potential increase in adult height in boys..., Wickman [/bib_ref]. Aromatase inhibitors have been given to prepubertal or pubertal boys for 1-2 years, to increase predicted adult height [bib_ref] Letrozole monotherapy in pre-and early-pubertal boys does not increase adult height, Varimo [/bib_ref]. In girls, aromatase inhibitors have been used in combination with GnRH analogues attempting to increase adult height in early maturing girls [bib_ref] Anastrozole plus leuprorelin in early maturing girls with compromised growth: the 'GAIL'..., Papadimitriou [/bib_ref] and in the experimental treatment of congenital adrenal hyperplasia [bib_ref] Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone..., Merke [/bib_ref]. Aromatase inhibitors have been used in gynaecomastia, McCune-Albright syndrome, aromatase overexpression in patients with large calcifying Sertoli cell tumours and familial male-limited precocious puberty [bib_ref] Aromatase inhibitors in puberty, Hero [/bib_ref]. The most common side effect is the loss of BMD. In boys, aromatase inhibitors given prior to the onset of puberty do not seem to change the timing [bib_ref] Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult..., Hero [/bib_ref]. In contrast, the situation is different once the central restraint of gonadotropin secretion is diminished at the onset of puberty when puberty is mainly controlled by the sex steroid-mediated feedback from the gonads. In both sexes, this feedback is mediated by oestrogen, and consequently, oestrogen depletion in boys at that time leads to increased gonadotropin and testosterone levels. ## Biochemical hormonal testing The assessment of the HPG axis includes the quantification of serum concentrations of gonadotropins, FSH and LH, as well as gonadal sex steroids oestradiol (E2) and testosterone (T). In addition, gonadal peptides like inhibin B, AMH (48) and insulin-like factor 3 (49) may add useful information about the gonadal Sertoli and Leydig cell function, respectively. AMH is also used as a marker of ovarian reserve. When puberty starts, the secretion of FSH and LH is very low and increases with pulsatility only at night time in peripubertal children. Ultrasensitive FSH and LH assays (i.e. detection limit < 0.1 IU/L) are required to separate prepubertal from pubertal children based on their serum concentrations [bib_ref] Peptide hormone analysis in diagnosis and treatment of differences of sex development:..., Johannsen [/bib_ref]. A basal LH concentration above 0.3 IU/L is considered evidence of pituitary activation, whereas a lower or even undetectable LH concentration does not exclude pubertal onset. Therefore, a short intravenous GnRH test may be needed, with a stimulated LH above 5 IU/L which is considered a pubertal response. Importantly, peak LH may reach values of almost 10 IU/L in 1-3 years old prepubertal children [bib_ref] The follicle-stimulating hormone (FSH) and luteinizing hormone (LH) response to a gonadotropinreleasing..., Vestergaard [/bib_ref]. The GnRH test is often used to diagnose central precocious puberty but has limited additional value in delayed puberty [bib_ref] GnRH stimulation testing and serum inhibin B in males: insufficient specificity for..., Mosbah [/bib_ref]. Reference ranges covering all ages including the pubertal transition period are available for FSH and LH using ultrasensitive assays [bib_ref] The LH/FSH ratio is not a sex-dimorphic marker after infancy: data from..., Ljubicic [/bib_ref]. The quantification of E2 and T at low concentrations found in pre-and peripubertal boys and girls requires specific and sensitive assays. E2 quantification is needed in the evaluation of girls with premature thelarche, precocious and delayed puberty, boys and men with gynaecomastia, patients with suspected hypogonadism, as well as monitoring of hypogonadal girls during puberty induction with oestrogen. High accuracy, specificity and precision, as well as standardisation of E2 assays, are mandatory according to the Endocrine Society [bib_ref] Measurement of estradiol -challenges ahead, Stanczyk [/bib_ref] [bib_ref] Requirement for mass spectrometry sex steroid assays in the, Handelsman [/bib_ref] , as well as to European guidelines [bib_ref] Steroid hormone analysis in diagnosis and treatment of DSD: position paper of..., Kulle [/bib_ref]. Some diurnal variation in E2 has been shown using an ultrasensitive immunoassay [bib_ref] Diurnal rhythm of 17 beta-estradiol secretion throughout pubertal development in healthy girls:..., Norjavaara [/bib_ref]. Sensitive mass spectrometry-based methods, such as the liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods, are now accepted as state-of-theart methods for the quantitative analysis of T and E2 [bib_ref] LC-MS/MS analysis of steroids in the clinical laboratory, Keevil [/bib_ref]. Reference ranges for E2 and T determined by LC-MS/MS are available [bib_ref] Sex-specific estrogen levels and reference intervals from infancy to late adulthood determined..., Frederiksen [/bib_ref] [bib_ref] Andersson AM & Juul A. Sex, age, pubertal development and use of..., Søeborg [/bib_ref]. ## Puberty induction general issues to consider ## Psychological function and social development Puberty is associated with numerous physical, psychological and social changes. Recent functional MRI studies on brain development in adolescence elucidated the impact of steroids on neuropsychological maturation [bib_ref] Understanding adolescence as a period of socialaffective engagement and goal flexibility, Crone [/bib_ref] [bib_ref] Understanding the role of puberty in structural and functional development of the..., Goddings [/bib_ref]. A better understanding of sex steroid action on the changes in cognitive, emotional and social functioning during the transition from childhood to adulthood has raised awareness that atypical pubertal development is not only harmful to physical maturation and health in general but also creates a delay in intellectual, emotional and social capacities. Therefore, the management of puberty and puberty induction should include the monitoring of psychosocial functioning. ## Informing the child The child needs to be informed about the medical condition in a continuous and age-appropriate process [bib_ref] Improving the communication of healthcare professionals with affected children and adolescents, Nordenström A &amp; Thyen [/bib_ref]. By discussing how to inform the child already at an early stage, parents will be able to prepare themselves. Parents need to understand and be prepared for the physical, psychological and social changes during adolescence in order to become aware of the challenges their child will come across. Advisory booklets or informative websites on how to prepare and support their child will empower parents and make it easier for them to communicate with their child about medical condition and the challenges they may encounter (see websites (https://www.dsdfamilies.org/charity; https:// www.dsdteens.org/; http://www.accordalliance. org/dsdguidelines/parents.pdf; https://www. fairview.org/patient-education/40119; https://www. connecticutchildrens.org/wp-content/uploads/2017/02/ DSD_Resources.pdf)). In particular, for adolescents with DSD, timely information and sex education are important. Psychological counselling, dedicated educational websites and contacts with other patients may be helpful. All DSD conditions per se may intensify parental focus on their child's behaviour, particularly with respect to assigned gender at birth in children with DSD. Some parents seek reinforcement of the decisions made and may start worrying when they experience insufficient reassurance. In psychological counselling, information on psychological aspects of child development including play behaviour, development of gender preferences and development of knowledge on sex and gender will be helpful to take away the turmoil. Importantly, gender role behaviour, interests and preferences are mostly neither possible nor desirable to change [bib_ref] Prenatal hormones and postnatal socialization by parents as determinants of male-typical toy..., Pasterski [/bib_ref] and cannot be used to predict gender identity [bib_ref] Human gender development, Hines [/bib_ref]. Acceptance of behaviour is needed to enable the child to develop a positive self-esteem that is necessary to cope with the challenges that children with DSD will meet in puberty and adulthood. Children need support from their parents. Parents who feel shame, shyness or inability to cope or to protect will need support and reinforcement of their parental competency. ## Gender development Prenatal androgen exposure and action influence future gender role behaviour and interests. This has been shown in studies of patients with 46,XX CAH and in children with 46,XY DSD raised male or female with different levels of prenatal androgen exposure [bib_ref] Psychological outcomes and gender-related development in complete androgen insensitivity syndrome, Hines [/bib_ref] [bib_ref] Sex-typed toy play behavior correlates with the degree of prenatal androgen exposure..., Nordenström [/bib_ref] [bib_ref] Gender role behavior, sexuality, and psychosocial adaptation in women with congenital adrenal..., Frisén [/bib_ref]. The influence of prenatal androgens on gender identity is less clear. It should be emphasised that gender role behaviour does not imply gender identity; follow-up studies indicate that, as adults, the vast majority of individuals with a DSD developed a gender identity in agreement with the gender assigned at birth [bib_ref] Congenital micropenis: long-term medical, surgical and psychosexual follow-up of individuals raised male..., Wisniewski [/bib_ref] [bib_ref] Gender dysphoria and gender change in androgen insensitivity or micropenis, Mazur [/bib_ref] [bib_ref] Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency, Cohen-Kettenis [/bib_ref] [bib_ref] Psychosexual development in adolescents and adults with disorders of sex development -results..., Jurgensen [/bib_ref] [bib_ref] Faradz SM & Dessens AB. Gender development in Indonesian children, adolescents, and..., Ediati [/bib_ref] [bib_ref] Dessens AB & Dutch Study Group on DSD. Recalled and current gender..., Callens [/bib_ref] [bib_ref] Cohen-Kettenis PT & dsd-LIFE group. Gender dysphoria and gender change in disorders..., Kreukels [/bib_ref]. Many individuals who changed gender may not only have been prenatally exposed to androgens but also in the first 6 months after birth (during the mini-puberty) and during puberty [bib_ref] Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency, Cohen-Kettenis [/bib_ref]. Patients living in countries outside Europe and Northern America often have limited possibilities for medical evaluation and treatment, leading to a delay in clinical management [bib_ref] Faradz SM & Dessens AB. Gender development in Indonesian children, adolescents, and..., Ediati [/bib_ref] A transition program can be tailored to the individual's needs and future clinical management and is preferably drafted in collaboration with the medical specialist who will become the patient's doctor in adulthood (89, 90, 91, 93). The program should test the adolescent's knowledge and skills, encourage the adolescent to discuss daily life challenges with the medical team and/or parents and challenge the adolescent to set goals for independence [bib_ref] A longitudinal, observational study of the features of transitional healthcare associated with..., Colver [/bib_ref]. The transition of young adults with gonadal dysfunction, whatever the reason, illustrates the importance of a multidisciplinary approach, to discuss both medical issues (about hormonal replacement therapy, long-term consequences in terms of sexuality, fertility) and social and psychological issues that arise in the context of these chronic conditions (89, 95). # Methods ## Guideline working group These guidelines were developed on behalf of the European Reference Network on Rare Endocrine Conditions (Endo-ERN). The following societies were represented: the European Society of Endocrinology (ESE) (Dekkers), the European Society for Paediatric Endocrinology (ESPE) (Vd Akker and Gawlik), CH/SOD association (Vitali) and the Turner Syndrome Support Society (Smyth). The working group had one in-person meeting (December 2019) and one virtual meeting (June 2020). All participants completed conflict of interest forms. A draft of the guideline was reviewed by five experts in the field (see 'Acknowledgments' section) and has been distributed to all Endo-ERN members for comments. In addition, the following societies and networks were asked to review the guidelines: ESPE, ESE and the European Academy of Andrology. Furthermore, patient representatives in the Endo-ERN were involved in the whole process. ## Target group and aims This guideline was developed for health care providers who may see patients with DSD or hypogonadotropic hypogonadism (HH) in need of treatment to induce or sustain puberty. In general, these patients should preferably be treated by a multidisciplinary team of experts in an Endo-ERN Reference Centre and their affiliated regional healthcare providers. General practitioners and patients might also find the guideline useful. Additionally, the guideline can serve as a source document for the preparation of patient information leaflets and educational materials. In clinical practice, when making treatment decisions, both the recommendations and the clinical judgement of the treating physician should be taken into account in a patientcentred, shared-decision process. Recommendations are not meant to replace clinical acumen. Certain recommendations may not be feasible in individual countries and must be interpreted in the context of available resources. ## Summary of methods used for guideline development This guideline used Grading of Recommendations, Assessment, Development and Evaluation (GRADE) as a methodological base [bib_ref] GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables, Guyatt [/bib_ref]. The first step was to define clinical questions; the second step was to perform a systematic literature search. After including all relevant articles for each clinical question, we rated the quality of the evidence and estimated an average effect for specific outcomes if possible. The quality of the evidence behind the recommendations is classified as very low (+OOO), low (++OO), moderate (+++O) or strong (++++) per For the recommendations, we considered the quality of the evidence, the balance of desirable and undesirable outcomes and individual values and preferences (patient preferences, goals for health, costs, management inconvenience, feasibility of implementation, etc.) [bib_ref] GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation..., Andrews [/bib_ref]. The recommendations are worded as 'recommend' (strong recommendation) or 'suggest' (weak recommendation). The meaning of a strong recommendation is that all reasonably informed persons (clinicians, politicians and patients) would want the management in accordance with the recommendation. For a weak recommendation, most persons would still act in accordance with the guideline but a substantial number would not [bib_ref] Going from evidence to recommendation-determinants of a recommendation's direction and strength, Andrews [/bib_ref]. Importantly, one cannot abstain from making recommendations when there is scarce evidence, as treatment decisions will have to be made anyway. Recommendations are accompanied by an explanation of why the recommendation was made. ## Clinical questions, eligibility criteria and endpoint definition At the start of this guideline process, six clinical questions were formulated, for which we performed a systematic literature search and review (See Supplementary Appendix 1 for details, see section on supplementary materials given at the end of this article). Question I: What is the optimal treatment to induce or sustain puberty in males with partial gonadal dysgenesis? Question II: What is the optimal treatment to induce or sustain puberty in males with HH? Question III: What is the optimal treatment to induce or sustain puberty in females with partial gonadal dysgenesis? Question IV: What is the optimal treatment to induce or sustain puberty in females with HH? Question V: What is the optimal treatment to induce or sustain puberty in patients with CAIS? Question VI: What is the optimal treatment to induce or sustain puberty in patients with PAIS? ## Description of search and selection of literature We performed a literature search using five electronic medical databases in February 2020 (PubMed, Embase, Web of Science, COCHRANE and Emcare). No language restrictions were imposed. Due to similarities in treatments of interest and clinical outcomes, one overarching search strategy was used for all six clinical questions. References of included articles were checked to identify potentially relevant articles. Only articles studying a minimum of ten patients (to avoid including small studies with a high risk of selection bias), which directly compared at least two treatments to induce or sustain puberty (or one treatment vs placebo), were eligible for inclusion. In total, we identified 6212 papers with our search strategy. For questions I, V and VI (puberty treatment in male patients with partial gonadal dysgenesis, CAIS and partial androgen insensitivity syndrome), after a formal search and assessment of potentially relevant papers, no papers were found. For question II (puberty treatment in males with HH, we included four papers. For question III (puberty treatment in females with partial gonadal dysgenesis), we included 22 papers, of which 1 was also included for question IV. For question IV (puberty treatment in females with HH), we included one paper, which was also included for question III. A flow diagram of study inclusion is presented in. ## Summary and interpretation of the evidence from the systematic literature review Clinical question I What is the optimal treatment to induce or sustain puberty in boys with partial gonadal dysgenesis? We found no studies on treatment to induce or sustain puberty in male patients with partial gonadal dysgenesis. ## Clinical question ii what is the optimal treatment to induce or sustain puberty in boys with hypogonadotropic hypogonadism? We included four studies on treatment to induce or sustain puberty in males with HH (100, 101, 102, 103), see Supplementary Appendix 2 [fig_ref] Table 1: Deficiencies of sexual development [/fig_ref] for details of included studies and individual study outcomes. The four studies compared the use of i.m. testosterone vs no treatment (100), monthly i.m. testosterone vs weekly i.m. hCG [bib_ref] Hormonal therapy and pubertal development in boys with selective hypogonadotropic hypogonadism, Bistritzer [/bib_ref] , high-vs low-dose GnRH [bib_ref] Induction of testicular growth and spermatogenesis by pulsatile, intravenous administration of gonadotrophin-releasing..., Delemarre-Van De Waal [/bib_ref] and GnRH vs hCG [bib_ref] Pulsatile GnRH is superior to hCG in therapeutic efficacy in adolescent boys..., Gong [/bib_ref]. The following outcomes were investigated: Tanner stage, penile length, testicular volume, spermatogenesis, Clinical question III What is the optimal treatment to induce or sustain puberty in female patients with partial gonadal dysgenesis? We included 22 studies on treatment to induce or sustain puberty in female patients with partial gonadal dysgenesis, of which 1 was also included for clinical question IV; see Supplementary Appendix 3 [fig_ref] Table 1: Deficiencies of sexual development [/fig_ref] for study details including individual study outcomes. There were 10 randomised trials, 1 non-randomised trial and 11 cohort studies. In total, the studies included 1472 patients (there may be partial overlap in some study populations). Various oestrogen treatment regimens were compared: oestrogen vs no oestrogen, early (age 12-14 years) vs late (age 14-17 years) start of oestrogen, individualised vs fixed dose, oral vs transdermal administration and high vs low oestrogen dose. Eight different outcomes were studied: Tanner stage, menarche, uterine size, BMD, height, weight, BMI and liver function. In only four instances at least two studies describe the same outcome (e.g. height) presented in the same way (e.g. in cm) for the same comparison. In [fig_ref] Figure 2 Oral: -conjugated oestrogen vs transdermal 17β oestradiol for reaching Tanner stage B3 [/fig_ref] , the number of patients to reach Tanner stage B3 during the study period for oral conjugated oestrogen vs transdermal 17β oestradiol was meta-analysed for two studies [bib_ref] Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a..., Nabhan [/bib_ref] [bib_ref] A randomized trial of transdermal and oral estrogen therapy in adolescent girls..., Shah [/bib_ref] ; no firm evidence for superiority, defined as patients reaching Tanner stage B3 or not, of one of the treatment modalities was found. In, final height was compared, in a placebocontrolled study, between patients with Turner treated with oestrogen (ethinyl E2) vs patients, not on oestrogen in a meta-analysis using two studies (one split into patients on additionally a high or low dose of growth hormone) [bib_ref] Growth hormone and low dose estrogen in Turner syndrome: results of a..., Quigley [/bib_ref]. Patients on oestrogen had a lower final height than patients on placebo (difference −2.9 cm; 95% CI: −4.9 to −0.8 cm); it should be noted that these patients were treated with growth hormone. In , final height was compared between early (age 10-12 years) and late (from age 12 years) start of oestrogen treatment (EE2 or E2) in a meta-analysis using six studies [bib_ref] Prepubertal ultra-low-dose estrogen therapy is associated with healthier lipid profile than conventional..., Ruszala [/bib_ref] [bib_ref] Growth hormone therapy of Turner syndrome: the impact of age of estrogen..., Chernausek [/bib_ref] [bib_ref] Final height in estrogentreated patients with Turner syndrome, Demetriou [/bib_ref] [bib_ref] Effect of oxandrolone and timing of pubertal induction on final height in..., Gault [/bib_ref] [bib_ref] Salutary effects of combining early very low-dose systemic estradiol with growth hormone..., Rosenfield [/bib_ref]. Early start of treatment did not result in a clearly lower final height than the late start of treatment (difference −1.0 cm; 95% CI: −4.0 to 1.9 cm). In , BMI was compared between early (age 10-12 years) and late (from age 12 years) start of oestrogen treatment in a meta-analysis using two studies [bib_ref] Prepubertal ultra-low-dose estrogen therapy is associated with healthier lipid profile than conventional..., Ruszala [/bib_ref]. The early start of treatment resulted in a lower, though not significantly, BMI than the late start of treatment (difference −0.9 points; 95% CI: −2.7 points to 0.9 points). For all formal comparisons, the number of studies was low, with broad CIs and genuine uncertainty regarding the effect estimates. ## Clinical question iv what is the optimal treatment to induce or sustain puberty in female patients with hypogonadotropic hypogonadism? We included 1 paper with 20 females with HH and treatment to induce or sustain puberty [bib_ref] A randomized trial of transdermal and oral estrogen therapy in adolescent girls..., Shah [/bib_ref] , which was also included for clinical question III and which did not present separate data for both patient categories. The GRADE evidence table is shown in Supplementary Appendix 4 [fig_ref] Table 1: Deficiencies of sexual development [/fig_ref] , including details of the study and its outcomes. Patients used either oral 17β oestradiol, transdermal 17β oestradiol or oral-conjugated equine oestrogen. Patients using oral or transdermal 17β oestradiol more often reached Tanner breast stage 3 and had lower height and weight at the end of the study period than patients using oral-conjugated equine oestrogen. The number of patients is too small to draw firm conclusions on preferred treatment. Oestrogen as add-on therapy for final height. ## Figure 4 Early (age 10-12 years) and late (from age 12 years) start of oestrogen for final height. ## Figure 5 Early (age 10-12 years) and late (from age ## Clinical question v what is the optimal treatment to induce or sustain puberty in women with complete androgen insensitivity syndrome? We found no studies on treatment to induce or sustain puberty in patients with CAIS. Clinical question VI What is the optimal treatment to induce or sustain puberty in patients with partial androgen insensitivity syndrome? We found no studies on treatment to induce or sustain puberty in patients with partial androgen insensitivity syndrome. ## Recommendations and rationales General R 1. [bib_ref] The timing of normal puberty and the age limits of sexual precocity:..., Parent [/bib_ref] We recommend that children and adolescents who need pubertal induction or sex hormone replacement to sustain puberty should be treated by a multidisciplinary team including a paediatric endocrinologist, adult endocrinologist, psychologist, urologist, gynaecologist, geneticist, surgeon and nurse specialist depending on the situation and specific requirements. ## Rationale Puberty and sexual maturation are sensitive and private matters and may be especially sensitive for individuals with a DSD. When the diagnosis is known since the neonatal period, the child and the parents can be informed and prepared well in advance of the time of puberty. If the diagnosis is made due to delayed, partial or absent pubertal development, the situation is more complex. In all cases, it is preferred that a specialised team with a multidisciplinary approach is involved (62). The medical diagnosis requires patients and parents to cope with uncertainties regarding health and future development and to understand a complicated medical condition often associated with societal beliefs about gender and 'normalcy'. As DSD conditions are rare, the expertise of medical professionals, also regarding many psychosocial aspects related to DSD, is essential. Discussing psychosocial aspects of DSD facilitates the acceptance of the condition and empowers parents to support their child whenever needed. ## Puberty induction in girls # Introduction Accumulating data show that initiation of puberty at an age comparable with peers is essential for normal physiologic development, including secondary sex characteristics, bone, muscle, and social, sexual and psychologic development. Delayed pubertal induction, which is often the case in patients without pubertal development, may have longstanding consequences. An orderly and timely induction of puberty with the 17β-oestradiol in some form is the appropriate approach. The use of combined oral contraceptives to induce puberty is not recommended. However, there are currently still many uncertainties regarding the optimal pubertal induction regimen. Most of the recommendations below regarding oestrogen dosing are based on clinical experience and data in girls with Turner syndrome. Literature sources are scant regarding other types of female hypogonadism. Clinical experience in combination with the evidence from Turner syndrome data can, to some extent, be extrapolated to these groups. In whom to consider puberty induction? ## R. 2.1 We recommend that an expert evaluation should be performed on any girl who does not show any sign of puberty by the age of 13 years, any girl who, by some definition, has delayed puberty (puberty s.d. score <−2) and all girls with a known condition/diagnosis that poses a risk of hypogonadism from the age of 8 years. ## Rationale Start of puberty in girls is typically defined by two signs of oestrogen action, the start of breast development, Tanner scale B2 and increased growth velocity. On average, this takes place at 10 years of age, the lower and upper limits of the normal range being after 8 years and before 13 years, respectively. Curve nomogram for pubertal progression exists [bib_ref] Pubertal progression and reproductive hormones in healthy girls with transient thelarche, Johansen [/bib_ref] : Evaluation in girls with pubertal delay includes a detailed medical and family history. Laboratory investigations of gonadotropin levels and sex steroids will aid in differentiating between primary and HH. Primary gonadal failure such as complete or partial gonadal dysgenesis is confirmed by increased FSH and LH. Ultrasound or MRI should be performed to identify a uterus or Müllerian structures; however, a small uterus 186:6 G20 Clinical Practice Guideline A Nordenström and others Pubertal induction: a clinical guideline https://eje.bioscientifica.com before oestrogen exposure may be missed by imagery. Bone age determination may be informative. Karyotype or chromosomal array should be considered in all girls with delayed puberty and/or short stature to detect sex chromosomal abnormalities. The most common cause of primary ovarian failure is Turner syndrome due to 45,X karyotype or 45,X/46,XX or 45,X/46,XY mosaicism. These girls may have additional symptoms associated to the syndrome including cardiac anomalies. With the presence of Y chromosome material, there may be some degree of prenatal virilisation. Girls with complete gonadal dysgenesis can have 46,XY karyotype and a uterus (Swyer syndrome). Girls with ovo-testis may have 46,XX, 46,XY or mosaicism. Puberty may start spontaneously but come to a halt or be accompanied by virilisation due to the testicular component of the ovo-testis. The presence of Y material and under-masculinisation increases the risk of germ cell tumours. The absence of menarche despite otherwise normal pubertal development should prompt a pelvic ultrasound to identify the uterus or Müllerian structures and to confirm or exclude Mayer-Rokitansky-Küster-Hauser syndrome or the Mullerian aplasia, renal anomalies, cervicothoracic somite dysplasia association [bib_ref] MRKH) syndrome: a comprehensive update, Herlin [/bib_ref]. Girls with 46,XY karyotype and deficiencies in testosterone or dihydrotestosterone synthesis virilise during puberty if their gonads have not been removed before puberty due to the activation of isoenzymes [bib_ref] Puberty in individuals with a disorder of sex development, Nordenström [/bib_ref]. They require a prompt diagnostic workup and psychological evaluation to discuss clinical management. Girls with a known diagnosis predisposing or clearly resulting in primary gonadal failure or hypogonadal hypogonadism should be seen from the age of 8 years or earlier. This follow-up allows the DSD team to identify the individuals' and family's needs for clinical and psychological support throughout puberty and adolescence. This also allows time for the team to explain the diagnosis and prepare and inform the patient and parents about treatment decisions. Girls with HH with low FSH, LH and anosmia such as in Kallmann syndrome or without anosmia require investigations to differentiate from constitutional delay or systemic diseases causing HPG axis suppression [bib_ref] Pubertal delay: the challenge of a timely differential diagnosis between congenital hypogonadotropic..., Bollino [/bib_ref] [bib_ref] ENDO-ERN expert opinion on the differential diagnosis of pubertal delay, Persani [/bib_ref]. ## R. 2.2 We recommend to individualise but consider puberty induction at the age of 11 in most girls with gonadal dysgenesis or other syndromes with the absence of spontaneous puberty, who do not show signs of puberty and have confirmed hypogonadism after testing (++OO). ## Rationale Regardless of the cause, in female hypogonadism with insufficient pubertal progression, appropriate oestrogen replacement therapy (ERT) mimicking the physiology in timing and pace is the mainstay of puberty induction. The aim is to maintain the signs of puberty and obtain longterm effects by normalising uterine growth, attaining peak bone mass, influencing normal development of the brain and influencing metabolism, as well as sexual and psychological functioning. In the present context, we discuss conditions such as gonadal dysgenesis, HH (also transient forms), Turner syndrome, Prader Willi syndrome and others. R 2. [bib_ref] Recent changes in pubertal timing in healthy Danish boys: associations with body..., Sørensen [/bib_ref] We recommend that spontaneous puberty and treatable causes of hypogonadism should be ruled out before starting puberty induction in girls. ## Rationale The reasons for the lack of expected pubertal progression can be transient and/or need causal treatment. Differential diagnosis of female delayed puberty should take into account the constitutional delay of growth and puberty (CDGP) and maturational delay in the HPG axis secondary to an underlying non-reproductive condition. CDGP is responsible for a third of all cases of pubertal delay in teenage girls [bib_ref] Delayed puberty: analysis of a large case series from an academic center, Sedlmeyer [/bib_ref] and is mainly considered as part of the spectrum of normal puberty. To diagnose CDGP, congenital HH (CHH) needs to be ruled out. However, in some cases, the initial work-up fails to provide an unequivocal diagnosis. Current studies show that CDGP and CHH have distinct genetic profiles which may aid in discriminating between these conditions. Other causes of hypogonadism, as well as other pituitary deficiencies, should be treated but should not delay puberty induction. ## R. 2.4 We recommend to start individualised puberty induction in girls at the age of 11 years in cases where there are no signs of pubertal development and a diagnosis of hypogonadism is confirmed, or at the age of 13 years if the constitutional delay is suspected. (+OOO) ## Rationale ERT should be initiated around 11 years of age in cases with known hypogonadism which is slightly later than average. However, starting puberty induction at a younger age resulted in a lower final height and a lower BMI than starting puberty induction at a later age. The main goal of all therapeutic protocols for puberty induction in hypogonadism should be to achieve an endocrine milieu similar to natural processes with gradual increase of the oestrogen dose to mimic physiological pubertal development and obtain an appropriate adult phenotype with respect to uterine (when present), breast and bone development, body composition, as well as adult stature. In order to imitate the natural dynamic of puberty advancement, an incremental increase in the dose is recommended over a period of 2-3 years until satisfactory physical effect, usually an adult dose, has been reached (119, 120). The age for the start of puberty treatment should be individualised. In individuals with tall stature and a tall final height prognosis, an earlier start of puberty treatment may be considered, for example in girls with 46,XY DSD. It may have to be delayed if CDGP is suspected and the results of a diagnostic work-up have to be awaited. In case of CDGP, treatment may be initiated as a short course of 3-6 months using low doses of oestradiol. Doses can be increased in order to mimic the normal course of puberty, but continuous monitoring for spontaneous resumption of progress and gonadotropin secretion is required. The age of puberty induction also affects other aspects of life. Historically, much-delayed induction of puberty to hypothetically increase final height had long-lasting negative effects on sexual life in young adult women with Turner syndrome (TS) [bib_ref] Relationship and sexual experiences in women with early-onset oestrogen deficiency: comparison between..., Attard [/bib_ref] [bib_ref] Self-esteem and social adjustment in young women with Turner syndrome -influence of..., Carel [/bib_ref]. ## R 2.5 When premature ovarian insufficiency is seen, that is if appropriate progression fails, we recommend to start sex hormone replacement treatment also in girls who had a normal spontaneous start of puberty. ## Rationale Young women with spontaneous pubertal development and menstruations but markedly elevated gonadotropins need regular follow-up to start ERT before symptoms of premature ovarian insufficiency appear. A considerable proportion of females with TS have spontaneous thelarche and/or menarche (20-40% show some degree of pubertal development, with menarche in approximately 16-20% and regular menstrual cycles in 6% of cases) [bib_ref] Prediction of spontaneous puberty in Turner syndrome based on mid-childhood gonadotropin concentrations,..., Hankus [/bib_ref] [bib_ref] Spontaneous pubertal development in Turner's syndrome. Italian Study Group for Turner's syndrome, Pasquino [/bib_ref] [bib_ref] Pubertal development profile in patients with Turner syndrome, Negreiros [/bib_ref]. A recent meta-analysis showed rates of menarche of 32 and 20% dependent on specific karyotype [bib_ref] Turner syndrome systematic review: spontaneous thelarche and menarche stratified by karyotype, Dabrowski [/bib_ref]. Nevertheless, 80% or more of girls and women with TS require or will require ERT to initiate, progress or maintain pubertal development [bib_ref] Sex hormone replacement therapy in Turner syndrome: impact on morbidity and mortality, Viuff [/bib_ref]. As indicated by some observations, FSH level below 10 mIU/mL at 12 years and below 6.7 mIU/mL during midchildhood (between 6 and 10 years) could be seen as an indicator of spontaneous puberty and the possibility of cyclical menstruation, but typically premature ovarian insufficiency within a few years will ensue [bib_ref] Prediction of spontaneous puberty in Turner syndrome based on mid-childhood gonadotropin concentrations,..., Hankus [/bib_ref] [bib_ref] Serum FSH level below 10 mIU/mL at twelve years old is an..., Aso [/bib_ref]. A similar situation may occur for females with mixed gonadal dysgenesis or partial gonadal dysgenesis. In females with ovo-testicular DSD and well-developed ovarian tissue, it often remains functional and menstruations have been reported to occur in 50% of cases [bib_ref] Pubertal outcomes and sex of rearing of patients with ovotesticular disorder of..., Kim [/bib_ref]. In individuals with spontaneous puberty and risk of premature ovarian failure, it is important to follow-up pubertal progression and measure gonadotropins in order to estimate ovarian reserve and assess the need for oestrogen replacement. AMH could be used as an additional laboratory marker. Values of AMH below -2 s.d. (4 pmol/L) predicted failure to enter puberty [bib_ref] AMH as predictor of premature ovarian insufficiency: a longitudinal study of 120..., Lunding [/bib_ref]. Inhibin B measurements have also been used to assess ovarian reserve [bib_ref] AMH as predictor of premature ovarian insufficiency: a longitudinal study of 120..., Lunding [/bib_ref] [bib_ref] Serum levels of anti-Müllerian hormone as a marker of ovarian function in..., Hagen [/bib_ref] [bib_ref] Anti-Müllerian hormone levels in girls and adolescents with Turner syndrome are related..., Visser [/bib_ref]. Undetectable inhibin B levels measured prior to pubertal onset were found in all patients with Turner syndrome and premature ovarian failure [bib_ref] LH, inhibin B and estradiol levels in Turner syndrome depend on age..., Hagen [/bib_ref]. However, due to its limited specificity (more than 1/3 of healthy girls have undetectable inhibin B levels during the menstrual cycle (follicular phase)), using inhibin B as a screening test to assess longitudinal ovarian reserve raises concerns [bib_ref] Inhibin A and B in adolescents and young adults with Turner's syndrome..., Gravholt [/bib_ref]. AMH appears to be a more reliable marker in this respect. In case of premature ovarian insufficiency, decision regarding the dosing and the type and route of hormonal replacement therapy should be based on patient's pubertal stage and the aim to mimic physiology. Treatment approach and monitoring R 2. [bib_ref] Pubertal correlates in black and white girls, Biro [/bib_ref] We recommend to use 17β-oestradiol for puberty induction or to sustain puberty in girls (++OO). ## Rationale Different types of sex hormones are used for ERT (see for details). Especially for pubertal induction, bioidentical human oestrogens (oestradiol/17β-oestradiol E2) are the dominant formulations used presently and are preferred to non-bioidentical (e.g. ethinyl E2, conjugated equine oestrogens, dienestrol, and mestranol), synthetic or derived from animal sources. We acknowledge that different formulations may not be available in all countries. The optimal type, route of administration and dose of E2 used for female puberty initiation are not well established. In line, no clear advantage was found for any type of hormone treatment for puberty induction or to sustain puberty in girls. Patients using 17β-oestradiol had a higher chance to reach Tanner stage B3 during the study period [fig_ref] Figure 2 Oral: -conjugated oestrogen vs transdermal 17β oestradiol for reaching Tanner stage B3 [/fig_ref] Oestrogens can be used orally or transdermally for puberty induction. Their use is complicated by the lack of oestrogen formulations dedicated to younger patients. Thus, paediatricians have to deal with oestrogen formulations aimed for use by adult women (off-label). The possibility to split a transdermal patch, and thereby split the dose, facilitates mimicking the spontaneous increase in concentration, as well as the diurnal pattern of serum oestradiol in early puberty [bib_ref] Estradiol matrix patches for pubertal induction: stability of cut pieces at different..., Ankarberg-Lindgren [/bib_ref] [bib_ref] Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic..., Ankarberg-Lindgren [/bib_ref]. Compared with oral E2, transdermal forms resulted in oestradiol, estrone and bioestrogen concentrations closer to normal in the high-dose transdermal group [bib_ref] Pharmacokinetics and pharmacodynamics of oral and transdermal 17β estradiol in girls with..., Taboada [/bib_ref]. The normalisation of gonadotropins was comparable after oral and transdermal oestrogen (138) but observed only after high-dose transdermal treatment [bib_ref] Pharmacokinetics and pharmacodynamics of oral and transdermal 17β estradiol in girls with..., Taboada [/bib_ref]. Data regarding the increase in the uterine size during oestrogen therapy are inconclusive, and only a few studies show that adult uterine volume can be achieved by using oral-conjugated oestrogens or oral contraceptives [bib_ref] Uterine development in Turner syndrome, Bakalov [/bib_ref]. Higher oral 17β-oestradiol dose for 5 years (2 mg vs 4 mg) in the years immediately after pubertal induction led to more girls with TS achieving a normal uterine size [bib_ref] Effect of dosage of 17β-estradiol on uterine growth in Turner syndrome -a..., Cleemann [/bib_ref]. See also Supplementary Appendix 3 [fig_ref] Table 1: Deficiencies of sexual development [/fig_ref]. The metabolic effects of transdermal and oral routes of oestrogen delivery are similar concerning multiple endpoints (bone mineralisation, body composition, BMI, lipids, glucose, insulin tolerance, protein turnover and lipolysis) [bib_ref] Insulin resistance and body composition in Turner syndrome: effect of sequential change..., Alves [/bib_ref] [bib_ref] Metabolic effects of oral versus transdermal estrogen in growth hormone-treated girls with..., Mauras [/bib_ref] [bib_ref] Weight gain in Turner syndrome: association to puberty induction? Longitudinal analysis of..., Reinehr [/bib_ref] , although it should be noted that firm evidence is lacking (see [fig_ref] Table 1: Deficiencies of sexual development [/fig_ref] for details). Available evidence points towards a liver protective effect of E2 supplementation [bib_ref] Increased occurrence of liver and gastrointestinal diseases and anaemia in women with..., Viuff [/bib_ref] [bib_ref] Vascular involvement of the liver in Turner's syndrome, Roulot [/bib_ref] [bib_ref] Quantitative liver functions in Turner syndrome with and without hormone replacement therapy, Gravholt [/bib_ref]. Results regarding the influence of different routes of oestrogen therapy on IGF1 concentration are inconsistent [bib_ref] Pharmacokinetics and pharmacodynamics of oral and transdermal 17β estradiol in girls with..., Taboada [/bib_ref] [bib_ref] Metabolic effects of oral versus transdermal estrogen in growth hormone-treated girls with..., Mauras [/bib_ref]. Bone age advancement, one of the major concerns during oestrogen therapy, was less significant with transdermal oestrogen [bib_ref] Retrospective evaluation of pubertal development and linear growth of girls with Turner..., Çakır [/bib_ref]. Moreover, transdermal E2 compared with conjugated oral oestrogens resulted in faster bone accrual (spine) [bib_ref] Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a..., Nabhan [/bib_ref]. A randomised trial comparing transdermal and oral 17β-oestradiol and oral-conjugated oestrogen therapy in adolescents with ovarian failure did not show differences in fibrinogen and antithrombin activity, glucose and insulin, liver enzymes activity, lipids concentration, plasma renin, as well as IGFBP3 and IGF1 levels [bib_ref] A randomized trial of transdermal and oral estrogen therapy in adolescent girls..., Shah [/bib_ref]. In TS, the long-term risk of breast cancer after longterm oral or transdermal oestrogen remains much lower than among control women (148). ## R 2.7 We recommend a follow-up frequency with a minimum of once every 3-6 months during pubertal induction or sex hormone replacement to sustain puberty in girls. ## Rationale When treatment is started, baseline values should be noted for parameters such as weight, height, Tanner stage, blood pressure, bone age and hormone measurements. The individual response to treatment and pubertal progress should be followed. Physical examination, including weight, height, blood pressure and Tanner stage should be assessed every 3-6 months to ensure the progress of puberty induction for each patient. Detailed history and discussion to monitor the compliance and resolve patient's doubts regarding side effects of the therapy and its practical aspects (e.g. dosing, storage) (135) should take place during every visit. In case Müllerian structure is present, pelvic ultrasonography before the start of puberty induction, before adding progesterone or at the time of the first breakthrough bleeding is required. In the context of increasing options for fertility treatment, adequate uterine development and regular monitoring of its dimensions are recommended [bib_ref] Clinical practice guidelines for the care of girls and women with Turner..., Gravholt [/bib_ref]. The dosing should be adjusted accordingly (see below). R 2. [bib_ref] Voice break in boys-temporal relations with other pubertal milestones and likely causal..., Busch [/bib_ref] We suggest titrating/adjusting the oestrogen therapy dose based on the appropriate progression of puberty during puberty induction or sex hormone replacement in girls. (+OOO) ## Rationale The main goal of all therapeutic protocols for puberty induction in hypogonadism should be to achieve an endocrine milieu similar to natural processes. For this purpose, a gradual increase over a period of 2-3 years until an adult dose of oestrogen is reached seems mandatory. Researchers used different schemes depending on their experiences, preferable administration route, patient's age, medicine pharmacodynamics/pharmacokinetics and local availability. If the dose is increased too fast, it may have a negative influence on, for example, breast development or growth [bib_ref] Growth hormone and 17 betaoestradiol treatment of Turner girls -2-year results, Naeraa [/bib_ref]. However, no studies were found comparing titration or adjustment of hormonal therapy for puberty induction based on puberty progression. For the initiation of oestrogen treatment with nocturnally administered E2 patches, the starting doses can be as low as 0.05-0.07 µg/kg, to mimic E2 levels during gonadarche. In older girls, when breast development is of high priority, the starting dose can be 0.08-0.12 µg/kg. Serum E2 levels of 17-23 pmol/L were found for doses of [bib_ref] Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a..., Nabhan [/bib_ref] [bib_ref] Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic..., Ankarberg-Lindgren [/bib_ref] [bib_ref] Use of percutaneous estrogen gel for induction of puberty in girls with..., Piippo [/bib_ref] [bib_ref] Late-onset puberty induction by transdermal estrogen in Turner syndrome girlsa longitudinal study, Gawlik [/bib_ref] [bib_ref] Individualised vs fixed dose of oral 17β-oestradiol for induction of puberty in..., Labarta [/bib_ref] [bib_ref] Puberty induction in Turner syndrome: results of oestrogen treatment on development of..., Bannink [/bib_ref]. However, due to differences in puberty induction protocols, comparison between protocols is difficult. Nevertheless, the dynamic of breast development seems similar in most of the studies: stage B2 was reached during the first months and B4 during or after approximately 2-2.5 years [bib_ref] Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a..., Nabhan [/bib_ref] [bib_ref] Late-onset puberty induction by transdermal estrogen in Turner syndrome girlsa longitudinal study, Gawlik [/bib_ref] [bib_ref] Puberty induction in Turner syndrome: results of oestrogen treatment on development of..., Bannink [/bib_ref] [bib_ref] Final height in girls with turner syndrome after long-term growth hormone treatment..., Van Pareren [/bib_ref] , a pace that is comparable to the pace of spontaneous puberty [bib_ref] Somatic pubertal development, Taranger [/bib_ref] [bib_ref] Pubertal correlates in black and white girls, Biro [/bib_ref]. Low-dose oral oestradiol therapy given as a fixed dose (0.2 mg/day during the first year followed by 0.5 mg/day during the second year) is well-tolerated, not interfering with growth, and produces satisfactory pubertal development in patients with TS not inferior to individualised dose (5-15 μg/kg/day during 2 years) [bib_ref] Individualised vs fixed dose of oral 17β-oestradiol for induction of puberty in..., Labarta [/bib_ref]. A number of different oestrogen dose titration models for female puberty induction have been proposed [bib_ref] Clinical practice guidelines for the care of girls and women with Turner..., Gravholt [/bib_ref] [bib_ref] Optimal pubertal induction in girls with Turner syndrome using either oral or..., Donaldson [/bib_ref]. ## R 2.9 We recommend that progesterone is added after puberty induction or during sex hormone replacement to sustain puberty in girls after breakthrough bleeding, after at least 2 years of treatment. (+OOO) ## Rationale If a uterus is present, progesterone must be added at some point because of the risk of endometrial cancer associated with long-term unopposed oestrogen [bib_ref] NAMS Recommendations for Clinical Care of Midlife Women Working Group. The North..., Shifren [/bib_ref]. Progestins, synthetic progestagens, are most frequently used. Progesterone is the only bioidentical progestagen. Progestagens, similarly to oestrogens, can be used orally, vaginally, transdermally, intranasally or intramuscularly. There is a lack of valuable data concerning the optimal progesterone induction scheme; no studies were found comparing the addition of progesterone after or during puberty induction. If optimal breast and uterine maturation has been achieved, it is assumed that progesterone should be added at the time of the first breakthrough bleeding or at least 2 years after oestrogen therapy initiation. In most protocols, a 10-day treatment given cyclically is preferred, as no evidence exists for the optimal duration (from min. 5 to max. 14 days). Oral, natural micronised progesterone (100-200 mg daily), oral dydrogesterone (10 mg daily) or medroxyprogesterone acetate (5-10 mg daily) or norethisterone (1 mg daily) and other preparations can be used [bib_ref] Optimal pubertal induction in girls with Turner syndrome using either oral or..., Donaldson [/bib_ref]. R 2. [bib_ref] Up-to-date review about minipuberty and overview on hypothalamic-pituitarygonadal axis activation in fetal..., Lanciotti [/bib_ref] We recommend to change pubertal induction treatment of oestrogen and progesterone to permanent adult sex hormone replacement therapy at the end of pubertal induction. ## Rationale The 2-to 3-year puberty induction is followed by the regimen of sex hormone therapy required in a young woman. Similar to puberty induction, transdermal or oral E2 should be the first choice; however, other, less recommended, options include EE2, depot E2 or equineconjugated oestrogens (the last two are available and are used in the United States). Suggested adult dosing for the preparations is presented in [bib_ref] Clinical practice guidelines for the care of girls and women with Turner..., Gravholt [/bib_ref] [bib_ref] Estrogen replacement in Turner syndrome: literature review and practical considerations, Klein [/bib_ref]. Decision regarding the optimal adult regimen is based on clinical features (effectiveness, tolerance), E2 levels and economic considerations. The presence of a uterus obliges to include progestogen in the regimen. However, there are no data clearly indicating the optimal route and regimen in female hypogonadism. Progestagens can be given cyclically or continuously, orally as a single or a component of contraceptive pills, transdermally combined with oestradiol and by intrauterine devices. ## R 2.11 Puberty induction in late-diagnosed patients must be individualised. A faster than normal increase in oestrogen doses can be considered in such cases. ## Rationale There are controversies concerning the optimal model of female puberty induction in patients with a delayed diagnosis or postponed initiation of oestrogen treatment. Late-onset puberty inductions need individualised approach to optimise the overall outcome with respect to patient's wishes, height, secondary sex characteristics development and psychosocial endpoints. The model of a faster increase in oestrogen dosing was presented in single studies regarding patients with Turner syndrome. In one such pilot study using a 1-year protocol with transdermal E2 therapy in 14-year-old girls (first 6 months 25 μg/day, thereafter 37.5 μg/day), a progressive increase in the puberty stage was observed; Tanner stage [bib_ref] Conjugated oral versus transdermal estrogen replacement in girls with Turner syndrome: a..., Nabhan [/bib_ref]. Another study with patients older than 14 years of age and a comparable simple protocol (12.5 μg/24 h for the first 2 months, thereafter 25.0 μg/24 h until breakthrough bleeding) suggested that easyto-use fixed-dose regimen for late-onset puberty induction allowed for a satisfactory rate of pubertal stage progression and did not influence the growth potential [bib_ref] Late-onset puberty induction by transdermal estrogen in Turner syndrome girlsa longitudinal study, Gawlik [/bib_ref]. Intentional delaying pubertal induction did not improve final height [bib_ref] Effect of oxandrolone and timing of pubertal induction on final height in..., Gault [/bib_ref] [bib_ref] Salutary effects of combining early very low-dose systemic estradiol with growth hormone..., Rosenfield [/bib_ref]. However, postponing pubertal induction in girls who are diagnosed particularly late and in whom short stature is a major concern should be discussed with the family [bib_ref] Effect of oxandrolone and timing of pubertal induction on final height in..., Gault [/bib_ref]. ## Puberty induction in boys # Introduction The initiation of puberty at an age comparable with peers is essential for normal physiologic development, including secondary sex characteristics, bone, muscle, and social, sexual and psychological development. In general, constitutional delay of pubertal development is more common among boys than girls, which may contribute to an even further delay of diagnosis and treatment with pubertal induction in boys with gonadal deficiency due to a DSD. In some cases, puberty may start but not progress properly, in which case a hormonal substitution is needed. A timely induction of puberty with testosterone in some form is appropriate. In case of pituitary deficiency with HH, alternative approaches are also possible (see R. 4). ## In whom to consider puberty induction? R. 3. [bib_ref] The timing of normal puberty and the age limits of sexual precocity:..., Parent [/bib_ref] We recommend expert evaluation of puberty in any boy who has delayed puberty as defined by a puberty s.d. score <−2 or no signs of puberty at the age of 14 years or fails to show adequate progression in puberty. ## Rationale The start of puberty in boys is defined by testicular growth ≥4 mL. The timing of puberty is physiologic if the age at which it occurs is within 2 s.d. of a reference population (puberty nomograms exist for Caucasian boys (159)). Although puberty usually starts before the age of 14 years in boys, its timing is influenced by several factors including ethnicity, genetics and factors such as obesity and nutrition [bib_ref] ) 186:6 G45 Clinical Practice Guideline A Nordenström and others Pubertal induction, Dwyer [/bib_ref]. Expert evaluation of puberty in boys with suspected pubertal delay starts with a detailed history (161) and the initial evaluation aims to differentiate CDGP from other forms of hypogonadism that may be permanent or secondary to other systemic diseases [bib_ref] ENDO-ERN expert opinion on the differential diagnosis of pubertal delay, Persani [/bib_ref] [bib_ref] Delayed puberty versus hypogonadism: a challenge for the pediatrician, Bozzola [/bib_ref]. Clinically, the pubertal stage is measured by scoring Tanner stages and testis volume using a Prader orchidometer. Growth velocity, biochemical testing of gonadotropins and sex steroids and radiological evaluation of bone age by X-ray of the left hand give additional information. The family history on the timing of pubertal development is essential in the evaluation process. CDGP is the most common cause of delayed puberty in teenage boys (~63%), with a majority (50-75%) of them having at least one parent with a history of delayed puberty [bib_ref] Delayed puberty: analysis of a large case series from an academic center, Sedlmeyer [/bib_ref] [bib_ref] Single-centre experience of testosterone therapy for boys with hypogonadism, Lucas-Herald [/bib_ref]. The diagnosis of CDGP can only be made after exclusion of conditions such as CHH or primary gonadal failure that leads to permanent hypogonadism, as well as chronic illnesses, or a tumour that may lead to a variable extent of delayed growth and puberty [bib_ref] Pubertal delay: the challenge of a timely differential diagnosis between congenital hypogonadotropic..., Bollino [/bib_ref] [bib_ref] ENDO-ERN expert opinion on the differential diagnosis of pubertal delay, Persani [/bib_ref]. Depending on age, gonadal failure can be confirmed biochemically by hypergonadotropic hypogonadism. A history of cryptorchidism (especially bilateral), micro-penis, midline defects, hypo or anosmia, deafness or renal anomalies increases the likelihood of CHH. Furthermore, complications such as failed orchidopexies in boys with CHH can produce a complex biochemical picture that needs careful interpretation. CDGP can often be difficult to distinguish from CHH which may also be associated with a positive family history [bib_ref] Pubertal delay: the challenge of a timely differential diagnosis between congenital hypogonadotropic..., Bollino [/bib_ref] [bib_ref] ENDO-ERN expert opinion on the differential diagnosis of pubertal delay, Persani [/bib_ref]. In addition, to a variable degree, CHH may be associated with other clinical features and an expert evaluation should explore this [bib_ref] Pubertal delay: the challenge of a timely differential diagnosis between congenital hypogonadotropic..., Bollino [/bib_ref] [bib_ref] ENDO-ERN expert opinion on the differential diagnosis of pubertal delay, Persani [/bib_ref]. Clinically, CDGP is transient and confirmed by a spontaneous progression of puberty. Although a karyotype or a chromosomal microarray is not routinely performed in boys with delayed puberty, this should be considered in those boys who have hypergonadotropic hypogonadism and do not have a predisposing condition such as a past history of testicular damage. Approximately 25% of boys with XY DSD have additional congenital malformations [bib_ref] Novel associations in disorders of sex development: findings from the I-DSD Registry, Cox [/bib_ref] and these boys are more likely to have copy number variations [bib_ref] Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a..., Nixon [/bib_ref]. Sex chromosome abnormalities, such as Klinefelter syndrome or 45,X/46,XY, may be associated with several distinct clinical features including behavioural problems, cardiovascular problems and increased sitting height percentage. Klinefelter is associated with tall stature and 45,X/46,XY with short stature [bib_ref] Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism, Bonomi [/bib_ref]. Thus, boys with delayed puberty and a past history of atypical genitalia, congenital malformations, hypergonadotropic hypogonadism or clinical features of sex chromosome disorders should also have a karyotype or a chromosomal microarray. ## 186:6 g27 clinical practice guideline A Nordenström and others Pubertal induction: a clinical guideline https://eje.bioscientifica.com R 3.2 All boys with a history of a condition that places them at risk of hypogonadism should undergo pubertal assessment from the age of 9 years. ## Rationale Several conditions that are associated with primary hypogonadism may present in early infancy with atypical genitalia. This includes sex chromosome disorders, disorders of gonadal development, disorders of androgen synthesis and lastly, disorders of androgen action. In these boys, a firm aetiological diagnosis of their DSD that is supported by endocrine and molecular genetic tests allows targeted follow-up that is appropriate for that specific diagnosis. In some conditions such as anorchia, in the absence of a specific aetiological diagnosis, the prospect of not undergoing spontaneous puberty is also unequivocally clear. The likelihood of developing hypogonadism is clearer for some conditions than for others, but ensuring that all these boys are followed up as per current recommendations in a standardised manner will ensure improved knowledge in the future [bib_ref] Standardised data collection for clinical follow-up and assessment of outcomes in differences..., Flück [/bib_ref]. Klinefelter syndrome is the most common cause of congenital male hypogonadism, and although these boys typically enter puberty at a normal age, they often have signs of gonadal dysfunction including gynaecomastia, small, firm testes, elevated gonadotropins and relatively low testosterone levels [bib_ref] Best Practice and Research, Wikström [/bib_ref] [bib_ref] Klinefelter syndrome: integrating genetics, neuropsychology, and endocrinology, Gravholt [/bib_ref]. These boys may also, in rare cases, have a past history of atypical genitalia and an ongoing history of learning difficulties or difficulties in social adjustment. In 45,X/46,XY sex chromosome mosaicism, spontaneous puberty has been reported to occur in 80% but may be less likely in those who present in the neonatal period with atypical genitalia. Over 50% of this 'early presentation' group (diagnosed due to genital anomalies and/or short stature) required testosterone supplementation in puberty compared to 15% in the late presentation group (diagnosed in adulthood due to infertility work up) [bib_ref] Clinical but not histological outcomes in males with 45,X/46,XY mosaicism vary depending..., Ljubicic [/bib_ref]. In partial gonadal dysgenesis, a disorder of gonadal development, absent pubertal development has been reported in 10-15% of adolescents [bib_ref] ) 186:6 G40 Clinical Practice Guideline A Nordenström and others Pubertal induction, Andrade [/bib_ref]. In the rest who have spontaneous initiation of puberty, the gonadal function may not be sufficient to sustain pubertal development, and most of the adolescents with partial gonadal dysgenesis demonstrated elevated gonadotropins with only about half having a serum testosterone in the normal range after puberty [bib_ref] ) 186:6 G40 Clinical Practice Guideline A Nordenström and others Pubertal induction, Andrade [/bib_ref]. In patients with steroidogenic factor 1 ( SF1) deficiency, Leydig cell function can be effective in puberty, even in patients who were severely under-virilised at birth [bib_ref] Testosterone production during puberty in two 46,XY patients with disorders of sex..., Tantawy [/bib_ref]. Testicular function may deteriorate over time. Boys with 46,XX testicular DSD who present with atypical genitalia often have primary hypogonadism. On the other hand, men who present to an assisted conception service and are discovered to have 46,XX karyotype rarely have a history of atypical genitalia in infancy but are infertile, due to the absence of the azoospermia factor genes on the Y chromosome [bib_ref] Clinical and genetic analysis in males with 46,XX disorders of sex development:..., Chen [/bib_ref] [bib_ref] Spermatogenic failure and the Y chromosome, Krausz C &amp; Casamonti [/bib_ref]. Testicular function in boys with ovotesticular DSD can be quite variable and depend on the androgen-producing capacity of the testicular component of the gonads [bib_ref] The long-term followup of 33 cases of true hermaphroditism: a 40-year experience..., Verkauskas [/bib_ref]. In conditions that are due to a genetic disorder of androgen synthesis, boys can undergo a variable range of spontaneous virilisation in puberty but may require topical or systemic androgen supplementation. In many patients with DSD, especially partial androgen insensitivity syndrome or Klinefelter syndrome, the affected boy may display additional features such as gynaecomastia, disordered growth or even precocious puberty. The monitoring of pubertal development includes both clinical measurements and laboratory assessments. Clinically, assessment of growth, Tanner stage and testicular volume with a Prader orchidometer are useful to detect pubertal onset and laboratory assessment includes the assessment of LH, FSH, total testosterone measurements, inhibin B and AMH. In some forms of primary testicular failure, a differential effect of the Leydig cell and Sertoli cell compartments within the testis may make the assessment of testicular volume misleading. In cases of selective Sertoli cell failure and/or lack of germ cells, testicular volume usually remains small although testosterone production may be active. Boys with partial hypogonadism may also show signs of precocious puberty [bib_ref] Central precocious puberty as a prelude to hypogonadism in a patient with..., Gong [/bib_ref]. As a greater number of infants with XY DSD are being raised as boys nowadays (175), it is likely that there will be a greater number of boys with a wide range of partial forms of hypogonadism who approach pubertal age and will need regular support. Thus, to see these boys at around 9 years allows the DSD team to gauge the need for clinical and psychological support as the patient proceeds through adolescence. Starting pubertal monitoring at a relatively early age provides the physician time to specify and explain the diagnosis and to make shared decisions with patient and parents on therapeutic options. ## R. 3.3 We recommend that all boys with permanent hypogonadism should undergo pubertal induction. ## Rationale Androgens are required to induce secondary sexual characteristics, achieve optimal adult male body Testosterone plays an important role in socio-emotional and cognitive development [bib_ref] The role of testosterone in social interaction, Eisenegger [/bib_ref] [bib_ref] Acute effects of steroid hormones and neuropeptides on human social-emotional behavior: a..., Bos [/bib_ref]. In boys with preexisting behavioural or intellectual disabilities, pubertal induction should be performed carefully and in close collaboration with a mental health specialist. Parents and caretakers of such boys should be informed about the effects of testosterone on impulsivity. In addition, pubertal induction should be accompanied by sexual education and by the provision of resources for sex education elaborated for individuals with intellectual disability. Studies show that this specific patient group remains too often insufficiently educated and prepared about sexual and emotional life situations [bib_ref] Sexual health education for adolescents and young adults with intellectual and developmental..., Roden [/bib_ref]. In boys with HH, there is a wide range of pubertal induction regimens, including the use of gonadotropins that are available, see section on 'hypogonadotropic hypogonadism'. There is no clear evidence that one regimen is superior to another and there is no clear evidence that supports the preferential use of any of these regimens instead of testosterone replacement for the purpose of achieving virilisation in boys with HH. The preparations used will depend on the preferences of the patient, ease of use as well as local availability and if fertility is considered. ## R. 3.4 In boys who are known to have a diagnosis with a high risk of hypogonadism, we recommend that pubertal induction can be started by the age of 12 years if there are no signs of pubertal development. (+OOO) ## Rationale The aim of pubertal induction in boys with hypogonadism should be to mimic normal physiology. Attention needs to be paid to the age-appropriate development of secondary sexual characteristics, growth acceleration, normal body proportions achievement, changes in body composition, avoidance of psychosocial consequences of delayed growth and puberty. Late-onset of puberty has been associated with a higher risk of anxiety and depression [bib_ref] Pubertal timing and the development of psychopathology in adolescence and beyond, Graber [/bib_ref] and increased cardiometabolic risk [bib_ref] Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes..., Day [/bib_ref]. There are also ethnic and familial variations in the onset and tempo of puberty, which may need to be considered when deciding to start pubertal induction in an individual patient. For instance, pubertal onset as determined by age at testicular volume of at least 4 mL varies from 10.6 years in the Chinese population to 11.4-11.7 years in Hong Kong, the Netherlands, Greece and Denmark [bib_ref] The physiology and timing of male puberty. Current Opinion in Endocrinology, Tinggaard [/bib_ref]. Surveys performed in the context of managing CDGP have shown that in paediatric endocrinology, pubertal induction in boys is usually started after the chronological age of 14 years [bib_ref] Best Practice and Research, Wikström [/bib_ref]. However, no studies were found comparing different age groups for the start of puberty induction in boys with (high risk of) hypogonadism (see section on Systematic literature review). Factors that may influence the timing of induction may include the bone age and the sociocultural perspective [bib_ref] A workshop on pubertal hormone replacement options in the United States, Drobac [/bib_ref]. In boys with conditions that predispose to permanent hypogonadism, such as bilateral anorchia or known CHH, surveys of practice suggest that pubertal induction may often be initiated at an age younger than 12 years and even as young as 10 years [bib_ref] Single-centre experience of testosterone therapy for boys with hypogonadism, Lucas-Herald [/bib_ref] [bib_ref] Testosterone therapy in adolescent boys: the need for a structured approach, Stancampiano [/bib_ref]. These studies also show that in several boys with DSD conditions associated with hypogonadism, testosterone therapy may be initiated at a later age possibly due to a partial hypogonadism in these boys. ## R. 3.5 we recommend that pubertal induction in boys with hypogonadism should be performed with testosterone (++oo) ## Rationale There is a wide range of testosterone preparations that are available for use in boys with hypogonadism (see . Recent studies show that in boys with early onset hypogonadism, i.m. forms of testosterone remain the commonest form of preparations [bib_ref] Single-centre experience of testosterone therapy for boys with hypogonadism, Lucas-Herald [/bib_ref]. Studies are scarce that compare different forms of testosterone (see section 4.1), but there is no clear evidence that one form of testosterone is superior to another [bib_ref] Androgen therapy in constitutional delay of growth, Lampit M &amp; Hochberg [/bib_ref] [bib_ref] crossover comparison study of the short-term effect of oral testosterone undecanoate and..., Ahmed [/bib_ref]. One study comparing testosterone vs no treatment to induce puberty found increased BMD in patients using testosterone compared to the control group (100). One study comparing testosterone vs hCG for puberty induction showed inconclusive results regarding Tanner stage progression, smaller testicular volume and similar height after use of testosterone compared to hCG [bib_ref] Hormonal therapy and pubertal development in boys with selective hypogonadotropic hypogonadism, Bistritzer [/bib_ref]. In healthy boys, testosterone measured by LC-MS/ MS starts to increase a year before the appearance of pubic hair growth, at 11.5 years on average. When measured by RIA, plasma testosterone starts to increase at a testicular volume between 3 and 6 mL with clear evidence of diurnal variation at a median age of 12.5 years [bib_ref] Changes of diurnal rhythm and levels of total and free testosterone secretion..., Ankarberg-Lindgren C &amp; Norjavaara [/bib_ref] [bib_ref] Andersson AM & Juul A. Longitudinal changes in circulating testosterone levels determined..., Mouritsen [/bib_ref]. While mimicking the gradual physiological rise in testosterone remains the objective of pubertal induction, it is unlikely that the wide range of pharmacological preparations that are currently available possess the pharmacodynamic and kinetic properties to achieve completely normal pubertal development, especially in the early stage of puberty. As an example, measured plasma testosterone after 25 mg testosterone reached an adult range for 1 day and for 2 days after 50 mg testosterone enanthate [bib_ref] Bioavailability and LH-suppressing effect of different testosterone preparations in normal and hypogonadal..., Nieschlag [/bib_ref]. For suggested testosterone formulations and doses, see . The addition of DHEAS in boys with hypogonadism is not recommended. Although the benefits of mimicking normal physiology or, indeed, the adverse effects of not mimicking normal physiology have not been studied thoroughly, it is clear from boys with precocious puberty that quick progress is associated with adverse behaviour as well as restricted growth prognosis. Thus, the dose of testosterone should be increased gradually to mimic normal growth and pubertal development. It is common to begin treatment with low-dose testosterone (i.e. 50 mg testosterone enanthate every month, 10 mg transdermal testosterone every other day or 40 mg oral testosterone undecanoate daily) and then gradually increase to the adult dose. The speed of this gradual increase will also need to be individualised based on the age as well as the mental maturity of the boy. ## R. 3.6 We recommend that all boys who receive pubertal induction therapy should have a structured endocrine assessment at baseline and at follow-up. ## Rationale Regular clinical follow-up is generally performed every 3-6 months to assess the effectiveness of testosterone therapy by assessing pubertal and skeletal maturation and height velocity. In the guidelines for adults on testosterone replacement therapy (TRT), monitoring is recommended and standardised [bib_ref] European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of..., Corona [/bib_ref] [bib_ref] Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline, Bhasin [/bib_ref]. There is clear evidence that systematic monitoring in adolescents on testosterone is performed to a variable extent [bib_ref] Single-centre experience of testosterone therapy for boys with hypogonadism, Lucas-Herald [/bib_ref] and it is possible that this variation is due to the wide range of conditions Testosterone preparations (refer: [bib_ref] An update on the available and emerging pharmacotherapy for adults with testosterone..., Kresch [/bib_ref] [bib_ref] Androgens during infancy, childhood, and adolescence: physiology and use in clinical practice, Mason [/bib_ref] [bib_ref] Testosterone therapy in adolescent boys: the need for a structured approach, Stancampiano [/bib_ref]. With greater knowledge of a wider range of effects of testosterone and the advent of several newer forms of testosterone replacement, the need for careful monitoring is becoming greater. A structured assessment can also be used to screen for adverse effects as well as titrate replacement. It should include the assessment of adverse signs such as local reactions, gynaecomastia, priapism, increased haematocrit, deranged liver function and inappropriate behavioural changes. highlights the advantages and disadvantages of specific preparations and further details can also be found in recent publications [bib_ref] Testosterone therapy in adolescent boys: the need for a structured approach, Stancampiano [/bib_ref] [bib_ref] An update on the available and emerging pharmacotherapy for adults with testosterone..., Kresch [/bib_ref] [bib_ref] Androgens during infancy, childhood, and adolescence: physiology and use in clinical practice, Mason [/bib_ref]. While there is no evidence that dose titration against a marker such as a haematocrit is necessary for pubertal induction, the regular assessment of haematocrit would be advisable, especially as the adolescent reaches a steady adult replacement dose [bib_ref] Testosterone therapy in adolescent boys: the need for a structured approach, Stancampiano [/bib_ref]. The care pathway can also ensure age-appropriate explanations and discussions about both endocrine and reproductive testicular functions with the appropriate experts in the multidisciplinary team. With increasing maturity, these discussions may cover issues regarding sexual function and fertility including biological fathering and other modes of fathering. Physiological variations in steroid metabolism as well as androgen sensitivity when combined with the wide range of preparations that are available increase the likelihood of inter-individual differences in how boys will respond to replacement therapy and there is a need for clinically relevant markers of androgen action. ## R. 3.7 We suggest adjusting the puberty induction treatment or changing the route of administration in case of relevant adverse effects/complications. ## Rationale The occurrence of relevant adverse effects is rare with testosterone [bib_ref] A multicenter, open-label, observational study of testosterone gel (1%) in the treatment..., Rogol [/bib_ref]. For injectable forms of TRT, priapism has rarely been reported. Testosterone undecanoate, the long-acting preparation, should not be used for induction of puberty or progression through the early stages of puberty, as it is likely to advance bone age too rapidly with a potential for truncating final height. When ingested orally, testosterone is absorbed well from the gut but is effectively metabolised and inactivated in the liver before it reaches the target organs ('first passeffect'). Testosterone induces liver enzymes that are responsible for its own metabolism. Testosterone gel provides a possibility for more physiologic serum testosterone levels and it can closely mimic natural diurnal variation in testosterone concentrations. It has only minor systemic side effects. However, published data on transdermal testosterone in pubertal induction are scarce. In many countries, testosterone formulations are not licenced for the induction of puberty. Transdermal gels are available in different formulations: 1% testosterone strength and the metereddose gel formulation of 2% or 2.5% testosterone strength. Topical testosterone has been repeatedly reported to cause undesirable exogenous testosterone exposure through passive transfer to members of the patients' household [bib_ref] Virilization of young children after topical androgen use by their parents, Kunz [/bib_ref]. Due to the alcoholic enhancer used and the occlusive nature of the systems, the application is associated with skin irritation in up to 60% of the subjects. R 3. [bib_ref] Voice break in boys-temporal relations with other pubertal milestones and likely causal..., Busch [/bib_ref] We suggest monitoring potential gynaecomastia in boys to timely discuss treatment options. ## Rationale Testosterone therapy can lead to gynaecomastia through its aromatisation to oestradiol; hence, regular monitoring of this potential side effect is requested. Gynaecomastia occurs in up to a third of patients on gonadotropins [bib_ref] Comparison of gonadotropin-releasing hormone and gonadotropin therapy in male patients with idiopathic..., Schopohl [/bib_ref] or testosterone [bib_ref] Testosterone replacement therapy for male hypogonadism: part III. Pharmacologic and clinical profiles,..., Seftel [/bib_ref] and usually (although not invariably) occurs during supraphysiological replacement doses. The risk and severity of gynaecomastia can be reversed by adjusting the dosage. It should be remembered that 50% of all adolescents develop gynaecomastia which typically presents in early puberty and lasts for 6-12 months. Similarly to physiological puberty, the most likely cause of gynaecomastia during TRT is a relative imbalance between oestrogen and androgen levels in the serum or at the tissue level [bib_ref] EAA clinical practice guidelines-gynecomastia evaluation and management, Kanakis [/bib_ref]. During the early proliferative phase, manifested clinically as breast pain and tenderness, medical therapy may be attempted [bib_ref] Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole, Rhoden El &amp; Morgentaler [/bib_ref]. Medical treatment of gynaecomastia aims to correct the oestrogen-androgen imbalance by three possible pathways: (i) blocking the effects of oestrogens on the breast (e.g. clomiphene, tamoxifen, raloxifene), (ii) administering androgens (e.g. danazol or DHT) and (iii) inhibiting oestrogen production (e.g. anastrozole, testolactone). Almost all data dealing with these treatments are based on uncontrolled studies, and in addition, the evaluation of their efficacy is further complicated by the fact that gynaecomastia may resolve spontaneously [bib_ref] Gynecomastia; the origins of mammary swelling in the male: an analysis of..., Treves [/bib_ref] [bib_ref] Treatment of gynecomastia, Gruntmanis [/bib_ref]. It must be noted that none of these therapies are approved for the treatment of gynaecomastia. It seems to be reasonable to try a 3 months trial in selected cases of recentonset gynaecomastia [bib_ref] Clinical practice. Gynecomastia, Braunstein [/bib_ref] because it offers rapid relief from pain, regardless of the magnitude of the response. If the gynaecomastia has been present for >1 year, it is unlikely to regress substantially, either spontaneously or with medical therapy, because fibrotic tissue is usually present. In such circumstances, surgical s.c. mastectomy, ultrasound-assisted liposuction and suction-assisted lipectomy are the best options for cosmetic improvement of Tanner stage III and above [bib_ref] The surgical management of high-grade gynecomastia, Tashkandi [/bib_ref]. R 3.9 Treatment in patients with a late diagnosis, without pubertal development or for whom the pubertal development has come to a halt, should be individualised. ## Rationale Patients who come to diagnosis at a later age, towards the late teenage years or as young adults, may have no pubertal development or a spontaneous start of puberty but a slow or no pubertal progress. This is often the case in young men with Klinefelter syndrome and can be the case in individuals with 45,X/46,XY, gonadal dysgenesis or androgen insensitivity. Adult endocrinologists often see patients with CHH in late adolescence or early adulthood with the main complaint of lack of pubertal development [bib_ref] Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism..., Bonomi [/bib_ref]. In such cases, the therapeutic approach is often more incisive than for younger patients, involving higher initial testosterone doses than those used by paediatric endocrinologists (200-250mg testosterone enanthate monthly, then every 2-3 weeks) to induce more rapid virilisation [bib_ref] Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism -pathogenesis, diagnosis..., Boehm [/bib_ref]. ## Pubertal induction in patients with hypogonadotropic hypogonadism Introduction HH is caused by congenital or acquired defects of the hypothalamic and/or pituitary compartment of the HPG axis. CHH forms can be isolated, part of an overlapping syndrome (such as CHARGE) or part of combined pituitary hormone deficits. Kallmann syndrome is associated with hypo-or anosmia. All these forms have strong genetic backgrounds [bib_ref] Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease, Cangiano [/bib_ref]. Acquired forms of HH, mainly associated with other pituitary hormone deficits, are usually the results of neoplastic, metabolic, immune, infectious, infiltrative, inflammatory or iatrogenic causes affecting the hypothalamic-pituitary region. HH can also be related to functional causes, which are usually characterised by a reversible negative effect on the HPG axis activation/ functionality. These include chronic and/or inflammatory systemic illness, malnutrition (e.g. anorexia nervosa), extreme exercise or stressful conditions and opioid use. Pubertal induction has to be considered in all cases with permanent HH after the diagnostic procedure has been carefully followed. The goals of the therapy for pubertal induction in male and female HH are not different from the ones reported for primary hypogonadism, although in this specific cohort of patients, the possibility of future fertility can be considered and, in males, specific treatment regimens can allow for the maturation of testes [bib_ref] Approach to the male patient with congenital hypogonadotropic hypogonadism, Young [/bib_ref] [bib_ref] Assessment of quality of life during gonadotrophin treatment for male hypogonadotrophic hypogonadism, Shiraishi [/bib_ref]. Briefly, the main goals will be the attainment of optimal masculinisation/feminisation and secondary sexual characteristics; the achievement of pubertal growth and an optimal target height; the prevention of osteoporosis by accruing normal bone mass and mineralisation; to allow for a normal psychosocial development; and in certain cases, to gain fertility [bib_ref] Clinical management of congenital hypogonadotropic hypogonadism, Young [/bib_ref] [bib_ref] Approach to the male patient with congenital hypogonadotropic hypogonadism, Young [/bib_ref] [bib_ref] Assessment of quality of life during gonadotrophin treatment for male hypogonadotrophic hypogonadism, Shiraishi [/bib_ref] [bib_ref] Transition in endocrinology: induction of puberty, Dunkel L &amp; Quinton [/bib_ref]. ## Timing of puberty induction In principle, the timing for pubertal induction in patients with a diagnosis of permanent HH does not differ from what has been recommended for boys and girls with hypogonadism. However, it should be pointed out that the main differential diagnosis of CHH is CDGP. It is a more common situation and also more frequent in boys compared to girls. This differential diagnosis is one of the greatest challenges for the clinician evaluating a pubertal delay [bib_ref] ENDO-ERN expert opinion on the differential diagnosis of pubertal delay, Persani [/bib_ref]. Unfortunately, to date, we do not have specific indicators that allow for a clear distinction between these two clinical conditions although a history of micropenis, bilateral cryptorchism, midline defect, hypo/anosmia, deafness or renal anomalies should raise the suspicion of CHH. For this reason, in patients with pubertal delay and uncertainty regarding the diagnosis of CHH or CDGP, it may sometime be necessary to delay the initiation of induction even beyond 14 years. Nonetheless, the decision must always be made according to the clinical situation in each individual case and in concern with the patient him/ herself and his/her parents [bib_ref] Clinical management of congenital hypogonadotropic hypogonadism, Young [/bib_ref] [bib_ref] Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism -pathogenesis, diagnosis..., Boehm [/bib_ref] [bib_ref] Transition in endocrinology: induction of puberty, Dunkel L &amp; Quinton [/bib_ref]. ## Treatment approach and monitoring Recommendations regarding treatment approach and monitoring for puberty induction in girls (R 2.1-2.9) apply equally to those with HH. Pubertal induction in girls with HH using gonadotropins has not been described, although gonadotropin-ovulation-induction is a standard fertility treatment in adult life. [fig_ref] Table 5: Treatment with gonadotropins for puberty induction or induction of spermatogenesis [/fig_ref] for the so far reported different treatment options using gonadotrophins. (+OOO) ## Rationale Pubertal induction in a boy can be carried out through two different possible approaches: the use of testosterone analogues similar to the treatment of primary hypogonadism or the use of exogenous gonadotropins. Preparations, doses and aim of the two possible treatments are indicated in R 3.1-3.5 and [fig_ref] Table 5: Treatment with gonadotropins for puberty induction or induction of spermatogenesis [/fig_ref]. Monitoring of patients with HH undergoing gonadotropin treatment does not differ from the recommendation for pubertal induction with testosterone (see R 3.5-R 3.8). To date only a few randomised studies have been published comparing these different treatment strategies and the patients recruited in these studies are often quite heterogeneous. It is therefore difficult to conclude which treatment strategy is more effective or preferred [bib_ref] Inducing puberty, Delemarre [/bib_ref]. A systematic review provided no firm evidence for an optimal induction approach (see section on Systematic literature review) [bib_ref] Effect of testosterone on bone density and bone metabolism in adolescent male..., Arisaka [/bib_ref] [bib_ref] Hormonal therapy and pubertal development in boys with selective hypogonadotropic hypogonadism, Bistritzer [/bib_ref] [bib_ref] Induction of testicular growth and spermatogenesis by pulsatile, intravenous administration of gonadotrophin-releasing..., Delemarre-Van De Waal [/bib_ref] [bib_ref] Pulsatile GnRH is superior to hCG in therapeutic efficacy in adolescent boys..., Gong [/bib_ref]. The two options, testosterone or gonadotropins [fig_ref] Table 5: Treatment with gonadotropins for puberty induction or induction of spermatogenesis [/fig_ref] , should be presented and discussed with the patient and his parents, also considering the availability of the different treatment options in the patient's country of residence. The most common treatment for pubertal induction in males with HH involves, as for primary hypogonadism, the use of i.m. injection of testosterone esters (enanthate, propionate or cypionate) [bib_ref] Clinical management of congenital hypogonadotropic hypogonadism, Young [/bib_ref] [bib_ref] Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism -pathogenesis, diagnosis..., Boehm [/bib_ref] [bib_ref] Transition in endocrinology: induction of puberty, Dunkel L &amp; Quinton [/bib_ref] [bib_ref] Inducing puberty, Delemarre [/bib_ref]. Although effective in inducing pubertal signs and symptoms, testosterone formulations neither stimulate testicular growth nor will they induce spermatogenesis. It is still unclear whether testosterone therapy for pubertal induction hinders future testis development or likelihood of spermatogenesis if gonadotropins are used in adulthood [bib_ref] Adolescent Hypogonadotropic Hypogonadism Study Group'. Testicular growth and spermatogenesis: new goals for..., Rohayem [/bib_ref] [bib_ref] Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a metaanalytic study, Rastrelli [/bib_ref]. Alternatively, a potential testicular development and fertility in males with HH can be achieved with puberty induction through the use of gonadotropins [bib_ref] Adolescent Hypogonadotropic Hypogonadism Study Group'. Testicular growth and spermatogenesis: new goals for..., Rohayem [/bib_ref] [bib_ref] Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with..., Dwyer [/bib_ref] [bib_ref] Treatment of gonadotropindeficient boys with recombinant human FSH: long-term observation and outcome, Raivio [/bib_ref] [bib_ref] Predictors of reproductive and non-reproductive outcomes of gonadotropin mediated pubertal induction in..., Cangiano [/bib_ref]. This might offer adolescent patients a significant psychological reassurance and may also enhance their self-confidence [bib_ref] Clinical management of congenital hypogonadotropic hypogonadism, Young [/bib_ref] [bib_ref] Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism -pathogenesis, diagnosis..., Boehm [/bib_ref]. On the other hand, although this has to be verified and demonstrated, it might also allow for the early identification of potential 'poor responders' (i.e. patients with severe oligozoospermia and a total sperm count <5 millions/mL) and thus give them the opportunity to consider a preventive and prophylactic sperm cryopreservation for future use in case of a worse spermatic response in adulthood. Different treatment protocols with gonadotropins can be used to induce puberty in adolescent males with HH: exogenous hCG alone or in combination with recombinant FSH [bib_ref] Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with..., Dwyer [/bib_ref] [bib_ref] Treatment of gonadotropindeficient boys with recombinant human FSH: long-term observation and outcome, Raivio [/bib_ref] [bib_ref] Predictors of reproductive and non-reproductive outcomes of gonadotropin mediated pubertal induction in..., Cangiano [/bib_ref] [bib_ref] Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent..., Barrio [/bib_ref] [bib_ref] Addition of recombinant follicle-stimulating hormone to human chorionic gonadotropin treatment in adolescents..., Zacharin [/bib_ref]. However, consistent evidence suggests that the combination therapy with recombinant FSH (rFSH)/hCG is significantly more effective than hCG alone both for inducing spermatogenesis and increasing testicular volume. Furthermore, some evidence suggests that a pre-treatment with rFSH followed by the combination with hCG or GnRH is even more effective in optimising the Sertoli cell maturation and is able to induce spermatogenesis even in extremely small testes, and cryopreservation of sperm subsequently allows for enhancing the future fertility of these patients [bib_ref] Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with..., Dwyer [/bib_ref] [bib_ref] Treatment of gonadotropindeficient boys with recombinant human FSH: long-term observation and outcome, Raivio [/bib_ref] [bib_ref] Treatment of prepubertal gonadotrophin-deficient boys with recombinant human follicle-stimulating hormone, Raivio [/bib_ref] [bib_ref] Recombinant human FSH treatment outcomes in five boys with severe congenital hypogonadotropic..., Kohva [/bib_ref]. Indeed, this approach mimics the physiological elevation of FSH during spontaneous pubertal development. Treatment with gonadotropins, whatever the protocol used, requires multiple weekly injections, although s.c. injections can be given. This aspect should be discussed with the patient and parents before the final decision. ## R 4.2 We suggest considering switching gonadotropins to testosterone in boys with HH after pubertal induction. ## Rationale If pubertal induction is made by the administration of rFSH and hCG in order to mimic physiology, we recommend switching to testosterone treatment in boys with HH after the completion of pubertal induction. Possible spermatogenesis should be considered. Although there is not enough evidence to recommend one treatment before the other, there are theoretical arguments based on the limited knowledge available on testis and Sertoli cell maturation with regard to fertility. During early puberty, the proliferation of immature Sertoli cells occurs under the stimulus of FSH. Hence, treatment with FSH stimulates the proliferation of immature Sertoli cells and spermatogonia [bib_ref] Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with..., Dwyer [/bib_ref] [bib_ref] Treatment of prepubertal gonadotrophin-deficient boys with recombinant human follicle-stimulating hormone, Raivio [/bib_ref] [bib_ref] Proliferation of Sertoli cells during development of the human testis assessed by..., Cortes [/bib_ref]. On the other hand, testosterone induces the differentiation of Sertoli cells via androgen receptor which begins to be expressed after the first 5 years of life [bib_ref] Physiological androgen insensitivity of the fetal, neonatal, and early infantile testis is..., Chemes [/bib_ref]. The combination of rFSH and hCG therapy for 6-24 months results in testicular growth in almost all and spermatogenesis in 80-95% of patients without undescended testes [bib_ref] Predictors of reproductive and non-reproductive outcomes of gonadotropin mediated pubertal induction in..., Cangiano [/bib_ref] [bib_ref] Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent..., Barrio [/bib_ref] [bib_ref] Loumaye E & FSH Study Group in Men's Infertility. Efficacy and safety..., Bouloux [/bib_ref] [bib_ref] Self-administered subcutaneous human menopausal gonadotrophin for the stimulation of testicular growth and..., Jones [/bib_ref]. The use of hCG without FSH priming could, therefore, in theory, cause premature differentiation of the pool of Sertoli and germ cells, thereby diminishing the chance of proliferation leading to lower fertility potential in adulthood. The shift from FSH/hCG therapy to testosterone should occur after sperm analysis, and in the case of sufficient sperm in the ejaculate, sperm cryopreservation (banking) should be considered, particularly in severe oligospermia. The reason behind this is that even if repeated gonadotropin treatment has been reported to induce quicker initiation of spermatogenesis [bib_ref] Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men:..., Liu [/bib_ref] [bib_ref] Predicting pregnancy and spermatogenesis by survival analysis during gonadotrophin treatment of gonadotrophin-deficient..., Liu [/bib_ref] , it is not certain. In cases with azoospermia, which then appear as 'poor responders' to gonadotropin stimulation, testicular sperm extraction (TESE) procedure might be considered, however, with uncertain outcome, before switching to TRT, especially in patients who are old and mature enough for this. Furthermore, since 'reversal' of CHH has been described (144) in 5-20% of patients with CHH, a brief therapy withdrawal (i.e. 4 months) after the conclusion of pubertal induction with gonadotropins and before the start of TRT might be considered in order to verify a spontaneous recovery of the HPG axis. ## Puberty induction in klinefelter # Introduction Klinefelter syndrome is the most common cause of congenital male hypogonadism. However, boys with this syndrome typically enter puberty at a normal age. With advancing adolescent age, the gonadal dysfunction becomes more marked and may be associated with a failure to progress in puberty [bib_ref] Best Practice and Research, Wikström [/bib_ref]. The diagnosis of Klinefelter syndrome affecting 1:600 men is often overlooked [bib_ref] Changes in the cohort composition of turner syndrome and severe non-diagnosis of..., Berglund [/bib_ref] [bib_ref] Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study, Bojesen [/bib_ref] with less than 10% diagnosed before puberty, probably due to the variable and sometimes subtle phenotype, especially in the mosaic forms. During or after puberty, boys with Klinefelter syndrome typically present with gynaecomastia and they have elevated FSH and low testosterone levels, although testosterone can also be at the lower end of the normal range with elevated LH [bib_ref] Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism, Bonomi [/bib_ref] [bib_ref] Best Practice and Research, Wikström [/bib_ref]. Patients have an increased incidence of cryptorchidism. In puberty, the testes grow initially and then regress, and in adulthood, testes are small and firm. There is a wide spectrum of the phenotype, many are never even diagnosed while some can have psychosocial difficulties and learning disabilities. The diagnosis is confirmed by karyotyping. We place a high value on the recommendation to treat adult patients with Klinefelter syndrome and low testosterone levels as well as accompanying symptoms of androgen deficiency with an adequately dosed testosterone replacement . ## Timing of puberty induction The general recommendations as formulated under R 3.1 and 3.3 (in whom to consider pubertal induction) apply to Klinefelter syndrome, although the most common situation is a normal start of puberty followed by a slow progression of puberty with small testes and development of gynaecomastia. ## Treatment approach and monitoring With regard to the timing of puberty, an individual prediction of pubertal onset for patients with Klinefelter syndrome can be estimated from the parents' pubertal history. Whether early testosterone replacement, when LH starts to rise above normal levels (>+2 s.d.), should be started is still not clear. Some advocate for early treatment as soon as LH starts to rise in order to prevent the adverse body composition, osteopenia/osteoporosis, impaired physical and psychological development, educational achievements and social integration which are commonly observed in the untreated newly diagnosed young adult [bib_ref] Klinefelter syndrome: integrating genetics, neuropsychology, and endocrinology, Gravholt [/bib_ref] [bib_ref] The psychosocial impact of Klinefelter syndrome -a 10 year review, Simm [/bib_ref] [bib_ref] Klinefelter's syndrome: a clinical and therapeutical update, Forti [/bib_ref] [bib_ref] Safety and efficacy of testosterone replacement therapy in adolescents with Klinefelter syndrome, Mehta [/bib_ref] [bib_ref] Endocrinological issues and hormonal manipulation in children and men with Klinefelter syndrome, Wosnitzer [/bib_ref]. However, others think that testosterone supplementation should be postponed until testosterone levels fall below the normal range (<−2 s.d.) [bib_ref] Testicular function during puberty and young adulthood in patients with Klinefelter's syndrome..., Rohayem [/bib_ref]. Some in the expert group advocated for aiming at securing sperm for cryopreservation before starting testosterone supplementation, while others, in the absence of scientific evidence for such an approach, advocated for commencing testosterone supplementation as soon as LH starts to rise. The recommendations regarding treatment and monitoring R 3.5-3.9 apply equally to Klinefelter. ## R. 5.3 We suggest performing sperm analysis if physically and mentally possible before the start of testosterone treatment in boys with Klinefelter Syndrome and spontaneous start of puberty. ## Rationale Randomised-controlled trials are needed to elucidate the influence of testosterone replacement therapy on pubertal development and spermatogenesis in patients with Klinefelter Syndrome. There are also no randomisedcontrolled trials evaluating the possible deleterious impact of testosterone treatment on successful sperm retrieval or its possible effects on reproductive outcomes in men with Klinefelter Syndrome. Testosterone preparations may theoretically suppress any remaining spermatogenesis if the endogenous LH drive is reduced; however, this has not been shown in clinical trials. Some advocate for assessing fertility status before the start of testosterone supplementation, while others do not. Therefore, individual decisions should be made until more evidence is gathered. In those patients who have no spermatozoa in their ejaculate, fertility preservation can be attempted through TESE. According to a recent literature review, spermatozoa can be found by TESE in up to half of the patients with Klinefelter syndrome aged 16-30 years old, of whom many had been treated with testosterone (240), although real-life studies report much lower values [bib_ref] Novel insights on testicular volume and testosterone replacement therapy in Klinefelter patients..., Garolla [/bib_ref]. Therefore, a TESE procedure for fertility preservation should not be performed in Klinefelter syndrome patients younger than 16 years and it can be postponed at least until the age of 30 since no significant differences were observed in TESE outcome in this age interval. The use of hCG or anti-oestrogens (aromatase inhibitors or selective oestrogen receptor modulators) on compassionate care grounds may have a positive effect on gonadotropin secretion even in the hypergonadotropic state as seen in Klinefelter syndrome [bib_ref] European Academy of Andrology Guideline Management of oligo-astheno-teratozoospermia, Colpi [/bib_ref]. Theoretically, this may result in higher levels of intra-testicular as well as circulating testosterone and maintained (or even augmented) spermatogenesis. However, no controlled trials are available and evidence is poor [bib_ref] Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at..., Mehta [/bib_ref]. Hence, such therapies cannot be recommended in general. No data have been published on the possible positive or negative effects of testosterone treatment in boys with Klinefelter syndrome and compensated hypergonadotropic hypogonadism. The guideline group acknowledges that different strategies are employed. Some suggest that in the absence of clinical signs and symptoms of hypogonadism, these boys should not be treated with testosterone [bib_ref] Testicular function during puberty and young adulthood in patients with Klinefelter's syndrome..., Rohayem [/bib_ref]. In some earlier studies, no benefit of TRT was observed in preventing obesity/ overweight [bib_ref] Endocrinological issues and hormonal manipulation in children and men with Klinefelter syndrome, Wosnitzer [/bib_ref] , and no significant differences in bone structure or bone biomarkers were reported in patients with Klinefelter with and without testosterone therapy [bib_ref] Bone geometry, volumetric density, microarchitecture, and estimated bone strength assessed by HR-pQCT..., Shanbhogue [/bib_ref]. However, a recent study advocates testosterone treatment in cases with elevated LH in order to potentially positively affect the muscle mass, the BMD and neuropsychological functioning [bib_ref] Klinefelter syndrome: integrating genetics, neuropsychology, and endocrinology, Gravholt [/bib_ref]. In young adults with Klinefelter syndrome, a recent placebo-controlled, randomised trial has shown that 6 months of testosterone treatment led to decreased total body and abdominal fat mass, as well as expected increases in haemoglobin and IGF-I [bib_ref] A placebo-controlled randomized study with testosterone in Klinefelter syndrome: beneficial effects on..., Høst [/bib_ref]. In adults, individualised transdermal and injection testosterone therapy resulted in comparable treatment efficacy when evaluating androgen-responsive parameters [bib_ref] Evaluation of the efficacy of transdermal and injection testosterone therapy in Klinefelter..., Kabilan [/bib_ref]. ## Androgen insensitivity syndrome (pais and cais) Androgen insensitivity syndrome (AIS) is a rare inherited condition caused by X-linked pathogenic mutations in the androgen receptor (AR) gene [bib_ref] A recurrent germline mutation in the 5'UTR of the androgen receptor causes..., Hornig [/bib_ref]. There are now more than 1000 mutations reported [bib_ref] The androgen receptor gene mutations database: 2012 update, Gottlieb [/bib_ref] , and the genotype-phenotype correlation is highly variable. The estimated prevalence is 1-5 per 100 000 births [bib_ref] Androgen receptor defects: historical, clinical, and molecular perspectives, Quigley [/bib_ref] [bib_ref] Incidence, prevalence, diagnostic delay, and clinical presentation of female 46,XY disorders of..., Berglund [/bib_ref]. The phenotype depends on the residual AR function. According to the residual sensitivity to testosterone, the external genitalia will be variably virilised [bib_ref] Different clinical presentations and management in complete androgen insensitivity syndrome (CAIS), Lanciotti [/bib_ref] [bib_ref] In-vitro characterization of androgen receptor mutations associated with complete androgen insensitivity syndrome..., Werner [/bib_ref] [bib_ref] Complete androgen insensitivity syndrome: a rare case of disorder of sex development, Pizzo [/bib_ref]. In general, three subgroups of AIS are defined. A complete absence of androgen receptor action leads to the clinical picture of CAIS. In these girls, the external genitalia are typically female. They have testes, which secrete testosterone with no (or markedly diminished) effect on the androgen receptor and Sertoli cells that produce AMH resulting in the regression of Mullerian structures prenatally. Thus, the uterus, fallopian tubes and upper part of the vagina are absent. Furthermore, Wolffian structures do not develop due to the insensitivity to testosterone. The testes are typically located within the abdomen, inguinal canal or in the labia majora [bib_ref] Incidence, prevalence, diagnostic delay, and clinical presentation of female 46,XY disorders of..., Berglund [/bib_ref]. Girls and women present during puberty with absence of menarche but with normal breast development due to the presence of androgens which are aromatised to oestrogens. Some girls (up to 50%) present with a bilateral inguinal hernia during infancy/childhood [bib_ref] Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series..., Audi [/bib_ref] [bib_ref] Complete androgen insensitivity syndrome: from bench to bed, Tyutyusheva [/bib_ref] [bib_ref] Inguinal hernia in female infants: a cue to check the sex chromosomes?, Deeb [/bib_ref]. Women with CAIS do not develop pubic and axillary hair. A blind-ending vagina is observed in almost all patients (from 2.5 to 8 cm long). Women with CAIS have a female gender identity and are female in their gender role behaviour [bib_ref] Human gender development, Hines [/bib_ref] [bib_ref] Psychological outcomes and gender-related development in complete androgen insensitivity syndrome, Hines [/bib_ref]. Reduced AR residual activity results in PAIS with variable virilisation of the external genitalia during fetal life. Individuals generally present with ambiguous genitalia at birth. Earlier studies described a grading scheme (grade 1-5) for the description of virilisation [bib_ref] Androgen receptor defects: historical, clinical, and molecular perspectives, Quigley [/bib_ref]. The residual activity of the AR also leads to a variable degree of virilisation of the external genitalia and the presence of gynaecomastia at the onset of puberty. Unfortunately, the phenotype-genotype correlation is poor [bib_ref] Correlation between genotype, phenotype and sex of rearing in 111 patients with..., Deeb [/bib_ref]. However, it has been shown that the degree of virilisation at birth estimated by the external masculinisation score (EMS) is a good predictor of the degree of virilisation at puberty [bib_ref] Changes over time in sex assignment for disorders of sex development, Kolesinska [/bib_ref] [bib_ref] Convergence of two repressors through heterodimer formation of androgen receptor and testicular..., Lee [/bib_ref]. In only 22% of the cases with a clinical diagnosis of PAIS, a pathogenic variant in the AR is found, making it a more complex and a highly variable clinical and diagnostic challenge [bib_ref] Characterization of mutant androgen receptors causing partial androgen insensitivity syndrome, Bellis [/bib_ref]. The mildest form of androgen insensitivity called mild androgen insensitivity syndrome is typically diagnosed in men with infertility without atypical genitalia [bib_ref] Detailed functional studies on androgen receptor mild mutations demonstrate their association with..., Zuccarello [/bib_ref] [bib_ref] Male infertility and androgen receptor gene mutations: clinical features and identification of..., Ferlin [/bib_ref] [bib_ref] The X chromosome and male infertility, Vockel [/bib_ref]. A detailed description of this form is outside the scope of this guideline. ## Gonadectomy in patients with complete androgen insensitivity syndrome Patients with CAIS and intraabdominal testes might be at increased risk of developing gonadal germ cell cancers (GGCC), mainly seminomas, but this risk seems to be low before/during puberty [bib_ref] A management protocol for gonad preservation in patients with androgen insensitivity syndrome, Weidler [/bib_ref] [bib_ref] Management of gonads in adults with androgen insensitivity: an international survey, Tack [/bib_ref] [bib_ref] Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): a retrospective..., Chaudhry [/bib_ref]. Historically, nearly all patients with CAIS underwent gonadectomy before puberty because of this risk. Delaying gonadectomy allows for spontaneous pubertal development which is thought to be more satisfactory to the individual and also allows the patient to be fully involved in the shared decision-making to remove their gonads or not. There is an ongoing debate about the need to perform gonadectomy after puberty since the risk of invasive GGCC development is still uncertain. In a recent publication by Tack et al., an algorithm was presented, in which they suggest performing gonadectomy after puberty in individuals with CAIS and only after careful counselling. Yearly follow-up if the gonads are retained was advised including self-examination and imaging [bib_ref] Management of gonads in adults with androgen insensitivity: an international survey, Tack [/bib_ref]. However, self-examination is only possible when the gonads are located in the inguinal region. Women with CAIS and intact gonads have an increased risk of developing low BMD due to bone insensitivity to testosterone and relative oestrogen deficiency. After gonadectomy, the risk of developing low BMD further increases. Treatment with sex steroids aims to prevent osteoporosis and other metabolic complications [bib_ref] Osteopenia as a feature of the androgen insensitivity syndrome, Soule [/bib_ref] [bib_ref] Altered bone mineral density in patients with complete androgen insensitivity syndrome, Bertelloni [/bib_ref] [bib_ref] Bone mineral density, body composition and metabolic profiles in adult women with..., Gava [/bib_ref] [bib_ref] The contribution of testosterone to skeletal development and maintenance: lessons from the..., Marcus [/bib_ref] [bib_ref] Bone mineral density in the complete androgen insensitivity and 5alpha-reductase-2 deficiency syndromes, Sobel [/bib_ref] [bib_ref] Height and bone mineral density in androgen insensitivity syndrome with mutations in..., Danilovic [/bib_ref] [bib_ref] Comparison of bone mineral density and body proportions between women with complete..., Han [/bib_ref]. Effects on cardiovascular health, quality of life, sexual health and mortality are less well studied [bib_ref] Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a..., Birnbaum [/bib_ref] [bib_ref] Morbidity, mortality, and socioeconomics in females with 46,XY disorders of sex development:..., Berglund [/bib_ref]. ## Pubertal induction in cais In whom to consider puberty induction? R 6. [bib_ref] The timing of normal puberty and the age limits of sexual precocity:..., Parent [/bib_ref] We recommend allowing girls with CAIS and retain gonads to go through spontaneous puberty. ## Rationale Puberty treatment is not indicated in girls with retained testes. In subjects with CAIS, androgen-responsive tissues including the pituitary gland are insensitive to testosterone, resulting in persistently elevated LH concentrations. Testosterone levels are within or above the normal male range in patients with retained testes. Testosterone is peripherally aromatised to oestrogen resulting in endogenous oestrogen levels which are above the male range but generally lower than the normal female range [bib_ref] ) 186:6 G49 Clinical Practice Guideline A Nordenström and others Pubertal induction, Hughes Ia &amp; Deeb [/bib_ref] [bib_ref] Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a..., Melo [/bib_ref]. These oestrogens induce breast development during puberty. In addition, this endogenous oestradiol has positive effects on the skeleton, brain and body habitus in patients with CAIS [bib_ref] Bone mineral density, body composition and metabolic profiles in adult women with..., Gava [/bib_ref]. The patients develop no or scarce pubic and axillary hair. It is generally perceived that in patients with CAIS and intact gonads, spontaneous puberty occurs at the same age as described in the general population although one study reported the start of breast development at a median age of 12-13 years [bib_ref] Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a..., Melo [/bib_ref]. Furthermore, in patients with CAIS, final height is generally above the mean female final height but below the average height of the male population [bib_ref] Comparison of bone mineral density and body proportions between women with complete..., Han [/bib_ref] [bib_ref] Pubertal growth in patients with androgen insensitivity: indirect evidence for the importance..., Zachmann [/bib_ref] [bib_ref] Puberty in subjects with complete androgen insensitivity syndrome, Papadimitriou [/bib_ref]. In individuals with intact gonads, oestrogen treatment can be considered in those with delayed puberty, particularly in individuals with tall stature with the aim to reduce final height. It is known that high dosages of oestrogens used during puberty can be successfully used to reduce final height in girls with constitutional tall stature [bib_ref] Sex steroid treatment of constitutionally tall stature, Drop [/bib_ref]. However, there are no studies reporting the effect of oestrogen treatment (dosage and timing) on the final height in patients with CAIS. Timing of puberty induction, treatment approach and monitoring R. 6.2 We recommend to start puberty induction at the age of 11 years in girls with CAIS who underwent gonadectomy. We recommend the same treatment protocols (for pubertal induction in girls with CAIS who have been gonadectomised ) as for other girls (R2.2-2.3, R2.6-2.8, R2.11). (+OOO) ## Rationale In girls with CAIS who have been gonadectomised, pubertal induction should start at the age of 11 years in accordance with the current treatment recommendations to mimic normal pubertal development. Treatment with sex hormones in patients with CAIS is generally only indicated when the gonads have been removed. The timing of puberty should be similar to other indications for pubertal induction in girls. Patients with CAIS treated with transdermal oestrogens were reported to have better bone health than those treated with oral formulations [bib_ref] Bone mineral density, body composition and metabolic profiles in adult women with..., Gava [/bib_ref]. The risks and benefits of oral vs transdermal E2 are likely to be similar to other cohorts in whom these therapies have been studied more comprehensively, with regard to liver and cardiovascular adverse effects [bib_ref] Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a..., Birnbaum [/bib_ref]. However, the benefits and disadvantages with regard to bone health and sexual function may differ for patients with other diagnoses. There are still conflicting data concerning the optimal dose of hormonal replacement therapy following puberty induction. Plasma oestradiol levels are positively associated with BMD. Therefore, routine monitoring of oestrogen concentrations by LC-MS/MS and bone density is recommended. Because of the absence of a uterus, the addition of treatment with progestins is generally not required. There is not enough evidence for a beneficial effect on brain, bone or other tissues to recommend the addition of progestin treatment. The use of testosterone rather than oestrogens in an attempt to mimic the hormonal levels of women with CAIS and intact gonads has been studied, particularly with regard to sexual function [bib_ref] Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a..., Birnbaum [/bib_ref] [bib_ref] Characteristic features of reproductive hormone profiles in late adolescent and adult females..., Doehnert [/bib_ref] [bib_ref] Hormonal management of complete androgen insensitivity syndrome from adolescence onward, Bertelloni [/bib_ref]. An unsolved aspect of the clinical care of young adults with CAIS and intact gonads is that although estrogen treatment is generally not recommended, low E2 plasma levels and BMD can be seen and thus, there may be a need for E2 or testosterone supplementation in these patients [bib_ref] Characteristic features of reproductive hormone profiles in late adolescent and adult females..., Doehnert [/bib_ref]. ## 186:6 g37 clinical practice guideline A Nordenström and others Pubertal induction: a clinical guideline https://eje.bioscientifica.com R 6. [bib_ref] Recent changes in pubertal timing in healthy Danish boys: associations with body..., Sørensen [/bib_ref] We recommend treatment monitoring every 3-6 months during puberty induction. ## Rationale Regular follow-up with clinical parameters (breast development, height), patient's satisfaction and bone density. We suggest yearly measurements of FSH and LH as well as E2 levels similarly to (R2). ## Pubertal induction in pais In whom to consider puberty induction? R. 7. [bib_ref] The timing of normal puberty and the age limits of sexual precocity:..., Parent [/bib_ref] We recommend that in all patients with PAIS, evaluation of gender identity should take place before considering puberty induction. ## Rationale The clinical picture of PAIS is variable and depends on the residual androgen receptor activity and other modifying partially unknown factors. The genital phenotype ranges from hypospadias to female appearance (284) [fig_ref] Table 1: Deficiencies of sexual development [/fig_ref]. Furthermore, the degree of virilisation at birth estimated by the EMS has been shown to be a good predictor of virilisation at puberty [bib_ref] Changes over time in sex assignment for disorders of sex development, Kolesinska [/bib_ref] [bib_ref] Convergence of two repressors through heterodimer formation of androgen receptor and testicular..., Lee [/bib_ref]. The external genitalia score (EGS) developed for evaluation in a wider spectrum of genital differences may be used in the future [bib_ref] The External Genitalia Score (EGS): a European multicenter validation study, Van Der Straaten [/bib_ref]. Careful counselling by a multidisciplinary team is therefore required before any decision about hormonal treatment is taken. An experienced psychologist should evaluate the patients' gender identity development, preferably from the age of 8 years. Structured psychological assessment of gender should be conducted. In case there are uncertainties about gender identity, puberty can be delayed by the use of GnRH agonists. Delay of puberty can be helpful in order to gain time to find out which gender will suit the individual best. Psychological follow-up is needed to evaluate gender development over time and keep an eye on the adolescent's mental health (emotional problems such as social phobia or depression need to be identified and treated). Recognising that gender identity is a non-binary phenomenon can facilitate satisfaction with one's gender. Detailed information is provided under 'Psychological Aspects'. However, pubertal treatment is essential for longterm wellbeing in all patients, and a decision regarding hormonal treatment eventually has to be made. ## Evaluation of pubertal development ## R. 7.2 We recommend that careful evaluation of patients' endocrine profile, phenotype and genotype is undertaken and that this information is used to consider the potential for virilisation during puberty (in patients with a male or undecided/binary identity). ## Rationale To evaluate the degree of pubertal development in PAIS, we recommend monitoring clinical signs of virilisation, height, full hormonal evaluation, degree of masculinisation at birth (EMS/EGS) and the genetic variant. At the onset of puberty, the hypothalamic GnRH pulse generator initiates pulsatile GnRH secretion resulting in pulsatile FSH and LH secretion from the pituitary gland. The resulting testosterone secretion from the Leydig cells in the testes fails to exert negative feedback to the hypothalamic-pituitary axis due to insufficient central AR action. However, the increased circulating testosterone is aromatised to oestradiol which exerts normal negative feedback on FSH levels that typically remain within the normal range. Thus, the LH/FSH ratio is typically relatively high in CAIS and PAIS [bib_ref] Andersson AM & Juul A. Sex differences in reproductive hormones during mini-puberty..., Johannsen [/bib_ref] [bib_ref] The LH/FSH ratio is not a sex-dimorphic marker after infancy: data from..., Ljubicic [/bib_ref]. Oestradiol circulates in highnormal concentrations (compared to the male reference range) resulting in gynaecomastia in many boys with PAIS [bib_ref] Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth,..., Hellmann [/bib_ref] [bib_ref] The long-term outcome of boys with partial androgen insensitivity syndrome and a..., Lucas-Herald [/bib_ref]. The testicular Sertoli cell markers inhibin B and AMH are within the normal prepubertal male range [bib_ref] Peptide hormone analysis in diagnosis and treatment of differences of sex development:..., Johannsen [/bib_ref]. In the physiological situation, inhibin B increases with pubertal onset, whereas AMH decreases when the Sertoli cells differentiate and start to express AR. With rising intratesticular testosterone levels, AMH secretion is inhibited in a subject with normal AR function, whereas a boy with PAIS continues to have prepubertal levels of AMH due to lack of inhibition. Inhibin B is usually within normal male ranges in boys with PAIS [bib_ref] Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth,..., Hellmann [/bib_ref]. It is difficult to predict the course of puberty in patients with PAIS. A study analysed EMS at birth in 27 PAIS patients in relation to the pubertal outcome and found that only six of nine patients with EMS < 5 at birth underwent spontaneous male onset of puberty, whereas all 18 patients with EMS ≥ 5 at birth experienced a spontaneous male onset of puberty. In contrast to the clinical findings, the functional analysis of AR variants did not appear to predict pubertal outcome. It remains to be seen to which degree the early (peripubertal) changes in reproductive hormones will guide the clinician in the prediction of spontaneous virilisation. ## Rationale In children with PAIS who have been raised as girls and identify as girls and who have not been gonadectomised, gonadectomy can be considered before or at the very beginning of puberty, to avoid virilisation and gender discomfort/dysphoria in addition to considerations regarding malignancy risk [bib_ref] MRKH) syndrome: a comprehensive update, Herlin [/bib_ref] [bib_ref] Anastrozole plus leuprorelin in early maturing girls with compromised growth: the 'GAIL'..., Papadimitriou [/bib_ref] [bib_ref] Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone..., Merke [/bib_ref] [bib_ref] Aromatase inhibitors in puberty, Hero [/bib_ref] [bib_ref] Evaluation of serum insulin-like factor 3 quantification by LC-MS/MS as a biomarker..., Albrethsen [/bib_ref]. Pubertal induction as recommended for other conditions in which pubertal induction is necessary applies. ## R 7.4 In boys with PAIS, we suggest considering additional testosterone treatment in mid puberty depending on the clinical and biochemical assessment of pubertal development. If clinical signs of hypoandrogenism such as micropenis and gynaecomastia are present, we suggest treating with the addition of testosterone for 6 months and then evaluating the effect. (+OOO) ## Rationale The clinical phenotype of individuals with PAIS who identify as males is highly variable from micropenis to severe hypospadias and/or bifid scrotum. It is a theoretical consideration that the inherent androgen insensitivity can be overcome by adding supraphysiological testosterone levels on top of the endogenous testosterone secretion. Anecdotally, patients report a beneficial effect on genital growth and wellbeing, but no randomised trials exist. Transdermal testosterone and long-acting i.m. injections have been tried [bib_ref] The long-term outcome of boys with partial androgen insensitivity syndrome and a..., Lucas-Herald [/bib_ref]. Clearly, serum testosterone concentrations cannot be used to monitor efficacy, which relies exclusively on clinical improvement and general wellbeing. Biochemically, haematocrit is suggested as a safety parameter. LH has also been suggested as a surrogate marker for optimal dosing of testosterone in males with PAIS. The majority of males with PAIS develop gynaecomastia [bib_ref] Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a..., Melo [/bib_ref] [bib_ref] Impaired sexual activity in male adults with partial androgen insensitivity, Bouvattier [/bib_ref] , which may theoretically either worsen (because of increased E2) or improve (because of lowered LH-induced aromatase activity) with pharmacological testosterone treatment [bib_ref] Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth,..., Hellmann [/bib_ref]. Breast cancer has only been described in a few cases [bib_ref] Functional and structural analysis of R607Q and R608K androgen receptor substitutions associated..., Poujol [/bib_ref]. The effect of medical treatment on gynaecomastia is variable and most males decide to undergo mastectomy. Based on the beneficial effects of oestrogen receptor blocking in pubertal gynaecomastia, this treatment modality could also be considered in male patients with PAIS [bib_ref] Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia, Lawrence [/bib_ref]. Successful use of tamoxifen, a selective oestrogen receptor blocker, to reduce gynaecomastia was described in two patients with PAIS [bib_ref] Tamoxifen treatment for pubertal gynecomastia in two siblings with partial androgen insensitivity..., Saito [/bib_ref]. However, long-term studies are lacking, and whether or not there is a role for oestrogen blockers to prevent gynecomastia remains to be studied. Other signs of under-virilisation in patients with PAIS raised as boys, such as hypospadias and cryptorchidism, have been surgically corrected during infancy or childhood in most patients. ## Future perspectives Most of the recommendations in this guideline are based on expert clinical experience and often a long-term clinical experience of treating a large number of individuals. Studies on pubertal induction specifically in individuals with a DSD are scarce. It is clear that further studies are needed. Just to mention a few, issues directly related to hormone treatment with improved formulations and optimal route of administration as well as timing and progression of puberty are needed. The function and importance of the mini-puberty are still largely unknown. The issue of fertility and how the possibility for future fertility can be improved for individuals with different diagnoses are attracting increased attention. Does the treatment with FSH and LH/ hCG before the start of testosterone increase the possibility of future fertility in CHH? Studies on optimisation of sex hormone replacement in AIS and how to avoid long-term consequences for these patients are warranted. Animal studies and stem-cell research may open possibilities for the development of novel technologies involving Leydig cell transplantation in male hypogonadism in the future [bib_ref] Advances in stem cell research for the treatment of primary hypogonadism, Li L &amp; Papadopoulos [/bib_ref]. Diagnostic difficulties to distinguish CHH vs CDGP are still largely unsolved and a clinical recurrent issue. Improved tools for identifying a halt in pubertal development would be of benefit for many patients. Improved psychosocial support for patients is essential. # Conclusion Disorders of sexual development comprise a large array of diagnoses and patients with CHH and DSD present different symptoms and needs, especially during puberty. The care for these individuals and their families needs to be individualised and requires the involvement of specialised multidisciplinary teams. [fig] Figure 2 Oral: -conjugated oestrogen vs transdermal 17β oestradiol for reaching Tanner stage B3. Yes denotes having reached Tanner stage 3; no denotes having not reached Tanner stage 3: the risk ratio expresses the probability ratio for reaching Tanner stage B3. [/fig] [fig] R 4. 1: We suggest discussing two treatment options for pubertal induction in boys with secondary eje.bioscientifica.com hypogonadism: testosterone or gonadotropins. See [/fig] [table] Table 1: Deficiencies of sexual development: DSD nomenclature and hypogonadotropic hypogonadism. [/table] [table] Table 2: Spontaneous puberty, sex hormone replacement and possibility of fertility in subjects with DSD conditions and hypogonadotropic hypogonadism. [/table] [table] Table 5: Treatment with gonadotropins for puberty induction or induction of spermatogenesis. [/table]

