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Calcium carbimide # Overview Calcium carbimide, sold as the citrate salt under the trade name Temposil, is an alcohol sensitizing agent. Its effects are similar to the drug disulfiram (Antabuse) in that it interferes with the normal metabolism of alcohol by preventing the breakdown of the metabolic byproduct acetaldehyde. The result is that when alcohol is consumed by users of calcium carbimide, they experience severe reactions which include symptoms such as sweating, difficulty breathing, rapid heartbeat, rash, nausea and vomiting, and headache. A recent 9-year study found that incorporation of supervised carbimide and the similar drug, disulfiram, into a comprehensive treatment program resulted in an abstinence rate of over 50%. Temposil was developed by Drs. Ken Ferguson and Gordon Bell, who self-tested the drug on themselves. It was patented in 1955 by the Alcoholism Research Foundation of Ontario.

Ergotamine and caffeine (oral) # 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 Ergotamine and caffeine (oral) is a ergot alkaloid, antimigraine and central nervous system agent that is FDA approved for the treatment of to abort or prevent vascular headache, e.g., migraine, migraine variants or so-called “histaminic cephalalgia”. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritus, nausea and vomiting, muscle weakness, numbness, paresthesia, visual disturbance and vertigo. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Indicated as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants or so-called “histaminic cephalalgia”. ### Dosing Information - For the best results, dosage should start at the first sign of an attack. - Take 2 tablets at the start of attack; 1 additional tablet every ½ hour, if needed for full relief (maximum 6 tablets per attack, 10 per week). - Early Administration Gives Maximum Effectiveness - Maximum Adult Dosage: Six tablets is the maximum dose for an individual attack. - Total weekly dosage should not exceed 10 tablets. Ergotamine tartrate and caffeine-tablets should not be used for chronic daily administration. - In carefully selected patients, with due consideration of maximum dosage recommendations, administration of the drug at bedtime may be an appropriate short-term preventive measure. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ergotamine/caffeine (oral) in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ergotamine/caffeine (oral) in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Ergotamine and caffeine (oral) FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ergotamine/caffeine (oral) in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ergotamine/caffeine (oral) in pediatric patients. # Contraindications - Coadministration of ergotamine with potent CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, and troleandomycin) has been associated with acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities, with some cases resulting in amputation. There have been rare reports of cerebral ischemia in patients on protease inhibitor therapy when ergotamine tartrate and caffeine was coadministered, at least one resulting in death. Because of the increased risk for ergotism and other serious vasospastic adverse events, ergotamine use is contraindicated with these drug and other potent inhibitors of CYP 3A4 (e.g., ketoconazole, itraconazole). - Ergotamine tartrate and caffeine may cause fetal harm when administered to pregnant women. Ergotamine tartrate and caffeine 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 product, the patient should be apprised of the potential hazard to the fetus. - Peripheral vascular disease, coronary heart disease, hypertension, impaired hepatic or renal function and sepsis. - Hypersensitivity to any of the components. # Warnings - Coadministration of ergotamine with potent CYP 3A4 inhibitors such as protease inhibitors or macrolide antibiotics has been associated with serious adverse events, for this reason, these drugs should not be given concomitantly with ergotamine. While these reactions have not been reported with less potent CYP 3A4 inhibitors, there is a potential risk for serious toxicity including vasospasm when these drugs are used with ergotamine. Examples of less potent CYP 3A4 inhibitors include: saquinavir, nefazodone, fluconazole, fluoxetine, grapefruit juice, fluvoxamine, zileuton, metronidazole, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP3A4 of other agents being considered for concomitant use with ergotamine. - There have been a few reports of patients on ergotamine tartrate and caffeine therapy developing retroperitoneal and/or pleuropulmonary fibrosis. There have also been rare reports of fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves with long-term continuous use of ergotamine tartrate and caffeine. Ergotamine tartrate should not be used for chronic daily administration. ### PRECAUTIONS - Although signs and symptoms of ergotism rarely develop even after long term intermittent use of the rectally administered drug, care should be exercised to remain within the limits of recommended dosage. - Ergotism is manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia. Ergotamine induces vasoconstriction by a direct action on vascular smooth muscle. In chronic intoxication with ergot derivatives, headache, intermittent claudication, muscle pains, numbness, coldness and pallor of the digits may occur. If the condition is allowed to progress untreated, gangrene can result. - While most cases of ergotism associated with ergotamine treatment result from frank overdosage, some cases have involved apparent hypersensitivity. There are few reports of ergotism among patients taking doses within the recommended limits or for brief periods of time. In rare instances, patients, particularly those who have used the medication indiscriminately over long periods of time, may display withdrawal symptoms consisting of rebound headache upon discontinuation of the drug. - Rare cases of solitary rectal or anal ulcer have occurred from abuse of ergotamine suppositories usually in higher than recommended doses or with continual use at the recommended dose for many years. Spontaneous healing occurs within usually 4-8 weeks after drug withdrawal. - There have been reports of drug abuse and psychological dependence in patients on ergotamine tartrate and caffeine therapy. Due to chronicity of vascular headaches, it is imperative that patients be advised not to exceed recommended dosages with long-term use to avoid ergotism. # Adverse Reactions ## Clinical Trials Experience - Vasoconstrictive complications of a serious nature may occur at times. These include ischemia, cyanosis, absence of pulse, cold extremities, gangrene, precordial distress and pain, EKG changes and muscle pains. Although these effects occur most commonly with long-term therapy at relatively high doses, they have also been reported with short-term or normal doses. Other cardiovascular adverse effects include transient tachycardia or bradycardia and hypertension. - Nausea and vomiting; rectal or anal ulcer (from overuse of suppositories). - Paresthesias, numbness, weakness, and vertigo. - Localized edema and itching. Fibrotic Complications: - Retroperitoneal pleuropulmonary fibrosis, fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves with long-term continuous use of ergotamine tartrate and caffeine. ## Postmarketing Experience There is limited information regarding Ergotamine and caffeine (oral) Postmarketing Experience in the drug label. # Drug Interactions - Ergotamine tartrate and caffeine should not be administered with other vasoconstrictors. Use with sympathominetics (pressor agents) may cause extreme elevation of blood pressure. The beta-blocker Inderal (propranolol) has been reported to potentiate the vasoconstrictive action of ergotamine tartrate and caffeine by blocking the vasodilating property of epinephrine. Nicotine may provoke vasoconstriction in some patients, predisposing to a greater ischemic response to ergot therapy. - The blood levels of ergotamine-containing drugs are reported to be elevated by the concomitant administration of macrolide antibiotics and vasospastic reactions have been reported with therapeutic doses of the ergotamine-containing drugs when coadministered with those antibiotics. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - There are no studies on the placental transfer or teratogenicity of the combined products of ergotamine tartrate and caffeine. Caffeine is known to cross the placenta and has been shown to be teratogenic in animals. Ergotamine crosses the placenta in small amounts, although it does not appear to be embryotoxic in this quantity. However, prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone leading to reduced myometrial and placental blood flow may have contributed to fetal growth retardation observed in animals. - Ergotamine tartrate and caffeine is contraindicated in pregnancy due to the oxytocic effects of ergotamine. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ergotamine and caffeine (oral) in women who are pregnant. ### Labor and Delivery - Ergotamine tartrate and caffeine is contraindicated in labor and delivery due to its oxytocic effect which is maximal in the third trimester. ### Nursing Mothers - Ergot drugs are known to inhibit prolactin but there are no reports of decreased lactation with ergotamine tartrate and caffeine. Ergotamine is excreted in breast milk and may cause symptoms of vomiting, diarrhea, weak pulse and unstable blood pressure in nursing infants. Because of the potential for serious adverse reactions in nursing infants from ergotamine tartrate and caffeine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use There is no FDA guidance on the use of Ergotamine and caffeine (oral) in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Ergotamine and caffeine (oral) in geriatric settings. ### Gender There is no FDA guidance on the use of Ergotamine and caffeine (oral) with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ergotamine and caffeine (oral) with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Ergotamine and caffeine (oral) in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Ergotamine and caffeine (oral) in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ergotamine and caffeine (oral) in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ergotamine and caffeine (oral) in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Ergotamine and caffeine (oral) Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Ergotamine and caffeine (oral) and IV administrations. # Overdosage - The toxic effects of an acute overdosage of ergotamine tartrate and caffeine are due primarily to the ergotamine component. The amount of caffeine is such that its toxic effects will be overshadowed by those of ergotamine. Symptoms include vomiting, numbness, tingling, pain and cyanosis of the extremities associated with diminished or absent peripheral pulses, hypertension or hypotension, drowsiness, stupor, coma, convulsion and shock. A case has been reported of reversible bilateral papillitis with ring scotomata in a patient who received five times the recommended daily adult dose over a period of 14 days. - Treatment consists of removal of the offending drug by induction of emesis. Maintenance of adequate pulmonary ventilation, correction of hypotension, and control of convulsions and blood pressure are important considerations. Treatment of peripheral vasospasm should consist of warmth, but not heat, and protection of the ischemic limbs. Vasodilators may be beneficial but caution must be exercised to avoid aggravating an already existent hypotension. # Pharmacology ## Mechanism of Action - Ergotamine is an alpha adrenergic blocking agent with a direct stimulating effect on the smooth muscle of peripheral and cranial blood vessels and produces depression of central vasomotor centers. The compound also has the properties of serotonin antagonism. In comparison to hydrogenated ergotamine, the adrenergic blocking actions are less pronounced and vasoconstrictive actions are greater. - Caffeine, also a cranial vasoconstrictor, is added to further enhance the vasoconstrictive effect without the necessity of increasing ergotamine dosage. - Many migraine patients experience excessive nausea and vomiting during attacks, making it impossible for them to retain any oral medication. In such cases, therefore, the only practical means of medication is through the rectal route where medication may reach the cranial vessels directly, evading the splanchnic vasculature and the liver. ## Structure - Ergotamine Tartrate and Caffeine Tablets USP - ergotamine tartrate USP . . . . . . . . . . . . . . . . . .1 mg - caffeine USP . . . . . . . . . . . . . . . . . . . . . . . . . . .100 mg - In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, compressible sugar, corn starch, magnesium stearate, mannitol, microcrystalline cellulose, sodium starch glycolate, sugar, and tartaric acid. Polishing and Film Coating Solutions may contain the following: FD&C Blue Lake #2, FD&C Yellow Lake #6, hydroxypropyl methylcellulose, polyethylene glycol, and titanium dioxide. The printing ink contains: amide resin, black pigment, natural resin, and wax. ## Pharmacodynamics There is limited information regarding Ergotamine and caffeine (oral) Pharmacodynamics in the drug label. ## Pharmacokinetics - Pharmacokinetic interactions (increased blood levels of ergotamine) have been reported in patients treated orally with ergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated orally with ergotamine and protease inhibitors (e.g. ritonavir) presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine (see CONTRAINDICATIONS). Ergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. ## Nonclinical Toxicology There is limited information regarding Ergotamine and caffeine (oral) Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Ergotamine and caffeine (oral) Clinical Studies in the drug label. # How Supplied Ergotamine Tartrate and Caffeine Tablets USP, 1 mg/100 mg are round, film coated buff colored tablet; printed "WW 120" in black ink and are available in: Bottles of 30 tablets. Bottles of 100 tablets. Bottles of 500 tablets. Manufactured By: West-ward Pharmaceutical Corp. Eatontown, NJ 07724 Revised November 2004 ## Storage - Store at 20°-25°C (68°-77°F). - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. # Images ## Drug Images ## Package and Label Display Panel PRINCIPAL DISPLAY PANEL NDC 0143-2120-01 Ergotamine Tartrate and Caffeine Tablets, USP 1 mg/100 mg Rx Only 100 Tablets West-ward Pharmaceuticals Corp. # Patient Counseling Information - Patients should be advised that two tablets of ergotamine tartrate and caffeine should be taken at the first sign of a migraine headache. No more than 6 tablets should be taken for any single migraine attack. No more than 10 tablets should be taken during any 7-day period. Administration of ergotamine tartrate and caffeine tablets should not exceed the dosing guidelines and should be used for chronic daily administration. Ergotamine tartrate and caffeine should be used only for migraine headaches. It is not effective for other types of headaches and it lacks analgesic properties. Patients should be advised to report to the physician immediately any of the following: numbness or tingling in the fingers and toes, muscle pain in the arms and legs, weakness in the legs, pain in the chest or temporary speeding or slowing of the heart rate, swelling or itching. # Precautions with Alcohol Alcohol-Ergotamine/caffeine (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Ergotamine and caffeine (oral) Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Ergotamine and caffeine (oral) Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Abrupt closure case 26 # Abrupt Closure ## Pre-intervention Shown below is a pre-intervention angiogram with significant diffuse in-stent lesion in the SVG to LAD. ## Intervention Shown below is an angiogram with ongoing intervention on the significant lesion described above. ## Post-intervention Shown below is a post-intervention angiogram with occlusion at the proximal part of SVG to LAD depicting abrupt closure.

TIP39 Tuberoinfundibular peptide of 39 residues is a protein that in humans is encoded by the PTH2 gene. TIP39 is related to parathyroid hormone (PTH; MIM 168450) and PTH-related protein (PTHRP; MIM 168470) and is a ligand for PTH receptor-2 (PTHR2; MIM 601469) (John et al., 2002). The molecular interaction of TIP39 with the PTH2 receptor has been characterized in full 3D molecular detail, identifying among other residues, Tyr-318 in transmembrane helix 5 as a key residue for high affinity binding

Apraxia Synonyms and keywords: Dyspraxia # Overview Praxis, a Greek work for act, work, or deed, is the ability to perform the learned movements. It usually comprises of three components, namely, ideation (what to do), motor planning (how to do), and execution (performing the movement correctly), that results in purposeful movements. Apraxia, however, is the inability to execute these skilled and learned purposeful movements when there is a breakdown in any component of praxis. This disorder makes it difficult to perform daily tasks and negatively impact the quality of life. Apraxia, a complex neurological disorder, with cognitive-motor dysfunction may be acquired or developmental. It can occur as a result of brain trauma/disease, and higher motor functional neuronal pathways damage in the setting of preserved comprehension, coordination, motivation, and elementary sensory and motor systems. The most common types of apraxia are 'Ideational' and 'Ideomotor'. # Historical Perspective - Steinthal introduced the term apraxiae (Greek word meaning inaction) in 1871. However, a German physician, Hugo Lipmann first established the conceptual knowledge and published complete description of apraxia after studying the gestures in a 48-year old stroke patient who had a left hemispheric stroke. - Lipmann noticed that, despite of resolution of the paresis, the patient was unable to perform tasks such as buttoning the shirt, with no affect on spontaneous movements, and doing simple tasks on command. He observed this phenomenon specifically in patients with left hemispheric lesions. He also concluded that the planning of the motor movements occurs in the motor area of the left side of the brain. Lipmann further proposed that the 'praxis' information flows from the posterior brain areas (parietal and occipital lobes) to the anterior (motor cortex). - The major subtypes classified by Lipmann were ideational, ideomotor, and limb-kinetic apraxia. - One of the behavioral neurologist, Norman Geschwind, presented that the superior longitudinal fasciculus involvement disconnects the Wernicke's area are from the left premotor cortex, leading to 'apraxia' # Classification - Ideomotor apraxia: Most common type of apraxia. Decreased performance of skilled motor performances despite integral language, sensory and motor function. Seen more frequently in neurodegenerative disorders and stroke patients. It can be classically demonstrated when a patient questioned verbally to make a motion with a limb. Patients with Ideomotor apraxia display spatial and temporal errors, inconvenient timing, amplitude, sequencing, configuration, limb position in space. It is an inability to carry out, learned motor acts, command, adequate motor, and sensory abilities. Ideomotor apraxia can be due to cerebral damage in numerous areas, including the left parietal lobe, the intrahemispheric association fibers, the dominant hemisphere motor association cortex, and the anterior corpus callosum. Patients often use their arm as an object relatively than indicating how to use the object . Patients are frequently able to achieve the same acts without struggle in their daily lives. This process has been called the "voluntary-automatic dissociation". These patients have a deficiency in their skill to plan or ample motor actions that depend on semantic memory. They can describe how to achieve a response, but incapable to "imagine" or do the movement. Though the capability to perform an act inevitably when cued remains complete, this is recognized as automatic-voluntary dissociation.In Ideomotor apraxia, there is difficulty or inability to execute familiar or learned movements on command despite of understanding the command and willingness to perform that action. The characteristic of this type of apraxia is the inability to a transitive movement. For example, the person can describe how a tool such as comb is used, but, when asked to use that tool, he is unable to perform the task (i.e. combing the hair) using the comb - Most common type of apraxia. - Decreased performance of skilled motor performances despite integral language, sensory and motor function. - Seen more frequently in neurodegenerative disorders and stroke patients. - It can be classically demonstrated when a patient questioned verbally to make a motion with a limb. Patients with Ideomotor apraxia display spatial and temporal errors, inconvenient timing, amplitude, sequencing, configuration, limb position in space. - It is an inability to carry out, learned motor acts, command, adequate motor, and sensory abilities. - Ideomotor apraxia can be due to cerebral damage in numerous areas, including the left parietal lobe, the intrahemispheric association fibers, the dominant hemisphere motor association cortex, and the anterior corpus callosum. - Patients often use their arm as an object relatively than indicating how to use the object . Patients are frequently able to achieve the same acts without struggle in their daily lives. This process has been called the "voluntary-automatic dissociation". - These patients have a deficiency in their skill to plan or ample motor actions that depend on semantic memory. They can describe how to achieve a response, but incapable to "imagine" or do the movement. Though the capability to perform an act inevitably when cued remains complete, this is recognized as automatic-voluntary dissociation.In Ideomotor apraxia, there is difficulty or inability to execute familiar or learned movements on command despite of understanding the command and willingness to perform that action. The characteristic of this type of apraxia is the inability to a transitive movement. For example, the person can describe how a tool such as comb is used, but, when asked to use that tool, he is unable to perform the task (i.e. combing the hair) using the comb - Ideational apraxia: As the name depicts, the problem is in conceptualization of the task. The person may be able to name the objects correctly but fails to coceptualize how that object is used. Inability to create a plan for or idea of a specific movement, for example, "pick up this pen and write down your name" - As the name depicts, the problem is in conceptualization of the task. - The person may be able to name the objects correctly but fails to coceptualize how that object is used. - Inability to create a plan for or idea of a specific movement, for example, "pick up this pen and write down your name" - Constructional apraxia: It is a condition resulting from neurological damage, which is demonstrated by the inability to construct and copy to command two- and three-dimensional stimuli. Constructional apraxia has been a classic sign of a parietal lobe lesion, and as a valuable tool to escalate the spatial abilities functioned by this lobe. It has become gradually clear that Constructional apraxia is a complex construct that can be observed with very different tasks that are only slightly interrelated, and hit various kinds of visuospatial, attentional, perceptual, planning, and motor mechanisms. The patient with constructional apraxia is unable to construct, draw, or copy simple configurations; for example, intersecting shapes; they have trouble drawing basic shapes or copying a simple diagram. inability to draw or construct simple configurations - It is a condition resulting from neurological damage, which is demonstrated by the inability to construct and copy to command two- and three-dimensional stimuli. - Constructional apraxia has been a classic sign of a parietal lobe lesion, and as a valuable tool to escalate the spatial abilities functioned by this lobe. - It has become gradually clear that Constructional apraxia is a complex construct that can be observed with very different tasks that are only slightly interrelated, and hit various kinds of visuospatial, attentional, perceptual, planning, and motor mechanisms. - The patient with constructional apraxia is unable to construct, draw, or copy simple configurations; for example, intersecting shapes; they have trouble drawing basic shapes or copying a simple diagram. - inability to draw or construct simple configurations - Buccofacial or orofacial apraxia: These patients cannot convey facial movements on requests, such as voluntary movements of the tongue, cheeks, lips, pharynx, or larynx on command, for example, include licking lips, whistling, coughing, or winking). - These patients cannot convey facial movements on requests, such as voluntary movements of the tongue, cheeks, lips, pharynx, or larynx on command, for example, include licking lips, whistling, coughing, or winking). - Limb-kinetic apraxia: It is the failure to make precise movements with an arm, finger, or leg. For example, a person may have trouble tying their shoes, waving hello, or typing on a computer. Inability to make fine, precise movements with a limb - It is the failure to make precise movements with an arm, finger, or leg. For example, a person may have trouble tying their shoes, waving hello, or typing on a computer. - Inability to make fine, precise movements with a limb - Gait apraxia: Apraxia of gait is a rare locomotion syndrome categorized by the incapability of lifting the feet from the floor regardless of discontinuous stepping action. The accountable site of lesions is in the basal ganglia and frontal lobe. - Apraxia of gait is a rare locomotion syndrome categorized by the incapability of lifting the feet from the floor regardless of discontinuous stepping action. - The accountable site of lesions is in the basal ganglia and frontal lobe. - Task-specific apraxia: These include- Sitting apraxia Dressing apraxia Eyelid opening apraxia -culomotor (difficulty moving the eye) - These include- Sitting apraxia Dressing apraxia Eyelid opening apraxia -culomotor (difficulty moving the eye) - Sitting apraxia - Dressing apraxia - Eyelid opening apraxia - oculomotor (difficulty moving the eye) # Pathophysiology - 'Praxis' comprises three components, which include ideation, motor planning, and execution to carry out the purposeful movement. There are particular regions of the brain that represent specific component functions, and these regions together work as a ‘praxis system’ to process and execute a purposeful movement. Dysfunction in any of these regions, namely, frontal and parietal cortex, basal ganglia, and the white matter which connects theses areas, leads to apraxia. - The movements which requires tools are transitive movements, and the ones which do not require tools are intransitive. The intransitive movements are gestural which can be meaningful (communicative), or meaningless movements (not representational). In apraxia, transitive movements are affected more frequently as compared to intransitive movements. - The observations of the patients in the clinical practice is the basis of most of the knowledge about 'apraxia'. Apraxia has been mostly seen in chronic left hemispheric lesions and Alzheimer's disease. The left hemispheric lesions cause more difficulty to perform transitive movements, as compared to intransitive movements and imitating gestures. Left hemisphere has a major role in 'praxis' and this may be due to specific stored representations in left hemisphere and their retrieval. On the other hand, Alzheimer's patients have preserved transitive movements, but shows deficits in gestures. Therefore, the type of apraxia depends on the type of neurological disease and the area of the brain affected by it. - Different brain regions which have role in cognition and movement are involved in complex 'Praxis' movements. The conceptualization of a purposeful task involves prefrontal, left premotor, middle temporal and parietal areas of the brain. - Neuroimaging studies have been done to investigate praxis correlations, but studies done so far vary widely on focus areas of praxis. One of the study reported left temporal lobe correlation with praxis because of its role in somatic memory retrieval. Left premotor cortex, left parietal lobule, and parietal cortex have also been shown to have a role in praxis as they are involved in knowledge of tools and their use, grasping movements, and spatiotemporal information integration, respectively. Stronger left lateralization (especially posterior parietal and premotor cortex) for gesture production in praxis has been suggested by neuroimaging studies. # Causes - The most common causes of apraxia are: Neurodegenerative illness Brain tumor Dementia Stroke Traumatic brain injury - Neurodegenerative illness - Brain tumor - Dementia - Stroke - Traumatic brain injury # Epidemiology and Demographics - The information available on the incidence of apraxia in adults is limited. - As apraxia is most common in children, the incidence is approximately 1 to 2 children per 1,000 (0.1%–0.2%) worldwide. - Prevalence rates of  apraxia range among 0 and 34% for patients with Right hemisphere stroke and 28–57% for patients with Left hemisphere stroke.Real tool-use loss prevalence rates were stated with 25–54% impaired level of patients. - Apraxia commonly affects individuals older than 50 years of age. Apraxia affects men and women equally # Differentiating Apraxia from Other Diseases # Risk Factors - Apraxia is a rare disease caused by stroke; it has the same risk factors as a stroke. High blood pressure High cholesterol Diabetes Smoking Prior stroke or cardiovascular disease Prior transient ischemic attack (TIA) Dialysis treatment - High blood pressure - High cholesterol - Diabetes - Smoking - Prior stroke or cardiovascular disease - Prior transient ischemic attack (TIA) - Dialysis treatment # Screening - There is insufficient evidence to recommend routine screening for apraxia. # Natural History, Complications, and Prognosis - The symptoms of apraxia typically develop during early or later years depending on the cause and the location affected. - Often, patients with apraxia are not aware of their shortfalls. Therefore, the history of a patient's capability to accomplish skilled movements should be obtained from the patient's caregiver or the patient himself. - Caregivers should be asked about the capability of patients to perform activities of daily living and perform tasks involving household tools such as using a toothbrush, knife, and fork appropriately, using kitchen utensils correctly and safely to prepare a meal; using tools such as scissors or hammer correctly. - Caregivers should also be asked about the whole activity level of the patient and whether decreases in his or her total actions have happened. - The patient may sit on the couch and watch television without showing interest in essential activities he or she use to do in the past. - This indifference can be related to many kinds of brain dysfunction, but it sporadically occurs because the patient is incapable of performing his or her usual activities. - Common complications of apraxia include: Broca's Aphasia Acalculi Right-left Confusion Alexia with agraphia Wernicke's Aphasia - Broca's Aphasia - Acalculi - Right-left Confusion - Alexia with agraphia - Wernicke's Aphasia - Patients with apraxia are not able to do things independently and may distress carrying out everyday responsibilities. Activities should be avoided that can lead to injury and take the appropriate safety actions. Over-all, patients with apraxia rely on others for their daily activities and need at least some notch of command; skilled nursing care may be obligatory. Patients with the tumor or degenerative diseases usually develop into amplified levels of dependence. - The prognosis for individuals with apraxia varies. With therapy, some patients improve significantly, while others may show very little improvement. Some individuals with apraxia may benefit from the use of a communication aid. # Diagnosis - Many tests have been developed to evaluate apraxia but most are difficult to apply in clinics as they are not rapid tests. Additionally, most of those lack in sensitivity and validity. De Renzi ideomotor apraxia test for ideomotor apraxia assessment, can be tested in either side brain damage. It is a 24-item scale test. Test of upper limb apraxia (TULIA) is a 48 item test, is preferred test as it has a good validity and reliability. It can be used to test- non-symbolic (meaningless) intransitive (communicative) transitive (tool-related) gestures.20 Apraxia Screen of TULIA (AST) is a short bedside test with 12 items, with a high sensitivity and specificity. The basis of this test is TULIA test. - De Renzi ideomotor apraxia test for ideomotor apraxia assessment, can be tested in either side brain damage. It is a 24-item scale test. - Test of upper limb apraxia (TULIA) is a 48 item test, is preferred test as it has a good validity and reliability. It can be used to test- non-symbolic (meaningless) intransitive (communicative) transitive (tool-related) gestures.20 - non-symbolic (meaningless) - intransitive (communicative) - transitive (tool-related) gestures.20 - Apraxia Screen of TULIA (AST) is a short bedside test with 12 items, with a high sensitivity and specificity. The basis of this test is TULIA test. - Physical examination of patients with Apraxia is usually dependent on what type of Apraxia they have for example Ideomotor apraxia, Buccofacial apraxia, and Constructional apraxia. Ideomotor apraxia Patients with ideomotor apraxia are tested based on the physical examination performed at the bedside with simple tests for the capability to use tools. For example, the patients cannot hammer a nail into the (unreal) wall in front of them; patients are given a pair of scissors to cut a piece of paper. However, different pantomimes could be made, including cutting with a saw, brushing teeth, peeling a potato or whipping eggs with an eggbeater. Any error in carrying out the above activities indicates a loss of familiarity about the movement to be completed. The response is recorded as an error. Buccofacial apraxia Patients cannot do skilled actions. Constructional apraxia Failure to copy or draw quality images. Localizes lesions involving frontal or parietal area. - Ideomotor apraxia Patients with ideomotor apraxia are tested based on the physical examination performed at the bedside with simple tests for the capability to use tools. For example, the patients cannot hammer a nail into the (unreal) wall in front of them; patients are given a pair of scissors to cut a piece of paper. However, different pantomimes could be made, including cutting with a saw, brushing teeth, peeling a potato or whipping eggs with an eggbeater. Any error in carrying out the above activities indicates a loss of familiarity about the movement to be completed. The response is recorded as an error. - Patients with ideomotor apraxia are tested based on the physical examination performed at the bedside with simple tests for the capability to use tools. - For example, the patients cannot hammer a nail into the (unreal) wall in front of them; patients are given a pair of scissors to cut a piece of paper. - However, different pantomimes could be made, including cutting with a saw, brushing teeth, peeling a potato or whipping eggs with an eggbeater. - Any error in carrying out the above activities indicates a loss of familiarity about the movement to be completed. - The response is recorded as an error. - Buccofacial apraxia Patients cannot do skilled actions. - Patients cannot do skilled actions. - Constructional apraxia Failure to copy or draw quality images. Localizes lesions involving frontal or parietal area. - Failure to copy or draw quality images. - Localizes lesions involving frontal or parietal area. - There are no ECG findings associated with apraxia. - There are no x-ray findings associated with apraxia. - There are no echocardiography/ultrasound findings associated with apraxia. - Brain CT scan may be helpful in the diagnosis of apraxia to evaluate for possible mass lesion or atrophy - Brain MRI may be helpful in the diagnosis of apraxia. Findings on MRI diagnostic of apraxia include atrophy, ischemic changes, and mass lesion. - There are no other imaging findings associated with apraxia. - Diagnostic study PET may be helpful in the diagnosis of apraxia. # Treatment - Generally, treatment for individuals with apraxia includes physical therapy, occupational therapy or speech therapy. If apraxia is a symptom of another disorder (usually a neurologic disorder), the underlying disorder should be treated. - No standardized treatment is available for apraxia. The frequency of limb apraxia in left hemispheric stroke patients is reported to be nearly 51%, and, hence, the therapeutic efforts are so far mostly concentrated towards stroke patients (left hemispheric stroke patients). Based on the studies, following treatment modalities have been considered so far- Rehabilitative treatment- 30 sessions, each lasting 50 minutes, 3 times weekly have been tried. Behavioral training Program-These include gesture-production exercises. - Rehabilitative treatment- 30 sessions, each lasting 50 minutes, 3 times weekly have been tried. - Behavioral training Program-These include gesture-production exercises. - With treatment, an improvement in praxis and daily living activities is seen in apraxia patients, based on some studies. The communicative gestures training has led to significant improvement of the gestures which were practiced during the training sessions, with some unpracticed gestures also showing some improvement. However, the sustainability of these positive results is not clear. Although rehabilitative training has been reported to benefit, but, for sustained benefit, training alone is not sufficient. - Noninvasive brain stimulation- This method had been used widely for many neurological disorders, but there is very limited data for its use in cognitive disorders. However, some studies have shown that this technique has been tried for therapeutic and investigational purpose for this complex neurological disorder and may show some positive results. This technique when used with rehabilitative training, may be useful. Through this technique and different stimulation settings, inhibitory or excitatory influences are exerted on cortical excitability or plasticity. The synergistic approach using this technique prior to rehabilitative training, not only increases the efficacy, but it also increases the sustainability of the improvement seen. Some examples of non-invasive brain stimulation techniques which have been used in some neurological conditions with some improvement in the cognitive function components of the disease can be tried- Transcranial direct current stimulation (tDCS)-low-level continuous electric current is delivered to influence plasticity and excitabililty of the cortex. In this, anodal tDCS works in excitatory ways, and cathodal tDCS in inhibitory ways. single-pulse or rTMS- It can be delivered in either low frequency (0.2–1 Hz) for inhibitory mode, or in high frequency (≥5 Hz) for excitatory mode. theta-burst stimulation (TBS)-It is also a magnetic stimulation method like rTMS, but it shows equal efficacy even with shorter stimulation period. paired associative stimulation (PAS)- This stimulation technique can be used to tackle physiological mechanisms underlying memory using long-term depression (LTD), and long-term potentiation (LTP). - Transcranial direct current stimulation (tDCS)-low-level continuous electric current is delivered to influence plasticity and excitabililty of the cortex. In this, anodal tDCS works in excitatory ways, and cathodal tDCS in inhibitory ways. - single-pulse or rTMS- It can be delivered in either low frequency (0.2–1 Hz) for inhibitory mode, or in high frequency (≥5 Hz) for excitatory mode. - theta-burst stimulation (TBS)-It is also a magnetic stimulation method like rTMS, but it shows equal efficacy even with shorter stimulation period. - paired associative stimulation (PAS)- This stimulation technique can be used to tackle physiological mechanisms underlying memory using long-term depression (LTD), and long-term potentiation (LTP). - There are no specific recommended therapeutic interventions for the management of Apraxia - Apraxia is believed to have an adverse impact on the Activity of Daily Living independence. There are limited information and research available regarding various treatments. Various interventions include: Daily living doings training: this method explains internal and external compensatory approaches that permit a functional mission to be accomplished. Sensory Stimulation: Including deep pressure stimulation, soft and sharp touch are useful to the patients' limbs. Chaining (forward or backward): This method is fragmented down into its sections. The task is done with assistance from the therapist separately from the final element through backward chaining, which the patient performs out unassisted. If positive next time, additional steps are presented. Forward chaining is the opposite of backward chaining; Proprioceptive stimulation: The patient props on and puts his weight through their upper and lower extremities; Cueing, physical or verbal stimuli: This technique enables each phase of the task to be completed - Daily living doings training: this method explains internal and external compensatory approaches that permit a functional mission to be accomplished. - Sensory Stimulation: Including deep pressure stimulation, soft and sharp touch are useful to the patients' limbs. - Chaining (forward or backward): This method is fragmented down into its sections. The task is done with assistance from the therapist separately from the final element through backward chaining, which the patient performs out unassisted. If positive next time, additional steps are presented. Forward chaining is the opposite of backward chaining; - Proprioceptive stimulation: The patient props on and puts his weight through their upper and lower extremities; - Cueing, physical or verbal stimuli: This technique enables each phase of the task to be completed - Surgical intervention is not recommended for the management of Apraxia. - There are no established measures for the primary prevention of Apraxia. Some steps can be used which include. Exercise regularly. Eat a healthy diet. Limit how much alcohol you drink. Quit smoking Check your blood pressure often. - Exercise regularly. - Eat a healthy diet. - Limit how much alcohol you drink. - Quit smoking - Check your blood pressure often. Effective measures for the secondary prevention of Apraxia include secondary prevention of stroke. - Aspirin, clopidogrel, extended-release dipyridamole, ticlopidine - Anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban, warfarin) - Blood pressure-lowering medications. - Diabetes Control - Low-fat diet - Cholesterol-lowering medications, Cessation of cigarette smoking, carotid revascularization - Weight loss and Exercise # Related Chapters - Dyspraxia

Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma Evidence-based recommendations on rituximab for treating relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma in adults. # Guidance This guidance replaces 'The clinical effectiveness and cost effectiveness of rituximab for follicular lymphoma' (NICE technology appraisal guidance 37 issued in March 2002). For details, see 'About this guidance'. Rituximab, within its marketing authorisation, in combination with chemotherapy, is recommended as an option for the induction of remission in people with relapsed stage III or IV follicular non-Hodgkin's lymphoma. Rituximab monotherapy as maintenance therapy, within its marketing authorisation, is recommended as an option for the treatment of people with relapsed stage III or IV follicular non-Hodgkin's lymphoma in remission induced with chemotherapy with or without rituximab. Rituximab monotherapy, within its marketing authorisation, is recommended as an option for the treatment of people with relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma, when all alternative treatment options have been exhausted (that is, if there is resistance to or intolerance of chemotherapy).# The technology Rituximab (MabThera, Roche) is a chimeric (mouse/human) genetically engineered monoclonal antibody. It targets the CD20 surface antigen of mature B-cell lymphocytes. Rituximab has a marketing authorisation in relapsed non-Hodgkin's follicular lymphoma as follows. Rituximab is indicated for the treatment of patients with stage III-IV follicular non-Hodgkin's lymphoma who are chemoresistant or who are in their second or subsequent relapse after chemotherapy. Rituximab maintenance therapy is indicated for patients with relapsed/refractory follicular non-Hodgkin's lymphoma responding to induction therapy with chemotherapy with or without rituximab. Allergic and skin reactions are the most common side effects of rituximab infusion. Infusion reactions can be complicated by bronchospasm and hypotension and can occasionally be severe or life threatening. Severe reactions are more common in patients with a high tumour burden, and the incidence and severity of infusion reactions decreases with successive infusions. Rituximab treatment is associated with blood and bone marrow toxicity manifested by neutropenia, leucopenia and infections. In addition, rituximab treatment is associated with flu-like symptoms and neurological problems. For full details of side effects and contraindications, see the summary of product characteristics. A single dose of rituximab is 375 mg/m2 body surface area. When used as monotherapy, this dose is given every week for 4 weeks. When used in combination with chemotherapy for induction of remission, this dose is given with each cycle of chemotherapy. For maintenance therapy, the same dose is given every 3 months until relapse or for a maximum of 2 years (a total of eight doses). The cost of one 100-mg vial is £174.63 and one 500-mg vial is £873.15 (excluding VAT; 'British national formulary' edition 53). For an average patient (body surface area 1.61.87 m2) the cost per dose is £1222. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer identified best supportive care as the comparator for rituximab monotherapy at second and subsequent relapse (the indication appraised in TA 37). No new evidence was provided for this indication. For the use of rituximab with chemotherapy for induction of remission in relapsed follicular non-Hodgkin's lymphoma, the main comparator identified was cyclophosphamide, hydroxydaunomycin, vincristine and prednisolone (CHOP) chemotherapy, and fludarabine-containing regimens were also considered appropriate. For the use of rituximab as maintenance therapy, the appropriate comparator was considered to be observation only. For the latter two indications the manufacturer identified two trials. The European Organisation for Research and Treatment of Cancer (EORTC) trial was an open-label study conducted in patients with follicular non-Hodgkin's lymphoma, in first and subsequent relapse, who had not previously received rituximab. Patients (N = 465) were randomised to induction with six cycles of CHOP chemotherapy plus rituximab (N = 234) or CHOP without rituximab (N = 231). Those patients in remission after six cycles (N = 334) were subject to a second randomisation: to observation only (N = 167) or eight doses of maintenance therapy with rituximab, given over 2 years (N = 167). For induction of remission, there was a statistically significant higher overall response rate following combination therapy with CHOP plus rituximab compared with CHOP alone (85% versus 72%, respectively; p < 0.0001). The median progression-free survival was also statistically significantly longer for patients who received combination therapy (33 months versus 20 months; p = 0.0003). For patients on rituximab maintenance, the median progression-free survival was 52 months compared with 15 months for patients being observed only, and this was statistically significant (p < 0.0001). When CHOP plus rituximab was used for induction, the median progression-free survival for patients who received rituximab maintenance therapy was 52 months compared with 23 months for patients being observed only (p = 0.0043), a risk reduction of 46%. When CHOP only was used for induction, the corresponding figures were 42 months and 12 months, respectively (p < 0.0001), and the risk reduction was 70%. Median overall survival could not be calculated because fewer than half the patients in each group had died at last reported follow-up. For patients who received CHOP plus rituximab for induction, the adverse effects reported with a  5% higher incidence than in the control group (CHOP only) were skin problems, infections, allergies and neutropenia. During the maintenance phase, patients on rituximab experienced a  5% higher incidence of flu-like symptoms, neurological problems, infections, blood and bone marrow problems, pulmonary problems and allergies, than those who were observed only. The German Low-Grade Lymphoma Study Group-Fludarabine, Cyclophosphamide, Mitoxantrone (GLSG-FCM) trial was an open-label study conducted in patients with indolent lymphomas. Patients (total N = 137; follicular non-Hodgkin's lymphoma N = 65) were randomised to induction with four cycles of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab. This randomisation was stopped early when patients in the FCM plus rituximab group had a statistically significant better outcome. In the maintenance period, patients (total N = 176; follicular non-Hodgkin's lymphoma N = 105) were randomised to rituximab therapy of two 4-weekly treatment blocks of rituximab at 3 and 6 months or observation only. For induction of remission in patients with follicular non-Hodgkin's lymphomas, the combined complete and partial response rates were statistically significantly higher following combination therapy with rituximab (94% versus 70%; p = 0.011) compared with FCM alone. For patients with follicular non-Hodgkin's lymphoma treated with FCM plus rituximab at induction, the median progression-free survival was not reached, whereas median progression-free survival was 21 months in those who received induction with FCM only; this difference was statistically significant (p = 0.0139). Fewer than half the patients in each group had died at last follow up, and there was no statistically significant difference in the proportions surviving to 2 years. For patients with follicular non-Hodgkin's lymphoma who received FCM plus rituximab induction, the median time to progression was 26 months in patients under observation only, but fewer than half of those receiving maintenance rituximab therapy had progressed; this was a statistically significant difference (p = 0.035). Adverse effects with a  5% higher incidence in the rituximab maintenance therapy group compared with the observation only group were blood and bone marrow problems, infection, fever, diarrhoea, pulmonary toxicity and liver enzyme elevation. The cost-effectiveness models submitted by the manufacturer were based on the EORTC trial. A four-arm model allowed for use of rituximab at induction compared with chemotherapy alone, with the responders in each of these arms being further randomised to rituximab maintenance or observation only. This allowed for comparison of four treatment strategies: rituximab and chemotherapy induction followed by rituximab maintenance; rituximab and chemotherapy induction followed by observation; chemotherapy induction followed by rituximab maintenance; and chemotherapy induction followed by observation. The four treatment strategies allowed for the comparison of six pairs of between-strategy comparisons. The model consisted of five states: progression-free in induction setting; progression-free in maintenance setting; progression-free not in induction/maintenance setting; progressive disease; and death. The model assumed maintenance treatment continued for 2 years or until disease progression. The time horizon for the model was 30 years and each cycle was 1 month. A two-arm model with similar structure and assumptions, comparing rituximab maintenance therapy with observation, was also submitted. The hazard rates were taken from the trial up to 24 months and extrapolated to 30 years using a Weibull function. In order to fit the parametric model to the survival data, data from the clinical trial were limited to 1500 days because this was the point at which the survival curves flattened. The hazard for death and progression for rituximab (that is, the duration of benefit) was assumed to be equivalent to baseline risk after 5 years. Quality of life scores for the health states were derived from a study commissioned by the manufacturer. A utility of 0.805 was attached to the progression-free states and of 0.618 to the progressive disease state. Each patient was assumed to relapse every 2 years and undergo further treatment. The cost of post-protocol treatments was based on the average costs observed in the trial. Patients received an average of 5.93 cycles of maintenance rituximab. Administration costs were calculated as being equal to an outpatient visit (£86). Follow-up costs were equal to an outpatient visit every 3 months for the progression-free state and an outpatient visit every month in the progressive disease state. The model was subjected to univariate sensitivity analysis, and a probabilistic sensitivity analysis was also conducted. From the four-arm model, the most effective treatment intervention, using rituximab for induction and maintenance, compared with the next most effective, using rituximab for maintenance alone, gave an incremental cost-effectiveness ratio (ICER) of £16,749 per quality-adjusted life year (QALY) gained. Comparing the use of rituximab for maintenance alone with no use of rituximab gave an ICER of £9076 per QALY gained. Decreasing the duration of treatment benefit to 2 years increased the ICER for using rituximab in induction and maintenance compared with rituximab as maintenance alone to £36,497 per QALY gained. Decreasing the time horizon to 4 years increased the ICER for the comparison of the same treatment strategies to £48,116 per QALY gained. The model was not sensitive to the utility values of the health states. The ERG considered that the manufacturer had not adequately described the methods for the systematic review of rituximab as monotherapy for induction at second or subsequent relapse (the indication appraised in TA 37) or explicitly reported on its results. However the ERG was confident that no relevant studies for this or any other indications had been missed. The ERG also confirmed that CHOP and fludarabine-containing regimens were the appropriate comparators for rituximab when used with chemotherapy for induction in relapsed follicular non-Hodgkin's lymphoma. The main clinical trial was conducted in patients who were rituximab-naive. In view of previous NICE guidance (TA 110 ), patients in routine practice in the NHS can be expected to have received rituximab with first-line chemotherapy. The ERG considered that the effectiveness of rituximab in patients who had previously received the drug was not certain. The ERG considered the four-arm model appropriate. The model assumed further treatment at relapse with attached costs, but it did not assume any health benefits from these treatments despite incurring the costs. The ERG noted that the best way to overcome this deficiency was to limit the gains to the observed period only. The ERG did not consider the two-arm model suitable because it did not differentiate between patients on the basis of treatment at induction. The ERG noted that the administration of rituximab was assumed to occur in the outpatient setting and was costed accordingly. Given the duration of infusion it was considered more appropriate for this to occur in the day-case setting and the ERG calculated a cost of £504. The ERG also recalculated post-progression treatment costs by aggregating treatments into a small number of meaningful categories. This avoided the wide variation in treatment costs, some of which are very expensive, skewing the average post-progression treatment costs of individual strategies. The new categories were 'chemotherapy', 'rituximab' and 'other'. It was assumed that 25% of patients in each treatment strategy would receive other treatments, and 75% would be split between chemotherapy and rituximab treatments depending upon previous use of rituximab. The ERG also added an estimated cost of £5000 towards terminal-care costs. The ERG considered that the choice of the Weibull model for the analysis had not been sufficiently justified. In addition, the manufacturer had assumed that the pairs of patient groups to be compared shared common parameters, estimating only three parameters rather than the four required to fit the functions independently. This approach made a proportional hazard assumption, which was not substantiated by reference to trial data. The ERG also noted the lack of an initial period of non-zero hazards for those groups that went on to be randomised at maintenance as these groups would have a protocol-driven event-free period. The ERG repeated the analyses overcoming the problems with model projections by limiting the extrapolation to use of the Kaplan-Meier estimates derived from the data to 1500 days. The ERG exploratory analyses with changes to costs and with outcomes limited to 1500 days using the Kaplan-Meier estimates gave the following results. The single use of rituximab, as either induction or maintenance when compared with no use gave ICERs of approximately £16,000 and £13,000 per QALY gained, respectively. Dual use of rituximab at induction and maintenance compared with no use was associated with an ICER of approximately £26,000 per QALY gained. The dual-use strategy compared with single-use strategies was associated with ICERs of about £43,000 per QALY gained for the use of rituximab at maintenance only and about £42,000 per QALY gained for the use at induction only. The ERG suggested that a comprehensive probabilistic sensitivity analysis in the form of a combined cost-effectiveness acceptability probability plot would indicate which strategy would have the highest probability of being preferred across a range of willingness to pay thresholds. The manufacturer provided additional analyses relating to the cost effectiveness of using rituximab for induction and maintenance compared with the use of rituximab for maintenance only, as requested by the Committee. All the following ICERs relate to the comparison of these two treatment strategies only. Changing the cost for administration and aggregating post-progression treatment costs as suggested by the ERG (see 3.11) and using the original four-arm model (see 3.6 and 3.7) increased the ICER to £24,161 per QALY gained. Excluding the event-free period when fitting the Weibull model (see 3.12) decreased the ICER to £21,379 per QALY gained. However, with the event-free period excluded, the exponential model gave the best fit and resulted in an ICER of £16,183 per QALY gained. When the proportional hazards assumption was relaxed and the Weibull functions were fitted independently with the event-free period excluded (see 3.12), the ICER decreased to £15,775 per QALY gained. One-way sensitivity analysis showed that these ICERs were sensitive to the assumed time horizon and duration of benefit. A time horizon of 4 years increased the ICERs to above £56,000 per QALY gained, and reducing the duration of treatment benefit to 3 years increased the ICERs to £24,000–£34,200 per QALY gained, depending on the survival model used. A probabilistic sensitivity analysis was conducted with the scenario that resulted in a deterministic ICER of £21,379, and this suggested that, at a threshold above £18,700, the use of rituximab for induction and maintenance had the greatest probability of being the most cost-effective option. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma, having considered evidence on the nature of the condition and the value placed on the benefits of rituximab by people with follicular non-Hodgkin's lymphoma, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. The Committee discussed the manufacturer's interpretation of the marketing authorisation, and was satisfied with this following clarification from the European Medicines Agency. It understood that rituximab can be used as follows: as monotherapy for the treatment of patients with stage III-IV follicular non-Hodgkin's lymphoma who are chemoresistant or who are in their second or subsequent relapse after chemotherapy as monotherapy maintenance therapy for patients with relapsed or refractory follicular non-Hodgkin's lymphoma responding to induction therapy with chemotherapy with or without rituximab in combination with chemotherapy as induction therapy for patients with relapsed follicular non-Hodgkin's lymphoma. # Clinical effectiveness The Committee considered the use of rituximab as recommended (only in the context of a prospective case series) in the original appraisal (TA 37): as monotherapy for the treatment of patients with relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma, when all alternative treatment options have been exhausted (that is, when there is resistance to or intolerance of chemotherapy). Resistance was defined as the absence of a response to the last course of chemotherapy following several courses of treatment. The guidance also applied to people who have or are likely to become intolerant of chemotherapy because of adverse effects that severely limit the safety of further treatment. The Committee was concerned that no new evidence for this use of rituximab was made available, particularly because it had been a condition of use that patients only received rituximab if their data were collected as part of a case series. It agreed with the ERG that there was a lack of clarity in the manufacturer's search for relevant new data. The clinical specialists pointed to the diminishing use of rituximab at last line because it has been licensed and recommended for earlier use as first-line therapy (TA 110 ), and they felt that no new evidence would now be collected at later stages of the treatment pathway. They stated that rituximab was still needed as a last-line option for frail patients in whom the use of toxic chemotherapy may not be possible. The Committee agreed that the previous recommendation should stand, but recognised the limitations of treatment recommendations based on the need for future data collection. The Committee concluded that rituximab monotherapy should continue to be recommended as an option for the treatment of patients with relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma, when all alternative treatment options have been exhausted. The Committee considered the evidence for the clinical effectiveness of rituximab monotherapy as maintenance therapy and the use of rituximab as induction therapy in relapsed follicular non-Hodgkin's lymphoma. Both of these indications were evaluated in the EORTC trial, and in both indications rituximab-treated patients had higher response rates and longer remissions than control patients. The Committee heard from clinical specialists that rituximab was a valuable treatment and that the possibility of maintaining remission was particularly encouraging. The Committee also heard from the patient representatives of the importance attached by patients to the remission state and the value of maintenance treatment in prolonging it. The Committee accepted that the EORTC trial demonstrated the effectiveness of rituximab for maintenance therapy and for the induction of remission in patients at first and second relapse. The Committee was mindful that the results from the EORTC trial were based on rituximab-naive patients. The number of rituximab-naïve patients is decreasing due to increased prescribing of rituximab as first-line therapy. The Committee considered that it was necessary to be cautious about the assumption that rituximab is as efficacious in patients who had already received it as in patients who are rituximab-naive. The clinical specialists stated that the evidence indicated that follicular non-Hodgkin's lymphoma could be re‑treated with rituximab with little or no loss of efficacy. Although it noted this as an area of uncertainty, the Committee accepted that this was biologically plausible given its mechanism of action. The Committee noted that rituximab maintenance therapy was associated with similar increases in progression-free survival in patients who had received rituximab at induction as in those who had only chemotherapy for induction. It also noted that the use of rituximab maintenance therapy following induction with chemotherapy alone resulted in a greater reduction in the risk of progression compared with rituximab maintenance therapy following induction with combined chemotherapy plus rituximab. However, the Committee was aware that the trial was not powered or designed to evaluate the relative efficacy of rituximab maintenance in patients who had or had not received rituximab at induction. The Committee was therefore unable to draw firm conclusions on the relative efficacy of rituximab maintenance therapy in patients who had and had not received rituximab for induction. The Committee also queried the extent to which induction therapy with CHOP was representative of the comparator treatments used in the NHS. The clinical specialists stated that CHOP was the main chemotherapy used in follicular non-Hodgkin's lymphoma patients at this stage but that fludarabine-containing regimens are also used to some extent. The Committee was also aware that the GLSG trial, using a fludarabine-based regimen, showed a similar magnitude of benefit as the EORTC trial, which used CHOP. However, the regimen of fludarabine used in the GLSG trial differed from that commonly used in the NHS and the trial population included people with other indolent lymphomas. The Committee considered it appropriate to focus its considerations on CHOP as the most important comparator within the NHS. # Cost effectiveness The Committee considered the manufacturer's economic model and the critique of it by the ERG. In particular, it discussed the costs included in the model and the approach to survival modelling and extrapolation. The Committee considered the changes to the costs in the manufacturer's model suggested by the ERG. It thought that it was appropriate to calculate costs at progression by aggregating treatments into categories, and it agreed with the ERG's assumptions as to how these would vary across the treatment strategies. It heard from clinical and patient specialists that, although the duration of second and subsequent infusions can sometimes be reduced to as little as 2 hours, for the most part, approximately 4 hours are necessary. The Committee also understood that the practice of rapid administration of rituximab was increasingly followed because its safety was now accepted by clinicians. The Committee concluded that it would currently be more appropriate to cost administration of rituximab as a day-case procedure than as an outpatient visit. The Committee also concurred with the ERG's approach of adding a terminal-care cost to the model and that the amounts assumed were appropriate. The Committee was not satisfied that the survival modelling adopted by the manufacturer was optimal and regarded the estimates resulting from the manufacturer's initial model as unreliable and requiring further analysis (see 3.14). The Committee first considered the cost effectiveness of rituximab when used as maintenance therapy. When considering rituximab monotherapy as maintenance, it was mindful that the clinical and patient specialists had strongly supported this use based on its potential to prolong remission, and the lack of alternative therapies for doing so. The Committee considered the results of the exploratory analysis performed by the ERG, which did not use model-based extrapolation but limited the analysis to 1500 days of the Kaplan-Meier estimates and made changes to costs as suggested by the ERG above (see 4.7). The Committee agreed that this approach overcame some of the concerns regarding the initial survival modelling. Based on this approach, the use of rituximab as maintenance only when compared with no use at all was associated with an ICER of approximately £13,000 per QALY gained. The Committee noted that the limited time horizon used in this approach could result a higher ICER than if a longer time horizon was used. The Committee concluded that, despite its concern that the EORTC population (from whom these calculations were derived) was not fully representative of UK patients (see 4.5), the use of rituximab for maintenance therapy following induction of remission with chemotherapy was likely to be a cost-effective use of NHS resources. Having accepted that rituximab maintenance therapy following induction with chemotherapy was likely to be a cost-effective use of NHS resources, the Committee then considered the use of rituximab as induction with chemotherapy. Given that patient experts and clinical specialists identified maintenance therapy as the clinical priority and that this is cost effective when compared with current standard treatment, the cost effectiveness of rituximab at induction was considered as an additional strategy over its use as maintenance alone. It is expected that rituximab maintenance will become standard therapy following this appraisal, and the Committee agreed that the appropriate comparator for the dual-use strategy was the next best use of resources – single use of rituximab as maintenance therapy as opposed to no use of rituximab. The Committee therefore considered the use of rituximab in combination with chemotherapy for induction in addition to use for maintenance. It noted that the use of rituximab in induction increased the proportion of patients who entered remission and became eligible for rituximab maintenance. It also noted that the ERG's exploratory analysis suggested an ICER of approximately £43,000 per QALY gained when compared with chemotherapy only for induction followed by rituximab maintenance therapy. However, the Committee was aware that this figure resulted from a curtailed time horizon and required further analysis to obtain more reliable estimates. The Committee was also aware that there were a number of concerns with the manufacturer's survival modelling raised by the ERG (see 4.7) and that further analysis (see 4.11) was required before obtaining reliable estimates of cost effectiveness. The manufacturer's original approach to the modelling of survival did not take account of the initial zero-hazard period, although there was a protocol-driven event-free period in the data. The Committee did not accept this approach because excluding the event-free period when fitting distributions could change the goodness-of-fit of any distribution fitted to trial data and influence the outcome of the cost-effectiveness analysis. The Committee noted that the additional analyses by the manufacturer excluded the event-free period when fitting functions and this resulted in an ICER of £21,379 using the Weibull model, with the exponential model being the best fit and resulting in an ICER of £16,183 per QALY gained (see 3.14). These analyses were calculated over a lifetime horizon, assuming a duration of treatment benefit of 5 years, which the Committee considered to be reasonable. The Committee also discussed that, in initially fitting the Weibull model to the RCT data, the manufacturer had made the assumption of proportional hazards such that the only difference between the fitted distributions was as a result of a treatment effect. The Committee requested further analysis because this strong assumption had not been substantiated by RCT data and could have resulted in an overestimation of the clinical and cost effectiveness of rituximab. The Committee noted that relaxing the proportional hazards assumption and independently fitting Weibull functions caused the ICERs to decrease to £15,775 per QALY gained (see 3.14). It also noted that, in the further analysis from the manufacturer, terminal-care costs were not included, but it was aware that including such a cost made little difference to the ICERs. The Committee considered the ICERs of approximately £16,000 per QALY using extrapolation from distributions that had been shown to be a good fit to clinical data to be the most appropriate of those presented in the manufacturer's reanalysis. It was, however, mindful that this figure could be an underestimate of the cost per QALY gained because in practice patients would not usually be rituximab-naive, whereas those in the evidence base were. On balance, the Committee concluded that the use of rituximab in combination with chemotherapy as induction therapy was likely to be a cost-effective use of resources.# Related NICE guidance Rituximab for the treatment of follicular lymphoma. NICE technology appraisal guidance 110 (2006). Rituximab for aggressive non-Hodgkin's lymphoma. NICE technology appraisal guidance 65 (2003).# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. The guidance on this technology was reviewed in March 2011. Details can be found on the NICE website. Andrew DillonChief ExecutiveFebruary 2008# Changes after publication February 2014: implementation section updated to clarify that rituximab is recommended as an option for treating relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. It replaces 'The clinical effectiveness and cost effectiveness of rituximab for follicular lymphoma' (NICE technology appraisal guidance 37 issued in March 2002). The Institute reviews each piece of guidance it issues. The review and re-appraisal of the use of rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma has resulted in a change in the guidance. In people with relapsed stage III or IV follicular non-Hodgkin's lymphoma, rituximab is now an option in combination with chemotherapy to induce remission or alone as maintenance therapy during remission. Rituximab monotherapy is also an option for people with relapsed or refractory disease when all alternative treatment options have been exhausted. 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 evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to 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 2008. 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.

Zap1p gene transcriptions "Zinc homeostasis in yeast is controlled primarily through the regulation of zinc uptake. Transcription of the ZRT1 and ZRT2 zinc transporters increases in zinc-limited cells, and this induction is dependent on the ZAP1 gene. Expression of ZAP1 itself increases in zinc-limited cells. (ZREs) in the promoters of the ZRT1, ZRT2, and ZAP1 genes. A ZRE consensus sequence, 5'-ACCYYNAAGGT-3', was identified and found to be both necessary and sufficient for zinc-responsive transcriptional regulation. ZREs are DNA binding sites for ZAP1." # Human genes # Consensus sequences The upstream activating sequence (UAS) for Zap1p is 5'-ACC(C/T)(C/T)(A/C/G/T)AAGGT-3' in the promoters of ZRT1 and ZRT2 regarding this zinc-regulated transcription factor . # Hypotheses - A1BG has no regulatory elements in either promoter. - A1BG is not transcribed by a regulatory element. - No regulatory element participates in the transcription of A1BG. # ZAP samplings Copying the apparent consensus sequence for Zap1p (ACCCTCA) and putting it in "⌘F" finds none located between ZSCAN22 and none between ZNF497 and A1BG as can be found by the computer programs. For the Basic programs (starting with SuccessablesZAP.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 looking for, and found: - negative strand, negative direction, looking for ACC(C/T)(C/T)NAAGGT, 0. - positive strand, negative direction, looking for ACC(C/T)(C/T)NAAGGT, 0. - positive strand, positive direction, looking for ACC(C/T)(C/T)NAAGGT, 0. - negative strand, positive direction, looking for ACC(C/T)(C/T)NAAGGT, 0. - complement, negative strand, negative direction, looking for TGG(A/G)(A/G)NTTCCA, 0. - complement, positive strand, negative direction, looking for TGG(A/G)(A/G)NTTCCA, 0. - complement, positive strand, positive direction, looking for TGG(A/G)(A/G)NTTCCA, 0. - complement, negative strand, positive direction, looking for TGG(A/G)(A/G)NTTCCA, 0. - inverse complement, negative strand, negative direction, looking for ACCTTN(A/G)(A/G)GGT, 0. - inverse complement, positive strand, negative direction, looking for ACCTTN(A/G)(A/G)GGT, 0. - inverse complement, positive strand, positive direction, looking for ACCTTN(A/G)(A/G)GGT, 0. - inverse complement, negative strand, positive direction, looking for ACCTTN(A/G)(A/G)GGT, 0. - inverse negative strand, negative direction, looking for TGGAAN(C/T)(C/T)CCA, 0. - inverse positive strand, negative direction, looking for TGGAAN(C/T)(C/T)CCA, 0. - inverse positive strand, positive direction, looking for TGGAAN(C/T)(C/T)CCA, 0. - inverse negative strand, positive direction, looking for TGGAAN(C/T)(C/T)CCA, 0. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff.

# GUIDELINE OBJECTIVES To make recommendations with respect to the role of adjuvant systemic chemotherapy in stage II and III colon cancer patients who have undergone complete resection with curative intent. # TARGET POPULATION The target population consists of adult patients with stage II and III colon cancer who have undergone complete resection with curative intent as primary therapy. # INTENDED USERS Intended users of this guidance document are clinicians involved in the delivery of adjuvant systemic chemotherapy for stage II and III colon cancer patients. # Stage II Colon Cancer Recommendation 1 The routine use of adjuvant chemotherapy for all patients with stage II colon cancer is not recommended. However, adjuvant therapy is a reasonable option for the subset of patients with high-risk stage II disease. While there is controversy about which tumour features denote high risk in stage II patients, this subset includes patients with inadequately sampled nodes, T4 lesions, perforation at the site of the tumour, or poorly differentiated histology in the absence of microsatellite instability (MSI) or mismatch repair deficiency (dMMR). # Qualifying Statements for Recommendation 1 - The clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity, the presence of high-risk prognostic features on individual prognosis, and patient preferences. - The enrolment of resected stage II patients in clinical trials is encouraged. Additional trials comparing adjuvant therapy with observation are needed and are ethically acceptable in stage II colon cancer. # Recommendation 2 When treated with adjuvant therapy, high-risk stage II patients should receive a fluoropyrimidine. There are insufficient data in support of oxaliplatin providing additional benefit to all high-risk individuals. The 2015 guideline recommendations have been ENDORSED, which means that the recommendations are still current and relevant for decision making. Please see Section 6: Document Assessment and Review for a summary of updated evidence published between 2015 and 2018, and for details on how this guideline was ENDORSED. # Qualifying Statements for Recommendation 2 - It would be reasonable to consider FOLFOX for high-risk patients as part of an informed discussion between patients and their medical oncologists regarding treatment options. # Added to the 2019 Endorsement - Additional evidence is expected that will inform decisions on duration of treatment with oxaliplatin-based treatment in patients with stage II disease. The following data are from a recent abstract (Iveson, ASCO, 2019), and thus should be considered with caution. The IDEA collaboration evaluated 3 vs 6 months of therapy in a randomized, pre-planned, pooled analysis of 4 RCTs focusing on high-risk stage II patients. The decision to use CAPOX or FOLFOX was left to the treating physician. Noninferiority was not met for DFS comparing 3 vs 6 months (HR 1.18, 95% CI 1.05 to 1.31; noninferiority margin was 1.2). Five-year DFS was 80.7% vs 84.0% for 3 and 6 months, respectively. There was a significant reduction in grade 3 to 5 toxicity with 3 months of therapy (irrespective of regimen). See Section 6 for details. Most patients suitable for oxaliplatin-based combination chemotherapy should discuss the differences between CAPOX and FOLFOX with their oncologist and choose a balance between efficacy and toxicity: - The IDEA results suggest that 3 months of CAPOX results in very similar efficacy to 6 months, whereas it appears that 3 months of FOLFOX resulted in slightly lower DFS (but the interaction test for duration and regimen was not statistically significant). - The duration of 5-FU monotherapy was not addressed in IDEA, and should remain 6 months. # Recommendation 3 Adjuvant chemotherapy with a fluoropyrimidine monotherapy regimen following surgery in patients who have MSI/dMMR is not recommended. MSI/dMMR testing should be performed for all stage II patients for whom adjuvant chemotherapy is being considered. In stage II (in the absence of high-risk features) where a patient does not require adjuvant chemotherapy, MSI/dMMR testing is not recommended as it will not influence that decision. # Qualifying Statements for Recommendation 3 - In patients with high-risk stage II colon cancer (e.g., T4) and high MSI/dMMR status (a low risk factor), the choice of treatment is between observation and FOLFOX, but data are lacking to guide this decision. # Stage III Colon Cancer # Qualifying Statements for Recommendation 4 - 5-FU may be given intravenously in combination with LV and oxaliplatin in the regimens known as FOLFOX or FLOX, or capecitabine may be given orally in combination with intravenous oxaliplatin in the regimen known as XELOX. These oxaliplatin-containing regimens have demonstrated superior overall survival when compared with 5-FU plus LV and are the recommended regimens. Oxaliplatin administration is associated with a 12.5% risk of severe neuropathy which is permanent in approximately 1% of patients. This needs to be considered in conjunction with the expected benefits of therapy. - Owing to the toxicity profile of FLOX, it is used less frequently than FOLFOX. - Some patients would not be considered appropriate for oxaliplatin-containing regimens. Examples include patients with underlying neurological conditions or at increased risk of neuropathy, patients at increased risk for infections, and patients likely to poorly tolerate infections as a result of chemotherapy. For these patients the treatment options are: o oral capecitabine which has equivalent efficacy to intravenous bolus 5-FU/LV. Capecitabine results in significantly less diarrhea, stomatitis, neutropenia, nausea/vomiting, and alopecia but significantly more hand-foot syndrome when compared with bolus 5-FU/LV. o 5-FU in combination with LV - Suitable patients should be offered entry into clinical trials testing new adjuvant treatments for resected stage III colon cancer. - Patients have begun their adjuvant treatment within four to nine weeks of surgery in the adjuvant randomized controlled trials of resected colon cancer. # Added to the 2019 Endorsement - The IDEA collaboration evaluated 3 vs 6 months of therapy in a randomized, pre-planned, pooled analysis of 6 individual trials focusing on stage III patients. The treatment choice of CAPOX or FOLFOX was left to the treating physician. Overall, noninferiority was not met for 3 vs 6 months (3-year DFS HR 1.07, 95% CI 1.0 to1.15; noninferiority margin was 1.12). Pre-planned sub-group analysis revealed superiority for 6 months of FOLFOX, whereas 3 months of CAPOX was found to be noninferior to 6 months. 3 months of treatment was associated with lower rates of adverse events independent of chemotherapy regimen (Grothey et al, NEJM, 2018). An unplanned analysis was devised sub-dividing patients into "low" and "high" risk stage III disease, and is the basis for our statements below. See Section 6 for details. - Low-risk stage III (T1-3 N1): 3 months of CAPOX is preferred over FOLFOX. Although the overall trial was negative for the primary endpoint, the shorter duration of treatment strikes a reasonable balance between efficacy and neurotoxicity of oxaliplatin (3 months noninferior to 6 months: HR 1.01, 95% CI 0.90 to 1.12). The pros and cons of 3 vs 6 months should be discussed with patients. Alternatively, 5-FU/capecitabine monotherapy for 6 months' duration remains an option, especially for patients with contraindications to oxaliplatin or preferences for oral chemotherapy. - High-risk stage III (T4 +/-N2): 6 months of oxaliplatin-based chemotherapy (CAPOX or FOLFOX). Although the overall trial was negative for the primary endpoint, the shorter duration of treatment resulted in lower DFS (6 months superior to 3 months: HR 1.12, 95% CI 1.03 to 1.23). The longer duration of therapy is associated with higher rates of neurotoxicity. The pros and cons of CAPOX vs FOLFOX need to be discussed with patients. # Recommendation 5 Although post hoc analyses of studies have not shown a clear benefit of adjuvant fluoropyrimidine plus oxaliplatin regimens in patients older than 70 years of age, it is reasonable to consider FOLFOX for patients older than 70 years as part of an informed discussion between patients and their medical oncologists regarding treatment options.

Paul G. Rogers Society for Global Health Research Established by Research!America in July 2006, the mission of the Paul G. Rogers Society for Global Health Research is to increase awareness of -- and make the case for greater U.S. investment in --- research to fight diseases that affect the world's poorest nations; this includes child and maternal health, chronic diseases (such as heart disease, diabetes and tobacco-related diseases), HIV/AIDS, infantile diarrhea, intestinal parasites, neglected tropical diseases (such as hookworm, lymphatic filariasis, sleeping sickness, river blindness and trachoma), malaria, malnutrition, obesity and under-nutrition. # Paul G. Rogers The Rogers Society was named for the former Florida Congressman and current Research!America chair emeritus, Paul G. Rogers, to honor his contributions to health care policy and advocacy. Rogers served as U.S. Congressman from Florida from 1955 to 1979 and as chair of the House Subcommittee on Health and the Environment from 1971 to 1979. # Paul G. Rogers Society for Global Health Research 2006-07 Ambassadors Selected in November 2006, the inaugural class of Ambassadors -- as members of the Society are called -- is composed of 27 global health research experts. These experts will serve as Society Ambassadors through June 2007. C. Ross Anthony, PhD Director of Global Health and Co-Director of the Center for Domestic and International Health Security, RAND Profile on C. Ross Anthony Margaret E. Bentley, PhD Associate Dean for Global Health, Professor of Nutrition, UNC at Chapel Hill School of Public Health Profile on Margaret E. Bentley Eric G. Bing, MD, PhD, MPH Department of Psychiatry, Charles R. Drew University of Medicine and Science Profile on Eric G. Bing Robert Edward Black, MD, MPH Chair, Department of International Health, The Johns Hopkins University Bloomberg School of Public Health Profile on Robert Edward Black Michael Cappello, MD Professor of Pediatrics, Microbial Pathogenesis, and Epidemiology and Public Health, Yale University School of Medicine Profile on Michael Cappello Lois K. Cohen, PhD Consultant, National Institute of Dental and Craniofacial Research Christopher J. Elias MD, MPH President, PATH Profile on Christopher Elias William B. Greenough, III, MD Professor, Division of Geriatric Medicine and Gerontology, The Johns Hopkins University School of Medicine Profile on William Greenough Richard L. Guerrant, MD Professor of Internal Medicine, Infectious Diseases; Thomas H. Hunter Professor of International Medicine; Director, Center for Global Health, University of Virginia School of Medicine Profile on Richard Guerrant Scott M. Hammer, MD Harold C. Neu Professor of Medicine; Chief, Division of Infectious Diseases, Columbia University Profile on Scott Hammer James E. K. Hildreth, PhD, MD Director, Comprehensive Center for Health Disparities Research in HIV; Professor of Internal Medicine Meharry Medical College Profile on Jame Hildreth King Holmes, MD, PhD Chair, Department of Global Health, University of Washington School of Public Health and Community Medicine Profile on King Holmes William Holzemer, RN, PhD Professor and Associate Dean for International Programs; Director, WHO Collaborating Center, University of California, San Francisco School of Nursing Profile on Bill Holzemer Peter J. Hotez, MD, PhD Founding Dean National School of Tropical Health, Baylor College of Medicine; Professor of Pediatrics and Microbiology and Virology; Director of Sabin Institute Michael Katz, MD Senior Vice President for Research and Global Programs, March of Dimes Birth Defects Foundation; Carpentier Professor, Emeritus, Pediatrics and Professor, Emeritus, Public Health, Columbia University Jeffrey P. Koplan, MD, MPH Vice President for Academic Health Affairs, Woodruff Health Sciences Center, Emory University Profile on Jeffrey Koplan Beverly McElmurry, EdD, RN Professor and Associate Dean for Global Health Leadership; Director, WHO Collaborating Centre, University of Illinois at Chicago College of Nursing Profile on Beverly McElmurry Marjorie Muecke, PhD, RN Assistant Dean for Global Health Programs and Adjunct Professor of Nursing,University of Pennsylvania School of Nursing Profile on Marjorie Muecke Christopher J. L. Murray, MD, DPhil Director, Global Health Initiative, Harvard University; Richard B. Saltonstall Professor of Public Policy, Harvard University School of Public Health Profile on Christopher Murray Gilbert S. Omenn, MD, PhD Professor of Internal Medicine, Human Genetics, and Public Health, University of Michigan Profile on Gilbert Omenn Nilda P. Peragallo, DrPH, RN Dean and Professor, School of Nursing and Health Studies, University of Miami Profile on Nilda Peragallo Les Roberts, PhD, MPH Program on Forced Migration and Health, Mailman School of Public Health, Columbia University Profile on Les Roberts Leon E. Rosenberg, MD Professor, Department of Molecular Biology, Princeton University Princeton University Profile on Leon Rosenberg Research!America profile on Leon Rosenberg Thomas G. Streit, CSC, PhD Department of Biological Sciences, University of Notre Dame Profile on Thomas Streit Sten H. Vermund, MD, PhD Amos Christie Chair in Global Health, Vanderbilt University Medical Center Profile on Sten Vermund Kenneth E. Warner, PhD Dean and Avedis Donabedian Distinguished University Professor of Public Health, University of Michigan School of Public Health Kenneth Warner Profile on Kenneth Warner Peter F. Wright, MD Chief, Division of Pediatric Infectious Disease, Vanderbilt University Medical Center Profile on Peter Wright # Paul G. Rogers Society for Global Health Research Advisory Council The Society Advisory Council was selected and established in 2006. The Advisory Council includes three Nobel Laureates and is chaired by John Edward Porter, former Illinois Congressman and current Research!America board chair. The Advisory Council selects the Ambassadors from a pool of peer-nominated global health experts. The Honorable John Edward Porter, Chair Dennis A. Ausiello, MD David Baltimore, PhD (Nobel Laureate) Gunter Blobel, MD, PhD Barry Bloom, PhD Ambassador Nancy G. Binker Roger J. Bulger, MD Thomas G. Burish, PhD Gail H. Cassell, PhD David R. Challoner, MD Rita R. Colwell, PhD, DSc Nils Daulaire, MD, MPH Susan Dentzer Dominick P. DePaola, DDS, PhD Harvey V. Fineberg, MD, PhD Robert S. Galvin, MD Helene D. Gayle., MD, MPH Joseph Goldstein, MD (Nobel Laureate) J. Warren Gorrell, Jr. Leland Hartwell, PhD (Nobel Laureate) Martha N. Hill, RN, PhD John P. Howe, MD Robert A. Ingram Donald E. Kennedy, PhD Gerald T. Keusch, MD Mathilde Krim, PhD Richard A. Lerner, MD Alan I. Leshner, PhD The Honorable Bob Michel William Novelli The Honorable Sandra Day O'Connor Herbert Pardes, MD William A. Peck William L. Roper, MD, MPD Isadore Rosenfeld, MD Allan Rosenfield, MD Steven A. Schroeder, MD M. Roy Schwarz, MD John R. Seffrin, PhD Harrison C. Spencer, MD, MPH The Honorable Louis W. Sullivan, MD Ciro Sumaya, MD, MPHTM M. Cass Wheeler Mary Woolley # Research!America Research!America received a grant from the Bill and Melinda Gates Foundation to establish the Society and provides advocacy leadership development to Society members. The organization facilitates Ambassadors' engagement in public outreach and advocacy through meetings, speaking engagements and a range of community-level activities to connect with policy makers, opinion leaders, the media and the public nationwide.

DCLRE1A DNA cross-link repair 1A protein is a protein that in humans is encoded by the DCLRE1A gene. DNA interstrand cross-links prevent strand separation, thereby physically blocking transcription, replication, and segregation of DNA. DCLRE1A is one of several evolutionarily conserved genes involved in repair of interstrand cross-links (Dronkert et al., 2000). # Function The protein DCLRE1A (DNA cross-link repair 1A) is also referred to as SNM1A (sensitive to nitrogen mustard 1A). DCLRE1A is a 5’ to 3’ exonuclease that forms a complex with the Cockayne syndrome B (CSB) protein. In this complex, CSB modulates the exonuclease activity of DCLRE1A and coordinates the efficient assembly of DCLRE1A to sites of DNA damage. In human cells, this complex is recruited to DNA inter-strand cross-links, a form of DNA damage. The complex then participates in the repair of the cross-linked DNA. DCLRE1A protein is thought to be recruited by CSB to facilitate cross-link unhooking following incision 5’ to the cross-link by another complex, the ERCC1/XPF nuclease complex. Failure of the DCLRE1A/CSB complex to carry out its repair function may contribute to the degenerative pathologies and premature aging features of Cockayne syndrome.

Sleep paralysis # Overview Sleep paralysis is a condition characterized by temporary paralysis of the body shortly after waking up (known as hypnopompic paralysis) or, less often, shortly before falling asleep (known as hypnagogic paralysis). Physiologically, it is closely related to the paralysis that occurs as a natural part of REM (rapid eye movement) sleep, which is known as REM atonia. Sleep paralysis occurs when the brain awakes from a REM state, but the bodily paralysis persists. This leaves the person fully aware, but unable to move. In addition, the state may be accompanied by hypnagogic hallucinations. More often than not, sleep paralysis is believed by the person affected by it to be no more than a dream. This explains many dream recountings which describe the person lying frozen and unable to move. The hallucinatory element to sleep paralysis makes it even more likely that someone will interpret the experience as a dream, since completely fanciful, or dream-like, objects may appear in the room alongside one's normal vision. # Symptoms The primary symptom of sleep paralysis is partial or complete skeletal muscle paralysis during the hypnopompic or hypnagogic states. In other words, it is the sense of being aware that one is unable to move or speak while falling asleep or waking up. Sleep paralysis may also be accompanied by hypnagogic hallucinations. These hallucinations can be auditory, tactile, and/or visual. The person affected by sleep paralysis may have trouble breathing, as if something was standing on top of his chest. Combined with the hallucinations, this can make the person feel scared of an evil presence, such as a witch (therefore the name "Old Hag Syndrome"). If a polysomnograph is taken, at least one of the following will be shown: skeletal muscle tone suppression, REM sleep at sleep onset, or dissociated REM sleep. The paralysis can persist anywhere from a few seconds to a few minutes before the person is able to either return to REM sleep or to become fully awake. If the person returns to REM sleep yet remains fully aware, they are likely to enter lucid dream state. # Possible causes Sleep paralysis occurs during REM sleep, thus preventing the body from manifesting movements made in the subject's dreams. Very little is known about the physiology of sleep paralysis. However, some have suggested that it may be linked to post-synaptic inhibition of motor neurons in the pons region of the brain. In particular, low levels of melatonin may stop the depolarization current in the nerves, which prevents the stimulation of the muscles, to prevent the body from enacting the dreamt activity (e.g. preventing a sleeper from flailing his legs when dreaming about running). Many people who commonly enter sleep paralysis also suffer from narcolepsy. However, various studies suggest that many or most people will experience sleep paralysis at least once or twice in their lives. Some reports read that various factors increase the likelihood of both paralysis and hallucinations. These include: - Sleeping in an upwards supine position - Irregular sleeping schedules; naps, sleeping in, sleep deprivation - Increased stress - Sudden environmental/lifestyle changes - A lucid dream that immediately precedes the episode. Also conscious induction of sleep paralysis is a common technique to enter a state of lucid dreams, also known as WILD . - Artificial sleeping aids, ADD medications and/or antihistamines - Recent use of hallucinogenic drugs # Treatment During paralysis episodes, patients may be advised to try moving the facial muscles and moving eyes from one side to the other. This may hasten the termination of the attack. Clonazepam is highly effective in the treatment of sleep paralysis. The initial dose is 0.5 mg at bedtime, while an increase to 1 mg per night might be necessary to maintain potency. Anecdotal reports indicate SSRIs such as fluoxetine markedly decrease the incidence of sleep paralysis. Several people who have been both on and off SSRIs have reported corresponding decreases and increases in sleep paralysis episodes. Others report no effects at all. # Cultural references Complete references to many cultures are given in the References section - In Japanese, sleep paralysis is referred to as kanashibari (金縛り, literally "bound or fastened in metal," from kane "metal" and shibaru "to bind, to tie, to fasten"). This term is occasionally used by English speaking authors to refer to the phenomenon both in academic papers and in pop psych literature. - In Hungarian folk culture sleep paralysis is called "lidércnyomás" ("lidérc pressing") and can be attributed to a number of supernatural entities like "lidérc", "boszorkány" (witch), "tündér" (fairy) or "ördögszerető". The word "boszorkány" itself stems from the Turkish root "bas-", meaning "to press". - Kurdish people call this phenomenon a "mottaka", they believe that some one, in a form of a ghost or perhaps an evil spirit, turns up on top the of the person in the middle of the night and suffocates him/her. Apparently this happens usually when some one has done something bad. - In New Guinea, people refer to this phenomenon as "Suk Ninmyo", believed to originate from sacred trees that use human essence to sustain its life. The trees are said to feed on human essence during night as to not disturb the human's daily life, but sometimes people wake unnaturally during the feeding, resulting in the paralysis. - In Turkey this is called "karabasan" ("black-pressing"). It is believed that it is a creature which attacks people in their sleep. - In Mexico, it´s believed that sleep paralysis is in fact the spirit of a dead person getting on the person and impeding movement, calling this "se me subió el muerto" (the dead person got on me). - Ogun Oru od a traditional explanation for nocturnal disturbances among the Yoruba of Southwest Nigeria; ogun oru (nocturnal warefare) involves an acute night-time disturbance that is culturally attributed to demonic infiltration of the body and psyche during dreaming. Ogun oru is characterized by its occurrence, a female preponderance, the perception of an underlying feud between the sufferer's earthly spouse and a ;spiritual' spouse, and the event of bewitchment through eating while dreaming. The condition is believed to be treatable through Christian prayers or elaborate traditional rituals designed to exorcise the imbibed demonic elements. - Several studies have shown that African-Americans may be predisposed to isolated sleep paralysis also known as "the witch is riding you," or "the haint is riding you." In addition, other studies have shown that African-Americans who have frequent episodes of isolated sleep paralysis, i.e., reporting having one or more sleep paralysis episodes per month coined as "sleep paralysis disorder," were predisposed to having panic attacks. This finding has been replicated by other independent researchers # Sleep paralysis in literature, art and music - (1605) Miguel de Cervantes makes mention of the phenomenon in Don Quixote when a tavern wench jumps into the bed of the soundly sleeping Sancho Panza, who, started, and feeling a prodigious weight upon him, thought he was labouring under the nightmare. - (1851) There is a particularly fascinating account of sleep paralysis in Herman Melville's novel Moby-Dick. Chapter 4 (The Counterpane) is an account of Ishmael's meditation on an episode of sleep paralysis in the middle of which he could not distinguish the difference between Queequeg's arm and the quilt. Indeed, he could not even distinguish the difference between his own body and his surroundings. He then recalls an earlier episode of sleep paralysis from his childhood, which he determines was the precise moment he discovered the feeling of "otherness" of his own body with respect to his surroundings. - (1936) An account can also be found in Ernest Hemingway's The Snows of Kilimanjaro, in which death approaches and sits upon the narrator's chest so that he cannot breathe. - (1969) The main character in Kingsley Amis' novel The Green Man also suffers from the affliction. - (1975) Maxine Hong Kingston recounts an episode in her book The Woman Warrior where her mother, Brave Orchid, suffers a night of sleep paralysis in the "Haunted Room", in which she claims she battles a "Sitting Ghost". - In Zimbabwean Shona culture the word Madzikirira is used referring to the fact that something will really be pressing you down and mostly they refer to the spiritual world where some other spirit especially evil one will be trying to use you. The people believe that witches can only be people of close relations to be effective and hence a witch can try to use your spirit to bewitch your relatives. - (2001) The progressive rock band Dredg explores the different aspects of sleep paralysis, on their album El Cielo. The booklet with El Cielo contains letters written by sufferers of sleeping disorders with descriptions of various experiences with or relating to sleep paralysis. Singer Gavin Hayes incorporates and expands upon the material found in the booklet for the lyrics to the album; all of the songs on the album (except the instrumentals) contain snippets of the text in the booklet. - (2006) Experimental band Fear Before the March of Flames talk about the struggles of dealing with constant sleep paralysis on their album "The Always Open Mouth". One of the songs is even called "Drowning the Old Hag". # Notes - ↑ When considered a disease, isolated sleep paralysis is classified as: Diseases Database 12182, MeSH D020188 - ↑ Jump up to: 2.0 2.1 J. A. Cheyne. "Sleep Paralysis and Associated Hypnagogic and Hypnopompic Experiences". Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Unknown parameter |accessmonthday= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ LaBerge, Stephen, (1990). Exploring the World of Lucid Dreaming. Falling Asleep Consciously, 118, 1039-1042. - ↑ J. A. Cheyne. "Preventing and Coping with Sleep Paralysis". Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Unknown parameter |accessmonthday= ignored (help) - ↑ Wills L, Garcia J. (2002) Parasomnias: epidemiology and management16(12):803-10. - ↑ lidérc, Magyar Néprajzi Lexikon, Akadémiai Kiadó, Budapest 1977, ISBN - ↑ boszorkány, Magyar Néprajzi Lexikon, Akadémiai Kiadó, Budapest 1977, ISBN - ↑ Aina OF, Famuyiwa OO (2007). "Ogun Oru: a traditional explanation for nocturnal neuropsychiatric disturbances among the Yoruba of Southwest Nigeria". Transcultural psychiatry. 44 (1): 44–54. doi:10.1177/1363461507074968. PMID 17379609. - ↑ Bell CC, Shakoor B, Thompson B, Dew D, Hughley E, Mays R, Shorter-Gooden K (1984). "Prevalence of isolated sleep paralysis in black subjects". Journal of the National Medical Association. 76 (5): 501–508. PMID 6737506.CS1 maint: Multiple names: authors list (link) - ↑ Bell CC, Dixie-Bell DD, Thompson B (1986). "Further studies on the prevalence of isolated sleep paralysis in black subjects". Journal of the National Medical Association. 78 (7): 649–659. PMID 3746934.CS1 maint: Multiple names: authors list (link) - ↑ Paradis CM, Friedman S (2006). "Sleep Paralysis in African Americans with Panic Disorder". Transcultural psychiatry. 43 (4): 692–694. PMID 15881272. Text "DOI: 10.1177/1363461505050720" ignored (help) - ↑ Friedman S, Paradis CM, Hatch M (1994). "Characteristics of African-Americans and white patients with panic disorder and agoraphobia". Hospital and Community Psychiatry. 45 (8): 798–803. PMID 7982696.CS1 maint: Multiple names: authors list (link)

Prochlorococcus Prochlorococcus is a genus of very small (0.6 µm) marine cyanobacteria with an unusual pigmentation (chlorophyll b) belonging to photosynthetic picoplankton. It is probably the most abundant photosynthetic organism on Earth. # Overview Although there had been several earlier records of very small chlorophyll-b-containing cyanobacteria in the ocean, Prochlorococcus was actually discovered in 1986 by Sallie W. (Penny) Chisholm of the Massachusetts Institute of Technology, Robert J. Olson of the Woods Hole Oceanographic Institution, and other collaborators in the Sargasso Sea using flow cytometry. The first culture of Prochlorococcus was isolated in the Sargasso Sea in 1988 (strain SS120) and shortly another strain was obtained from the Mediterranean Sea (strain MED). The name Prochlorococcus originated from the fact it was originally assumed that Prochlorococcus was related to Prochloron and other chlorophyll b containing bacteria, called prochlorophytes, but it is now known that prochlorophytes form several separate phylogenetic groups within the cyanobacteria subgroup of the bacteria kingdom. Marine cyanobacteria are to date the smallest known photosynthetic organisms: Prochlorococcus is the smallest at just 0.5 to 0.8 micrometres across. Possibly they are also the most plentiful species on Earth: a single millilitre of surface seawater may contain 100,000 cells or more. Worldwide, there are estimated to be 100 octillion individuals. Prochlorococcus is ubiquitous between 40°N and 40°S and dominates in the oligotrophic (nutrient poor) regions of the oceans. The light harvesting pigment complement of Prochlorococcus is unique, consisting predominantly of divinyl derivatives of chlorophyll a (Chl a2) and b (Chl b2) and lacking monovinyl chlorophylls. Prochlorococcus occupies two distinct niches, leading to the nomenclature of the low light (LL) and high light (HL) groups , which vary in pigment ratios (LL possess a high ration of chlorophyll b2: a2 and HL low b2: a2), light requirements, nitrogen and phosphorus utilization, copper and virus sensitivity. These "ecotypes" can be differentiated on the basis of the sequence of their ribosomal RNA gene. Recently the genomes of several strains of Prochlorococcus have been sequenced .

Sandbox ammu save Editing West nile virus historical perspective # Overview WNV was first isolated in 1937 in Uganda from a hospitalized patient who presented with isolated fever. Between 1950 and 1960, small villages in the Mediterranean basin had repeated outbreaks, especially in Israel and Egypt. These outbreaks allowed researchers to study the molecular and clinical features of the disease and further understand its mode of transmission and natural history. Several WNV outbreaks were recorded in the second half of the 20th century in Europe, Middle East, Far East, and Africa. It was not until 1999 when the first WNV outbreak was documented in USA, making WNV a worldwide infection. Perhaps the most severe outbreak documented was in 2002 in USA, recording the highest number of meningoencephalitis from a single WNV outbreak. The first description of a person-to-person transmission was reported in 2002 among patients with blood transfusions and tissue transplantation. # Discovery WNV was first discovered following its isolation in 1937 from a hospitalized patient presenting with isolated fever in the West Nile district of Northern Uganda. Initial reports described a virus whose physical and pathological characteristics resemble that of St. Louis encephalitis virus and Japanese B encephalitis virus. Early studies noted the frequent involvement of the CNS among infected patients, suggesting neurotropism of the virus. It was not until the 1950-1960 Mediterranean basin outbreaks in small towns that clinical and pathological features of West Nile virus were really revealed. # Famous outbreaks The first epidemic was documented in 1951 in Isreal, when Bernkopf and colleagues isolated WNV among 123 cases. Further understanding of the viral pattern, mode of transmission, and pathogenesis was conducted by studies in 1951-1954 following outbreaks in Cairo, Egypt. The first report of neurological sequelae following WNV infection was documented in 1957 during an outbreak in Israel. Other outbreaks in other regions, such as Europe, India, South Africa, were later described in the 1970s and 1980s. In 1996, an outbreak of WNV in Romania in Europe spiraled a series of outbreaks in the Middle East, North Africa, and Europe region. Unlike early reports that mostly included children, these outbreaks unveiled adult preponderance and an increased rate of CNS complications associated with the disease. In 1999, the first outbreak in USA initially described 8 cases, most of which had neurological symptoms, in Queens, New York City. The 1999 outbreak in USA finally marked the global spread of the virus. The outbreak eventually infected a total of 62 individuals, whose symptoms were mostly severe and necessitated hospitalization. Although initially believed to be caused by an endemic arbovirus, WNV was eventually demonstrated to be the agent responsible for the outbreak after the discovery of a coinciding outbreak among infected birds within the same geographical region and during the same time frame Only 3 years after its documented presence in USA, the clinically most severe WNV outbreak occurred in North America in 2002, where the largest number of meningoencephalitis from a single outbreak was recorded. In the same year, the first human-to-human transmission was discovered; it was attributed to transmission via blood transfusion and tissue transplantation. # Development of diagnostic and treatment strategies - The first WNV MAC-ELISA-based commercial diagnostic test for arboviruses was also developed and later commercialized to assays that may be used in the field. - Following the 1999 outbreak in USA, the first animal vaccine was developed and later approved by the U.S. department of agriculture (USDA). The WNV-DNA virus is considered the only USDA-approved vaccine. # Impact on cultural history - The 1999 outbreak in New York in USA drove the Center of Disease Control (CDC) to fund its own Zoo Surveillance Program at Cornell University School of Veterinary Medicine. During the outbreak, CDC assigned other channels to test infected bird species that might help in identifying the virus. The delay in diagnosis was presumed to be a significant element for the outbreak's detrimental outcomes. - Following the 1999 outbreak, WNV was considered a nationally reportable disease in USA. Annual meetings were held in USA to provide public health information about WNV, and guidelines for surveillance, prevention, and control of WNV were developed and frequently updated. - ArboNET, a real-time disease reporting network developed by CDC, was first launched in 2000 after the 1999 outbreak to follow WNV disease in humans and animals. - Funding to the CDC - Enhanced Laboratory Capacity (ELC) cooperative agreement program reached $2.7 million dollars in 2000. In a few years, the program's funding was higher than $20 million dollars. Grants were utilized to train arbovirologists and to fund research programs, lab diagnosis, and surveillance programs.

Osmium tetroxide Osmium tetroxide is the chemical compound with the formula OsO4. The compound is noteworthy for its many uses, despite the rarity of osmium. It also has a number of interesting properties, one being that the solid is volatile. # Physical properties Osmium tetroxide exists as a pale yellow-brown crystalline solid with a characteristic acrid odor similar to ozone. In fact, the element name osmium is derived from osme, Greek for odor. OsO4 is volatile: it sublimes at room temperature. It is soluble in a wide range of organic solvents, and moderately soluble in water, with which it reacts reversibly to form osmic acid (see below). Pure osmium tetraoxide is probably colourless and it has been suggested that its yellow hue is due to osmium dioxide (OsO2) impurities although osmium (IV) oxide normally exists as a black powder so this may not be true. # Structure and electron configuration With a d0 configuration, Os(VIII) is expected to form tetrahedral complexes when bound to four ligands. Tetrahedral structures are seen for the electronically related oxides MnO4− and CrO42−. The osmium of OsO4 has a formal oxidation state of 8+, the highest oxidation state known for a transition metal. The osmium atom has eight valence electrons. If one assumes that two electrons are donated by each of the four oxide ligands, the total electron count for the complex is 16, as also seen for the isoelectronic species permanganate and chromate. # Synthesis OsO4 is formed slowly when osmium powder reacts with O2 at 298 K. Reaction of bulk solid requires heating to 670 K. # Reactions ## Oxofluorides Osmium forms several oxofluorides, all of which are very sensitive to moisture. Purple cis-OsO2F4 forms at 77 K in an aqueous solution of HF: OsO4 also reacts with F2 to form yellow OsO3F2: OsO4 reacts with one equivalent of F at 298 K and 2 equivalents at 253 K: ## Oxidation of alkenes OsO4 catalyzes the cis-dihydroxylation of alkenes by hydrogen peroxide or related sources of oxygen atoms in the presence of water. The reaction that is catalyzed is In terms of mechanism, OsVIIIO4 adds to alkenes R2C=CR2 to afford cyclic "esters" R4C2O2OsVIO2, which undergo hydrolysis to give the vicinal diol and release a reduced osmium oxide (OsVI): Lewis bases such as tertiary amines and pyridines increase the reaction rate. This "ligand-acceleration" arises via the formation of adduct OsO4L, which adds more rapidly to the alkene. If the amine is chiral, then the dihydroxylation can proceed with enantioselectivity (see Sharpless asymmetric dihydroxylation). Since OsO4 is toxic and expensive, it is used in catalytic amounts. The osmium catalyst is regenerated by oxidizing agents, such as H2O2, N-methylmorpholine N-oxide (NMO, see Upjohn dihydroxylation), and K3Fe(CN)6. These oxidizing reagents do not react with the alkenes on their own. Other sources of osmium tetroxide include potassium osmate(VI) dihydrate (K2OsO4·2H2O) and osmium (III) chloride hydrate (OsCl3.xH2O) which oxidise to osmium (VIII) in the presence of such oxidants. ## Miscellaneous reactions OsO4 dissolves in alkaline aqueous solution to give the osmate anion: OsO4 is a Lewis acid, and when the Lewis bases are amines, the oxides can undergo substitution. Thus with NH3 one obtains the nitrido-oxide: The - anion is isoelectronic and isostructural with OsO4. Using primary amine tert-BuNH2 one obtains the corresponding imido derivative: OsO4 undergoes "reductive carbonylation" in methanol at 400 K and 200 bar of pressure to produce the triangular cluster Os3(CO)12: In this reaction osmium changes oxidation state by eight units. # Uses ## Organic synthesis In organic synthesis OsO4 is widely used to oxidise alkenes to the vicinal diols, adding two hydroxyl groups at the same side (syn addition). See reaction and mechanism above. This reaction has been made both catalytic (Upjohn dihydroxylation) and asymmetric (Sharpless asymmetric dihydroxylation). Osmium tetroxide is also used in catalytic amount in the Sharpless oxyamination to give vicinal amino-alcohols. In combination with sodium periodate, OsO4 is used for the oxidative cleavage of alkenes (the Lemieux-Johnson oxidation). Here the periodate serves both to cleave the diol formed by dihydroxylation, and to reoxidize the OsO3 back to OsO4. The net transformation is identical to that produced by ozonolysis. Below an example from the total synthesis of Isosteviol. ## Biological staining OsO4 is a widely used staining agent used in transmission electron microscopy (TEM) to provide contrast to the image. As a lipid stain, it is also useful in scanning electron microscopy (SEM) as an alternative to sputter coating. It embeds a heavy metal directly into cell membranes, creating a high secondary electron emission without the need for coating the membrane with a layer of metal, which can obscure details of the cell membrane. Additionally, osmium tetroxide is also used for fixing biological samples in conjunction with HgCl2. Its rapid killing abilities are used to quickly kill specimen like protozoa. Osmium tetroxide is also used as a stain for lipids in optical microscopy. OsO4 also stains the human cornea (see safety considerations). ## Polymer Staining It is also used to stain copolymers preferentially, the best known example being block copolymers where one phase can be stained so as to show the microstructure of the material. For example, styrene-butadiene block copolymers have a central polybutadiene chain with polystyrene end caps. When treated with OsO4, the butadiene matrix reacts preferentially and so absorbs the oxide. The presence of a heavy metal is sufficient to block the electron beam, so the polystyrene domains are seen clearly in thin films in TEM. ## Osmeth OsO4 can be recycled and stored in the form of osmeth, a golden crystalline solid. Osmeth is OsO4 complexed with hexamine and does not emit toxic fumes as opposed to pure OsO4. It can be dissolved in tetrahydrofuran (THF) and diluted in an aqueous buffer solution to make a dilute (0.25%) working solution of OsO4. ## Osmium ore refining OsO4 is an intermediate in osmium ore refining. Osmium residues are reacted with Na2O2 forming 2- anions, which, when reacted with chlorine (Cl2) gas and heated, form OsO4. The oxide is dissolved in alcoholic NaOH forming 2- anions, which, when reacted with NH4Cl, forms OsO2Cl2(NH4)4. This is ignited under hydrogen (H2) gas leaving behind pure osmium (Os). ## Buckminsterfullerene adduct OsO4 allowed for the confirmation of the soccer ball model of buckminsterfullerene, a 60 atom carbon allotrope. The adduct, formed from a derivative of OsO4, was C60(OsO4)(4-tert-butylpyridine)2. The adduct broke the fullerene's symmetry allowing for crystallization and confirmation of the structure of C60 by x-ray crystallography. # Safety considerations OsO4 is highly poisonous, even at low exposure levels, and must be handled with appropriate precautions. In particular, inhalation at concentrations well below those at which a smell can be perceived can lead to pulmonary edema, and subsequent death. Noticeable symptoms can take hours to appear after exposure. OsO4 also stains the human cornea, which can lead to blindness if proper safety precautions are not observed. On the April 6, 2004 British intelligence sources believed they had foiled a plot to detonate a bomb involving OsO4. Experts interviewed by New Scientist affirmed osmium tetroxide's toxicity, though some highlighted the difficulties of using it in a weapon: osmium tetroxide is very expensive. The osmium tetroxide may be destroyed by the blast; what remaining toxic fumes may also be dispersed by the blast as well.

NFATC4 Nuclear factor of activated T-cells, cytoplasmic 4 is a protein that in humans is encoded by the NFATC4 gene. # Function The product of this gene is a member of the nuclear factors of activated T cells DNA-binding transcription complex. This complex consists of at least two components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor (TCR) stimulation and an inducible nuclear component. Other members of this family of nuclear factors of activated T cells also participate in the formation of this complex. The product of this gene plays a role in the inducible expression of cytokine genes in T cells, especially in the induction of the IL-2 and IL-4. NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation. Indeed, NFAT3 (NFATc4) is an inhibitor of cell motility by blocking the expression of LCN2. # Interactions NFATC4 has been shown to interact with CREB-binding protein.

Cefoxitin clinical pharmacology # CLINICAL PHARMACOLOGY ## Clinical Pharmacology Following an intravenous dose of 1 gram, serum concentrations were 110 mcg/mL at 5 minutes, declining to less than 1 mcg/mL at 4 hours. The half-life after an intravenous dose is 41 to 59 minutes. Approximately 85 percent of cefoxitin is excreted unchanged by the kidneys over a 6-hour period, resulting in high urinary concentrations. Probenecid slows tubular excretion and produces higher serum levels and increases the duration of measurable serum concentrations. Cefoxitin passes into pleural and joint fluids and is detectable in antibacterial concentrations in bile. In a pubished study of geriatric patients ranging in age from 64 to 88 years with normal renal function for their age (creatinine clearance ranging from 31.5 to 174.0 mL/min), the half-life for cefoxitin ranged from 51 to 90 minutes, resulting in higher plasma concentrations than in younger adults. These changes were attributed to decreased renal function associated with the aging process.

Dietary fiber # Overview Dietary fibers are the indigestible portion of plant foods that move food through the digestive system, absorbing water and making defecation easier. Dietary fiber consists of non-starch polysaccharides such as cellulose and many other plant components such as dextrins, inulin, lignin, waxes, chitins, pectins, beta-glucans and oligosaccharides. # Classification Sources of dietary fiber are usually divided according to whether they are water-soluble or not. ## Insoluble fiber Insoluble fiber is not viscous. Insoluble fiber may bind water and thus reduces transit time in the colon. The plum's skin is an example of an insoluble fiber source. Other sources of insoluble fiber include whole wheat, wheat and corn bran, flax seed lignans and vegetables such as celery, green beans and potato skins. ## Soluble fiber Soluble fiber is viscous. Soluble fiber undergoes metabolic processing via fermentation, yielding end-products with broad, significant health effects. The plum's is an example of soluble fiber. Soluble fiber is in oats, oat ß-glucan, psyllium (ispaghula), barley, soybeans, dried beans and peas, and citrus. Soluble fiber may affect cholesterol absorption more than insoluble fiber does. Soluble, viscous fiber may help diabetes. ### Fermentable fiber The American Association of Cereal Chemists defined soluble fiber this way: “the edible parts of plants or similar carbohydrates resistant to digestion and absorption in the human small intestine with complete or partial fermentation in the large intestine”. There are several key words in that statement that invite analysis and comment for considering fermentable fiber. edible parts of plants — indicates that all parts of a plant we eat — skin, pulp, seeds, stems, leaves, roots — contain fiber. Both insoluble and soluble sources are in those plant components. carbohydrates — complex carbohydrates, such as long-chained sugars also called starch, oligosaccharides or polysaccharides, are excellent sources of fiber. resistant to digestion and absorption in the human small intestine — foods providing nutrients are digested by gastric acid and digestive enzymes in the stomach and small intestine where the nutrients are released then absorbed through the intestinal wall for transport via the blood throughout the body. A food resistant to this process is undigested, as insoluble and soluble fibers are. They pass to the large intestine only affected by their absorption of water (insoluble fiber) or dissolution in water (soluble fiber). complete or partial fermentation in the large intestine — the large intestine comprises a segment called the colon within which additional nutrient absorption occurs through the process of fermentation. Fermentation occurs by the action of colonic bacteria on the food mass, producing gases and short-chain fatty acids. It is these short-chain fatty acids — butyric, ethanoic (acetic), propionic, and valeric acids — that might have significant health properties. ### Short-chain fatty acids Short-chain fatty acids are used by the intestinal mucosa or absorbed through the colonic wall into the portal circulation (supplying the liver) that transports them into the general circulatory system. Particularly, butyric acid has extensive physiological actions that promote health effects, among which are: - Stabilizes blood glucose levels by acting on pancreatic insulin release and liver control of glycogen breakdown - Suppresses cholesterol synthesis by the liver and reduces blood levels of LDL cholesterol and triglycerides responsible for atherosclerosis - Lowers colonic pH (i.e., raises the acidity level in the colon) which protects the lining from formation of colonic polyps and increases absorption of dietary minerals - Stimulates production of T helper cells, antibodies, leukocytes, cytokines and lymph mechanisms having crucial roles in immune protection - Increases proliferation of colonic bacteria beneficial for intestinal health — Bifidobacteria and Lactobacilli (serving a probiotic function) - Improves barrier properties of the colonic mucosal layer, inhibiting inflammatory and adhesion irritants Summarizing these effects, fermentable fibers yield the important short-chain fatty acids that affect blood glucose and lipid levels, improve the colonic environment and regulate immune responses. # Regulatory guidance on fiber products On average, North Americans consume less than 50% of the dietary fiber levels required for good health. In the preferred food choices of today's youth, this value may be as low as 20%, a factor considered by experts as contributing to the obesity crisis seen in many developed countries. Recognizing the growing scientific evidence for physiological benefits of increased fiber intake, regulatory agencies such as the US Food and Drug Administration (FDA) have given approvals to food products making health claims for fiber. In clinical trials to date, these fiber sources were shown to significantly reduce blood cholesterol levels -- thus are important to general cardiovascular health -- and to lower risk of onset for some types of cancer. Soluble (fermentable) fiber sources gaining FDA approval are - Psyllium seed husk (7 grams per day) - Beta-glucan from oat bran, whole oats, oatrim or rolled oats (3 grams per day) - Beta-glucan from whole grain or dry-milled barley (3 grams per day) Other examples of fermentable fiber sources (from plant foods or biotechnology) used in functional foods and supplements include inulin, fructans, xanthan gum, cellulose, guar gum, fructooligosaccharides (FOS) and oligo- or polysaccharides. Consistent intake of fermentable fiber through foods like berries and other fresh fruit, vegetables, whole grains, seeds and nuts is now known to reduce risk of some of the world’s most prevalent diseases — obesity, diabetes, high blood cholesterol, cardiovascular disease, and numerous gastrointestinal disorders. In this last category are constipation, inflammatory bowel disease, ulcerative colitis, hemorrhoids, Crohn’s disease, diverticulitis, and colon cancer--all disorders of the intestinal tract where fermentable fiber can provide healthful benefits. Insufficient fiber in the diet can complicate defecation. Low-fiber feces are dehydrated and hardened, making them difficult to evacuate -- defining constipation and possibly leading to development of hemorrhoids. Although many researchers believe that dietary fiber intake reduces risk of colon cancer, one study, conducted by researchers at the Harvard School of Medicine of over 88,000 women, did not show a statistically significant relationship between higher fiber consumption and lower rates of colorectal cancer or adenomas. # Summary of definition and potential health benefits In June 2007, the British Nutrition Foundation issued a statement to define dietary fiber more concisely and list the potential health benefits established to date: ‘Dietary fiber’ has been used as a collective term for a complex mixture of substances with different chemical and physical properties which exert different types of physiological effects. The use of certain analytical methods to quantify ‘dietary fiber’ by nature of its indigestibility results in many other indigestible components being isolated along with the carbohydrate components of dietary fiber. These components include resistant starches and oligosaccharides along with other substances that exist within the plant cell structure and contribute to the material that passes through the digestive tract. Such components are likely to have physiological effects. Yet, some differentiation has to be made between these indigestible plant components and other partially digested material, such as protein, that appears in the large bowel. Thus, it is better to classify fiber as a group of compounds with different physiological characteristics, rather than to be constrained by defining it chemically. Diets naturally high in fiber can be considered to bring about five main physiological consequences: - improvements in gastrointestinal health - improvements in glucose tolerance and the insulin response - reduction of hyperlipidemia, hypertension and other coronary heart disease risk factors - reduction in the risk of developing some cancers - increased satiety and hence some degree of weight management Therefore, it is not appropriate to state that fiber has a single all encompassing physiological property as these effects are dependent on the type of fiber in the diet. The beneficial effects of high fiber diets are the summation of the effects of the different types of fiber present in the diet and also other components of such diets. Defining fiber physiologically allows recognition of indigestible carbohydrates with structures and physiological properties similar to those of naturally occurring dietary fibers. # Guidelines on fiber intake The American Dietetic Association (ADA) recommends a minimum of 20-35 g/day for a healthy adult depending on calorie intake (e.g., a 2000 cal/8400 kJ diet should include 25 g of fiber per day). The ADA's recommendation for children is that intake should equal age in years plus 5 g/day (e.g., a 4 year old should consume 9 g/day). No guidelines have yet been established for the elderly or very ill. Patients with current constipation, vomiting, and abdominal pain should see a physician. Certain bulking agents are not commonly recommended with the prescription of opioids because the slow transit time mixed with larger stools may lead to severe constipation, pain, or obstruction. The British Nutrition Foundation has recommended a minimum fiber intake of 12-24 g/day for healthy adults. # Sources of fiber Current recommendations from the United States National Academy of Sciences, Institute of Medicine, suggest that adults should consume 20-35 grams of dietary fiber per day, but the average American's daily intake of dietary fiber is only 12-18 grams. The American Dietetic Association recommends consuming a variety of fiber-rich foods. The five most fiber-rich plant foods, according to the Micronutrient Center of the Linus Pauling Institute, are legumes (15-19 grams of fiber per US cup serving, including several types of beans, lentils and peas), wheat bran (17 grams per cup), prunes (12 grams), Asian pear (10 grams each) (3.6% by weight), and quinoa (9 grams). Remarkable among plant foods, the Amazonian palmberry, açaí (Euterpe oleracea Mart.), has been analyzed by two research groups reporting its content of dietary fiber is 25-44% of total mass in freeze-dried powder. Rubus fruits such as raspberry (8 grams of fiber per serving) and blackberry (7.4 grams of fiber per serving) are exceptional sources of fiber. ## Soluble fiber Soluble fiber is found in varying quantities in all plant foods, including: - legumes (peas, soybeans, and other beans) - oats, rye, chia, and barley - some fruits and fruit juices (particularly prune juice, plums and berries) - certain vegetables such as broccoli and carrots - root vegetables such as potatoes, sweet potatoes, and onions (skins of these vegetables are sources of insoluble fiber) - psyllium seed husk (a mucilage soluble fiber). - inulin Legumes also typically contain shorter-chain carbohydrates indigestible by the human digestive tract but which may be metabolized by bacterial fermentation in the large intestine (colon), yielding short-chain fatty acids and gases (flatulence). ## Insoluble fiber Sources of insoluble fiber include: - whole grain foods - bran - nuts and seeds - vegetables such as green beans, cauliflower, zucchini, and celery - the skins of some fruits, including tomatoes # Fiber supplements There are many types of soluble fiber supplements available to consumers for nutritional purposes, treatment of various gastrointestinal disorders, and for such possible health benefits as lowering cholesterol levels, reducing risk of colon cancer, and losing weight. Soluble fiber supplements may be beneficial for alleviating symptoms of irritable bowel syndrome, such as diarrhea and/or constipation and abdominal discomfort. Prebiotic soluble fiber products, like those containing inulin or oligosaccharides, may contribute to relief from inflammatory bowel disease, as in Crohn's disease, ulcerative colitis, and Clostridium difficile, due in part to the short-chain fatty acids produced with subsequent anti-inflammatory actions upon the bowel. Fiber supplements may be effective in an overall dietary plan for managing irritable bowel syndrome by modification of food choices. ## Psyllium husk Psyllium seed husk may reduce the risk of heart disease by lowering cholesterol levels, and is known to help alleviate the symptoms of irritable bowel syndrome, though it often causes uncomfortable bloating. Psyllium husk may be used as a bulk-forming laxative. The FDA allows foods containing 1.7 g of psyllium husk soluble fiber or .75 g of oat or barley soluble fiber as beta-glucans to claim that reduced risk of heart disease can result from regular consumption. The FDA statement template for making this claim is: Soluble fiber from foods such as , as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease. A serving of supplies __ grams of the soluble fiber from necessary per day to have this effect. In clinical studies approved by the FDA, the cholesterol-lowering benefit of soluble fiber from psyllium, when taken as directed and combined with a low-fat, low-cholesterol diet, was 4 to 6 percent for total blood cholesterol and 4 to 8 percent for LDL (bad) cholesterol vs. a low-fat diet alone. ## Inulins Inulins are a group of oligosaccharides occurring naturally in many plants. They belong to a class of carbohydrates known as fructans. Inulin is used increasingly in prepared foods due to its favorable nutritional characteristics. Subtly sweet, it can be used to replace sugar, fat, and flour, and is often used to improve the flow and mixing qualities of powdered nutritional supplements. Inulin is advantageous because it contains 25-30% the food energy of sugar or other carbohydrates and 10-15% the food energy of fat. As a prebiotic fermentable fiber, its metabolism by gut flora yields short-chain fatty acids (discussed above) which increase absorption of calcium, magnesium, and iron, resulting from upregulation of mineral-transporting genes and their membrane transport proteins within the colon wall. Among other potential beneficial effects noted above, inulin promotes an increase in the mass and health of intestinal Lactobacillus and Bifidobacterium populations. ## Vegetable gums Vegetable gum fiber supplements are relatively new to the market. Often sold as a powder, vegetable gum fibers dissolve easily with no aftertaste. They are effective for the treatment of irritable bowel syndrome (Parisi, 2002). Examples of vegetable gum fibers are guar gum (example brand Benefiber reformulated to wheat dextrin in 2006) and acacia gum. # Misconceptions Fiber does not bind to minerals and vitamins and therefore does not restrict their absorption, but rather evidence exists that fermentable fiber sources improve absorption of minerals, especially calcium. The food's phytate content is mainly responsible for the reduced bioavailability of certain minerals and vitamins like calcium, zinc, vitamin C and magnesium.

Avatrombopag for treating primary chronic immune thrombocytopenia Evidence-based recommendations on avatrombopag (Doptelet) for treating primary chronic immune thrombocytopenia in adults. # Recommendations Avatrombopag is recommended, within its marketing authorisation, as an option for treating primary chronic immune thrombocytopenia (ITP) refractory to other treatments (for example, corticosteroids, immunoglobulins) in adults. It is only recommended if the company provides it according to the commercial arrangement. Why the committee made these recommendations Current treatment for newly diagnosed primary chronic ITP usually includes corticosteroids and immunoglobulins. This is followed by thrombopoietin receptor agonists (TPO‑RAs). Avatrombopag is another TPO‑RA. Clinical trial evidence shows that avatrombopag is more effective than placebo at increasing the number of platelets in the blood (cells that help the blood to clot) to a level that meaningfully reduces the risk of bleeding. Avatrombopag may be as effective as other TPO‑RAs, but it has only been compared with them indirectly, which is uncertain. There are also uncertainties with some assumptions in the economic modelling. Despite this, avatrombopag is likely to provide benefit for people who have primary chronic ITP. Also, the cost-effectiveness estimates are below what NICE normally considers an acceptable use of NHS resources. So, avatrombopag is recommended.# Information about avatrombopag # Marketing authorisation indication Avatrombopag (Doptelet, Swedish Orphan Biovitrum) is 'indicated for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments (e.g., corticosteroids or immunoglobulins)'. # Dosage in the marketing authorisation The dosage schedule is available in the summary of product characteristics for avatrombopag. # Price The list price of a 10‑tablet pack of avatrombopag 20 mg is £640.00 (excluding VAT; BNF online, accessed June 2022). The company has a commercial arrangement. This makes avatrombopag available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by Swedish Orphan Biovitrum, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence. # The condition ## Immune thrombocytopenia (ITP) is an autoimmune condition that is chronic in most affected adults ITP is characterised by a platelet count less than 100×109 per litre. This reduced platelet count is caused by abnormally high platelet destruction and reduced platelet production. ITP is a rare condition. About 3,000 to 4,000 adults in the UK are estimated to have ITP at any one time. To make a diagnosis, any other possible causes of thrombocytopenia, including impaired bone marrow, need to be excluded. Most diagnosed cases in adults progress to chronic ITP that may be difficult to control. Symptoms include fatigue, spontaneous bruising and regular bleeding episodes. The patient experts highlighted that the fatigue can be debilitating, reducing cognitive function and making it difficult to focus. The fatigue also often contributes towards increased bruising. This is because reduced coordination related to the fatigue may cause people to bump into things more often. Bleeding episodes can range from minor bleeds to severe, life-threatening haemorrhages. The patient experts emphasised the effect ITP has on mental as well as physical health. This is because many people with ITP worry about maintaining high enough platelet levels to prevent bleeding episodes. Treatment for ITP is usually introduced when the platelet count drops below 30×109 per litre. Current treatments include corticosteroids, immunoglobulins, thrombopoietin receptor agonists (TPO‑RAs) and immunosuppressants such as rituximab. The patient and clinical experts highlighted that the current treatments have disadvantages, including unpleasant and potentially harmful side effects, and the need for dietary changes. They emphasised a need for another treatment option that offered more normality for those affected by ITP. The committee concluded that ITP is a chronic condition that significantly affects the lives of those affected by it. ## People with chronic ITP would welcome new treatment options that maintain platelet counts at a level that prevents bleeds ITP is a burden to people with the condition, as well as their families and carers. This burden is often linked to the unpredictable nature of the condition and the side effects of treatment. Also, some people with ITP need to inject some treatments themselves, so need to plan their life around injection dates, and ensure safe storage and administration of these treatments. The patient experts highlighted that this could affect everyday life. Self-injecting can also cause increased anxiety. One patient expert described how they still had stress about injecting 5 years into treatment. Also, soreness and bruising can occur at the injection site, particularly in people whose platelet counts are low. There is an oral TPO‑RA, but this can cause side effects including chronic gastrointestinal issues and increased risk of blood clots. It can also be affected by diet, and people taking it may need to restrict what foods they eat, and when they eat them. Both the patient and clinical experts highlighted that this has a large effect on everyday life, adherence to treatment and effectiveness. Some treatments for ITP also cause immunosuppression, which increases the risk of infection. One patient expert explained that they had had 22 infections in an 18‑month period when taking an immunosuppressant for ITP. Infections can cause a drop in platelet count, which may need hospitalisation and rescue therapy if uncontrolled. Both the patient and clinical experts agreed that avatrombopag, an oral treatment with no dietary restrictions and no immunosuppression would be an advance in ITP treatment in the UK. They also agreed it could improve quality of life for people with ITP by increasing platelet count without being a difficult treatment to take. The committee agreed that a new treatment option for maintaining platelet counts would be welcomed by people with ITP. # Treatment pathway and comparators ## The company's positioning of avatrombopag in the treatment pathway is appropriate The company's positioning of avatrombopag was aligned with avatrombopag's marketing authorisation, that is, for treating primary chronic ITP in adults refractory to other treatments. When someone is diagnosed with ITP, they have an 'initial' treatment that includes corticosteroids, immunoglobulins or both. The clinical experts explained that TPO‑RAs would not be used before corticosteroids and immunoglobulins but would be used if this initial treatment failed. The committee concluded that avatrombopag is likely to be used after initial treatment of newly diagnosed chronic ITP. It agreed that the company's positioning of avatrombopag in the treatment pathway was appropriate. ## The relevant comparators for avatrombopag are other TPO-RAs In its submission, the company considered other TPO‑RAs (eltrombopag and romiplostim) to be the only appropriate comparators for avatrombopag. The company's rationale for this was that: TPO‑RAs are considered to be well-established standard care for ITP it would be inappropriate to consider rituximab or surgical splenectomy as the comparators given the availability of 2 other TPO‑RAs.The ERG agreed that the company's positioning of avatrombopag was reasonable. But it highlighted uncertainty around the variations in rituximab use in clinical practice. The committee queried at what point in the treatment pathway TPO‑RAs are prescribed in the NHS. The clinical experts explained that, while care is individualised to people with ITP, clinicians generally use TPO‑RAs before rituximab. They also explained that, before the COVID‑19 pandemic, rituximab's use varied across the UK. But international guidance changes have caused a shift in practice to use TPO‑RAs first after initial treatment has failed. This is because rituximab can suppress the immune system. They also confirmed that clinicians rarely offer splenectomy in the first year of diagnosis and do not consider it as an alternative to TPO‑RAs. The committee concluded that eltrombopag and romiplostim were the appropriate comparators for avatrombopag. # Clinical effectiveness ## The population of Study 302 may represent the likely NHS population, but there are uncertainties The key clinical evidence for avatrombopag came from 1 clinical trial, Study 302, and its 72‑week open-label extension. Study 302 was a 26‑week, phase 3, multicentre, randomised, double-blind, parallel-group trial of avatrombopag compared with placebo. The company also submitted clinical evidence from 2 open-label clinical trials: Study 305, a discontinued phase 3, multicentre, randomised, double-blind, parallel-group trial of avatrombopag compared with eltrombopag CL‑003, a 28‑day, phase 2, double-blind, randomised, controlled trial of avatrombopag compared with placebo, and CL‑004, a 6‑month rollover study for people who completed CL‑003.The company only included Study 302 data in the economic model because it considered that it contained robust comparative data on key efficacy and safety outcomes. It stated that the results of the other studies largely supported the safety and efficacy profile of avatrombopag. But it did not think it was appropriate to include the data from these studies in the economic model. The ERG noted that, although Study 302 did not have a UK site, the baseline characteristics of its population would likely be applicable and relevant to an NHS population. But the committee noted that the trial's population may have been younger than the NHS population. The clinical experts explained that they would not expect the response to avatrombopag to be age specific. But more fatal bleeds and infection events may happen in older people, which the clinical experts thought may not have been fully captured in the trial. The committee also noted that 72% of the avatrombopag group were women compared with 47% in the placebo group. There were also people in the trial who had had a splenectomy, which would normally be done after treatment with avatrombopag. Neither the ERG nor the clinical experts thought that this would have had a meaningful effect on the trial results. The committee concluded that the population in Study 302 may represent the NHS population but that there were uncertainties in the study population's baseline characteristics. It took this into account in its decision making. ## The clinical trials of avatrombopag has recruitment and attrition issues, resulting in a limited evidence base There were 49 people in Study 302, 32 in the avatrombopag group and 17 in the placebo group. Twenty two people on avatrombopag completed the trial, while 7 stopped because of inadequate treatment effects and 3 stopped for other reasons. One person on placebo completed the trial, while 15 stopped because of inadequate treatment effects and 1 stopped for other reasons. The clinical experts explained that it is difficult to have a true 'placebo' group for chronic ITP treatments. This is because people in a placebo group would not be expected to stay in a trial if they had extremely low platelets and bleeding episodes. This led to limitations when estimating the durable platelet response rate in the placebo group over the course of Study 302. The ERG was concerned with the robustness of the efficacy and safety data from Study 302 because of the imbalanced drop-out between the avatrombopag and placebo groups. During the first committee meeting, it highlighted that this also affected the results of the company's network meta-analysis (NMA) that indirectly compared avatrombopag with other TPO‑RAs (see section 3.9) and used durable platelet response rate as the outcome. This was because the durable platelet response rate was a key outcome assessed in the NMA presented to the first committee meeting. The committee was aware that Study 305 was stopped early, and that the results of this study were not included in the economic model. It questioned why it was stopped early. The company explained that the trial protocol for Study 305 mandated unpleasant screening and monitoring procedures for people in the trial, and this contributed to recruitment challenges. It also commented that the trial started when eltrombopag was approved and became commercially available. It thought that people may have been reluctant to enrol and be randomised to avatrombopag, a non-approved treatment. So, the trial was stopped before durable platelet response rate could be measured. But the company thought that data from the study could have been used to provide information on other outcomes, including bleeding episodes. At the first committee meeting, the committee had concerns around the limitations of Study 302. In response, the company stated that there was a growing evidence base and clinical experience of using avatrombopag. It also stated that the efficacy of avatrombopag has been shown in randomised controlled trials and real-world settings. The committee understood that there was a limited evidence base for the clinical efficacy of avatrombopag because of recruitment and attrition issues in the clinical trials. ## Avatrombopag may improve cumulative platelet response and durable platelet response rate, but the clinical evidence is highly uncertain The primary outcome of Study 302 was the median cumulative number of weeks of platelet response, measured over 26 weeks. A platelet response was defined as 50×109 per litre or more. Evidence suggested that the median cumulative number of weeks of platelet response was 12.4 weeks with avatrombopag and 0 weeks with placebo (p<0.0001). Other outcomes measured included: secondary: proportion of people with a platelet response without rescue therapy at day 8 (avatrombopag 65.6%, placebo 0%; p<0.0001) proportion of people with a reduction in concomitant ITP medication (avatrombopag 33.3%, placebo 0%; p=0.13) exploratory: durable platelet response rate, that is, the proportion of people who had a platelet response for 6 or more of the last 8 weeks of treatment (avatrombopag 34.4%, placebo 0%; p=0.009) incidence of any grade of bleeding (avatrombopag 43.8%, placebo 52.9%; p=0.54) use of rescue therapy (avatrombopag 21.9%, placebo 11.8%; p=0.47). The ERG noted that the evidence suggested that, compared with placebo, avatrombopag improved the median cumulative number of weeks of platelet response over 26 weeks and the durable platelet response rate. But it highlighted that the interpretation of the evidence was difficult because of the high drop-out in the placebo group. The committee commented that a platelet response without any form of treatment is improbable. It noted the statistically significant difference in proportion of people with a platelet response without rescue therapy at day 8 between avatrombopag and placebo. It contrasted this with the relatively smaller difference between the 2 groups for the outcome of incidence of bleeds. It questioned what the most clinically meaningful outcomes for assessing clinical effectiveness would be. The clinical experts explained that time spent above a platelet count threshold is a clinically meaningful outcome, but this can be difficult to reach because ITP is variable. They thought that a platelet count of 30×109 per litre or more could usually be taken as a response in practice. But they added that a platelet count of 50×109 per litre or more indicates a clinically meaningful response. The company explained that sometimes a platelet count of 20×109 per litre or more reduces bleeding risk and that there could be bleeding with a count of 50×109 per litre or more. So, the company thought that the proportion of people with a platelet count of 50×109 per litre or more without rescue therapy at day 8 could not be a reliable indicator for incidence of bleeds. It thought this was particularly so, given the imbalanced drop-out and follow-up times of the 2 groups in Study 302. The committee was aware that results on long-term durable platelet response rate were not recorded in another trial, Study 305. This was because the trial was stopped before they could be measured. The committee concluded that the evidence from Study 302 suggested that avatrombopag improved cumulative platelet response and the durable platelet response rate, but that this was highly uncertain. ## The frequency of adverse reactions is broadly similar between avatrombopag and placebo In Study 302, the incidence of adverse reactions was compared between the avatrombopag and placebo groups at 26 weeks. Because of the imbalanced treatment durations between these groups (mean 22.8 weeks for avatrombopag compared with mean 8.9 weeks for placebo), the ERG adjusted the treatment duration times to allow a fair comparison. The adjusted analysis suggested that the frequencies of adverse reactions were broadly similar (avatrombopag 4.3%, placebo 6.6%; p value not reported). The ERG noted that higher adverse-reaction incidence rates were seen in Study 305 and CL‑003/004. But the incidence rates for the avatrombopag and comparator groups in these studies were largely similar. The committee highlighted that the small number of people in Study 302 meant that only adverse reactions occurring in more than 10% to 20% would have been identified. It concluded that, within the limitations of the data, the frequency of adverse reactions was broadly similar between avatrombopag and placebo. # NMA using durable platelet response rate as the outcome ## The ERG's continuity correction method proportional to sample size may be appropriate, but there are uncertainties The company presented a series of NMAs to the first committee meeting because there was no direct comparison available. These NMAs compared avatrombopag's efficacy and safety with other TPO‑RAs (eltrombopag and romiplostim), fostamatinib and placebo. The ERG highlighted that fostamatinib was included unnecessarily because it was not included in the final scope as a comparator and is not recommended by NICE. The ERG did not consider it in its own analysis. A frequentist approach using fixed effect models was considered appropriate by both the company and ERG after the technical engagement before the first committee meeting. The NMAs were done for 6 outcomes, including: binary outcomes, reported as odds ratios (ORs): proportion of people with a durable platelet response (durable platelet response rate) proportion of people with reduced concomitant ITP medications incidence rate ratio outcomes: any bleeding episodes bleeding episodes with World Health Organization bleeding assessment score grades 2 to 4 need for rescue therapy any adverse events.The NMA for durable platelet response rate was done despite it not being the primary outcome of Study 302. The company stated that this was because it was the only platelet response outcome that could provide meaningful comparative effectiveness data between avatrombopag, and eltrombopag and romiplostim. During its first meeting, the committee's discussion focused on the durable platelet response rate NMA because it was the only outcome that informed the company's model. The committee understood that the company had chosen durable platelet response rate as the outcome for the feasibility of this NMA because all trials assessed it in a similar way. It noted that 2 other trials included in the NMA for this outcome had zero event or response in its placebo group because of early drop-out or no response. So, the company adjusted the zero events or response in placebo groups to calculate the ORs. Its first continuity correction attempt resulted in an OR of 102.80 (95% credible interval 3.87 to 2,796,448) for avatrombopag compared with placebo. The ERG pointed out that this estimate lacked face validity compared with the evidence from Study 302. It also noted that the company did not provide any detail on how it had corrected for zero events in placebo groups. The ERG preferred another continuity correction method. This involved adding 0.5 to both event and non-event cells in each treatment group to OR. It resulted in an OR of 18.72 (95% CrI 1.02 to 340) for avatrombopag compared with placebo using Study 302 as an example. During technical engagement, the company argued that this approach by the ERG was not appropriate. This was because people were randomised into placebo (n=17) and treatment groups (n=32) in a 1 to 2 proportion in Study 302. The company considered that the ERG's approach introduced directional bias and made the OR highly uncertain. In response to the ERG's critique at technical engagement, the company revised its correction method. It did this by adding an adjustment value to each treatment group proportional to the sample size of the trial, but only to event cells. The company stated that this method was based on Sweeting et al. (2004). When there was a zero event or response cell in the placebo group, an adjustment value of 0.35 (17 of 49) was added to the placebo events cell but subtracted from placebo no-events cell. Also, an adjustment value of 0.65 (32 of 49) was added to any avatrombopag events cell but subtracted from an avatrombopag no-events cell. This was done to maintain the original number of people in each treatment group (17 in the placebo group and 32 in the avatrombopag group). This correction method resulted in an OR of 27.49 (95% confidence interval 0.88 to 855.90) for avatrombopag compared with placebo. The ERG acknowledged that Sweeting et al. suggested an option of correcting zero events or response by adding adjustment values proportional to the sample size to the cells. But it thought that the company had implemented the method incorrectly. This was because, according to Sweeting et al., any adjustments must be applied to both event and no-event cells. This then increases the total number of people in each group as well. So, the ERG did a study-specific sensitivity analysis that correctly implemented the adjustment method suggested by Sweeting et al. As a result, when there was a zero events or response cell in the placebo group, an adjustment value of 0.35 (17 of 49) was added to both events and no-events cells for the placebo group. Also, an adjustment value of 0.65 (32 of 49) was added to both events and no-events cells in the avatrombopag group. This resulted in an OR of 26.91 (95% CI 0.87 to 835.27). During the first committee meeting, the company stated that it agreed with the ERG's sensitivity analysis. The committee considered that any correction should have been done across both events and no events and would ideally have been weighted according to sample size. It concluded that the proportional to sample size approach used in the ERG's sensitivity analysis may have been appropriate for correcting zero events in placebo groups. But it considered that any correction methods would have been associated with a high level of uncertainty when assessing avatrombopag's clinical effectiveness relative to other TPO‑RAs. The committee took this into account in its decision making. # NMA using mean platelet count as a continuous outcome ## An alternative NMA with mean platelet count as a continuous outcome is needed The committee noted the uncertainties associated with the clinical evidence from Study 302 during its first meeting because of the: high attrition in the placebo group (see section 3.6) uncertainties associated with the correction of zero events involved in the NMA analysis on the outcome of durable platelet response rate (see sections 3.9 and 3.10).The committee was aware that a durable platelet response would be unlikely with placebo. This would have made it challenging to compare treatments that had been compared with placebo for this outcome, regardless of the approach taken to adjust for the zero events. The committee was aware that the company's NMA results on the outcome of 'any bleeding events' suggested that avatrombopag may be associated with a lower risk of bleeding compared with placebo (OR 0.32, 95% CI 0.16 to 0.61), eltrombopag (OR 0.43, 95% CI 0.22 to 0.84) or romiplostim (OR 0.39, 95% CI 0.18 to 0.85). But durable platelet response rate was the only outcome that informed the model. The committee was aware that there is an alternative way of exploring avatrombopag's clinical effectiveness relative to other TPO‑RAs, while avoiding the issue of zero events or response in placebo groups. This was to assess mean platelet count as a continuous outcome and transform the resulting estimates into response probabilities for the economic model using an appropriate distributional assumption. Given the uncertainties in the NMA for durable platelet response rate, the committee requested to see the results of an NMA with mean platelet count as a continuous outcome. ## The alternative NMA with mean platelet count as a continuous outcome does not resolve all the uncertainties After the first committee meeting, the company provided an additional NMA comparing avatrombopag's efficacy with other TPO‑RAs (eltrombopag and romiplostim). The outcome was change in mean platelet count from baseline at 25 to 26 weeks. This outcome, along with a distributional assumption, was used to derive the probability of avatrombopag, eltrombopag and romiplostim achieving a platelet count over 30×109 per litre or 50×109 per litre. The company used a Bayesian approach for this NMA, in both a fixed and random effects model. Results showed that avatrombopag was associated with a greater improvement in mean platelet count from baseline compared with placebo: 56.73 (95% CrI 30.62 to 83.13). But there was no difference between avatrombopag and eltrombopag: 1.30 (95% CrI, -27.57 to 30.24), or romiplostim: 10.46, (95% CrI -18.93 to 39.92). The additional analysis also showed that the probability for reaching a 30×109 per litre or a 50×109 per litre platelet count threshold was almost 100% for all treatments compared. Both the company and ERG highlighted the limitations associated with this additional NMA. The company noted the issue around mean change estimates having to be derived from median values for comparators. It also noted the high level of drop-out in the placebo group of Study 302, with only 1 person left at the end of 26‑week follow up. The ERG was particularly concerned with the last observation carried forward (LOCF) method the company had used to input missing data from the placebo group. It pointed out that LOCF was a less conservative approach to replace missing values compared with what had been done in the original NMA by zero correction methods. Also, the last recorded trial observation might have been made when the person was still on treatment and before the loss of efficacy or adverse events. So, it may have overestimated the efficacy of treatment compared with data at later timepoints. The ERG considered that the company should have explored the other more conservative missing data replacement methods. It continued that the company did not provide sufficient justifications for choosing the change in mean platelet count from baseline as the outcome for this additional NMA. This was because there were alternative outcomes that could have been explored. These included, for example, assessing the continuous outcome accounting for multiple timepoints, or adjusting for baseline imbalances. Other uncertainties associated with this additional NMA and noted by the ERG included: The mean platelet count fluctuated over time, but the company chose the 26‑week follow-up timepoint for this analysis. This provided a limited view of the treatment response over time compared with the original NMA analysis using durable platelet response rate as the outcome. The results of this additional NMA markedly differed from the NMA presented to the first committee meeting in terms of ranking efficacy of TPO‑RAs.The company explained that it had chosen change in mean platelet count from baseline as the continuous outcome for this additional NMA and LOCF to input missing data because of time and resource reasons. Also, it chose the timepoint at 26‑week follow up because this was consistent with the timepoint at which the durable platelet response rate was measured in the trial. It continued that, although the ranking efficacy of TPO‑RAs differed between the 2 analyses, both suggested that avatrombopag had the highest probabilities of being the best treatment. Given the high uncertainties, the ERG considered that this additional NMA did not resolve the uncertainties associated with avatrombopag's clinical effectiveness relative to other TPO‑RAs. It noted that durable platelet response rate may be a more appropriate outcome for measuring treatment response to avatrombopag, as supported by its clinical expert. The committee noted that this additional NMA was requested in the hope to validate the NMA results with durable platelet rate as the outcome. This was because of the uncertainties associated with the zero correction methods in the company's original NMA (see section 3.10). The committee understood that this additional NMA was also subject to high uncertainties. This was because of the limitations in the evidence from Study 302, and the company's choice of change in mean platelet count from baseline as the continuous outcome. It is aware that durable platelet response rate is commonly used for assessing treatment response and has been used in previous appraisals for ITP. It agreed that the additional NMA did not resolve the uncertainties in the evidence, and it took this into account in its decision making. # Avatrombopag's clinical effectiveness relative to other TPO-RAs ## Avatrombopag's treatment effect on durable platelet response rate may be similar to other TPO-RAs, but there are high uncertainties The committee discussed the uncertainties associated with the 2 NMAs presented by the company. It recalled its discussions on whether durable platelet response would be likely with placebo (see section 3.6 and section 3.7). It was aware of the limitations in the evidence from both Study 302 and the 2 NMAs given the high attrition rate on the placebo arm. It noted that the outcome on durable platelet response rate may be more appropriate for assessing avatrombopag's treatment effect and informing the model. But the committee noted the considerable challenges when interpreting the results of the NMAs because there were exceptionally wide credible intervals and a high level of uncertainty in the results as a consequence. So, it was difficult for the committee to accept avatrombopag's superiority over other TPO‑RAs. The committee was aware that avatrombopag is an oral treatment and associated with less dietary restrictions compared with the other oral treatment available for ITP (see section 3.2). Considering the challenges with the evidence generation, the committee concluded that, on balance, avatrombopag's treatment effect on durable platelet response rate may be broadly similar to other TPO‑RAs. But it noted that there are high uncertainties. The committee took this into account in its decision making. # Economic model ## The company's economic model structure is appropriate for decision making The economic model was a Markov cohort model consisting of 4 mutually exclusive health states: 'active treatment' (up to 24 weeks waiting for a response), 'responder', 'no treatment no response' (watch and wait) and 'death'. People began in the 'active treatment' state with a platelet count of less than 30×109 per litre and remained there until their response status was determined. People moved to the 'responder' state if their platelet count increased to more than 50×109 per litre. There, they continued active treatment. People stopped active treatment and moved to the 'no treatment no response' state if their platelet count did not increase above 50×109 per litre while on active treatment. 'Responders' could also stop treatment and move to the 'no treatment no response' state if relapse occurred. People in the 'no treatment no response' state restarted active treatment if a bleeding episode occurred, or if there was a need for rescue therapy. At this point, they had an alternative active treatment from their first-line treatment option. People could move into the 'death' state from any of the other model states. Each model cycle lasted 4 weeks, with a time horizon of 56 years representing a lifetime horizon. The ERG considered the model structure to be broadly representative of ITP, and appropriate for modelling the effect of TPO‑RAs. The clinical experts noted that people with a low platelet count would typically have active treatment. But they explained that this is not the only factor considered when determining treatment. But the platelet response threshold of 50×109 per litre is widely used to define treatment response and has been used in previous NICE technology appraisals for ITP. The committee concluded that the economic model structure was appropriate for decision making. ## The 12-week timeframe for assessing non-response might be appropriate but there are uncertainties The company used durable platelet response rate to measure the clinical effectiveness of avatrombopag. During the first committee meeting, the company took a pragmatic approach and assumed a 24‑week timeframe to assess response to TPO‑RA treatments in the model based on Study 302. The ERG noted that, according to the summaries of product characteristics for TPO‑RAs, treatment should be stopped if there is no response within 4 weeks of prescribing the maximum dose. The clinical experts explained that they would expect to assess response over a period of 8 to 12 weeks rather than 24 weeks. They anticipated that the time taken to titrate an oral treatment would be 4 to 8 weeks, followed by 4 weeks at maximum dose to determine response. They also noted that choice of TPO‑RA could affect this. For example, romiplostim has 10 dosing levels so it can take longer to titrate and to determine response to its maximum dose. The committee queried the effect on the cost-effectiveness analysis of changing this timeframe. The ERG explained that the 24‑week was a relatively short timeframe because the model considered a lifetime horizon. It thought that this may have been the reason why its scenario analysis with an 8‑week timeframe had a small effect on the cost-effectiveness results. The committee considered that the 24‑week timeframe to assess response did not reflect clinical practice. After the first committee meeting, the company updated its base case to reflect a 12‑week timeframe for assessing response to treatment in the model. The company stated that it had updated this to be in line with the ERG's base case after the technical engagement and before the first committee meeting. The ERG clarified that its base case presented at the first committee meeting did not use a 12‑week timeframe. It noted that it was considered unlikely that people would remain on avatrombopag for 24 weeks if there was no response. But it explained that either an 8‑week or 12‑week time frame would not align with the definition of durable platelet rate used in the model. This was defined as a platelet response equal or larger than 50×109 per litre for at least 6 of the last 8 weeks of treatment. But the ERG updated the model to use a 12‑week timeframe for assessing response after the first committee meeting. It noted that this had a minor effect on the cost-effective estimates. The committee agreed with this and understood that the 12‑week timeframe was closer to clinical practice, but it noted the uncertainties associated with its use in the model. It concluded that the 12‑week timeframe for assessing non-response might be appropriate but there were uncertainties. ## The company's approach to modelling subsequent treatments is acceptable The company used a mixed treatment approach to model subsequent lines of treatment in the model. These included other TPO‑RAs and non-TPO‑RAs but did not consider treatment sequencing of TPO‑RAs. As a result, response rates for subsequent lines may have been higher than for first-line treatment in the company's model (see section 3.17). The company did not consider that assessing treatment sequencing in the model was plausible from a clinical perspective. This was because it considered that avatrombopag and other TPO‑RAs had similar efficacy, safety, and long-term treatment durations. Also, avatrombopag would be considered for use in people who are suitable for other TPO‑RAs. The ERG disagreed with the company. It stated that a comprehensive assessment of fixed treatment sequences, weighted according to treatment pathways in UK clinical practice, would have more appropriately reflected treatment variability. The ERG did a scenario analysis simulating sequences of treatment options. It noted that, when compared with sequences without avatrombopag, sequences including avatrombopag appeared to provide similar value for money as avatrombopag compared with other TPO‑RAs in the single-line model. But this assumed identical treatment durations among TPO‑RAs. The clinical experts explained that treatment for ITP is highly individualised in practice because the condition is variable. Also, there is no fixed treatment sequence that is followed in clinical practice. People with ITP are also able to switch between TPO‑RAs if their condition stops responding or they become intolerant to a specific one. The committee acknowledged that it was difficult to determine fixed treatment sequences for ITP. It concluded that the company's approach to modelling subsequent treatments was acceptable. ## Defining response differently between TPO-RAs and non-TPO-RAs leads to uncertainties in the model The company defined response for TPO‑RAs as durable platelet response rate (see section 3.7). But it defined the response for non-TPO‑RAs based on NICE's technology appraisal guidance on romiplostim for treating chronic ITP. This definition combined data on efficacy from different studies and took a weighted average. The subsequent lines of treatments that included a mix of TPO‑RAs and non-TPO‑RAs had mixed treatment response definitions. The ERG noted that the response rates used in subsequent lines of treatment for non-TPO‑RAs were high relative to the response rates used in the model for TPO‑RAs. The company explained that, because subsequent lines of treatment included treatments unlicensed for ITP, there was a lack of published evidence for durable platelet response rate for non-TPO‑RAs. But avatrombopag, eltrombopag and romiplostim all had a similar definition of durable platelet response rate (platelet response over 50×109 per litre for at least 6 of the last 8 weeks of treatment). The company also explained that its approach of using different definitions for TPO‑RAs and non-TPO‑RAs could have underestimated the response associated with avatrombopag. But it pointed out that a similar approach had been taken in previous NICE technology appraisals. The ERG highlighted that, in fact, the previous appraisals only included non-TPO‑RAs at subsequent lines, which was different to the company's model. The ERG also noted that it was unclear whether this approach was conservative for avatrombopag. The committee considered that similar definitions for response for TPO‑RAs and non-TPO‑RAs would have been preferrable. But it was also aware that this was not possible given the lack of evidence for non-TPO‑RAs. It concluded that having different definitions for responses for TPO‑RAs and non-TPO‑RAs led to uncertainties in the model. It took this into account in its decision making. ## The same treatment duration of 109 cycles for all TPO-RAs in the long term may be appropriate but there are uncertainties The company assumed long-term treatment duration to be 109 model cycles (436 weeks, or about 8.4 years) for all TPO‑RAs. It assumed the constant stopping rate to be 0.9% per 4‑week model cycle. The company took these estimates from Lee et al. (2013). This fitted a survival curve to: romiplostim data based on a phase 3, placebo-controlled, 24‑week trial and a follow-on, open-label extension of up to 6.0 years eltrombopag data based on results from the open-label EXTEND trial of up to 5.5 years.The company estimated a mean treatment duration of 393 cycles for romiplostim and 109 cycles for eltrombopag, based on data from Lee et al. The ERG highlighted that the difference in mean times on treatment between eltrombopag and romiplostim suggested that there was a difference in treatment durations and stopping rates between TPO‑RAs. During technical engagement, the company provided the results from a survey that it did among 9 clinicians in the UK. It explained that the results supported similar long-term treatment duration between TPO‑RAs. The clinical experts noted that 109 cycles is already a long time for people to be on treatments, so 393 cycles would be unrealistic. They noted that TPO‑RAs may have similar treatment durations and stopping rates, but that some people might stay longer on oral treatment options with less dietary restrictions. The committee noted that about 31% (10 of 32) of people stopped avatrombopag in Study 302. This would equate to about 1.7% per month stopping avatrombopag during its 72‑week extension period. The clinical experts explained that sometimes people stop treatments because their condition becomes stable. The committee was aware the company's approach of using stopping rates from Lee et al. represented a departure from the approach taken by NICE's technology appraisal guidance on romiplostim and eltrombopag. These appraisals modelled time on treatment using patient-level data from the pivotal trials. The company explained that the estimates from Lee et al. were based on longer trial periods (up to 6.0 years for romiplostim and 5.5 years for eltrombopag) than Study 302 (26 weeks plus a 72‑week extension). During its first meeting, the committee considered that treatment duration might be similar between TPO‑RAs. But it requested more scenario analyses to enable it to compare what the company assumed in the model, including: estimated treatment duration based on modelling stopping rates from Study 302 a scenario using the empirical data from the extension of Study 302.The company provided these scenario analyses after the first committee meeting. It fitted a log-normal distribution to the Kaplan–Meier data from the trial and its extension. This resulted in an average treatment duration of 57 cycles (229 weeks or 4.4 years) based on Study 302 alone, and 633 cycles (2,531 weeks or 48 years) with the extension. The company stated that the treatment duration of 109 cycles used in the model was based on long-term trials for the comparators. So, it would be more appropriate to include the extension of Study 302 when determining treatment duration. The ERG explained that the company's approach of analysing data from Study 302 was reasonable because it was similar to that used in Lee et al. But the ERG highlighted that only a few people were at risk in the extension (less than 10 people at risk in 1 year). These small numbers at risk were extrapolated into the longer term, resulting in an average treatment duration of about 48 years for avatrombopag. This was clinically unlikely giving the starting age of 45 years in the model. The company explained that this new extrapolation was presented to confirm that avatrombopag's treatment duration could be as long as other TPO‑RAs. It explained that its original treatment duration of 109 cycles remained unchanged in its base case. The committee noted the uncertainties. On balance, it considered that it was likely that TPO‑RAs would have similar treatment durations in the long term. It concluded that a long-term treatment duration of 109 model cycles for all TPO‑RAs was appropriate for decision making. # Resource use and costing in the economic model ## It is appropriate to cost bleeding episodes based on NHS reference costs using the weighted average In its original submission, the company stratified rescue therapy events into bleed related and non-bleed related. But it nested bleed-related rescue therapies within bleeding episodes. The company also commissioned independent market research to inform the resource use associated with non-minor bleeding episodes. Resources used included hospital stays, diagnostic imaging, blood test and therapeutic interventions. The ERG preferred to cost rescue therapies and bleed-specific unit costs independently. It noted that the company's bleed-specific unit costs informed by its market research data were much higher than those based on NHS reference costs, and those applied in NICE's technology appraisal guidance on romiplostim and eltrombopag. The ERG also noted that there was no clear reporting of which bleed-specific costs were excluded from NHS reference costs and how using the market research captured these alleged omissions. It explained that, because bleed-related rescue therapies were nested within bleeding episodes, the bleed-specific costs were also difficult to interpret. The company aligned its approach to costing to that of the ERG's by modelling bleeding episodes and rescue therapies independently after the technical engagement, except for bleed-specific unit costs. The company took the midpoint between the NHS reference costs and its market research data to represent bleed-specific unit costs and presented it to the first committee meeting. The ERG remained concerned because the company's market research data for bleed-specific unit costs may still have included the costs of rescue therapies. It highlighted that taking this midpoint suggested that bleed-specific costs may not be independent from the costs of rescue therapy, and that this midpoint was still difficult to interpret. The committee noted that there was a lack of detail on the methods of the company's market research. The committee considered that the ERG's approach of using the NHS reference costs would have been appropriate. But the committee recognised that there might be additional resources not covered by the NHS reference costs. So, it requested to see the detailed methods of the company's market research, and how the company derived the bleed-specific unit costs from its qualitative survey questions. After the first committee meeting, the company provided further details on the methods of it market research. It did not use costs from this market research but updated its analyses using NHS reference costs for bleed-specific unit costs in the model. This was in line with the ERG's approach. But the company's bleed-specific unit costs were based on the highest unit cost for the different types of bleeds, rather the weighted average as done by the ERG. The company justified this because duration of different bleeds in people with ITP tend to be longer than the general population. It also explained that this was because additional time is usually needed to increase the person's platelet count and to stabilise the bleed, and bleeds in these people tend to be more severe. The committee questioned where this information had come from. The company explained that it had sought further advice from UK clinicians. But it acknowledged that it was reliant on clinical opinion and there was no published evidence to support these claims. The ERG explained that the company's approach may be reasonable. But it noted that the company's selection of highest unit costs for each type of bleed deviated from methods used in previous appraisals for ITP. Given the uncertainties in the evidence and the model, the committee concluded that the ERG's approach of using the weighted average costs for bleed-specific unit costs was preferrable. # Cost-effectiveness estimates ## Uncertainties remain in the clinical evidence and in the company's modelling assumptions The committee noted that unresolved uncertainties remained in the company's evidence base and model assumptions, including: the recruitment and attrition issues with avatrombopag studies (see section 3.6 and section 3.7) the results from the NMA on durable platelet response rate (see sections 3.9 and 3.10) the different definitions of response between TPO‑RAs and non-TPO‑RAs (see section 3.17) the long-term treatment duration (see section 3.18) the company's approach to costing bleeding episodes in the model (see section 3.19) probabilistic sensitivity analyses were only conducted for pairwise comparisons because of how the company's model was designed. ## Avatrombopag is likely to be cost effective for primary chronic ITP in adults NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the incremental cost-effectiveness ratio (ICER). The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. At the first committee meeting, the committee concluded that the true ICER was not known because of the uncertainties in the clinical evidence provided and in the modelling. The company attempted to reduce these uncertainties by providing updated analyses. In addition, the company provided a comparison of the net cost to the NHS that showed avatrombopag had a cost similar to or lower than its comparators. When the company updated its base case after the first committee meeting, the ICER was below what NICE normally considers an acceptable use of NHS resources. Because of confidential commercial arrangements for avatrombopag and comparator treatments, the cost-effectiveness results cannot be reported here. Scenario analyses exploring other areas of uncertainty did not increase the ICER above an acceptable use of NHS resources. There was further assurance provided with the comparison of costs. So, the committee considered that avatrombopag is cost effective for primary chronic ITP in adults. ## It is unclear whether there are additional benefits of avatrombopag not captured in the model There were no equality issues identified for avatrombopag. The company considers avatrombopag to be innovative because it will offer an additional effective treatment choice to those with chronic ITP. More treatment options are needed because people with ITP can experience loss of response or adverse events with current treatment options. The company also highlighted that there may be uncaptured benefits with avatrombopag because it is an oral treatment and can be taken without the need for dietary restrictions. This might improve treatment adherence. The patient experts emphasised the importance of having the choice of a treatment such as avatrombopag because anxiety around injecting is common, and maintaining dietary restrictions is burdensome. The company also noted that, unlike eltrombopag, avatrombopag does not cause hepatoxicity. This means that less monitoring is needed, and that it can be used for people with ITP who also have liver disease. The committee concluded there might be additional benefits with avatrombopag. But, given the uncertainties in the evidence and in the model (see section 3.20), it was unclear whether there were any not captured in the cost-effectiveness analysis. # Conclusion ## Avatrombopag is recommended as an option for treating primary chronic ITP in adults Avatrombopag is recommended for use in the NHS as an option for treating primary chronic ITP in adults. The cost-effectiveness estimates for people with ITP were uncertain because of uncertainties within the clinical evidence and in the modelling. But they were highly likely to be below what is considered an acceptable use of NHS resources.

Endoscopic thoracic sympathectomy for primary facial blushing # Recommendations Current evidence on the efficacy and safety of endoscopic thoracic sympathectomy (ETS) for primary facial blushing is adequate to support the use of this procedure with normal arrangements for clinical governance, consent and audit. Clinicians wishing to undertake ETS for primary facial blushing should ensure that patients understand the risks of the procedure. In particular they should explain that: there is a risk of serious complications hyperhidrosis is usual after the procedure: this can be severe and distressing and some patients regret having had the procedure (especially because of subsequent and persistent hyperhidrosis) the procedure sometimes does not reduce facial blushing.Clinicians should also provide patients considering the procedure with clear written information. In view of the risk of side effects this procedure should only be considered in patients suffering from severe and debilitating primary facial blushing that has been refractory to other treatments. This procedure should only be undertaken by clinicians trained and experienced in thoracic endoscopy, and there should be the capacity to deal with intraoperative complications. Further research into ETS for primary facial blushing should include clear information on patient selection and should seek to identify which patient characteristics might predict severe side effects. All complications should be reported. Outcomes should include measurements of efficacy, including quality of life and social functioning both in the short and long term, and in particular the frequency and severity of compensatory hyperhidrosis.# Indications and current treatments Blushing or facial reddening is an involuntary reaction, usually as a result of a strong emotional response that stimulates the sympathetic nervous system to increase the flow of blood to the skin of the face. People with facial blushing may also have hyperhidrosis (excessive sweating). Conservative treatment for facial blushing includes oral medications such as beta-blockers or anticholinergics. When anxiety is the cause of blushing, psychological treatments such as cognitive behavioural therapy may be used. If blushing fails to respond to conservative medical treatment or behavioural therapy, then surgical sympathectomy is an option: this can be done either by open or endoscopic approaches. Endoscopic sympathectomy is now usually the preferred technique because it is associated with less pain, improved cosmesis and more rapid recovery than open sympathectomy.# The procedure The aim of endoscopic thoracic sympathectomy (ETS) for primary facial blushing is to reduce the frequency and duration of blushing by dividing the sympathetic nerves that lie along the sympathetic chain beside the vertebral column. ETS is usually done with the patient under general anaesthesia. Small incisions are made in the axilla and an endoscope is inserted. The lung is partially collapsed. The sympathetic chain is visualised and the chosen part of the chain is divided by electrocautery or endoscopic scissors, or surgical clips may be applied. The extent of division varies but usually involves the part of the sympathetic chain over the second or third ribs, or both. Gas is removed from the pleural space, allowing the lung to re-expand, and the wounds are closed. The procedure is then usually repeated on the other side.# Efficacy This section describes efficacy outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. In a case series of 831 patients with facial blushing who had endoscopic thoracic sympathectomy (ETS), mean symptom improvement score (assessed on a visual analogue scale; scores from 0 to 10, with 10 indicating worst possible symptoms) decreased from 9 before the procedure to 3 after the procedure in patients with facial blushing at a mean follow-up of 29 months; this difference was significant (p<0.0001). A case series of 80 patients (12 patients with isolated facial blushing) reported complete resolution in 33% (4/12) of patients with isolated facial blushing at a mean follow-up of 20 months. A case series of 180 patients with isolated facial blushing reported symptom recurrence (1 month to 1 year after the procedure) in 2% (4/173) of patients; all patients subsequently underwent reoperation with 'good results'. In the case series of 80 patients (59 patients with facial blushing, isolated or in association with hyperhidrosis) quality of life (assessed on a 5-point Likert scale) was reported to be 'much better' in 63% (37/59) of patients, and there was 'some improvement' in 15% (9/59) of patients and 'no change' in 8% (5/59) of patients. A case series of 1700 patients (648 patients with blushing or blushing with hyperhidrosis) reported satisfaction rates of 74% in patients with facial blushing (n=536) at a mean follow-up of 15 years (absolute number not reported). In a case series of 1152 patients, 85% of the 244 patients with facial blushing reported being 'totally satisfied' at a mean follow-up of 8 months (absolute number not reported). The specialist advisers stated that key efficacy outcomes were symptom improvement, absence of symptoms and the patient's perception of improvement of symptoms.# Safety This section describes safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the interventional procedure overview. A non-systematic review article reported that 5 patients died because of major intrathoracic bleeding after endoscopic thoracic sympathectomy (ETS) but the total number of patients treated by the procedure was not documented: in 2 patients a trocar lacerated the subclavian artery; in 1 patient an intercostal vein was damaged; the causes in the other 2 patients were not described. An additional 4 deaths after ETS were reported in the non-systematic review article: 3 were due to problems related to anaesthetic technique, and 1 patient had an unexplained cerebral event 'some hours' after ETS. The total number of patients treated by the procedure was not documented. Compensatory hyperhidrosis occurring mainly at the axillae, trunk and groin (assessed using Hyperhidrosis Disease Severity Scale; scores range from 1 to 4, with higher score indicating intolerable sweating interfering with daily activities) was reported to be 'intolerable' in 4% (n=1) of patients, 'hardly tolerable' in 21% (n=5) of patients, and 'tolerable' in 54% (n=13) of patients with facial blushing in a case series of 73 patients (denominator unclear). Half of the patients had compensatory hyperhidrosis within 1 month of the procedure. Severe compensatory hyperhidrosis on the trunk and regret associated with having had the procedure was reported in 6% of patients in the case series of 831 patients at a mean follow-up of 29 months (absolute number not reported). Compensatory hyperhidrosis that was considered 'incapacitating' and regret associated with having had the procedure was reported in 11% (190/1700) of patients with facial blushing or hyperhidrosis at a mean follow-up of 15 years. Horner's syndrome on one side of the face was reported in 10% (2/21) of patients with facial blushing in a case series of 202 patients (1 patient underwent blepharoplasty; no further details) and in 1 patient in the case series of 180 patients with isolated facial blushing: this resolved after 2 days. Pneumothorax (needing a chest tube) was reported in 1 patient in the case series of 180 patients with isolated facial blushing. A chest drain was needed postoperatively (no further details provided) in 9% (5/59) of patients with facial blushing in the case series of 80 patients. Worsening of symptoms was reported in 1 patient and worsening of quality of life was reported in 14% (8/59) of patients with isolated facial blushing or blushing with hyperhidrosis (n=59) in the case series of 80 patients. In the case series of 1152 patients (244 patients with facial blushing), 13% of patients were 'dissatisfied to some extent' and 2% regretted the operation at a mean follow-up of 8 months (absolute numbers not reported). A randomised controlled trial (comparing sympathectomy of the second versus the second and third thoracic ganglia) of 100 patients with isolated facial blushing reported that overall 13% (12/93) of patients regretted the operation (reasons not reported) at a mean follow-up of 12 months; there was no significant difference between the groups treated by different extents of sympathectomy. Additional safety events reported in a series of endoscopic thoracic sympathectomies done for a variety of indications were bleeding, haemothorax, chylothorax, pulmonary embolus and brachial plexus damage; it is unclear if these events were in patients with facial blushing. The specialist advisers listed harlequin face, post-thoracoscopy chronic pain, and wound infection as adverse events reported in the literature. They listed anecdotal adverse events as air embolism and arm ischaemia. Theoretical adverse events were reported as death, dry hands and visceral injury.# Further information For related NICE guidance see the NICE website. # Information for patients NICE has produced information on this procedure for patients and carers (Information for the public). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedures 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. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. NICE produces guidance, standards and information on commissioning and providing high-quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England. # Changes after publication November 2014: 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 have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Care Excellence 2014. 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. ISBN: 978-1-4731-0436-5

Benign paroxysmal torticollis # Overview Benign paroxysmal torticollis (BPT) is a rare medical disorder affecting infants. # Symptoms and Characteristics The defining characteristic of BPT is a tilting of an infant’s head in recurrent episodes, for varying periods of time. Furthermore, the child’s trunk may bend in the same direction as the head, giving the baby an overall curved shape; this complaint is known as tortipelvis. In addition to this, the individual may also, but not necessarily, experience vomiting, pallor, ataxia, agitation, infantile migraine, unsteadiness of gait upon learning to walk, general malaise and nystagmus. The periods in which the child’s head is tilted and other symptoms appear can last anywhere from a few minutes to a few weeks, with a frequency of anywhere from two per year to two per month. # Causes The cause of benign paroxysmal torticollis in infants is thought to be migrainous. More than 50% of infants have a family history of migraine in first degree relatives. The cause is likely to be genetic. # Pathophysiology The mechanism of action of benign paroxysmal torticollis is not yet understood. It has been suggested that unilateral vestibular dysfunction or vascular disturbance in the brain stem may be responsible for the condition. # Diagnosis Diagnosis of BPT can be difficult because it is rare. # Treatment No known treatment for BPT currently exists. However, the condition it is self-limiting and resolves after about eighteen months. # Prognosis Benign paroxysmal torticollis disappears in the early years of life with no medical intervention. However, some cases of benign paroxysmal torticollis cases can evolve into benign paroxysmal vertigo of childhood, migrainous vertigo or typical migraines. # History The condition was first described by CH Snyder in 1969 in an article titled “Paroxysmal torticollis in infancy. A possible form of labyrinthitis.” in the American Journal of Diseases of Children.

Voice therapy (trans) Voice therapy or voice training refers to any non-surgical technique used to improve or modify the human voice. Because voice is a gender cue, transsexual women frequently undertake voice therapy as a part of gender transition in order to make their voices sound female, and therefore increase their passability as females in society. Transgender people and crossdressers who present as women may also desire to feminize their voices and therefore undertake voice therapy. # Overview Voice feminization is the desired goal of changing a perceived male sounding voice to a perceived female sounding voice. The term voice feminization is used to describe what the desired outcome of surgical techniques, speech therapy, self-help programs and a general litany of other techniques to acquire a female-sounding voice. The methods used for voice feminization vary from professional techniques used for vocal training, speech therapy by trained speech pathologists and several Pitch altering surgeries. Vocal sound is produced by air traveling upwards from the lungs through the opening of the larynx called the glottis where the vocal folds vibrate and phonation or voicing occurs. The vibrating vocal folds produce a sound that is modified by chambers (like rooms) of the throat and mouth creating resonance frequencies. The size of the chambers directly affects these frequencies. As the size of the chambers increase the deeper (or lower) the formant frequencies become. These chambers play a very important role in the perception of the timbre (rich, nasal, flat) of the voice. The articulators (tongue, lips, jaw, and soft palate etc.) shape the sound into recognizable speech. Then it is the prosodic features (speaking rate, inflection, pauses) which makes unique speech patterns. There are several frequencies or harmonics produced at the lips. The fundamental frequency (F0) or the number of times per second that the vocal folds vibrate (in hertz), the conversational fundamental frequency is approximately 200 Hz for adult women and 125 Hz for adult men. Many of the voice feminization techniques, including those of surgeons, focus on the fundamental frequency but do little to address the how the sound is modified by the articulators or prosodic features. Speech therapists and professional voice coaches offer training in both changing the fundamental frequency and how to change the perception of voice quality. Voice masculinization is the opposite of voice feminization, being the change of a voice from feminine to masculine. Voice masculinization is not generally required for transsexual men as the masculinising effects of testosterone on the larynx are usually sufficient to produce a masculine voice. # Differences between male and female voices ## Physiological Pitch.: Females usually have higher-pitched voices than males. Many people believe that this is the only essential difference between male and female voices; however, that is not the case. The fundamental frequency (F0) of male voices typically ranges from 100 to 150 Hz while ranging from 170 to 220 Hz in females. In a 1988 study in which listeners identified the sex of a speaker by voice alone, all individuals identified as male had an average F0 of 160 Hz or less; all identified as female had an average F0 above 160 Hz. Resonance, also known as timbre, is another important voice characteristic. According to Melanie Anne Phillips, resonance is more significant in "gendering" one's voice than pitch. One TS woman who raised her average F0 from 110 Hz to 205 Hz over four months was still frequently identified as male on the telephone, which may have been due to the resonance of her voice. However, Anne Lawrence believes that pitch is a more significant gender cue than resonance. An additional factor is the different size of the average vocal tract of males and females. ## Psychological Like other gendered characteristics, considerable overlap exists between male and female vocal characteristics, especially the psychological ones. Transsexual women who go through puberty as males will usually develop voices characteristic of males. Hormone therapy does not alter a transwoman's voice once it has masculinized therefore, transwomen who intend to pass as females need to have help with vocal training to feminize their voices. Vocal training is done formally with the help of several types of professionals and privately by the use of self-help resources including audio or video tapes programs, books, information garnered from websites or chat groups that shares this particular interest. Some transwomen, such as Lynn Conway have feminized their voices with no assistance. The advantage of going through a speech pathologist instead of many of the other professional that offer training or trying to learn on your own with self-help programs is that vocal cords can easily become irritated and even develop callous-like growths called vocal fold nodules as the result of incorrect use of the voice and from modifying one’s voice too quickly. Individuals who participate in a voice feminization program are trained to self-monitor and become more aware of their vocal quality. They learn to recognize where and how they produce sound, how they are resonating that sound, and how they physically carry themselves and their voice. Related aspects of communication are also addressed including: breathing patterns, gender related non-verbal communication and vocal hygiene. Some transwomen find voice training to be difficult, while others consider it unnecessary. While most transwomen would prefer to have completely feminine voices, many are unable to achieve this goal. Some post-transition transwomen have masculine voices, and many have peculiar female voices that may draw attention. Voice scientists, speech pathologists, language pathologists and ENT physicians (otolaryngology) organize voice production into five components. They are: - Respiration - power source - Phonation - sound source - Resonance - sound modifier - Articulation - speech modifier - Prosody - melodic aspects of speech In training for a feminine voice, all five components are usually included. ### Things that help make a voice feminine - Pitch Feminine voices are higher; this may be the most important concern. - Pitch Range Men tend to be more monotone, varying the pitch helps feminize the voice. - Speech Rate - Men typically speak at a steady rate, while women tend to speak in shorter bursts followed by pauses. - Language patterns - The language that women use differs from that of men, although the degree of variation can be quite different from one language to the next (relative to English, it is extremely pronounced in Japanese, for instance). Tag Questions - Example: "It's a beautiful day, isn't it?" A man, on the other hand, would be more likely to simply declare, "It is a beautiful day." - Tag Questions - Example: "It's a beautiful day, isn't it?" A man, on the other hand, would be more likely to simply declare, "It is a beautiful day." - Supportive environment - As with any skill, speaking with a feminine voice may be easier without the stress of extreme consequences for failure (for example, being identified as a transsexual by someone to whom one is not out.) Additionally, opportunities to use the feminine voice in conversational situations (as opposed to speech-therapeutic ones) may be helpful in polishing the skill. NB: These suggestions are based on literature from language and gender scholarship such as Lakoff (1975) and the work of Deborah Tannen. However, this work has been critiqued heavily for representing only stereotypes of how women speak, rather than how women actually speak, and additionally for representing middle-class white heterosexual women to the exclusion of all others. # Vocal surgeries While hormone replacement therapy and gender reassignment surgery can cause a more feminine outward appearance, they do little to alter the pitch or sound of the voice. The existing vocal structure can be surgically altered using procedures that include - Cricothyroid approximation (CTA) (is the most common) - Laryngoplasty - Thyrohyoid approximation - Laryngeal reduction surgery (surgical shortening of the vocal cords) - Laser assisted voice adjustment (LAVA) While these surgeries exist and can elevate the vocal pitch, there is limited evidence to their overall effectiveness at raising the fundamental frequency over the course of several years. All of these surgeries have little or no effect on resonce or any other vocal characteristic. Many in the transsexual community regard voice surgery as inadvisable. Anecdotal evidence suggests that voice surgery often raises pitch above female norms and that it may result in raspiness, or rarely, complete loss of voice. Deirdre McCloskey is one transwoman who experienced complications from voice surgery.

Vascular surgery Vascular surgery is a subspecialty of general surgery in which diseases of the vascular system, or arteries and veins, are managed, largely via surgical intervention, and was originally founded by Dr. Clyde Otis Hagood Jr. The vascular surgeon is trained in the diagnosis and management of diseases affecting all parts of the vascular system except that of the heart and brain. Cardiothoracic surgeons manage surgical disease of the heart and its vessels. Neurosurgeons manage surgical disease of the vessels in the brain (eg intracranial aneurysms). # Breadth of discipline - Arterial diseases ( especially in Diabetics ) Aneurysms Ischemia Limb ischemia Acute limb ischemia Thrombectomies Embolectomies Anti-coagulation and Thrombolysis Chronic limb ischemia see intermittent claudication and peripheral artery occlusive disease Diabetic foot ulcers Mesenteric ischemia Renal ischemia Extracranial cerebrovascular disease Carotid Endarterectomy and other carotid surgery Surgery of the vertebral system - Aneurysms - Ischemia Limb ischemia Acute limb ischemia Thrombectomies Embolectomies Anti-coagulation and Thrombolysis Chronic limb ischemia see intermittent claudication and peripheral artery occlusive disease Diabetic foot ulcers Mesenteric ischemia Renal ischemia - Limb ischemia Acute limb ischemia Thrombectomies Embolectomies Anti-coagulation and Thrombolysis Chronic limb ischemia see intermittent claudication and peripheral artery occlusive disease Diabetic foot ulcers - Acute limb ischemia Thrombectomies Embolectomies Anti-coagulation and Thrombolysis - Thrombectomies - Embolectomies - Anti-coagulation and Thrombolysis - Chronic limb ischemia see intermittent claudication and peripheral artery occlusive disease Diabetic foot ulcers - see intermittent claudication and peripheral artery occlusive disease - Diabetic foot ulcers - Mesenteric ischemia - Renal ischemia - Extracranial cerebrovascular disease Carotid Endarterectomy and other carotid surgery Surgery of the vertebral system - Carotid Endarterectomy and other carotid surgery - Surgery of the vertebral system - Venous disease Deep Vein Thrombosis Thrombophelebitis Varicose Veins and Varicosities Venous malformations - Deep Vein Thrombosis - Thrombophelebitis - Varicose Veins and Varicosities - Venous malformations - Lymphatic disease Lymphoedema - Lymphoedema - Vascular Medicine Medical disorders with a significant vascular components, for example: Raynaud's syndrome Scleroderma - Medical disorders with a significant vascular components, for example: Raynaud's syndrome Scleroderma - Raynaud's syndrome - Scleroderma # Training Previously considered a field within general surgery, it is now considered a specialty in its own right. As a result, training has been, or is being re-structured from previously having to complete full general surgery training followed by a period of further vascular surgery training, to being trained in vascular surgery alone from start to finish. Programs of training are slightly different depending on the region of the world one is in. # Surgical Procedures By no means exhaustive, but below are a number of common procedures and indications for vascular surgeons.

Buprenorphine Sublingual and Buprenorphine and Naloxone Sublingual (patient information) # Why this medication is prescribed Buprenorphine (Subutex) and buprenorphine and naloxone (Suboxone) are used to treat opioid dependence (addiction to opioid drugs, including heroin and narcotic painkillers). Buprenorphine is in a class of medications called opioid partial agonist-antagonists, and naloxone is in a class of medications called opioid antagonists. Buprenorphine alone and the combination of buprenorphine and naloxone prevent withdrawal symptoms when someone stops taking opioid drugs by producing similar effects to these drugs. # How this medication should be used Buprenorphine and the combination of buprenorphine and naloxone come as sublingual tablets to taken under the tongue. They are usually taken once a day. To help you remember to take buprenorphine or buprenorphine and naloxone, take it 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. Take buprenorphine or buprenorphine and naloxone exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. You will start your treatment with buprenorphine, which you will take in the doctor's office. Your doctor will start you on a low dose of buprenorphine and will increase your dose for several days before switching you to buprenorphine and naloxone. Your doctor may increase or decrease your buprenorphine and naloxone dose until the medication works properly. Place the tablets under your tongue until they melt. This should take 2 to 10 minutes. If you are taking more than two tablets, either place them all under your tongue at the same time or place them under your tongue 2 at a time. Do not chew the tablets or swallow them whole. Do not stop taking buprenorphine and naloxone without talking to your doctor. Stopping buprenorphine and naloxone too quickly can cause withdrawal symptoms. Your doctor will tell you when and how to stop taking buprenorphine and naloxone. # Other uses for this medicine This medication may be prescribed for other uses; ask your doctor or pharmacist for more information. # Special precautions Before taking buprenorphine or buprenorphine and naloxone: - tell your doctor and pharmacist if you are allergic to buprenorphine, naloxone, or any other medications. - do not take antidepressants ('mood elevators'), narcotic pain killers, sedatives, sleeping pills, or tranquilizers while taking buprenorphine or buprenorphine and naloxone. - tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking. Be sure to mention any of the following: acetaminophen (Tylenol, others); antifungals such as fluconazole (Diflucan), itraconazole (Sporanox), and ketoconazole (Nizoral); carbamazepine (Tegretol); cholesterol-lowering medications (statins); cimetidine (Tagamet); clarithromycin (Biaxin); cyclosporine (Neoral, Sandimmune); danazol (Danocrine); delavirdine (Rescriptor); dexamethasone (Decadron); diltiazem (Cardizem, Dilacor, Tiazac); erythromycin (E.E.S., E-Mycin, Erythrocin); ethosuximide (Zarontin);fluoxetine (Prozac, Sarafem); fluvoxamine (Luvox); HIV protease inhibitors such as indinavir (Crixivan), nelfinavir (Viracept), and ritonavir (Norvir); iron products; isoniazid (INH, Nydrazid); medications for anxiety, mental illness, and seizures; methotrexate (Rheumatrex); metronidazole (Flagyl);nefazodone (Serzone); niacin (nicotinic acid); oral contraceptives (birth control pills); phenobarbital (Luminal, Solfoton); phenytoin (Dilantin); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane); troglitazone (Rezulin); troleandomycin (TAO); verapamil (Calan, Covera, Isoptin, Verelan); and zafirlukast (Accolate). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. - tell your doctor if you drink large amounts of alcohol and if you have or have ever had adrenal problems such as Addison's disease; benign prostatic hypertrophy (BPH, enlargement of the prostate gland); difficulty urinating; head injury; hallucinations (seeing things or hearing voices that do not exist); a curve in the spine that makes it hard to breathe; gallbladder disease; stomach conditions; and thyroid, kidney, liver, or lung disease. - tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking buprenorphine or buprenorphine and naloxone, call your doctor. - if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking buprenorphine or buprenorphine and naloxone. - you should know that buprenorphine or buprenorphine and naloxone may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you. - remember that alcohol can add to the breathing difficulties that can be caused by this medication. - you should know that buprenorphine or buprenorphine and naloxone may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start taking buprenorphine or buprenorphine and naloxone. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up. # Special dietary instructions Talk to your doctor about drinking grapefruit juice while taking this medicine. # What to do if you 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 ## Minor Side Effects Buprenorphine or buprenorphine and naloxone may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: - headache - stomach pain - constipation - vomiting - difficulty falling asleep or staying asleep - sweating ## Severe Side Effects Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them, call your doctor immediately: - hives - skin rash - itching - difficulty breathing or swallowing - slowed breathing - upset stomach - extreme tiredness - unusual bleeding or bruising - lack of energy - loss of appetite - pain in the upper right part of the stomach - yellowing of the skin or eyes - flu-like symptoms Buprenorphine or buprenorphine and naloxone may cause other side effects. Call your doctor if you have any unusual problems while taking this medication. 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 . # Storage conditions needed for this medication 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). Buprenorphine or buprenorphine and naloxone can be a target for people who abuse prescription medications or street drugs. Keep your medication in a safe place to protect from theft. 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. Symptoms of overdose may include: - pinpoint pupils - extreme drowsiness - dizziness - blurred vision - slowed breathing # Other information Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to buprenorphine and naloxone. In case of an emergency, you or a family member should tell the treating doctor or emergency room staff that you are taking buprenorphine or buprenorphine and naloxone. Do not inject buprenorphine or buprenorphine and naloxone sublingual tablets. Severe reactions may happen, including withdrawal symptoms. Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription. # Brand names - Suboxone® - Subutex®

Longitudinal studies # Overview A longitudinal study is a correlational research study that involves repeated observations of the same items over long periods of time — often many decades. It is a type of observational study. Longitudinal studies are often used in psychology to study developmental trends across the life span, and in sociology to study life events throughout lifetimes or generations. The reason for this is that unlike cross-sectional studies, longitudinal studies track the same people, and therefore the differences observed in those people are less likely to be the result of cultural differences across generations. Because of this benefit, longitudinal studies make observing changes more accurate and they are applied in various other fields. In medicine, the design is used to uncover predictors of certain diseases. In advertising, the Communicus System, the design is used to identify the changes that advertising has produced in the attitudes and behaviors of those within the target audience who have seen the advertising campaign. Because longitudinal studies are observational, in the sense that they observe the state of the world without manipulating it, it has been argued that they may have less power to detect causal relationships than do experiments. But because of the repeated observation at the individual level, they have more power than cross-sectional observational studies, by virtue of being able to exclude time-invariant unobserved individual differences, and by virtue of observing the temporal order of events. Longitudinal studies allow social scientists to distinguish short from long-term phenomena, such as poverty. If the poverty rate is 10% at a point in time, this may mean that 10% of the population are always poor, or that the whole population experiences poverty for 10% of the time. It is not possible to conclude which of these possibilities is the case using one-off cross-sectional studies. Types of longitudinal studies include cohort studies and panel studies. Cohort studies sample a cohort, defined as a group experiencing some event (typically birth) in a selected time period, and studying them at intervals through time. Panel studies sample a cross-section, and survey it at (usually regular) intervals. A retrospective study is a longitudinal study that looks back in time. For instance a researcher may look up the medical records of previous years to look for a trend. # Examples - Born in Bradford - British Household Panel Survey - Busselton Health Study - Dunedin Longitudinal Study - Framingham Heart Study - German Socio-economic Panel Study - Health and Retirement Study - Household, Income and Labour Dynamics in Australia Survey - Luxembourg Income Study (LIS) - Minnesota Twin Family Study - National Longitudinal Survey of Youth - Panel Study of Belgian Households - Panel Study on Income Dynamics - Seven Up! - Wisconsin Longitudinal Study ## Repeated cross-sectional surveys - General Social Survey - World Values Survey

CRYBB2 Beta-crystallin B2 is a protein that in humans is encoded by the CRYBB2 gene. # Function Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N-terminal and C-terminal extensions. Beta-crystallins, the most heterogeneous, differ by the presence of the C-terminal extension (present in the basic group, none in the acidic group). Beta-crystallins form aggregates of different sizes and are able to self-associate to form dimers or to form heterodimers with other beta-crystallins. This gene, a beta basic group member, is part of a gene cluster with beta-A4, beta-B1, and beta-B3. A chain-terminating mutation was found to cause type 2 cerulean cataracts. # Interactions CRYBB2 has been shown to interact with Hsp27, CRYGC, CRYAA and CRYAB.

Local anesthetic # Overview A local anesthetic is a drug that causes reversible local anesthesia and a loss of nociception. When it is used on specific nerve pathways (nerve block), effects such as analgesia (loss of pain sensation) and paralysis (loss of muscle power) can be achieved. Clinical local anesthetics belong to one of two classes: aminoamide and aminoester local anesthetics. synthetic local anesthetics are structurally related to cocaine. They differ from cocaine mainly in that they have no abuse potential and do not act on the sympathoadrenergic system, i.e. they do not produce hypertension or local vasoconstriction, with the exception of Ropivacaine and Mepivacaine that do produce weak vasoconstriction. Local anesthetics vary in their pharmacological properties and they are used in various techniques of local anesthesia such as: - Topical anesthesia (surface) - Infiltration - Plexus block - Epidural (extradural) block - Spinal anesthesia (subarachnoid block) The local anesthetic lidocaine (lignocaine) is also used as a Class Ib antiarrhythmic drug. # Mechanism of action All local anesthetics are membrane stabilizing drugs; they reversibly decrease the rate of depolarization and repolarization of excitable membranes (like neurons). Though many other drugs also have membrane stabilizing properties, all are not used as local anesthetics, for example propranolol. Local anesthetic drugs act mainly by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell membrane, in particular the so-called voltage-gated sodium channels. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is inhibited. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel. Local anesthetic drugs bind more readily to "open" sodium channels, thus onset of neuronal blockade is faster in neurons that are rapidly firing. This is referred to as state dependent blockade. Local anesthetics are weak bases and are usually formulated as the hydrochloride salt to render them water-soluble. At the chemical's pKa the protonated (ionised) and unprotonated (unionised) forms of the molecule exist in an equilibrium but only the unprotonated molecule diffuses readily across cell membranes. Once inside the cell the local anesthetic will be in equilibrium, with the formation of the protonated (ionised form), which does not readily pass back out of the cell. This is referred to as "ion-trapping". In the protonated form, the molecule binds to the local anaesthetic binding site on the inside of the ion channel near the cytoplasmic end. Acidosis such as caused by inflammation at a wound partly reduces the action of local anesthetics. This is partly because most of the anaesthetic is ionised and therefore unable to cross the cell membrane to reach its cytoplasmic-facing site of action on the sodium channel. All nerve fibres are sensitive to local anesthetics, but generally, those with a smaller diameter tend to be more sensitive than larger fibres. Local anesthetics block conduction in the following order: small myelinated axons (e.g. those carrying nociceptive impulses), non-myelinated axons, then large myelinated axons. Thus, a differential block can be achieved (i.e. pain sensation is blocked more readily than other sensory modalities). # Undesired Effects ## Localized Adverse Effects The local adverse effects of anesthetic agents include neurovascular manifestations such as prolonged anesthesia (numbness) and paresthesia (tingling, feeling of "pins and needles", or strange sensations). These are symptoms of localized nerve impairment or nerve damage. ### Risks The risk of temporary or permanent nerve damage varies between different locations and types of nerve blocks . ### Recovery Permanent nerve damage after a peripheral nerve block is rare. Symptoms are very likely to resolve within a few weeks. The vast majority of those affected (92–97%), recover within four to six weeks. 99% of these people have recovered within a year. It is estimated that between 1 in 5,000 and 1 in 30,000 nerve blocks result in some degree of permanent persistent nerve damage . It is suggested that symptoms may continue to improve for up to 18 months following injury. ### Causes Causes of localized symptoms include: - neurotoxicity due to allergenic reaction, - excessive fluid pressure in a confined space, - severing of nerve fibers or support tissue with the syringe/catheter, - injection-site that puts pressure on the nerve, or - injection-site infection that produces inflammatory pressure on the nerve and/or necrosis. ## General Adverse Effects (See also local anesthetic toxicity) General systemic adverse affects are due to the pharmacological effects of the anesthetic agents used. The conduction of electric impulses follows a similar mechanism in peripheral nerves, the central nervous system, and the heart. The effects of local anesthetics are therefore not specific for the signal conduction in peripheral nerves. Side effects on the central nervous system and the heart may be severe and potentially fatal. However, toxicity usually occurs only at plasma levels which are rarely reached if proper anesthetic techniques are adhered to. Additionally, persons may exhibit allergenic reactions to the anesthetic compounds and may also exhibit cyanosis due to methemoglobinemia. Depending on local tissue concentrations of local anesthetics, there may be excitatory or depressant effects on the central nervous system. At lower concentrations, a relatively selective depression of inhibitory neurons results in cerebral excitation, which may lead to generalized convulsions. A profound depression of brain functions occurs at higher concentrations which may lead to coma, respiratory arrest and death. Such tissue concentrations may be due to very high plasma levels after intravenous injection of a large dose. Another possibility is direct exposure of the central nervous system through the CSF, i.e. overdose in spinal anesthesia or accidental injection into the subarachnoid space in epidural anesthesia. The conductive system of the heart is quite sensitive to the action of local anesthetics. Lidocaine is often used as an antiarrhythmic drug and has been studied extensively, but the effects of other local anesthetics are probably similar to those of Lidocaine. Lidocaine acts by blocking sodium channels, leading to slowed conduction of impulses. This may obviously result in bradycardia, but tachyarrhythmia can also occur. With high plasma levels of lidocaine there may be higher-degree atrioventricular block and severe bradycardia, leading to coma and possibly death. There is evidence that Intralipid, a commonly available intravenous lipid emulsion, can be effective in treating severe cardiotoxicity secondary to local anaesthetic overdose, including human case reports of successful use in this way ('lipid rescue'). Adverse reactions to local anesthetics (especially the esters) are not uncommon, but true allergy is very rare. Allergic reactions to the esters is usually due to a sensitivity to their metabolite, para-aminobenzoic acid (PABA), and does not result in cross-allergy to amides. Therefore, amides can be used as alternatives in those patients. Non-allergic reactions may resemble allergy in their manifestations. In some cases, skin tests and provocative challenge may be necessary to establish a diagnosis of allergy. There are also cases of allergy to paraben derivatives, which are often added as preservatives to local anesthetic solutions. - Allergic reactions during anaesthesia The systemic toxicity of prilocaine is comparatively low, however its metabolite, o-toluidine, is known to cause methemoglobinemia. As methemoglobinemia reduces the amount of hemoglobin that is available for oxygen transport, this side effect is potentially life-threatening. Therefore dose limits for prilocaine should be strictly observed. Prilocaine is not recommended for use in infants. # Local anesthetics in clinical use - Amino esters Benzocaine Chloroprocaine Cocaine Cyclomethycaine Dimethocaine/Larocaine Propoxycaine Procaine/Novocaine Proparacaine Tetracaine/Amethocaine - Benzocaine - Chloroprocaine - Cocaine - Cyclomethycaine - Dimethocaine/Larocaine - Propoxycaine - Procaine/Novocaine - Proparacaine - Tetracaine/Amethocaine - Amino amides Articaine Bupivacaine Carticaine Cinchocaine/Dibucaine Etidocaine Levobupivacaine Lidocaine/Lignocaine Mepivacaine Piperocaine Prilocaine Ropivacaine Trimecaine - Articaine - Bupivacaine - Carticaine - Cinchocaine/Dibucaine - Etidocaine - Levobupivacaine - Lidocaine/Lignocaine - Mepivacaine - Piperocaine - Prilocaine - Ropivacaine - Trimecaine Esters are prone to producing allergic reactions, which may necessitate the use of an Amide. The names of Amides contain an "i" somewhere before the -aine. Esters do not. - Combinations Lidocaine/prilocaine (EMLA) - Lidocaine/prilocaine (EMLA) # Natural local anesthetics - Saxitoxin - Tetrodotoxin Naturally occurring local anesthetics not derived from cocaine are usually neurotoxins, and have the suffix -toxin in their names. Unlike cocaine produced local anesthetics which are intracellular in effect, saxitoxin & tetrodotoxin bind to the extracellular side of sodium channels.

Ipidacrine # Overview Ipidacrine (Neiromidin) is a novel substance synthesized by the National Research Center for Biologically Active Compounds in the Russian Federation. This compound contains the structure of 4-aminopyridine and is structurally very similar to tacrine. Ipidacrine is a reversible acetylcholinesterase inhibitor used in memory disorders of different origins. Ipidacrine directly stimulates impulse transmission in the CNS and neuromuscular synapses by blocking membrane potassium channels. Neiromidin enhances not only choline, but also adrenaline, serotonin, histamine and oxytocin effects on smooth muscle.

Emergent stress testing in young people # Overview Stress testing has frequently been used to assess adult patients with suspected or known coronary artery disease (CAD) based on pre-test probability. Pre-test probability is the assessment of a patient and their likelihood of CAD based on clinical history and symptoms. Stress testing to diagnose myocardial ischemic syndrome is usually indicated only in patients with an intermediate pre-test probability. The average age of a patient who undergoes a stress test is typically between 45-60 years. Increasing age is one of many positive risk factors for CAD. However, there have been several cases in which young adults and adolescents have presented with chest pain and were found to have had a myocardial infarction (MI). Since chest pain can be a complaint among children, the question becomes whether or not an emergent stress test is needed. The most common reason for stress testing is chest pain. All patients who present with acute or chronic chest pain need to be evaluated to determine the course or urgency of further non-invasive vs. invasive testing. Inpatient stress testing can be done if a recent MI or an acute unstable coronary syndrome has been excluded. . Among children presenting with chest pain, the symptoms often tend to be benign. Given the fact that the majority of children have no probable cardiac risk factors, their pre-test probability is already very low. Yet there are several conditions that can cause ischemic chest pain and other cardiac abnormalities so a thorough careful history and physical examination should always be performed. The presenting symptom can be secondary to congenital defects as well as acquired diseases. Kawasaki disease has a common manifestation of coronary artery aneurysms which can progress to coronary stenosis. Acute MI is one of the main causes of death in children with Kawasaki disease. Another acquired condition is sickle cell disease in which children can frequently present with chest pain, have an MI and have normal coronary arteries. Other issues that could cause ischemic chest pain are coronary vasospasm, pericarditis or myocarditis, cocaine use, or other conditions causing anatomic congenital cardiovascular abnormalities. Acute symptoms in children should be dealt with accordingly to rule out an MI, congenital defects or diseases. Based on above indications, an emergent stress test may not be warranted. To help determine the etiology of the symptom, ECG, echocardiogram, MRI, cardiac enzymes, drug screening, blood testing for hypercoagulability and coronary angiograms may be more useful. Or for chronic chest pain associated with exertion, an outpatient stress test could also be helpful. Whether or not stress testing is emergent in children should again be considered similarly to adult emergent stress testing. Comprehensive assessment of acute or chronic problems and the consideration of the child’s pre-test probability being significantly low are compelling points that an emergent stress test may not be necessary.

KvLQT1 Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the KCNQ1 gene. Kv7.1 is a voltage-gated potassium channel present in the cell membranes of cardiac tissue and in inner ear neurons among other tissues. In the cardiac cells, Kv7.1 mediates the IKs (or slow delayed rectifying K+) current that contributes to the repolarization of the cell, terminating the cardiac action potential and thereby the heart's contraction. # Structure KvLQT1 is made of six membrane-spanning domains S1-S6, two intracellular domains, and a pore loop. The KvLQT1 channel is made of four KCNQ1 subunits, which form the actual ion channel. # Function This gene encodes a protein for a voltage-gated potassium channel required for the repolarization phase of the cardiac action potential. The gene product can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. The gene is located in a region of chromosome 11 that contains a large number of contiguous genes that are abnormally imprinted in cancer and the Beckwith-Wiedemann syndrome. Two alternative transcripts encoding distinct isoforms have been described. # Clinical significance Mutations in the gene can lead to a defective protein and several forms of inherited arrhythmias as Long QT syndrome which is a prolongation of the QT interval of heart repolarization, Short QT syndrome, and Familial Atrial Fibrillation. KvLQT1 are also expressed in the pancreas, and KvLQT1 Long QT syndrome patients has been shown to have hyperinsulinemic hypoglycaemia following an oral glucose load. Currents arising from Kv7.1 in over-expression systems have never been recapitulated in native tissues - Kv7.1 is always found in native tissues with a modulatory subunit. In cardiac tissue, these subunits comprise KCNE1 and yotiao. Though physiologically irrelevant, homotetrameric Kv7.1 channels also display a unique form of C-type inactivation that reaches equilibrium quickly, allowing KvLQT1 currents to plateau. This is different from the inactivation seen in A-type currents, which causes rapid current decay. # Ligands - ML277: potent and selective channel activator # Interactions KvLQT1 has been shown to interact with PRKACA, PPP1CA and AKAP9. KvLQT1 can also associate with any of the five members of the KCNE family of proteins, but interactions with KCNE1, KCNE2, KCNE3 are the only interactions within this protein family that affect the human heart. KCNE2, KCNE4, and KCNE5 have been shown to have an inhibitory effect on the functionality of KvLQT1, while KCNE1 and KCNE3 are activators of KvLQT1. KvLQT1 can associate with KCNE1 and KCNE4 with the activation effects of KCNE1 overriding the inhibitory effects of KCNE4 on the KvLQT1 channel, and KvLQT1 will commonly associate with anywhere from two to four different KCNE proteins in order to be functional. However, KvLQT1 most commonly associates with KCNE1 and forms the KvLQT1/KCNE1 complex since it has only been seen to function in vivo when associated with another protein. KCNQ1 will form a heteromer with KCNE1 in order to slow its activation and enhance the current density at the plasma membrane of the neuron. In addition to associating with KCNE proteins, the N-terminal juxtamembranous domain of KvLQT1 can also associate with SGK1, which stimulates the slow delayed potassium rectifier current. Since SGK1 requires structural integrity to stimulate KvLQT1/KCNE1, any mutations present in the KvLQT1 protein can result in reduced stimulation of this channel by SGK1. General mutations in KvLQT1 have been known to cause a decrease in this slow delayed potassium rectifier current, longer cardiac action potentials, and a tendency to have tachyarrhythmias. # KvLQT1/KCNE1 KCNE1 (minK), can assemble with KvLQT1 to form a slow delayed potassium rectifier channel. KCNE1 slows the inactivation of KvLQT1 when the two proteins form a heteromeric complex, and the current amplitude is greatly increased compared to WT-KvLQT1 homotetrameric channels. KCNE1 associates with the pore region of KvLQT1, and its transmembrane domain contributes to the selectivity filter of this heteromeric channel complex. The alpha helix of the KCNE1 protein interacts with the pore domain S5/S6 and with the S4 domain of the KvLQT1 channel. This results in structural modifications of the voltage sensor and the selectivity filter of the KvLQT1 channel. Mutations in either the alpha subunit of this complex, KvLQT1 or the beta subunit, KCNE1, can lead to Long QT Syndrome or other cardiac rhythmic deformities. When associated with KCNE1, the KvLQT1 channel activates much more slowly and at a more positive membrane potential. It is believed that two KCNE1 proteins interact with a tetrameric KvLQT1 channel, since experimental data suggests that there are 4 alpha subunits and 2 beta subunits in this complex. KVLQT1/KCNE1 channels are taken up from the plasma membrane through a RAB5 dependent mechanism, but inserted into the membrane by RAB11, a GTPase.

Argon # Overview Argon (Template:PronEng) is a chemical element designated by the symbol Ar. Argon has atomic number 18 and is the third element in group 18 of the periodic table (noble gases). Argon is present in the Earth's atmosphere at slightly less than 1%, making it the most common noble gas on Earth. Its full outer shell makes argon stable and resistant to bonding with other elements. Its triple point temperature of 83.8058 K is a defining fixed point in the International Temperature Scale of 1990. # Characteristics Argon has approximately the same solubility in water as oxygen gas and is 2.5 times more soluble in water than nitrogen gas. This highly stable chemical element is colorless, odorless, tasteless and nontoxic in both its liquid and gaseous forms. Argon is inert under most conditions and forms no confirmed stable compounds at room temperature. Although argon is a noble gas, it has been found to have the capability of forming some compounds. For example, the creation of argon hydrofluoride (HArF), a metastable compound of argon with fluorine and hydrogen, has been reported by researchers at the University of Helsinki in 2000. Although the neutral ground-state chemical compounds of argon are presently limited to HArF, argon can form clathrates with water when atoms of it are trapped in a lattice of the water molecules. Also argon-containing ions e.g. ArH+ and excited state complexes e.g. ArF are well known. Theoretical calculations on computers have shown several argon compounds that should be stable but for which no synthesis routes are currently known. # History Argon (Greek αργόν meaning "the lazy one," in reference to its chemical inactivity) was suspected to be present in air by Henry Cavendish in 1785 but was not discovered until 1894 by Lord Rayleigh and Sir William Ramsay in an experiment in which they removed all of the oxygen and nitrogen from a sample of air. Argon was also encountered in 1882 through independent research of H.F. Newall and W.N. Hartley. Each observed new lines in the color spectrum of air but were unable to identify the element responsible for the lines. Argon became the first member of the noble gases to be discovered. The symbol for argon is now Ar, but up until 1957 it was A. # Applications There are several different reasons why argon is used in particular applications: - An inert gas is needed. In particular, argon is the cheapest alternative when diatomic nitrogen is not sufficiently inert. - Low thermal conductivity is required. - The electronic properties (ionization and/or the emission spectrum) are necessary. Other noble gases would probably work as well in most of these applications, but argon is by far the cheapest. Argon is inexpensive since it is a byproduct of the production of liquid oxygen and liquid nitrogen, both of which are used on a large industrial scale. The other noble gases (except helium) are produced this way as well, but argon is the most plentiful since it has the highest concentration in the atmosphere. The bulk of argon applications arise simply because it is inert and relatively cheap. Argon is used: - As a fill gas in incandescent lighting, because argon will not react with the filament of light bulbs even at high temperatures. - As an inert gas shield in many forms of welding, including metal inert gas welding and tungsten inert gas welding. - For extinguishing fires where damage to equipment is to be avoided (see photo). - As the gas of choice for the plasma used in ICP spectroscopy - As a non-reactive blanket in the processing of titanium and other reactive elements, - As a protective atmosphere for growing silicon and germanium crystals, and in partial pressure heat treat furnaces. - By museum conservators to protect old materials or documents, which are prone to gradual oxidation in the presence of air. - To keep open bottles of wine from oxidizing, and in a number of dispensing units and keeper cap systems. - In winemaking to top off barrels, displacing oxygen and thus preventing the wine from turning to vinegar during the aging process. - In the pharmaceutical industry to top off bottles of intravenous drug preparations (for example intravenous paracetamol), again displacing oxygen and therefore prolonging the drug's shelf-life. - Used to cool the seeker head of the US Air Force version of the AIM-9 Sidewinder missile. The gas is stored at high pressure, and the expansion of the gas cools the seeker. The next most common reason for using argon is its low thermal conductivity. It is used for thermal insulation in energy efficient windows. Argon is also used in technical scuba diving to inflate a dry suit, because it is inert and has low thermal conductivity. Argon is also used for the specific way it ionizes and emits light. It is used in plasma globes and calorimetry in experimental particle physics. Blue argon lasers are used in surgery to weld arteries, destroy tumors, and to correct eye defects. In microelectronics, argon ions are used for sputtering. Finally, there are a number of miscellaneous uses. Argon-39, with a half life of 269 years, has been used for a number of applications, primarily ice core and ground water dating. The argon-40/potassium-40 ratio is used in dating igneous rocks. Cryosurgery procedures such as cryoablation use liquified argon to destroy cancer cells. In surgery it is used in a procedure called "argon enhanced coagulation" which is a form of argon plasma beam electrosurgery. The procedure carries a risk of producing gas embolism in the patient and has resulted in the death of one person via this type of accident. # Occurrence Argon constitutes 0.934% by volume and 1.29% by mass of the Earth's atmosphere, and air is the primary raw material used by industry to produce purified argon products. Argon is isolated from air by fractionation, most commonly by cryogenic fractional distillation, a process that also produces purified nitrogen, oxygen, neon, krypton and xenon. The Martian atmosphere in contrast contains 1.6% of argon-40 and 5 ppm of argon-36. The Mariner spaceprobe fly-by of the planet Mercury in 1973 found that Mercury has a very thin atmosphere with 70% argon, believed to result from releases of the gas as a decay product from radioactive materials on the planet. In 2005, the Huygens probe also discovered the presence of argon-40 on Titan, the largest moon of Saturn. # Compounds Argon’s complete octet of electrons indicates full s and p subshells. This full outer energy level makes argon very stable and extremely resistant to bonding with other elements. Before 1962, argon and the other noble gases were considered to be chemically inert and unable to form compounds; however, compounds of the heavier noble gases have since been synthesized. In August 2000, the first argon compounds were formed by researchers at the University of Helsinki. By shining ultraviolet light onto frozen argon containing a small amount of hydrogen fluoride, argon hydrofluoride (HArF) was formed. It is stable up to 40 kelvins (−233 °C). The discovery of argon difluoride (ArF2) was announced in 2003. But this is unconfirmed and most probably incorrect. # Isotopes The main isotopes of argon found on Earth are 40Ar (99.6%), 36Ar (0.34%), and 38Ar (0.06%). Naturally occurring 40K with a half-life of 1.25Template:E years, decays to stable 40Ar (11.2%) by electron capture and positron emission, and also to stable 40Ca (88.8%) via beta decay. These properties and ratios are used to determine the age of rocks. In the Earth's atmosphere, 39Ar is made by cosmic ray activity, primarily with 40Ar. In the subsurface environment, it is also produced through neutron capture by 39K or alpha emission by calcium. 37Ar is created from the decay of 40Ca as a result of subsurface nuclear explosions. It has a half-life of 35 days. # Potential hazards Although argon is non-toxic, it does not satisfy the body's need for oxygen and is a simple asphyxiant. People have suffocated by breathing argon by mistake.

Polyhydramnios (patient information) For the WikiDoc page for this topic, click here # Overview Polyhydramnios is the presence of excessive amniotic fluid surrounding the unborn infant. # Considerations - Amniotic fluid is a clear, slightly yellowish liquid that surrounds the unborn baby (fetus) during pregnancy. It is contained in the amniotic sac. - While in the womb, the baby floats in the amniotic fluid. Amniotic fluid surrounds and cushions the infant throughout development. The amount of amniotic fluid is greatest at around 34 weeks into the pregnancy (gestation). - The amniotic fluid constantly moves (circulates) as the baby swallows and "inhales" the fluid, and then releases or "exhales" the fluid through urine. - The amniotic fluid helps: - The developing baby move in the womb, which allows for proper bone growth - The lungs to develop properly - Keep a relatively constant temperature around the baby, protecting from heat loss - Protect the baby from outside injury by cushioning sudden blows or movements # What causes Polyhydramnios? - Polyhydramnios can occur if the fetus does not swallow and absorb amniotic fluid in normal amounts. This can happen due to: - Gastrointestinal disorders, such as duodenal atresia, esophageal atresia, gastroschisis, and diaphragmatic hernia - Brain and nervous system (neurological) problems, such as anencephaly and myotonic dystrophy - A variety of other causes, such as poorly controlled diabetes, achondroplasia, Beckwith-Wiedemann syndrome - Polyhydramnios may also be related to increased fluid production, which occurs with: - Certain fetal lung disorders - Multiple gestation (for example, twins or triplets) - Hydrops fetalis - Sometimes, no specific cause for polyhydramnios is found. # Diagnosis - This condition is discovered during pregnancy. You may have noticed that your belly is getting large very quickly. You doctor or nurse measures the size of your uterus at every visit. - If your uterus is growing faster than expected, or it is larger than normal for your baby's gestational age, the doctor or nurse may: - Have you come back sooner than normal to re-measure - Perform an ultrasound - If the health care provider finds a fetal abnormality (birth defect), you may need an amniocentesis to test for a genetic defect. - Women with polyhydramnios are also more likely to go into labor early. Mild polyhydramnios that shows up in the later part of pregnancy does not often cause serious problems. More severe polyhydramnios may be treated with medications or by having extra fluid removed. - The baby will be delivered in a hospital with specialists who can provide immediate evaluation and treatment. # Where to find medical care for Polyhydramnios? Directions to Hospitals Treating Polyhydramnios # Source

Zinc sulfate # 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 Zinc sulfate is a parenteral mineral- trace mineral that is FDA approved for the prophylaxis of prophylaxis of zinc deficiency. Common adverse reactions include indigestion, nausea, vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Zinc Sulfate Injection, USP is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain plasma levels and to prevent depletion of endogenous stores. - Dosing Information - Zinc Sulfate Injection, USP provides 1 mg zinc/mL. For metabolically stable adults receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day. An additional 2 mg zinc/day is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost, or an additional 17.1 mg zinc/kg of stool or ileostomy output is recommended. Frequent monitoring of zinc blood levels is suggested for patients receiving more than the usual maintenance dosage level of zinc. - For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day is suggested. - Aseptic addition of Zinc Sulfate Injection, USP to the TPN solution under a laminar flow hood is recommended. Zinc is physically compatible with the electrolytes and vitamins usually present in the amino acid/dextrose solution used for TPN. - Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Zinc sulfate in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Zinc sulfate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Zinc sulfate in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Zinc sulfate in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Zinc sulfate in pediatric patients. # Contraindications There is limited information regarding Zinc sulfate Contraindications in the drug label. # Warnings There is limited information regarding Zinc sulfate Warnings' in the drug label. # Adverse Reactions ## Clinical Trials Experience - There is limited information regarding Clinical Trial Experience of Zinc sulfate in the drug label. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Zinc sulfate in the drug label. # Drug Interactions There is limited information regarding Zinc sulfate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zinc sulfate in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Zinc sulfate during labor and delivery. ### Nursing Mothers - There is no FDA guidance on the use of Zinc sulfate with respect to nursing mothers. ### Pediatric Use - There is no FDA guidance on the use of Zinc sulfate with respect to pediatric patients. ### Geriatic Use - There is no FDA guidance on the use of Zinc sulfate with respect to geriatric patients. ### Gender - There is no FDA guidance on the use of Zinc sulfate with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Zinc sulfate with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Zinc sulfate in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Zinc sulfate in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Zinc sulfate in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Zinc sulfate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Zinc Sulfate Injection, USP provides 1 mg zinc/mL. For metabolically stable adults receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day. An additional 2 mg zinc/day is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost, or an additional 17.1 mg zinc/kg of stool or ileostomy output is recommended. Frequent monitoring of zinc blood levels is suggested for patients receiving more than the usual maintenance dosage level of zinc. - For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day is suggested. - Aseptic addition of Zinc Sulfate Injection, USP to the TPN solution under a laminar flow hood is recommended. Zinc is physically compatible with the electrolytes and vitamins usually present in the amino acid/dextrose solution used for TPN. - Parenteral drug products should be inspected visually for particulate matter and discoloration, whenever solution and container permit. ### Monitoring - There is limited information regarding Monitoring of Zinc sulfate in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Zinc sulfate in the drug label. # Overdosage - Symptoms of zinc overdosage resulting from oral ingestion of zinc sulfate in large amounts (30 and 44 grams, respectively) have resulted in death. Symptoms include nausea, vomiting, dehydration, electrolyte imbalances, dizziness, abdominal pain, lethargy and incoordination. Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. Normal plasma levels for zinc vary from approximately 88 to 112 mcg/100 mL. Plasma levels sufficient to produce symptoms of toxic manifestations in humans are not known. Calcium supplements may confer a protective effect against zinc toxicity. # Pharmacology ## Mechanism of Action - Zinc has been identified as a cofactor for over 70 different enzymes, including alkaline phosphatase, lactic dehydrogenase and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration and the senses of taste and smell. - Providing zinc during TPN prevents development of the following deficiency symptoms: Parakeratosis, hypogeusia, anorexia, dysosmia, geophagia, hypogonadism, growth retardation and hepatosplenomegaly. At plasma levels below 20 mcg zinc/100 mL, dermatitis followed by alopecia has been reported for TPN patients. ## Structure - Zinc Sulfate Injection, USP is a sterile, nonpyrogenic solution intended for use as an additive to solutions for Total Parenteral Nutrition (TPN). Each mL contains Zinc Sulfate (Anhydrous) 2.46 mg, Water for Injection q.s. pH adjusted with Sulfuric Acid. It contains no preservatives. Discard any unused portion. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Zinc sulfate in the drug label. ## Pharmacokinetics - There is limited information regarding Pharmacokinetics of Zinc sulfate in the drug label. ## Nonclinical Toxicology - There is limited information regarding Nonclinical Toxicology of Zinc sulfate in the drug label. # Clinical Studies - There is limited information regarding Clinical Studies of Zinc sulfate in the drug label. # How Supplied - Zinc Sulfate Injection, USP 1 mg/mL - NDC 0517-6110-25- 10 mL SDV- packed in a box of 25 ## Storage - Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - There is limited information regarding Patient Counseling Information of Zinc sulfate in the drug label. # Precautions with Alcohol - Alcohol-Zinc sulfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names M2 Zinc 50, Zn Plus Protein. # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price

Dust cell A dust cell (or alveolar macrophage) is a type of macrophage found in the pulmonary alveolus, near the pneumocytes, but separated from the wall. Activity of the dust cells is relatively high, because they are located at one of the major boundaries between the body and the outside world. Dust cells are another name for monocyte derivatives in the lungs that reside on respiratory surfaces and clean off particles such as dust or microorganisms. Dust cells are frequently seen to contain granules of inorganic material such as carbon that they have picked up from respiratory surfaces. Such black granules may be especially common in smoker's lungs or long-term city dwellers.