Chiral ligand In chemistry a chiral ligand is a specially adapted ligand used for asymmetric synthesis. This ligand is an enantiopure organic compound which combines with a metal center by chelation to form a asymmetric catalyst. This catalyst engages in a chemical reaction and transfers its chirality to the reaction product which as a result also becomes chiral. In an ideal reaction one equivalent of catalyst can turn over many more equivalents of reactant which enables the synthesis of a large amount of a chiral compound from achiral precursors with the aid of a very small (often expensive) chiral ligand. The first such ligand, the diphosphine DiPAMP was developed by in 1968 by William S. Knowles (Nobel Prize in Chemistry 2001) and ultimately used in the industrial production of L-DOPA. # Privileged ligands Many thousands of chiral ligands have been prepared and tested since then but only several compound classes have been found to have a general scope. These ligands are therefore called privileged ligands . Important members depicted below are BINOL, BINAP, TADDOL, DIOP, BOX and DuPhos, all available as enantiomeric pairs. Other members are Salen and the cinchona alkaloids. Many of these ligands posses C2 symmetry which limits the number of possible reaction pathways and thereby increasing enantioselectivity. # Chiral fence Chiral ligands do their magic by asymmetric induction somewhere along the reaction coordinate. The image depicted on the right gives a general idea how a chiral ligand may induce an enantioselective reaction. The ligand (in green) has C2 symmetry with its nitrogen, oxygen or phosphorus atoms hugging a central metal atom (in red). In this particular ligand the right side is sticking out and its left side points away. The substrate in this reduction is benzophenone and the reagent (in blue) a hydride ion. In absence of the metal and the ligand the re face approach of the hydride ion gives the (S)-enantiomer and the si face approach the (R)-enantiomer in equal amounts (a racemic mixture like expected). The ligand/metal presence changes all that. The carbonyl group will now coordinated with the metal and due to the steric bulk of the phenyl group it will only be able to do so with its si face exposed to the hydride ion with in the ideal situation exclusive formation of the (R) enantiomer. The re face will simple hit the chiral fence . Note that when the ligand is replaced by its mirror image the other enantiomer will form and that a racemic mixture of ligand will once again yield a racemic product. Also note that if the steric bulk of both carbonyl substituents is very similar the strategy will fail. # Chiral counterions In a novel concept, so-called chiral ions team up with traditional cationic catalysts in asymmetric synthesis as demonstrated in this allene hydroxyalkoxylation in which the active catalyst is a salt of gold(I) and a phosphate of a chiral binaphthol :

Carnett's test In the evaluation of abdominal pain, a positive Carnett's test may indicate that the abdominal wall is the source of pain. In an uncontrolled case series of 1116 patients with Anterior Cutaneous Nerve Entrapment Syndrome (ACNES), 87% had a positive Carnett's test. A study of acute pain in the emergency department found no benefit from assessing the Carnett's sign.

Thoracoscopic excision of mediastinal parathyroid tumours # Guidance There is limited evidence to support the efficacy of thoracoscopic excision of mediastinal parathyroid tumours. The evidence on safety is also very limited in quantity, and in view of potential complications of the procedure it should only be used with special arrangements for clinical governance, consent, audit and research. Clinicians wishing to undertake thoracoscopic excision of mediastinal parathyroid tumours should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the potential complications of the procedure and provide them with clear written information. In addition, use of the Institute's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having thoracoscopic excision of mediastinal parathyroid tumours (see section 3.1). It is recommended that clinicians undertaking this procedure should collaborate in the collection and review of data. Patient selection for thoracoscopic excision of mediastinal parathyroid tumours should be carried out in specialist units and in the context of a multidisciplinary team that includes a thoracic surgeon experienced in thoracoscopic techniques. Preoperative imaging should always be undertaken to confirm the location of the mediastinal tumour.# The procedure # Indications There are usually four parathyroid glands situated in the neck, but in about 10% of people one or more of the glands are located in the mediastinum. Parathyroid tumours (most commonly benign adenomas) can develop in any of these glands. Parathyroid adenomas are a cause of primary hyperparathyroidism, characterised by the excessive production of parathyroid hormone, which results in high blood calcium levels. Symptoms and signs include tiredness, depression, confusion, constipation, polydipsia, polyuria, the development of kidney stones, bone pain and fractures. The management of hyperparathyroidism may include dietary modification and the use of parathyroid hormone inhibitors. Surgical treatment may be required for some patients. Parathyroid tumours situated in the neck can be removed surgically, usually through a cervical incision; however, tumours located in the mediastinum require a thoracotomy. Mediastinal parathyroid adenomas may also be treated by angiographic ablation or by computed tomography (CT)-guided ethanol ablation. Thoracoscopic excision of mediastinal parathyroid adenoma aims to reduce the morbidity and potential complications that may be associated with open procedures. # Outline of the procedure The location of the tumour is determined by imaging (for example CT, ultrasound or scintigraphy). Under general anaesthesia, a number of ports are placed in the intercostal spaces for the thoracoscope and instruments. One lung may be deflated to aid visualisation. The ectopic parathyroid gland is identified and dissected while keeping its capsule intact. The vascular pedicle is clipped and the gland is removed through one of the ports. A chest drain may be inserted. The ports are closed and the lung is inflated if necessary. # Efficacy In three case series and five case reports, successful excision without conversion to open surgery was achieved in 100% (7/7, 4/4, 4/4, 3/3, 2/2, 1/1, 1/1, 1/1) of patients. In one case series of four patients, the case report of two patients, and all three case reports of one patient, serum calcium levels were normalised in all patients shortly after thoracoscopic excision of mediastinal parathyroid adenoma. In the first single case report, a normalised serum calcium level (2.5 mmol/l) was maintained at 3-year follow-up. For more details, refer to the 'Sources of evidence' section. The Specialist Advisers listed key efficacy outcomes as improvement in serum calcium and parathyroid hormone levels, histological confirmation of parathyroidectomy and low rate of conversion to open surgery. # Safety One case report described a small apical pneumothorax following the procedure, which had resolved at 2-week follow-up. A case series of three patients reported transient hoarseness in one patient, which was presumed to have resulted from damage to the left recurrent laryngeal nerve. For more details, refer to the 'Sources of evidence' section. The Specialist Advisers stated that anecdotal and theoretical complications include bleeding, infection, chest wall pain, arrhythmias and catastrophic damage to the mediastinal contents, including the great veins and major arteries. # Other comments It was noted that suspicion of parathyroid malignancy may influence the choice of surgical technique used.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. The Institute has identified relevant audit criteria and developed an audit tool (which is for use at local discretion). The Institute has produced technology appraisals guidance on cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. Andrew DillonChief ExecutiveDecember 2007 # Sources of evidence The following document, which summarises the evidence, was considered by the Interventional Procedures Advisory Committee when making its provisional recommendations. 'Interventional procedure overview of thoracoscopic excision of mediastinal parathyroid tumours', June 2007. # Information for patients NICE has produced information describing its guidance on this procedure for patients and their carers ('Understanding NICE guidance'). It explains the nature of the procedure and the decision made, and has been written with patient consent in mind.# Changes since publication The guidance was considered for reassessment in January 2011 and it was concluded that NICE will not be updating this guidance at this stage. However, if you believe there is new evidence which should warrant a review of our guidance, please contact us. January 2012: minor maintenance.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2007. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk

Lopressor injection/warnings # Heart Failure Beta blockers, like Lopressor, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. If signs or symptoms of heart failure develop, treat the patient according to recommended guidelines. It may be necessary to lower the dose of Lopressor or to discontinue it. # Ischemic Heart Disease Do not abruptly discontinue Lopressor therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with beta-blockers. When discontinuing chronically administered Lopressor, particularly in patients with coronary artery disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, Lopressor administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue Lopressor therapy abruptly even in patients treated only for hypertension. # Use During Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. # Bradycardia Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of Lopressor. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders may be at increased risk. Monitor heart rate and rhythm in patients receiving Lopressor. If severe bradycardia develops, reduce or stop Lopressor. # Exacerbation of Bronchospastic Disease Patients with bronchospastic disease, should, in general, not receive beta blockers, including Lopressor. Because of its relative beta1 selectivity, however, Lopressor may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1 selectivity is not absolute use the lowest possible dose of Lopressor and consider administering Lopressor in smaller doses three times daily, instead of larger doses two times daily, to avoid the higher plasma levels associated with the longer dosing interval (see Adult Indications and Dosage). Bronchodilators, including beta2 agonists, should be readily available or administered concomitantly. # Diabetes and Hypoglycemia Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. # Pheochromocytoma If Lopressor is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle. # Thyrotoxicosis Lopressor may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm.

Ventricular tachycardia overview # Overview Ventricular tachycardia is a tachycardia that originates in one of the ventricles of the heart. This is a potentially life-threatening arrhythmia because it may lead to ventricular fibrillation and sudden death. In 1906 Gallavardin discovered the reasons behind the cardiac instability which led to ventricular tachycardia, and put forth the idea that VT could convert into ventricular fibrillation. Thomas Lewis gave the first electrocardiographic description of ventricular tachycardia in 1909. It was first suggested in 1921 that coronary occlusion could be the main cause of ventricular tachycardia. Many advancements have been made in the diagnosis and management protocols of ventricular tachycardia since that time.Ventricular tachycardia refers to a rhythm with a heart rate in excess of 100 (and in some definitions 120) beats per minute that arises distal to the bundle of His. Ventricular tachycardia can be classified based on morphology and duration of tachyarrhythmia. The morphology of the QRS complexes on the ECG maybe monomorphic ventricular tachycardia or polymorphic ventricular tachycardia. In sustained VT duration of VT lasts > 30 sec or VT300bpm, cycle length 140 msec, there is AV dissociation, there are positive or negative QRS complexes in all the precordial leads, and the morphology of the QRS complexes resembles that of a previous premature ventricular contraction (PVC). Common risk factors associated with VT/ VF include prior history of hypertension, Prior MI, ST-segment changes at presentation, chronic obstructive pulmonary disease. Risk factors of occurrence of VF before primary PCI in STEMI patients include alcohol consumption, preinfarction angina, anterior infarct location, complete coronary occlusion at the time of coronary angiography. Risk factors associated with VT/ VF after primary PCI include lower blood pressure, higher heart rate, poor coronary flow at the end of the procedure, incomplete resolution of ST elevation. Risk factors associated with monomorphic VT early after CABG include prior MI, ventricular scar, LV dysfunction, placement of a bypass graft across a noncollateralized occluded coronary vessel to a chronic infarct zone.Ventricular arrhythmia may include the range from triple premature ventricular contraction s (PVCs) to ventricular fibrillation. Clinical presentation varies from asymptomatic to cardiac arrest. Ventricular tachycardia can cause life-threatening or fatal hemodynamic compromise or it can degenerate into a life-threatening rhythm called ventricular fibrillation. Common complications of ventricular tachycardia include sudden cardiac death, cardiomyopathy, ventricular fibrillation, and infection related to ICD. The prognosis of ventricular tachycardia in patients largely depends upon the presence and severity of underlying cardiac disease. Mortality of ventricular tachycardia is higher in patients with coronary artery disease and presence of LV dysfunction. Prognosis is generally good in patients with right ventricular dysplasia, idiopathic ventricular tachycardia or ventricular fibrillation treated medically. Contrary to previous studies, VT or VF at any time after STEMI was associated with higher mortality rate within 90 days. Late VT or VF (after 48 hours of hospital admission) after STEMI was associated with a higher risk of death than early VT or VF (within 48 hours of hospital admission). ECG is the first diagnostic test that should be obtained in hemodynamically stable Ventricular tachycardia. For detection of tachyarrhythmia symptoms related exercise such as cathecolaminergic polymorphic VT, Exercise stress test is recommended. Findings on resting ECG associated with diagnosis of VT include evidence of structural hear disease such as prior MI or chamber enlargement, evidence of inherited arrhythmia disorders such as long QT syndrome, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy. QRS duration and conduction abnormality may have prognostic value in structural heart disease.The symptoms of ventricular tachycardia will depend on the ventricular rate, the duration of tachycardia, and the presence of underlying disease. In general, the symptoms include palpitations, lightheadedness, syncope, dyspnea, chest pain, cardiac arrest. Symptoms related to underlying heart disease include dyspnea at rest or on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, edema. Precipitating factors maybe exercise, or emotional stress. In patient presented with VT clinical history should be taken about coronary heart disease, valvular heart disease (mitral valve prolapse), congenital heart disease, thyroid disease, acute kidney injury, Chronic kidney disease, electrolyte abnormalities, stroke, embolic events, lung disease,epilepsy (arrhythmic syncope can be misdiagnosed as epilepsy), alcohol, illicit drug use, and use of over-the-counter medications causing QT prolongation and torsades de pointed. It is important to notify about the family history of SCD in first relatives, repetitive spontaneous pregnancy losses (concerning cardiac channelopathy), IHD, hypertrophic cardiomyopathy , dilated cardiomyopathy, ARVC, congenital heart disease, cardiac channelopathies( Long QT, Brugada, Short QT, CPVT), conduction disorders, pacemakers/ICDs, and Neuromuscular disease associated with cardiomyopathies (Muscular dystrophy, epilepsy).Physical examination should consist of a thorough cardiac exam, lung exam, and close monitoring of vital signs. Findings on physical exam may include hemodynamic instability, cannon a wave in jugolar venous pulsation, rales in lung fields, lower limbs edema, evidence of sternotomy scar due to previous CABG, and ICD pocket. Laboratory findings predicting sudden cardiac arrest and ventricular tachycardia include elevated level of Natriuretic peptides—B-type (BNP) or N-terminal pro-BNP as the marker of myocardial stress and fibrosis in heart failure disease, highly sensitive troponin T indicating cardiomyocyte injury, screening about hypokalemia, hypomagnesemia and also toxic level of digoxin, cocaine, tricyclic antidepressant.Finding on ECG associated with VT include: AV dissociation, atypical right bundle branch block or left bundle branch block characteristics, QRS> 140 ms for wide complex tachycardia with [[right bundle branch block pattern and QRS > 160 ms for wide complex tachycardia with left bundle branch block pattern, concordance or same polarity in all precordioal leads, rightward superior QRS axis.There are no x-ray findings associated with ventricular tachycardia. However, an x-ray may be helpful in the diagnosis underlying cause of ventricular tachycardia such as congestive heart failure, sternotomy suture, ICD wires and pocket.Echocardiography is an available and helpful modality for diagnosis and predicting the underlying causes of ventricular tachycardia and sudden cardiac arrest. Findings on an echocardiography include assessment of myocardial function, valvular structural and functional disease, congenital heart disease, cardiomyopathy, heart failure, prior MI.When structural heart disease is suspected in the context of ventricular tachycardia, it is necessary to have an accurate evaluation of the structure and function of the atria and ventricles. While echocardiography is the available modality, MRI is used when the assessment provided by echocardiography is not satisfactory. In addition, MRI seems to have an important role in the evaluation of suspected arrhythmogenic right ventricular cardiomyopathy because MRI provides a good assessment of the right ventricular structure, function, and fatty infiltration if present.Coronary angiography has an important role in diagnosis and treatment of myocardial ischemia-induced life-threatening VT, VF. Myocardial ischemia may induce recurrent polymorphic VT, or VF and is treatable by coronary revascularization. Evidence of ST segment elevation or early post resuscitated ECG changes suggestive of ischemia may lead to ventricular arrhythmia and sudden cardiac arrest and required urgent revascularization. In patients with low evidence of myocardial ischemia, coronary angiography is not recommended. For patients suspected anomalous origin of the coronary arteries leading SCA , coronary angiography is warranted.The mainstay of medical therapy in hemodynamic stable VT is suppression of tachyarrhythmia with antiarrhythmic medications such as amiodarone, sotalol, lidocaine, betablocker alongside with correction of hypokalemia, hypomagnesemia and hypocalcemia. In addition, treatment the underlying cause of VT including IHD or decompensated heart failure should be warranted. For treatment of unstable tachyarrhythmia (with chest pain, dyspnea, pulmonary edema, altered mental status), other than VF or pulselessVT, synchronized cardioversion should be warranted.In Synchronized cardioversion the amount of energy delivered is less than defibrillation and also the shock is delivered in different parts of the cardiac cycle. R-on -T phenomena may happen if the electrical defibrillated shock is delivered during the refractory period (on the latter part of T wave) which is vulnerable to induce VF. For prevention of this phenomena and monitoring R wave for each QRS complex for delivery of shock in cardiac cycle, the defibrillator is placed on synchronize mode. The recommendation energy for synchronized cardioversion is 50-200 jouls. Catheter ablation is useful for treating ventricular arrhythmia when drugs are ineffective. Monomorphic VT is a suitable target for ablation. Ablation can be used for polymorphic VT or VF if an initiating PVC focus or substrate is accessible. Cardiac surgery is rarely performed for treating ventricular tachycardia in case of highly symptomatic patients with failed antiarrhythmic medications or unsuccessful ventricular ablation. Inaccessible sites for ventricular ablation including area deep in the myocardium, beneath epicardial fat, or near the coronary arteries may lead to unsuccessful ablation. Surgical ablation of ventricular arrhythmia can be done during other surgical intervention such as placement of LVAD or at the time of left ventricular aneurysectomy which is a substrate for VT.Primary prevention strategy for heart failure patients with NYHA class II or III, and LVEF ≤35% at least 40 days after myocardial infarction is ICD implantation. In patients with LVEF ≤30% and prior MI and NYHA class I symptoms , ICD implantation was associated with survival benefit. Analysis of MADIT, MADIT-II, and SCD-HeFT showed survival benefit of ICD implantation for primary prevention of ventricular arrhythmia. There is not survival benefit of ICD implantation in patients with NYHA class IV heart failure.Secondary prevention strategies following SCA and unstable VT include ICD implantation, and medications. Based on meta-analysis of AVID trial implantation of ICD for secondary prevention of ventricular arrhythmia was superior to antiarrhythmic drugs in patients who survived of sudden cardiac arrest or unstable VT. Before ICD implantation, the reversible causes of ventricular arrhythmia including myocardial ischemia, electrolyte disturbance, proarrhythmic medication effect may be corrected. ICD implantation improved outcome in well-tolerated VT and structurally heart disease. Among patients with ischemia heart disease and syncope due to inducible sustained monomorphic VT, ICD is recommended even if there is not other criteria for primary prevention. # Historical Perspective In 1906 Gallavardin discovered the reasons behind the cardiac instability which leads to ventricular tachycardia, and put forth the idea that VT could convert into ventricular fibrillation. Thomas Lewis gave the first electrocardiographic description of ventricular tachycardia in 1909. It was first suggested in 1921 that coronary occlusion could the main cause of ventricular tachycardia. Many advancements have been made in the diagnosis and management protocols of ventricular tachycardia since that time. # Classification Ventricular tachycardia refers to a rhythm with a heart rate in excess of 100 (and in some definitions 120) beats per minute that arises distal to the bundle of His. Ventricular tachycardia can be classified based on morphology and duration of tachyarrhythmia. The morphology of the QRS complexes on the ECG maybe (monomorphic ventricular tachycardiaor polymorphic ventricular tachycardia). In sustained VT duration of VT lasts > 30 sec or VT< 30 sec that needs to termination due to compromised hemodynamic. Nonsustained, or unsustained VT is more than 3 consecutive premature ventricular complexes with spontaneously termination. Bidirectional VT is a type of VT with beat to beat changing QRS frontal plane axis indicating of digoxin toxicity or catecholaminergic polymorphic VT.Torsades de pointed is a type of polymorphic VT in the setting of long QT interval which is characterized by twisting of the points, waxing and waning QRS amplitude, Long-short sequence with long-coupling interval to the first VT beat, maybe initiated after bradycardia such as high grade AV block.Ventricular flutter is explained as a regular ventricular arrhythmia with rate about 300 beat per minute (bpm), or cycle length 200 ms, sinusoidal monophorphic QRS complexes, Without any isoelecterical interval between successive QRS complexes. Ventricular fibrillation is a rapid, grossly irregular electrical activity with variation in morphologic waveforms by ventricular rate >300bpm, cycle length <200 ms. VT/ VF storm is an electerical storm or cardiac instability due to ≥ 3 episodes of sustained VT, VF or shock delivery from ICD within 24 hours. # Pathophysiology The underlying mechanism of VT is due to automaticity arising in either the myocardium or in the distal conduction system. The most common underlying substrate for ventricular tachycardia is ischemic heart disease. Myocardial scarring from any process increases the likelihood of electrical reentrant circuits. These circuits generally include a zone where normal electrical propagation is slowed by the scar. Ventricular scar formation from a prior myocardial infarction (MI) is the most common cause of sustained monomorphic VT. The morphology of ventricular tachycardia often depends on its cause. VT in a structurally normal heart typically results from mechanisms such as triggered activity and enhanced automaticity. If VT is hemodynamically tolerated, the incessant tachyarrhythmia may cause a dilated cardiomyopathy. This may develop over a period of weeks to years and may resolve with successful suppression of the VT. # Causes Ischemic heart disease is a common cause of ventricular tachycardia. Other causes of ventricular tachycardia include congenital heart disease, valvular heart disease, dilated non-ischemic cardiomyopathy, sarcoidosis, infiltrative cardiomyopathy, inflammatory cardiomyopathy, and inherited channelopathies. In addition, illicit drug use with sympathetic activity such as cocaine and methamphetamine, and drugs with QT interval prolongation effect and also electrolyte disturbances such as hypokalemia, hypomagnesemia, and hypocalcemia may cause ventricular tachycardia. # Differentiating Ventricular Tachycardia from other Disorders When wide QRS tachycardia is present on the ECG, it is necessary to rapidly differentiate whether it is caused by ventricular tachycardia (VT) or a supraventricular tachycardia (SVT) with aberrant conduction. While the ECG provides the most reliable data to distinguish VT from SVT with aberrant conduction, the clinical history and the age of the patient may also provide additional discriminatory information regarding the cause of the wide QRS tachycardia. While older patients with a prior history of myocardial infarction are more likely to have VT, young hemodynamically stable patients presenting with paroxysmal tachycardia are more likely to have SVT with aberrant conduction. Nevertheless, the primary tool to differentiate VT from SVT with aberrant conduction is the ECG. There are several findings that are more common in ventricular tachycardia, and there are also more sophisticated electrophysiologic algorithms such as the Brugada and Vereckei algorithms that can be used to distinguish VT from SVT with aberrant conduction. The diagnosis of VT is more likely if: There is a history of myocardial infarction or structural heart disease, the electrical axis is -90 to -180 degrees (a “northwest” or “superior” axis), the QRS is > 140 msec, there is AV dissociation, there are positive or negative QRS complexes in all the precordial leads, and the morphology of the QRS complexes resembles that of a previous premature ventricular contraction (PVC). # Epidemiology and Demographics VT is more prevalent among patients with coronary artery disease. Eldery patients are more commonly affected by ideopathic VT. Ideopathic VT is commonly observed in women.There is no racial predilection for VT. # Risk Factors Common risk factors associated with VT/ VF include prior history of hypertension, Prior MI, ST-segment changes at presentation, chronic obstructive pulmonary disease. Risk factors of occurrence of VF before primary PCI in STEMI patients include alcohol consumption, preinfarction angina, anterior infarct location, complete coronary occlusion at the time of coronary angiography. Risk factors associated with VT/ VF after primary PCI include lower blood pressure, higher heart rate, poor coronary flow at the end of the procedure, incomplete resolution of ST elevation. Risk factors associated with monomorphic VT early after CABG include prior MI, ventricular scar, LV dysfunction, placement of a bypass graft across a noncollateralized occluded coronary vessel to a chronic infarct zone. # Screening In a young patient with lone atrial fibrillation, short QT syndrome should be excluded. In a patient with a family history of sudden cardiac death a physical examination should be performed. # Natural History, Complications and Prognosis Ventricular arrhythmia may include the range from triple premature ventricular contraction s (PVCs) to ventricular fibrillation. Clinical presentation varies from asymptomatic to cardiac arrest. Ventricular tachycardia can cause life-threatening or fatal hemodynamic compromise or it can degenerate into a life-threatening rhythm called ventricular fibrillation. Common complications of ventricular tachycardia include sudden cardiac death, cardiomyopathy, ventricular fibrillation, and infection related to ICD. The prognosis of ventricular tachycardia in patients largely depends upon the presence and severity of underlying cardiac disease. Mortality of ventricular tachycardia is higher in patients with coronary artery disease and presence of LV dysfunction. Prognosis is generally good in patients with right ventricular dysplasia, idiopathic ventricular tachycardia or ventricular fibrillation treated medically. Contrary to previous studies, VT or VF at any time after STEMI was associated with higher mortality rate within 90 days. Late VT or VF (after 48 hours of hospital admission) after STEMI was associated with a higher risk of death than early VT or VF (within 48 hours of hospital admission). # Diagnosis ## Diagnostic study of choice ECG is the first diagnostic test that should be obtained in hemodynamically stable Ventricular tachycardia. For detection of tachyarrhythmia symptoms related exercise such as cathecolaminergic polymorphic VT, Exercise stress test is recommended. Findings on resting ECG associated with diagnosis of VT include evidence of structural hear disease such as prior MI or chamber enlargement, evidence of inherited arrhythmia disorders such as long QT syndrome, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy. QRS duration and conduction abnormality may have prognostic value in structural heart disease. ## History and Symptoms The symptoms of ventricular tachycardia will depend on the ventricular rate, the duration of tachycardia, and the presence of underlying disease. In general, the symptoms include palpitations, lightheadedness, syncope, dyspnea, chest pain, cardiac arrest. Symptoms related to underlying heart disease include dyspnea at rest or on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, edema. Precipitating factors maybe exercise, or emotional stress. In patient presented with VT clinical history should be taken about coronary heart disease, valvular heart disease (mitral valve prolapse), congenital heart disease, thyroid disease, acute kidney injury, chronic kidney disease, electrolyte abnormalities, stroke, embolic events, lung disease,epilepsy (arrhythmic syncope can be misdiagnosed as epilepsy), alcohol, illicit drug use, and use of over-the-counter medications causing QT prolongation and torsades de pointed. It is important to notify about the family history of SCD in first relatives, repetitive spontaneous pregnancy losses (concerning cardiac channelopathy), IHD, hypertrophic cardiomyopathy , dilated cardiomyopathy, ARVC, congenital heart disease, cardiac channelopathies( Long QT, Brugada, Short QT, CPVT), conduction disorders, pacemakers/ICDs, and Neuromuscular disease associated with cardiomyopathies (Muscular dystrophy, epilepsy). ## Physical Examination Physical examination should consist of a thorough cardiac exam, lung exam, and close monitoring of vital signs. Findings on physical exam may include hemodynamic instability, cannon a wave in jugular venous pulsation, rales in lung fields, lower limbs edema, evidence of sternotomy scar due to previous CABG, and ICD pocket. ## Laboratory Findings Serial cardiac enzymes, serum electrolytes as well as calcium, magnesium and phosphate levels, should be obtained. A toxicology screen should also be obtained to assess for illicit drugs as the cause of the VT, as well as levels of medications that may have caused the VT. ## Electrocardiogram Finding on ECG associated with VT include: AV dissociation, atypical right bundle branch block or left bundle branch block characteristics, QRS> 140 ms for wide complex tachycardia with [[right bundle branch block pattern and QRS > 160 ms for wide complex tachycardia with left bundle branch block pattern, concordance or same polarity in all precordioal leads, rightward superior QRS axis. ## Chest X Ray There are no x-ray findings associated with ventricular tachycardia. However, a chest x-ray may be helpful in the diagnosis underlying cause of ventricular tachycardia such as congestive heart failure, sternotomy suture, ICD wires and pocket. ## Echocardiography Echocardiography is an available and helpful modality for diagnosis and predicting the underlying causes of ventricular tachycardia and sudden cardiac arrest. Findings on an echocardiography include assessment of myocardial function, valvular structural and functional disease, congenital heart disease, cardiomyopathy, heart failure, prior MI. ## Cardiac MRI When structural heart disease is suspected in the context of ventricular tachycardia, it is necessary to have an accurate evaluation of the structure and function of the atria and ventricles. While echocardiography is the available modality, MRI is used when the assessment provided by echocardiography is not satisfactory. In addition, MRI seems to have an important role in the evaluation of suspected arrhythmogenic right ventricular cardiomyopathy because MRI provides a good assessment of the right ventricular structure, function, and fatty infiltration if present. ## Coronary angiography Coronary angiography has an important role in diagnosis and treatment of myocardial ischemia-induced life-threatening VT, VF. Myocardial ischemia may induce recurrent polymorphic VT, or VF and is treatable by coronary revascularization. Evidence of ST segment elevation or early post resuscitated ECG changes suggestive of ischemia may lead to ventricular arrhythmia and sudden cardiac arrest and required urgent revascularization. In patients with low evidence of myocardial ischemia, coronary angiography is not recommended. For patients suspected anomalous origin of the coronary arteries leading SCA , coronary angiography is warranted. # Treatment ## Medical therapy The mainstay of medical therapy in hemodynamic stable VT is suppression of tachyarrhythmia with antiarrhythmic medications such as amiodarone, sotalol, lidocaine, betablocker alongside with correction of hypokalemia, hypomagnesemia and hypocalcemia. In addition, treatment the underlying cause of VT including IHD or decompensated heart failure should be warranted. ## Electrical Cardioversion For treatment of unstable tachyarrhythmia (with chest pain, dyspnea, pulmonary edema, altered mental status), other than VF or pulselessVT, synchronized cardioversion should be warranted.In Synchronized cardioversion the amount of energy delivered is less than defibrillation and also the shock is delivered in different parts of the cardiac cycle. R-on -T phenomena may happen if the electrical defibrillated shock is delivered during the refractory period (on the latter part of T wave) which is vulnerable to induce VF. For prevention of this phenomena and monitoring R wave for each QRS complex for delivery of shock in cardiac cycle, the defibrillator is placed on synchronize mode. The recommendation energy for synchronized cardioversion is 50-200 jouls. ## Catheter ablation Catheter ablation is useful for treating ventricular arrhythmia when drugs are ineffective. Monomorphic VT is a suitable target for ablation. Ablation can be used for polymorphic VT or VF if an initiating PVC focus or substrate is accessible. ## Surgery Cardiac surgery is rarely performed for treating ventricular tachycardia in case of highly symptomatic patients with failed antiarrhythmic medications or unsuccessful catheter ablation. Inaccessible sites for ventricular ablation including area deep in the myocardium, beneath epicardial fat, or near the coronary arteries may lead to unsuccessful ablation. Surgical ablation of ventricular arrhythmia can be done during other surgical intervention such as placement of LVAD or at the time of left ventricular aneurysectomy which is a substrate for VT. ## Primary prevention Primary prevention strategy for heart failure patients with NYHA class II or III, and LVEF ≤35% at least 40 days after myocardial infarction is ICD implantation. In patients with LVEF ≤30% and prior MI and NYHA class I symptoms , ICD implantation was associated with survival benefit. Analysis of MADIT, MADIT-II, and SCD-HeFT showed survival benefit of ICD implantation for primary prevention of ventricular arrhythmia. There is not survival benefit of ICD implantation in patients with NYHA class IV heart failure. ## Secondary prevention Secondary prevention strategies following SCA and unstable VT include ICD implantation, and medications. Based on meta-analysis of AVID trial implantation of ICD for secondary prevention of ventricular arrhythmia was superior to antiarrhythmic drugs in patients who survived of sudden cardiac arrest or unstable VT. Before ICD implantation, the reversible causes of ventricular arrhythmia including myocardial ischemia, electrolyte disturbance, proarrhythmic medication effect may be corrected. ICD implantation improved outcome in well-tolerated VT and structurally heart disease. Among patients with ischemia heart disease and syncope due to inducible sustained monomorphic VT, ICD is recommended even if there is not other criteria for primary prevention.

Body bag A body bag is a non-porous bag designed to contain a human body, used for the storage and transport of corpses. Body bags can also be used for the storage of corpses within morgues. Before purpose-made body bags were available, cotton mattress covers were sometimes used, particularly in combat zones during the Second World War. However, the subsequent rubber (and now plastic) body-bag designs are much superior, not least because they prevent leakage of body fluids, which often occurs after someone dies. The dimensions of a body-bag are generally around 36 inches by 90 inches. In modern warfare, body bags have been used to contain the bodies of dead soldiers. Governments typically have reserves of body bags, both for anticipated wars and natural disasters. During the Cold War, vast reserves of body bags were built up in anticipation of millions of fatalities from nuclear war. This was the subject of Adrian Mitchell's haunting protest poem "Fifteen Million Plastic Bags". Body bags are sometimes portrayed in films and television as being made of a heavy black plastic. Lightweight white body bags have since become popular because it is much easier to spot a piece of evidence that may have been jostled from the body in transit on a white background than on a black background. Even so black body-bags are still in general use, as the adjacent photo taken in 2008 shows. Other typical colours include orange, blue, or grey. Regardless of their colour, body bags are made of thick plastic and have a full-length zipper on them. Sometimes the zipper runs straight down the middle. Alternatively, the path of the zipper may be J-shaped or D-shaped. Depending on the design, there are sometimes handles (two on each side) to facilitate lifting. It is possible to write information on the plastic surface of a bodybag using a marker pen, and this often happens - either in situ (particularly when a large number of bodies are being collected) or at the mortuary, before being stored in refrigerated cabinets. Alternatively, some designs of body bag have transparent label pockets as an integral part of the design, into which a name-card can be inserted. In any case, a conventional toe tag can easily be tied to one of the lifting handles if required. Body bags are not designed to be washed and re-used, with good reason: aside from the obvious hygiene concerns, re-use of body bags could easily contaminate evidence in the case of a suspicious death. As a result, body bags are routinely discarded and incinerated after one use. Although body bags are most often used for the transport of human remains from their place of discovery to a funeral home or mortuary, they can also be used for temporary burials such as in a combat zone. In such situations, proper funerals are impossible due to imminent enemy attack. This was the situation during the Falklands War of 1982, during which British casualties were placed in grey plastic bodybags and then laid in mass graves. Some months after the conflict ended, all remains were exhumed from their temporary graves to receive a conventional funeral service with full military honours. The term body bag is sometimes used for fashion or other bags worn on the body (sling body bag or across body bag) and this sense has no connection with either of the two above senses.

Zanamivir Inhalation (patient information) # Why is this medication prescribed Zanamivir is used in adults and children to treat some types of influenza ('flu') in people who have had symptoms of the flu for less than 2 days. This medication is also used to prevent some types of flu in adults and children when they have spent time with someone who has the flu or when there is a flu outbreak. Zanamivir is in a class of medications called neuraminidase inhibitors. It works by stopping the growth and spread of the flu virus in your body.Zanamivir helps shorten the time you have flu symptoms such as nasal congestion, sore throat, cough, muscle aches, tiredness, weakness, headache, fever, and chills. # How should this medicine be used Zanamivir comes as a powder to inhale (breathe in) by mouth. To treat influenza, two inhalations of zanamivir are used twice daily for 5 days. You should inhale the doses about 12 hours apart and at the same time each day., However, on the first day of treatment, your doctor may tell you to inhale the doses closer together. To help prevent the spread of influenza in people living in the same household, two inhalations of zanamivir are used once a day for 10 days. To help prevent the spread of influenza in a community, two inhalations of zanamivir are used once a day for 28 days. When using zanamivir to prevent influenza it should be inhaled at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Use zanamivir exactly as directed. Do not use more or less of it or use it more often than prescribed by your doctor. Zanamivir comes with a plastic inhaler called a Diskhaler (device for inhaling powder) and five Rotadisks (circular foil blister packs containing four doses of medication). Do not put a hole in or open any medication blister pack until inhaling a dose with the Diskhaler. Carefully read the manufacturer's instructions that describe how to prepare and inhale a dose of zanamivir using the Diskhaler Be sure to ask your pharmacist or doctor if you have any questions about how to prepare or inhale this medication. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part that you do not understand. Use zanamivir exactly as directed. Do not use more or less of it or use it more often than prescribed by your doctor. The use of the inhaler for a child should be supervised by an adult who understands how to use zanamivir and has been instructed in its use by a healthcare provider. Continue to take zanamivir even if you start to feel better. Do not stop taking zanamivir without talking to your doctor. If you feel worse or develop new symptoms during or after treatment, or if your flu symptoms do not start to get better, call your doctor. Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient. # Other uses for this medicine This medication may be prescribed for other uses; ask your doctor or pharmacist for more information. # What special precautions should I follow Before using zanamivir - tell your doctor and pharmacist if you are allergic to zanamivir, any other medications, any food products, or lactose (milk proteins). - tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects. - tell your doctor if you have or have ever had asthma or other breathing problems ,bronchitis (swelling of the air passages that lead to the lungs),emphysema (damage to air sacs in the lungs);or heart,kidney, liver, or other lung disease. - if you use an inhaled medication to treat asthma, emphysema, or other breathing problems and you are scheduled to take that medication at the same time as zanamivir, you should take your regular medication before taking zanamivir. - tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking zanamivir, call your doctor. - you should know that zanamivir may cause serious or life-threatening breathing problems, more commonly in patients with asthma or emphysema. If you have trouble breathing or have wheezing after your dose of zanamivir, stop using zanamivir and get medical attention. If you have difficulty breathing, and have been prescribed a rescue medication, use your rescue medication immediately and then call for medical attention. Do not take any more zanamivir without first talking to your doctor. # What special dietary instructions should I follow Unless your doctor tells you otherwise, continue your normal diet. # What should I do if I forget a dose If you forget to inhale a dose, inhale it as soon as you remember it. If it is 2 hours or less until the next dose, skip the missed dose and continue your regular dosing schedule. Do not inhale a double dose to make up for a missed one. # Side Effects ## Mild side effects Zanamivir may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: - headache - dizziness - nausea - vomiting - diarrhea - cough - irritation of the nose - infection of the ear, nose, sinuses, throat, or bronchi (breathing tubes of the lung) ## Severe side effects If you experience any of the following symptoms, call your doctor immediately: - difficulty breathing - wheezing - shortness of breath - hives - rash - itching - difficulty swallowing - swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs - hoarseness If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online or by phone . # What storage conditions are needed for this medicine Keep this medication in the container it came in and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication. # In case of emergency/overdose In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911. # What other information should I know You should maintain proper hygiene, wash your hands frequently, and avoid situations such as sharing cups and utensils that can spread the influenza virus to others. Ask your doctor if you should receive a flu vaccination each year. Zanamivir does not take the place of a yearly flu vaccine. The Diskhaler should only be used for zanamivir. Do not use the Diskhaler to take other medications that you inhale. Do not let anyone else use your medication.Your prescription is probably not refillable. # Brand names - Relenza®

Van der Woude syndrome (patient information) For the WikiDoc page for this topic, click here # Overview Van der Woude syndrome is a condition that affects the development of the face. Many people with this disorder are born with a cleft lip, a cleft palate (an opening in the roof of the mouth), or both. Affected individuals usually have depressions (pits) near the center of the lower lip, which may appear moist due to the presence of salivary and mucous glands in the pits. Small mounds of tissue on the lower lip may also occur. In some cases, people with van der Woude syndrome have missing teeth. People with van der Woude syndrome who have cleft lip and/or palate, like other individuals with these facial conditions, have an increased risk of delayed language development, learning disabilities, or other mild cognitive problems. The average IQ of individuals with van der Woude syndrome is not significantly different from that of the general population. # What are the symptoms of Van der Woude syndrome? # What are the causes of Van der Woude syndrome? Mutations in the IRF6 gene cause van der Woude syndrome. The IRF6 gene provides instructions for making a protein that plays an important role in early development. This protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. The IRF6 protein is active in cells that give rise to tissues in the head and face. It is also involved in the development of other parts of the body, including the skin and genitals. Mutations in the IRF6 gene that cause van der Woude syndrome prevent one copy of the gene in each cell from making any functional protein. A shortage of the IRF6 protein affects the development and maturation of tissues in the face, resulting in the signs and symptoms of van der Woude syndrome. # Who is at risk for Van der Woude syndrome? Individuals with parents that carry a mutation in IRF6 gene are at risk. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition. Occasionally, an individual who has a copy of the altered gene does not show any signs or symptoms of the disorder. # How to know you have Van der Woude syndrome? # When to seek urgent medical care # Treatment options # Diseases with similar symptoms # Where to find medical care for Van der Woude syndromee Directions to Hospitals Treating Van der Woude syndrome # Prevention of Van der Woude syndrome # What to expect (Outlook/Prognosis)

Aminosalicylic acid description # Description PASER granules are a delayed release granule preparation of aminosalicylic acid (p-aminosalicylic acid; 4-aminosalicylic acid) for use with other anti-tuberculosis drugs for the treatment of all forms of active tuberculosis due to susceptible strains of tubercle bacilli. The granules are designed for gradual release to avoid high peak levels not useful (and perhaps toxic) with bacteriostatic drugs. Aminosalicylic acid is rapidly degraded in acid media; the protective acid-resistant outer coating is rapidly dissolved in neutral media so a mildly acidic food such as orange, apple or tomato juice, yogurt or apple sauce should be used. Aminosalicylic acid (p-aminosalicylic acid) is 4-Amino-2-hydroxybenzoic acid. PASER granules are the free base of aminosalicylic acid and do NOT contain sodium or a sugar. The molecular formula is C7H7NO3 with a molecular weight of 153.14. With heat p-aminosalicylic acid is decarboxylated to produce CO2 and m-aminophenol. If the airtight packets are swollen, storage has been improper. DO NOT USE if packets are swollen or the granules have lost their tan color and are dark brown or purple. The structural formula is: PASER granules are supplied as off-white tan colored granules with an average diameter of 1.5 mm and an average content of 60% aminosalicylic acid by weight. The acid resistant outer coating will be completely removed by a few minutes at a neutral pH. The inert ingredients are: - Colloidal silicon dioxide - Dibutyl sebacate - Hydroxypropyl methyl cellulose - Methacrylic acid copolymer - Microcrystalline cellulose - Talc The packets contain 4 grams of aminosalicylic acid for oral administration three times a day by sprinkling on apple sauce or yogurt to be eaten without chewing. Suspension in an acidic fruit drink such as orange juice or tomato juice will protect the coating for at least 2 hours. Swirling the juice in the glass will help resuspend the granules if they sink.

BTG1 Protein BTG1 is a protein that in humans is encoded by the BTG1 gene. # Function The BTG1 gene locus has been shown to be involved in a t(8;12)(q24;q22) chromosomal translocation in a case of B-cell chronic lymphocytic leukemia. It is a member of a family of antiproliferative genes. BTG1 expression is maximal in the G0/G1 phases of the cell cycle and downregulated when cells progressed through G1. It negatively regulates cell proliferation. # Interactions BTG1 has been shown to interact with: - CNOT7, - CNOT8, - HOXB9, and - PRMT1. # Clinical relevance Recurrent mutations in this gene have been associated to cases of diffuse large B-cell lymphoma. # Maintenance of adult neural stem cells Recent data, obtained in a new model of mouse lacking the BTG1 gene, indicate that BTG1 is essential for the proliferation and expansion of stem cells in the adult neurogenic niches, i.e. the dentate gyrus and sub ventricular zone (see for review). In particular, BTG1 keeps adult neural stem cells in quiescence, preserving the neural stem cells pool from depletion. In the absence of BTG1, the stem and progenitor cells initially hyper proliferate and then in the longer period lose the ability to proliferate and expand. Other recent data indicate that physical exercise can fully reconstitute the proliferative defect of stem cells that follows the ablation of the BTG1 gene, suggesting that the pool of neural stem cells maintains a hidden form of plasticity which is tightly controlled by BTG1; hence, BTG1 might prevent the depletion of stem cells in the presence of strong neurogenic stimuli or of neural degenerative stimuli. Btg1 plays a role also in the expansion of cerebellar granule precursor cells. In fact the deletion of Btg1 leads in mouse to uncontrolled proliferation of the cerebellar precursor cells during the early postnatal period. Consequently, in the adult, the cerebellum lacking Btg1 is significantly larger and the motor coordination is heavily impaired. The closest homolog of BTG1 is BTG2, which also controls the proliferation and differentiation of adult neural stem cells; the role of BTG2, however, appears to differ from that of BTG1 being probably more relevant in controlling the terminal differentiation of neural stem and progenitor cells in the adult neurogenic niches.

Anellovirus Not much is known about the family of Anelloviri, having been recently discovered. It has been classified as a vertebrate virus and consisting of a non-enveloped capsid, which is round with isometric, icosahedral symmetry. The genome is not segmented and contains a single molecule of circular, negative-sense, single-stranded DNA. The complete genome is 3000-4000 nucleotides long. . # Literature - ↑ ICTVdB Management (2006). 00.107.0.01. Anellovirus. In: ICTVdB - The Universal Virus Database, version 4. Büchen-Osmond, C. (Ed), Columbia University, New York, USA

Umbilical cord prolapse # Overview Cord prolapse is an obstetric emergency during pregnancy or labour that endangers the life of the fetus. It occurs when the umbilical cord presents itself outside of the uterus while the fetus is still inside. It can happen when the water breaks – with the gush of water the cord comes along. Usually, thereafter the fetus will engage and squash the cord, cutting off oxygen supplies and leading to brain damage of the fetus, or stillbirth. Before that happens, the baby must be delivered quickly by caesarean section. In the meantime, the woman adopts the knee-elbow position, and an attendant reaches into the vagina and pushes the presenting part (usually the head) back in so that it does not suffocate the cord. It is useless to try to push the cord back in. Another technique is to infuse 500ml of fluid by catheter into the mother's bladder, in order to displace the presenting part upward, and to reduce compression on the prolapsed cord. # Risk Factors Potential predisposing risk factors include: - Premature rupture of the amniotic sac - polyhydramnios (having too much amniotic fluid) the cord may be forced out with the more forceful gush of waters - long umbilical cord # Natural History, Complications and Prognosis The mortality rate for the fetus is given as 11-17%. This applies to hospital births or very quick transfers in a first world environment. One series is reported where there was no mortality in 24 cases with the novel intervention of infusing 500ml of fluid by catheter into the bladder, in order to displace the presenting part upward and reduce compression on the prolapsed cord. # Treatment ### Contraindicated medications Umbilical cord prolapse is considered an absolute contraindication to the use of the following medications: - Oxytocin ## Surgery Some practitioners will attempt to reduce pressure on the cord and deliver vaginally right away. Frequently the attempt to resolve the prolapsed cord and deliver the baby vaginally fails, and an emergency caesarean section must be performed immediately. While the patient is being prepared for a caesarean, the woman is placed in the Trendelenburg position or the knee-elbow position, and an attendant reaches into the vagina and pushes the presenting part out of the pelvic inlet and back into the pelvis to remove the pressure from the umbilical cord. If attempts to deliver the baby promptly fail, the fetus' oxygen and blood supply are occluded and brain damage or death will occur.

# Purpose and scope Lead is a widely used metal found in many compounds and products and which can give rise to life-threatening poisoning and long-term negative effects on health. Lead exposure is a significant public health concern; it is estimated to have accounted for 0.90 million deaths from long-term effects and 21.7 million disability-adjusted life years in 2019 (1). Children are particularly vulnerable, and WHO has estimated that lead exposure accounts for 30% of the global burden of idiopathic developmental intellectual disability (2). Individual lead poisoning cases continue to occur; in addition, there have been a number of mass lead-poisoning events around the world, mostly related to contamination of the environment or of food (3)(4)(5)(6). The purpose of this guideline is to assist physicians in making decisions about the diagnosis and treatment of lead exposure for individual patients and in mass poisoning incidents. The guideline can also be used to inform evidence-based treatment protocols. It presents evidenceinformed recommendations on interpretation of blood lead concentrations, gastrointestinal (GI) decontamination after ingestion of lead, nutritional supplementation to mitigate the effects of lead exposure and chelation therapy to facilitate elimination of lead. The guideline does not include discussion of methods for preventing lead exposure, such as screening and environmental and household interventions, which will be the subject of a separate guideline. # Methods for guideline development This guideline was developed according to the procedure laid out in the WHO Handbook for Guideline Development (7). For external contributors, conflict of interest was managed in accordance with WHO policy and procedures. Work was guided by a steering group that comprised members of staff from WHO departments concerned with public health, environment and food safety at headquarters and in four regions. Development was supported by a guideline development group comprising 15 external experts from the six WHO regions, who provided expertise in public health, clinical toxicology, children's environmental health and lead poisoning prevention and management, including in low-resource settings. A group at the Medical Toxicology and Information Services (later, ESMS Global) in London, United Kingdom, was commissioned to conduct systematic reviews of evidence for the management of lead poisoning. Assessments of the certainty of evidence according to GRADE (grading of recommendations, assessment, development and evaluation) were carried out with the support of a team at the Department for Evidence-based Medicine and Clinical Epidemiology at Danube University, Krems, Austria. The WHO steering group drafted the initial scope and outline of the guideline, an initial list of possible interventions and a set of research questions to be used for the systematic evidence reviews. The guideline development group extended this work and identified the critical and important outcomes relevant to the clinical management of lead exposure for which evidence would be assessed. The threshold blood lead concentration for action was agreed by the guideline development group on the basis of extensive evaluations of the toxicity of lead at low levels of exposure carried out by WHO and national agencies. Evidence reviews were conducted for the following interventions: GI decontamination, chelation therapy and nutritional supplements. The review protocols were based on the model used by the Cochrane Collaboration. Systematic searches were carried out in bibliographic databases and clinical trial registers. No date limits were set for the literature searches for chelation therapy and GI decontamination, and the last searches were conducted in March 2020 and July 2020, respectively. For nutritional interventions, a date limit of 1990 was set, and the last searches were conducted in March 2020. The quality of the body of evidence for chelation therapy in non-pregnant individuals and for nutritional supplements was assessed with the GRADE approach, in which the certainty of evidence for each outcome in the studies found was rated as "high", "moderate", "low" or "very low". This was based on ratings of study design limitations, inconsistency of results, indirectness, imprecision and publication bias. Evidence profiles were constructed for each outcome, which included assessment and judgement of the criteria. The final rating of the certainty of evidence was based on further consideration of these criteria. At meetings of the guideline development group, the evidence found in each review was presented, with a GRADE evaluation. The guideline development group took note of the evidence, formulated recommendations and proposed the strength of each recommendation. In addition to the certainty of the evidence, the following factors were considered in determining the strength and direction of the final recommendations: values and preferences, the balance of benefits and harms, resource implications, equity, acceptability and feasibility. GRADEPro guideline development tool evidence-to-decision tables (/) were used to note and synthesize these considerations and record the reasons for the strength of the recommendations. Strong recommendations are those for which the group was confident that the desirable effects of adherence to the recommendation outweigh the undesirable effects. For a conditional recommendation, the group concluded that the desirable effects of adherence probably outweigh the undesirable effects but was not confident of this interpretation. The interpretations were also considered from the perspectives of patients, physicians and policy-makers. Each recommendation was adopted by consensus, defined as agreement by at least 80% of the participants. Recommendations were drafted in face-to-face meetings of the guideline development group and finalized in a series of online meetings and email discussions. In the course of discussing the recommendations, the guideline development group identified three good practice statements. These were not identified through systematic evidence retrieval, synthesis and grading but are considered good clinical practice according to clinical experience in the management of patients with lead exposure. Informal consultations on the recommendations were held at two WHO technical meetings, in Ahmedabad, India, in June 2017 and in Cairo, Egypt, in December 2018. The external reviewers included clinicians who would potentially be users of the guideline when managing cases of lead exposure. The draft guideline was reviewed by eight external peer reviewers. The guideline was revised and then finalized in a series of online and email discussions of the guideline development group between July 2020 and July 2021. # Background and sources of lead exposure There are many sources of lead exposure due to its widespread use and environmental contamination. Most of the lead in the environment is due to human extraction, processing and use of lead. Lead has many uses, in particular in storage batteries, ammunition, pipes and many alloys such as those used for solder. Inorganic lead compounds are found in pigments, paints, glazes and plastics. Lead and lead compounds are also found in some cosmetics, traditional medicines and spices. Organic lead compounds were used extensively as additives in petrol, but this use is now banned in all countries. There are multiple sources and pathways of exposure. The most important routes of exposure to lead and its compounds are ingestion and inhalation. Most cases of oral lead poisoning result from regular ingestion of small amounts of lead-containing material such as contaminated dust or soil, flakes of lead paint, contaminated food and spices, lead-containing traditional medicines or from ingestion of a lead foreign body. Young children are particularly likely to ingest contaminated soil and dust. Inhalation of lead as fumes or particles is a major occupational route of exposure. Absorption of lead from the GI tract is affected by dietary factors, age, nutritional status, genetic factors and the form of the lead. Infants and young children absorb a greater proportion of ingested lead than adults. Fasting and dietary deficiencies of iron or calcium are reported to enhance absorption. Once absorbed, lead is initially bound to erythrocytes in the blood and is distributed to soft tissues and bone. Blood and soft tissues represent the active pool and bone the storage pool. The blood lead concentration reflects recent exposure to lead from exogenous sources and, when there has been previous exposure to lead, also includes lead redistributed from skeletal stores. In individuals who are exposed chronically, bone contains > 90% of the body burden of lead in adults and > 70% in children. Lead can be released from bone during metabolic processes that increase bone turnover, such as occur during pregnancy, lactation and the menopause. Exposure to lead, even at very low levels, has been associated with a range of negative health effects, and no level without deleterious effects has been identified (8)(9)(10). Young children are particularly vulnerable to the neurotoxic effects of lead, which include impaired cognitive and behavioural development that can have life-long impacts (11). The effects of the greatest public health significance, i.e. adverse neurodevelopmental effects in children and cardiovascular disease in adults, are nonspecific and largely subclinical. There is considerable inter-individual variation in the dose-response relation for lead toxicity, and the presenting signs and symptoms are highly variable in both adults and children. The toxic effects include GI features such as anorexia, abdominal pain, nausea, vomiting, diarrhoea or constipation; neurological features such as headache, lethargy, irritability, ataxia, tonic-clonic convulsions, opisthotonus, cerebral oedema and raised intracranial pressure; haematological features such as anaemia, possibly with basophilic stippling; and signs of renal and hepatic dysfunction. Lead encephalopathy is more common in children than adults, and survivors may have sequalae such as mental retardation and convulsive disorders. # Diagnosis of lead poisoning Diagnosis of lead poisoning and treatment decisions are based on the history, clinical examination and the results of investigations, including the blood lead concentration, biomarkers of effect such as in a full blood count and, if relevant, medical imaging. The venous blood lead concentration is the definitive biomarker of exposure and risk on which management decisions are routinely based. Information about the collection and analysis of blood samples for lead can be found in WHO guidance (12). # Results of the evidence review A systematic evidence review was not considered necessary to determine the threshold blood lead concentration at which interventions should be initiated to manage lead exposure and poisoning because reviews by international and national bodies, including WHO, were already available (8)(9)(10)13), which document the adverse health impacts of lead, particularly at low exposure levels of 5 µg/dL and below. For GI decontamination, evidence was available only from case reports and case series and was therefore rated as of very low certainty (14). The nature of ingestion was diverse. The most commonly reported measures used were removal of the lead-containing material from the GI tract and the blood lead concentration, although the latter was often confounded by administration of chelation therapy. For nutritional interventions, several randomized controlled trials (RCTs) were found for calcium, iron and zinc supplementation (15). For calcium, four small, RCTs were identified in children, one in pregnant women and one RCT plus a linked non-randomized study in lactating women. In the case of iron, three RCTs were identified in children. These provided very low-certainty evidence that calcium supplementation is associated with a small reduction in the blood lead concentration in children, and moderate-certainty evidence was available of a small reduction in pregnant women. There was also low-certainty evidence of a reduction in blood lead concentration in lactating women and very lowcertainty evidence of a faster decline in breastmilk lead concentrations and a reduction in the release of lead from bone as compared with the placebo group. Studies of iron supplementation in iron-deficient children provided very low-certainty evidence of a small reduction in the blood lead concentration. For children who were not iron-deficient, there was moderate-certainty evidence of no effect on blood lead concentration or cognitive or behavioural outcomes. An RCT of zinc supplementation in children provided moderate-certainty evidence of no effect on blood lead concentration or cognitive or behavioural outcomes. There were a few RCTs on chelation therapy in nonpregnant patients, and the other types of controlled study were subject to a high risk of bias (16)(17)(18)(19). Most of the evidence was from case series, which were confounded by the effect of removal from lead exposure. Low-tomoderate-certainty evidence was identified for a lack of benefit on short-and long-term outcomes in children with blood lead concentrations < 45 µg/dL (19). For patients with higher blood lead concentrations, very low-certainty evidence was found for reduction of the blood lead concentration, increased urinary excretion of lead, improvement in signs and symptoms of lead poisoning in all age groups and reduced mortality in children. For pregnant women, the only evidence identified was from case reports and was, therefore, of very low certainty (20). The main outcomes reported were maternal and newborn blood lead concentrations, and it was not possible to draw conclusions about the impact of chelation on other outcomes, such as reversal of toxic effects in the fetus. There were insufficient studies for a meta-analysis of the evidence, and the reviews were qualitative. In view of the mainly low-or very low-certainty evidence, recommendations were informed by the clinical experience of guideline development group members. Tables summarizing the findings for each intervention and the evidence-to-decision tables that explain the decisions for reaching each recommendation are available online (21). The guideline development group agreed that the following guiding principles were applicable to all the recommendations for clinical management of exposure to lead. The agreement was based on consensus and not on systematic evidence retrieval, synthesis or grading. - Action should be taken as soon as possible to terminate or reduce lead exposure. Lead has no physiological role in the body, and no level of exposure has been identified that does not have a deleterious effect (8,9). As long as exposure continues, lead will be absorbed, with consequent negative effects on health; further, lead will also be stored in tissues and bone, forming a sink from which it can be remobilized back into blood. All lead exposure is potentially preventable (22). - Chelation therapy is of limited value during continuing exposure. It may, however, be necessary as a lifesaving measure for children with severe poisoning who continue to be exposed, for example when it is not immediately possible to remove lead from the GI tract or until the source of exposure has been identified and terminated. - As the medical management of people exposed to lead can be complex, it is advisable to seek advice from a clinical toxicologist or other medical practitioner with experience and expertise in the management of lead poisoning. This is particularly important if use of chelation is being considered before exposure has been addressed. # Summary of WHO recommendations for clinical management of lead exposure The WHO recommendations are summarized in the table below. Note that, in all cases of lead exposure, action should be taken to identify the source of lead and stop ongoing exposure, as this will, in itself, reduce the blood lead concentration and improve clinical features of toxicity. # No. Recommendation Strength of recommendation (certainty of evidence) # Blood lead concentration that should initiate clinical intervention 1 In all cases of suspected or confirmed lead exposure the patient or carer should be given information about potential sources of lead exposure, methods for reducing continuing exposure and the importance of good nutrition, in particular adequate dietary intake of iron and calcium. # Good practice statement 2 For an individual with a blood lead concentration ≥ 5 µg/dL, the source(s) of lead exposure should be identified and appropriate action taken to reduce and terminate exposure. # Strong (high-certainty evidence of the toxicity of low-level exposure to lead) Gastrointestinal decontamination after ingestion of a lead foreign body or other lead-containing material 1 Take measures to remove solid lead objects, such as bullets, lead pellets, jewellery, fishing or curtain weights, that are known to be in the stomach. # Strong (very low-certainty evidence) 2 Consider whole bowel irrigation (WBI) for removing solid lead objects, such as bullets, lead pellets, jewellery, fishing or curtain weights, that are known to have passed through the stomach. If WBI fails, i.e. the object or objects are not removed, and there is evidence of lead absorption, e.g. an increasing blood lead concentration or features of lead toxicity, consider endoscopic or surgical removal. # Conditional (very low-certainty evidence) 3 Consider surgical removal of solid lead objects, such as bullets or lead pellets, that are known to be in the appendix if the patient shows clinical signs of appendicitis or an increasing blood lead concentration. If the patient is clinically well, surgical removal is not necessary, but the blood lead concentration should be measured periodically to check for lead absorption. Treatment options should be reviewed if the patient becomes symptomatic or if the blood lead concentration starts rising. # Conditional (very low-certainty evidence) Strength of recommendation (certainty of evidence) Consider WBI for removing liquid or solid lead-containing substances, such as paint chips, lead-containing complementary or alternative medicines, or ceramic glaze, when this material is known to be dispersed in the gut. # Conditional (very low-certainty evidence) # Nutritional interventions in children and pregnant and lactating women exposed to lead Children ≤ 10 years of age For a child (≤ 10 years) with a blood lead concentration ≥ 5 µg/dL who has, or is likely to have, inadequate calcium intake, administration of calcium supplementation is recommended. The dose should be sufficient to ensure that the total calcium intake meets the national age-appropriate recommended nutrient intake value. # Strong (very low-certainty evidence) 2 For a child (≤ 10 years) with a blood lead concentration of ≥ 5 µg/dL who has, or is likely to have iron-deficiency, administration of iron supplementation is recommended. The dose should be in line with WHO guidelines (23,24) or standard clinical practice. # Strong (very low-certainty evidence) Pregnant women 1 For a pregnant woman with a blood lead concentration of ≥ 5 µg/dL, who has, or is likely to have, inadequate calcium intake, administration of calcium supplementation is recommended. The dosage should be sufficient to bring the total calcium intake to national guidelines for calcium in pregnant women or to the WHO/ FAO-recommended nutrient intake value (1.2 g) (25). This should be given as soon as the pregnancy is recognized, for the duration of the pregnancy. # Strong (moderate-certainty evidence) Lactating women 1 Initiation or continuation of calcium supplementation is suggested for lactating women who have a blood lead concentration of ≥ 5 µg/dL. This should be for the duration of lactation. # Conditional (low-to very low-certainty evidence) # Recommendation Strength of recommendation (certainty of evidence) Chelation therapy in individuals exposed to lead Children ≤ 10 years of age For a child (≤ 10 years) with a blood lead concentration ≥ 45 µg/dL, oral or parenteral chelation therapy is recommended. # Strong (very low-certainty evidence) 2 For a child (≤ 10 years) with a blood lead concentration of 40-44 µg/dL, when there is doubt about the accuracy of the measurement, a persistently elevated blood lead concentration in spite of measures to stop exposure or significant clinical features of lead poisoning, oral chelation therapy should be considered. # Conditional (very low-certainty evidence) For a child ≤ 10 years with a blood lead concentration ≥ 70 µg/dL, there should be close monitoring for signs of clinical deterioration, including regular neurological assessments, during and after chelation therapy while the concentration remains high. # Good practice statement 4 For a child (≤ 10 years) with lead encephalopathy, urgent hospital admission and parenteral chelation therapy are recommended. # Strong (very low-certainty evidence) # Non-pregnant adolescents (11-18 years) and adults (≥ 19 years) with blood lead concentration 45-70 µg/dL 1 For a non-pregnant adolescent girl or woman of child-bearing age who has a blood lead concentration of 45-70 µg/dL but who does not show clinical features of lead poisoning, oral chelation therapy should be considered. # Conditional (very low-certainty evidence) 2 For a male patient aged ≥ 11 years or a woman who is no longer of child-bearing age who has a blood lead concentration of 45-70 µg/dL but who does not show clinical features of lead poisoning, chelation therapy is not indicated. The patient should, however, be re-evaluated within 2-4 weeks to ensure that the blood lead concentration is decreasing and the patient remains well. # Conditional (very low-certainty evidence) # Recommendation Strength of recommendation (certainty of evidence) For a non-pregnant adolescent or adult with a blood lead concentration of 45-70 µg/dL and who has mild-moderate clinical features of lead poisoning (such as abdominal pain, constipation, arthralgia, headache, lethargy), chelation therapy is suggested. # Conditional (very low-certainty evidence) Non-pregnant adolescents (11-18 years) and adults (≥ 19 years) with blood lead concentrations of > 70-100 µg/dL 1 An adolescent or an adult with a blood lead concentration > 70-100 µg/dL should be closely monitored for signs of clinical deterioration, regardless of whether chelation therapy is given. # Good practice statement 2 For a non-pregnant adolescent or an adult with a blood lead concentration > 70-100 µg/dL but who does not show significant neurological features of toxicity, chelation therapy is suggested. # Conditional (very low-certainty evidence) For a non-pregnant adolescent or adult with a blood lead concentration > 70-100 µg/dL and with significant neurological features of lead toxicity (e.g. irritability, drowsiness, ataxia, convulsions, coma) or lead encephalopathy, urgent parenteral chelation therapy is recommended. # Strong (very low-certainty evidence) Pregnant women 1 For a pregnant woman with lead encephalopathy, regardless of trimester, urgent chelation therapy is recommended. The preferred chelating agent depends on the stage of the pregnancy and available data on safety of use in pregnancy. # Strong (very low-certainty evidence) 2 For a pregnant woman with a blood lead concentration ≥ 45 µg/ dL, with or without clinical features of lead poisoning, but without lead encephalopathy: i. in the first trimester: the guideline development group could not make a recommendation because of an uncertain balance of risks and benefits; # No recommendation ii. in the second or third trimester: chelation therapy is recommended. # Strong (very low-certainty evidence) The anticipated outcomes of these WHO recommendations are reduced likelihood, improvement in or resolution of lead-related health impacts. It is expected that these would be valued by the patient, their carer in the case of children and by society as a whole. Health equity considerations include the fact that individuals in economically deprived and disadvantaged populations bear the greatest burden of lead exposure, particularly in low-and middle-income countries (1,26). Other sources of vulnerability may exacerbate the health impacts of lead exposure, including a high prevalence of nutritional deficiencies. Addressing these will have important benefits, independently of termination of lead exposure, but is not a substitute for the latter. Pregnant women in low-and middle-income countries who are poor, not well educated and live in rural areas have lower coverage with health interventions and worse health outcomes than more advantaged women (27). They are also more likely to have inadequate calcium intake (27). Provision of calcium supplements, particularly if part of a programme of antenatal and postnatal support, could improve health outcomes. In settings where working with lead is an important livelihood, options for stopping exposure may be limited. This is particularly true where individuals or communities lack the necessary influence or power to improve their work or environmental conditions. Feasibility considerations include lack of resources and expertise for the diagnosis and treatment of lead poisoning; the availability of chelating agents is limited in many low-and middle-income countries (28), although the four recommended chelating agents are included in the WHO Model List of Essential Medicines (29). The diagnosis of lead exposure requires access to analytical laboratory services; however, screening can be carried out by analysis of a capillary blood sample in a point-of-care analyser, which is relatively low-cost and simple to operate (12). The feasibility and acceptability of terminating lead exposure depend on the source of exposure and availability and the costs of the required intervention(s). At low blood lead concentrations, the toxic effects will be mainly subclinical and, without understanding of the potential long-term impacts of exposure, there may be less motivation to take action. # Considerations for implementation of the recommendations # General considerations Health-care providers, in particular family doctors, community health nurses, paediatricians, obstetricians and midwives, should be trained in identifying the risk factors for lead exposure and the prevention, diagnosis and management of lead poisoning. Identification and confirmation of lead exposure require access to analytical equipment and laboratory services for measuring blood lead concentrations. WHO guidance is available on the selection of analytical methods and on establishing a laboratory service for this purpose (12). When lead exposure is suspected but the blood lead concentration is < 5 µg/dL, a follow-up measurement may be carried out after 6-12 months to rule out a continuing source of lead exposure. # Specific considerations # GI decontamination The most appropriate method of GI decontamination varies from case to case. Factors to be taken into account include the size, nature and quantity of the lead object(s) or lead-containing material ingested, the time that the material has been in the stomach or other parts of the GI tract, evidence of lead absorption, the clinical condition of the patient and the availability of resources for the intervention. Endoscopic procedures are standard practice for the removal of foreign bodies when there is a risk of harm to the patient, and evidence-based and evidenceinformed clinical guidelines have been developed by national and international professional societies (30-32). In the case of objects in the stomach, the use of oesophagogastroduodenoscopy may obviate surgery. General skill in abdominal surgery (including laparoscopic methods) should be available at secondary and tertiary medical services. WHO guidance on appendectomy is available (32). WBI should be conducted only with an iso-osmotic polyethylene glycol-electrolyte solution. # Nutritional supplementation with iron and calcium In all cases, nutrition counselling should be given to promote diet diversity and food combinations that improve calcium and iron absorption. This should be combined with counselling on methods for reducing lead exposure. For pregnant women, this information can be provided during routine antenatal care visits. Calcium and iron may compete for absorption; therefore, if supplementation with both nutrients is required, they should be taken at different times of the day. Calcium intake can be assessed by taking a dietary history and comparing intake with nationally recommended values. As the optimal dose for mitigating the effect of lead exposure is unknown, reference should be made to national intake value guidelines where possible or to WHO/FAO guidance (25). Care should be taken in sourcing calcium supplements, as those derived from biological sources such as animal bone may be contaminated with lead. For children, it is suggested that their dietary calcium intake be re-assessed after 3 months. If it is still inadequate and the blood lead concentration remains elevated, consideration should be given to a further period of supplementation. For pregnant women, calcium should be given for the duration of pregnancy and consideration given to extending administration into lactation. Iron deficiency can be determined from an estimate of the serum ferritin concentration and a marker of inflammation (e.g. C-reactive protein or α1-acid glycoprotein) (34). If this is not available, evaluation of anaemia is a non-specific marker of iron deficiency. Note that anaemia may also be a feature of lead toxicity. The optimal dose and duration of iron supplementation to mitigate the effects of lead exposure are unknown; therefore, reference should be made to WHO guidance for treating iron deficiency (23,24), which recommends a minimum treatment duration of 3 months, after which iron status should be re-assessed to evaluate continuation. In malaria-endemic areas, the possible harm of iron supplementation (24) should be balanced against the additional susceptibility of children with malaria to the neurotoxicity of lead (35) and the possibility that iron may be of benefit. # Chelation therapy In application of these recommendations to individual patients, some room must be left for clinical judgement about potential vulnerability to lead toxicity, the circumstances, nature and chronicity of exposure, clinical features, the blood lead concentration or trends in concentrations, and the location of treatment. Some allowance may also be required for possible inaccuracy in the measurement of blood lead concentrations. After chelation therapy, the blood lead concentration may rebound as lead stored in soft tissues and bone is released and the concentration in blood re-equilibrates. It is therefore important to re-check the blood lead concentration after a period for re-equilibration, to determine whether further chelation is necessary. An interval of 2-4 weeks is suggested, with the shorter interval for higher initial blood lead concentrations. Admission to a treatment centre is advised in the following situations: - The patient shows significant neurological features of toxicity, e.g. irritability, drowsiness, ataxia, convulsions, coma or lead encephalopathy. - Parenteral chelation therapy is required. - The patient is particularly vulnerable because of comorbid conditions such as malaria. - It is not otherwise possible to remove the patient from lead exposure, e.g. if their home environment is heavily contaminated and alternative accommodation is not available. - It would otherwise be difficult to monitor the patient and the effectiveness of management measures, e.g. because of logistical issues. - The ability of the patent to adhere to treatment is in doubt. # Selection of chelating agents For non-pregnant patients, the evidence for the effectiveness of individual chelating agents and chelating agent combinations was of very low-certainty, and there were no good-quality studies in which chelating agents were compared alone or in combination. For patients with severe lead poisoning, in particular lead encephalopathy, very low-certainty evidence suggests that chelation with succimer, sodium calcium edetate or dimercaprol, alone or in combination, could improve survival as compared with no chelation. It has been standard practice in some settings to treat lead encephalopathy with dimercaprol before giving sodium calcium edetate; however, the systematic evidence reviews did not find adequate evidence to determine whether this combination was more effective than alternative regimens. Penicillamine is used mainly for treating mild-moderate poisoning. The availability and costs of chelating agents bear on the choice of agent for treating individual patients. The guideline development group made the following suggestions: - for mild to moderate poisoning: succimer or penicillamine; - for severe poisoning: sodium calcium edetate alone or in combination with succimer (if an oral medicine can be administered safely) or with dimercaprol. For pregnant women in the first trimester, potential harm to the fetus by lead must be balanced against potential harm by the chelating agent. Limited data were available on the safety of chelation in pregnancy. The United States Food and Drug Administration categorizes the risk of fetal harm as follows: sodium calcium edetate is in category B (experimental animal studies do not demonstrate a risk to the fetus, and there are no adequate studies in pregnant women); succimer and dimercaprol are in category C (experimental animal data suggest a fetal risk); and penicillamine is in category D (known fetal risk) (36). In the second and third trimesters, teratogenicity is no longer a concern. On the basis of the available, but very limited, evidence and practical considerations, it is suggested that chelating agents be used on the same basis as in non-pregnant patients, described above. Ideally, chelation should be administered by or in consultation with medical practitioners experienced in the management of lead poisoning and the management of high-risk pregnancy. While the decision to give chelation usually depends on measurement of the blood lead concentration, there may be circumstances, such as in an outbreak, in which there is strong evidence of widespread exposure to lead. In such circumstances, the guideline development group considered that it would be justified to initiate treatment in a patient of any age with encephalopathy while awaiting confirmation of the blood lead concentration. The end-point of chelation therapy is not clear cut but should include resolution of clinical features of lead poisoning and a reduction in the blood lead concentration that is maintained on reassessment. Increases in blood lead concentration after chelation therapy are common and often related to remobilization of lead from bone stores, although it is also important to be alert to potentially ongoing lead exposure. Some patients may require multiple courses of chelation therapy, and it is important to consider the risk-benefit of such therapy carefully, with input from an expert in the management of lead poisoning. If a patient has had four or five courses of chelation therapy and the blood lead concentration remains persistently > 45 µg/dL and has not fallen significantly from the baseline blood lead concentration, further investigation is strongly advised to determine whether measures to terminate exposure have been ineffective or whether there is a previously unrecognized source of lead exposure. # Integration and implementation of the recommendations in the management of lead poisoning The WHO recommendations for specific aspects of the management of lead exposure should be integrated into an overall management plan for a case or cases of lead poisoning. Decisions about the management of lead poisoning should be made on the basis of the clinical condition of the patient, the circumstances of exposure, the blood lead concentration and the best interests of the patient according to the resources available for treatment. Once lead exposure has been confirmed by measurement of an elevated blood concentration, the steps in management of exposure are: - taking a history to identify the source(s) of exposure; - evaluation of the severity of exposure by clinical examination and investigations; - termination and mitigation of exposure, including improving nutrition; - GI decontamination if indicated; - chelation therapy if indicated; - other supportive measures if required, for example for management of lead encephalopathy; and - follow-up to determine whether further management measures are necessary. # Research implications The systematic reviews of evidence identified very few good-quality studies of the effectiveness of the treatment interventions for lead exposure, and more evidence would increase the certainty of the recommendations. It is recognized, however, that, for some interventions, conducting RCTs would be ethically and/or practically difficult. # Gastrointestinal decontamination Many variables influence the effectiveness of GI decontamination methods after ingestion of lead, and the number of cases of lead ingestion for which GI decontamination could be considered is probably small. This makes it difficult to accumulate a sufficient number of comparable cases for a meaningful study, and it is likely that any evidence of the effectiveness of methods of GI decontamination will continue to be based on case reports or small case series. These would be more useful if the interventions and outcomes were better documented. # Nutritional interventions The available studies on nutritional interventions were conducted with patients who had relatively low blood lead concentrations, and they did not address the question of whether such interventions would be of benefit to patients with severe lead poisoning. In addition, there were no data on the value of combining nutritional supplementation with chelation therapy. This would be of interest, as chelating agents are known to also increase the elimination of some trace elements. More and better studies are needed to determine whether the efficacy of increasing iron or calcium intake in the diet differs from that of supplements, as well as the optimal dose and duration of supplementation. Studies are also needed on the impact of calcium supplementation on outcomes other than blood lead concentration, e.g. neurocognitive development. Studies should also be conducted on whether different age groups, e.g. young children, adolescents or adults, benefit more. # Chelation therapy Data are lacking on the impact of chelation therapy on longer-term outcomes, such as neurocognitive development, behaviour and cardiovascular disease. Also, the threshold blood lead concentration for chelation that is effective in improving outcomes in different age groups has not been established. More data are needed on adherence to treatment in out-patient settings and the link to outcomes. The safety of chelating agents in patients with glucose-6-phosphate dehydrogenase deficiency is not yet established. Better documentation of cases of chelation therapy in pregnancy should be provided. # Considerations for implementation of the guideline WHO recognizes lead as one of 10 key chemicals of public health concern and is working with partners and policy-makers to raise awareness about the importance of preventing and managing lead exposure (22). To support implementation of this guideline, a derivative product will be developed that presents the recommendations in a format that can be more easily used by clinicians and that will be translated into other languages. A specific implementation plan will be developed, and the WHO regional offices and partners will take into account the challenges identified. There are two important challenges to implementation of the guideline. The first is the limited availability of goodquality laboratory services for diagnosis of lead poisoning. WHO is advocating for greater availability of toxicology laboratories as a core capacity requirement under the International Health Regulations (2005). WHO's brief guide on methods for the analysis of lead in blood, published in 2020, is available in all six United Nations languages (12). The second challenge is the limited availability of chelating agents in many low-and middle-income countries, despite the inclusion of the four chelating agents on the WHO Model List of Essential Medicines. WHO will use the guidance to further advocate for greater availability of chelating agents as part of universal health coverage and improvements in the procurement of essential medicines through inter-country cooperation. With regard to nutritional interventions, WHO is developing guidelines on single and multi-nutrient supplementation to improve the health of children and pregnant women. WHO is also working with FAO to update guidance on nutrient requirements for children. WHO's initiative for strengthening and establishing poisons centres will be fully engaged in implementation of the guidelines, as these specialized centres are one of the target users. Working with partners and, as resources permit, training workshops for health-care providers will be organized in selected countries on the identification of risk factors and the diagnosis and management of lead exposure, supplemented by online courses.

Epimer In chemistry, an epimer is a stereoisomer of another compound that has a different configuration at only one of several stereogenic centers. Stereoisomers include enantiomers and diastereomers, both which contain a stereogenic center (excluding geometric isomers, which is a class of diastereomers). For example, the sugars α-glucose and β-glucose are epimers. In α-glucose, the -OH group on the first (anomeric) carbon is in the direction opposite the methylene group. In β-glucose, the -OH group is oriented in the same direction as the methylene group . These two molecules are both epimers and anomers. In this case β-D-glucopyranose and β-D-mannopyranose are epimers because the differ only in the stereochemistry at the 2 position. The hydroxyl group in β-D-glucopyranose is equatorial (in the "plane" of the ring) while in β-D-mannopyranose the 2 hydroxyl group is axial (up from the "plane" of the ring). These two molecules are epimers but not anomers. In chemical nomenclature one of the epimeric pairs is given the prefix epi- for example in quinine and epi-quinine. When the pairs are enantiomers the prefix becomes ent-.