Moyamoya disease overview Please help WikiDoc by adding content here. It's easy! Click here to learn about editing. # Overview Moyamoya syndrome is a disease in which certain arteries in the brain are constricted. Blood flow is blocked by the constriction, and also by blood clots (thrombosis).The blood vessels develop collateral circulation around the blocked vessels to compensate for the blockage, but the collateral vessels are small, weak, and prone to hemorrhage, aneurysm and thrombosis. On X-rays, these collateral vessels have the appearance of a "puff of smoke" ("もやもや (moyamoya)" in Japanese). The disease causes constrictions primarily in the internal carotid artery, which travels from the neck up inside the skull just under the brain in the cavernous sinus. At the Circle of Willis, the internal carotid artery flows into the middle cerebral artery, which continues into the brain, and the anterior cerebral artery, which is part of the Circle of Willis. Moyamoya disease often extends to the middle and anterior cerebral arteries. When the internal carotid artery becomes completely blocked, the fine collateral circulation that it supplies is obliterated. Patients often survive on the collateral circulation from the back (posterior) of the Circle of Willis, from the basilar artery. # Causes The condition is believed to be hereditary and linked to q25.3, on chromosome 17. Moyamoya can be either congenital or acquired. Patients with Down syndrome, neurofibromatosis, or sickle cell disease can develop moyamoya malformations. It is more common in women than in men, although about a third of those affected are male. Brain radiation therapy in children with neurofibromatosis increases the risk of its development. # Risk Factors Women have a higher risk of recurrent stroke and may be experiencing a distinct underlying pathophysiology compared to patients from Japan. # CT The diagnosis is initially suggested by CT, MRI, or angiogram. In fact, the name derives from its angiographic image; the "puff of smoke," which is how moyamoya loosely translates from Japanese, refers to the appearance of multiple compensatorily dilated striate vessels seen on angiography. Contrast-enhanced T1-weighted images are better than FLAIR images for depicting the leptomeningeal ivy sign in moyamoya disease. # MRI MRI and MRA should be performed for the diagnosis and follow-up of moyamoya disease. Diffusion-weighted imaging can also be used for following the clinical course of children with moyamoya disease, in whom new focal deficits are highly suspicious of new infarcts. # Other Imaging Findings Often nuclear medicine studies such as SPECT (single photon emission computerized tomography) are used to demonstrate the decreased blood and oxygen supply to areas of the brain involved with moyamoya disease. Conventional angiography provided the conclusive diagnosis of moyamoya disease in most cases and should be performed before any surgical considerations. # Treatment ## Medical Therapy Drugs such as antiplatelet agents (e.g., aspirin) are usually given to prevent clots, but surgery is usually recommended. Since moyamoya tends to affect only the internal carotid artery and nearby sections of the adjacent anterior and middle cerebral arteries, surgeons can direct other arteries, such as the external carotid artery or the superficial temporal artery to replace its circulation. The arteries are either sewn directly into the brain circulation, or placed on the surface of the brain to reestablish new circulation after a few weeks. Although there is a 4% risk of stroke soon (30 days) after surgery, there is a 96% probability of remaining stroke-free over the next 5 years.

Isotopes of nickel Naturally occurring nickel (Ni) is composed of 5 stable isotopes; 58Ni, 60Ni, 61Ni, 62Ni and 64Ni with 58Ni being the most abundant (68.077% natural abundance). 18 radioisotopes have been characterised with the most stable being 59Ni with a half-life of 76,000 years, 63Ni with a half-life of 100.1 years, and 56Ni with a half-life of 6.077 days. All of the remaining radioactive isotopes have half-lives that are less than 60 hours and the majority of these have half-lives that are less than 30 seconds. This element also has 1 meta state. Nickel-56 is produced in large quantities in type Ia supernovae and the shape of the light curve of these supernovae corresponds to the decay of nickel-56 to cobalt-56 and then to iron-56. Nickel-59 is a long-lived cosmogenic radionuclide with a half-life of 76,000 years. 59Ni has found many applications in isotope geology. 59Ni has been used to date the terrestrial age of meteorites and to determine abundances of extraterrestrial dust in ice and sediment. Nickel-60 is the daughter product of the extinct radionuclide 60Fe (half-life = 1.5 Myr). Because the extinct radionuclide 60Fe had such a long half-life, its persistence in materials in the solar system at high enough concentrations may have generated observable variations in the isotopic composition of 60Ni. Therefore, the abundance of 60Ni present in extraterrestrial material may provide insight into the origin of the solar system and its early history. Nickel-62 has the highest binding energy per nucleon of any isotope for any element. Isotopes heavier than 62Ni cannot be formed by nuclear fusion without losing energy. Nickel-48, discovered in 1999, is the most proton-rich nickel isotope known . With 28 protons and 20 neutrons 48Ni is "doubly magic" (like 208Pb) and therefore unusually stable The isotopes of nickel range in atomic weight from 48 u (48-Ni) to 78 u (78-Ni). Nickel-78's half-life was recently measured to be 110 milliseconds and is believed to be an important isotope involved in supernova nucleosynthesis of elements heavier than iron. Standard atomic mass: 58.6934(2) u # Table ## Notes - Values marked # are not purely derived from experimental data, but at least partly from systematic trends. Spins with weak assignment arguments are enclosed in parentheses. - Uncertainties are given in concise form in parentheses after the corresponding last digits. Uncertainty values denote one standard deviation, except isotopic composition and standard atomic mass from IUPAC which use expanded uncertainties.

Cromolyn (nasal) # 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 Cromolyn (nasal) is a mast cell stabilizer that is FDA approved for the treatment of nasal symptoms due to hay fever and nasal allergies. Common adverse reactions include stinging, nosebleeds, and sores in the nose. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - To prevent and relieve nasal symptoms of hay fever and other nasal allergies: - Runny/itchy nose - sneezing - allergic stuffy nose ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cromolyn (nasal) in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non-Guideline-Supported Use of Cromolyn (nasal) in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Cromolyn (nasal) in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cromolyn (nasal) in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cromolyn (nasal) in pediatric patients. # Contraindications There is limited information regarding Contraindications of Cromolyn (nasal) in pediatric patients. # Warnings Do not use - If you are allergic to any of the ingredients Ask a doctor before use if you have - Fever - Discolored nasal discharge - Sinus pain - Wheezing When using this product - It may take several days of use to notice an effect. Your best effect may not be seen for 1 to 2 weeks. - Brief stinging or sneezing may occur right after use - Do not use it to treat sinus infection, asthma, or cold symptoms - Do not share this bottle with anyone else as this may spread germs Stop use and ask a doctor if - Shortness of breath, wheezing, or chest tightness occurs - Hives or swelling of the mouth or throat occurs - Your symptoms worsen - You have new symptoms - Your symptoms do not begin to improve within two weeks - You need to use for more than 12 weeks If pregnant or breast-feeding - Ask a health professional before use. Keep out of reach of children. - If swallowed, get medical help or contact a Poison Control Center right away. (1-800-222-1222) # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Cromolyn (nasal) in the drug label. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Cromolyn (nasal) in the drug label. # Drug Interactions There is limited information regarding Drug Interactions of Cromolyn (nasal) in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Cromolyn (nasal) in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cromolyn (nasal) in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cromolyn (nasal) during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Cromolyn (nasal) with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Cromolyn (nasal) with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Cromolyn (nasal) with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Cromolyn (nasal) with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cromolyn (nasal) with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Cromolyn (nasal) in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Cromolyn (nasal) in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cromolyn (nasal) in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cromolyn (nasal) in patients who are immunocompromised. # Administration and Monitoring ### Administration - Nasal ### Monitoring There is limited information regarding Monitoring of Cromolyn (nasal) in the drug label # IV Compatibility There is limited information regarding IV Compatibility of Cromolyn (nasal) in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Cromolyn (nasal) in the drug label. # Pharmacology ## Mechanism of Action There is limited information regarding Mechanism of action of Cromolyn (nasal) in the drug label. ## Structure There is limited information regarding Structure of Cromolyn (nasal) in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Cromolyn (nasal) in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Cromolyn (nasal) in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Cromolyn (nasal) in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Cromolyn (nasal) in the drug label. # How Supplied There is limited information regarding Cromolyn (nasal) How Supplied in the drug label. ## Storage There is limited information regarding Cromolyn (nasal) Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Cromolyn (nasal) in the drug label. # Precautions with Alcohol - Alcohol-Cromolyn (nasal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - NASALCROM® # Look-Alike Drug Names There is limited information regarding Cromolyn (nasal) Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price

Water softening A water softener reduces the dissolved calcium, magnesium, and to some degree manganese and ferrous iron ion concentration in hard water. (A common water softener is sodium carbonate; formula Template:SodiumTemplate:Carbonate.) These "hardness ions" cause three major kinds of undesired effects. Most visibly, metal ions react with soaps and calcium-sensitive detergents, hindering their ability to lather and forming a precipitate—the familiar "bathtub ring". Presence of "hardness ions" also inhibits the cleaning effect of detergent formulations. Second, calcium and magnesium carbonates tend to precipitate out as hard deposits to the surfaces of pipes and heat exchanger surfaces. This is principally caused by thermal decomposition of bi-carbonate ions but also happens to some extent even in the absence of such ions. The resulting build-up of scale can restrict water flow in pipes. In boilers, the deposits act as an insulation that impairs the flow of heat into water, reducing the heating efficiency and allowing the metal boiler components to overheat. In a pressurized system, this can lead to failure of the boiler. Third, the presence of ions in an electrolyte, in this case, hard water, can also lead to galvanic corrosion, in which one metal will preferentially corrode when in contact with another type of metal, when both are in contact with an electrolyte. However the sodium (or potassium) ions released during conventional water softening are much more electrolytically active than the calcium or magnesium ions that they replace and galvanic corrosion would be expected to be substantially increased by water softening and not decreased. Similarly if any lead plumbing is in use, softened water is likely to be substantially more plumbo-solvent than hard water. # Ion-exchange resin devices Conventional water-softening devices intended for household use depend on an ion-exchange resin in which "hardness" ions trade places with sodium ions that are electrostatically bound to the anionic functional groups of the polymeric resin. A class of minerals called zeolites also exhibits ion-exchange properties; these minerals were widely used in earlier water softeners. Water softeners may be desirable when the source of water is a well, whether municipal or private. ## How it works The water to be treated passes through a bed of the resin. Negatively-charged resins absorb and bind metal ions, which are positively charged. The resins initially contain univalent hydrogen, sodium or potassium ions, which exchange with divalent calcium and magnesium ions in the water. As the water passes through the resin column, the hardness ions replace the hydrogen, sodium or potassium ions which are released into the water. The "harder" the water, the more hydrogen, sodium or potassium ions are released from the resin and into the water. Resins are also available to remove carbonate, bi-carbonate and sulphate ions which are absorbed and hydroxyl ions released from the resin. Both types of resin may be provided in a single water softener. ## Regeneration As these resins become loaded with undesirable cations and anions they gradually lose their effectiveness and must be regenerated. If a cationic resin is used (to remove calcium and magnesium ions) then regeneration is usually effected by passing a concentrated brine, usually of sodium chloride or potassium chloride, or hydrochloric acid solution through them. For anionic resins a solution of sodium or potassium hydroxide (lye) is used. Most of the salts used for regeneration gets flushed out of the system and may be released into the soil or sewer. These processes can be damaging to the environment, especially in arid regions. Some jurisdictions prohibit such release and require users to dispose of the spent brine at an approved site or to use a commercial service company. Most water softener manufacturers provide metered control valves to minimize the frequency of regeneration. It is also possible on most units to adjust the amount of reagent used for each regeneration. Both of these steps are recommended to minimize the impact of water softeners on the environment and conserve on reagent use. Using acid to regenerate lowers the pH of the regeneration waste. In industrial scale water softening plants, the effluent flow from re-generation process can be very significant. Under certain conditions, such as when the effluent is discharged in admixture with domestic sewage, the calcium and magnesium salts may precipitate out as hardness scale on the inside of the discharge pipe. This can build up to such an extent so as to block the pipe as happened to a major chlor-alkali plant on the south Wales coast in the 1980s. If potassium chloride is used the same exchange process takes place except that potassium is exchanged for the calcium, magnesium and iron instead of sodium. This is a more expensive option and may be unsuited for people on potassium-restricted diets. # Effects of sodium For people on a low-sodium diet, the increase in sodium levels (for systems releasing sodium) in the water can be significant, especially when treating very hard water. A paper by Kansas State University gives an example: "A person who drinks two litres (2L) of softened, extremely hard water (assume 30 gpg) will consume about 480 mg more sodium (2L x 30 gpg x 8 mg/L/gpg = 480 mg), than if unsoftened water is consumed." This is a significant amount, as they state: "The American Heart Association (AHA) suggests that the 3 percent of the population who must follow a severe, salt-restricted diet should not consume more than 400 mg of sodium a day. AHA suggests that no more than 10 percent of this sodium intake should come from water. The EPA’s draft guideline of 20 mg/L for water protects people who are most susceptible." Most people who are concerned with the added sodium in the water generally have one tap (US: faucet) in the house that bypasses the softener, or have a reverse osmosis unit installed for the drinking water and cooking water, which was designed for desalinisation of sea water. # Chelating agents Chelators are used in chemical analysis, as water softeners, and are ingredients in many commercial products such as shampoos and food preservatives. Citric acid is used to soften water in soaps and laundry detergents. A commonly used synthetic chelator is EDTA.

Battered person syndrome # Overview Battered person syndrome is a physical and psychological condition that is classified as ICD-9 code 995.81 "Battered person syndrome" NEC or otherwise included within DSM-IV as a sub-category of post-traumatic stress disorder. This condition has been used as a defense by women who have experienced long-term physical and psychological abuse, and have killed their abusers. This was called battered woman syndrome by Lenore Walker (1979). # Symptomology ICD9 code 995.81 shows the syndrome as including "battered person/man/spouse syndrome NEC" and any person presenting with identified physical descriptors rather than psychological descriptors falls under the general heading of "Adult physical abuse", classified under "Injury and Poisoning" . In lay terms, this is a reference to any person who, because of constant and severe domestic violence usually involving physical abuse by a partner, becomes depressed and unable to take any independent action that would allow him or her to escape the abuse. The condition explains why abused people often do not seek assistance from others, fight their abuser, or leave the abusive situation. Sufferers have low self-esteem, and often believe that the abuse is their fault. Such persons usually refuse to press criminal charges against their abuser, and refuse all offers of help, often becoming aggressive or abusive to others who attempt to offer assistance. Often sufferers will even seek out their very abuser for comfort shortly after an incident of abuse. # Law and medicine intersection Although the medical condition is not gender specific, the law has been persuaded to remedy perceived gender bias in the operation of the defense of self-defense by admitting evidence of the medical condition as the basis of an excuse (the "battered woman defense") for women who use excessive violence to escape from an abusive relationship and kill their abusers. This has been problematic because there is no consensus in the medical profession that such abuse results in a mental conditions severe enough to excuse alleged offenders. Nevertheless, the law makes reference to DSM-IV mental disorders even though neither the ICD nor the DSM medical classifications as currently drafted, include the syndrome in the sense used by lawyers. # Notes

Constant visual observation # Overview Constant visual observation, often abbreviated to "constant visual", is a term used in various mental health services, prisons and special schools to describe the status of a prisoner or patient who poses a threat to himself or a third party, and must therefore be kept under constant observation. There are essentially two levels of constant visual observations. The highest level, employed only for those patients who are considered to be extremely high risk to either themselves or a third party, involves a care worker remaining within arms reach of the service user at all times. The second level involves only maintaining a constant watch on a patient, sometimes from a distance. Constant visual observations have been criticised by many service user groups.

Cat eye syndrome # Overview Cat Eye Syndrome is a very rare malformation involving Chromosome 22. The short arm (p) and a small section of the long arm (q) are present three (trisomic) or four times (tetrasomic) instead of the usual two times. The additional chromosome 22 usually arises spontaneously (de novo), though it has been reported to have been passed down in families, and some reports show the parents as mosaic for the marker chromosome but who show no phenotypic (outer) symptoms of the syndrome. The chromosomal area included in the Cat Eye Syndrome "critical region" is 22pter-->q11. # History The first association of the common abnormalities common to CES was established over 100 years ago (1898) by Haab, and first described in association with a small marker chromosome in 1965 by Schachenmann. A first report of a familial trisomy 22 pter-->q11happened in 1972 by Bühler et al. Early reports of Cat Eye Syndrome discuss the possibility of chromosome 13 involvement. Now, CES is considered to be present with the chromosome 22 trisomy findings. # Genetics 22q11.2 is a very unstable region of chromosome 22, which is involved in other syndromes, such as 22q11 deletion (a microdeletion of that area of the chromosome) and supernumerary der(22) syndrome, also known as trisomy 22 or partial trisomy 11/22. # Presentation The most common association of symptoms include coloboma of the iris, renal abnormalities, and imperforate anus. Life expectancy is not significantly reduced in those patients who do not present with life threatening abnormalities. The term "Cat Eye" syndrome was coined due to the particular appearance of the vertical colobomas in the eyes of some patients. However, over 1/2 of the CES patients in the literature do not display this trait. # Characteristics - Anal atresia (abnormal obstruction of the anus) - Unilateral or bilateral iris coloboma (absence of tissue from the colored part of the eyes) - Palpebral fissures (downward slanting openings between the upper and lower eyelids) - Preauricular pits/tags (small depressions/growths of skin on the outer ears) - Cardiac defects - Kidney problems (missing, extra, or underdeveloped kidneys) - Short stature - Scoliosis/Skeletal problems - Mental retardation -- although most are borderline normal to mildly retarded, and a few even have normal intelligence, CES patients occasionally exhibit moderate to severe retardation. - Micrognathia (smaller jaw) - Hernias - Cleft palate - Rarer malformations can affect almost any organ

Direct pathway of movement The striatum modulates movement by two pathways: a direct pathway and an indirect pathway. In the direct pathway, striatal neurons directly inhibit neurons in the globus pallidus internus, which reduces the inhibition of the thalamic neurons responsible for excitation of the premotor cortex. Thus, the direct pathway facilitates movement, and anything inhibiting it (e.g. Parkinson's disease) causes akinesia.

ZP4 Zona pellucida sperm-binding protein 4, ZP-4 or avilesine, named after its discoverer Manuel Avilés Sánchezis a protein that in humans is encoded by the ZP4 gene. # Function The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The nascent protein contains a N-terminal signal peptide sequence, a conserved zona pellucida-like domain, a consensus furin cleavage site, and a C-terminal transmembrane domain. It is hypothesized that furin cleavage results in release of the mature protein from the plasma membrane for subsequent incorporation into the zona pellucida matrix. However, the requirement for furin cleavage in this process remains controversial based on mouse studies. Previously, this gene has been referred to as ZP1 or ZPB and thought to have similar functions as mouse Zp1. However, a human gene with higher similarity and chromosomal synteny to mouse Zp1 has been assigned the symbol ZP1 and this gene has been assigned the symbol ZP4.

Practice Guidelines for the Management of Community-Acquired Pneumonia in Adults Executive Summary signs, and normal mental status. In step 2, patients not assigned to risk class I are stratified in classes II-V on the basis of points assigned for 3 demographic variables (age, sex, and nursing home residency), 5 comorbid conditions (summarized above), 5 physical examination findings, and 7 laboratory and/or radiographic findings. Patients in risk classes I and II do not usually require hospitalization, those in risk class III may require brief hospitalization, and those in risk classes IV and V usually require hospitalization. It should be noted that social factors, such as outpatient support mechanisms and probability of adherence, are not included in this assessment. Laboratory tests. All patients thought to have pneumonia should undergo chest radiography. The following laboratory values should be determined for patients who are hospitalized: complete blood cell count and differential, serum creatinine, blood urea nitrogen, glucose, electrolytes, and liver function tests. HIV serology with informed consent should be considered, especially for persons aged 15-54 years. Oxygen saturation should be assessed. There should be 2 pretreatment blood cultures, as well as Gram staining and culture of expectorated sputum. Selected patients should have microbiological studies for tuberculosis and legionella infection. The preferred tests for detection of Legionella species are the urinary antigen assay for Legionella pneumophila serogroup 1 and culture with selective media. The rationale for performing microbiological studies to establish an etiologic diagnosis is based on attempts to improve care of the individual patient with pathogen-specific treatment; to improve care of other patients and to advance knowledge by detecting epidemiologically important organisms (Legionella, penicillin-resistant Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus); to implement contacttracing and antimicrobial prophylaxis in appropriate settings (such as cases of Neisseria meningitidis infection, Haemophilus influenzae type B infection, and tuberculosis); to prevent antibiotic abuse; and to reduce antibiotic expense. Antimicrobial therapy. Recommendations are provided for pathogen-specific treatment in cases in which an etiologic diagnosis is established or strongly suspected. If this information is not available initially but is subsequently reported, changing to the antimicrobial agent that is most cost-effective, least toxic, and most narrow in spectrum is encouraged. Recommendations for treating patients who require empirical antibiotic selection are based on severity of illness, pathogen probabilities, resistance patterns of S. pneumoniae (the most commonly implicated etiologic agent), and comorbid conditions. The recommendation for outpatients is administration of a macrolide, doxycycline, or fluoroquinolone with enhanced activity against S. pneumoniae. For patients who are hospitalized, the recommendation is administration of a fluoroquinolone alone or an extended-spectrum cephalosporin (cefotaxime or ceftriaxone) plus a macrolide. Patients hospitalized in the intensive care unit (ICU) should receive ceftriaxone, cefotaxime, ampicillin-sulbactam, or piperacillin-tazobactam in combination with a fluoroquinolone or macrolide. b-lactams, other than those noted, are not recommended. Intravenous antibiotics may be switched to oral agents when the patient is improving clinically, is hemodynamically stable, and is able to ingest drugs. Most patients show a clinical response within 3-5 days. Changes evident on chest radiographs usually lag behind the clinical response, and repeated chest radiography is generally not indicated for patients who respond. The failure to respond usually indicates an incorrect diagnosis; host failure; inappropriate antibiotic; inappropriate dose or route of administration; unusual or unanticipated pathogen; adverse drug reaction; or complication, such as pulmonary superinfection or empyema. Prognosis. The most frequent causes of lethal communityacquired pneumonia are S. pneumoniae and Legionella. The most frequent reason for failure to respond is progression of pathophysiological changes, despite appropriate antibiotic treatment. Pneumococcal pneumonia. S. pneumoniae, the most common identifiable etiologic agent of pneumonia in virtually all studies, accounts for about two-thirds of bacteremic pneumonia cases, and pneumococci are the most frequent cause of lethal community-acquired pneumonia. Management has been complicated in recent years by the evolution of multidrug resistance. b-lactams (amoxicillin, cefotaxime, and ceftriaxone) are generally regarded as the drugs of choice, although pneumonia caused by resistant strains (MIC, у2 mg/mL) may not respond as readily as pneumonia caused by more susceptible strains. The activity of macrolides and doxycycline or other b-lactams, including cefuroxime, is good against penicillin-susceptible strains but less predictable with strains that show reduced penicillin-susceptibility. Vancomycin, linezolid, and quinupristin/ dalfopristin are the only drugs with predictable in vitro activity. Fluoroquinolones are generally active against strains that are susceptible or resistant to penicillin, but recent reports indicate increasing resistance in selective locations that correlate with excessive fluoroquinolone use. Prevention. The major preventive measures are use of influenza vaccine and use of pneumococcal vaccine, according to guidelines of the Advisory Council on Immunization Practices of the Centers for Disease Control and Prevention (CDC). Performance indicators. Recommendations for performance indicators include the collection of blood culture specimens before antibiotic treatment and the institution of antibiotic treatment within 8 h of hospitalization, since both are supported on the basis of evidence-based trials. Additional performance indicators recommended are laboratory tests for Legionella in patients hospitalized in the ICU, demonstration of an infiltrate on chest radiographs of patients with an ICD-9 (International Classification of Diseases, 9th edition) code for pneumonia, and measurement of blood gases or pulse oximetry within 24 h of admission. # Introduction Lower respiratory tract infections are the major cause of death in the world and the major cause of death due to infectious diseases in the United States. Recent advances in the field include the identification of new pathogens (Chlamydia pneumoniae and hantavirus), new methods of microbial detection (PCR), and new antimicrobial agents (macrolides, b-lactam agents, fluoroquinolones, oxazolidinones, and streptogramins). Despite extensive studies, there are few conditions in medicine that are so controversial in terms of management. Guidelines for management were published in 1993 by the American Thoracic Society [bib_ref] Guidelines for the initial empiric therapy of community-acquired pneumonia: proceedings of an, Niederman [/bib_ref] , the British Thoracic Society [bib_ref] Guidelines for the management of communityacquired pneumonia in adults admitted to hospital, British Thoracic Society [/bib_ref] , and the Canadian Infectious Disease Society [bib_ref] Antimicrobial treatment of communityacquired pneumonia in adults: a conference report. Canadian Community-Acquired..., Mandell [/bib_ref] , as well as the Infectious Diseases Society of America (IDSA) in 1998 [bib_ref] Community-acquired pneumonia in adults: guidelines for management. Infectious Diseases Society of America, Bartlett [/bib_ref]. The present guidelines represent revised recommendations of the IDSA. Compared with previous guidelines, these guidelines are intended to reflect updated information, provide more extensive recommendations in selected areas, and indicate an evolution of opinion. These therapeutic guidelines are restricted to community-acquired pneumonia (CAP) in immunocompetent adults. Recommendations are given alphabetical ranking to reflect their strength and a Roman numeral ranking to reflect the quality of supporting evidence [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref]. This is customary for quality standards from the IDSA [bib_ref] Purpose of quality standards for infectious diseases, Gross [/bib_ref]. It should be acknowledged that no set of standards can be constructed to deal with the multitude of variables that influence decisions regarding site of care, diagnostic evaluation, and selection of antibiotics. Thus, these standards should not supplant good clinical judgement. ## Epidemiology Magnitude CAP is commonly defined as an acute infection of the pulmonary parenchyma that is associated with at least some symptoms of acute infection, accompanied by the presence of an acute infiltrate on a chest radiograph or auscultatory findings consistent with pneumonia (such as altered breath sounds and/ Moderate evidence to support a recommendation for use C Poor evidence to support a recommendation D Moderate evidence to support a recommendation against use E Good evidence to support a recommendation against use Quality of evidence I Evidence from at least 1 randomized, controlled trial II Evidence from at least 1 well-designed clinical trial without randomization III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees or localized rales), in a patient not hospitalized or residing in a long-term-care facility for у14 days before onset of symptoms. Symptoms of acute lower respiratory infection may include several (in most studies, at least 2) of the following: fever or hypothermia, rigors, sweats, new cough with or without sputum production or change in color of respiratory secretions in a patient with chronic cough, chest discomfort, or the onset of dyspnea. Most patients also have nonspecific symptoms, such as fatigue, myalgias, abdominal pain, anorexia, and headache. Pneumonia is the sixth most common cause of death in the United States. From 1979 through 1994, the overall rates of death due to pneumonia and influenza increased by 59% (on the basis of ICD-9 codes on death certificates) in the United States [bib_ref] Trends in infectious diseases mortality in the United States, Pinner [/bib_ref]. Much of this increase is due to a greater proportion of persons aged у65 years; however, age-adjusted rates also increased by 22%, which suggests that other factors may have contributed to a changing epidemiology of pneumonia, including a greater proportion of the population with underlying medical conditions at increased risk of respiratory infection. Annually, 2-3 million cases of CAP result in ∼10 million physician visits, 500,000 hospitalizations, and 45,000 deaths in the United States [bib_ref] Incidence of community-acquired pneumonia requiring hospitalizations: results of a population-based active surveillance..., Marston [/bib_ref]. The incidence of CAP that requires hospitalization is estimated to be 258 persons per 100,000 population and 962 per 100,000 persons aged у65 years [bib_ref] Incidence of community-acquired pneumonia requiring hospitalizations: results of a population-based active surveillance..., Marston [/bib_ref]. Although mortality has ranged from 2% to 30% among hospitalized patients in a variety of studies, the average is ∼14% [bib_ref] Prognosis and outcomes of patients with community-acquired pneumonia, Fine [/bib_ref]. Mortality is estimated to be !1% for patients not hospitalized [bib_ref] Prognosis and outcomes of patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref]. The incidence of CAP is heavily weighted toward the winter months. ## Prognosis, risk stratification, and the initial site-of-treatment decision Knowledge about the prognosis of a disease allows physicians to inform their patients about the expected natural history of an illness, the likelihood of potential complications, and the probability of successful treatment. Understanding the prognosis of CAP is of particular clinical relevance, since it ranges from rapid recovery from symptoms without functional impairment to serious morbid complications and death. The abil-ity to accurately predict medical outcomes in cases of CAP has a major impact on management. The decision to hospitalize a patient or to treat him or her as an outpatient (figure 1) is perhaps the single most important clinical decision made by physicians during the entire course of illness, which has direct bearing on the location and intensity of laboratory evaluation, antibiotic therapy, and costs. The estimated total treatment cost for an episode of CAP managed in the hospital is $7500 (US dollars) [bib_ref] The cost of treating patients with communityacquired pneumonia, Lave [/bib_ref] , 120-fold higher than the cost of outpatient treatment. Numerous studies have identified risk factors for death in cases of CAP [bib_ref] Prognosis and outcomes of patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Pneumonia: with special reference to pneumococcus lobar pneumonia, Heffron [/bib_ref]. These factors were well-defined in the pre-penicillin era; studies of adults showed an increased risk with alcohol consumption, increasing age, the presence of leukopenia, the presence of bacteremia, and radiographic changes [bib_ref] Pneumonia: with special reference to pneumococcus lobar pneumonia, Heffron [/bib_ref]. More recent studies have confirmed these findings [bib_ref] Guidelines for the management of communityacquired pneumonia in adults admitted to hospital, British Thoracic Society [/bib_ref] [bib_ref] Assessing prognosis and predicting patient outcomes in community-acquired pneumonia, Gilbert [/bib_ref] [bib_ref] Risk factors for pneumonia in the elderly, Koivula [/bib_ref] [bib_ref] The impact of alcohol-related diagnoses on pneumonia outcomes, Saitz [/bib_ref] [bib_ref] Predicting hospital-associated mortality for medical patients, Daley [/bib_ref] [bib_ref] Changes in sickness at admission following the introduction of the prospective payment..., Keeler [/bib_ref] [bib_ref] Community-acquired pneumonia requiring hospitalization: 5-year prospective study, Marrie [/bib_ref]. Independent associations with increased mortality have also been demonstrated for a variety of comorbid illnesses, such as active malignancies [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Predicting hospital-associated mortality for medical patients, Daley [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] , immunosuppression [bib_ref] Hospitalization decision in patients with community-acquired pneumonia: a prospective cohort study, Fine [/bib_ref] [bib_ref] Predictors of mortality in the immunocompromised patient with pulmonary infiltrates, Poe [/bib_ref] , neurological disease [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] [bib_ref] Positive response to any of seven intradermal antigens predicts favorable outcome in..., Marrie [/bib_ref] [bib_ref] Clinical prognostic indices of fatality in elderly patients admitted to hospital with..., Starczewski [/bib_ref] , congestive heart failure [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Changes in sickness at admission following the introduction of the prospective payment..., Keeler [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] , coronary artery disease [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] , and diabetes mellitus [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] [bib_ref] Pulmonary complications of diabetes mellitus: pneumonia, Koziel [/bib_ref]. Signs and symptoms independently associated with increased mortality consist of dyspnea [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] , chills [bib_ref] outcome and prognostic factors in community-acquired pneumonia requiring hospitalization, Ortqvist [/bib_ref] , altered mental status [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] [bib_ref] Clinical prognostic indices of fatality in elderly patients admitted to hospital with..., Starczewski [/bib_ref] [bib_ref] Prognosis of patients hospitalized with community-acquired pneumonia, Fine [/bib_ref] , hypothermia or hyperthermia [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Predicting hospital-associated mortality for medical patients, Daley [/bib_ref] [bib_ref] Changes in sickness at admission following the introduction of the prospective payment..., Keeler [/bib_ref] [bib_ref] Hospitalization decision in patients with community-acquired pneumonia: a prospective cohort study, Fine [/bib_ref] , tachypnea [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] [bib_ref] Clinical prognostic indices of fatality in elderly patients admitted to hospital with..., Starczewski [/bib_ref] [bib_ref] Community-acquired pneumonia in adults in British hospitals in 1982-1983: a survey of..., Andrews [/bib_ref] , and hypotension (diastolic and systolic) [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] [bib_ref] Prognosis of patients hospitalized with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Community-acquired pneumonia in adults in British hospitals in 1982-1983: a survey of..., Andrews [/bib_ref] [bib_ref] Predicting death in patients hospitalized for community-acquired pneumonia, Farr [/bib_ref]. Laboratory and radiographic findings independently associated with increased mortality are hyponatremia [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] , hyperglycemia [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] , azotemia [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] [bib_ref] Community-acquired pneumonia in adults in British hospitals in 1982-1983: a survey of..., Andrews [/bib_ref] [bib_ref] Predicting death in patients hospitalized for community-acquired pneumonia, Farr [/bib_ref] , hypoalbuminemia [bib_ref] Predicting hospital-associated mortality for medical patients, Daley [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] [bib_ref] Positive response to any of seven intradermal antigens predicts favorable outcome in..., Marrie [/bib_ref] [bib_ref] outcome and prognostic factors in community-acquired pneumonia requiring hospitalization, Ortqvist [/bib_ref] , hypoxemia [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] , liver function test abnormalities [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] , and pleural effusion [bib_ref] Do pulmonary radiographic findings at presentation predict mortality in patients with community-acquired..., Hasley [/bib_ref]. Infections due to gram-negative bacilli or S. aureus, postobstructive pneumonia, and aspiration pneumonia are also independently associated with higher mortality [bib_ref] The hospital admission decision for patients with community-acquired pneumonia, Fine [/bib_ref]. Despite our knowledge regarding the associations of clinical, laboratory, and radiographic factors and patient mortality, there is wide geographic variation in hospital admission rates for CAP [bib_ref] Variation in hospital admissions among small areas: a comparison of Maine and..., Mcmahon [/bib_ref] [bib_ref] Are hospital services rationed in New Hampshire or overutilized in Boston?, Wennberg [/bib_ref]. This variation suggests that physicians do not use a uniform strategy to relate the decision to hospitalize to the prognosis. In fact, physicians often overestimate the risk of death for patients with CAP, and the degree of overesti- . Evaluation for diagnosis and management of community-acquired pneumonia, including site, duration, and type of treatment. b-Lactam: cefotaxime, ceftriaxone, or a b-lactam / b-lactamase inhibitor. Fluoroquinolone: levofloxacin, moxifloxacin, or gatifloxacin or another fluoroquinolone with enhanced antipneumococcal activity. Macrolide: erythromycin, clarithromycin, or azithromycin. CBC, complete blood cell count; ICU, intensive care unit. *Other tests for selected patients: see text, Diagnostic Evaluation: Etiology. ** [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref] mation is independently associated with the decision to hospitalize [bib_ref] The hospital admission decision for patients with community-acquired pneumonia, Fine [/bib_ref]. Over the past 10 years, at least 13 studies have used multivariate analysis to identify predictors of prognosis for patients with CAP . The Pneumonia PORT developed a methodologically sound clinical prediction rule that quantifies short-term mortality for patients with this illness [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref]. Used as a guideline, this rule may help physicians make decisions about the initial location and intensity of treatment for patients with this illness [fig_ref] Table 2: Comparison of risk class-specific mortality rates in the derivation and validation cohorts [/fig_ref]. The Pneumonia PORT prediction rule was derived with 14,199 inpatients with CAP; it was independently validated with 38,039 inpatients with CAP and 2287 inpatients and outpatients prospectively enrolled in the Pneumonia PORT cohort study. With this rule, patients are stratified into 5 severity classes by means of a 2-step process. In step 1, patients are classified as risk class I (the lowest severity level) if they are aged р50 years, have none of 5 important comorbid conditions (neoplastic disease, liver disease, congestive heart failure, cerebrovascular disease, or renal disease), and have normal or only mildly deranged vital signs and normal mental status. In step 2, all patients who are not assigned to risk class I on the basis of the initial history and physical examination findings alone are stratified into classes II-V, on the basis of points assigned for 3 demographic variables (age, sex, and nursing home residence), 5 comorbid conditions (listed above), 5 physical examination findings (altered mental status, tachypnea, tachycardia, systolic hypotension, hypothermia, or hyperthermia), and 7 laboratory or radiographic findings (acidemia, elevated blood urea nitrogen, hyponatremia, hyperglycemia, anemia, hypoxemia, or pleural effusion; table 3). Point assignments correspond with the following classes: р70, class II; 71-90, class III; 91-130, class IV; and 1130, class V. In the derivation and validation of this rule, mortality was low for risk classes I-III (0.1%-2.8%), intermediate for class IV (8.2%-9.3%), and high for class V (27.0%-31.1%). Increases in risk class were also associated with subsequent hospitalization and delayed return to usual activities for outpatients and with rates of admission to the ICU and length of stay for inpatients in the Pneumonia PORT validation cohort. On the basis of these observations, Pneumonia PORT investigators suggest that patients in risk classes I or II generally are candidates for outpatient treatment, risk class III patients are potential candidates for outpatient treatment or brief inpatient observation, and patients in classes IV and V should be hospitalized [fig_ref] Table 4: Risk-class mortality rates [/fig_ref]. Estimates from the Pneumonia PORT cohort study suggest that these recommendations would reduce the proportion of patients receiving traditional inpatient care by 31% and that there would be a brief observational inpatient stay for an additional 19%. The effectiveness and safety of applying the Pneumonia PORT prediction rule to the initial site of care for an independent population of patients with CAP have been examined with use of a modified version of the Pneumonia PORT prediction rule [bib_ref] Safely increasing the proportion of patients with community-acquired pneumonia treated as outpatients:..., Atlas [/bib_ref]. Emergency room physicians were educated about the rule and were encouraged to treat those in risk classes I-III as outpatients, with close, structured follow-up and provision of oral clarithromycin at no cost to the patient, if desired. The outcomes for those treated at home during this intervention phase were compared with the outcomes for historical control subjects from the time period immediately preceding the intervention. During the intervention period, there were 166 eligible patients classified as "low risk" for short-term mortality (risk classes I-III) for comparison with 147 control subjects. The percentage treated initially as outpatients was higher during the intervention period than during the control period (57% vs. 42%; relative increase of 36%; ). When initial plus sub-P p .01 sequent hospitalization was used as the outcome measure, there was a trend toward more outpatient care during the intervention period, but the difference was no longer statistically significant (52% vs. 42%; ). None of those initially treated P p .07 in the outpatient setting during the intervention period died within 4 weeks of presentation. A second multicenter controlled trial subsequently assessed the effectiveness and safety of using the Pneumonia PORT prediction rule for the initial site-of-treatment decision [bib_ref] A controlled trial of a critical pathway for treatment of community-acquired pneumonia, Marrie [/bib_ref]. In this trial, 19 emergency departments were randomly assigned either to continue conventional management of CAP or to implement a critical pathway that included the Pneumonia PORT prediction rule to guide the admission decision. Emergency room physicians were educated about the rule and were encouraged to treat those in risk classes I-III as outpatients with oral levofloxacin. Overall, 1743 patients with CAP were enrolled in this 6-month study. Use of the prediction rule resulted in an 18% reduction in the admission of low-risk patients (31% vs. 49%; ). Use of the rule did not result in an increase in mor-P p .013 tality or morbidity and did not compromise patients' 30-day functional status. These studies support use of the Pneumonia PORT prediction rule to help physicians identify low-risk patients who can be safely treated in the outpatient setting. The IDSA panel endorses the findings of the Pneumonia PORT prediction rule, which identifies valid predictors for mortality and provides a rational foundation for the decision regarding hospitalization. However, it should be emphasized that the PORT prediction rule is validated as a mortality prediction model and not as a method to triage patients with CAP. New studies are required to test the basic premise underlying the use of this rule in the initial site-of-treatment decision, so that patients classified as "low risk" and treated in the outpatient setting will have outcomes equivalent to or better than those of similar "low-risk" patients who are hospitalized. It is important to note that prediction rules are meant to contribute to rather than to supersede physicians' judgment. Another limitation is that factors other than severity of illness must also be considered in determining whether an individual patient is a candidate for outpatient care. Patients designated as "low risk" may have important medical and psychosocial contraindications to outpatient care, including expected compliance problems with medical treatment or poor social support at home. Ability to maintain oral intake, history of substance abuse, cognitive impairment, and ability to perform activities of daily living must be considered. In addition, patients may have rare conditions, such as severe neuromuscular disease or immunosuppression, which are not included as predictors in these prediction rules but increase the likelihood of a poor prognosis. Prediction rules may also oversimplify the way physicians interpret important predictor variables. For example, extreme alterations in any one variable have the same effect on risk stratification as lesser changes, despite obvious differences in clinical import (e.g., a systolic blood pressure of 40 mm Hg vs. one of 88 mm Hg). Furthermore, such rules discount the cumulative importance of multiple simultaneous physiological derangements, especially if each derangement alone does not reach the threshold that defines an abnormal value (e.g., systolic blood pressure of 90/40 mm Hg, respiratory rate of 28 breaths/ min, and pulse of 120 beats/min). Finally, prediction rules often neglect the importance of patients' preferences in clinical decision-making. This point is highlighted by the observation that the vast majority of low-risk patients with CAP do not have their preferences for site of care solicited, despite strong preferences for outpatient care [bib_ref] Preference for home vs. hospital care among low-risk patients with community-acquired pneumonia, Coley [/bib_ref]. ## Role of specific pathogens in cap Prospective studies evaluating the causes of CAP in adults have failed to identify the cause of 40%-60% of cases of CAP and have detected у2 etiologies in 2%-5% [bib_ref] Guidelines for the management of communityacquired pneumonia in adults admitted to hospital, British Thoracic Society [/bib_ref] [bib_ref] Prognosis of patients hospitalized with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] New and emerging etiologies for community-acquired pneumonia with implications for therapy: a..., Fang [/bib_ref] [bib_ref] Community-acquired pneumonia: impact of immune status, Mundy [/bib_ref]. The most common etiologic agent identified in virtually all studies of CAP is S. pneumoniae, which accounts for about two-thirds of all cases of bacteremic pneumonia cases [bib_ref] Prognosis and outcomes of patients with community-acquired pneumonia, Fine [/bib_ref]. Other pathogens implicated less frequently include H. influenzae (most strains of which are nontypeable), Mycoplasma pneumoniae, C. pneumoniae, S. aureus, Streptococcus pyogenes, N. meningitidis, Moraxella catarrhalis, Klebsiella pneumoniae and other gramnegative rods, Legionella species, influenza virus (depending on the season), respiratory syncytial virus, adenovirus, parainfluenza virus, and other microbes. The frequency of other etiologies is dependent on specific epidemiological factors, as with Chlamydia psittaci (psittacosis), Coxiella burnetii (Q fever), Francisella tularensis (tularemia), and endemic fungi (histoplasmosis, blastomycosis, and coccidioidomycosis). Comparisons of relative frequency of each of the etiologies of pneumonia are hampered by the varying levels of sensitivity and specificity of the tests used for each of the pathogens that they detect; for example, in some studies, tests used for legionella infections provide a much higher degree of sensitivity and possibly specificity than do tests used for pneumococcal infections. Thus, the relative contribution of many causes to the incidence of CAP is undoubtedly either exaggerated or underestimated, depending on the sensitivity and specificity of tests used in each of the studies. ## Etiology-specific diagnoses and the clinical setting No convincing association has been demonstrated between individual symptoms, physical findings, or laboratory test results and specific etiology [bib_ref] New and emerging etiologies for community-acquired pneumonia with implications for therapy: a..., Fang [/bib_ref]. Even time-honored beliefs, such as the absence of productive cough or inflammatory sputum in pneumonia due to Mycoplasma, Legionella, or Chlamydia species, have not withstood close inspection. On the other hand, most comparisons have involved relatively small numbers of patients and have not evaluated the potential for separating causes by use of constellations of symptoms and physical findings. In one study, as yet unconfirmed, that compared patients identified in a prospective standardized fashion, a scoring system using 5 symptoms and laboratory abnormalities was able to differentiate most patients with legionnaires' disease from the other patients [bib_ref] Clinical diagnosis of legionnaires' disease (LD) using a multivariate model [abstract K55, Keller [/bib_ref]. A similar type of system has been devised for identifying patients with hantavirus pulmonary syndrome (HPS) [bib_ref] Clinical features that differentiate hantavirus pulmonary syndrome from three other acute respiratory..., Moolenaar [/bib_ref]. If validated, such scoring systems may be useful for identifying patients who should undergo specific diagnostic tests (which are too expensive to use routinely for all patients with CAP) and be empirically treated with specific antimicrobial drugs while test results are pending. Certain pathogens cause pneumonia more commonly among persons with specific risk factors. For instance, pneumococcal pneumonia is especially likely to occur in the elderly and in patients with a variety of medical conditions, including alcoholism, chronic cardiovascular disease, chronic obstructed airway disease, immunoglobulin deficiency, hematologic malig-nancy, and HIV infection. However, outbreaks occur among young adults under conditions of crowding, such as in army camps or prisons. S. pneumoniae is second only to Pneumocystis carinii as the most common identifiable cause of acute pneumonia in patients with AIDS [bib_ref] Preventing bacterial respiratory tract infections among persons infected with human immunodeficiency virus, Keller [/bib_ref] [bib_ref] Pneumococcal disease during HIV infection: epidemiologic, clinical and immunologic perspectives, Janoff [/bib_ref] [bib_ref] Community-acquired pneumonia in a cohort of former injection drug users with and..., Boschini [/bib_ref]. Legionella is an opportunistic pathogen; legionella pneumonia is rarely recognized in healthy young children and young adults. It is an important cause of pneumonia in organ transplant recipients and in patients with renal failure and occurs with increased frequency in patients with chronic lung disease, smokers, and possibly those with AIDS [bib_ref] Surveillance for legionnaires' disease: risk factors for morbidity and mortality, Marston [/bib_ref]. Although M. pneumoniae historically has been thought primarily to involve children and young adults, some evidence suggests that it causes pneumonia in healthy adults of any age [bib_ref] Incidence of community-acquired pneumonia requiring hospitalizations: results of a population-based active surveillance..., Marston [/bib_ref]. There are seasonal differences in incidence of many of the causes of CAP. Pneumonia due to S. pneumoniae, H. influenzae, and influenza occurs predominantly in winter months, whereas C. pneumoniae appears to cause pneumonia year-round. Although there is a summer prevalence of outbreaks of legionnaires' disease, sporadic cases occur with similar frequency during all seasons [bib_ref] Incidence of community-acquired pneumonia requiring hospitalizations: results of a population-based active surveillance..., Marston [/bib_ref] [bib_ref] Surveillance for legionnaires' disease: risk factors for morbidity and mortality, Marston [/bib_ref]. Some studies suggest that there is no seasonal variation in mycoplasma infection; however, other data suggest that its incidence is greatest during the fall and winter months [bib_ref] Mycoplasma infections of man, Chanock [/bib_ref]. . Rationale for establishing an etiologic diagnosis. ## Improve care of the individual patient To permit optimal antibiotic selection specifically directed at the causative agent To allow for a rational basis for change from parenteral to oral therapy and for a change in therapy necessitated by an adverse drug reaction To permit antibiotic selection that limits the consequences of injudicious antibiotic use in terms of cost to the patient, inducible resistance (e.g., inducible b-lactamases), and adverse drug reactions Improve care of other patients and advance knowledge To identify pathogens of potential epidemiological significance, such as Legionella, hantavirus, and penicillin-resistant Streptococcus pneumoniae To identify newly emergent pathogens (hantavirus) To identify drug-resistant pathogens and monitor trends (drug-resistant S. pneumoniae, b-lactamase-producing Haemophilus influenzae, or methicillin-resistant Staphylococcus aureus) To prompt contact-tracing and antimicrobial prophylaxis (Neisseria meningitidis, H. influenzae type b, Mycobacterium tuberculosis) To permit antibiotic selection that limits the effects of antibiotic overuse on the community Doing so is cost efficient Average cost of standard microbiological studies is !1% of the average hospital bill Narrow-spectrum agents may be less expensive Although many reports indicate that the yield of pathogens in expectorated sputum from patients with CAP is only 30%-40%, this yield may often be increased with improved techniques; furthermore, a negative specimen may enhance the probability of an atypical agent (which may influence the antimicrobial choice), and a specimen of good quality that does not show or yield S. aureus or gram-negative bacilli provides good evidence that these organisms are not present; this information may prove useful for patients who do not respond, because conventional cultures of posttreatment specimens are relatively useless There are other temporal variations in incidence of some causes of pneumonia. The frequency and severity of influenza vary as a result of antigenic drift and, occasionally, as a result of antigenic shift. For less clear reasons, increases in incidence of mycoplasma infections occur every 3-6 years [bib_ref] Mycoplasma infections of man, Chanock [/bib_ref] [bib_ref] Infections due to species of Mycoplasma and Ureaplasma: an update, Taylor-Robinson [/bib_ref]. Yearto-year variations may also occur with pneumococcal pneumonia [bib_ref] The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta, Hofmann [/bib_ref]. Little is known about geographic differences in the incidence of pneumonia. Surveillance data from the CDC suggest that legionnaires' disease occurs with highest incidence in northeastern states and states in the Great Lakes area [bib_ref] Surveillance for legionnaires' disease: risk factors for morbidity and mortality, Marston [/bib_ref] ; however, differences in ascertainment of disease may be a contributing factor. The incidence of pneumonia due to pathogens that are environmentally related would be expected to vary with changes in relevant environmental conditions. For example, the incidence of legionnaires' disease is dependent on the presence of pathogenic Legionella species in water, amplification of the bacteria in reservoirs with the ideal nutritional milieu, use of aerosol-producing devices (which can spread contaminated water via aerosol droplets), ideal meteorological conditions for transporting aerosols to susceptible hosts, and presence of susceptible hosts. Alterations in any of these variables would probably lead to variations in incidence. Likewise, increasing rainfall, with associated increases in the rodent population, was hypothesized to be the basis for the epidemic of HPS in the southwestern United States in 1993 [bib_ref] Hantaviruses and hantavirus pulmonary syndrome, Butler [/bib_ref]. ## Diagnostic evaluation Pneumonia should be suspected in patients with newly acquired lower respiratory symptoms (cough, sputum production, and/or dyspnea), especially if accompanied by fever, altered breath sounds, and rales. It is recognized that there must be a balance between reasonable diagnostic testing (table 5) and empirical therapy. The importance of establishing the diagnosis of pneumonia and its cause is heightened with the increasing concern about antibiotic overuse. ## Chest radiography The diagnosis of CAP is based on a combination of clinical and laboratory (including microbiological) data. The differential diagnosis of lower respiratory symptoms is extensive and includes upper and lower respiratory tract infections, as well as noninfectious causes (e.g., reactive airways disease, atelectasis, congestive heart failure, bronchiolitis obliterans with organizing pneumonia [BOOP], vasculitis, pulmonary embolism, and pulmonary malignancy). Most cases of upper respiratory tract infection and AB are of viral origin, do not require antimicrobial therapy, and are the source of great antibiotic abuse [bib_ref] Antibiotic prescribing for adults with colds, upper respiratory tract infections and bronchitis..., Gonzales [/bib_ref] [bib_ref] Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on..., Gonzales [/bib_ref]. By contrast, antimicrobial therapy is usually indicated for pneumonia, and a chest radiography is usually necessary to establish the diagnosis of pneumonia. Physical examination to detect rales or bronchial breath sounds is neither sensitive nor specific for detecting pneumonia [bib_ref] Diagnosing pneumonia by physical examination: relevant or relic?, Wipf [/bib_ref]. Chest radiography is considered sensitive and, occasionally, is useful for determining the etiologic diagnosis, the prognosis, and alternative diagnoses or associated conditions. Chest radiographs in patients with P. carinii pneumonia (PCP) are false-negative for up to 30% of patients, but this exception is not relevant for the immunocompetent adult host [bib_ref] HIV infection among patients in US acute-care hospitals, Janssen [/bib_ref]. One study showed spiral CT scans are significantly more sensitive in detecting pulmonary infiltrates [bib_ref] High-resolution computed tomography for the diagnosis of community-acquired pneumonia, Syrjala [/bib_ref] , but the clinical significance of these results is unclear, and the IDSA panel does not endorse the routine use of this technology because of the preliminary nature of the data and high cost of the procedure. At times of limited resources, it may seem attractive to treat patients for CAP on the basis of presenting manifestations, without radiographic confirmation. This approach should be discouraged, given the cost and potential dangers of antimicrobial abuse in terms of side effects and resistance. Indeed, the prevalence of pneumonia among adults with respiratory symptoms that suggest pneumonitis ranges from only 3% in a general outpatient setting to 28% in an emergency department [bib_ref] Clinical prediction rule for pulmonary infiltrates, Heckerling [/bib_ref] [bib_ref] Prediction of pneumonia in outpatients with acute cough: a statistical approach, Diehr [/bib_ref]. The IDSA panel recommends that chest radiography be included in the routine evaluation of patients for whom pneumonia is considered a likely diagnosis (A-II). ## Etiology The emphasis on microbiological studies (Gram staining and culture of expectorated sputum) in the IDSA guidelines represents a difference from the guidelines of the American Thoracic Society [bib_ref] Guidelines for the initial empiric therapy of community-acquired pneumonia: proceedings of an, Niederman [/bib_ref]. Arguments against microbiological studies include the low yield in many reports and the lack of documented benefit in terms of cost or outcome. A concern of the IDSA panel members is our perception that the quality of microbiological technology, as applied to respiratory secretions, has deteriorated substantially, compared with that in an earlier era [bib_ref] Pneumonia: with special reference to pneumococcus lobar pneumonia, Heffron [/bib_ref]. Furthermore, it is our perception that regulations of the Clinical Laboratory Improvement Act, which discourage physicians from examining sputum samples microscopically, contributed to this decline. Although no data clearly demonstrate the cost-effectiveness or other advantages of attempts to identify pathogens, studies specifically designed to address this issue have not been reported. Our rationale for the preservation of microbiological and immunologic testing is summarized in table 6, which classifies advantages with regard to the individual patient, society, and costs. The desire to identify the etiologic agent is heightened by concern about empirical selection of drugs, because of the increasing microbial resistance, unnecessary costs, and avoidable side effects. In addition, the work of prior investigators and their microbiological findings provide the rationale considered essential to the creation of guidelines based on probable etiologic agents. A detailed history may be helpful for suggesting a diagnosis. Epidemiological clues that may lead to diagnostic considerations are listed in table 7. Certain findings have historically been identified as clues to specific causes of pneumonia, although these have not been confined to controlled studies. Acute onset, a single episode of shaking with chills (rigor), and pleurisy suggest pneumococcal infection. Prodromal fever and myalgia followed by pulmonary edema and hypotension are characteristic of HPS. Underlying COPD is more often seen with pneumonia due to H. influenzae or M. catarrhalis, separately or together with S. pneumoniae. Putrid sputum indicates infection caused by anaerobic bacteria. Although many studies of CAP have found that clinical features often do not distinguish etiologic agents [bib_ref] New and emerging etiologies for community-acquired pneumonia with implications for therapy: a..., Fang [/bib_ref] [bib_ref] Pneumonia due to Legionella pneumophila and pneumococcal pneumonia: similarities and differences on..., Granados [/bib_ref] [bib_ref] Community-acquired pneumonia: the future of the microbiology laboratory: focused diagnosis or syndromic..., Macdonald [/bib_ref] , others support the utility of clinical clues for supporting an etiologic diagnosis [bib_ref] Clinical diagnosis of legionnaires' disease (LD) using a multivariate model [abstract K55, Keller [/bib_ref] [bib_ref] Early recognition of Streptococcus pneumoniae in patients with community-acquired pneumonia, Bohte [/bib_ref]. Once the clinical diagnosis of CAP has been made, consideration should be given to microbiological diagnosis with bacteriologic studies of sputum and blood [bib_ref] Initial investigation and treatment of the patient with severe community-acquired pneumonia, Ortqvist [/bib_ref] [bib_ref] Diagnosis of bacterial infection of the lung, Bartlett [/bib_ref] [bib_ref] Community-acquired pneumonia, Bartlett [/bib_ref] [bib_ref] The value of the sputum gram's stain in communityacquired pneumonia, Boerner [/bib_ref] [bib_ref] Management of pneumonia in the prospective payment era: a need for more..., Dans [/bib_ref] [bib_ref] Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections..., Ieven [/bib_ref]. Practice standards for collection, transport, and processing of respiratory secretions to detect common bacterial pathogens are summarized in table 8. Many pathogens require specialized tests for their detection, which are summarized in table 9. The rapid . Recommendations for expectorated sputum collection, transport, and processing. Specimen should be obtained by deep cough and have gross purulence; it should be obtained before treatment with antimicrobial agents and in the presence of a health care provider Specimen should be immediately transported to the laboratory for prompt processing A purulent portion is selected for Gram staining and culture; Quellung staining should be done when available Cytological screening should be done under low-power magnification (ϫ100) to determine the cellular composition (see text, Diagnostic Evaluation: Etiology); cytological assessment is not necessary for screening specimens for detection of respiratory viruses, Legionella species, or mycobacteria Culture should be performed with use of standard techniques and results reported with semiquantitative assessment; most pathogens are recovered in 3-4ϩ growth, indicating 15 colonies, in the second quadrant. diagnostic test for routine use is Gram staining of respiratory secretions, usually expectorated sputum; others include direct fluorescent antibody (DFA) staining of sputum or urinary antigen assay for Legionella, for use in selected cases, urinary antigen assay for S. pneumoniae, acid-fast bacilli (AFB) staining for detection of mycobacterial infections, and several tests for influenza. Many rapid diagnostic tests, such as PCR, are in early development, not commonly available, or not sufficiently reliable [bib_ref] Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections..., Ieven [/bib_ref]. PCR testing for detection of Mycobacterium tuberculosis is the only PCR test for detection of a respiratory tract pathogen that has been cleared by the US Food and Drug Administration (FDA), but it is recommended for use only with specimens that contain AFB on direct smears. Diagnostic procedures that provide identification of a specific etiology within 24-72 h can still be useful for guiding continued therapy. The etiologic diagnosis can be useful for both prognostic and therapeutic purposes. Once a diagnosis has been established, the failure to respond to treatment can be dealt with in a logical fashion based on the causative organism and its documented antibiotic susceptibility, rather than by empiric selection of antimicrobial agents with a broader or different spectrum. Furthermore, if a drug reaction develops, an appropriate substitute can be readily selected. Performance of blood cultures within 24 h of admission for CAP is associated with a significant reduction in 30-day mortality [bib_ref] Influence of blood culture results on antibiotic choice in treatment of bacteremia, Arbo [/bib_ref]. With regard to sputum bacteriology, several studies have suggested that mortality associated with CAP in hospitalized patients is the same for those with and without an etiologic diagnosis [bib_ref] Community-acquired pneumonia: importance of initial noninvasive bacteriologic and radiologic investigations, Levy [/bib_ref] [bib_ref] The value of routine microbial investigation in community-acquired pneumonia, Trevisani [/bib_ref] [bib_ref] The value of routine microbial investigation in community-acquired pneumonia, Woodhead [/bib_ref]. These studies were not specifically designed to test the hypothesis. Instead, the conclusion is based on retrospective analyses of cases with and without an etiologic diagnosis. Other outcomes also of interest that have not been assessed are length of stay, cost, resource use, and morbidity. Some studies, although uncontrolled, do suggest benefit of these diagnostic studies [bib_ref] Diagnostic fiberoptic bronchoscopy and protected brush culture in patients with communityacquired pneumonia, Ortqvist [/bib_ref] [bib_ref] A criterion based audit of community-acquired pneumonia, May [/bib_ref] [bib_ref] Severe community-acquired pneumonia: etiology, prognosis, and treatment, Pachon [/bib_ref] [bib_ref] A new diagnostic approach to the patient with severe pneumonia, Sorensen [/bib_ref] [bib_ref] Sputum gram stain assessment in community-acquired bacteremic pneumonia, Gleckman [/bib_ref] [bib_ref] Severe community-acquired pneumonia: epidemiology and prognostic factors, Torres [/bib_ref]. For example, Boerner and Zwadyk [bib_ref] The value of the sputum gram's stain in communityacquired pneumonia, Boerner [/bib_ref] reported that a positive early diagnosis by sputum Gram staining correlated with more rapid resolution of fever after initiation of antimicrobial therapy. An additional study by Torres et al. [bib_ref] Severe community-acquired pneumonia: epidemiology and prognostic factors, Torres [/bib_ref] showed that inadequate antibiotic treatment was clearly related to poor outcomes, which suggests that the establishment of an etiologic diagnosis is important. The frequency of microbiological studies for CAP patients is highly variable. A report from the Pneumonia PORT study, with analysis of 1343 hospitalized patients during 1991-1994, showed that the frequencies of sputum Gram staining and sputum culture within 48 h of admission were 53% and 58%, respectively [bib_ref] Processes and outcomes of care for patients with community-acquired pneumonia: results from..., Fine [/bib_ref]. These studies were done on only 8%-11% of 944 outpatients with CAP. Participating centers in this and most other published studies of CAP are academic institutions at which microbiological studies are probably more frequent than in other health care settings. The finding of a likely pathogen in blood cultures averages 11% in published reports concerning hospitalized patients with CAP [bib_ref] Prognosis and outcomes of patients with community-acquired pneumonia, Fine [/bib_ref]. The yield with sputum studies is highly variable, ranging from 29% to 90% for hospitalized patients and usually !20% for outpatients [bib_ref] Guidelines for the management of communityacquired pneumonia in adults admitted to hospital, British Thoracic Society [/bib_ref] [bib_ref] Prognosis of patients hospitalized with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Predicting death in patients hospitalized for community-acquired pneumonia, Farr [/bib_ref] [bib_ref] Safely increasing the proportion of patients with community-acquired pneumonia treated as outpatients:..., Atlas [/bib_ref] [bib_ref] Clinical diagnosis of legionnaires' disease (LD) using a multivariate model [abstract K55, Keller [/bib_ref] [bib_ref] Influence of blood culture results on antibiotic choice in treatment of bacteremia, Arbo [/bib_ref] [bib_ref] Sputum gram stain assessment in community-acquired bacteremic pneumonia, Gleckman [/bib_ref] [bib_ref] Severe community-acquired pneumonia: epidemiology and prognostic factors, Torres [/bib_ref] [bib_ref] Processes and outcomes of care for patients with community-acquired pneumonia: results from..., Fine [/bib_ref]. The large variation among studies is presumably explained by variations in the quality of microbiological analyses, epidemiological patterns, and the patient population served. It is our consensus that establishment of an etiologic diagnosis, with performance of blood cultures before initiation of antimicrobial treatment (A-I) and sputum Gram staining and culture (B-II), has value for patients who require hospitalization. The goal is to establish a specific diagnosis that can be used for more precise and often more cost-effective use of antimicrobial agents. On the other hand, the utility of diagnostic studies for CAP of less severity (not requiring hospitalization) is unclear. More studies are needed to verify the significance of diagnostic studies in these cases. Etiologic diagnosis. Confidence in the accuracy of the diagnosis depends on the pathogen and on the diagnostic test, as follows. 1. Diagnosis definite: a definite etiology is established by a compatible clinical syndrome plus the recovery of a probable etiologic agent from an uncontaminated specimen (blood, pleural fluid, transtracheal aspirate, or transthoracic aspirate) or the recovery from respiratory secretions of a likely pathogen that does not colonize the upper airways (e.g., M. tuberculosis, Legionella species, influenza virus, or P. carinii; table 10) (A-I). Some serological tests are regarded as diagnostic, although the results are usually not available in a timely manner or the diagnostic criteria are controversial. 2. Diagnosis probable: a probable etiologic diagnosis is established by a compatible clinical syndrome with detection (by staining or culture) of a likely pulmonary pathogen in respiratory secretions (expectorated sputum, bronchoscopic aspirate, or quantitatively cultured bronchoscopic bronchoalveolar lavage [BAL] fluid or brush catheter specimen). With semiquantitative culture, the pathogen should be recovered in moderate to heavy growth (B-II). Tests or specimens used for etiologic diagnosis. The following tests or types of specimens are used to establish an etiologic diagnosis. 1. Body fluids: blood culture specimens (with у2 needlesticks performed at separate sites) should be obtained from patients who require hospitalization for acute pneumonia (A-I). Potentially infected body fluids from other anatomic sites, including pleural fluid, joint fluid, and CSF, should have Gram staining and culture if warranted by the clinical presentation. 2. Sputum examination (table 8 and [fig_ref] Figure 2: Procedures for diagnosis and for outpatient and hospitalcentered management of community-acquired pneumonia... [/fig_ref] : the value of Gram staining of expectorated sputum is debated [bib_ref] Early recognition of Streptococcus pneumoniae in patients with community-acquired pneumonia, Bohte [/bib_ref] [bib_ref] Diagnosis of bacterial infection of the lung, Bartlett [/bib_ref] [bib_ref] Community-acquired pneumonia, Bartlett [/bib_ref] [bib_ref] Community-acquired pneumonia: importance of initial noninvasive bacteriologic and radiologic investigations, Levy [/bib_ref] [bib_ref] The value of routine microbial investigation in community-acquired pneumonia, Trevisani [/bib_ref] [bib_ref] The value of routine microbial investigation in community-acquired pneumonia, Woodhead [/bib_ref] [bib_ref] Sputum gram stain assessment in community-acquired bacteremic pneumonia, Gleckman [/bib_ref] [bib_ref] Severe community-acquired pneumonia: epidemiology and prognostic factors, Torres [/bib_ref] [bib_ref] Processes and outcomes of care for patients with community-acquired pneumonia: results from..., Fine [/bib_ref] [bib_ref] Etiological diagnosis of bacterial pneumonia by gram stain and quantitative culture of..., Kalin [/bib_ref] [bib_ref] Importance of the sputum gram stain in communityacquired pneumonia, Mutha [/bib_ref] [bib_ref] Diagnostic significance of the sputum gram's stain in pneumonia, Walsh [/bib_ref] , but we recommend this relatively simple, inexpensive procedure for guiding initial selection of antimicrobial therapy, provided that a deep-cough specimen is obtained before antibiotic therapy, rapidly transported, and properly processed in the laboratory within a few hours of collection (B-II). Therapy with antimicrobial agents should not be delayed for acutely ill patients because of the difficulty in obtaining specimens for microbiological studies. Routine laboratory tests should include Gram staining, cytological screening, and aerobic culture of specimens that satisfy cytological criteria. Cytological criteria for judging the acceptability of specimens include the relative number of polymorphonuclear cells (PMN) and squamous epithelial cells (SEC) in patients with normal or elevated WBC counts, determined with use of a low-powerfield examination (LPF); the acceptable values range from [bib_ref] Acid aspiration induced lung injury: new insights and therapeutic options, Matthay [/bib_ref] SEC/LPF to !25 SEC/LPF, based on correlation PMNϩ ! 10 of culture results with clinical findings and results of transtracheal aspiration (A-I) [bib_ref] Microscopic and bacteriologic analysis of expectorated sputum, Murray [/bib_ref] [bib_ref] Microscopic and bacteriological comparison of paired sputa and transtracheal aspirates, Geckler [/bib_ref]. Some authorities recommend a criterion of 110 WBC per SEC. Mycobacteria and Legionella species are exceptions, since microscopic criteria may yield misleading results. Cultures should be performed rapidly [bib_ref] Transportation delay and the microbiological quality of clinical specimens, Jefferson [/bib_ref] , although the consequence of time delays in processing is disputed [bib_ref] Survival of Streptococcus pneumoniae in sputum from patients with pneumonia, Williams [/bib_ref]. Interpretations of expectorated sputum cultures should include clinical correlations and semiquantitative results. In office practice, it may not be realistic to perform Gram staining in a timely manner to guide antibiotic decisions, but a slide may be prepared, air-dried, and heat-fixed for subsequent interpretation (C-III). Numerous studies support the use of routine microscopic examination of a gram-stained sputum sample, with recognition of lancet-shaped gram-positive diplococci that suggest S. pneumoniae. Most show the sensitivity of sputum Gram staining for patients with pneumococcal pneumonia to be 50%-60% and the specificity to be 180% [bib_ref] Early recognition of Streptococcus pneumoniae in patients with community-acquired pneumonia, Bohte [/bib_ref] [bib_ref] Community-acquired pneumonia, Bartlett [/bib_ref] [bib_ref] The value of the sputum gram's stain in communityacquired pneumonia, Boerner [/bib_ref] [bib_ref] Management of pneumonia in the prospective payment era: a need for more..., Dans [/bib_ref] [bib_ref] Sputum gram stain assessment in community-acquired bacteremic pneumonia, Gleckman [/bib_ref]. In a prospective study of 144 patients admitted to the hospital with CAP, 59 (41%) had a valid specimen obtained, with the cytological criteria of [bib_ref] Acid aspiration induced lung injury: new insights and therapeutic options, Matthay [/bib_ref] PMN and !10 SEC evident on low-power magnification. The gram-stained smears of 47 valid specimens by these criteria showed a predominant bacterial morphotype that predicted the blood culture isolate in 40 (85%) valid specimens; physicians could have selected appropriate antimicrobial therapy for 190% of patients on the basis of gram-staining results [bib_ref] Sputum gram stain assessment in community-acquired bacteremic pneumonia, Gleckman [/bib_ref]. In haemophilus pneumonia, the Gram stain reading is even more reliable because of the profuse number of organisms that are regularly present. The finding of many WBC with no bacteria in a patient who has not already received antibiotics can reliably exclude infection by most ordinary bacterial pathogens. The validity of the gram-stain reading, however, is directly related to the experience of the interpreter [bib_ref] Evaluation of housestaff physicians' preparation and interpretation of sputum gram stains for..., Fine [/bib_ref]. Routine cultures of expectorated sputum are neither sensitive nor specific when the common bacteriologic methods of many laboratories are used. The most likely explanation for unreliable microbiological data is that the specimen did not provide a rich enough source of inflammatory material from the lower respiratory tract, either because the patient was unable to cough up a reliable specimen or because the health care provider did not give sufficient priority to obtaining such a specimen. Other reasons include prior administration of antibiotics, delays in processing the specimen, insufficient attention to separating sputum from saliva before streaking slides or culture plates, and difficulty with interpretation because of the contamination by the flora of the upper airways. The flora may include potential pathogens (leading to falsepositive cultures), and the normal flora often overgrow the true pathogen (leading to false-negative cultures), especially with fastidious pathogens such as S. pneumoniae. In cases of bacteremic pneumococcal pneumonia, S. pneumoniae may be isolated in sputum culture in only 40%-50% of cases when standard microbiological techniques are used [bib_ref] The nonvalue of sputum culture in the diagnosis of pneumococcal pneumonia, Barrett-Connor [/bib_ref] [bib_ref] Nonvalue of sputum culture in the management of lower respiratory tract infections, Lentino [/bib_ref]. The yield of S. pneumoniae is substantially higher from transtracheal aspirates [bib_ref] Diagnostic accuracy of transtracheal aspiration bacteriologic studies, Bartlett [/bib_ref] [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref] [bib_ref] Superinfections of the lung: an evaluation by serial transtracheal aspirations, Benner [/bib_ref] [bib_ref] Etiologic diagnosis of lower respiratory tract infections, Hoeprich [/bib_ref] , transthoracic needle aspirates [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref] [bib_ref] The reliability of sputum typing and its relation to serum therapy, Bullowa [/bib_ref] , and quantitative cultures of BAL aspirates [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref] [bib_ref] Diagnostic fiberoptic bronchoscopy in patients with community-acquired pneumonia: comparison between bronchoalveolar lavage..., Jimenez [/bib_ref]. Prior antibiotic therapy may reduce the yield of common respiratory pathogens in cultures of respiratory tract specimens from any source and is often associated with false-positive cultures for upper airway contaminants, such as gram-negative bacilli or S. aureus [bib_ref] Diagnosis of bacterial infection of the lung, Bartlett [/bib_ref] [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref]. 3. Induced sputum: the utility of these specimens for detecting pulmonary pathogens other than P. carinii or M. tuberculosis is poorly established. 4. Serological studies: these tests are usually not helpful in the initial evaluation of patients with CAP (C-III) but may provide data useful for epidemiological surveillance. Cold agglutinins in a titer у1:64 support the diagnosis of M. pneumoniae infection, with a sensitivity of 30%-60%, but this test has poor specificity. IgM antibodies to M. pneumoniae require up to 1 week to reach diagnostic titers; reported results for sensitivity are variable [bib_ref] Comparison of PCR, culture, and serological tests for diagnosis of Mycoplasma pneumoniae..., Dorigo-Zetsma [/bib_ref] [bib_ref] Diagnosis of Mycoplasma pneumoniae pneumonia in children, Waris [/bib_ref]. The serological responses to Chlamydia and Legionella species take even longer [bib_ref] Diagnosis of Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydia pneumoniae lower respiratory infection..., Ramirez [/bib_ref] [bib_ref] Evidence that Chlamydia pneumoniae causes pneumonia and bronchitis, Grayston [/bib_ref]. The acute antibody test for Legionella in legionnaires' disease is usually negative or demonstrates a low titer [bib_ref] Legionnaires' disease, Edelstein [/bib_ref] [bib_ref] Reevaluation of the definition of legionnaires' disease: use of the urinary antigen..., Plouffe [/bib_ref]. Some authorities have accepted an acute titer у1:256 as a criterion for a probable or presumptive diagnosis, but 1 study showed that this titer had a positive predictive value of only 15% [bib_ref] Reevaluation of the definition of legionnaires' disease: use of the urinary antigen..., Plouffe [/bib_ref]. If serological tests are to be used, an acute-phase serum specimen must be obtained from selected patients. Then, if the etiology of a case remains in question, a convalescent-phase serum can be obtained, and serological studies of paired sera can be performed. This method to identify causative agents is primarily for epidemiological information. These data indicate that there are no commonly available serological tests that can be used to accurately guide therapy for acute infections caused by M. pneumoniae, C. pneumoniae, or Legionella (D-III). 5. Antigen detection: antigen-detection methods for identification of microorganisms in sputum and in other fluids have been studied for 170 years with a variety of techniques-counter-immunoelectrophoresis, latex agglutination, immunofluorescence, and enzyme immunoassay (EIA). Although their use for identification of bacterial agents (i.e., S. pneumoniae) has been favored in many European centers, they have been less acceptable to North American laboratories. Cost, time requirements, and relative lack of sensitivity and specificity (depending on the method) are potential limitations. The FDA has recently approved an immunochromatographic membrane assay to detect S. pneumoniae antigen in urine. Results may be obtained as quickly as 15 min after initiation of the test. According to the package insert, the test has a sensitivity of 86% and a specificity of 94%. Disadvantages are the limited experience with the assay, the need for cultures in order to determine susceptibility to guide therapy, and the lack of published data on performance characteristics. The IDSA panel endorses this test as a complement to sputum and blood cultures (C-III). The Quellung test also is a rapid assay to detect S. pneumoniae but requires adequate expertise. Rapid, commercially available EIAs are available for detection of respiratory syncytial virus (RSV), adenovirus, and parainfluenza viruses 1, 2, and 3. The sensitivities of these tests are 180%. Rapid methods to detect influenza virus are of special interest because of the availability of antiviral agents that must be given within 48 h of the onset of symptoms. These tests show sensitivities of 70%-85% and a specificity 190%. Clinical detection of influenza on the basis of typical symptoms during an influenza epidemic appears more sensitive. The urinary antigen tests have been shown to be sensitive and specific for detection of L. pneumophila serogroup 1, which accounts for ∼70% of reported legionella cases in the United States [bib_ref] Surveillance for legionnaires' disease: risk factors for morbidity and mortality, Marston [/bib_ref] [bib_ref] Legionnaires' disease, Edelstein [/bib_ref] ; other possible advantages are the technical ease with which the test is performed and the validity of results after several days of effective antibiotic treatment. DFA staining of respiratory secretions is technically demanding, shows optimal results with L. pneumophila, and shows poor sensitivity and specificity when not performed by experts using only certain antibodies. Culture and urine antigen testing show sensitivity of 50%-60% and a specificity of 195%. A negative laboratory test does not exclude Legionella, particularly if the case is caused by organisms other than L. pneumophila serogroup 1, but a positive culture or urine antigen assay is virtually diagnostic. The IDSA panel recommends urinary antigen assays and sputum culture on selective and nonselective media, with specimen decontamination before plating, to detect legionnaires' disease (A-II). 6. DNA probes and amplification: several rapid diagnostic tests that use nucleic acid amplification for the evaluation of respiratory secretions or serum are presently under development, especially for Chlamydia, Mycoplasma, and Legionella [bib_ref] Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections..., Ieven [/bib_ref]. The reagents for these tests have not been cleared by the FDA, and their availability is generally restricted to research and reference laboratories [bib_ref] Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections..., Ieven [/bib_ref] [bib_ref] Diagnosis of Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydia pneumoniae lower respiratory infection..., Ramirez [/bib_ref]. If such tests become available, they may be helpful in establishing early diagnosis and allowing for directed therapy at the time of care. Their greatest potential utility is anticipated for the detection of M. pneumoniae, Legionella, and selected pathogens that infrequently colonize the upper airways in the absence of disease [fig_ref] Table 9: Diagnostic studies for specific agents of community-acquired pneumonia [/fig_ref] 7. Invasive diagnostic tests (transtracheal aspiration, bronchoscopy, and percutaneous lung aspiration; table 3): transtracheal aspiration was previously used to obtain uncontaminated lower respiratory secretions that were valid for culture for the detection of anaerobic organisms, as well as common aerobic pathogens [bib_ref] Diagnosis of bacterial infection of the lung, Bartlett [/bib_ref] [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref]. This procedure is now infrequently performed because of concern about adverse effects and the lack of personnel skilled in the technique. A consequence of reduced use of transtracheal aspiration is the lack of any method to detect anaerobic bacteria in the lung in the absence of empyema or bacteremia. The utility of fiber-optic bronchoscopy is variable, depending on pathogen and technique. Because aspirates from the inner channel of the bronchoscope are subject to contamination by the upper airway flora, they should not be cultured anaerobically, since they have the same limitations as expectorated spu-tum [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref] [bib_ref] Should fiberoptic bronchoscopy aspirates be cultured?, Bartlett [/bib_ref]. For recovery of common bacterial pathogens, quantitative culture of BAL or of a protected-brush catheter specimen is considered superior [bib_ref] Diagnosis of bacterial pulmonary infections during quantitative protected catheter cultures obtained during..., Pollock [/bib_ref] [bib_ref] A fiberoptic bronchoscopy technique to obtain uncontaminated lower airway secretions for bacterial..., Wimberly [/bib_ref]. The techniques for collection, transport, and processing of specimens for quantitative culture are available from published sources [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref] [bib_ref] Diagnosis of bacterial pulmonary infections during quantitative protected catheter cultures obtained during..., Pollock [/bib_ref] [bib_ref] A fiberoptic bronchoscopy technique to obtain uncontaminated lower airway secretions for bacterial..., Wimberly [/bib_ref]. Bronchoscopy is impractical for routine use, because it is expensive, requires technical expertise, and may be difficult to perform in a timely manner. Some authorities favor its use in patients with a fulminant course, who require admission to an ICU, or have complex pneumonia unresponsive to antimicrobial therapy [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref] [bib_ref] Diagnostic fiberoptic bronchoscopy in patients with community-acquired pneumonia: comparison between bronchoalveolar lavage..., Jimenez [/bib_ref] [bib_ref] Assessing prognosis and predicting patient outcomes in community-acquired pneumonia, Gilbert [/bib_ref] [bib_ref] Fiberoptic bronchoscopy, Fulkerson [/bib_ref]. Bronchoscopy is especially useful for the detection of selected pathogens, such as P. carinii, Mycobacterium species, and cytomegalovirus [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref]. The IDSA panel recommends blood cultures and expectorated sputum Gram staining and culture as the only microbiological studies to be considered routine for patients hospitalized with CAP. Transtracheal aspiration, transthoracic needle aspiration, and bronchoscopy should be reserved for selected patients and then used only with appropriate expertise (B-III). With regard to recommendations about diagnostic approach, table 5 lists diagnostic studies recommended for hospitalized patients, according to severity of illness (B-II). ## Special considerations pneumococcal pneumonia S. pneumoniae is among the leading infectious causes of illness and death worldwide for young children, persons who have underlying chronic systemic conditions, and the elderly. A metaanalysis of 122 reports of CAP in the English-language literature from 1966 through 1995 showed that S. pneumoniae accounted for two-thirds of 17000 cases in which an etiologic diagnosis was made, as well as for two-thirds of the cases of lethal pneumonia [bib_ref] Prognosis and outcomes of patients with community-acquired pneumonia, Fine [/bib_ref]. In the United States, it is estimated that 125,000 cases of pneumococcal pneumonia necessitate hospitalization each year. A vaccine for the most common serotypes of S. pneumoniae is available, and the Advisory Committee on Immunization Practices recommends that the vaccine be administered to all persons aged у65 years and younger patients who have underlying medical conditions associated with increased risk for pneumococcal disease and its complications. Revaccination is recommended after 5-7 years. Until recently in the United States, S. pneumoniae was nearly uniformly susceptible to penicillin, which allowed clinicians to treat patients with severe pneumococcal infection with penicillin G alone or nearly any other commonly used antibiotic, without testing for drug susceptibility. Resistance of S. pneumoniae to penicillin and to other antimicrobial drugs, first noted in Australia and Papua New Guinea in the 1960s, was found to be a major problem in South Africa in the 1970s and, subsequently, in many countries in Europe, Africa, and Asia in the 1980s. In the United States, nonsusceptibility to penicillin has increased markedly during the last decade [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Antimicrobial resistant of Streptococcus pneumoniae in the United States, 1979-1987. The Pneumococcal..., Spika [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] and appears to be continuing [bib_ref] Surveillance of resistance among respiratory tract pathogens in the United States, Thornsberry [/bib_ref] [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref] [bib_ref] Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in..., Doern [/bib_ref]. The susceptibility of S. pneumoniae to penicillin is currently defined by the National Committee for Clinical Laboratory Standards (NCCLS) as follows. Susceptible isolates are inhibited by 0.06 mg/mL (i.e., the MIC is р0.06 mg/mL). Isolates with reduced susceptibility (also known as intermediate resistance) are inhibited by 0.1-1.0 mg/mL, and resistant isolates by у2.0 mg/mL. Amoxicillin is more effective than penicillin against pneumococci in vitro, with MIC thresholds that are higher. An important problem with these definitions is that, from a clinical point of view, the MIC has entirely different meaning, depending on the infection being treated. A strain with reduced susceptibility (e.g., MIC, 0.5 mg/mL) behaves as a susceptible organism when it causes pneumonia (see below) but probably not when it causes meningitis [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref] [bib_ref] Bacteriologic response to oral cephalosporins: are established susceptibility breakpoints appropriate in the..., Dagan [/bib_ref]. On the basis of present definitions and depending on the source of the isolates, as of June 1999 in the United States, ∼25%-35% of S. pneumoniae isolates from infected persons were intermediately resistant or resistant to penicillin [bib_ref] Surveillance of resistance among respiratory tract pathogens in the United States, Thornsberry [/bib_ref] [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref] [bib_ref] Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in..., Doern [/bib_ref]. Variations occur from city to city and within segments of the population or even within institutions in a single city, so the actual results vary greatly, depending on the source of the isolates. NCCLS definitions are based on levels achieved in CSF in cases of meningitis. Much higher levels are achieved in blood and in alveoli. For these reasons, in treating pneumonia with generally accepted doses of penicillins, intermediate resistance is not clinically important; resistance may be important, especially if it is high-grade (e.g., MIC, 14 mg/mL). Rates of resistance are substantially higher in many European countries than in the United States, with notable exceptions, such as the Netherlands and Germany; in these countries, accepted standards of practice strictly limit antibiotic usage, especially among very young children. Resistance to penicillin is only one small part of the picture. Although the majority of strains with reduced susceptibility to penicillin are susceptible to certain third-generation cephalosporins, such as cefotaxime or ceftriaxone (defined by an MIC р0.5 mg/mL), intermediate resistance to these drugs (MIC, 1.0 mg/mL), and resistance (MIC, 12.0 mg/mL) are increasing [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref]. In accordance with these definitions, up to one-half of strains with reduced penicillin susceptibility also have reduced susceptibility to these cephalosporins [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref]. A greater proportion exhibit resistance to other third-generation and to second-generation cephalosporins. As is the case for penicillin, pneumonia caused by intermediately resistant or even some resistant isolates is likely to respond to treatment with standard doses of cefotaxime or ceftriaxone. Cefuroxime is less active against S. pneumoniae, and the activity of this or other cephalosporins cannot be predicted by results of in vitro susceptibility tests with cefotaxime or ceftriaxone. Most important, resistance extends far beyond the b-lactam antibiotics. Although the genetics of pneumococcal resistance is complex, b-lactam-resistant organisms often have acquired genes that confer resistance to other classes of antimicrobials through transformation or conjugative transposons. Thus, pneumococci that are penicillin-resistant are also often resistant to other antibiotics, and the most appropriate term to characterize them is multiply antibiotic-resistant [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref] these data reflect the general situation in the United States as of October 1999). Resistance to some of these antimicrobials can be overcome by increasing the dose of antibiotic. Macrolides are an example. In the United States, most macrolide resistance is a result of increased drug efflux encoded by mefE (erythromycin MIC, 2-32 mg/mL, and susceptible to clindamycin); it is possible that this resistance may be overcome by achievable levels of macrolides [bib_ref] Pneumococcal macrolide resistance: myth or reality?, Amsden [/bib_ref]. In Europe, most macrolide resistance is due to a ribosomal methylase encoded by ermAM; this results in high-grade resistance to macrolides and resistance to clindamycin that probably cannot be overcome. It is important to emphasize that resistance to newer macrolides, such as azithromycin or clarithromycin, parallels resistance to erythromycin. The prevalence of resistance to tetracyclines among pneumococci is similar to that of resistance to macrolides, but resistance to trimethoprim-sulfamethoxazole (TMP-SMZ) is far more prevalent, and use of this combination is discouraged [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Surveillance of resistance among respiratory tract pathogens in the United States, Thornsberry [/bib_ref] [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref] [bib_ref] Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in..., Doern [/bib_ref]. Among FDA-approved drugs, only vancomycin and linezolid are currently effective against essentially all pneumococci. Fluoroquinolones are active against 198% of strains, including penicillin-resistant strains, but resistance to these drugs has begun to increase in some areas where they are used extensively [bib_ref] Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada, Chen [/bib_ref] [bib_ref] Emergence of fluoroquinolone resistance among multiply resistant strains of Streptococcus pneumoniae in..., Ho [/bib_ref] [bib_ref] Streptococcus pneumoniae resistance to fluoroquinolones, Wise [/bib_ref] [bib_ref] Increased incidence of ciprofloxacin resistance in penicillin-resistant pneumococci in Northern Ireland, Goldsmith [/bib_ref]. Of the newer drugs, the oxazolidinones [bib_ref] Activities of RPR 106972 (a new oral streptogramin), cefditoren (a new oral..., Spangler [/bib_ref] and glycopeptides [bib_ref] Comparative activities of LY 333328, a new glycopeptide, against penicillin-susceptible and -resistant..., Fasola [/bib_ref] appear to be most promising, with MICs for drug-resistant S. pneumoniae being no higher than those for penicillin-susceptible strains. Resistance to the streptogramins appears to parallel that to the macrolides. Studies of oral outpatient therapy for pneumonia, in which the majority of cases have probably been due to S. pneumoniae, have shown a good outcome, regardless what therapy is given; however, these studies were not designed to examine antibiotic resistance among pneumococci. Recommended antimicrobial agents for empirical treatment of pneumococcal pneumonia include amoxicillin (500 mg thrice daily), cefuroxime axetil (500 mg twice daily), cefpodoxime (200 mg twice daily), cefprozil (500 mg twice daily), and azithromycin, clarithromycin, erythromycin, or a quinolone or doxycycline in ordinarily prescribed dosages. Amoxicillin is preferred to penicillin because of more reliable absorption, longer half-life, and slightly more favorable MICs. Although recent surveillance studies indicate increasing resistance to macrolides, to date there is a paucity of reports of clinical failure in patients without risk factors for infection with drug-resistant S. pneumoniae [bib_ref] Pneumococcal macrolide resistance: myth or reality?, Amsden [/bib_ref]. With increasing use, however, there is concern about reduced efficacy of macrolides. In hospitalized patients, pneumococcal pneumonia caused by organisms that are susceptible or intermediately resistant to penicillin responds to treatment with penicillin (2 million units every 4 h), ampicillin (1 g every 6 h), cefotaxime (1 g every 8 h), or ceftriaxone (1 g every 24 h). Pneumonia due to penicillinor cephalosporin-resistant organisms probably requires higher doses of these drugs. Retrospective studies [bib_ref] Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in..., Pallares [/bib_ref] [bib_ref] Bacteremia with Streptococcus pneumoniae: implications for therapy and prevention. Franklin County Pneumonia..., Plouffe [/bib_ref] have shown a similar outcome after treatment with standard doses of a penicillin or a cephalosporin, without regard to whether pneumonia was due to susceptible or nonsusceptible organisms, but the number of subjects infected with resistant pneumococci (MIC, у2 mg/mL) was very small, and there was a trend toward worse outcomes in both studies [bib_ref] Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in..., Pallares [/bib_ref] [bib_ref] Bacteremia with Streptococcus pneumoniae: implications for therapy and prevention. Franklin County Pneumonia..., Plouffe [/bib_ref]. A CDC study found mortality associated with treated pneumococcal pneumonia to be increased 3-fold when the condition was due to penicillin-resistant pneumococci and 7-fold when due to ceftriaxone-resistant pneumococci, even after adjusting for severity of underlying illness and previous hospitalization, both of which increase the likelihood that resistant pneumococci will be present [bib_ref] Mortality from invasive pneumococcal pneumonia in an era of antibiotic resistance, 1995-1997, Feikin [/bib_ref]. This study, however, did not determine the nature of the treatment in each case. It seems likely that, ultimately, penicillin or ceftriaxone may not reliably cure infection caused by strains of S. pneumoniae for which penicillin MICs are у4 mg/mL and ceftriaxone MICs are у8 mg/mL. At present, many authorities treat pneumococcal pneumonia, even in critically ill patients, with cefotaxime (1 g every 6-8 h) or ceftriaxone (1 g every 12-24 h). Many patients have received 1-2 g of ampicillin (with or without sulbactam) every 6 h, with a good response. Although vancomycin is nearly certain to provide antibiotic coverage, there is a strong impetus not to use this drug until it is proven to be needed because of fear of the emergence of resistant organisms. Vancomycin or a fluoroquinolone should be used for initial treatment of pneumococcal pneumonia in critically ill patients who are allergic to b-lactam antibiotics. Quinupristin/dalfopristin or linezolid are other op- tions, but experience with these antimicrobial agents for pneumococcal pneumonia is extremely limited. ## Aspiration pneumonia Aspiration pneumonia is broadly defined as the pulmonary sequela of abnormal entry of material from the stomach or upper respiratory tract into the lower airways. The term generally applies to large-volume aspiration. There are at least 3 distinctive forms [bib_ref] Triple threat of aspiration pneumonia, Bartlett [/bib_ref] , based on the nature of the inoculum, the clinical presentation, and management guidelines: toxic injury of the lung (such as due to gastric acid aspiration or Mendelson's syndrome), obstruction (with a foreign body or fluids), or infection [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref]. These syndromes are reviewed elsewhere [bib_ref] Acid aspiration induced lung injury: new insights and therapeutic options, Matthay [/bib_ref] [bib_ref] Anaerobic bacterial infections of the lung and pleural space, Bartlett [/bib_ref]. Most studies show that aspiration is suspected in 5%-10% of patients hospitalized with CAP, although the criteria for this diagnosis are often not provided. In general, the diagnosis should be suspected when patients have a condition that predisposes them to aspiration (usually compromised consciousness or dysphagia) and radiographic evidence of involvement of a dependent pulmonary segment (lower lobes are dependent in the upright position; the superior segments of the lower lobes and posterior segments of the upper lobes are dependent in the recumbent position). Aspiration pneumonia is the presumed cause of nearly all cases of anaerobic pulmonary infection, and microaerophiles and anaerobes from the mouth flora are the anticipated pathogens in bacterial infections associated with aspiration. ## Anaerobic bacterial infections The frequency of infection that involves anaerobes among patients with CAP is not known, because the methods required to obtain uncontaminated specimens that are valid for anaerobic culture are rarely used. The usual specimens are transtracheal aspirates, pleural fluid, transthoracic needle aspirates, and uncontaminated specimens from metastatic sites [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref] [bib_ref] Bacteriologic diagnosis in anaerobic pleuropulmonary infections, Bartlett [/bib_ref] [bib_ref] Quantitative culture of bronchoalveolar lavage from patients with anaerobic lung abscesses, Henriquez [/bib_ref] ; a limited experience suggests that quantitative cultures of protected-brush or BAL specimens collected at bronchoscopy may be acceptable [bib_ref] Invasive diagnostic techniques in pulmonary infections, Bartlett [/bib_ref] [bib_ref] Diagnosis of bacterial pulmonary infections during quantitative protected catheter cultures obtained during..., Pollock [/bib_ref] [bib_ref] A fiberoptic bronchoscopy technique to obtain uncontaminated lower airway secretions for bacterial..., Wimberly [/bib_ref] [bib_ref] Bacteriologic diagnosis in anaerobic pleuropulmonary infections, Bartlett [/bib_ref]. Anaerobic and microaerophilic bacteria are the most common etiologic agents of lung abscess and aspiration pneumonia and are relatively common isolates in empyema [bib_ref] Anaerobic bacterial infections of the lung and pleural space, Bartlett [/bib_ref]. Characteristically, many bacterial species are isolated from infected tissues. Patients with anaerobic bacterial infection may also present with pneumonitis that is indistinguishable from other common forms of bacterial pneumonia on the basis of clinical features [bib_ref] Anaerobic bacterial pneumonitis, Bartlett [/bib_ref]. Clinical clues to this diagnosis include a predisposition to aspiration, infection of the gingival crevice (gingivitis), putrid discharge, necrosis of tissue with abscess formation or a bronchopulmonary fistula, infection complicating airway obstruction, chronic course, and infection in a dependent pulmonary segment [bib_ref] Anaerobic bacterial infections of the lung and pleural space, Bartlett [/bib_ref]. Anaerobes may also account for a substantial number of cases of CAP that do not have these characteristic features [bib_ref] Diagnosis of bacterial pulmonary infections during quantitative protected catheter cultures obtained during..., Pollock [/bib_ref] [bib_ref] Anaerobic bacterial infections of the lung and pleural space, Bartlett [/bib_ref] [bib_ref] Clindamycin compared with penicillin for the treatment of anaerobic lung abscess, Levison [/bib_ref]. With regard to therapy, the only comparative therapeutic trials for anaerobic lung infections have been with lung abscess, and these show clindamycin to be superior to iv penicillin [bib_ref] Clindamycin compared with penicillin for the treatment of anaerobic lung abscess, Levison [/bib_ref] [bib_ref] Clindamycin vs. penicillin for anaerobic lung infections: high rate of penicillin failures..., Gudiol [/bib_ref]. Using metronidazole alsone as antimicrobial therapy is associated with a high failure rate, presumably because of the role played by facultative and microaerophilic streptococci. Amoxicillin-clavulanate (A-I) also appears to be effective [bib_ref] Monotherapy using amoxicillin/ clavulanic acid as treatment of first choice in community-acquired..., Germaud [/bib_ref]. Antibiotics that are virtually always active against anaerobes in vitro include imipenem, meropenem, metronidazole, chloramphenicol, and any combination of a b-lactam / b-lactamase inhibitor. Moxifloxacin, gatifloxacin, and trovafloxacin also have good in vitro activity against most anaerobes. Macrolides, cephalosporins, and doxycycline have variable activity. TMP-SMZ and aminoglycosides are not active against most anaerobes. The IDSA panel recommends clindamycin, a b-lactam / blactamase inhibitor, imipenem, and meropenem as preferred drugs for treating pulmonary infections when anaerobic bacteria are established or suspected as the cause (B-I). ## C. pneumoniae pneumonia Although prevalence varies from year to year and within geographic settings, C. pneumoniae causes ∼5%-15% of cases of CAP [bib_ref] Incidence of community-acquired pneumonia requiring hospitalizations: results of a population-based active surveillance..., Marston [/bib_ref] [bib_ref] New and emerging etiologies for community-acquired pneumonia with implications for therapy: a..., Fang [/bib_ref] [bib_ref] Community-acquired pneumonia: impact of immune status, Mundy [/bib_ref] [bib_ref] Chlamydia pneumoniae (TWAR), Kuo [/bib_ref] [bib_ref] Pneumonia due to Chlamydia pneumoniae: prevalence, clinical features, diagnosis, and treatment, Kauppinen [/bib_ref] [bib_ref] Diagnostic methods for intracellular pathogens, Hammerschlag [/bib_ref] ; the majority of cases of pneumonia are relatively mild and associated with low mortality [bib_ref] Chlamydia pneumoniae (TWAR), Kuo [/bib_ref] [bib_ref] Pneumonia due to Chlamydia pneumoniae: prevalence, clinical features, diagnosis, and treatment, Kauppinen [/bib_ref]. C. pneumoniae pneumonia may present with sore throat, hoarseness, and headache as important nonpneumonic symptoms; other findings include sinusitis, reactive airways disease, and empyema. Reinfection is common, and hospitalization due to pneumonia caused by C. pneumoniae usually occurs for older patients who have reinfection, in which comorbidities undoubtedly play a significant role in the clinical course. When C. pneumoniae is found in association with other pathogens, particularly S. pneumoniae, the associated pathogen appears to determine the clinical course of the pneumonia [bib_ref] Chlamydia pneumoniae (TWAR), Kuo [/bib_ref]. Infection can be suspected with culture of C. pneumoniae, DNA detection and PCR, and serology (most specifically by microimmunofluorescent antibodies) [bib_ref] Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections..., Ieven [/bib_ref] [bib_ref] Diagnosis of Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydia pneumoniae lower respiratory infection..., Ramirez [/bib_ref] [bib_ref] Chlamydia pneumoniae (TWAR), Kuo [/bib_ref] [bib_ref] Pneumonia due to Chlamydia pneumoniae: prevalence, clinical features, diagnosis, and treatment, Kauppinen [/bib_ref] [bib_ref] Diagnostic methods for intracellular pathogens, Hammerschlag [/bib_ref]. However, cell culture is not routinely available except in research laboratories; in addition, PCR technology is not standardized, reagents for PCR are not FDA cleared, and serology is problematic because of nonspecificity [bib_ref] Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections..., Ieven [/bib_ref] [bib_ref] Prevalence of asymptomatic nasopharyngeal carriage of Chlamydia pneumoniae in subjectively healthy adults:..., Hyman [/bib_ref]. The preferred diagnostic finding is documentation of a 4-fold increase in titer from acute to convalescent specimens, with supporting evidence by PCR or culture. Accordingly, most laboratories cannot confirm a diagnosis of C. pneumoniae pneumonia in a timely fashion, so treatment must be empirical (A-II). For therapy, the IDSA panel recommends a macrolide, doxycycline, or a fluoroquinolone (B-II) [bib_ref] Pneumonia due to Chlamydia pneumoniae: prevalence, clinical features, diagnosis, and treatment, Kauppinen [/bib_ref] [bib_ref] Antimicrobial susceptibility and therapy of infections caused by Chlamydia pneumoniae, Hammerschlag [/bib_ref]. ## Legionnaires' disease Legionella is implicated in 2%-6% of CAP cases in most hospital-based series; some groups report higher rates that presumably reflect local epidemiology and/or more sensitive laboratory techniques [bib_ref] Incidence of community-acquired pneumonia requiring hospitalizations: results of a population-based active surveillance..., Marston [/bib_ref] [bib_ref] New and emerging etiologies for community-acquired pneumonia with implications for therapy: a..., Fang [/bib_ref] [bib_ref] Community-acquired pneumonia: impact of immune status, Mundy [/bib_ref] [bib_ref] Clinical diagnosis of legionnaires' disease (LD) using a multivariate model [abstract K55, Keller [/bib_ref]. Risk is related to exposure, increasing age, smoking, and compromised cell-mediated immunity such as in transplant recipients [bib_ref] Surveillance for legionnaires' disease: risk factors for morbidity and mortality, Marston [/bib_ref]. Although rare in immunocompetent adults aged !30 years, Legionella can be a major cause of lethal pneumonia, with mortality rates of 5%-25% among immunocompetent hosts and substantially higher rates among immunosuppressed hosts [bib_ref] Surveillance for legionnaires' disease: risk factors for morbidity and mortality, Marston [/bib_ref]. Tests commonly cost $50-$100 each, so routine use for hospitalized patients is not usually advocated [fig_ref] Table 9: Diagnostic studies for specific agents of community-acquired pneumonia [/fig_ref]. Major indications for testing include severe illness in adults requiring admission to the ICU, pneumonia in hospitalized patients with no other likely etiology (i.e., negative Gram stain), pneumonia in compromised hosts, evidence suggesting Legionella is endemic or epidemic in the area, lack of response to b-lactam antibiotics, or clinical features that suggest Legionella as the cause (C-III) [bib_ref] Reevaluation of the definition of legionnaires' disease: use of the urinary antigen..., Plouffe [/bib_ref]. Epidemiological risk factors for legionnaires' disease include recent travel with an overnight stay outside the home, recent changes in domestic plumbing, renal or hepatic failure, diabetes, and systemic malignancy [bib_ref] Surveillance for legionnaires' disease: risk factors for morbidity and mortality, Marston [/bib_ref]. Some authorities feel that the following constellation of clinical features suggests this diagnosis: high fever, hyponatremia, CNS manifestations, lactate dehydrogenase levels 1700 units/mL, or severe disease. Methods of laboratory detection include culture, serology, DFA staining, urinary antigen assay, and PCR. DFA stains require substantial expertise for interpretation, and selection of reagents is critical. PCR is expensive, and there are no FDAcleared reagents. Tests recommended by the IDSA panel are urinary antigen assay for L. pneumophila serogroup 1, which is not technically demanding and reliably and rapidly detects up to 70% of cases of legionnaires' disease, and culture on selective media, which detects all strains but is technically demanding [bib_ref] Surveillance for legionnaires' disease: risk factors for morbidity and mortality, Marston [/bib_ref] (B-II). Historically, the preferred therapeutic agent has been erythromycin, usually in a total daily dose of 2-4 g iv, with or without rifampin (600 mg po q.d.); erythromycin (500 mg po q.i.d., to complete 2-3 weeks of treatment) can be substituted after there has been clinical response. Many authorities now consider azithromycin or a fluoroquinolone to be preferred for severe disease. This preference is based on results superior to those with erythromycin in animal models and, in addition, on poor tolerance of erythromycin [bib_ref] Surveillance for legionnaires' disease: risk factors for morbidity and mortality, Marston [/bib_ref] [bib_ref] Antimicrobial chemotherapy for legionnaires' disease: a review, Edelstein [/bib_ref] [bib_ref] Antimicrobial therapy for legionnaires' disease: time for a change, Edelstein [/bib_ref]. FDA-approved drugs for administration against Legionella are erythromycin, azithromycin, ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, and gatifloxacin. A delay in therapy is associated with increased mortality [bib_ref] Delay in appropriate therapy of legionella pneumonia associated with increased mortality, Heath [/bib_ref]. The IDSA panel considers doxycycline, azithromycin, ofloxacin, ciprofloxacin, and levofloxacin to be preferred for legionnaires' disease, on the basis of available data (B-II). These drugs are available for oral and parenteral administration. The duration of treatment should be 10-21 days, although less for azithromycin because of its long half-life. ## Hps HPS is a frequently lethal systemic disease of previously healthy young adults that was originally recognized in May 1993. At least 5 viruses have been implicated [bib_ref] Hantavirus: a global disease problem, Schmaljohn [/bib_ref] [bib_ref] Long-term studies of hantavirus reservoir populations in the Southwestern United States: rationale,..., Mills [/bib_ref] [bib_ref] An outbreak of hantavirus pulmonary syndrome, Toro [/bib_ref]. The most common in the United States is Sin Nombre virus, which is carried by the deer mouse. Cases of HPS have been reported in nearly every region of the United States, but most cases have been found in the Four Corners area: New Mexico, Arizona, Utah, and Colorado. The median age of patients for the first 100 United States cases was 35 years, and the overall case fatality rate was 52% [bib_ref] Hantavirus pulmonary syndrome: the first 100 US cases, Khan [/bib_ref]. Common features of the prodromal phase include fever, chills, myalgias, headache, nausea, vomiting, and/or diarrhea. A cough is common but is not a prominent early feature. Initial symptoms resemble those of other common viral infections. Characteristic features often become evident after the 3-6 day prodrome and include characteristic laboratory changes, chest radiographic evidence of capillary leakage (adult respiratory distress syndrome [ARDS]), and oxygen desaturation. Other, more common causes of ARDS for consideration are chronic pulmonary disease, malignancy, trauma, burns, and surgery. Among lethal cases of HPS, the median time of death is 5 days after onset of the disease. Typical laboratory findings include hemoconcentration, thrombocytopenia, leukocytosis with a left shift, and circulating immunoblasts. Additional laboratory findings include an elevated serum lactate dehydrogenase level, arterial partial pressure of oxygen !90 mm Hg, and increased serum lactate level. The diagnosis is established by detection of hantavirusspecific IgM, increasing titers of hantavirus-specific IgG, hantavirus-specific RNA (by PCR) in clinical specimens, or hantavirus antigen (by immunohistochemistry) [bib_ref] Hantavirus pulmonary syndrome: the first 100 US cases, Khan [/bib_ref]. These laboratory tests should be performed or confirmed at a reference laboratory. Treatment consists of supportive care that often requires intubation and mechanical ventilation with positive end-expiratory pressure. These patients also require hemodynamic support. Ribavirin inhibits Sin Nombre virus in vitro, but the initial clinical experience has been disappointing. A controlled trial is ongoing. ## M. pneumoniae pneumonia M. pneumoniae is a common cause of respiratory tract infections, primarily in those aged 5-9 years and in young adults. This organism causes a small percentage of cases of CAP requiring hospitalization . The incubation period is 2-4 weeks, so epidemics in closed populations evolve slowly. The most common presentation is tracheobronchitis; ∼3% of patients who are acutely infected with Mycoplasma have pneumonia demonstrable by chest radiography. Common symptoms with pneumonia include a prodromal period with fever, chills, headache, and sore throat, followed by a cough that is dry or produces mucoid sputum [bib_ref] Mycoplasma infections of man, Chanock [/bib_ref] [bib_ref] Mycoplasma pneumoniae pneumonia in an urban area, Foy [/bib_ref]. The cough is frequently most severe at night and may persist for 3-4 weeks. A possible clue to this diagnosis is a history of contact with a person with a similar condition, characterized by a long incubation period. Extrapulmonary manifestations may include cold hemagglutination and hemolytic anemia; nausea; vomiting; and, rarely, myocarditis, skin rash, and, diverse neurological syndromes. Laboratory tests to confirm infection due to M. pneumoniae include culture, serology, and PCR [bib_ref] Infections due to species of Mycoplasma and Ureaplasma: an update, Taylor-Robinson [/bib_ref] [bib_ref] Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections..., Ieven [/bib_ref] [bib_ref] Comparison of PCR, culture, and serological tests for diagnosis of Mycoplasma pneumoniae..., Dorigo-Zetsma [/bib_ref] [bib_ref] Diagnosis of Mycoplasma pneumoniae pneumonia in children, Waris [/bib_ref]. Fastidious growth requirements and long incubation periods limit utility of culture, and most laboratories do not offer this test. IgM and IgG antibody values become elevated in most cases, but the response is often delayed, so the utility of these tests for early detection is limited, and reported results are variable [bib_ref] Comparison of PCR, culture, and serological tests for diagnosis of Mycoplasma pneumoniae..., Dorigo-Zetsma [/bib_ref] [bib_ref] Diagnosis of Mycoplasma pneumoniae pneumonia in children, Waris [/bib_ref]. Some authorities consider PCR to be particularly promising [bib_ref] Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections..., Ieven [/bib_ref] [bib_ref] Comparison of PCR, culture, and serological tests for diagnosis of Mycoplasma pneumoniae..., Dorigo-Zetsma [/bib_ref]. Current problems with amplification techniques include great variability due to differences in methods of sample collection, sample preparation, and amplification procedures; there are also no FDA-cleared reagents for PCR for detection of Mycoplasma. Cold agglutinin titers у1:64 support this diagnosis, and the cold agglutinin response correlates with the severity of pul-monary symptoms, but the test lacks both sensitivity and specificity. It is suggested that a single CF antibody titer у1:64, combined with a cold agglutinin titer у1:64, supports this diagnosis [bib_ref] Mycoplasma infections of man, Chanock [/bib_ref] [bib_ref] Infections due to species of Mycoplasma and Ureaplasma: an update, Taylor-Robinson [/bib_ref]. The antibody response usually develops at 7-10 days after the onset of symptoms and shows peak levels at ∼3 weeks. Changes on chest radiography are nonspecific. Most common is a unilateral infiltrate, but one-third of patients have bilateral changes. The IDSA panel concludes that no available diagnostic test reliably and rapidly detects M. pneumoniae. Thus, therapy must usually be empirical (B-II). The panel recommends treatment with tetracycline or a macrolide for most cases; an alternative is a fluoroquinolone (B-III). Treatment should be given for 2-3 weeks to reduce the risk of relapse. The role of antibiotic therapy for extrapulmonary manifestations is not established. ## P. carinii pneumonia (pcp) PCP is not included in the guidelines for management of CAP in the immunocompetent host because it is seen exclusively in patients with defective cell-mediated immunity. Nevertheless, this is a relatively common and important form of pneumonia, especially in patients with HIV infection who may still be unaware of the underlying infection. One study of 385 consecutive hospitalizations for CAP in an urban hospital in 1991 showed that 46% of patients had HIV infection, and 19% of these patients were unaware of their HIV status at the time of admission [bib_ref] Community-acquired pneumonia: impact of immune status, Mundy [/bib_ref]. The point to emphasize is that PCP is the most common initial AIDS-defining diagnosis and should be suspected in selected patients, even in the absence of known immunodeficiency. Characteristic clinical features of PCP include nonproductive cough, fever, and dyspnea that evolve over a period of weeks. The average patient has had pulmonary symptoms for 4 weeks at the time of initial presentation; this relatively slow tempo of disease distinguishes PCP in patients with AIDS from common forms of bacterial pneumonia. The usual associated laboratory features include lymphopenia (total lymphocyte count, !1000 cells/mL), CD4 lymphopenia (!200 cells/mL in 195% of patients), arterial hypoxemia, and chest radiographic evidence of bilateral interstitial infiltrates with a highly characteristic "ground glass" appearance. Up to 30% of patients have negative chest radiographs, which makes this illness the only relatively common form of pneumonia associated with false-negative chest radiographs [bib_ref] Shortcomings of chest radiography in detecting Pneumocystis carinii pneumonia, Opravil [/bib_ref]. The diagnostic yield with induced sputum averages 60% but varies greatly, depending on quality control [bib_ref] Rapid noninvasive diagnosis of Pneumocystis carinii from induced liquefied sputum, Zaman [/bib_ref]. The yield with bronchoscopy exceeds 95%. The disease is uniformly fatal if not treated. TMP-SMZ, dapsone-trimethoprim, and clindamycin-primaquine appear to be equally effective for treating patients who have moderately severe disease [bib_ref] Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii..., Safrin [/bib_ref]. No currently recommended therapy for CAP is probably effective for PCP. The mortality rate among treated patients who are hospitalized is usually reported to be 15%-20%. ## Influenza Influenza is clearly the most common serious viral airway infection of adults in terms of morbidity and mortality. Seasonal epidemics in the United States are commonly associated with у20,000 deaths that are ascribed to this infection and its complications, primarily bacterial superinfections. The great pandemics of influenza in the past century were of "Spanish flu," which in 1918 was responsible for 120 million deaths worldwide, Asian influenza (1957), and Hong Kong influenza (1968). The great majority of deaths in annual influenza epidemics are of patients who are aged 165 years, and a disproportionate number are of residents of chronic care facilities. The most common cause of bacterial superinfection is S. pneumoniae; in an era when S. aureus was the principal cause of hospital-acquired infection, this organism was prevalent [bib_ref] Asian influenza A in Boston, Martin [/bib_ref]. Rapid identification tests are available and can lead to an etiologic diagnosis in 15-20 min with a sensitivity of 70%-90%. A diagnosis can often be made with comparable sensitivity on the basis of typical symptoms in nonvaccinated patients during an influenza epidemic. In general, influenza A is more severe and shows greater antigenic heterogeneity than does influenza B. Amantadine or rimantadine appears to reduce the duration and severity of symptoms in patients with influenza A, but these drugs have no activity against influenza B [bib_ref] Oral rimantadine hydrochloride therapy of influenza A virus H3N2 subtype infection in..., Hayden [/bib_ref]. Zanamivir [bib_ref] Treating influenza with zanamivir, Read [/bib_ref] [bib_ref] Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of..., Hayden [/bib_ref] and oseltamivir [bib_ref] Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza, Hayden [/bib_ref] are active against influenza A and B viruses. The relative efficacy of these neuraminidase inhibitors versus that of amantadine and rimantadine for treating or preventing influenza A is unknown [bib_ref] Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza, Hayden [/bib_ref]. Clinical trials to date show that all 4 drugs reduce the duration of fever by 1-1.5 days when given within 48 h of the onset of symptoms. All 4 antimicrobial agents are also effective in influenza prevention, but the most effective prophylaxis is with annual administration of vaccine, which has been shown to have efficacy of 160% for preventing transmission in 10 of the last 11 influenza seasons. Efficacy for prevention is reduced in elderly residents of chronic care facilities, but effectiveness in preventing mortality is often reported to be 70%-80% in this latter population, depending, to some extent, on the match between the epidemic strain and the constituents of the vaccine [bib_ref] The efficacy of influenza vaccine in elderly persons: a meta-analysis and review..., Gross [/bib_ref]. A provocative report suggests that vaccination of health care providers in chronic care facilities is as important, or more important, than vaccination of the patients [bib_ref] Influenza vaccination of health care workers in long-term care hospitals reduces the..., Potter [/bib_ref]. Another report showed an 88% rate of vaccine efficacy and reduced absence for respiratory illness among hospital-based health care workers [bib_ref] Effectiveness of influenza vaccine in health care professionals, Wilde [/bib_ref]. These data emphasize the importance of vaccine strategies that target the populations at greatest risk, including persons aged у65 years, patients with cardiopulmonary disease, and residents of nursing homes and their care providers (A-I). ## Empyema The traditional definition of pleural empyema is pus in the pleural space. More recent investigators have used pleural fluid analyses; a pleural effusion with a pH !7.2 usually indicates a need for drainage [bib_ref] Pleural fluid chemical analysis in parapneumonic effusions: a meta-analysis, Heffner [/bib_ref]. This complication occurs in 1%-2% of all cases of CAP and in up to 5%-7% of hospitalized patients with CAP [bib_ref] Bacteremic and nonbacteremic pneumococcal pneumonia: a prospective study, Musher [/bib_ref] [bib_ref] Parapneumonic effusions, Light [/bib_ref]. The incidence of empyema has decreased substantially from the preantibiotic era, when S. pneumoniae accounted for about two-thirds of cases, and the bacteriology also has changed. A meta-analysis of 1289 cases of empyema reported during 1970-1995 shows that S. pneumoniae now is isolated in only 5%-10% of cases; the majority involve anaerobic bacteria, S. aureus, and/or gram-negative bacilli. Many are mixed infections. It is uncertain in how many culturenegative cases are caused by pneumococci that were eradicated by prior antibiotic treatment. Most studies of CAP show that up to 57% of patients have pleural effusions identified by routine chest radiography [bib_ref] Management of complicated parapneumonic effusions, Sahn [/bib_ref]. Empyema is infrequent in these patients, but it is important to recognize because of its implications regarding the need for adequate drainage as a critical component of effective management. Some authorities recommend thoracentesis for any parapneumonic effusion that measures 110 mm on a lateral decubitus radiograph [bib_ref] Management of complicated parapneumonic effusions, Sahn [/bib_ref]. Standard tests to be performed on pleural fluid include appropriate stains and culture for aerobic and anaerobic bacteria, as well as measurement of pH, lactic dehydrogenase concentration, and leukocyte and differential counts. Particularly important is the pH determination, for which the fluid must be obtained anaerobically, placed on ice, and transported immediately to the laboratory. Drainage is required when there is pus in the pleural space, a positive Gram stain or culture, or a pH !7.2. Neither the lactic dehydrogenase level nor the glucose level is as sensitive as pH for this prediction. The drainage may be done with a chest tube, image-guided catheters, thoracoscopy, or thoracotomy. The relative merits and indications for use of image-guided chest tubes, catheters with thrombolytics, and thoracoscopic or thoracotomy decortication are not well defined. ## Ab AB is one of the most common yet least understood (and overtreated) problems seen in an outpatient setting. Bronchitis ranks among the most common conditions seen in an outpatient setting, accounting for ∼42% of all primary diagnoses assigned for patients with cough (compared with 5% for pneumonia) [bib_ref] National trends in the use of antibiotics by primary care physicians for..., Metlay [/bib_ref]. Because clinical manifestations of AB may be similar to those of pneumonia, distinguishing between these conditions by chest radiography is paramount to optimizing therapy. AB is generally used to describe a transient (usually !15 days' duration) respiratory illness that occurs among patients without chronic lung inflammatory conditions and is characterized by cough (with or without sputum, fever, and/or substernal discomfort) and in the absence of radiographic findings of pneumonia. However, there is no clear consensus on the definition of AB. The lack of a standardized case definition of AB or established value of microbiological studies and the high rate of spontaneous resolution interfere with the establishment of a firm diagnosis and rational implementation of appropriate treatment [bib_ref] Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on..., Gonzales [/bib_ref]. The differential diagnosis of cough requires consideration of both infectious and noninfectious etiologies. Among noninfectious causes are smoking, asthma, postnasal drip syndrome, angiotensin-converting enzyme inhibitors, and pollutants. Cough due to infection includes a spectrum of conditions, such as nasopharyngeal infection (common cold), AB, chronic bronchitis, sinusitis, and pneumonia. A better understanding that cough (even with sputum or if prolonged) is an expected part of uncomplicated viral respiratory infection and not necessarily indicative of bacterial infection should help practitioners and patients avoid unnecessary antimicrobial use [bib_ref] Preventing the emergence of antibiotic resistance, Schwartz [/bib_ref] [bib_ref] Rhinovirus infections in an industrial population. II. Characteristics of illness and antibody..., Gwaltney [/bib_ref]. Approximately 40% of persons experimentally infected with rhinovirus experience cough as a prominent symptom. The cough persists longer than other symptoms; in fact, after 14 days, ∼20% of such patients still have cough [bib_ref] Rhinovirus infections in an industrial population. II. Characteristics of illness and antibody..., Gwaltney [/bib_ref]. Auscultatory findings are nonspecific and are often normal, but variable findings, such as localized rales, wheezing, and prolonged expiratory phase, may be noted, especially in patients with reactive airway disease. Distinguishing AB from nonserious pneumonia has important therapeutic and prognostic implications. Published studies of pneumonia indicate that no combination of clinical findings can reliably define the presence of pneumonia [bib_ref] Does this patient have communityacquired pneumonia?, Metlay [/bib_ref]. Although the absence of any vital sign abnormality or any abnormalities on chest auscultation substantially reduces the likelihood of pneumonia, this constellation of findings does not rule out this illness. Therefore, the only standard criterion to differentiate these conditions is chest radiography. The syndrome of AB is most often associated with respiratory viruses for which antibacterial therapy is unwarranted [bib_ref] Antibiotic prescribing for adults with colds, upper respiratory tract infections and bronchitis..., Gonzales [/bib_ref] [bib_ref] Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on..., Gonzales [/bib_ref] [bib_ref] Airway infection, Nirourmand [/bib_ref]. However, no well-controlled studies that use modern diagnostic methods have been performed recently that would enable systematic evaluation of the role of respiratory pathogens. The most common viruses identified have been the common cold viruses, rhinovirus and coronavirus; others include influenza virus, adenovirus, parainfluenza virus, and RSV. A small proportion of cases are of nonviral etiology. M. pneumoniae, C. pneumoniae, and Bordetella pertussis have been linked to AB [bib_ref] Role of the microbiology laboratory in the diagnosis of lower respiratory tract..., Reimer [/bib_ref]. There is little evidence that S. pneumoniae or H. influenzae has an important role in the etiology of AB in adults with community-acquired infections in the absence of chronic obstructive lung disease, airway violation (e.g., tracheostomy), immunosuppression (e.g., AIDS), or serious associated disease, such as cystic fibrosis. For persons with acute exacerbation of chronic obstructive pulmonary disease, semiquantitative analysis of sputum by microscopic examination and culture suggest that H. influenzae and S. pneumoniae may be in greater concentrations than in the absence of exacerbation [bib_ref] Acute bacterial exacerbations in bronchitis and asthma, Chodosh [/bib_ref]. The data, however, are inconsistent [bib_ref] Role of infection in chronic bronchitis, Gump [/bib_ref] , and most exacerbations appear to be due to factors other than bacterial infection. The value of antibacterial agents in the treatment of immunocompetent patients with AB has not been confirmed, and the use of these agents is not recommended. Several controlled trials suggest that antibiotics for the majority of patients with cough due to AB are of no measurable benefit [bib_ref] Antibiotic prescribing for adults with colds, upper respiratory tract infections and bronchitis..., Gonzales [/bib_ref] [bib_ref] Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on..., Gonzales [/bib_ref] [bib_ref] Management of complicated parapneumonic effusions, Sahn [/bib_ref] [bib_ref] Treatment of acute bronchitis in adults without underlying lung disease, Mackay [/bib_ref] [bib_ref] Acute bronchitis, Hueston [/bib_ref] [bib_ref] Randomized, placebocontrolled trials of antibiotics for acute bronchitis: a critical review of..., Orr [/bib_ref]. Conflicting results of clinical trials may be explained by variations in methodology and patient type (including patients with acute exacerbations of chronic bronchitis). In contrast, some studies have demonstrated bronchodilators (e.g., albuterol) to be more effective than antibiotics for the relief of symptoms [bib_ref] Treatment of acute bronchitis in adults without underlying lung disease, Mackay [/bib_ref] [bib_ref] Acute bronchitis, Hueston [/bib_ref]. Despite information that antibiotics are generally not indicated for AB, studies indicate that primary care providers use them in the majority of cases [bib_ref] High-resolution computed tomography for the diagnosis of community-acquired pneumonia, Syrjala [/bib_ref]. This overuse of antibiotics increases the pressure that leads to antimicrobial resistance. Several reasons are given to justify use of antibiotics in AB: (1) patients' expectations; (2) the possible benefit of preventing secondary bacterial infection; and (3) the possibility of treatable causes (i.e., infections with Mycoplasma or Chlamydia). It must be remembered that there are no data showing that treatment against these organisms has a favorable effect in bronchitis. In addition, a recent study found that patients' satisfaction did not depend on receipt of an antibiotic prescription, as long as physicians explained the rationale for management [bib_ref] Antibiotics and respiratory infections: are patients more satisfied when expectations are met?, Hamm [/bib_ref] , and another study showed that antibiotic abuse in cases of AB was reduced when both physicians and patients were warned of the consequences of this practice [bib_ref] Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on..., Gonzales [/bib_ref]. Numerous studies support this recommendation, including a meta-analysis that showed only a slight benefit was gained with antibiotic therapy. The authors concluded that the disadvantages of antibiotics outweigh this modest benefit [bib_ref] Antibiotics in acute bronchitis: a meta-analysis, Bent [/bib_ref]. Until cost-effective, accurate, and rapid diagnostic tests (i.e., PCR of throat swab specimens) are available to confirm causes such as Mycoplasma or Chlamydia, the IDSA panel recommends reserving antibiotic therapy (i.e., with macrolides or tetracyclines) for patients with severe or persistent disease (e.g., [bib_ref] Pneumococcal macrolide resistance: myth or reality?, Amsden [/bib_ref] days' duration) [bib_ref] Parapneumonic effusions, Light [/bib_ref] and then only if there is a reasonable likelihood of pertussis [bib_ref] Prevalence and incidence of adult pertussis in an urban population, Nenning [/bib_ref]. (The rationale for antibiotic treatment late in the course of pertussis is to reduce transmission.) The IDSA panel agrees with others in encouraging all physicians to identify methods to decrease unnecessary antimicrobial use for AB by improving their clinical approach or by communicating with patients concerning the lack of benefit, possible side effects, and development of resistance associated with such therapy [bib_ref] Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on..., Gonzales [/bib_ref] [bib_ref] Management of complicated parapneumonic effusions, Sahn [/bib_ref]. The practice of withholding antibiotics to most patients with cough illness is supported by the literature and is not associated with an increase in office visits [bib_ref] Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on..., Gonzales [/bib_ref]. The cost of follow-up visits for those patients whose conditions do not improve over a few days should be balanced against the high likelihood of spontaneous resolution and the risk to the patients and the community of unnecessary antibiotic use. An exception to this admonition is consideration of an anti-influenza agent administered within 48 h of the onset of symptoms. ## Pneumonia in the context of bioterrorism There is increasing appreciation of the potential for bioterrorism, either from dissidents or from foreign countries. The relevance of this to pneumonia guidelines is based on the observation that several microbes that could be used as weapons would be expressed as pneumonia. A number of microbes could be disseminated as biological weapons by aerosol as an invisible, odorless, tasteless inoculum that could afflict as many as thousands of patients after an incubation period of days to weeks. In this setting, the etiologic agents most likely to cause severe pulmonary infection are Bacillus anthracis, Yersinia pestis, and F. tularensis [bib_ref] The looming threat of bioterrorism, Henderson [/bib_ref] [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref]. Recognition of these conditions would be by medical practitioners, and it is critical to implement appropriate strategies to establish the diagnosis, treat afflicted patients, and provide preventive treatment to those exposed. Thus, the "first responders" for bioterrorism are expected to be physicians in office practice, emergency rooms, ICUs, and in the discipline of infectious diseases. It should be acknowledged that national planning for a civilian medical and public health response is only now being initiated. B. anthracis, the cause of inhalational anthrax, is one of the organisms that could be used for biological terrorism that causes the most concern because of the environmental stability of its spores, the small inoculum necessary to produce fulminant infection, and the high associated mortality rate. The incubation period is quite variable-most cases present in the first several days after exposure, but the incubation period can be у6 weeks [bib_ref] Anthrax: civilian medical and public health management following use of a biological..., Inglesby [/bib_ref]. The initial symptoms are nonspecific, with fever, malaise, chest pain, and a nonproductive cough. This may be followed by brief improvement and then severe respiratory distress, shock, and death. This is not a true pneumonia; chest radiographs most often show a highly characteristic widened mediastinum without parenchymal infiltrates. The diagnosis is established with positive blood cultures that may be initially dismissed as having a "Bacillus contaminant," unless there are multiple such "contaminants" in a single facility; sputum cultures are negative. The mortality rate without treatment is 195%. In fact, the mortality rate remains 180% if treatment is not initiated before the de-velopment of clinical symptoms [bib_ref] Plague as a biological weapon: medical and public health management. Working Group..., Inglesby [/bib_ref]. Administration of iv penicillin in high doses has historically been considered the preferred therapy, but reports of engineered resistance have been published. Thus, empirical treatment before sensitivity tests of the responsible strain should be oral or iv ciprofloxacin, with doxycycline or penicillin as an alternative. Sensitivity tests for initial cases may be used to dictate antibiotic choices for subsequent patients. Treatment should be continued for 60 days because of the potential problem of prolonged incubation, with delayed but equally lethal disease. Since no human-to-human transmission occurs, standard isolation precautions are appropriate. Particularly important will be prophylaxis for those who are in the region of exposure; determining the population at risk will require emergent assessment by public health officials. The preferred regimens are ciprofloxacin (500 mg po b.i.d.), doxycycline (100 mg po b.i.d.), or amoxicillin (500 mg po q8h), depending on susceptibility of the epidemic strain. Prophylaxis should be continued for 60 days. Ciprofloxacin and doxycycline are advocated, because they are highly active in vitro and have established efficacy in the animal model [bib_ref] Anthrax: civilian medical and public health management following use of a biological..., Inglesby [/bib_ref]. Other fluoroquinolones are probably equally effective. These factors are emphasized because of the possibility that regional supplies may be limited with large-scale exposures. F. tularensis causes infections per year in the United States but caused hundreds of thousands of infections in Europe in World War II. Its potential as a biological weapon was substantiated by extensive studies performed by the US biological weapons program in the 1960s. There are multiple forms of disease, but the most common following aerosol exposure is "typhoidal" or "pneumonic" tularemia. The average incubation period is 3-5 days [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref]. Symptoms are nonspecific and include fever, malaise, and nonproductive cough. Chest radiographs show evidence of pneumonia with or without mediastinal adenopathy. If tularemia is suspected, the organism may be cultured from blood, sputum, or pharyngeal exudates, but only with difficulty. Culture media that contains cysteine or other sulfhydryl compounds should be used. This organism represents a hazard to laboratory personnel, and culture should be attempted only in a BL-3 laboratory. The usual method for diagnosis is serology, which is positive in the second week of disease in 50%-70% of cases. Standard treatment is with streptomycin or gentamicin; tetracycline and chloramphenicol are also effective but are associated with higher rates of relapse. Tetracycline has been used effectively as postexposure prophylaxis. There is minimal risk of personto-person spread. The recommendation for prophylaxis for exposed persons is administration of tetracycline or doxycycline for 2 weeks. Y. pestis is also a potential biological weapon of great concern because of it has a fulminant course of infection, causes death in the absence of antibiotic treatment, and can be spread from person to person. Clinical features of pneumonia plague include high fever, chills, headache, cough, bloody sputum, leukocy-tosis, and radiographic changes that show bilateral pneumonia, with rapid progression to septic shock and death [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref]. The acutely swollen, tender lymph node or bubo that is highly characteristic of bubonic plague is unlikely to be present. The diagnosis is established with culture of sputum or blood; sputum Gram stain shows typical safety-pin, bipolar-staining gram-negative coccobacilli. Health care workers are at risk for aerosol exposure, so respiratory precautions should be taken until patients have had 48 h of therapy. The standard treatment for plague pneumonia is administration of streptomycin or gentamicin in standard doses for 10 days [bib_ref] Plague as a biological weapon: medical and public health management. Working Group..., Inglesby [/bib_ref]. Alternatives for the mass-casualty setting are tetracyclines or fluoroquinolones given orally for 10 days. Administration of tetracyclines or fluoroquinolones for 7 days is the preferred prophylaxis when face-to-face contact has occurred or exposure is suspected. The licensed plague vaccine has not been found to protect against or ameliorate pneumonic plague and has no role in this setting. ## Management Management recommendations within this document are restricted to immunocompetent adults with acute CAP and are stratified on the basis of whether patients are treated as outpatients or are hospitalized (figure 2). Emphasis is accorded to the following: 1. Rational use of the microbiology laboratory: patients who are candidates for hospitalization with acute pneumonia should have blood cultures performed and an expectorated sputum specimen collected (in the presence of the physician whenever possible) before antimicrobial administration, unless these procedures would substantially delay initiation of treatment (B-II). Consensus is lacking as to the need for microbiological diagnosis for outpatients, although preparation of an air-dried, heat-fixed slide of sputum (obtained before antimicrobial treatment for subsequent Gram staining) is desirable. Investigation for selected microbial pathogens, such as Legionella and Mycobacterium, will depend on clinical features. 2. Pathogen-directed antimicrobial therapy: an attempt should be made to achieve pathogen-directed antimicrobial therapy for hospitalized patients [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref]. This decision should be made when relevant information becomes available, and its strength is greatest in cases when an established etiologic agent has been identified, according to criteria described above. Empirical selection of antimicrobial agents, when necessary, should be directed against the pathogens that are most common and treatable, according to the setting [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref]. Antibiotic regimens selected empirically should be changed when results of culture and in vitro sensitivity tests become available, on the assumption that clinical and microbiological correlations support this tactic. 3. Prompt antimicrobial treatment: antimicrobial treatment should be initiated promptly after the diagnosis of pneumonia is established with radiography and after Gram stain results are available to facilitate antimicrobial selection. For patients requiring hospitalization for acute pneumonia, it is important to initiate therapy in a timely fashion; an analysis of 14,000 patients showed that a 18-h delay from the time of admission to initiation of antibiotic therapy was associated with an increase in mortality (B-II) [bib_ref] Quality of care, process and outcomes in elderly patients with pneumonia, Meehan [/bib_ref]. Antibiotic treatment should not be withheld from acutely ill patients because of delays in obtaining appropriate specimens or the results of Gram stains and cultures. 4. Decisions regarding hospitalization based on prognostic criteria, as summarized in table 4 (A-I): in addition, this decision will be influenced by other factors, such as the availability of home support, probability of compliance, and availability of alternative settings for supervised care. Many patients with CAP are hospitalized for a concurrent disease process. Studies show that 25%-50% of admissions for CAP are for these other considerations, which extend beyond those listed as admission criteria in table 4 [bib_ref] A prediction rule to identify low-risk patients with community-acquired pneumonia, Fine [/bib_ref] [bib_ref] Safely increasing the proportion of patients with community-acquired pneumonia treated as outpatients:..., Atlas [/bib_ref]. ## Management of patients who do not require hospitalization Diagnostic studies. The diagnosis of pneumonia requires the demonstration of an infiltrate on chest radiography. Posteroanterior and lateral chest radiography is recommended when pneumonia is suspected (A-II), although obtaining these radiographs may not always be practical. Additional diagnostic studies for patients who are candidates for hospitalization are summarized in table 5 (B-II). For patients who are not seriously ill and do not require hospitalization, it is desirable to perform a sputum Gram stain, with or without culture. A complete blood cell count with differential is sometimes useful to assess the illness further, in terms of detecting the severity of the infection, presence of associated conditions, and chronicity of infection. Pathogen-directed therapy. Treatment options are obviously simplified if the etiologic agent is established or strongly suspected. Antibiotic decisions based on microbial pathogens are summarized in table 14 (C-III). Empirical antibiotic decisions. The selection of antibiotics in the absence of an etiologic diagnosis (when Gram stains and cultures are not diagnostic) is based on multiple variables, including severity of the illness, the patient's age, antimicrobial intolerance or side effects, clinical features, comorbidities, concomitant medications, exposures, and epidemiological setting (B-II) (tables 7 and 15). Preferred antimicrobials. The antimicrobial agents preferred for most patients are (in no special order) a macrolide (erythromycin, clarithromycin, or azithromycin; clarithromycin or azithromycin is preferred if H. influenzae is suspected), doxycycline, or a fluoroquinolone (levofloxacin, moxifloxacin, gatifloxacin, or another fluoroquinolone with enhanced activity against S. pneumoniae). Alternative options. Amoxicillin-clavulanate and some second-generation cephalosporins (cefuroxime, cefpodoxime, and cefprozil) are appropriate for infections ascribed to S. pneumoniae or H. influenzae. These agents are not active against atypical agents. Some authorities prefer macrolides or doxycycline for patients aged !50 years who have no comorbidities and fluoroquinolones for patients who are aged 150 years or have comorbidities. ## Management of patients who are hospitalized Diagnostic studies. Diagnostic studies recommended for hospitalized patients are summarized in table 5 (B-II). Patients hospitalized for acute pneumonia should have blood cultures performed, preferably of specimens obtained from separate sites у10 min apart and before antibiotic administration (B-II). A deep-cough expectorated sputum sample procured by a nurse or physician should be obtained before antibiotic administration (B-II). This sample should be transported to the laboratory for Gram staining and culture within 2 h of collection. Testing for Legionella species, M. tuberculosis, and other pathogens should be requested when indicated. Antimicrobial treatment should be initiated promptly and should not be delayed by an attempt to obtain pretreatment specimens for microbiological studies from acutely ill patients (B-III). Induced sputum sam- Empirical therapy. Recommendations for empirical treatment of hospitalized patients are different in these guidelines than in the 1998 version [bib_ref] Community-acquired pneumonia in adults: guidelines for management. Infectious Diseases Society of America, Bartlett [/bib_ref]. A regimen of treatment with a blactam plus a macrolide or monotherapy with a fluoroquinolone is preferred. The rationale for recommending these regi-mens is based on studies showing that these regimens were associated with a significant reduction in mortality, compared with that associated with administration of cephalosporin alone [bib_ref] Associations between initial antimicrobial regimens and medical outcomes for elderly patients with..., Gleason [/bib_ref]. Another study supports this observation [bib_ref] Treatment outcomes associated with community-acquired pneumonia (CAP) in US hospitals: a 3000..., Guglielmo [/bib_ref]. Caution is necessary in the interpretation of these studies, since they may reflect temporal or geographic differences. These studies did not have a sufficient number of patients treated only with macrolides to justify conclusions about that category, although recent studies suggest azithromycin monotherapy is equivalent to a b-lactam or a b-lactam plus erythromycin. The recommendation of combination treatment for patients hospitalized in the ICU is based on limited data supporting monotherapy with macrolides or fluoroquinolones for patients who are critically ill with pneumococcal pneumonia. Recommendations for treating CAP that is sufficiently severe to require hospitalization in the ICU are the use of a b-lactam combined with a fluoroquinolone or a b-lactam combined with a macrolide. The goal is to provide optimal therapy for the 2 most commonly identified causes of lethal pneumonia, S. pneumoniae and Legionella. Fluoroquinolones alone are not recommended, because most therapeutic trials for these antimicrobial agents (and for macrolides) exclude seriously ill patients; thus, rigorously collected clinical data concerning seriously ill patients are limited. Preferred antimicrobials. The antimicrobial agents preferred for most patients are as follows (in no special order): in general medical wards, cefotaxime or ceftriaxone plus a macrolide (azithromycin, clarithromycin, or erythromycin) or a fluoroquinolone alone (levofloxacin, gatifloxacin, moxifloxacin, trovafloxacin, or another fluoroquinolone with enhanced activity against S. pneumoniae; fluoroquinolones with in vitro activity against most clinically significant anaerobic pulmonary pathogens include trovafloxacin, moxifloxacin, and gatifloxacin); and, in ICUs, a b-lactam (cefotaxime, ceftriaxone, ampicillin-sulbactam, or piperacillin-tazobactam) plus either a macrolide or a fluoroquinolone. Special considerations. For structural disease of the lung, such as bronchiectasis or cystic fibrosis, consider use of a regimen that will be active against Pseudonomas aeruginosa. For b-lactam allergy, consider a regimen of fluoroquinolone with or without clindamycin. For suspected aspiration, consider a fluoroquinolone with or without a b-lactam / b-lactamase in-hibitor (ampicillin-sulbactam or piperacillin-tazobactam), metronidazole, or clindamycin (some fluoroquinolones have good in vitro activity against anaerobes and may not require combination with a second antimicrobial agent [see note about fluoroquinolones in previous paragraph]). ## Antibiotic considerations Antibiotics are the mainstay of treatment for pneumonia. Guidelines for their selection, summarized in tables 14 (B-II) and 15 (B-II), are based largely on clinical experience and/or in vitro activity. Treatment options are simplified if an etiologic diagnosis is established or highly suspect on the basis of results of rapid tests, such as Gram staining or use of other special stains, antigen detection, or amplification techniques [fig_ref] Table 1: Categories for ranking recommendations in the therapeutic guidelines [/fig_ref]. The selection of antimicrobial agents is based on multiple variables, including severity of illness, the patient's age, ability to tolerate side effects, clinical features, comorbidity, prior exposure, epidemiological setting, and cost [fig_ref] Table 7: Epidemiological conditions related to specific pathogens in patients with selected community-acquired pneumonia [/fig_ref] , as well as the prevalence of drug resistance among respiratory tract pathogens. Suggested regimens for consideration for empirical administration to patients hospitalized for acute pneumonia are summarized in table 15, with a distinction between regimens for general use and regimens for patients who require treatment in the ICU (B-II). The following discussion reviews salient issues. b-Lactams and related agents. All b-lactams exert their an-tibacterial effects by interfering with synthesis of the peptidoglycan component of the bacterial cell wall. The b-lactams are inactive against M. pneumoniae and C. pneumoniae, and are ineffective in the treatment of Legionella. The antibacterial spectrum of the penicillins varies from narrow-spectrum agents with activity largely limited to gram-positive cocci (penicillin G, penicillin V, and oxacillin) to expanded-spectrum agents with activity against many gram-negative bacilli (piperacillin, ticarcillin, and mezlocillin). Parenteral penicillin G, parenteral cefotaxime, parenteral ceftriaxone, and oral amoxicillin are generally viewed as the b-lactam drugs of choice for treating infections with S. pneumoniae, against which penicillin MICs are р1.0 mg/ mL [bib_ref] Antimicrobial resistant of Streptococcus pneumoniae in the United States, 1979-1987. The Pneumococcal..., Spika [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Surveillance of resistance among respiratory tract pathogens in the United States, Thornsberry [/bib_ref] [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref]. Alternatives to penicillin are generally preferred for infections that involve S. pneumoniae resistant to penicillin (MIC, у2 mg/mL), including ampicillin, cefotaxime, and ceftriaxone. Penicillins combined with b-lactamase inhibitors (amoxicillin-clavulanate, ticarcillin-clavulanate, ampicillin-sulbactam, and piperacillin-tazobactam) are active against b-lactamaseproducing organisms, such as H. influenzae, anaerobes, and M. catarrhalis, but these combinations offer no advantage over penicillin G against S. pneumoniae. Ticarcillin has less activity than other penicillins against S. pneumoniae. Cephalosporins. These drugs generally show enhanced activity against aerobic gram-negative bacilli as when going from first-to second-to third-generation agents. The antimicrobial agents in this class most active against strains of S. pneumoniae are cefotaxime and ceftriaxone [bib_ref] Diagnosing pneumonia by physical examination: relevant or relic?, Wipf [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] , and the clinical relevance of in vitro resistance to these drugs for treating pneumonia has been questioned. Cefuroxime is substantially less active in vitro than cefotaxime and ceftriaxone and has been anecdotally associated with treatment failures [bib_ref] Failure of treatment of pneumonia associated with highly resistant pneumococcus in a..., Dowell [/bib_ref]. Parenteral cephalosporins that should not be used for pneumococcal pneumonia include first-generation agents, such as cefazolin and cephalexin, and third-generation drugs, such as ceftizoxime and ceftazidime. Oral cephalosporins that are preferred on the basis of their in vitro activity against S. pneumoniae are cefuroxime, cefpodoxime, and cefprozil. Most second-and third-generation cephalosporins show moderate to good activity against H. influenzae and M. catarrhalis. Cephalosporins with the best in vitro activity against anaerobic gram-negative bacilli (Prevotella and Bacteroides species) are cefoxitin, cefotetan, and cefmetazole, although there are no published studies of the use of these drugs for anaerobic lung infections. Other cephalosporins are less active against anaerobes in vitro. Carbapenems. Meropenem and imipenem are active against a broad spectrum of aerobic and anaerobic gram-positive and gram-negative organisms, including most strains of S. pneumoniae and P. aeruginosa, and virtually all strains of H. influenzae, M. catarrhalis, anaerobes, and methicillin-susceptible S. aureus. Activity against penicillin-resistant S. pneumoniae is generally adequate. Macrolides. Erythromycin has a limited antimicrobial spectrum of activity and is poorly tolerated because of gastroin-testinal side effects. Newer macrolides that are better tolerated but more expensive include azithromycin and clarithromycin. All 3 appear to be effective for treating pulmonary infections caused by M. pneumoniae, C. pneumoniae, and Legionella. About 5% of penicillin-resistant S. pneumoniae isolates are resistant to macrolides in vitro; this rate is substantially higher for strains with intermediate-or high-level penicillin resistance [bib_ref] Preventing bacterial respiratory tract infections among persons infected with human immunodeficiency virus, Keller [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref] , so caution is necessary with empirical use in suspected cases of pneumococcal pneumonia. There are 2 mechanisms of macrolide resistance by S. pneumoniae. First, the M phenotype, because of an efflux mechanism, is associated with MICs of 2-8 mg/mL and, in theory, may be overcome by high doses; this mechanism is prevalent in the United States. Second, the ERM phenotype, due to ribosomal alterations, is associated with MICs у64 mg/mL; this mechanism predominates in Europe. Cases of macrolide failure have been described anecdotally but have been infrequent so far [bib_ref] Pneumococcal macrolide resistance: myth or reality?, Amsden [/bib_ref]. Macrolides have reasonably good activity against anaerobes, except for fusobacteria. Community-acquired strains of S. aureus are usually susceptible to macrolides. Most bacteria are susceptible or resistant to all 3 macrolides, but there are some differences. Erythromycin is relatively inactive against H. influenzae. Clarithromycin also has relatively limited in vitro activity against H. influenzae; however, its 14-OH metabolite augments the activity of the parent compound [bib_ref] Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides, Hardy [/bib_ref] [bib_ref] Antimicrobial activities and postantibiotic effects of clarithromycin, 14-hydroxy-clarithromycin, and azithromycin in epithelial..., Bergman [/bib_ref]. Of the 3 macrolides, azithromycin is the most active agent in vitro against Legionella, H. influenzae, and M. pneumoniae, whereas clarithromycin is the most active against S. pneumoniae and C. pneumoniae. Azithromycin and erythromycin are available for iv administration. A multicenter prospective study of 864 immunocompetent outpatients with CAP showed erythromycin to be cost-effective antimicrobial therapy [bib_ref] Medical outcomes and antimicrobial costs with the use of the American Thoracic..., Gleason [/bib_ref] , and a recent trial showed monotherapy with iv azithromycin was equivalent to a regimen of cefuroxime with or without erythromycin for patients hospitalized with CAP [bib_ref] Azithromycin vs cefuroxime plus erythromycin for empirical treatment of community-acquired pneumonia in..., Vergis [/bib_ref]. The IDSA panel felt the latter report supported azithromycin for initial empirical treatment, but concern was expressed that most of the participants were not very ill, the comparator arm was not ideal, and in vitro activity of azithromycin against S. pneumoniae was suboptimal. Quinolones. Currently available agents in this class for pulmonary infections are ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, moxifloxacin, gatifloxacin, and trovafloxacin. These drugs are active in vitro against most clinically significant aerobic gram-positive cocci, gram-negative bacilli, H. influenzae, M. catarrhalis, Legionella species, M. pneumoniae, and C. pneumoniae. Levofloxacin, sparfloxacin, moxifloxacin, gatifloxacin, and trovafloxacin show enhanced in vitro activity against S. pneumoniae, including penicillin-resistant strains [bib_ref] The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta, Hofmann [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Antimicrobial resistant of Streptococcus pneumoniae in the United States, 1979-1987. The Pneumococcal..., Spika [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Surveillance of resistance among respiratory tract pathogens in the United States, Thornsberry [/bib_ref] [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref] , and initial clinical trials show good results [bib_ref] A multicenter, randomized study comparing the efficacy and safety of intravenous and/or..., File [/bib_ref] [bib_ref] Once-daily sparfloxacin versus highdosage amoxicillin in the treatment of community-acquired, suspected pneumococcal..., Aubier [/bib_ref]. One study showed clinical outcomes with levofloxacin were significantly better than with a cephalosporin regimen for empirical treatment of CAP [bib_ref] A multicenter, randomized study comparing the efficacy and safety of intravenous and/or..., File [/bib_ref]. Trovafloxacin has been asso-ciated with excessive rates of hepatotoxicity, so its use is generally restricted to hospitalized patients who lack alternative antibiotic options. Sparfloxacin has high rates of photosensitivity reactions and higher rates of QT-interval prolongation than other fluoroquinolones. Ciprofloxacin is slightly less active in vitro, and there are anecdotal reports of clinical failures for pneumococcal pneumonia; some authorities feel that a dosage of 750 mg twice daily is adequate for empirical use. Support for the concern about increasing resistance by S. pneumoniae is found in reports of increases in the MICs of fluoroquinolones against sequentially collected strains of S. pneumoniae in Hong Kong [bib_ref] Emergence of fluoroquinolone resistance among multiply resistant strains of Streptococcus pneumoniae in..., Ho [/bib_ref] , England [bib_ref] Streptococcus pneumoniae resistance to fluoroquinolones, Wise [/bib_ref] , Ireland [bib_ref] Increased incidence of ciprofloxacin resistance in penicillin-resistant pneumococci in Northern Ireland, Goldsmith [/bib_ref] , and Canada [bib_ref] Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada, Chen [/bib_ref]. Ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and trovafloxacin are available for iv administration. Aminoglycosides. The aminoglycosides (gentamicin, tobramycin, netilmicin, and amikacin) show a concentration-dependent bactericidal effect that permits a single-daily-dose regimen. These agents are active in vitro against the aerobic and facultative gram-negative bacilli, including P. aeruginosa. Some authorities feel aminoglycosides should not be used as single agents for treating gram-negative bacillary pneumonia. Poor clinical results may be due to suboptimal dosing or to possible inactivation of the drug by the acidic environment at the site of infection [bib_ref] Penetration of antibiotics into respiratory secretions, Pennington [/bib_ref] [bib_ref] Endobronchial pH: relevance to aminoglycoside activity in gram-negative bacillary pneumonia, Bodem [/bib_ref]. Tetracyclines. There are multiple members of this class, but the one most frequently used in clinical practice today is doxycycline, on the basis of tolerance, convenience of twicedaily dosing, good bioavailability, and low price [bib_ref] Tetracyclines, chloramphenicol, erythromycin and clindamycin, Wilson [/bib_ref]. Among respiratory tract pathogens, the tetracyclines are active in vitro against the "atypical" organisms, including M. pneumoniae, C. pneumoniae, and Legionella [bib_ref] A multicenter, randomized study comparing the efficacy and safety of intravenous and/or..., File [/bib_ref]. S. pneumoniae and H. influenzae in the past have been quite susceptible to these agents [bib_ref] Doxycycline activity against Streptococcus pneumoniae, Shea [/bib_ref] [bib_ref] Doxycycline revisited, Joshi [/bib_ref] , but ∼15% of pneumococci are now resistant . Vancomycin. Vancomycin shows universal activity against S. pneumoniae [bib_ref] The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta, Hofmann [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Antimicrobial resistant of Streptococcus pneumoniae in the United States, 1979-1987. The Pneumococcal..., Spika [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Surveillance of resistance among respiratory tract pathogens in the United States, Thornsberry [/bib_ref] [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref] [bib_ref] Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in..., Doern [/bib_ref]. It is also active against other grampositive organisms, including methicillin-resistant S. aureus. There is substantial concern about excessive vancomycin use because it promotes the evolution of enterococci that are resistant to vancomycin and of S. aureus strains that are only intermediately susceptible. Pneumococcal tolerance of vancomycin has also recently been described, although the clinical relevance of this finding is unknown. Clindamycin. Clindamycin exhibits good in vitro activity against gram-positive cocci, including pneumococci that resist macrolides by the efflux pump mechanism and most methicillinsusceptible S. aureus [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Antimicrobial resistant of Streptococcus pneumoniae in the United States, 1979-1987. The Pneumococcal..., Spika [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Surveillance of resistance among respiratory tract pathogens in the United States, Thornsberry [/bib_ref] [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref] [bib_ref] Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in..., Doern [/bib_ref] ]. Many authorities consider clindamycin to be the preferred drug for anaerobic pulmonary infections, including aspiration pneumonia and putrid lung abscess [bib_ref] Acid aspiration induced lung injury: new insights and therapeutic options, Matthay [/bib_ref] [bib_ref] Quantitative culture of bronchoalveolar lavage from patients with anaerobic lung abscesses, Henriquez [/bib_ref] [bib_ref] Anaerobic bacterial pneumonitis, Bartlett [/bib_ref] [bib_ref] Clindamycin compared with penicillin for the treatment of anaerobic lung abscess, Levison [/bib_ref] [bib_ref] Clindamycin vs. penicillin for anaerobic lung infections: high rate of penicillin failures..., Gudiol [/bib_ref]. It is inactive against H. influenzae, atypical etiologic agents, and a varying proportion of erythromycin-resistant S. aureus. TMP-SMZ. TMP-SMZ is active in vitro against a broad spectrum of gram-positive and gram-negative organisms but has increasingly lost its efficacy against S. pneumoniae [bib_ref] The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta, Hofmann [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Antimicrobial resistant of Streptococcus pneumoniae in the United States, 1979-1987. The Pneumococcal..., Spika [/bib_ref] [bib_ref] Antimicrobial resistance in Streptococcus pneumoniae: an overview, Appelbaum [/bib_ref] [bib_ref] Surveillance of resistance among respiratory tract pathogens in the United States, Thornsberry [/bib_ref] [bib_ref] Management of infections due to antibioticresistant Streptococcus pneumoniae, Kaplan [/bib_ref] [bib_ref] Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in..., Doern [/bib_ref]. About 20%-25% of S. pneumoniae strains are resistant, and 170% of penicillin-resistant S. pneumoniae isolates are not susceptible to TMP-SMZ. TMP-SMZ is active against such diverse pathogens as Nocardia asteroides, P. carinii, and Stenotrophomonas maltophilia. Antiviral agents. Amantadine and rimantadine are inhibitors of hemagglutinin that have established efficacy in treating and preventing influenza A [bib_ref] Oral rimantadine hydrochloride therapy of influenza A virus H3N2 subtype infection in..., Hayden [/bib_ref]. Relenza and oseltamivir have established efficacy for treatment of influenza A and B and also appear effective for prevention [bib_ref] Treating influenza with zanamivir, Read [/bib_ref] [bib_ref] Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of..., Hayden [/bib_ref] [bib_ref] Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza, Hayden [/bib_ref]. For treatment, all 4 of these drugs must be given within 40-48 h of the onset of influenza symptoms. Therapeutic trials show a mean reduction in the duration of influenza symptoms, including fever of ∼1-1.5 days and a substantial reduction in viral shedding. Amantadine and rimantadine are comparably effective in comparative trials; rimantadine is more expensive but has less CNS toxicity. Relenza and oseltamavir are recently FDA-approved neuraminidase inhibitors that appear equally effective, although no trials comparing these drugs with each other or these drugs with amantadine and rimantadine have been reported. Possible advantages of the neuraminidase inhibitors are the additional activity against influenza B, lack of CNS toxicity, and reduced probability of resistance; disadvantages are the higher price, the somewhat awkward aerosol-delivery device for and possible wheezing with relenza, and gastrointestinal side effects of oseltamivir. The IDSA panel endorses the use of these antiviral agents for treating influenza (B-I). The need to initiate therapy within 40-48 h requires a rapid diagnostic test for influenza detection or empirical treatment based on typical clinical features in an influenza epidemic. The 4 drugs for influenza A appear equally effective; therefore, selection should be based on availability, toxicity, and cost. ## Length and route of treatment We are not aware of any controlled trials that have specifically addressed the question of how long pneumonia should be treated. This decision is usually based on the pathogen, response to treatment, comorbid illness, and complications. Until further data are forthcoming, it seems reasonable to treat pneumonia caused by S. pneumoniae until the patient has been afebrile for 72 h (C-III). Pneumoniae caused by bacteria that can necrose pulmonary parenchyma (e.g., S. aureus, P. aeruginosa, Klebsiella, and anaerobes) should probably be treated for у2 weeks. Pneumonia caused by M. pneumoniae or C. pneumoniae [bib_ref] Antibiotics for pneumonia therapy, Mandell [/bib_ref] [bib_ref] Chlamydia pneumoniae, strain TWAR pneumonia, Grayston [/bib_ref] [bib_ref] Comparison of azithromycin and erythromycin in the treatment of atypical pneumonias, Schonwald [/bib_ref] should probably be treated for at least 2 weeks, as should legionnaires' disease in immunocompetent individuals (B-II). Azithromycin may be used for shorter courses of treatment because of its very long half-life in tissues [bib_ref] Sequential antibiotic therapy: effective cost management and patient care, Mandell [/bib_ref]. As cost considerations and pressure to treat patients with pneumonia outside the hospital increase, there is rising interest in the use of oral therapy. For many drugs that are well absorbed from the gut, there is no clear advantage of parenteral therapy. Nevertheless, for most patients admitted to the hospital, common practice is at least to begin therapy with iv drugs. Although no studies verify a superior outcome, this practice is justified by concern for absorption in acutely ill patients. Changing from iv to oral therapy is associated with a number of economic, health care, and social benefits. It reduces costs of treatment and shortens length of hospital stay. Numerous randomized controlled trials support this practice [bib_ref] Comparison of a disease-specific and a generic severity of illness measure for..., Fine [/bib_ref] , providing that the patient's condition is improving clinically and is hemodynamically stable, the patient is able to ingest drugs, and the gastrointestinal tract is functioning normally (A-I). In most cases, these conditions are met within 3 days, and oral therapy can be given at that time. Ideally, the drug that was given parenterally or a closely related one is given orally; if no such oral formulation is available, an oral agent with a similar spectrum of activity should be selected on the basis of in vitro or predicted sensitivity patterns of the established or probable pathogen. As a general matter, the IDSA panel endorses use of bioavailable and active oral antimicrobial agents for patients whose medical conditions are stable and who tolerate these drugs (A-III). Assessment of response to treatment. The expected response to treatment should take into account the immunologic capacity of the host, the severity of the illness, the pathogen, and the chest radiographic findings. Subjective response is usually noted within 1-3 days of initiation of treatment. Objective parameters include respiratory symptoms (cough, dyspnea), fever, partial pressure of oxygen, peripheral leukocyte count, and findings on serial radiographs. The most carefully documented response is fever or time to defervescence. With pneumococcal pneumonia in young adults, the average duration of fever after treatment is 2.5 days; in bacteremic pneumonia cases, it is 6-7 days; and in elderly patients who are febrile, it also appears to be longer. Patients with M. pneumoniae are usually afebrile within 1-2 days after treatment, whereas immunocompetent patients with legionnaires' disease defervesce in an average of 5 days. Blood cultures in cases of bacteremic pneumonia are usually negative within 24-48 h of treatment. The pathogen is usually also suppressed in respiratory secretions within 24-48 h; the major exceptions are P. aeruginosa (or other gram-negative bacilli), which may persist despite appropriate treatment, and M. pneumoniae, which usually persists despite effective therapy. Followup cultures of blood and sputum are not indicated for patients who respond to therapy, except for those with tuberculosis. Chest radiographic findings usually clear more slowly than clinical findings, and multiple radiographs are generally not required (A-II) [bib_ref] Management of pneumonia in the prospective payment era: a need for more..., Dans [/bib_ref]. During the first several days of treatment, there is often radiographic progression despite a good clinical response, presumably reflecting continued inflammatory changes, even in the absence of viable bacteria. Follow-up radiography during hospitalization may be indicated to assess the position of an endotracheal tube, to assess the position of a line, and to exclude pneumothorax after central line placement or to determine reasons for failure to respond, such as pneumothorax, empyema, progression of infiltrate, cavitation, pulmonary edema, or ARDS. With regard to host factors, age and presence or absence of comorbid illness are important determinants of the rate of resolution. Radiographs of most patients with bacteremic pneumococcal pneumonia who are aged !50 years clear by 4 weeks; however, in older patients, patients with underlying illness (particularly alcoholism or chronic obstructive pulmonary disease), or patients with extensive pneumonia on presentation, the rate of resolution slows considerably, and only 20%-30% may show clearing by 4 weeks [bib_ref] The radiographic resolution of Streptococcus pneumoniae pneumonia, Jay [/bib_ref] [bib_ref] Comparative radiographic features of community-acquired legionnaires' disease, pneumococcal pneumonia, Mycoplasma pneumoniae, and..., Macfarlane [/bib_ref]. L. pneumophila infection may take substantially longer to clear; only 55% of such infections show complete resolution by 12 weeks [bib_ref] Chlamydia pneumoniae, strain TWAR pneumonia, Grayston [/bib_ref]. Some authorities advocate follow-up radiography at 7-12 weeks after treatment for selected patients who are aged 140 years and/or smokers, to document resolution of infiltrates and to exclude underlying diseases such as neoplasm. Patients who fail to respond. When patients fail to respond or their conditions deteriorate after initiation of empirical therapy, a number of possibilities should be considered (figure 3) (C-III). 1. Incorrect diagnosis (not an infection or underlying noninfectious disease with infectious component): noninfectious illnesses that may account for the clinical and radiographic findings include congestive heart failure, pulmonary embolus, atelectasis, sarcoidosis, neoplasms, radiation pneumonitis, pulmonary drug reactions, vasculitis, ARDS, pulmonary hemorrhage, and inflammatory lung disease. 2. Correct diagnosis: if a correct diagnosis has been made, but the patient fails to respond, the physician should consider each of the following components of the host-drug-pathogen triad. (a) Host-related problem: the overall reported mortality for hospitalized patients with CAP is 10%-15%; this figure includes patients with an established or likely etiologic diagnosis who are treated with appropriate antibiotics [bib_ref] Prognosis and outcomes of patients with community-acquired pneumonia, Fine [/bib_ref]. The mortality rate for patients with bacteremic pneumococcal pneumonia caused by penicillin-susceptible strains of S. pneumoniae and treated with penicillin has been consistently reported at у20% [bib_ref] Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in..., Pallares [/bib_ref]. The usual explanation is that physiological events, often in the form of cascades, have been set in motion and are not reversed by simply killing the infecting organism. Occasional patients have local lesions that preclude optimal response, such as obstruction by a neoplasm or a foreign body. Empyema is an infrequent but important cause of failure to respond. Other complications include adverse drug reactions, other complications of medical management such as fluid over- (b) Drug-related problem: whether a specific pathogen has been isolated, if a correct etiologic diagnosis of pneumonia has been made, but the patient does not appear to be responding, the physician should always consider the possibility of a medication error, an inappropriate dosing regimen, a problem with compliance, malabsorption, a drug-drug interaction that reduces antimicrobial levels, or other factors that may alter drug delivery to the site of infection. Drug fever or another adverse drug reaction may obscure response to successful therapy. (c) Pathogen-related problem: the causative organism may have been identified correctly but may be resistant to the antibiotic administered. Examples might include a penicillin-resistant pneumococcus, methicillin-resistant S. aureus, or a multiresistant gram-negative-bacillus rod. The wide variety of other pathogens that might not be identified and would not be expected to respond to some or all of the regimens recommended for empirical use include M. tuberculosis, fungi, viruses, Nocardia, C. psittaci, hantavirus, C. burnetii, or P. carinii. In some cases, these or other organisms may represent copathogens. 3. Assessment of a nonresponding patient: the assessment of a patient who fails to respond to initial empirical therapy should take into account the possibilities outlined above and in [fig_ref] Figure 3: Possible factors to be considered when patients fail to respond or their... [/fig_ref]. Tests appropriate to the individual disease entities should be used to exclude noninfectious possibilities. Specific examples include ventilation-perfusion lung scans and, in selected cases, pulmonary angiography to identify pulmonary embolus, identification of antineutrophil cytoplasmic antibody, and bronchoscopy or open-lung biopsy to diagnose a variety of noninfectious causes. Some host factors that might influence the range of pathogens, as well as the response, include HIV infection, cystic fibrosis, neoplasms, recent travel, and unusual exposures. For those cases in which infection is responsible for the clinical and radiographic findings, issues relating to the host-drugpathogen triad should be taken into account during the work up. To rule out an endobronchial lesion or foreign body, bronchoscopy and/or CT scanning may be of help. To ensure that a sequestered focus of infection, such as a lung abscess or empyema, has not developed, thereby preventing access of the drugs to the pathogens, CT scanning of the chest may be useful. For pleural effusions detected on chest radiograph, ultrasonography can localize the collection and provide an estimate of the volume of fluid. Infection caused by an unsuspected organism or a resistant pathogen must always be a concern with regard to the nonresponding patient. An aggressive attempt to obtain appropriate expectorated sputum samples may lead to identification of such organisms on stain or culture, although the validity of such posttreatment specimens must be questioned because of the inability to culture S. pneumoniae and other fastidious pathogens and frequent overgrowth by S. aureus and gramnegative bacilli. In selected cases, bronchoscopy may be necessary; 1 study suggested that helpful information may be provided by this procedure for up to 41% of patients with CAP whose initial empirical antimicrobial therapy fails [bib_ref] Severe community-acquired pneumonia: etiology, prognosis, and treatment, Pachon [/bib_ref]. ## Prevention of cap The annual impact of influenza is highly variable. During winters when influenza is epidemic, its impact on CAP is sizable as a result of both primary influenza pneumonia and secondary bacterial pneumonia. Influenza vaccine is effective in limiting severe disease caused by influenza virus [bib_ref] Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza, Hayden [/bib_ref] and is recommended to be given annually to persons at increased risk for complications, as well as to health care workers (A-I). Polyvalent vaccines of pneumococcal capsular polysaccharides have been shown to be effective in preventing pneumococcal pneumonia in American military recruits [bib_ref] Prevention of pneumococcal pneumonia by immunization with specific capsular polysaccharides, Macleod [/bib_ref] and in young adult African males [bib_ref] Prevention of pneumococcal pneumonia by vaccination, Austrian [/bib_ref]. The currently available 23valent vaccine is ∼60% effective in preventing bacteremic pneumococcal infection in immunocompetent adults [bib_ref] The protective efficacy of polyvalent pneumococcal polysaccharide vaccine, Shapiro [/bib_ref]. Efficacy tends to decline with age and may be unmeasurable in immunocompromised hosts [bib_ref] Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations, Butler [/bib_ref] [bib_ref] Efficacy of pneumococcal vaccine in high-risk patients: results of a Veterans' Administration..., Simberkoff [/bib_ref]. Despite controversies over efficacy [bib_ref] Efficacy of pneumococcal vaccine in high-risk patients: results of a Veterans' Administration..., Simberkoff [/bib_ref] [bib_ref] Pneumococcal vaccination: controversies and opportunities, Spika [/bib_ref] [bib_ref] Pneumococcal vaccine after 15 years of use: another view, Fedson [/bib_ref] , the fatality rate of bacteremic pneumococcal infection among those aged 164 years and/or with a variety of underlying systemic illnesses remains high, the potential for benefit in individual cases cannot be denied, and the vaccine is essentially free of serious side effects. Accordingly, the IDSA panel endorses current CDC guidelines for pneumococcal vaccine (B-II). More than half of patients hospitalized with pneumococcal disease have had other hospitalizations within the previous 5 years [bib_ref] Pneumococcal bacteremia in Charleston County, South Carolina: a decade later, Breiman [/bib_ref]. Unvaccinated patients with risk factors for pneumococcal disease and influenza should consequently be vaccinated during hospitalization whenever possible (C-III). There is no contraindication for use of either pneumococcal or influenza vaccine immediately after an episode of pneumonia (i.e., before hospital discharge). The vaccines are inexpensive and can be given simultaneously. ## Performance indicators The following are recommended performance indicators: (1) blood cultures before antibiotic therapy for hospitalized patients (studies indicate that compliance with this recommendation is associated with a significant reduction in mortality [bib_ref] Influence of blood culture results on antibiotic choice in treatment of bacteremia, Arbo [/bib_ref] ; (2) initiation of antibiotic therapy within 8 h of hospitalization (prior studies indicate that compliance with this recommendation is associated with a significant reduction in mortality [bib_ref] The looming threat of bioterrorism, Henderson [/bib_ref] ; (3) use of culture and/or urinary antigen testing for detecting Legionella species in 50% of patients hospitalized in the ICU for enigmatic CAP; (4) demonstration of an infiltrate by chest radiography or other imaging technique for all patients with an ICD-9-code diagnosis of CAP who do not have AIDS or neutropenia; and (5) measurement of blood gases or performance of pulse oximetry before admission or within 8 h of admission. [fig] Figure 2: Procedures for diagnosis and for outpatient and hospitalcentered management of community-acquired pneumonia in adults. [/fig] [fig] Outpatients: Generally preferred are (not in any particular order): doxycycline, a macrolide, or a fluoroquinolone Selection considerations (see text, Management of Patients Who Do Not Require Hospitalization)These agents have activity against the most likely pathogens in this setting, which include Streptococcus pneumoniae, Mycoplasma pneumoniae, and Chlamydia pneumoniae Selection should be influenced by regional antibiotic susceptibility patterns for S. pneumoniae and the presence of other risk factors for drug-resistant S. pneumoniae Penicillin-resistant pneumococci may be resistant to macrolides and/or doxycycline For older patients or those with underlying disease, a fluoroquinolone may be a preferred choice; some authorities prefer to reserve fluoroquinolones for such patientsHospitalized patients General medical ward Generally preferred are: an extended spectrum cephalosporin combined with a macrolide or a b-lactam / b-lactamase inhibitor combined with a macrolide or a fluoroquinolone (alone) Intensive care unit Generally preferred are: an extended-spectrum cephalosporin or b-lactam / b-lactamase inhibitor plus either fluoroquinolone or macrolide Alternatives or modifying factors (see text, Management of Patients Who Are Hospitalized, Special considerations) Structural lung disease: antipseudomonal agents (piperacillin, piperacillin-tazobactam, carbapenem, or cefepime) plus a fluoroquinolone (including high-dose ciprofloxacin) b-Lactam allergy: fluoroquinolone ‫ע‬ clindamycin Suspected aspiration: fluoroquinolone with or without clindamycin, metronidazole, or a b-lactam / b-lactamase inhibitor NOTE. b-Lactam / b-lactamase inhibitor: ampicillin-sulbactam or piperacillin-tazobactam. Extendedspectrum cephalosporin: cefotaxime or ceftriaxone. Fluoroquinolone: gatifloxacin, levofloxacin, moxifloxacin, or other fluoroquinolone with enhanced activity against S. pneumoniae (for aspiration pneumonia, some fluoroquinolones show in vitro activity against anaerobic pulmonary pathogens, although there are no clinical studies to verify activity in vivo). Macrolide: azithromycin, clarithromycin, or erythromycin. ‫,ע‬ with or without. [/fig] [fig] Figure 3: Possible factors to be considered when patients fail to respond or their conditions deteriorate after initiation of empirical therapy load, pulmonary superinfection or sepsis from an iv line, or any of a host of medical complications related to hospitalization. [/fig] [table] Table 1: Categories for ranking recommendations in the therapeutic guidelines. [/table] [table] Table 2: Comparison of risk class-specific mortality rates in the derivation and validation cohorts.NOTE. No statistically significant differences in overall mortality or mortality within risk class existed among patients in the MedisGroups derivation, MedisGroups validation, and overall Pneumonia Patient Outcome Research Team (PORT) validation cohorts (n denotes the no. of patients within each risk class in the derivation and validation cohorts). P values for the comparisons of mortality across risk classes are as Risk class I was determined by the absence of all predictors identified in step 1 of the prediction rule. Risk classes II-V were determined by a patient's total risk score, which is computed by use of the point scoring system shown in table 3. [/table] [table] Table 3: Scoring system for step 2 of the prediction rule: assignment to risk classes II-V. a A total point score for a given patient is obtained by adding the patient's age in years (age Ϫ10, for females) and the points for each applicable patient characteristic. Points assigned to each predictor variable were based on coefficients obtained from the logistic regression model used in step 2 of the prediction rule.b Any cancer except basal or squamous cell cancer of the skin that was active at the time of presentation or diagnosed within 1 year of presentation. c A clinical or histologic diagnosis of cirrhosis or other form of chronic liver disease such as chronic active hepatitis. d Systolic or diastolic ventricular dysfunction documented by history and physical examination, as well as chest radiography, echocardiography, Muga scanning, or left ventriculography. e A clinical diagnosis of stroke, transient ischemic attack, or stroke documented by MRI or computed axial tomography. f A history of chronic renal disease or abnormal blood urea nitrogen and creatinine values documented in the medical record. g Disorientation (to person, place, or time, not known to be chronic), stupor, or coma. h In the Pneumonia Patient Outcome Research Team cohort study, an oxygensaturation value !90% on pulse oximetry or intubation before admission was also considered abnormal. [/table] [table] Table 4: Risk-class mortality rates. [/table] [table] Table 5: Diagnostic studies for evaluation of community-acquired pneumonia. recommended for detection of M. tuberculosis or Pneumocystis carinii Bronchoscopy (see text under Special Considerations: Pnemococcal Pneumonia) Transtracheal aspiration: recommended only in cases of enigmatic pneumonia, to be done by persons skilled in the technique, preferably before antibiotic treatment Optional Additional cytological or microbiological tests, as listed in table 8, depending on clinical features, available resources, underlying conditions, and/or epidemiological associations of the patient Serum: to be frozen and saved for serological analysis, if needed b a Should be deep-cough specimen obtained before antibiotic therapy. Gram stain should be interpreted by trained personnel and culture done only if specimen is adequate by cytological criteria, except for Legionella and mycobacteria. Consider diagnostic studies for endemic fungi and mycobacteria when clinical features suggest infection with these. For hospitalized patients with severe pneumonia or clinical features that suggest legionnaires' disease, perform culture and urinary antigen testing for Legionella. Inability to obtain specimens for diagnostic studies should not delay antibiotic treatment of acutely ill patients. [/table] [table] Table 7: Epidemiological conditions related to specific pathogens in patients with selected community-acquired pneumonia. [/table] [table] Table 9: Diagnostic studies for specific agents of community-acquired pneumonia. Standard culture microbiological test(s) Serology and other tests Bacteria and bacteria-like Gram-stain morphology Expectorated sputum; uncont. specimen; bronchoscopy Urinary antigen assay for S. pneumoniae Expectorated or induced sputum; uncont. specimen; bronchoscopy CF; ID; antigen assay (blood, urine, respiratory secretions) for H. capsulatum antigen NOTE. AFB, acid-fast bacilli; DFA, direct fluorescent antibody; FDA, US Food and Drug Administration; GMS, Gomori methenamine silver stain; HAI, hemagglutination inhibition; HPS, hantavirus pulmonary syndrome; ID, immunodiffusion; IFA, immunofluorescence assay; LA, latex agglutination; MIF, microimmunofluorescence; RIA, radioimmunofluorescence; uncont. specimen, uncontaminated specimen of pleural fluid, blood, transtracheal or transthoracic aspirate, or lung biopsy specimen.On respiratory secretions unless otherwise stated.PCR is available at selected reference laboratories, but reagents for detecting M. pneumoniae and C. pneumoniae are not FDA cleared. PCR is FDA cleared for detection of Mycobacterium tuberculosis in specimens for which smears are positive for AFB. [/table]

Cystic fibrosis overview # Overview Cystic fibrosis is an autosomal recessive disease that caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genetic mutation result in defective transport of chloride, and secondarily sodium and eventually abnormal viscous mucoid secretions mostly in lungs and GI tract. Infertility due to atresia/absent vasa deferentia and abnormal/absent seminal vesicles is the associated condition of cystic fibrosis. Cystic fibrosis has to be differentiated from asthma, bronchiolitis, emphysema and primary ciliary dyskinesia (Kartagener syndrome). Immunoreactive trypsinogen (IRT) of serum is raised in newborns with cystic fibrosis and has been used as a screening test. The most significant complications are seen in airways and most common chronic pulmonary infection include P. aeruginosa, S. aureus and H. influenzae. Gastrointestinal complications include pancreatic insufficiency, pancreatitis, gastroesophageal reflux disease, distal intestinal obstruction syndrome, constipation and small intestinal bacterial overgrowth. The sweat chloride test is the gold standard test for the diagnosis of cystic fibrosis. Most common symptoms include salty sweat, constant coughing, diarrhea or greasy stools, stomach pain, constipation and poor weight gain. Also abdominal distension and digital clubbing may be detected. Lung examination may presents hyperresonant lungs, Wheeze or crackles. Most common chest CT scan findings include peribronchial thickening, mucous plugging and Bronchiectasis. Medical treatments has targeted following consequences of the defect such as GI and pulmonary mucus plugging and infection. Treatment include mucolytic agents (dornase alfa, N-acetyl-L-cysteine), airway surface rehydration, anti-infective agents, anti-inflammatory agents and potentiators of CFTR protein defect. # Historical Perspective In the late 1930s cystic fibrosis was first recognized as a disease. In 1949, Lowe and colleagues suggested this theory that cystic fibrosis must be caused by a defect in a single gene. In 1959, the measurement of sweat electrolyte concentrations was established as the mainstay of diagnosing CF. In 1989, the CFTR gene was discovered first. In 1990, scientists successfully added cloned normal gene to cystic fibrosis cells which corrected the chloride transportion # Classification Cystic fibrosis may be classified according to CFTR protein function abnormality into 6 groups: lack of production (Class 1), failure to reach the site of action due to misfolding (class 2), defects in gating (class 3), reduced ion conductance (class 4), abnormally low channel numbers (class 5) and decreased half-life (class 6). Cystic fibrosis classes 1,2 and 3 are the most common types which have associated with pancreatic insufficiency. # Pathophysiology Cystic fibrosis is an autosomal recessive disease that caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Substitution of a single amino acid is the most common type of CFTR gene mutation. CFTR gene functions as a chloride channel (pumps chloride from the intracellular space to the extracellular space) found on the surface of the epithelial cells. The genetic mutations result in defective transport of chloride, and secondarily sodium and eventually abnormal viscous mucoid secretions mostly in lungs (results in airway surface liquid depletion, decreased mucociliary transport, inflammation and infection) and GI tract (results in reduced volume of pancreatic secretion, pancreatic tissue destruction and fibrosis, malnutrition and poor growth). Infertility due to atresia/absent vasa deferentia and abnormal/absent seminal vesicles is the associated condition of cystic fibrosis. # Causes Cystic fibrosis is caused by mutations in the CFTR gene. The genetic mutations result in defective transport of chloride, and secondarily sodium, by epithelial cells and eventually abnormal viscous mucoid secretions mostly in lungs and GI tract. # Differentiating cystic fibrosis from Other Diseases Cystic fibrosis has to be differentiated from other conditions with similar presentation of cough and wheeze like common cold, asthma, bronchiolitis, emphysema, primary ciliary dyskinesia (Kartagener syndrome), bronchitis, bronchiectasis, foreign body aspiration, pneumoconiosis, interstitial lung disease, cardiogenic pulmonary edema, GERD and sarcoidosis. # Epidemiology and Demographics The incidence of cystic fibrosis is approximately 1 in 2500 livebirths. It is a life-limiting disease (100% mortality rate), and a cure for the disease remains elusive. Most patients with cystic fibrosis are diagnosed in first 2 years of life. The onset of symptoms is before the first month of life in 12%, between 1-6 months of age in 75%, and between 6-12 months of age in 7% of patients. Although cystic fibrosis has been reported in all racial and ethnic groups, it mostly affects Caucasians of Northern European descent. It affects men and women equally. # Risk Factors Every person inherits two CFTR genes, one from each parent. Children who inherit two mutated CFTR genes from both parents will have cystic fibrosis. # Screening Newborn screening identified most of the children with cystic fibrosis before the symptoms develop. It offers this opportunity for early diagnosis and improved outcomes. Immunoreactive trypsinogen (IRT) of serum is raised in newborns with cystic fibrosis and has been used as a screening test. A raised IRT in the first week of life is a sensitive test but not specific for cystic fibrosis. # Natural History, Complications, and Prognosis Malnutrition and poor growth (due to loss of pancreatic exocrine function) leads to death in the first decade of life for most untreated patients. The most significant complications are seen in airways (responsible for 80% of mortality) and most common chronic pulmonary infection include P. aeruginosa, S. aureus and H. influenzae. In cystic fibrosis 98% of men are infertile due to aspermia. Lung complications are currently the primary causes of morbidity and are responsible for 80% of mortality in these patients and gastrointestinal complications include pancreatic insufficiency, pancreatitis, gastroesophageal reflux disease, distal intestinal obstruction syndrome, constipation and small intestinal bacterial overgrowth. In cystic fibrosis, obstructive lung disease and other lung complications are currently the primary causes of morbidity and are responsible for 80% of mortality. At present time survival probability of children is 40-50 years. Women with cystic fibrosis have a shortened life expectancy compared to men. # Diagnosis ## Diagnostic study of choice The sweat chloride test is the gold standard test for the diagnosis of cystic fibrosis. A sweat chloride value of more than 59 mmol/L is diagnostic for cystic fibrosis, 30-59 mmol/L needs more evaluation with CFTR genetic analysis and less than 30 is indicates that cystic fibrosis is unlikely. ## History and Symptoms Most common symptoms in cystic fibrosis include salty sweat, constant coughing, diarrhea or greasy stools, stomach pain, constipation and poor weight gain. Less common symptoms include nasal polyp, hemoptysis and skin irritation. ## Physical Examination In cystic fibrosis abdominal distension and digital clubbing may be detected. In HEENT examination there is nasal polyps and signs of rhinosinusitis (purulent nasal discharge, mucosal edema, turbinate hypertrophy and tenderness on palpitation of the sinuses). Lung examination may presents hyperresonant lungs, Wheeze or crackles and Productive cough with mucoid or purulent sputum. ## Laboratory Findings Immunoreactive trypsinogen (IRT) of serum is raised in newborns with cystic fibrosis and has been used as a screening test. ## Electrocardiogram There are no electrocardiogram findings associated with cystic fibrosis. ## X-ray In cystic fibrosis the chest radiographic features may overlap with many other disorders, particularly those characterized by inflammatory or destructive changes of the airways. Atelectasis is common in infancy. Most patients with CF demonstrate some of the classic chest radiographic findings that reflect chronic bronchiectasis include hyperinflation, bronchial thickening and dilatation, peribronchial cuffing, mucoid impaction, cystic radiolucencies, increase in interstitial marking and cattered nodular densities. ## Ultrasound In cystic fibrosis, ultrasound findings include small cystic degeneration could be observed in the pancreatic tail. Transabdominal ultrasound of the pancreas demonstrated a higher pancreatic echogenicity, as a measure of pancreatic lipomatosis in pancreatic insufficient CF patients. Echogenic bowel is found on ultrasound in 50% to 78% of fetuses affected with cystic fibrosis. It is thought to be caused by changes in the consistency of meconium in the small intestine as a result of abnormalities in pancreatic enzyme secretion. The sonographic findings include diffuse echogenic bowel, focal echogenic bowel with calcifications, hyperechoic mass and bowel dilation. ## CT scan Computed tomography (CT scan) findings in patients with cystic fibrosis are more sensitive as compared to the pulmonary function tests. Most common chest CT scan findings include peribronchial thickening, mucous plugging and Bronchiectasis. Less common findings include abscesses, emphysematous bullae, hyperinflation, collapse, consolidation, ground-glass opacities, acinar nodules and thickening of interlobular and intralobular septa. Abdomen CT scan in patients with cystic fibrosis may include these findings diffuse and complete fatty replacement of pancreas, Fibrosis of the pancreas and Intestinal obstruction. ## MRI MRI may be helpful in determining the cause of linear lung markings in cystic fibrosis. It is also helpful in differentiating mucous plugging and peribronchial thickening from normal pulmonary blood vessels. Because of MRI absence of ionising radiation and possibility for obtaining functional information, it is helpful for assessing lung disease in children who require repetitive follow up imaging for a long time. MRI studies of the pancreas have demonstrated different patterns of fatty infiltration, ductal changes, pancreatic cysts, calcifications and hypoechoic areas representing fibrosis. ## Other Imaging Findings There are no other imaging findings for cystic fibrosis. ## Other Diagnostic Studies Other diagnostic studies in patients with cystic fibrosis include sweat chloride test (measures the chloride content of the sweat) and nasal potential differences (performed by running different solutions through the nose) which used to detect changes in CFTR function. A sweat chloride value of more than 59 mmol/L is diagnostic for cystic fibrosis and less than 30 mmol/L indicates that cystic fibrosis is unlikely. Also Pulmonary function test (PFT) is important in monitoring lung function in patients with cystic fibrosis. However, it is only an indirect measure of lung structure and is insensitive to local or early damage. # Treatment ## Medical Therapy Medical treatments for patients with cystic fibrosis has targeted following consequences of the defect such as GI and pulmonary mucus plugging and infection. Treatment include mucolytic agents (dornase alfa, N-acetyl-L-cysteine), airway surface rehydration (hypertonic saline, osmotic agents), anti-infective agents (for prophylaxis, eradication of early infection and suppression of chronic infection), anti-inflammatory agents (NSAIDs, inhaled corticosteroids, LTB4 receptor antagonists and Azithromycin) and potentiators of CFTR protein defect. ## Surgery Cystic fibrosis patients with a large pneumothorax should undergo chest tube insertion and even surgical pleurodesis in case of recurrent large pneumothorax. When medical treatment for pulmonary complications fails, lung transplantation is the only option. ## Primary Prevention There is no known way for the primary prevention of cystic fibrosis. ## Secondary Prevention In cystic fibrosis secondary prevention include airway clearance techniques, dornase alpha, hypertonic saline, antibiotics, immunizations, physical activity, nutritional support for pancreatic insufficiency and extra salt and water.

Navigational images # overview Although not a 'feature' of the MediaWiki software, an image can be made to link to a specified page if desired. Some people find trawling through this page understandably confusing, so here is the short version: - You can use the re-direct feature on an image page, but when used, the target page shows all sorts of unwanted information that gets transcluded from the image page itself. - For MediaWiki sites that support the embedding of external_images (which is basically all MediaWiki websites except the Wikipedia and Meta) you can use the 'clickpic' template. See that link for information on how to use it. - For website such as Wikipedia that preclude the use of embedding external images you can superimpose hyperlinks onto images. None of the methods outlined below work on Wikipedia as of December 2006. For more detailed explanations, see below. # Method 1: Employing image redirects One way to do this is by putting a redirect on the image page. For example, on Meta the internal image links to the page Help:Redirect. The image File:Amtrak schematic.png from Commons, redirecting on Meta to the Main Page, is not displayed. If the redirect is within the same project, then a redirect message with a link to the image page (MediaWiki:Redirectedfrom) is inserted on the target page. To use the same image on another page without a redirect or with a different target, a copy of the image has to be uploaded under another name. However, an image on Commons may have its own image page on each project, e.g. File:Zuid Holland-Position.png, which could have a redirect on the image page on this project, which would then be accessible by the link :Zuid_Holland-Position.png&redirect=no. # Method 2: Using the external link format In projects that allow the embedding of external_images (in which case you see images in the lefthand column of the table below) there are the following possibilities: (The image can be an internally or externally held image, and the target can be an external URL or a wiki page). ## Thumbnail One application is linking a small version of an image to a large one. Example where both are external: gives The alternate text is the name of the image, after the last slash in the URL. If you have control over the image, give it a meaningful name; you could even include a text like "click to enlarge" in the name. # Method 3: Superimposing a linked text onto an image A linked text can be superimposed onto an image, see Help:Composite images. In particular there can be a dummy text such as an &nbsp; character in a very large font, covering the whole image. Using Template:Tim: top{{navimg|xsize=50|ysize=50|image=Wikimedia-logo.svg|link=MediaWiki}}bottom gives: topTemplate:Navimgbottom Similarly with Template:Tim for an external link: topTemplate:Navimgxbottom However, if the browser is set to ignore font sizes specified in web pages then only part of the area in the image links to the specified page, and the rest of the image to the image page. Check the hoverbox or status line to see the target at any position of the mouse cursor. Some versions of the template have the same hoverbox for the two areas. The image cannot be inline. Positioning can be done e.g. with a table.

Elbow The elbow-joint is a ginglymus or hinge joint. Three bones form the elbow joint: the humerus of the upper arm, and the paired radius and ulna of the forearm. The bony prominence at the very tip of the elbow is the olecranon process of the ulna. # Movements Two main movements are possible at the elbow: - The hinge-like bending and straightening of the elbow (flexion and extension) happens at the articulation ("joint") between the humerus and the ulna. - The complex action of turning the forearm over (pronation or supination) happens at the articulation between the radius and the ulna (this movement also occurs at the wrist joint). In the anatomical position (with the forearm supine), the radius and ulna lie parallel to each other. During pronation, the ulna remains fixed, and the radius rolls around it at both the wrist and the elbow joints. In the prone position, the radius and ulna appear crossed. Most of the force through the elbow joint is transferred between the humerus and the ulna. Very little force is transmitted between the humerus and the radius. (By contrast, at the wrist joint, most of the force is transferred between the radius and the carpus, with the ulna taking very little part in the wrist joint). # Muscles, arteries, and nerves The muscles in relation with the joint are: - in front, the Brachialis - behind, the Triceps brachii and Anconæus - laterally, the Supinator, and the common tendon of origin of the Extensor muscles - medially, the common tendon of origin of the Flexor muscles, and the Flexor carpi ulnaris The arteries supplying the joint are derived from the anastomosis between the profunda and the superior and inferior ulnar collateral branches of the brachial, with the anterior, posterior, and interosseous recurrent branches of the ulnar, and the recurrent branch of the radial. These vessels form a complete anastomotic network around the joint. The nerves of the joint are a twig from the ulnar, as it passes between the medial condyle and the olecranon; a filament from the musculocutaneous, and two from the median. # Portions of joint The elbow-joint comprises three different portions. All these articular surfaces are enveloped by a common synovial membrane, and the movements of the whole joint should be studied together. The combination of the movements of flexion and extension of the forearm with those of pronation and supination of the hand, which is ensured by the two being performed at the same joint, is essential to the accuracy of the various minute movements of the hand. The hand is only directly articulated to the distal surface of the radius, and the ulnar notch on the lower end of the radius travels around the lower end of the ulna. The ulna is excluded from the wrist-joint by the articular disk. Thus, rotation of the head of the radius around an axis passing through the center of the radial head of the humerus imparts circular movement to the hand through a very considerable arc. # Ligaments The trochlea of the humerus is received into the semilunar notch of the ulna, and the capitulum of the humerus articulates with the fovea on the head of the radius. The articular surfaces are connected together by a capsule, which is thickened medially and laterally, and, to a less extent, in front and behind. These thickened portions are usually described as distinct ligaments. The major ligaments are the ulnar collateral ligament, radial collateral ligament, and annular ligament. # Synovial membrane The synovial membrane is very extensive. It extends from the margin of the articular surface of the humerus, and lines the coronoid, radial and olecranon fossæ on that bone; it is reflected over the deep surface of the capsule and forms a pouch between the radial notch, the deep surface of the annular ligament, and the circumference of the head of the radius. Projecting between the radius and ulna into the cavity is a crescentic fold of synovial membrane, suggesting the division of the joint into two; one the humeroradial, the other the humeroulnar. Between the capsule and the synovial membrane are three masses of fat: - the largest, over the olecranon fossa, is pressed into the fossa by the Triceps brachii during the flexion; - the second, over the coronoid fossa, - and the third, over the radial fossa, are pressed by the Brachialis into their respective fossæ during extension. # Terminology: "Elbow" and "Ell" The now obsolete length unit ell relates closely to the elbow. This becomes especially visible when considering the Germanic origins of both words, Elle (ell, defined as the length of an arm from shoulder to fingertips) and Ellbogen (elbow). It is unknown when or why the second "l" was dropped from English usage of the word, but a more precise suggested spelling would be "ellbow" for the joint and "ellbone" for the ulna, the etymological originator of both unit and joint. # Carrying angle When the arm is extended, with the palm facing forward or up, the bones of the humerus and forearm are not perfectly aligned. The deviation from a straight line (generally on the order of 5-10°) occurs in the direction of the thumb, and is referred to as the carrying angle (visible in the right half of the picture, right). In females the carrying angle is greater than in males. The carrying angle can influence how objects are held by individuals - those with a more extreme carrying angle may be more likely to supinate the forearm when holding objects in the hand to keep the elbow closer to the body. # Diagnostic Findings ## MRI (Images courtesy of RadsWiki) - Normal elbow: Cor MPGR - Normal elbow: Cor IR - Normal elbow: Cor PD - Normal elbow: Axl PD - Normal elbow: Sag PD - Normal elbow: Sag IR

Primary mediastinal large B-cell lymphoma overview # Overview Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL). It is also considered a distinct type of non-Hodgkin lymphoma (NHL) in the World Health Organization (WHO) classification system. It occurs in the thymus gland. The small gland in the center of the chest behind the sternum where lymphocytes mature, multiply and become T cells. or lymph nodes in the center of the chest. On microscopic histopathological analysis, large-sized cells and alveolar fibrosis are characteristic findings of primary mediastinal large B-cell lymphoma. The incidence of primary mediastinal large B-cell lymphoma increases with age; the median age at diagnosis is 35 years. The symptoms of the primary mediastinal large B-cell lymphoma include fever, weight loss, night sweats, skin rash, facial swelling, cough, shortness of breath, and painless swelling in the neck, axilla, groin, thorax, or abdomen. Lymph node or mediastinal mass biopsy is diagnostic of primary mediastinal large B-cell lymphoma. The predominant therapy for primary mediastinal large B-cell lymphoma is chemotherapy. Adjunctive radiotherapy, stem cell transplant, and biological therapy may be required. The optimal therapy for primary mediastinal large B-cell lymphoma depends on the clinical presentation. # Historical Perspective # Classification There is no established system for the classification of primary mediastinal large B-cell lymphoma. However it was designated as a separate disorder in 2001 by World health organization. There are different stages of primary mediastinal large B-cell lymphoma, depending on the metastatic stage of disease. # Pathophysiology Primary mediastinal large B-cell lymphoma arises from thymus. The small gland in the center of the chest behind the sternum where lymphocytes mature, multiply and become T cells. or lymph nodes in the center of the chest. On microscopic histopathological analysis, large-sized cells and alveolar fibrosis are characteristic findings of primary mediastinal large B-cell lymphoma. The incidence of primary mediastinal large B-cell lymphoma increases with age. The pathophysiology primarily involves constitutional activation of JAK2 pathway through different genetic mechanisms involved. # Causes The cause of primary mediastinal large B-cell lymphoma has not been identified. # Differentiating Xyz from Other Diseases Primary mediastinal large B-cell lymphoma must be differentiated from other diseases that cause swollen face, superior vena cava syndrome, and fever, night sweats and weight loss such as hodgkin's lymphoma, thymoma, and other non hodgkin's lymphomas. # Epidemiology and Demographics Primary mediastinal large B-cell lymphoma represents 4% of overall non-hodgkins lymphomas and affects females predominantly. # Risk Factors There are no established risk factors for Primary mediastinal large B-cell lymphoma. # Screening According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for primary mediastinal large B-cell lymphoma. # Natural History, Complications, and Prognosis # Diagnosis ## Diagnostic Study of Choice ## History and Symptoms ## Physical Examination ## Laboratory Findings ## Electrocardiogram ## X-ray ## Echocardiography and Ultrasound ## CT scan ## MRI ## Other Imaging Findings ## Other Diagnostic Studies # Treatment ## Medical Therapy ## Interventions ## Surgery ## Primary Prevention ## Secondary Prevention

African American Study Of Kidney Disease And Hypertension # Complete Title of Study African American Study of Kidney Disease and Hypertension ABPM Pilot Study # Study Acronym (The trial's abbreviation if there is one) AASK # Principal Investigator, Co-investigators, and Collaborating Institutions Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Study Chair: Mahboob Rahman, M.D. Institution: University Hospitals, Cleveland Principal Investigator: Jackson T. Wright, Jr., MD, Ph.D., FACP Institution: University Hospitals of Cleveland Principal Investigator: Janice Lea, MD Institution: Emory Center for Hypertension and Renal Disease Research Principal Investigator: Francis B. Gabbai, MD Institution: University of California, San Diego Principal Investigator: Otelio S. Randall, MD Institution: Howard University Principal Investigator: Lawrence Appel, MD, MPH Institution: Johns Hopkins University Principal Investigator: Keith Norris, MD Institution: Charles Drew Medical Center Principal Investigator: DeAnna Cheek, MD Institution: Medical University of South Carolina Principal Investigator: Michael Lipkowitz, MD Institution: Lenox Hill Hospital Principal Investigator: Lee Hebert, MD Institution: Ohio State University Principal Investigator: George Bakris, MD Institution: University of Chicago Principal Investigator: Stephen G. Rostand, MD Institution: University of Alabama at Birmingham Principal Investigator: Geraldine Bichier, MD Institution: University of Florida Principal Investigator: Gabriel Contreras, MD Institution: University of Miami Principal Investigator: Kenneth Jamerson, MD Institution: University of Michigan Principal Investigator: Miroslav J. Smogorzewski, MD Institution: University of Southern California Principal Investigator: Robert D. Toto, MD Institution: University of Texas Southwestern Medical Center at Dallas Principal Investigator: Julia A. Lewis, MD Institution: Vanderbilt University # Overview of Trial This pilot study began after the last scheduled AASK Cohort study visit. Eligible participants were treated for 6 weeks on each of 3 antihypertensive regimens. The sequence of the regimens was random. Each period of the three periods had 2 visits, one visit at 3 weeks and one visit at 6 weeks. In the last week of each 6-week period, a 24-hour ABPM was obtained. The primary outcome variable was nocturnal BP; each pair wise difference between the regimens was calculated. The study was conducted in participants in the African-American Study of Kidney Disease (AASK) Cohort study as a randomized three period cross-over trial. Eighty five percent of AASK cohort participants were on an ACE inhibitor or angiotensin receptor blocker; the most commonly used ACE inhibitor is ramipril. The strategies used in this pilot study remained ramipril-based, to maintain the overall blood pressure control achieved up until the start of the cohort study. The antihypertensive regimens were as follows: - AM dosing of ramipril and other once daily medications in the participants antihypertensive regimen (termed USUAL) - Bedtime dosing of ramipril and other once a day medications in the participant's antihypertensive regimen (termed HS-DOSING) - their current antihypertensive regimen plus an additional antihypertensive agent dosed at bed time; the choice of the additional agent will be tailored based on prespecified clinical guidelines (termed ADD-ON DOSING) The "usual arm" served as the comparator arm. The "hs dosing" and "add-on dosing" arms tested practical strategies that could be tested in a subsequent clinical outcomes trial and that could be implemented in clinical practice. Investigators hypothesized that both arms would reduce nocturnal BP in comparison to "usual dosing". They further hypothesized that the "hs dosing" arm would raise daytime BP somewhat but have no net effect on 24 hour BP and that the "add on dosing" arm would have no effect on daytime BP but lower 24 hour BP. # Disease State(s) Studied (e.g. acute MI, breast cancer, etc.) Hypertensive Renal Disease # Study Phase (e.g. Phase I,II,III,IV) Study Phases are defined here Phase II, Phase III # Study Design (e.g. multicenter, randomized, double blind, placebo controlled) Treatment, Randomized, Open Label, Active Control, Crossover Assignment, Efficacy Study # Study Arms and How They Were Treated (Intervention) (Explanation here) 180 were randomized to 3 different treatment arms: - The USUAL arm: Active Comparator USUAL treatment - The patient's antihypertensive regimen at the baseline visit was the comparison (or control) regimen. All once a day medications were administered in the morning. - USUAL treatment - The patient's antihypertensive regimen at the baseline visit was the comparison (or control) regimen. All once a day medications were administered in the morning. - The HS Dosing arm: Experimental In this period, the patient's antihypertensive regimen at the baseline visit was standardized for the once/day medications to be given at bedtime. - In this period, the patient's antihypertensive regimen at the baseline visit was standardized for the once/day medications to be given at bedtime. - The ADD-ON DOSING arm: Experimental This regimen started with the USUAL regimen to which an additional agent (ramipril, diltiazem, or hydralazine) was added at bed time. The intent of the ADD ON therapy was to lower nocturnal BP with minimal impact on daytime BP. Thus, agents with < 24 hr duration of action were preferred. The specific choice and dose of add-on therapy (of the three agents) was up to the site investigator considering the clinical situation of each participant. - This regimen started with the USUAL regimen to which an additional agent (ramipril, diltiazem, or hydralazine) was added at bed time. The intent of the ADD ON therapy was to lower nocturnal BP with minimal impact on daytime BP. Thus, agents with < 24 hr duration of action were preferred. The specific choice and dose of add-on therapy (of the three agents) was up to the site investigator considering the clinical situation of each participant. # Primary Pre-Specified Endpoint Night time blood pressure (time frame: night time blood pressure from APBM at weeks 6, 12, and 18) # Secondary Endpoints Blood pressure in the clinic daytime blood pressure (time frame: measured at weeks 6, 12, and 18) # Inclusion Criteria - Participant in the AASK Cohort Study - Ability and willingness to provide informed consent - Completion of a technically adequate ABPM at CO48 AASK cohort study visit. - Participants must have had at least 2 visits in the last 12 months of the Cohort Study (July 1 2006 to June 1 2007) - The average of last two BPs measured at least one week apart in the Cohort Study must be less than or equal to 140/90 mm Hg. This excluded a small percentage of the AASK cohort population; however, it enrolled a group of participants with stable BP who should not require adjustments to their antihypertensive medications during the course of this study. - Antihypertensive medications at baseline visit: This refers to the participant's antihypertensive regimen at the time of the baseline visit; the transition period may be used to adjust the participant's antihypertensive regimen to meet these criteria, based on the clinical judgement of the site investigator. # Exclusion Criteria - Arm circumference greater than 50 cms. - ESRD requiring renal replacement therapy or kidney transplantation - Institutionalized participants - Shift workers working at night - MI or CVA within 3 months of AASK Cohort close out visit - Participants with known ejection fraction less than 40% - Females known to be pregnant or lactating - Participants likely to reach end stage renal disease within the next six weeks, in the judgement of the site investigator # Outcome: Primary endpoint (Report both relative risk reduction and absolute risk reduction as well as number needed to treat if available) None reported # Outcome: Secondary endpoint (Report both relative risk reduction and absolute risk reduction as well as number needed to treat if available) None reported # Outcome: Exploratory endpoints (Report both relative risk reduction and absolute risk reduction as well as number needed to treat if available) None reported # Outcome: Safety endpoints (Report both relative risk and absolute risk as well as number needed to harm if available) None reported # Conclusions of the Investigators (Quote the investigators conclusions here) None reported # Commentary, Discussion and Limitations of the Trial (Anyone can add comments) None reported # Slides None reported # Video Commentary None reported # References (How to insert a reference) None reported # External sites for further information (How to insert links) None reported # Detailed information about the trial None reported # Ages 18 years and older # Gender (Indicate whether men, women or both were enrolled) Both men and women were eligible for the study # Accepts Healthy Volunteers (Answer yes or no) No # Enrollment Period (Study start and end date) Study start date: November 2007 Study completion date: December 2008 Primary completion date: December 2008 (Final data collection date for primary outcome measure) # Recruitment Status (explanation) Study has been completed # Enrollment (Total number of patients enrolled) # Study Sponsor (e.g. Investigator initiated or company name) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) # Source of Data (Where is this data on this page coming from: publication, principal investigator, or co-investigator) The content of the clinical trial wiki consists of fields that have been suggested by the World Health Organization and wwww.clinicaltrials.gov.

Angiopoietin 1 Angiopoietin 1 is a type of angiopoietin and is encoded by the gene ANGPT1. Angiopoietins are proteins with important roles in vascular development and angiogenesis. All angiopoietins bind with similar affinity to an endothelial cell-specific tyrosine-protein kinase receptor. The protein encoded by this gene is a secreted glycoprotein that activates the receptor by inducing its tyrosine phosphorylation. It plays a critical role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme. The protein also contributes to blood vessel maturation and stability, and may be involved in early development of the heart. During pregnancy, angiopoietins act complimentary to the VEGF system and contribute to endothelial cell survival and the remodeling of vessels. Few studies have examined the role of angiopoietins in human pregnancy complications like preeclampsia and intrauterine growth restriction (IUGR). A knockout model of ANGPT1 was introduced in mice embryos. Results showed that embryos began to appear abnormal by day 11 and were dead by day 12.5 of pregnancy. The embryos showed prominent defects in endocardial and myocardial development as well as a less complex vascular network. # Interactions Angiopoietin 1 has been shown to interact with TEK tyrosine kinase. # Placental Malaria Recently, studies in malaria-endemic areas suggest that placental malaria (PM) may be associated with a dysregulation in angiopoietins. Increased levels of angiopoietin-1 appear to be associated with a decrease in placental weight and placental barrier thickness in women infected with Plasmodium (the causative agent of malaria). In a mouse model of PM, Plasmodium infection of pregnant mice led to decreased angiopoietin-1, increased angiopoietin-2, and an elevated ratio of angiopoietin-2/angiopoietin-1 in the placenta. This suggests that angiopoietin levels could be clinically significant biomarkers to identify mothers infected with PM.

Chorionic villi # Overview Chorionic villi are villi that sprout from the chorion in order to give a maximum area of contact with the maternal blood. Embryonic blood is carried to the villi by the branches of the umbilical arteries, and after circulating through the capillaries of the villi, is returned to the embryo by the umbilical veins. Thus, the villi are part of the border between maternal and fetal blood during pregnancy. # Development The chorion undergoes rapid proliferation and forms numerous processes, the chorionic villi, which invade and destroy the uterine decidua and at the same time absorb from it nutritive materials for the growth of the embryo. They undergo several stages, depending on their composition. Until about the end of the second month of pregnancy the villi cover the entire chorion, and are almost uniform in size, but after this they develop unequally. # Relations The villi can also be classified by their relations: ## Floating villi These villi are found floating freely in the intervillous space. They exhibit a bi-layered epithelium consisting of cytotrophoblasts with overlaying syncytium (syncytiotrophoblast). ## Anchoring (stem) villi These villi act to stablise mechanical integrity of the placental-maternal interface. # Tissue composition and cell types The bulk of the villi consist of connective tissues in which blood vessels are found. Most of the cells in the connective tissue core of the villi are fibroblasts. Macrophages known as Hofbauer cells are also present. # Additional images - Section through the embryo. - Transverse section of a chorionic villus. - Primary chorionic villi. Diagrammatic. Primary chorionic villi. Diagrammatic. - Secondary chorionic villi. Diagrammatic. Secondary chorionic villi. Diagrammatic. - Human embryo of about fourteen days, with yolk-sac.