Calcitonin (injection) # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Calcitonin (injection) is a calcitonin receptor agonist that is FDA approved for the treatment of Paget's disease of bone, hypercalcemia, and postmenopausal osteoporosis. Common adverse reactions include flushing, injection site reaction, nausea, arthralgia, epistaxis, rhinitis, and sinusitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Indications ### Treatment of Paget's disease of bone Miacalcin injection is indicated for the treatment of symptomatic Paget's disease of bone in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary hydroxyproline excretion. There is no evidence that the prophylactic use of calcitonin is beneficial in asymptomatic patients. Miacalcin injection should be used only in patients who do not respond to alternative treatments or for whom such treatments are not suitable (e.g., patients for whom other therapies are contraindicated or for patients who are intolerant or unwilling to use other therapies). ### Treatment of Hypercalcemia Miacalcin injection is indicated for the early treatment of hypercalcemic emergencies, along with other appropriate agents, when a rapid decrease in serum calcium is required, until more specific treatment of the underlying disease can be accomplished. It may also be added to existing therapeutic regimens for hypercalcemia such as intravenous fluids and furosemide, oral phosphate or corticosteroids, or other agents. ### Treatment of Postmenopausal Osteoporosis Miacalcin injection is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. The evidence of efficacy for calcitonin injection is based on increases in total body calcium observed in clinical trials. Fracture reduction efficacy has not been demonstrated. Miacalcin injection should be reserved for patients for whom alternative treatments are not suitable (e.g., patients for whom other therapies are contraindicated or for patients who are intolerant or unwilling to use other therapies). ### Important Limitations of Use Due to the possible association between malignancy and calcitonin use, the need for continued therapy should be re-evaluated on a periodic basis. ## Dosage ### Paget's disease of bone The recommended dose of Miacalcin injection for treatment of symptomatic Paget's disease of bone is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly. ### Hypercalcemia The recommended starting dose of Miacalcin injection for early treatment ofhypercalcemiais 4 International Units/kg body weight every 12 hours by subcutaneous or intramuscular injection. If the response to this dose is not satisfactory after one or two days, the dose may be increased to 8 International Units/kg every 12 hours. If the response remains unsatisfactory after two more days, the dose may be further increased to a maximum of 8 International Units/kg every 6 hours. ### Postmenopausal Osteoporosis The recommended dose of Miacalcin injection for treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly. The minimum effective dose of Miacalcin injection for the prevention of vertebral bone mineral density loss has not been established. ### Preparation and Administration Visually inspect Miacalcin vials. Miacalcin injection is a clear, colorless, solution. If the solution is not clear and colorless, or contains any particles, or if the vial is damaged, do not administer the solution. If the volume of Miacalcin injection to be injected exceeds 2 mL, intramuscular injection is preferable and the total dose should be distributed across multiple sites of injection. Instruct patients to use sterile injection technique when administering Miacalcin injection, and to dispose of needles properly. ### Recommendations for Calcium and Vitamin D Supplementation Patients who use Miacalcin injection for treatment of postmenopausal osteoporosis should receive adequate calcium (at least 1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Calcitonin in adult patients. ### Non–Guideline-Supported Use - Cancer pain - Subcutaneous 400 international units per day by continuous infusion - Prophylaxis of fracture of bone - osteoporosis due to corticosteroids - 100 international units every other day subcutaneously # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Calcitonin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Calcitonin in pediatric patients. # Contraindications Hypersensitivity to calcitonin or any of the excipients. Reactions have included anaphylaxis with death, bronchospasm, and swelling of the tongue or throat. # Warnings ### Hypersensitivity Reactions Serious hypersensitivity reactions have been reported in patients receiving Miacalcin injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. Appropriate medical support and monitoring measures should be readily available when Miacalcin injection is administered. If anaphylaxis or other severe hypersensitivity/allergic reactions occur, initiate appropriate treatment. For patients with suspected hypersensitivity to calcitonin, skin testing should be considered prior to treatment utilizing a dilute, sterile solution of Miacalcin injection. Healthcare providers may wish to refer patients who require skin testing to an allergist. A detailed skin testing protocol is available from the Medical Services Department of Novartis Pharmaceuticals Corporation. ### Hypocalcemia Hypocalcemia associated with tetany (i.e., muscle cramps, twitching) and seizure activity has been reported with Miacalcin injection therapy. Hypocalcemia must be corrected before initiating therapy. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients at risk for hypocalcemia, provisions for parenteral calcium administration should be available during the first several administrations of calcitonin and serum calcium and symptoms of hypocalcemia should be monitored. Use of Miacalcin injection for the treatment of Paget’s disease or postmenopausal osteoporosis is recommended in conjunction with an adequate intake of calcium and vitamin D. ### Malignancy In a meta-analysis of 21 randomized, controlled clinical trials with calcitonin (nasal spray or investigational oral formulations), the overall incidence of malignancies reported was higher among calcitonin-treated patients (4.1%) compared with placebo-treated patients (2.9%). This suggests an increased risk of malignancies in calcitonin-treated patients compared to placebo-treated patients. It is not possible to exclude an increased risk when calcitonin is administered long-term subcutaneously, intramuscularly, or intravenously. The benefits for the individual patient should be carefully considered against possible risks. ### Antibody Formation Circulating antibodies to calcitonin have been reported with Miacalcin injection. The possibility of antibody formation should be considered in any patient with an initial response to Miacalcin injection who later stops responding to treatment. ### Urine Sediment Abnormalities Coarse granular casts and casts containing renal tubular epithelial cells were reported in young adult volunteers at bed rest who were given injectable calcitonin to study the effect of immobilization on osteoporosis. There was no other evidence of renal abnormality and the urine sediment normalized after calcitonin was stopped. Periodic examinations of urine sediment should be considered. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of calcitonin injection was assessed in open-label trials several months to two years in duration. The most common adverse reactions are discussed below. - Nausea: Nausea with or without vomiting has been noted in about 10% of patients treated with calcitonin. It is most evident when treatment is first initiated and tends to decrease or disappear with continued administration. - Dermatologic Reactions: Local inflammatory reactions at the site of subcutaneous or intramuscular injection have been reported in about 10% of patients. Flushing of face or hands occurred in about 2%-5% of patients. Skin rashes and pruritus of the ear lobes have also been reported. - Other Adverse Reactions: Nocturia, feverish sensation, pain in the eyes, poor appetite, abdominal pain, pedal edema, and salty taste have been reported in patients treated with calcitonin injection. A meta-analysis of 21 randomized, controlled clinical trials with calcitonin (nasal spray or investigational oral formulations) was conducted to assess the risk of malignancies in calcitonin-treated patients compared to placebo-treated patients. The trials in the meta-analysis ranged in duration from 6 months to 5 years and included a total of 10883 patients (6151 treated with calcitonin and 4732 treated with placebo). The overall incidence of malignancies reported in these 21 trials was higher among calcitonin-treated patients (254/6151 or 4.1%) compared with placebo-treated patients (137/4732 or 2.9%). Findings were similar when analyses were restricted to the 18 nasal spray only trials . The meta-analysis results suggest an increased risk of overall malignancies in calcitonin-treated patients compared to placebo-treated patients when all 21 trials are included and when the analysis is restricted to the 18 nasal spray only trials (see Table 1). It is not possible to exclude an increased risk when calcitonin is administered by the subcutaneous, intramuscular, or intravenous route because these routes of administration were not investigated in the meta-analysis. The increased malignancy risk seen with the meta-analysis was heavily influenced by a single large 5-year trial, which had an observed risk difference of 3.4% . Imbalances in risks were still observed when analyses excluded basal cell carcinoma (see Table 1); the data were not sufficient for further analyses by type of malignancy. A mechanism for these observations has not been identified. Although a definitive causal relationship between calcitonin use and malignancies cannot be established from this meta-analysis, the benefits for the individual patient should be carefully evaluated against all possible risks. ## Postmarketing Experience Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been reported during post-approval use of Miacalcin injection. - Allergic / Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving calcitonin injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. - Skin and subcutaneous tissue disorders: Urticaria - Hypocalcemia: Hypocalcemia with tetany (i.e. muscle cramps, twitching) and seizure activity have been reported. - Body as a Whole: influenza-like symptoms, fatigue, edema (facial, peripheral, and generalized) - Musculoskeletal: arthralgia, musculoskeletal pain - Cardiovascular: hypertension - Gastrointestinal: abdominal pain, diarrhea - Urinary System: polyuria - Nervous System: dizziness, headache, paresthesia, tremor - Vision: visual disturbance ### Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of Miacalcin may trigger the development of anti-calcitonin antibodies. Circulating antibodies to calcitonin after 2-18 months of treatment have been reported in about one-half of the patients with Paget’s disease in whom antibody studies were done. In some cases, high antibody titers are found; these patients usually will have a loss of response to treatment. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies among different calcitonin products may be misleading. # Drug Interactions No formal drug interaction studies have been performed with Miacalcin injection. Concomitant use of calcitonin and lithium may lead to a reduction in plasma lithium concentrations due to increased urinary clearance of lithium. The dose of lithium may require adjustment. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Risk Summary There are no adequate and well-controlled studies in pregnant women. Miacalcin injection should be used during pregnancy only if the potential benefit justifies the use as compared with potential risks to the patient and fetus. Based on animal data, Miacalcin is predicted to have low probability of increasing the risk of adverse developmental outcomes above background risk. calcitonin has been shown to cause a decrease in fetal birth weights in rabbits when given by subcutaneous injection in doses 4-18 times the parenteral dose recommended for human use (of 54 International Units/m2). No embryo/fetal toxicities related to Miacalcin were reported from maternal subcutaneous daily doses in rats up to 80 International Units /kg/day from gestation day 6 to 15. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Calcitonin (injection) in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Calcitonin (injection) during labor and delivery. ### Nursing Mothers It is not known whether this drug is excreted in human milk. No studies have been conducted to assess the impact of Miacalcin on milk production in humans, its presence in human breast milk, or its effects on the breastfed child. Because many drugs are excreted in human milk, caution should be exercised when Miacalcin is administered to a nursing woman. Calcitonin has been shown to inhibit lactation in rats. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use Clinical studies of Miacalcin injection did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Calcitonin (injection) with respect to specific gender populations. ### Race There is no FDA guidance on the use of Calcitonin (injection) with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Calcitonin (injection) in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Calcitonin (injection) in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Calcitonin (injection) in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Calcitonin (injection) in patients who are immunocompromised. # Administration and Monitoring ### Administration - Subcutaneous - Intramuscular ### Monitoring - Serious hypersensitivity reactions have been reported in patients receiving Miacalcin injection, e.g., bronchospasm, swelling of the tongue or throat, ]]anaphylactic shock]], and death due to anaphylaxis. Appropriate medical support and monitoring measures should be readily available when Miacalcin injection is administered. - In patients at risk for hypocalcemia, provisions for parenteral calcium administration should be available during the first several administrations of calcitonin and serum calcium and symptoms of hypocalcemia should be monitored. # IV Compatibility There is limited information regarding the compatibility of Calcitonin (injection) and IV administrations. # Overdosage The pharmacologic actions of Miacalcin injection suggest that hypocalcemic tetany could occur in overdose. Therefore, provisions for parenteral administration of calcium should be available for the treatment of overdose. A dose of calcitonin l000 International Units subcutaneously may produce nausea and vomiting. Doses of 32 International Units per kg per day for 1-2 days demonstrate no other adverse effects. Data on chronic high-dose administration are insufficient to assess toxicity. # Pharmacology There is limited information regarding Calcitonin (injection) Pharmacology in the drug label. ## Mechanism of Action calcitonin is a calcitonin receptor agonist. calcitonin acts primarily on bone, but direct renal effects and actions on the gastrointestinal tract are also recognized. calcitonin appears to have actions essentially identical to calcitonins of mammalian origin, but its potency per mg is greater and it has a longer duration of action. The actions of calcitonin on bone and its role in normal human bone physiology are still not completely elucidated, although calcitonin receptors have been discovered in osteoclasts and osteoblasts. ## Structure Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. Miacalcin (calcitonin) injection, synthetic is a synthetic polypeptide of 32 amino acids in the same linear sequence that is found in calcitonin of salmon origin. This is shown by the following graphic formula: It is provided in sterile solution for subcutaneous or intramuscular injection. Each milliliter contains: calcitonin 200 International Units. Inactive Ingredients (per mL): acetic acid, USP, 2.25 mg; phenol, USP, 5.0 mg; sodium acetate trihydrate, USP, 2.0 mg; sodium chloride, USP, 7.5 mg; water for injection, USP. The activity of Miacalcin injection is stated in International Units based on bioassay in comparison with the International Reference Preparation of calcitonin for Bioassay, distributed by the National Institute for Biological Standards and Control, Holly Hill, London. ## Pharmacodynamics Single injections of calcitonin caused a marked transient inhibition of the ongoing bone resorptive process. With prolonged use, there is a persistent, smaller decrease in the rate of bone resorption. Histologically, this is associated with a decreased number of osteoclasts and an apparent decrease in their resorptive activity. In healthy adults, who have a relatively low rate of bone resorption, the administration of exogenous calcitonin results in decreases in serum calcium within the limits of the normal range. In healthy children and in patients whose bone resorption is more rapid, decreases in serum calcium are more pronounced in response to calcitonin. Studies with injectable calcitonin show increases in the excretion of filtered phosphate, calcium, and sodium by decreasing their tubular reabsorption. Some evidence from studies with injectable preparations suggests that calcitonin may have effects on the gastrointestinal tract. Short-term administration of injectable calcitonin results in marked transient decreases in the volume and acidity of gastric juice and in the volume and the trypsin and amylase content of pancreatic juice. Whether these effects continue to be elicited after each injection of calcitonin during chronic therapy has not been investigated. ## Pharmacokinetics The absolute bioavailability of calcitonin is approximately 66% and 71% after intramuscular or subcutaneous injection, respectively. After subcutaneous administration, peak plasma levels are reached in approximately 23 minutes. The terminal half-life is approximately 58 minutes for intramuscular administration and 59 to 64 minutes for subcutaneous administration. The apparent volume of distribution is 0.15-0.3 L/kg. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility The incidence of pituitary adenomas was increased in rats after one and two years of subcutaneous exposure to synthetic calcitonin. The significance of this finding to humans is unknown because pituitary adenomas are very common in rats as they age, the pituitary adenomas did not transform into metastatic tumors, there were no other clear treatment- related neoplasms, and synthetic calcitonin related neoplasms were not observed in mice after two years of dosing. Rat findings: The only clear neoplastic finding in rats dosed subcutaneously with calcitonin was an increase in the incidence of pituitary adenomas in male Fisher 344 rats and female Sprague Dawley rats after one year of dosing and male Sprague Dawley rats dosed for one and two years. In female Sprague Dawley rats, the incidence of pituitary adenomas after two years was high in all treatment groups (between 80% and 92% including the control groups) such that a treatment-related effect could not be distinguished from natural background incidence. The lowest dose in male Sprague Dawley rats that developed an increased incidence of pituitary adenomas after two years of dosing (1.7 International Units/kg/day) is approximately 1/6th of the maximum recommended subcutaneous dose in humans (100 International Units/day) based on body surface area conversion between rats and humans. The findings suggest that calcitonin reduced the latency period for development of non-functioning pituitary adenomas. Mouse findings: No carcinogenicity potential was evident in male or female mice dosed subcutaneously for two years with synthetic calcitonin at doses up to 800 International Units/kg/day. The 800 International Units/kg/day dose is approximately 39 times the maximum recommended subcutaneous dose in humans (100 International Units/day) based on body surface area conversion between mice and humans. Synthetic calcitonin tested negative for mutagenicity using Salmonella typhimurium (5 strains) and Escherichia coli (2 strains), with and without rat liver metabolic activation, and was not clastogenic in a chromosome aberration test in Chinese Hamster V79 cells. There was no evidence that calcitonin was clastogenic in the in vivo mouse micronucleus test. Effects of calcitonin on fertility have not been assessed in animals. # Clinical Studies ### Paget's disease of bone The trials used for the basis of approval for calcitonin injection for treatment of Paget's disease of bone were conducted in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary hydroxyproline excretion. In open-label clinical trials of several months to two years duration with historical controls, biochemical abnormalities were substantially improved (more than 30% reduction) in about 2/3 of patients studied and bone pain was improved in a similar fraction. A small number of documented instances of reversal of neurologic deficits have occurred, including improvement in the basilar compression syndrome, and improvement of spinal cord and spinal nerve lesions. There is too little experience to predict the likelihood of improvement of any given neurologic lesion. Hearing loss is improved infrequently (4 of 29 patients studied by audiometry). Patients with increased cardiac output due to extensive Paget's disease of bone have had measured decreases in cardiac output while receiving calcitonin. The number of treated patients in this category is too small to predict how likely such a result will be. There is no evidence that the prophylactic use of calcitonin is beneficial in asymptomatic patients. ### Hypercalcemia In four open-label clinical trials enrolling 53 patients, calcitonin has been shown to lower elevated serum calcium levels of patients with carcinoma (with or without metastases), multiple myeloma, and primary hyperparathyroidism (lesser response). These patients were treated with calcitonin only when other methods of lowering serum calcium (hydration, oral phosphate, corticosteroids) were unsuccessful or unsuitable. With patients’ pre-therapy serum calcium levels as controls, reduction in serum calcium was evident within 1-2 hours of administration. The peak effect occurred within 24-48 hours of injection and administration of calcitonin every 12 hours maintained a hypocalcemic effect for approximately 5-8 days, the time period evaluated for most patients in the clinical trials. The average reduction of 8-hour post-injection serum calcium was approximately 9% (2-3 mg/dL). Patients with higher values of serum calcium tended to show greater reductions during calcitonin treatment. ### Postmenopausal Osteoporosis The trials used for the basis of approval for calcitonin injection for treatment of postmenopausal osteoporosis were two randomized, open-label, 2-year studies in postmenopausal women 50–74 years of age with total body calcium <85% of expected normal, and vertebral osteopenia (by x-ray criteria) and/or at least one atraumatic compression fracture. The primary efficacy endpoint was total body calcium measured by neutron activation analysis. Patients were randomized to calcitonin injection 100 International Units daily (subcutaneously or intramuscularly) at bedtime, or control. All subjects received daily supplements of 1200 mg calcium carbonate and 400 International Units of vitamin D. In both studies, total body calcium increased from baseline with calcitonin therapy at 1 year, followed by a trend to decreasing total body calcium (still above baseline) at 2 years. Thoracic and lumbar spine X-rays (AP/lateral) were obtained yearly. For the two studies combined (34 calcitonin and 35 control subjects), in the first year there was a total of 6 new vertebral compression fractures in the calcitonin group and 5 in the control group. In the second year there were 7 new fractures in each group. No evidence currently exists to indicate whether Miacalcin injection decreases the risk of osteoporotic fracture. A controlled study, which was prematurely discontinued, failed to demonstrate any benefit of calcitonin on fracture rate. No adequate controlled trials have examined the effect of calcitonin injection on vertebral bone mineral density beyond 1 year of treatment. Therefore, the minimum effective dose of Miacalcin injection for prevention of vertebral bone mineral density loss has not been established. In clinical studies of postmenopausal osteoporosis, bone biopsy and radial bone mass assessments at baseline and after 26 months of daily injectable calcitonin indicate that calcitonin therapy results in the formation of normal bone. # How Supplied How Supplied Miacalcin (calcitonin) injection, synthetic is available as a sterile solution in individual 2 mL multi-dose vials containing 200 International Units per mL ## Storage Store in refrigerator between 2°C-8°C (36°F-46°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Instruct patients and other persons who may administer Miacalcin injection in sterile injection technique. Also instruct patients to dispose of needles properly. Inform patients of the potential increase in risk of malignancy. Advise patients with postmenopausal osteoporosis or Paget's disease of bone to maintain an adequate calcium (at least 1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day) intake. Instruct patients to seek emergency medical help or go to the nearest hospital emergency room right away if they develop any signs or symptoms of a serious allergic reaction. # Precautions with Alcohol Alcohol-Calcitonin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Miacalcin # Look-Alike Drug Names There is limited information regarding Calcitonin (injection) Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Gingko biloba The Ginkgo (Ginkgo biloba; in Chinese 銀杏, pinyin romanization, yín xìng), frequently misspelled as "Gingko", and also known as the Maidenhair Tree after Adiantum, is a unique tree with no close living relatives. The ginkgo is classified in its own division, the Ginkgophyta, comprising the single class Ginkgoopsida, order Ginkgoales, family Ginkgoaceae, genus Ginkgo and is the only extant species within this group. It is one of the best-known examples of a living fossil, because Ginkgoales are not known from the fossil record after the Pliocene. For centuries it was thought to be extinct in the wild, but is now known to grow in at least two small areas in Zhejiang province in Eastern China, in the Tian Mu Shan Reserve. However, recent studies indicate high genetic uniformity among ginkgo trees from these areas, arguing against a natural origin of these populations. Therefore, it has been suggested that the ginkgo trees in these areas appear to have been planted and preserved by Chinese monks over a period of about 1000 years. Whether native ginkgo populations still exist has not been demonstrated unequivocally and is therefore uncertain. The relationship of Ginkgo to other plant groups remains uncertain. It has been placed loosely in the divisions Spermatophyta and Pinophyta, but no consensus has been reached. Since Ginkgo seeds are not protected by an ovary wall, it can morphologically be considered a gymnosperm. The apricot-like structures produced by female ginkgo trees are technically not fruits, but are the seeds having a shell that consists of a soft and fleshy section (the sarcotesta), and a hard section (the sclerotesta). # Description Ginkgos are very large trees, normally reaching a height of 20–35 m (66-115 feet), with some specimens in China being over 50 m (164 feet). The tree has an angular crown and long, somewhat erratic branches, and is usually deep rooted and resistant to wind and snow damage. Young trees are often tall and slender, and sparsely branched; the crown becomes broader as the tree ages. During autumn, the leaves turn a bright yellow, then fall, sometimes within a short space of time (1–15 days). A combination of resistance to disease, insect-resistant wood and the ability to form aerial roots and sprouts makes ginkgos very long-lived, with some specimens claimed to be more than 2,500 years old: A 3,000 year-old ginkgo has been reported in Shandong province in China. Some old Ginkgos produce aerial roots, known as chi chi (Japanese; "nipples") or zhong-ru (Mandarin Chinese), which form on the undersides of large branches and grow downwards. Chi chi growth is very slow, and may take hundreds of years to occur. The function, if any, of these thick aerial roots is unknown. ## Stem Ginkgo branches grow in length by growth of shoots with regularly spaced leaves, as seen on most trees. From the axils of these leaves, "spur shoots" (also known as short shoots) develop on second-year growth. Short shoots have very short internodes (so that several years' growth may only extend them by a centimeter or two) and their leaves are ordinarily unlobed. They are short and knobby, and are arranged regularly on the branches except on first-year growth. Because of the short internodes, leaves appear to be clustered at the tips of short shoots, and reproductive structures are formed only on them (see picture to above left— seeds and leaves are visible on short shoots). In Ginkgos, as in other plants that possess them, short shoots allow the formation of new leaves in the older parts of the crown. After a number of years, a short shoot may change into a long (ordinary) shoot, or vice versa. ## Leaves The leaves are unique among seed plants, being fan-shaped with veins radiating out into the leaf blade, sometimes bifurcating (splitting) but never anastomosing to form a network. Two veins enter the leaf blade at the base and fork repeatedly in two; this is known as dichotomous venation. The leaves are usually 5-10 cm (2-4 inches), but sometimes up to 15 cm (6 inches) long. The old popular name "Maidenhair tree" is because the leaves resemble some of the pinnae of the Maidenhair fern Adiantum capillus-veneris. Leaves of long shoots are usually notched or lobed, but only from the outer surface, between the veins. They are borne both on the more rapidly-growing branch tips, where they are alternate and spaced out, and also on the short, stubby spur shoots, where they are clustered at the tips. ## Reproduction Ginkgos are dioecious, with separate sexes, some trees being female and others being male. Male plants produce small pollen cones with sporophylls each bearing two microsporangia spirally arranged around a central axis. Female plants do not produce cones. Two ovules are formed at the end of a stalk, and after pollination, one or both develop into seeds. The seed is 1.5-2 cm long. Its fleshy outer layer (the sarcotesta) is light yellow-brown, soft, and fruit-like. It is attractive in appearance, but contains butanoic acid and smells like rancid butter (which contains the same chemical) or feces when fallen. Beneath the sarcotesta is the hard sclerotesta (what is normally known as the "shell" of the seed) and a papery endotesta, with the nucellus surrounding the female gametophyte at the center. The fertilization of ginkgo seeds occurs via motile sperm, as in cycads, ferns, mosses and algae. The sperm are large (about 250-300 micrometres) and are similar to the sperm of cycads, which are slightly larger. Ginkgo sperm were first discovered by the Japanese botanist Sakugoro Hirase in 1896. The sperm have a complex multi-layered structure, which is a continuous belt of basal bodies that form the base of several thousand flagella which actually have a cilia-like motion. The flagella/cilia apparatus pulls the body of the sperm forwards. The sperm have only a tiny distance to travel to the archegonia, of which there are usually two or three. Two sperm are produced, one of which successfully fertilizes the ovule. Although it is widely held that fertilization of ginkgo seeds occurs just before or after they fall in early autumn, embryos ordinarily occur in seeds just before and after they drop from the tree. # Distribution and habitat Although Ginkgo biloba and other species of the genus were once widespread throughout the world, the tree currently occurs in the wild only in the northwest of Zhejiang province in the Tianmu Shan mountain reserve in eastern China, but even its status as a naturally occurring species there is questionable. In other areas of China it has been long cultivated and it is common in the southern third of the country. It has also been commonly cultivated in North America for over 200 years, but during that time it has never become significantly naturalised. Where it occurs in the wild it is found infrequently in deciduous forests and valleys on acidic loess (i.e. fine, silty soil) with good drainage. The soil it inhabits is typically in the pH range of 5 to 5.5. # Taxonomy and naming The species was initially described by the father of taxonomy Linnaeus in 1771, the specific epithet biloba derived from the Latin bis 'two' and loba 'lobed', referring to the shape of the leaves. ## Etymology The older Chinese name for this plant is 銀果 yínguǒ ('silver fruit'). The most usual names today are 白果 bái guǒ ('white fruit') and 銀杏 yínxìng ('silver apricot'). The former name was borrowed directly in Vietnamese (as bạch quả). The latter name was borrowed in Japanese (as ぎんなん "ginnan") and Korean (as 은행 "eunhaeng"), when the tree itself was introduced from China. The scientific name Ginkgo appears to be due to a process akin to folk etymology. Chinese characters typically have multiple pronunciations in Japanese, and the characters 銀杏 used for ginnan can also be mistakenly pronounced ginkyō. Engelbert Kaempfer, the first Westerner to see the species in 1690, wrote down this incorrect pronunciation in his Amoenitates Exoticae (1712); his y was misread as a g, and the misspelling stuck. # Prehistory The Ginkgo is a living fossil, with fossils recognisably related to modern Ginkgo from the Permian, dating back 270 million years. They diversified and spread throughout Laurasia during the middle Jurassic and Cretaceous, but became much rarer thereafter. By the Paleocene, Ginkgo adiantoides was the only Ginkgo species left in the Northern Hemisphere (but see below) with a markedly different (but not well-documented) form persisting in the Southern Hemisphere, and at the end of the Pliocene Ginkgo fossils disappeared from the fossil record everywhere apart from a small area of central China where the modern species survived. It is in fact doubtful whether the Northern Hemisphere fossil species of Ginkgo can be reliably distinguished; given the slow pace of evolution in the genus, there may have been only 2 in total; what is today called G. biloba (including G. adiantoides), and G. gardneri from the Paleocene of Scotland. At least morphologically, G. gardneri and the Southern Hemisphere species are the only known post-Jurassic taxa that can be unequivocally recognised, the remainder may just as well have simply been ecotypes or subspecies. The implications would be that G. biloba had occurred over an extremely wide range, had remarkable genetic flexibility and though evolving genetically never showed much speciation. The occurrence of G. gardneri, it seems a Caledonian mountain endemic, and the somewhat greater diversity on the Southern Hemisphere, suggests that old mountain ranges on the Northern Hemisphere could hold other, presently undiscovered, fossil Ginkgo species. Since the distribution of Ginkgo was already relictual in late prehistoric times, the chances that ancient DNA from subfossils can shed any light on this problem seem remote. While it may seem improbable that a species may exist as a contiguous entity for many millions of years, many of the Ginkgo's life-history parameters fit. These are: extreme longevity; slow reproduction rate; (in Cenozoic and later times) a wide, apparently contiguous, but steadily contracting distribution coupled with, as far as can be demonstrated from the fossil record, extreme ecological conservatism (being restricted to light soils around rivers); and a low population density. Ginkgo has been used for classifying plants with leaves that have more than four veins per segment, while Baiera for those with less than four veins per segment. Sphenobaiera has been used to classify plants with a broadly wedge-shaped leaf that lacks a distinct leaf stem. Trichopitys is distinguished by having multiple-forked leaves with cylindrical (not flattened) thread-like ultimate divisions; it is one of the earliest fossils ascribed to the Ginkgophyta. # Cultivation and uses Ginkgo has long been cultivated in China; some planted trees at temples are believed to be over 1,500 years old. The first record of Europeans encountering it is in 1690 in Japanese temple gardens, where the tree was seen by the German botanist Engelbert Kaempfer. Because of its status in Buddhism and Confucianism, the Ginkgo is also widely planted in Korea and parts of Japan; in both areas, some naturalization has occurred, with Ginkgos seeding into natural forests. In some areas, most intentionally planted Ginkgos are male cultivars grafted onto plants propagated from seed, because the male trees will not produce the malodorous seeds. The popular cultivar 'Autumn Gold' is a clone of a male plant. Ginkgos adapt well to the urban environment, tolerating pollution and confined soil spaces. They rarely suffer disease problems, even in urban conditions, and are attacked by few insects. For this reason, and for their general beauty, ginkgos are excellent urban and shade trees, and are widely planted along many streets. The ginkgo is the official tree of the city of Kumamoto, and two leaves form the symbol of the University of Tokyo, the main campus of which is famous for its numerous ginkgos. Ginkgos are also popular subjects for growing as penjing and bonsai; they can be kept artificially small and tended over centuries. Furthermore, the trees are easy to propagate from seed. Extreme examples of the Ginkgo's tenacity may be seen in Hiroshima, Japan, where four trees growing between 1–2 km from the 1945 atom bomb explosion were among the few living things in the area to survive the blast (photos & details). While almost all other plants (and animals) in the area were destroyed, the ginkgos, though charred, survived and were soon healthy again. The trees are alive to this day. ## Culinary use The nut-like gametophytes inside the seeds are particularly esteemed in Asia, and are a traditional Chinese food. Ginkgo nuts are used in congee, and are often served at special occasions such as weddings and the Chinese New Year (as part of the vegetarian dish called Buddha's delight). In Chinese culture, they are believed to have health benefits; some also consider them to have aphrodisiac qualities. Japanese cooks add Ginkgo seeds (called ginnan) to dishes such as chawanmushi, and cooked seeds are often eaten along with other dishes. The seeds are available canned, sold as "White Nuts", and can be found in many Asian food stores in the West. When eaten by children, in large quantities (over 5 seeds a day), or over a long period of time, the raw gametophyte (meat) of the seed can cause poisoning by MPN (4-methoxypyridoxine). MPN is heat-stable. Studies have demonstrated that convulsions caused by MPN can be prevented or terminated with pyridoxine. Some people are sensitive to the chemicals in the sarcotesta, the outer fleshy coating. These people should handle the seeds with care when preparing the seeds for consumption, wearing disposable gloves. The symptoms are dermatitis or blisters similar to that caused by contact with poison-ivy. However, seeds with the fleshy coating removed are perfectly safe to handle. ## Medicinal uses The extract of the Ginkgo leaves contains flavonoid glycosides and terpenoids (ginkgolides, bilobalides) and has been used pharmaceutically. It has many alleged nootropic properties, and is mainly used as memory and concentration enhancer, and anti-vertigo agent. However, studies differ about its efficacy. Some controversy has arisen over the conclusions drawn by some studies that were allegedly funded by a firm which marketed Ginkgo. Slate, an Internet-based magazine owned by The Washington Post Company, reported in April 2007: In 2002, a long-anticipated paper appeared in JAMA (Journal of the American Medical Association) titled "Ginkgo for memory enhancement: a randomized controlled trial." This Williams College study, sponsored by the National Institute on Aging rather than Schwabe, examined the effects of ginkgo consumption on healthy volunteers older than 60. The conclusion, now cited in the National Institutes of Health's ginkgo fact sheet, said: "When taken following the manufacturer's instructions, ginkgo provides no measurable benefit in memory or related cognitive function to adults with healthy cognitive function." Out of the many conflicting research results, Ginkgo extract may have three effects on the human body: improvement in blood flow (including microcirculation in small capillaries) to most tissues and organs; protection against oxidative cell damage from free radicals; and blockage of many of the effects of platelet-activating factor (platelet aggregation, blood clotting) that have been related to the development of a number of cardiovascular, renal, respiratory and CNS (Central Nervous System) disorders. Ginkgo can be used for intermittent claudication. According to some studies, in a few cases, Ginkgo can significantly improve attention in healthy individuals. The effect is almost immediate and reaches its peak in 2.5 hours after the intake. A 2004 conference paper summarizes how various trials indicate that Ginkgo shows promise in the treatment of Alzheimer's disease, though a 2008 study found it ineffective at treating dementia. There have been studies which suggest there may be a link between ginkgo and the easing of the symptoms of tinnitus. Ginkgo is commonly added to energy drinks, but the amount is typically so low it does not produce a noticeable effect, except perhaps via a placebo effect from Ginkgo being listed on the label. Ginkgo supplements are usually taken in the range of 40–200 mg per day. A 2003 study conducted by the Department of Dermatology, Postgraduate Institute of Medical Education and Research in Chandigarh, India concluded that Ginkgo is an effective treatment for arresting the development of vitiligo. ### Side effects Ginkgo may have some undesirable effects, especially for individuals with blood circulation disorders and those taking anticoagulants such as ibuprofen, aspirin, or warfarin, although recent studies have found that ginkgo has little or no effect on the anticoagulant properties or pharmacodynamics of warfarin. Ginkgo should also not be used by people who are taking certain types of antidepressants (MAOIs and SSRIs) or by pregnant women without first consulting a doctor. Ginkgo side effects and cautions include: possible increased risk of bleeding, gastrointestinal discomfort, nausea, vomiting, diarrhea, headaches, dizziness, heart palpitations, and restlessness. If any side effects are experienced, consumption should be stopped immediately.

Dihydrogen monoxide hoax The dihydrogen monoxide hoax involves listing negative effects of water under an unfamiliar scientific name, then asking individuals to help control the seemingly dangerous substance (caused by most people knowing the word "monoxide" as part of the name of the poisonous gas "carbon monoxide"). The hoax is designed to illustrate how the lack of scientific knowledge and an exaggerated analysis can lead to misplaced fears. Dihydrogen monoxide, shortened to DHMO, is a scientific name for water that, while technically correct, is almost never employed. The hoax was apparently created by Eric Lechner, Lars Norpchen and Matthew Kaufman, housemates while attending UC Santa Cruz in 1990, revised by Craig Jackson in 1994, and brought to widespread public attention in 1997 when Nathan Zohner, a 14-year-old student, gathered petitions to ban "DHMO" as the basis of his science project, titled "How Gullible Are We?" # Original Web appearance The first appearance on the web was attributed by the Pittsburgh Post-Gazette to the so-called Coalition to Ban Dihydrogen Monoxide, a hoax organization started by Craig Jackson following the initial newsgroup discussions. The site included the following "warning": Dihydrogen monoxide: - is called "hydroxyl acid", the substance is the major component of acid rain. - contributes to the "greenhouse effect". - may cause severe burns. - contributes to the erosion of our natural landscape. - accelerates corrosion and rusting of many metals. - may cause electrical failures and decreased effectiveness of automobile brakes. - has been found in excised tumors of terminal cancer patients. Despite the danger, dihydrogen monoxide is often used: - as an industrial solvent and coolant. - in nuclear power plants. - in the production of styrofoam. - as a fire retardant. - in many forms of cruel animal research. - in the distribution of pesticides. Even after washing, produce remains contaminated by this chemical. - as an additive in certain "junk-foods" and other food products. The original webpage is no longer accessible, but a October 31 1996 version has been mirrored by The Internet Archive. # Terminology "Dihydrogen monoxide" may sound dangerous to those with a limited knowledge of chemistry or who hold to an ideal of a "chemical-free" life. The term monoxide has negative connotations due to its being part of the name of the highly poisonous carbon monoxide. The water molecule has the chemical formula H2O, meaning each molecule of water is composed of two hydrogen atoms and one oxygen atom. Literally, the term "dihydrogen monoxide" means "two hydrogen, one oxygen", consistent with its molecular formula: the prefix di- in dihydrogen means "two", the prefix mono- in monoxide means "one", and an oxide is a compound that contains one or more oxygen atoms. The use of numerical prefixes is typical nomenclature for compounds formed by covalent bonds, which are present in water. The prefix for the first named element is often dropped if the elements involved commonly form only one compound, or even if the number of atoms of the first-named element is the same in all the compounds of the two (or more) elements. Thus H2S is often simply called hydrogen sulfide, and lithium oxide is a common name for Li2O. However, the names dihydrogen sulfide, dilithium oxide, and dilithium monoxide are also commonly used both in industry and in universities. The mono- prefix is often dropped for the second-named element if it is the only common compound the elements form. Thus for instance the IUPAC name of H2S is hydrogen sulfide rather than hydrogen monosulfide. However, since carbon and oxygen can form several compounds (carbon monoxide, carbon dioxide, tricarbon dioxide, and dicarbon monoxide), the mono- prefix is kept, as it is with silicon monoxide and silicon dioxide. Indeed, hydrogen and oxygen do form another common compound, H2O2. (Using prefix nomenclature, H2O2 would be called dihydrogen dioxide—also known as hydrogen peroxide.) Thus, keeping the mono- in dihydrogen monoxide does serve to distinguish it from another compound. Water has a regular scientific or systematic name of hydrogen oxide, as well as an alkali name of hydrogen hydroxide and several acid names such as hydroxic acid, hydroxylic acid, and hydroxilic acid. Incidentally, the term "hydroxyl acid" used in the original hoax is slightly incorrect, as it does not follow convention. Additional names of μ-oxido dihydrogen and oxidane have been developed for this compound. Under the 2005 revisions of IUPAC nomenclature of inorganic chemistry, there is no single correct name for every compound. The primary function of chemical nomenclature is to ensure that the person who hears or reads a chemical name is under no ambiguity as to which chemical compound it refers: each name should refer to a single substance. It is considered less important to ensure that each substance should have a single name, although the number of acceptable names is limited. Water is one acceptable name for this compound. The other IUPAC recommendation is oxidane. # Public efforts involving DHMO - In 1989, Eric Lechner, Lars Norpchen and Matthew Kaufman circulated a Dihydrogen Monoxide contamination warning on the UC Santa Cruz Campus via photocopied fliers. The concept originated one afternoon when Matthew recalled a similar warning about "Hydrogen Hydroxide" that had been published in his mother's hometown paper, the Durand (Michigan) Express, and the three then worked to coin a term that "sounded more dangerous". Eric typed up the original warning flier on Matthew's computer, and a trip to the local photocopying center followed that night. - In 1994, Craig Jackson created a web page for the Coalition to Ban DHMO. The page spread widely on the net and off, including publication as an ad in a 1995 issue of Analog Magazine. - The Friends of Hydrogen Hydroxide was created by Dan Curtis Johnson partly as a foil on the Coalition page, to provide evidence of 'misguided' supporters of dihydrogen monoxide. This form of collaborative connivance is a classic tool of internet spoofers. - In 1997, Nathan Zohner, a 14-year-old junior high student at Eagle Rock Junior High School in Idaho Falls, Idaho, gathered 43 votes to ban the chemical, out of 50 people surveyed among his classmates. Zohner received the first prize at Greater Idaho Falls Science Fair for analysis of the results of his survey. In recognition of his experiment, journalist James K. Glassman coined the term "Zohnerism" to refer to "the use of a true fact to lead a scientifically and mathematically ignorant public to a false conclusion." - In 1998, drawing inspiration from Jackon's web page and Zohner's research, Tom Way created the hoax website , including links to some legitimate sites such as the Environmental Protection Agency and National Institutes of Health. Evaluating such sites can be instructive in developing critical thinking and information literacy skills. - On April 1, 1998 (April Fools' Day), a member of the Australian Parliament announced a campaign to ban dihydrogen monoxide internationally. - In 2001 a staffer in New Zealand Green Party MP Sue Kedgley's office responded to a request for support for a campaign to ban dihydrogen monoxide by saying she was "absolutely supportive of the campaign to ban this toxic substance". This was criticised in press releases by the National Party, whom 6 years later ironically had one of their MP's fall for the very same hoax. - The idea was used for a segment of an episode of the Penn & Teller show Bullshit!, in which an actor and a camera crew gathered signatures from concerned environmentalists who wanted to ban DHMO. - In March 2004, Aliso Viejo, California almost considered banning the use of foam containers at city-sponsored events because dihydrogen monoxide is part of their production. A paralegal had asked the city council to put it on the agenda; he later attributed it to poor research. The law was pulled from the agenda before it could come to a vote, but not before the city received a raft of bad publicity. - In 2006, in Louisville, Kentucky, David Karem, executive director of the Waterfront Development Corporation, a public body that operates Waterfront Park, which features a large, accessible public fountain, wished to deter bathers from using the fountain. "Counting on a lack of understanding about water's chemical makeup," he arranged for signs reading: "DANGER WATER - CONTAINS HIGH LEVELS OF HYDROGEN - KEEP OUT" to be posted on the fountain at public expense. - An online petition to the British prime minister was correctly identified by the prime minister's office as a hoax, and rejected. - In one episode of the children's science show How 2, Fred Dinenage used a glass of water in a perspex box to carry out the hoax, before drinking the water then explaining the truth. - In 2007 Jacqui Dean, New Zealand National Party MP, fell for the hoax, writing a letter to Associate Minister of Health Jim Anderton asking "Does the Expert Advisory Committee on Drugs have a view on the banning of this drug?"

Caval opening The caval opening is a hiatus in the diaphragm of humans through which passes the inferior vena cava, the wall of which is adherent to the margins of the opening, and some branches of the right phrenic nerve. It is located approximately at the level of the eighth thoracic vertebra (T8), and passes through the diaphragm's central tendon. It is quadrilateral in form, and is placed at the junction of the right and middle leaflets of the central tendon, so that its margins are tendinous. By being situated in the tendinous part of the diaphragm, it is stretched open every time inspiration occurs. Since thoracic pressure decreases upon inspiration and draws the caval blood upwards toward the right atrium, increasing the size of the opening allows more blood to return to the heart, maximizing the efficacy of lowered thoracic pressure returning blood to the heart.

Daclizumab Daclizumab (Zenapax) is a humanized monoclonal antibody to the IL-2Rα receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants. It is given in multiple doses, the first 1 hour before the transplant operation and 5 further doses given at two week intervals after the transplant. These saturate the receptors and prevent T cell activation and thus prevent formation of antibodies against the transplant. Like the similar drug basiliximab, daclizumab reduces the incidence and severity of acute rejection in kidney transplantation without increasing the incidence of opportunistic infections. Daclizumab can also be used in place of a calcineurin-inhibitor (ciclosporin or tacrolimus) in the early phase after kidney transplantation when the kidney is recovering and vulnerable to calcineurin-inhibitor toxicity. This has been shown to be beneficial in non-heart beating donor kidney transplantation. In the United Kingdom, the National Institute for Health and Clinical Excellence has recommended its use be considered for all kidney transplant recipients. Daclizumab is now being tested as a possible Multiple Sclerosis treatment in a phase 2 clinical trial across the United States and Europe, which started 2006 and will end in 2007. It has also been used to arrest the progression of autoimmune diseases, especially birdshot retinochoroidopathy.

Markovnikov's rule In chemistry, Markovnikov's rule or Markownikoff's rule is an observation based on Zaitsev's rule. It was formulated by the Russian chemist Vladimir Vasilevich Markovnikov in 1870 . In chemical reactions found particularly in organic chemistry, the rule states that with the addition of H-X to an alkene, the acid hydrogen (H) becomes attached to the carbon with the greatest number of hydrogens, and the halide (X) group becomes attached to the carbon with the fewest number. The same is true when an alkene reacts with water in an addition reaction to form alcohol. The hydroxyl group (OH) bonds to the carbon that has the greater number of carbon-carbon bonds, while the hydrogen bonds to the carbon on the other end of the double bond, that has more carbon-hydrogen bonds. The chemical basis for Markovnikov's Rule is the formation of the most stable carbocation during the addition process. The addition of the hydrogen to one carbon atom in the alkene creates a positive charge on the other carbon, forming a carbocation intermediate. The more substituted the carbocation (the more bonds it has to carbon or to electron-donating substituents) the more stable it is, due to induction and hyperconjugation. The major product of the addition reaction will be the one formed from the more stable intermediate. Therefore, the major product of the addition of HX (where X is some atom more electronegative than H) to an alkene has the hydrogen atom in the less substituted position and X in the more substituted position. It is important to note, however, that the other less substituted, less stable carbocation will still be formed to some degree, and will proceed to form the minor product with the opposite attachment of X. The rule may be summarized as "the rich get richer and the poor get poorer" or "them that has gets": a carbon rich in substituents will gain more substituents and the carbon with more hydrogens attached will get the hydrogen in many organic addition reactions. # Historic context One the organic reactions Markovnikov based his rule on (first performed in 1865) was that of hydrogen iodide with vinyl bromide. In another manifestation of his rule he observed that the halogen atom added to the carbon atom already carrying an halogen atom Geminal halide hydrolysis of the initial reaction product with moist or hydrogenated (rarely used) silver oxide to ethanal proved the 1,1 substitution pattern. It has been observed that the original 1869 Markovnikov publication was sloppy and that he did not do much experimental work himself. The rule itself appeared only as a four-page footnote in a 26-page article and summarized by Markovnikov as "Them as has, gits.", which may also explain why his rule took 60 years to catch on. # Anti Markovnikov rule Mechanisms which avoid the carbocation intermediate may react through other mechanisms that are regioselective, against what Markovnikov's rule predicts, such as free radical addition. Such reactions are said to be anti-Markovnikov, since the halogen adds to the less substituted carbon.This reaction is exactly opposite of Markovnikov reaction,and hence the name. Again, like the positive charge, the radical is most stable when in the more substituted position. Anti-Markovnikov behaviour extends to other chemical reactions than just additions to alkenes. One Anti-Markovnikov manifestation is observed in hydration of phenylacetylene that, gold-catalyzed, gives regular acetophenone but with a special ruthenium catalyst the other regioisomer 2-phenylacetaldehyde : Anti-Markovnikov behaviour can also manifest itself in certain rearrangement reactions. In a titanium(IV) chloride catalyzed formal nucleophilic substitution at enantiopure 1 in the scheme below, two racemic products are formed 2a and 2b  : This product distribution can be rationalized by assuming that loss of the hydroxy group in 1 gives the tertiary carbocation A which rearranges to the seemingly less attractive secondary carbocation B. Chlorine can approach this center from two faces leading to the observed mixture of isomers.

Sandbox g38 # Sterile pyuria - Sterile pyuria - Definitions - Pyuria: the presence of 10 or more white cells per cubic millimeter in a urine specimen, 3 or more white cells per high-power field of unspun urine, a positive result on Gram’s stain of an unspun urine specimen, or a urinary dipstick test that is positive for leukocyte esterase - Sterile pyuria: the persistent finding of white cells in the urine in the absence of bacteria, as determined by means of aerobic laboratory techniques (on a 5% sheep-blood agar plate and MacConkey agar plate) - Bacteriuria: bacterial colony counts of more than 1000 colony-forming units (CFU) per milliliter in urine - Causes - Infectious etiologies - Gynecologic infection - Urethritis due to chlamydia, Neisseria gonorrhoeae, mycoplasma, or ureaplasma - Prostatitis - Balanitis - Appendicitis - Viral infection of the lower genitourinary tract - Genitourinary tuberculosis - Fungal infection - Parasitic disease such as trichomoniasis or schistosomiasis - Non-infectious etiologies - Current use of antibiotics - Recently treated urinary tract infection (within past 2 weeks) - Presence or recent use of a urinary catheter - Recent cystoscopy or urologic endoscopy - Urinary tract stones - Foreign body such as surgical mesh in the urethra or a retained stent - Urinary tract neoplasm - Pelvic irradiation - Urinary fistula - Polycystic kidney - Rejection of a renal transplant - Renal-vein thrombosis - Interstitial nephritis or analgesic nephropathy - Papillary necrosis - Interstitial cystitis - Inflammatory disease such as systemic lupus erythematosus or Kawasaki’s disease - Pathogen-directed antimicrobial therapy - Tuberculosis - Preferred regimen: Isoniazid AND Rifampin AND Ethambutol AND Pyrazinamide for 3–6 months - Gonorrhea - Preferred regimen: Ceftriaxone 250 mg IM in a single dose, then (Azithromycin 1 g PO in a single dose OR Doxycycline 100 mg PO bid for 7 days) - Chlamydia - Preferred regimen: Azithromycin 1 g PO in single dose OR Doxycycline 100 mg PO bid for 7 days - Alternative regimen: Erythromycin base 500 mg PO qid for 7 days - Mycoplasma and ureaplasma - Preferred regimen: Azithromycin OR Levofloxacin OR Moxifloxacin - Genital herpes - Preferred regimen: Acyclovir 400 mg PO tid for 7–10 days or Acyclovir 200 mg PO five times a day for 7–10 days OR Famciclovir 250 mg PO tid for 7–10 days OR Valacyclovir 1 g PO bid for 7 days - Trichomoniasis - Preferred regimen: Metronidazole 2 g PO in a single dose) OR Tinidazole 2 g PO in a single dose - Fungal infections - Preferred regimen: Fluconazole OR Posaconazole OR Echinocandins OR Amphotericin B - Schistosomiasis - Preferred regimen: Praziquantel 20 mg/kg PO bid for 1–2 days

Erythema multiforme (patient information) For the WikiDoc page for this topic, click here # Overview Erythema multiforme is a skin disorder due to an allergic reaction or infection. # What are the symptoms of Erythema multiforme? - Fever - General ill feeling - Itching of the skin - Joint aches - Multiple skin lesions: - Start quickly and may return - May spread - May appear as a nodule, papule, or macule and may look like hives - Central sore surrounded by pale red rings, also called a "target", "iris", or "bulls-eye" - May have vesicles and blisters of various sizes (bullae) - Located on the upper body, legs, arms, palms, hands, or feet - May involve the face or lips - Usually even on both sides (symmetrical) Other symptoms that may occur with this disease: - Bloodshot eyes - Dry eyes - Eye burning, itching, and discharge - Eye pain - Mouth sores - Vision problems # What causes Erythema multiforme? Erythema multiforme is a type of hypsersensitivity reaction that occurs in response to medications, infections, or illness. Medications include: - Barbiturates - Penicillins - Phenytoin - Sulfonamides Infections include: - Herpes simplex - Mycoplasma The exact cause is unknown. The disorder is believed to involve damage to the blood vessels of the skin, followed by damage to skin tissues. Some forms of this condition are more severe than others. - Erythema multiforme minor is not very serious. Most erythema multiforme is caused by herpes simplex or mycoplasma infections. - Erythema multiforme major is more severe, and is known as Stevens-Johnson syndrome. The more severe form is usually caused by reactions to medications, rather than infections. # Who is at highest risk? Erythema multiforme occurs primarily in children and young adults. # Diagnosis The diagnosis is based mainly on the appearance of the skin lesion, especially if there is a history of risk factors or related diseases. Tests may include: - Nikolsky's sign - Skin lesion biopsy and microscopic examination of the tissue # When to seek urgent medical care? Go to the emergency room or call the local emergency number (such as 911) if you have symptoms of erythema multiforme. If a large area of the body is involved, it is an emergency situation. # Treatment options Treatment goals include: - Controlling the illness that is causing the condition - Preventing infection - Treating the symptoms Stop taking any suspected medications, with your doctor's approval. Treatment of mild symptoms may include: - Medications such as antihistamines to control itching - Moist compresses applied to the skin - Oral antiviral medication if it is caused by herpes simplex - Over-the-counter medications (such as acetaminophen) to reduce fever and discomfort - Topical anesthetics (especially for mouth lesions) to ease discomfort that interferes with eating and drinking Treatment of severe symptoms may include: - Antibiotics to control any skin infections - Corticosteroids to control inflammation - Hospitalization and treatment in an intensive care or burn care unit for severe cases, Stevens-Johnson syndrome, and toxic epidermal necrolysis - Intravenous immunoglobulins (IVIG) to stop the disease process Practicing good hygiene and staying away from other people may help prevent secondary infections. Skin grafting may be helpful in cases in which large areas of the body are affected. # Where to find medical care for Erythema multiforme? Directions to Hospitals Treating Erythema multiforme # What to expect (Outlook/Prognosis)? Mild forms of erythema multiforme usually get better in 2 - 6 weeks, but they may return. More severe forms may be difficult to treat. Stevens-Johnson syndrome and toxic epidermal necrolysis have high death rates. # Possible complications - Body-wide infection, sepsis - Loss of body fluids, shock - Occasionally, lesions on internal organs causing: - Heart inflammation (myocarditis) - Lung inflammation (pneumonitis) - Kidney inflammation (nephritis) - Liver inflammation (hepatitis) - Permanent skin damage and scarring - Skin infection (cellulitis) # Sources

HDB Tirofiban decreases rate of periprocedural myocardial infarction compared to placebo in patients with poor responsiveness to clopidogrel and aspirin: Results of the 3T/2R study September 2, 2008 by Leah H. Biller ESC Congress 2008- Munich, Germany: Investigators from Italy reported that for poor responders to standard oral antiplatelet agents, treatment with high-dose bolus (HDB) tirofiban after elective percutaneous coronary intervention (PCI) decreased the rate of periprocedural myocardial infarction compared to placebo. The main results of the 3T/2R (Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin or Resistance to clopidogrel) study were presented by Dr. Marco Valgimigli at the ESC 2008 Congress Hot Line Update III Session . For patients undergoing PCI, the risk of plaque rupture has been combated with antiplatelet therapy as part of standard clinical practice. Studies have shown, however, that treatment with clopidogrel and aspirin (oral antiplatelet drugs) is not uniformly effective for all patients and in fact responsiveness to these drugs is markedly variable; moreover, poor responsiveness to clopidogrel has been linked to stent thrombosis, post-stent ischemic events and periprocedural myocardial infarction . The risk of thrombotic events after PCI has been shown to increase 1.8 to 10 fold for poor responders . While the individual patient’s response to cardiovascular drugs such as anti-hypertension and lipid lowering has been studied and is considered in planning treatment, individual responsiveness to oral antiplatelet agents has remained largely unaddressed. The 3T/2R study aimed to investigate the potential role of HDB tirofiban to decrease thrombotic events for those patients with poor response to standard clopidogrel and aspirin therapy. Out of 1277 patients scheduled to undergo elective PCI for stable or low-risk coronary disease at ten European sites, 263 poor responders were selected based on point-of-care assays (VerifyNow™ Aspirin and P2Y12 assays (Accumetrics, USA)). Patients were randomized in a double blind manner to either HDB tirofiban (25µg/kg in 3 min followed by 14-24 hour infusion at 0.15µg/kg/min) or placebo with standard clopidogrel and aspirin. The primary endpoint was an increase in Troponin I or T elevation greater than 3 times the upper limit of normal (ULN) within 48 hours post-PCI, indicating a periprocedural myocardial infarction according to the universal definition. Patients receiving HDB tirofiban had a decreased rate of periprocedural myocardial infarction compared to those receiving placebo plus standard therapy (20.4% versus 35.1% respectively; Relative Risk Reduction = 42%; 95% CI = 61-12; p = 0.009 for superiority). At 30-day follow-up, the HDB tirofiban group had a significant reduction in major adverse cardiovascular events (21.2% versus 36.6% for the placebo plus standard therapy group, p = 0.0065). Bleeding rates were low in both trial arms and not significantly different. The findings of the 3T/2R study suggest the importance of considering individual patients’ responsiveness to standard antiplatelet therapy (via point-of care assays); moreover, the results demonstrate proof of concept for the potential of HDB tirofiban treatment in poor responders. Further investigation should utilize additional methods of testing for clopidogrel and aspirin responsiveness. The 3T/2R study was sponsored by the University of Ferrara, Italy. The study was supported in part by an unrestricted research grant from Merck, USA and Iroko, USA.

The Living Guidelines: Preventing Thromboembolism Suggest Revisions to the CLASS I Guidelines # Class I Guidelines - Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except those with lone AF or contraindications. (Level of Evidence: A) - The selection of the antithrombotic agent should be based upon the absolute risks of stroke and bleeding and the relative risk and benefit for a given patient. (Level of Evidence: A) - For patients without mechanical heart valves at high risk of stroke, chronic oral anticoagulant therapy with a vitamin K antagonist is recommended in a dose adjusted to achieve the target intensity INR of 2.0 to 3.0, unless contraindicated. Factors associated with highest risk for stroke in patients with AF are prior thromboembolism (stroke, TIA, or - Anticoagulation with a vitamin K antagonist is recommended for patients with more than 1 moderate risk factor. Such factors include age 75 y or greater, hypertension, HF, impaired LV systolic function (ejection fraction 35% or less or fractional shortening less than 25%), and diabetes mellitus. (Level of Evidence: A) - INR should be determined at least weekly during initiation of therapy and monthly when anticoagulation is stable. (Level of Evidence: A) - Aspirin, 81–325 mg daily, is recommended as an alternative to vitamin K antagonists in low-risk patients or in those with contraindications to oral anticoagulation. (Level of Evidence: A) - For patients with AF who have mechanical heart valves, the target intensity of anticoagulation should be based on the type of prosthesis, maintaining an INR of at least 2.5. (Level of Evidence: B) - Antithrombotic therapy is recommended for patients with atrial flutter as for those with AF. (Level of Evidence: C)

2C-N 2C-N, or 2,5-Dimethoxy-4-nitrophenethylamine, is a psychedelic phenethylamine of the 2C family. It was first synthesized by Alexander Shulgin, sometimes used as an entheogen. # Chemistry The full name of the chemical is 2-(2,5-dimethoxy-4-nitrophenyl)ethanamine. Salts of 2C-N have a bright yellow to orange color due to the presence of the nitro group, unlike all other members of the 2C family in which the salts are white. # Dosage In his book PiHKAL (Phenethylamines I Have Known and Loved), Shulgin lists the dosage range as 100-150 mg. 2C-N is generally taken orally, and effects typically last 4 to 6 hours. # Dangers There have been no reported deaths or hospitalizations from 2C-N, but its safety profile is unknown. # Law 2C-N is unscheduled and uncontrolled in the United States, but possession and sales of 2C-N may potentially be prosecuted under the Federal Analog Act because of its structural similarities to 2C-T-7 or 2C-B. The legality of 2C-N is under scrutiny as of July 2004, due to Operation Web Tryp. 2C-N and most (possibly all) other compounds featuring in PiHKAL are illegal drugs in the United Kingdom. # Reference - ↑ Template:CitePiHKAL

Tar (tobacco residue) Tar is the common name for the resinous partially combusted particulate matter produced by the burning of tobacco, cannabis, and other plant material in the act of smoking. Tar is purportedly the most destructive component in habitual tobacco smoking, accumulating in the smoker's lungs over time and damaging them through various biochemical and mechanical processes. Tar includes the majority of mutagenic and carcinogenic agents in tobacco smoke (IARC, 1986). Polycyclic aromatic hydrocarbons (PAH), for example, are genotoxic via epoxidation. There is a common misconception that the tar in cigarettes is equivalent to the tar used on roads. As a result of this, cigarette companies in the United States, when prompted to give tar/nicotine ratings for cigarettes, usually use "tar", in quotation marks, to indicate that it is not the road surface component. Tar is occasionally referred to as an acronym for total aerosol residue although it's possible this is a backronym. The European Union currently limits the tar yield of cigarettes to 10mg.

Ascending paralysis # Overview Ascending paralysis refers to a form of paralysis where the presentation appears in the lower limbs before the upper limbs. It can be associated with: - Guillain-Barré syndrome (another name for this condition is "Landry's ascending paralysis") - Tick paralysis It can be contrasted to "descending paralysis", which occurs in conditions such as botulism.

Basement membrane corneal dystrophy Synonyms and keywords: Epithelial basement membrane dystrophy # Overview Epithelial basement membrane dystrophy (EBMD), also known as map-dot-fingerprint dystrophy and Cogans's microcystic dystrophy, is a disorder of the eye that can cause pain and dryness. It is sometimes included in the group of corneal dystrophies. It diverges from the formal definition of corneal dystrophy in being in most cases non-familial. It also has a fluctuating course, while for a typical corneal dystrophy the course is progressive. When it is considered part of this group, it is the most common type of corneal dystrophy. # Pathophysiology In some families autosomal dominant inheritance and point mutations in the TGFBI gene encoding keratoepithelin have been identified, but according to the International Committee for Classification of Corneal Diseases (IC3D) the available data still does not merit a confident inclusion of EBMD in the group of corneal dystrophies. In view of this, the more accurate designation of the disease is possibly not dystrophy but corneal degeneration. The main pathological feature of the disease is thickened, multilaminar and disfigured basement membrane of corneal epithelium. The change in the structure affects the epithelium, some cells of which may become entrapped in the rugged membrane and fail to migrate to the surface where they should undergo desquamation. # Signs and symptoms Patients may complain of severe problems with dry eyes. It can also be asymptomatic, and only discovered because of subtle lines and marks seen during an eye exam. EBMD is a bilateral anterior corneal dystrophy characterized by grayish epithelial fingerprint lines, geographic map-like lines, and dots (or microcysts) on slit-lamp examination. Findings are variable and can change with time. While the disorder is usually asymptomatic, up to 10% of patients may have recurrent corneal erosions, usually beginning after age 30; conversely, 50% of patients presenting with idiopathic recurrent erosions have evidence of this dystrophy. # Treatment Phototherapeutic keratectomy (PTK) done by an ophthalmologist can restore and preserve useful visual function for a significant period of time in patients with anterior corneal dystrophies including EMBD.

Adenosine A2B receptor The adenosine A2B receptor, also known as ADORA2B, is a G-protein coupled adenosine receptor, and also denotes the human adenosine A2b receptor gene which encodes it. # Mechanism This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. This protein also interacts with netrin-1, which is involved in axon elongation. # Gene The gene is located near the Smith-Magenis syndrome region on chromosome 17. # Ligands Research into selective A2B ligands has lagged somewhat behind the development of ligands for the other three adenosine receptor subtypes, but a number of A2B-selective compounds have now been developed, and research into their potential therapeutic applications is ongoing. ## Agonists - BAY 60-6583 - NECA (N-ethylcarboxamidoadenosine) - (S)-PHPNECA - high affinity and efficacy at A2B, but poor selectivity over other adenosine receptor subtypes - LUF-5835 - LUF-5845 - partial agonist ## Antagonists and inverse agonists - Compound 38: antagonist, high affinity and good subtype selectivity - ATL-801 - CVT-6883 - MRS-1706 - MRS-1754 - OSIP-339,391 - PSB-603 - PSB-0788 - PSB-1115

Y-chromosomal Aaron Y-chromosomal Aaron is the name given to the hypothesised most recent common ancestor of many of the patrilineal Jewish priestly caste known as Kohanim (singular "Kohen", "Cohen", or Kohane). In the Hebrew Bible this ancestor is identified as Aaron, the brother of Moses. Research published in 1997 and thereafter has indicated that a large proportion of contemporary Jewish Kohanim share a set of Y chromosomal genetic markers, known as the Cohen Modal Haplotype, which may well derive from this single common ancestor. # Background Although membership in the Jewish community is traditionally passed maternally (see: Who is a Jew?), membership in the group that originally comprised the Jewish priesthood ("Kohens" or Kohanim), is patrilineal, and modern Kohens claim descent from Aaron, brother of Moses. For human beings the normal number of chromosomes is 46, of which 23 are inherited from each parent. Two chromosomes, the X chromosome and Y chromosome, determine gender. Women have two X chromosomes, one inherited from their mother, and one inherited from their father. Men have an X chromosome inherited from their mother, and a Y chromosome inherited from their father. Males who share a common patrilineal ancestor should also share a Y chromosome, diverging only with respect to accumulated mutations. Since Y-chromosomes are passed from father to son, all Kohanim men should theoretically have almost identical Y chromosomes; this can be tested with a genealogical DNA test. As the rate that mutations accumulate on the Y chromosome is relatively constant, scientists can estimate the elapsed time since two men had a common ancestor. (See molecular clock.) # Initial studies The Cohen hypothesis was first tested by Prof. Karl Skorecki and collaborators from Haifa, Israel, in 1997. In their study, "Y chromosomes of Jewish priests," published in the journal Nature, they found that the Kohanim appeared to share a different probability distribution compared to the rest of the Jewish population for the two Y-chromosome markers they tested (YAP and DYS 19); and that furthermore the probabilities appeared to be shared by both Sephardi and Ashkenazi Cohens, pointing to a common Cohen population origin before the Jewish diaspora at the time of the Roman empire. A subsequent study the next year (Thomas MG et al, 1998) increased the number of Y-STR markers tested to six, as well as testing more SNP markers. Again, they found that a clear difference was observable between the Cohanim population and the general Jewish population, with many of the Cohen STR results clustered around a single pattern they named the Cohen Modal Haplotype: Here, becoming increasingly specific, xDE is the proportion who were not in Haplogroups D or E (from the original paper); xDE,PR is the proportion who were not in haplogroups D, E, P, Q or R; Hg J is the proportion who were in Haplogroup J (from the slightly larger panel studied by Behar et al (2003)); CMH.1 means "within one marker of the CMH-6"; and CMH is the proportion with a 6/6 match. The final two columns show the conditional proportions for CMH.1 and CMH, given membership of Haplogroup J. The data shows that the Cohanim were more than twice as likely to belong to Haplogroup J than the average non-Cohen Jew; and of those who did belong to Haplogroup J, the Cohanim were more than twice as likely to have an STR pattern close to the CMH-6, suggesting a much more recent common ancestry for most of them compared to an average non-Cohen Jew of Haplogroup J. Thomas et al dated the origin of the shared DNA to approximately 3,000 years ago (with variance arising from different generation lengths). The techniques used to find Y-chromosomal Aaron were first popularized in relation to the search for the patrilineal ancestor of all contemporary living humans, Y-chromosomal Adam. ## Responses The finding led to excitement in religious circles, with some seeing it as providing some "proof" of the historical veracity of the Bible or other religious convictions, but there was also criticism that the paper's evidence was being overstated. # Cohens in other haplogroups Behar's 2003 data points to the following Haplogroup distribution for Cohens as a whole: The detailed breakdown by 6-marker haplotype (the paper's online-only table B) suggests that some at least even of these groups (eg E3b, R1b) contain more than one distinct Cohen lineage. It is possible that still further other lineages may also exist, but were not captured in the sample. # Does a CMH prove Cohen ancestry? One source of early confusion was a widespread popular notion that only Cohens or only Jews could have the Cohen Modal Haplotype. It is now clear that this is not the case. The Cohen Modal Haplotype, whilst notably frequent amongst Cohens, is also far from unusual in the general populations of haplogroups J1 and J2 with no particular link to the Cohen ancestry. These haplogroups occur widely throughout the Middle East and beyond ,. So whilst many Cohens have haplotypes close to the CMH, a far larger number of such haplotypes worldwide belong to people with no likely Cohen connection at all. Statistically the value of matching the CMH can be assessed using Bayes' theorem, which in its odds form can be written: In words, this says that the odds in favour of Cohen ancestry C (ie the probability of having Cohen ancestry, divided by the probability of not having Cohen ancestry), having observed some piece of data D, is given by the odds one would assign given only one's initial information I, multiplied by the probability of having observed D if C is true, divided by the probability of having observed D if C is false. (In fact, for convenience we shall work with the reciprocal of this equation, ie work in terms of odds against, rather than odds on). The proportion of the whole male Jewish population that has Cohen ancestry has been estimated at 5%. So if we take that 5% as our initial estimate of the probability of shared Cohen ancestry, then on the basis of the data above: - Not belonging to haplogroups D or E improves the odds for a Sephardi Jew from 19/1 against to (19/1)*(0.85/1.00) = 16.2/1 against (a 5.8% probability) - Not belonging to haplogroups D,E,P,Q or R takes the odds to (19/1)*(0.63/0.88) = 13.6/1 against (6.8% probability). - Membership of Haplogroup J improves the odds to (19/1)*(0.37/0.75) = 9.4/1 against (9.6% probability). - Being within the CMH.1 group takes the odds to (19/1)*(0.14/0.61) = 4.4/1 against (18.7% probability). - A full 6/6 match takes the odds to (19/1)*(0.10/0.56) = 3.4/1. (22.7% probability). Even a full 6/6 match for the 6 marker CMH thus cannot "prove" Cohen ancestry. It can only somewhat strengthen a previously existing belief. But for populations where the background probability assessment of shared Cohen ancestry must be vanishingly low, such as almost all non-Jews, even a full 6/6 match makes only a small difference. For individuals in such populations the CMH likely indicates Haplogroup J, but a completely different ancestry to the Cohanim. # Higher resolution The discussion above applies to the so far published scientific papers. However, in principle some more resolution could be obtained by determining the Cohen haplogroup more narrowly, and/or testing more Y-STR markers to determine whether there is an extended characteristic Cohen haplotype. ## Haplogroup placement The largest population of Kohanim which most closely match the Cohen haplotype cluster are believed to belong to subgroup J1 of haplogroup J. Individuals with the genetic Cohen Modal Haplotype can be found in subgroup J2 as well, and occasionally in more genealogically distant haplogroups too; however these are not closely related to the cluster in Haplogroup J1. The subdivision of J2 which most closely matches the genetic signature of the J1 Cohens is subclade J2a1b, a large fraction of members of which will also have a 6/6 match for the 6-marker CMH. However, this is an example of (re)convergence of haplotypes of different genetic lines, which it is believed have been not been closely related for at least the last 10,000 years; the group in J2a1b who have the 6-marker CMH are devoid of any Cohen traditions in their families. On the other hand, there are families in Haplogroup J2 who do have a Cohen religious tradition and are proud of it (as there are in several other haplogroups, including Haplogroup R1b). The haplotypes of these Haplotype J2 Kohanim cluster in a unique, small offshoot of J2a1*, close to haplotypes of the J2a1k clade, not the J2a1b clade. These J2 Kohanim typically have a 4/6 match for the 6-marker CMH (with DYS19=15 rather than 14, and DYS388=15 rather than 16). They do not match the 12-marker J1-extended CMH, and they do not share a common ancestor with the J1 Kohanim in a Biblical timeframe; but they are equal co-inheritors of a patrilineal tradition which appears to date back well before the Diaspora. As it happens, three of the four markers for which they do match the CMH-6 were the markers tested by Malaspina et al (2001). This appears to explain the finding of that paper that "typing a limited number of Italian Cohanim (A. Novelletto unpublished obs.) for the STRs used here, we determined that the Cohen Modal Haplotype ('an important component in the sharing of Ashkenazic and Sephardic Israelite Y chromosomes', Thomas et al. 2000) does indeed belong to network 1.2" (ie the population having DYS413a,b<=18, which is the signature of the J2a1 subclades). ## More detailed Cohen haplotypes In the table below, the first line gives the original 6 marker Cohen Modal Haplotype (CMH-6), which was the basis for the original published papers. The second gives an extended 12 marker haplotype (CMH-12) informally released by the private company FTDNA, based on further work by much of the same research team. It has not yet been peer group reviewed by other scientists or published in the open technical literature. The next sequence of rows identify other 6-marker haplotypes in haplogroup J found to occur more than once in the sample of 145 Cohanim tested in Behar et al (2003) (table B (web-only) in that paper). Probable extensions of these haplotypes to 12 markers are shown, where it has been possible to find corresponding clusters of Cohen-type names in publicly accessible DNA databases, together with the apparent sub-clade of haplogroup J. This is more possible for the apparently Ashkenazi clusters than for Sephardis, who are much less strongly represented in the databases. Finally, for comparison, the 12-marker modal haplotypes for the haplogroups J1 and J2 are also shown. It is apparent that in both cases, their haplotype clusters are also centred very close to the Cohen modal haplotype. However, because of the much greater time that has elapsed since the mutations occurred that define the haplogroups, there has been much more time for Y-STR mutations to build up; so, although they have almost the same centre as the Cohen cluster, the J1 and J2 haplotype clusters are much more diffusely spread out. Thus although the CMH-6 is also very near to the most probable haplotype for both J1 and J2, its occurrence frequency is only about 1 to 8% amongst arbitrary members of haplogroup J with no particular Cohen connection. # Other carriers of the DNA Critics of the theory point out that the Cohen Modal Haplotype has also been found in significant numbers in groups of non-Jews, notably Italians. However proponents of the theory are quick to explain these anomalies. They state that history records the migration of large numbers of Jews to Italy who married and took part in building the Colosseum. However, the Cohen Haplotype has also been found among significant numbers of non-Jewish Arab and Kurdish populations. Although this too could be explained in part by miscegenation, assimilation, and conversions, there is an alternate possibility that the marker precedes all of these populations and is a precursor to some common ancestral group. ## Lemba The Cohen Modal Haplotype has also been found in the Lemba of Southern Africa, who have a tradition of Jewish ancestry (Thomas MG et al 2000). ## Kurds The Cohen Modal Haplotype has also been found in some groups of Kurds. There are a number of Kurdish Jews. # Y-chromosomal Levi? A similar investigation was made with men who consider themselves Levites. Whereas the priestly Kohanim are considered descendants of Aaron, who in turn was a descendant of Levi, son of Jacob, the Levites (a lower rank of the Temple) are considered descendants of Levi through other lineages. Levites should also therefore share common Y-chromosomal DNA. The investigation of Levites found high frequencies of multiple distinct markers, suggestive of multiple origins for the majority of non-Aaronid Levite families. One marker, however, present in more than 50% of Eastern European (Ashkenazi) Jewish Levites points to a common male ancestor or very few male ancestors within the last 2000 years for many Levites of the Ashkenazi community. This common ancestor belonged to the haplogroup R1a1 which is typical of Eastern Europeans, rather than the haplogroup J of the Cohen modal haplotype, and most likely lived at the time of the Ashkenazi settlement in Eastern Europe. . The E3b1 haplogroup has been observed in all Jewish groups world wide. It is considered to be the second most prevalent haplogroup among the Jewish population. According to one major paper, . It has also been observed in moderate numbers among individuals from Ashkenazi, Sephardic and Samaritan backgrounds that contain the E3b1 haplogroup, having a tradition of descending from the tribe of Levi, suggesting that the E3b1 Levites may have existed in Israel before the Diaspora of 70 C.E. The Samaritan community is a small, isolated, and highly endogamous group today numbering some 650 members who have maintained extensive genealogical records for the past 13–15 generations. Since the Samaritans maintain extensive and detailed genealogical records, it is possible to construct accurate pedigrees and specific maternal and paternal lineages. The Samaritan community in the Middle East survives as a distinct religious and cultural sect and constitutes one of the oldest and smallest ethnic minorities in the world. Y-Chromosome studies have shown that the majority of Samaritans belong to haplogroups J1 and J2 while the Samaritan Cohanim belong to haplogroup E3b1a.. In 1623-1624 the last member of the high-priestly family, which claimed descent from the eldest son of Aaron, died. The office was then given to the junior branch, descended from Uzziel, the son of Kohath. Since that date the priest has called himself "ha-kohen ha-Lewi," (Heb. "The Levite Priest") instead of "ha-kohen ha-gadol" (Heb. "The High Priest") as in previous times. The approximately 650 individuals comprising the total group of present day Samaritans trace their ancestry over a period of more than 2,000 years to the Biblical Israelite tribes of Ephraim, Menashe and Levi. As a religious sect, the Samaritans broke away from the main stream of Judaism around the fifth century B.C.E.