Brain stem The brain stem is the lower part of the brain, adjoining and structurally continuous with the spinal cord. Most sources consider the pons, medulla oblongata, and midbrain all to be part of the brainstem. Differentiation of the brain stem from the cerebrum is complex, with regard to both anatomy and taxonomy. Some taxonomies describe the brain stem as the medulla and mesencephalon, whereas others include diencephalic regions. # General anatomy ## Ventral view/medulla and pons The most medial part of the medulla is the anterior median fissure. Moving laterally on each side are the pyramids. The pyramids contain the fibers of the corticospinal tract, or the upper motor neuronal axons as they head inferiorly to synapse on lower motor neuronal cell bodies within the ventral horn of the spinal cord. The anterolateral sulcus is lateral to the pyramids. Emerging from the anterolateral sulci are the hypoglossal nerve (CN XII) rootlets. Lateral to these rootlets and the anterolateral sulci are the olives. The olives are swellings in the medulla containing underlying inferior olivary nuclei (containing various nuclei and afferent fibers). Lateral (and dorsal) to the olives are the rootlets for cranial nerves IX and X (glossopharyngeal and vagus, respectively). The pyramids end at the pontomedullary junction, noted most obviously by the large basal pons. Between the basal pons, cranial nerve 6, 7 and 8 emerge (medial to lateral). These cranial nerves are the abducens nerve, facial nerve and the vestibulocochlear nerve, respectively. At the level of the midpons, the large trigeminal nerve, CN V, emerges. At the rostral pons, the occulomotor nerve emerges at the midline. Laterally, the trochlear nerve has emerged after emerging out of the dorsal rostral pons and wrapping around to the anterior. ## Dorsal view/medulla and pons The most medial part of the medulla is the posterior median fissure. Moving laterally on each side is the fasciculus gracilis, and lateral to that is the fasciculus cuneatus. Superior to each of these, and directly inferior to the obex, are the gracile tubercles and cuteanus tubercles, respectively. Underlying these are their respective nuclei. The obex marks the end of the 4th ventricle and the beginning of the central canal. The posterior intermediate sulci separates the fasciculi gracilis from the fasciculi cuneatus. Lateral to the fasciculi cuneatus is the lateral funiculus. Superior to the obex is the floor of the 4th ventricle. In the floor of the 4th ventricle, various nuclei can be visualized by the small bumps that they make in the overlying tissue. In the midline and directly superior to the obex is the vagal trigone and superior to that it the hypoglossal trigone. Underlying each of these are motor nuclei for the respective cranial nerves. Superior to these trigones are fibers running laterally in both directions. These fibers are known collectively as the striae medullares. Continuing in a rostral direction, the large bumps are called the facial colliculi. Each facial colliculus, contrary to their names, do not contain the facial nerve nuclei. Instead, they have facial nerve axons traversing superficial to underlying abducens (CN VI) nuclei. Lateral to all these bumps previously discussed is an indented line, or sulcus that runs rostrally, and is known as the sulcus limitans. This separates the medial motor neurons from the lateral sensory neurons. Lateral to the sulcus limitans is the area collectively known as the vestibular area, which is involved in special sensation. Moving rostrally, the inferior, middle, and superior cerebellar peduncles are found connecting the midbrain to the cerebellum. Directly rostral to the superior cerebellar peduncle, there is the superior medullary velum and then the two trochlear nerves. This marks the end of the pons as the inferior colliculus is directly rostral and marks the caudal midbrain. Spinal Cord to Medulla Transitional Landmark: From a ventral view, there can be seen a decussation of fibers between the two pyramids. This decussation marks the transition from medulla to spinal cord. Superior to the decussation is the medulla and inferior to it is the spinal cord. ## Midbrain The midbrain is divided into three parts. The first is the tectum, which is "roof" in Latin. The tectum includes the superior and inferior colliculi and is the dorsal covering of the cerebral aqueduct. The inferior colliculus, involved in the special sense of hearing sends its inferior brachium to the medial geniculate body of the diencephalon. Superior to the inferior colliculus, the superior colliculus marks the rostral midbrain. It is involved in the special sense of vision and sends its superior brachium to the lateral geniculate body of the diencephalon. The second part is the tegmentum and is ventral to the cerebral aqueduct. Several nuclei, tracts and the reticular formation is contained here. Last, the ventral side is comprised of paired cerebral peduncles. These transmit axons of upper motor neurons. ## Midbrain internal structures Periaqueductal Gray: The area around the cerebral aqueduct, which contains various neurons involved in the pain desensitization pathway. Neurons synapse here and, when stimulated, cause activation of neurons in the raphe nucleus magnus, which then project down into the dorsal horn of the spinal cord and prevent pain sensation transmission. Occulomotor nerve nucleus: This is the nucleus of CN III. Trochlear nerve nucleus: This is the nucleus of CN IV. Red Nucleus: This is a motor nucleus that sends a descending tract to the lower motor neurons. Substantia nigra: This is a concentration of neurons in the ventral portion of the midbrain that uses dopamine as its neurotransmitter and is involved in both motor function and emotion. Its dysfunction is implicated in Parkinson's Disease. Reticular formation: This is a large area in the midbrain that is involved in various important functions of the midbrain. In particular, it contains lowermotor neurons, is involved in the pain desensitization pathway, is involved in the arousal and consciousness systems, and contains the locus ceruleus, which is involved in intensive alertness modulation and in autonomic reflexes. Central tegmental tract: Directly anterior to the floor of the 4th ventricle, this is a pathway by which many tracts project up to the cortex and down to the spinal cord. # Embryology The adult human brainstem emerges from two of the three primary vesicles formed of the neural tube. The mesencephalon is the second of the three primary vesicles, and does not further differentiate into a secondary vesicle. This will become the midbrain. The third primary vesicle, the rhombencephalon, will further differentiate into two secondary vesicles, the metencephalon and the myelencephalon. The metencephalon will become the cerebellum and the pons. The myelencephalon will become the medulla. # Physiology There are three main functions of the brainstem. The first is its role in conduit functions. That is, all information related from the body to the cerebrum and cerebellum and vice versa, must traverse the brain stem. The ascending pathways coming from the body to the brain are the sensory pathways, and include the spinothalamic tract for pain and temperature sensation and the dorsal column, fasciculus gracilis, and cuneatus for touch, proprioception, and pressure sensation (both of the body). The facial sensations have similar pathways, and will travel in the spinothalamic tract and the medial lemniscus also). Descending tracts are upper motor neurons destined to synapse on lower motor neurons in the ventral horn and intermediate horn of the spinal cord. In addition, there are upper motor neurons that originate in the brainstem's vestibular, red, tactile, and reticular nuclei, which also descend and synapse in the spinal cord. Second, the cranial nerves 3-12 emerge from the brain stem. Third, the brain stem has integrative functions (it is involved in cardiovascular system control, respiratory control, pain sensitivity control, alertness, and consciousness). Thus, brain stem damage is a very serious and often life-threatening problem. The practical results of an improperly functioning brainstem are not just related to physical injury. Behavioral and physical signs can also manifest when there is incomplete pons or mid brain development. Such underdevelopment can affect behavior, academic performance, coordination, anxiety, speech, and focus. Habilitation, the process of first occurrence rehabilitation, makes use of programmatic exercise with the goals of completing development through inducement of neural plasticity # Physical signs of brainstem disease Diseases of the brainstem can result to abnormalities in the function of cranial nerves, which may lead to visual disturbances, pupil abnormalities, changes in sensation, muscle weakness, hearing problems, vertigo, swallowing and speech difficulty, voice change, and co-ordination problems. Less obvious cases may complain of poor reading comprehension, lack of focus, altered vigilance, clumsiness, or poor social skills. Often physical signs to an untrained examiner are not obvious as challenge testing (to reduce cortical compensations) are required during examination. Localizing neurological lesions in the brainstem may be very precise with imaging studies, although the clinical utility of such localization relies upon a clear understanding of brainstem anatomical structures on their functions. # Physical rehabilitation of brainstem disease While rehabilitation of brainstem disorders has traditionally belonged to the domain of physiatry or neurology more recently publicly accessible programs have become available that incorporate concepts which promote neural plasticity. At least one hospital system, Bon Sequours, St. Francis in Greenville, SC, has incorporated a movement based restorative therapy programs that focus on brainstem neuroplasticity for the treatment of common conditions such as Fibromyalgia.

Zoon's balanitis Synonyms and keywords: ZB, Plasma cell balanitis # Overview Zoon's balanitis is a rare non-veneral idiopathic chronic benign inflammatory mucositis of genitalia. In 1952, for the first time in medical literature, Zoon recognized a distinct entity in patients with chronic balanitis,and named it has balanoposthite chronique circonscrite bénigne á plasmocytes or balanitis chronica circumscripta plasmacellularis. The exact pathogenesis of Zoon's balanitis is not clearly known. Patients with Zoon's balanitis presents with well circumscribed single or multiple orange-red in colour lesions with characteristic glazed appearance and multiple pinpoint redder spots "cayenne pepper spots" most commonly involving glans penis. Diagnosis of Zoon's balanitis is confirmed by biopsy. Management of Zoon's balanitis includes both medical and surgical modalities. # Historical Perspective - In 1952, for the first time in medical literature, Zoon recognized a distinct entity in patients with chronic balanitis, named it has balanoposthite chronique circonscrite bénigne á plasmocytes” or “balanitis chronica circumscripta plasmacellularis. - In 1954, Garnier reported similar lesions in vulva. - In 1956, Nikolowski described identical lesions in oral mucosa. - In 1963, Kortnig described idential lesions in conjunctiva. # Classification There is no established classification system for Zoon's balanitis. # Pathophysiology ## Pathogenesis The exact pathogenesis of Zoon's balanitis is not clearly known, but following theories have been postulated: - Accumulation of epithelial debris and secretions between foreskin and penis proximal to coronal sulcus, smegma, poor genital hygiene, repeated local infections, and hot and humid weather results in chronic physical irritation or sub-clinical trauma. Chronic physical irritation or sub-clinical trauma in-turn results in skin lesions along the line of trauma. - Chronic infection with Mycobacterium smegmatis and human papillomaviruses (HPV) was found to be associated with development of Zoon's balanitis. ### Histopathology Zoon's balanitis has distinctive histopathological features, which include: ### Epidermal - Epidermal changes include early thickening with acanthosis and parakeratosis of epidermis, which is followed by atrophy, erosion and spongiosis of epidermis. - Scattered neutrophils may be found in superficial erosions of the epidermis. - Spongiosis accentuation may occur in the lower half of spinous zone. - Subepidermal clefts, necrotic keratinocytes, and lozenge keratinocytes may be seen in the later stages of Zoon's balanitis. ### Dermal - Dermal changes include patchy lichenoid infiltrate of lymphocytes and plasma cells in papillary dermis, which are replaced by neutrophils, eosinophils, lymphocytes and erythrocytes. - Dermal vascular dilatation with singular vertical or oblique orientation of proliferated individual vessels is a characteristic feature of Zoon's balanitis. - In the later stages, upper dermis may show fibrosis which correlates well with sub-epidermal clefts, epidermal atrophy, and plasma cell infiltrates. # Epidemiology and Demographics There are no comprehensive studies studying the epidemiology and demographics of Zoon's disease in general population. A recent study has reported that out of 226 patients examined in a genitourinary medicine clinic over a period of 3 years, about 26(10%) of patients were diagnosed with Zoon's balanitis. # Screening There is no established screening guidelines for Zoon's balanitis. # Natural History, Complications, and Prognosis ## Natural history If left untreated, patients with Zoon's balanitis may develop pain, phimosis and paraphimosis. Studies have reported that there could be an increased risk of transformation of these lesions into squamous cell carcinoma. ## Complications Complications of Zoon's balanitis include: - Phimosis - Paraphimosis - Risk of transformation into malignancy(Squamous cell carcinoma) ## Prognosis Prognosis is usually good with treatment. # Diagnosis ## History and symptoms Patients with Zoon's balanitis could present with asymptomatic or symptomatic lesions with: - Itching (pruritis) in the genitalia region - Discomfort in urination(dysuria) - Pain in the genital region - Blood stain discharge from the lesions - Difficult or painful sexual intercourse ## Physical examination Characteristic lesions seen in Zoon's balanitis are: - Well circumscribed single or multiple, orange-red in colour lesions with characteristic glazed appearance and multiple pinpoint redder spots "cayenne pepper spots"(please click here to view the image) most commonly affecting the glans penis. Inner surface of prepuce and coronal sulcus may also be involved. - Though uncommon, lesions of Zoon's balanitis may also involve other sites which include labia minora in females, oral mucosa, conjunctiva, urethra, cheeks, and epiglottis. Clinical criteria for diagnosing Zoon's balanitis include the following: - Shiny, erythematous patches on the glans, prepuceor both - Lesions present for more than 3 months - Absence of lesions which are suggestive of Lichen planus or psoriasis elsewhere on the body - Poor response to topical therapies - Absence of concurrent infections which are ruled out after performing tzanck, potassium hydroxide, gram stain and VDRL test ## Laboratory findings Laboratory findings in Zoon's balanitis include: Reflectance confocal microscopy A nucleated honeycomb pattern and vermicular vessels is a clue for benign inflammatory genital skin disease Dermoscopy Focal/diffuse orange-yellowish structure with fewer areas representing hemosiderin deposition and curved vessels due to epidermal thinning help in distinguishing ZB from carcinoma in situ. ### Biopsy Epidermal thickening which is followed by epidermal atrophy, at times with erosions Dermis Plasma cell infiltrate with haemosiderin and extravasated red blood cells. # Treatment Management of Zoon's balanitis includes general measures, medical and surgical modalities: ## General measures Good hygiene which include retracting the foreskin regularly and gentle cleansing of entire glans, preputial sac, and foreskin were found effective in treating Balanitis in general. ## Medical Therapy ## Surgery # Prevention ## Primary Prevention There is no established primary prevention measures for preventing of Zoon's balanitis. ## Secondary prevention There is no established secondary prevention measures for Zoon's balanitis.

Social work knowledge building The history of social work is a history plagued by a fundamental question – is social work a profession? This debate can be traced back to the early 20th century debate between Mary Richmond's Charity Organization Society (COS) and Jane Addams's Settlement House Movement. The essence of this debate was whether the problem should be approached from COS’ traditional, scientific method focused on efficiency and prevention or the Settlement House Movement’s immersion into the problem, blurring the lines of practitioner and client . The impetus for both movements was the glaring reality of social problems and the question over how to best attack them. This debate is arguably the earliest example of a larger debate within social work – how is knowledge acquired? This debate pits positivism against post-positivism in the pursuit of achieving respect as a profession. The positivistic argument asserts knowledge has to be observable and testable (quantitative), free from bias, and ultimately replicable if it is to have any merit. Post-positivists argue there is no way to completely eliminate bias, and knowledge can be obtained via qualitative research methods. The debate reached its greatest intensity in the 1980s, reflecting the debate within the larger world of the social sciences. Subsequently, most of those interested in social work knowledge building have joined in a consensus that both perspectives are necessary to fully understand the complex realities encountered by social work practitioners. Today, most text books intended for social work research courses, while they may devote more pages to quantitative approaches, also include one or more chapters on qualitative approaches, and make an effort not to favor one over the other Meanwhile, practitioners, and often educators in social work practice, have felt left out of the debate. A frequent complaint was that social work programs were favoring research over practice skills in faculty hiring, thus weakening their ability to teach practice skills to new practitioners. The reliance among practitioners on shared practice wisdom, and the development of skills and techniques through clinical supervision and mentorship was not considered as valid as knowledge building by either camp. There have been attempts to bridge the gap between practice-based knowledge and knowledge obtained through more formal research approaches. One such strategy is single-subject research--also known as Single Subject Design (SSD), in which the clinician, working together with the client, carefully specifies a target of intervention, then measures its frequency, duration, intensity, or any relevant characteristics during a baseline period when no intervention is tried. Following this, an intervention is introduced, and measurement of the target problem is continued. Two claims made for SSD were that it would improve clinical work, since effectiveness of interventions could be determined, and that single cases could be aggregated into research reports, which, published, would constitute an empirically verified set of interventions for clinical use. Although SSD has been championed by social work graduate programs for more than two decades, there is little evidence that it has been widely adopted by social work practitioners. The current state of social work knowledge building is characterized by two realities. There is a great deal of traditional research, both qualitative and quantitative being carried out, primarily by university-based researchers, but also in different fields, by researchers based in institutes, foundations, or social service agencies. Meanwhile, the majority of social work practitioners continue to look elsewhere for knowledge. This is a state of affairs that has persisted since the outset of the profession in the first decade of the twentieth century. One reason for the practice-research gap is that practitioners deal with situations that are unique and idiosyncratic, while research deals with regularities and aggregates. The translation between the two is often imperfect. A hopeful development for bridging this gap is the compilation in many practice fields of collections of "best practices," largely taken from research findings, but also distilled from the experience of respected practitioners.

Isthmus An isthmus (Template:IPAEng, Template:Lang-el, plural isthmuses or isthmi) is a narrow strip of land that is bordered on two sides by water and connects two larger land masses. It is the inverse of a strait (which lies between two land masses and connects two larger bodies of water). Isthmi are naturally good places to build canals. The Panama Canal, for instance, which connects the Atlantic and Pacific Oceans, drastically reduces the naval travel time between the east and west coasts of America. # List of isthmuses - Auckland isthmus, which connects the North Auckland Peninsula|Northland Peninsula to the rest of New Zealand's North Island. - Isthmus of Avalon, which connects the populous Avalon Peninsula to the rest of Newfoundland. - Isthmus of Corinth, which connects the Peloponnese peninsula to the rest of Greece. - Isthmus of Gibraltar, which joins Gibraltar to mainland Spain. - Karelian Isthmus between Gulf of Finland and Lake Ladoga. - Isthmus of Kra, which joins the Malay Peninsula with mainland Asia. - Isthmus of Kushimoto in Japan - connects Honshū with Cape Shiono-Misaki. - La Coupée isthmus in Sark. - Madison Isthmus, between Lake Mendota and Lake Monona in Madison, Wisconsin. - Mavis Grind isthmus in Shetland, UK. - Isthmus of Médanos - licks Venezuela to Médanos. - Neck in Bruny Island, Tasmania - connects North and South Bruny. - Ofqui Isthmus, Aysen Region, Chile. - Isthmus of Panama - arguably the most famous isthmus, connects North America and South America. - Isthmus of Perekop between Crimea and Ukraine proper. - Isthmus of Potidea, connecting the Kassandra peninsula with the mainland of Greece. - Quezon Province, in Luzon, Philippines - connecting Bicol peninsula with mainland Luzon. - Adam's Bridge, between India and Sri Lanka (a former Isthmus). - Isthmus of Suez - the isthmus between North Africa and Southwest Asia, in Egypt where the Suez Canal is located. - Isthmus of Summerside, connecting the Western section of Prince Edward Island, Canada with the remainder of the island. - Isthmus of Tehuantepec - connects Yucatan and Central America with the rest of Mexico. - Isthumus of Nahant connecting Nahant, Massachusetts to Massachusetts.

Mepolizumab for treating severe eosinophilic asthma Evidence-based recommendations on mepolizumab (Nucala) for treating severe eosinophilic asthma in adults. # Recommendations Mepolizumab, as an add-on therapy, is recommended as an option for treating severe refractory eosinophilic asthma, only if: it is used for adults who have agreed to and followed the optimised standard treatment plan and the blood eosinophil count has been recorded as 300 cells per microlitre or more and the person has had at least 4 exacerbations needing systemic corticosteroids in the previous 12 months, or has had continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months or the blood eosinophil count has been recorded as 400 cells per microlitre or more and the person has had at least 3 exacerbations needing systemic corticosteroids in the previous 12 months (so they are also eligible for either benralizumab or reslizumab).Mepolizumab is recommended only if the company provides it according to the commercial arrangement. If mepolizumab, benralizumab or reslizumab are equally suitable, start treatment with the least expensive option (taking into account drug and administration costs). At 12 months: stop mepolizumab if the asthma has not responded adequately or continue mepolizumab if the asthma has responded adequately and assess response each year.An adequate response is defined as: a clinically meaningful reduction in the number of severe exacerbations needing systemic corticosteroids or a clinically significant reduction in continuous oral corticosteroid use while maintaining or improving asthma control. These recommendations are not intended to affect treatment with mepolizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations 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 For severe refractory eosinophilic asthma, standard therapy alone does not work well enough. So people usually also have benralizumab or mepolizumab if: their blood eosinophil count is 300 cells per microlitre or more and they have had at least 4 severe exacerbations needing systemic corticosteroids in the previous 12 months or continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months. People can have benralizumab or reslizumab if their blood eosinophil count is 400 cells per microlitre or more and they have had at least 3 severe exacerbations in the previous 12 months. There is no evidence directly comparing mepolizumab with benralizumab and reslizumab. But an indirect comparison suggests that it works as well as benralizumab and reslizumab for people with a blood eosinophil count of 400 cells per microlitre or more. Mepolizumab is cost saving compared with benralizumab and reslizumab. So it is now also recommended for people with a blood eosinophil count of 400 cells per microlitre or more and at least 3 severe exacerbations in the previous 12 months.# Information about mepolizumab # Marketing authorisation indication Mepolizumab (Nucala, GlaxoSmithKline) has a marketing authorisation in the UK as an 'add-on treatment for severe refractory eosinophilic asthma in adults, adolescents and children aged 6 years and older'. # Dosage in the marketing authorisation Mepolizumab is available as a powder for solution for injection in vials, or as a solution for injection in pre-filled syringes and pre-filled pens. The dosage schedule is available in the summary of product characteristics. # Price The list price of mepolizumab is £840 per 100 mg dose (excluding VAT; BNF online, accessed November 2020). The company has a commercial arrangement. This makes mepolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee considered evidence submitted by GlaxoSmithKline, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence. The company proposed that this technology be considered in a fast track appraisal using cost-comparison methodology. # New treatment option ## People with severe eosinophilic asthma will welcome a new treatment option Severe refractory eosinophilic asthma is a debilitating condition, which does not respond well enough to standard therapy and has many distressing symptoms. Asthma exacerbations can happen without warning, be life threatening, cause fear, and result in hospitalisation and intubation. People with uncontrolled severe eosinophilic asthma are often unable to work and may need help with day-to-day activities because of the symptoms. These physical and psychological pressures negatively affect quality of life. The patient experts highlighted an urgent need for more biological treatments for people who are not eligible for benralizumab or reslizumab or whose asthma does not respond to them. These people would otherwise need more intensive treatment with oral corticosteroids, which are associated with major side effects including diabetes, glaucoma, weight gain, loss of bone density and raised blood pressure. The clinical experts explained that the clinical community would welcome treatment criteria for biologicals to be standardised. The committee concluded that people with severe eosinophilic asthma with a blood eosinophil count of 400 cells per microlitre or more and at least 3 severe asthma exacerbations would welcome a new treatment option. # Clinical effectiveness ## The indirect treatment comparison of mepolizumab, benralizumab and reslizumab is appropriate NICE originally recommended mepolizumab for treating severe refractory eosinophilic asthma in adults with: a blood eosinophil count of 300 cells per microlitre or more and at least 4 severe exacerbations needing systemic corticosteroids in the past 12 months or if they have had continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months.The company proposed extending this recommendation, in line with NICE's technology appraisal guidance on benralizumab and reslizumab, to include people with: a blood eosinophil count of 400 cells per microlitre or more and at least 3 severe exacerbations needing systemic corticosteroids in the past 12 months.The company's evidence submission did not include any head-to-head trials directly comparing mepolizumab with benralizumab and reslizumab. It presented an indirect treatment comparison (ITC) of mepolizumab, benralizumab and reslizumab in severe eosinophilic asthma. The ITC included 9 placebo-controlled studies. The primary outcomes included: exacerbation needing treatment with oral corticosteroids exacerbation needing an emergency department visit or hospitalisation Asthma Control Questionnaire score and change from baseline pre-bronchodilator forced expiratory volume in 1 second.The committee noted the limitations of the company's ITC, namely that potentially relevant studies were omitted. The 75 mg treatment arms from DREAM and MENSA were omitted to ensure that the data reflected the licensed dose of 100 mg. The ERG was unable to fully assess the effect of excluding these on the final efficacy results. It considered that omitting ZONDA and SIRIUS from the ITC was appropriate because of their different primary outcomes. The ERG also noted variation between studies in length of follow up, dosing and administration, asthma severity, blood eosinophil counts and previous exacerbations. But it recognised that most of the pairwise meta-analyses had low heterogeneity. It also noted that corticosteroid reduction was among the outcomes missing from the ITC. However, its clinical advisers suggested that a reduction in exacerbations may also imply a reduction in corticosteroid use so the ERG did not consider this to be an issue. The committee concluded that the ITC of mepolizumab, benralizumab and reslizumab is appropriate. ## There is sufficient evidence that mepolizumab has comparable efficacy to benralizumab and reslizumab The results of the ITC for the primary outcomes broadly favoured mepolizumab over benralizumab and reslizumab for the subgroups in the trials with an eosinophil count of 400 cells per microlitre or more. But no evidence of a difference between treatments was found when the full trial populations were compared. The analysis for the comparison of mepolizumab with benralizumab and reslizumab was done for people with: a blood eosinophil count of 400 cells per microlitre or more and at least 1 severe exacerbation in the reslizumab arm or 2 severe exacerbations in the mepolizumab and benralizumab arms.However, the ERG stated that although this broader subgroup was not exactly aligned to the population being considered, it was closer than any other analysis. The ERG confirmed that there was a low risk that mepolizumab was less effective than benralizumab and reslizumab for severe eosinophilic asthma. The committee concluded that there was sufficient evidence that mepolizumab has comparable efficacy to benralizumab and reslizumab. # Cost comparison ## A 10-year time horizon is more appropriate for decision making The company did a cost comparison of mepolizumab with benralizumab and reslizumab. The costs were presented over a 1-year time horizon and were not discounted. The analysis compared: mepolizumab 100 mg; a powdered vial for mixing, a pre-filled syringe and pre-filled pen, administered subcutaneously every 4 weeks benralizumab 30 mg; a pre-filled syringe and pre-filled pen, administered subcutaneously every 4 weeks for the first 3 doses, then every 8 weeks and reslizumab with a weight-dependent dose (assuming a mean weight of 78 kg for the UK adult population); concentrate for intravenous infusion administered every 4 weeks.The analysis included drug, administration and monitoring costs. Oral corticosteroid costs were not included in the analysis. The analysis assumed that there were no differences in adverse event costs based on a Cochrane review that found no excess serious adverse events with any anti-interleukin-5 treatments (such as mepolizumab, benralizumab and reslizumab). It was uncertain whether a 1-year time horizon was sufficient to capture the key differences in costs between treatments. This was particularly because of the loading dose for benralizumab, and differences in dosing frequency and administration costs over time. However, an ERG scenario showed that mepolizumab remained cost saving over a 10-year time horizon. The ERG did not consider monitoring costs to be a key driver of the results. The committee concluded that a 10-year time horizon was more appropriate for decision making. ## Self-administration has a small effect on the cost-comparison results The committee questioned the proportion of people likely to self-administer the drug and the effect of this on savings with mepolizumab. The company explained that around 97% of people are currently self-administering and only 3% need mepolizumab to be given by a nurse. The clinical experts advised that the largest saving from those self-administering is in secondary care, with savings related to pharmacy and nurse time. However, people being set up for self-administration would need slightly longer appointments. The ERG explained that in the context of the drug costs, administration cost differences have little effect. The committee concluded that self-administration has a small effect on the cost-comparison results and the incremental savings with mepolizumab are mainly related to lower drug costs. ## Mepolizumab results in cost savings when compared with benralizumab and reslizumab The company's cost comparison included a range of assumptions for: administration and monitoring costs -ral corticosteroid use the comparable safety profile of mepolizumab, benralizumab and reslizumab over a 1-year time horizon.Assuming equivalent effectiveness and based on the list price for all treatments, mepolizumab had incremental cost savings compared with benralizumab and reslizumab. Mepolizumab remained cost saving in the additional ERG scenario over a 10-year time horizon. The committee concluded that, at list price, mepolizumab was cost saving compared with benralizumab and reslizumab for people with an eosinophil count of 400 cells per microlitre or more, and at least 3 severe exacerbations per year. Mepolizumab, benralizumab and reslizumab are available to the NHS with confidential commercial arrangements. The ERG analysis including these commercial arrangements did not change the committee's conclusion. ## Mepolizumab is recommended The committee concluded that mepolizumab met the criteria to be recommended based on a cost comparison, because the overall health benefits are similar to those of benralizumab and reslizumab. The committee concluded that mepolizumab could be recommended as an option for treating severe refractory eosinophilic asthma in adults with: a blood eosinophil count of 300 cells per microlitre or more and at least 4 exacerbations needing systemic corticosteroids in the previous 12 months or continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months or a blood eosinophil count of 400 cells per microlitre or more and at least 3 exacerbations needing systemic corticosteroids in the previous 12 months.

Coptis aspleniifolia Coptis aspleniifolia, commonly known as Fern-Leaved Goldthread, is found in the northern two-thirds of British Columbia, in Alaska, and along the Cascades into Washington and is a native plant of the Coast (temperate) Forest Region. It is often found in the understory of the herb layer of carniferous mountain forests as part of a multilayered canopy system on gleysolic or organic soils on watering sights. Also found in wetwoods and bogs, the Fern-leaved Goldthread is not invasive or poisonous. On a rating system created by the province ranging from S1, critically imperiled or rare – S5, “common, widespread, and abundant in the province”, the Fern-leaved Goldthread is an S5. An evergreen perennial, the Fern-leaved Goldthread is mostly hairless and 5-30cm tall. Its leaves resemble those of Ferns, are all basal, dark-green and glossy and divided into 5 or more segments. The Fern-leaved Goldthread blooms late April/May with a pale greenish white/yellow flower. It has 2-3 nodding flowers per stalk, 5-7 delicate septals and 5-7 thin petals. The Fern-leaved Goldthread is a member of the Buttercup Family. The Fern-leaved Goldthread is named for its leaves which are structured similar to the common fern and for its roots, which are vibrant golden hue when peeled. The Fern-leaved Goldthread is an important part of the ecosystem, serving as a protective ground cover, keeping moisture in the ground by providing shade, as well as primary nutritional food source for deer.

Wiskott-Aldrich syndrome Synonyms and keywords: Aldrich syndrome # Overview Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet counts), immune deficiency, and bloody diarrhea (due to the low platelet counts). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene. # Historical Perspective The syndrome is named after Dr Robert Anderson Aldrich, an American pediatrician who described the disease in a family of Dutch-Americans in 1954, and Dr Alfred Wiskott, a German pediatrician who first noticed the syndrome in 1937. Wiskott described three brothers with a similar disease, whose sisters were unaffected. In 2006 a German research group analysed family members of Wiskott's three cases, and surmised that they probably shared a novel frameshift mutation of the first exon of the WAS gene. # Classification Jin et al (2004) employ a numerical grading of severity: - Grade 0.5: intermittent thrombopenia - Grade 1.0: thrombopenia and small platelets - Grade 2.0: thrombopenia and normally responsive eczema or occasional upper respiratory tract infections. - Grade 2.5: thrombopenia and therapy-responsive but severe eczema or airway infections requiring antibiotics - Grade 3.0: both eczema and airway infections requiring antibiotics - Grade 4.0: eczema continuously requiring therapy and/or severe or life threatening infections - Grade 5.0: autoimmune disease or malignancy in an XLT/WAS patient. # Pathophysiology In the Wiskott–Aldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts. Wiskott–Aldrich syndrome was linked in 1994 to mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein (WASp). It was later discovered that the disease X-linked thrombocytopenia (XLT) was also due to WASp mutations, but different ones from those that cause full-blown Wiskott–Aldrich syndrome. Furthermore, the rare disorder X-linked neutropenia has been linked to particular mutations of the WASp gene. The WASp gene codes for the protein by the same name, which is 502 amino acids long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by binding to the Arp2/3 complex. In T-cell, WASp is important because it is known to be activated via T-cell receptor (TCR) signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse. The immune deficiency is caused by decreased antibody production, and an inability for T cells to become polarized (making it a combined immunodeficiency). This leads to increased susceptibility to infections, particularly of the ears and sinuses. T cells are unable to reorganize their actin cytoskeleton. The type of mutation to the WASp gene correlates significantly with the degree of severity: those that led to the production of a truncated protein caused significantly more symptoms than those with a missense mutation but a normal-length WASp. Although autoimmune disease and malignancy occur in both types of mutation, those patients with truncated WASp carry a higher risk. A defect in CD43 molecule has been found to be associated in patients with Wiskott–Aldrich syndrome. # Causes In Wiskott–Aldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts. Wiskott–Aldrich syndrome was linked in 1994 to mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein (WASp). It was later discovered that the disease X-linked thrombocytopenia (XLT) was also due to WASp mutations, but different ones from those that cause full-blown Wiskott–Aldrich syndrome. Furthermore, the rare disorder X-linked neutropenia has been linked to particular mutations of the WASp gene. The WASp gene codes for the protein by the same name, which is 502 amino acids long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by binding to the Arp2/3 complex. In T-cell, WASp is important because it is known to be activated via T-cell receptor (TCR) signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse. The immune deficiency is caused by decreased antibody production, and an inability for T cells to become polarized (making it a combined immunodeficiency). This leads to increased susceptibility to infections, particularly of the ears and sinuses. T-cells are unable to reorganize their actin cytoskeleton. The type of mutation to the WASp gene correlates significantly with the degree of severity: those that led to the production of a truncated protein caused significantly more symptoms than those with a missense mutation but a normal-length WASp. Although autoimmune disease and malignancy occur in both types of mutation, those patients with truncated WASp carry a higher risk. A defect in CD43 molecule has been found to be associated in patients with Wiskott–Aldrich syndrome. # Differentiating Wiskott-Aldrich Syndrome From Other Disorders of Humoral Imuunodeficiency Wiskott-Aldrich Syndrome should be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials: - Malignancy: can cause the reduction in the immunoglobulin production. - Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia.. - Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency. - Other causes of primary humoral immunodeficiencies. - Smoking: may cause IgG2 subclass deficiency. - Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins. # Differentiating Wiskott-Aldrich Syndrome From Other Bleeding Diseases - Wiskott-Aldrich syndrome must be differentiated from other bleeding disorders. Different causes of bleeding disorders can be differentiated based on their clinical manifestation and laboratory findings. These features have discussed in the below table: # Risk Factors - Positive family history of Wiskott-Aldrich syndrome, can be considered as a risk factor. # Screening - Flow cytometry: Anti-WASp antibody can be used to detect presence or absence of WAS protein. However, flow cytometry may not detect expression of mutated, reduced or poor WASp. - Anti-WASp antibody can be used to detect presence or absence of WAS protein. However, flow cytometry may not detect expression of mutated, reduced or poor WASp. - Identification of carriers: Known female carriers can be identified by using DNA mutation analysis of WAS gene. - Prenatal diagnosis: DNA analysis from chorionic villus sampling can be performed. # Natural History, Complications, and Prognosis - If left untreated, patients with Wiscott-Aldrich syndrome may progress to develop manifestations associated with thrombocytopenia, and abnormal platelet function, defective innate and adaptive immunity which include, severe bleeding (eg, epistaxis, purpura, life threatening gastrointestinal and intracranial hemorrhages), recurrent and severe bronchopulmonary infections. Malignancy and autoimmunity risk has also increased. These conditions may increase the risk of death. - Common complications of Wiscott-Aldrich syndrome include: Recurrent infections with bacterial, viral, fungal and opportunistic organisms. Most common clinical manifestations include otitis media, sinusitis, pneumonia, meningitis, skin infections, and sepsis. Bleeding diathesis (eg, epistaxis, ecchymoses, petechiae, hematemesis, intracranial and gastrointestinal hemorrhages) Autoimmune manifestations may occur in the form of autoimmune hemolytic anemia, immune thrombocytopenic purpura and neutropenia, vasculitis involving small and large vessels, inflammatory bowel disease, and immune-mediated damage to the kidneys and joints. Increased risk of malignancy such as lymphoma, leukaemia is a frequent occurence in Wiskott-Aldrich syndrome. - Recurrent infections with bacterial, viral, fungal and opportunistic organisms. Most common clinical manifestations include otitis media, sinusitis, pneumonia, meningitis, skin infections, and sepsis. - Bleeding diathesis (eg, epistaxis, ecchymoses, petechiae, hematemesis, intracranial and gastrointestinal hemorrhages) - Autoimmune manifestations may occur in the form of autoimmune hemolytic anemia, immune thrombocytopenic purpura and neutropenia, vasculitis involving small and large vessels, inflammatory bowel disease, and immune-mediated damage to the kidneys and joints. - Increased risk of malignancy such as lymphoma, leukaemia is a frequent occurence in Wiskott-Aldrich syndrome. - Prognosis is generally poor. 5-year survival rates in patients with Wiscott-Aldrich syndrome who had received stem cell transplantation is approximately 73.7% to 80%. # Diagnosis ## Diagnostic Study of Choice - The first laboratory test to be performed in the diagnosis of Wiskott-Aldrich syndrome is complete blood count with differential and peripheral blood smears. - The diagnosis of Wiskott-Aldrich syndrome is suspected if a male patient who presents with bruises, petechiae, eczema, recurrent infections and the presence of congenital thrombocytopenia(< 70 000/mm3) with small platelet volume <5·0fl (micro thrombocytopenia) on the peripheral blood smear. - Identification of WAS gene mutations using DNA sequence analysis of WAS gene and detection of WASp expression by flow cytometry are necessary to confirm the diagnosis. ## History and Symptoms - Patients with Wiskott-Aldrich syndrome have - Common symptoms of Wiskott-Aldrich syndrome include: Easy bruising Petechiae Purpura Eczema Prolonged and excessive bleeding after circumcision or from umbilical stump Recurrent infections Epistaxis (Nose bleeds) Hematemesis Hematuria Melena - Easy bruising - Petechiae - Purpura - Eczema - Prolonged and excessive bleeding after circumcision or from umbilical stump - Recurrent infections - Epistaxis (Nose bleeds) - Hematemesis - Hematuria - Melena ## Physical Examination - The following findings may be found in the physical examination of the patients with Wiscott-Aldrich syndrome. These include: Failure to thrive Skin examination shows bruises, petechiae, purpura, and eczema due to low platelet count. suppurative skin lesions may also be seen. Lymphadenopathy Rales and wheezing on auscultation if there is an underlying lung infection. Hepatosplenomegaly ENT examination: Carefully examine sinuses to rule out sinusitis, ears for any tympanic membrane abnormalities to rule out otitis media and throat for pharyngitis and other opportunistic infections such as oral thrush. CNS examination may be performed for symptoms associated with intracranial hemorrhage and infections. - Failure to thrive - Skin examination shows bruises, petechiae, purpura, and eczema due to low platelet count. suppurative skin lesions may also be seen. - Lymphadenopathy - Rales and wheezing on auscultation if there is an underlying lung infection. - Hepatosplenomegaly - ENT examination: Carefully examine sinuses to rule out sinusitis, ears for any tympanic membrane abnormalities to rule out otitis media and throat for pharyngitis and other opportunistic infections such as oral thrush. - CNS examination may be performed for symptoms associated with intracranial hemorrhage and infections. ## Laboratory Findings - Laboratory findings consistent with the diagnosis of Wiscott-Aldrich syndrome include: Complete blood count (CBC) and peripheral smear may show anemia, thrombocytopenia, decreased platelet size and volume. Immunologic studies may show following findings: Decreased levels of serum IgG and IgM and elevated levels of serum IgA and IgE antibodies. Reduction in T lymphocyte count and their function. Variable antibody response to vaccines, protein and polysaccharide antigens. Decreased or absent concentrations of isohemagglutinins. Abnormal T and B lymphocyte proliferative response to mitogens. Abnormal phagocytic response Natural Killer cell defects may also be found. - Complete blood count (CBC) and peripheral smear may show anemia, thrombocytopenia, decreased platelet size and volume. - Immunologic studies may show following findings: Decreased levels of serum IgG and IgM and elevated levels of serum IgA and IgE antibodies. Reduction in T lymphocyte count and their function. Variable antibody response to vaccines, protein and polysaccharide antigens. Decreased or absent concentrations of isohemagglutinins. Abnormal T and B lymphocyte proliferative response to mitogens. Abnormal phagocytic response Natural Killer cell defects may also be found. - Decreased levels of serum IgG and IgM and elevated levels of serum IgA and IgE antibodies. - Reduction in T lymphocyte count and their function. - Variable antibody response to vaccines, protein and polysaccharide antigens. - Decreased or absent concentrations of isohemagglutinins. - Abnormal T and B lymphocyte proliferative response to mitogens. - Abnormal phagocytic response - Natural Killer cell defects may also be found. ## Electrocardiogram - There are no specific electrocardiogram findings associated with Wiskott-Aldrich syndrome. ## X-ray - There are no specific x-ray findings associated with Wiskott-Aldrich syndrome. However, a chest x-ray may be helpful in the diagnosis of complications, which include pneumonia. ## Echocardiography or Ultrasound - There are no specific echocardiography/ ultrasound findings associated with Wiscott-Aldrich syndrome. ## CT scan - There are no CT scan findings associated with Wiscott-Aldrich syndrome. However, a CT scan may be helpful in the diagnosis of complications of this syndrome, which include pneumonia, internal hemorrhage, to diagnose malignancy and to assess splenic enlargement. ## MRI - There are no specific MRI findings associated with Wiskott-Aldrich syndrome. # Treatment ## Medical Therapy - Mainstay therapy for Wiskott-Aldrich syndrome is conservative therapy and supportive care, which includes: Prophylactic antimicrobial agents should be given to treat bacterial, viral, fungal and opportunistic infections. Trimethoprim/sulfamethoxazole: 5mg/kg/day can be given to treat most bacterial and pneumocystis jirovecii pneumonia. Acyclovir: 200mg/twice daily may be given to treat viral infections (eg, HSV-1) Fluconazole: 3mg/kg/day may be given to treat fungal infections. Platelet transfusions: Platelet transfusions can be given to treat bleeding episodes such as life-threatening gastrointestinal and intracranial hemorrhages. Platelet transfusions can also be given to patients who are undergoing any surgical procedure. If a patient can be chosen for transfusion, platelets and blood products should be irradiated and must be obtained from a CMV free donor. Intravenous immunoglobulins: Preferred regimen: 400 to 600 mg/kg can be given every three weeks Immunosuppressive agents: Rituximab can be given to treat autoimmune cytopenias such as hemolytic anemia, neutropenia, associated with Wiskott- Aldrich syndrome. Thrombopoietic agents: Eltrombopag may be helpful in increasing platelet count in patients with Wiskott-Aldrich syndrome but it may not improve platelet surface activation. Gene therapy: Gene therapy is an alternative curative treatment for Wiskott-Aldrich syndrome, which is still going under trials. - Prophylactic antimicrobial agents should be given to treat bacterial, viral, fungal and opportunistic infections. Trimethoprim/sulfamethoxazole: 5mg/kg/day can be given to treat most bacterial and pneumocystis jirovecii pneumonia. Acyclovir: 200mg/twice daily may be given to treat viral infections (eg, HSV-1) Fluconazole: 3mg/kg/day may be given to treat fungal infections. - Trimethoprim/sulfamethoxazole: 5mg/kg/day can be given to treat most bacterial and pneumocystis jirovecii pneumonia. - Acyclovir: 200mg/twice daily may be given to treat viral infections (eg, HSV-1) - Fluconazole: 3mg/kg/day may be given to treat fungal infections. - Platelet transfusions: Platelet transfusions can be given to treat bleeding episodes such as life-threatening gastrointestinal and intracranial hemorrhages. Platelet transfusions can also be given to patients who are undergoing any surgical procedure. If a patient can be chosen for transfusion, platelets and blood products should be irradiated and must be obtained from a CMV free donor. - Platelet transfusions can be given to treat bleeding episodes such as life-threatening gastrointestinal and intracranial hemorrhages. Platelet transfusions can also be given to patients who are undergoing any surgical procedure. - If a patient can be chosen for transfusion, platelets and blood products should be irradiated and must be obtained from a CMV free donor. - Intravenous immunoglobulins: Preferred regimen: 400 to 600 mg/kg can be given every three weeks - Preferred regimen: 400 to 600 mg/kg can be given every three weeks - Immunosuppressive agents: Rituximab can be given to treat autoimmune cytopenias such as hemolytic anemia, neutropenia, associated with Wiskott- Aldrich syndrome. - Thrombopoietic agents: Eltrombopag may be helpful in increasing platelet count in patients with Wiskott-Aldrich syndrome but it may not improve platelet surface activation. - Gene therapy: Gene therapy is an alternative curative treatment for Wiskott-Aldrich syndrome, which is still going under trials. ## Surgery - Hematopoietic stem cell transplantation (HSCT): HSCT is the only standard curative treatment for Wiskott-Aldrich syndrome. - HSCT is the only standard curative treatment for Wiskott-Aldrich syndrome. - Splenectomy: Splenectomy may be considered for some patients with Wiskott-Aldrich syndrome . Splenectomy may be found to improve platelet count as well as size of the platelets . However, sepsis is a life-threatening complication after splenectomy. Prophylactic antibiotics should always be used to prevent infections. Primary Prevention - There are no established measures for the primary prevention of the Wiskott-Aldrich syndrome. However genetic mutation analysis and prenatal molecular diagnosis can be helpful in decreaing the occurance . ## Secondary Prevention - There are no established measures for the secondary prevention of the Wiskott-Aldrich syndrome.

User contributions # Overview User contributions pages list the edits that a particular user has made. These pages are project specific, so a user contributions page for meta will not show the edits that user has made to Wikipedia or any other project. Checking your contributions is useful to refresh your memory about which pages you have worked on (and to easily access these again), but can also be used to find out whether there have been any subsequent edits (see below). This makes it possible to "watch" pages even if you haven't put them on your watchlist. Other users' user contribution pages can also be accessed and are useful for seeing how other users have contributed. They can be used to track down vandals, copyright violations, etc. # Accessing a user contributions page ## Accessing your own user contributions page - To access your own user contributions page, click My contributions. This is displayed either at the top of the page, or on the left hand side. ## Accessing other user's user contributions page - If the user has an account (username): bring up the user page and click User contributions - this works even if the user page has not been edited yet (i.e. an edit box displays). - If the user has no login name, two methods are: Click on the IP address in Recent Changes or Page History Put the IP address in the search box and press Go - Click on the IP address in Recent Changes or Page History - Put the IP address in the search box and press Go # Using a user contributions page Below is an example of an user contributions page using the default skin: Example of a user contributions page Edits are shown from newest to oldest. Each edit takes up one line which shows; time & date, the page name and the edit summary, as well as other diagnostic information. Lets have a look at some of the functions of this page: - The username or IP of the contributor appears here. - You can select a namespace to filter your results. For example, to see only templates select Template from the drop down list and press Go. - This gives the time and date of the edit. - (hist) takes you to the page history, so you can see all edits made to that page. This can be useful if someone has updated a page you have worked on, and you want to see their changes. - (diff) takes you to a diff page showing the changes between that edit and the current revision. The current revision appears below the changes so you can see how the page is now rendered. - m stands for minor edit (small corrections to a page). These help you understand the type of changes that have been made. - This is the name of the page the edit took place on. The current page name is used, so if the page has been renamed the name displayed will be different. - This is the edit summary. It is the text the user wrote in the edit summary box (below the edit box). - (top) signifies that the edit is the current revision. The page is as the user last saved it. This can be used to watch pages (if your last edit to the page does not display (top) the page has been changed). Sysops also have a rollback link here, see Help:Reverting. - This edit summary begins with an arrow link and grey text. This means the user has only edited a section of the page (named in the grey text). This text is automatically added when you edit a section. The black text is a standard edit summary and is added by the user. - This user has few edits, so all their edits fit onto one page. When their edits span more than one page, the black text in brackets will become links. These links take you to the users most recent edits (Latest), oldest edits (Earliest) or the next or previous page of edits (Next n / Previous n). - The blue numbers list the number of edits displayed on a page - 20, 50, 100, 250 or 500. A higher number increases the length of a page but reduces the number of pages The number you select replaces n in the links to the previous or next pages e.g. (Next 100 / Previous 100). ## Also shown - The creation of a new page ## Not shown - Edits from a page that has been deleted afterwards (unless it has been restored) - Uploading a new image with the same name as one that already exists, thus replacing it - The deletion or restoration (undeletion) of a page (if the user is a sysop) # URLs and links A user contributions URL looks like this: :Contributions&target=XX or :Contributions/XX (for this wiki) where XX is the user name or IP address. Change the sub-site to view your contributions on that particular subsite. (www.wikipedia.org, meta.wikimedia.org, etc.) To link to a user contributions page you can also use this shorter form: Special:Contributions/XX. Interwiki links work as normal e.g. w:Special:Contributions/XX. You can view edits from only one namespace. Each namespace has an associated number. Restricting to one namespace can be done with the long form URL only (in this example the namespace is number 4): :Contributions&target=XX&namespace=4 # Privacy Your contributions can be viewed by anyone - please be mindful of this.

Molecule In chemistry, a molecule is defined as a sufficiently stable electrically neutral group of at least two atoms in a definite arrangement held together by strong chemical bonds. In organic chemistry and biochemistry, the term molecule is used less strictly and also is applied to charged organic molecules and biomolecules. Molecules are distinguished from polyatomic ions in the strict sense. This definition has evolved as knowledge of the structure of molecules has increased. Earlier definitions were less precise defining molecules as the smallest particles of pure chemical substances that still retain their composition and chemical properties. This definition often breaks down since many substances in ordinary experience, such as rocks, salts, and metals, are composed of atoms or ions, but are not made of molecules. In the kinetic theory of gases the term molecule is often used for any gaseous particle regardless of their composition. According to this definition noble gases would also be considered molecules despite the fact that they are composed of a single non-bonded atom. # History The term "molecule", from the French molécule meaning "extremely minute particle," was coined by French philosopher Rene Descartes in the 1620s. Although the existence of molecules was accepted by many chemists since the early 19th century as a result of Dalton's laws of Definite and Multiple Proportions (1803-1808) and Avogadro's law (1811), there was some resistance among positivists and physicists such as Mach, Boltzmann, Maxwell, and Gibbs, who saw molecules merely as convenient mathematical constructs. The work of Perrin on Brownian motion (1911) is considered to be the final proof of the existence of molecules. In a molecule, at least two atoms are joined by shared pairs of electrons in a covalent bond. It may consist of atoms of the same chemical element, as with oxygen (O2), or of different elements, as with water (H2O). Atoms and complexes connected by non-covalent bonds such as hydrogen bonds or ionic bonds are generally not considered single molecules. No typical molecule can be defined for ionic (salts) and covalent crystals (network solids) which are composed of repeating unit cells that extend either in a plane (such as in graphite) or three-dimensionally (such as in diamond or sodium chloride). The science of molecules is called molecular chemistry or molecular physics, depending on the focus. Molecular chemistry deals with the laws governing the interaction between molecules that results in the formation and breakage of chemical bonds, while molecular physics deals with the laws governing their structure and properties. In practice, however, this distinction is vague. In molecular sciences, a molecule consists of a stable system (bound state) comprising two or more atoms. Polyatomic ions may sometimes be usefully thought of as electrically charged molecules. The term unstable molecule is used for very reactive species, i.e., short-lived assemblies (resonances) of electrons and nuclei, such as radicals, molecular ions, Rydberg molecules, transition states, van der Waals complexes, or systems of colliding atoms as in Bose-Einstein condensates. # Molecular size Most molecules are far too small to be seen with the naked eye, but there are exceptions. DNA, a macromolecule, can reach macroscopic sizes, as can molecules of many polymers. The smallest molecule is the diatomic hydrogen (H2), with an overall length of roughly twice the 74 picometres (0.74 Å) bond length. Molecules commonly used as building blocks for organic synthesis have a dimension of a few Å to several dozen Å. Single molecules cannot usually be observed by light (as noted above), but small molecules and even the outlines of individual atoms may be traced in some circumstances by use of an atomic force microscope. Some of the largest molecules are macromolecules or supermolecules. # Molecular formula The empirical formula of a molecule is the simplest integer ratio of the chemical elements that constitute the compound. For example, in their pure forms, water is always composed of a 2:1 ratio of hydrogen to oxygen, and ethyl alcohol or ethanol is always composed of carbon, hydrogen, and oxygen in a 2:6:1 ratio. However, this does not determine the kind of molecule uniquely - dimethyl ether has the same ratio as ethanol, for instance. Molecules with the same atoms in different arrangements are called isomers. The empirical formula is often the same as the molecular formula but not always. For example the molecule acetylene has molecular formula C2H2, but the simplest integer ratio of elements is CH. The molecular formula reflects the exact number of atoms that compose a molecule. The molecular mass can be calculated from the chemical formula and is expressed in conventional atomic mass units equal to 1/12th of the mass of a neutral carbon-12 (12C isotope) atom. For network solids, the term formula unit is used in stoichiometric calculations. # Molecular geometry Molecules have fixed equilibrium geometries—bond lengths and angles— about which they continuously oscillate through vibrational and rotational motions. A pure substance is composed of molecules with the same average geometrical structure. The chemical formula and the structure of a molecule are the two important factors that determine its properties, particularly its reactivity. Isomers share a chemical formula but normally have very different properties because of their different structures. Stereoisomers, a particular type of isomers, may have very similar physico-chemical properties and at the same time very different biochemical activities. # Molecular Theory There are four statements of facts concerning molecules. These facts are: 1. All matter are composed of tiny particles called molecules. 2. There are spaces between molecules. 3. Molecules are constantly moving. 4. Molecules attract one another. These statements together form the Molecular Theory. # Molecular spectroscopy Molecular spectroscopy deals with the response (spectrum) of molecules interacting with probing signals of known energy (or frequency, according to Planck's formula). Scattering theory provides the theoretical background for spectroscopy. The probing signal used in spectroscopy can be an electromagnetic wave or a beam of particles (electrons, positrons, etc.) The molecular response can consist of signal absorption (absorption spectroscopy), the emission of another signal (emission spectroscopy), fragmentation, or chemical changes. Spectroscopy is recognized as a powerful tool in investigating the microscopic properties of molecules, in particular their energy levels. In order to extract maximum microscopic information from experimental results, spectroscopy is often coupled with chemical computations. # Theoretical aspects The study of molecules by molecular physics and theoretical chemistry is largely based on quantum mechanics and is essential for the understanding of the chemical bond. The simplest of molecules is the hydrogen molecule-ion, H2+, and the simplest of all the chemical bonds is the one-electron bond. H2+ is composed of two positively-charged protons and one negatively-charged electron bound by photon exchange, which means that the Schrödinger equation for the system can be solved more easily due to the lack of electron–electron repulsion. With the development of fast digital computers, approximate solutions for more complicated molecules became possible and are one of the main aspects of computational chemistry. When trying to define rigorously whether an arrangement of atoms is "sufficiently stable" to be considered a molecule, IUPAC suggests that it "must correspond to a depression on the potential energy surface that is deep enough to confine at least one vibrational state". This definition does not depend on the nature of the interaction between the atoms, but only on the strength of the interaction. In fact, it includes weakly-bound species that would not traditionally be considered molecules, such as the helium dimer, He2, which has one vibrational bound state but is so loosely bound that it is only likely to be observed at very low temperatures.

Human height # Overview Human height varies according to both "nature" and "nurture". The particular human genome that an individual inherits is a large part of the first variable (nature), and a combination of health and environmental factors present before adulthood (when growth stops) are a major part of the second determinant ("nurture"). Hereditary factors include both genes and chromosomes, and are inborn. Environmental factors are events that occur before adult height is reached, such as diet, exercise, and living conditions. When populations share genetic background and environmental factors, average height is frequently characteristic within the group. Exceptional height variation (around 20% deviation from average) within such a population is usually due to gigantism or dwarfism; which are medical conditions due to specific genes or to endocrine abnormalities. In regions of extreme poverty or prolonged warfare, environmental factors like malnutrition during childhood and/or adolescence may account for marked reductions in adult stature even without the presence of any of these medical conditions. This is one reason that immigrant populations from regions of extreme poverty to regions of plenty may show an increase in stature, despite sharing the same gene pool. The average height for each sex within a population is significantly different, with adult males being (on average) taller than adult females. This difference may be attributed to sex chromosomal differences, XY (male) as opposed to XX (female). Women ordinarily reach their greatest height at a younger age than men. Vertical growth stops when the long bones stop lengthening, which occurs with the closure of epiphyseal plates. These plates are bone growth centers that disappear ("close") under the hormonal surges brought about by the completion of puberty. Puberty generally occurs several years earlier in young women than in young men, and so final adult height is reached earlier in women. Adult height for one sex in a particular ethnic group follows more or less a normal distribution. Adult height between ethnic groups often differs significantly, as presented in detail in the chart below. For example, the average height of women from the Czech Republic is currently greater than that of men from Malawi. This may be due to genetic differences, to childhood lifestyle differences (nutrition, sleep patterns, physical labor) or to both. At 2.57 metres (8 ft 5.5 in), Leonid Stadnyk is the world's tallest living man and is from Ukraine. The tallest man in modern history was Robert Pershing Wadlow from Alton, Illinois, who was born in 1918 and stood 8 ft 11.1 inches (2.72 m) at the time of his death in 1940. The maximal height that an individual attains in adulthood is not maintained throughout life if that life is a very long one. Again, depending on chromosomal (male v. female), genetic, and environmental factors, there is shrinkage of stature that may begin in middle age in some individuals but is universal in the extremely aged. This decrease in height is due to such factors as decreased height of inter-vertebral discs because of dessication, atrophy of soft tissues, and postural changes secondary to degenerative disease. # Average adult height around the world Below are average adult heights by country. (The original studies and sources should be consulted for details on methodology and the exact populations measured, surveyed, or considered.) # Determinants of growth and height The study of human growth is known as auxology. Growth and height have long been recognized as a measure of the health and wellness of individuals, hence part of the reasoning for the use of growth charts. For individuals, as indicators of health problems, growth trends are tracked for significant deviations and growth is also monitored for significant deficiency from genetic expectations. Genetics is a major factor in determining the height of individuals, though it is far less influential in regard to populations. Average height is increasingly used as a measure of the health and wellness (standard of living and quality of life) of populations. Attributed as a significant reason for the trend of increasing height in parts of Europe is the egalitarian populations where proper medical care and adequate nutrition are relatively equally distributed. Changes in diet (nutrition) and a general rise in quality of health care and standard of living are the cited factors in the Asian populations. Average height in the United States has remained essentially stagnant since the 1950s even as the racial and ethnic background of residents has shifted. Severe malnutrition is known to cause stunted growth in North Korean, portions of African, certain historical European, and other populations. Diet (in addition to needed nutrients; such things as junk food and attendant health problems such as obesity), exercise, fitness, pollution exposure, sleep patterns, climate (see Allen's rule and Bergmann's Rule for example), and even happiness (psychological well-being) are other factors that can affect growth and final height. Height is, like other phenotypic traits, determined by a combination of genetics and environmental factors. Genetic potential plus nutrition minus stressors is a basic formula. Genetically speaking, the heights of mother and son and of father and daughter correlate, suggesting that a short mother will more likely bear a shorter son, and tall fathers will have tall daughters. Humans grow fastest (other than in the womb) as infants and toddlers (birth to roughly age 2) and then during the pubertal growth spurt. A slower steady growth velocity occurs throughout childhood between these periods; and some slow, steady, declining growth after the pubertal growth spurt levels off is common. These are also critical periods where stressors such as malnutrition (or even severe child neglect) have the greatest effect. Conversely, if conditions are optimal then growth potential is maximized; and also there is catch-up growth — which can be significant — for those experiencing poor conditions when those conditions improve. Moreover, the health of a mother throughout her life, especially during her critical periods, and of course during pregnancy, has a role. A healthier child and adult develops a body that is better able to provide optimal prenatal conditions. The pregnant mother's health is important as gestation is itself a critical period for an embryo/fetus, though some problems affecting height during this period are resolved by catch-up growth assuming childhood conditions are good. Thus, there is an accumulative generation effect such that nutrition and health over generations influences the height of descendants to varying degrees. The age of the mother also has some influence on the her child's height. Although 2 Esdras recorded that "Those born in the strength of youth" were taller than "those born during the time of old age, when the womb is failing", studies in modern times have observed a gradual increase in height with maternal age. The precise relationship between genetics and environment is complex and uncertain. Human height is 90% heritable and has been considered polygenic since the Mendelian-biometrician debate a hundred years ago. The only gene so far attributed with normal height variation is HMGA2. This is only one of many, as each copy of the allele concerned confers an additional 0.4 cm, accounting for just 0.3% of population variance. ## Race and height The Nilotic peoples of Sudan such as the Dinka have been described as the tallest in the world, with the males in some communities having average heights of 1.9 m (6 ft 3 in) and females at 1.8 m (5 ft 11 in). A notable example is Manute Bol, who, at 2.31m(7ft 7in), was the tallest basketball player in the NBA. The Dinka are characterized as having long legs, narrow bodies and short trunks, an adaptation to hot weather. However, a 1995 study casts doubt on the claim of extraordinary height in Dinka, which after studying the average height of Dinka males in one location, listed the actual number as 1.76 m (5 ft 9.45 in.) Adults of the Pygmy peoples have an approximate average height of 1.5 m (4 ft 11 in). # Process of growth Growth in stature, determined by its various factors, results from the lengthening of bones via cellular divisions chiefly regulated by somatotropin (human growth hormone (hGH)) secreted by the anterior pituitary gland. Somatotropin also stimulates the release of another growth inducing hormone insulin-like growth factor 1 (IGF-1) mainly by the liver. Both hormones operate on most tissues of the body, have many other functions, and continue to be secreted throughout life; with peak levels coinciding with peak growth velocity, and gradually subsiding with age after adolescence. The bulk of secretion occurs in bursts (especially for adolescents) with the largest during sleep. Exercise promotes secretion. Adolescents who take steroids can experience stunted growth. A positive net nutrition is also important, with proteins and various other nutrients especially important. The majority of linear growth occurs as growth of cartilage at the epiphysis (ends) of the long bones which gradually ossify to form hard bone. The legs compose approximately half of adult human height, and leg length is a somewhat sexually dimorphic trait. Height is also attained from growth of the spine, and contrary to popular belief, men are the "leggier" sex with a longer leg to torso ratio, conversely to women's longer torso to leg ratio. (The illusion of the proportion being the other way around is caused by fatty deposits placed high on women's hips.) Some of this growth occurs after the growth spurt of the long bones has ceased or slowed. The majority of growth during growth spurts is of the long bones. Additionally, the variation in height between populations and across time is largely due to changes in leg length. The remainder of height consists of the cranium. Height is sexually dimorphic and statistically it is more or less normally distributed, but with heavy tails. # Height abnormalities Most intra-population variance of height is genetic. Short stature and tall stature are usually not a health concern. If the degree of deviation from normal is significant, hereditary short stature is known as familial short stature and tall stature is known as familial tall stature. Confirmation that exceptional height is normal for a respective person can be ascertained from comparing stature of family members and analyzing growth trends for abrupt changes, among others. There are, however, various diseases and disorders that cause growth abnormalities. Most notably, extreme height may be pathological, such as gigantism (very rare) resulting from childhood hyperpituitarism, and dwarfism which has various causes. Rarely, no cause can be found for extreme height; very short persons may be termed as having idiopathic short stature. The Food and Drug Administration (FDA) in 2003 approved hGH treatment for those 2.25 standard deviations below the population mean (approximately the lowest 1.2% of the population). An even rarer occurrence, or at least less used term and recognized "problem", is idiopathic tall stature. If not enough growth hormone is produced and/or secreted by the pituitary gland, then a patient with growth hormone deficiency can undergo treatment. This treatment involves the injection of pure growth hormone into thick tissue to jump-start the growth process. # Role of an individual's height Tallness has been suggested to be associated with better cardio-vascular health and overall better-than-average health and longevity (Njolstad et al. 1996, McCarron et al 2002). However, height may not be causative of better health and longevity (Miura et al. 2002). Other studies have found no association, or suggest that shorter stature is associated with better health (Samaras & Elrick, 1999). On the other hand, being excessively tall can cause various medical problems, including cardiovascular issues, due to the increased load on the heart to supply the body with blood, and issues resulting from the increased time it takes the brain to communicate with the extremities. For example, Robert Wadlow, the tallest man known to verifiable history, developed walking difficulties as his height continued to increase throughout his life. In many of the pictures of the later portion of his life, Wadlow can be seen gripping something for support. Late in his life he was forced to wear braces on his legs and to walk with a cane, and he died after developing an infection in his legs because he was unable to feel the irritation and cutting caused by his leg braces (it is important to note that he died in 1940, before the widespread use of modern antibiotics). Height extremes of either excessive tallness or shortness can cause social exclusion and discrimination for both men and women (heightism). Epidemiological studies have also demonstrated a positive correlation between height and intelligence. The reasons for this association appear to include that height serves as a biomarker of nutritional status or general mental and physical health during development, that common genetic factors may influence both height and intelligence, and that both height and intelligence are affected by adverse early environmental exposures. In addition, an individual's height can be largely a part of what social clique, or group that they fall in to, though this is usually associated with pre-teens and teenagers. For example, in some schools, students on the basketball team might be "cool," and those with short stature wouldn't likely make the team. Therefore, in some cases, this could contribute to them being classified as "uncool," which can be detrimental to that particular individual's self-esteem. A study done on men in Sweden has shown that there is a strong correlation between subnormal stature and suicide. This can also sometimes be translated over into the corporate world. Individuals with short stature can sometimes appear to not have any leadership ability or power, since some people might not take them seriously due to their short stature. However, this is not always the case with most employers. Historically this assumption has not always reflected reality; for instance Napoleon was not much taller than 5ft according to sources (though Napoleon's height is subject to great debate, and he may have been as tall as 5' 7", see Napoleon's height for further information). Ignatius Loyola, founder of the Jesuit order was 5'. Both Lenin and Stalin were of below average height. A modern example would be Deng Xiaoping of China who undertook massive reforms to the Chinese economy in the 1980s and was reported to have only been 5' 2". # The role of height in sports Height often plays a crucial role in sports. For most sports, height is useful as it affects the leverage between muscle volume and bones towards greater speed of movement. It is most valuable in sports like basketball and volleyball, where the "short" players are almost always well above average in height compared to the general population. In men's professional basketball, the guards, the smallest players, are usually around 6'2" to 6'6" (1.88 to 1.98 m), and the centers, the tallest players, are generally from 6'10" to 7'2" (2.08 to 2.18 m). Famous basketball player Shaquille O'Neal is listed at 7'1" (2.16 m). In some sports, such as horse racing, auto racing, figure skating, diving, and gymnastics, a smaller frame is more valuable. In other sports, the role of height is specific to particular positions (i.e . In American Football, running backs have an advantage if they are shorter than the defenders due to lower centers of gravity and decreased visibility.) In Rugby Union Height is Vital for key positions such as Second Row who catch the ball while being hoisted up in lineouts. In weightlifting shorter levers are advantageous and taller than average competitors usually compete in the 105 kg + group. ## Association football (Soccer) For example, in Association football, tall goalkeepers have an advantage because they have greater armspans and can jump higher easily, so one will rarely, if ever, see a short goalkeeper at the professional level. However, shorter goalkeepers will have an easier time reaching low shots as they can reach the ground fractionally sooner than taller keepers. In wide positions and certain attacking ones, height is not always important with some of the best players in the world (e.g. Garrincha, Edgar Davids, Romário and Maradona) being shorter than average and in many cases gaining an advantage with their low center of gravity. However, height is generally considered advantageous for central defenders and for target men forwards who usually aim to score with their head for instance Jan Koller, Ruud van Nistelrooy, Niall Quinn and Peter Crouch. ## Cricket Similarly, in cricket, some great batsmen like Donald Bradman 5'7", Sachin Tendulkar 5'5", Brian Lara 5'6", Sunil Gavaskar 5'4" and Aravinda De Silva 5'2" are/were short. On the other hand, many successful fast bowlers are/were well over 6'; for example past greats Joel Garner, Courtney Walsh, and Curtly Ambrose were all 6'6"(198 cm) or taller. Glenn McGrath is also 6'5½" (197 cm). In general, taller bowlers have a higher point of release in their bowling action, making it easier for them to make the ball rear-up from a length. Also, they can generate more pace with longer arms and the sling action associated with bowling. But, taller batsmen also have greater ease of hitting the ball compared to short-heighted. Some greats like Clive Lloyd are above 6'. England's star batsman Kevin Pietersen is 6'4" tall, while New Zealand all-rounder Jacob Oram measures 6'7". ## Rowing In rowing, being tall is a big advantage, because the taller you are the longer your stroke can potentially be, thus moving the boat more effectively. The average male Olympic rower is 6'3.5", and the average female Olympic rower is 5'8", well over the average height. ## Rugby Union In rugby union, lineout jumpers, generally Template:Locks, are usually the tallest players on the pitch, as this increases their chance of winning clean ball, whereas Template:Scrum-half are usually relatively short. As examples, current world-class locks Victor Matfield, Chris Jack, and Paul O'Connell are all at least 6'6"/1.98 m, and Simon Shaw even gets up to roughly 6'9", while the sport's all-time leader in international appearances, scrum-half George Gregan, is 5'8"/1.73m. Currently the tallest professional players are Devin Toner and Andries Bekker, who are both 6'10". The tallest man ever to have played was 7'0" tall Richard Metcalfe. ## Rugby League Unlike rugby union, height was not seen as important in Rugby League, due to the absence of line-outs. However, recent tactics of cross-field kicking has resulted in the success of taller outside backs. Israel Folau (194cm) and Krisnan Inu (185cm) are examples of the trend in taller wingers and centres, and are both known for their remarkable jumping skills in defense or attack. ## American Football (Gridiron) In American Football, a tall quarterback is at an advantage because it is easier for him to see over the heads of large offensive and defensive linemen while he is in the pocket in a passing situation. At 5'9", Doug Flutie was initially considered to be too short to become a NFL quarterback despite his Heisman Trophy-winning success at the college level. Tall wide receivers have an advantage of being able to outjump shorter defensive backs to catch highly thrown passes. By contrast, shorter defensive backs are utilized because of their typically greater agility, as the ability to change directions instantly is a prerequisite for the position. Short running backs are at an advantage because their shorter stature and lower center of gravity generally makes them harder to tackle effectively. In addition, they can easily "hide" behind large offensive linemen, making it harder for defenders to react at the beginning of a play. Thus, in the NFL and in NCAA Division I football, running backs under 6 ft 0 in (1.83 m) are more common than running backs over 6 ft 3 in (1.91 m). Former Heisman Trophy winner and Pro Football Hall of Famer Barry Sanders, thought by some to be the greatest running back in history, is a classic example of a running back with an extraordinarily low center of gravity, as he stood only 5 ft 7 1/2 in (1.71 m). However, Jim Brown, another player often considered the greatest running back of all time, was more than 6 ft 2 in (1.88 m) tall, demonstrating benefits conferred by the greater power and leverage which height provides. Kickers are generally short, they are shorter because this allows them to get under the ball easier. Punters are generally very tall because of longer legs achieving greater leg swing and this translates into more power on the ball. ## Baseball In baseball, pitchers tend to be taller than position players. Being taller means longer legs, which power pitches use to generate velocity and a release point closer to the plate, which means the ball reaches the batter more quickly. While taller position players have a larger strike zone, most position players are at least of average height because the larger frame allows them to generate more power. Most successful modern pitchers are safely over 6 feet/1.83 m, some to extremes (e.g., the 6'10"/2.08 m Randy Johnson), with the 5'11"/1.80 m Pedro Martínez a notable exception. ## Ice Hockey While the history of the NHL is filled with diminutive players who achieved greatness (Theo Fleury, Martin St. Louis,) the game's physical style has put a premium on imposing players, particular over 6 feet tall and over 200 pounds (Mario Lemieux, Chris Pronger). Taller, bigger players have a longer reach, are able to give out and sustain punishing body checks, and are generally seen as indispensable for a team looking to go deep into the playoffs. Zdeno Chára, at 6 ft 9 in (2.06 m), is the tallest player ever to play in the NHL. ## Wrestling Height can be both helpful and detrimental in wrestling. Since taller people have more bone mass, they will generally be slightly weaker than shorter people in the same weight class. This difference is made up in part by their longer arms, which allow them a longer reach and make cradles easier. Also, taller peoples' legs are longer and harder to defend from shorter wrestlers. ## Sumo Professional sumo wrestlers are required to be at least 173 cm tall. Some aspiring sumo athletes have silicon implants added to the tops of their heads to reach the necessary height. The average height for a sumo wrestler is 180 cm, far above the national average in Japan. # History of human height Average Height of Troops Born in the Mid-Nineteenth Century, by Country or Place Source - Tallest in the World: Native Americans of the Great Plains in the Nineteenth Century - European Heights in the Early 18th Century In the 18th and 19th centuries, Europeans in North America were far taller than those in Europe and were the tallest in the world. The original indigenous population of Plains Native Americans was also among the tallest populations of the world at the time. Several nations, including many nations in Europe, have now surpassed the US, particularly the Netherlands, and the Scandinavian nations. In the late nineteenth century, the Netherlands was a land renowned for its short population, but today it has the 2nd tallest average in the world, with young men averaging 185 cm (6'1 ft) tall and only shorter than the peoples of the Dinaric Alps (a section largely within the former Yugoslavia which encompasses: all of present-day Montenegro, a sovereign republic; Herzegovina, its entire region within another republic; hinterland and coastal Croatia, Serbia), where males average 185.6 cm (6 ft 1.1 in) tall. The Dinarians and Dutch are now well known in Europe for extreme tallness. In Africa, the Maasai, Dinka and Tutsi populations are known for their tallness. Average male height in impoverished Vietnam and North Korea remains comparatively small at 163 cm (5 ft 4 in) and 165 cm (5 ft 5 in), respectively. Currently, young adult North Korean males are actually significantly shorter. This contrasts greatly with the extreme growth occurring in surrounding Asian populations with correlated increasing standards of living. Young South Koreans are about 12 cm (5.5 inches) taller than their North Korean counterparts, on average. There is also an extreme difference between older North Koreans and young North Koreans who grew up during the famines of the 1990s-2000s. North Korean and South Korean adults older than 40, who were raised when the North and South's economies were about equal, are generally of the same average height. In the early 1970s, when anthropologist Barry Bogin first visited Guatemala, he observed that Mayan Indian men averaged only 157.5 cm (5 ft 2 in) in height and the women averaged 142.2 cm (4 ft 8 in). Bogin took another series of measurements after the Guatemalan Civil War had erupted, during which up to a million Guatemalans had fled to the United States. He discovered that Mayan refugees, who ranged from six to twelve years old, were significantly taller than their Guatemalan counterparts. By 2000, the American Maya were 10.24 cm (4 in) taller than the Guatemalan Maya of the same age, largely due to better nutrition and access to health care. Bogin also noted that American Maya children had a significantly lower sitting height ratio, (i.e. relatively longer legs, averaging 7.02 cm longer) than the Guatemalan Maya. # Bibliography - Fitting the Task to the Man, 1987 (for heights in USA and Japan) - Eurostats Statistical Yearbook 2004 (for heights in Germany) - Netherlands Central Bureau for Statistics, 1996 (for average heights) - Mean Body Weight, Height, and body mass index, United States 1960 - 2002 - UK Department of Health - Health Survey for England - Statistics Norway, Conscripts, by height, Per cent - Statistics Sweden (in Swedish) - Burkhard Bilger. "The Height Gap." The New Yorker - A collection of data on human height, referred to here as "karube" but originally collected from other sources, was originally available here but is no longer. A copy is available here. (an English translation of this Japanese page would make it easier to evaluate the quality of the data...). - Aminorraya, A. et al.: Growth Charts of Heights and Weights of Male Children and Adolescents of Isfahan, Iran. Journal of Health and Population Nutrition, 21(4):2003, p. 341-346 - Blaha, P. et al.: 6. Celostatni antropologicky vyzkum deti a mladeze 2001, Ceska republika , Charles University in Prague 2005 - Bogin, B.A. (1999) Patterns of human growth. 2nd ed Cambridge U Press - Bogin, B.A. (2001) The growth of humanity Wiley-Liss - Cavelaars, A.E.J.M.,Kunst, A.E.,Geurts, J.J.M.,Crialesi, R.,Grotvedt, L.,Helmert U. Persistent variations in average height between countries and between socio-economic groups: an overview of 10 European countries. Annals of Human Biology. 27(4),407 - 421. - Deurenberg P., Kalpana Bhaskaran, Petrina Lim Kim Lian: Singaporean Chinese adolescents have more subcutaneous adipose tissue than Dutch Caucasians of the same age and body mass index. Asia Pacific Journal of Clinical Nutrition, 12(3):2003, p. 261-265 - Eveleth, P.B. & Tanner, J.M. (1990) Worldwide variation in human growth, 2nd ed. Cambridge University Press. - Lintsi, M., Kaarma, H.: Growth of Estonian seventeen-year-old boys during the last two centuries. Economics and Human Biology 4 (2006) 89–103. - Miura, K. Nakagawa, H. & Greenland, P. (2002) Invited commentary: height-cardiovascular disease relation: where to go from here? Am. J. Epidemiol. 155:688–689. - Ruff, C. (2002) Variation in human body size and shape. Ann. Rev. Anthropol. 31:211-232. - Average height of adolescents in the Dinaric Alps - Average height of young Spaniards (in Spanish) - Differences between height (stature) and recumbent length - Mandel, MD, E. Zimlichman, MD, F. B. Mimouni, MD, FACN, FAAP, I. Grotto, MD, MPH, and Y. Kreiss, MD Height-Related Changes in Body Mass Index: A Reappraisal - A. Case, PhD, C. Paxson, PhD, Stature and Status: Height, Ability, and Labor Market Outcomes - Global Height Trends in Industrial and Developing Countries, 1810-1984: An Overview 2006 10 20

Public domain 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 Public domain comprises the body of knowledge and innovation (especially creative works such as writing, art, music, and inventions) in relation to which no person or other legal entity can establish or maintain proprietary interests within a particular legal jurisdiction. This body of information and creativity is considered to be part of a common cultural and intellectual heritage, which, in general, anyone may use or exploit, whether for commercial or non-commercial purposes. About 15 percent of all books are in the public domain, including 10 percent of all books that are still in print. If an item ("work") is not in the public domain, it may be the result of a proprietary interest such as a copyright, patent, or other sui generis right. The extent to which members of the public may use or exploit the work is limited to the extent of the proprietary interests in the relevant legal jurisdiction. However, when the copyright, patent or other proprietary restrictions expire, the work enters the public domain and may be used by anyone for any purpose. # No legal restriction on use A creative work is said to be in the public domain if there are no laws which restrict its use by the public at large. For instance, a work may be in the public domain if no laws establish proprietary rights over the work, or if the work or its subject matter are specifically excluded from existing laws. Because proprietary rights are founded in national laws, an item may be public domain in one jurisdiction but not another. For instance, some works of literature are public domain in the United States but not in the European Union and vice versa. The underlying idea that is expressed or manifested in the creation of a work generally cannot be the subject of copyright law (see idea-expression divide). Mathematical formulae will therefore generally form part of the public domain, to the extent that their expression in the form of software is not covered by copyright; however, algorithms can be the subject of a software patent in some jurisdictions. Works created before the existence of copyright and patent laws also form part of the public domain. The Bible and the inventions of Archimedes are in the public domain. However, copyright may exist in translations or new formulations of these works. Although "intellectual property" laws are not designed to prevent facts from entering the public domain, collections of facts organized or presented in a creative way, such as categorized lists, may be copyrighted. Collections of data with intuitive organization, such as alphabetized directories like telephone directories, are generally not copyrightable. In some countries copyright-like rights are granted for databases, even those containing mere facts. A sui generis database rights regime is in place in the European Union. Works of the United States Government and various other governments are excluded from copyright law and may therefore be considered to be in the public domain in their respective countries. They may also be in the public domain in other countries as well. # Expiration All copyrights and patents have always had a finite term, though the terms for copyrights and patents differ. When terms expire, the work or invention is released into public domain, in most countries, this is 20 years. A trademark registration may be renewed and remain in force indefinitely provided the trademark is used, but could otherwise become generic. Copyrights are more complex than patents; generally, in current law, the copyright in a published work expires in all countries (except Colombia, Côte d'Ivoire, Guatemala, Honduras, Mexico, Samoa, and Saint Vincent and the Grenadines) when any of the following conditions are satisfied : - The work was created and first published before January 1, 1923, or at least 95 years before January 1 of the current year, whichever is later; - The last surviving author died at least 70 years before January 1 of the current year; - No Berne Convention signatory has passed a perpetual copyright on the work; and - Neither the United States nor the European Union has passed a copyright term extension since these conditions were last updated. (This must be a condition because the exact numbers in the other conditions depend on the state of the law at any given moment.) These conditions are based on the intersection of United States and European Union copyright law, which most other Berne Convention signatories recognize. Note that copyright term extension under U.S. tradition usually does not restore copyright to public domain works (hence the 1923 date), but European tradition does because the EU harmonization was based on the copyright term in Germany, which had already been extended to life plus 70. ## United States law Copyright law in the United States has changed several times. Although it is held under Feist v. Rural that Congress does not have the power to re-copyright works that have fallen into the public domain, re-copyrighting has happened: "After World War I and after World War II, there were special amendments to the Copyright Act to permit for a limited time and under certain conditions the recapture of works that might have fallen into the public domain, principally by aliens of countries with which we had been at war." Works created by an agency of the United States government are public domain at the moment of creation. Examples include military journalism, federal court opinions (but not necessarily state court opinions), congressional committee reports, and census data. However, works created by a contractor for the government are still subject to copyright. Even public domain documents may have their availability limited by laws limiting the spread of classified information. ### Since 1978 Before 1978, unpublished works were not covered by the federal copyright act. Rather, they were covered under (perpetual) common law copyright. The Copyright Act of 1976, effective 1978, abolished common law copyright in the United States so that all works, published or unpublished, are now covered by federal statutory copyright. The claim that "pre-1923 works are in the public domain" is correct only for published works; unpublished works are under federal copyright for at least the life of the author plus 70 years. For a work made for hire, the copyright in a work created before 1978, but not theretofore in the public domain or registered for copyright, subsists from January 1, 1978, and endures for a term of 95 years from the year of its first publication, or a term of 120 years from the year of its creation, whichever expires first. If the work was created before 1978 but first published on or before December 31, 2002, the work is covered by federal copyright until 2047. ### 1964 to 1977 Works published with notice of copyright or registered in unpublished form prior to January 1, 1964, had to be renewed during the 28th year of their first term of copyright to maintain copyright for a full 95-year term. Until the Berne Convention Implementation Act of 1988, the lack of a proper copyright notice would place an otherwise copyrightable work into the public domain, although for works published between January 1, 1978 and February 28, 1989, this could be prevented by registering the work with the Library of Congress within 5 years of publication. After March 1, 1989, an author's copyright in a work begins when it is fixed in a tangible form; neither publication nor registration is required, and a lack of a copyright notice does not place the work into the public domain. ### Sound recordings Sound recordings fixed before February 15, 1972, were generally covered by common law or in some cases by statutes enacted in certain states, not by federal copyright law. The 1976 Copyright Act, effective 1978, provides federal copyright for unpublished and published sound recordings fixed on or after February 15, 1972. Recordings fixed before February 15, 1972, are still covered, to varying degrees, by common law or state statutes. Any rights or remedies under state law for sound recordings fixed before February 15, 1972, are not annulled or limited by the 1976 Copyright Act until February 15, 2067. ### Term extensions Critics of copyright term extensions have said that Congress has achieved a perpetual copyright term "on the installment plan." ## British law British government works are restricted by either Crown Copyright or Parliamentary Copyright. Published Crown Copyright works become public domain at the end of the year 50 years after they were published, unless the author of the work held copyright and assigned it to the Crown. In that case, the copyright term is the usual life of author plus 70 years. Unpublished Crown Copyright documents become public domain at the end of the year 125 years after they were first created. However, under the legislation that created this rule, and abolished the traditional common law perpetual copyright of unpublished works, no unpublished works will become public domain until 50 years after the legislation came into effect. Since the legislation became law on 1 August 1989, no unpublished works will become public domain under this provision until 2039. Parliamentary Copyright documents become public domain at the end of the year 50 years after they were published. Crown Copyright is waived on some government works provided that certain conditions are met. ## Laws of Canada, Australia, and other Commonwealth nations These numbers reflect the most recent extensions of copyright in the United States and Europe. Canada and New Zealand have not, as of 2006, passed similar twenty-year extensions. Consequently, their copyright expiry times are still life of the author plus 50 years. Australia passed a 20-year copyright extension in 2004, but delayed its effect until 2005, and did not make it revive already-expired copyrights. Hence, in Australia works by authors who died before 1955 are still in the public domain. As a result, works ranging from Peter Pan to the stories of H. P. Lovecraft are public domain in both countries. (The copyright status of Lovecraft's work is debatable, as no copyright renewals, which were necessary under the laws of that time, have been found. Also, two competing parties have independently claimed copyright ownership on his work.) As with most other Commonwealth of Nations countries, Canada and Australia follow the general lead of the United Kingdom on copyright of government works. Both have a version of Crown Copyright which lasts for 50 years from publication. New Zealand also has Crown Copyright, but has a much greater time length, at 100 years from the date of publication. India has a government copyright of sixty years from publication, to coincide with its somewhat unusual life of the author plus sixty years term of copyright. ## Thai law According to Thai copyright law, the copyright term is the life of author plus 50 years. When the author is a legal entity or an anonymous person, the copyright term is 50 years from the date of publication. Works of applied art (defined as drawings/paintings, sculpture, prints, architecture, photography, and drafts) have a copyright term of 50 years from publication. Republication of works after the expiration of the copyright term does not reset the copyright term. Thai state documents are public domain. ## Japanese law Japanese copyright law does not mention public domain. Hence, even when some materials are said to be "in the public domain" there can be some use restrictions. In that case, the term copyright-free is sometimes used instead. Many pre-1953 both Japanese and non-Japanese films are considered to be in the public domain in Japan. ## Examples Examples of inventions whose patents have expired include the inventions of Thomas Edison. Examples of works whose copyrights have expired include the works of Carlo Collodi, Mozart, and most of the works of Mark Twain, excluding the work first published in 2001, A Murder, a Mystery, and a Marriage. In the United States, the images of Frank Capra's classic film, It's a Wonderful Life (1946) entered into the public domain in 1974, because someone inadvertently failed to file a copyright renewal application with the Copyright Office during the 28th year after the film's release or publication. It wasn't until 1993 when Republic Pictures relied on the 1990 United States Supreme Court ruling in Stewart v. Abend to enforce its claim of copyright to portions of the film's sound track. As a result, only NBC is currently licensed to show the film on U.S. network television, the colourized versions have been withdrawn and Republic got exclusive video rights to the film (under license with Artisan Entertainment). Rights to It's a Wonderful Life now belong to Paramount Pictures. Currently four shorts by the Three Stooges are in the public domain due to accidental failure to renew their copyrights in the '60s. These are Disorder in the Court, Brideless Groom, Malice in the Palace, and Sing a Song of Six Pants. Other features and films from the Stooges are known to be in public domain as well. Several episodes of The Lucy Show are similarly in the public domain. Some works may never fully lapse into the public domain, such as the play Peter Pan by J. M. Barrie. While the copyright of this work expired in the United Kingdom in 1987, it has been granted special treatment under the Copyright, Designs and Patents Act 1988 (Schedule 6) that requires certain royalties to be paid for performances within the UK, so long as Great Ormond Street Hospital continues to exist. J. M. Barrie had bequeathed the rights to Peter Pan to the hospital in perpetuity as an endowment. # Disclaimer of interest Laws may make some types of works and inventions ineligible for monopoly; such works immediately enter the public domain upon publication. Many kinds of mental creations, such as publicized baseball statistics, are never covered by copyright. However, any special layout of baseball statistics, or the like, would be covered by copyright law. For example, while a phonebook is not covered by copyright law, any special method of laying out the information would be. For example: U.S. copyright law, 17 U.S.C. § 105, releases all works created by the U.S. government into the public domain. U.S. patent applications containing a copyright notice must also include a disclaimer of certain exclusive rights as part of the terms of granting the patent to the invention (leaving open the question regarding copyright of patents with no such notice). Agreements that Germany signed at the end of World War I released such trademarks as "aspirin" and "heroin" into the public domain in many areas. Another example would be Charles Darwin's theory of evolution. Being an abstract idea it has therefore never been patentable. After Darwin constructed his theory, he did not disclose it for over a decade (see Development of Darwin's theory). He could have kept his manuscript in his desk drawer forever but once he published the idea, the idea itself entered public domain. However, the carrier of his ideas, in the form of a book titled The Origin of Species, was covered by copyright (though, since he died in 1882, the copyright has since expired). ## Copyright In the past, in some jurisdictions such as the USA, a work would enter the public domain with respect to copyright if it was released without a copyright notice. This was true prior to March 1, 1989 (according to the USA Copyright office), but is no longer the case. Any work (of certain, enumerated types) receives copyright as soon as it is fixed in a tangible medium. It is commonly believed by non-lawyers that it is impossible to put a work into the public domain. Although copyright law generally does not provide any statutory means to "abandon" copyright so that a work can enter the public domain, this does not mean that it is impossible or even difficult, only that the law is somewhat unclear. Congress may not have felt it necessary to codify this part of the law, because abandoning property (like a tract of land) to the public domain has traditionally been a matter of common law, rather than statute. (Alternatively, because copyright has traditionally been seen as a valuable right, one which required registration to achieve, it would not have made sense to contemplate someone abandoning it in 1976 and 1988.) ### Statutory law There are several references to putting copyrighted work into the public domain. The first reference is actually in a statute passed by Congress, in the Computer Software Rental Amendments Act of 1990 (H.R. 5498 of the 101st Congress). Although most of the Act was codified into Title 17 of the U.S. Code, there is a very interesting provision relating to "public domain shareware" which was not, and is therefore often overlooked. Sec. 105. Recordation of Shareware (a) IN GENERAL- The Register of Copyrights is authorized, upon receipt of any document designated as pertaining to computer shareware and the fee prescribed by section 708 of title 17, United States Code, to record the document and return it with a certificate of recordation. (b) MAINTENANCE OF RECORDS; PUBLICATION OF INFORMATION- The Register of Copyrights is authorized to maintain current, separate records relating to the recordation of documents under subsection (a), and to compile and publish at periodic intervals information relating to such recordations. Such publications shall be offered for sale to the public at prices based on the cost of reproduction and distribution. (c) DEPOSIT OF COPIES IN LIBRARY OF CONGRESS- In the case of public domain computer shareware, at the election of the person recording a document under subsection (a), 2 complete copies of the best edition (as defined in section 101 of title 17, United States Code) of the computer shareware as embodied in machine-readable form may be deposited for the benefit of the Machine-Readable Collections Reading Room of the Library of Congress. (d) REGULATIONS- The Register of Copyrights is authorized to establish regulations not inconsistent with law for the administration of the functions of the Register under this section. All regulations established by the Register are subject to the approval of the Librarian of Congress. One purpose of this legislation appears to be to allow "public domain shareware" to be filed at the Library of Congress, presumably so that the shareware would be more widely disseminated. Therefore, one way to release computer software into the public domain might be to make the filing and pay the $20 fee. This could have the effect of "certifying" that the author intended to release the software into the public domain. It does not seem that registration is necessary to release the software into the public domain, because the law does not state that public domain status is conferred by registration. Judicial rulings supports this conclusion, see below. By comparing paragraph (a) and (c), one can see that Congress distinguishes "public domain" shareware as a special kind of shareware. Because this law was passed after the Berne Convention Implementation Act of 1988, Congress was well aware that newly created computer programs (two years worth, since the Berne Act was passed) would automatically have copyright attached. Therefore, one reasonable inference is that Congress intended that authors of shareware would have the power to release their programs into the public domain. This interpretation is followed by the Copyright Office in 37 C.F.R. § 201.26. The Berne Convention Implementation Act of 1988 states in section twelve that the Act "does not provide copyright protection for any work that is in the public domain." The congressional committee report explains that this means simply that the Act does not apply retroactively. Some interest groups lobbied heavily to make the Act retroactive in order to increase the U.S.'s negotiating leverage with other countries, because the U.S. often asks developing countries to allow the copyrighting of previously public-domain work. Although the only part of the act that does mention "public domain" does not speak to whether authors have the right to dedicate their work to the public domain, the remainder of the committee report does not say that they intended copyright should be an indestructible form of property. Rather the language speaks to getting rid of formalities in order to comply with Berne (non-compliance had become a severe impediment in trade negotiations) and making registration and marking optional, but encouraged. A fair reading is that the Berne Act did not intend to take away author's right to dedicate works to the public domain, which they had (by default) under the 1976 Act. Although there is support in the statutes for allowing work to be dedicated to the public domain, there cannot be an unlimited right to dedicate work to the public domain because of a quirk of U.S. copyright law which grants the author of a work the right to cancel "the exclusive or nonexclusive grant of a transfer or license of copyright or of any right under a copyright" thirty-five years later, unless the work was originally a work for hire. It is unsettled how this section would mesh with a purported public domain dedication. Any of these interpretations are possible: - No effect. Any holder of a copyright can release it to the public domain. This interpretation is probably wrong, because then an author would lose the right to his "termination right," which in practical terms means a royalty. To prevent paying the royalty, a comic book company could release the copyright to the public domain but hold onto the trademark, which would suffice to prevent knock-off comics from being made. Because the Captain America case (Marvel v. Simon) showed that this termination right cannot be alienated before death, this interpretation is almost certainly wrong. - Some effect. An author may release his own work into the public domain, and a company holding a work for hire may release his work into the public domain. But a company which has purchased a copyright from an author (as was the case with most of the "Golden Age" comic book writers) cannot. Although the distinction of allowing an author to release his own work is not explicit in the statute, it may not be literally inconsistent (it is not a "transfer" or a "license," and it arguably is not a grant of a right under copyright), and this reading is necessary to comply with the 1990 Act discussed above, as well as the case law discussed below. - Strong effect. Only a company holding a work for hire can release the work into the public domain. Because of the references to "shareware" (above) and "programmers" (below), and the fact that many software companies in the 1980s were quite small (and thus did not have employees), this reading seems inconsistent with the intent of Congress. ### Case law Another form of support comes from the seminal case Computer Associates Int'l v. Altai, 982 F.2d 693. This case set the standard for determining copyright infringement of computer software and is still followed today. Moreover, it was decided by the Second Circuit appellate court, which is famous for handing down some of the most well-reasoned American copyright decisions. In this case, it discusses the public domain. (c) Elements Taken from the Public Domain Closely related to the non-protectability of scenes a faire, is material found in the public domain. Such material is free for the taking and cannot be appropriated by a single author even though it is included in a copyrighted work. ... We see no reason to make an exception to this rule for elements of a computer program that have entered the public domain by virtue of freely accessible program exchanges and the like. See 3 Nimmer Section 13.03  ; see also Brown Bag Software, slip op. at 3732 (affirming the district court’s finding that “‘laintiffs may not claim copyright protection of an . . . expression that is, if not standard, then commonplace in the computer software industry.’“). Thus, a court must also filter out this material from the allegedly infringed program before it makes the final inquiry in its substantial similarity analysis. This decision holds that computer software may enter the public domain through "freely accessible program exchanges and the like," or by becoming "commonplace in the computer industry." Relying only on this decision, it is unclear whether an author can dedicate his work to the public domain simply by labeling it as such, or whether dedication to the public domain requires widespread dissemination. This could make a distinction in a CyberPatrol-like case, where a software program is released, leading to litigation, and as part of a settlement the author assigns his copyright. If the author has the power to release his work into the public domain, there would be no way for the new owner to stop the circulation of the program. A court may look on an attempt to abuse the public domain in this way with disfavor, particularly if the program has not been widely disseminated. Either way, a fair reading is that an author may choose to release a computer program to the public domain if he can arrange for it to become popular and widely disseminated. ### Treatise analysis The treatise cited (Nimmer), holds in its most recent edition: It is axiomatic that material in the public domain is not protected by copyright, even when incorporated into a copyrighted work. ... An enormous amount of public domain software exists in the computer industry, perhaps to a much greater extent than is true of other fields. Nationwide computer "bulletin boards" permit users to share and distribute programs. In addition, computer programming texts may contain examples of actual code that programmers are encouraged to copy. Programmers often will build existing public domain software into their works. The courts thus must be careful to limit protection only to those elements of the program that represent the author's original work. Although Computer Associates only mentioned the issue in passing, Nimmer observes that the public domain is particularly rich and valuable for computer programs. He seems to say that a computer program author who wishes to release his work into the public domain may either include it in a book as example code or post it on a "bulletin board" and encourage sharing and distribution. (Nimmer is the treatise most widely cited in copyright opinions, and is generally authoritative.) ## Patent With regard to patents, on the other hand, public use or publishing the details of an invention before applying for a patent will generally place an invention in the public domain and (in theory) prevent its subsequent patenting by anyone – an effective disclaimer. For example, a chemistry journal publishing a formula prevents patenting the formula by anyone. This tactic was commonly used by Bell Labs. The famous Bell Labs Technical Journal was sent free of charge to the library of the U.S. Patent Office to establish a base of prior art without the inconvenience, cost, and hassle of filing patent applications for inventions of no immediate monetary value. (Unix was famously described in this journal.) This is sometimes called "defensive disclosure" - one way to make sure you are not later accused of infringing a patent on your own invention. There is an exception to this rule, however: in U.S. (not European) law, an inventor may file a patent claim up to one year after publishing a description (but not, of course, if someone else published or used it first). In practice, patent examiners only consider other patents and the books they have in their library for prior art, largely because the patent office has an elaborate classification system for inventions. This means that an increasing number of issued patents may be invalid, based upon prior art that was not brought to the examiner's attention. Once a patent is issued, it is very expensive to invalidate. Publishing a description on a website as a preemptive disclosure does very little in a practical sense to release an invention to the public domain; it might still be considered "patentable", although erroneously. However, anyone aware of an omitted prior art citation in an issued patent may submit it to the US Patent Office and request a "reexamination" of the patent during the enforceable period of the patent (that is, its life plus statute of limitations). This may result in loss of some or all of the patent on the invention, or it may backfire and actually strengthen the claims. An applicant may also choose to file a Statutory Invention Registration, which has the same effect as a patent for prior art purposes. These SIRs are relatively expensive. These are used strategically by large companies to prevent competitors from obtaining a patent. Section 102(c) says that an invention that has been "abandoned" cannot be patented. There is precious little case-law on this point. It is largely a dead letter. If an inventor has an issued patent, there are several ways to release it to the public domain (other than simply letting it expire). First, he can fail to pay the maintenance fee the next time it is due, about every four years. Alternatively he can file a terminal disclaimer under 37 CFR 1.321 for a reasonable fee. The regulations explicitly say that the "patentee may disclaim or dedicate to the public the entire term, or any terminal part of the term, of the patent granted. Such disclaimer is binding upon the grantee and its successors or assigns." Usually this is used during the application process to prevent another patent from a "double patenting" invalidation. Lastly, he may grant a patent license to the world, although the issue of revocability may raise its head again. ## Trade secret If guarded properly, trade secrets are forever. A business may keep the formula to Coca-Cola a secret. However, once it is disclosed to the public, the former secret enters public domain, although an invention using the former secret may still be patentable in the United States if it is not barred by statute (including the on-sale bar). Some businesses choose to protect products, processes, and information by guarding them as trade secrets, rather than patenting them. Hershey Foods, Inc., for example, does not patent some of its processes, such as the recipe for Reese's, but rather maintains them as trade secrets, to prevent competitors from easily duplicating or learning from their invention disclosures. One risk, however, is that anyone may reverse engineer a product and thus discover (and copy and publish) all of its secrets, to the extent they are not covered by other laws (e.g., patent, contract). ## Trademark A trademark registration is renewable. If a trademark owner wishes to do so, he may maintain a registration indefinitely by paying renewal fees, using the trademark and defending the registration. However, a trademark or brand can become unenforceable if it becomes the generic term for a particular type of product or service – a process called "genericide." If a mark undergoes genericide, people are using the term generically, not as a trademark to exclusively identify the particular source of the product or service. One famous example is "thermos" in the United States. Because trademarks are registered with governments, some countries or trademark registries may recognize a mark, while others may have determined that it is generic and not allowable as a trademark in that registry. For example, the drug "acetylsalicylic acid" (2-acetoxybenzoic acid) is better known as aspirin in the United States – a generic term. In Canada, however, "aspirin" is still a trademark of the German company Bayer. Bayer lost the trademark after World War I, when the mark was sold to an American firm. So many copycat products entered the marketplace during the war that it was deemed generic just three years later. Terms can be deemed "generic" in two ways. First, any potential mark can be deemed "generic" by a trademark registry, that refuses to register it. In this instance, the term has no secondary meaning that helps consumers identify the source of the product; the term serves no function as a "mark". Second, a mark, already in use, may be deemed generic by a court or registry after the mark is challenged as generic – this is known as "genericide". In this instance, the term previously had a secondary meaning, but lost its source-identifying function. To avoid "genericide", a trademark owner must balance between trying to dominate the market, and dominating their market to such an extent that their product name defines the market. A manufacturer who invents an amazing breakthrough product which cannot be succinctly described in plain English (for example, a vacuum-insulated drinking flask) will likely find its product described by the trademark ("Thermos"). If the product continues to dominate the market, eventually the trademark will become generic ("thermos"). However, "genericide" is not an inevitable process. In the late 1980s "Nintendo" was becoming synonymous with home video game consoles but Nintendo was able to reverse this process through marketing campaigns. Xerox was also successful in avoiding its name becoming synonymous with the act of photocopying (although, in some languages (Russian) and countries (like India), it became generic). Trademarks currently thought to be in danger of being generic include Jell-O, Band-Aid, Rollerblade, Google, Spam, Hoover, and Sheetrock. Google vigorously defends its trademark rights. Although Hormel has resigned itself to genericide , it still fights attempts by other companies to register "spam" as a trademark in relation to computer products . When a trademark becomes generic, it is as if the mark were in the public domain. Trademarks which have been genericized in particular places include: Escalator, Trampoline, Raisin Bran, Linoleum, Dry Ice, Shredded Wheat (generic in US), Mimeograph, Yo-Yo, Kerosene, Cornflakes, Cube Steak, Lanolin, and High Octane, (Source: Xerox ad, reprinted in Copyright, Patent, Trademark, ..., by Paul Goldstein, 5th ed., p. 245) as well as Aspirin (generic in the United States, but not in Canada), Allen wrench, Beaver Board, Masonite, Coke, Pablum, Styrofoam, Heroin, Bikini, Chyron, Weedwhacker, Kleenex, Linux (generic in Australia) and Zipper. ## Domain name People may buy and sell domain names. Sometimes, people advertise them as their own "intellectual property". In early 2000, the record-breaker domain name "business.com" was sold for $8 million (this was resold in July 2007 for $345 million). A domain name never enters public domain. If nobody owns it, it simply doesn't exist. Top level domains, such as .com, are controlled by the ICANN (Internet Corporation for Assigned Names and Numbers). A domain name is sometimes described as a lease, but this has only a shred of truth in it. In fact it is much closer to a trademark. While a leaseholder of, say, real estate cannot be ejected from the property by anybody (except the government, in rare cases), domain names are subject to cybersquatting suits and trademark suits. # Public domain and the Internet The term "public domain" is often poorly understood and has created significant legal controversy. Historically, most parties attempting to address public domain issues fell into two camps: - Businesses and organizations who could devote staff to resolving legal conflicts through negotiation and the court system. - Individuals and organizations using materials covered by the fair use doctrine, reducing the need for substantial governmental or corporate resources to track down individual offenders. With the advent of the Internet, however, it became possible for anybody with access to this worldwide network to "post" copyrighted or otherwise-licensed materials freely and easily. This aggravated an already established but false belief that if something is available through a free source, it must be public domain. Once such material was available on the net, it could be perfectly copied among thousands or even millions of computers very quickly and essentially without cost. ## Freely obtained does not mean free to republish These factors have reinforced the false notion that "freely obtained" means "public domain." One could argue that the Internet is a publicly-available domain, not licensed or controlled by any individual, company, or government; therefore, everything on the Internet is public domain. This specious argument ignores the fact that licensing rights are not dependent on the means of distribution or consumer acquisition. (If someone gives a person stolen merchandise, it is still stolen, even if the receiving party was not aware of it.) Chasing down copyright violations based on the idea that information is inherently free has become a primary focus of industries whose financial structure is based on their control of the distribution of such media. ## (Almost) everything written down is copyrighted Another complication is that publishing exclusively on the Internet has become extremely popular. In countries party to the Berne Convention, an author's original works are covered by copyright as soon as the work is put into a "fixed" form; no formal copyright notice or registration is necessary. But such laws were passed at a time when the focus was on materials that could not be as easily and cheaply reproduced as digital media, nor did they comprehend the ultimate impossibility of determining which set of electronic bits is original. Technically, any Internet posting (such as blogs or emails) could be considered copyrighted material unless explicitly stated otherwise. The distribution of many types of Internet postings (particularly Usenet articles and messages sent to electronic mailing lists) inherently involves duplication. The act of posting such a work can therefore be taken to imply consent to a certain amount of copying, as dictated by the technical details of the manner of distribution. However, it does not necessarily imply total waiver of copyright. ## Furthering the public domain with the Internet Many people are using the Internet to contribute to the public domain, or make works in the public domain more accessible to more people. For example, Project Gutenberg and LibriVox coordinate the efforts of people who transcribe works in the public domain into electronic form. Some projects exist for the sole purpose of making material available into the public domain or under no-cost licenses. The IMSLP (International Music Score Library Project) is attempting to create a virtual library containing all public domain musical scores, as well as scores from composers who are willing to share their music with the world free of charge. Note that there are many works that are not part of the public domain, but for which the owner of some proprietary rights has chosen not to enforce those rights, or to grant some subset of those rights to the public. See, for example, the Free Software Foundation which creates copyrighted software and licenses it without charge to the public for most uses under a class of license called "copyleft", forbidding only proprietary redistribution. Wikipedia does much the same thing with its content under the GNU Free Documentation License. Sometimes such work is inadvertently referred to as "public domain" in colloquial speech. Note also that while some works (especially musical works) may be in the public domain, U.S. law considers performances or (some) transcriptions of those works to be derivative works, potentially subject to their own copyrights. Similarly, a film adaptation of a public-domain story (such as a fairy tale or a classic work of literature) may itself be copyrightable. ## Kopimi There is an established form of copyright antonym called kopimi, a wordplay on "copy me." Kopimi is not a license, it is simply a message that expresses the author's desire for people to modify and distribute the work. ## Media in the public domain There are hundreds of movies, cartoons and television shows that have fallen into the public domain. Some of these movies are considered classics, such as The Gold Rush (1925) starring Charlie Chaplin, A Star Is Born (1937), and Night of the Living Dead (1968). The works either did not include a proper copyright notice when published, or the copyright was not renewed and therefore the content is now in the public domain.