Pelvic myoneuropathy Steven C. Campbell, M.D., Ph.D. # Overview Pelvic myoneuropathy is a new term given to the most common form of non-bacterial pelvic pain experienced by men. It is sometimes referred to as nonbacterial chronic Prostatitis or male Chronic Pelvic Pain Syndrome (CP/CPPS or CPPS). The mechanisms of pelvic myoneuropathy may also underlie the etiology of IC (Interstitial cystitis). For a full description of the symptoms and treatment of pelvic myoneuropathy, see the article on prostatitis. This article will merely expand on the definition of pelvic myoneuropathy. # Definition Pelvic myoneuropathy, in its most simplified and broadest terms, describes a process in which people of a particular genetic type and often with tense, anxious, and frequently atopic (allergy-prone) dispositions, develop a chronic process in the pelvis that involves muscles, nerves and mast cells. Such individuals tend to tense the muscles of their pelvic floors subconsciously and continuously. This clenching of deep muscles can be provoked either by the individual's tense disposition, or it can be the result of a "guarding" response to a preceding trauma to the pelvic or spinal area, pelvic surgery, bicycling, long periods of sitting and stress at work, and in some cases, urinary tract infections (prostatitis and cystitis). Other common events that lead to injury are: - chronic tense holding patterns that develop in childhood as a result of sexual abuse, traumatic toilet training, abnormal bowel patterns, guilt surrounding sexual feelings, dance training or stress - repetitive minor trauma or straining with constipation or urinary obstruction - other inflammations of pelvic organs such as urethritis, proctitis or anal fissures, or referred pain from other attaching muscle groups or viscera or nerves. The subsequent muscle spasm and hypertonicity of the pelvic muscles leads to a hyperirritability of the muscle fibers. The hyperirritable bundles of fibers within the muscles of the pelvic floor become "knotted", inelastic and unable to contract or relax. Trigger points are formed. The overstimulated nerves innervating these muscles, through a complex process involving central sensitization, intermingling of afferent (sensory) fibers, neural wind-up, intercommunication among nerve plexuses, neural cross-talk, viscerosomatic convergence, the nature of visceral afferentes, and individual variations of anatomy and neurophysiology, eventually set up a process in the tissues of the genitourinary tract that leads to pathology. This pathology results when the nerve endings overproduce chemicals called neuropeptides. Neuropeptides stimulate powerful immune defence cells called mast cells. Once stimulated, these cells produce a wide range of chemicals (histamine, TNF-alpha, inflammatory prostaglandins, leukotrienes) that cause pain, inflammation and the symptoms of sterile prostatitis, urethritis, orchalgia, epididymitis, and/or interstitial cystitis. Therapy is multimodal, involving intrapelvic deep muscle "trigger point" massage and release, specific stretching exercises, stress control and special forms of pelvic muscle relaxation training, nerve therapy (neurontin, elavil, botox), mast cell protectives and mast cell byproduct amelioratives (ProstaQ, Q-Urol, antihistamines, alpha-blockers, etc).

Nitrendipine # Overview Nitrendipine is a dihydropyridine calcium channel blocker. It is used in the treatment of primary (essential) hypertension to decrease blood pressure. # Molecular Problem Hypertension is the chronic condition where the blood pressure is elevated beyond normal levels that vary among individuals. The elevated levels in blood pressure increases the systemic vascular pressure, which increases the workload of the heart. The mechanical stress on the heart initiates a protein cascade involving G-proteins, cyclic-AMP and PKA that result in activation of genes that produce more cardiac muscle cells. The increased stress on the heart causes the heart to enlarge to accommodate the workload. However, the enlarged heart also needs structural support, which is why it produces scarring. The enlargement of the heart can make it hard for some cells to get nutrients because they are too distant from the blood vessels. Also, scarring can interfere with the electrical signals that cause the heart to contract and it also limits the ability of the heart to contract and relax. In both cases there is an increase risk of heart failure. # Nature of the Treatment Nitrendipine is given to hypertensive individuals in 20 mg oral tablets every day. This amount is effective in reducing blood pressure by 15-20% within 1–2 hours of administration . With long-term treatments, the dosage may rise to as much as 40 mg/day; in elderly individuals, a lower dosage of up to 5 mg/day may be equally effective (this reduction in drug amount is attributed to decreased liver function or “first pass” metabolism) . Once digested, Nitrendipine is absorbed into the blood and binds to plasma proteins. The majority (98%) is bound to plasma proteins and 70-80% of its inactive polar metabolites are also bound to plasma proteins . Following hepatic metabolism, 80% of the 20 mg dose can be recovered in the first 96 hours as inactive polar metabolites. The specific volume of distribution of the drug is 2-6 L/kg. In terms of drug half-life, Nitrendipine has a half-life of 12–24 hours . The reported side effects include: headache, flushing, edema and palpitations. These side effects can all be attributed to the vasodilation effect of this drug . # Mechanism of Action Once Nitrendipine is ingested, it is absorbed by the gut and metabolized by the liver before it goes into the systemic circulation and reaches the cells of the smooth muscles and cardiac muscle cells. It binds more effectively with L-type calcium channels in smooth muscle cells because of its lower resting membrane potential. The Nitrendipine diffuses into the membrane and binds to its high affinity binding site on the inactivated L-type calcium channel that’s located in between each of the 4 intermembrane components of the α1 subunit . The exact mechanism of action of Nitrendipine is unknown, but it is believed to have important tyrosine and threonine residues in its binding pocket and its binding interferes with the voltage sensor and gating mechanism of the channel . Thought to have a domain-interface model of binding. In hypertension, the binding of Nitrendipine causes a decrease in the probability of open L-type calcium channels and reduces the influx of calcium. The reduced levels of calcium prevent smooth muscle contraction within these muscle cells. Prevention of muscle contraction enables smooth muscle dilation. Dilation of the vasculature reduces total peripheral resistance, which decreases the workload on the heart and prevents scarring of the heart or heart failure.

Sandbox Listeriosis medical therapy # Overview Ampicillin, with or without gentamicin, is considered the drug of choice for listeriosis. Patients intolerant of penicillins may be managed with trimethoprim-sulfamethoxazole alternatively. Suggested minimum duration of therapy depends on clinical manifestations: bacteremia should be treated for 2 weeks, meningitis for 3 weeks, endocarditis for 4 to 6 weeks, and brain abscess or rhomboencephalitis for at least 6 weeks. # Principles of Therapy - Ampicillin, amoxicillin, and penicillin G have been considered effective for listeriosis. For patients unable to tolerate beta-lactams, trimethoprim-sulfamethoxazole may be used alternatively. Chloramphenicol is not regarded as an acceptable option due to high treatment failure and relapse rates. - Addition of an aminoglycoside, which provides synergistic bactericidal effects to ampicillin, is generally recommended for the treatment of listerial bacteremia, endocarditis, brain abscess, meningitis, or rhomboencephalitis. - Bacteremia should be treated for 2 weeks, meningitis for 3 weeks, endocarditis for 4 to 6 weeks, and brain abscess or rhomboencephalitis for at least 6 weeks. - Meningitis is the most common clinical manifestation, and antibiotics that penetrate well into the CSF should be chosen. - Gastroenteritis caused by Listeria monocytogenes is usually self-limited and complete recovery typically occurs within 2 days. Patients who have ingested food implicated in outbreaks and who have a high risk of invasive illness may consider oral herapy with ampicillin or trimethoprim-sulfamethoxazole for several days. # Medical Therapy for Listeria monocytogenes Adapted from Clin Infect Dis. 1997;24(1):1-9., Clin Infect Dis. 2005;40(9):1327-32., and Clin Infect Dis. 2004;39(9):1267-84. ▸ Click on the following categories to expand treatment regimens.

Tolosa-Hunt syndrome # Overview Tolosa–Hunt syndrome (THS) is a rare disorder characterized by severe and unilateral headaches with extraocular palsies, usually involving the third, fourth, fifth, and sixth cranial nerves, and pain around the sides and back of the eye, along with weakness and paralysis (ophthalmoplegia) of certain eye muscles. In 2004, the International Headache Society provided a definition of the diagnostic criteria which included granuloma. # Causes The exact cause of THS is not known, but the disorder is thought to be, and often assumed to be, associated with inflammation of the areas behind the eyes (cavernous sinus and superior orbital fissure). # Signs and symptoms Symptoms are usually limited to one side of the head, and in most cases the individual affected will experience intense, sharp pain and paralysis of muscles around the eye. Symptoms may subside without medical intervention, yet recur without a noticeable pattern. In addition, affected individuals may experience paralysis of various facial nerves and drooping of the upper eyelid (ptosis). Other signs include double vision, fever, chronic fatigue, vertigo or arthralgia. Occasionally the patient may present with a feeling of protrusion of one or botheyeballs (exophthalmos). # Diagnosis THS is usually diagnosed via exclusion, and as such a vast amount of laboratory tests are required to rule out other causes of the patient's symptoms. These tests include a complete blood count, thyroid function tests and serum protein electrophoresis. Studies of cerebrospinal fluid may also be beneficial in distinguishing between THS and conditions with similar signs and symptoms. MRI scans of the brain and orbit with and without contrast, magnetic resonance angiography or digital subtraction angiography and a CT scan of the brain and orbit with and without contrast may all be useful in detecting inflammatory changes in the cavernous sinus, superior orbital fissure and/or orbital apex. Inflammatory change of the orbit on cross sectional imaging in the absence of cranial nerve palsy is described by the more benign and general nomenclature of orbital pseudotumor. Sometimes a biopsy may need to be obtained to confirm the diagnosis, as it is useful in ruling out a neoplasm. Differentials to consider when diagnosing THS include craniopharyngioma, migraine and meningioma. # Treatment Treatment of THS is usually completed using corticosteroids (often prednisolone) and immunosuppressive agents (such as methotrexate or azathioprine). Corticosteroids act as analgesia and reduce pain (usually within 24–72 hours), as well as reducing the inflammatory mass, whereas immunosuppressive agents help reduce the autoimmune response. Treatment is then continued in the same dosages for a further 7–10 days and then tapered slowly. Radiotherapy has also been proposed. # Prognosis The prognosis of THS is usually considered good. Patients usually respond to corticosteroids, and spontaneous remission can occur, although movement of ocular muscles may remain damaged. Roughly 30–40% of patients who are treated for THS experience a relapse. # Epidemiology THS is uncommon in both the United States and internationally. In New Zealand, there is only one recorded case . Both genders, male and female, are affected equally, and it typically occurs around the age of 60.

Overview template # Introduction to the Overview Page The Overview page is a summary of all the other microchapters. The overview page for a microchaptered page will show the main subtitles of the page, with a brief overview of the content of each microchapter within each subtitle. This page is best created last, and aims to summarize the important aspects of the disease. To see an example of an Overview page on Pericarditis within a microchaptered page, click here. The aim is to convey the most important information for a "quick glance" at the disease. Below is the general template to follow when creating an Overview for a microchaptered page. Whether all the subheadings are needed and how extensive they are, will depend on the complexity of the disease page you are creating. # Overview - This section is the general overview statement for the disease. It should include the name of the main page in the first sentence. - This section will be an overview statement of all the overview statements below it. - It should not contain any synonyms or keywords (as these should be at the top of the page listed next to Synonyms and keywords:). - It should be aimed to be written at a medical student or intern level of understanding. To view an example of an overview section on an overview page, click here. # Historical Perspective - Historical perspective of a disease discusses the initial discovery of the disease, the major outbreaks/events associated with the disease, and the initial diagnostic and therapeutic discoveries related to the disease. - This section should contain the name of the disease you are describing in the first sentence. - The overview of the historical perspective of a disease should be a short description of the landmark discoveries associated with the disease. It is ideally written after the main historical perspective microchapter is written, to summarize the key points of the microchapter. It can be the same as the overview that is seen on the historical perspective microchapter. - To view a template and examples of the Historical Perspective overview statement, click here. # Classification - Classification of a disease varies based on the type of disease. For example, certain cancers may be classified based on stage and grade, whereas a drug allergy may be classified based on the type of drug reaction. - This section should contain the name of the disease you are describing in the first sentence. - The overview of the classification of a disease should be a short description of the way in which the disease is classified. It is ideally written after the main classification microchapter is written, to summarize the key points of the microchapter. It can be the same as the overview statement that is seen on the classification microchapter. - To view a template and examples of the Classification overview statement, click here. # Pathophysiology - Pathophysiology is the study of the biological and physical manifestations of a disease as they correlate with the underlying abnormalities and physiological disturbances. - This section should contain the name of the disease you are describing in the first sentence. - The overview of the pathophysiology of a disease should be a short description of the basic disease process. It is ideally written after the main pathophysiology microchapter is written, to summarize the key points of the microchapter. It can be the same as the overview statement that is seen on the pathophysiology microchapter. - To view a template and examples of the Pathophysiology overview statement, click here. # Causes - This section summarizes the main causes of the disease. - The overview for causes of a disease should ideally be written after the main causes microchapter is written, to summarize the key points of the microchapter. It can be the same as the overview statement found on the main causes microchapter for the disease. - To view a template and examples of the Causes (Non-microbiology) overview statement, click here. - To view a template and examples of the Causes (Microbiology) overview statement, click here. # Differentiating (Disease name) from other Conditions - In this section, give a brief description of the main diseases that need to be differentiated from the disease you are describing. - The overview of the differentiation of a disease should ideally be written after the main microchapter is written. It can be the same as the overview statement found on the main "differentiating disease from other conditions" microchapter for the disease. - To view a template and examples of the Differential Diagnosis overview statement, click here. # Epidemiology and Demographics - Epidemiology is the scientific study of the causes, distribution, and control of disease populations. Demographics are the objective characteristics of a population age, marital status, family size, racial origin, present or prior disease, religion, income, and education and how they relate to a specific disease. - This section should contain the name of the disease you are describing in the first sentence. - The overview of the epidemiology and demographics of a disease should ideally be written after the main epidemiology and demographics microchapter is written. It can be the same as the overview statement found on the main epidemiology and demographics microchapter for the disease. - To view a template and examples of the Epidemiology and Demographics overview statement, click here. # Risk Factors - Risk factors are variables associated with an increased risk of disease or infection.This section should outline the risk factors that have the highest correlation with the disease. - The overview of the risk factors of a disease should ideally be written after the main risk factors microchapter is written, to summarize the key points of the microchapter. It can be the same as the overview statement found on the main risk factors microchapter for the disease. - To view a template and examples of the Risk Factors overview statement, click here. # Natural History, Complications and Prognosis - The natural history of a disease describes how the disease would progress without treatment. The complications describe the negative consequences of the disease and treatment, and the prognosis describes the outcomes of the disease. - This section should contain the name of the disease you are describing in the first sentence. - The overview of the natural history, complications and prognosis is ideally written after the main microchapter is written, to summarize the key points of the microchapter. It can be the same as the overview statement that is seen on the natural history, complications and prognosis microchapter page. - To view a template and examples of the Natural History, Complications and Prognosis overview statement, click here. # Diagnosis - The diagnosis of a disease details the most important signs, symptoms, tests, and other studies that lead to the diagnosis of a disease. - This section should contain the name of the disease you are describing in the first sentence. - The overview of the diagnosis of a disease should ideally be written after the main diagnosis microchapters are written, to summarize the key points of the microchapters. ## History and Symptoms - Describe the main aspects of the patient history that should be focused on, and the symptoms that lead to, or exclude the diagnosis of the disease you are describing. You should use the name of the disease in the first sentence. For an example of this subsection, click here. - This section can be the same as the overview section on the history and symptoms page. - To view a template and examples of the History and Symptoms overview statement, click here. ## Physical Examination - Describe the main physical examination findings that can lead to or exclude the diagnosis of the disease you are describing. You should include the name of the disease in the first sentence. For an example, click here - This section can be the same as the overview section physical examination page. - To view a template and examples of the Physical Examination overview statement, click here. ## Laboratory Findings - List the main laboratory studies that can lead to or exclude the diagnosis of the disease you are describing. You should include the name of the disease in the first sentence. - This section should be the same as the overview statement on the laboratory findings page. - To view a template and examples of the Laboratory Findings overview statement, click here. ## Electrocardiogram - If EKG findings are pertinent to the diagnosis of the disease you are describing, you can provide the findings here. - This section can be the same as the overview statement found on the Electrocardiogram page. - To view a template and examples of the Electocardiogram overview statement, click here. ## Chest X Ray - If chest x ray findings are pertinent to the disease page you are making, you can briefly describe them here. - This can be the same as the overview statement on the chest x ray page. - To view a template and examples of the Chest X Ray overview statement, click here. ## CT Scan - If CT findings are pertinent to the page you are making, you can briefly describe them here. - This section can be the same as the overview section on the CT page. - To view a template and examples of the CT Scan overview statement, click here. ## Echocardiography or Ultrasound - If echocardiography or ultrasound findings are pertinent to the page you are making, you can describe them here. - This section can be the same as the overview section on the echocardiography and ultrasound page. - To view a template and examples of the Echocardiography or Ultrasound overview statement, click here. ## Other Imaging Findings - List the most important diagnostic studies, such as imaging and other studies, that can lead to or exclude the diagnosis of the disease you are describing. You should name any "gold standard" studies here, and include the name of the disease in the first sentence. - To view a template and examples of the Other Imaging Findings overview statement, click here. # Treatment - Treatment describes the various, most commonly used methods in treating the disease you are describing. - This section should contain the name of the disease you are describing in the first sentence. - The overview of the treatments for a disease should ideally be written after the main treatment microchapter is written, to summarize the key points of the microchapter. It can be the same as the overview statement found on the main risk factors microchapter for the disease. ## Medical Therapy - Medical therapy describes all non-surgical therapies that are provided for the patient. - This section should contain the name of the disease you are describing in the first sentence followed by the indication to treat the patient (if applicable) and the name of the therapy. - To view a template and examples of the Medical Therapy overview statement, click here. ## Surgery - Surgery describes all surgeries and therapeutic procedures that are provided for the patient. - This section should contain the name of the disease you are describing in the first sentence followed by the indication to surgically manage the patient (if application) and the name of the surgery. - To view a template and examples of the Surgery overview statement, click here. ## Prevention - Prevention describes all strategies that prevent from the occurrence of the disease. Prevention may be either primary (prevent occurrence of the disease), secondary (diagnose and treat existent disease in early stages), tertiary (reduce the negative impact of extant disease), and quaternary (methods to avoid results of unnecessary interventions). At least primary and secondary prevention are usually discussed in each chapter. - This section should contain the name of the disease you are describing in the first sentence. The availability or lack of vaccine availability of a vaccine against the disease should be clearly written. Other strategies for the prevention of the disease should be outlined and classified as either primary, secondary, tertiary, or quaternary. - To view a template and examples of the Prevention overview statement, click here.

Sandbox m # Overview Both type I and type II varieties of complex regional pain syndrome share a common diagnostic criteria. They both consist of having a spontaneous onset of pain that is not limited to the distribution of a single nerve, a history of edema, or abnormal sweating. The only difference lies in the nature of the inciting event. # Diagnostic Criteria CRPS types I and II share the common diagnostic criteria shown below. - Spontaneous pain or allodynia/hyperalgesia is not limited to the territory of a single peripheral nerve, and is disproportionate to the inciting event. - There is a history of edema, skin blood flow abnormality, or abnormal sweating in the region of the pain since the inciting event. - No other conditions can account for the degree of pain and dysfunction. The two types differ only in the nature of the inciting event. Type I CRPS develops following an initiating noxious event that may or may not have been traumatic, while type II CRPS develops after a nerve injury.

Coagulation factor IX # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Coagulation factor IX is an antihemophilic factor that is FDA approved for the prevention of bleeding episodes in adult and pediatric patients with hemophilia B and peri-operative management in adult and pediatric patients with hemophilia B. Common adverse reactions include nausea, injection site reaction, injection site pain, headache, dizziness and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Indications ### Control and Prevention of Bleeding Episodes in Hemophilia B - Coagulation Factor IX (Recombinant), is indicated for the control and prevention of bleeding episodes in adult and pediatric patients with hemophilia B (congenital factor IX deficiency or Christmas disease). ### Peri-operative Management in Patients with Hemophilia B - Coagulation Factor IX (Recombinant), is indicated for peri-operative management in adult and pediatric patients with hemophilia B. - Coagulation Factor IX (Recombinant), isNOT indicated for: - A.treatment of other factor deficiencies (e.g., factors II, VII, VIII, and X), - B.treatment of hemophilia A patients with inhibitors to factor VIII, - C.reversal of coumarin-induced anticoagulation, - D.treatment of bleeding due to low levels of liver-dependent coagulation factors. ## Dosage ### General Considerations for Administration - For Intravenous Use after Reconstitution - Treatment with Coagulation Factor IX (Recombinant), should be initiated under the supervision of a physician experienced in the treatment of hemophilia B. - Each vial of coagulation factor IX has the rFIX potency in the International Units (IU) stated on the vial. - Dosage and duration of treatment for all factor IX products depend on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition, age and recovery of factor IX. - To ensure that the desired factor IX activity level has been achieved, precise monitoring using the factor IX activity assay is advised. Doses should be titrated using the factor IX activity, pharmacokinetic parameters, such as half-life and recovery, as well as taking the clinical situation into consideration in order to adjust the dose as appropriate. - Dosing of coagulation factor IX may differ from that of plasma-derived factor IX products. Subjects at the low end of the observed factor IX recovery may require upward dosage adjustment of coagulation factor IX to as much as two times (2X) the initial empirically calculated dose in order to achieve the intended rise in circulating factor IX activity. - The safety and efficacy of coagulation factor IX administration by continuous infusion have not been established. ### Method of Calculating Initial Estimated Dose - The method of calculating the factor IX dose is shown in TABLE 1. - In adult PTPs, on average, one International Unit (IU) of coagulation factor IX per kilogram of body weight increased the circulating activity of factor IX by 0.8 ® 0.2 IU/dL (range 0.4 to 1.2 IU/dL). The method of dose estimation is illustrated in TABLE 2. If you use 0.8 IU/dL average increase of factor IX per IU/kg body weight administered, then: - Coagulation factor IX is administered by intravenous (IV) infusion after reconstitution of the lyophilized powder with the supplied pre-filled diluent (0.234% sodium chloride solution) syringe. - Patients should follow the specific reconstitution and administration procedures provided by their physicians. - For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling. - Reconstitution, product administration, and handling of the administration set must be done with caution. Discard all equipment, including any reconstituted coagulation factor IX product, in an appropriate container. Place needles used for venipuncture in a sharps container after single use. Percutaneous puncture with a needle contaminated with blood from an infected patient can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Coagulation factor IX in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Coagulation factor IX in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ## Indication ### Control and Prevention of Bleeding Episodes in Hemophilia B - Coagulation Factor IX (Recombinant), is indicated for the control and prevention of bleeding episodes in adult and pediatric patients with hemophilia B (congenital factor IX deficiency or Christmas disease). ### Peri-operative Management in Patients with Hemophilia B - Coagulation Factor IX (Recombinant), is indicated for peri-operative management in adult and pediatric patients with hemophilia B. ## Dosage ### Average Recovery Pediatric Patients (<15 years) in Clinical Trial - In pediatric patients, on average, one international unit of coagulation factor IX per kilogram of body weight increased the circulating activity of factor IX by 0.7 ® 0.3 IU/dL (range 0.2 to 2.1 IU/dL; median of 0.6 IU/dL per IU/kg). The method of dose estimation is illustrated in TABLE 3. If you use 0.7 IU/dL average increase of factor IX per IU/kg body weight administered, then: - Doses administered should be titrated to the patient's clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to coagulation factor IX. Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests, including serial factor IX activity assays, be performed. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Coagulation factor IX in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Coagulation factor IX in pediatric patients. # Contraindications - Coagulation factor IX is contraindicated in patients who have manifested life-threatening, immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster protein. # Warnings ### General - The clinical response to coagulation factor IX may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor IX should be determined, and a sufficient dose of coagulation factor IX should be administered to achieve a satisfactory clinical response. If the patient's plasma factor IX level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected, and appropriate testing performed. ### Anaphylaxis and Severe Hypersensitivity Reactions - Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with coagulation factor IX and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors. Advise patients to discontinue use of the product and contact their physician and/or seek immediate emergency care. - Coagulation factor IX contains trace amounts of hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. ### Thromboembolic Complications - The safety and efficacy of coagulation factor IX administration by continuous infusion have not been established. There have been post-marketing reports of thrombotic events in patients receiving continuous-infusion coagulation factor IX through a central venous catheter, including life-threatening superior vena cava (SVC) syndrome in critically ill neonates. ### Nephrotic Syndrome - Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in hemophilia B patients with factor IX inhibitors and a history of allergic reactions to factor IX. The safety and efficacy of using coagulation factor IX for immune tolerance induction have not been established. ### Neutralizing Antibodies (Immunogenicity) - Patients using coagulation factor IX should be monitored for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of coagulation factor IX. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor IX inhibitor concentration should be performed. - Patients with factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent challenge with factor IX.2 Patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. Patients should be observed closely for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product. Because of the potential for allergic reactions with factor IX concentrates, the initial (approximately 10 - 20) administrations of factor IX should be performed under medical supervision where proper medical care for allergic reactions could be provided. ### Monitoring Laboratory Tests - Patients should be monitored for factor IX activity levels by the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained, when clinically indicated. Patients should be monitored for the development of inhibitors if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with the recommended dose of coagulation factor IX. Assays used to determine if factor IX inhibitor is present should be titered in Bethesda Units (BUs). # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - During uncontrolled open-label clinical studies with coagulation factor IX (Recombinant), conducted in previously treated patients (PTPs), 113 adverse reactions with known or unknown relation to coagulation factor IX therapy were reported among 38.5% (25 of 65) of subjects (with some subjects reporting more than one event) who received a total of 7,573 infusions. These adverse reactions are summarized in TABLE 5. - In the 63 previously untreated patients (PUPs), who received a total of 5,538 infusions, 10 adverse reactions were reported among 9.5% of the patients (6 out of 63) having known or unknown relationship to coagulation factor IX. These events are summarized in TABLE 6. - For adverse reactions thought to be related to the administration of coagulation factor IX, the rate of infusion should be decreased or the infusion stopped. ### Immunogenicity - In clinical studies with 65 PTPs (defined as having more than 50 exposure days), a low-titer inhibitor was observed in one patient. The inhibitor was transient, the patient continued on study and had normal factor IX recovery pharmacokinetics at study completion (approximately 15 months after inhibitor detection). - In clinical studies with pediatric PUPs, inhibitor development was observed in 2 out of 63 patients (3.2%), both were high-titer (> 5 BU) inhibitors detected after 7 and 15 exposure days, respectively. Both patients were withdrawn from the study. ## Postmarketing Experience - The following post-marketing adverse reactions have been reported for coagulation factor IX: inadequate factor IX recovery, inadequate therapeutic response, inhibitor development, anaphylaxis, angioedema, dyspnea, hypotension, and thrombosis. - Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - The safety and efficacy of BeneFIX administration by continuous infusion have not been established. There have been post-marketing reports of thrombotic events, including life-threatening SVC syndrome in critically ill neonates, while receiving continuous-infusion coagulation factor IX through a central venous catheter. Cases of peripheral thrombophlebitis and DVT have also been reported. In some, coagulation factor IX was administered via continuous infusion, which is not an approved method of administration. # Drug Interactions - None known. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction and lactation studies have not been conducted with coagulation factor IX (Recombinant). It is not known whether coagulation factor IX can affect reproductive capacity or cause fetal harm when given to pregnant women. Coagulation factor IX should be administered to pregnant women only if needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Coagulation factor IX in women who are pregnant. ### Labor and Delivery - There is no information available on the effect of factor IX replacement therapy on labor and delivery. Use only if needed. ### Nursing Mothers - It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if coagulation factor IX is administered to nursing mothers. - Use only if needed. ### Pediatric Use - Safety, efficacy, and pharmacokinetics of coagulation factor IX have been evaluated in previously treated (PTP) and previously untreated pediatric patients (PUP). On average, lower recovery has been observed in pediatric patients (<15 years). A dose adjustment may be needed. ### Geriatic Use - Clinical studies of coagulation factor IX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be individualized. ### Gender There is no FDA guidance on the use of Coagulation factor IX with respect to specific gender populations. ### Race There is no FDA guidance on the use of Coagulation factor IX with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Coagulation factor IX in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Coagulation factor IX in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Coagulation factor IX in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Coagulation factor IX in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous. - Coagulation factor IX is administered by intravenous (IV) infusion after reconstitution with the pre-filled diluent (0.234% sodium chloride solution) syringe. ### Monitoring - Patients using coagulation factor IX should be monitored for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. - Patients should be monitored for factor IX activity levels by the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained, when clinically indicated # IV Compatibility - There is limited information regarding IV Compatibility. # Overdosage - No symptoms of overdose have been reported. # Pharmacology There is limited information regarding Coagulation factor IX Pharmacology in the drug label. ## Mechanism of Action - Coagulation factor IX temporarily replaces the missing clotting factor IX that is needed for effective hemostasis. ## Structure - Coagulation factor IX (Recombinant), is a purified protein produced by recombinant DNA. It has a primary amino acid sequence that is identical to the Ala148 allelic form of plasma-derived factor IX, and has structural and functional characteristics similar to those of endogenous factor IX. Coagulation factor IX is produced by a genetically engineered Chinese hamster ovary (CHO) cell line that is extensively characterized. No human or animal proteins are added during the purification and formulation processes of coagulation factor IX. - Coagulation factor IX is not derived from human blood and contains no preservatives, and the manufacture of coagulation factor IX includes no added animal or human components. The stored cell banks are free of human blood or plasma products. The CHO cell line secretes recombinant factor IX into a defined cell culture medium that does not contain any proteins derived from animal or human sources, and the recombinant factor IX is purified by a chromatography purification process that does not require a monoclonal antibody step. The process also includes a membrane nanofiltration step that has the ability to retain molecules with apparent molecular weights >70,000 Da (such as large proteins and viral particles). Coagulation factor IX is a single component by SDS-polyacrylamide gel electrophoresis evaluation. The potency (in International Units, IU) is determined using an in vitro one-stage clotting assay against the World Health Organization (WHO) International Standard for Factor IX concentrate. One International Unit is the amount of factor IX activity present in 1 mL of pooled, normal human plasma. The specific activity of coagulation factor IX is greater than or equal to 200 IU per milligram of protein. - Coagulation factor IX is formulated as a sterile, nonpyrogenic, lyophilized powder preparation. Coagulation factor IX is intended for intravenous (IV) injection. It is available in single-use vials containing the labeled amount of factor IX activity, expressed in IU. Each vial contains nominally 250, 500, 1000, 2000, or 3000 IU of Coagulation Factor IX (Recombinant). After reconstitution of the lyophilized drug product, the concentrations of excipients are 0.234% sodium chloride, 8 mM L-histidine, 0.8% sucrose, 208 mM glycine, 0.004% polysorbate 80. All dosage strengths yield a clear, colorless solution upon reconstitution. ## Pharmacodynamics - The activated partial thromboplastin time (aPTT) is prolonged in people with hemophilia B. Treatment with factor IX concentrate may normalize the aPTT by temporarily replacing the factor IX. The administration of coagulation factor IX, Coagulation Factor IX (Recombinant), increases plasma levels of factor IX, and can temporarily correct the coagulation defect in these patients. ## Pharmacokinetics - After single intravenous (IV) doses of 50 IU/kg of previously marketed coagulation factor IX, Coagulation Factor IX (Recombinant) , in 37 previously treated adult patients (>15 years), each given as a 10-minute infusion, the mean increase from pre-infusion level in circulating factor IX activity was 0.8 ® 0.2 IU/dL per IU/kg infused (range 0.4 to 1.4 IU/dL per IU/kg) and the mean biologic half-life was 18.8 ® 5.4 hours (range 11 to 36 hours). In the original randomized, cross-over pharmacokinetic study in previously treated patients (PTPs), the in vivo recovery using previously marketed coagulation factor IX was statistically significantly less (28% lower, p<0.05) than the recovery using a highly purified plasma-derived factor IX product (pdFIX). A summary of pharmacokinetic data for coagulation factor IX and pdFIX are presented in TABLE 7. - There was no significant difference in biological half-life. Structural differences of the coagulation factor IX molecule compared with pdFIX were shown to contribute to the lower recovery. In subsequent evaluations for up to 24 months, the pharmacokinetic parameters were similar to the initial results. - In a subsequent randomized, cross-over pharmacokinetic study, coagulation factor IX reconstituted in 0.234% sodium chloride diluent was shown to be pharmacokinetically equivalent to the previously marketed coagulation factor IX (reconstituted with Sterile Water for Injection) in 24 previously treated patients (≥12 years) at a dose of 75 IU/kg. In addition, pharmacokinetic parameters were followed up in 23 previously treated patients after repeated administration of coagulation factor IX for six months and found to be unchanged compared with those obtained at the initial evaluation. A summary of pharmacokinetic data are presented in TABLE 8: ### Pediatric Patients (≤15 years) - Nineteen (19) previously treated pediatric patients (range 4 to ≤15 years) underwent pharmacokinetic evaluations for up to 24 months. Fifty-eight previously untreated patients less than 15 years of age at baseline underwent at least one recovery assessment within 30 minutes post-infusion in the presence or absence of hemorrhage during the study. A total of 202 recovery assessments collected during the 60-month period from these 58 PUPs are combined with 19 recovery assessments from PTPs and were summarized by age group in TABLE 9. There was one recovery assessment in a neonate, which had a value of 0.46 IU/dL per IU/kg. The overall mean recovery and FIX elimination half-life values were 0.7 ® 0.3 IU/dL per IU/kg and 20.2 ® 4.0 hours, respectively. - Data from 57 PUP subjects who underwent repeat recovery testing for up to 60 months demonstrated that the average incremental FIX recovery was consistent over time, as shown in FIGURE 1. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - Coagulation factor IX (Recombinant), has been shown to be nonmutagenic in the Ames assay and non-clastogenic in a chromosomal aberrations assay. No investigations on carcinogenesis or impairment of fertility have been conducted. # Clinical Studies - Efficacy of coagulation factor IX has been evaluated in clinical studies in which a total of 128 subjects received coagulation factor IX either for the treatment of bleeding episodes on an on-demand basis, for the prevention of bleeds (prophylaxis) or for management of hemostasis in the surgical setting (surgical prophylaxis). - Fifty-six PTPs and sixty-three PUPs were treated for bleeding episodes on an on-demand basis or for the prevention of bleeds (see Tables 9 and 10). The PTPs were followed over a median interval of 24 months (mean 23.4 ® 5.3 months) and for a median of 83.5. The PUPs were followed over a median interval of 37 months (mean 38.1 ® 16.4 months) and for a median of 89 exposure days. - Fifty-five PTPs and fifty-four PUPs received coagulation factor IX for the treatment of bleeding episodes (see TABLE 10). Bleeding episodes that were managed successfully included hemarthrosis and bleeding in soft tissue and muscle. Data concerning the severity of bleeding episodes were not reported. In the PTPs, 88% of total infusions administrated for on-demand treatment were rated as an "excellent" or "good" response. - A total of 20 PTPs were treated with coagulation factor IX for secondary prophylaxis (the regular administration of FIX replacement therapy to prevent bleeding in patients who may have already demonstrated clinical evidence of hemophilic arthropathy or joint disease) at some regular interval during the study with a mean of 2.0 infusions per week (see Table 11). Thirty-two PUPs were administered coagulation factor IX for routine (primary and secondary) prophylaxis (see TABLE 11). Twenty-four PUPs were administered coagulation factor IX at least twice weekly, and eight PUPs were administered coagulation factor IX once weekly. Seven PTPs experienced a total of 26 spontaneous bleeding episodes within 48 hours after an infusion. Six spontaneous bleeds within 48 hours after an infusion were reported in 5 PUPs. Prophylaxis therapy was rated as "excellent" or "effective" in 93% of PTPs receiving prophylaxis one to two times per week. - Management of hemostasis was evaluated in the surgical setting in both PTPs and PUPs (see TABLE 12). Thirty-six surgical procedures have been performed in 28 PTPs with 23 major surgical procedures performed (including 6 complicated dental extractions). Thirty surgical procedures have been performed in 23 PUPs. Twenty-eight of these procedures were considered minor. Hemostasis was maintained throughout the surgical period; however, one PTP subject required evacuation of a surgical wound-site hematoma, and another PTP subject who received coagulation factor IX after a tooth extraction required further surgical intervention due to oozing at the extraction site. There was no clinical evidence of thrombotic complications in any of the subjects. - Among the PTP surgery subjects, the median increase in circulating factor IX activity was 0.7 IU/dL per IU/kg infused (range 0.3 – 1.2 IU/dL; mean 0.8 ® 0.2 IU/dL per IU/kg). The median elimination half-life for the PTP surgery subjects was 19.4 hours (range 10 – 37 hours; mean 21.3 ® 8.1 hours). - Nine of the major surgical procedures were performed in 8 PUPs using a continuous-infusion regimen. Five of the surgical procedures were performed in PUPs using a continuous-infusion regimen over 3 to 5 days. Although circulating factor IX levels targeted to restore and maintain hemostasis were achieved with both pulse replacement and continuous infusion regimens, clinical trial experience with continuous infusion of coagulation factor IX for surgical prophylaxis in hemophilia B has been too limited to establish the safety and clinical efficacy of administration of the product by continuous infusion. - All subjects participating in the PTP, PUP and surgery studies were monitored for clinical evidence of thrombosis . No thrombotic complications were reported in PUPs or surgery subjects. One PTP subject experienced a renal infarct 12 days after a dose of coagulation factor IX for a bleeding episode; the relationship of the infarct to the prior administration of coagulation factor IX is uncertain. Laboratory studies of thrombogenecity (fibrinopeptide A and prothrombin fragment 1 + 2) were obtained in 41 PTPs and 7 surgery subjects prior to infusion and up to 24 hours following infusion. The results of these studies were inconclusive. Out of 29 PTP subjects noted to have elevated fibrinopeptide A levels post-infusion of coagulation factor IX, 22 also had elevated levels at baseline. Surgery subjects showed no evidence of significant increase in coagulation activation. # How Supplied - Coagulation Factor IX (Recombinant), is supplied in kits that include single-use vials which contain nominally 250, 500, 1000, 2000, or 3000 IU per vial with sterile pre-filled diluent syringe, vial adapter reconstitution device, sterile infusion set, and two (2) alcohol swabs, one bandage, and one gauze pad. *Actual factor IX activity in IU is stated on the label of each vial. - Product labeled "Room Temperature Storage". Store at 2 to 30°C (36 to 86°F). - Product labeled for refrigeration. Store at 2 to 8°C (36 to 46°F). ## Storage - Store at 2 to 30°C (36 to 86°F). - If the product kit is labeled for room temperature storage, it can be stored at room temperature (not to exceed 30°C or 86°F) or under refrigeration (2 to 8°C or 36 to 46°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise patients to report any adverse reactions or problems following BeneFIX administration to their physician or healthcare provider. - Allergic-type hypersensitivity reactions are possible. Inform patients of the early signs of hypersensitivity reactions and anaphylaxis. Advise patients to discontinue use of the product and contact their physicians if these symptoms occur. - Advise patients to contact their physician or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to factor IX replacement therapy, as in some cases this may be a manifestation of an inhibitor. # Precautions with Alcohol - Alcohol-Coagulation factor IX interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - BENEFIX ® # Look-Alike Drug Names - There is limited information regarding Look-Alike Drug Names. # Drug Shortage Status # Price

Tazarotene # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Tazarotene is a retinoid that is FDA approved for the {{{indicationType}}} of plaque psoriasis and acne vulgaris. Common adverse reactions include pruritus, erythema, desquamation, dry skin, and burning sensation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - It is recommended that treatment starts with TAZORAC® Cream, 0.05%, with strength increased to 0.1% if tolerated and medically indicated. Apply a thin film (2 mg/cm2) of TAZORAC® Cream once per day, in the evening, to cover only the psoriatic lesions. If a bath or shower is taken prior to application, the skin should be dry before applying the cream. If emollients are used, they should be applied at least an hour before application of TAZORAC® Cream. Because unaffected skin may be more susceptible to irritation, application of TAZORAC® Cream to these areas should be carefully avoided. - Cleanse the face gently. After the skin is dry, apply a thin layer (2 mg/cm2) of TAZORAC® Cream 0.1% once per day, in the evening, to the skin areas where acne lesions appear. Use enough to cover the entire affected area. - TAZORAC® Cream is for topical use only. TAZORAC® Cream is not for ophthalmic, oral, or intravaginal use. If contact with eyes occurs, rinse thoroughly with water. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tazarotene in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tazarotene in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Cleanse the face gently. After the skin is dry, apply a thin layer (2 mg/cm2) of TAZORAC® Cream 0.1% once per day, in the evening, to the skin areas where acne lesions appear. Use enough to cover the entire affected area. - TAZORAC® Cream is for topical use only. TAZORAC® Cream is not for ophthalmic, oral, or intravaginal use. If contact with eyes occurs, rinse thoroughly with water. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Tazarotene in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Tazarotene in pediatric patients. # Contraindications - Pregnancy - TAZORAC® Cream may cause fetal harm when administered to a pregnant woman. Tazarotene elicits teratogenic and developmental effects associated with retinoids after topical or systemic administration in rats and rabbits. TAZORAC® Cream is contraindicated in women who are pregnant or may become pregnant. - If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential hazard to the fetus. - Hypersensitivity - TAZORAC® Cream is contraindicated in individuals who have shown hypersensitivity to any of its components. # Warnings ### Precautions - Embryofetal Toxicity - Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In patients treated topically over sufficient body surface area, exposure could be in the same order of magnitude as in orally treated animals. Although there may be less systemic exposure in the treatment of acne of the face alone due to less surface area for application, tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans. - There were thirteen reported pregnancies in subjects who participated in the clinical trials for topical tazarotene. Nine of the subjects were found to have been treated with topical tazarotene, and the other four had been treated with vehicle. One of the subjects who was treated with tazarotene cream elected to terminate the pregnancy for non-medical reasons unrelated to treatment. The other eight pregnant women who were inadvertently exposed to topical tazarotene during clinical trials subsequently delivered apparently healthy babies. As the exact timing and extent of exposure in relation to the gestation times are not certain, the significance of these findings is unknown. - Females of Child-bearing Potential - Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when TAZORAC® Cream is used. The possibility that a female of child-bearing potential is pregnant at the time of institution of therapy should be considered. - A negative result for pregnancy test should be obtained within 2 weeks prior to TAZORAC® Cream therapy. TAZORAC® Cream therapy should begin during a menstrual period. - Local Irritation - Application of TAZORAC® Cream may cause excessive irritation in the skin of certain sensitive individuals. Some individuals may experience excessive pruritus, burning, skin redness or peeling. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the dosing should be reduced to an interval the patient can tolerate. However, efficacy at reduced frequency of application has not been established. Alternatively, patients with psoriasis who are being treated with the 0.1% concentration can be switched to the lower concentration. Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Therapy can be resumed, or the drug concentration or frequency of application can be increased as the patient becomes able to tolerate treatment. - Concomitant topical medications and cosmetics that have a strong drying effect should be avoided. It is also advisable to "rest" a patient's skin until the effects of such preparations subside before use of TAZORAC® Cream is begun. - TAZORAC® Cream, should not be used on eczematous skin, as it may cause severe irritation. - Weather extremes, such as wind or cold, may be more irritating to patients using TAZORAC® Cream. - Photosensitivity and Risk for Sunburn - Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided unless deemed medically necessary, and in such cases, exposure should be minimized during the use of TAZORAC® Cream. Patients must be warned to use sunscreens (minimum SPF of 15) and protective clothing when using TAZORAC® Cream. Patients with sunburn should be advised not to use TAZORAC® Cream until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using TAZORAC® Cream. - TAZORAC® Cream should be administered with caution if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - In human dermal safety trials, TAZORAC® Cream, 0.05% and 0.1% did not induce allergic contact sensitization, phototoxicity, or photoallergy. - Psoriasis - The most frequent adverse reactions reported with TAZORAC® Cream, 0.05% and 0.1% occurring in 10 to 23% of subjects, in descending order, included pruritus, erythema, and burning. Reactions occurring in greater than 1 to less than 10% of subjects, in descending order, included irritation, desquamation, stinging, contact dermatitis, dermatitis, eczema, worsening of psoriasis, skin pain, rash, hypertriglyceridemia, dry skin, skin inflammation, and peripheral edema. - TAZORAC® Cream, 0.1% was associated with a greater degree of local irritation than the 0.05% cream. The rates of irritation adverse reactions reported during psoriasis trials with TAZORAC® Cream, 0.1% were 0.1-0.4% higher than those reported for TAZORAC® Cream, 0.05%. - Acne - The most frequent adverse reactions reported during clinical trials with TAZORAC® Cream 0.1% in the treatment of acne, occurring in 10-30% of subjects, in descending order included desquamation, dry skin, erythema, and burning sensation. Reactions occurring in 1 to 5% of subjects included pruritus, irritation, face pain, and stinging. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tazarotene in the drug label. # Drug Interactions - No formal drug-drug interaction studies were conducted with TAZORAC® Cream. - In a trial of 27 healthy female subjects between the ages of 20–55 years receiving a combination oral contraceptive tablet containing 1 mg norethindrone and 35 mcg ethinyl estradiol, concomitant use of tazarotene administered as 1.1 mg orally (mean ± SD Cmax and AUC0-24 of tazarotenic acid were 28.9 ± 9.4 ng/mL and 120.6 ± 28.5 ng∙hr/mL) did not affect the pharmacokinetics of norethindrone and ethinyl estradiol over a complete cycle. - The impact of tazarotene on the pharmacokinetics of progestin only oral contraceptives (i.e., minipills) has not been evaluated. Close # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - There are no adequate and well-controlled studies with TAZORAC® Cream in pregnant women. TAZORAC® Cream is contraindicated in women who are or may become pregnant. Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when TAZORAC® Cream is used. The possibility that a female of child-bearing potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy test should be obtained within 2 weeks prior to TAZORAC® Cream therapy, which should begin during a menstrual period. Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In subjects treated topically over sufficient body surface area, exposure could be in the same order of magnitude as in orally treated animals. Although there may be less systemic exposure in the treatment of acne of the face alone due to less surface area for application, tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans. - In rats, a tazarotene gel, 0.05% formulation, administered topically during gestation days 6 through 17 at 0.25 mg/kg/day resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day tazarotene gel during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies. - Systemic exposure to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 1.2 and 13 times, respectively, that in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 4 and 44 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - When tazarotene was given orally to experimental animals, developmental delays were seen in rats; and teratogenic effects and post-implantation loss were observed in rats and rabbits at doses producing 1.1 and 26 times, respectively, the systemic exposure seen in a psoriatic patient treated topically with tazarotene cream, 0.1% at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study and 3.5 and 85 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, a number of classic developmental effects of retinoids were observed including decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights. A low incidence of retinoid-related malformations at that dose was observed. The dose produced a systemic exposure 3.4 times that observed in a psoriatic patient treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tazarotene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tazarotene during labor and delivery. ### Nursing Mothers - After single topical doses of 14C-tazarotene gel to the skin of lactating rats, radioactivity was detected in milk, suggesting that there would be transfer of drug-related material to the offspring via milk. It is not known whether this drug is excreted in human milk. The safe use of TAZORAC® Cream during lactation has not been established. A decision should be made whether to discontinue breast-feeding or to discontinue TAZORAC® Cream therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. ### Pediatric Use - The safety and efficacy of tazarotene have not been established in patients with psoriasis under the age of 18 years, or in patients with acne under the age of 12 years. ### Geriatic Use - TAZORAC® Cream for the treatment of acne has not been clinically tested in persons 65 years of age or older. - Of the total number of subjects in clinical trials of TAZORAC® Cream for plaque psoriasis, 120 were over the age of 65. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Currently there is no other clinical experience on the differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Tazarotene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tazarotene with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tazarotene in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tazarotene in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tazarotene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tazarotene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Tazarotene in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Tazarotene in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Excessive topical use of TAZORAC® Cream, 0.05% and 0.1% may lead to marked redness, peeling, or discomfort. - TAZORAC® Cream, 0.05% and 0.1% are not for oral use. Oral ingestion of the drug may lead to the same adverse effects as those associated with excessive oral intake of Vitamin A (hypervitaminosis A) or other retinoids. ### Management - If oral ingestion occurs, the patient should be monitored, and appropriate supportive measures should be administered as necessary. ## Chronic Overdose There is limited information regarding Chronic Overdose of Tazarotene in the drug label. # Pharmacology ## Mechanism of Action - Tazarotene is a retinoid prodrug which is converted to its active form, the carboxylic acid of tazarotene, by deesterification. Tazarotenic acid binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ, but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown. ## Structure - TAZORAC® (tazarotene) Cream, 0.05% and 0.1% is for topical use and contains the active ingredient, tazarotene. Each gram of TAZORAC® Cream, 0.05% and 0.1% contains 0.5 and 1 mg of tazarotene, respectively in a white cream base. - Tazarotene is a member of the acetylenic class of retinoids. Chemically, tazarotene is ethyl 6-nicotinate. The compound has an empirical formula of C21H21NO2S and molecular weight of 351.46. The structural formula is shown below: - TAZORAC® Cream contains the following inactive ingredients: benzyl alcohol 1%; carbomer 1342; carbomer homopolymer type B; edetate disodium; medium chain triglycerides; mineral oil; purified water; sodium hydroxide; sodium thiosulfate; and sorbitan monooleate. ## Pharmacodynamics - The pharmacodynamics of TAZORAC® Cream are unknown. ## Pharmacokinetics - Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Little parent compound could be detected in the plasma. Tazarotenic acid was highly bound to plasma proteins (greater than 99%). Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways. The half-life of tazarotenic acid was approximately 18 hours, following topical application of tazarotene to normal, acne or psoriatic skin. - In a multiple dose trial with a once daily dose for 14 consecutive days in 9 psoriatic subjects (male=5; female=4), measured doses of TAZORAC® Cream, 0.1% were applied by medical staff to involved skin without occlusion (5 to 35% of total body surface area: mean ± SD: 14 ± 11%). The Cmax of tazarotenic acid was 2.31 ± 2.78 ng/mL occurring 8 hours after the final dose, and the AUC0-24h was 31.2 ± 35.2 ng∙hr/mL on day 15 in the five subjects who were administered clinical doses of 2 mg cream/cm2. - During clinical trials with TAZORAC® Cream, 0.05% or 0.1% treatment for plaque psoriasis, three out of 139 subjects with their systemic exposure monitored had detectable plasma tazarotene concentrations, with the highest value at 0.09 ng/mL. Tazarotenic acid was detected in 78 out of 139 subjects (LLOQ = 0.05 ng/mL). Three subjects using tazarotene cream 0.1% had plasma tazarotenic acid concentrations greater than 1 ng/mL. The highest value was 2.4 ng/mL. However, because of the variations in the time of blood sampling, the area of psoriasis involvement, and the dose of tazarotene applied, actual maximal plasma levels are unknown. - TAZORAC® Cream 0.1% was applied once daily to either the face (N=8) or to 15% of body surface area (N=10) of female subjects with moderate to severe acne vulgaris. The mean Cmax and AUC values of tazarotenic acid peaked at day 15 for both dosing groups during a 29 day treatment period. Mean Cmax and AUC0-24h values of tazarotenic acid from subjects in the 15% body surface area dosing group were more than 10 times higher than those from subjects in the face-only dosing group. The single highest Cmax throughout the trial period was 1.91 ng/mL on day 15 in the exaggerated dosing group. In the face-only group, the mean ± SD values of Cmax and AUC0-24h of tazarotenic acid on day 15 were 0.10 ± 0.06 ng/mL and 1.54 ± 1.01 ng∙hr/mL, respectively, whereas in the 15% body surface area dosing group, the mean ± SD values of Cmax and AUC0-24h of tazarotenic acid on day 15 were 1.20 ± 0.41 ng/mL and 17.01 ± 6.15 ng∙hr/mL, respectively. The steady state pharmacokinetics of tazarotenic acid had been reached by day 8 in the face-only and by day 15 in the 15% body surface area dosing groups. - In a Phase 3 clinical trial, TAZORAC® Cream, 0.1% was applied once daily for 12 weeks to each of 48 subjects (22 females and 26 males) with facial acne vulgaris. The mean ± SD values of plasma tazarotenic acid at weeks 4 and 8 were 0.078 ± 0.073 ng/mL (N=47) and 0.052 ± 0.037 ng/mL (N=42), respectively. The highest observed individual plasma tazarotenic acid concentration was 0.41 ng/mL at week 4 from a female subject. The magnitude of plasma tazarotenic acid concentrations appears to be independent of gender, age, and body weight. ## Nonclinical Toxicology - Carcinogenesis - A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased carcinogenic risks. Based on pharmacokinetic data from a shorter term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic exposure in the rat equivalent to 0.6 times that seen in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/kg/cm2 over a 35% body surface area in a controlled pharmacokinetic study. This estimated systemic exposure in rats was 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% cream at 2 mg/cm2 over a 15% body surface area. - A long-term topical application study of up to 0.1% of tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcinogenic effects when compared to vehicle control animals. Systemic exposures at the highest dose was 3.9 times that seen in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 13 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - In evaluation of photo co-carcinogenicity, median time to onset of tumors was decreased, and the number of tumors increased in hairless mice following chronic topical dosing with intercurrent exposure to ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel formulation for up to 40 weeks. - Mutagenesis - Tazarotene was found to be non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in the in vivo mouse micronucleus test. - Impairment of Fertility - No impairment of fertility occurred in rats when male animals were treated for 70 days prior to mating and female animals were treated for 14 days prior to mating and continuing through gestation and lactation with topical doses of tazarotene gel up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat would be equivalent to 0.6 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area in a controlled pharmacokinetic study, and 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of up to 1 mg/kg/day tazarotene. That dose produced a systemic exposure that was 1.9 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area, and 6.3 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - No impairment of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through gestation day 7 with oral doses up to 2 mg/kg/day of tazarotene. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose . That dose produced a systemic exposure that was 3.4 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area and 11 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. - Reproductive capabilities of F1 animals, including F2 survival and development, were not affected by topical administration of tazarotene gel to female F0 parental rats from gestation day 16 through lactation day 20 at the maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat would be equivalent to 0.6 times that observed in a psoriatic patient treated with 0.1% tazarotene cream at 2 mg/cm2 over a 35% body surface area, and 2 times the maximum systemic exposure in acne patients treated with tazarotene cream, 0.1% at 2 mg/cm2 over a 15% body surface area. # Clinical Studies - In two 12-week vehicle-controlled clinical trials, TAZORAC® Cream, 0.05% and 0.1% was significantly more effective than vehicle in reducing the severity of stable plaque psoriasis. TAZORAC® Cream, 0.1% and 0.05% demonstrated superiority over vehicle cream as early as 1 week and 2 weeks, respectively, after starting treatment. - In these trials, the primary efficacy endpoint was “clinical success,” defined as the proportion of subjects with none, minimal, or mild overall lesional assessment at Week 12, and shown in Table 1. “Clinical success” was also significantly greater with TAZORAC® Cream, 0.05% and 0.1% versus vehicle at most follow-up visits. - At the end of 12 weeks of treatment, TAZORAC® Cream, 0.05% and 0.1% was consistently superior to vehicle in reducing the plaque thickness of psoriasis. Improvements in erythema and scaling were generally significantly greater with TAZORAC® Cream, 0.05% and 0.1% than with vehicle. TAZORAC® Cream, 0.1% was also generally more effective than TAZORAC® Cream, 0.05% in reducing the severity of the individual signs of disease. However, TAZORAC® Cream, 0.1% was associated with a greater degree of local irritation than TAZORAC® Cream, 0.05%. - Acne - In two large vehicle-controlled trials, subjects age 12 years and over with facial acne vulgaris of a severity suitable for monotherapy with a topical agent were enrolled. After face cleansing in the evening, TAZORAC® Cream, 0.1% was applied once daily to the entire face as a thin layer. TAZORAC® Cream, 0.1% was significantly more effective than vehicle in the treatment of facial acne vulgaris. Efficacy results after 12 weeks of treatment are shown in Table 3: # How Supplied - TAZORAC® Cream is a white cream available in concentrations of 0.05% and 0.1%. It is supplied in a collapsible aluminum tube with a tamper-evident aluminum membrane over the opening and a white polypropylene screw cap, in 30 g and 60 g sizes. - Storage: Store at 20°C to 25°C (68°F to 77°F). Excursions permitted from -5°C to 30°C (23°F to 86°F). ## Storage There is limited information regarding Tazarotene Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient of the following: - Fetal risk associated with TAZORAC® Cream for females of childbearing potential. Advise patients to use an effective method of contraception during treatment to avoid pregnancy. Advise the patient to stop medication if she becomes pregnant and call her doctor. - For the patient with psoriasis, apply TAZORAC® Cream only to psoriasis skin lesions, avoiding uninvolved skin. - If undue irritation (redness, peeling, or discomfort) occurs, reduce frequency of application or temporarily interrupt treatment. Treatment may be resumed once irritation subsides. - Moisturizers may be used as frequently as desired. - Patients with psoriasis may use a cream or lotion to soften or moisten skin at least 1 hour before applying TAZORAC® Cream. - Avoid exposure of the treated areas to either natural or artificial sunlight, including tanning beds and sun lamps. Use sunscreen and protective clothing if exposure to sunlight is unavoidable when using TAZORAC® Cream. - Avoid contact with the eyes. If TAZORAC® Cream gets in or near their eyes, rinse thoroughly with water. - Not for ophthalmic, oral, or intravaginal use. - Wash their hands after applying TAZORAC® Cream. # Precautions with Alcohol - Alcohol-Tazarotene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TAZORAC® # Look-Alike Drug Names There is limited information regarding Tazarotene Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Sodium borate # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies. # Overview Sodium borate is a OTC pellet that is FDA approved for the treatment of Canker sores (mouth ulcers). Common adverse reactions include vomiting and diarrhoea, abdominal pain, rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Canker sores (mouth ulcers) ### Dosage - Directions: (adults/children) Dissolve 5 pellets under the tongue 3 times a day until symptoms are relieved or as directed by a physician. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sodium borate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium borate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - Canker sores (mouth ulcers) ### Dosage - Directions: (adults/children) Dissolve 5 pellets under the tongue 3 times a day until symptoms are relieved or as directed by a physician. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sodium borate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium borate in pediatric patients. # Contraindications There is limited information regarding Sodium borate Contraindications in the drug label. # Warnings - Stop use and ask a physician if symptoms persist for more than 3 days or worsen. - Keep out of reach of children. - Do not use if pellet-dispenser seal is broken. # Adverse Reactions ## Clinical Trials Experience - vomiting and diarrhoea, abdominal pain, rash ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Sodium borate in the drug label. # Drug Interactions There is limited information regarding Sodium borate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - If pregnant or breast-feeding, ask a health professional before use. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sodium borate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sodium borate during labor and delivery. ### Nursing Mothers - If pregnant or breast-feeding, ask a health professional before use. ### Pediatric Use There is no FDA guidance on the use of Sodium borate with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Sodium borate with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Sodium borate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sodium borate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sodium borate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sodium borate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sodium borate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sodium borate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Sodium borate in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Sodium borate in the drug label. # Overdosage There is limited information regarding Overdose of Sodium borate in the drug label. # Pharmacology ## Mechanism of Action There is limited information regarding Sodium borate Mechanism of Action in the drug label. ## Structure - Active Ingredient: - Inactive Ingredients: Lactose, sucrose. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Sodium borate in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Sodium borate in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Sodium borate in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Sodium borate in the drug label. # How Supplied There is limited information regarding Sodium borate How Supplied in the drug label. ## Storage - Store at room temperature. # Images ## Drug Images ## Package and Label Display Panel ### Ingredients and Appearance # Patient Counseling Information There is limited information regarding Patient Counseling Information of Sodium borate in the drug label. # Precautions with Alcohol - Alcohol-Sodium borate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - BORAX® # Look-Alike Drug Names There is limited information regarding Sodium borate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Carmustine (implant) # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Carmustine (implant) is an alkylationg agent that is FDA approved for the treatment of high-grade malignant glioma, glioblastoma multiforme. Common adverse reactions include headache, nausea and vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indication - Carmustine is indicated for the treatment of patients with: - newly-diagnosed high-grade malignant glioma as an adjunct to surgery and radiation, and recurrent glioblastoma multiforme as an adjunct to surgery. ### Dosage - The recommended dose of carmustine is eight 7.7 mg wafers for a total of 61.6 mg implanted intracranially. The safety and effectiveness of repeat administration have not been studied. - Following maximal tumor resection, confirmation of tumor pathology and establishment of hemostasis, place up to a maximum of eight carmustines to cover as much of the resection cavity as possible. Should the size and shape of the resected cavity not accommodate eight wafers, place the maximum number of wafers feasible within the cavity. Slight overlapping of the wafers is acceptable. Wafers broken in half may be used, but discard wafers broken in more than two pieces. Oxidized regenerated cellulose (Surgicel®) may be placed over the wafers to secure them against the cavity surface. After placement of the wafers, irrigate the resection cavity and close the dura in a water-tight fashion. - Carmustines contain a cytotoxic drug. Follow applicable special handling and disposal procedures.1 - Each wafer is packaged within two nested aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outside surface of the outer laminated aluminum foil pouch is a peelable overwrap and is not sterile. - Deliver carmustines to the operating room in their outer aluminum foil pouch, unopened. Do not open the pouch until the wafers are ready to be implanted. Carmustines in unopened outer foil pouches are stable at room temperature for six hours at a time for up to three cycles within a 30-day period. - Exposure to carmustine can cause severe burning and hyperpigmentation of the skin. Use double gloves when handling carmustines. Discard the outer gloves into a biohazard waste container after use. Use a dedicated surgical instrument for wafer implantation. If repeat neurosurgical intervention is indicated, handle residual wafers or wafer remnants as potential cytotoxic agents. - Instructions for Opening Pouch Containing carmustine - Read all steps of the instructions prior to opening the pouch. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carmustine (implant) in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carmustine (implant) in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Carmustine (implant) in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carmustine (implant) in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carmustine (implant) in pediatric patients. # Contraindications - Condition1 # Warnings - Seizures occurred in 37% of patients treated with carmustines for recurrent glioma in Study 2. New or worsening (treatment emergent) seizures occurred in 20% of patients; 54% of treatment emergent seizures occurred within the first 5 post-operative days. The median time to onset of the first new or worsened post-operative seizure was four days. Institute optimal anti-seizure therapy prior to surgery. - Monitor patients for seizures postoperatively. - Brain edema occurred in 23% of patients with newly diagnosed glioma treated with carmustines in Study 1. Additionally, one GLIADEL-treated patient experienced intracerebral mass effect unresponsive to corticosteroids which led to brain herniation. Monitor patients closely for intracranial hypertension related to brain edema, inflammation, or necrosis of the brain tissue surrounding the resection. In refractory cases, consider re-operation and removal of carmustines or Wafer remnants. - Impaired neurosurgical wound healing including wound dehiscence, delayed wound healing, and subdural, subgleal, or wound effusions occur with carmustine treatment. In Study 1, 16% of carmustine-treated patients with newly diagnosed glioma experienced impaired intracranial wound healing and 5% had cerebrospinal fluid leaks. In Study 2, 14% of carmustine-treated patients with recurrent glioma experienced wound healing abnormalities . Monitor patients post-operatively for impaired neurosurgical wound healing. - Meningitis occurred in 4% of patients with recurrent glioma receiving carmustines in Study 2. Two cases of meningitis were bacterial; one patient required removal of the Wafers four days after implantation; the other developed meningitis following reoperation for recurrent tumor. One case was diagnosed as chemical meningitis and resolved following steroid treatment. In one case the cause was unspecified, but meningitis resolved following antibiotic treatment. Monitor postoperatively for signs of meningitis and central nervous system infection. - Carmustine migration can occur. To reduce the risk of obstructive hydrocephalus due to wafer migration into the ventricular system, close any communication larger than the diameter of a Wafer between the surgical resection cavity and the ventricular system prior to Wafer implantation. Monitor patients for signs of obstructive hydrocephalus. - Carmustines can cause fetal harm when administered to a pregnant woman. Carmustine, the active component of carmustine, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose on a mg/m2 basis and embryotoxic in rabbits at exposures similar to the exposure at the recommended human dose on a mg/m2 basis. Advise females of reproductive potential to avoid pregnancy after implantation of carmustines. If the patient becomes pregnant after carmustine implantation, warn the patient about the potential hazard to the fetus. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety of carmustines was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 240 adult patients with newly-diagnosed high-grade malignant glioma who received up to eight carmustines or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 1). - The population in Study 1 was 67% male and 97% White, and the median age was 53 years (range: 21-72). Eighty-seven percent had a Karnofsky performance status ≥ 70 and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of glioblastoma multiforme as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; an additional 11% received no radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy. - Deaths occurred within 30 days of wafer implantation in 5 (4%) of patients receiving carmustines compared to 2 (2%) of patients receiving placebo. Deaths on the GLIADEL arm resulted from cerebral hematoma/edema (n=3), pulmonary embolism (n=1) and acute coronary event (n=1). Deaths on the placebo arm resulted from sepsis (n=1) and malignant disease (n=1). - The incidence of common adverse reactions in carmustine-treated patients is listed in Table 1. The incidence of local adverse reactions is shown in Table 2. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Carmustine (implant) in the drug label. # Drug Interactions There is limited information regarding Carmustine (implant) Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Carmustine can cause fetal harm when administered to a pregnant woman. There have been no studies with carmustine; however, carmustine, the active component of carmustine, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose on a mg/m2 basis and embryotoxic in rabbits at exposures similar to exposures at the recommended human dose on a mg/m2 basis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. - There are no studies assessing the reproductive toxicity of carmustine; however, carmustine, the active component of carmustine, is embryotoxic and teratogenic in rats at intraperitoneal doses of 0.5mg/kg/day or greater when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 0.12 the recommended human dose, eight wafers of 7.7 mg carmustine/wafer, on a mg/m2 basis). Carmustine was embryotoxic in rabbits at intravenous doses of 4.0 mg/kg/day (about 1.2 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carmustine (implant) in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carmustine (implant) during labor and delivery. ### Nursing Mothers - It is not known if carmustine, the active component of carmustine, is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from carmustine, a decision should be made whether to discontinue nursing or not to administer the drug, taking into account the importance of the drug to the mother. ### Pediatric Use There is no FDA guidance on the use of Carmustine (implant) with respect to pediatric patients. ### Geriatic Use Clinical trials of carmustine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Carmustine (implant) with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carmustine (implant) with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Carmustine (implant) in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Carmustine (implant) in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carmustine (implant) in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carmustine (implant) in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intracranial Implant ### Monitoring There is limited information regarding Monitoring of Carmustine (implant) in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Carmustine (implant) in the drug label. # Overdosage There is limited information regarding Carmustine (implant) overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology There is limited information regarding Carmustine (implant) Pharmacology in the drug label. ## Mechanism of Action - Although it is generally agreed that carmustine alkylates DNA and RNA, it is not cross-resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. ## Structure - The structural formula is: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Carmustine (implant) in the drug label. ## Pharmacokinetics - Carmustine concentrations delivered by carmustine in human brain tissue have not been determined. - Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m2, the average terminal half-life, clearance and steady-state volume of distribution were 22 minutes, 56 mL/min/kg and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200-mg/m2 dose of 14C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO2. Carmustine degrades both spontaneously and metabolically. The relevance of these data to elimination of intracranial implant-delivered carmustine are unknown. - Carmustines are biodegradable when implanted into the human brain. Wafer remnants may be observed on brain imaging scans or at re-operation. Wafer remnants were visible in 11 of 18 patients on CT scans obtained 49 days after implantation of carmustine. More than 70% of the copolymer degrades within three weeks. Wafer remnants have been present at re-operation and autopsy up to 232 days after carmustine implantation, and consisted mostly of water and monomeric components with minimal detectable carmustine present. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Carmustine (implant) in the drug label. # Clinical Studies # How Supplied - Carmustine is supplied in a single dose treatment box containing eight individually pouched wafers. Each wafer contains 7.7 mg of carmustine and is packaged in two aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outer pouch is a peelable overwrap. The outside surface of the outer pouch is not sterile. - NDC for single dose treatment box: 24338-050-08 ## Storage - Store carmustine at or below -20ºC (-4ºF). - Do not keep unopened foil pouches at ambient room temperature for more than six hours at a time for up to three cycles within a 30-day period. - Carmustine is a cytotoxic drug and special handling and disposal procedures should be considered.1 # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Seizures: Advise patients to report any new or change in their seizure activity. - Intracranial Hypertension: Advise patients to report severe headaches, nausea, vomiting or new onset visual disturbances. - Impaired Neurosurgical Wound Healing: Advise patients to report any evidence of wound dehiscence, fever or cerebrospinal fluid leak. - Meningitis: Advise patients to report symptoms of meningitis such as fever or stiff neck. - Embryo-Fetal Toxicity: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use effective contraception during treatment with GLIADEL. - Nursing Infants: Advise nursing mothers to discontinue nursing after carmustine implantation. # Precautions with Alcohol - Alcohol-Carmustine (implant) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GLIADEL® # Look-Alike Drug Names There is limited information regarding Carmustine (implant) Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

MSMB Beta-microseminoprotein is a protein that in humans is encoded by the MSMB gene. For historical reasons, the scientific literature may also refer to this protein as Prostate secretory protein 94 (PSP94), microseminoprotein (MSP), microseminoprotein-beta (MSMB), beta-inhibitin, prostatic inhibin peptide (PIP), and inhibitin like material (ILM). # Distribution MSMB is one of the three major proteins secreted by the epithelial cells of the prostate and has a concentration in seminal plasma of 0.5 to 1 mg/mL Two comprehensive studies of beta-microseminoprotein in tissue have shown that it is secreted by epithelial cells in many other organs: liver, lung, breast, kidney, colon, stomach, pancreas, esophagus, duodenum, salivary glands, fallopian tube, corpus uteri, bulbourethral glands and cervix. This list corresponds closely to the sites from which all late onset cancers develop. # Evolution and structure MSMB is a rapidly evolving protein. Solution structures of human and porcine MSMB show remarkable similarity despite having only 51% of amino acids in common. The C-terminus domain of MSMB contains two two-stranded β-sheets; these have no resemblance to other structural motifs. The rapid evolution of MSMB can be attributed to either sexual selection or innate pathogen defense; the wide distribution of MSMB in the body and the fungicidal properties of the C-terminus suggest that innate pathogen defense plays a role in driving this evolution. # Function Beta-microseminoprotein is a member of the immunoglobulin binding factor family. This protein has been reported to have inhibin-like properties, though this finding has been disputed. It may have a role as an autocrine paracrine factor in uterine, breast and other female reproductive tissues. Two alternatively spliced transcript variants encoding different isoforms are described for this gene. Despite having only 4 out of 11 amino acids in common, both the porcine and human fungicidal peptide on MSMB's C-terminus are potently fungicidal in the absence of calcium ions. The protein inhibits growth of cancer cells in an experimental model of prostate cancer, though this property is cell line specific. # Clinical significance Two large genome-wide association studies showed that decreased expression of the MSMB protein caused by the rs10993994 single nucleotide polymorphism is associated with an increased risk of developing prostate cancer (odds ratio for CT allele pair ~1.2x, and for TT allele pair ~1.6x when compared to the low risk CC allele pair). A 2003 study proposed using a truncated form of the MSMB protein called PSP61 as a biomarker for benign prostatic hyperplasia (BPH): this study found PSP61 in the expressed prostatic secretion of 10 out of ten 10 men suffering from BPH, but did not find it in 10 out of 10 age-matched BPH-free men. This truncated form of the MSMB protein lacks the fungicidal peptide identified in 2012. The expression of MSMB is found to be decreased in prostate cancer, so it may be used as a biomarker for prostate cancer. Urinary MSMB has been found to be superior than urinary PSA at differentiating men with prostate cancer at all Gleason grades.