Abdominal aortic aneurysm: diagnosis and management This guideline covers diagnosing and managing abdominal aortic aneurysms. It aims to improve care by helping people who are at risk to get tested, specifying how often to monitor asymptomatic aneurysms, and identifying when aneurysm repair is needed and which procedure will work best. # Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Diagnosis ## Identifying people at risk of abdominal aortic aneurysms Inform all men aged 66 or over who have not already been screened about the NHS abdominal aortic aneurysm (AAA) screening programme, and advise them that they can self-refer. Encourage men aged 66 or over to self-refer to the NHS AAA screening programme if they have not already been screened and they have any of the following risk factors: chronic obstructive pulmonary disease (COPD) coronary, cerebrovascular or peripheral arterial disease family history of AAA hyperlipidaemia hypertension they smoke or used to smoke. Consider an aortic ultrasound for women aged 70 and over if AAA has not already been excluded on abdominal imaging and they have any of the following risk factors: COPD coronary, cerebrovascular or peripheral arterial disease family history of AAA hyperlipidaemia hypertension they smoke or used to smoke. Be aware that people of European family origin are at a higher risk of an AAA. ## Identifying asymptomatic abdominal aortic aneurysms Offer an aortic ultrasound to people in whom a diagnosis of asymptomatic AAA is being considered if they are not already in the NHS screening programme. Refer people with an AAA that is 5.5 cm or larger to a regional vascular service, to be seen within 2 weeks of diagnosis. Refer people with an AAA that is 3.0 cm to 5.4 cm to a regional vascular service, to be seen within 12 weeks of diagnosis. Offer an aortic ultrasound to people with a suspected AAA on abdominal palpation. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying asymptomatic abdominal aortic aneurysms . Full details of the evidence and the committee's discussion are in evidence review A: risk factors for predicting presence of an abdominal aortic aneurysm and evidence review B: imaging techniques to diagnose abdominal aortic aneurysms. Loading. Please wait. ## Identifying symptomatic or ruptured abdominal aortic aneurysms Think about the possibility of ruptured AAA in people with new abdominal and/or back pain, cardiovascular collapse, or loss of consciousness. Be aware that ruptured AAA is more likely if they also have any of the following risk factors: an existing diagnosis of AAA age over 60 they smoke or used to smoke history of hypertension. Be aware that AAAs are more likely to rupture in women than men. Offer an immediate bedside aortic ultrasound to people in whom a diagnosis of symptomatic and/or ruptured AAA is being considered. Discuss immediately with a regional vascular service if: the ultrasound shows an AAA or the ultrasound is not immediately available or it is non-diagnostic, and an AAA is still suspected. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on identifying symptomatic or ruptured abdominal aortic aneurysms . Full details of the evidence and the committee's discussion are in evidence review B: imaging techniques to diagnose abdominal aortic aneurysms and evidence review N: signs, symptoms and risk factors predicting ruptured or symptomatic unruptured aneurysms before arrival at the hospital, and in non-specialist hospital settings. Loading. Please wait. ## Imaging technique When measuring aortic size with ultrasound, report the inner-to-inner maximum anterior-posterior aortic diameter, in accordance with the NHS AAA screening programme. Clearly document any additional measurements taken. Offer thin-slice contrast-enhanced arterial-phase CT angiography to people who are being evaluated for elective AAA repair. Consider thin-slice contrast-enhanced arterial-phase CT angiography for people with a suspected ruptured AAA who are being evaluated for AAA repair. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on imaging technique . Full details of the evidence and the committee's discussion are in evidence review B: imaging techniques to diagnose abdominal aortic aneurysms. Loading. Please wait. ## Providing information to people with a diagnosed AAA Give people with AAA of any size information explaining: what an AAA is that most AAAs do not cause any problems that AAAs can rupture, and what this means that AAAs are likely to get larger over time, and that larger AAAs are more likely to rupture that AAA may run in families, so they should tell close relatives that they may have an increased risk of AAA and may need assessment (see recommendations 1.1.2 and 1.1.3) what options for aneurysm repair are available, when repair should be considered and the potential benefits and risks (see recommendations 1.5.1 and 1.5.2), and when it might be better to not have repair (see recommendation 1.1.14) their risk of cardiovascular disease and how this risk can be reduced (see recommendation 1.4.6, and see the section on identifying and assessing cardiovascular disease risk in the NICE guideline on cardiovascular disease). If AAA repair is not currently suitable for a person, explain why, based on their individual circumstances. For example: Small AAAs only have a very low chance of rupture and there are risks to aneurysm repair, so in this case people do not benefit from repair. AAA growth is unpredictable, so until their AAA meets the criteria in recommendation 1.5.1 it is not possible to know whether repair will be suitable for a particular person. On average, people with poor overall health do not benefit from AAA repair. There is no reliable way to assess whether a particular person will benefit or be harmed, so repair for people with poor overall health is an unnecessary risk even if their AAA meets the criteria in recommendation 1.5.1. Check that people understand their options, and give them time for reflection and discussion. Encourage them to discuss the options with their family and friends. For more guidance on providing information, see the section on enabling patients to actively participate in their care in the NICE guideline on patient experience in adult NHS services. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on providing information to people with a diagnosed AAA . Full details of the evidence and the committee's discussion are in evidence review K: effectiveness of endovascular aneurysm repair, open surgical repair and non-surgical management of unruptured abdominal aortic aneurysms. Loading. Please wait. # Monitoring and reducing the risk of rupture ## Reducing the risk of rupture Offer a referral to a stop smoking service to people with an abdominal aortic aneurysm (AAA) who smoke. For more guidance, see the NICE guideline on tobacco: preventing uptake, promoting quitting and treating dependence. Ensure that people with an AAA who have hypertension receive care in line with the NICE guideline on hypertension in adults. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reducing the risk of rupture . Full details of the evidence and the committee's discussion are in evidence review C: risk factors associated with abdominal aortic aneurysm growth or rupture. Loading. Please wait. ## Monitoring the risk of rupture Offer surveillance with aortic ultrasound to people with an asymptomatic AAA. Use the same surveillance frequency as the NHS AAA screening programme. See recommendation 1.1.5 on when to refer people to a regional vascular unit. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring the risk of rupture . Full details of the evidence and the committee's discussion are in evidence review D: monitoring for abdominal aortic aneurysm expansion and risk of rupture. Loading. Please wait. # Emergency transfer to regional vascular services Be aware that there is no evidence that any single symptom, sign or prognostic risk assessment tool can be used to determine whether people with a suspected or confirmed ruptured abdominal aortic aneurysm (AAA) should be transferred to a regional vascular service. When making transfer decisions, be aware that people with a confirmed ruptured AAA who have a cardiac arrest and/or have a persistent loss of consciousness have a negligible chance of surviving AAA repair. For guidance on care of people with a ruptured AAA for whom repair is considered inappropriate, see the NICE guideline on care of dying adults in the last days of life. When people with a suspected ruptured or symptomatic unruptured AAA have been accepted by a regional vascular service for emergency assessment, ensure that they leave the referring unit within 30 minutes of the decision to transfer. Emergency departments, ambulance services and regional vascular services should collaborate to: provide a protocol for the safe and rapid transfer of people with a suspected ruptured or symptomatic unruptured AAA who need emergency assessment at a regional vascular service train clinical staff involved in the care of people with a suspected ruptured or symptomatic unruptured AAA in the transfer protocol review the transfer protocol at least every 3 years. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on emergency transfer to regional vascular services . Full details of the evidence and the committee's discussion are in evidence review O: signs, symptoms and risk factors indicating suitability for transfer to a regional vascular service and evidence review P: time period for transfer to regional vascular services. Loading. Please wait. ## Supporting people during transfer Consider a restrictive approach to volume resuscitation (permissive hypotension) for people with a suspected ruptured or symptomatic AAA during emergency transfer to a regional vascular service. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on supporting people during transfer . Full details of the evidence and the committee's discussion are in evidence review Q: permissive hypotension during transfer of people with ruptured abdominal aortic aneurysm to regional vascular services. Loading. Please wait. # Predicting and improving surgical outcomes ## Predicting surgical outcomes for unruptured aneurysms Consider cardiopulmonary exercise testing when assessing people for elective repair of an asymptomatic abdominal aortic aneurysm (AAA), if it will assist in shared decision making. For guidance on other preoperative tests, see the NICE guideline on routine preoperative tests for elective surgery. Do not use the following risk assessment tools to determine whether or not repair is suitable for a person with an asymptomatic unruptured AAA: British Aneurysm Repair score Carlisle Calculator Comorbidity Severity Score Glasgow Aneurysm Scale Medicare risk prediction tool Modified Leiden score Physiological and Operative Severity Score for enUmeration of Mortality (POSSUM) Vascular-POSSUM Vascular Biochemical and Haematological Outcome Model (VBHOM) Vascular Governance North West (VGNW) risk model. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on predicting surgical outcomes in unruptured aneurysms . Full details of the evidence and the committee's discussion are in evidence review G: tests for predicting outcomes after repair of unruptured abdominal aortic aneurysms and evidence review H: risk assessment tools for predicting surgical outcomes of patients who undergo elective abdominal aortic aneurysm repair. Loading. Please wait. ## Predicting surgical outcomes for ruptured aneurysms Do not use any single symptom, sign or patient-related risk factor to determine whether aneurysm repair is suitable for a person with a ruptured AAA. Do not use patient risk assessment tools (scoring systems) to determine whether aneurysm repair is suitable for a person with a ruptured AAA. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on predicting surgical outcomes for ruptured aneurysms . Full details of the evidence and the committee's discussion are in evidence review S: risk factors for predicting survival after abdominal aortic aneurysm rupture. Loading. Please wait. ## Improving surgical outcomes Offer people with an AAA information, support and interventions for secondary prevention of cardiovascular disease. For more information refer to the NICE guidance on: tobacco: preventing uptake, promoting quitting and treating dependence diet, nutrition and obesity and exercise medicines optimisation lipid modification and statin therapy diabetes management hypertension diagnosis and management. Do not routinely offer preoperative beta blockers to people having AAA repair. Do not offer remote ischaemic preconditioning to people having AAA repair. For guidance on preventing and treating surgical site infections and on preventing venous thromboembolism, see the NICE guidelines on surgical site infections and reducing the risk of venous thromboembolism. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on improving surgical outcomes . Full details of the evidence and the committee's discussion are in evidence review J: pre- and postoperative interventions to optimise outcomes after abdominal aortic aneurysm repair. Loading. Please wait. # Repairing unruptured aneurysms ## When to consider repair Consider aneurysm repair for people with an unruptured abdominal aortic aneurysm (AAA), if it is: symptomatic asymptomatic, larger than 4.0 cm and has grown by more than 1 cm in 1 year (measured inner-to-inner maximum anterior-posterior aortic diameter on ultrasound) asymptomatic and 5.5 cm or larger (measured inner-to-inner maximum anterior-posterior aortic diameter on ultrasound). ## Discussing the benefits and risks of repair or conservative management When discussing aneurysm repair with people who have an unruptured AAA, explain the overall balance of benefits and risks with repair and with conservative management, based on their current health and their expected future health. The decision on whether repair is preferred over conservative management should be made jointly by the person and their clinician after assessment of a number of factors, including: aneurysm size and morphology the person's age, life expectancy, fitness for surgery, and any other conditions they have the risk of AAA rupture if they do not have repair the short- and long-term benefits and risks, and the other disadvantages of repair such as having to stay in hospital, the risks of the operation, the recovery period, the potential need for further procedures and the need for surveillance imaging appointments the uncertainties around estimates of risk for AAAs larger than 5.5 cm (measured inner-to-inner maximum anterior-posterior aortic diameter on ultrasound). ## Open surgical repair, standard endovascular aneurysm repair or conservative management Offer open surgical repair for people with unruptured AAAs meeting the criteria in recommendation 1.5.1, unless it is contraindicated because of their abdominal copathology, anaesthetic risks, and/or medical comorbidities. Consider endovascular aneurysm repair (EVAR) for people with unruptured AAAs who meet the criteria in recommendation 1.5.1 and who have abdominal copathology, such as a hostile abdomen, horseshoe kidney or a stoma, or other considerations, specific to and discussed with the person, that may make EVAR the preferred option. Consider EVAR or conservative management for people with unruptured AAAs meeting the criteria in recommendation 1.5.1 who have anaesthetic risks and/or medical comorbidities that would contraindicate open surgical repair. ## Complex endovascular aneurysm repair If open surgical repair and complex EVAR are both suitable options, only consider complex EVAR if: the following has been discussed with the person: the risks of complex EVAR compared with the risks of open surgical repair the uncertainties around whether complex EVAR improves perioperative survival or long-term outcomes, when compared with open surgical repair it will be performed with special arrangements for consent and for audit and research that will determine the clinical and cost effectiveness of complex EVAR when compared with open surgical repair, and all patients are entered onto the National Vascular Registry. For people who have anaesthetic risks and/or medical comorbidities that would contraindicate open surgical repair, only consider complex EVAR if: the following has been discussed with the person: the risks of complex EVAR compared with the risks of conservative management the uncertainties around whether complex EVAR improves perioperative survival or long-term outcomes it will be performed with special arrangements for consent and for audit and research that will determine the clinical and cost effectiveness of complex EVAR when compared with conservative management, and all patients are entered onto the National Vascular Registry. NICE amended recommendations 1.5.1 to 1.5.7, after the committee's proposed recommendations were reviewed by NICE's Board. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on repairing unruptured aneurysms . Full details of the evidence and the committee's discussion are in: evidence review F: thresholds for abdominal aortic aneurysm repair evidence review K: effectiveness of endovascular aneurysm repair, open surgical repair and non-surgical management of unruptured abdominal aortic aneurysms evidence review K2: observational evidence on the effectiveness of endovascular aneurysm repair compared with open surgical repair of unruptured abdominal aortic aneurysms. Loading. Please wait. ## Anaesthesia and analgesia Consider epidural analgesia in addition to general anaesthesia for people having open surgical repair of an unruptured AAA. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on anaesthesia and analgesia during unruptured aneurysm repair . Full details of the evidence and the committee's discussion are in evidence review L: anaesthesia and analgesia for people having surgical repair of an abdominal aortic aneurysm. Loading. Please wait. # Repairing ruptured aneurysms Consider endovascular aneurysm repair (EVAR) or open surgical repair for people with a ruptured infrarenal abdominal aortic aneurysm (AAA). Be aware that: EVAR provides more benefit than open surgical repair for most people, especially men over 70 and women of any age -pen surgical repair is likely to provide a better balance of benefits and harms in men under 70. Consider open surgical repair for people with a ruptured AAA if standard EVAR is unsuitable. Do not offer complex EVAR to people with a ruptured AAA if open surgical repair is suitable, except as part of a randomised controlled trial comparing complex EVAR with open surgical repair. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on repairing ruptured aneurysms . Full details of the evidence and the committee's discussion are in evidence review T: effectiveness of endovascular aneurysm repair compared with open surgical repair of ruptured abdominal aortic aneurysms. Loading. Please wait. ## Anaesthesia and analgesia Consider using local infiltrative anaesthesia alone for people having EVAR of a ruptured AAA. For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on anaesthesia and analgesia during ruptured aneurysm repair . Full details of the evidence and the committee's discussion are in evidence review L: anaesthesia and analgesia for people having surgical repair of an abdominal aortic aneurysm. Loading. Please wait. ## Abdominal compartment syndrome Be aware that people can develop abdominal compartment syndrome after EVAR or open surgical repair of a ruptured AAA. Assess people for abdominal compartment syndrome if their condition does not improve after EVAR or open surgical repair of a ruptured AAA. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on abdominal compartment syndrome . Full details of the evidence and the committee's discussion are in evidence review U: preventing abdominal compartment syndrome following repair of ruptured abdominal aortic aneurysm. Loading. Please wait. # Monitoring for complications after endovascular aneurysm repair Enrol people who have had endovascular aneurysm repair (EVAR) into a surveillance imaging programme. Base the frequency of surveillance imaging on the person's risk of EVAR-related complications. Consider contrast-enhanced CT angiography or colour duplex ultrasound for assessing abdominal aortic aneurysm (AAA) diameter and EVAR device limb kinking. Use contrast-enhanced CT angiography if an endoleak is suspected. If contrast-enhanced CT angiography is contraindicated, use contrast-enhanced ultrasound. Do not exclude endoleaks based on a negative colour duplex ultrasound alone in people who have had EVAR. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring for complications after endovascular aneurysm repair . Full details of the evidence and the committee's discussion are in evidence review V: postoperative surveillance after surgical repair of abdominal aortic aneurysms and evidence review W: accuracy of imaging techniques in identifying complications after surgery. Loading. Please wait. # Managing endoleaks after endovascular aneurysm repair Consider open, endovascular or percutaneous intervention for type 1 and type 3 endoleaks following endovascular aneurysm repair (EVAR). Consider intervention for type 2 endoleaks in people who have abdominal aortic aneurysm (AAA) expansion following EVAR. Consider further investigation of type 5 endoleaks following EVAR. For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing endoleaks after endovascular aneurysm repair . Full details of the evidence and the committee's discussion are in evidence review X: managing complications after abdominal aortic aneurysm repair. Loading. Please wait. # Terms used in this guideline This section defines terms that have been used in a specific way for this guideline. For general definitions, please see the NICE glossary. ## Standard and complex EVAR Standard EVAR is defined as any EVAR procedure: using a standard infrarenal device (an unmodified off-the-shelf stent graft) and following the manufacturer's 'instructions for use' for the device used and without any adjunctive procedures (planned use of endo-anchors and planned permanent instrumentation of aortic branch vessels, such as 'chimney' or 'snorkel' procedures). Any EVAR procedure that does not fit into the definition above is classed as 'complex EVAR'. Complex EVAR also covers fenestrated, branched, customised or internal iliac branch devices, and physician-modified stent grafts. ## Endoleak The persistence of blood flow outside an endovascular stent–graft but within the aneurysm sac in which the graft is placed. There are 5 types of endoleak: Type 1 – blood flowing into the aneurysm because of an incomplete or ineffective seal at either end of a stent–graft Type 2 – blood flowing into an AAA from side branches of the aorta Type 3 – blood flowing into an AAA through defects in the endograft Type 4 – blood flowing through the stent–graft fabric into an AAA Type 5 – continued AAA expansion without radiographic evidence of a leak site. ## Hostile abdomen An abdomen that is difficult to perform open surgery within, because of adverse anatomical features. For AAA repair, these features can include large abdominal wall defects or intra-abdominal adhesions. A hostile abdomen is most common in people who have had multiple previous episodes of intra-abdominal open surgery. ## Infrarenal abdominal aortic aneurysm An abdominal aortic aneurysm arising below the arteries that supply the kidneys. ## Permissive hypotension A method of fluid administration that aims to reduce bleeding by keeping a person's blood pressure within a lower-than-normal range.# Recommendations for research The guideline committee has made the following recommendations for research. # Key recommendations for research ## Monitoring frequencies and repair thresholds What are the most effective and cost-effective frequencies for monitoring people with unruptured abdominal aortic aneurysms (AAA) of different diameters, and what is the optimal AAA threshold size (inner-to-inner maximum anterior-posterior diameter on ultrasound) for repair? More frequent monitoring increases the chances of identifying aneurysms that have grown large enough to be considered for repair. However, monitoring requires resources and the absolute risk of AAA rupture is relatively low, so there are opportunity costs to consider. It is important to establish how often aneurysms should be monitored to keep the risk of rupture as low as possible while making the best use of NHS resources. The optimal threshold for repair of an AAA is not clear. There is good evidence that in most cases people do not need repair for aneurysms measuring smaller than 5.5 cm (inner-to-inner maximum anterior-posterior aortic diameter) on ultrasound. However, for some people a threshold above 5.5 cm may be more appropriate. ## Effectiveness of endovascular aneurysm repair and open surgical repair of complex unruptured and ruptured abdominal aortic aneurysms What is the effectiveness and cost effectiveness of complex endovascular aneurysm repair (EVAR) versus open surgical repair in people for whom open surgical repair is suitable for: elective repair of an unruptured AAA or emergency repair of a ruptured AAA? EVAR is a widely performed non-invasive alternative to open surgical repair. However, it is more expensive. Although standard EVAR has been shown to produce no long-term benefit over open surgical repair in people with an unruptured infrarenal abdominal aortic aneurysm, it is less clear whether this is the same in people with who would need complex EVAR to repair their AAA. The committee's view was that, because current practice is subject to strong prior beliefs about the relative benefits and harms of EVAR and open surgical repair for complex AAA, randomisation is critical to provide an unbiased estimate of comparative effectiveness. ## Macrolides for slowing aneurysm growth and reducing the risk of rupture What are the benefits and harms of macrolides (such as azithromycin) for reducing AAA growth rates and the risk of rupture? Small AAAs are currently managed by monitoring, until the aneurysm reaches a diameter at which surgical repair is considered. There are currently no non-surgical interventions available to prevent AAAs from growing, and subsequently rupturing. A randomised controlled trial would be useful to determine whether macrolides reduce the rate of AAA growth and the risk of rupture. ## Metformin for slowing aneurysm growth and reducing the risk of rupture What are the benefits and harms of metformin for reducing AAA growth rates and the risk of rupture? Observational study data suggest an association between diabetes and slower AAA growth, and it has been proposed that this may be due to the use of metformin. A randomised controlled trial is needed to determine whether metformin reduces the rate of AAA growth and the risk of rupture. ## Tranexamic acid for preventing and treating excessive blood loss during EVAR or open surgical repair Does tranexamic acid reduce blood loss and so improve survival in people who are having repair (EVAR or open surgical repair) of a ruptured AAA? Tranexamic acid is used to reduce blood loss in major trauma, postpartum bleeding and surgery. By slowing down blood loss from a ruptured AAA, the use of tranexamic acid may improve survival from ruptured AAA. A randomised controlled trial is needed to determine whether tranexamic acid improves survival in people having EVAR or open surgical repair of a ruptured AAA. ## Prehabilitation (including preoperative exercise programmes) for improving the outcome of aneurysm repair What is the clinical effectiveness and cost effectiveness of prehabilitation, including preoperative exercise programmes, for improving outcomes of people who are having repair of an AAA? NHS providers have started devoting resources to prehabilitation programmes, based on a relatively small body of evidence. Research is needed to determine if prehabilitation is effective and the optimal form it should take. # Other recommendations for research ## Direct oral anticoagulants after abdominal aortic aneurysm repair What are the benefits of postoperative use of direct oral anticoagulants (DOACs) for improving outcomes after repair of AAA? ## Permissive hypotension Does permissive hypotension improve survival of patients undergoing repair of ruptured AAA? ## Surveillance after endovascular aneurysm repair What are the risks, benefits and cost implications of different surveillance protocols in people who have undergone EVAR?# Rationale and impact # Identifying asymptomatic abdominal aortic aneurysms ## Why the committee made the recommendations Recommendations 1.1.1 to 1.1.6 The committee were mindful that the NHS abdominal aortic aneurysm (AAA) screening programme does not cover men under 65 or women of any age. This means some men and all women who are at risk of AAA are not currently screened. The recommendations highlight these groups and specify risk factors significantly associated with AAA that could be used to help with opportunistic screening. There are also men who have no risk factors for AAA and were not seen by the screening programme when they turned 65. As their risk of AAA is low, the committee only recommended informing them about the NHS AAA screening programme and how it works. Men can then self-refer if they feel screening is right for them. Evidence from cross-sectional studies also found that people of Hispanic, African-American and Asian family origin were individually less likely than people of European family origin to have an AAA, so the committee wished to raise awareness of this. Aortic ultrasound is recommended because it is the standard technique used in clinical practice and in the screening programme. It has high diagnostic accuracy, and is associated with lower costs and fewer side effects than CT. People with an AAA diameter of 5.5 cm or larger (inner-to-inner maximum anterior-posterior aortic diameter on ultrasound) need to be seen by a regional vascular service within 2 weeks because their aneurysm is at higher risk of rupture. The committee recommended that people with aneurysms less than 5.5 cm in diameter are seen within 12 weeks of diagnosis because this is the timeframe set by the NHS AAA screening programme. ## How the recommendations might affect practice The recommendations outlining key risk factors will increase the number of people being screened and improve AAA diagnosis. The recommendations should also promote equal access to healthcare, because they provide guidance on when a potential AAA should be investigated in women, who are currently not covered by the NHS AAA screening programme. Using aortic ultrasound to detect AAAs is good practice. The recommendations ensure that the time within which people with newly-identified aneurysms are seen by regional vascular services is proportional to the risk of rupture. These timings match the timeframe the NHS AAA screening programme uses for people they assess. Return to recommendations # Identifying symptomatic or ruptured abdominal aortic aneurysms ## Why the committee made the recommendations Recommendations 1.1.7 to 1.1.9 Based on their own experience, the committee highlighted the most important signs and symptoms of ruptured AAAs, because: non-specialists commonly fail to diagnose them improved diagnosis should increase the chance of survival urgent discussion of a suspected ruptured AAA with a regional vascular service will improve the chances of appropriate treatment and survival. Aortic ultrasound is the standard technique for detecting the presence of AAA in a person with a suspected ruptured aneurysm. A ruptured AAA is a surgical emergency, and bedside ultrasound is the quickest reliable method to confirm the presence of an AAA. An immediate discussion with the regional vascular unit ensures appropriate management is started as soon as possible. The committee recognised that the sensitivity of aortic ultrasound is not 100% and several factors can make it difficult to visualise the aorta. Since AAA rupture is a life-threatening surgical emergency, they agreed that it would be safest to discuss any non-diagnostic ultrasound findings with the regional vascular unit. ## How the recommendations might affect practice There is variation in awareness of AAA among non-specialists. Implementing the recommendations should reduce this variation and increase the chance of ruptured AAA being diagnosed earlier. Using bedside aortic ultrasound to detect AAAs is common practice. Preventing delays to repair through immediate discussions with a regional vascular unit should improve outcomes for people with ruptured AAAs. Return to recommendations # Imaging technique ## Why the committee made the recommendations Recommendations 1.1.10 to 1.1.12 The committee agreed that it was important to take consistent measurements of aneurysm size throughout the NHS, so that results are comparable. The NHS AAA screening programme specifies inner-to-inner maximum anterior-posterior aortic diameter on ultrasound, and the committee agreed this would be the most appropriate measurement on which to base practice across the whole NHS. The committee recommended thin-slice contrast-enhanced arterial-phase CT angiography for imaging in people being evaluated for elective repair, because it is widely recognised as the gold standard technique for assessing aneurysm anatomy before repair. For suspected ruptured AAAs, CT angiography should also be considered. However, the committee recognised that some people will need immediate transfer for repair without waiting for a CT scan. No evidence was found demonstrating whether or not post-processing techniques affected postoperative outcomes for people having elective or emergency AAA repair. As post-processing techniques are an established part of clinical practice, the committee agreed not to make recommendations in this area. ## How the recommendations might affect practice Implementing a consistent measurement method to be used across the NHS (and that matches the method used in the NHS AAA screening programme) will improve the reproducibility of results, improving surveillance for individuals with AAA and the ability to analyse data at the population level. Thin-slice contrast-enhanced arterial-phase CT angiography is widely used for imaging in people being evaluated for AAA repair, so this recommendation is unlikely to make a major difference to current practice. The recommended timings reflect current standards within the NHS AAA screening programme. As post-processing techniques are established in practice, a lack of recommendations on these will not have an impact. Return to recommendations # Providing information to people with a diagnosed AAA ## Why the committee made the recommendations Recommendations 1.1.13 to 1.1.15 The committee agreed some consensus recommendations on what information should be provided to people who have been diagnosed with an AAA. In particular, the recommendations cover information for people who are not being considered for repair, either because their AAA is too small (data from the NHS screening programme show that the risk of rupture for an AAA below 5.5 cm is only 0.4% per year) or because their medical comorbidities mean the risks of repair outweigh the benefits. It is important to avoid making people anxious about not being offered repair, but also to avoid giving the impression that AAA repair is always beneficial if the aneurysm meets the criteria for treatment (see recommendation 1.5.1). Explaining how the decision to repair is made (based on the person's health at that particular time) and the uncertainties around this will help people to better understand the options available. The committee emphasised that clinicians should ensure that people understand their options and the balance of risks they face. They noted that several clinic visits, including opinions from specialists such as anaesthetists, geriatricians, and cardiologists, are likely to be needed. Return to recommendations # Reducing the risk of rupture ## Why the committee made the recommendations Recommendations 1.2.1 and 1.2.2 The committee focused on modifiable risk factors that could influence the management of people with known AAAs. There was some evidence that high blood pressure increases the chance of AAA growth and rupture, and the committee knew from their own experience that people with an AAA do not always receive appropriate management for high blood pressure. There is also evidence that smoking increases the risk of AAA rupture. As a result, the committee referred to the NICE guidelines on these topics. The committee agreed that there was not enough high-quality evidence to make clinical recommendations on non-surgical interventions for slowing aneurysm growth and reducing the risk of rupture. In light of this, they made research recommendations on 2 drug interventions that might reduce aneurysm growth and rupture risk. ## How the recommendations might affect practice The NICE guidelines on hypertension and stop smoking services cover current practice, so organisations are unlikely to need to change practice. Non-surgical interventions for small AAAs are not usually used outside of clinical trials, so a lack of recommendations will have little impact on practice. Return to recommendations # Monitoring the risk of rupture ## Why the committee made the recommendations Recommendations 1.2.3 and 1.2.4 The committee recommended ultrasound surveillance because ultrasound is current practice and no evidence was found for other imaging techniques. They recommended that monitoring frequency should be in line with the NHS AAA screening programme to ensure consistency across the whole NHS. The screening programme surveillance intervals are based on evidence on risk of rupture, depending on the size of the AAA. This means that people with larger aneurysms are monitored more frequently, offering the best balance between benefits and costs. The committee are aware that the NHS AAA screening programme may change the surveillance intervals it uses in the future. If this happens, the committee agreed that regional vascular services should change to match the new intervals, to ensure that they continue to provide care based on best practice. ## How the recommendations might affect practice Changing monitoring intervals to reflect those used in the NHS AAA screening programme will maintain a consistent standard across the NHS, and ensure that the most effective imaging intervals are used. Return to recommendations # Emergency transfer to regional vascular services ## Why the committee made the recommendations Recommendations 1.3.1 to 1.3.5 There was no evidence on symptoms, signs or risk assessment tools for deciding whether people with ruptured aneurysms are likely to survive transfer to a regional vascular service. Based on their own experience, the committee highlighted specific circumstances (cardiac arrest and persistent loss of consciousness) in which people are unlikely to survive transfer and subsequent aortic repair. This will help reduce the number of people being given ineffective and invasive treatment at the end of life. The committee referred to the NICE guideline on care of dying adults in the last days of life to ensure that appropriate and compassionate care is given to people with a ruptured AAA when the decision has been made not to operate. There was also no evidence on how quickly people with ruptured AAA should be transferred to regional vascular units. In the absence of evidence, the committee adapted recommendations from the NICE guideline on service delivery for major trauma. They agreed, based on their experience of emergency transfer, that the timing specified for people with major trauma was appropriate for people with ruptured AAA and manageable for referring units. ## How the recommendations might affect practice The recommendations on assessing people for transfer will raise awareness among emergency staff, but will have little resource impact on clinical practice. The recommendations on transfer speed will improve practice by minimising variation in transfer times across the NHS. The timeframe recommended is the same as for major trauma, and the committee agreed that this is a reasonably similar situation. The NICE guideline on care of dying adults cover current practice, so organisations are unlikely to need to change practice. Return to recommendations # Supporting people during transfer ## Why the committee made the recommendation Recommendation 1.3.6 As there was no evidence specific to the use of permissive hypotension during transfer of people with ruptured or symptomatic AAA, the committee agreed that a consensus recommendation was needed in this important clinical area. As a result the committee adapted recommendations from the NICE guideline on assessment and initial management for major trauma. ## How the recommendation might affect practice The recommendation will reduce the likelihood of inappropriate fluid administration during transfer of people with ruptured AAA. This, in turn, will improve the outcomes of endovascular aneurysm repair and open surgical repair procedures. The recommendation is in line with NICE recommendations on fluid administration for other major trauma, and the committee agreed that this was appropriate for ruptured AAA. Return to recommendation # Predicting surgical outcomes in unruptured aneurysms ## Why the committee made the recommendations Recommendations 1.4.1 and 1.4.3 There was limited evidence that cardiopulmonary exercise testing can help predict outcomes following endovascular aneurysm repair (EVAR) and open surgical repair. While the evidence was limited, the committee agreed that cardiopulmonary exercise testing could have a useful role in shared decision-making between healthcare professionals and patients when the benefits and harms of surgery are uncertain. There are other tests for assessing people before surgery, but there was no evidence available for them. One study found that higher estimated glomerular filtration rate (eGFR) was associated with improved outcomes after elective EVAR, but it did not give clear eGFR thresholds that could be used in decision-making. In the absence of evidence, the committee referred to the NICE guideline on routine preoperative tests for elective surgery. Some of the studies reviewed for that guideline focused on people having elective AAA repair. The evidence highlighted that none of the risk assessment tools had a high enough predictive accuracy at predicting postoperative outcomes. The specific tools listed are the ones for which evidence was available. This evidence led the committee to conclude that these tools would not improve decision-making and could potentially lead to inappropriate decisions about patient management. They agreed that this could lead to harm, and therefore advised that risk assessment tools should not be used. ## How the recommendations might affect practice The use of cardiopulmonary exercise testing will have limited impact on practice as it is only recommended in situations where it will help in shared decision-making. Risk assessment tools are not widely used outside the context of research on AAA. Therefore, the recommendations will have little impact on practice. Return to recommendations # Predicting surgical outcomes for ruptured aneurysms ## Why the committee made the recommendations Recommendations 1.4.4 and 1.4.5 There is evidence that some risk factors and risk assessment tools are associated with poor postoperative outcomes. However, it is not clear how any particular factor or combination of factors could be used to decide if aneurysm repair is suitable for a person with a ruptured AAA. The committee emphasised that there is a potential for harm if clinicians base their decision to repair solely on risk assessment tools and scores, because some people would be inappropriately offered or denied repair. ## How the recommendations might affect practice The recommendations will have a beneficial impact, by ensuring decisions about care are not made based on inappropriate factors or tools. This, in turn, should prevent inappropriate decisions being made about whether or not to offer repair. Return to recommendations # Improving surgical outcomes ## Why the committee made the recommendations Recommendations 1.4.6 to 1.4.9 The committee made a recommendation on cardiovascular disease because it is common in people with AAA and it is best practice to reduce the risk of problems in people who have it. The other NICE guidelines that are referenced include recommendations to help reduce this risk. The evidence showed that giving beta blockers just before surgery is not beneficial, and may be harmful by lowering low blood pressure and heart rate. The committee noted that some people with AAA may need to take beta blockers for other conditions (such as atrial fibrillation). As a result, they recommended against routine use before AAA repair, rather than recommending against beta blockers altogether. Remote ischaemic preconditioning was not recommended because there was evidence that it does not improve outcomes and that it can cause problems such as an irregular heartbeat. The committee recommended further research because there was not enough evidence to make recommendations on prehabilitation (including exercise programmes before surgery), or on any interventions after AAA repair. ## How the recommendations might affect practice Providing support to reduce the risk of problems from cardiovascular disease is already current practice. In addition, beta blockers and routine ischaemic preconditioning are not currently in routine use before AAA repair, so these recommendations should have a minimal impact on practice. Return to recommendations # Repairing unruptured aneurysms ## Why NICE made the recommendations Recommendations 1.5.1 to 1.5.7 A number of factors should be considered before treating asymptomatic aneurysms, one of which is size. It is standard practice to repair large aneurysms (over 5.5 cm in diameter on ultrasound, measured using an anterior-posterior diameter inner-to-inner), and to monitor smaller aneurysms (less than 4 cm in diameter) until they become larger. Repair is sometimes offered for aneurysms below 5.5 cm if they are growing rapidly, or if they are symptomatic. However, data from the NHS screening programme show that, for aneurysms below 5.5 cm, the risk of rupture remains very low (0.4% per year). It is clear from the evidence that there is no benefit to repairing aneurysms that are below 5.5 cm, asymptomatic and not growing rapidly. Based on this evidence, we highlighted factors that would help healthcare professionals decide when to repair aneurysms. Given the risks and other disadvantages of AAA repair, conservative management is sometimes a better option. Because of this, healthcare professionals need to explain the balance of benefits and risks to people with AAAs, so they can make an informed decision. The evidence showed that, compared with open surgical repair for people with an unruptured infrarenal abdominal aortic aneurysm, elective EVAR has medium- and long-term harms that outweigh its short-term benefits. EVAR is associated with fewer perioperative deaths, and less time in hospital in general (and critical care in particular). But it also has worse long-term survival than open surgical repair, and more long-term complications, leading to further procedures. Even when taking the short-term benefits of EVAR into account, all plausible cost-effectiveness estimates show that EVAR either: has higher net costs and lower net benefits than open surgical repair or is substantially above the range NICE normally considers to be a cost-effective use of NHS resources. There is a small group of people who have abdominal copathology or other considerations that mean open surgical repair is unsuitable. Examples of copathologies include people who have internal scar-tissue from previous abdominal surgery (a so-called hostile abdomen), people who have a single, fused kidney that is wrapped around the aorta ('horseshoe kidney'), and people who have a stoma. Although there was no evidence on this population, EVAR is a potential option for these people, as the risks of open surgical repair may be much higher for them. This recommendation should not be used to extend EVAR to people who could reasonably have open surgical repair. Open surgical repair is contraindicated for some people with an unruptured AAA because of anaesthetic risks and/or medical comorbidities. For these people, the risk of their AAA rupturing if no repair is attempted has to be balanced against: the perioperative risks and long-term complications of EVAR the uncertainty around whether they will benefit from EVAR the large costs of EVAR. With all this in mind, it is clear that practice needs to be rebalanced. Conservative management is a better option than EVAR for many people. However, NICE also acknowledged stakeholder comments highlighting the importance of individualised care. For some people, EVAR may be appropriate. Clinicians should discuss the risks of EVAR and conservative management with people with AAAs, taking into account the uncertainty that EVAR will provide a benefit. People who are not offered repair may be anxious about having an AAA but not receiving treatment for it. However, a better explanation of the risks they face, in the context of their other life-limiting comorbidities, can help with anxiety. To help with this, the committee made consensus recommendations (see recommendations 1.1.13 to 1.1.14) on the information to cover when discussing repair with people who have an AAA. The evidence for complex EVAR was limited in quantity and quality. However, complex EVAR grafts and procedures are much more expensive than standard EVAR, so the difference in cost between EVAR and open surgical repair is likely to be even greater than for infrarenal AAAs. In addition, using standard EVAR stent grafts for complex AAA usually violates the manufacturer's 'instructions for use'. Although there is currently no evidence that complex EVAR has better outcomes than open surgical repair, people with complex AAAs have higher perioperative mortality rates than people with infrarenal AAAs. Because of this, an increased perioperative survival benefit may be more important for them, and may justify the use of complex EVAR. This would differentiate complex EVAR from standard EVAR, which clearly does not provide enough short-term benefits to outweigh the worse long-term outcomes or the increased cost (when compared with open surgical repair). Open surgical repair is contraindicated for some people with an unruptured AAA because of anaesthetic risks and/or medical comorbidities. For these people, the risk of their AAA rupturing if no repair is attempted has to be balanced against: the perioperative risks and long-term complications of complex EVAR the uncertainty around whether they will benefit from complex EVAR the large costs of complex EVAR. With all this in mind, it is clear that conservative management is a better option than complex EVAR for many people. However, NICE also acknowledged stakeholder comments highlighting the importance of individualised care. For some people, complex EVAR may be appropriate. Clinicians should discuss the risks of complex EVAR and conservative management with people with AAAs, taking into account the uncertainty that complex EVAR will provide a benefit. As with standard EVAR, NICE acknowledged that in the face of the evidence reviewed, practice needs to be rebalanced towards open surgical repair in this scenario as well. But, because of the limited evidence for complex EVAR and the importance of individualised care, NICE concluded that it is important for clinicians and people with AAA to discuss the uncertainties and weigh up the risks and benefits of repair, in order to make an informed decision. More evidence on this procedure would be helpful, and NICE has made a recommendation for research comparing complex EVAR with open surgical repair. For each of the recommendations, NICE considered whether there were any specific groups that would benefit from standard or complex EVAR for unruptured AAAs. We explored groups defined by age, sex, AAA diameter and life expectancy, but it was not possible with the current evidence to identify any specific groups in which the benefits would outweigh the harm and costs. The key randomised controlled trials (RCTs) in this area are relatively old. NICE looked at more recent observational evidence, to see if changes in surgical and endovascular techniques and technology have led to different outcomes. The observational studies are at high risk of bias, but their findings are broadly in line with the RCTs. They show that, while outcomes from EVAR have improved over the last 15 years, outcomes from open surgical repair have also improved by roughly the same amount. This means the difference in outcomes between the two has remained fairly constant. Registries like the National Vascular Registry can provide a useful snapshot of current practice, and the analyses that informed NICE's decision-making made use of data from them. However, they are not designed to evaluate the comparative benefits and harms of different surgical approaches, such as EVAR and open surgical repair. Therefore, they cannot be considered a reasonable alternative to RCT data. In addition, an analysis using the registry data showed that EVAR still did not provide greater long-term benefits than open surgical repair, and that it still has higher net costs. NICE acknowledged the need to rebalance practice towards open repair and identified the possible implementation challenges. Possible increased perioperative mortality with open surgical repair: Improvements in practice since the RCTs were published have led to better standards for open surgical repair and EVAR alike. In addition, the NHS AAA screening programme means that AAAs are more likely to be diagnosed earlier than in the past, so people can have repair when they are younger and healthier. For these reasons, open surgical repair of unruptured AAAs can be provided with a low incidence of morbidity and mortality. The risk that vascular units will have trouble meeting an increased demand for open surgical repair: All vascular surgeons should be competent to perform open surgical repair of AAAs, and the Intercollegiate Surgical Curriculum Programme's Vascular surgery curriculum puts more emphasis on open surgical repair than on EVAR. This means that future surgeons should be well prepared to provide open surgical repair with a low incidence of morbidity and mortality. Potential shortage of beds in the NHS: As people who have open surgical repair spend more time in hospital immediately after the procedure, there may be a small, short-term increase in waiting times for AAA repair. However, an analysis comparing waiting times showed that open surgical repair would still provide greater benefit than EVAR for a lower cost even with a substantial increase in waiting times for open surgical repair. The possibility that reducing the number of EVAR procedures performed for unruptured aneurysms will make it difficult to provide EVAR for ruptured aneurysms: There are a number of ways this implementation issue might be addressed: vascular services could be centralised further (for example by establishing aortic units) in line with the recommendations, EVAR can be offered in certain situations. The evidence did not show any benefit from goal-directed therapy for people having repair of an unruptured AAA. Goal-directed therapy covers a broad range of different haemodynamic monitoring and management practices, some of which are routinely performed during major surgery. The committee recognised that it was not possible to specify which practices should or should not be performed and agreed that drafting recommendations would be too prescriptive. ## How the recommendations might affect practice The recommendation on when to repair unruptured aneurysms is unlikely to impact on current clinical practice because it reflects what is already being done within the NHS. Data from the NHS AAA screening programme indicate that the risk of rupture for AAAs that are smaller than 5.5 cm is very low. The recommendations on EVAR could have a large impact on practice and will also affect the timing and type of information about treatment options given to patients. In light of the evidence reviewed, practice needs to be rebalanced towards open surgical repair for infrarenal aneurysms. The recommendations will minimise harm by reducing long-term mortality and the need for re-intervention as a result of the problems with EVAR. The reduction in EVAR, and so EVAR-related re-interventions, will result in significant cost savings for the NHS. A lack of recommendations on goal-directed therapy will not impact on practice. Basic haemodynamic management is routinely performed during most surgical procedures, but goal-directed therapy is not widely adopted during AAA surgery. Return to recommendations # Anaesthesia and analgesia during unruptured aneurysm repair ## Why the committee made the recommendation Recommendation 1.5.8 The committee noted that there was some evidence that adding an epidural to general anaesthesia reduced the need for further analgesia for people having open surgical repair of an unruptured AAA. This was consistent with their own clinical experience of better pain control and reduced postoperative respiratory complications with an epidural. Adding an epidural is fairly widespread in current practice, and the committee agreed that it should be recommended as an option. No evidence was found on anaesthesia and analgesia for people undergoing EVAR for unruptured AAA. The committee agreed that no recommendations were needed in this area because they had recommended that EVAR should not be used to treat unruptured infrarenal abdominal aortic aneurysm, except in clinical trials or for people for whom open surgical repair is unsuitable because of abdominal copathology. ## How the recommendations might affect practice The use of an epidural in addition to general anaesthesia for people having open surgical repair of an unruptured AAA is already fairly widespread in current practice. Therefore the overall impact of the recommendation is likely to be small, although it may reduce existing variation. Return to recommendation # Repairing ruptured aneurysms ## Why the committee made the recommendations Recommendations 1.6.1 to 1.6.3 The evidence showed that, compared with open surgical repair, a strategy that uses EVAR (where anatomically possible) to repair ruptured infrarenal abdominal aortic aneurysm provides a reasonable balance of benefits and costs. As the average cost-effectiveness results for EVAR were favourable, the committee discussed whether they should recommend EVAR whenever it is possible. They decided not to, for 2 reasons. Firstly, there is uncertainty in the evidence for EVAR from the IMPROVE trial. People who had EVAR for a ruptured AAA in this trial were followed up for at most 7 years. People who had EVAR for an unruptured AAA in the EVAR-1 trial were followed up for 15 years, and the committee noted that these data indicate that EVAR leads to increasingly worse survival when compared with open surgical repair, because follow-up duration increases (see why NICE made the recommendations on repairing unruptured aneurysms). The medium-term survival data from the IMPROVE trial give some indication that a similar long-term pattern may develop in trials of ruptured AAA, with the survival curves converging as follow-up gets longer. Therefore, it is possible that longer-term data would show EVAR to be worse than open surgical repair for people with ruptured AAA as well. Secondly, there was evidence that the balance of benefits and costs for EVAR varies between different groups of people with ruptured AAAs. In particular, most women have better short-term survival after EVAR, whereas the evidence favours open surgical repair for younger men. Therefore, the committee recommended that either EVAR or open surgical repair can be considered, and provided detail on the groups for which each approach is likely to be best. Complex EVAR is only recommended within the context of an RCT because there is currently no evidence to support it as an option for people with ruptured complex AAA. Open surgical repair of these aneurysms is recommended as the only approach that should be used in people for whom emergency repair is suitable until the safety and effectiveness of complex EVAR has been established in this setting. No evidence on the use of tranexamic acid in people with a ruptured AAA was identified. The committee was aware that tranexamic acid is included in some major haemorrhage protocols and some patients, without major trauma, may receive it before undergoing surgery. In the committee's experience, tranexamic acid is not routinely used in people with a ruptured AAA, so it agreed to recommend research in this area. There was no evidence on goal-directed therapy for people having repair of a ruptured aneurysm. Goal-directed therapy covers a broad range of different haemodynamic monitoring and management practices; some of which are routinely performed during major surgery. The committee recognised that it was not possible to specify which practices should or should not be performed and agreed that drafting recommendations would be too prescriptive. ## How the recommendations might affect practice The recommendations will have little impact on current practice, as both standard EVAR and open surgical repair are currently offered to people with ruptured infrarenal AAAs. In relation to complex EVAR, the recommendation not to use it outside of RCTs will limit the use of a technically complex and expensive procedure in people for whom open surgery is a safe and suitable option. Because the guideline recommends that fewer EVAR procedures should be performed for unruptured aneurysms (see the section on repairing unruptured aneurysms), surgical teams may have less opportunity to develop the skills they need to provide EVAR in emergency cases. The committee were mindful of this issue, but were convinced by the evidence showing that, overall, people with AAAs would be worse off if EVAR procedures were performed for unruptured aneurysms just to maintain EVAR expertise. Elective EVAR will still be available in certain circumstances and centralisation of aortic services may maintain expertise. However, neither training nor service models were in the scope of this guideline, so the committee did not review any evidence and were unable to make any specific recommendations in these areas. A lack of recommendations on goal-directed therapy will not impact on practice. Basic haemodynamic management is routinely performed during most surgical procedures, but goal-directed therapy is not widely adopted during AAA surgery. A lack of recommendations on tranexamic acid will have little impact on practice. Tranexamic acid is used in varying degrees across the NHS, but it is not standard practice for people with ruptured or symptomatic AAAs who are being transferred before surgery. Return to recommendations # Anaesthesia and analgesia during ruptured aneurysm repair ## Why the committee made the recommendation Recommendation 1.6.4 No evidence was identified on the optimal use of anaesthesia and analgesia in people having open surgical repair or EVAR of a ruptured AAA. The committee agreed, based on their knowledge and experience, that general anaesthesia alone is widely accepted as best practice for open surgical repair, so did not make a recommendation on this. The committee made a recommendation on the use of local infiltrative anaesthesia alone in people having EVAR for ruptured AAA because it was considered that increased awareness of this option was needed. ## How the recommendation might affect practice The committee agreed that the potential impact of this recommendation on practice is unclear, because it is difficult to predict the proportion of people for whom EVAR under local infiltrative anaesthesia might be an option. The main aim of this recommendation is to raise awareness of this option. Return to recommendation # Abdominal compartment syndrome ## Why the committee made the recommendations Recommendations 1.6.5 and 1.6.6 There was no evidence relating to preventing or managing abdominal compartment syndrome in people who are having AAA repair. The committee agreed it was important to raise awareness of this potentially life-threatening condition, and made recommendations to highlight that it can occur after both endovascular aneurysm repair and open surgical repair. ## How the recommendations might affect practice The recommendations will ensure that clinicians are aware of abdominal compartment syndrome in people who have undergone repair of ruptured AAA. This may result in better postoperative assessment and management. Return to recommendations # Monitoring for complications after endovascular aneurysm repair ## Why the committee made the recommendations Recommendations 1.7.1 to 1.7.5 Imaging surveillance is needed after EVAR, because there is a risk that people will develop complications from the procedure or need another operation. These risks are lower after open surgical repair, so surveillance is not standard practice and in this case the committee did not recommend it. The committee noted that the frequency of EVAR surveillance is highly variable in practice. In the absence of evidence on how often imaging should be done, the committee agreed a recommendation to tailor surveillance to the perceived risk of complications. This should focus attention and resources on the people at greatest risk, and help to identify complications earlier. In practice, identifying complications after EVAR usually involves sequential imaging, with ultrasound frequently used as the first-line test and other imaging modalities used to detect specific complications. Imaging modalities may be complimentary, and the clinical significance of some imaging findings remains unclear, which makes identifying a true reference standard difficult. Contrast-enhanced CT angiography was widely used as a gold standard in the evidence that was reviewed. However, this has led to some abnormalities that are detected on other imaging modalities, but not on CT, being defined as false positives (for that modality, rather than as false negatives for CT). This may have introduced bias, and makes it difficult to rely on CT as a reference standard. The evidence showed that colour duplex ultrasound was highly accurate at identifying changes in sac size when compared with contrast-enhanced CT angiography. Increases in sac size are often believed to indicate an endoleak even if no leak can be seen on the ultrasound. There was little evidence on graft kinking, but the committee agreed based on their experience that colour duplex ultrasound and CT angiography were equally as effective at detecting this type of complication. In the evidence reviewed, contrast-enhanced ultrasound was the only imaging technique that had acceptable accuracy for directly identifying endoleaks when compared with contrast-enhanced CT angiography. Importantly, other imaging techniques had unacceptably high rates of false-negative results. For this reason, the committee agreed that in situations where the definitive exclusion (or identification) of endoleak is important (for example where endoleak is suspected) either contrast-enhanced CT angiography or contrast-enhanced ultrasound should be used. Contrast-enhanced ultrasound was not recommended for assessing other complications because the evidence for its use only covered endoleaks. The committee agreed that it is particularly important not to falsely exclude an endoleak, so the sensitivity of a diagnostic test is more important than its specificity. While colour duplex ultrasound is highly accurate at identifying changes in sac size (which may indicate an endoleak), the available evidence shows that it has suboptimal sensitivity for directly detecting type I and III endoleaks. In addition, the accuracy of ultrasound was shown to be dependent on the operator, so its accuracy may be variable in practice. This variability in diagnostic accuracy, and resultant potential for harm if an endoleak is missed, led the committee to recommend that colour duplex ultrasound alone should not be used to confirm or exclude the presence of endoleaks. ## How the recommendations might affect practice There is variation in which imaging techniques are used for surveillance. Some centres use ultrasound only, and some use contrast-enhanced CT angiography and ultrasound. Colour duplex ultrasound is widely used, but contrast-enhanced ultrasound is not. These recommendations are not likely to alter surveillance regimens substantially because many centres use imaging tests in a complementary fashion, often relying on sac size as a trigger for further investigation if necessary. Sonographers will need training in administering contrast agents if contrast-enhanced ultrasound is to be more widely adopted. Return to recommendations # Managing endoleaks after endovascular aneurysm repair ## Why the committee made the recommendations Recommendations 1.8.1 to 1.8.3 Endoleaks following EVAR are common. They can have a negative impact on patient prognosis and long-term quality of life, and further interventions are frequently needed to repair them. In the absence of evidence, the committee made recommendations based on their experience because: it is good practice to repair type I and III endoleaks and some type II endoleaks healthcare professionals are not all aware that type II endoleaks without sac expansion can be managed conservatively there are circumstances when sac expansion occurs without imaging evidence of a leak site (called type V endoleak), and these situations need further investigation. ## How the recommendations might affect practice The recommendations will have minimal impact on current practice because it is common practice to intervene for type I and type III endoleaks, and type II endoleaks if there is evidence of aneurysm sac expansion. Return to recommendations# Context Abdominal aortic aneurysms develop when the wall of the aorta in the abdomen weakens, causing it to bulge and form a balloon-like expansion. When the abdominal aorta reaches a diameter at least 1.5 times the normal size, or greater than 3 cm in total, it is called an abdominal aortic aneurysm (AAA). The increased stress on the aortic wall may eventually cause the AAA to rupture (burst). The subsequent internal bleeding is frequently fatal before emergency repair can be attempted. When people have emergency repair for rupture, up to half will not survive to leave hospital. There is a long period of growth before an AAA ruptures. The rate of growth may depend on a number of factors, including increasing age, smoking, blood pressure and a family history of aneurysm. Most AAAs are asymptomatic, and they are often diagnosed opportunistically during clinical examination or investigation for another condition. Because of this it is difficult to establish their prevalence. There is a national screening programme which enrols men at age 65 and suggests a prevalence of about 1.3% in this population. The prevalence is falling. The prevalence of AAAs is approximately 6 times lower in women, but the rate of aneurysm rupture is significantly higher. The guideline committee carefully considered the impact of their recommendations on women during guideline development.

Quinine Sulfate contraindications # Contraindications QUALAQUIN is contraindicated in patients with the following: - Prolonged QT interval. One case of a fatal ventricular arrhythmia was reported in an elderly patient with a prolonged QT interval at baseline, who received quinine sulfate intravenously for P. falciparum malaria . - Glucose-6-phosphate dehydrogenase (G6PD) deficiency. - Hemolysis can occur in patients with G6PD deficiency receiving quinine. - Known hypersensitivity reactions to quinine. These include, but are not limited to, the following [see Warnings and Precautions} Thrombocytopenia Idiopathic thrombocytopenia purpura (ITP) and Thrombotic thrombocytopenic purpura (TTP) Hemolytic uremic syndrome (HUS) Blackwater fever (acute intravascular hemolysis, hemoglobinuria, and hemoglobinemia) - These include, but are not limited to, the following [see Warnings and Precautions} - Thrombocytopenia - Idiopathic thrombocytopenia purpura (ITP) and Thrombotic thrombocytopenic purpura (TTP) - Hemolytic uremic syndrome (HUS) - Blackwater fever (acute intravascular hemolysis, hemoglobinuria, and hemoglobinemia) - Known hypersensitivity to mefloquine or quinidine: cross-sensitivity to quinine has been documented . Myasthenia gravis. Quinine has neuromuscular blocking activity, and may exacerbate muscle weakness. Optic neuritis. Quinine may exacerbate active optic neuritis . - Myasthenia gravis. Quinine has neuromuscular blocking activity, and may exacerbate muscle weakness. - Optic neuritis. Quinine may exacerbate active optic neuritis .

Paraphilia Synonyms and keywords: Fetishism, Voyeurism, Zoophilia, Pedophilia, Sexual perversion, Zoophilism, Abnormal sexual activity # Overview Paraphilias are characterized by severe deviant sexual desire or urge resulting in actions that may cause significant impairment in functioning as well as distress (for oneself and/or others). Paraphilic behavior may occur intermittently or may persist for the entire life. To begin with, paraphilia occurs in the form of fantasy, and the paraphilic behavior manifests later in life. Mostly the individuals with this condition do not seek treatment themselves due to the pleasure they obtain from it and in some cases, the associated stigma. Paraphilias are not illegal but the resulting behaviors are. Timely treatment is important to prevent sexual offenses like pedophilia or serial rapes. Patients may have more than one type of paraphilia and therefore, it is essential to evaluate them thoroughly to provide optimal management. # Historical Perspective - The term 'Paraphilia' is Greek in origin and is derived from the words-'Para'(deviation) and 'philia'(attraction). - From biblical times, human societies across the world, have placed restrictions on many types of sexual behaviors. The level of acceptability is based on cultural variations across the globe. - There is controversy in what should be called sexual deviation, mainly based on various factors like the degree of consent, age of the involved individuals, degree of distress caused, location of sexual behavior, degree of unacceptable by others, etc. - The term 'Sadism' originated from Marquis de Sade (1740-1814). He was placed in a lunatic asylum multiple times and ultimately, died there. His mental instability is considered to have resulted in this pattern of sexual behavior. - The term 'Masochism' came from Baron Leopold von Sacher Masoch (1835-1895), who was of European origin. - With the publication of Psychopathia Sexualis at the end of the nineteenth century, sexual deviance was considered a medical condition. Psychopathia Sexualis was written by a German psychiatrist Krafft-Ebing, who described the sexual murders in this publication. # Classification - Earlier the non-reproductive sexual behaviors were considered pathological and criminalized. However, over years the boundaries of pathology have been confined to the absence of sexual consent. - The inclusion of the pathological classification of paraphilias in the DSM and ICD has been criticized for a long time. It is based on the thin line of difference between something that is a normal variation or just unusual, and something that is pathological. - According to DSM-III, a patient could have more than one paraphilias but the extent of the multiplicity was not described until later editions. - Till DSM-IV-TR, the diagnostic category of paraphilia was scrutinized for logic, clarity, and consistency. - DSM-IV-TR included paraphilias in the chapter ‘Sexual and Gender Identity Disorders’. - There were proposals to remove paraphilias as a diagnostic category from DSM-5. Some considered the concept of paraphilic disorder as more ideological than scientific. - Despite the ongoing controversies, in DSM-5, the paraphilias have been assigned a separate chapter and are termed Paraphilic disorders. - According to DSM-5, paraphilia as such does not require psychiatric intervention. Paraphilia causing harm to others or severe distress to oneself, is termed paraphilic disorder and needs treatment. - It has been found that DSM-5 diagnostic criteria for paraphilias can increase the false-positive rates by diagnosing without assessing the underlying motivation (may not necessarily be paraphilic sexual arousal). As a result, attaining this diagnosis can produce many legal consequences. - ICD-10 does not comprise a clear-cut definition of paraphilia. It simply refers to paraphilia as a disorder of sexual preference. # Pathophysiology ## Monoamine Hypothesis - Norepinephrine, serotonin, and dopamine are the monoamines involved in the physiology of sexual behavior. - Side effects of certain medications like antidepressants and neuroleptics show that the alteration of monoamine levels can adversely affect sexuality. - Monoamines modulate impulsivity, anxiety, depression, and antisocial behavior. Dysregulation of the neurotransmitters may also produce these conditions in patients with paraphilic disorders. - The medications that act by increasing the serotonergic function have been found to suppress the paraphilic behavior. This further supports the monoamine hypothesis. ## Role of Testosterone Sex-steroid genetics influences both antisocial traits, and sexual behavior. The relationship between testosterone and paraphilia is further evident by the positive response seen in these patients with antiandrogen therapy. # Differential Diagnosis It is important to differentiate paraphilias from others like - Impulse disorder not otherwise specified (NOS) - Bipolar affective disorder - Cyclothymic disorder - Substance-induced anxiety disorder - Substance intoxication (like cocaine, or alcohol) - Dissociative disorder - Delusional disorder (erotomania) - Gender identity disorder - Obsessive-compulsive disorder - Cognitive disorders like dementia - Delirium - Parkinson’s disease - Other neurological disorders # Epidemiology and Demographics - The exact prevalence of Paraphilic Disorders is difficult to estimate. - Only a few patients seek treatment and most of the data is obtained from the paraphilic cases caught up in the legal system. ## Age - Although discrepancies in studies exist, on average no specific age group has been predisposed to develop Paraphilia. - Literature has revealed that paraphilias mostly begin in childhood and are manifested later in adolescence. ## Gender - Paraphilic behavior is seen mostly in men. However, there are studies that show no prominent gender-differences. ## Race - Limited studies have been done about racial predilection. - Most studies present mixed results and it can be concluded that no specific race is predisposed to develop paraphilia. # Risk Factors - Noxious child-rearing experiences, non-sexual and sexual both - Childhood emotional abuse - Childhood sexual abuse # Natural History, Complications, and Prognosis - Patients with paraphilias have high chances of relapse. - After 15 years, pedophiles attracted to boys are likely to commit the crime again (35%) as compared to those attracted to girls (16%). - Good prognostic factors are Early treatment Individuals with good ego strength and high motivation for treatment Patients with normal adult sexual experiences - Early treatment - Individuals with good ego strength and high motivation for treatment - Patients with normal adult sexual experiences - Poor prognostic factors are Coexisting mental disorders Early-onset of paraphilic behaviors Lack of remorse for their behaviors Substance misuse Pedophilia with a sexual interest in boys - Coexisting mental disorders - Early-onset of paraphilic behaviors - Lack of remorse for their behaviors - Substance misuse - Pedophilia with a sexual interest in boys - The risk of recurrence depends on Static risk factors (history of sexual abuse) - The factors that do not change during treatment Dynamic risk factors (impulsivity, hypersexuality, or personality disorders) - These can be addressed during psychotherapy - Static risk factors (history of sexual abuse) - The factors that do not change during treatment - Dynamic risk factors (impulsivity, hypersexuality, or personality disorders) - These can be addressed during psychotherapy # Comorbidities Various comorbid conditions exist with paraphilias like - Major Depressive Disorder - Anxiety disorders - Substance abuse - Erotomania - Suicidality - Gender identity disorder - Autism Spectrum Disorder (ASD) - Mental Retardation - Antisocial Personality Disorder - Personality change due to General Medical Condition # Diagnosis ## DSM-5 Diagnostic Criteria - Following conditions have been described in the chapter on Paraphilia - Exhibitionistic Disorder - Fetishistic Disorder - Frotteuristic Disorder - Paedophilic Disorder - Sexual Masochism Disorder - Sexual Sadism Disorder - Voyeuristic Disorder - Transvestic Disorder - Other specified Paraphilic Disorder - Unspecified Paraphilic Disorder ### Voyeuristic Disorder - A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from observing an unsuspected naked person. - B. Action has been taken on the urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies. - C. The individual is at least 18 years old. Specify if: - In a controlled environment(the individual is living in an institution etc). - In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment). ### Exhibitionistic Disorder - A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from exposure of one's genitals to an unsuspected person. - B. Action has been taken on these urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies. Specify whether: - Sexually aroused by exposing genitals to the prepubertal children. - Sexually aroused by exposing genitals to physically mature individuals. - Sexually aroused by exposing genitals to the prepubertal children as well as physically mature individuals. Specify if: - In a controlled environment(the individual is living in an institution etc). - In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment). ### Frotteuristic Disorder - A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from touching or rubbing against a non-consenting person, as manifested by fantasies, or behavior. - B. Action has been taken on these urges with a non-consenting person, or significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies. Specify if: - In a controlled environment(the individual is living in an institution etc). - In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment). ### Sexual Masochism Disorder - A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from being beaten, bound, humiliated, or made to suffer; is manifested in the form of fantasies, urges, or behaviors. - B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies. Specify if: With asphyxiophilia: If the individual experiences sexual arousal due to restriction of breathing. Specify if: - In a controlled environment(the individual is living in an institution etc). - In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment). ### Sexual Sadism Disorder - A. Over a minimum period of six months, the existence of recurrent and intense sexual arousal from the psychological or physical suffering of another person; is manifested in the form of urges, fantasies, or behaviors. - B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies. Specify if: - In a controlled environment(the individual is living in an institution etc). - In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment). ### Pedophilic Disorder - A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior involving sexual activity with a child or many children of age 13 or younger. - B. Significant distress/ interpersonal difficulty is caused by these sexual urges or fantasies, or the individual has acted on these sexual urges. - C. The individual is at least 16 years old and a minimum of 5 years older than the child. Specify whether: - Exclusive type (attracted to children only). - Non-exclusive type. Specify if: - Sexually attracted to males only. - Sexually attracted to females only. - Sexually attracted to both. Specify if: - Limited to incest. ### Fetishistic Disorder - A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior from the use of non-living objects, or a focus on non-genital body part/parts. - B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies, or behavior. - C. The fetish objects are not limited to clothing or objects designed for tactile genital stimulation. Specify if: - Body part/parts. - Non-living object/objects. - Other. Specify if: - In a controlled environment(the individual is living in an institution etc). - In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment). ### Transvestic Disorder - A. Over a minimum period of six months, the existence of recurrent and intense sexually arousing fantasies, urges, or behavior from cross-dressing. - B. Significant distress/ socio-occupational functioning impairment is caused by these sexual urges or fantasies, or behavior. Specify if: - With fetishism. - With autogynephilia - Sexual arousal by thoughts or images of self as a female. Specify if: - In a controlled environment(the individual is living in an institution etc). - In full remission (individual has not acted on these urges and has not resulted in distress over the last 5 years, while in an uncontrolled environment). ### Other Specified Paraphilic Disorder - Significant distress/ socio-occupational functioning impairment is caused by the symptoms characteristic of a paraphilic disorder but does not completely fulfill the criteria of any of the categories in the Paraphilic Disorders. ### Unspecified Paraphilic Disorder - Used in the conditions where the clinician chooses not to mention the reason that the criteria are not fulfilled for a specific paraphilic disorder. # Treatment - A treatment plan comprising of psychotherapy, and/or pharmacotherapy is usually needed to suppress the paraphiliac fantasies and behaviors. - The treatment depends on the intensity and frequency of paraphiliac sexual fantasies as well as the risk of sexual violence. - The very severe conditions may lead to sexual offenses, like rape and it is necessary to manage such patients aggressively with hormonal intervention. - The treatment regime consists of six levels with escalating degrees of medical intervention, based on the severity of the disorder. ## Pharmacotherapy - Three main classes of medications used in paraphilias are antidepressants, hormones, and gonadotrophin-releasing hormone (GnRH) analogs. - Treatment of comorbidities is very important to improve the quality of life. - Treatment with antiandrogens has the drawback that it may increase psychotic symptoms and depression risk. ### Antidepressants - Antidepressants are used to treat paraphilias because of their action on involved neurotransmitters. The mechanism of action is supported by the monoamine hypothesis. - The comorbidities such as obsessive-compulsive spectrum disorders share the dysfunction of similar neurotransmitters. Therefore, antidepressants can treat both the disorders simultaneously. - Antidepressants commonly used are Selective Serotonin Reuptake Inhibitors(SSRI) such as Fluoxetine, Paroxetine, and Escitalopram act on serotonergic (5-HT2) receptors and have become the standard of care. Additionally, SSRIs treat the comorbid conditions like depression, OCD, or anxiety disorders. Tricyclic Antidepressants(TCA) such as Imipramine, Clomipramine, and Desipramine. - Selective Serotonin Reuptake Inhibitors(SSRI) such as Fluoxetine, Paroxetine, and Escitalopram act on serotonergic (5-HT2) receptors and have become the standard of care. Additionally, SSRIs treat the comorbid conditions like depression, OCD, or anxiety disorders. - Tricyclic Antidepressants(TCA) such as Imipramine, Clomipramine, and Desipramine. ### Hormones - Estrogen - Steroid antiandrogens Medroxyprogesterone- It is synthetic progesterone and acts by reducing the testosterone levels. They act by suppressing the hypothalamic-pituitary-gonadal axis, reducing the Luteinizing hormone(LH) release and further compromising the androgen production. Cyproterone acetate is a synthetic steroid, similar in structure to progesterone. It acts as an antiandrogen by binding to androgen receptors and reducing the cellular uptake of testosterone. - Medroxyprogesterone- It is synthetic progesterone and acts by reducing the testosterone levels. They act by suppressing the hypothalamic-pituitary-gonadal axis, reducing the Luteinizing hormone(LH) release and further compromising the androgen production. - Cyproterone acetate is a synthetic steroid, similar in structure to progesterone. It acts as an antiandrogen by binding to androgen receptors and reducing the cellular uptake of testosterone. ### Gonadotrophin Releasing Hormone Analogue (GnRH Analogue) - They reduce the circulating testosterone, in turn, reducing aggression and hypersexuality. ## Psychotherapy - In subjects that are not at high risk of victimization, cognitive behavioral therapy(CBT) is the first-line treatment. - CBT addresses the cognitive distortions, along with empathy training, relapse prevention, sexual impulse control training, and biofeedback. ## Combined Pharmacotherapy and Psychotherapy - The combination therapy has a better response compared to either therapy used alone. Very few evidence-based treatment options are available for a complex condition like paraphilia, and further research is warranted to effectively prevent the relapses.

Emergency medical technician-basic Emergency Medical Technician-Basic (EMT-B) is the entry level of prehospital emergency medical provider in the United States. EMT-Bs are employed in a variety of industries. EMT-Bs are not trained to provide definitive medical care, but instead focus on rapid in-field treatment and transport to higher medical providers. EMT-Bs work in conjunction with other medical providers such as paramedics, nurses, and physicians, as well as with other EMT-Bs. When operating in the prehospital environment, their actions are governed by protocols and procedures set by their system's physician medical director. # Education and training EMT-B training is regulated at both the state and federal level. At the federal level, the National Highway Traffic Safety Administration (NHTSA) has developed a minimum content and hour requirement that all states must at least meet. This requirement is known as the National Standard Curriculum. Under the NHTSA curriculum, students receive 110 hours of lecture and lab time covering anatomy, physiology, legal aspects of medical care, assessment, and treatment of medical, trauma, behavioral, and obstetric emergencies. In addition to class time, the NHTSA recommends clinical rotations on board ambulances and in emergency departments, but these experiences are less regulated due to local variations. Utilizing NHTSA guidelines, the National Registry of Emergency Medical Technicians have developed and implemented a certification tests for the NHTSA EMT levels, including the EMT-Basic level. As of 2006, 39 US states utilize the NREMT EMT-Basic exam as part of the state licensing and/or certification procedure. Once certified, EMT-Basics are required to obtain continuing education hours to recertify at the end of the certification period. Recertification requirements and conditions vary from state to state. Continuing education courses can cover a variety of topics, provided that they cover material relevant to the work performed by EMT-Basics. This can include background material, such as college courses covering anatomy, physiology, or psychology, to more applied courses that are either standardized, such as a Prehosptial Trauma Life Support (PHTLS), or tailored to the needs of an individual EMS system or region. # Scope of practice The scope of medical practice for EMT-Bs is regulated by state law, and can very significantly both among states as well as inside states. In general, EMT-Bs provide what is considered basic life support and are limited to essentially non-invasive procedures. Besides employing basic medical assessment skills, typical procedures provided by EMT-Bs include CPR, Automated external defibrillation, mechanical ventilation using a bag-valve mask, placement of air way adjuncts such as oropharyngeal and nasopharyngeal airways, splinting (including spinal immobilization and traction splints), and suctioning. In addition, EMT-Bs are trained to assist patients with administration of preprescribed nitroglycerin, Metered-dose inhaler such as albuterol, and epinephrine auto injectors such as the EpiPen. Individually, each state is free to add or subtract to their EMT-Bs scope of practice as they please. For example, EMT-Bs working in California (known as EMT-Is (one)) are not allowed to administer activated charcoal, an NHTSA approved intervention, under a standard certification. Local EMS systems (i.e. counties in California) can apply to the state to implement an extended scope of practice for EMT-Basics that includes activated charcoal as well as other pharmaceutical interventions not normally allowed to be administered by EMT-Basics. Oregon, though, allows EMT-Bs to utilize a type of advanced airway known as a pharyngeal esophageal airway device. An example of such a device is the Combitube. # Employment of EMT-Bs

Arachnodactyly Arachnodactyly, also known as spider fingers refers to abnormally long and slender fingers. Toes and feet are also usually affected. # Differential Diagnosis of Diseases Associated with Arachnodactyly In alphabetical order: - Achard Syndrome - Homocystinuria - Lutembacher's Syndrome - Marfan's Syndrome - MASS Syndrome (heritable disorder involving Mitral valve, Aorta, Skeleton, Skin) - Spondylocostal Dysostosis - Van der Hoeve's Syndrome # Pathological Findings Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology - Arachnodactyly: Gross, natural color, long fingers - Arachnodactyly: Gross, both feet 50 yo f with aortic dissection and mitral valve prolapse extremities suggest Marfan's syndrome but no cystic aortic lesions

ST6GAL1 Beta-galactoside alpha-2,6-sialyltransferase 1 is an enzyme that in humans is encoded by the ST6GAL1 gene. The protein encoded by this gene is a type II membrane protein that catalyzes the transfer of sialic acid from CMP-sialic acid to galactose-containing substrates. The encoded protein, which is normally found in the Golgi but which can be proteolytically processed to a soluble form, is involved in the generation of the cell-surface carbohydrate determinants and differentiation antigens HB-6, CDw75, and CD76. This protein is a member of glycosyltransferase family 29. Three transcript variants encoding two different isoforms have been found for this gene. Transcripts of ST6GAL1 are found in mouse high endothelial cells of mesenteric lymph node and Peyer's patches, and it could be involved in the B cell homing to Peyer's patches.

Alkaptonuria (patient information) For the WikiDoc page for this topic, click here # Overview Alkaptonuria is a rare condition in which a person's urine turns a dark brownish-black color when exposed to air. # What are the symptoms of Alkaptonuria? Urine in an infant's diaper may darken and can turn almost black after several hours. However, many persons with this condition may not know they have it until mid-adulthood (around age 40), when joint and other problems occur. Symptoms may include: - Arthritis (especially of the spine) that gets worse over time - Darkening of the ear - Dark spots on the white of the eye (sclera) and cornea # What causes Alkaptonuria? A defect in the HGD gene causes alkaptonuria. The gene defect makes the body unable to properly break down certain amino acids (tyrosine and phenylalanine). As a result, a substance called homogentisic acid builds up in the skin and other body tissues. The acid leaves the body through the urine. The urine turns brownish-black when it mixes with air. Alkaptonuria is inherited, which means it is passed down from parents to their children. To get this disease, each of your parents must pass you a copy of the faulty HGD gene. # When to seek urgent medical care? Call your health care provider if you notice that your own urine or your child's urine becomes dark brown or black when it is exposed to air. # Diagnosis A urine test (urinalysis) is done to test for alkaptonuria. If ferric chloride is added to the urine, it will turn the urine a black color in patients with this condition. # Treatment options Some patients benefit from high-dose vitamin C. This has been shown to decrease the build-up of brown pigment in the cartilage and may slow the development of arthritis. # Diseases with similar symptoms - Ankylosing Spondylitis - Acute intermittent porphyria # Where to find medical care for Alkaptonuria? Directions to Hospitals Treating Alkaptonuria # Prevention of Alkaptonuria There is no know prevention of alkaptonuria. # What to expect (Outlook/Prognosis)? The outcome for people affected with alkaptonuria is generally expected to be good. Some possible complications include people with this condition also can get arthritis in adulthood. The build-up of homogentisic acid in the cartilage causes arthritis in about 50% of older adults with alkaptonuria. - Homogentisic acid also can build up on the heart valves, especially the mitral valve. This can sometimes lead to the need for valve replacement. - Coronary artery disease may develop earlier in people with alkaptonuria. - Kidney stones and prostate stones may be more common in people with alkaptonuria. # Possible complications People with this condition also can get arthritis in adulthood. The build-up of homogentisic acid in the cartilage causes arthritis in about 50% of older adults with alkaptonuria. - Homogentisic acid also can build up on the heart valves, especially the mitral valve. This can sometimes lead to the need for valve replacement. - Coronary artery disease may develop earlier in people with alkaptonuria. - Kidney stones and prostate stones may be more common in people with alkaptonuria. # Sources Medline Plus: Alkaptonuria

depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Background This report presents CDC's recommendations for case definitions for Acute Idiopathic Pulmonary Hemorrhage (AIPH) among infants and CDC's plan for retrospective surveillance for AIPH among infants, including a study to evaluate the feasibility of using International Classification of Diseases (ICD) (1) codes for surveillance for AIPH. In 1994 and 1997, CDC reported clusters of acute pulmonary hemorrhage (APH) among infants (2,3) in Cleveland, Ohio. During 1992, a similar cluster occurred in the Chicago area (4). In Cleveland, risk factors for illness included male sex; lack of breast-feeding; residence in households with smokers; residence in homes where water damage had occurred during the previous 6 months; and residence in homes with increased quantities of fungi, including Stachybotrys atra. Reviews by CDC staff and external consultants of these investigations identified shortcomings in the conduct of the studies (5). These panels concluded that the investigations did not prove an association between APH among infants and exposure to molds, specifically S. chartarum (atra). These reviewers recommended that CDC, pediatric pulmonologists, and state and local public health officials collaborate to - develop a standard surveillance case definition; - develop standard protocols for data collection and environmental assessment; - implement surveillance for AIPH; - investigate cases of AIPH among infants, particularly when clusters are identified, considering associations with multiple possible etiologies; and - enhance sampling and laboratory analytic methods to improve assessment of environmental exposures to molds and fungi (5). In response to the reviewers' recommendations, CDC staff developed a plan to conduct surveillance for AIPH, investigate clusters of cases, and conduct studies. In formulating this response, CDC convened three meetings to establish a case definition and classification scheme for public health surveillance for AIPH, recommend a standard home environmental investigation protocol, and outline a plan for surveillance and investigation of AIPH among infants. As a consequence of these meetings, CDC has determined that a series of surveillance activities should be initiated to direct future efforts. In addition to providing an overview of the results of the three meetings, this report describes surveillance activities and how results from those activities can guide efforts to investigate the burden and etiology of AIPH among infants. AIPH among infants is a diagnosis of exclusion. Certain syndromes (Box 1) and other disease states can occur with pulmonary hemorrhage. Thus, differential diagnoses and neonatal medical problems that can cause pulmonary hemorrhage should be ruled out. # Meeting Panelists and Goals Three meetings of panelists were convened to advise CDC staff regarding investigation of AIPH among infants. The Case Definition Panel included three pediatric pulmonologists, one pediatric intensive care specialist, one pediatric pathologist, two epidemiologists, and one environmental epidemiologist. The purpose of this panel was to recommend a case definition for use in public health surveillance for AIPH to facilitate case finding. Case finding will facilitate documentation of the burden of the condition and identification of possible etiologic agents or risk factors. The Surveillance Implementation Panel included one pediatrician, one pediatric pulmonologist, one forensic pathologist, three epidemiologists (including one state epidemiologist), and four environmental epidemiologists (including one state epidemiologist and one toxicologist). Its purpose was to recommend a standard approach for public health surveillance for AIPH. The Home/Indoor Environment and Laboratory Investigation Panel included two mycologists, one biochemist, two microbiologists, two industrial hygienists, two toxicologists, and one environmental epidemiologist. Its purpose was to recommend standard approaches and protocols for environmental data collection, laboratory analysis, and data interpretation during public health surveillance for AIPH. For each of the three areas, group discussion led by a moderator was based on prepared questions. Participants produced written summaries, which form the basis of the recommendations provided in this report. # BOX 1. Pulmonary hemorrhage terminology The term used for the cluster of cases reported in Cleveland- was pediatric idiopathic pulmonary hemorrhage and hemosiderosis. The term pulmonary hemorrhage has been used to describe situations with identifiable causes of bleeding. † Idiopathic pulmonary hemosiderosis (IPH) § or primary hemosiderosis ¶ has been used to denote presumably idiopathic bleeds or the accumulation of iron as hemosiderin. § The terms pulmonary hemorrhage and primary hemosiderosis are often used interchangeably. The new International Classification of Diseases, Tenth Revision (ICD-10) mortality coding system † † has no code for idiopathic pulmonary hemosiderosis. The CDC definition of a case of AIPH in an infant uses the term pulmonary hemosid-erosis as a pathological finding to denote the possible occurrence of pulmonary hemorrhage, and not to describe a clinical syndrome. The term pulmonary hemorrhage encompasses multiple clinical syndromes, including - diffuse pulmonary hemorrhage; § § - pulmonary hemorrhage of the newborn (ICD-9: 770.3; ICD-10: P26) ¶ ¶ or hemoptysis; - cough with hemorrhage; - pulmonary hemorrhage not otherwise specified 786.3; ICD-10 R04, R04.2); and - idiopathic pulmonary hemosiderosis (ICD-9: 516.1, no ICD-10 code). # Case Definition Case Classification and Severity Criteria AIPH is the sudden onset of pulmonary hemorrhage in a previously healthy infant in whom differential diagnoses and neonatal medical problems that might cause pulmonary hemorrhage have been ruled out. Pulmonary hemorrhage can appear as hemoptysis or blood in the nose or airway with no evidence of upper respiratory or gastrointestinal bleeding. Patients have acute, severe respiratory distress or failure, requiring mechanical ventilation and chest radiograph (CXR), and usually demonstrate bilateral infiltrates. AIPH among infants and sudden infant death syndrome (SIDS) potentially share similar risk factors (e.g., age group and maternal cigarette smoking). Also, in certain cases, SIDS is associated with pulmonary hemorrhage found at autopsy (6,7). Thus, factors that are known risk factors for SIDS should be identified when evaluating an infant possibly having AIPH. Potential information sources for case-identification and casestatus classification during an investigation of pulmonary hemorrhage are provided (Table 1). # Clinically Confirmed Cases of AIPH Among Infants Criteria for a confirmed case include pulmonary hemorrhage in a previously healthy infant aged 32 weeks, with no history of neonatal medical problems that might cause pulmonary hemorrhage, and whose condition meets all of the following three criteria: - Abrupt or sudden onset of overt bleeding or obvious evidence of blood in the airway, including -epistaxis, hemoptysis, or frank blood in the airway below the larynx at visualization, not caused by any medical procedure (e.g., laryngoscopy or intubation); or -identification of hemosiderin-laden macrophages (>20% of pulmonary macrophages containing hemosiderin on bronchoalveolar lavage or biopsy specimen). A source of bleeding from the nose and oropharynx should be ruled out at the time of admission. - Severe-appearing illness leading to acute respiratory distress or respiratory failure, resulting in hospitalization in a pediatric intensive care unit (PICU) or neonatal intensive care unit (NICU) with intubation and mechanical ventilation. - Diffuse unilateral or bilateral pulmonary infiltrates visible on CXR or computerized tomography (CT) of the chest. CXR or chest CT findings should be documented within 48 hours of examination of the infant. A previously healthy infant should - have been discharged from the hospital after birth with an uneventful course before the occurrence of bronchoalveolar hemorrhage; - never have been previously intubated, nor required respiratory support with oxygen; - not have evidence of physical abuse; - not have any abnormality identified on admission or follow-up bronchoscopy that would explain the bleeding; and - not have neonatal medical problems that can cause pulmonary hemorrhage. CDC will adhere closely to this case definition, requiring that all the criteria be met for a confirmed case. The definition for a clinically confirmed case excludes pulmonary hemorrhage among older children and infants with restricted access to a PICU. Because no criteria exist for postmortem examinations, this definition excludes infants who die before hospital and PICU admission, whose illness might have met the case definition. However, the definitions for probable and suspect cases (see the following) will capture the majority of these cases and allow identification of illness among infants who die before examination by a physician. # Probable Cases of AIPH Among Infants Criteria for a probable case include a previously healthy infant aged 32 weeks, - who has a sudden onset of bleeding from the airway, with or without respiratory distress, with or without intubation, and with or without pulmonary infiltrates on CXR or chest CT; or - who died and had evidence of bleeding from the airway found on autopsy or postmortem; had been in respiratory distress; would or should have been intubated in the opinion of a clinician; and would have had infiltrates on CXR or chest CT. # Suspected Cases of AIPH Among Infants Criteria for a suspected case include a previously healthy infant, - who died and had evidence of bleeding from the airway found on autopsy or postmortem or who - either did not have chest imaging studies or had imaging studies that indicated no pulmonary infiltrates. Respiratory distress or intubation is not required for a suspected case. # Severity Classification Scheme for AIPH Among Infants Because of the potential for variation in symptoms among infants for each of the criteria, different case combinations might be related to the timing or duration of symptoms, disease severity, pathologic processes, or etiologic agents associated with AIPH among infants. A discussion of the proposed case-classification categories for AIPH among infants is provided (Tables 2 and 3). # Discussion - Bleeding might begin in a localized region of one lung with dispersion of blood to other areas of the lung through the airways - Initial chest radiograph (CXR) might indicate unilateral infiltrates, but following dispersion indicates diffuse infiltrates - Infants with unilateral infiltrates are considered confirmed for AIPH, but their characteristics might be different from infants with diffuse infiltrates - Not considered confirmed because identification depends on lavage or biopsy finding of hemosiderin-laden macrophages and not on active bleeding or recovering blood from below the larynx - Work of breathing might vary for infants with a similar pathology (e.g., resulting from different body temperature, serum glucose levels, and duration of respiratory distress) - Infants who do not need intubation would not have acute bleeding directly identified from below the glottis - Upon initial examination, infants' circumstances might vary; information should be collected to identify these circumstances as best as possible during data abstraction so that the categories can be expanded if needed during data analysis - The circumstances might be that 1) the attending physician intended to intubate an infant who died; 2) the clinician who reviewed the death of an infant with postmortem findings consistent with pulmonary hemorrhage secondary to clinical respiratory failure thought the infant should have been intubated; 3) the infant died before arrival at the hospital and therefore was not intubated nor received thoracic imaging studies - Age-specific normochromic, normocytic, or microangiopathic anemia might indicate different pathophysiologic processes and in conjunction with appropriate clinical signs and symptoms might be supportive of a diagnosis of AIPH - Rankings of 1-5 represent categories with decreasing levels of certainty; 1 = highly probable, and 5 = least probable. The letter designations a, b, and c represent approximately equivalent levels within each category (see also Table 2). # MMWR March 12, 2004 A summary of clinical features of AIPH among infants (Table 4) (Box 2) and neonatal medical problems and differential diagnoses that should be ruled out before classifying a case as AIPH among infants (Box 3) are included. Other differential diagnoses associated with pulmonary hemorrhage are listed (Table 5). # Feasibility Study To Determine the Concordance of ICD Codes for Pulmonary Hemorrhage with the CDC Case Definition Prospective nationwide surveillance for cases of AIPH among infants is difficult to justify on the basis of the available epidemiologic data. In addition to the limitations reported for the Cleveland study (5), no risk factors were conclusively linked to disease in the Chicago investigation ( 4), and only one other cluster (in Detroit) was reported during 1992-1996 (7). CDC will retrospectively review cases of pulmonary hemorrhage to determine the public health impact of AIPH among infants and to generate hypotheses regarding the importance of risk factors possibly associated with AIPH among infants. If that review indicates that AIPH among infants is a separate clinical entity and that these cases have occurred in clusters, or that an increase in incidence or mortality is associated with these cases, CDC will initiate prospective surveillance and case ascertainment to identify cases for epidemiologic studies designed to confirm or disprove associations between pulmonary hemorrhage host factors, environmental factors, and biologic agents, including such molds as S. chartarum (5). # Retrospective Review by Using Existing Data Sources The ability to use existing data sources should substantially facilitate both determining the public health impact of AIPH among infants. However, the reliable data regarding mortality from pulmonary hemorrhage is only available at the national level. CDC conducted a preliminary evaluation of ICD codes for surveillance of pulmonary hemorrhage among infants to determine whether existing data sources can be used to estimate the magnitude of the problem of AIPH among infants. CDC examined data from the National Hospital Discharge Survey (NHDS) and National Mortality Data. Possible cases of AIPH among infants were identified by using ICD-9 codes 770. 3, 784.7, 784.8, 786.3, and 516.1 (Table 6). Infants identified by ICD-9 codes 770.3 and 786.3 differ from the cases reported in Cleveland. In the national datasets, the majority of cases of pulmonary hemorrhage had diagnoses such as prematurity or immaturity and death occurring within the first 7 days of life. The Cleveland cases occurred among stable, healthy, mature infants who had been discharged from the hospital to their homes after birth and subsequently experienced pulmonary hemorrhage (8)(9)(10). Thus, the estimates of deaths and hospital admissions for cases of pulmonary hemorrhage using ICD codes 770.3 and 786.3 does not distinctly identify infants with AIPH as defined by CDC. In addition, these national datasets do not determine if infants had identifiable etiologies or complications before their discharge from the hospital or their death. Because the estimated number of hospitalized cases with a primary diagnosis of pulmonary hemorrhage was less than the number of deaths, these national datasets might not be reliable for surveillance for infantile pulmonary hemorrhage. These analyses might be better performed by using state-based data. A retrospective review for AIPH among infants will be performed in metropolitan cities in those states with the highest death rates and with >100 deaths associated with pulmonary hemorrhage among infants, on the basis of relevant ICD-9 and ICD-10 codes used from 1979 to the most recent available data. By focusing on PICUs and NICUs with substantial numbers of deaths, cases from innercity catchment areas, where the incidence of AIPH among infants is suspected to be higher, will be captured. Potential cases will be identified by using standardized methods of case ascertainment and data collection from hospital discharge and mortality data sources, based on ICD codes. Potential cases will be compared with the recommended case definition by reviewing medical records related to all cases of pulmonary hemorrhage observed since 1979 among children aged <2 years. This retrospective review of AIPH among infants will - determine whether AIPH among infants is a distinct clinical entity within existing ICD-9/ICD-10 diagnostic codes for pulmonary hemorrhage; - describe the epidemiology of pulmonary hemorrhage; - identify trends in the frequency of cases and the geographic distribution and clustering of cases; - estimate the public health impact of AIPH among infants; - identify groups at high risk for AIPH among infants; and - determine the need for prospective surveillance as a source of cases for a case-control study. The data will be reviewed to determine how these cases, including the apparent case clusters of AIPH among infants in Cleveland and Chicago, have been coded on hospital discharge abstracts, and how deaths attributed to the syndrome have been characterized on death certificates. Both Ohio and Illinois meet the criteria of >100 deaths from pulmonary hemorrhage. In Cleveland and Chicago, this review also will # TABLE 4. Clinical features of acute idiopathic pulmonary hemorrhage (AIPH) among infants Finding No evidence of cow milk protein allergy or associated respiratory, heart, kidney, or pancreatic disease- Abrupt cessation of crying or unusual crying or irritability hours to days before the initial recognition of blood in the airway † Not observed § Decreased muscle tone and dusky pallor minutes to hours before progressing to sudden onset of hypoxemic respiratory distress or failure ¶ Hours to days before onset of respiratory failure Accompanies or immediately precedes respiratory failure † † Acute and appears to be idiopathic § § Characterized by tachypnea, grunting, and chest retractions ¶ ¶ Diffusely diminished breath sounds without the presence of rales or rhonchi* Often requires intubation and mechanical ventilation; intubation when required is for 2-7 days † † † Often demonstrates bilateral pulmonary infiltrates within the first 24 hours § § § Typically, alveolar infiltrates begin to clear within the first 24-48 hours ¶ ¶ ¶ Atraumatic intubation; bronchoscopy including inspection of upper airway Typically, no source from the lung or gastrointestinal tract; presumed to be from diffuse alveolar capillary injury † † † † Typically, found in bronchoalveolar lavage fluid; might not be present in an infant experiencing an acute, initial pulmonary bleed § § § § Indicates evidence of bleeding into the lungs; finding >20% of total pulmonary macrophages containing hemosiderin can be consistent with pulmonary hemorrhage that occurred >48 hours before examination ¶ ¶ ¶ ¶ First 48 hours, fragmented or damaged red blood cells, hemoglobinuria; microangiopathic anemia might be indicative of a hemolytic process; normochromic normocytic might be consistent with acute, abrupt blood loss* Serum negative for antiglomerular basement membrane antibody, anticytoplasmic neutrophilic antibody, complement titers, serum immune complexes, and antinuclear antibody † † † † † None; spontaneous recovery with or without supportive care indicates these pathophysiologic processes are not the cause of bleeding # BOX 2. Clinical descriptions of pulmonary hemorrhage In early texts, pulmonary hemorrhage was not commonly described in children, although it was noted to occur.- Blood found in the airways or alveoli of humans can result from different anatomic sites. Specific sites can include alveoli, large or small conducting airways, or the nasopharynx and gastrointestinal tract with pulmonary aspiration. Regardless of the origin of blood entering the lung, substantial amounts of blood lead to impaired gas exchange, altered pulmonary mechanics, and respiratory distress. Different pathophysiologic processes are associated with pulmonary hemorrhage. These can be divided into - conditions where bleeding occurs at sites of normal tissue with mechanical disruption causing a loss of vascular integrity (e.g., intentional suffocation and mitral valve disease); - vascular inflammation, whereby the inflammatory process causes a loss of vascular integrity (e.g., vasculitis secondary to such conditions as collagen vascular diseases); - vascular malformations, whereby a combination of altered vascular integrity and physical influences (e.g., Laplace's law † ) lead to disruption of the blood vessel; and - coagulopathies, which usually also require additional physical disruption of the blood vessel through greater than normal transpulmonary vascular pressures. The manifestations of pulmonary hemorrhage can be classified into different syndromes. Diffuse pulmonary hemorrhage is usually diagnosed by bronchoscopy, either by virtue of grossly bloody lavage fluid or by the presence of hemosiderin-laden macrophages in bronchoalveolar lavage. In biopsy and autopsy tissue, the diagnosis is made on the basis of the presence of recent blood and hemosiderin in the alveolar spaces or the interstitium. § In the immunocompromised host, intra-alveolar bleeding can result from thrombocytopenia often associated with other factors. Diffuse pulmonary hemorrhage (DPH) can either be secondary to other disease states, associated with other organ dysfunction, or be isolated. Isolated causes of DPH include lung immaturity, cow milk hypersensitivity, pulmonary capillary hemangiomatosis, and idiopathic causes. ¶ Pulmonary hemorrhage of the newborn (ICD-9: 770.3; ICD-10: P26) is manifested by focal hemorrhage into airspaces or the interstitium in the lungs of infants with hyaline membrane disease, bronchopulmonary dysplasia, and other neonatal pulmonary disorders. These infants are most often male, preterm, small for gestational age, and have a history of perinatal stress. † † The etiology and pathogenesis of the disorder has not been elucidated. Hemoptysis, cough with hemorrhage, pulmonary hemorrhage not otherwise specified (ICD-9: 786.3; ICD-10 R04, R04.2) is an acute manifestation of bleeding from the airway. This ICD category captures all the nonneonatal (and certain neonatal) diagnoses of pulmonary hemorrhage. Children with pulmonary hemorrhage might not appear to have hemoptysis if they swallow their sputum. Consensus is lacking on the meaning of the term idiopathic pulmonary hemosiderosis (ICD-9: 516.1, no ICD-10 code). One pathology text states that the term denotes a separate clinical entity of which diffuse pulmonary hemorrhage is the major manifestation. § § A later edition of the same text ¶ ¶ notes that the presence of hemosiderin in lung macrophages indicates degradation products of hemoglobin. Hemosiderin is thus a pathologic state indicative of bleeding of any type into the lungs* secondary to the processing of hemoglobin in the red blood cells in the airway by alveolar macrophages. † † † Adults with active alveolar hemorrhage have high hemosiderin scores in bronchoalveolar lavage fluid, § § § but hemosiderin-containing macrophages have limited differential diagnostic value. ¶ ¶ ¶ In one clinical text, the term means diffuse recurrent intrapulmonary hemorrhage that is not secondary to bleeding from trauma, bleeding from the airways, tumors, or left ventricular failure. Another author † † † † describes variants of primary and secondary pulmonary hemosiderosis. On review of National Hospital Discharge Survey data for 1979-1996 and national mortality data for 1979-1998 for ICD-9 code 516.1 for infants, no instances were found in either dataset where ICD-9 code 516.1 was the primary listed diagnosis. However, in 207 cases, this code was the other listed diagnosis. This indicates that idiopathic pulmonary hemorrhage is usually an accompanying diagnosis to other diagnoses that result in hospitalization or death among infants. If performed, environmental assessment of the home to gather pertinent risk-assessment data should use standard protocols designed by trained environmental health professionals. At a minimum, the assessment should involve visual inspection, including checks for dampness, water damage, obvious mold, evidence of pests, and environmental tobacco smoke. Depending on the assessed need for further evaluation and the resources available, additional investigation might include determining moisture content, settled dust sampling, air sampling for different allergens, and biologically active compounds, and other investigations as needed. # Conclusion CDC recommends a definition for a clinically confirmed case of AIPH among infants on the basis of 1) evidence of blood in the airway; 2.) age <1 year; 3) absence of medical conditions related to pulmonary hemorrhage; and 4) severe acute respiratory distress or respiratory failure, requiring admission to a PICU with intubation and mechanical ventilation. CDC recommends that PICUs report cases that meet the CDC case definition to state health departments and to CDC. CDC will retrospectively analyze state-level mortality and hospitalization data based on ICD codes and will retrospec- tively review discharges for pulmonary hemorrhage in selected PICUs. These studies will - distinguish between the clinical findings associated with different symptoms of AIPH among infants; - determine whether ICD codes capture cases that meet the CDC-recommended case definition for AIPH among infants; - determine whether AIPH among infants is a distinct recognizable clinical entity; - determine the proportion of cases ascertained retrospectively through ICD-9 codes that meet the clinical case definition by estimating PPV of ICD-coded data; and - define the magnitude of AIPH among infants and the need for conducting etiologic studies. CDC will review the Cleveland and Chicago case series to determine the degree to which the present case definition applies to them. In addition, CDC will evaluate the present case definition on the basis of data from initial surveillance findings and modify it as appropriate. If these reviews establish that AIPH among infants is a public health problem on the basis of increasing numbers or clusters of cases geographically or temporally, targeted prospective case surveillance will be initiated. If prospective surveillance is initiated, CDC will maintain a database of current cases of AIPH among infants, reported by PICUs that meet the case definition. The database will serve as a source of cases for casecontrol studies to determine etiology. CDC will work with state and local health departments to investigate clusters of AIPH among infants cases. ('tr st-"w r-the) e e

Hydroxymethylglutaryl-CoA synthase In molecular biology, Hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase EC 2.3.3.10 is an enzyme which catalyzes the reaction in which Acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). It is the second reaction in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis. This reaction is over-activated in patients with diabetes mellitus type 1 if left untreated, due to prolonged insulin deficiency and the exhaustion of substrates for gluconeogenesis and the TCA cycle, notably oxaloacetate. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of diabetic ketoacidosis. The 3 substrates of this enzyme are acetyl-CoA, H2O, and acetoacetyl-CoA, whereas its two products are (S)-3-hydroxy-3-methylglutaryl-CoA and CoA. In humans, the protein is encoded by the HMGCS1 gene on chromosome 5. # Classification This enzyme belongs to the family of transferases, specifically those acyltransferases that convert acyl groups into alkyl groups on transfer. # Nomenclature The systematic name of this enzyme class is acetyl-CoA:acetoacetyl-CoA C-acetyltransferase (thioester-hydrolysing, carboxymethyl-forming). Other names in common use include (S)-3-hydroxy-3-methylglutaryl-CoA acetoacetyl-CoA-lyase, (CoA-acetylating), 3-hydroxy-3-methylglutaryl CoA synthetase, 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl coenzyme A synthetase, 3-hydroxy-3-methylglutaryl-CoA synthase, 3-hydroxy-3-methylglutaryl-coenzyme A synthase, beta-hydroxy-beta-methylglutaryl-CoA synthase, HMG-CoA synthase, acetoacetyl coenzyme A transacetase, hydroxymethylglutaryl coenzyme A synthase, and hydroxymethylglutaryl coenzyme A-condensing enzyme. # Mechanism HMG-CoA synthase contains an important catalytic cysteine residue that acts as a nucleophile in the first step of the reaction: the acetylation of the enzyme by acetyl-CoA (its first substrate) to produce an acetyl-enzyme thioester, releasing the reduced coenzyme A. The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA. # Biological role This enzyme participates in 3 metabolic pathways: synthesis and degradation of ketone bodies, valine, leucine and isoleucine degradation, and butanoate metabolism. # Species distribution HMG-CoA synthase occurs in eukaryotes, archaea and certain bacteria. ## Eukaryotes In vertebrates, there are two different isozymes of the enzyme (cytosolic and mitochondrial); in humans the cytosolic form has only 60.6% amino acid identity with the mitochondrial form of the enzyme. HMG-CoA is also found in other eukaryotes such as insects, plants and fungi. ### Cytosolic The cytosolic form is the starting point of the mevalonate pathway, which leads to cholesterol and other sterolic and isoprenoid compounds). ### Mitochondrial The mitochondrial form is responsible for the biosynthesis of ketone bodies. The gene for the mitochondrial form of the enzyme has three sterol regulatory elements in the 5' flanking region. These elements are responsible for decreased transcription of the message responsible for enzyme synthesis when dietary cholesterol is high in animals: the same is observed for 3-hydroxy-3-methylglutaryl-CoA and the low density lipoprotein receptor. ## Bacteria In bacteria, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of Gram-positive pathogens utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in eukaryotes. # Structural studies As of late 2007, 4 structures have been solved for this class of enzymes, with PDB accession codes 1XPK, 1XPL, 1XPM, and 2P8U.

Green sulfur bacteria The green sulfur bacteria are a family of obligately anaerobic photoautotrophic bacteria. Most closely related to the nonetheless distant Bacteroidetes, they are accordingly assigned their own phylum. Green sulfur bacteria are non-motile (except Chloroherpeton thalassium, which may glide) and come in spheres, rods, and spirals. Photosynthesis is achieved using bacteriochlorophyll (BChl) c, d, or e, in addition to BChl a and chlorophyll a, in chlorosomes attached to the membrane. They use sulfide ions, hydrogen or ferrous iron as an electron donor and the process is mediated by the type I reaction centre and Fenna-Matthews-Olson complex. Elemental sulfur deposited outside the cell may be further oxidized. By contrast, the photosynthesis in plants uses water as electron donor and produces oxygen. Chlorobium tepidum has emerged as a model organism for the group, and although only ten genomes have been sequenced, these are quite comprehensive of the family's biodiversity. Their 2-3 Mb genomes encode 1750-2800 genes, 1400-1500 of which are common to all strains. The apparent absence of two-component histidine-kinases and response regulators suggest limited phenotypic plasticity. Their small dependence on organic molecule transporters and transcription factors also indicate that these organisms are adapted to a narrow range of energy-limited conditions, an ecology shared with the simpler cyanobacteria, Prochlorococcus and Synechococcus A species of green sulfur bacteria has been found living near a black smoker off the coast of Mexico at a depth of 2,500 meters beneath the surface of the Pacific Ocean. At this depth, the bacteria, designated GSB1, lives off the dim glow of the thermal vent since no sunlight can penetrate to that depth.

TMEM249 TMEM 249 is a protein that in humans is encoded by the C8orfk29 gene. # Gene # Locus TMEM 249 is located near the end of the long arm of chromosome 8 in humans. # Common aliases TMEM 249 is also known as C8orfk29. # Primary sequence & variants/isoforms The primary sequence found at NCBI and Aceview on NCBI predicts there are five spliceforms, with four closely resembling one another and the fifth missing a large 5' intron region. Softberry reinforces the Aceview data by predicting five exons, which are seen in four of the five spliceforms of Aceview. The general structure of the TMEM 249 transcript has a large 5' UTR followed by exon 1, then a large intron followed by exon 2, a small intron then exon 3. The rest of the protein follows exon 3 with a large intron, exon 4 a small intron then exon 5, the 3' UTR. The primary transcript contains all five exons and produces a protein that is 235 Amino Acids long. Transcript 1 and 2 are translated in the 3' to 5' direction while transcripts 3 through 5 are translated in the 5' to 3' direction. Note that the gene is encoded on the minus strand within the chromosome. # Homology / Evolution # Paralogs The only known paralog of human TMEM 249 is found in the second isoform of the protein in Gorillas. Of the 217 amino acids aligned between gorilla and human TMEM 249, 96% are in complete consensus and 99% are conserved. # Orthologs TMEM 249 orthologs includes all groups of life except birds, fungi, archea, protists, and plants. The most distant ortholog, Rozella allomycis, was the most diverged species that qualified as an ortholog. The last shared ancestor between Rozella allomycis and Homo sapiens is the Opisthokonts. # Homologs No homologs or homologous domains exist within TMEM 249. # Phylogeny No fungi orthologs were found in the search for similar sequences, so it could be assumed that the gene may have arisen in Opisthokonts and proliferated down the animal tree. This would mean the protein diverged too late to evolve through the fungi tree. This would explain why there are no found plant orthologs as the gene would have arose after animals and plants diverged evolutionarily. # Protein # Domains and motifs There are three predicted transmembrane domains. It is unknown whether these transmembrane domains affect the larger structure of the protein complex once properly expressed in tissue. Evolutionary analysis showed that these transmembrane domains are highly conserved across all ortholog taxa. # Post-translational modifications There is an area near the 3’ end of the protein that is predicted to be heavily serine phosphorylated. This end of the protein is likely on the cytosolic half of the protein and serves in some activation function of a pathway. # Secondary structure TMEM249 has a highly varied structure. Prediction data supports alternating regions of beta sheets and alpha helices. These predictions may support a beta barrel or "helix barrel" through the membrane made up of multiple protein monomers of TMEM249. # Expression # Promoter The promoter region was found using Eldorado from Genomatix.de (source), the region occupies a region upstream of the 5’ region of TMEM 249 on the minus strand of chromosome 8. This promoter binds a number of transcription factors as determined by Eldorado at Genomatix.de. # Tissue Expression TMEM 249 expression is present at a high level in a wide variety of human tissues. GEO tissue profiles for this protein show that this protein is present in a wide variety of locations within the human body. The human protein atlas claims an even wider expression scope for this protein(source). # Function / Biochemistry # Interacting Proteins There were no known protein interactions for TMEM 249. # Clinical Significance TMEM249 has no known link to medical disease. # Mutations There exist a number of SNPs for TMEM 249 in humans. The mutations are scattered for the most part, with the largest changes in amino acids occurring in the domain of unknown function.