Temple (anatomy) Temple indicates the side of the head behind the eyes. The bone beneath is the temporal bone. # Anatomy Cladists classify land vertebrates based on the presence of an upper hole, a lower hole, both, or neither in the cover of dermal bone which formerly covered the temporalis muscle. Those with no holes are called anapsida. The muscle whose origin is the temple and whose insertion is the jaw is the temporalis muscle. The brain has a lobe, called the temporal lobe. # Etymology This use of temple is a separate etymology than the word "temple" for "place of worship". Both come from Latin, but the word for the place of worship comes from templum, whereas the word for the part of the head comes from Vulgar Latin *tempula, modified from tempora, plural form ("both temples") of tempus, a word that meant both "time" and the part of the head. Due to the common source with the word for time, the adjective for both is "temporal" (both "pertaining to time" and "pertaining to the temple").

Cementoblast # Overview A cementoblast is a biological cell that forms from the follicular cells around the root of a tooth, and whose biological function is cementogenesis, which is the creation of cementum (the hard tissue that covers the root of the tooth). Cementoblasts lay down the organic matrix of cementum which later gets mineralised by minerals from oral fluids. Thus the cementoblasts lay down collagen and secrete osteocalcin and sialoprotein. They possess all the organelles associated with protein synthesis such as RER and Golgi apparatus. The mechanism of differentiation of the cementoblasts is controversial but circumstantial evidence suggests that an epithelium or epithelial componenet may cause dental follicle cells to differentiate into cementoblasts, characterised by an increase in length. The initially formed cementum in coronal two-thirds of the root is acellular, but when the cementoblasts get trapped in lacunae in their own matrix like bone cells, the cementum is called cellular or secondary cementum and is present only in the apical third of the root. Once in this situation, the cementoblasts lose their secretory activity and become cementocytes.

Central nervous system disease # Overview A central nervous system (CNS) disease can affect either the spinal cord (myelopathy) or brain (encephalopathy), both of which are part of the central nervous system. # CNS Composition and Functions ## Spinal Cord - The spinal cord transmits sensory information from the peripheral nervous system. - It also conducts motor information to the body's skeletal, cardiac, and smooth muscles, and glands. - There are 31 pairs of spinal nerves along the spinal cord. These nerves each contain both sensory and motor axons. - The spinal cord is protected by vertebrae and connects the peripheral nervous system to the brain, and it acts as a "minor" coordinating center. ## Brain - It allows the body to function. - The brain is protected by the skull; however, if the brain is damaged, the results to the human body can be very consequential. - For more information, click here. # Types of Disease ## Bipolar Disorder - Bipolar disorder is a serious illness of the nervous system. - Symptoms can include both signs of major depression and mania. - Mood swings from the highs of mania to the lows of deep depression usually occur over several weeks to months. - New research suggests that bipolar disorder is actually a neurological disease genetically related to Parkinson's disease. - For more information, click here. ## Catalepsy - Catalepsy is a nervous disorder characterized by immobility and muscle rigidity, along with decreased sensitivity to pain. - It is considered a symptom of serious diseases of the nervous system (e.g., Parkinson's disease, epilepsy, etc.) rather than a disease by itself. - Cataleptic fits can range in duration from several minutes to weeks. - The condition often responds to benzodiazepines (e.g., lorazepam) in pill and I.V. form. - For more information, click here. ## Epilepsy/Seizures - Epilepsy is an unpredictable, serious, and potentially fatal disorder of the nervous system, thought to be the result of faulty electrical activity in the brain. - Epileptic seizures result from abnormal, excessive, or hypersynchronous neuronal activity in the brain. - Approximately 50 million people worldwide have epilepsy, and nearly 80% of epilepsy occurs in developing countries. - Epilepsy becomes more common as people age. - Onset of new cases occurs more frequently in infants and the elderly. - Epileptic seizures may occur in recovering patients as a consequence of brain surgery. - For more information, click here. ## Encephalitis - Encephalitis is an inflammation of the brain. - It is usually caused by a foreign substance or a viral infection. - Symptoms of this disease include headache, neck pain, drowsiness, nausea, and fever. - If caused by the West Nile virus, it may be lethal to humans, as well as birds and horses. - For more information, click here. ## Meningitis - Meningitis is an inflammation of the meninges (membranes) of the brain and spinal cord. - It is most often caused by a bacterial or viral infection. - Fever, vomiting, and a stiff neck are all symptoms of meningitis. - For more information, click here. ## Migraine - Migraine is a chronic, often debilitating neurological disorder characterized by recurrent moderate to severe headaches. - It is often associated with a number of autonomic nervous system symptoms. - For more information, click here. ## Tropical Spastic Paraparesis - Tropical spastic paraparesis is caused by human T-lymphotropic virus. - Patients present with weakness, muscle spasms, and sensory disturbance. - For more information, click here. ## Arachnoid Cysts - Arachnoid cysts are filled with cerebrospinal fluid and covered by arachnoidal cells that may develop in the brain or spinal cord. - They are a congenital disorder, and can be asymptomatic. - However, if there is a large cyst, symptoms may include headache, seizures, ataxia (lack of muscle control), andhemiparesis. - Macrocephaly and ADHD are common presentations among children, while presenile dementia, hydrocephalus (an abnormality of the dynamics of the cerebrospinal fluid), and urinary incontinence are symptoms for the elderly patients (65 and older). - For more information, click here. ## Huntington's Disease - Huntington's disease is a degenerative neurological disorder that is inherited. - Degeneration of neuronal cells occurs throughout the brain, especially in the striatum. - There is a progressive decline that results in abnormal movements. - Statistics show that Huntington’s disease may affect 10 per 100,000 people of Western European descent. - For more information, click here. ## Alzheimer’s Disease - Alzheimer’s disease is a neurodegenerative disorder typically found in people over the age of 65 years. - Worldwide, approximately 24 million people have dementia; 60% of these cases are due to Alzheimer’s disease. - Clinical sign of Alzheimer’s disease is progressive cognition deterioration. - The ultimate cause is unknown. - For more information, click here. ## Attention Deficit/Hyperactivity Disorder (ADHD) - ADHD (often highly debated and controversial) is now largely considered to be a genuine organic disorder of the nervous system, according to the United States government. - It can be seriously debilitating in the severe forms. - The symptoms are thought to be caused by structural as well as biochemical imbalances in the brain; in particular, low levels of the neurotransmitters dopamine and norepinephrine, which are responsible for controlling and maintaining attention and movement. - Many people with ADHD continue to have symptoms well into adulthood. - Also of note is an increased risk of the development of Dementia with Lewy bodies (DLB), and a direct genetic association of attention deficit disorder to Parkinson's disease. - For more information, click here. ## Locked-in Syndrome - Locked-in syndrome usually results from a stroke that damages part of the brainstem. - In this condition, the body and most of the facial muscles are paralysed but consciousness remains intact along with the ability to perform certain eye movements. - For more information, click here. ## Parkinson's Disease - Parkinson’s disease (PD) is a progressive illness of the nervous system. - It is caused by the death of dopamine-producing brain cells that affect motor skills and speech. - Symptoms may include bradykinesia (slow physical movement), muscle rigidity, and tremors. - Behavioral changes, thinking disturbance, sensation disorders, and seborrheic dermatitis are some of PD's numerous non-motor symptoms. - Interestingly, Parkinson's disease, attention deficit/hyperactivity disorder (ADHD), and bipolar disorder appear to have some connection to one another, as all three nervous system disorders involve lower than normal levels of the dopamine (In ADHD, PD, and the depressive phase of bipolar disorder) or too much dopamine (In mania or manic states of bipolar disorder) in different areas of the brain. - For more information, click here. ## Tourette's Syndrome - Tourette's syndrome is an inherited neurological disorder. - Early onset may be during childhood, and it is characterized by physical and verbal tics. - The exact cause of Tourette's syndrome, other than genetic factors, is unknown. - For more information, click here. ## Multiple sclerosis - Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease, meaning that the myelin sheath of neurons is damaged. - Symptoms of MS include visual and sensation problems, muscle weakness, and depression. - For more information, click here. # Causes ## Trauma - Any type of traumatic brain injury (TBI) or injury to the spinal cord can result in a wide spectrum of disabilities in a person. - Depending on the section of the brain or spinal cord that suffers the trauma, the outcome may be anticipated. ## Infections - An infection is a condition that results from the invasion by microorganisms. - Infectious diseases are transmitted in several ways. - Some of these infections may affect the brain or spinal cord directly. ## Degeneration - Degenerative spinal disorders involve a loss of function in the spine. - Pressure on the spinal cord and nerves may be associated with vertebral disc herniation or displacement. - Brain degeneration also causes central nervous system diseases. - Studies have shown that obese people may have severe degeneration in the brain due to the loss of tissue affecting cognition. ## Structural Defects - Common structural defects include birth defects, anencephaly, hypospadias, and spina bifida. - Children born with structural defects may have malformed limbs, heart problems, and facial abnormalities. ## Tumors - A tumor is an abnormal growth of body tissue. - In the beginning, tumors can be non-cancerous, but if they become malignant, they are cancerous. - In general, they appear when there is a problem with cellular division. - Problems with the body’s immune system can also lead to tumor development. ## Autoimmune Disorders - An autoimmune disorder is a condition where the immune system attacks healthy body tissue. - This is caused by a loss of tolerance to proteins in the body, resulting in immune cells recognizing these as 'foreign' and directing an immune response against them. - For more information, click here. ## Stroke - A stroke is an interruption of the blood supply to the brain. - Approximately every 40 seconds, someone in the US has a stroke. - This can happen when a blood vessel is blocked by a blood clot or when a blood vessel ruptures, causing blood to leak to the brain. - If the brain can not get enough oxygen and blood, brain cells can die, leading to permanent damage. - For more information, click here. # Signs and Symptoms - Every disease has different signs and symptoms. - Some of the signs and symptoms are listed below: Headache Pain in the face, back, arms, or legs An inability to concentrate Loss of feeling Memory loss Loss of muscle strength Tremors Seizures Increased reflexes Spasticity Tics Paralysis Slurred speech - Headache - Pain in the face, back, arms, or legs - An inability to concentrate - Loss of feeling - Memory loss - Loss of muscle strength - Tremors - Seizures - Increased reflexes - Spasticity - Tics - Paralysis - Slurred speech # Treatment - There is a wide range of treatment modalities available for central nervous system diseases. - These can range from medical therapy or rehabilitation to surgery.

Enasidenib # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Enasidenib is a isocitrate dehydrogenase-2 inhibitor that is FDA approved for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Enasidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. - The recommended starting dose of Enasidenib is 100 mg taken orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. - Do not split or crush Enasidenib tablets. Administer Enasidenib tablets orally about the same time each day. If a dose of Enasidenib is vomited, missed, or not taken at the usual time, administer the dose as soon as possible on the same day, and return to the normal schedule the following day. - Assess blood counts and blood chemistries for leukocytosis and tumor lysis syndrome prior to the initiation of Enasidenib and monitor at a minimum of every 2 weeks for at least the first 3 months during treatment. Manage any abnormalities promptly. - Interrupt dosing or reduce dose for toxicities. See TABLE 1 for dosage modification guidelines. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Enasidenib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Enasidenib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Enasidenib FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Enasidenib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Enasidenib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None # Warnings - In the clinical trial, 14% of patients treated with Enasidenib experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with Enasidenib included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, and as early as 10 days and at up to 5 months after Enasidenib initiation. - If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt Enasidenib until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended. - Based on animal embryo-fetal toxicity studies, Enasidenib can cause embryo-fetal harm when administered to a pregnant woman. In animal embryo-fetal toxicity studies, Enasidenib caused embryo-fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose. Advise females of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. Advise males with female partners of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. Pregnant women, patients becoming pregnant while receiving Enasidenib, or male patients with pregnant female partners should be apprised of the potential risk to the fetus. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety evaluation of single-agent Enasidenib is based on 214 patients with relapsed or refractory AML who were assigned to receive 100 mg daily . The median duration of exposure to Enasidenib was 4.3 months (range 0.3 to 23.6). The 30-day and 60-day mortality rates observed with Enasidenib were 4.2% (9/214) and 11.7% (25/214), respectively. - The most common adverse reactions (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. - Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure. - Overall, 92 of 214 patients (43%) required a dose interruption due to an adverse reaction; the most common adverse reactions leading to dose interruption were differentiation syndrome (4%) and leukocytosis (3%). Ten of 214 patients (5%) required a dose reduction due to an adverse reaction; no adverse reaction required dose reduction in more than 2 patients. Thirty-six of 214 patients (17%) permanently discontinued Enasidenib due to an adverse reaction; the most common adverse reaction leading to permanent discontinuation was leukocytosis (1%). - Adverse reactions reported in the trial are shown in TABLE 2. - Other clinically significant adverse reactions occurring in ≤10% of patients included: - Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, acute respiratory distress syndrome. - Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in TABLE 3. ### Elevated Bilirubin - Enasidenib may interfere with bilirubin metabolism through inhibition of UGT1A1. Thirty-seven percent of patients (80/214) experienced total bilirubin elevations ≥2 x ULN at least one time. Of those patients who experienced total bilirubin elevations ≥2 x ULN, 35% had elevations within the first month of treatment, and 89% had no concomitant elevation of transaminases or other severe adverse events related to liver disorders. No patients required a dose reduction for hyperbilirubinemia; treatment was interrupted in 3.7% of patients, for a median of 6 days. Three patients (1.4%) discontinued Enasidenib permanently due to hyperbilirubinemia. ### Non-infectious Leukocytosis - Enasidenib can induce myeloid proliferation resulting in a rapid increase in white blood cell count. ### Tumor Lysis Syndrome - Enasidenib can induce myeloid proliferation resulting in a rapid reduction in tumor cells which may pose a risk for tumor lysis syndrome. ## Postmarketing Experience There is limited information regarding Enasidenib Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Enasidenib Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on animal embryo-fetal toxicity studies, Enasidenib can cause fetal harm when administered to a pregnant woman. There are no available data on Enasidenib use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of Enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 0.1 times the steady state clinical exposure based on the AUC at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. - Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data (Animal) - Enasidenib administered to pregnant rats at a dose of 30 mg/kg twice daily during organogenesis (gestation days 6-17) was associated with maternal toxicity and adverse embryo-fetal effects including post-implantation loss, resorptions, decreased viable fetuses, lower fetal birth weights, and skeletal variations. These effects occurred in rats at approximately 1.6 times the clinical exposure at the recommended human daily dose of 100 mg/day. - In pregnant rabbits treated during organogenesis (gestation days 7-19), Enasidenib was maternally toxic at doses equal to 5 mg/kg/day or higher (exposure approximately 0.1 to 0.6 times the steady state clinical exposure at the recommended daily dose) and caused spontaneous abortions at 5 mg/kg/day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enasidenib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Enasidenib during labor and delivery. ### Nursing Mothers Risk Summary - There are no data on the presence of Enasidenib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Enasidenib and for at least 1 month after the last dose. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - No dosage adjustment is required for Enasidenib based on age. In the clinical study, 61% of 214 patients were aged 65 years or older, while 24% were older than 75 years. No overall differences in effectiveness or safety were observed between patients aged 65 years or older and younger patients. ### Gender There is no FDA guidance on the use of Enasidenib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Enasidenib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Enasidenib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Enasidenib in patients with hepatic impairment. ### Females of Reproductive Potential and Males Pregnancy Testing - Based on animal embryo-fetal toxicity studies, Enasidenib can cause fetal harm when administered to a pregnant woman. - Obtain a pregnancy test on females of reproductive potential prior to starting treatment with Enasidenib. ### Contraception Females - Advise females of reproductive potential to avoid becoming pregnant while receiving Enasidenib. Advise females of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose. Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time. Males - Advise males with female partners of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. ### Infertility - Based on findings in animals, Enasidenib may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. ### Immunocompromised Patients There is no FDA guidance one the use of Enasidenib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administer at the same time each day. - Do not split or crush tablets. - Missed dose or vomiting: Administer as soon as possible on the same day and return to the normal schedule the following day. ### Monitoring - Screen for presence of IDH2 mutations prior to initiation of treatment. - Disease response or stabilizations may indicate efficacy. - Blood counts and blood chemistries: Prior to treatment and at least every 2 weeks for the first 3 months during treatment. - Pregnancy test: Prior to treatment. # IV Compatibility There is limited information regarding the compatibility of Enasidenib and IV administrations. # Overdosage There is limited information regarding Enasidenib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Enasidenib is a small molecule inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme. Enasidenib targets the mutant IDH2 variants R140Q, R172S, and R172K at approximately 40-fold lower concentrations than the wild-type enzyme in vitro. Inhibition of the mutant IDH2 enzyme by Enasidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, Enasidenib decreased 2-HG levels, reduced blast counts and increased percentages of mature myeloid cells. ## Structure ## Pharmacodynamics Cardiac Electrophysiology - The potential for QTc prolongation with Enasidenib was evaluated in an open-label study in patients with advanced hematologic malignancies with an IDH2 mutation. Based on the QTc data for a single dose of 30 mg to 650 mg and multiple doses of 100 mg daily in the fasted state, no large mean changes in the QTc interval (>20 ms) were observed following treatment with Enasidenib. ## Pharmacokinetics - The peak plasma concentration (Cmax) is 1.3 mcg/mL after a single dose of 100 mg, and 13 mcg/mL (CV% 46.3) at steady state for 100 mg daily. The area under concentration time curve (AUC) of Enasidenib increases in an approximately dose proportional manner from 50 mg (0.5 times approved recommended dosage) to 450 mg (4.5 times approved recommended dosage) daily dose. Steady-state plasma levels are reached within 29 days of once-daily dosing. Accumulation is approximately 10-fold when administered once daily. ### Absorption - The absolute bioavailability after 100 mg oral dose of Enasidenib is approximately 57%. After a single oral dose, the median time to Cmax (Tmax) is 4 hours. ## =Distribution - The mean volume of distribution (Vd) of Enasidenib is 55.8 L (CV% 29). Human plasma protein binding of Enasidenib is 98.5% and of its metabolite AGI-16903 is 96.6% in vitro. - Enasidenib is not a substrate for P-glycoprotein or BCRP, while AGI-16903 is a substrate of both P-glycoprotein and BCRP. Enasidenib and AGI-16903 are not substrates of MRP2, OAT1, OAT3, OATP1B1, OATP1B3, and OCT2. ### Elimination - Enasidenib has a terminal half-life of 137 hours (CV% 41) and a mean total body clearance (CL/F) of 0.74 L/hour (CV% 71). Metabolism - Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated metabolite, represented 10% of the circulating radioactivity. - In vitro studies suggest that metabolism of Enasidenib is mediated by multiple CYP enzymes (e.g., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UGTs (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15). Further metabolism of the metabolite AGI-16903 is also mediated by multiple enzymes (e.g., CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9). Excretion - Eighty-nine percent (89%) of Enasidenib is eliminated in feces and 11% in the urine. Excretion of unchanged Enasidenib accounts for 34% of the radiolabeled drug in the feces and 0.4% in the urine. ### Specific Populations - No clinically meaningful effect on the pharmacokinetics of Enasidenib was observed for the following covariates: age (19 years to 100 years), race (White, Black, or Asian), mild hepatic impairment , renal impairment (defined as creatinine clearance ≥30 mL/min by Cockcroft-Gault formula), sex, body weight (39 kg to 136 kg), and body surface area. ### Drug Interaction Studies - In vitro studies suggest that Enasidenib inhibits the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and UGT1A1. Enasidenib inhibits P-gp, BCRP, OAT1, OATP1B1, OATP1B3, and OCT2, but not MRP2 or OAT3. Enasidenib induces CYP2B6 and CYP3A4. - In vitro studies suggest that the metabolite AGI-16903 inhibits the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. AGI-16903 inhibits BCRP, OAT1, OAT3, OATP1B1, and OCT2, but not P-gp, MRP2, or OATP1B3. - Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time. ## Nonclinical Toxicology - Carcinogenicity studies have not been performed with Enasidenib. - Enasidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Enasidenib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay, or in an in vivo rat bone marrow micronucleus assay. - Fertility studies in animals have not been conducted with Enasidenib. In repeat-dose toxicity studies with twice daily oral administration of Enasidenib in rats up to 90-days in duration, changes were reported in male and female reproductive organs including seminiferous tubular degeneration, hypospermia, atrophy of the seminal vesicle and prostate, decreased corpora lutea and increased atretic follicles in the ovaries, and atrophy in the uterus. # Clinical Studies - The efficacy of Enasidenib was evaluated in an open-label, single-arm, multicenter, two-cohort clinical trial (Study AG221-C-001, NCT01915498) of 199 adult patients with relapsed or refractory AML and an IDH2 mutation, who were assigned to receive 100 mg daily dose. Cohort 1 included 101 patients and Cohort 2 included 98 patients. IDH2 mutations were identified by a local diagnostic test and retrospectively confirmed by the Abbott RealTime™ IDH2 assay, or prospectively identified by the Abbott RealTime™ IDH2 assay, which is the FDA-approved test for selection of patients with AML for treatment with Enasidenib. Enasidenib was given orally at starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage adverse events. - The baseline demographic and disease characteristics are shown in TABLE 4. The baseline demographics and disease characteristics were similar in both study cohorts. - Efficacy was established on the basis of the rate of complete response (CR)/complete response with partial hematologic recovery (CRh), the duration of CR/CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in TABLE 5 and were similar in both cohorts. The median follow-up was 6.6 months (range, 0.4 to 27.7 months). Similar CR/CRh rates were observed in patients with either R140 or R172 mutation. - For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5 months) and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2 months). Of the 46 patients who achieved a best response of CR/CRh, 39 (85%) did so within 6 months of initiating Enasidenib. - Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day post baseline period. Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post baseline period. # How Supplied - 50-mg tablet: Pale yellow to yellow oval-shaped film-coated tablet debossed “ENA” on one side and “50” on the other side. - 30-count bottles of 50-mg tablets with a desiccant canister (NDC 59572-705-30). - 100-mg tablet: Pale yellow to yellow capsule-shaped film-coated tablet debossed “ENA” on one side and “100” on the other side. - 30-count bottles of 100-mg tablets with a desiccant canister (NDC 59572-710-30). ## Storage - Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C-30°C (59°F-86°F). Keep the bottle tightly closed. Store in the original bottle (with a desiccant canister) to protect from moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Differentiation Syndrome - Advise patients on the risks of developing differentiation syndrome as early as 10 days and during the first 5 months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, bone pain, rapid weight gain or swelling of their arms or legs, to their healthcare provider for further evaluation. ### Tumor Lysis Syndrome - Advise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values. ### Gastrointestinal Adverse Reactions - Advise patients on risk of experiencing gastrointestinal reactions such as diarrhea, nausea, vomiting, decreased appetite, and changes in their sense of taste. Ask patients to report these events to their healthcare provider, and advise patients how to manage them. ### Elevated Blood Bilirubin - Inform patients that taking Enasidenib may cause elevated blood bilirubin, which is due to its mechanism of action, and not due to liver damage. Advise patients to report any changes to the color of their skin or the whites of their eyes to their healthcare provider for further evaluation. ### Embryo-Fetal Toxicity and Use of Contraceptives - Advise female patients with reproductive potential to use effective contraceptive methods while receiving Enasidenib and to avoid pregnancy while on treatment and for 1 month after completion of treatment. Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during Enasidenib treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time. ### Lactation - Advise women not to breastfeed during treatment with Enasidenib and for at least 1 month after the final dose. ### Dosing and Storage Instructions - Advise patients not to chew or split the tablets but swallow whole with a cup of water. - Instruct patients that if they miss a dose or vomit after a dose of Enasidenib, to take it as soon as possible on the same day and return to normal schedule the following day. Warn patients not to take 2 doses to make up for the missed dose. - Keep Enasidenib in the original container. Keep the container tightly closed with desiccant canister inside to protect the tablets from moisture. # Precautions with Alcohol Alcohol-Enasidenib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Idhifa # Look-Alike Drug Names There is limited information regarding Enasidenib Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price

Hormone therapy in perimenopause and postmenopause (HT) This short version of the interdisciplinary S3 guideline on hormone therapy in peri-and postmenopause (HT) is intended as a decision-making instrument for physicians and women considering HT. It is designed to assist daily practice. This short version summarises the long version that contains detailed information about the development of the guideline, particularly about establishing the evidence levels. The statements and recommendations, quoted completely, are marked with the relevant levels of evidence (LoE) and grades of recommendation. The classification system from the Centre for Evidence-based Medicine in Oxford was used in this guideline (see ''Attachment''). # Introduction Peri-and post-menopausal women often seek medical assistance because of climacteric symptoms (e.g. hot flushes and sweating), considering HT for the treatment of these symptoms. They hope for alleviation of these symptoms and possibly an improvement in their quality of life. While ageing, the symptoms may change, and there may be dysfunctions or diseases that also depend on sex hormones. This situation can influence the assessment of the risk-benefit ratio. The prevention of diseases that frequently develop in postmenopausal women is also often an issue when discussing HT. ## Compounds, forms of application, pharmacology There are clinically relevant differences between the available estrogens, progestins and estrogen-progestin combinations as well as between the various forms of application of HT. These differences apply to the benefit as well as to some risks, and they should be taken into account when managing individual cases. ## Climacteric symptoms and their treatment During the climacteric period, women often suffer from vasomotor complaints (hot flushes) and vaginal dryness. These symptoms were the most consistent findings observed in studies in this period of life. Other problems such as disturbed sleep, various physical symptoms, pain, urinary tract disorders, sexual problems and mood fluctuations have a less consistent association with the menopausal transition period. Estrogens are the most effective treatment for hot flushes and vaginal atrophy. The frequency of these complaints can be markedly reduced by HT, or the symptoms will even disappear completely. There are other complaints associated with the climacteric period which may be relieved with HT. If HT is indicated, an improvement of the woman's general well-being is possible. # Statements Hot flushes and vaginal dryness are associated with the transition from premenopause to postmenopause; the frequency of reports on these symptoms varies (LoE 2a). Other complaints like disturbed sleep, various physical symptoms, urinary tract disorders, sexual problems, or mood fluctuations are inconsistently reported symptoms (LoE 2a). Degree of consensus: strong consensus Estrogens are effective for the treatment of hot flushes (LoE 1a) Conjugated equine estrogens, oral 17b-estradiol, and transdermal 17b-estradiol reduce hot flushes to a comparable degree (LoE 1a). An additional treatment with progestins does not interfere with the effect of estrogens on vasomotor complaints (LoE 1a). Tibolone is effective in the treatment of hot flushes (LoE 1a). There is no difference in the effect of estrogen therapy on hot flushes between women with natural menopause and women after bilateral oophorectomy . (see also the chapter on urogenital symptoms). Degree of consensus: strong consensus In women who were treated with various estrogens or estrogen-progestin combinations, positive as well as negative effects on the quality of life were found, but in some instances no effect was noted (LoE 1a). Degree of consensus: consensus ## Recommendations When assessing the risk-benefit ratio, one should bear in mind that the only two complaints most consistently reported by women during the menopausal transition are hot flushes and vaginal dryness (A). Degree of consensus: consensus Hot flushes can be treated with estrogens or, if applicable, estrogen-progestin combinations, or with tibolone (A). When deciding on the indication, the risks and benefits presented in this guideline should be taken into account (A). Degree of consensus: strong consensus The sole improvement of a woman's so-called general well-being or health-related quality of life is not an indication for HT (B HT is not indicated for the primary or secondary prevention of coronary heart disease in women at any age because there are other strategies with proven efficacy. However, numerous findings from observational studies suggest that HT may reduce the risk of myocardial infarction, when started early. In contrast to these findings, the WHI study, a randomized controlled trial, found a non-significant trend of risk reduction by ET in women aged 50-59 years, but not in older women. With combined estrogen-progestin therapy (EPT), the risk was increased at the beginning of treatment, but not after treatment duration of 5.6 years. Particularly, older women and women with a predisposition for cardiovascular disease had an increased risk at the beginning of treatment. Especially in older women ([60 years), systemic HT should only be initiated after careful assessment of risks and benefits, taking any pre-existing risk factors into consideration. ## Recommendation HT is not indicated for the primary or secondary prevention of coronary heart disease (B). There are other strategies with proven efficacy for primary or secondary prevention (A). Degree of consensus: strong consensus ## Cerebrovascular disease HT increases the risk for an ischaemic cerebrovascular event. This risk should always be considered in the assessment of risks and benefits, particularly in older women. # Statement HT increases the risk for an ischaemic cerebrovascular event (LoE 1a). Degree of consensus: strong consensus ## Recommendation The increased risk of stroke must always be considered in the assessment of risks and benefits of HT (A). ## Degree of consensus: strong consensus Thromboembolic disease HT increases the risk of venous thrombosis and pulmonary embolism, particularly in the first year of use and in the presence of risk factors such as congenital coagulation disorders. A meta-analysis of observational studies shows that the risk is lower with transdermal HT. # Statement Oral HT increases the risk of venous thrombosis and pulmonary embolism (VTE) (LoE 1a). Degree of consensus: strong consensus ## Recommendation The increased risk of VTE must be considered while assessing the risks and benefits of HT. The risk is particularly high in the first year of HT use and further increases if there are additional predisposing risk factors for venous thrombosis (A). ## Degree of consensus: strong consensus ## Skin ageing Available data are insufficient to make reliable statements on the effects of HT on the processes of skin ageing. Smaller comparative studies have, in part, shown a positive effect of estrogens on parameters of skin ageing. The limited number of randomized studies with small numbers of cases and significant methodological flaws, respectively have not yielded any reliable results. # Statement An alleviation of skin ageing processes by HT has not been proven (LoE 2b). ## Degree of consensus: strong consensus Recommendation HT is not indicated for alleviating the processes of skin ageing (A). Degree of consensus: strong consensus ## Signs of skin androgenisation There is only a small number of evaluable trials using HT with anti-androgenic progestins (cyproterone acetate [CPA], chlormadinone acetate [CMA], dienogest , and drospirenone [DRSP]) in the climacteric period. In particular, it is impossible to state if HT with anti-androgenic progestins can result in a significant improvement of androgenic skin changes, because there have been no specific trials addressing this question. However, if a combined estrogen-progestin therapy is indicated, women with cutaneous signs of androgenisation should primarily receive preparations with an anti-androgenic progestin compound instead of a preparation with a progestin deriving from the 19-nortestosterone group. # Statement Alleviation of the signs of skin androgenisation with HT has not been proven (LoE 5). ## Degree of consensus: strong consensus Recommendation HT is not indicated to alleviate signs of skin androgenisation (A). ## Degree of consensus: strong consensus ## Diseases of the gall bladder and gall ducts HT increases the risk of gall duct disease. This is mainly the effect of the estrogen compound. The risk is probably less profound with transdermal estrogen application. # Statement There is evidence that diseases of the gall bladder and gall ducts, particularly cholecystolithiasis, cholecystitis/ cholangitis as well as cholecystectomies, occur more frequently with HT (LoE Ib). Degree of consensus: strong consensus ## Recommendation When assessing the risks and benefits of HT, the increased risk of cholecystitis/cholangitis, cholecystolithiasis and cholecystectomies must be taken into account (A). ## Degree of consensus: consensus ## Cognition There is limited evidence from older clinical trials that ET has a short-term positive effect on cognition when used in premenopausal women after bilateral oophorectomy. The long-term effects of HT started during the menopausal transition or during the early postmenopausal period are unknown. Neither ET nor EPT were able to prevent the decline of cognitive functions in older postmenopausal women, either as short-or long-term treatment. The evidence is insufficient to assess if special forms of HT may confer any benefit. Observational studies have demonstrated a reduction of the risk for dementia, e.g. Alzheimer's disease, with the use of HT. However, these studies are heterogeneous and show a substantial bias. Therefore, based on the insufficient quality of the data, it is not possible to make recommendations on the basis of available evidence. # Statement In the Women's Health Initiative Memory Study (WHIMS), the relationship between HT and dementia in women over 65 years was investigated as part of the WHI. The endpoint ''mild cognitive impairment'' did not show any difference between HT and placebo, either with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA), or with CEE alone. With the endpoint ''possible dementia'', there was a significantly increased relative risk for the combination of CEE and MPA, but not for CEE alone, versus placebo. In women with a diagnosis from mild to moderate Alzheimer's dementia, there was no significant difference between 1-year ET and placebo as to the overall appearance of the Alzheimer's dementia. # Statements HT does not show any benefit on the signs of dementia in women with Alzheimer's disease (LoE 1a). Degree of consensus: strong consensus Continuous combined HT increases the risk of dementia in women aged over 65 years (LoE 2a). Degree of consensus: strong consensus ## Recommendation HT should not be recommended to decrease the risk of dementia (A). ## Degree of consensus: strong consensus Breast cancer The use of HT increases the risk of breast cancer. The increased risk was seen after duration of use of 5 or more years. Meta-analyses incorporating both observational studies and randomized controlled trials have also shown an increased risk of breast cancer with ET alone. The effect was weaker than with EPT. In addition, the increase of risk by ET, compared with EPT, was only seen after a longer duration of use. The WHI did not show any increased risk after a mean duration of ET use of 7.1 years. After HT is discontinued, the risk decreases. After a few years, the risk does not differ from the risk of women who never used HT. # Statements EPT increases the risk of breast cancer (LoE 1b). ET increases the risk of breast cancer to a lesser degree than EPT (LoE 2a). Degree of consensus: strong consensus/consensus ## Recommendation The increased risk of breast cancer must be considered while assessing the benefits and risks of HT (A). ## Degree of consensus: strong consensus ## Ht in cancer patients According to a recent randomized trial, HT use after breast cancer leads to a markedly increased risk of recurrence. Assessing the risk of HT after endometrial, ovarian or colorectal cancer is difficult because only few observational studies are available. These did not demonstrate an increased risk of recurrence when HT was used. Yet, the number of cases is too low to draw reliable conclusions about the safety of HT after treatment of the cancer entities mentioned earlier. # Statements HT increases the risk of recurrence when used after breast cancer (LoE 2b). The risk of HT use after treated endometrial, ovarian or colorectal cancer has not been studied sufficiently (LoE 2b). Since lack of data, no statement is possible regarding other types of tumours (LoE 5). Degree of consensus: strong consensus/consensus Recommendation HT is contraindicated after breast cancer treatment (A). ## Degree of consensus: strong consensus ## Premature menopause Women with premature menopause (\40 years of age) are a heterogeneous group. The available studies have mostly investigated women with surgical oophorectomy. From a clinical point of view, it seems to make sense to use HT in women with premature menopause, at least until the average age of natural menopause (about 50 years). # Statements It is unclear whether the benefits and risks of HT in women with premature menopause differ from those in women with natural menopause aged around 50 years (LoE 2a). HT is appropriate for the treatment of hot flushes and vaginal atrophy in symptomatic women with premature menopause (LoE 2a). Degree of consensus: strong consensus/consensus ## Recommendation In women with premature menopause, HT can be used until the average age of natural menopause (0). ## Degree of consensus: consensus ## Alternative therapies Currently, there is no evidence that herbal remedies have a reliable effect on vasomotor complaints. Isoflavones or Cimicifuga racemosa can be considered in cases of mild hot flushes or sweating, since a decrease of climacteric complaints is possible in few cases. It is not possible to predict if this treatment will be effective in the individual case. In cases of severe vasomotor complaints, a sufficient therapeutic effect cannot be expected. If there are contraindications against hormonal therapies, and the woman expresses an urgent desire for treatment, selective serotonin re-uptake inhibitors (SSRI) and gabapentin may be considered as an individual experimental treatment. It should be noted that neither medication is currently approved for this indication. Therefore, a medical justification based on the risk-benefit assessment is needed, and the patient must be thoroughly informed about the situation (''off label use''). For all alternative therapies, there is a lack of data on long-term safety. # Statements Isoflavone containing supplements made from soybeans or red clover, or a nutrition rich in phytoestrogens, do not reduce hot flushes, or only marginally, if at all (LoE 1a). Currently, the possible risks of alternative therapies cannot be assessed with sufficient reliability (LoE 1a). Degree of consensus: strong consensus ## Recommendation Phytoestrogens and other herbal or non-hormonal therapies cannot be recommended as an alternative to HT (0). ## Degree of consensus: strong consensus ## Risk communication Risk communication is defined as communication about the probabilities of expected benefits and the possible risks of harm by HT, with the patient and possibly with an accompanying person. For an individual assessment and evaluation of the probability of benefit and the risk of harm, individual factors such as the woman's general state of health, age, age at menopause, previous HT, duration of use, dosage and type of HT, and diseases while using HT should be taken into consideration. In order to give adequate information about the risks to the woman seeking advice, the doctor must be familiar with the principles of risk calculation. He or she should also be able to communicate the probabilities in such a way that the patient can make her own individual decision for or against the initiation of HT. The figures necessary for this communication can be found in the long version and in the balance sheet (see ''attachments''). Notes: Users can add a minus-sign ''-'' to denote the level of that fails to provide a conclusive answer because: either a single result with a wide confidence interval or a systematic review with troublesome heterogeneity. Such evidence is inconclusive, and therefore can only generate Grade D recommendations * By homogeneity we mean a systematic review that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. Not all systematic reviews with statistically significant heterogeneity need be worrisome, and not all worrisome heterogeneity need be statistically significant. As noted above, studies displaying worrisome heterogeneity should be tagged with a ''-'' at the end of their designated level Clinical Decision Rule. (These are algorithms or scoring systems that lead to a prognostic estimation or a diagnostic category.) à See note above for advice on how to understand, rate and use trials or other studies with wide confidence intervals § Met when all patients died before the Rx became available, but some now survive on it; or when some patients died before the Rx became available, but none now die on it § § By poor quality cohort study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both exposed and non-exposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of patients. By poor quality case-control study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both cases and controls and/or failed to identify or appropriately control known confounders § § § Split-sample validation is achieved by collecting all the information in a single tranche, then artificially dividing this into ''derivation'' and ''validation'' samples An ''Absolute SpPin'' is a diagnostic finding whose specificity is so high that a positive result rules-in the diagnosis. An ''Absolute SnNout'' is a diagnostic finding whose sensitivity is so high that a negative result rules-out the diagnosis àà Good, better, bad and worse refer to the comparisons between treatments in terms of their clinical risks and benefits Good reference standards are independent of the test, and applied blindly or objectively to applied to all patients. Poor reference standards are haphazardly applied, but still independent of the test. Use of a non-independent reference standard (where the 'test' is included in the 'reference', or where the 'testing' affects the 'reference') implies a level 4 study Better-value treatments are clearly as good but cheaper, or better at the same or reduced cost. Worse-value treatments are as good and more expensive, or worse and the equally or more expensive ** Validating studies test the quality of a specific diagnostic test, based on prior evidence. An exploratory study collects information and trawls the data (e.g. using a regression analysis) to find which factors are 'significant' *** By poor quality prognostic cohort study we mean one in which sampling was biased in favour of patients who already had the target outcome, or the measurement of outcomes was accomplished in \80% of study patients, or outcomes were determined in an unblinded, nonobjective way, or there was no correction for confounding factors **** Good follow-up in a differential diagnosis study is[80%, with adequate time for alternative diagnoses to emerge (for example 1-6 months acute, 1-5 years chronic) Arch Gynecol Obstet (2011) The balance sheet listed above is intended for demonstration of the risk of HT with respect to different endpoints. ## Attachment ## Levels of evidence There are different indices available to quantify the effect of interventions: Absolute risk reduction (ARR) describes the absolute difference in the rate of undesirable events in the experimental group (E) compared with the control group (C) if the experimental treatment is effective (ARR = C -E). The reciprocal value of the ARR is the number needed to treat (1/ARR = NNT). NNT is a clinically intuitive measure for endpoints to describe the effects of a certain treatment. It represents the number of patients who must be treated to prevent one additional undesirable event. The absolute risk increase (ARI) describes the absolute difference in the rate of undesirable events in the experimental group in comparison with the control group if the experimental treatment is worse (ARI = |C -E|). The reciprocal value of the ARI is the number needed to harm (NNH). NNH is a clinically intuitive measure for endpoints to describe the unwanted effects of a certain treatment. It represents the number of patients who must be treated to cause one additional undesirable event. The relative risk reduction (RRR) describes the relative decrease in the rate of undesirable events in the experimental study group as compared with the control group (RRR = |C -E|/C). Example: Phlebothrombosis If the yearly rate of phlebothrombosis in postmenopausal users of oral ET is 22 in 10,000 women, and the rate in non-users is 11 in 10,000 women, the RR is RR ¼ 22 10; 000=year Ä 11 10; 000=year ¼ 2 This means a doubled risk of phlebothrombosis when using ET for 1 year. An RR of more than 1.0 indicates an increased risk. An RR of 1.2 signifies a risk increase by 20%. An RR of less than 1.0 indicates a decrease of risk. An RR of 0.5, for example, would mean a risk decrease by 50%-the probability of an event when using ET would then be only half as high as with non-use. For the evaluation of risks, it is often more useful to state the absolute risk (AR). The AR describes the risk difference by calculating the difference in the incidence between exposed and non-exposed populations. In the example used above (phlebothrombosis in ET users) the AR is AR ¼ 22 10; 000=year À 11 10; 000=year ¼ 11 10; 000=year This means that there will be 11 additional phlebothromboses per year for every 10,000 women using oral ET. Changes in the AR are, however, significantly influenced by the pre-existing risk found in the exposed persons. ## Report on guidelines and methods The long version, the list of references and the detailed report on guidelines and methods are published in German on the DGGG homepage (http://www.dggg.de, area ''Leitlinien''). This guideline was developed under the aegis of the DGGG and approved by the following institutions: Medical associations

SLC19A2 Thiamine transporter 1, also known as thiamine carrier 1 (TC1) or solute carrier family 19 member 2 (SLC19A2) is a protein that in humans is encoded by the SLC19A2 gene. SLC19A2 is a thiamine transporter. Mutations in this gene cause thiamine-responsive megaloblastic anemia syndrome (TRMA), which is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anemia and sensorineural deafness. # Structure The SLC19A2 gene is located on the q arm of chromosome 1 in position 24.2 and spans 22,062 base pairs. The gene produces a 55.4 kDa protein composed of 497 amino acids. In the encoded protein (TC1), a multi-pass membrane protein located in the cell membrane, the N-terminus and C-terminus face the cytosol. This gene has 6 exons while the protein has 12 putative transmembrane domains, with 3 phosphorylation sites in putative intracellular domains, 2 N-glycolysation sites in putative extracellular domains, and a 17-amino acid long G protein-coupled receptor signature sequence. The thiamine transporter protein encoded by SLC19A2 has a 40% shared amino acid identity with the folate transporter SLC19A1. The N-terminal domain and the sequence between the C-terminal domain and sixth transmembrane domain are required for proper localization of this protein to the cell membrane. # Function The encoded protein is a high-affinity transporter specific to the intake of thiamine. Thiamine transport is not inhibited by other organic cations nor affected by sodium ion concentration; it is stimulated by a proton gradient directed outward, with an optimal pH between 8.0 and 8.5. TC1 is transported to the cell membrane by intracellular vesicles via microtubules. # Clinical significance Mutations in the SLC19A2 gene can cause thiamine-responsive megaloblastic anemia syndrome (TRMA), which is an autosomal recessive disease characterized by megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Onset is typically between infancy and adolescence, but all of the cardinal findings are often not present initially. The anemia, and sometimes the diabetes, improves with high doses of thiamine. Other more variable features include optic atrophy, congenital heart defects, short stature, and stroke. A 3.8 kb transcript is expressed variably in most tissues, highest in skeletal and cardiac muscle, followed by medium expression placenta, heart, liver, kidney cells and low expression in lung cells. In melanocytic cells SLC19A2 gene expression may be regulated by MITF. # Interactions This protein interacts with CERS2.

Chloride channel # Overview Chloride channels are a superfamily of poorly understood ion channels consisting of approximately 13 members. It is now recognised that chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell proliferation and differentiation. A number of different gene products have been shown to function as chloride channels. Based on sequence homology the chloride channels can be subdivided into a number of groups. The importance of one such group, the CLC family of chloride channels, can be seen from the diseases that develop when the channel does not function normally. # Pathology Bartter's syndrome, which is associated with renal salt wasting and hypokalemic alkalosis, is due to the defective transport of chloride ions and associated ions in the thick ascending loop of Henle. CLC-Kb has been implicated. Another inherited disease that affects the kidney organs is Dent's Disease, characterised by low molecular weight proteinuria and hypercalciuria where mutations in CLC-5 are implicated. Thomsen disease is associated with domininate mutations and Becker disease with recessive mutations in CLCN1. # Functions Chloride channels are important for setting cell resting membrane potential and maintaining proper cell volume. These channels conduct Cl- as well as other anions such as HCO3-, I-, SCN-, and NO3-. The structure of these channels is also not other known channels. Chloride channel subunits contain between 1 and 12 transmembrane segments. Some members of this family are activated by voltage, while others are activated by Ca2+, extracellular ligands, and pH among other modulators. # Commercial Applications Chloride channels are disrupted in fleas, causing death, with some organic materials. Selamectin is the active ingredient in Revolution, a topical insecticide and antihelminthic used on dogs and cats. Selamectin works by replacing glutamate which normally interacts with receptors that open chloride channels at muscle synapses found in parasites. Unlike glutamate, selamectin activates the chloride current without desensitization, thereby producing prolonged hyperpolarization and impaired muscle contraction. # Genes - CLCN1, CLCN2, CLCN3, CLCN4, CLCN5, CLCN6, CLCN7 - CLCNKA, CLCNKB - CLIC1, CLIC2, CLIC3, CLIC4, CLIC5, CLIC6 - CLNS1A, CLNS1B - CLCA1, CLCA2, CLCA3, CLCA4

Nuphar lutea Nuphar lutea, the spatterdock, yellow water-lily, cow lily, or yellow pond-lily, is an aquatic plant of the family Nymphaeaceae, native to Eurasia. It grows in eutrophic freshwater beds, with its roots fixed into the ground and its leaves floating on the water's surface. The plant's inflorescence is a solitary, terminal hermaphrodite flower, pollinated by insects, which blooms from June to September in the Northern Hemisphere. The flower is followed by achenes which are distributed by the water current. Spatterdock was long used in traditional medicine, with the root applied to the skin and/or both the root and seeds eaten for a variety of conditions. The seeds are edible, and can be ground into flour. The root is edible too, but can prove to be incredibly bitter in some plants. Possible botanical synonyms include Nuphar luteum (L.) Sibthorp & Sm. and Nuphar advena (Ait) Ait f.

Valproic acid capsule delayed release overdosage # Overdosage Over dosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate over dosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

GADD45G Growth arrest and DNA-damage-inducible protein GADD45 gamma is a protein that in humans is encoded by the GADD45G gene on chromosome 9. GADD45G is also known as CR6, DDIT2, GRP17, OIG37, and GADD45gamma. GADD45G is involved in several different processes, including sexual development, human-specific brain development, tumor suppression, and the cellular stress response. GADD45G interacts with several other proteins that are involved in DNA repair, cell cycle control, apoptosis, and senescence. Low expression of GADD45G has been associated with many types of cancer. # History GADD45G was originally cloned by Beadling under the name CR6 in 1993. In this experiment, several genes including GADD45G were noted for being induced by IL-2, and they were identified as immediate early response genes in T lymphocytes. Its role as a tumor suppressor was discovered in 1999 by Zhang. It received the name OIG37 from Nakayama due to its regulation by Oncostatin M, which was found to be able to inhibit growth. Finally, it also became known as Gadd-related protein 17 during its isolation from a cDNA library by Suzuki due to its homology with Gadd45. # Structure and function GADD45G is a member of a group of genes whose transcript levels are increased following stressful growth arrest conditions and treatment with DNA-damaging agents. The protein encoded by this gene responds to environmental stresses by mediating activation of the p38/JNK pathway via MTK1/MEKK4 kinase. GADD45G is in turn regulated upstream by NF-κB. The crystal structure of GADD45G reveals a dimer made of four parallel helices. The central region contains a highly acidic patch where it allows for interaction with cdc2, PCNA, and p21. The parallel isoform of GADD45G is the active form. This gene plays a role in cell cycle regulation. GADD45G prevents the kinase ability of the cyclin b1/Cdk1 complex in a fashion that does not break apart the complex. It plays a role in the activation of the S and G2/M checkpoints. In the male sexual development pathway, GADD45G is essential for activating SRY, leading to proper formation of the gonads and sex-determination. This could occur through GADD45G interaction with the p38 MAPK signaling pathway. Deletion of an enhancer close to the GADD45G gene is correlated to increased proliferation of neuronal cells, which could account for part of the difference in neural development between humans and other species. The deletion of the enhancer reduces the expression of the gene in the forebrain allowing for more brain growth in humans. GADD45G is involved with dental epithelial cell proliferation. GADD45G is expressed in enamel knots, where it regulates gene expression and cell growth. The gene modulates p21-mediated epithelial cell proliferation by activating the p38 MAPK pathway during the development of teeth. There is differential expression of the Xenopus homolog of GADD45G in embryonic development. It plays a large role in neural and brain development with GADD45A. GADD45G and GADD45A knockdowns are related to improper gastrulation, defective head growth, and shorter axes. GADD45G and GADD45A act redundantly to control cell growth, allow the cells to move from pluripotentcy helping cells differentiate. # Interactions GADD45G carries out its many previously stated functions with many different interactions. GADD45G was found to inhibit Cdk1 kinase activity, which would cause disruption of cell growth. It also interacts with CRIF, which causes the inhibition of Cdc2-cyclin B1 and Cdk-cyclin E. GADD45 also works with the cyclin-dependent kinase inhibitor p21, which can cause growth arrest as well. GADD45G is found to be involved with the p38 MAPK pathway through interactions with MAP3K4, which can be important in sex-determination. Additionally, GADD45G regulates DNA replication and repair through its interactions with PCNA. # Tissue distribution In humans, GADD45G is expressed most in the skeletal muscle, kidney and liver. This gene has a low expression in the heart, brain, spleen, lung and testis. GADD45G is highly expressed in the placenta. In the embryonic mouse, Gadd45g is expressed in the neural tube, cranial and dorsal root ganglia and the dorsal midbrain. Mammalian renal inner medullary (IM) cells routinely face and resist hypertonic stress. Such stress causes DNA damage to which IM cells respond with cell cycle arrest. All three GADD45 isoforms GADD45A, GADD45B, and GADD45G are induced by acute hypertonicity in murine IM cells. Maximum induction occurs 16-18 h after the onset of hypertonicity. GADD45G is induced more strongly (7-fold) than GADD45B (3-fold) and GADD45A (2-fold). Hypertonicity of various forms (NaCl, KCl, sorbitol, or mannitol) always induces GADD45 transcripts, whereas non-hypertonic hyperosmolality (urea) has no effect. Actinomycin D does not prevent hypertonic GADD45 induction, indicating that mRNA stabilization is the mechanism that mediates this induction. # Clinical significance In numerous kinds of cancerous cells, GADD45G is down regulated. There is a low expression due to methylation of the GADD45G promotor. This low expression can also be explained by increased NF-κB activation. GADD45G methylation is seen in many cancers. In esophageal cancer the expression level and methylation status of the gene are involved in the prognosis of esophageal squamous cell carcinoma. Demethylation of the gene can have some beneficial effects. Similar circumstances are seen in gastric cardio adenocarcinomas where GADD45G is silenced. GADD45G methylation levels are also measured in the diagnosis of pancreatic and colorectal cancers. In the pituitary gland, GADD45G is a growth suppressor. There is a loss of expression of the gene in many pituitary cancerous masses. The gene plays a role in prostate cancer as a tumor suppressor as well. In these cancerous cells, Vitamin D can induce the expression of GADD45G. GADD45G could possibly be a target of therapeutic benefit for prostate cancer. In cancerous liver cells, GADD45G is down regulated.It participates in negatively regulating the Jak-Stat3 signaling pathway. It acts as a tumor suppressor in HCC cells by promoting cell death or growth arrest. When GADD45G expression is low, liver cells may be able to bypass the growth arrest stage, leading to cancerous cells. The presence of GADD45G in the urinary system is also related to renal disease. The renal cells expressing the gene were damaged. The upregulation of Gadd45g due to hormones may account for the changes in the mouse uterus.

Sumatriptan injection (patient information) # Why is this medication prescribed Sumatriptan is used to treat the symptoms of migraine headaches (severe, throbbing headaches that sometimes are accompanied by nausea and sensitivity to sound and light). Sumatriptan is in a class of medications called selective serotonin receptor agonists. It works by narrowing blood vessels in the brain and by stopping pain signals from being sent to the brain. Sumatriptan does not prevent migraine attacks. # How should this medicine be used Sumatriptan is taken by injection, just under your skin, as soon as your migraine symptoms appear. You should feel relief of your symptoms within 1 hour (maybe within 10 minutes). If your symptoms then return after the first injection, you may take a second injection after 1 hour. But do not use more than two injections in a 24-hour period. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take sumatriptan exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Sumatriptan comes in an autoinjection device so that you can self-inject this medication into your thigh or deltoid area (shoulder joint). Your doctor or pharmacist should show you how to load the injector and administer the medication. Also read the instruction pamphlet and be sure that you understand the correct injection technique before you use the autoinjector. Try the autoinjector for the first time in your doctor's office so that he/she can be sure that you are using it correctly and can monitor any side effects. # Other uses for this medicine This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. # What special precautions should I follow Before using sumatriptan: - tell your doctor and pharmacist if you are allergic to sumatriptan or any other drugs. - do not use sumatriptan if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Eldepryl, Emsam) or tranylcypromine (Parnate) during the past 2 weeks or if you have taken another medication for migraine headaches such as dihydroergotamine (D.H.E. 45, Migranal), methysergide (Sansert), almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt, Maxalt-MLT), or zolmitriptan (Zomig) during the past 24 hours. - tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, herbal products and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, in Symbyax), fluvoxamine, paroxetine (Paxil), and sertraline (Zoloft), and selective serotonin/norepinephrine reuptake inhibitors (SNRIs) such as duloxetine (Cymbalta) and venlafaxine (Effexor). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. - tell your doctor if you smoke, if you have a strong family history of heart disease, if you are postmenopausal, or if you are a man over 40. Also tell your doctor if you have or have ever had high blood pressure; angina (recurring chest pain); a heart attack; diabetes; high cholesterol; obesity; stroke; transient ischemic attack (mini-stroke); ischemic bowel disease; coronary artery disease; seizures; or blood vessel, kidney, or liver disease. - tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking sumatriptan, call your doctor. # What should I do if I forget a dose Sumatriptan is not for routine use. Use it only to relieve your migraine headache as soon as symptoms of the migraine appear. # Side effects ## Mild side effects Sumatriptan may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: - pain or redness at the site of injection - flushing - tingling feeling - feeling of warmth or heaviness - drowsiness - upset stomach - vomiting - muscle cramps ## Severe side effects If you experience any of the following symptoms, call your doctor immediately: - pain or tightness in chest or throat - fast heartbeat - difficulty breathing - wheezing - redness, swelling, or itching of the eyelids, face, or lips - skin rash, lumps, or hives - changes in vision # What storage conditions are needed for this medicine Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature, away from light, excess heat, and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of needles, syringes, and the medication. # In case of emergency/overdose In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911. # What other information should I know Keep all appointments with your doctor. Never inject this medication any place except under the skin of your thigh or shoulder. Call your doctor if you continue to have symptoms. Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription. # Brand names - Imitrex Injection®

Aortic valve replacement # Overview Aortic valve replacement is a cardiac surgery procedure in which a patient's aortic valve is replaced by a different valve. The aortic valve can be affected by a range of diseases; the valve can either become leaky (aortic insufficiency / regurgitation) or partially blocked (aortic stenosis). Aortic valve replacement currently requires open heart surgery. percutaneous aortic valve replacement, which allows the implantation of valves using a catheter without open heart surgery is still being evaluated in clinical trials and is appearing to be promising in patients who are at high risk to undergo open heart surgery. # Types of Heart Valves There are two basic types of artificial heart valve: mechanical valves and tissue valves. ## Tissue valves Tissue heart valves are usually made from animal tissues, either animal heart valve tissue or animal pericardial tissue. The tissue is treated to prevent rejection and calcification. There are alternatives to animal tissue valves. In some cases a homograft - a human aortic valve -- can be implanted. Homograft valves are donated by patients and harvested after the patient dies. The durability of homograft valves is probably the same for porcine tissue valves. Another procedure for aortic valve replacement is the Ross procedure (or pulmonary autograft). In a Ross procedure, the aortic valve is removed and replaced with the patient's own pulmonary valve. A pulmonary homograft (pulmonary valve taken from a cadaver) is then used to replace the patients own pulmonary valve. This procedure was first used in 1967 and is used primarily in children. ## Mechanical valves Mechanical valves are designed to outlast the patient, and have typically been stress-tested to last several hundred years. Although mechanical valves are long-lasting and generally only one surgery is needed, there is an increased risk of blood clots forming with mechanical valves. As a result, mechanical valve recipients must generally take anti-coagulant drugs such as warfarin for the rest of their lives, which effectively makes them borderline hemophiliacs. ## Valve selection Tissue valves tend to wear out faster with increased flow demands - such as with a more active (typically younger person). Tissue valves typically last 10-15 years in less active (typically elderly) patients, but wear out faster in younger patients. When a tissue valve wears out and needs replacement, the person must undergo another valve replacement surgery. For this reason, younger patients are often recommended mechanical valves to prevent the increased risk (and inconvenience) of another valve replacement. # Surgical Procedure Aortic valve replacement is most frequently done through a median sternotomy, meaning the chestbone is sawed in half. Once the pericardium has been opened, the patient is placed on cardiopulmonary bypass machine, also referred to as the heart-lung machine. This machine takes over the task of breathing for the patient and pumping his blood around while the surgeon replaces the heart valve. Once the patient is on bypass, an incision is made in the aorta. The surgeon then removes the patient's diseased aortic valve and a mechanical or tissue valve is put in its place. Once the valve is in place and the aorta has been closed, the patient is taken off the heart-lung machine. Transesophageal echocardiogram (TEE, an ultra-sound of the heart done through the esophagus) can be used to verify that the new valve is functioning properly. Pacing wires are usually put in place, so that the heart can be manually paced should any complications arise after surgery. Drainage tubes are also inserted to drain fluids from the chest and pericardium following surgery. These are usually removed within 36 hours while the pacing wires are generally left in place until right before the patient is discharged from the hospital. # Hospital Stay and Recovery Time Immediately after aortic valve replacement, the patient will frequently stay in a cardiac surgery intensive care unit for 12-36 hours. After this, the patient is often moved to a lower-dependency unit and then to a cardiac surgery ward. Total time spent in hospital following surgery is usually between 4 and 10 days, unless complications arise. Recovery from aortic valve replacement will take 1-3 months if the patient is in good health. Patients are advised not to do any heavy lifting for 6-8 weeks following surgery to avoid damaging the sternum (breast bone) while it heals. # Surgical Outcome and Risk of Procedure The risk of death or serious complications from aortic valve replacement is typically quoted as being between 1-5%, depending on the health and age of the patient, as well as the skill of the surgeon. Older patients, as well as more fragile ones, are sometimes inelegible for surgery because of elevated risks. # 2008 and Incorporated 2006 ACC/AHA Guidelines for the Management of Patients with Valvular Heart Disease (DO NOT EDIT) ## Antithrombotic Therapy for Prosthetic Heart Valves (DO NOT EDIT) ## Intraoperative Assessment (DO NOT EDIT) ## Follow-Up Visits in Patients With Complications (DO NOT EDIT) ## Treatment of Coronary Artery Disease (DO NOT EDIT) ## Patients Undergoing Coronary Artery Bypass Surgery (DO NOT EDIT) # Sources - 2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease

Asymmetric synthesis Asymmetric synthesis, also called chiral synthesis, enantioselective synthesis or stereoselective synthesis, is organic synthesis which introduces one or more new and desired elements of chirality. This is important in the field of pharmaceuticals because the different enantiomers or diastereomers of a molecule often have different biological activity. # Approaches There are three main approaches to asymmetric synthesis: - chiral pool synthesis - asymmetric induction - asymmetric catalysis In practice, a mixture of all three is often used in order to maximize the advantages of each method. Chirality must be introduced to the substance first. Then, it must be maintained. Care needs to be taken when planning the synthesis: the chirality might be removed by a chemical change that makes the substance isotropic. This process is called epimerization. For example, a SN1 substitution reaction converts a molecule that is chiral by merit of non-planarity into a planar molecule, which has no handedness. (To visualise, draw the outlines of both of your hands on paper, and cut the images out. You can now superimpose the images, even if the hands themselves do not superimpose.) In a SN2 substitution reaction on the other hand the chirality inverts, i.e. when you start with a right-handed mixture, you'll end up with left-handed one. (A visualization could be inverting an umbrella. The mechanism looks just the same.) # Chiral pool synthesis Chiral pool synthesis is the easiest approach: a chiral starting material is manipulated through successive reactions using achiral reagents which retain its chirality to obtain the desired target molecule. This is especially attractive for target molecules having the similar chirality to a relatively inexpensive naturally occurring building block such as a sugar or amino acid. However, the number of possible reactions the molecule can undergo are restricted, and tortuous synthetic routes may be required. Also, this approach requires a stoichiometric amount of the enantiopure starting material, which may be rather expensive if not occurring in nature, whereas chiral catalysis requires only a catalytic amount of chiral material. # Asymmetric induction What many strategies in chiral synthesis have in common is asymmetric induction. The aim is to make enantiomers into diastereomers, since diastereomers have different reactivity, but enantiomers do not. To make enantiomers into diastereomers, the reagents or the catalyst need to be incorporated with an enantiopure chiral center. The reaction will now proceed differently for different enantiomers, because the transition state of the reaction can exist in two diastereomers with respect to the enantiopure center, and these diastereomers react differently. Asymmetric induction can also occur intramolecularly when given a chiral starting material. This chirality transfer can be exploited, especially when the goal is to make several consecutive chiral centers to give a specific enantiomer of a specific diastereomer. Aldol reaction, for example, is inherently diastereoselective; if the aldehyde is enantiopure, the resulting aldol adduct is diastereomerically and enantiomerically pure. One such strategy is the use of a chiral auxiliary which forms an adduct to the starting materials and physically blocks the other trajectory for attack, leaving only the desired trajectory open. Assuming the chiral auxiliary is enantiopure, the different trajectories are not equivalent, but diastereomeric. # Asymmetric catalysis Small amounts of chiral, enantiomerically pure (or enriched) catalysts promote reactions and lead to the formation of large amounts of enantiomerically pure or enriched products.Mostly, three different kinds of chiral catalysts are employed: - metal ligand complexes derived from chiral ligands - chiral organocatalysts and - biocatalysts. The first methods were pioneered by William S. Knowles and Ryoji Noyori (Nobel Prize in Chemistry 2001). Knowles in 1968 replaced the achiral triphenylphosphine ligands in Wilkinson's catalyst by the chiral phosphine ligands P(Ph)(Me)(Propyl) thus creating the first asymmetric catalyst. This experimental catalyst was employed in an asymmetric hydrogenation with a modest 15% enantiomeric excess result. The methodology was ultimately used by him (while working for the Monsanto company) in an asymmetric hydrogenation step in the industrial production of L-DOPA: In the same year and independently Noyori published his chiral ligand for a cyclopropanation reaction of styrene. In common with Knowles the enantiomeric excess for this first generation ligand was dissapointingly low: 6%. Examples of asymmetric catalysis include: - BINAP, a chiral phosphine, used in combination with compounds of ruthenium or rhodium. These complexes catalyse the hydrogenation of functionalised alkenes well on only one face of the molecule. This process also developed by Ryoji Noyori is commercialized as the industrial synthesis of menthol using a chiral BINAP-rhodium complex. - The other part of that Nobel prize concerned the Sharpless bishydroxylation - Naproxen is synthesized with a chiral phosphine ligand in a Hydrocyanation reaction - asymmetric catalytic reduction and oxidation ## Biocatalysis & organocatalysis Biocatalysis makes use of enzymes to effect chemical reagents stereoselectively. Some small organic molecules can also be used to help accelerate the desired reaction; this method is known as organocatalysis. If the organic molecule is chiral, it may react preferentially with the substrate of a certain chirality. # Alternatives Apart from asymmetric synthesis, racemic mixtures of compounds may be separated by various techniques in chiral resolution. Where the cost in time and money of making such racemic mixtures is low, or if both enantiomers may find use, this approach may remain cost-effective.

FERMT3 Fermitin family homolog 3) (FERMT3), also known as kindlin-3 (KIND3), MIG2-like protein (MIG2B), or unc-112-related protein 2 (URP2) is a protein that in humans is encoded by the FERMT3 gene. The kindlin family of proteins, member of the B4.1 superfamily, comprises three conserved protein homologues, kindlin 1, 2, and 3. They each contain a bipartite FERM domain comprising four subdomains F0, F1, F2, and F3 that show homology with the FERM head (H) domain of the cytoskeletal Talin protein. Kindlins have been linked to Kindler syndrome, leukocyte adhesion deficiency, cancer and other acquired human diseases. They are essential in the organisation of focal adhesions that mediate cell-extracellular matrix junctions and are involved in other cellular compartments that control cell-cell contacts and nucleus functioning. Therefore, they are responsible for cell to cell crosstalk via cell-cell contacts and integrin mediated cell adhesion through focal adhesion proteins and as specialised adhesion structures of hematopoietic cells they are also present in podosome's F actin surrounding ring structure. Isoform 2 may act as a repressor of NF-kappa-B and apoptosis # Evolution It has been suggested that the evolutionary source of a single ancestral Kindlin protein is the earliest metazoa, the Parazoa. Within vertebrates, these ancestral proteins were subjected to duplication processes in order to arrive at the actual Kindlin family. In comparison with other members of the B4.1 superfamily of proteins, the FERM domains in Kindlin homologues have a greater degree of conservation. The presence of an inserted pleckstrin homology domain within the FERM domain, suggests that the metazoan evolution of the FERM domain is the origination from a proto-talin protein in unicellular or proto-multicellular organisms. # Function The FERMT3 protein has a key role in the regulation of hemostasis and thrombosis. This protein may also help maintain the membrane skeleton of erythrocytes. Kindlin 3 is a cytoskeletal signalling protein involved in the activation of the glycoprotein receptor, integrin. Together with the Talin protein it binds cooperatively to beta integrin’s cytoplasmic domain causing tail reorientation, thus altering the molecule’s conformation. Modification of integrin’s conformation serves to dissociate alpha and beta subunits by disrupting their interactions and helping the molecule adopt a high affinity state. FERMT3 functions as a stabilizer of the cytoskeleton and regulates its dynamics in cell and organelle motility. # Clinical significance FERMT3 mutations can result in autosomal recessive leukocyte adhesion deficiency syndrome-III (LAD-III). a deficiency in beta1, beta2 and beta3 integrin activation in platelets and leukocytes that causes haemorrhaging and recurrent infections. Loss of FERMT3 expression in leukocytes compromises their adhesion to the inflamed endothelia and affects neutrophil granulocyte binding and spreading while selectin mediated rolling is unaffected. It has also been found that FERMT3 lowers Natural Killer cell’s activation threshold, such that a loss of FERMT3 affects single receptor activation of NK cell-mediated cytotoxicity but has no impact on multiple receptors, where the protein deficiency is overcome and target cells are killed. FERMT3 deficiency on β(2) integrin function depend on both cell type (Natural killer cell or Leukocytes) and the integrin activation stimulus. The prevention of the beta-3 activation is specifically related to LAD-3, causing Glanzmann's thrombasthenia symptoms, a condition in which patients bleed excessively. Leukocyte adhesion deficiency is diagnosed clinically and by complete blood counts that reveal leukocytosis with neutrophilia. Management and treatment of this disease aim to control these recurrent infections by antibiotics and blood transfusions, with bone marrow transplantation as the only curative measure. Failure to express the FERMT3 protein disrupts the ability to form clots and coagulate by preventing integrin αIIβ3-mediated platelet aggregation.

ApoA-1 Milano A naturally-occurring mutated strain of the apoA-1 protein found in human HDL. First identified by Cesare Sirtori in Milan, it has been shown to significantly reduce arterial plaque. Discovered by accident, the mutation was found to be present in about 3.5% of a tiny village called Limone sul Garda in northern Italy. It has been traced to a mutation in a single man living in the village in the 1700s. Due to its enormous apparent efficacy, some have speculated that development of synthetic apoA-1 Milano may be a key factor in eradicating coronary heart disease. No drugs are currently commercially available based on apoA-1 Milano. Rights to apoA-1 Milano were acquired in 2003 by Pfizer. Clinically known as ETC-216, Pfizer has not moved trials forward, posssibley because the drug must be administred intravenously, thus limiting its application as compared to oral medications.

Behavioural genetics Behavioural genetics is the field of biology that studies the role of genetics in animal (including human) behaviour. The field is an overlap of genetics, ethology and psychology. Classically, behavioural geneticists have studied the heritability of behavioural traits. # History In 1869, Francis Galton published the first empirical work in human behavioural genetics, Hereditary Genius. Here, Galton intended to demonstrate that "a man's natural abilities are derived by inheritance, under exactly the same limitations as are the form and physical features of the whole organic world." Like most seminal work, he overstated his conclusions. His was a family study on the inheritance of giftedness and talent. Galton was aware that resemblance among familial relatives can be a function of both shared genes and shared environments. Contemporary behavioural genetics studies special populations—in human research, twins and adoptees and in animal research, specially bred strains and lines—to separate genetic from environmental effects. The initial impetus behind behavioural genetic research was to demonstrate that there were indeed genetic influences on behaviour. In psychology, this phase lasted for the first half of the 20th century largely because of the overwhelming influence of behaviourism in the field. Later behavioural genetic research focused on quantitative methods, and today there is a large emphasis on applying techniques from molecular genetics to isolate individual genes that influence behaviour. # Contemporary behavioural genetics Currently, the largest branch of behavioural genetics is psychiatric genetics which studies phenotypes such as schizophrenia, bipolar disorder, and alcoholism. Recent trends in behaviour genetics has indicated an additional focus toward researching the heritability of human characteristics typically studied in developmental psychology. For instance, a major focus in developmental psychology has been to characterize the influence of parenting styles of children. However, in most studies, genes are a confounding variable. Because children share 50% of their genes with each parent, any observed effects of parenting styles could be effects of having many of the same genes as a parent (e.g. harsh aggressive parenting styles have been found to correlate with similar aggressive child characteristics- is it the parenting or the genes?). Thus, behaviour genetics research is currently undertaking to distinguish the effects of the family environment from the effects of genes. This branch of behaviour genetics research is becoming more closely associated with mainstream developmental psychology and the sub-field of developmental psychopathology as it shifts its focus to the heritability of such factors as emotional self-control, attachment, social functioning, aggressiveness etc.. Several academic bodies exist to support behavior genetic research, including the International Behavioural and Neural Genetics Society, Behavior Genetics Association and the International Society for Twin Studies.Behavior genetic work features prominently in several more general societies, for instance the International Society for Psychiatric Genetics and the International Behavioral Neuroscience Society. # Methods of behavioural genetics Behavioural geneticists use several designs to answer questions about the nature and mechanisms of genetic influences on behavior. All of these designs are unified by being based around human relationships which disentangle genetic and environmental relatedness. So, for instance, some researchers study adopted twins: the adoption study. In this case the adoption disentangles the genetic relatedness of the twins (either 50% or 100%) from their family environments. Likewise the classic twin study contrasts the differences between identical twins and fraternal twins within a family compared to differences observed between families. This core design can be extended: the so-called "extended twin study" which adds additional family members, increasing power and allowing new genetic and environmental relationships to be studied. Excellent examples of this model are the Virginia 20,000, and the QIMR twin studies. Also possible are the "children of twins" design (holding maternal genetic contribution equal across children with paternal genetics and family environments; and the "virtual twins" design - unrelated children adopted into a family who are very close or identical in age to biological children or other adopted children in the family. The classical twin study has been severely criticized and is used less and less frequently nowadays.

Fremitus Fremitus is a palpable vibration on the human body. In common medical usage, it usually refers to (tactile) vocal fremitus, although there are several other types. # Bronchial fremitus See rhonchal fremitus below. # Hepatic fremitus Hepatic fremitus is a vibration felt over the patient's liver. It is thought to be caused by a severely inflamed and necrotic liver rubbing up against the peritoneum. The name 'Monash sign' has been suggested for this clinical sign, after the Monash Medical Centre in Melbourne, Australia (Nagappan et al, 2001). # Hydatid fremitus Hydatid fremitus is a vibratory sensation felt on palpating a hydatid cyst. # Pectoral fremitus See vocal fremitus below. # Pericardial fremitus Pericardial fremitus is a vibration felt on the chest wall due to the friction of the surfaces of the pericardium over each other. See pericardial friction rub for the auditory analog of this sign. # Periodontal fremitus Periodontal fremitus occurs in either of the alveolar bones when an individual sustains trauma from occlusion. It is a result of teeth exhibiting at least slight mobility rubbing against the adjacent walls of their sockets, the volume of which has been expanded ever so slightly by inflammatory responses, bone resorption or both. As a test to determine the severity of periodontal disease, a patient is told to close his or her mouth into maximum intercuspation and is asked to grind his or her teeth ever so slightly. Fingers placed in the labial vestibule against the alveolar bone can detect fremitus. # Pleural fremitus Pleural fremitus is a palpable vibration of the wall of the thorax caused by friction between the parietal and visceral pleura of the lungs. See pleural friction rub for the auditory analog of this sign. # Rhonchal fremitus Rhonchal fremitus, also known as bronchial fremitus, is a palpable vibration produced during breathing caused by partial airway obstruction. The obstruction can be due to mucus or other secretions in the airway, bronchial hyperreactivity, or tumors. See rhonchus (rhonchi) for the auditory analog of this sign. # Subjective fremitus Subjective fremitus is a vibration felt by the patient on humming with the mouth closed. # Tactile fremitus See vocal fremitus below. # Tussive fremitus Tussive fremitus is a vibration felt on the chest when the patient coughs. # Vocal fremitus Vocal Fremitus, also called pectoral fremitus, or tactile vocal fremitus, is a vibration felt on the patient's chest during low frequency vocalization. Commonly, the patient is asked to repeat the phrase 'boy oh boy' (or any other diphthong such as 'toy boat' and 'blue balloons') while the examiner attempts to detect vibrations on the chest wall. The phrase 'ninety-nine' is also commonly used. The German language equivalent neun und neunzig, is a diphthong, and is appropriate. Vocal fremitus is normally more intense in the right second intercostal space, as well as in the interscapular region, as these areas are closest to the bronchial bifurcation. Vocal fremitus is pathologically increased over areas of consolidation and decreased or absent over areas of pleural effusion or pneumothorax (collapsed lung). The reason for increased fremitus in a consolidated lung is the fact that the sound waves travel quicker through liquid (the consolidation) than air. Conversely, the reason for decreased fremitus in a pleural effusion (or any pathology separating the pleura), is that this increased space between the pleura acts as a barrier to the sound waves. It has recently been suggested that the artifacts caused by eliciting vocal fremitus during breast ultrasonography can be used to differentiate between benign and malignant tumors (Sohn and Baudendistel, 1995).

Cumulative incidence # Overview Cumulative incidence (sometimes referred to as incidence proportion) is a measure of disease frequency which counts the proportion of a candidate population that becomes diseased/develops disease over a specified period of time. Cumulative incidence measures occurrence of new cases of disease. It involves the transition from one state to another, such as non-disease to diseased state (incidence of disease) or diseased to non-diseased (incidence of cure). # Types of Cumulative Incidence Calculations Specific forms of cumulative incidence include: - Crude mortality rate: number of deaths due to any cause/100,000 population during a specified time period - Infant mortality rate: number of infant deaths due to any cause/1,000 population during a specified time period - Morbidity rate: number of illnesses due to any cause/1,000 population during a specified time period - Live birth rate: number of live births/1,000 population or childbearing women during a specified time period - Case fatality rate: number of deaths due to disease X/number of people with disease X during a specified time period - Attack rate: number of new cases of disease/number population at risk at beginning of time period during specified time period # Calculating Cumulative Incidence It may also be calculated by the incidence rate multiplied by duration. Basic equation: Cumulative Incidence = # new (incident) cases/total population at risk Applied: CI = IRi - ti (where IRi is the incidence rate, ti is the specified time period)

Rectal # Overview The rectum (from the Latin rectum intestinum, meaning straight intestine) is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long. At its commencement its caliber is similar to that of the sigmoid colon, but near its termination it is dilated, forming the rectal ampulla. # Role in human defecation The rectum intestinum acts as a temporary storage facility for feces. As the rectal walls expand due to the materials filling it from within, stretch receptors from the nervous system located in the rectal walls stimulate the desire to defecate. If the urge is not acted upon, the material in the rectum is often returned to the colon where more water is absorbed. If defecation is delayed for a prolonged period, constipation and hardened feces results. When the rectum becomes full the increase in intrarectal pressure forces the walls of the anal canal apart allowing the fecal matter to enter the canal. The rectum shortens as material is forced into the anal canal and peristaltic waves propel the feces out of the rectum. The internal and external sphincter allow the faeces to be passed by muscles pulling the anus up over the exiting feces. # Medical procedures For the diagnosis of certain ailments, a rectal exam may be done. Suppositories may be inserted into the rectum as a route of administration for medicine. The endoscopic procedures colonoscopy and sigmoidoscopy are performed to diagnose diseases such as cancer. ## Temperature taking Body temperature can also be taken in the rectum. Rectal temperature can be taken by inserting a mercury thermometer for 3 to 5 minutes, or a digital thermometer until it "beeps", not more than 25 mm (1 inch) into the rectum via the anus. Due to recent concerns related to mercury poisoning, the use of mercury thermometers is now discouraged. Normal rectal temperature generally ranges from 36 to 38 °C (97.6 to 100.4 °F) and is about 0.5 °C (1 °F) above oral (mouth) temperature and about 1 °C (2 °F) above axillary (armpit) temperature. Many pediatricians recommend that parents take infants and toddler's temperature in the rectum for two reasons: - (1) Rectal temperature is the closest to core body temperature and in children that young, accuracy is critical. - (2) Younger children are unable to cooperate when having their temperature taken by mouth (oral) which is recommended for children, ages 6 and above and for adults. In recent years, the introduction of ear (tympanic) thermometers and changing attitudes on privacy and modesty have led some parents and doctors to discontinue taking rectal temperatures. # Sexual stimulation Due to the proximity of the anterior wall of the rectum to the vagina in females or to the prostate in males and the shared nerves thereof, rectal stimulation or penetration can result in sexual arousal. For further information on this aspect, see anal sex. # Additional images - Organs of the female reproductive system. - Median sagittal section of pelvis, showing arrangement of fasciæ. - The arteries of the pelvis. - Section of mucous membrane of human rectum. X 60. - The blood vessels of the rectum and anus. - Median sagittal section of male pelvis. - Median sagittal section of female pelvis. - Sagittal section of the lower part of a female trunk, right segment. - Error creating thumbnail: File missing The rectum can be seen the left of this illustration. - Cross section microscopic shot of the rectal wall.

Glucuronidation # Overview Glucuronide: a glycoside that yields glucuronic acid upon hydrolysis. Glucaronic acid: an acid, C6H10O7, formed by the oxidation of glucose, found combined with other products of metabolism in the blood and urine. Glucuronidase (beta-glucuronidase): an enzyme that hydrolyzes a glucuronide, destroying glucuronidation, especially that which occurs widely (as in liver and spleen) and hydrolyzes the beta form of a glucuronide Glucuronidation plays many roles in the body, not just that of binding estrogen, thus one may have low or normal levels of glucaronic acid along with low, normal or high levels of estrogen. The healthy body employs many different detoxification pathways, in the liver and elsewhere, of which glucuronidation is one. Glucuronidation removes several toxic and potentially toxic chemicals from our system, such as polycyclic aromatic hydrocarbons, steroid hormones, some nitrosamines, heterocyclic amines, some fungal toxins, and aromatic amines. It also removes "used" hormones, such as estrogen and T4, that are produced naturally by the body. This, glucuronidation represents a major means of converting most drugs, steroids, and many toxic and endogenous substances to metabolites that can then be excreted into the urine or bile. The liver, spleen, and gut may be damaged or otherwise impaired by several means: - Liver disease or disorder, such as hepatitis - Drugs or toxic exposure disrupts phase 1 or phase 2 function - Accidental ingestion of toxic substances (such as plants, poisons, drug overdose, mercury) - Intentional ingestion of substances which overload detox pathways (such as nicotine, acetaminophen, NSAIDs, xenobiotics, therapeutic glycosides, etc. Many of these toxic and otherwise therapeutic substances (xenobiotics, drugs) disrupt the glucuronidation by impairing it, stopping it, or causing the binds to be rupture, separating the bound molecules from its inert transport. The toxins that are thus not removed by normal binding and excretion may settle elsewhere in the body, causing tumors and other signs of toxicity. Glucuronidase is an enzyme that inhibits the glucuronidation process, breaking apart the bound toxins. Calcium D-glucarate (a calcium salt that is found in some plants, such as apples, grapefruit, broccoli and alfalfa) suppresses that enzyme, restoring this particular detoxification pathway. A benefical fungus, Saccharomyces boulardii, helps reduce some of the gut organisms that produce glucuronidase. For more information related to glucuronidation, please see the 2002 Update in my Estrogen Dominance article. Acetaminophen Users: Acetaminophen also affects the glutathione detoxification pathway in the liver, so those taking acetaminophen products should also take a glutathione supplement.

Homelessness and Ill Health The Royal College of Physicians has a long tradition of concern for the factors which affect health as well as for the treatment of disease. This report continues that tradition by drawing attention to the relationships between health and homelessness. The number of people who are homeless has risen sharply over the past decade. Some become homeless because of ill health and most experience deterioration in their health as a result of homelessness. Many have difficulty in obtaining appropriate medical care. By gathering together a wide range of published data, this report aims to define the relationship between homelessness and health and makes recommendations to government, local authorities, family health service authorities and GP fundholders for the coordination and improvement of services for people who are homeless. There are three main groups of homeless people. Only one group, comprising many families with children or pregnant women (described in this report as Group I), are officially recognised as homeless. In 1992 there were 169,966 of these statutorily recognised homeless households in Britain. Rough sleepers and direct access hostel dwellers (described in this report as Group II) are not officially homeless and not included in official statistics. In the 1992 Census there were 2,827 rough sleepers and 19,417 hostel dwellers in Britain. The third group comprises those who are sharing accommodation or are otherwise inadequately housed. As very little information exists about these people, this report concentrates on Groups I and II. The types of housing that are available in Great Britain are: owner-occupied and private-rented, for both of which an adequate and reliable income is required; and local authority or housing association rented housing, together described as social-rented housing, where access is intended to be based on need rather than ability to pay. Poor health and disability limit people's access to housing, because they often reduce employment opportunities and hence income, so home-ownership or private renting are out of reach. The social-rented sector has decreased considerably in size over the past few years, making access to it more difficult. The mechanisms intended to ensure that people in poor health have adequate housing (medical priority for rehousing) do not work effectively. Homeless families (Group I) have been shown to experience more mental, physical and obstetric health problems than comparable housed groups. They make greater use of hospital and community services. This is probably related not only to their health problems but also to the difficulties they have in gaining access to primary care. For many of them, a 'healthy lifestyle' is unattainable in crowded accommodation with inadequate cooking and recreational facilities. Single homeless people (Group II) have a higher risk of death and disease than comparable housed people. Excess deaths are due mainly to suicide, accidents and violence, and alcohol-related and respiratory diseases. Single homeless people are prone to a wide spectrum of physical illnesses, involving all bodily systems. Among the specific conditions common in this group are tuberculosis, chronic obstructive airways disease (bronchitis), foot problems, infestations and epilepsy. The physical vulnerability of single homeless people, together with problems of compliance with treatment, pose special problems in relation to tuberculosis, where drug resistance may emerge with potential public health implications. Single homeless people are more likely to have serious mental illness than the general population. Schizophrenia is the most commonly diagnosed disorder. The effects of mental illness, together with associated social and economic problems, can precipitate housing crises which the individuals concerned are unable to resolve and they thus become homeless. Community care programmes developed by health and social services do not take adequate account of housing need and so are not able to deal with these problems. Various initiatives have been introduced in an attempt to improve health care for homeless people. On the whole, although valuable, they are small-scale and uncoordinated and have only a limited impact on these very considerable problems. Although the longterm goal is to provide homeless people with services that are integrated with those for the rest of the population, special arrangements are needed in the meantime for primary care, accident and emergency services, community care and discharge planning. This report confirms the strong relationships between homelessness and health. It recommends that the Government, Local Authorities, the Housing Corporation and the NHS should, as a matter of urgency, develop a coordinated approach to the development of a housing and community care policy. This is seen as a prerequisite for progress in this field. Since it is unlikely that there will be rapid, dramatic improvements in the underlying causes of homeless-Journal of the Royal College of Physicians of London Vol. 28 No. 6 November/December 1994 ness, there should be short-term arrangements to improve access to health care for homeless people. In addition, future official statistics should include single homeless people (Group II); there should be regular monitoring of the health of homeless people; and current research on health and homelessness should be extended. Detailed recommendations are given below. ## Recommendations to government The report draws particular attention to the different, and sometimes unintentionally conflicting policies of different agencies. Improvements could be achieved and resources more effectively deployed if there were better integration. ## ? The Government, Local Authorities, the Housing Corporation and the NHS should together undertake a wide-ranging review of housing and community care policies, addressing the opportunities for integration and the barriers to progress. The aim should be to develop a coordinated action plan which identifies and provides the organisational, management and resource requirements to allow the implementation and evaluation of a coherent joint policy. (Recommendation 2 of the report.) The statistics collected on homelessness by the Department of the Environment should be expanded to include rough sleepers and hostel dwellers (Group II homeless people), and such people should be officially recognised as homeless. The Government, through the proposed Regional Offices of the NHS Executive, should take steps to ensure that homeless people are not disadvantaged because of the financial implications of their care for GP fundholders. Although capitation mechanisms should take this into account, in the shorter term, arrangements should be considered, which could: i organise the funding of special practices for homeless people in such a way that these practices would be allowed to administer their own budgets and hence compete with GP fundholders; ii restructure deprivation payments to GPs by including a per capita payment which incorporates an amount based on the number of homeless people registered at the practice; iii coordinate a nationwide service for handling the medical records of homeless people, thus ensuring that information is transferred smoothly between practices; iv set national health targets relevant to the health needs of homeless people; v coordinate a national strategy to provide better health care to homeless people. (Recommendation 9 of the report.) Such a strategy would permit homeless people to choose where they wish to receive care either from a non-fundholding practice, a fundholding practice or a special practice.

Burow's solution Burow's solution is a pharmacological preparation made of aluminium acetate dissolved in water. It was invented in the mid-1800s by Karl August Burow, an ophthalmologist. The preparation has astringent and antibacterial properties and is used to treat a number of skin conditions such as insect bites, rashes caused by poison ivy and poison sumac, swelling, allergies and bruises. Burow's solution is traditionally applied in cold compresses over the affected area. Burow's solution is available over the counter as a generic preparation. Bayer also manufactures a modified form of the preparation under the commercial name Domeboro.

Dental sealant Dental sealants are a dental treatment consisting of applying a plastic material to one or more teeth, for the intended purpose of preventing dental caries (cavities) or other forms of tooth decay. # Development Since the 1970s, in the United States, the incidence of tooth decay on the smooth surfaces of teeth has declined, in part because of fluoridation becoming widespread in public water supplies as well as improved dental hygiene among the public. However, because the teeth in the back of the mouth (molars and premolars) have numerous pits and fissures on their biting surfaces, certain areas of these teeth are often difficult to clean even with vigorous tooth-brushing. To remedy this, research into dental sealants began in the 1960s and by the early 1970s, the first generation of sealants became available and were approved by the FDA. # Application Dental sealants are usually applied in a dentist's office. The dentist or assistant first cleans and dries the tooth to be treated, then paints a thin layer of liquid plastic material on the pits and fissures of the tooth. After application of the plastic liquid, blue spectrum natural light is shined on the applied material for a few seconds to cure the plastic. Alternatively, some brands of sealants self-cure via a chemical process. After curing, the plastic becomes a hard, thin layer covering the treated portions of the tooth. Despite the incredible pressures effected on teeth during chewing each day, dental sealants may remain effective for five years or longer, although sealants do wear naturally and may become damaged over time. Bacteria and food particles may eventually become entrapped under the dental sealants, and can thus cause decay in the very teeth intended to be protected.

Mcm1 regulatory factor gene transcriptions # Human genes # Interactions # Consensus sequences Consensus sequences: NN(A/C/T)(A/C/T)NC(C/T)(A/C/T)(A/C/T)(A/T)(A/C/T)(A/C/T)N(A/G)(C/G/T)(A/C/T)NNN. The primary consensus sequence is apparently TT(A/T)CCNN(A/T)TNGG(A/T)AA. A "subset of bound and unbound motif occurrences contained all of the most highly conserved nucleotides of the 16-bp pseudosymmetric motif (TTnCCnnnTnnGGnAA) ( Shore and Sharrocks 1995; Hughes and de Boer 2013)." # Samplings Copying a consensus regulatory element: TT(A/T)CCNN(A/T)TNGG(A/T)AA and putting the sequence in "⌘F" finds no locations for this sequence in any A1BG direction as can be found by the computer programs. For the Basic programs testing consensus sequence TT(A/T)CCNN(A/T)TNGG(A/T)AA (starting with SuccessablesMcm.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), the programs are, are looking for, and found: - negative strand, negative direction, looking for TT(A/T)CCNN(A/T)TNGG(A/T)AA, 0. - positive strand, negative direction, looking for TT(A/T)CCNN(A/T)TNGG(A/T)AA, 0. - positive strand, positive direction, looking for TT(A/T)CCNN(A/T)TNGG(A/T)AA, 0. - negative strand, positive direction, looking for TT(A/T)CCNN(A/T)TNGG(A/T)AA, 0. - complement, negative strand, negative direction, looking for AA(A/T)GGNN(A/T)ANCC(A/T)TT, 0. - complement, positive strand, negative direction, looking for AA(A/T)GGNN(A/T)ANCC(A/T)TT, 0. - complement, positive strand, positive direction, looking for AA(A/T)GGNN(A/T)ANCC(A/T)TT, 0. - complement, negative strand, positive direction, looking for AA(A/T)GGNN(A/T)ANCC(A/T)TT, 0. - inverse complement, negative strand, negative direction, looking for TT(A/T)CCNA(A/T)NNGG(A/T)AA, 0. - inverse complement, positive strand, negative direction, looking for TT(A/T)CCNA(A/T)NNGG(A/T)AA, 0. - inverse complement, positive strand, positive direction, looking for TT(A/T)CCNA(A/T)NNGG(A/T)AA, 0. - inverse complement, negative strand, positive direction, looking for TT(A/T)CCNA(A/T)NNGG(A/T)AA, 0. - inverse negative strand, negative direction, looking for AA(A/T)GGNT(A/T)NNCC(A/T)TT, 0. - inverse positive strand, negative direction, looking for AA(A/T)GGNT(A/T)NNCC(A/T)TT, 0. - inverse positive strand, positive direction, looking for AA(A/T)GGNT(A/T)NNCC(A/T)TT, 0. - inverse negative strand, positive direction, looking for AA(A/T)GGNT(A/T)NNCC(A/T)TT, 0. # Rossi samplings Copying a responsive elements consensus sequence TTnCCnnnTnnGGnAA and putting the sequence in "⌘F" finds none between ZNF497 and A1BG or none between ZSCAN22 and A1BG as can be found by the computer programs. For the Basic programs testing consensus sequence TTnCCnnnTnnGGnAA (starting with SuccessablesMcmR.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), the programs are, are looking for, and found: - negative strand, negative direction, looking for TTNCCNNNTNNGGNAA, 0. - positive strand, negative direction, looking for TTNCCNNNTNNGGNAA, 0. - positive strand, positive direction, looking for TTNCCNNNTNNGGNAA, 0. - negative strand, positive direction, looking for TTNCCNNNTNNGGNAA, 0. - inverse complement, negative strand, negative direction, looking for TTNCCNNANNNGGNAA, 0. - inverse complement, positive strand, negative direction, looking for TTNCCNNANNNGGNAA, 0. - inverse complement, positive strand, positive direction, looking for TTNCCNNANNNGGNAA, 0. - inverse complement, negative strand, positive direction, looking for TTNCCNNANNNGGNAA, 0. ## McmR random dataset samplings - McmRr0: 0. - McmRr1: 0. - McmRr2: 0. - McmRr3: 0. - McmRr4: 0. - McmRr5: 0. - McmRr6: 0. - McmRr7: 0. - McmRr8: 0. - McmRr9: 0. - McmRr0ci: 0. - McmRr1ci: 0. - McmRr2ci: 0. - McmRr3ci: 0. - McmRr4ci: 0. - McmRr5ci: 0. - McmRr6ci: 0. - McmRr7ci: 0. - McmRr8ci: 0. - McmRr9ci: 0.

Urogenital folds # Overview The urogenital folds (or urogenital ridges, or urethral folds) are an embryological structure which give rise to a portion of the external genitalia. # Differentiation It differentiates into two structures: - gonadal ridge -- medial -- primarily reproductive system - nephrogenic cord -- lateral -- primarily urinary system # Derivatives - In the female, the urogenital folds become the labia minora. In contrast, the labia majora are formed by the labioscrotal folds - In the male, they form the spongy urethra and a portion of the shaft of the penis, not including the glans. # Pathology In the male, failure of the urogenital folds to fuse during development leads to a condition known as hypospadias. # Obsolete meanings Less commonly, urogenital fold refers to the fold in the mesonephros which is the precursor of e.g. the suspensory ligament of the ovary. This is the case in older versions of Gray's anatomy. See development of the urinary and reproductive organs, particularily the "The Mesonephros, Müllerian Duct, and Genital Gland" section for this meaning.

TCT 2011 schedule Here is the page we will use to coordinate the TV events at TCT 2011. Open time slots are indicated below in red. Filming will take place in front of the Main Arena in the Moscone South building. # Click on Date for Detailed Schedule Tuesday November 8, 2011 Wednesday November 9, 2011 Thursday November 10, 2011 # Tuesday November 8, 2011 ## 9:00 AM 9:00 AM - 9:30 AM - Interviewee: Dr. Ron Waksman - Topic: DESERT: A Large-Scale, Multicenter, Case-Controlled Study Examining the Predictors of Stent Thrombosis - Embargo lift: 11:50 AM on Wednesday, November 9, 2011 ## 9:30 AM 9:30 AM - 10:00 AM - Interviewee: Dr. Justin Davies - Topic: ADVISE: Validation of a Vasodilator Independent Measure of Coronary Fractional Flow Reserve - Embargo lift: 12:25 PM on Friday, November 11, 2011 ## 10:00 AM 10:00 AM - 10:30 AM - Interviewee: Dr. David Cohen - Topic: PARTNER Cohort A QOL - Embargo lift: 11:33 AM on Thursday, November 10, 2011 ## 10:30 AM 10:30 AM - 11:00 AM - Interviewee: Dr. Dominick Angiolillo - Topic: BRIDGE: A prospective, Double-Blind, Multicenter, Randomized Placebo-Controlled Trial of Intravenous Cangrelor in Patients Awaiting Surgery - Embargo lift: 12:45 PM on Wednesday, November 9, 2011 ## 1:00 PM 1:00 PM - 1:30 PM - Interviewee: Dr. Gennaro Sardella - Topic: Comparison of high reloading ROsuvastatin and Atorvastatin pretreatment inpatients undergoing elective PCI to reduce the incidence of MyocArdial periprocedural necrosis (ROMA II Reload) - Embargo lift: 7:30 PM on Thursday, November 10, 2011 ## 1:30 PM 1:30 PM - 2:00 PM - Interviewee: Dr. Anna Sonia Petronio - Topic: MUSTELA: A Prospective, Randomized Trial of Thrombectomy vs. No Thrombectomy in Patients with ST-Segment Elevation Myocardial Infarction and Thrombus-Rich Lesions - Embargo lift: 12:35 PM on Thursday, November 10, 2011 ## 2:00 PM 2:00 PM - 2:30 PM - Interviewee: Dr. Harald Rittger - Topic: PEPCAD-DES: A Prospective, Randomized Trial of a Paclitaxel-Coated Balloon vs. Uncoated Balloon Angioplasty in Patients with Restenosis of Drug-Eluting Stents - Embargo lift: 11:40 AM on Friday, November 11, 2011 ## 2:30 PM OPEN TIME SLOT ## 3:00 PM OPEN TIME SLOT ## 3:30 PM 3:30 PM - 4:00 PM - Interviewee: Dr. Clemens von Birgelen - Topic: TWENTE: A Prospective, Randomized Trial of Zotarolimus-Eluting Stents and Everolimus-Eluting Stents in Patients with Coronary Artery Disease - Embargo lift: 12:05 PM on Friday, November 11, 2011 ## 4:00 PM 4:00 PM - 4:30 PM - Interviewee: Dr. Leif Thuesen - Topic: STACCATO: A Prospective, Randomized Trial of Transapical Transcatheter Aortic Valve Replacement vs. Surgical Aortic Valve Replacement in Low-Surgical-Risk Elderly Patients with Aortic Stenosis - Embargo lift: 11:51 AM on Thursday, November 10, 2011 ## 4:30 PM 4:30 PM - 5:00 PM - Interviewee: Dr. Tullio Palmerini and Dr. Mark Connolly - Topic: Debate on EES ## 5:00 PM 5:00 PM - 5:30 PM - Interviewee: Dr. Ajay Kirtane - Topic: TCT Wrap-up # Wednesday November 9, 2011 ## 10:00 AM OPEN TIME SLOT ## 10:30 AM 10:30 AM - 11:00 AM - Interviewee: Dr. Enrico Romagnoli - Topic: RIFLE STEACS: A Prospective, Randomized Trial of Radial vs. Femoral Vascular Access in Patients with ST-Segment Elevation Myocardial Infarction - Embargo lift: 12:25 PM on Thursday, November 10, 2011 ## 1:00 PM 1:00 PM - 1:30 PM - Interviewee: Dr. Matthew Reynolds - Topic: PARTNER Cohort A CE: Cost-Effectiveness Analysis from a Prospective, Randomized Trial of Transcatheter Aortic Valve Replacement vs. Surgical Aortic Valve Replacement in High-Surgical-Risk Patients with Aortic Stenosis - Embargo lift: 12:45 PM on Thursday, November 10, 2011 ## 1:30 PM 1:30 PM - 2:00 PM - Interviewee: Dr. Roxana Mehran - Topic: PARIS: A Large-Scale, Prospective, Multicenter Registry Studying the Patterns of and Reasons for Non-Adherence to Antiplatelet Agents in Stented Patients - Embargo lift: 12:00 PM on Wednesday, November 9, 2011 ## 2:00 PM OPEN TIME SLOT ## 2:30 PM 2:30 PM - 3:00 PM - Interviewee: Dr. Pieter R. Stella - Topic: DEB-AMI: A Prospective, Randomized Trial of Paclitaxel-Coated Balloons plus Bare Metal Stents vs Paclitaxel-Eluting Stents vs Bare Metal Stents Alone in Patients with ST-Segment Elevation Myocardial Infarction - Embargo lift: 12:45 PM on Thursday, November 10, 2011 ## 3:00 PM 3:00 PM - 3:30 PM - Interviewee: Dr. Dietmar Trenk - Topic: TRIGGER-PCI: A Prospective, Randomized Trial of Prasugrel vs. Clopidogrel in Clopidogrel-Hyporesponsive Patients with Stable Ischemic Heart Disease Undergoing Percutaneous Coronary Intervention - Embargo lift: 12:35 PM on Wednesday, November 9, 2011 ## 3:30 PM 3:30 PM - 4:00 PM - Interviewee: Dr. Ajay Kirtane - Topic: TCT Wrap-up ## 5:00 PM 5:00 PM - 5:30 PM - Interviewee: Dr. Sigmund Silber - Topic: TCT Wrap-up in German ## 5:30 PM 5:30 PM - 6:00 PM - Interviewee: Dr. Stefan James - Topic: TCT Wrap-up from a Scandinavian Perspective # Thursday November 10, 2011 ## 11:00 AM 11:00 AM - 11:30 AM - Interviewee: Dr. Juan Gaspar - Topic: TCT Wrap-up in Spanish ## 11:30 AM 11:30 AM - 12:00 PM - Interviewee: Dr. Didier Carrié - Topic: NEXT: A Prospective, Randomized Trial Comparing Cre8, a Polymer-Free Stent Eluting Sirolimus, to a Paclitaxel-Eluting Stent - Embargo lift: 11:30 AM on Friday, November 11, 2011 ## 1:00 PM 1:00 PM - 1:30 PM - Interviewee: Dr. Subhash Banerjee - Topic: COBRA: A Prospective, Randomized Trial of Cryoplasty vs. Conventional Balloon Post-dilation of Nitinol Stents in the Superficial Femoral Artery of Patients with Diabetes Mellitus - Embargo lift: 1:00 PM on Friday, November 11, 2011 ## 1:30 PM 1:30 PM - 2:00 PM - Interviewee: Prof. Ian Meredith - Topic: EVOLVE: A Prospective, Randomized Trial of Two Dose Formulations of a Bioabsorbable Polymer-based Everolimus-Eluting Stent vs. a Durable Polymer-based Everolimus-Eluting Stent - Embargo lift: 11:10 AM on Friday, November 11, 2011 ## 2:00 PM 2:00 PM - 2:30 PM - Interviewee: Dr. Derek So - Topic: Rapid GENE: A Prospective, Randomized Trial of Prasugrel vs. Clopidogrel in CYP2C19*2 Carriers Identified by Rapid Point-of-Care Genotyping - Embargo lift: 1:00 PM on Wednesday, November 9, 2011 ## 2:30 PM 2:30 PM - 3:00 PM - Interviewee: Dr. Raj Makkar - Topic: PARTNER Cohort B 2-Year: A Prospective, Randomized Trial of Transcatheter Aortic Valve Replacement vs. Standard Therapy in Patients with Inoperable Aortic Stenosis - Embargo lift: 11:25 AM on Thursday, November 10, 2011 ## 3:00 PM 3:00 PM - 3:30 PM - Interviewee: Dr. Ajay Kirtane - Topic: TCT Wrap-up ## 3:30 PM 3:30 PM - 4:00 PM - Interviewee: Dr. Gert Richardt - Topic: ROTAXUS: A Prospective, Randomized Trial of High-Speed Rotational Atherectomy Prior to Paclitaxel-Eluting Stent Implantation in Complex Calcified Coronary Artery Lesions - Embargo lift: 12:15 PM on Friday, November 11, 2011 ## 4:30 PM 4:30 PM - 5:00 PM - Interviewee: Dr. Giora Weisz - Topic: TCT Wrap-up in Hebrew

Short bowel syndrome overview # Overview Short bowel syndrome is a malabsorption disorder caused by the surgical removal of the small intestine. Most cases are acquired, although some children are born with a congenital short bowel. It does usually not develop unless a person has lost more than two-thirds of their small intestine. Intestine has the ability to adapt following resection. Adaptation depends on multiple factors including individual, intestinal and therapeutic measurements. Successful adaptation depends on the length of remaining intestine, portion of the resected intestine, and early introduction of nutrition therapy. Total intestinal adaptation defines as when patient is weaned from parenteral nutrition. The hallmark of short bowel syndrome is diarrhea. Complications might happen due to malnutrition, surgery and parenteral nutrition. Management of short bowel syndrome consists of medical and surgical therapy. Medical therapy consists of nutritional therapy and pharmacotherapy. Patients who have severe or worsened malabsorption might require surgery including intestinal transplant. Effective measures must be adopted for secondary prevention of complications following total parenteral nutrition including liver disease, cholelithiasis, kidney stone, small bowel bacterial overgrowth, lactic acidosis, lactic acidosis. # Historical Perspective The first successful intestinal resection was performed in 1880. In 1935, Haymond following research on many patients with bowel resection, reported that 30 to 50% loss of bowel was well tolerated. Total parenteral nutrition (TPN) was introduced during 1960s which helped patients to survive following bowel resection. # Classification Based on the length of the remaining bowel, short bowel syndrome may be divided into end-jejunostomy, jejunocolonic anastomosis, ileocolonic anastomosis. Severity varies from mild to severe. All of them require home parenteral nutrition except ileocolonic anastomosis which has excellent prognosis and rarely needs parenteral nutrition. Based on the etiology, short bowel syndrome may be divided into three categories such as vascular abnormalities, mucosal disease of intestine and causes without preexisting intestinal disease. # Pathophysiology Short bowel syndrome occurrs as a result of bowel resection following various diseases of the gut such as Crohn's disease, malignancies, ischemia, and trauma. Short bowel syndrome occurs when the length of the small intestine is less than 2 meters and requires nutritional therapy to prevent malnutrition. Post bowel resection, adaptation might occur which includes structural, motility and functional changes in the remaining intestine. Changes usually start in the first 24 hours following bowel resection and last for about two years. Adaptation depends upon multiple factors including individual, intestinal and therapeutic measurements. Following bowel resection, adaptation occurs in three phases including acute, adaptive, and maintenance phases. Successful adaptation depends on the length of remaining intestine, portion of the resected intestine, and early introduction of nutrition therapy. The term total intestinal adaptation is used when the patient is weaned from parenteral nutrition. The main reason for malabsorption following bowel resection is reduced absorptive capacity of the small intestine due to loss of surface area. On gross and microscopic examination, the resected bowel segment may show the underlying causes including Crohn's disease, malignancies or ischemia. # Causes Short bowel syndrome in adults is usually caused by surgical removal of the intestine due to different diseases including Crohn's disease, mesenteric ischemia, malignancies or radiation enteritis. Less common causes include trauma, volvulus, adhesion and iatrogenic surgery on gastrointestinal system. # Differentiating short bowel syndrome from Other Diseases # Epidemiology and Demographics The incidence and prevalence of short bowel syndrome is difficult to estimate. All the data is derived from patients receiving home parenteral nutrition. Therefore, there are different distributions around the world. The incidence of short bowel syndrome was estimated to be 1-2 cases per 100,000 individuals worldwide per year. The prevalence of short bowel syndrome is approximately 0.3-4 per 100,000 individuals in the USA to 0.1-4 per 100,000 individuals in Europe. It affects all age groups. There is no racial predilection to short bowel syndrome and is reported worldwide. Short bowel syndrome affects men and women equally. # Risk Factors Common risk factor for the development of short bowel syndrome may be iatrogenic including any operation on the gastrointestinal system. # Screening There is insufficient evidence to recommend routine screening for short bowel syndrome. # Natural History, Complications, and Prognosis The symptoms of short bowel syndrome usually develop immediately following bowel resection. Diarrhea may cause massive fluid and electrolyte loss. Immediately after surgery, intestinal adaptation develops in three phases, including acute, adaptive and maintenance phase. During the adaptation, structural, motility and functional changes occur. Patients need hydration and nutritional support via parenteral, enteral and oral routes. Length of remaining small bowel is the most important prognostic factor. Patients with more than 200 cm length of small bowel, usually do not need parenteral nutrition. Patients with shorter small bowel may not wean off from parenteral nutrition support. Complications might occur due to malnutrition, surgery and parenteral nutrition. Malnutrition presents with vitamin, mineral and essential fatty acids deficiencies. Complications related to surgery including thrombosis, infection, hemorrhage, atelectasis and anastomosis disruption might occur. Small intestinal bacterial overgrowth due to stasis and obstruction might also occur. Chronic liver disease following parenteral nutrition is a common complication in short bowel syndrome. There is no definite cure for short bowel syndrome. However, medications and nutritional therapy significantly improve the quality of life and survival of the patients. Prognosis of short bowel syndrome depends on the location and size of the bowel resection, underlying pathology, nutrition support, pharmacotherapy, and extent of intestinal adaptation. The 2 and 5-year survival rate of patients with short bowel syndrome are approximately 80% and 70%, respectively. # Diagnosis ## Diagnostic Criteria Short bowel syndrome is mainly diagnosed based on clinical presentation. There are no established criteria for the diagnosis of short bowel syndrome. History of bowel resection and clinical manifestation including diarrhea and malnutrition would confirm the diagnosis. ## History and Symptoms The hallmark of short bowel syndrome is diarrhea. A positive history of operation on gastrointestinal system and symptoms of malabsorption is suggestive of short bowel syndrome. The most common symptoms of short bowel syndrome include dehydration, abdominal pain, and fatigue. ## Physical Examination Patients with short bowel syndrome usually appear weak and tired. Physical examination of patients with short bowel syndrome is usually remarkable for signs of malabsorption, dehydration and abdominal tenderness. ## Laboratory Findings Laboratory findings consistent with the diagnosis of short bowel syndrome include anemia, hypoalbuminemia, low level of vitamins, minerals, and micronutrients. Level of acute phase reactants is high. Abnormal liver function tests including elevated liver enzymes and bilirubin might be seen. Fluid and electrolyte imbalance might be present. Fecal fat test is usually positive. ## Electrocardiogram There are no ECG findings associated with short bowel syndrome. In case of malnutrition and electrolyte imbalance, an ECG may be helpful. Hypokalemia might present with arrhythmia, ST segment depression, low T wave, prominent U waves and QRS prolongation. Hypocalcemia might present with QT interval prolongation. Hypomagnesemia might present with QT interval prolongation and ventricular and supraventricular arrhythmia. ## X-ray An abdominal x-ray may be helpful in the diagnosis of short bowel syndrome. Abdominal x-ray helps to rule out ileus or intestinal obstruction. Upper gastrointestinal series might demonstrate strictures and dilation of the bowel. ## Ultrasound There are no abnormal echocardiographic findings associated with short bowel syndrome. Ultrasound may be helpful in the diagnosis of complications of short bowel syndrome including gallstones and liver diseases. Doppler ultrasound might be used to diagnose venous thrombosis. ## CT scan Abdominal CT scan with contrast may be helpful in the diagnosis of short bowel syndrome complications including dilation, obstruction of the bowel and signs of liver diseases. ## MRI There are no MRI findings associated with short bowel syndrome. ## Other Imaging Findings There are no other imaging findings associated with short bowel syndrome. ## Other Diagnostic Studies There are no other diagnostic studies associated with short bowel syndrome. # Treatment ## Medical Therapy Management of short bowel syndrome is complicated and requires close collaboration of all medical team members including the physician, nutritionist, and nurse with the patient and their families. Medical therapy consists of nutritional therapy and pharmacotherapy. Nutritional therapy is essential for short bowel syndrome and to restore the intestinal adaptation. It could be provided through oral, enteral and parenteral routes. The ultimate goal is to provide necessary nutrients via oral route other than parenteral or enteral routes. All patients require enough fluid, electrolytes, supplements and calories. Medications are used to control symptoms of short bowel syndrome include antimotility agents, antisecretory agents, and trophic agents. Lifelong follow-up is usually needed. ## Surgery Surgery is not the first-line treatment option for patients with short bowel syndrome. Surgery is usually reserved for patients with the goal to wean them off parenteral nutrition. Patients who have severe or worsened malabsorption might require surgery including intestinal transplant. Transplant is contraindicated in patients with active infection or malignancies. Approximately half of the patients with short bowel syndrome will require surgery. Bianchi procedure and serial transverse enteroplasty (STEP) are performed to lengthen dilated bowel. Stricturoplasty might be necessary. Intestinal transplant is reserved for patients who have life-threatening complications of intestinal failure, irreversible permanent total parenteral nutrition requirement and episodes of sepsis or loss of venous access. ## Primary Prevention There are no established measures for the primary prevention of short bowel syndrome. However, treating underlying causes including Crohn's disease and malignancies might prevent short bowel syndrome. ## Secondary Prevention There are several ways to prevent complications of short bowel syndrome. Management strategies and regular follow-up are needed to find and treat complications accordingly. Effective measures must be done for secondary prevention of complications following total parenteral nutrition including liver disease, cholelithiasis, kidney stone, small bowel bacterial overgrowth, lactic acidosis, lactic acidosis. Hydration, consuming supplements, antibiotic therapy, and regular monitoring with blood tests, ultrasound and scans are recommended.

Neurosis Neurosis, also known as psychoneurosis or neurotic disorder, is a "catch all" term that refers to any mental imbalance that causes distress, but, unlike a psychosis or some personality disorders, does not prevent or affect rational thought. It is particularly associated with the field of psychoanalysis, which is one school of thought in psychology or psychiatry. # History and use of the term To differentiate between neurosis and neurotic: "Neurotic", or affected by neurosis, has come to describe a person with any degree of depression or anxiety, depressed feelings, lack of emotions, low self-confidence, and/or emotional instability. The term was coined by the Scottish doctor William Cullen in 1769 to refer to "disorders of sense and motion" caused by a "general affection of the nervous system." For him, it described various nervous disorders and symptoms that could not be explained physiologically. It derives from the Greek word neuron (nerve) with the suffix -osis (diseased or abnormal condition). The term was however most influentially defined by Sigmund Freud over a century later. The American DSM-III has eliminated the category of Neurosis altogether. This largely reflects a decline in the fashionability of psychoanalysis, and the progressive expurgation of psychoanalytical terminology from the DSM. Those who retain a psychoanalytical perspective, which would include a majority of psychologists in countries such as France, continue to use the term 'neurosis'. According to The American Heritage Dictionary, however, it is "no longer in scientific use." # Psychoanalytical account of neurosis As an illness, neurosis represents a variety of psychiatric conditions in which emotional distress or unconscious conflict is expressed through various physical, physiological, and mental disturbances, which may include physical symptoms (e.g., hysteria). The definitive symptom is anxieties. Neurotic tendencies are common and may manifest themselves as depression, acute or chronic anxiety, obsessive-compulsive tendencies, phobias, and even personality disorders, such as borderline personality disorder or obsessive-compulsive personality disorder. It has perhaps been most simply defined as a "poor ability to adapt to one's environment, an inability to change one's life patterns, and the inability to develop a richer, more complex, more satisfying personality." Neurosis should not be mistaken for psychosis, which refers to loss of touch with reality. The term connotes an actual disorder or disease, but under its general definition, neurosis is a normal human experience, part of the human condition. Most people are affected by neurosis in some form. A psychological problem develops when neuroses begin to interfere with, but not significantly impair, normal functioning, and thus cause the individual anxiety. Frequently, the coping mechanisms enlisted to help "ward off" the anxiety only exacerbate the situation, causing more distress. It has even been defined in terms of this coping strategy, as a "symbolic behavior in defense against excessive psychobiologic pain is self-perpetuating because symbolic satisfactions cannot fulfill real needs." According to psychoanalytic theory, neuroses may be rooted in ego defense mechanisms, but the two concepts are not synonymous. Defense mechanisms are a normal way of developing and maintaining a consistent sense of self (i.e., an ego), while only those thought and behavior patterns that produce difficulties in living should be termed neuroses. # Effects and symptoms There are many different specific forms of neuroses: pyromania, obsessive-compulsive disorder, anxiety neurosis, hysteria (in which anxiety may be discharged through a physical symptom), and an endless variety of phobias. According to Dr. George Boeree, effects of neurosis can involve: ...anxiety, sadness or depression, anger, irritability, mental confusion, low sense of self-worth, etc., behavioral symptoms such as phobic avoidance, vigilance, impulsive and compulsive acts, lethargy, etc., cognitive problems such as unpleasant or disturbing thoughts, repetition of thoughts and obsession, habitual fantasizing, negativity and cynicism, etc. Interpersonally, neurosis involves dependency, aggressiveness, perfectionism, schizoid isolation, socio-culturally inappropriate behaviors, etc. # Treatment Although neuroses are targeted by psychoanalysis, psychotherapy, counseling, or other psychiatric techniques, there is still controversy over whether these professionals can perform accurate and reliable diagnoses, and whether many of the resulting treatments are also appropriate, effective, and reliable. Some studies show no benefit is gained from talk therapies. However, some benefit is gained from other kinds of untrained personal companionship and discussion. # Jung's theory of neurosis Carl Jung's theory of neurosis is based on a self-regulating psyche. A neurosis consists not only of conflicts between conscious and unconscious forces or complexes. The unconscious also produces invaluable constructive guidance. The language the unconscious uses is a universal symbolism, often of a mythological nature. The leadership role of unconscious fantasies, such as dreams and visions, is more relevant to finding the gradient along which an individual should develop than an arbitrary presumption or method. Correctly reading symbolic emanations requires, besides knowledge of mythological motifs, an understanding of the ambiguous nature of symbols and the ability to interpret them from the unconscious attitude compensating that of the ego. Jung encouraged active imagination in this process. Jung found his approach particularly fitting for people who are successfully adjusted by normal social standards, but who nevertheless have issues with the meaning of their life. I have frequently seen people become neurotic when they content themselves with inadequate or wrong answers to the questions of life (Jung, 1989:140). The majority of my patients consisted not of believers but of those who had lost their faith (Jung, 1989:140). is blind to the fact that, with all his rationality and efficiency, he is possessed by "powers" that are beyond his control. His gods and demons have not disappeared at all; they have merely got new names. They keep him on the run with restlessness, vague apprehensions, psychological complications, an insatiable need for pills, alcohol, tobacco, food – and, above all, a large array of neuroses. (Jung, 1964:82). Jung found that the unconscious finds expression primarily through an individual’s inferior psychological function, whether it is thinking, feeling, sensing, or intuition. The characteristic effects of a neurosis on the dominant and inferior functions are discussed in Psychological Types. Jung saw collective neuroses in politics... "Our world is, so to speak, dissociated like a neurotic" (Jung, 1964:85).

Excimer laser-assisted nonocclusive anastomosis Excimer laser assisted nonocclusive anastomosis (ELANA) is a technique in vascular surgery and neurosurgery to create a bypass without interrupting blood supply in the recipient blood vessels. The ELANA technique is a subtle modification of existing methods to establish a connection between blood vessels (anastomosis) to create a bypass in or to the brain. The only real differences involve how the recipient artery is opened. In conventional techniques the recipient artery is temporarily interrupted (occluded with clips) and opened using microscissors or scalpel while in the ELANA technique blood flow is not interrupted and the opening (arteriotomy) is created with radiation from a 308nm Excimer Laser delivered through a catheter inserted in the vessel that will become the bypass while blood continues to flow through the artery that receives the bypass. This subtle difference, however, is very important for the safety of the procedure and eliminates the risk of ischemia to the regions supplied by the artery receiving the bypass. The technique is most valuable in neurosurgery, as brain cells are particularly sensitive to the lack of blood supply (ischemia) that would be caused by traditional methods of bypass creation. The bypasses created with the help of the ELANA can be to one of the major arteries in the brain (extracranial to intracranial EC-IC bypass) or between two arteries in the brain (intracranial to intracranial). Surgeons are creating such a bypass mainly as a step in the treatment of patients with unclippable and uncoilable giant aneurysms or tumors at the skull base or to treat patients at risk of stroke who can not be treated otherwise. The ELANA technique has been extensively described in medical literature. It was developed in 1993 by Cornelis A.F. Tulleken, professor of neurosurgery at the University Medical Center Utrecht, the Netherlands, to find a way to treat patients with a bypass to a major cerebral artery without the risk of cerebral ischemia during the procedure. The surgery of some patients has been reported upon in the media e.g., in The New York Times in December 2006.