PEDF Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), is a multifunctional secreted protein that has anti-angiogenic, anti-tumorigenic, and neurotrophic functions. Found in vertebrates, this 50 kDa protein is being researched as a therapeutic candidate for treatment of such conditions as choroidal neovascularization, heart disease, and cancer. In humans, pigment epithelium-derived factor is encoded by the SERPINF1 gene. # Discovery Pigment epithelium-derived factor (PEDF) was originally discovered by Joyce Tombran-Tink and Lincoln Johnson in the late 1980s. This group was studying human retinal cell development by identifying secreted factors produced by the retinal pigmented epithelium (RPE), a layer of cells that supports the retina. Upon noticing RPE produced a factor that promoted the differentiation of primitive retinal cells into cells of a neuronal phenotype, they set out to determine the identity of the factor. They isolated proteins unique to RPE cells and tested the individual proteins for neurotrophic function, meaning promoting a neuronal phenotype. A neurotrophic protein around 50 kilodaltons (kDa) was identified and temporarily named RPE-54 before being officially termed pigment epithelium-derived factor. Soon thereafter, the same laboratory sequenced the PEDF protein and compared it to a human fetal eye library. They found that PEDF was a previously uncharacterized protein and a member of the serpin (serine protease inhibitor) family. # Gene The gene encoding human PEDF was localized to the 17th chromosome at position 17p13.1. The human PEDF gene is around 15.6kb, and the mRNA transcript is around 1.5kb. Immediately upstream of the PEDF gene lies a 200bp promoter region with putative binding sites for the transcription factors HNF4, CHOP, and USF. The PEDF gene consists of 8 exons and 7 introns. The PEDF gene is present in vertebrates from human to fish, but not present in sea squirts, worms, or fruit flies. Sea squirts express several serpin genes, suggesting that the PEDF gene may have arisen from another serpin family member after the evolution of vertebral animals. The gene most homologous to PEDF is its adjacent neighbor on chromosome 17, SerpinF2. # Protein The PEDF protein is a secreted protein of roughly 50kDa size and 418 amino acids in length. The N-terminus contains a leader sequence responsible for protein secretion out of the cell at residues 1-19. A 34-mer fragment of PEDF (residues 24-57) was shown to have antiangiogenic properties, and a 44-mer (residues 58-101) was shown to have neurotrophic properties. A BLAST search reveals a putative receptor binding site exists between residues 75-124. A nuclear localization sequence (NLS) exists about 150 amino acids into the protein. The additional molecular weight is partly due to a single glycosylation site at residue 285. Near the C-terminus at residues 365-390 lies the reactive center loop (RCL) which is normally involved in serine protease inhibitor activity; however, in PEDF this region does not retain the inhibitory function. In 2001, the crystal structure of PEDF was successfully generated. The PEDF structure includes 3 beta sheets and 10 alpha helices. This discovery demonstrated that PEDF has an asymmetrical charge distribution across the whole protein. One side of the protein is heavily basic and the other side is heavily acidic, leading to a polar 3-D structure. They proposed that the basic side of the protein contains a heparin binding site. # Signaling PEDF expression is upregulated by plasminogen kringle domains 1-4 (also known as angiostatin) and the kringle 5 (K5) domain. Hypoxia, or low oxygen conditions, leads to the downregulation of PEDF. This effect is due to hypoxic conditions causing matrix metalloproteinases (MMPs) to proteolytically degrade PEDF. In addition, amyloid beta has been shown to decrease PEDF mRNA levels. Secreted PEDF binds a receptor on the cell surface termed PEDF-R. PEDF-R has phospholipase A2 activity which liberates fatty acids from glycerolipids. PEDF enhances gamma-secretase activity, leading to the cleavage of the VEGF receptor 1 (VEGFR-1) transmembrane domain. This action interferes with VEGF signaling thereby inhibiting angiogenesis. Laminin receptor is also a target for PEDF, and the interaction occurs between residues 24-57 of PEDF, a region known to regulate antiangiogenic function. PEDF induces PPAR-gamma expression which in turn induces p53, a tumor suppressor gene involved in cell cycle regulation and apoptosis. Thrombospondin, an antiangiogenic protein, is upregulated by PEDF. PEDF stimulates several other well known signaling cascades such as the Ras pathway, the NF-κB pathway, and extrinsic apoptosis cascades. # Function PEDF has a variety of functions including antiangiogenic, antitumorigenic, and neurotrophic properties. Endothelial cell migration is inhibited by PEDF. PEDF suppresses retinal neovascularization and endothelial cell proliferation. The antiangiogenic residues 24-57 were shown to be sufficient at inhibiting angiogenesis. PEDF is also responsible for apoptosis of endothelial cells either through the p38 MAPK pathway or through the FAS/FASL pathway Antiangiogenic function is also conferred by PEDF through inhibition of both VEGFR-1 and VEGFR-2. The antitumorigenic effects of PEDF are not only due to inhibition of supporting vasculature, but also due to effects on the cancer cells themselves. PEDF was shown to inhibit cancer cell proliferation and increase apoptosis via the FAS/FASL pathway. VEGF expression by cancer cells is inhibited by PEDF. PEDF also displays neurotrophic functions. Retinoblastoma cells differentiate into neurons due to the presence of PEDF. Expression of PEDF in the human retina is found at 7.4 weeks of gestation, suggesting it may play a role in retinal neuron differentiation. # Clinical significance PEDF, a protein with many functions, has been suggested to play a clinical role in choroidal neovascularization, cardiovascular disease, diabetes, diabetic macular edema, osteogenesis imperfecta and cancer. As an antiangiogenic protein, PEDF may help suppress unwanted neovascularization of the eye. Molecules that shift the balance towards PEDF and away from VEGF may prove useful tools in both choroidal neovascularization and preventing cancer metastasis formation.

Aarskog-Scott syndrome Synonyms and Keywords: Aarskog disease, Aarskog-Scott syndrome, AAS, Faciodigitogenital syndrome, Faciogenital dysplasia, FGDY, Scott Aarskog syndrome # Overview Aarskog-Scott syndrome is a rare inherited disease distinguish by short stature, facial abnormalities, skeletal and genital anomalies. The Aarskog-Scott syndrome (AAS) is also known as the Aarskog syndrome, faciodigitogenital syndrome, shawl scrotum syndrome and facial genital dysplasia. In The United States of America in order to categorise a condition as a rare disease it should affect fewer than 200,000 people. Rare diseases also called as orphan diseases. Orphan Drug Act was passed on 1983 by congress for the rare diseases. Today an average of 25-30 million americans have been reported with rare diseases. The number of people with individual rare disease may be less but overall the number of people with rare diseases are large in number. # Historical Perspective - In 1970, Aarskog-Scott syndrome (AAS) was first described by Aarskog, a Norwegian pediatrician and human geneticist. - In 1971, Scott described the association between ligamentous laxity which results in hyperextensibility of the fingers, genu recurvatum, flat feet and Aarskog-Scott syndrome (AAS). - In 1973, Sugarman et al described an Mexican-American family in which 2 half brothers and their 2 maternal uncles had Aarskog syndrome. - In 1993, Teebi et al suggested that the disease Aarskog-Scott syndrome (AAS) follows autosomal dominant inheritance. - In 1978, Escobar and Weaver described a patient who is had symptoms of Noonan syndrome than Aarskog-Scott syndrome (AAS). - In 1981, Grier et al. suggested that Aarskog-Scott syndrome (AAS) follows autosomal dominant pattern of inheritance. - In 1984, Van den Bergh et al. mentioned a patient with Aarskog-Scott syndrome (AAS) development of syndrome of benign intracranial hypertension after minor head trauma. - In 1994, Fernandez et al. mentioned 10 Japanese patients who are positive with Aarskog syndrome. - In 1998, Logie and Porteous concluded that in patients with Aarskog-Scott syndrome (AAS) have normal intelligence. - In 2002, Lebel et al. is the one who found a missense mutation in the FGD1 gene. - In 2005, Orrico et al. described attention deficit-hyperactivity disorder (ADHD) in patient with Aarskog-Scott syndrome (AAS). - In 2010, Orrico et al. genetically confirmed 11 patients for Aarskog-Scott syndrome. # Classification - There is no established system for the classification of Aarskog-Scott syndrome (AAS). # Pathophysiology - Aarskog-Scott syndrome (AAS) is transmitted in X-linked recessive mode of inheritance. - In some cases Aarskog-Scott syndrome (AAS) is transmitted in autosomal dominant mode of inheritance. - It is understood that Aarskog-Scott syndrome (AAS) is the result caused by a mutation in FGD1 gene. - FGD1 gene mapped to the Xp11.21 region is located on X chromosome. - Normally, in most of the situations males have one X chromosome and females have two X chromosomes. - When mutation occurs in FGD1 gene of males may result in the Aarskog-Scott syndrome (AAS). - But, in females the mutation had to occur in both X chromosomes to manifest the disease Aarskog-Scott syndrome (AAS). - In females if the mutation occurs in only one X chromosome then it results in mild features of Aarskog-Scott syndrome (AAS). - The gene FGD1 specifically encodes for guanine nucleotide exchange factor (GEF). - Guanine nucleotide exchange factor (GEF) inturn activates Cdc42 which belongs to Ras homology of the p21 GTPases. - Upon activation of Cdc42, FGD1 proteins they activate the following: Fibroblasts Cytoskeletal elements which are involved in Cellular signaling Adhesion Migration c- N-terminal kinase (JNK) signaling cascade which involves: Cell growth Apoptosis Cellular differentiation - Fibroblasts - Cytoskeletal elements which are involved in Cellular signaling Adhesion Migration - Cellular signaling - Adhesion - Migration - c- N-terminal kinase (JNK) signaling cascade which involves: Cell growth Apoptosis Cellular differentiation - Cell growth - Apoptosis - Cellular differentiation - These abnormalities of FGD1/Cdc42 signaling pathway may produce an defective embryonic development and abnormal endochondral and intramembranous bone formation and leads to Aarskog-Scott syndrome (AAS). # Causes ### Genetic Cause - Aarskog-Scott syndrome (AAS) is caused by a mutation in the FGD1 gene. # Differentiating Aarskog-Scott syndrome from other Diseases - Aarskog-Scott syndrome (AAS) must be differentiated from Robinow syndrome, Noonan syndrome, pseudohypoparathyroidism, Silver-Russell and SHORT syndrome. # Epidemiology and Demographics ## Incidence - The incidence of Aarskog-Scott syndrome (AAS) is unknown. - Till now there are 29 cases of Aarskog-Scott syndrome (AAS) had been diagnosed worldwide. ## Prevalence - The prevalence of Aarskog-Scott syndrome (AAS) is 1/25 000 worldwide. - The prevalence of Aarskog-Scott syndrome (AAS) is 1-9 per 1,000,000 in Europe. ## Age - Aarskog-Scott syndrome (AAS) commonly affects individuals of younger age especially in childwood. ## Race - There is no racial predilection to Aarskog-Scott syndrome (AAS). ## Gender - Aarskog-Scott syndrome (AAS) affects men more commonly than in women. # Risk Factors There are no established risk factors for Aarskog-Scott syndrome (AAS). # Screening There is insufficient evidence to recommend routine screening for Aarskog-Scott syndrome (AAS). # Natural History, Complications and Prognosis ## Natural History - The symptoms of Aarskog-Scott syndrome (AAS) usually develop in the first decade of life, and start with symptoms such as delayed growth spurt. - The symptoms of Aarskog-Scott syndrome (AAS) typically develop in 2 to 4 years of age. ## Complications - Common complications of Aarskog-Scott syndrome (AAS) include: Cryptorchidism Spina bifida occulta Cervical spine abnormalities Scoliosis Camptodactyly Lymphoedema Optic nerve hypoplasia Retinal vessel tortuosity - Cryptorchidism - Spina bifida occulta - Cervical spine abnormalities - Scoliosis - Camptodactyly - Lymphoedema - Optic nerve hypoplasia - Retinal vessel tortuosity ## Prognosis - Prognosis is generally good with Aarskog-Scott syndrome (AAS) patients. # Diagnostic study of choice - Aarskog-Scott syndrome (AAS) is primarily diagnosed based on clinical presentation based on Teebi criteria which includes: Short stature Hypertelorism Fold of the lower lip Brachydactyly Interdigital webbing Shawl scrotum Long philtrum Mild facial hypoplasia - Short stature - Hypertelorism - Fold of the lower lip - Brachydactyly - Interdigital webbing - Shawl scrotum - Long philtrum - Mild facial hypoplasia # History and Symptoms ## Common Symptoms Common symptoms of Aarskog-Scott syndrome (AAS) include: - Short stature (evident by 1-3 years of age) - Mental retardation - Hypertelorism - Umbilical hernia - Shawl scrotum - Hypospadias - Undescended testes # Physical Examination ### HEENT Facial features are very prominent and important for the diagnosis of Aarskog-Scott syndrome (AAS) which include: - Round face - Facial edema with downward slanting palpebral fissures - Short nose along with anteverted nares - Long philtrum - Ocular hypertelorism with ptosis - Maxillary hypoplasia - A broad upper lip with a crease below the lower lip - Abnormal auriculares ### Neck - Short neck - Webbing of sides of the neck ### Chest - Mild pectus excavatum (sunken chest) ### Abdomen - Protruding navel - Inguinal hernias ### Genitourinary - Shawl Scrotum - Undescended testicles ### Extremities - Small, broad hands and feet - Short fingers and toes (brachydactyly) - Clinodactyly - Mild webbing between the fingers and toes - Simian crease - Broad thumbs and big toes # Laboratory Findings - There are no diagnostic laboratory findings associated with Aarskog-Scott syndrome (AAS). # Electrocardiogram - There are no ECG findings associated with Aarskog-Scott syndrome (AAS). # X-Ray Findings - Scoliosis- a) Early postoperative X-ray (b) 10 years follow-up X-ray.Case courtesy Kerim SariyilmazThere are no x-ray findings associated with Aarskog-Scott syndrome (AAS). However, an x-ray may be helpful in the diagnosis of complications of Aarskog-Scott syndrome (AAS), which include: Skeletal abnormalities Tooth abnormalities Scoliosis - Skeletal abnormalities - Tooth abnormalities - Scoliosis # Echocardiography and Ultrasound - The ultrasound can help in detecting the undescended testis associated with Aarskog-Scott syndrome (AAS). # CT-Scan Findings - Head CT scan may be helpful in the diagnosis of Aarskog-Scott syndrome (AAS). Findings on CT scan suggestive Aarskog-Scott syndrome (AAS) include: Cystic development - Cystic development # MRI Findings - There are no MRI findings associated with Aarskog-Scott syndrome (AAS). # Medical Therapy - There is no treatment for Aarskog-Scott syndrome (AAS); the mainstay of therapy is symptomatic care. - Patients with short stature are treated with growth hormone, which shows promising results in increasing the height of the patients. # Interventions - There are some recommended therapeutic interventions for the management of Aarskog-Scott syndrome (AAS), which includes speech pathologists, audiologists and eye specialists who can improve the quality of the patient's life. # Surgery - Surgery is usually reserved for patients with congenital or structural malformations which involves the following: Hypospadias(opening of the penis is on the underside rather than the tip) Inguinal or umbilical hernias Cryptorchidism(undescended testis) - Hypospadias(opening of the penis is on the underside rather than the tip) - Inguinal or umbilical hernias - Cryptorchidism(undescended testis) # Primary Prevention - There are no established measures for the primary prevention of Aarskog-Scott syndrome (AAS). # Secondary Prevention - There are no established measures for the secondary prevention of Aarskog-Scott syndrome (AAS).

Wilson disease protein Wilson disease protein (WND), also known as ATP7B protein, is a copper-transporting P-type ATPase which is encoded by the ATP7B gene. The ATP7B protein is located in the trans-Golgi network of the liver and brain and balances the copper level in the body by excreting excess copper into bile and plasma. Genetic disorder of the ATP7B gene may cause Wilson's disease, a disease in which copper accumulates in tissues, leading to neurological or psychiatric issues and liver diseases. # Gene Wilson disease protein is associated with ATP7B gene,approximate 80 Kb, located on human chromosome 13 and consists of 21 exons.The mRNA transcribed by ATP7B gene has a size of 7.5 Kb, and which encodes a protein of 1465 amino acids. The gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least two putative copper-binding sites. This protein functions as a monomer, exporting copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Wilson disease is caused by various mutations. One of the common mutations is single base pair mutation,H1069Q. # Structure ATP7B protein is a copper-transporting P-type ATPase, synthesized as a membrane protein of 165 KDa in human hepatoma cell line, and which is 57% homologous to menkes disease associated protein ATP7A. ATP7B consists of several domains: - Phosphatase domain (TGEA motif Thr-Gly-Glu-Ala) - Phosphorylation domain (DKTGT motif Asp-Lys-Thr-Gly-Thr) - ATP binding domain (TGDN motif) - Metal binding domain (six Copper binding motifs at the N-terminus in the cytosol) - Eight Transmembrane segments The CPC motif (Cys-Pro-Cys) in transmembrane segment 6 characterizes the protein as a heavy metal transporting ATPase. The copper binding motif also shows a high affinity to other transition metal ions like zinc Zn(II), cadmium Cd(II), gold Au(III), and mercury Hg(II). However, copper is able to decrease the zinc binding affinity at low concentration and increase copper binding affinity dramatically with increasing concentration to ensure a strong binding between the motif and copper. As a P-type ATPases, ATP7B undergoes auto-phosphorylation of a key conserved aspartic acid (D) residue in the DKTGT motif. The ATP binding to the protein initiates the reaction and copper binds to the transmembrane region. Then phosphorylation occurs at the aspartic acid residue in the DKTGT motif with Cu release. Then dephosphorylation of the aspartic acid residue recovers the protein to ready for the next transport. # Function Most of ATP7B protein is located in the trans-Golgi network (TGN) of hepatocytes, which is different from its homologous protein ATP7A. Small amount of ATP7B is located in the brain. As a copper-transporting protein, one major function is delivering copper to copper dependent enzymes in Golgi apparatus(e.g.holo-ceruloplasmin(CPN)). In the human body, liver plays an important role in copper regulation including removal of extra copper. ATP7B participates in the physiological pathway in the copper removal process in two ways: secreting copper into plasma and excreting copper into bile. # Interactions ## ATOX1 ATP7B receives copper from cytosolic protein Antioxidant 1 copper chaperone (ATOX1). This protein targets ATP7B directly in liver in order to transport copper. ATOX1 transfers copper from cytosol to the metal binding domain of ATP7B which control the catalytic activity of ATP7B. Several mutations in ATOX1 can block the copper pathways and cause Wilson disease. ## GLRX ATP7B interacts with Glutaredoxin-1(GLRX). Subsequent transport is promoted through the reduction of intramolecular disulphide bonds by GLRX catalysis. # Associations with Wilson disease Wilson disease happens when accumulation of copper inside the liver causes mitochondrial damage and cell destruction and shows symptoms of hepatic disease. Then, the loss of excretion of copper in bile leads to an increasing concentration of copper level in urine and causes kidney problems. Therefore, symptoms of Wilson disease could be various including kidney disease and neurological disease. The major cause is the malfunction of ATP7B by single base pair mutations, deletions, frame-shifts, splice errors in ATP7B gene.

EHR Resolution July 4, 2015 We, the undersigned practicing physicians of America, do warrant the following: Whereas the "Meaningful Use of Electronic Health Records" program, as designed by a commission, composed of 23 persons, 9 of whom were physicians, two of whom were practicing, enacted by the Hitech Act of 2009, was imposed against the will and the professional judgement of the majority of America's experienced clinicians, Whereas, a legible, coherent, succinct and complete medical document is key and central to the safe, effective and efficient care of the patient, and physicians across this nation have found EHR systems which are compliant with this program to have significant and widespread deficits in these areas, Whereas, we are trained and licensed medical professionals, responsible to prevent, diagnose and treat illness and injury, who sign and take personal and legal responsibility for our diagnoses and recommended courses of action, Therefore, we hereby declare, as one profession, that as the captain of a ship is bound to avoid the reef, for his or her passengers' sake, and the pilot the mountaintop, so must physicians have the ultimate authority, and bear ultimate responsibility, for the medical care of patients who have entrusted them with their lives. And that, along with the nation's largest nurses union, the National Nurses United, and which patients do support the premise of this resolution, we call for an IMMEDIATE moratorium on this program, including any and all penalties associated, for a minimum period of two years (with an interim report at one year), to allow for collection of feedback from physician and other end users of these systems, and experimentation, in collaboration with other experts and stakeholders, in improvement of the same. That in the interim, America's physicians and surgeons will have both the right and obligation, to create a legible, coherent, succinct and complete medical document, to the best of their ability, and by whatever means each deems necessary, before signing said document, and assuming responsibility for its content, and that thoughtful, focused, problem solving care for the individual patient before him or her, will resume its rightful place as the prime directive of the physician, and that data collection, and all other objectives, will be assigned to others, whenever possible, And that, any attempt by any person or entity, not the physician in attendance, to force the physician to do otherwise, and thus to violate his or her oath, shall be considered by these signatories to constitute the practice of medicine without license, or malpractice, and we call on our state legislatures to enforce the same, for the sake of all.

Immune system An immune system is a collection of mechanisms within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own healthy cells and tissues in order to function properly. Detection is complicated as pathogens adapt and evolve new ways to successfully infect the host organism. To survive this challenge, several mechanisms evolved that recognize and neutralize pathogens. Even simple unicellular organisms such as bacteria possess enzyme systems that protect against viral infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants, fish, reptiles, and insects. These mechanisms include antimicrobial peptides called defensins, phagocytosis, and the complement system. More sophisticated mechanisms, however, developed relatively recently, with the evolution of vertebrates. The immune systems of vertebrates such as humans consist of many types of proteins, cells, organs, and tissues, which interact in an elaborate and dynamic network. As part of this more complex immune response, the vertebrate system adapts over time to recognize particular pathogens more efficiently. The adaptation process creates immunological memories and allows even more effective protection during future encounters with these pathogens. This process of acquired immunity is the basis of vaccination. Disorders in the immune system can cause disease. Immunodeficiency diseases occur when the immune system is less active than normal, resulting in recurring and life-threatening infections. Immunodeficiency can either be the result of a genetic disease, such as severe combined immunodeficiency, or be produced by pharmaceuticals or an infection, such as the acquired immune deficiency syndrome (AIDS) that is caused by the retrovirus HIV. In contrast, autoimmune diseases result from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include rheumatoid arthritis, diabetes mellitus type 1 and lupus erythematosus. These critical roles of immunology in health and disease are areas of intense scientific study. # Layered defense in immunity The immune system protects you from dying from infection with layered defenses of increasing specificity. Most simply, physical barriers prevent pathogens such as bacteria and viruses from entering the body. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. However, if pathogens successfully evade the innate response, vertebrates possess a third layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered. Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are those components of an organism's body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response. # Surface barriers Several barriers protect organisms from infection, including mechanical, chemical and biological barriers. The waxy cuticle of many leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of the mechanical barriers that are the first line of defense against infection. However, as organisms cannot be completely sealed against their environments, other systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms. Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials. Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens. In the stomach, gastric acid and proteases serve as powerful chemical defenses against ingested pathogens. Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such as pH or available iron. This reduces the probability that pathogens will be able to reach sufficient numbers to cause illness. However, since most antibiotics non-specifically target bacteria and do not affect fungi, oral antibiotics can lead to an “overgrowth” of fungi and cause conditions such as a vaginal candidiasis (yeast infection). There is good evidence that re-introduction of probiotic flora, such as pure cultures of the lactobacilli normally found in yoghurt, helps restore a healthy balance of microbial populations in intestinal infections in children and encouraging preliminary data in studies on bacterial gastroenteritis, inflammatory bowel diseases, urinary tract infection and post-surgical infections. # Innate immunity Microorganisms that successfully enter an organism will encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms. Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way. This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms. ## Humoral and chemical barriers ### Inflammation Inflammation is one of the first responses of the immune system to infection. The symptoms of inflammation are redness and swelling, which are caused by increased blood flow into a tissue. Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens. ### Complement system The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to “complement” the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response. Many species have complement systems, including non-mammals like plants, fish, and some invertebrates. In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response. The speed of the response is a result of signal amplification that occurs following sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback. The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane. ## Cellular barriers of the innate system Leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system. The innate leukocytes include the phagocytes (macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. Innate cells are also important mediators in the activation of the adaptive immune system. Phagocytosis is an important feature of cellular innate immunity performed by cells called 'phagocytes' that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines. Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome. Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism. Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals. Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, normally representing 50% to 60% of the total circulating leukocytes. During the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis, and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce a wide array of chemicals including enzymes, complement proteins, and regulatory factors such as interleukin 1. Macrophages also act as scavengers, ridding the body of worn-out cells and other debris, and as antigen-presenting cells that activate the adaptive immune system. Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines. They are named for their resemblance to neuronal dendrites, as both have many spine-like projections, but dendritic cells are in no way connected to the nervous system. Dendritic cells serve as a link between the innate and adaptive immune systems, as they present antigen to T cells, one of the key cell types of the adaptive immune system. Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response. They are most often associated with allergy and anaphylaxis. Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma. Natural killer (NK cells) cells are leukocytes that attack and destroy tumor cells, or cells that have been infected by viruses. # Adaptive immunity The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen. The adaptive immune response is antigen-specific and requires the recognition of specific “non-self” antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it. ## Lymphocytes The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a “non-self” target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a “self” receptor called a major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the killer T cell and the helper T cell. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors. In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes whole pathogens without any need for antigen processing. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture. ### Killer T cells Killer T cell are a sub-group of T cells that kill cells infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional. As with B cells, each type of T cell recognises a different antigen. Killer T cells are activated when their T cell receptor (TCR) binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cell's plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis. T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T cells (see below). ### Helper T cells Helper T cells regulate both the innate and adaptive immune responses and help determine which types of immune responses the body will make to a particular pathogen. These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks. Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T cell (e.g. Lck) that are responsible for T cell's activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell. The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells. In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell's surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells. ### γδ T cells γδ T cells possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, γδ T cells straddle the border between innate and adaptive immunity. On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia will respond to stressed epithelial cells. ### B lymphocytes and antibodies A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell. As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.CD20 antigen is also found on B lymphocytes. ### Alternative adaptive immune system Although the classical molecules of the adaptive immune system (e.g. antibodies and T cell receptors) exist only in jawed vertebrates, a distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called variable lymphocyte receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity. ## Immunological memory When B cells and T cells are activated and begin to replicate, some of their offspring will become long-lived memory cells. Throughout the lifetime of an animal, these memory cells will remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can either be in the form of passive short-term memory or active long-term memory. ### Passive memory Passive immunity is usually short-term, lasting between a few days and several months. Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly across the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother. Breast milk also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies. This is passive immunity because the fetus does not actually make any memory cells or antibodies, it only borrows them. In medicine, protective passive immunity can also be transferred artificially from one individual to another via antibody-rich serum. ### Active memory and immunization Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through vaccination. The principle behind vaccination (also called immunization) is to introduce an antigen from a pathogen in order to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism. This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed. Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based on acellular components of micro-organisms, including harmless toxin components. Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity. # Disorders of human immunity The immune system is a remarkably effective structure that incorporates specificity, inducibility and adaptation. Failures of host defense do occur, however, and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities. ## Immunodeficiencies Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence. In developed countries, obesity, alcoholism, and illegal drug abuse are common causes of poor immune function. However, malnutrition is the most common cause of immunodeficiency in developing countries. Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Deficiency of single nutrients such as iron; copper; zinc; selenium; vitamins A, C, E, and B6; and folic acid (vitamin B9) also reduces immune responses. Additionally, the loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection. Immunodeficiencies can also be inherited or 'acquired'. Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and some types of cancer cause acquired immunodeficiency. ## Autoimmunity Overactive immune responses comprise the other end of immune dysfunction, particularly the autoimmune disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with “self” peptides. One of the functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity. ## Hypersensitivity Hypersensitivity is an immune response that damages the body's own tissues. They are divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE released from mast cells and basophils. Type II hypersensitivity occurs when antibodies bind to antigens on the patient's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies. Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions. Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis (poison ivy). These reactions are mediated by T cells, monocytes, and macrophages. # Other mechanisms of host defense It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not generate lymphocytes or an antibody-based humoral response. Many species, however, utilize mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the most structurally-simple forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages. Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity. The complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses. Unlike animals, plants lack phagocytic cells, and most plant immune responses involve systemic chemical signals that are sent through a plant. When a part of a plant becomes infected, the plant produces a localized hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease to other parts of the plant. Systemic acquired resistance (SAR) is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent. RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication. # Tumor immunology Another important role of the immune system is to identify and eliminate tumors. The transformed cells of tumors express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources; some are derived from oncogenic viruses like human papillomavirus, which causes cervical cancer, while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (e.g. melanocytes) into tumors called melanomas. A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes. The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells. Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal. NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors. Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system. Clearly, some tumors evade the immune system and go on to become cancers. Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells. Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes. In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells. Paradoxically, macrophages can promote tumor growth when tumor cells send out cytokines that attract macrophages which then generate cytokines and growth factors that nurture tumor development. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells. # Physiological regulation Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive and innate immune responses. Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such as testosterone seem to be immunosuppressive. Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D. It is conjectured that a progressive decline in hormone levels with age is partially responsible for weakened immune responses in aging individuals. Conversely, some hormones are regulated by the immune system, notably thyroid hormone activity. The immune system is enhanced by sleep and rest, and is impaired by stress. Diet may affect the immune system; for example, fresh fruits, vegetables, and foods rich in certain fatty acids may foster a healthy immune system. Likewise, fetal undernourishment can cause a lifelong impairment of the immune system. In traditional medicine, some herbs are believed to stimulate the immune system, such as echinacea, licorice, ginseng, astragalus, sage, garlic, elderberry, shitake and lingzhi mushrooms, and hyssop, as well as honey. Studies have suggested that such herbs can indeed stimulate the immune system, although their mode of action is complex and difficult to characterize. # Manipulation in medicine The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system (see immunization). Immunosuppressive drugs are used to control autoimmune disorders or inflammation when excessive tissue damage occurs, and to prevent transplant rejection after an organ transplant. Anti-inflammatory drugs are often used to control the effects of inflammation. The glucocorticoids are the most powerful of these drugs; however, these drugs can have many undesirable side effects (e.g., central obesity, hyperglycemia, osteoporosis) and their use must be tightly controlled. Therefore, lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine. Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. However, the killing is indiscriminate and other organs and cell types are affected, which causes toxic side effects. Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways. Larger drugs (>500 Da) can provoke a neutralizing immune response, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 Da). In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids; however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set. A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells. The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics. # Manipulation by pathogens The success of any pathogen is dependent on its ability to elude host immune responses. Therefore, pathogens have developed several methods that allow them to successfully infect a host, while evading immune-mediated destruction. Bacteria often overcome physical barriers by secreting enzymes that digest the barrier — for example, by using a type II secretion system. Alternatively, using a type III secretion system, they may insert a hollow tube into the host cell, which provides a direct conduit for proteins to move from the pathogen to the host; the proteins transported along the tube are often used to shut down host defenses. An evasion strategy used by several pathogens to circumvent the innate immune system is intracellular replication (also called intracellular pathogenesis). Here, a pathogen spends a majority of its life-cycle inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium falciparum) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement. Many pathogens secrete compounds that diminish or misdirect the host's immune response. Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, e.g., the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis. Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L). The mechanisms used by viruses to evade the adaptive immune system are more complicated. The simplest approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the invader's surface, while keeping essential epitopes concealed. HIV, for example, regularly mutates the proteins on its viral envelope that are essential for entry into its host target cell. These frequent changes in antigens may explain the failures of vaccines directed at these proteins. Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. In HIV, the envelope that covers the viron is formed from the outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self". # History of immunology Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known mention of immunity was during the plague of Athens in 430 BC. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. This observation of acquired immunity was later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease. Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not until Robert Koch's 1891 proofs, for which he was awarded a Nobel Prize in 1905, that microorganisms were confirmed as the cause of infectious disease. Viruses were confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed. Immunology made a great advance towards the end of the 19th century, through rapid developments, in the study of humoral immunity and cellular immunity. Particularly important was the work of Paul Ehrlich, who proposed the side-chain theory to explain the specificity of the antigen-antibody reaction; his contributions to the understanding of humoral immunity were recognized by the award of a Nobel Prize in 1908, which was jointly awarded to the founder of cellular immunology, Elie Metchnikoff.

Crizotinib for treating ROS1-positive advanced non-small-cell lung cancer Evidence-based recommendations on crizotinib (Xalkori) for treating ROS1-positive advanced non-small-cell lung cancer in adults. # Recommendations Crizotinib is recommended for use within the Cancer Drugs Fund as an option for treating ROS1‑positive advanced non-small-cell lung cancer (NSCLC) in adults, only if the conditions in the managed access agreement are followed. This recommendation is not intended to affect treatment with crizotinib 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 ROS1‑positive advanced NSCLC is a recently discovered type of NSCLC and there are limited data about how well existing treatments work. Evidence for crizotinib in ROS1‑positive advanced NSCLC comes from a small, single-arm study that included mostly people with previously treated disease. Although the study showed crizotinib to be effective at shrinking tumours and slowing disease progression, the lack of data comparing it with other treatments makes the size of the benefit uncertain. Because of the limited evidence in ROS1‑positive NSCLC, the company presented data from 2 randomised controlled trials for crizotinib in ALK‑positive NSCLC instead (comparing crizotinib with chemotherapy) as proxy data for ROS1‑positive advanced NSCLC. However, using data from a proxy population is far from ideal, and makes the assessment of clinical and cost effectiveness highly uncertain. Crizotinib meets NICE's criteria to be considered a life-extending end-of-life treatment, but there are uncertainties in the clinical- and cost-effectiveness estimates. For previously treated disease, the range of cost-effectiveness estimates was broader than for untreated disease and all estimates are higher than what NICE normally considers acceptable for end-of-life treatments. Crizotinib therefore cannot be recommended for routine use in the NHS to treat ROS1‑positive advanced NSCLC. Crizotinib is innovative but there were no relevant additional benefits that had not been captured in the quality-adjusted life-year calculations. Collecting further data on its use in the Cancer Drugs Fund would help address uncertainties in crizotinib's survival benefit, and the comparability of ROS1‑positive and ALK‑positive advanced NSCLC. Using crizotinib in a managed approach would also encourage standardisation of ROS1 status testing in non-squamous NSCLC. Therefore, crizotinib can be recommended for use within the Cancer Drugs Fund to treat ROS1‑positive NSCLC.# Information about crizotinib Marketing authorisation Crizotinib (Xalkori, Pfizer) as monotherapy is indicated 'for the treatment of adults with ROS1‑positive advanced non-small-cell lung cancer (NSCLC)'. Dosage in the marketing authorisation mg twice daily (500 mg daily) taken orally. Dosing interruption and/or dose reduction may be needed based on individual safety and tolerability. If necessary, dose may be reduced to 200 mg twice daily and then 250 mg once daily. An accurate and validated assessment for ROS1 should be done by laboratories with demonstrated proficiency in the specific test being used before starting crizotinib therapy. It is important that a well-validated and robust methodology is chosen to avoid false-negative or false-positive results. For further details see the summary of product characteristics. The summary of product characteristic states that there is limited information available in patients with ROS1‑positive NSCLC with non-adenocarcinoma histology, including squamous cell carcinoma. Price The list price of crizotinib is £4,689 for 60 capsules (excluding VAT; British national formulary online, accessed December 2017). The company has a commercial arrangement. This makes crizotinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion The appraisal committee (section 5) considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence. # Clinical need ## The ROS1 oncogene is a recent discovery and both patients and clinicians would welcome a targeted therapy The clinical experts observed that less than 2% of people with non-small-cell lung cancer (NSCLC) have ROS1‑positive advanced NSCLC. The ROS1 oncogene is thought to be found almost exclusively in non-squamous NSCLC, mainly in tumours with adenocarcinoma histology. The committee noted that the ROS1 oncogene was only recently discovered; so limited information is available on the natural history, patient characteristics and the clinical effectiveness of chemotherapy for tumours that are ROS1‑positive. The clinical experts highlighted that from the limited information available, there appear to be similarities between ROS1‑positive advanced NSCLC and ALK‑positive NSCLC: for example, both are most often seen in younger patients who do not smoke. In the absence of any targeted therapy until now, ROS1‑positive advanced NSCLC is treated with cytotoxic chemotherapy that can cause unpleasant side effects. The committee noted the patient expert's statement that people with advanced or metastatic NSCLC often feel debilitated by multiple and distressing symptoms. It also noted that the clinical experts considered crizotinib a step-change in treatment because it is taken orally, and offers a marked improvement in quality of life. The committee concluded that crizotinib has a better safety PROFILE than standard care (cytotoxic chemotherapy) and would be valued by both patients and clinicians. # ROS1 testing ## ROS1 status should be tested upfront in all non-squamous NSCLC The marketing authorisation for crizotinib states that it is necessary to have an accurate and validated assay for ROS1 before treatment with crizotinib is started. The company proposed initial testing with immunohistochemistry (IHC), and follow-up confirmation testing for positive cases with the highly accurate FISH (fluorescence in situ hybridisation) test. The clinical experts explained that only a few centres test for ROS1, and that assay methods vary. The committee understood that although the marketing authorisation for crizotinib did not specify non-squamous disease, ROS1‑positive NSCLC is almost exclusively seen in non-squamous tumours (see section 3.1) and therefore the testing would most likely be in people with non-squamous tumours only. The committee discussed when ROS1 testing should be done: it could be done at diagnosis, along with testing for other mutations (such as EGFR and ALK), or later, once people have tested negatively for other mutations (because the different mutations are mutually exclusive). The clinical experts highlighted practical difficulties in testing different mutations at different stages, because more biopsy samples might be needed and the risk of delayed or missed diagnoses with sequential testing. The committee also noted that any delay in diagnosing ROS1‑positive advanced NSCLC would delay access to therapy. It agreed that testing for ROS1 status in all newly diagnosed non-squamous NSCLC would be the best strategy, in line with testing for other types of tumour expression in NSCLC. # Comparators ## There are different comparators for crizotinib in untreated and previously treated disease The committee noted that crizotinib's UK marketing authorisation does not specify whether it should be used to treat squamous or non-squamous disease. It also noted that the summary of product characteristic states that there is limited information available in patients with ROS1‑positive NSCLC with non-adenocarcinoma histology, including squamous cell carcinoma. The committee understood that the ROS1 oncogene is mainly present in adenocarcinoma, which is a subtype of non-squamous NSCLC. It agreed that crizotinib would most likely be used in patients with non-squamous NSCLC in clinical practice in the NHS. In line with the final scope issued by NICE, the committee considered untreated and previously treated ROS1‑positive advanced NSCLC separately when determining the most appropriate comparators for crizotinib. ## Untreated disease: pemetrexed plus platinum-based therapy is the appropriate comparator The company considered that pemetrexed plus platinum-based chemotherapy (cisplatin or carboplatin) was the appropriate comparator for crizotinib in untreated ROS1‑positive advanced NSCLC. As such, it excluded all other comparators identified in the final scope issued by NICE. The committee understood that NICE's guideline on lung cancer diagnosis and management recommends platinum-based combination chemotherapy for untreated disease (and docetaxel, gemcitabine, paclitaxel or vinorelbine alone for people who cannot tolerate combination chemotherapy). NICE's technology appraisal guidance on pemetrexed for the first-line treatment of NSCLC recommends pemetrexed plus cisplatin for adenocarcinoma or large-cell carcinoma. Pemetrexed is also recommended as maintenance treatment after pemetrexed plus cisplatin for locally advanced or metastatic non-squamous NSCLC in adults whose disease has not progressed (NICE technology appraisal guidance on pemetrexed maintenance treatment for non-squamous NSCLC after pemetrexed and cisplatin), and after platinum-based chemotherapy plus gemcitabine, paclitaxel or docetaxel (NICE technology appraisal guidance on pemetrexed for the maintenance treatment of NSCLC). The company excluded pemetrexed as maintenance treatment after pemetrexed plus cisplatin, stating that only around 15% of patients would be eligible. It also noted that patients newly diagnosed with ROS1‑positive advanced NSCLC are generally young and physically fit, and so it was appropriate to exclude single-agent chemotherapy as a comparator (because this is only recommended for people who cannot tolerate combination chemotherapy). The committee understood that the ROS1 oncogene is most common in non-squamous NSCLC and concluded that pemetrexed plus platinum-based chemotherapy was the most appropriate comparator for crizotinib in untreated, ROS1‑positive advanced NSCLC. ## Previously treated disease: it is inappropriate to exclude standard care docetaxel plus nintedanib as a comparator For crizotinib in previously treated ROS1‑positive advanced NSCLC, the company considered docetaxel alone to be the best comparator. It excluded nintedanib plus docetaxel as a comparator, despite NICE's technology appraisal guidance on nintedanib for previously treated locally advanced, metastatic, or locally recurrent NSCLC recommending this as an option for previously treated NSCLC of adenocarcinoma histology. The company stated that it was not possible to compare crizotinib with nintedanib plus docetaxel, because data on nintedanib plus docetaxel were available only for unselected NSCLC. In response to consultation, the company further explained that using pooled chemotherapy in the analysis (that is, docetaxel or pemetrexed in line with treatment options in PROFILE 1007) is a conservative approach because pemetrexed is more effective than docetaxel. However, the committee understood that nintedanib plus docetaxel is more effective than docetaxel alone for treating adenocarcinoma, such that it is considered standard care in the NHS for people who can tolerate it. The committee was not convinced by the company's rationale for excluding nintedanib plus docetaxel as a comparator. It concluded that the company should have included nintedanib plus docetaxel as a comparator, because it is thought that the ROS1 oncogene is most common in non-squamous NSCLC and agreed to consider this omission in its decision-making. # Clinical effectiveness ## Direct evidence for crizotinib's effectiveness in ROS1‑positive advanced NSCLC is extremely limited because there are no comparative data The clinical-effectiveness evidence for crizotinib in ROS1‑positive advanced NSCLC is from a small (n=53), single-arm study called PROFILE 1001. The trial was done at 8 sites across the US, Australia and South Korea. Only 7 patients had untreated disease; the other 46 had had at least 1 previous chemotherapy. Most patients (96%) had NSCLC of adenocarcinoma histology but 2 patients had non-adenocarcinoma histology. Patients were followed-up for a median of 25.4 months. As determined by the investigators, 5 patients had complete response and 32 patients had partial response (according to Response Evaluation Criteria In Solid Tumours ) giving an overall objective response rate of 69.8% (95% confidence interval 55.7 to 81.7). Median overall survival was not reached at the time of analysis and the company does not intend to carry out any interim analysis in the near future. Median progression-free survival was 19.8 months. The clinical experts stated that these results were clinically meaningful because, in unselected NSCLC, chemotherapy provides progression-free survival of around 5 months in untreated disease and just 3 months in previously treated disease. From the evidence available from PROFILE 1001, the committee agreed that crizotinib can induce durable tumour shrinkage and slow disease progression, particularly in previously treated ROS1‑positive advanced NSCLC. In response to consultation, the company highlighted that its original submission included results from a UK clinical audit by the Royal Marsden and other small studies in ROS1‑positive advanced NSCLC that supported the efficacy and safety of crizotinib. The committee noted that the clinical audit reported a median progression-free survival of 12.1 months for both untreated and previously treated disease, and that the OxOnc study reported a median overall survival of 32.5 months at the data cut-off in July 2016 (median overall survival was not reached in the other studies). The committee also noted that although the OxOnc study recruited more patients than PROFILE 1001, it was done in Asia and therefore may not be applicable to UK settings. The committee noted that there is no available evidence on the effectiveness of crizotinib compared with chemotherapy for ROS1‑positive advanced NSCLC and concluded that the lack of comparative data makes any assessment of comparative effectiveness (and any economic analysis) very challenging. ## The effectiveness of crizotinib compared with chemotherapy is based on its use in ALK‑positive advanced NSCLC and so is highly uncertain Because of the limited clinical-effectiveness data available for ROS1‑positive advanced NSCLC, the company provided results from 2 randomised controlled trials that compared crizotinib with chemotherapy in untreated (PROFILE 1014) and previously treated (PROFILE 1007) ALK‑positive NSCLC. The company stated that these results could be extrapolated to ROS1‑positive advanced NSCLC. Both trials were considered during the development of previous NICE technology appraisal guidance (crizotinib for untreated ALK-positive advanced NSCLC and crizotinib for previously treated ALK-positive advanced NSCLC). The committee was aware that in both the PROFILE 1014 and PROFILE 1007 trials, progression-free survival was statistically significantly longer with crizotinib compared with chemotherapy (pemetrexed plus platinum for untreated disease and pemetrexed plus docetaxel for previously treated disease). The committee was also aware that the overall survival results (unadjusted for patient crossover) from PROFILE 1014 and PROFILE 1007 suggested that there were no statistically significant differences between crizotinib and chemotherapy in each of these trials. However, the crossover-adjusted hazard ratio results suggested that crizotinib statistically significantly improved overall survival compared with chemotherapy in patients with ALK‑positive advanced NSCLC. The committee noted the ERG's comments that in both trials, the proportional hazards assumption (the relative risk of an event is fixed irrespective of time) was not valid for progression-free survival so any hazard ratios for progression-free survival should be interpreted with caution. The ERG also highlighted that the overall survival estimates were unreliable because of high rates of crossover, and that statistical methods for adjustment were not reported transparently. The committee agreed that the results showed crizotinib to be more effective than chemotherapy for ALK‑positive NSCLC, but that its relative effectiveness in ROS1‑positive advanced NSCLC remained uncertain. ## The only comparative evidence for crizotinib in ROS1‑positive advanced NSCLC is from proxy data in ALK‑positive NSCLC The committee discussed the relevance of the PROFILE 1014 and PROFILE 1007 results to ROS1‑positive advanced NSCLC. In its submission, the company strongly advocated that data from ALK‑positive NSCLC could be used as a proxy for ROS1‑positive advanced NSCLC. It stated that: The kinase domains of ALK and ROS1 share 77% of amino acids in the ATP-binding sites. Both ALK‑positive and ROS1‑positive advanced NSCLC are similar in terms of clinical behaviour including response to crizotinib, patient characteristics and histology (both are predominantly adenocarcinoma). The European Medicines Agency supported the generalisability of data from ALK‑positive NSCLC to ROS1‑positive advanced NSCLC when granting crizotinib's marketing authorisation in this indication. Twelve UK clinical experts from a company-sponsored advisory board agreed that the data were an appropriate proxy for ROS1‑positive advanced NSCLC.The committee considered the histology of ALK‑positive NSCLC. It understood that the inclusion criteria in PROFILE 1014 specified non-squamous NSCLC and most patients (93%) in PROFILE 1007 had adenocarcinoma histology. The ALK‑positive mutation is more common in people with non-squamous advanced NSCLC than in people with squamous advanced NSCLC and that the testing for the ALK mutation is routinely done in the non-squamous population only. The committee therefore accepted the company's view that both are predominantly of adenocarcinoma histology. The clinical experts stated that in their experience ROS1‑positive advanced NSCLC is even more sensitive to crizotinib than ALK‑positive NSCLC. The committee acknowledged this, but noted the ERG's concern that any documented similarities between ALK‑positive and ROS1‑positive advanced NSCLC may not hold true as more patients with ROS1‑positive advanced NSCLC are identified. The committee noted that median progression-free survival in the ROS1‑positive trial (PROFILE 1001) and the ALK‑positive trials (PROFILE 1014 and PROFILE 1007) differed enough (19.3 months compared with 10.9 months and 7.7 months respectively) to seriously question the comparability of the 2 patient populations. The committee was aware that there are no randomised trials planned for crizotinib in ROS1‑positive advanced NSCLC and comparative data on efficacy is not expected. Furthermore, even the non-comparative data for its use in ROS1‑positive advanced NSCLC were very limited, particularly for untreated disease. The committee agreed that using data from a proxy population was far from ideal, and considered whether it should accept analyses based on treatment effects from a proxy population. Having taken into account the relatively small patient population and the clinical experts' views on the innovative nature of crizotinib, the committee agreed to explore the proxy data in its decision-making. However, it regarded this approach as very unusual and stated that this should not set a precedent for the use of data from proxy populations in future appraisals. # Cost-effectiveness analyses ## All cost-effectiveness analyses are based on proxy data so results are extremely uncertain The committee recognised that the company had presented a revised base-case analysis in response to consultation incorporating some of the committee's preferred assumptions, and a number of scenario analyses that explored alternative values for the overall and post-progression survival benefit of crizotinib. All analyses included a higher utility value for people taking pemetrexed plus platinum-based chemotherapy (see section 3.12) and higher costs for treating pulmonary embolism (see section 3.13). It also incorporated testing costs for untreated disease and assumed sequential testing for previously treated disease (see section 3.2). The committee understood that all the testing costs were for non-squamous NSCLC only. The revised base case incorporated an overall survival benefit for crizotinib of 18.2 months for untreated disease and 20.9 months for previously treated disease. The scenario analyses incorporated a range of values for the overall and post-progression survival benefit of crizotinib explored the impact of excluding testing costs.The committee noted that the revised analyses still extrapolated data for both crizotinib and the comparators from ALK‑positive NSCLC and that it had not presented a revised analysis of the PROFILE 1001 scenario (that used data from ROS1‑positive NSCLC population to model the intervention arm but extrapolated the relative effectiveness from ALK‑positive NSCLC to model the comparator arm). It considered that even with the new analyses, there was still a high degree of uncertainty because of the use of proxy data. Without any reliable evidence on the effectiveness of the comparator treatments in ROS1‑positive advanced NSCLC (see section 3.6), the committee concluded that all of the cost-effectiveness estimates were associated with uncertainty that needed to be accounted for in its decision-making. # Overall survival ## The relationship between overall and progression-free survival is unclear and the size of crizotinib's overall survival benefit is difficult to establish The ERG had questioned the company's original modelled overall survival gain with crizotinib (see table 1), given that the modelled progression-free survival gain was considerably less (9.5 months for untreated disease and 5.7 months for previously treated disease). The committee recalled that the overall survival data from PROFILE 1014 and PROFILE 1007 were confounded by high crossover rates, and that adjustment methods had not been reported transparently (see section 3.7). The clinical experts explained that progression-free survival gains would be expected to result in some overall survival benefit, but the exact relationship is difficult to predict. Nevertheless, the experts agreed that a modelled overall survival gain almost 3 times higher than the modelled progression-free survival gain was most likely to be an overestimate. In its response to consultation and based on clinical expert opinion, the company reported analyses using a range of values for overall and post-progression survival to explore the additional survival benefit with crizotinib. ## Table 1 Summary of the company's analyses Survival gain for crizotinib (months) Analysis Untreated disease Previously treated disease OS PPS OS PPS Original base case Revised base case Scenarios (adapted from ERG) Other scenarios Abbreviations: ERG, evidence review group; OS, overall survival; PPS, post-progression survival. - The company considered that these scenarios were not clinically plausible. Survival gains are from the ERG's critique of the company's response to consultation. The company presented further analyses but these were marked as commercial in confidence so cannot be reported here. The company highlighted that that overall survival gains of at least 13.1 months for untreated disease and at least 16.2 months for previously treated disease had been accepted for crizotinib in the ALK‑positive population (see NICE technology appraisal guidance on crizotinib for untreated ALK-positive advanced non-small-cell lung cancer and crizotinib for previously treated ALK-positive advanced NSCLC) and considered these clinically plausible. The ERG agreed that some post-progression clinical benefit with crizotinib was plausible, but noted that the size of the benefit was highly uncertain and the company's estimates of survival gain were not adequately justified. The committee understood that compared with its original analyses, the company's revised base case included a more conservative post-progression benefit for untreated disease but a larger benefit for previously treated disease (see table 1). The committee concluded that even with the new analyses from the company, there was considerable uncertainty around the size of survival benefit in the progression free and progressed states because the relationship between overall survival and progression-free survival is unclear. ## The mid-point between the ERG's and company's new scenario analyses for overall survival modelling is preferred To explore the uncertainty in the overall survival benefit with crizotinib, the ERG did 2 scenario analyses in its critique of the company's original submission: In the first, the ERG applied the hazard ratio for progression-free survival to the unadjusted (for crossover) overall survival curve of the crizotinib treatment arm. In the second, the ERG assumed no survival benefit other than survival gained in the progression-free state. For this scenario, the ERG adapted the overall survival curve for the comparator to make survival in the progressed state equal for both treatment arms. This means that any survival benefit was attributable to the survival benefit in the progression-free state.For the first scenario analysis, the committee was not convinced that the hazard ratio from 1 outcome could be applied equally to another. The committee considered the ERG's second scenario analysis to be more informative in terms of overall survival modelling, but it did not agree with the way the ERG implemented the analysis. The committee considered that adjusting the crizotinib overall survival curve (to make the survival gain in the post-progression state equal to the modelled survival in the post-progression state of the comparator arm) would have been a better approach. Overall, the committee considered that some relative advantage for crizotinib after disease progression was plausible. In its response to consultation, the company did 4 scenario analyses to explore the clinical plausibility of each of the overall survival models (see section 3.10). This included the company's amendments to the ERG's second scenario analysis that adapted the overall survival curve for crizotinib and included a clinical benefit for crizotinib in the progressed state. The committee understood that these scenarios improved the cost effectiveness of crizotinib for both untreated and previously treated disease. The committee was aware from correspondence with 1 of the clinical experts who had attended the first committee meeting that the company's modelled survival benefits for untreated and previously treated disease were plausible for this small group of young patients with few comorbidities. The expert explained that response to crizotinib in patients with the ROS1‑positive mutation is similar to patients with the ALK‑positive mutation, so an average survival benefit of 24 months is reasonable for both untreated and previously treated disease. The committee concluded that the overall survival gain for crizotinib was somewhere between the company's new scenario analyses using the lower bounds of clinical benefit (that is, an overall survival benefit of 13.1 months for untreated disease and 16.2 months for previously treated disease) and the ERG's estimates assuming no benefit in the progressed state, but reiterated that this analysis was still based on a proxy population and therefore considerable uncertainty remained. # Utility values ## The company's new utility values for the comparator in untreated disease are appropriate for decision-making The company used a utility value of 0.81 for people having crizotinib in both the progression-free and progressed disease states. For people having the pemetrexed plus platinum-based chemotherapy, the company used a utility value of 0.72. People subsequently having docetaxel or best supportive care were given utility values of 0.61 and 0.47 respectively. The committee noted that almost all the values used (with the exception of the utility value for people having pemetrexed plus platinum-based chemotherapy) were the same values accepted by the appraisal committees during the development of NICE technology appraisal guidance on crizotinib for ALK‑positive NSCLC (crizotinib for untreated ALK-positive advanced NSCLC and crizotinib for previously treated ALK-positive advanced NSCLC). During the appraisal of crizotinib for untreated ALK‑positive advanced NSCLC, the ERG had provided exploratory analyses using a utility value for people having pemetrexed plus platinum-based chemotherapy of 0.75 which was deemed appropriate by the committee at the time. The committee agreed that for consistency it would take this slightly higher utility value into account, and that this would decrease crizotinib's perceived cost effectiveness. The committee also noted that the company had not included disutility to account for any adverse reactions, and agreed that this would add further uncertainty to the results. In response to consultation, the company preferred to use a utility of 0.75 for pemetrexed plus platinum-based chemotherapy when patients were not taking treatment and 0.72 when patients were taking treatment. The committee noted that this approach had only a small effect on the cost-effectiveness results and concluded that the utility values used in the company's new analyses were appropriate for decision-making. # Costs ## It is appropriate to include revised costs for treating pulmonary embolism and administering crizotinib The company included higher costs for treating pulmonary embolism as part of its revised base case, noting that these costs were consistent with values used during the development of NICE technology appraisal guidance on ceritinib for untreated ALK-positive NSCLC. The ERG noted that including higher costs for treating pulmonary embolism had only a small effect on the cost effectiveness of crizotinib. The committee understood that the company did not change the administration costs of crizotinib in its revised base case, and noted that including the NHS reference cost for delivering oral chemotherapy (HRG code SB11Z) increased the incremental cost-effectiveness ratios (ICERs) for both untreated and previously treated disease. It also understood that a similar administration cost using HRG code SB11Z was included in a previous NICE technology appraisal in the ALK‑positive population (crizotinib for previously treated ALK-positive advanced NSCLC). The committee concluded that it was appropriate to include higher costs for treating pulmonary embolism and administering crizotinib. # The most plausible ICERs ## The most plausible ICERs for crizotinib are uncertain and not clearly within the range normally considered to be cost-effective use of NHS resources The committee agreed that the new ICERs presented by the company were highly uncertain because of the use of proxy data from ALK‑positive advanced NSCLC and uncertainties in the overall survival extrapolation. For previously treated disease, the committee noted that the ICER range was broader than for untreated disease. The committee recalled that, as a starting point for its discussion, it would consider ICERs at the mid-point between the company's new scenario that included a clinical benefit for crizotinib in the progressed state (assuming an overall survival gain of 13.1 months for untreated disease and 16.2 months for previously treated disease) and the ERG's scenario assuming no survival benefit in the progressed state (see section 3.11). Having considered that some post-progression clinical benefit with crizotinib was plausible but the size was uncertain (see section 3.10), and having established its preferred assumptions for upfront testing costs (see section 3.2) and higher administration costs (see section 3.13), the committee considered that the most plausible ICERs would be: For crizotinib compared with pemetrexed plus platinum-based chemotherapy in untreated disease: around or above £50,000 per quality-adjusted life year (QALY) gained (the exact ICERs were presented as commercial in confidence and therefore cannot be presented here). However, the committee agreed that this estimate came with far too much uncertainty to conclude on a figure below £50,000 without further evidence. For crizotinib compared with docetaxel in previously treated disease: well above £50,000 per QALY gained (the exact ICERs were presented as commercial in confidence and therefore cannot be presented here). The committee agreed that had crizotinib been compared with nintedanib plus docetaxel, the ICER would be even higher. # End of life ## Crizotinib meets both criteria to be considered a life-extending treatment at the end of life The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's technology appraisal process and methods. The company stated that there is limited data on overall survival with chemotherapy in people with ROS1‑positive advanced NSCLC. In the proxy population with ALK‑positive NSCLC, median overall survival ranged from 6 months to 22 months and there is no evidence that it would be better in people with ROS1‑positive advanced NSCLC. The company also highlighted that median overall survival was not reached in PROFILE 1001, and median progression-free survival was 19.3 months, so overall survival with crizotinib in ROS1‑positive advanced NSCLC would be at least 19.3 months. The committee agreed that crizotinib for ROS1‑positive advanced NSCLC met the first criterion to be considered a life-extending treatment at the end of life. The committee noted that the mean overall survival gained with crizotinib, as estimated in the company's revised base case, was 18.2 months for untreated disease and 20.9 months for previously treated disease. Therefore crizotinib may offer, on average, at least 3 months' extension to life compared with standard care. However, it noted the considerable uncertainty around the company's modelling of overall survival and considered that any estimate of an overall survival gain compared with standard care was very uncertain. The committee noted that crizotinib was considered life-extending for people with both untreated and previously treated ALK‑positive NSCLC. Based on the clinical experts' testimony that the ALK‑positive NSCLC population could be used as a proxy for people with ROS1‑positive advanced NSCLC, the committee thought it likely that there was an overall survival gain with crizotinib of over 3 months. The committee concluded that crizotinib met both criteria to be considered a life-extending, end-of-life treatment. ## Crizotinib cannot be recommended for routine use in the NHS Despite meeting both end-of-life criteria, the most plausible ICERs for crizotinib compared with standard care in the company's revised base case were not clearly within the range normally considered to be a cost-effective use of NHS resources. Given the high level of uncertainty in the analyses, the committee concluded that it could not recommend crizotinib for routine use in the NHS to treat ROS1‑positive advanced NSCLC. # Innovation ## Crizotinib represents a step-change in the treatment of ROS1‑positive advanced NSCLC The company stated that crizotinib is innovative because it is the first targeted therapy for ROS1‑positive advanced NSCLC. The US Food and Drug Administration also assigned crizotinib a breakthrough therapy designation, and the marketing authorisation was granted through a priority review. The committee emphasised that the European Medicines Agency had approved crizotinib in this indication based on just 1 single-arm study. The company highlighted that as an oral therapy, crizotinib gives patient more autonomy. Moreover, the company claimed that its quick and durable effect may have wider societal benefits that were not captured in the cost-effectiveness analysis. The committee agreed that crizotinib represents a step-change in the treatment of ROS1‑positive advanced NSCLC. However, the committee concluded that there were no relevant additional benefits that had not been captured in the QALY calculations. # Cancer Drugs Fund ## Using crizotinib in the Cancer Drugs Fund would provide important data and encourage standardisation of ROS1 testing Having concluded that crizotinib could not be recommended for routine use in the NHS to treat ROS1‑positive NSCLC, the committee considered whether it could be recommended for use in the Cancer Drugs Fund. The committee discussed the new arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting the addendum to the NICE process and methods guides. The committee was aware that the overall survival data from PROFILE 1001 were immature and no further analysis was expected in near future. The company stated that some clinical experts consider further comparative trials to be unethical, because of crizotinib's efficacy in treating ROS1‑positive NSCLC in PROFILE 1001. The committee was aware that there are ongoing single-arm observational studies that will provide additional information. However, these studies would only partly address the uncertainties about crizotinib's relative clinical effectiveness. The committee agreed with NHS England that because ROS1‑positive lung cancer has only recently been described, and information on the population characteristics, natural history and prognosis is limited, it would be of great value to collect data about the use of crizotinib in ROS1‑positive advanced NSCLC through the Cancer Drugs Fund. The committee concluded that collecting data on the demographics of people with ROS1‑positive advanced NSCLC, treatment length and disease progression on crizotinib would help to address the uncertainties around the survival benefit and the comparability of ROS1‑positive and ALK‑positive advanced NSCLC populations. The clinical experts commented that the clinical community would welcome an opportunity to contribute to this data collection through the Cancer Drugs Fund; the representative from NHS England indicated that such data could be collected for up to 5 years. The committee further concluded that crizotinib's use through the Cancer Drugs Fund would also encourage standardisation of ROS1 testing. ## Crizotinib is recommend for use in the Cancer Drugs Fund for both untreated and previously treated ROS1‑positive NSCLC Having determined that the most plausible ICER for crizotinib in untreated disease was around or above £50,000 per QALY gained, the committee concluded that crizotinib had plausible potential to represent cost effectiveness through its use in the Cancer Drugs Fund. The ICER based on the current evidence is higher than the range normally considered to be a cost-effective use of NHS resources, but the committee considered that crizotinib's clinical effectiveness was promising and its use through the Cancer Drugs Fund would provide important data to resolve the clinical uncertainties and encourage standardisation of ROS1 testing. For previously treated disease, the committee noted that the ICER range was broader than for untreated disease. The committee noted that when testing for ROS1 became routine practice, most people with ROS1‑positive NSCLC would first have crizotinib and the number of people eligible for crizotinib as a later-line treatment would decrease over time. The committee therefore agreed that it would not make a distinction between untreated and previously treated disease in its recommendations. The committee concluded that it could recommended crizotinib as an option for use within the Cancer Drugs Fund to treat ROS1‑positive NSCLC, only if the conditions in the managed access agreement are followed. ## Crizotinib is most likely to be used in the Cancer Drugs Fund for non-squamous NSCLC only The committee further considered the population for which crizotinib would most likely be used within the Cancer Drugs Fund. It recalled that: in clinical practice, crizotinib is most likely to be used for non-squamous NSCLC; the comparators chosen by the company were for non-squamous NSCLC; the trial results from PROFILE 1001 and the ALK‑positive proxy data from PROFILE 1014 and 1007 were almost exclusively in people with non-squamous histology and predominately in adenocarcinoma; and the testing costs included in the cost-effectiveness analysis were based on a non-squamous lung cancer population. The committee was aware that the incidence of ROS1 in squamous NSCLC is around 1.7% to 1.8%, but recognised that testing of ROS1 status in all patients with NSCLC would be very costly for the Cancer Drugs Fund. It accepted that ROS1 testing and the use of crizotinib in the Cancer Drugs Fund would be in people with non-squamous NSCLC only. # Other factors ## ROS1 testing at diagnosis would reduce potential inequitable access to targeted therapies The company commented that regional variations in access to ROS1 testing could lead to inequitable access, and advocated testing at diagnosis of all non-squamous NSCLC for ROS1 status. The company highlighted that sequential testing (that is, done after testing for EGFR and ALK) would also delay access to crizotinib. The committee agreed that variation in access to treatment does not normally constitute an equality issue under equality legislation. However, the committee considered this potential equality issue and agreed that if crizotinib becomes an available treatment option, ROS1 testing should be done at diagnosis to help prevent potential inequality of access.

Taho Tahô is a Philippine snack food made of fresh soft/silken tofu, arnibal (brown sugar syrup), and sago "pearls" (similar to tapioca pearls). This staple comfort food is a signature sweet and can be found all over the country. # History The history of taho is debatable, but early records suggest it may trace its origin to China. Prior to the Spanish Occupation, Chinese were common traders with Filipinos, thus influencing Philippine cuisine. As douhua is fairly similar in consistency to the taho base, it is thought that early Filipinos adopted, sweetened and used it to create this delicacy. # Processing and preparation Most taho vendors prepare their goods before dawn. The main ingredient, fresh soft/silken tofu is processed to a consistency that is very similar to a very fine custard. Brown sugar is then heated and caramelized to create a viscous amber-colored syrup called arnibal. Sago "pearls," purchased from the local market or palengkê, are boiled to a gummy consistency until they are a transluscent white. # Marketing The Magtataho or taho vendors are a common sight in the Philippines. They are typically male and carry two large aluminum buckets that hang from each end of a long wooden plank or yoke. These buckets are made to fit the needs of a typical magtataho. One of the buckets has a hinged lid in the center and carries nothing but the tofu base, which comprises the bulk of the dessert; the other has a hinged lid that divides the bucket diagonally into two compartments, with one side containing the arnibal and the other containing sago "pearls". Often, this bucket also has another smaller compartment near the lid for keeping change. This contraption is carried on the shoulders, not unlike a yoke, as the vendors ply their route. Taho vendors peddle their product in a trademark manner, calling its name in a full, rising inflection as they walk at a leisurely pace either along the sidewalk or, in rural communities, in the middle of the road. As most magtataho keep a habitual route, it is not uncommon for vendors to call out "Tahoooooô!" to attract a customer's attention. Though vendors are most likely to ply their routes early in the morning, it is not uncommon for a magtataho to be spotted in the late afternoon or the evening as well. This is particularly common in the heart of Manila, most particularly by Manila Bay. # Eating Most magtataho carry plastic cups for their product, often in two sizes (though vendors in residential communities tend to use their customers' cups and price their product accordingly). Using a wide, shallow metal "sandok" or scoop, they skim the surface of the bean curd and toss out any excess water, subsequently scooping the bean curd itself into a cup. Then, using a long thin metal ladle, they scoop sago "pearls" and arnibal into the cup, loosely mixing it in. Taho is enjoyed either with a spoon or by simply "drinking" it from the cup. Though traditionally served warm, cold varieties exist in supermarkets and in food stalls in cafeterias which have the bean curd in a solid, unbroken state. These pre-packed cups tend to contain a firmer tofu which need to be broken up and is sold either with a plastic spoon or a wooden popsicle stick. Due to the increase in popularity of taho over the years, its traditional form may also be found in restaurants or at receptions with a native food theme. A nationwide chain, "Uncle Finn's Soya" is also known for setting up kiosks in mall openings or food courts, thus making the sweet treat available all day.

Cochlea The cochlea is the auditory portion of the inner ear. Its core component is the Organ of Corti, the sensory organ of hearing, which is distributed along the partition separating fluid chambers in the coiled tapered tube of the cochlea. The name is from the Latin for snail, which is from the Greek kokhlias "snail, screw," from kokhlos "spiral shell,"(etymology) in reference to its coiled shape; the cochlea is coiled in most mammals, monotremes being the exceptions. # Anatomy ## Structures The cochlea is a spiralled, hollow, conical chamber of bone. Its structures include: - the scala vestibuli (containing perilymph), which lies superior to the cochlear duct and abuts the oval window. - the scala tympani (containing perilymph), which lies inferior to the scala media and terminates at the round window. - the scala media (containing endolymph), which is the membraneous cochlear duct containing the organ of Corti. - the helicotrema is the location where the scala tympani and the scala vestibuli merge - Reissner's membrane separates the scala vestibuli from the scala media. - The basilar membrane, a main structural element that determines the mechanical wave propagation properties of the cochlear partition, separates the scala media from the scala tympani. - The Organ of Corti is the sensory epithelium, a cellular layer on the basilar membrane, powered by the potential difference between the perilymph and the endolymph. It is lined with hair cells—sensory cells topped with hair-like structures called stereocilia. ## Function In brief: the cochlea is filled with a watery liquid, which moves in response to the vibrations coming from the middle ear via the oval window. As the fluid moves, thousands of "hair cells" are set in motion, and convert that motion to electrical signals that are communicated via neurotransmitters to many thousands of nerve cells. These primary auditory neurons transform the signals into electrical impulses known as action potentials, which travel along the auditory nerve to structures in the brainstem for further processing. The stapes of the middle ear transmits to the fenestra ovalis (oval window) on the outside of the cochlea, which vibrates the perilymph (fluid) in the scala vestibuli (upper chamber of the cochlea). This motion of perilymph in turn vibrates the endolymph in the scala media, the perilymph in the scala tympani, the basilar membrane, and organ of Corti, thus causing movements of the hair bundles of the hair cells, acoustic sensor cells that convert vibration into electrical potentials. The hair cells in the organ of Corti are tuned to certain sound frequencies, being responsive to high frequencies near the oval window and to low frequencies near the apex of the cochlea. The hair cells are arranged in four rows in the organ of Corti along the entire length of the cochlear coil. Three rows consist of outer hair cells (OHCs) and one row consists of inner hair cells (IHCs). The inner hair cells provide the main neural output of the cochlea. The outer hair cells, instead, mainly receive neural input from the brain, which influences their motility as part of the cochlea’s mechanical pre-amplifier. The input to the OHC is from the olivary body via the medial olivocochlear bundle. For very low frequencies (below 20Hz), the pressure waves propagate along the complete route of the cochlea - up scala vestibuli, around helicotrema and down scala tympani to the round window. Frequencies this low do not activate the organ of Corti and are below the threshold for hearing. Higher frequencies do not propagate to the helicotrema but are transmitted through the endolymph in the cochlear duct to the perilymph in the scala tympani. A very strong movement of the endolymph due to very loud noise may cause hair cells to die. This is a common cause of partial hearing loss and is the reason why users of firearms or heavy machinery should wear earmuffs or earplugs. ## Detailed anatomy The walls of the hollow cochlea are made of bone, with a thin, delicate lining of epithelial tissue. This coiled tube is divided through most of its length by a membrane partition. Two fluid-filled spaces (scalae) are formed by this dividing membrane. The fluid in both is called perilymph: a clear solution of electrolytes and proteins. The two scalae (fluid-filled chambers) communicate with each other through an opening at the top (apex) of the cochlea called the helicotrema, a common space that is the one part of the cochlea that lacks the lengthwise dividing membrane. At the base of the cochlea each scala ends in a membrane that faces the middle ear cavity. The scala vestibuli ends at the oval window, where the footplate of the stapes sits. The footplate rocks when the ear drum moves the ossicular chain; sending the perilymph rippling with the motion, the waves moving away from footplate and towards helicotrema. Those fluid waves then continue in the perilymph of the scala tympani. The scala tympani ends at the round window, which bulges out when the waves reach it -providing pressure relief. This one-way movement of waves from oval window to round window occurs because the middle ear directs sound to the oval window, but shields the round window from being struck by sound waves from the external ear. It is important, because waves coming from both directions, from the round and oval window would cancel each other out. In fact, when the middle ear is damaged such that there is no tympanic membrane or ossicular chain, and the round window is oriented outward rather than set under a bit of a ledge in the round window niche, there is a maximal conductive hearing loss of about 60 dB. The lengthwise partition that divides most of the cochlea is itself a fluid-filled tube, the third scalae. This central column is called the scala media or cochlear duct. Its fluid, endolymph, also contains electrolytes and proteins, but is chemically quite different from perilymph. Whereas the perilymph is rich in sodium salts, the endolymph is rich in potassium salts. The cochlear duct is supported on three sides by a rich bed of capillaries and secretory cells (the stria vascularis), a layer of simple squamous epithelial cells (Reissner's membrane), and the basilar membrane, on which rests the receptor organ for hearing - the organ of Corti. The cochlear duct is almost as complex on its own as the ear itself. The ear is a very active organ. Not only does the cochlea "receive" sound, it generates it! Some of the hair cells of the cochlear duct can change their shape enough to move the basilar membrane and produce sound. This process is important in fine tuning the ability of the cochlea to accurately detect differences in incoming acoustic information. The sound produced by the inner ear is called an otoacoustic emission (OAE), and can be recorded by a microphone in the ear canal. Otoacoustic emissions are important is some types of tests for hearing impairment. # Comparative physiology The coiled form of cochlea is unique to mammals. In birds and in other non-mammalian vertebrates the compartment containing the sensory cells for hearing is occasionally also called “cochlea”, although it is not coiled up. Instead it forms a blind-ended tube, also called the cochlear duct. This difference apparently evolved in parallel with the differences in frequency range of hearing and in frequency resolution between mammals and non-mammalian vertebrates. Most bird species do not hear above 4–5 kHz, the currently known maximum being ~ 11 kHz in the barn owl. Some marine mammals hear up to 200 kHz. The superior frequency resolution in mammals is due to their unique mechanism of pre-amplification of sound by active cell-body vibrations of outer hair cells. A long coiled compartment, rather than a short and straight one, provides more space for frequency dispersion and is therefore better adapted to the highly derived functions in mammalian hearing. As the study of the cochlea should fundamentally be focused upon the level of hair cells, it is important to note the anatomical and physiological differences between the hair cells of various species. In birds, for instance, instead of outer and inner hair cells, there are tall and short hair cells. There are several similarities of note in regard to this comparative data. For one, the tall hair cell is very similar in function to that of the inner hair cell and the short hair cell is very similar in function to that of the outer hair cell. One unavoidable difference, however, is that while all hair cells are attached to a tectorial membrane in birds, only the outer hair cells are attached to the tectorial membrane in mammals.