Colorectal cancer (CRC) is the second leading cause of cancer deaths in Canada and the United States. A positive family history (FH) significantly increases the risk of developing CRC, and screening programs can substantially reduce CRC incidence and mortality. These consensus recommendations were developed by the Canadian Association of Gastroenterology (CAG), with US and Canadian experts, and endorsed by the American Gastroenterological Association. The purpose was to systematically and critically review the literature and provide specific recommendations See editorial on page 1298.# BACKGROUND & AIMS: A family history (FH) of colorectal cancer (CRC) increases the risk of developing CRC. These consensus recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on screening these high-risk individuals. METHODS: Multiple parallel systematic review streams, informed by 10 literature searches, assembled evidence on 5 principal questions around the effect of an FH of CRC or adenomas on the risk of CRC, the age to initiate screening, and the optimal tests and testing intervals. The GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach was used to develop the recommendations. RESULTS: Based on the evidence, the Consensus Group was able to strongly recommend CRC screening for all individuals with an FH of CRC or documented adenoma. However, because most of the evidence was very-low quality, the majority of the remaining statements were conditional ("we suggest"). Colonoscopy is suggested (recommended in individuals with 2 first-degree relatives ), with fecal immunochemical test as an alternative. The elevated risk associated with an FH of 1 FDRs with CRC or documented advanced adenoma suggests initiating screening at a younger age (eg, 40-50 years or 10 years younger than age of diagnosis of FDR). In addition, a shorter interval of every 5 years between screening tests was suggested for individuals with 2 FDRs, and every 5-10 years for those with FH of 1 FDR with CRC or documented advanced adenoma compared to average-risk individuals. Choosing screening parameters for an individual patient should consider the age of the affected FDR and local resources. It is suggested that individuals with an FH of 1 second-degree relatives only, or of nonadvanced adenoma or polyp of unknown histology, be screened according to averagerisk guidelines. CONCLUSIONS: The increased risk of CRC associated with an FH of CRC or advanced adenoma warrants more intense screening for CRC. Well-designed prospective studies are needed in order to make definitive evidence-based recommendations about the age to commence screening and appropriate interval between screening tests. for CRC screening of individuals with an FH of nonhereditary CRC or adenoma. This is the first guideline to use systematic reviews and the GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach to make recommendations for screening for CRC in this high-risk population. Multiple parallel systematic review streams, informed by 10 literature searches, assembled evidence on 5 principal questions: (1) effect of an FH of CRC on an individual's risk of CRC, (2) effect of an FH of adenoma on an individual's risk of CRC, (3) age at which screening should begin, (4) optimal screening tests, and (5) optimal testing intervals for individuals with an FH of CRC or adenoma. The GRADE approach was used to assess the quality of evidence. Questions were developed through an iterative online platform, and then statements were developed and voted on by a group of specialists. Consensus was reached on 19 statements addressing 5 main patient risk categories, including individuals with 2 or more first-degree relative (FDRs) with CRC, 1 FDR with CRC, 1 or more FDRs with advanced adenoma, 1 or more seconddegree relatives (SDRs) with CRC, and 1 or more FDR with any non-advanced adenoma (Table 1). Because of the lack of high-quality data, the majority of statements are conditional recommendations ("we suggest"). However, based on moderate-quality evidence, the Consensus Group is able to strongly recommend CRC screening over no screening for all individuals with an FH of CRC or documented adenoma. In addition, despite very-lowquality evidence, colonoscopy is recommended in individuals with 2 or more FDRs with CRC, because of the high-risk of life-threatening negative consequences of missed lesions. Based on available data and consensus, Table 2 provides a concise summary of the preferred and secondchoice screening tests, the age at which screening should begin, and the interval for screening according to the level of elevated CRC risk for each patient subgroup. For individual at highest risk (2 or more FDRs with a history of CRC), we recommend screening with colonoscopy, which we suggest begin at age 40-50 years or 10 years younger than the age of diagnosis of the FDR (whichever is earlier), at an interval of every 5 years. For individuals with 1 FDR with a history of CRC or advanced adenoma, we suggest commencing CRC screening at age 40-50 years or 10 years younger than the age of diagnosis of the FDR (whichever is earlier), at an interval of every 5-10 years. For those with an FH of CRC, colonoscopy is suggested with fecal immunochemical test (FIT) as an alternative, while both tests are suggested options for those with an FH of advanced adenoma. Finally, it is suggested that individuals with an FH of 1 or more SDRs only, or of nonadvanced adenoma or polyp of unknown histology be screened according to average-risk guidelines. Except for the statements for those at the highest risk, age ranges are provided. The relationship between the age at which an affected FDR was diagnosed with CRC and an individual's risk of developing CRC is difficult to define. The evidence shows that the risk falls on a continuum, and that there is no clearly defined age above or below which a clear inflection in risk can be recognized. The Consensus Group carefully considered the issue of recommending a range of years, acknowledging that some clinicians and programs may wish for greater precision. However, the evidence in cases where a range was recommended does not support a specific age point. Definitive statements in these circumstances are misleading and imply a degree of certainty that does not currently exist. Furthermore, specifying a range allows some flexibility, including consideration of the age of the affected FDR and local resources, and underscores the need for further data, which will hopefully lead to greater clarity in the future. The Consensus Group acknowledged that heritable cancers tend to occur at an earlier age and that this heritable risk decreases with advancing age of the diagnosis of the CRC in the FDR. That being the case, the age of the affected relative should be considered when making clinical decisions regarding screening. For example, having an FDR diagnosed at 75-90 years of age is unlikely to seriously impact an individual's risk of CRC, while an FDR diagnosed at age 35 years is probably highly relevant. Therefore, we acknowledge that national or provincial programs may wish to set specific FDR age cutoffs for screening, based on additional factors, including feasibility, cost, and cost-effectiveness. From an evidence perspective, we are, unfortunately, not able to provide clear guidance at this time. Future research should prioritize prospective studies that assess the optimal time to initiate screening and appropriate intervals between screening tests. # Introduction Colorectal cancer (CRC) is the second leading cause of cancer in Canada, and the fourth leading cause in the United States. 1,2 It is the second leading cause of cancer deaths in both countries, with approximately 9400 Canadians, and 50,260 Americans dying of the disease annually. The 2017 estimated incidence of new cases CRC was 26,800 Canadians, and 135,430 Americans, and the prevalence of individuals living with CRC was 105,195 Canadians (2009) and 1.3 million Americans (2014). 1,2 A systematic review (SR) estimated the prevalence of an individual having 1 or more first-degree relatives (FDRs) with CRC to be 3%-10%, and of having 2 or more FDRs with CRC to be about 0.3%. 3 Many of these individuals with a positive family history (FH) are at an increased risk of developing CRC. However, the magnitude of the individual's increased risk appears to be dependent on the degree of relationship to the affected relative, age of the affected relative at time of diagnosis, and the age of the individual. Overall CRC burden in a family (ie, total number of individuals with CRC on the same side of the family) also increases the magnitude of the individual's CRC risk. This may be a red flag for an inherited CRC syndrome. 4 CRC usually develops from premalignant polyps, and CRC screening can be used to detect and remove these polyps or localized cancer. Evidence from studies conducted in individuals primarily at "average risk" for CRC shows that screening (with endoscopy or occult blood tests) can reduce CRC mortality and incidence. Guidelines and the introduction of population-based screening programs have led to substantially increased uptake of CRC screening. Rates in the United States and Canada were about 25%-35% before 2003, but have increased to 55%-60% in 2012-2013 surveys. 8,9 Individuals with an FH of CRC are more likely to adhere to CRC screening recommendations compared to those with no FH. 3 But even among this higher-risk population, participation rates remain less than optimal. 3, While a variety of guidelines for screening individuals for CRC are available, the majority apply to patients at average risk, or those at highest risk due to inherited germline mutations associated with CRC and polyposis. 4,23,24 The few guidelines that make detailed recommendations for screening individuals with an FH of CRC or adenoma have not systematically reviewed the literature in this specific population. 17,19,20 Recent guidelines from the US Multi-Society Task Force on CRC screening used a modified process to systematically review published literature on this topic, however, systematic assessments of the methodological quality of the individual studies were not presented, and the paper was published after our consensus meeting. 22 For this guideline, systematic literature searches were conducted and the quality of evidence (QoE) and strength of recommendations were rated using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. 25 This guideline specifically excludes individuals with hereditary syndromes, such as Lynch syndrome, familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer. However, hereditary CRCs occurring due to mutations and defects in certain genes account for about 5% of all CRC. 4 Given the substantial risk of CRC and extracolonic cancers warranting specific screening strategies, it is important to identify these patients with hereditary syndromes. The National Comprehensive Cancer Network proposed 9 recommendations (summarized in Table 3) for patients who should be referred to a genetics provider for further assessment of a hereditary cancer syndrome. In addition, many jurisdictions and hospitals have implemented universal screening programs for CRC and endometrial cancers that include microsatellite instability or immunohistochemistry to identify patients at risk of Lynch syndrome. These individuals should be managed according to appropriate guidelines for individuals with hereditary gastrointestinal cancer syndromes. 4,23,24 The purpose of this guideline was to systematically and critically review the literature and provide specific recommendations for CRC screening of individuals with an FH of nonhereditary CRC or adenoma. # Methods # Scope and Purpose Questions around screening for CRC in individuals with an FH of nonhereditary CRC or adenomas were identified and discussed by the participants, aided by evidence derived from review of the literature on CRC screening. Specifically, the processes focused on 5 principal questions. # Sources, Literature Searches, and Systematic Reviews Evidence for these consensus guidelines was gathered via multiple parallel SR streams. The SRs were informed by a series of 10 literature searches. The scope, search strategy, and yield of each literature search are shown in Supplementary Table 1. All SRs (and the corresponding metaanalyses, where applicable) were performed by the 2 GRADE methodologists (GL and FT), with one exception, an SR of prospective studies on the risk of CRC among individuals with an FH of CRC/adenoma vs those without, which was led by Ahmed M. Abou-Setta, with the data being independently confirmed by the GRADE methodologists. All searches, data extractions, and analyses were performed by 1 investigator and double-checked by a second investigator, with any disagreements resolved by consensus. Most of the literature searches supported more than 1 of the SRs, and most SRs depended on 2 or more literature searches. The streams of evidence and the research questions they addressed are briefly summarized in Table 4. The results of the SRs (along with the assessments of the QoE) were forwarded to the Consensus Group members 1 week before the face-to-face meeting. All analyses were performed using the Cochrane Collaboration's Review Manager (RevMan). # Assessment of the Quality of Evidence The GRADE approach 25 was used by 2 nonvoting methodologists (GL, FT) to assess the following: risk of bias (of individual studies and overall, across studies), indirectness, inconsistency, imprecision, and other aspects (including publication bias) in order to determine the overall quality (trustworthiness) of evidence for each statement. As is described in GRADE 25,26 and used in prior Canadian Association of Gastroenterology (CAG) consensus documents, the descriptors of high, moderate, low, or very low were used to grade the QoE for each statement. One week before the face-to-face meeting, the voting members of the CRC Consensus Group had access to the GRADE assessments (including evidence profiles, the results of the SRs and meta-analyses conducted for this guideline, # Consensus Process The Consensus Group included 8 voting members: the meeting chair (DL), and 6 other gastroenterologists and clinical epidemiologists, as well as a family physician. The voting group included 2 participants from the United States (NJS, DAL). Nonvoting members included the moderator (JKM) and 2 GRADE methodologists (GIL, FT), 1 of whom acted as a co-moderator (GIL). The meeting was observed by members of the CAG and the Canadian Partnership Against Cancer. A patient advocate provided valuable insight during the initial guideline development. A web-based platform (ECD solutions, Atlanta, GA) was used by the CAG to facilitate the consensus process before the 2-day face-to-face meeting held in Banff, Alberta, Canada in March 2017. Voting members used the platform to answer the principal questions to be addressed during the meeting and provided valuable comments, feedback, and suggested sources of evidence. All participants had access to the results of literature searches and relevant references. At the meeting, the GRADE methodologists presented the data and provided the group with a review of the GRADE evaluations leading to the QoE determination for each of the questions. A modification of the Evidence-to-Decision (EtD) framework was applied to facilitate ranking of multiple screening methods for each specific population. The EtD framework is a formalized approach that enables a structured and transparent discussion on 12 criteria (is the problem a priority; how substantial are the desirable anticipated effects; how substantial are the undesirable anticipated effects; what is the overall certainty of the evidence on effects; is there important uncertainty about or variability in how much individuals value the main outcomes; do the desirable effects outweigh the undesirable effects; how large are the resource requirements; what is the certainty of evidence for the resource requirements; are the net benefits worth the incremental cost; what would be the impact on health equity; is the intervention/ option acceptable to key stakeholders; and is the intervention feasible to implement). 31 Recommendation statements were developed that were subsequently voted on anonymously via touchpads. If 75% of participants voted 4 (agree) or 5 Table 3.National Comprehensive Cancer Network Criteria for Further Genetic Risk Evaluation 4 Criteria Individuals meeting the revised Bethesda Guidelines Individuals with a family history that meets Amsterdam Criteria Individuals with colorectal (or endometrial) cancer with microsatellite instability or immunohistochemistry consistent with Lynch syndrome Individuals with papillary thyroid cancer that is the cribriform-morular variant, or hepatoblastoma Individuals with a diagnosis of CRC and >10 colorectal adenomas Individuals with a personal history of 20 adenomas Individuals with multiple gastrointestinal hamartomatous polyps or serrated polyposis syndrome Individuals from a family with a known hereditary syndrome associated with CRC with or without a known mutation Individuals with a desmoid tumor, multifocal or bilateral CHRPE CHRPE, congenital hypertrophy of retinal pigment epithelium. (strongly agree) on a scale of 1 to 5 (with 1, 2, and 3 indicating disagree strongly, disagree, and uncertain, respectively), a statement was then accepted. Once accepted, the "strength" of the recommendation (strong vs conditional) was determined based on 4 components: (1) QoE, (2) benefit-to-harm balance, (3) patients' values/preferences, and (4) resource requirements. 32 When the QoE was low or very low, unless at least 1 of the other 3 factors was overwhelmingly strong, the strength of the recommendation would typically default (without a vote) to "conditional," using the phrasing, "we suggest." If the QoE was moderate or high, the statement's strength was determined by an anonymous vote; if 75% of participants voted "strong, then the recommendation would be designated as "strong" and the phrasing was "we recommend." The GRADE approach notes that a conditional recommendation should prompt clinicians to ". . . recognize that different choices will be appropriate for different patients and that they must help each patient to arrive at a management decision consistent with her or his values and preferences," whereas a strong recommendation is indicative of a more broadly applicable statement ("most patients should receive the recommended course of action"). 32 In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months before the consensus meeting were provided by all participants, reviewed by the CAG ethics committee, and made available to all group members. # Canadian Association of Gastroenterology Approval and American Gastroenterological Association Endorsement The chair (DL) and 1 of the GRADE methodologists (GL) initially drafted the manuscript, which was then reviewed and revised by the remaining members of the Consensus Group, both individually and jointly during a teleconference. The manuscript was then made available to all CAG members for comments for a 2-week period before submission for publication, as per CAG policy for all clinical practice guidelines. Finally, the recommendations were reviewed, commented on, and endorsed by the American Gastroenterological Association. # Role of the Funding Sources

Prostaglandin EP1 receptor Prostaglandin E2 receptor 1 (EP1) is a 42kDa prostaglandin receptor encoded by the PTGER1 gene. EP1 is one of four identified EP receptors, EP1, EP2, EP3, and EP4 which bind with and mediate cellular responses principally to prostaglandin E2) (PGE2) and also but generally with lesser affinity and responsiveness to certain other prostanoids (see Prostaglandin receptors). Animal model studies have implicated EP1 in various physiological and pathological responses. However, key differences in the distribution of EP1 between these test animals and humans as well as other complicating issues make it difficult to establish the function(s) of this receptor in human health and disease. # Gene The PTGER1 gene is located on human chromosome 19 at position p13.12 (i.e. 19p13.12), contains 2 introns and 3 exons, and codes for a G protein coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see rhodopsin-like receptors#Subfamily A14). # Expression Studies in mice, rats, and guinea pigs have found EP1 Messenger RNA and protein to be expressed in the papillary collecting ducts of the kidney, in the kidney, lung, stomach, thalamus, and in the dorsal root ganglia neurons as well as several central nervous system sites. However, the expression of EP1 In humans, its expression appears to be more limited: EP1 receptors have been detected in human mast cells, pulmonary veins, keratinocytes, myometrium, and colon smooth muscle. # Ligands ## Activating ligands The following standard prostaglandins have the following relative potencies in binding to and activating EP1: PGE2≥PGE1>PGF2alpha>PGD2. The receptor binding affinity Dissociation constant Kd (i.e. ligand concentration needed to bind with 50% of available EP1 receptors) is ~20 nM and that of PGE1 ~40 for the mouse receptor and ~25 nM for PGE2 with the human receptor. Because PGE2 activates multiple prostanoid receptors and has a short half-life in vivo due to its rapidly metabolism in cells by omega oxidation and beta oxidation], metabolically resistant EP1-selective activators are useful for the study of EP1's function and could be clinically useful for the treatment of certain diseases. Only one such agonist that is highly selective in stimulating EP1 has been synthesized and identified, ONO-D1-OO4. This compound has a Ki inhibitory binding value (see Biochemistry#Receptor/ligand binding affinity) of 150 nM compared to that of 25 nM for PGE2 and is therefore ~5 times weaker than PGE2. ## Inhibiting ligands SC51322 (Ki=13.8 nM), GW-848687 (Ki=8.6 nM), ONO-8711, SC-19220, SC-51089, and several other synthetic compounds given in next cited reference are selective competitive antagonists for EP1 that have been used for studies in animal models of human diseases. Carbacylin, 17-phenyltrinor PGE1, and several other tested compounds are dual EP1/EP3 antagonists (most marketed prostanoid receptor antagonists exhibit poor receptor selectivity). # Mechanism of cell activation When initially bound to PGE2 or other stimulating ligand, EP1 mobilizes G proteins containing the Gq alpha subunit (Gαq/11)-G beta-gamma complex. These two subunits in turn stimulate the Phosphoinositide 3-kinase pathway that raises cellular cytosolic Ca2+ levels thereby regulating Ca2+-sensitive cell signal pathways which include, among several others, those that promote the activation of certain protein kinase C isoforms. Since, this rise in cytosolic Ca2+ can also contract muscle cells, EP1 has been classified as a contractile type of prostanoid receptor. The activation of protein kinases C feeds back to phosphorylate and thereby desensitizes the activated EP1 receptor (see homologous desensitization but may also desensitize other types of prostanoid and non-prostanoid receptors (see heterologous desensitization). These desensitizations limit further EP1 receptor activation within the cell. Concurrently with the mobilization of these pathways, ligand-activated EP1 stimulates ERK, p38 mitogen-activated protein kinases, and CREB pathways that lead to cellular functional responses. # Function Studies using animals genetically engineered to lack EP1 and supplemented by studies using treatment with EP1 receptor antagonists and agonists indicate that this receptor serves several functions. 1) It mediates hyperalgesia due to EP11 receptors located in the central nervous system but suppresses pain perception due to E1 located on dorsal root ganglia neurons in rats. Thus, PGE2 causes increased pain perception when administered into the central nervous system but inhibits pain perception when administered systemically; 2) It promotes colon cancer development in Azoxymethane-induced and APC gene knockout mice. 3) It promotes hypertension in diabetic mice and spontaneously hypertensive rats. 4) It suppresses stress-induced impulsive behavior and social dysfunction in mice by suppressing the activation of Dopamine receptor D1 and Dopamine receptor D2 signaling. 5) It enhances the differentiation of uncommitted T cell lymphocytes to the Th1 cell phenotype and may thereby favor the development of inflammatory rather than allergic responses to immune stimulation in rodents. Studies with human cells indicate that EP1 serves a similar function on T cells. 6) It may reduce expression of Sodium-glucose transport proteins in the apical membrane or cells of the intestinal mucosa in rodents. 7) It may be differentially involved in etiology of acute brain injuries. Pharmacological inhibition or genetic deletion of EP1 receptor produce either beneficial of deleterious effects in rodent models of neurological disorders such as ischemic stroke, epileptic seizure, surgically induced brain injury and traumatic brain injury. # Clinical studies EP1 receptor antagonists have been studied clinically primarily to treat hyperalgesia. Numerous EP antagonists have been developed including SC51332, GW-848687X, a benzofuran-containing drug that have had some efficacy in treating various hyperalgesic syndromes in animal models. None have as yet been reported to be useful in humans.

Nasal hair # Overview Nasal hair, or Nose hair is the hair in the nose. Adult humans have hairs in the anterior nasal passage. These hairs act as a fibrous filter for inhaled particles. Diffusion of ultra fine particles to the nasal hair occurs mostly for particles < 5 nm. Nasal hair has important implications for the health of the human body because a lack of nasal hair could invite the transport of potentially harmful particles into the respiratory system. Nasal hair should not be confused with cilia of the nasal cavity, which are the microscopic cellular strands that, unlike macroscopic nasal hair, draw mucus up toward the oropharynx via their coordinated, back-and-forth beating. # Nasal Hair and Attraction In some cultures, nose hair protruding from the nostrils may be thought of as unattractive, as is hair protruding from one's ears. A number of devices have been sold to trim the nose hair, including miniature rotary clippers and attachments for electric shavers. However, given the function of nasal hairs, many physicians recommend trimming them lightly, if at all. # Footnotes

Restructuring Electrophysiology During the COVID-19 Pandemic: A Practical Guide From a New York City Hospital Network The coronavirus disease 2019 crisis is a global pandemic of a novel infectious disease with far-ranging public health implications. With regard to cardiac electrophysiology (EP) services, we discuss the "real-world" challenges and solutions that have been essential for efficient and successful (1) ramping down of standard clinical practice patterns and (2) pivoting of workflow processes to meet the demands of this pandemic. The aims of these recommendations are to outline: (1) essential practical steps to approaching procedures, as well as outpatient and inpatient care of EP patients, with relevant examples, (2) successful strategies to minimize exposure risk to patients and clinical staff while also balancing resource utilization, (3) challenges related to redeployment and restructuring of clinical and support staff, and (4) considerations regarding continued collaboration with clinical and administrative colleagues to implement these changes. While process changes will vary across practices and hospital systems, we believe that these experiences from 4 different EP sections in a large New York City hospital network currently based in the global epicenter of the coronavirus disease 2019 pandemic will prove useful for other EP practices adapting their own practices in preparation for local surges.Paralleling the procedural and outpatient experience, day-today life of the administrative aspects of the inpatient EP services have changed completely during the COVID-19 pandemic(Table 2). FIGURE 1. Discussion points for regular daily communication between the hospital and EP leadership. It is important to troubleshoot clinical and administrative challenges and understand the broader balance of hospital needs with EP division resources during dynamic workflow changes. # Introduction In March 2020, New York City became the new global epicenter of the coronavirus (COVID-19) pandemic. The exponentially rising New York City COVID-19 caseload and the preceding experiences in China, Italy, and Washington state demonstrated a stark reminder that a catastrophe like a pandemic may potentially overwhelm even the most advanced health systems. In 2009, during the influenza A (H1N1) pandemic, the Institute of Medicine detailed "crisis standards of care," defined as a "substantial change in the usual health care operations and the level of care it is possible to deliver… justified by specific circumstances and… in recognition that crisis operations will be in effect for a sustained period."All medical departments in New York City instituted their respective crisis and contingency protocols while trying to maintain the highest possible quality of care for the upcoming months. In Lombardy, Italy, the unique organizational issues of an interventional cardiology department in treating patients during the pandemic crisis were recently described, including recommendations for patient riskstratification, cardiologist team reassignment, interhospital collaboration, and safety considerations.With regard to electrophysiology (EP) services, the surge in COVID-19 activity in New York City presented multiple challenges, requiring considerable "ramp down" and structural reorganization specific to the field of EP, as many services do not remain idle during this time period. We describe the changes in usual operations implemented in our 4 dedicated EP laboratory sections across the NewYork-Presbyterian (NYP) enterprise (i.e., Columbia University Irving Medical Center, Weill Cornell Medical Center, Queens, and Brooklyn Methodist Hospital). Our collective experience across the 4 NYP EP services may be representative of the rapid institutional changes that are required during a pandemic or national disaster. Therefore, we believe that these details of "how to ramp down" can serve as a practical guide and be of particular interest to other EP sections as rapidly rising cases of COVID-19 threaten other parts of the country. We additionally relay a handful of case scenarios from our experience that point out examples for how EP sections can prepare their policies and procedures (with prior CUIMC Institutional Review Board approval). ## Step 1: acknowledge that a public health crisis has arrived Understanding the potential scope of the COVID-19 problem has been challenging at all levels of policy-making, including national, state, and local, and within individual organizations. In the early days of March 2020, there was considerable debate across the country, including over social media, about the scope of scaling back and reprioritization of services, including whether nonurgent EP procedures should be postponed. Although the answer to these questions seems obvious in retrospect, the timing of when to begin canceling cases has often been staggered and made at the local level. To offer an example of the global sense of how the COVID-19 crisis has impacted our hospital network, as of the writing of this article on April 16, 2020, the entire NYPH medical system (which includes more than these 4 hospitals) reported 2317 COVID+ inpatients (598 at Columbia, 471 at Weill Cornell, 424 at Queens, 326 at Brooklyn Methodist, and remainder at affiliate hospitals); a total of 743 of these patients were located in ICUs given the severity of their illnesses. To meet these demands, one goal of the network has been to increase intensive care unit (ICU) bed capacity from a baseline of approximately 400 ICU beds to over 1000 ICU beds, a herculean task requiring a complete transformation of all hospital resources, including staff duties and physical plant. We describe the pivoting of operations within the context of 3 broad categories of reorganization, including (1) procedure-related and inpatient care, (2) outpatient care, and (3) administrative restructuring. ## Procedure-related and inpatient care ## Step 2: decide what urgent ep procedures are possible We follow the recently consolidated HRS/ACC/AHA COVID-19 practice guidance. [bib_ref] Guidance for cardiac electrophysiology during the coronavirus (COVID-19) pandemic from the Heart..., Lakkireddy [/bib_ref] Such a rapid and complete ramp down requires effort to communicate with and reassure scheduled patients that the procedure can be safely postponed. In reality, a decision about procedure triage is not necessarily a black and white one but includes shades of gray. For example: - We adopted a policy to perform procedures only in patients felt to have a likelihood of significant clinical deterioration within a short period of time, which has varied, depending on local availability of ancillary staff and PPE resources, from between 48 hours to 1-2 weeks. - All other prescheduled elective cases have been canceled without a reschedule date. - Direct admissions or transfers are very limited, given the surge of ED patients requiring admission. - As procedural areas have been converted into ICUs, the availability of procedural space for EP procedures must be carefully discussed with hospital leadership. The EP procedural volume has decreased along with the overall non-COVID+ volume in the hospital. In our experience, lab volume has decreased by 80%-95% across all sites. The majority of procedures performed are implantable devices, predominantly permanent pacemakers (PPMs) for high-grade atrioventricular block (AVB). Across our institutions, to date, only one ablation has been performed, which occurred just before the start of the patient surge. One device system extraction due to recalcitrant sepsis with a visible lead vegetation was performed. Patients with ventricular tachycardia (VT) have been to date managed medically, usually with amiodarone (and in many cases as outpatients with frequent follow-up, as described below). As the time spent operating under these conditions increases, we anticipate the increased possibility that patients will breakthrough medical therapy and require ablation therapy. In short, if the case is not urgent, it is not done. ## Step 3: consider how to optimize use of staff to minimize exposure during procedures while preserving ppes Workflows that have been ingrained for years all need to be reconsidered. For example, we maintain one operational EP lab at each center, sometimes shared with cath lab colleagues. In order to preserve PPE, and because staff, including specialized scrub technicians and nurses, have been "redeployed" to other units, we function by the mantra, "If it can be done by one person, then it should be done by one person." Cases are performed by a single attending. A surgical mask is placed on all patients, and if a patient's respiratory status is in question or tenuous before a procedure, then consideration of endotracheal intubation is discussed before patient transport to minimize aerosolization risk in the lab. N95 masks are used by operating physicians for all cases. As many anesthesia teams have been redeployed to assist with central lines and intubations, conscious sedation administered by the EP MD (with backup anesthesia services) is utilized if felt to be a reasonable option that does not compromise patient safety. ## Step 4: coordinate with your ep group, other clinical sections, and ep sections from network hospitals Frequent updates are required for appropriate communication in the era of social distancing, including updates regarding staff who are ill and not able to work. For example: - Daily morning meetings, conducted by videoconference, have allowed for the 11 EP attendings, as well as nurse practitioners and administrative staff, in the Columbia practice to remain in active communication. This venue allows for discussion of challenging cases, deliberation of how to message recommendations in a unified way (e.g., regarding COVID-related consultation questions), schedule shared responsibilities, and contingency plan. Smaller EP groups remain in communication via telephone. - Preplanning and coordination of urgent procedures with colleagues of other disciplines, including anesthesia, nursing, blood bank, backup surgery (the latter 2 for urgent extractions), allows for these representatives to deploy already stretched staff/resources and expedite throughput of patients. - Discussion and coordination with colleagues in other hospitals allow for "reality checks" regarding local practice patterns, and brainstorming of strategies to address shared challenges. The following is a summary of significant lab practice changes, specific cases, and "pearls" from our collective experience: - One area of deliberation has involved the timing of stable pacemaker-dependent outpatients with devices at elective replacement interval (ERI). As there is variation between companies in battery longevity and case reports of rapid unexpected battery depletion after ERI 4 and remote monitoring interrogations may further deplete the battery, we recommend performing a generator change within 1 month after the onset ERI in these patients, which we believe is in keeping with the HRS/ACC/AHA guidelines which classify these cases as non-elective/urgent. [bib_ref] Guidance for cardiac electrophysiology during the coronavirus (COVID-19) pandemic from the Heart..., Lakkireddy [/bib_ref] A list of patients monitored at home with devices around ERI should be maintained, so accurate contact information is important. - We have performed implantable cardioverter-defibrillator (ICD) placement on stable outpatients wearing an external ICD and awaiting a permanent implantable device or inpatients with multiple episodes of nonsustained VT and systolic dysfunction (HRS/ACC/AHA classification as semi-urgent 3 ). Device implantations are discharged the same day, when feasible, and ideally with remote monitoring capability. - In the case of a COVID-negative patient presenting to the hospital in high-grade AVB, we arranged to perform an expedited same-day PPM (including lab team mobilization on weekends). Similarly, we are prepared to perform same day and secondary prevention ICD placement in heart failure patients with VT. - In the case of an unstable transcatheter aortic valve replacement at high-risk for AVB, we coordinated with the structural © 2020 Wolters Kluwer Health, Inc. All rights reserved. www.critpathcardio.com | 3 valve team to be on-site and perform a PPM immediately following valve deployment in the same operating room if the patient developed irreversible AVB, facilitating same-day discharge. Coordination between cath and EP nursing (if not cross-trained) must be considered, as nursing staff may have been redeployed to other units. - For atrial fibrillation with rapid ventricular response refractory to medical therapy requiring cardioversion, computed tomography angiography scans are used (whenever possible) to ruleout left atrial appendage thrombi instead of transesophageal echocardiograms to minimize aerosolized exposure to transesophageal echocardiograms and anesthesia staff. Intracardiac echocardiogram to assess for thrombus has also been considered for appropriate candidates. - Attempt to perform device interrogations remotely. It is important to coordinate as early as possible with all device companies, as well as with clinical colleagues in the emergency department (ED), to establish remote monitoring capability in the ED and even ICUs. Indications for interrogation are limited to frank syncope, documented device malfunction, recurrent ICD shocks, need for a program change, and rule-out atrial fibrillation/flutter + cryptogenic stroke. - We have rotated device representative assistance in an effort to minimize exposure risk. - For hospitals that do not routinely perform device implantations on weekends, implement a strategy of opening the EP lab during this time period to implant a PPM in AVB patients and expedite patient flow/free up ICU bed space. - Urgent device implants have been performed while tolerating higher than usual international normalized ratios (e.g., international normalized ratio > 3.0), when benefit:risk ratio deemed appropriate. - Some patients have had procedures, including generator changes and direct current cardioversions, performed outside the metro New York area to minimize exposure risk and preserve PPE and other hospital resources. ## Step 5: strategize how to manage inpatient ep consultations Inpatient consult volume has diminished to approximately 1/3 of its baseline during the pandemic. Consultations are evaluated by one person to minimize exposure. Based on guidance regarding emergency healthcare provision during this crisis in the state of New York, if in-person consultation is not deemed to be necessary for diagnosis and treatment, then provider discretion is used to forego such potential exposure. Careful attention to communicate case presentations and recommendations thoroughly among consulting teams, consultants, and patients is paramount. Real-world applications of these points include: - Consults are performed remotely if possible via the electronic medical record, including Health Insurance Portability and Accountability Act (HIPAA)-compliant texts of electrocardiograms (ECGs) and telemetry strips sent to the consultant via the media section of the EMR. Some centers have remote access to inpatient telemetry. Telephone consultation with COVID+ inpatients (when possible), as well as discussions over the phone with family/friends (who are not able to remain with patients during this time period), has been utilized. - In the case of COVID-positive patients, we use telemetry to determine the rhythm and measure the QTc, preferably with lead II. COVID-19 related consults have included atrial fibrillation, atrial tachycardia, sinus arrest, accelerated idioventricular rhythm and VT in patients with myocarditis, and QTc prolongation with torsades. - Physician protection is paramount, and refresher web-based videos of donning and doffing were reviewed by all clinical staff. ## Outpatient care Step 6: Set Up Telehealth and Address Its Challenges With the onset of the COVID-19 pandemic, telemedicine across the country advanced dramatically within 1 week. Guided in part by changes in billing restrictions regarding televisits, as well as HIPAA restrictions, we transitioned nearly all patients to telehealth visits using videoconferencing capability native to electronic medical record system or using third-party video applications. 5 A summary of outpatient challenges, considerations, and recommendations is presented in [fig_ref] TABLE 1: Challenges, Responsibilities, and Considerations for Clinic Staff, Clinicians, and Patients During the... [/fig_ref]. For front-end staff: To facilitate remote "work from home" EP, some challenges and solutions have included: - For staff without access to appropriate computer equipment, the division purchased and loaned iPads for some staff at one hospital to perform televisits and loaned laptop computers for other staff who needed to access the electronic record system. - Recognize the increased efforts required to (1) contact patients to shift previously scheduled outpatient in-person visits and device checks to televisits, (2) remind patients not to come to clinic in-person, (3) obtain appropriate training to accommodate this change in workflow, (4) have staff guide patients through the process of being televisit-ready. Additional staff (e.g., medical assistants) are often required to be deployed to accomplish these tasks. - Coordination of call-forwarding of office numbers and fax management to staff now working from home. - Brainstorming flexible work solutions for those staff now with children at home from school or ill relatives needed to be addressed. Our network has been heavily involved in coordinating and communicating options to staff. - Working with informational technology (IT) staff (who themselves required additional support due to increased demand) to ensure adequate password access, virtual private network (VPN) access, and access to all required remote systems from home. - While supporting flexibility and addressing barriers to homebased work, reinforcing the need for prioritization of workrelated commitments while based in a home environment. - Reaching consensus regarding changes in workflow patterns, including televisits, that are occurring due to the COVID-19 crisis. Interestingly, whereas in the past, patients were resistant to setting up telemedicine, we have found that patients are now amenable to this option and have expressed satisfaction with reduced travel time and peace of mind regarding social distancing. For clinical providers performing televisits, potential challenges and solutions of rapid adaptation to telehealth have included: - Review if and how it is possible to perform televisits through the electronic medical record system, if possible. - In this crisis setting with relaxed HIPAA regulations, other third-party applications have also been utilized for televisits, and specific accounts have been opened for each attending, with a discussion of individuals' preferences. All video conference visits have been deemed eligible for reimbursement by Centers for Medicare & Medicaid Services, provided that documentation confirms the patient consented to telemedicine and specifies the time spent in consultation. Documentation of televisit type is noted in case other modalities, such as telephone visits, are deemed acceptable for billing. - If smartphones are used, consider whether personal phone number is viewable while using these different modalities. For patients, the following potential challenges and solutions have included: - Each patient's televisit capabilities must be assessed. Some patients may not be technologically adept, or not have access to a smartphone, laptop, WiFi, or e-mail. Although a telephonebased evaluation is not reimbursed at this time, we have found it is still an effective way to provide care to anxious patients who are unable to access telehealth in other ways. We have found that the following basic telemedicine "pearls" help smoothen the experience for patient and caregiver: - Communicate an exact time when the patient should log in to prevent miscommunication. Remind patients that providers may be late to calls, and to please allow for a certain time period to lapse before logging off. - Consider enlisting family members to assist patients requiring technical help to initiate or complete a visit. - When speaking to the patient, look directly into the camera on your computer to simulate eye contact. Explain to the patient that if you look away, it is to take notes. - Ensure appropriate lighting is present in the physician's home "office" space. - Patients transmitting remotely who were coming for an annual visit were rescheduled for a time in the distant future with continued remote monitoring; patients who had remote monitoring-capable devices but were not enrolled were called by an MD or NP and encouraged to enroll, and a remote monitor was sent to them; patients with devices incapable of remote monitoring were scheduled for an outpatient session in the future, with timing dependent on prior history, including estimation of battery life. - Postprocedure "wound care" follow-up has been accomplished through a dedicated, staffed e-mail address where patients may send photos of their wound site. Rapid provision and in-servicing in the use of remote home interrogators is imperative, as patients can send remote downloads from their home monitors to serve as postprocedure interrogations. - Apple watch, Kardia recordings, and mailed Holters and patch monitors have been used to assess for arrhythmias and to follow the QT interval. [bib_ref] Standard and precordial leads obtained with an apple watch, Gil [/bib_ref] Remote ECG transmissions have been useful to document exacerbations of arrhythmias, such as atrial fibrillation, in otherwise stable outpatients, as well as provide reassurance to those patients with heightened anxiety in general during the COVID-19 crisis. - When higher-risk patients are seen in person, the EP administrative staff is informed. A screening for COVID-19 symptoms must be performed before the visit. If possible, efforts should be made to have the consult at a less utilized "off-site" away from the hospital. At least one hospital has transitioned all outpatient visits off-site, as this option was felt to minimize exposure risk to outpatients (versus a facility with a high percentage of COVID+ patients). - Examples of patients who had in-person appointments during the COVID-19 surge in our system include assessments for patients with a concern for radiation skin injury after prolonged biventricular device placement, poor wound-healing in a device patient that required cleaning and adhesive, a thorough device interrogation in a PPM-dependent patient with a question of RV lead integrity, and an ICD interrogation for a patient with a lead conduction fracture and increasing episodic noise. - Lastly, it is an enormous challenge to manage patients who are shocked by their ICD at home during the COVID-19 pandemic. In our experience, due to patient reluctance and/or limited availability of ED and inpatient resources, cases ordinarily managed with ED visits/admissions or direct admissions may not be possible. To date, of 4 patients with multiple ICD shocks due to VT, all were medically managed after presenting to the ED for assessment of vitals and baseline laboratory testing and released home with careful follow-up, without inpatient admission. Examples include: - A patient with history of familial dilated cardiomyopathy and a subcutaneous ICD received 3 successive shocks for monomorphic VT. He was advised to take an extra dose of carvedilol and was transported by ambulance to a local ED, where he received an intravenous amiodarone load and was discharged on oral amiodarone 24 hours later without recurrent events, with plan to follow-up at a later date, as medical resources allow. - A patient with history of ischemic cardiomyopathy and a single lead ICD was brought to a network hospital site after receiving 7 shocks for monomorphic VT in the ventricular fibrillation zone in the setting of medication noncompliance. He received intravenous amiodarone 150 mg bolus and 6 hours of an infusion at 1 mg/min before being discharged on metoprolol and oral amiodarone load. - MD scheduling: Given the dramatic decrease in EP-centered patient volume, each on-call physician is involved in direct patient care at each hospital. As mentioned above, one attending performs procedures alone, with a backup physician available for assistance if needed. This system allowed for the flexibility of physician staff to continue to attend to their prescheduled responsibilities, including outpatient telehealth visits and inpatient rounding within the Cardiology division, and to record staff available for possible redeployment. - Contingency Planning for Deployment and Illness: Continuous flexibility regarding the rotation of MD staff should be maintained to adjust for physicians who fall ill or are redeployed in other areas of the hospital system, including ready availability of staff. 7 - Internal Redeployment: Providers and staff (physicians included) with patient-facing duties who have relevant medical comorbidities, and/or older age have been redeployed to nonpatient-facing duties, [bib_ref] Older clinicians and the surge in novel coronavirus disease 2019 (COVID-19), Buerhaus [/bib_ref] including -Covering inpatient as well as outpatient remote televisits, including for colleagues who have been redeployed -Talking to patient families over the phone who are unable to be physically with their loved ones in the hospital -Fielding overnight and weekend calls to relieve inpatient-based colleagues -Curbside consultations with junior EP staff members -Continuing teaching duties of trainees when appropriate -Administrative scheduling (i.e., to see patients remotely, talk with patients' families). Practically, we have created a schedule to delegate and track specific responsibilities for each MD that is accessible through a shared EP drive or the internet, with the goals of transparency and equitable balance of responsibilities. This has allowed for regular updating, including - One procedure attending in-house per day for procedures, clinic or floor work - One attending at home for procedural backup - Remaining attendings and fellows on a list to be deployed to non-EP areas (e.g., ICU/expanding ICD footprints or clinic as needed due to the expansion of ICU units, hospitalists, and general medicine services). - Contingency planning for fellows and non-MD staff: Other staff members' responsibilities have also changed considerably, often directed by hospital leadership, including department chiefs. These include: - Emergency temporary attending privileges have been granted to fellows in their board certified/eligible fields. - Nurse practitioners and physician-assistants have been transitioned to outpatient remote practices and also redeployed to surging EDs, cough/fever clinics, and ICUs. - Contingency planning for coverage of fellow duties and nonclinical staff is considered on a daily basis. - Satellite offices have been consolidated to minimize exposure risk and allow for redeployment of staff to other needed areas. Each deployment is managed centrally in conjunction with the Cardiology and Medicine divisions, depending on the particular needs of the hospital, and staff has also been deployed to hospitals within the network, as emergency privileges for all clinicians within the network hospitals were authorized. Further staff responsibilities include designating colleagues to coordinate research efforts with Institutional Review Board and other departments on topics of more urgent COVID-related interest (e.g., QTc in the setting of COVID-19 treatment, obtaining 7-lead ECGs off telemetry in units since unable to perform frequent 12-lead ECGs on COVID-19 patients). ## Step 8: communicate with hospital leadership regularly Lastly, but certainly not least in importance, is the need for regular, 2-way communication between sections and hospital leadership . For larger EP practices, we recommend that at least one staff member directly communicates with hospital and clinical division leaders each day for several reasons. These communications allow EP staff to: - Understand and appreciate the broader institutional picture, including the scope of the pandemic and its impact on the network - Discuss resource use and capacity - Discuss staff allocation, challenges, and illnesses - Troubleshoot daily clinical and administrative challenges - Provide and receive feedback in the setting of altered workflows - Convey that EP practices are relatively smaller compared with other services, and deployment needs of the hospital should be balanced with the need for availability of a core number of EP staff with specialized skills necessary to perform urgent/emergent EP procedures - Coordinate staffing changes regarding ill/exposed staff members from Workforce Health & Safety and Infection Prevention & Control departments. - Obtain information regarding possible housing, travel, and meal options for staff, including (1) the provision of temporary housing while working and unable to travel back-and-forth, or desiring of isolating from loved ones at home, (2) reimbursement of parking expenses for staff who normally travel without vehicles, (3) shuttle schedules for urban commuters, and (4) meal provisions while at work. These resources have been provided to us by the network system, including temporary housing provision for over 1800 staff members. All this information is relayed during a daily EP section videoconference. The point-person is responsible for communicating directly to hospital/clinical leadership. ## Table 2. key points when considering administrative restructuring and both external and internal redeployment ## Restructuring and redeployment One procedure attending in-house per day One attending at home for procedural backup; (others on a redeployment wait-list) Remaining attendings/fellows on a list to be deployed to non-EP areas Elderly, at-risk physicians reassigned to televisits, overnight calls, teaching duties, curbsides from EP in-house colleagues Emergency temporary attending privileges granted to fellows Contingency planning for coverage of fellow duties considered on a daily basis Designate colleagues to coordinate research efforts with Institutional Review Board Practically, our shared morning workflow proceeds as follows: - Holding a regularly scheduled video conference among physicians and ancillary staff to discuss health check-ins, hospital capacity updates, and procedural and ethical discussions. An agenda is circulated before each meeting, and minutes are kept. Depending on local staffing and workflow, frequency of meetings has varied from daily to a few times per week. - Video conferences allow for the continuation of fellow education conferences, which are performed remotely with PowerPoint lectures and electrogram-based "quizzes." - Solicit questions, suggestions, and feedback, including reviewing the importance of appropriate PPE use, as well as experiences and best-practice tips for donning and doffing PPE. We find that these daily meetings also present a much-needed opportunity to decompress and maintain positive morale among staff, as more deliberate communication with colleagues is necessary to overcome the physical barriers to "curbside encounters" imposed by social distancing. Striving to maintain regularly scheduled weekly electrogram conferences and case reviews helps to maintain a sense of camaraderie and "normalcy" during these challenging times. # Conclusions During the COVID-19 pandemic in New York City, restructuring in the form of multiple "ramp down" and pivot modifications have been rapidly applied to the EP services across the NYPH hospital system, resulting in deployment of EP resources in a streamlined but not idle fashion. It is obviously better to prepare in advance for such ramp down, with contingency protocols in place before the COVID-19 pandemic reaches a hospital system. We understand that not all EP practices are the same, and groups will face different challenges, including managing the financial burden and sequelae of decreased volume, as well as the possible "second surge" of both inpatients and outpatients who have remained at home with EP disorders until peak COVID-19 surging has dissipated. Nevertheless, we hope our experience is useful for EP sections in other parts of the country and world who, unfortunately, anticipate an influx of COVID-19 cases. As we learn from each other how to face an unprecedented modern pandemic, continued communication, collaboration, and preparedness are critical to helping our patients and each other. [table] TABLE 1: Challenges, Responsibilities, and Considerations for Clinic Staff, Clinicians, and Patients During the Transition to Telehealth Visits During the COVID-19 Pandemic [/table]

Trovafloxacin (patient information) # IMPORTANT WARNING Trovafloxacin is no longer available in the U.S. If you are currently taking trovafloxacin, you should call your doctor to discuss switching to another treatment. Trovafloxacin may cause serious liver injury leading to liver transplantation or death, especially when it is taken for more than 2 weeks. Trovafloxacin should be used only for serious infections. Talk to your doctor about the risk of taking trovafloxacin. If you experience any of the following symptoms, call your doctor immediately: increased fatigue, loss of appetite, yellowing of the skin and eyes, severe stomach pain with nausea and vomiting, or dark urine. Keep all appointments with your doctor and the laboratory. Your doctor may order certain lab tests to check your response to trovafloxacin. # Why is this medication prescribed Trovafloxacin is an antibiotic used to treat certain infections caused by bacteria, such as pneumonia and skin, urinary, respiratory, sinus, gynecological, sexually transmitted, and gastrointestinal tract infections. Antibiotics will not work for colds, flu, or other viral infections. This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information. # How should this medicine be used Trovafloxacin comes as a tablet to take by mouth. It usually is taken once a day with or without food. Follow the directions on your prescription label carefully and ask your doctor or pharmacist to explain any part you do not understand. Take trovafloxacin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Continue to take trovafloxacin even if you feel well. Do not stop taking trovafloxacin without talking to your doctor. # What special precautions should I follow Before taking trovafloxacin - tell your doctor and pharmacist if you are allergic to trovafloxacin, alatrofloxacin, cinoxacin (Cinobac), ciprofloxacin (Cipro), enoxacin (Penetrex), erythromycin, levofloxacin (Levaquin), lomefloxacin (Maxaquin), nalidixic acid (NegGram), norfloxacin (Noroxin), ofloxacin (Floxin), sparfloxacin (Zagam), or any other drugs. - tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially other antibiotics, anticoagulants (blood thinners) such as warfarin (Coumadin), cyclosporine (Neoral, Sandimmune), medications containing caffeine (NoDoz, Vivarin), morphine, probenecid (Benemid), sucralfate (Carafate), theophylline (Theo-Dur), and vitamins. - you should know that antacids (Mylanta, Maalox), iron or zinc supplements, or vitamins that contain iron or zinc may interfere with trovafloxacin. Take antacids, supplements, or vitamins 2 hours before or 4 hours after trovafloxacin. - tell your doctor if you have or have ever had liver or kidney disease, epilepsy, or any other neurological disorder. - tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking trovafloxacin, call your doctor immediately. - you should know that this drug may make you drowsy. Do not drive a car or operate machinery until you know how trovafloxacin will affect you. - plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Trovafloxacin may make your skin sensitive to sunlight. # What special dietary instructions should I follow Do not eat or drink a lot of caffeine-containing products, such as coffee, tea, cola, or chocolate. Avoid large amount amounts of these substance while taking trovafloxacin. # What should I do if I forget a dose Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. # Side Effects ## Mild side effects Although side effects from trovafloxacin are not common, they can occur. Tell your doctor if any of these symptoms are severe or do not go away: - dizziness - lightheadedness - headache - drowsiness - upset stomach - vomiting - diarrhea ## Severe side effects If you experience any of the following symptoms, or those listed in the IMPORTANT WARNING section, call your doctor immediately: - skin rash or hives - itching - sunburn - swelling of the face or throat - difficulty breathing or swallowing - depression - hallucinations - seizures - change in vision - vaginal infection - pain, inflammation, or rupture of a tendon If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online or by phone . # What storage conditions are needed for this medicine Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication. # In case of emergency/overdose In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911. # What other information should I know Do not let anyone else take your medication. Your prescription is probably not refillable. If you still have symptoms of infection after you finish the trovafloxacin, call your doctor. # Brand names - Trovan®

Mastoiditis overview # Overview Mastoiditis is the infection of mastoid air cells in the process of temporal bone. It is mostly a complication of ear diseases such as acute otitis media and chronic otitis media, and it tends to occur in children. However after development of antibiotics, acute otitis media complications have decreased significantly. # Historical perspective Mastoiditis was first described by Hippocrates in the 5th century B.C.E. The first recorded surgical incision for treatment of medial ear infection was in the 16th century C.E., performed by French physician Ambroise Pare. Initial therapies for middle ear diseases were surgical, particularly mastoidectomy, which was first performed by French physician Jean-Louis Petit in the 17th century C.E. German physicians Hermann Schwartze, Anton von Troltsch, and Adam Politzer published the first journal dedicated to ear pathology and treatment in 1865. Antibiotic therapy for mastoiditis treatment emerged with the invention of mass production of penicillin in 1940 by Alexander Fleming, Howard Florey, and Ernst Chain. The pneumococcal conjugate vaccine (PCV) emerged in 2000, greatly reducing the incidence of otitis media and mastoiditis by vaccinating individuals against the causative pathogens. # Classification Mastoiditis may be classified into acute, subacute, and chronic forms, depending on the timing of presentation and duration. # Pathophysiology Mastoiditis is the infection in the cavities of mastoid process of temporal bone that occurs after otitis media. At birth, the mastoid consists of a single cavity, which is connected to the middle ear by a canal. As the child grows, the mastoid bone becomes pneumatized, resulting in a series of connected cavities, lined by a mucosa diverted from respiratory epithelium. There is a relationship between the middle ear, the eustachian tube, and the mastoid. This connection has a fundamental role in the pathogenesis of mastoiditis. In the setting of acute otitis media, the mucosa that lines the middle ear and mastoid air cells become inflamed. In most cases of acute otitis media, inflammation resolves, but it sometimes persists, leading to bacterial and fluid accumulation within the mastoid air cells. Gradually, as a result of pressure rising in the mastoid, air cell septae may be destroyed and mastoiditis could proceed to osteomyelitis. The mastoid is near vital organs in the head and neck and mastoid infection may cause serious complications. There is evidence of genetic predisposition to recurrent otitis media and therefore mastoiditis. The following genes have been identified as having potential pathogenic qualities for otitis media: CAPN14, GALNT14, BPIFA3, BPIFA1, BMP5, GALNT13, NELL1, and TGFB3. # Causes Mastoiditis results from middle ear infection. The most common bacteria that cause acute mastoiditis are Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. Staphylococci, Pseudomonas species, and polymicrobials are predominantly seen in non-acute mastoiditis. Pseudomonas aeruginosa may be found in children with acute mastoiditis as a consequence of recurrent acute otitis media and antibiotic use. # Differentiating Mastoiditis from other Diseases Mastoiditis must be differentiated from other diseases that cause postauricular inflammation or swelling such as lymphadenopathy, periauricular cellulitis, auricle perichondritis, mumps, and mastoid tumors. These diseases may be distinguished from mastoiditis via clinical findings and laboratory testing. # Epidemiology and Demographics Mastoiditis incidence is 1.2–6.1 per 100,000 inhabitants in developed countries. Serious progressions appear more frequently in young children. After using pneumococcal vaccination, the rate of acute otitis media and mastoiditis decreased dramatically. However, there is a concern about rising incidence, which is connected to inadequate antibiotic dosing in otitis media, choice of antibiotics, and increasing resistance of bacteria. Acute mastoiditis is most common among children under two years of age. Men and women are affected equally by mastoiditis. Otitis media and therefore mastoiditis are more prevalent in developing countries, specifically Sub-Saharan West Africa, Southeast Asia, and Oceania. Risk factors that may contribute to higher incidence in developing countries include exposure to HIV, malnutrition, a large proportion of children under 5 years in the population, and higher chance of water contamination. # Risk Factors The risk factors for mastoiditis are related to acute otitis media risk factors. Risk factors are allergy, upper respiratory tract infection, snoring, previous history of acute otitis media, passive smoking, mother smoking during pregnancy, and low social status. Exposure of infants to day-care centers is a controversial risk factor. # Screening There is insufficient evidence to recommend routine screening for mastoiditis. # Natural History, Complications and Prognosis If left untreated, mastoiditis will result in severe complications such as intracranial extension and permanent neurological deficits or death. The consequences of mastoiditis have been reduced after introduction of antimicrobial agents and adequate therapy of acute otitis media. However, if mastoiditis is not eradicated completely, it may give rise to severe complications. These complications are extracranial, such as osteomyelitis, labyrinthitis, facial nerve palsy, Bezold's abscess, hearing loss, subperiosteal abscess, or intracranial, such as epidural and subdural abscess, meningitis, temporal bone or brain abscess and venous sinus thrombosis. The prognosis of mastoiditis is good with treatment. Excellent outcomes can be expected for those who are managed without delay. # Diagnosis ## History and Symptoms History and symptoms of mastoiditis range from asymptomatic disease to symptomatic and progressive mastoiditis with serious life-threatening complications. History should be taken considering onset, duration, and progression of symptoms, allergies, previous history of acute otitis media, upper respiratory tract infection, associated symptoms (otalgia, fever, confusion), medications including antibiotic usage in acute otitis media, snoring, attendance to day care, history of trauma, co-morbid conditions like diabetes, immunodeficiency, and smoking. Common symptoms of mastoiditis are: ear pain, fever, feeling of "fullness" in the ear, recent episode of acute otitis media, discharge from the affected ear, partial hearing loss, irritability (in infants), headache, and lethargy/malaise. Neurological symptoms from chronic mastoiditis and otitis media with effusion include poor attention span, delayed speech development, clumsiness, and poor balance. Less common symptoms are gastrointestinal symptoms such as vomiting and diarrhea, meningismus, and torticollis ## Physical Examination Mastoiditis physical examination includes posterior auricular signs such as postauricular swelling, erythema, tenderness, protrusion of pinna, and sagging external ear canal. Otoscopic examination of the middle ear shows erythema, bulging, cloudy appearance, and immobility of the tympanic membrane. Partial hearing loss from fluid buildup is indicative of otitis media, revealed by tympanometry. Acute mastoiditis patients are usually ill-appearing and usually present with low-grade fever, while complicated mastoiditis patients may present with severely ill appearance. ## Laboratory Findings There are no diagnostic blood laboratory findings associated with mastoiditis. Some patients with mastoiditis may have elevated ESR, CRP, and white blood cells with a left shift. These laboratory findings are nonspecific and not helpful in making the diagnosis. It is very important to obtain clinical specimens for microbiology. Microbial results are crucial in the proper antimicrobial choice for treatment. There are multiple types of bacteria that may cause mastoiditis like Streptococcus species and Staphylococcus aureus, and there are rising concerns about antibiotic resistance in some microorganisms. The obtained fluid or pus should be sent for Gram stain, aerobic and anaerobic culture, and antimicrobial susceptibility testing. Specimens for mastoiditis treatment could be obtained via multiple sites such as middle ear via tympanocentesis or myringotomy, percutaneous aspiration from subperiosteal abscess, cerebrospinal fluid, or blood cultures. ## X-ray There are no diagnostic X-ray findings associated with mastoiditis. ## CT scan High Resolution CT scans of the temporal bone in mastoiditis patients are the preferred diagnostic tool and may reveal mastoiditis and its complications. CT findings in acute mastoiditis are: partial-to-complete opacification of mastoid air cells, erosion of mastoid air cell bony septum, mastoid cortex destruction and irregularity, periosteal thickening, periosteal disruption, and subperiosteal abscess. CT findings in subacute and chronic mastoiditis are: markers for inflammation, sclerosis, or opacification of mastoid process, tympanic membrane changes including thickening, retraction, tympanic membrane perforation, or calcification, ossicle erosion or other possible causes for hearing loss, determination of cholesteatoma, intratemporal complications such as petrositis, labyrinthitis, subperiosteal abscess, or labyrinthine fistula, intracranial complications such as brain abscess and meningitis, presence of fibrous tissue, tympanosclerosis, formation of new bone matter, ossicle erosion, and displacement and extension of cholesteatoma to sinuses. ## MRI Both CT and MRI are used in the evaluation of mastoiditis and its complications. MRI in mastoiditis plays a role in the detection of cholesteatoma, also when intracranial and some intratemporal complications are suspected. Specifically, MRI has shown superiority in assessing the severity of intracranial involvement and abscess border visualization. ## Ultrasound There are no ultrasound findings associated with mastoiditis. ## Other Imaging Findings There are no other diagnostic findings for mastoiditis. ## Other Diagnostic Studies Other mastoiditis imaging findings include otoscopic images of the tympanic membrane displaying middle ear effusion and infection. Also, tympanograms may be used for measuring pressure from fluid buildup in the middle ear. # Treatment ## Medical Therapy Medical treatment for acute and subacute mastoiditis without intracranial complications consists of intravenous antibiotics and myringotomy. Antibiotics for acute mastoiditis must cover the most common bacterial pathogens: Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus (including methicillin-resistant S. aureus). If there is a history of recurrent acute otitis media or recent antibiotic usage, the intravenous antibiotic also should cover Pseudomonas aeruginosa. Bacteria commonly covered include Streptococcus pneumonia, Group A streptococcus, and Staphylococcus aureus. The empiric antibiotics are ampicillin-sulbactam or ampicillin; add vancomycin for severe infection with adjacent complications or suspicion of MRSA. For chronic mastoiditis, bacteria commonly covered are Pseudomonas aeruginosa, Staphylococcus aureus and anaerobes. Antibiotics include piperacillin-tazobactam or piperacillin, and ofloxacin otic solution; add vancomycin for severe infection with adjacent complications or suspicion of MRSA. ## Surgery Different surgical procedures may be performed to treat mastoiditis. Myringotomy is surgical perforation of the tympanic membrane. It should be considered the primary treatment in all cases of infectious mastoiditis following otitis media, particularly when there is an unperforated tympanic membrane or inadequate drainage. Tympanocentesis should be performed in all mastoiditis patients to obtain middle ear fluid for culture and susceptibility testing. Myringotomy accompanied by the additional insertion of a tympanostomy tube is indicated in some cases, such as Eustachian tube dysfunction, suppurative complications requiring additional drainage, and when tympanic membrane must be repaired from Eustachian tube dysfunction. Definitive surgery is mastoidectomy, which is the surgical removal of the mastoid cortical bone and underlying air cells. Indications for mastoidectomy may include subperiosteal abscess such as postauricular fluctuance or mass, chronic suppurative otitis media or cholesteatoma, progression of postauricular swelling or fluctuance, fever, and other clinical findings or continuous drainage despite parenteral antimicrobial therapy and myringotomy. ## Primary Prevention Preventing mastoiditis primarily involves preventing development of otitis media and nasopharyngitis. This is achieved by administration of the pneumococcal and influenza vaccines, frequently washing hands, and avoiding fluid transmission and respiratory droplets from nasopharyngitis patients. Preventing exposure to air pollution, as potential middle ear irritants such as secondhand smoke helps prevent otitis media, is also helpful in preventing mastoiditis. For infants, preventative measures include avoiding pacifiers, avoiding daycare enrollment, and breastfeeding until at least 6 months of age. A prophylactic regimen of antibiotics can prevent otitis media in at-risk infants and children. ## Secondary Prevention For mastoiditis following chronic or recurrent otitis media, preventing recurrence of the disease involves surgery, assuming the manifestation is not self-limited. Myringotomy with tympanostomy tube and mastoidectomy is the most common surgical preventative measure.

Smoke inhalation # Overview Smoke inhalation is the primary cause of death in victims of indoor fires. # Pathophysiology The smoke injures or kills by a combination of thermal damage, poisoning and pulmonary irritation caused by carbon monoxide, cyanide and other combustion products. # Epidemiology and Demographics It is estimated that "50-80% of fire deaths are the result of smoke inhalation injuries rather than burns." # Diagnosis ## History and Symptoms Symptoms range from coughing and vomiting to nausea, sleepiness and confusion. ## Physical Examination ### HEENT Burns to the nose, mouth and face; singed nostril hairs; and difficulty breathing / carbonaceous sputum (burned saliva) are also signs of smoke inhalation injury. # Treatment ## Medical Therapy Any person with apparent signs of smoke inhalation should be immediately evaluated by a medical professional such as a firefighter-paramedic or physician. Advanced medical care may be necessary to save the life of the patient, including mechanical ventilation, even if the person is conscious and alert. Pending advanced intervention, the patient should be brought into fresh air and given medical oxygen if available.

Trabecula A trabecula (plural trabeculae. From Latin for small beam.) is a small, often microscopic, tissue element in the form of a small beam, strut or rod, generally having a mechanical function, and usually but not necessarily composed of dense collagenous tissue. On histological section, a trabecula can look like a septum, but in three dimensions they are topologically distinct, with trabeculae being roughly rod or pillar-shaped and septa being sheet-like. Trabeculae are usually composed of dense fibrous tissue, i.e. mainly of collagen, and in most cases provide mechanical strengthening or stiffening to a soft solid organ, such as the spleen. They can be composed of other materials, such as bone or muscle. When crossing fluid-filled spaces, trabeculae may have the function of resisting tension (as in the penis) or providing a cell filter (as in the eye.) Multiple perforations in a septum may reduce it to a collection of trabeculae, as happens to the walls of some of the pulmonary alveoli in emphysema. # Examples of trabeculae - trabeculae of bone - trabeculae of corpora cavernosa of penis - trabeculae of corpus spongiosum of penis - trabecular meshwork of the eye - trabeculae of spleen - trabeculae carneae - septomarginal trabecula # Etymology Diminutive form of Latin trabs, which means a beam or bar. In the 19th century, the neologism trabeculum (with an assumed plural of trabecula) became popular, but is less etymologically correct. Trabeculum persists in some countries as a synonym for the trabecular meshwork of the eye, but this can be considered poor usage on the grounds of both etymology and descriptive accuracy.

CHEK2 CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers. # Gene location The CHEK2 gene is located on the long (q) arm of chromosome 22 at position 12.1. Its location on chromosome 22 stretches from base pair 28,687,742 to base pair 28,741,904. # Protein structure The CHK2 protein encoded by the CHEK2 gene is a serine threonine kinase. The protein consists of 543 amino acids and the following domains: - N-terminal SQ/TQ cluster doman (SCD) - Central forkhead-associated (FHA) domain - C-terminal serine/threonine kinase domain (KD) The SCD domain contains multiple SQ/TQ motifs that serve as sites for phosphorylation in response to DNA damage. The most notable and frequently phosphorylated site being Thr68. CHK2 appears as a monomer in its inactive state. However, in the event of DNA damage SCD phosphorylation causes CHK2 dimerization. The phosphorylated Thr68 (located on the SCD) interacts with the FHA domain to form the dimer. After the protein dimerizes the KD is activated via autophosphorylation. Once the KD is activated the CHK2 dimer dissociates. # Function and mechanism The CHEK2 gene encodes for checkpoint kinase 2 (CHK2), a protein that acts a tumor suppressor. CHK2 regulates cell division, and has the ability to prevent cells from dividing too rapidly or in an uncontrolled manner. When DNA undergoes a double-strand break, CHK2 is activated. Specifically, DNA damage-activated phosphatidylinositol kinase family protein (PIKK) ATM phosphorylates site Thr68 and activates CHK2. Once activated, CHK2 phosphorylates downstream targets including CDC25 phosphatases, responsible for dephosphorylating and activating the cyclin-dependent kinases (CDKs). Thus, CHK2’s inhibition of the CDC25 phosphatases prevents entry of the cell into mitosis. Furthermore, the CHK2 protein interacts with several other proteins including p53 (p53). Stabilization of p53 by CHK2 leads to cell cycle arrest in phase G1. Furthermore, CHK2 is known to phosphorylate the cell-cycle transcription factor E2F1 and the promyelocytic leukemia protein (PML) involved in apoptosis (programmed cell death). # Association with cancer The CHK2 protein plays a critical role in the DNA damage checkpoint. Thus, mutations to the CHEK2 gene have been labeled as causes to a wide range of cancers. In 1999, genetic variations of CHEK2 were found to correspond to inherited cancer susceptibility. Bell et al. (1999) discovered three CHEK2 germline mutations among four Li–Fraumeni syndrome (LFS) and 18 Li–Fraumeni-like (LFL) families. Since the time of this discovery, two of the three variants (a deletion in the kinase domain in exon 10 and a missense mutation in the FHA domain in exon 3) have been linked to inherited susceptibility to breast as well as other cancers. Beyond initial speculations, screening of LFS and LFL patients has revealed no or very rare individual missense variants in the CHEK2 gene. Additionally, the deletion in the kinase domain on exon 10 has been found rare among LFS/LFL patients. The evidence from these studies has suggests that CHEK2 is not a predisposition gene to Li–Fraumeni syndrome. ## Breast cancer Inherited mutations in the CHEK2 gene have been linked to certain cases of breast cancer. Most notably, the deletion of a single DNA nucleotide at position 1100 in exon 10 (1100delC) produces a nonfunctional version of the CHK2 protein, truncated at the kinase domain. The loss of normal CHK2 protein function leads to unregulated cell division, accumulated damage to DNA and in many cases, tumor development. The CHEK2*1100del mutation is most commonly seen in individuals of Eastern and Northern European descent. Within these populations the CHEK2*1100delC mutation is seen in 1 out of 100 to 1 out of 200 individuals. However, in North America the frequency drops to 1 out of 333 to 1 out of 500. The mutation is almost absent in Spain and India. Studies show that a CHEK2 1100delC corresponds to a two-fold increased risk of breast cancer and a 10-fold increased risk of breast cancer in males. A CHEK2 mutation known as the I157T variant to the FHA domain in exon 3 has also been linked to breast cancer but at a lower risk than the CHEK2*1100delC mutation. The estimated fraction of breast cancer attributed to this variant is reported to be around 1.2% in the US. Two more CHEK2 gene mutations, CHEK2*S428F, an amino-acid substitution to the kinase domain in exon 11 and CHEK2*P85L, an amino-acid substitution in the N-terminal region (exon 1) have been found in the Ashkenazi Jewish population. ## Other cancers Mutations to CHEK2 have been found in hereditary and nonhereditary cases of cancer. Studies link the mutation to cases of prostate, lung, colon, kidney, and thyroid cancers. Links have also been drawn to certain brain tumors and osteosarcoma. Unlike BRCA1 and BRCA2 mutations, CHEK2 mutations do not appear to cause an elevated risk for ovarian cancer. # Meiosis CHEK2 regulates cell cycle progression and spindle assembly during mouse oocyte maturation and early embryo development. Although CHEK2 is a down stream effector of the ATM kinase that responds primarily to double-strand breaks it can also be activated by ATR (ataxia-telangiectasia and Rad3 related) kinase that responds primarily to single-strand breaks. In mice, CHEK2 is essential for DNA damage surveillance in female meiosis. The response of oocytes to DNA double-strand break damage involves a pathway hierarchy in which ATR kinase signals to CHEK2 which then activates p53 and p63 proteins. In the fruitfly Drosophila, irradiation of germ line cells generates double-strand breaks that result in cell cycle arrest and apoptosis. The Drosophila CHEK2 ortholog mnk and the p53 ortholog dp53 are required for much of the cell death observed in early oogenesis when oocyte selection and meiotic recombination occur. # Interactions CHEK2 has been shown to interact with: - BRCA1 - GINS2 - MDC1 - MSH2 - MUS81 - PLK1 - PLK3