Acute Lymphoblastic Leukemia (ALL) is a highly aggressive hematological -malignancy resulting from the proliferation and expansion of lymphoid blasts in the blood, bone marrow and other organs. 1 ALL occurs with a bimodal distribution with an early peak in children 4 -5 years old followed by a second peak at ~ 50 years of age 2 with the worldwide incidence being ~ 1 -4.75/100,000 individuals with a male:female prevalence of roughly 13:1. 1 It is the most common childhood acute leukemia accounting for ~ 80% of the pediatric leukemias but contributing to only 20% of adult leukemias. Although significant progress has been made in treating adult ALL the overall survival amongst adults 18 to 60 years old is only 35% in contrast to childhood ALL in which overall survival at five years is more than 80%. 1 Over the past two decades the treatment of adult ALL has changed significantly with the introduction of pediatric protocols for the treatment of adolescents and young adults, the addition of tyrosine kinase (TKI) inhibitors for the treatment of Philadelphia positive/BCR-ABL positive ALL, a reevaluation of the role of allogeneic stem cell transplantation for standard risk ALL patients, the incorporation of minimal residual disease into risk assessments and most recently the introduction of novel agents such blinatumomab, inotuzumab and chimeric antigen receptor -T cell therapy for relapsed/refractory ALL. # Search Strategy The PubMed database was searched for relevant studies, guidelines and consensus documents published using the search term 'Acute Lymphoblastic Leukemia'. Clinical trials, clinical practice guidelines, systematic reviews and meta analyses written in English were included. # Target Population The following recommendations apply to adult cancer patients with suspicion or diagnosis of ALL. 2. Pre-treatment risk stratification should be ascertained for all patients using age and cytogenetics/FISH and/or molecular studies. # Summary of Recommendations Post-treatment risk stratification should include the outcomes of minimal residual disease assessment using either flow cytometry or PCR (see below) Principles of Treatment Initiation 1. Induction therapy should only be administered in a leukemia centre with physician and nursing expertise in the management of acute leukemias. - Induction therapy should not be initiated until the BCR-ABL status is known. If the patient is symptomatic, a steroid pre-phase should be indicated. Initiation of induction therapy should be accompanied by tumour lysis syndrome (TLS) prophylaxis, including hydration, urate lowering agents and close monitoring of TLS chemistries. Treatment of Ph/BCR-ABL negative ALL 1. Eligible adults under age 60 should be treated with a pediatric-based protocol. a. In Alberta the current standard regimen is the modified Dana Farber Cancer Institute (DFCI) protocol. b. Patients with co-morbidities, or those unable to tolerate the full DFCI protocol, may be treated with a less intensive regimen, such as the modified DFCI protocol for patients age 60 or over. 2. Fit adults age 60-75 should be treated with curative intent. a. The Princess Margaret Hospital modified DFCI protocol for adults above age 60 has produced favourable results in this population compared to other regimens and may be used. Other curative-intent regimens are also acceptable. 3. Patients over age 75, or those under age 75 with major co-morbidities precluding intensive chemotherapy, should be considered for palliative chemotherapy with corticosteroids and vincristine +/-low-dose asparaginase, followed by low-dose maintenance chemotherapy if CR is achieved. Treatment of Ph/BCR-ABL positive ALL 1. Ph/BCR-ABL positive patients who are fit for chemotherapy should be treated with a BCR-ABL tyrosine kinase inhibitor (TKI) combined with induction and post-remission therapy. a. A less intensive induction regimen with corticosteroids, vincristine and TKI (e.g. Chalandon protocol) is preferred for initial induction, as it produces higher CR rates due to lower induction mortality. In younger, fit patients, this should be followed by intensification (e.g. HyperCVAD Part B + TKI, as per the Chalandon protocol). b. Patients achieving a hematologic CR should be continued on post-remission chemotherapy + TKI. This may consist of the modified Princess Margaret Hospital DFCI CNS, intensification and maintenance phases, or HyperCVAD + TKI. Asparaginase should not be used due to increased toxicity when used concurrently with TKI. c. Imatinib (600 -800mg per day), is currently the standard first line TKI drug. i. Patients with intolerance to, or not achieving an adequate response to, imatinib should be switched to a second generation TKI such as dasatinib ii. Ponatinib should be used in patients with a T315I mutation iii. For patients with CNS disease at diagnosis, dasatinib should be used upfront due to its superior CNS penetration. d. Patients with Ph/BCR-ABL positive ALL who are elderly, or otherwise unfit for intensive chemotherapy or transplant, should be treated with the Chalandon induction protocol cycle A, or corticosteroids + TKI, followed by low-dose maintenance chemotherapy + TKI. e. TKIs should be continued indefinitely in patients who are not transplanted. f. Patients not transplanted should be closely monitored for disease progression with serial PCR testing every 3 months. Reappearance of PCR positivity, if confirmed, should prompt a change in TKI and referral for allogeneic HSCT, if a potential candidate. g. Patients with persistence of, or reappearance of BCR-ABL transcripts by PCR, should have mutational testing, specifically to look for the presence of a T315I mutation. # Role of MRD (minimal or measurable residual disease) assessments - Ph/BCR-ABL negative patients should have MRD assessments following induction chemotherapy, or by week 16, by flow cytometry or molecular techniques. a. MRD positive B-ALL patients, defined as > 0.1% of mononuclear cells by flow (>10 -3, should receive immuno-therapy using 1-2 cycles of blinatumomab with an intent to achieve MRD negativity. b. MRD positive T-ALL patients should receive intensified chemotherapy with an intent to achieve MRD negativity. c. MRD positive patients post-intensive induction or at week 16, defined as > 0.1% of mononuclear cells by flow, should be considered for allogeneic HSCT in CR1, as these patients are at higher risk of relapse. - Ph/BCR-ABL positive patients should have MRD assessments following induction chemotherapy, or by week 16, by quantitative PCR. a. Patients who are MRD positive by PCR at the end of a two-cycle induction using the Chalandon protocol, or by week 16 using other protocols, should be switched to a second generation TKI such as dasatinib. If already on a 2 nd generation TKI, the patient should be switched to ponatinib. The TKI should be combined with either chemotherapy or blinatumomab. b. MRD positive patients at these timepoints should be referred for allogeneic HSCT in CR1, as per below. Role of allogeneic stem cell transplantation 1. Allogeneic HSCT should not be routinely performed in patients with Ph/BCR-ABL negative ALL in CR-1. However, patients with the following high-risk features should be considered for HSCT: i. t(4;11) with MLL (KMT2A) rearrangement ii. Early T-cell precursor (ETP) ALL iii. Lack of attainment of hematologic CR with first induction iv. MRD positivity at end of induction or by week 16, as per above. v. Inability to deliver sufficient asparaginase dosing during intensification therapy a. There is no clear evidence that other cytogenetic abnormalities, or specific cell surface markers, constitute high risk features when using a pediatric-based regimen b. It is also not clear whether patients with a high-risk feature at baseline who achieve MRD negativity after induction therapy require a transplant. 2. Fit BCR-ABL positive patients up to age 70 may be considered for allogeneic HSCT in CR-1. a. Patients with BCR-ABL positivity by PCR, either post-induction or by week 16 (depending on the regimen), should be referred for allogeneic HSCT, as per 6.1.3. If an HLA matched related or unrelated donor is unavailable, a haploidentical transplant should be considered. b. Patients achieving early MRD negativity by PCR, either post-induction or by week 16 (depending on the regimen), may be continued on post-induction chemotherapy together with TKI without a transplant. Transplant is also an option in these patients. c. Reappearance of PCR positivity with monitoring, if confirmed, should prompt a referral for allogeneic HSCT, if a potential candidate, as per above. # CNS prophylaxis 1. Intrathecal chemotherapy: All patients should receive intrathecal chemotherapy prophylaxis, starting with the initiation of induction therapy, and continuing through maintenance therapy, for 11-12 total doses. a. If the initial CSF is positive, intrathecal chemotherapy should be administered twice weekly until CSF clearance is confirmed on at least 3 occasions. Cranial Radiation: Cranial radiation may be omitted from CNS prophylaxis, unless there is evidence of fixed CNS disease. # CAR T-Cell Therapy: - Indicated for fit B-ALL patients relapsing after allogeneic HSCT, refractory to 2 induction regimens, or relapsed and not considered suitable candidates for HSCT. Patients should be referred for apheresis prior to administering salvage immunosuppressive chemotherapy such as corticosteroids or cyclophosphamide, to avoid interfering with the quality of the product. Patients should in most cases receive bridging/cytoreductive therapy following apheresis, to prevent clinical deterioration due to disease progression and to achieve cytoreduction prior to CAR T infusion. This may consist of either chemotherapy or antibody-based therapy. # Discussion and Recommendations Pathogenesis ALL is thought to arise from interactions between exogenous or endogenous exposures, genetic susceptibility, and chance. Infection was the first suggested causal exposure for childhood acute lymphoblastic leukemia. After the Hiroshima and Nagasaki atomic detonations, ionizing radiation quickly became established as an exposure leading to childhood ALL. 3 Chromosomal translocations occurring in utero during fetal hematopoiesis have been suggested as the primary cause for pediatric ALL while postnatal genetic events are considered secondary contributors. 4,5 Many of these chromosomal rearrangements disrupt genes that regulate normal haematopoiesis and lymphoid development (e.g. RUNX1, ETV6), activate oncogenes (eg, MYC), or constitutively activate tyrosine kinases (e.g. ABL1). Patients with trisomy 21, Klinefelter's syndrome and inherited diseases with excessive chromosomal fragility such as Fanconi's anemia, Bloom's syndrome and ataxiatelangiectasia have a higher risk of developing ALL. 6 However, in the majority of ALL patients no gross chromosomal alteration is noted suggesting that additional submicroscopic genetic alterations likely contribute to leukaemogenesis. 5 Genome-wide association studies of childhood 5 have noted common allelic variants in IKZF1, ARID5B, CEBPE, and CDKN2A which have been significantly and consistently associated with childhood ALL. 5 Others have investigated the associations of genetic polymorphisms in folate pathway and DNA repair genes with susceptibility to ALL. 7 Although several genetic alterations have well established roles in leukemogenesis (e.g. activating mutations in NOTCH1) the roles of many others remains elusive. # Clinical Manifestations, Diagnosis, and Work-up Clinical manifestations of ALL are highly variable. At presentation patients may have a multitude of constitutional symptoms, easy bruising, bleeding, dyspnea, dizziness, and infections due to anemia, thrombocytopenia and neutropenia. Extremity and joint pain may be the only presenting symptoms in some patients. 8 Lymphadenopathy, splenomegaly and/or hepatomegaly are seen on physical examination in approximately 20% of patients. 8 Abdominal masses from gastrointestinal involvement or chin numbness from cranial nerve involvement may be seen but are more suggestive of mature B-ALL. Less than 10% of patients have symptomatic central nervous system (CNS) involvement. Tlineage ALL with a mediastinal mass can cause stridor and wheezing, pericardial effusions, and superior vena cava syndrome. Testicular involvement is rare in adults. 9 The diagnosis of ALL begins with an evaluation of the peripheral blood film which may identify the presence of blasts. Patients presenting with only a mediastinal mass or lymphadenopathy require a tissue biopsy. All patients should have a bone marrow examination. As per the 2008 and 2016 WHO classifications, in contrast to myeloid malignancies, there is no agreed-upon lower limit for the percentage of blasts required to establish a diagnosis of lymphoblastic leukemias. 10 Despite this, some guidelines suggest that the diagnosis of ALL requires demonstration of > 20% blasts in the bone marrow aspirate/biopsymaterial. 8 By convention the term lymphoma is used when the process is confined to a mass lesion with no or minimal evidence of peripheral blood and bone marrow involvement. Based on morphologic, genetic and immunophenotypic features, lymphoblastic lymphoma is indistinguishable from ALL, and is in fact not distinguished in the WHO 2016 classification. The assessment of immunophenotype by flow cytometry is essential to establishing the diagnosis. 9 The initial immunophenotyping panel should be comprehensive enough to establish a leukemia associated phenotype (LAP) to allow for use in minimal disease monitoring (MRD). Cytogenetic examination with examination of metaphases and/or fluorescence in situ hybridization (FISH) is crucial (eg, for BCR-ABL and MLL-AF4) particularly in cases in which cytogenetics are unavailable or have failed. Screening by polymerase chain reaction (PCR) for the BCR-ABL transcripts is also essential as it significantly impacts treatment. Determination of the BCR-ABL breakpoint is also required for subsequent molecular monitoring. Some labs also evaluate blast cells with molecular methods for the detection of patient-specific immunoglobulin and T-cell receptor (Ig/TCR) rearrangements 9 ; however, this is not routinely performed within Alberta. If bone marrow transplant is a consideration, tissue typing of both the patient and siblings should also be performed at diagnosis. If there are no HLA-matched siblings, consideration should be given to prompt initiation of an unrelated donor search. The initial work-up of patients with ALL should include a thorough history and physical examination as well as baseline laboratory investigations including complete blood count, chemistry with extended electrolytes, tests of renal and liver function including amylase and lipase, a disseminated intravascular coagulation panel, and a tumour lysis panel. Cardiac imaging e.g. echocardiogram, multigated acquisition (MUGA) scan or cardiac MRI should be undertaken for all patients due to the use of anthracyclines. Bone marrow studies or peripheral blood studies incorporating, as noted above, immunophenotyping, cytogenetics, and molecular studies should be completed. Ideally results of BCR-ABL testing should be available prior to the initiation of induction therapy, and should be available within 5 days. Lastly, patients eligible for allogeneic stem cell transplantation, and their siblings should have human leukocyte antigen (HLA) typing performed. # Classification and Prognostication # Classification of ALL: The WHO 2016 classification is largely based on recurrent cytogenetic abnormalities, but also includes molecular markers such at KMT2A and BCR-ABL (Table 1). There is also a new provisional entity encompassing the BCR-ABL-like genotype (described later), which is not to this point readily diagnosed using routine testing. B-lymphoblastic leukemia/lymphoma NOS encompasses all subtypes not otherwise defined by one of the recognized abnormalities. It is notable that this classification does not primarily distinguish between different immunophenotypic features, apart from the provisional T cell entities. It also does not distinguish between Tlymphoblastic lymphoma and T-ALL, acknowledging the widely held view that these are different clinical presentations of the same disease, and should be managed similarly. On the other hand, early T-cell precursor (ETP) lymphoblastic leukemia has been identified as a distinct subtype with unque biologic and clinical characteristics. # Prognostic Factors in ALL: Prognostic models for ALL have been refined continuously with improvements in therapy rendering some prognostic variables invalid. 9 The following represent clinical, cytogenetic and important molecular risk factors. It is important to note that many of these factors were defined using adultbased protocols and more studies are needed to evaluate their significance with pediatric based protocols. # Clinical Prognostic Factors: # Age, Gender and Ethnicity Age is an important prognostic factor in ALL. In children age (infant or ≥10 years old) is an unfavourable risk group especially those younger than 6 months old. 5,17 Regardless of the treatment protocol utilized older adults are regarded as a prognostically unfavorable group. One study noted that the outcomes of patients aged over 55 had a probability of survival of 20% at 3 years while others have noted that patients over the age of 35 have poorer outcomes. Recent data suggest that adolescents and young adults benefit with improved overall survival if treated according to pediatric protocols. 1 Several studies have suggested that the influence of age may relate to the increased prevalence of poor-risk features while others have suggested that it is independent of cytogenetic and molecular aberrations. 16,17 The ability to tolerate chemotherapy likely plays an important role. 13,18,19 Together with age, male gender and race (Hispanic or of African descent) have been considered negative prognostic factors in pediatric ALL Inaba, 2013 #20. Racial differences in prognosis have been linked to socioeconomic factors but also to differences in genomic variations. For example, germline single nucleotide polymorphisms of PDE4B and ARID5B are associated with Native American genetic ancestry and somatic CRLF2 were over-represented in children with a Hispanic background. # White Blood Cell Count In children, a presenting leucocyte count (≥50 × 10⁹/L) has been associated with a worse prognosis. 17 In many, but not all adult studies of ALL, high-risk ALL has been defined as WBC ≥ 30 x 10 9 /L for Bcell ALL and ≥100x10 9 /L for T-cell ALL. 1,11, Although most early studies identifying this factor used adult-based protocols, subgroup analyses in larger studies show that these continue to be important prognostic factors with pediatric-inspired regimens Brandwein, 2011 #51;Boissel, 2003 #357. In their study of the DFCI protocol in adults a high WBC (>30 x 10 9 /L for Pre-B ALL or >100 x 10 9 /L for T-ALL) was associated with inferior RFS and OS. 20 However, subsequent studies incorporating early MRD detection into multivariate models have demonstrated that baseline WBC was no longer an independent predictor of relapse (see section on MRD). 21 The SEER database demonstrated a better prognosis with B cell as compared with T cell immunophenotype in patients < age 20 years; while in patients ≥ 20 years of age, T cell immunophenotype was more favorable. 22 This was confirmed in a metanalysis by Kako 23 Amongst adults T-cell ALL accounts for 14-22% of adult ALL 24 and is thought to be of favourable prognosis. In both the LALA 87 and the UKALL/EGOG 2993 trial, T-ALL was associated with male gender, age <35 -39 years old, CNS involvement and a high WBC count. The LALA-87 investigators also noted a higher incidence of a mediastinal mass and anemia. 15,24 In this study for patients age <40 treated with chemotherapy alone 3 year DFS was superior in the group with a T-cell phenotype relative to a B-ALL phenotype (59% vs. 20%). No difference in DFS was seen in patients with B-or T-ALL patients treated with allo-or auto -HSCT. 24 Similarly, Both Rowe et al. and Larson et al. noted that improved OS in patients with T-cell antigen expression relative to B-lineage antigens. 13,18 Kantarjian et al. using Hyper-CVAD noted similar results. 12 Using the pediatric Dana Farber Cancer Institute (DFCI) protocol a trend toward improved clinical outcomes was observed in adolescents 25 and adults 20,26 with T-ALL. The GRAALL study group 94 noted that when using a pediatric protocol at 42 months, EFS was estimated to be 62% (95% CI, 50% to 72%) in T-ALL patients and 52% (95% CI, 42% to 59%) in BCP-ALL patients (p=0.09). Within the T-cell ALL subset the prognosis is worse for pro-, pre-and mature-T subtypes (CD1a-, CD3-/CD3+) compared with the CD1a+ cortical/thymic phenotype. The early T-cell precursor ALL which retains stem cell-like features is associated with a dismal prognosis with conventional chemotherapy 27 in both adult and pediatric T-ALL. 28 As noted above, several studies have suggested that patients with B-cell phenotype fare worse than those with T-ALL. Patients with a CD10-negative pro-B phenotype are considered as high-risk particularly when associated with t(4;11)/abn q23. 1,26 The pre-B subtype expressing cytoplasmic heavy chains has a bad outlook when harboring MLL rearrangements. The CD20 antigen is expressed in nearly half of B-cell ALL and its impact on clinical outcomes is controversial. Maury et al. when using the pediatric GRAALL 2003 protocol in adults aged 15-60 years old with Ph-negative ALL noted that CD 20 expression did not influence achievement of complete remission but was associated with a higher cumulative incidence of relapse (CIR) and lower EFS at 42 months (42% vs. 29%) in patients with a WBC ≥ 30 ×10 9 /L (P=0.006). Thomas et al. also noted an inferior survival in CD20 positive patients using the adult-based hyper-CVAD protocol. 29 In contrast, a retrospective analysis by the Princess Margaret Hospital groups in adult patients, most of whom had received a pediatricbased regimen, did not find any association between CD20 expression and outcome 30 and in-fact there appeared to be a trend towards a favourable EFS in those showing CD20 positivity. # Cytogenetic Studies Karyotype is an important prognostic factor with a number of cytogenetic abnormalities being associated with altered prognosis in ALL (Table 2). The frequency of cytogenetic aberrations varies between adult and childhood ALL and may partially explain the differences in clinical outcomes between patient populations. 8 Whether cytogenetic abnormalities remains important with the use of pediatric protocols in adult patients remains unclear; some studies suggest that most abnormalities are not independent predictors of outcome in adults treated with such protocols, with the exception of KMT2A-associated abnormalities. 20,21,26 The Philadelphia chromosome, characterized by the t(9;22) translocation resulting in production of a BCR-ABL1 fusion gene and protein, is the most common cytogenetic and molecular abnormality in adult ALL. The frequency is age-dependent, being present in approximately 8-10% of adolescents, 15-30% of younger and middle aged adults, and 40-50% of elderly ALL patients. 9 Over two-thirds have the p190 gene, with the remaining harbouring the p190 gene. Until recently the BCR-ABL1 fusion gene marked the most unfavourable subgroup of adult ALL. With chemotherapy alone the CR rate was 75%-80%, median DFS about 10 months and 5-year survival below 10-20%. 26,31,32 Most studies demonstrated superior outcomes with allogeneic HSCT compared to chemotherapy alone. 26,31,32 Combinations of tyrosine kinase inhibitors (TKIs) with chemotherapy have produced superior outcomes to chemotherapy alone, as will be discussed later. The t(4;11) is present in up to 60 % of infants younger than 12 months but is uncommon in adult patients, constituting 5-10% of cases. When rearranged, the MLL (now called KMT2A) gene has been found to be associated with inferior RFS and OS in adult patients when using a pediatric protocol. 20 The t(1;19) is uncommon in adults; its prognostic significance is unclear, with conflicting data. Garg et al. noted that adults treated with Hyper CVAD had a significantly better CRD and OS compared with all other patients. 33 However, Foa et al. found that this abnormality is frequently associated with early treatment failure, and recommended that these patients should be considered for intensified treatment strategies. 34 The t(12;21) abnormality leading to ETV6-RUNX1 fusion is detectable in about 25 % of children and 3 % of adults with B-ALL. Patients generally have a favorable prognosis. 35,36 Hyperdiploidy (>50 chromosomes) is seen in approximately 25% -30% of paediatric cases and 7% of adults and represents the most common chromosomal abnormality in children. It is associated with a favourable prognosis regardless of age and leukocyte count at presentation. 37,38 Its characteristic genetic feature is the nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21, with individual trisomies or tetrasomies being seen in over 75% of cases. The individual structural abnormalities do not appear to influence outcome in patients with hyperdiploidy except for the t(9;22), which is associated with a poor prognosis. 39 The favourable prognosis may reflect an increased propensity of these cells to undergo apoptosis. 17 In contrast, 5 % to 6 % of ALL patients, independent of age, have the loss of various chromosomes, resulting in a hypodiploid clone with fewer than 44 -46 chromosomes. These patients generally have a poor prognosis, especially those with near-haploid and low-hypodiploid clones. 17,36,40 Recent data suggest that complex karyotypes (≥ five chromosomal abnormalities) occur more frequently with increasing age and may be associated with inferior survival. 15,26,41 Intrachromosomal amplification of chromosome 21 (iAMP21) occurs at an incidence up to 2 % in older children with B-cell precursor ALL Harrison, 2005 #1056 and is defined by at least three copies of the RUNX1 gene (Children's Oncology Group, COG, definition for iAMP21). iAMP21 has been shown to be linked to a dismal outcome when patients are treated with standard therapy, because it is associated with an increased risk of both early and late relapses. 36, It is rare in adults. Many of these prognostic factors may be regimen dependent. Many older studies used adult-based protocol. In contrast, using pediatric based regimens, most of these cytogenetic abnormalities have not been found to be of prognostic importance in adults, with the notable exception of t(4;11). # Molecular Studies Molecular genetics has identified several gene mutations, translocations and amplifications that may have prognostic significance in ALL. IKZF1 encodes IKAROS which has been established as one of the most clinically relevant tumor suppressors in ALL. It is a DNA-binding zinc finger transcription factor that regulates the development and function of the immune system and acts as a master regulator of normal hematopoietic differentiation and proliferation, particularly in lymphoid lineage. 48 Deletion of a single IKZF1 allele or mutations of a single copy of IKZF1 were first detected in 15 % of pediatric B-cell ALL and in more than 80 % of Ph+ ALL cases, either de novo Ph+ ALL or chronic myeloid leukemia at progression to lymphoid blast crisis suggesting a critical role in the pathogenesis of Ph+ ALL. The incidence in adults is about 50% in B-cell ALL and about 65% when BCR-ABL positive. Recent data further suggest that together with Ph+ve ALL, mutations in IKZF1 are also a hallmark of 'BCR-ABL1-like ALL. 5 Alteration of the IKAROS gene is associated with increased risk of treatment failure and relapse in both BCR-ABL1-positive and BCR-ABL1-negative disease independent of commonly used risk stratification features such as age, sex, white cell count, and levels of minimal residual disease (MRD). 21,52 PAX5 encodes a transcription factor known as B-cell specific activator protein, that plays a key role in B-cell commitment by activating essential components of the B-cell receptor signaling and repressing the transcription of genes necessary for T-lymphopoiesis. 53 Monoallelic deletion of PAX5 have been observed in about 30 % of children and adults 54,55 and have been demonstrated to not influence treatment outcome. 36,55,56 The CDKN2A/B locus encodes for the INK4-class cyclin dependent kinase inhibitors p15INK4B, p16INK4A and for p14ARF. CDKN2A and CDKN2B deletions have been identified in 29 % and 25 % of BCR-ABL1-positive ALL patients, respectively. 57 The association with prognosis is still controversial. 36,57,58 Four independent groups in late 2009 and early 2010 identified that up to 50 % of BCR-ABL1-like ALL cases have dysregulated expression of CRLF2, the gene encoding the cytokine receptor-like 2 factor. 56, Overall aberrant expression of CRLF2 was found in 12. Mutations of NOTCH1, a transmembrane receptor-encoding gene that regulates normal T-cell development, have been detected in in about 60% of T-ALL. 63 Early studies in paediatric T-ALL showed that NOTCH1 mutations may be associated with a favourable prognosis. 21, Similarly, in adult T-ALL patients, studies have demonstrated a better prognosis for patients with NOTCH1 and/or FBXW7 mutations, 67,69 but this could not be validated in a series of 88 patients treated in the MRC UKALLXII/ECOGE2993 protocol 70 or by the Zhu et al who in fact noted that Chinese adult TALL patients with mutated NOTCH1 had poorer survival compared with those with wild-type NOTCH1. 71 Overall these studies seem to suggest that NOTCH activation is associated with improved early therapeutic response. However, this early benefit translates into improved overall survival only in some series, probably due to differences in therapy. 63 Gene Expression Profiling: # BCR-ABL like ALL Mullighan and colleagues identified some patients with Ph-negative ALL which had a gene expression profile almost identical to Ph+ ALL and which were termed Ph-like ALL. 54,56,72 This genesignature has been noted in approximately 15% of pediatric cases, but the frequency is as high as 33% in adults with B-ALL. 73 Genetic alterations of activating kinases or cytokine receptor signaling, incuding ABL, JAK2, CSF1 and EPOR, are commonly observed in addition to overexpression of cytokine receptor-like factor 2 (CRLF2) and frequent deletions of IKZF1. 54,56,72,74 Some studies have found higher levels of MRD after induction therapy, 74,75 increased relapse rates and inferior overall survival. 8 However, reliable testing for this genotype is not routinely available in most laboratories, including in Alberta. # Early T-cell precursor acute lymphoblastic leukaemia (ETP -ALL) ETP -ALL accounts for 12% of paediatric T-ALL. It is an aggressive leukaemia characterised by an immature immunophenotype with lack of CD1a and CD8 expression, weak CD5 expression 76 and aberrant expression of myeloid and stem cell markers (CD117, CD34, HLA-DR, CD13, CD33, CD11b, or CD65) on at least 25% of lymphoblasts. 8 The long-term response to therapy is one of the worst among recognized high-risk forms of childhood ALL. 27 In one study, the 10 year OS was 19% compared with 84% in the non-ETP ALL. 27 Similarly inferior outcomes have been reported in adults with ETP-ALL. 77,78 The mutational spectrum in ETP-ALL is similar to myeloid tumours with a high frequency of activating mutations in the cytokine receptor and RAS signaling pathways including NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3, and BRAF, raising the possibility that addition of myeloid-directed therapies might improve the outcome of ETP ALL. 79 Given the poor outcomes with conventional ALL regimens, most ETP-ALL patients are referred for allogeneic HSCT in CR1, where there are data suggesting a survival benefit. 78 # Pharmacogenetics and pharmacogenomics Genome-wide analyses have identified specific gene signatures which may be prognostically relevant when associated with drug resistance e.g. polymorphism of genes metabolizing thiopurines, methotrexate, and cytarabine all of which have been associated with variable treatment response and are a mechanisms of drug resistance. 1 Rocha et al noted that the glutathioneS-transferasel1(GSTM1) non-null genotype was associated with a higher risk of recurrence, which was increased further by the thymidylate synthetase (TYMS) 3/3 genotype. Others have observed that hyperdiploid cells accumulate more methotrexate polyglutamates as they possess extra copies of the gene encoding reduced folate carrier, an active transporter of methotrexate. Hareedy et al found significant associations between variants in genes coding for enzymes and transporters related to the 6mercaptopurine pathway and clinical outcomes as well as hematological toxicity (neutropenia, agranulocytosis and leukopenia) in pediatric patients with acute lymphoblastic leukemia. 80 The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. Gregers et al. noted statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL. 81 # iAMP of chromosome 21 Poor prognosis 2% of older children with B-ALL. Favourable prognosis 25-30% of cases; nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21; The favourable prognosis may reflect an increased propensity of these cells to undergo apoptosis. Poor prognosis 5-6% of ALL patients; near haploid and lowhypodiploid have the worst prognosis. # Complex Karyotype Poor prognosis More than 5 chromosomal abnormalities. # Molecular Genetics IKZF1 mutations Poor prognosis Most commonly present in BCR-ABL + ALL or BCR-ABL like ALL. # Abnormality Clinical Impact Notes PAX5 No effect on treatment outcomes 30% of adults and paediatric patients. # Pre-Treatment Risk Stratification Over the past twenty years there has been continued debate regarding the risk stratification of patients with ALL with different groups using the above clinical, immunophenotype, cytogenetics and molecular tests to variably group patients into those that are standard risk, high risk or very high risk of having a leukemia relapse. As discussed, many of these discrepancies may be related to the type of treatment reigmens used (adult vs pediatric-based), and whether MRD analysis is taken into consideration in risk stratification. Recent studies have found that, using pediatric-based protocols, most cytogenetic abnormalities are not independent predictors except for certain abnormalities, such as KMT2A-based abnormalities, t(9;22) and possibly hypodiploidy. 21,45 Given the poor prognosis of patients with Ph+ve ALL, the initial risk stratification for all patients should be based on the presence or absence of t(9;22)/BCR-ABL1. Amongst Ph-ve patients the NCCN considers those with hypodiploidy ( 30 for B-cell ALL and >100 for T-cell ALL were important risk factors, 20 MRD has since been demonstrated to be a more important predictor on multivariate analysis (discussed below). However, age remains an important predictor of outcome in nearly all studies, with patients > age 30-35 having worse outcomes than so-called AYA (adolescent and young adult) patients. 20 Recent evidence suggests that molecular profiling, and specifically the detection of a Ph-like genetic signature as discussed, may be the most important pre-treatment predictor of outcome in adults and children with BCR-ABL negative B-ALL. However, detection is time consuming and labour intensive, and is not routinely available at most centres, including in Alberta. All patients should be classified as having B-cell or T-cell ALL based upon immunophenotyping results. Although some of the above noted prognostic factors are beyond the scope of routine clinical laboratories, all patients, should undergo cytogenetic evaluation and, if unsuccessful, FISH for the determination of the most clinically significant abnormalities, in particular BCR-ABL and MLL gene rearrangements. There is no convincing evidence that other cytogenetic abnormalities or cell surface markers add to risk-stratification when using paediatric or paediatric inspired protocols. Given the increasing recognization of minimal residual assessments, all patients should have immunophneotyping performed. This can be used to guide post-induction treatment. # Post-Treatment Risk Stratification # Role of MRD Assessments in the Management of Patients with ALL: Measurable (or minimal) residual disease (MRD) refers to the detection of small amounts of residual disease, undetectable by morphology. Techniques for MRD detection include multiparameter flow cytometry (MPFC) or molecular techniques. For BCR-ABL+ ALL, molecular detection is readily performed by qRT-PCR for BCR-ABL1, and is regarded as the gold standard for MRD detection. For BCR-ABL negative ALL, many European studies have used immunoglobulin gene rearrangements for MRD detection; however, this technique is labour intensive and requires detection of the specific rearrangement for each patient. Consequently, MPFC is widely used for MRD detection due to its ease, and has a sensitivity of 10 -3 -10 -4 ; it is the technique used in Alberta. Based on the paediatric literature, a number of studies over the past 15 years have explored the role of MRD in adults with ALL. Most of these have suggested that MRD may be the single most important factor predicting clinical outcomes. 9 A number of investigators have described differences in patterns and dynamics of clearance of MRD between adult and childhood ALL as well as between B-and T-cell ALL. Foroni et al. noted that MRD decreased faster in children than in adults particularly in the first 6 months of CR 96 while Parekh et al. noted that MRD clearance was slower with T-ALL. 97 Bruggemann and colleagues measured MRD at 9 different time points ranging from 11 days post-induction up to to 52 weeks post induction. 98 Only a minority of patients had undetectable MRD at day +11 while at 6 weeks approximately 50% had undetectable MRD. Several groups have explored the prognostic value of MRD in adult ALL patients. Bruggman and colleagues noted that a combination of MRD measurements at day 11, day 24 and 16 weeks could classify patients into those with a low likelihood of ALL relapse (MRD -ve at day 11 and day 24), high likelihood of relapse (MRD + at week 16) or intermediate risk of relapse (all others). 98 Similar findings were noted by Bassan and colleagues who measured MRD at week 10 and week 22 post induction chemotherapy. 46 Regardless of whether they were SR, HR or VHR by traditional criteria, patients who were MRD negative had significantly better DFS relative to those that were MRD positive. Whether treatment intensification can negate the negative effects of residual disease has also been investigated by several investigators. Bassan and colleagues assessed MRD at week, week 16 and week 22. 46 Patients that were MRD negative or with unknown MRD status but standard risk by traditional criteria received maintenance treatment only while patients that were MRD positive or with unknown MRD but high risk or very high risk by traditional criteria received an allogeneic SCT or autologous blood stem cell harvest/reinfusion with subsequent maintenance therapy. MRD positive patients receiving either SCT or intensive chemotherapy had improvements in DFS with no significant difference between those that received SCT and intensive chemotherapy. Moreover, patients who became MRD negative had improved DFS relative to those who remained MRD positive. Similar results were noted by Gokbuget et al. where 5 year CCR improved for MRD positive patients undergoing an allo SCT. 99 Ribera and colleagues noted that allo SCT in MRD -ve patients was unnecessary and counterproductive as it led to worse DFS and overall survival both in the whole series and an intention to-treat-analysis. 100 Beldjord et al. assessed 423 adult patients with Ph-negative ALL treated with a pediatric protocol. 21 MRD1 was evaluated at 6 weeks after induction initiation and MRD2 after the first consolidation phase i.e. 12 weeks after induction initiation. A study by the GRAALL group, using a pediatric inspired protocol for adults with B-ALL, evaluated the role of allogeneic HSCT according to MRD response with induction therapy. 47 Patient who were MRD positive, defined as a level > 10 -3 following induction therapy, had a significantly higher relapse rate and inferior OS as compared to those who achieved a level 10 -3 who underwent subsequent HSCT in CR1 had a significantly superior RFS and OS as compared to those who were not transplanted. In contrast, those with MRD levels < 10 -3 following induction did not benefit from HSCT. These effects were seen for both B-ALL and T-ALL. The Edmonton group subsequently analyzed outcomes following DFCI induction therapy. Between 2013-2019 patients with BCR-ABL negative ALL underwent induction therapy with this protocol, and MRD postinduction was assessed by multiparameter flow cytometry, with a sensitivity of 0.1%. Of 46 patients who achieve CR, 26 (57%) were MRD negative and 43% were MRD positive. The cumulative incidence of relapse was 45% in patients who were MRD positive at a level of >0.1%, as compared with 12% in MRD negative patients (p=0.05) (unpublished data). These results essentially mirror those reported by the GRAALL group as described above. These data further support the conclusion that patients who fail to achieve a 3 log reduction in MRD levels with intensive induction therapy represent a high-risk group for relapse, and that these patients should be considered for HSCT in CR1. In contrast, those who achieve who achieve a >3 log reduction with induction can be successfully managed by chemotherapy alone with a low relapse risk and favourable prognosis. A subsequent German study (Herold et al, 2017) found a strong association between MRD positivity and a Ph-like genotype; Ph like B-ALL patients only achieved a 33% MRD negativity rate, as comparted with 79% for Ph negative and non-Ph-like B-ALL patients (p=0.02) Therefore, MRD may represent a surrogate marker for a more resistant disease biology which is more destined to relapse with conventional chemotherapy. # Treatment of MRD positive B-ALL: Blinatumomab is a bispecific tumour-engaging (BiTE) antibody with an anti-CD19 domain that binds to B-cells, including B-ALL cells, and an anti-CD3 domain that engages T lymphocytes to lyse the B cells. A large European study 101 was recently published, evaluating the role of blinatumomab in 116 B-ALL patients in hematologic CR with MRD positivity, defined as a level > 0.1% by qRT-PCR. Patients were permitted to received up to 4 treatment cycles, and could undergo allogeneic HSCT at any time after the first cycle. Overall, 78% of patients achieved an MRD negative state, with a sensitivity of 10 -4 after one blinatumomab treatment cycle. Two additional patients achieved this after 2 cycles. Of patient in first CR, 83% achieved MRD negativity. The treatment was well-tolerated. The median OS of the patients who achieved MRD negativity was 38.9 months, vs. 12.5 months in those who did not achieve MRD negativity (p=0.002); corresponding RFS were 23.6 vs. 5.7 months, respectively (p=0.002). With a median follow-up of 24 months, 49% of patient who underwent subsequent HSCT remained in continuous CR, as compared with 25% who did not undergo HSCT. By comparison, in Edmonton BCR-ABL negative B-ALL patients who were MRD positive at a level > 0.1% by flow cytometry after DFCI induction therapy were treated with intensified chemotherapy, using cycles 1A and 1B of Hyper-CVAD, between 2013-2018. Of 13 patients, only 5 (38%) were able to achieve MRD negativity; treatment was associated with considerable toxicity, including severe myelosuppression and mucositis. These data indicate that (1) blinatumomab is able to induce a high rate of MRD negativity, usually after one cycle, with good tolerance, (2) patients who achieve MRD negativity have superior outcomes compared with those who do not, (3) patients who subsequently undergo allogeneic HSCT have favourable outcomes as compared with those who do not, and (4) intensified chemotherapy is less effective at inducing MRD negativity but is associated with considerably more toxicity. The use of blinatumomab for MRD positive B-ALL has now been widely incorporated into standard ALL protocols in Europe and North America. Taken together, these data indicate that MRD assessment provides critical prognostic information in adults with ALL. There is convincing evidence in pediatric and adult ALL that a high level of MRD at the end of induction therapy is associated with a higher relapse rate. Furthermore, the persistence of MRD during consolidation and maintenance therapy, or its the re-emergence, all seem to herald relapse. In contrast, negative MRD results are associated with a favorable prognosis. It is therefore recommended that all patients have MRD ascertained at the end of intensive induction therapy, or early during intensification. Patients with persistent MRD at a level > 0.1% should receive further treatment with an intent to achieve MRD negativity; for B-ALL the treatment of choice is blinatumomab, while for T-ALL intensified chemotherapy would be appropriate. Furthermore, these patients should be referred for allogeneic HSCT if suitable candidates, optimally after achieving MRD negativity. In contrast, patient achieving MRD negativity do not appear to benefit from transplant, provided they can successfully complete the subsequent treatment protocol. # Treatment Approaches in ALL In general, the treatment of ALL is complex consisting of several different chemotherapy cycles and, for some patients, stem-cell transplantation. 1 A number of different approaches have been used as discussed below. # Adult Multidrug Regimens: Starting in the 1960s, researchers at St. Jude Children's Research Hospital designed combination therapies of available anti-leukemia drugs that were delivered in a sequence of extended courses of therapy. 9 Since then several multidrug combinations have been developed centered on a vincristine, prednisone, and anthracycline combination, with or without asparaginase and cyclophosphamide. This concept was modified in children to the Berlin-Frankfurt Munster (BFM) ALL model and later, by Hoelzer et al., to adult ALL. 11,102 Studies using this approach are presented in Table 5. Despite variations in chemotherapy regimens, variable use of allogeneic SCT or auto SCT the 5 year overall survivals ranged from 35 -60% in various subgroups with induction mortality ranging of 5-10%. The second treatment model pioneered at the M.D. Anderson Cancer Center consists of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and cytarabine (Hyper-CVAD). The regimen consists of a total of eight courses: four courses of hyper-CVAD (courses 1, 3, 5, and 7) alternate with four courses of MTX and HIDAC (courses 2, 4, 6, and 8). 103,104 In the original report the mortality was 6% and the overall CR rate was 91%. The estimated median survival time was 35 months with a 5-year estimated survival of 39%. Younger age was associated with better survival (age 60 estimated 5-year survival rate of 25%). In an updated report of patients aged 15 -92 years old, the CR rate for patients age ≤30 years was 99% and for patients age ≥60 years 80%, mostly because of a higher induction mortality. Kantarjian, 2004 #710. The addition of rituximab was associated with CCR and OS rates of 60% and 58%, respectively. Treatment with Rituximab-hyper-CVAD was associated with improvement in 3-year CRD rates compared with hyper-CVAD (78% vs. 53%). In patients age < 60 improvements in 3-year OS (75% v47%; P 0=.003) rates favoring rituximab were observed. 105 The Pediatric Approach: A third approach was the adoption of pediatric protocols or "pediatric inspired"regimens particularly for adolescents and young adults variably defined as patients 15 to 35-45 years old. 1, 106 These regimens have common features, including significantly increasing the non-myelosuppressive agents such as vincristine and steroids, using much higher cumulative doses of asparaginase for prolonged asparagine depletion, and administering very early and extended intrathecal methotrexate together with high-dose systemic methotrexate. Several studies from Europe and the USA reported that pediatric inspired approaches are feasible in adolescents and adults (Table 6 and 7). These studies have shown that prolonged administration of non-myelosupressive agents such as asparaginase, vinca alkaloids and steroids is feasible and tolerated in a substantial portion of adults. Based on these studies, pediatric based regimens have now been widely accepted as the standard of care for younger adults with ALL. # CNS Prophylaxis and Treatment: Because of the high risk (up to 50%) of CNS relapse, CNS prophylaxis is an essential part of any treatment regimen for ALL. Standard approaches include the use of repeated (11)(12) doses of intrathecal (IT) chemotherapy. This has been demonstrated in many studies to reduce the risk of CNS relapse to 10% or less. Although many protocols use triple intrathecal chemotherapy with methotrexate, cytarabine and corticosteroids, a recent pediatric randomized study did not show any difference in CNS relapse rates between this approach and single-agent methotrexate. 112 A baseline LP is required to rule out CSF disease at diagnosis. If positive, the usual approach is to administer intrathecal chemotherapy twice weekly until the CSF has been adequately cleared (as evidenced by 3 consecutive negative results). Although the standard cerebrospinal fluid (CSF) diagnostic approach consists of morphologic analysis of a cytospin preparation, studies have shown that flow cytometry of CSF provides greater sensitivity, 113 and may thus be a more reliable indicator of blast clearance. Most older treatment protocols incorporated prophylactic cranial radiation; however, this adds significant short-term and potential long-term toxicities. Recent pediatric studies have demonstrated that routine cranial radiation can be safely deleted without adversely impacting CNS relapse rates; 114 this is particularly the case if high-dose intravenous methotrexate, which has good CNS penetration, is used. However, if evidence of fixed leptomeningeal disease is present based on the presence of focal neurologic symptoms and corresponding MRI findings, CNS radiotherapy is indicated as intrathecal chemotherapy alone is usually insufficient. # Provincial Recommendations for Treatment of ALL # Adolescents and Young Adults (AYA): Adolescents and young adults have been variably defined as those aged 15 -35 (40) years old. A multitude of accumulating evidence suggests that this group of patients is best treated with a pediatric or a pediatric inspired protocol. Ram et al. conducted a systematic review of 11 studies that compared adult and pediatric protocols. 115 Overall, all-cause mortality, relapse rates and non-relapse mortality were lower in the pediatric groups whereas CR rates and EFS were higher in the pediatric groups. It is important to note that in many of these studies the median age ranged from 12.9 -31 with only two studies including patients over age 55. The native E. coli asparaginase used in the DFCI 91-01 protocols is no longer available in Canada, and has been replaced by pegylated asparaginase (Pegaspargase). This should be given no more frequently than once every 3 weeks in adults due to its long half-life (see Appendix C and D). # Patients Aged 35(40)-60: The use of pediatric protocols for the treatment of adolescents has inspired some groups to explore the use of pediatric protocols in older adults however the data are not clear whether this represents a significant difference relative to adult protocols. When using the paediatric GRAALL-2003 protocol improvemnets in EFS and OS were noted at 42 months but only for patients <age 45. 94 Similarly, Storring and colleagues, when using a modified DFCI paediatric regimen 20 # Recommendations for Patients Aged 35(40)-60: These data suggest that although results in patients 30-60 years old may be inferior to those in adolescents and young adults a use of a pediatric protocol may benefit these patients with 3-5 year OS improving from an historic 35-40% to 50-70%. The lower OS observed in some studies may be related to the preferential use of allo-SCT in this cohort of patients. Nonetheless, we recommend that patients in this age range continue to be treated with the DFCI protocol (Appendix A-C). However, given the increased toxicities seen in middle-aged adults, some patients, particularly those age 50-60, may require changing to a less toxic regimen such as the modified DFCI protocol for older patients (see below). # Patients Aged >60: The outcome of patients above age 60 treated with standard ALL chemotherapy has been generally poor. Larson et al. using the CALGB 8811 protocol noted a 3 year OS of only 17% with a median survival of only 1 month. 82 Brandwein et al. noted similar results when using a multitude of different adult based chemotherapy regimens. 116 In their study the 3 year OS was only 18.4%. Using the HyperCVAD protocol Kantarjian et al. noted a 5 year OS of 17%. 12 Thus, it appears that the majority of older patients with ALL will succumb to their disease although some older patients may remain long-term survivors. Whether a paediatric inspired regimen might benefit this older subset of patients was investigated by Martell et al. who evaluated the outcomes of 51 patients treated with a modified DFCI paediatric regimen at the PMH (Appendix B). 109 Modifications from the full-dose DFCI 91-01 protocol during induction included the substitution of dexamethasone for two 4-d pulses instead of daily prednisone, reduction of the methotrexate dose from 4 g/m2 to 40 mg/m2, reduction in the asparaginase dose from 25 000 to 12 000 iu/m 2 and removal of one vincristine dose. In the CNS prophylaxis phase cranial radiation was removed. In the intensification phase seven cycles were given instead of 10, the dexamethasone dose was reduced to 6 mg PO BID and the asparaginase reduced to 6000 iu/m 2 from 12500 iu/m 2. In the maintenance phase parenteral methotrexate was switched to oral, and the dexamethasone dose was again reduced from 6 mg/m 2 BID to 6 mg PO BID. For patients who developed progressive grade ≥2 neuropathy, intravenous vinblastine 10 mg was substituted for vincristine. Median age was 65 (60 -79), 12 patients were over the age of 70, 35 patients were BCR-ABL negative and 16 were BCR -ABL positive. CR rate was 75% for the entire cohort with 20% induction mortality. Interestingly CR rate was 81% in BCR -ABL positive patients and 71% in BCR -ABL1 negative patients. The estimated 5-year OS was 40.5% for the BCR-ABL1 negative patients, and 47.3% for the BCR-ABL1+ patients but there was no significant difference in OS between these two groups. The estimated 5-year OS for BCR-ABL1 negative patients presenting with low WBC (defined as <30 x 10 9 /L for B-ALL or <100 x 10 9 /L for T-ALL) was 44.3% respectively. # Recommendations for Patients Aged >60: Given that some medically fit patients above age 60 may be cured of ALL we recommend that eligible patients over age 60 be treated with curative intent therapy. Although, there are no randomized studies, based upon data from the PMH group, the modified DFCI provided superior results relative to historical controls. We therefore recommend that the modified DFCI protocol be used for older ALL patients (Appendix C). A more recent report from the Spanish PETHEMA group also showed reasonably good activity with their protocols, although relapse rates remained high. 117 Patients over age 75, or those age 60-75 with major co-morbidities precluding intensive chemotherapy, should be considered for palliative chemotherapy with corticosteroids and vincristine +/-low-dose asparaginase. Such patients should continue to receive central nervous system prophylaxis and may benefit from incorporation of a CNS phase. Patients not tolerating DFCI-type intensification, or judged to be unfit for such treatment, may be moved directly to the DFCI maintenance phase. # Philadelphia Chromosome or BCR-ABL Positive ALL: Tyrosine kinase inhibitors (TKI's) have become the standard of care for Ph+/BCR-ABL+ ALL and have led to improvements in the outcomes for all age groups. 1 The earliest TKI used in ALL was imatinib. Although, different chemotherapy regimens and schedules of imatinib have been assessed, all showed improvements in overall survival and reduction in the relapse rate. In the first large study done by the French GRAAPH-2003 group, the combination of imatinib with induction and postremission therapy 121 led to higher estimated OS (65% vs. 39%), lower CIR (30% vs. 49%) and improved DFS (51% vs. 31%) at 18 months in comparison to historical controls treated with the LALA-94 protocol. An Italian study also reported 5-year OS of 38% and DFS of 39% with imatinib combined with chemotherapy and again these results were significantly superior to a historical cohort receiving chemotherapy alone. 122 In the large UKALL/ECOG2993 trial investigators reported an improved post-induction CR rate with imatinib, improved 4 year OS, EFS and a considerable reduction in relapse risk in the imatinib cohort. 123 Lastly, The M.D. Anderson group also combined imatinib with their standard hyper-CVAD protocol and reported CR rates of 93% as well as results that were substantially superior to their retrospective results with chemotherapy. 124 Second and third generation TKI's have also been assessed in Ph+ ALL. Kim et al evaluated the outcomes of Nilotinib with multiagent chemotherapy for adult patients with newly diagnosed Ph+ve ALL. After achieving CR, subjects received either 5 courses of consolidation, followed by 2year maintenance with nilotinib, or allo-HCT. Amongst the 90 evaluable subjects the CR rate was 91%, the 2-year RFS was 72% and the 2-year OS was 72%. Unlike nilotinib, dasatinib has the ability to peneterate the CNS. Single agent dasatinib is associated with short-term cytogenetic remission and median relapse free survivals of only 3.3 months. Studies of dasatinib in combination with chemotherapy, however, have been associated with excellent response rates approaching 100% with minimal toxicity. 72,125 Ponatinib was evaluated in Ph+/BCR-Abl+ by Jabbour and colleagues for patients up to age 60 with previously untreated Ph +ve ALL. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously each subsequent cycle of hyper-CVAD. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The 2-year EFS rate was 81% (95% CI for the 37 patients enrolled in the study. 128 Several investigators have combined TKI's with paediatric based regimens used for the treatment of adult patients. Thyagu et al. evaluated the outcomes of 32 ALL patients age 18-60 with Philadelphia positive ALL treated between 2001 and December 2008 with imatinib. Ninety-four percent of patients (94%) achieved a CR and, of the 28 patients proceeding to intensification therapy, 16 received a HSCT. The 3-year OS was 56% in the transplanted group vs. 50% in the non-transplanted group. 129 They also noted increased rates of peripheral neuropathy, ileus, myopathies, deconditioning, infections and abnormal liver enzymes in a high proportion of patients. Therefore, a number of modifications were made to the original DFCI protocol. 129 Using an unmodified DFCI protocol, Deangelo et al. reported similar results amongst 18 Ph +ve patients treated with imatinib, 11 of whom went on to transplant. The 4 year DFS was 54% and 4 year OS was 53%. 95 Martell et al. also treated 16 BCR-ABL positive patients aged 62 -75 with a modified DFCI protocol together with imatinib. The CR rate was 81% with an induction mortality of 19% and the estimated 5-year OS was 47.3% for the BCR-ABL1+ patients. 109 Monotherapy with TKI has been explored in several studies particularly in elderly patients, who had an extremely poor outcome with chemotherapy alone. Ottmann et al evaluated imatinib monotherapy in 27 patients older than 55 years of age, and observed CR in 26 patients and a partial remission in the remaining patient. 130 Vignetti et al. treated patients aged 61 to 83 years with Ph-+ ALL with a 45day induction of imatinib 800 mg daily plus prednisone (40 mg/m 2 daily). Post-remission therapy was not specified. All 29 assessable patients (100%) experienced a CR. At 12 months, the OS and DFS probabilities were 74% and 48%, respectively. 131 The French GRAALL group conducted a large randomised controlled trial comparing a reduced intensity induction with imatinib, vincristine and dexamethasone (Arm A) to standard imatinib/hyper-CVAD A part (Arm B) in 268 adults with Ph+ve ALL up to age 60; both arms then received a second cycle with Hyper-CVAD B part. 132 The CR rate was higher in arm A than in arm B (98% vs 91%), mainly related to a lower induction death rate in Arm A, whereas the MMolR rate was similar in both arms (66% vs 64%). The OS was superior in the patients that subsequently proceeded to allogeneic HSCT; however, on subgroup analysis, patients who had achieved MRD negativity (defined as a >4 log reduction in BCR-ABL transcripts by PCR) by the end of the second induction cycle had a similar RFS with or without allogeneic HSCT. In contract patients who were MRD positive at that timepoint had a significantly better RFS with allogeneic HSCT, compared to those who were not transplanted. Therefore, MRD assessment with this regimen could be used to help identify a high-risk cohort for whom HSCT was beneficial. Foa et al. evaluated a similar regimen consisting of dasatinib (70 mg twice daily for 84 days) together with prednisone 60 mg/m 2 daily for 32 days plus two doses of intrathecal methotrexate in untreated patients with Ph +ve ALL. 125 Post remission therapy was not defined with two patients receiving no further therapy, 19 continuing on TKI only (16 dasatinib, 2 imatinib and 1 imatinib-dasatinib), 10 receiving intensive chemotherapy with TKI, 4 having an auograft and 18 receiving an allogeneic HSCT. Overall, 53 patients aged 24 -76 were treated. A CR rate of 100% was seen with 92.5% by day 22 and no deaths occurred during induction. Of the patients that had MRD measured by PCR 10 achieved levels lower than 10 -3 and 8 had a complete molecular remission. Twenty-three patients relapsed after completing induction with 12/17 relapsing patients showing a T315I mutation. This trial demonstrated impressive remission rates for dasatinib and steroids only but at the same time underscored the importance of adding intensive chemotherapy and/or HSCT to maintain durable remissions. More recent studies suggest that the treatment landscape is changing. The MD Anderson group evaluated the use of ponatinib + Hyper-CVAD chemotherapy in fit patients with BCR-ABL+ ALL. 133 The 3-year EFS of 69% and OS of 84%, without transplant, were significantly superior to a historical group that had received dasatinib + Hyper-CVAD. These results suggest that using ponatinib with intensive chemotherapy upfront may potentially circumvent the need for transplant in CR1 for most patients. More recently the Italian GIMEMA group reported on a chemo-free regimen using dasatinib + blinatumomab. 134 The CR rate was 98%, with 70-80% eventually achieving a complete molecular response; at a median follow-up of 18 months, the OS was 95% and DFS 88%. The MD Anderson group is currently using a combination of ponatinib + blinatumomab for 4 cycles, followed by ponatinib maintenance therapy, as their standard frontline regimen; the CR rate was 100% and 86% achieved a complete molecular response 154. While very promising, follow-up is brief, and these treatments are not currently approved as upfront therapy for BCR-ABL+ ALL. # Recommendations Philadelphia Chromosome or BCR-ABL Positive ALL: All patients with Ph+/BCR-ABL+ve ALL should receive a TKI combined with chemotherapy. No randomized studies are available comparing different TKI's in adults; therefore, a firm recommendation regarding the choice of TKI upfront cannot be made. Currently, only imatinib (600-800 mg daily) is approved as first line therapy. Patients intolerant to imatinib should be switched to another TKI such as dasatinib; dasatinib may also be preferred for patients with CNS disease due to its excellent CNS penetration. Patients with documented T315I BCR-ABL mutations, or those refractory to or progressing on, a 2 nd generation TKI, should be treated with ponatinib. Fit BCR-ABL+ve ALL patients should be treated with a TKI combined with induction and postremission chemotherapy. Given recent studies showing higher remission rates and decreased mortality using corticosteroids, TKI + vincristine during induction, this combination is recommenedd as initial induction therapy (see Appendix F); however, such patients require additional intensive chemotherapy +/-HSCT to maintain a durable remission. Given data suggesting increased toxicity of asparaginase and vincristine with TKI, asparaginase should be deleted, and vinblastine substituted for vincristine, in the post-remission phases. Patients above age 65, particularly, those with major co-morbidities, poor performance status or ineligible for SCT should be treated with steroid and TKI +/-vincristine or vinblastine. Post induction therapy should be individualized based upon patient tolerance. Patients not transplanted should continue TKI indefinitely. BCR-ABL monitoring by quantitative RT-PCR should be performed in all patients, post-induction and then every 3 months. Patients with inadequate response or loss of response should be switched to a second or third generation TKI as indicated and, depending on circumstances, may require switching from chemotherapy to blinatumomab. # Role of Allogeneic Stem Cell Transplantation In the largest adult ALL trial to date (MRC-ECOG UKALLXII/E2993) patients in first complete remission 35, WBC >30,000/ mL for B-lineage or WBC >100,000/mL for T-ALL, Philadelphia chromosome positivity, t(4;11), t(8;14), complex karyotype, low hypodiploidy or triploidy. All other patients were considered standard risk. In a donor versus no-donor analysis, patients with a sibling donor had improved OS than those with no donor (53% vs. 45%). In the standard risk group, the OS at 5 years was 62% for patients with a donor compared to 52% for patients with no donor (P=.02). In contrast, for high-risk patients OS was 41% for those with a donor vs. 35% for those without a donor (p=0.2) likely due to the high non-relapse mortality. The 10 year relapse rate was substantially lower in patients with a donor (24% for standard risk and 37% for high-risk) versus those without a donor (49% standard risk and 37% high-risk). 19 The Spanish PETHEMA group reported similar findings in their cohort of high-risk patients defined as those with age 30-50 years old, WBC count >25,000/ mL, Ph +ve, t(4;11)/other 11q23 rearrangements, or t(1;19). 87 In contrast, two French studies both reported that there was an advantage for high-risk patients having a donor. 86,135 A meta-analysis of 7 studies that included 1274 patients also noted improvements in overall survival for patients with donors relative to those in the no-donor groups undergoing allogeneic stem-cell transplantation. When only high-risk patients were analyzed, the survival advantage was greater. 136 More recently, Gupta et al. conducted a meta-analysis using individual patient data from a total of 20 trials that included a donor no-donor comparison. Overall survival at 5 years was significantly better in the donor arm (49.9% vs 42.7%, p=.003). However, because TRM was much higher in those age >35 both in the donor and no-donor arms there was no difference in OS in this age group. Interestingly, unlike in previous studies and using standardized definitions of high/standard risk, there was no evidence that survival differed by risk category. It was therefore concluded that patients age35. Despite the above data, it remains unclear whether adult patients treated with paediatric protocols would gain a benefit from SCT. In their study of a 156 BCR-ABL -ve patients treated with the DFCI protocol the 5 year OS amongst patients receiving an allogeneic SCT was 44% while for those not undergoing a SCT the survival was 74% with the difference possibly related to transplant related mortality. Seftel and colleagues compared 422 Ph-ve ALL patients aged 18-50 years with 108 patients receiving DFCI chemotherapy 155. Expectedly, treatment related mortality was higher in those receiving a SCT (37% vs. 6%). At 4 years, the incidence of relapse was similar for those receiving SCT and chemotherapy (24% vs. 23%), however, both DFS and OS were improved for those receiving chemotherapy alone (40% vs. 71% for DFS and 45% vs. 73% for OS). Dhedin and colleagues further assessed the the role of allogeneic stem cell transplantation in Ph-ve ALL adult patients with at least 1 conventional high-risk factor treated with the paediatric inspired GRAALL 2003 and 2005 protocols. 47 In all, 522 patients age 15 to 55 years old were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission while 240 (46%) did not. As with previous studies, the lower CIR observed in the SCT was counterbalanced by a higher NRM. When analyzing SCT in CR1 as a time-dependent event RFS and OS were not significantly improved in the SCT cohort. No significant effect of SCT on RFS was noted in patients younger or older than age 45 or on any prespecified baseline risk factor. RFS and OS were significantly longer, however, in patients who presented with morphologic poor early BM blast clearance or in late CR patients. Furthermore, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) >10 -3 but not in good MRD responders. For pediatric-based protocols, asparaginase is a critical agent in achieving the high cure rates reported. There is evidence in both pediatric and adult studies with the DFCI protocol that the inability to deliver the intended asparabinase dosing during intensification (defined as >80%) is associated with a higher relapse rate. 20,137 Therefore, the inability to deliver effective asparaginase dosing (e.g. due to pancreatitis) places the patients in a higher risk category and warrants consideration of allogeneic HSCT. # Recommendations for Ph-/BCR-ABL-ALL: These data suggest that patients with Ph-/BCR-ABL -ve ALL treated with a paediatric protocol who attain an MRD negative complete remission are at low risk of subsequent relapse and will not benefit from an allogeneic SCT. It is therefore recommended that such patients not proceed with allogeneic SCT, unless they are unable to complete the protocol. Given that patients with MLL (KMT2A) rearrangements remain a high-risk group with pediatric based regimens, SCT may be a reasonable recommendation for younger ALL patients with this abnormality. Failure to achieve a complete hematologic remission after the first induction cycle is also generally considered a high risk features; transplantation is also recommended for these patients. Although high presenting WBC has been identified in the past as a high-risk feature, its prognostic value is superceded by MRD based on data from GRAALL. Failure to deliver effective asparaginase dosing during intensification should also warrant consideration of allogeneic SCT. Patients who are MRD +ve at >10 -3 (or >0.1%) after induction therapy, or >10 -4 (<0.01%) at 16-18 weeks, are at higher risk of relapse and may benefit from transplant. Such patients should be considered for allogeneic HSCT, optimally after receiving further cytoreduction to attain an MRD negative state prior to transplant. # Role of SCT in Patients with Ph/BCR-ABL Positive ALL: The UKALLXII/ECOG 2993 study evaluated the outcome of allo-SCT in Ph+/BCR-ABL+ patients younger than 55 years of age achieving complete remission with an adult ALL protocol. Of the 267 patients, 76 (28%) proceeded to alloHSCT in first CR (45 with cells from a sibling and 31 with cells from a MUD) whereas 86 received chemotherapy alone. The median EFS for all 267 Ph+ patients was 9 months and the median OS was 13 months. At 10 years, OS was 39% for sib alloHSCT, 31% for MUD alloHSCT, and 13% for chemotherapy. Comparing the outcome after any alloHSCT with the outcome after chemotherapy alone, OS, EFS, and RFS were all significantly superior for patients receiving any alloHSCT over those receiving chemotherapy alone. Whereas the leading cause of death in chemotherapy treated patients was relapse, the leading cause of death after transplantation was TRM, which was 27% after sib HSCT and 39% after MUD HSCT. 31 Limited information is available comparing adult Ph+ patients receiving a paediatric protocol with those undergoing an allo SCT. Thyagu et al. treated 32 patients with Ph+ ALL with DFCI protocol together with imatinib. Of the 28 patients proceeding to intensification therapy, 16 underwent an allo-SCT. The 3 year OS was 56% in the transplanted group and 50% in the non-transplanted group. 129 Recent studies in the pediatric setting noted that children receiving intensive multidrug chemotherapy with imatinib had a survival higher than 80% compared to 35% in historical controls, and even better than related or unrelated HSCT (>60%). In the recent US Children's' Oncology Group study, the outcomes at 3 years were not significantly different for those treated with chemotherapy plus imatinib compared with those assigned to alloHSCT. 138 However, limited patient numbers precluded rigorous subgroup analysis. Recent studies in adults are also demonstrating the impact of molecular status on relapse risk in Ph+ ALL. The MD Anderson Cancer Center 139 found that molecular positivity at a variety of time points was associated with a significantly higher cumulative incidence of relapse. The French GRAAPH study 132 found that the benefit of alloHCT in CR1 was restricted to patients who were molecularly positive post-induction chemotherapy. On subgroup analysis, patients who had achieved MRD negativity (defined as a >4 log reduction in BCR-ABL transcripts by PCR) by the end of the second induction cycle had a similar RFS with or withour allogeneic HSCT. In contract patients who were MRD positive at that timepoint had a significantly better RFS with allogeneic HSCT, compared to those who were not transplanted. Therefore, MRD assessment with this regimen could be used to help identify a high risk cohort for which HSCT was clearly indicated. In contrast, a study using nilotinib plus chemotherapy 140 found that overall survival was superior in patients undergoing HSCT regardless of MRD status; however, 60% of patients achieving molecular negativity remained free of relapse at 30 months without a transplant. Taken together, these data suggest that some patients who achieve MRD negativity early on may remain relapse-free with continuing chemotherapy + TKI, potentially sparing them the toxicity associated with transplant. # Recommendations for the Role of SCT in Patients with Ph/BCR-ABL Positive ALL: Although allogeneic HSCT remains the standard post-remission approach for many patients with BCR-ABL positive ALL, patients who achieve early MRD negativity by PCR (e.g. after induction with the Chalandon protocol) may be continued on post-induction chemotherapy + TKI without a transplant; these patients should continue with indefinite TKI and regular PCR monitoring. However, all patients with persistent molecular positivity should be referred for allogeneic HSCT if otherwise eligible. Consideration should be given to switching to a more potent TKI such as dasatinib or ponatinib in these MRD+ patients prior to transplant. Furthermore, patients with subsequent recurrence of MRD detectable disease by PCR should also be referred for transplant. # Role of Cranial Radiation CNS involvement at the time of presentation is uncommon in adults with ALL being reported in 5% to 7% of patients. 141 Before the use of central nervous system (CNS) prophylaxis, the CNS was the most frequently reported site of initial recurrence in children with ALL, accounting for up to 75% of cases. 141 Similarly, amongst adults with ALL, CNS recurrence occurs in approximately 30% of those in a hematological remission. 1 Aur et al. published the results of St. Jude Total Study V in 1971 demonstrating that 2,400 cGy cranial radiation and five doses of intrathecal methotrexate greatly diminished CNS relapse resulting in the first cures of childhood ALL. 142 Subsequently, widespread incorporation of CNS prophylaxis led to the largest single "step up" in 10-year survival from approximately 20% to 60% among those diagnosed from 1970 to 1972 versus 1972 to 1975. 142 Given the significant risk of CNS relapse current adult and pediatric protocols incorporate CNS prophylaxis with both systemic and intrathecal chemotherapy and/or radiation. Cranial irradiation is an effective form of CNS-directed treatment, but its effectiveness is offset by substantial rates of secondary neoplasms, endocrinopathies, growth impairment, neurocognitive dysfunction, and neurotoxic effects. Amongst the pediatric population, Pui et al. found that prior cranial radiation was associated with a 20.9% cumulative risk of second neoplasms at 20 years in addition to a higher mortality and a greater likelihood of being unemployed when compared to an age matched general population. 142 Subsequently, multiple trials compared CNS prophylaxis using intrathecal chemotherapy and/or intravenous methotrexate with cranial radiation. These trials demonstrated the efficacy of IT/IV therapy without cranial radiation leading to use of cranial irradiation for patients at especially high risk of CNS relapse and elimination of cranial radiation for infants or very young children, irrespective of their presenting features Jeha, 2009 #199. More recently, in the St Jude Total XV and Dutch Childhood Oncology Group acute lymphoblastic leukaemia-9 protocols cranial irradiation is replaced by triple intrathecal chemotherapy with methotrexate, hydrocortisone, and cytarabine for all newly diagnosed patients. The 5 year cumulative risk of isolated CNS relapse was 27% with the St Jude and 26% with the Dutch Childhood Oncology Group protocol similar to the relapse rates observed with prophylactic cranial irradiation (15-45%). In the largest study to date Vora and colleagues 143 obtained data on 16623 patients aged 1 to 18 years old treated between 1996 and 2007 by 10 cooperative groups. In their analysis cranial radiation was associated with a reduced risk of relapse but only in patients with overt CNS disease at time of presentation. In other patients there was no difference in CNS relapse between those that received and did not receive cranial radiation. These data suggest that, in the context of a pediatric protocol prophylactic cranial irradiation can be safely omitted in patients in the context of effective intrathecal and systemic chemotherapy. # Recommendations for the Role of Cranial Radiation: Given the above data we recommend that cranial irradiation not be used for CNS prophylaxis in patients receiving a pediatric protocol such as the DFCI if intrathecal or systemic chemotherapy is used, unless there is evidence of fixed intracranial disease at presentation on MRI. # Supportive Care Supportive care remains an important aspect of the care of the ALL patient throughtout all phases of treatment. All patients should be transfused packed red blood cells as per institutional guidelines and particularly for symptomatic anemia. Similarly, platelets should be transfused to maintain platelet counts > 10 x 10 9 /L. All patients receive prophylaxis, and if indicated, treatment for tumour lysis syndrome with allopurinol and/or rasburicase during induction therapy. Disseminated intravascular coagulation should be treated aggressively with clotting factor replacement. Patients with signs and symptomns of febrile neutropenia should be managed with broad spectrum antibiotics and intensive care support as necessary. As corticosteroids may mask fevers in such patients, broad spectrum antibiotics should be instituted for clinical suspicion of sepsis (e.g. unexplained hypotension) even in the absence of fever. Antifungal prophylaxis against Candida is recommended during induction due to the risk of Candida septicemia. Clinicians should be continuously aware of both the short-and long-term consequences of potential toxicities associated with specific agents used in ALL and use prevention, treatment or dose adjustment as necessary: # Treatment of Relapsed ALL Adult ALL patients experiencing hematologic relapse have a poor prognosis with conventional chemotherapy salvage regimens. CR2 rates have been in the 30-50% range. Second remissions are invariably brief unless followed by allogeneic HSCT, and OS is in the 10-20% range. 147,148 Recent studies have demonstrated the superiority of antibody-based therapies for relapsed patients with B-ALL. Blinatumomab, a BiTE antibody construct described earlier (see MRD Section)was evaluated in the Phase III randomized TOWER trial 156. Adult B-ALL patients with relapsed (CR1 CR2) or refractory disease were randomized to receive either blinatumomab for 2 cycles, followed by up to 3 consolidation cycles, or conventional salvage chemotherapy. The CR rate was higher with blinatumomab (44% vs. 25%, p=0.001), and OS was significantly longer in the blinatumomab arm (7.7 months vs. 4 months, p=0.01). Responses in the blinatumomab arm were influenced by tumour burden: The CR rate was 65% in those with 50% BM blasts; nevertheless, CR rates were higher in both subgroups as compared with the chemotherapy arm. Although this study only included patients with BCR-ABL negative ALL, a subsequent study demonstrated a 36% CR rate in patients with relapsed/refractory BCR-ABL+ B-ALL, all of whom had failed second or later generation TKI's. 149 Inotuzumab ozogamicin is an anti-CD22 antibody conjugated to the toxin calicheamycin. The immunoconjugate is internalized into CD22+ B-cells, followed by release of the calicheamicin, which induces DNA strand breaks. The INO-VATE trial was a Phase III randomized study in patients with relapsed/refractory CD22+ B-ALL. 150 Patients were randomized to receive inotuzumab or conventional salvage chemotherapy. The CR rate was significantly higher in the inotuzumab arm (81% vs. 29%, p50% BM blasts). Notably, this study included patients with BCR-ABL+ ALL, where a 79% CR rate was reported. In addition to being more effective, both antibody drugs were well tolerated. The major toxicities of blinatumomab included cytokine release syndrome and neurologic toxicity, both of which were usually grade 1-2 and treated successfully with corticosteroids. The major toxicities of inotuzumab were nausea, febrile neutropenia and veno-occlusive disease (VOD/SOS) of the liver. The latter was a particular issue in patients who received >3 cycles and in those who subsequently proceeded to allogeneic HSCT using a duel alkyator conditioning regimen. For patients with relapsed/refractory T-ALL, there are currently no available antibody-based therapies outside of clinical trials. Conventional salvage chemotherapy, using a non-cross resistant regimen (e.g. Hyper-CVAD), may be used, or nelarabine. The latter is a prodrug of ara-G which is converted to ara-GTP, after which it is then incorporated into DNA, resulting in cytotoxicity. It has demonstrated single agent activity in relapsed/refractory T-ALL, with a 31% CR rate and 41% ORR. 151 However, responses are not durable, and require subsequent allogeneic HSCT if treated with creative intent. Major toxicities of nelarabine include myelosuppression and neurotoxicity. Neurotoxic effects may be either central or peripheral, and may be severe and irreversible. # Recommendations for Relapsed ALL: Based on the two pivotal TOWER and INO-VATE trials, patients with relapsed or refractory BCR-ABL negative B-ALL should be treated with either blinatumomab or inotuzumab as salvage therapy. Although there are no clear recommendations with respect to the choice of agent, inotuzumab would generally be preferred in patients with higher disease burdens (> 50% BM blasts), based on higher responses rates in this group. In patients with lower disease burden, blinatumomab with be preferred for patients who are intended to proceed to subsequent allogeneic HSCT, due to the risk of VOD/SOS with inotuzumab. For patient who receive inotuzumab with an intention to proceed to HSCT, patients should optimally not receive more than 2 cycles, and dual alkylator HSCT conditioning regimens should subsequently be avoided. Inotuzumab may also be preferred in patients who are intended to proceed to subsequent CAR-T therapy using an anti-CD19 construct (see below), in order to minimize the risk of preselection of a CD19 negative subclone. However, conventional chemotherapy or blinatumomab may be preferred in patients who are at risk of VOD/SOS (patients who are early post-HSCT or have pre-existing liver issues). Patients with relapsed BCR-ABL positive B-ALL on imatinib may be reinduced with a second generation TKI such as dasatinib + chemotherapy. Mutational analysis should be performed at relapse and, if a T315I mutation is detected, ponatinib should be used. Those failing a second generation TKI, should be treated with either inotuzumab or blinatumomab, optimally combined with ponatinib. Patients with relapsed/refractory T-ALL should receive either salvage chemotherapy with a non-cross resistant regimen (e.g. Hyper-CVAD) or nelarabine. Regardless of salvage therapy, subsequent relapse is inevitable unless the patient proceeds to allogeneic HSCT or CAR T-cell therapy (see below). # CAR T-Cell Therapy Chimeric antigen receptor (CAR) T-cell therapy is a treatment in which T lymphocytes are removed from a patient via apheresis, transfected ex vivo with a gene rendering them immunogenic against certain cancer cells, grown and subsequently reinfused into the patient. The activated T-cells then circulate, attack and kill the cancer cells. This treatment has demonstrated considerable activity in patients with relapsed and refractory B-ALL. Most studies to date have utilized anti-CD19 CAR T-cells. Tisagenlecleusel is the first such therapy to be approved in children and young adults up to age 25 with relapsed/refractory B-ALL. Complete remission rates of 81% were reported, 152 with a one-year event-free survival (EFS) of 50%, in a cohort of multiple relapsed patients, many of whom had previously received allogeneic HSCT. Another study of 53 multiply relapsed and refractory B-ALL patients, including many older patients age 30-70 years, from Memorial Sloan Kettering Cancer Center (MSKCC) using a similar anti-CD19 CAR T-cell product, demonstrated an 83% CR rate, a median EFS of 6.1 months and OS of 12.9 months (Park et al, 2021). In this study, patients with a low disease burden (defined as 5% BM blasts at time of infusion. The ZUMA-3 study, using a different anti-CD19 CAR T-cell product, reported a CR rate of 83% and a median remission duration of 17.6 months (Shah et al, 2021). CAR T-cell therapy is associated with significant early toxicities, including cytokine release syndrome (CRS), sometimes requiring ICU support +/-tocilizumab, and neurotoxicity; patients therefore require close monitoring in the first two weeks. The MSKCC group 153 and others have reported that the severity of these toxicities is greater in patients with higher tumour burden at the time of CAR-T infusion. CAR T-cell therapy has become available in Alberta as of 2021, in both Edmonton and Calgary, using both commercial and local investigational products. It is currently being used for patients who have failed at least two different treatment regimens; however, the field is rapidly evolving, and it is likely that it will be evaluated at earlier stages of disease. As some patients relapse with CD19-negative disease, other studies are investigating the use of dual anti-CD19/CD22 CAR-T products. Potential candidates for this treatment should be referred early for apheresis, prior to administering salvage immunosuppressive chemotherapy, so as not to negatively interfere with the quality of the apheresis product. Most patients will the need some bridging cytoreductive therapy. The latter has a dual purpose: (1) to prevent clinical deterioration while the CAR T product is being prepared, and (2) to reduce the disease burden, potentially reducing the toxicity of the procedure and the risk of subsequent relapse. Optimal cytoreductive strategies are unclear; depending on the patient, it may include non-intensive chemotherapy, inotuzumab or blinatumomab. The latter, although less toxic than other treatments, could potentially increase the risk of emergence of a CD19 negative subclone, so most experts recommend avoiding this if possible. Inotuzumab should be avoided in patients at higher risk of VOD/SOS, including those who are early post-HSCT or who have pre-existing liver disease. # Recommendations for CAR-T: CAR T-cell therapy is indicated for fit patients with B-ALL who have relapsed after allogeneic HSCT, are not otherwise candidates for HSCT, or who have refractory disease. Early referral to the centre's Cellular Therapy Program is recommended. Patient should not receive salvage T-cell depleting immunosuppressive therapies such as corticosteroids or cyclophosphamide until after apheresis, so as not to impair the quality of the collection. Following apheresis, bridging/cytoreductive therapy should be given, particularly for high tumour burden or rapidly progressive disease, with an aim to control disease-related complications and reduce the overall tumour burden, while avoiding excessive treatment-related toxicities. # Future directions The treatment landscape of ALL has undergone major changes in the past 5 years, and it is likely that further changes will occur as new information becomes available. A number of multicenter randomized clinical trials have been evaluating the role of blinatumomab and inotuzumab, in combination with standard frontline chemotherapy regimens, in both younger and older patients with B-ALL. Results from these trials should be available in the next 2-3 years and, if positive, may move these agents into frontline treatment protocols. For BCR-ABL positive ALL, the combination of ponatinib with Hyper-CVAD chemotherapy has shown very favourable results, without transplant, compared with historical cohorts who had received first of second generation TKI's. 133 More intriguingly, chemo-free protocols, using blinatumomab combined with either dasatinib or ponatinib, have shown very encouraging results in early studies. 134,154 If successful, these may fundamentally change how these patients are treated in the future, and may render transplants unnecessary. As described above, CAR-T cell therapy has shown considerable activity in multiply relapsed and refractory B-ALL. Dual CAR-T constructs, targeting both CD19 and CD22, are in clinical trials, and offer the promise of lowering relapse rates. Moreover, CAR-T therapies will be evaluated in earlier stages of the disease, after first relapse and, eventually, in first CR for high-risk patients with MRD positive disease. This may, if successful, potentially replace the need for allogeneic HSCT for many patients, thereby eliminating the problems associated with GVHD. Appendix A: Original DFCI Protocol 91-01 (Used for pediatric patients) 92 Phase of Therapy Time Period Chemotherapy Induction 28 Days Vincristine 1.5 mg/m2/dose IV, maximum 2 mg, days 3, 10, 17, 24; prednisone 40 mg/m2/d IV/PO for 28 days; doxorubicin 30 g/m2/dose IV, days 1 and 2 methotrexate 4 g/m2 IV for one dose on day 3 IT cytarabine, dosed by age, one dose on day 0 IT cytarabine, dosed by age, one dose on day 17 CNS Therapy 3 Weeks SR girls: IT methotrexate/cytarabine for 4 doses during 2 weeks, then every 18 weeks SR boys and all HR patients: cranial XRT 18 Gy, randomly assigned to hyperfractionated (0.9 Gy bid) or conventional (1.8 Gy daily) with IT methotrexate/cytarabine for 4 doses during 2 weeks Intensification Every 3 weeks for 30 weeks SR: vincristine (2 mg/m2 IV every 3 weeks, maximum 2 mg); dexamethasone 6 mg/m2/d PO for 5 days; methotrexate 30 mg/m2 IV or IM every week; mercaptopurine,randomly assigned to high-dose 1,000 mg/m2 IV for 20 hours, weeks 1 and 2) or conventional 50 # Development and Revision History This guideline was reviewed and endorsed by the Alberta Provincial Hematology Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, hematologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Hematology Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2016. # Levels of Evidence

Peptidoglycan Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of eubacteria. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine and N-acetylmuramic acid residues. Attached to the N-acetylmuramic acid is a peptide chain of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Some Archaea have a similar layer of pseudopeptidoglycan. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. A common misconception is that peptidoglycan gives the cell its shape; however, whereas peptidoglycan helps maintain the structure of the cell, it is actually the MreB protein that facilitates cell shape. Peptidoglycan is also involved in binary fission during bacterial cell reproduction. The peptidoglycan layer is substantially thicker in Gram-positive bacteria (20 to 80 nm) than in Gram-negative bacteria (7 to 8 nm), with the attachment of the S-layer. Peptidoglycan forms around 90% of the dry weight of Gram-positive bacteria but only 10% of Gram-negative strains. In Gram-positive strains, it is important in attachment roles and sterotyping purposes. # Antibiotic inhibition Some antibacterial drugs such as penicillin interfere with the production of peptidoglycan by binding to bacterial enzymes known as penicillin-binding proteins or transpeptidases. Penicillin-binding proteins form the bonds between oligopeptide crosslinks in peptidoglycan. For a bacterial cell to reproduce through binary fission, more than a million peptidoglycan subunits (NAM-NAG+oligopeptide) must be attached to existing subunits. Mutations in transpeptidases that lead to reduced interactions with an antibiotic are a significant source of emerging antibiotic resistance. Considered the human body's own antibiotic, lysozymes found in tears work by breaking the β-(1,4)-glycosidic bonds in peptidoglycan (see below) and thereby destroying many bacterial cells. Antibiotics such as penicillin commonly target bacterial cell wall formation (of which peptidoglycan is an important component) because animal cells do not have cell walls. # Structure The peptidoglycan layer in the bacterial cell wall is a crystal lattice structure formed from linear chains of two alternating amino sugars, namely N-acetylglucosamine (GlcNAc or NAG) and N-acetylmuramic acid (MurNAc or NAM). The alternating sugars are connected by a β-(1,4)-glycosidic bond. Each MurNAc is attached to a short (4- to 5-residue) amino acid chain, normally containing D-alanine, D-glutamic acid, and mesodiaminopimelic acid. These three amino acids do not occur in proteins and are thought to help protect against attacks by most peptidases. Cross-linking between amino acids in different linear amino sugar chains by an enzyme known as transpeptidase result in a 3-dimensional structure that is strong and rigid. The specific amino acid sequence and molecular structure vary with the bacterial species.

ROS1 Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene. # Function This proto-oncogene, highly expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor. # Role in cancer ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the anaplastic lymphoma kinase (ALK) protein; it is encoded by the c-ros oncogene and was first identified in 1986. The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined. Nonetheless, as gene rearrangement events involving ROS1 have been described in lung and other cancers, and since such tumors have been found to be remarkably responsive to small molecule tyrosine kinase inhibitors, interest in identifying ROS1 rearrangements as a therapeutic target in cancer has been increasing. Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive. Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines. In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient. Since that discovery, multiple studies have demonstrated an incidence of approximately 1% in lung cancers, demonstrated oncogenicity, and showed that inhibition of tumor cells bearing ROS1 gene fusions by crizotinib or other ROS1 tyrosine kinase inhibitors was effective in vitro. Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions. Preclinical and clinical work suggests multiple potential mechanisms of drug resistance in ROS1 + lung cancer, including kinase domain mutations in ROS1 and bypass signaling via RAS and EGFR. Although the most preclinical and clinical studies of ROS1 gene fusions have been performed in lung cancer, ROS1 fusions have been detected in multiple other tumor histologies, including ovarian carcinoma, sarcoma, cholangiocarcinomas and others. Crizotinib or other ROS1 inhibitors may be effective in other tumor histologies beyond lung cancer as demonstrated by a patient with an inflammatory myofibroblastic tumor harboring a ROS1 fusion with a dramatic response to crizotinib. # Preclinical findings From a large-scale survey of tyrosine kinase activity in non-small cell lung cancer (NSCLC), and identified more than 50 distinct tyrosine kinases and over 2500 downstream substrates, with the goal of identifying candidate oncogenes. In a sampling of 96 tissue samples from NSCLC patients, approximately 30% displayed high levels of phosphotyrosine expression; further analysis was conducted to identify highly phosphorylated tyrosine kinases in NSCLC from a panel of 41 NSCLC cell lines, and 150 patient samples. Among the top 20 receptor tyrosine kinases identified in this analysis, 15 were identified in both cell lines and tumors, and among these were both ALK and These initial findings paved the way for more expansive analyses of ROS1 kinase fusions in NSCLC and other cancers. # Fusion prevalence In patients with NSCLC, approximately 2% are positive for a ROS1 gene rearrangement, and these rearrangements are mutually exclusive of ALK rearrangement. ROS1 fusion-positive patients tend to be younger, with a median age of 49.8 years, and never-smokers, with a diagnosis of adenocarcinoma. There is a higher representation of Asian ethnicity and patients with Stage IV disease. ROS1 rearrangements are estimated to be roughly half as common as ALK-rearranged NSCLCs. Similar to ALK-rearranged, ROS1-rearranged NSCLC have younger age of onset and a non-smoking history. A benefit of a small-molecule ALK, ROS1 , and cMET inhibitor, crizotinib, was also shown in this patient group. ROS1 expression was found in approximately 2% of NSCLC patients, and its expression was limited to those patients with ROS1 gene fusions. Similar findings were reported in a separate analysis of 447 NSCLC samples, of which 1.2% were found to be positive for ROS1 rearrangement; this study also confirmed the activity of the ALK/ROS1 /cMET inhibitor crizotinib in ROS1 -positive tumors. ROS1 fusions were also identified in approximately 2% of adenocarcinomas and 1% of glioblastoma samples in an assessment of kinase fusions across different cancers. Table 1: Sampling of ROS1 Rearrangements Observed in NSCLC and Other Cancers. All of the kinase fusions retain the tyrosine kinase domain of ROS1 . List is not exhaustive. (Adapted from Stumpfova 2012). - Multiple variant isoforms observed CD74; cluster of differentiation 74, long/short isoforms; EZR; ezrin; FIG; fused in glioblastoma; SDC4; LRIG3; leucine-rich repeats and immunoglobulin-like domains 3; SDC; syndecan 4; SLC34A2; solute carrier family 34 (sodium phosphate), member 2; TPM3; tropomyosin 3 # As a drug target Several drugs target ROS1 fusions in cancer, with varying levels of success; most of the drugs to date have been tested only for ROS1-positive non-small cell lung carcinoma (NSCLC). However, some clinical trials (like those for entrectinib, DS-6051b, and TPX-0005) accept patients with ROS1 cancer in any type of solid tumor. - Crizotinib is approved for treating metastatic ROS1-positive NSCLC in many countries. In clinical trials, crizotinib was shown to be effective for 70-80% of ROS1+ NSCLC patients, but it does not effectively treat the brain. Some patients have a response that lasts for years. Crizotinib is available to patients with solid tumors other than NSCLC through clinical trials. - Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 started in 2015 to test the drug in patients with ROS1/NTRK/ALK gene rearrangements. - Lorlatinib (also known as PF-06463922) was shown in an ongoing Phase 2 clinical trial to be effective in some ROS1+ NSCLC patients, and treats the cancer in the brain as well as the body. Lorlatinib has the potential to overcome certain resistance mutations that develop during treatment with crizotinib. - Ceritinib demonstrates clinical activity (including treating the brain) in ROS1+ NSCLC patients who had previously received platinum-based chemotherapy. In preclinical studies, ceritinib is unable to overcome most ROS1 resistance mutations, including ROS1 G2032R. It has more severe side effects than crizotinib for some patients. Ceritinib is US FDA approved for first line treatment of ALK+ metastatic non-small cell lung cancer. - TPX-0005 preclinical data suggests it is a potent inhibitor of ROS1+ cancer. A Phase I clinical trial opened in March 2017 for patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements. - DS-6051b preclinical data show it is active against ROS1-positive cancers. It is an ongoing clinical trial. - Cabozantinib preclinical data has shown the drug might overcome crizotinib resistance in ROS1+ cancer in early studies. However, the required dosage makes the drug difficult to tolerate for many patients. Cabozantinib is US FDA approved for metastatic medullary thyroid cancer (as Cometriq) and renal cell carcinoma (as Cabometyx). # Global ROS1 Initiative The Global ROS1 Initiative is a worldwide, multi-stakeholder collaboration with a goal of improving patient outcomes and accelerating research for any type of ROS1+ cancer. It is the first such collaboration focused on cancers driven by a single oncogene and was initiated by ROS1+ cancer patients and carers who call themselves "The ROS1ders."; their website tracks targeted therapies, clinical trials, world experts and new developments for ROS1+ cancers. Partners in the Initiative include patient-focused nonprofits Bonnie J. Addario Lung Cancer Foundation and Addario Lung Cancer Medical Institute, clinicians who treat ROS1+ patients, ROS1 researchers, pharmaceutical firms and biotech companies.

Monomelic amyotrophy Monomelic amyotrophy (also known as MMA, Hirayama's disease, Sobue disease or Juvenile nonprogressive amyotrophy) is an untreatable, focal, lower motor neuron disease that primarily affects young (15 - 25 year-old) males in India and Japan. MMA is marked by insidious onset of muscular atrophy, which stabilizes at a plateau after two to five years from which it neither improves nor worsens. There is no pain or sensory loss associated with MMA. Unlike other lower motor neuron diseases, MMA is not believed to be hereditary and fasciculations (involuntary muscle twitches) are rare. EMG tests reveal loss of the nerve supply, or denervation, in the affected limb without conduction block (nerve blockage restricted to a small segment of the nerve). Increased sweating, coldness and cyanosis have been reported for a few patients, indicating involvement of the sympathetic nervous system. While MMA will cause weakness and/or wasting in only one limb, EMG and NCV tests often show signs of reinnervation in the unaffected limbs. # Treatment There is no cure for MMA. Treatment consists of muscle strengthening exercises and training in hand coordination. # Prognosis The symptoms of MMA usually progress slowly for one to two years before reaching a plateau, and then remain stable for many years. Disability is generally slight. Rarely, the weakness progresses to the opposite limb. There is also a slowly progressive variant of MMA known as O'Sullivan-McLeod syndrome, which only affects the small muscles of the hand and forearm and has a slowly progressive course. # Epidemiology MMA occurs in males between the ages of 15 and 25. Onset and progression are slow. MMA is seen most frequently in Asia, particularly in Japan and India; it is much less common in North America.

Cystic duct # Overview The cystic duct is the short duct that joins the gall bladder to the common bile duct. It usually lies next to the cystic artery. It is of variable length. It contains a 'spiral valve', which does not provide much resistance to the flow of bile. # Function Bile can flow in both directions between the gallbladder and the common hepatic duct and the (common) bile duct. In this way, bile is stored in the gallbladder in between meal times and released after a fatty meal. # Clinical significance During a cholecystectomy, the cystic duct is clipped two or three times and a cut is made between the clips, freeing the gallbladder to be taken out. # Additional images - The gall-bladder and bile ducts laid open. - The portal vein and its tributaries.

Kiaa1107 KIAA1107 is a protein that in humans is encoded by the KIAA1107 gene. KIAA1107 is a Serine-rich protein, whose expression was found to increase in white matter of Multiple Sclerosis brain lesions. # Gene ## General Information KIAA1107 is a protein encoding gene, located on chromosome 1 in Homo sapiens. Its exact location is at cytogenetic band 1p22.1, with the genomic location of 92,067,052 bp - 92,184,723 bp from pter, with 17,672 total bases. The KIAA1107 gene contains nine known exons. # Protein ## General Properties Uncharacterized Protein KIAA1107 is 1401 amino acids in length in the most common variant, isoform A, found in Homo sapiens. The predicted molecular weight of isoform A in Homo sapiens is 149.6 kdal. ## Composition KIAA1107 has a higher frequency of Serine and Aspartate and a lower frequency of Tyrosine than in the average protein in Homo sapiens. Uncharacterized protein is composed of 7.5% Aspartate and 14.0% Serine, which constitutes it as a Serine-rich protein. This protein also consists of 0.7% Tyrosine, which is considered to be below average in human proteins. # mRNA ## Isoforms Transcription of KIAA1107 produces 6 different mRNAs, with 4 alternatively spliced variants and 2 unspliced forms. Variant A is the most commonly occurring and longest variant of KIAA1107 in humans. Variant A contains nine exons (1-9) present in their standard form. Variant B contains seven exons (3-9) present in standard form. Variant C-U contains one exon, which is an alternatively spliced variant of exon 8. Variant D contains five exons (1-4, 5a) with 1-4 occurring in their standard form and an alternative form of exon 5. Variant E contains three exons, which are alternatively spliced forms of exons 3, 4, and 5. Variant F-U contains one exon, which is an alternatively spliced form of exon 5a, which occurs in variant D. ## Conserved Domains There is a domain, DUF4596, present from 1311 - 1354 in KIAA1107. The function of this domain is unknown. # Expression ## Tissue Expression Expression of KIAA1107 does not appear to be ubiquitous in Homo sapiens. KIAA1107 is found to be expressed mostly in the brain, with lower levels of expression occurring in the bladder, mammary gland, muscle, prostate, and testis. Within the brain, KIAA1107 is expressed highest in the pineal gland, prefrontal cortex, cingulate cortex, and subthalamic nucleus. ## Disease Association KIAA1107 was found to be over expressed in brain white matter with Multiple Sclerosis brain lesions when compared to control white matter. The average non-diseased sample had negligible expression of KIAA1107, while in the diseased sample it was expressed higher than almost any other gene (95th-98th percentile of expression). # Homology ## Orthologs Orthologs of KIAA1107 exist in most vertebrates. The most distant homolog of KIAA1107 was found in, a fish, the Amazon Molly. There were no homologs found for sharks and rays, which would suggest that KIAA1107 originated in fish. There are no human paralogs for KIAA1107.

FLNB Filamin B, beta (FLNB), also known as Filamin B, beta (actin binding protein 278), is a cytoplasmic protein which in humans is encoded by the FLNB gene. FLNB regulates intracellular communication and signalling by cross-linking the protein actin to allow direct communication between the cell membrane and cytoskeletal network, to control and guide proper skeletal development. Mutations in the FLNB gene are involved in several lethal bone dysplasias, including boomerang dysplasia and atelosteogenesis type I. # Interactions FLNB has been shown to interact with GP1BA, Filamin, FBLIM1, PSEN1, CD29 and PSEN2.

Nasal Congestion overview Please help WikiDoc by adding more content here. It's easy! Click here to learn about editing. # Overview Nasal congestion is the blockage of the nasal passages usually due to membranes lining the nose becoming swollen from inflamed blood vessels. It is also known as nasal blockage, nasal obstruction, blocked nose, runny nose, and stuffy nose. # Pathophysiology Many people think that a nose gets congested (stuffy) from too much thick mucus. However, in most cases, the nose becomes congested when the tissues lining it become swollen. The swelling is due to inflamed blood vessels. # Diagnosis ## X ray X-rays of the sinuses and chest x-ray ## CT CT scan of sinuses are required in some patients to make the diagnosis.

miR-134 miR-134 is a family of microRNA precursors found in mammals, including humans. MicroRNAs are typically transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product. The excised region or, mature product, of the miR-134 precursor is the microRNA mir-134. miR-134 was one of a number of microRNAs found to be increasingly expressed in schizophrenia. # Functions miR-134 is a brain-specific microRNA; in rats it is localised specifically in hippocampal neurons and may indirectly regulate synaptic development through antisense pairing with LIMK1 mRNA. In the human brain, SIRT1 is thought to mediate CREB protein through miR-134, giving the microRNA a role in higher brain functions such a memory formation. miR-134 has also been reported to function in mouse embryonic stem cells as part of a complex network regulating their differentiation. # Applications miR-134 levels in circulating blood could potentially be used as a peripheral biomarker for bipolar disorder.

Rosenhan experiment # Background The Rosenhan experiment was a famous experiment into the validity of psychiatric diagnosis conducted by David Rosenhan in 1972. It was published in the journal Science under the title "On being sane in insane places". Rosenhan's study consisted of two parts. The first involved the use of healthy associates or 'pseudopatients', who briefly simulated auditory hallucinations in an attempt to gain admission to 12 different psychiatric hospitals in 5 different states in various locations in the United States. The second involved asking staff at a psychiatric hospital to detect non-existent 'fake' patients. In the first case hospital staff failed to detect a single pseudopatient, in the second the staff falsely detected large numbers of genuine patients as impostors. The study is considered an important and influential criticism of psychiatric diagnosis. The study concluded "It is clear that we cannot distinguish the sane from the insane in psychiatric hospitals" and also illustrated the dangers of depersonalization and labelling in psychiatric institutions. It suggested that the use of community mental health facilities which concentrated on specific problems and behaviors rather than psychiatric labels might be a solution and recommended education to make psychiatric workers more aware of the social psychology of their facilities. # The Pseudopatient Experiment For the purposes of the study, eight 'pseudopatients' (associates of Rosenhan selected to be a group of varied and healthy individuals) attempted to gain admission into psychiatric hospitals. During psychiatric assessment they claimed to be hearing voices that were often unclear, but noticeably said the words "empty", "hollow" and "thud". No other psychiatric symptoms were claimed, and apart from giving false names and employment details, further biographical details were truthfully reported. If admitted, the pseudopatients were asked to 'act normally', report that they felt fine and no longer heard voices. The pseudopatients were: a psychology graduate student in his twenties, three psychologists, a pediatrician, a psychiatrist, a painter and a housewife. None had a history of mental illness. After being admitted, the experimental subjects acted normally and did not display any obvious psychopathology. Subjects were to remain as inpatients until they were discharged by the staff at their hospitals, who were not privy to the experiment and believed the subjects to be real psychiatric patients. All eight were admitted, seven with a diagnosis of schizophrenia, the last with bipolar disorder. None of the pseudopatients were detected during their admission by hospital staff, although other psychiatric patients seemed to be able to correctly identify them as impostors. While the staff failed to identify sanity, in the first three hospitalisations notes of patient responses were kept and 35 of the total of 118 patients did express a suspicion that the pseudopatients were sane. All were discharged with a diagnosis of schizophrenia "in remission". Their stays ranged from 7 to 52 days and the average was 19 days. During their stay, hospital notes indicated that staff interpreted much of the pseudopatient's behaviour in terms of mental illness. For example, one observer, apparently oblivious to the irony, labeled the note-taking of one pseudopatient as "writing behaviour" and considered it pathological. # The non-existent impostor experiment For this experiment, Rosenhan used a well-known research and teaching hospital, whose staff had heard of the results of the initial study but claimed that similar errors could not be made at their institution. Rosenhan arranged with them that during a three month period, one or more pseudopatients would attempt to gain admission and the staff would rate every incoming patient as to the likelihood they were an impostor. Out of 193 patients, 41 were considered to be impostors and a further 42 were considered suspect. In reality, Rosenhan had sent no pseudopatients and all patients suspected as impostors by the hospital staff were genuine patients (unless they were other impostors unknown to the study, which seems unlikely). This led to a conclusion that "any diagnostic process that lends itself too readily to massive errors of this sort cannot be a very reliable one". Studies by others found similarly problematic diagnostic results. # Related experiments Maurice K. Temerlin split 25 psychiatrists into two groups and had them listen to an actor portraying a character of normal mental health. One group was told that the actor "was a very interesting man because he looked neurotic, but actually was quite psychotic" while the other was told nothing. Sixty percent of the former group diagnosed psychoses, most often schizophrenia, while none of the control group did so. Loring and Powell gave 290 psychiatrists a transcript of a patient interview and told half of them that the patients were black and the other half white; they concluded of the results that "Clinicians appear to ascribe violence, suspiciousness, and dangerousness to black clients even though the case studies are the same as the case studies for the white clients". # Impact Rosenhan published his findings in Science, criticising the validity of psychiatric diagnosis and the disempowering and demeaning nature of patient care experienced by the associates in the study. His article generated an explosion of controversy. Many defended psychiatry, arguing that psychiatric diagnosis must rely heavily on the patient's own report of their experiences. Hence, mis-diagnosis in the presence of fake symptoms no more demonstrates problems with psychiatric diagnosis than would lying about other medical symptoms. As an example, psychiatrist Robert Spitzer wrote in a 1975 criticism of Rosenhan's study: However, despite the perceived shortcomings of Rosenhan's study, Spitzer felt that there was still a laxness in the field. He played an important role in updating psychiatric diagnosis, eventually resulting in the Diagnostic and Statistical Manual of Mental Disorders, in an attempt to introduce more rigor and reliability. Lauren Slater says in her 2004 book Opening Skinner's Box that she repeated Rosenhan's study, by presenting at the emergency rooms of different hospitals with a single auditory hallucination. She writes that she was not admitted to any of them but was instead given prescriptions for antipsychotics and antidepressants. Her claims were questioned by Robert Spitzer and others; she replied (through her attorney) that she considered her work to be "anecdote, not systematic research, and certainly not a 'replication' of Rosenhan's study."

Bile salt-dependent lipase Bile salt-dependent lipase (or BSDL), also known as carboxyl ester lipase (or CEL) is an enzyme produced by the adult pancreas and aids in the digestion of fats. Bile salt-stimulated lipase (or BSSL) is an equivalent enzyme found within breast milk. BSDL has been found in the pancreatic secretions of all species in which it has been looked for. BSSL, originally discovered in the milk of humans and various other primates, has since been found in the milk of many animals including dogs, cats, rats, and rabbits. # Enzymatic activity More than 95% of the fat present in human milk and in infant formulas is in the form of triacylglycerols (TG). In adults, TGs are thought to be broken down or hydrolyzed mainly by the colipase-dependent lipase enzyme. In the newborn, CDL activity in the duodenum is lower than in adults. Both BSDL and BSSL have a broad substrate specificity and, like CDL, are capable of hydrolyzing triacylglycerides (in addition to phospholipids, esters of cholesterol, and lipid-soluble vitamins). In particular, they can hydrolyze esters of the essential fatty acids (n-3 and n-6 PUFAs) and DHA. BSDL production in the newborn pancreas is quite low when compared with production in the mammary gland or adult pancreas. However, newborn infants absorb lipids relatively well, considering the low level of CDL and BSDL they produce. This observation has led to the suggestion that BSDL produced by lactating mammary gland and present within milk, may compensate for the low levels of other TG-digesting enzymes and aid newborns in lipid absorption. The importance of BSSL in breast milk for the preterm infant nutrition was suggested at 2007. It was also directly shown recently.

Hydrocele overview Steven C. Campbell, M.D., Ph.D. # Overview A hydrocele denotes a pathological accumulation of serous fluid in a bodily cavity. A hydrocele testis is the accumulation of fluids around a testicle, and is fairly common. It may be treated surgically. It can occur in infants undergoing peritoneal dialysis. A hydrocele testis is due to fluid secreted from a remnant piece of peritoneum wrapped around the testis in the tunica vaginalis. It can also be as a result of cancer, trauma (such as a hernia), or orchitis. It can also be the result of a plugged inguinal lymphatic system caused by repeated chronic infection of Wucheria bancrofti or Brugia malayi, two mosquito-borne parasites of Africa and S.E. Asia, respectively. As such the condition would be a part of more diffuse sequelae commonly referred to as elephantiasis. # Epidemiology and Demographics Most hydroceles are present at birth (congenital). Otherwise, the condition generally affects men older than 40. # Diagnosis ## History and Symptoms The main symptom is a painless, swollen testicle , which feels like a water balloon. A hydrocele may occur on one or both sides. # Treatment ## Primary Prevention There is no way to prevent varicoceles in adults or hydroceles in baby boys . Avoid injury to the scrotum to prevent hydrocele in adult males.

On May 14, 1796, Edward Jenner, an English physician, inoculated James Phipps, age 8, with material from a cowpox lesion on the hand of a milkmaid. Jenner subsequently demonstrated that the child was protected against smallpox. This procedure became known as vaccination, which resulted in the global eradication of smallpox 181 years later.# Introduction This report provides technical guidance regarding common immunization concerns for health-care providers who administer vaccines to children, adolescents, and adults. Vaccine recommendations are based on characteristics of the immunobiologic product, scientific knowledge regarding the principles of active and passive immunization, the epidemiology and burden of diseases (i.e., morbidity, mortality, costs of treatment, and loss of productivity), the safety of vaccines, and the cost analysis of preventive measures as judged by public health officials and specialists in clinical and preventive medicine. Benefits and risks are associated with using all immunobiologics. No vaccine is completely safe or 100% effective. Benefits of vaccination include partial or complete protection against the consequences of infection for the vaccinated person, as well as overall benefits to society as a whole. Benefits include protection from symptomatic illness, im-proved quality of life and productivity, and prevention of death. Societal benefits include creation and maintenance of herd immunity against communicable diseases, prevention of disease outbreaks, and reduction in health-care-related costs. Vaccination risks range from common, minor, and local adverse effects to rare, severe, and life-threatening conditions. Thus, recommendations for immunization practices balance scientific evidence of benefits for each person and to society against the potential costs and risks of vaccination programs. Standards for child and adolescent immunization practices and standards for adult immunization practices (1,2) have been published to assist with implementing vaccination programs and maximizing their benefits. Any person or institution that provides vaccination services should adopt these standards to improve immunization delivery and protect children, adolescents, and adults from vaccine-preventable diseases. To maximize the benefits of vaccination, this report provides general information regarding immunobiologics and provides practical guidelines concerning vaccine administration and technique. To minimize risk from vaccine administration, this report delineates situations that warrant precautions or contraindications to using a vaccine. These recommendations are intended for use in the United States be- # General Recommendations on Immunization # Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP) MMWR February 8, cause vaccine availability and use, as well as epidemiologic circumstances, differ in other countries. Individual circumstances might warrant deviations from these recommendations. The relative balance of benefits and risks can change as diseases are controlled or eradicated. For example, because wild poliovirus transmission has been interrupted in the United States since 1979, the only indigenous cases of paralytic poliomyelitis reported since that time have been caused by live oral poliovirus vaccine (OPV). In 1997, to reduce the risk for vaccine-associated paralytic polio (VAPP), increased use of inactivated poliovirus vaccine (IPV) was recommended in the United States (3). In 1999, to eliminate the risk for VAPP, exclusive use of IPV was recommended for routine vaccination in the United States (4), and OPV subsequently became unavailable for routine use. However, because of superior ability to induce intestinal immunity and to prevent spread among close contacts, OPV remains the vaccine of choice for areas where wild poliovirus is still present. Until worldwide eradication of poliovirus is accomplished, continued vaccination of the U.S. population against poliovirus will be necessary. # Timing and Spacing of Immunobiologics General Principles for Vaccine Scheduling Optimal response to a vaccine depends on multiple factors, including the nature of the vaccine and the age and immune status of the recipient. Recommendations for the age at which vaccines are administered are influenced by age-specific risks for disease, age-specific risks for complications, ability of persons of a certain age to respond to the vaccine, and potential interference with the immune response by passively transferred maternal antibody. Vaccines are recommended for members of the youngest age group at risk for experiencing the disease for whom efficacy and safety have been demonstrated. Certain products, including inactivated vaccines, toxoids, recombinant subunit and polysaccharide conjugate vaccines, require administering >2 doses for development of an adequate and persisting antibody response. Tetanus and diphtheria toxoids require periodic reinforcement or booster doses to maintain protective antibody concentrations. Unconjugated polysaccharide vaccines do not induce T-cell memory, and booster doses are not expected to produce substantially increased protection. Conjugation with a protein carrier improves the effectiveness of polysaccharide vaccines by inducing T-celldependent immunologic function. Vaccines that stimulate both cell-mediated immunity and neutralizing antibodies (e.g., live attenuated virus vaccines) usually can induce prolonged, often lifelong immunity, even if antibody titers decline as time progresses (5). Subsequent exposure to infection usually does not lead to viremia but to a rapid anamnestic antibody response. Approximately 90%-95% of recipients of a single dose of a parenterally administered live vaccine at the recommended age (i.e., measles, mumps, rubella , varicella, and yellow fever), develop protective antibody within 2 weeks of the dose. However, because a limited proportion of recipients (13 years fail to respond to the first dose of varicella vaccine; 99% of recipients seroconvert after two doses (8). The recommended childhood vaccination schedule is revised annually and is published each January. Recommendations for vaccination of adolescents and adults are revised less frequently, except for influenza vaccine recommendations, which are published annually. Physicians and other health-care providers should always ensure that they are following the most up-to-date schedules, which are available from CDC's National Immunization Program website at (accessed October 11, 2001). # Spacing of Multiple Doses of the Same Antigen Vaccination providers are encouraged to adhere as closely as possible to the recommended childhood immunization schedule. Clinical studies have reported that recommended ages and intervals between doses of multidose antigens provide optimal protection or have the best evidence of efficacy. Recommended vaccines and recommended intervals between doses are provided in this report (Table 1). In certain circumstances, administering doses of a multidose vaccine at shorter than the recommended intervals might be necessary. This can occur when a person is behind schedule and needs to be brought up-to-date as quickly as possible or when international travel is impending. In these situations, an accelerated schedule can be used that uses intervals between doses shorter than those recommended for routine vaccination. Although the effectiveness of all accelerated schedules has not been evaluated in clinical trials, the Advisory Committee on Immunization Practices (ACIP) believes that the immune response when accelerated intervals are used is acceptable and will lead to adequate protection. The accelerated, or minimum, inter- # PPV2 -7 yrs § § § --- Combination vaccines are available. Using licensed combination vaccines is preferred over separate injections of their equivalent component vaccines (Source: CDC. Combination vaccines for childhood immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). MMWR 1999;48:5). When administering combination vaccines, the minimum age for administration is the oldest age for any of the individual components; the minimum interval between doses is equal to the greatest interval of any of the individual antigens. † A combination hepatitis B-Hib vaccine is available (Comvax ® , manufactured by Merck Vaccine Division). This vaccine should not be administered to infants aged 8 weeks after Hepatitis B2 and 16 weeks after Hepatitis B1, and it should not be administered before age 6 months. ¶ Calendar months. The minimum interval between DTaP3 and DTaP4 is recommended to be >6 months. However, DTaP4 does not need to be repeated if administered >4 months after DTaP3. † † For Hib and PCV, children receiving the first dose of vaccine at age >7 months require fewer doses to complete the series ( . § § For a regimen of only polyribosylribitol phosphate-meningococcal outer membrane protein (PRP-OMP, PedvaxHib ® , manufactured by Merck), a dose administered at age 6 months is not required. ¶ ¶ During a measles outbreak, if cases are occurring among infants aged 6 months can be undertaken as an outbreak control measure. However, doses administered at age 5 days earlier than the minimum interval or age should not be counted as valid doses and should be repeated as age-appropriate. The repeat dose should be spaced after the invalid dose by the recommended minimum interval as provided in this report (Table 1). For example, if Haemophilus influenzae type b (Hib) doses one and two were administered only 2 weeks apart, dose two is invalid and should be repeated. The repeat dose should be administered >4 weeks after the invalid (second) dose. The repeat dose would be counted as the second valid dose. Doses administered >5 days before the minimum age should be repeated on or after the child reaches the minimum age and >4 weeks after the invalid dose. For example, if varicella vaccine were administered at age 10 months, the repeat dose would be administered no earlier than the child's first birthday. Certain vaccines produce increased rates of local or systemic reactions in certain recipients when administered too frequently (e.g., adult tetanus-diphtheria toxoid , pediatric diphtheria-tetanus toxoid , and tetanus toxoid) (10,11). Such reactions are thought to result from the formation of antigen-antibody complexes. Optimal record keeping, maintaining patient histories, and adhering to recommended sched-ules can decrease the incidence of such reactions without adversely affecting immunity. # Simultaneous Administration Experimental evidence and extensive clinical experience have strengthened the scientific basis for administering vaccines simultaneously (i.e., during the same office visit, not combined in the same syringe). Simultaneously administering all vaccines for which a person is eligible is critical, including for childhood vaccination programs, because simultaneous administration increases the probability that a child will be fully immunized at the appropriate age. A study conducted during a measles outbreak demonstrated that approximately one third of measles cases among unvaccinated but vaccine-eligible preschool children could have been prevented if MMR had been administered at the same visit when another vaccine was administered (12). Simultaneous administration also is critical when preparing for foreign travel and if uncertainty exists that a person will return for further doses of vaccine. Simultaneously administering the most widely used live and inactivated vaccines have produced seroconversion rates and rates of adverse reactions similar to those observed when the vaccines are administered separately (13)(14)(15)(16). Routinely administering all vaccines simultaneously is recommended for children who are the appropriate age to receive them and for whom no specific contraindications exist at the time of the visit. Administering combined MMR vaccine yields results similar to administering individual measles, mumps, and rubella vaccines at different sites. Therefore, no medical basis exists for administering these vaccines separately for routine vaccination instead of the preferred MMR combined vaccine (6). Administering separate antigens would result in a delay in protection for the deferred components. Response to MMR and varicella vaccines administered on the same day is identical to vaccines administered a month apart (17). No evidence exists that OPV interferes with parenterally administered live vaccines. OPV can be administered simultaneously or at any interval before or after parenteral live vaccines. No data exist regarding the immunogenicity of oral Ty21a typhoid vaccine when administered concurrently or within 30 days of live virus vaccines. In the absence of such data, if typhoid vaccination is warranted, it should not be delayed because of administration of virus vaccines (18). Simultaneously administering pneumococcal polysaccharide vaccine and inactivated influenza vaccine elicits a satisfactory antibody response without increasing the incidence or severity of adverse reactions (19). Simultaneously administering pneumococcal polysaccharide vaccine and inactivated influenza vaccine is strongly recommended for all persons for whom both vaccines are indicated. Hepatitis B vaccine administered with yellow fever vaccine is as safe and immunogenic as when these vaccines are administered separately (20). Measles and yellow fever vaccines have been administered safely at the same visit and without reduction of immunogenicity of each of the components (21,22). Depending on vaccines administered in the first year of life, children aged 12-15 months can receive <7 injections during a single visit (MMR, varicella, Hib, pneumococcal conjugate, diphtheria and tetanus toxoids and acellular pertussis , IPV, and hepatitis B vaccines). To help reduce the number of injections at the 12-15-month visit, the IPV primary series can be completed before the child's first birthday. MMR and varicella vaccines should be administered at the same visit that occurs as soon as possible on or after the first birthday. The majority of children aged 1 year who have received two (polyribosylribitol phosphate-meningococcal outer membrane protein ) or three (PRP-tetanus , diphtheria CRM 197 protein conjugate ) prior doses of Hib vaccine, and three prior doses of DTaP and pneumococcal conjugate vaccine have developed protection (23,24). The third (PRP-OMP) or fourth (PRP-T, HbOC) dose of the Hib series, and the fourth doses of DTaP and pneumococcal conjugate vaccines are critical in boosting antibody titer and ensuring continued protection (24)(25)(26). However, the booster dose of the Hib or pneumococcal conjugate series can be deferred until ages 15-18 months for children who are likely to return for future visits. The fourth dose of DTaP is recommended to be administered at ages 15-18 months, but can be administered as early as age 12 months under certain circumstances (25). For infants at low risk for infection with hepatitis B virus (i.e., the mother tested negative for hepatitis B surface antigen at the time of delivery and the child is not of Asian or Pacific Islander descent), the hepatitis B vaccine series can be completed at any time during ages 6-18 months. Recommended spacing of doses should be maintained (Table 1). Use of combination vaccines can reduce the number of injections required at an office visit. Licensed combination vaccines can be used whenever any components of the combination are indicated and its other components are not contraindicated. Use of licensed combination vaccines is preferred over separate injection of their equivalent component vaccines (27). Only combination vaccines approved by the Food and Drug Administration (FDA) should be used. Individual vaccines must never be mixed in the same syringe unless they are specifically approved for mixing by FDA. Only one vaccine (DTaP and PRP-T Hib vaccine, marketed as TriHIBit ® ) is FDA-approved for mixing in the same syringe. This vaccine should not be used for primary vaccination in infants aged 2, 4, and 6 months, but it can be used as a booster after any Hib vaccine. # Nonsimultaneous Administration Inactivated vaccines do not interfere with the immune response to other inactivated vaccines or to live vaccines. An inactivated vaccine can be administered either simultaneously or at any time before or after a different inactivated vaccine or live vaccine (Table 2). The immune response to one live-virus vaccine might be impaired if administered within 30 days of another livevirus vaccine (28,29). Data are limited concerning interference between live vaccines. In a study conducted in two U.S. health maintenance organizations, persons who received varicella vaccine 30 days after MMR (30). In contrast, a 1999 study determined that the response to yellow fever vaccine is not affected by monovalent measles vaccine administered 1-27 days earlier (21). The effect of nonsimultaneously administering rubella, mumps, varicella, and yellow fever vaccines is unknown. To minimize the potential risk for interference, parenterally administered live vaccines not administered on the same day should be administered >4 weeks apart whenever possible (Table 2). If parenterally administered live vaccines are separated by 4 weeks after the last, invalid dose. Yellow fever vaccine can be administered at any time after single-antigen measles vaccine. Ty21a typhoid vaccine and parenteral live vaccines (i.e., # Spacing of Antibody-Containing Products and Vaccines Live Vaccines Ty21a typhoid and yellow fever vaccines can be administered at any time before, concurrent with, or after administering any immune globulin or hyperimmune globulin (e.g., hepatitis B immune globulin and rabies immune globulin). Blood (e.g., whole blood, packed red blood cells, and plasma) and other antibody-containing blood products (e.g., immune globulin, hyperimmune globulin, and intravenous immune globulin ) can inhibit the immune response to measles and rubella vaccines for >3 months (31,32). The effect of blood and immune globulin preparations on the response to mumps and varicella vaccines is unknown, but commercial immune globulin preparations contain antibodies to these viruses. Blood products available in the United States are unlikely to contain a substantial amount of antibody to yellow fever vaccine virus. The length of time that interference with parenteral live vaccination (except yellow fever vaccine) can persist after the antibody-containing product is a function of the amount of antigen-specific antibody contained in the product (31)(32)(33). Therefore, after an antibody-containing product is received, parenteral live vaccines (except yellow fever vaccine) should be delayed until the passive antibody has degraded (Table 3). Recommended intervals between receipt of various blood products and measles-containing vaccine and varicella vaccine are listed in this report (Table 4). If a dose of parenteral live-virus vaccine (except yellow fever vaccine) is administered after an antibody-containing product but at an interval shorter than recommended in this report, the vaccine dose should be repeated unless serologic testing indicates a response to the vaccine. The repeat dose or serologic testing should be performed after the interval indicated for the antibody-containing product (Table 4). Although passively acquired antibodies can interfere with the response to rubella vaccine, the low dose of anti-Rho(D) globulin administered to postpartum women has not been demonstrated to reduce the response to the RA27/3 strain rubella vaccine (34). Because of the importance of rubella immunity among childbearing-age women (6,35), the postpartum vaccination of rubella-susceptible women with rubella or MMR vaccine should not be delayed because of receipt of anti-Rho(D) globulin or any other blood product during the last trimester of pregnancy or at delivery. These women should be vaccinated immediately after delivery and, if possible, tested >3 months later to ensure immunity to rubella and, if necessary, to measles (6). Interference can occur if administering an antibodycontaining product becomes necessary after administering MMR, its individual components, or varicella vaccine. Usually, vaccine virus replication and stimulation of immunity will occur 1-2 weeks after vaccination. Thus, if the interval be- Antibody-containing products 2 weeks - Blood products containing substantial amounts of immunoglobulin, including intramuscular and intravenous immune globulin, specific hyperimmune globulin (e.g, hepatitis B immune globulin, tetanus immune globulin, varicella zoster immune globulin, and rabies immune globulin), whole blood, packed red cells, plasma, and platelet products. † Yellow fever and oral Ty21a typhoid vaccines are exceptions to these recommendations. These live attenuated vaccines can be administered at any time before, after, or simultaneously with an antibody-containing product without substantially decreasing the antibody response. § The duration of interference of antibody-containing products with the immune response to the measles component of measles-containing vaccine, and possibly varicella vaccine, is dose-related (see Table 4). tween administering any of these vaccines and subsequent administration of an antibody-containing product is <14 days, vaccination should be repeated after the recommended interval (Tables 3,4), unless serologic testing indicates that antibodies were produced. A humanized mouse monoclonal antibody product (palivizumab) is available for prevention of respiratory syncytial virus infection among infants and young children. This product contains only antibody to respiratory syncytial virus; hence, it will not interfere with immune response to live or inactivated vaccines. # Inactivated Vaccines Antibody-containing products interact less with inactivated vaccines, toxoids, recombinant subunit, and polysaccharide vaccines than with live vaccines (36). Therefore, administering inactivated vaccines and toxoids either simultaneously with or at any interval before or after receipt of an antibody-containing product should not substantially impair development of a protective antibody response (Table 3). The vaccine or toxoid and antibody preparation should be administered at different sites by using the standard rec- # Interchangeability of Vaccines from Different Manufacturers Numerous vaccines are available from different manufacturers, and these vaccines usually are not identical in antigen content or amount or method of formulation. Manufacturers use different production processes, and their products might contain different concentrations of antigen per dose or different stabilizers or preservatives. Available data indicate that infants who receive sequential doses of different Hib conjugate, hepatitis B, and hepatitis A vaccines produce a satisfactory antibody response after a complete primary series (37)(38)(39)(40). All brands of Hib conjugate, hepatitis B, § and hepatitis A vaccines are interchangeable within their respective series. If different brands of Hib conjugate vaccine are administered, a total of three doses is considered adequate for the primary series among infants. After completing the primary series, any Hib conjugate vaccine can be used for the booster dose at ages 12-18 months. Data are limited regarding the safety, immunogenicity, and efficacy of using acellular pertussis (as DTaP) vaccines from different manufacturers for successive doses of the pertussis series. Available data from one study indicate that, for the first three doses of the DTaP series, one or two doses of Tripedia ® (manufactured by Aventis Pasteur) followed by Infanrix ® (manufactured by GlaxoSmithKline) for the remaining doses(s) is comparable to three doses of Tripedia with regard to immunogenicity, as measured by antibodies to diphtheria, tetanus, and pertussis toxoid, and filamentous hemagglutinin (41). However, in the absence of a clear serologic correlate of protection for pertussis, the relevance of these immunogenicity data for protection against pertussis is unknown. Whenever feasible, the same brand of DTaP vaccine should be used for all doses of the vaccination series; however, vaccination providers might not know or have available the type of DTaP vaccine previously administered to a child. In this situation, any DTaP vaccine should be used to continue or complete the series. Vaccination should not be deferred because the brand used for previous doses is not available or is unknown (25,42). # Lapsed Vaccination Schedule Vaccination providers are encouraged to administer vaccines as close to the recommended intervals as possible. However, longer-than-recommended intervals between doses do not reduce final antibody concentrations, although protection might not be attained until the recommended number of doses has been administered. An interruption in the vaccination schedule does not require restarting the entire series of a vaccine or toxoid or the addition of extra doses. # Unknown or Uncertain Vaccination Status Vaccination providers frequently encounter persons who do not have adequate documentation of vaccinations. Providers should only accept written, dated records as evidence of vaccination. With the exception of pneumococcal polysaccharide vaccine (43), self-reported doses of vaccine without written documentation should not be accepted. Although vaccinations should not be postponed if records cannot be found, an attempt to locate missing records should be made by contacting previous health-care providers and searching for a personally held record. If records cannot be located, these persons should be considered susceptible and should be started on the age-appropriate vaccination schedule. Serologic testing for immunity is an alternative to vaccination for certain antigens (e.g., measles, mumps, rubella, varicella, tetanus, diphtheria, hepatitis A, hepatitis B, and poliovirus) (see Vaccination of Internationally Adopted Children). # Contraindications and Precautions Contraindications and precautions to vaccination dictate circumstances when vaccines will not be administered. The majority of contraindications and precautions are temporary, and the vaccination can be administered later. A contraindication is a condition in a recipient that increases the risk for a serious adverse reaction. A vaccine will not be administered when a contraindication is present. For example, administering influenza vaccine to a person with an anaphylactic allergy to egg protein could cause serious illness in or death of the recipient. National standards for pediatric immunization practices have been established and include true contraindications and precautions to vaccination (Table 5) (1). The only true contraindication applicable to all vaccines is a history of a severe allergic reaction after a prior dose of vaccine or to a vaccine constituent (unless the recipient has been desensitized). Severely immunocompromised persons should not receive live vaccines. Children who experience an encephalopathy <7 days after administration of a previous dose of diphtheria and tetanus toxoids and whole-cell pertussis vac- § The exception is the two-dose hepatitis B vaccination series for adolescents aged 11-15 years. Only Recombivax HB ® (Merck Vaccine Division) should be used in this schedule. Engerix-B ® is not approved by FDA for this schedule. A precaution is a condition in a recipient that might increase the risk for a serious adverse reaction or that might compromise the ability of the vaccine to produce immunity (e.g., administering measles vaccine to a person with passive immunity to measles from a blood transfusion). Injury could result, or a person might experience a more se- # Contraindication Severe allergic reaction after a previous dose or to a vaccine component # Precautions Infant weighing 28 days. Substantially immunosuppressive steroid dose is considered to be >2 weeks of daily receipt of 20 mg or 2 mg/kg body weight of prednisone or equivalent. † † Measles vaccination can suppress tuberculin reactivity temporarily. Measles-containing vaccine can be administered on the same day as tuberculin skin testing. If testing cannot be performed until after the day of MMR vaccination, the test should be postponed for >4 weeks after the vaccination. If an urgent need exists to skin test, do so with the understanding that reactivity might be reduced by the vaccine. § § See text for details. ¶ ¶ If a vaccinee experiences a presumed vaccine-related rash 7-25 days after vaccination, avoid direct contact with immunocompromised persons for the duration of the rash. vere reaction to the vaccine than would have otherwise been expected; however, the risk for this happening is less than expected with a contraindication. Under normal circumstances, vaccinations should be deferred when a precaution is present. However, a vaccination might be indicated in the presence of a precaution because the benefit of protection from the vaccine outweighs the risk for an adverse reaction. For example, caution should be exercised in vaccinating a child with DTaP who, within 48 hours of receipt of a prior dose of DTP or DTaP, experienced fever >40.5C (105F); had persistent, inconsolable crying for >3 hours; collapsed or experienced a shock-like state; or had a seizure <3 days after receiving the previous dose of DTP or DTaP. However, administering a pertussis-containing vaccine should be considered if the risk for pertussis is increased (e.g., during a pertussis outbreak) (25). The presence of a moderate or severe acute illness with or without a fever is a precaution to administration of all vaccines. Other precautions are listed in this report (Table 5). Physicians and other health-care providers might inappropriately consider certain conditions or circumstances to be true contraindications or precautions to vaccination. This misconception results in missed opportunities to administer recommended vaccines (44). Likewise, physicians and other health-care providers might fail to understand what constitutes a true contraindication or precaution and might administer a vaccine when it should be withheld. This practice can result in an increased risk for an adverse reaction to the vaccine. Conditions often inappropriately regarded as contraindications to vaccination are listed in this report (Table 5). Among the most common are diarrhea and minor upperrespiratory tract illnesses (including otitis media) with or without fever, mild to moderate local reactions to a previous dose of vaccine, current antimicrobial therapy, and the convalescent phase of an acute illness. The decision to administer or delay vaccination because of a current or recent acute illness depends on the severity of symptoms and the etiology of the disease. All vaccines can be administered to persons with minor acute illness (e.g., diarrhea or mild upper-respiratory tract infection with or without fever). Studies indicate that failure to vaccinate children with minor illnesses can seriously impede vaccination efforts (45)(46)(47). Among persons whose compliance with medical care cannot be ensured, use of every opportunity to provide appropriate vaccinations is critical. The majority of studies support the safety and efficacy of vaccinating persons who have mild illness (48)(49)(50). For example, in the United States, >97% of children with mild illnesses produced measles antibody after vaccination (51). Only one limited study has reported a lower rate of seroconversion (79%) to the measles component of MMR vaccine among children with minor, afebrile upper-respiratory tract infections (52). Therefore, vaccination should not be delayed because of the presence of mild respiratory tract illness or other acute illness with or without fever. Persons with moderate or severe acute illness should be vaccinated as soon as they have recovered from the acute phase of the illness. This precaution avoids superimposing adverse effects of the vaccine on the underlying illness or mistakenly attributing a manifestation of the underlying illness to the vaccine. Routine physical examinations and measuring temperatures are not prerequisites for vaccinating infants and children who appear to be healthy. Asking the parent or guardian if the child is ill and then postponing vaccination for those with moderate to severe illness, or proceeding with vaccination if no contraindications exist, are appropriate procedures in childhood immunization programs. A family history of seizures or other central nervous system disorders is not a contraindication to administration of pertussis or other vaccines. However, delaying pertussis vaccination for infants and children with a history of previous seizures until the child's neurologic status has been assessed is prudent. Pertussis vaccine should not be administered to infants with evolving neurologic conditions until a treatment regimen has been established and the condition has stabilized (25). # Vaccine Administration Infection Control and Sterile Technique Persons administering vaccines should follow necessary precautions to minimize risk for spreading disease. Hands should be washed with soap and water or cleansed with an alcoholbased waterless antiseptic hand rub between each patient contact. Gloves are not required when administering vaccinations, unless persons administering vaccinations are likely to come into contact with potentially infectious body fluids or have open lesions on their hands. Syringes and needles used for injections must be sterile and disposable to minimize the risk of contamination. A separate needle and syringe should be used for each injection. Changing needles between drawing vaccine from a vial and injecting it into a recipient is unnecessary. Different vaccines should never be mixed in the same syringe unless specifically licensed for such use. Disposable needles and syringes should be discarded in labeled, puncture-proof containers to prevent inadvertent needle-stick injury or reuse. Safety needles or needle-free injection devices also can reduce the risk for injury and February 8, 2002 should be used whenever available (see Occupational Safety Regulations). # Recommended Routes of Injection and Needle Length Routes of administration are recommended by the manufacturer for each immunobiologic. Deviation from the recommended route of administration might reduce vaccine efficacy (53,54) or increase local adverse reactions (55)(56)(57). Injectable immunobiologics should be administered where the likelihood of local, neural, vascular, or tissue injury is limited. Vaccines containing adjuvants should be injected into the muscle mass; when administered subcutaneously or intradermally, they can cause local irritation, induration, skin discoloration, inflammation, and granuloma formation. # Subcutaneous Injections Subcutaneous injections usually are administered at a 45degree angle into the thigh of infants aged 12 months. Subcutaneous injections can be administered into the upper-outer triceps area of an infant, if necessary. A 5/8-inch, 23-25-gauge needle should be inserted into the subcutaneous tissue. # Intramuscular Injections Intramuscular injections are administered at a 90-degree angle into the anterolateral aspect of the thigh or the deltoid muscle of the upper arm. The buttock should not be used for administration of vaccines or toxoids because of the potential risk of injury to the sciatic nerve (58). In addition, injection into the buttock has been associated with decreased immunogenicity of hepatitis B and rabies vaccines in adults, presumably because of inadvertent subcutaneous injection or injection into deep fat tissue (53,59). For all intramuscular injections, the needle should be long enough to reach the muscle mass and prevent vaccine from seeping into subcutaneous tissue, but not so long as to involve underlying nerves and blood vessels or bone (54,(60)(61)(62). Vaccinators should be familiar with the anatomy of the area into which they are injecting vaccine. An individual decision on needle size and site of injection must be made for each person on the basis of age, the volume of the material to be administered, the size of the muscle, and the depth below the muscle surface into which the material is to be injected. Although certain vaccination specialists advocate aspiration (i.e., the syringe plunger pulled back before injection), no data exist to document the necessity for this procedure. If aspiration results in blood in the needle hub, the needle should be withdrawn and a new site should be selected. Infants (persons aged <12 months). Among the majority of infants, the anterolateral aspect of the thigh provides the largest muscle mass and is therefore the recommended site for injection. For the majority of infants, a 7/8-1-inch, 22-25-gauge needle is sufficient to penetrate muscle in the infant's thigh. # Toddlers and Older Children (persons aged >12 months-18 years). The deltoid muscle can be used if the muscle mass is adequate. The needle size can range from 22 to 25 gauge and from 7/8 to 1¼ inches, on the basis of the size of the muscle. For toddlers, the anterolateral thigh can be used, but the needle should be longer, usually 1 inch. # Adults (persons aged >18 years). For adults, the deltoid muscle is recommended for routine intramuscular vaccinations. The anterolateral thigh can be used. The suggested needle size is 1-1½ inches and 22-25 gauge. # Intradermal Injections Intradermal injections are usually administered on the volar surface of the forearm. With the bevel facing upwards, a 3/8-3/4-inch, 25-27-gauge needle can be inserted into the epidermis at an angle parallel to the long axis of the forearm. The needle should be inserted so that the entire bevel penetrates the skin and the injected solution raises a small bleb. Because of the small amounts of antigen used in intradermal vaccinations, care must be taken not to inject the vaccine subcutaneously because it can result in a suboptimal immunologic response. # Multiple Vaccinations If >2 vaccine preparations are administered or if vaccine and an immune globulin preparation are administered simultaneously, each preparation should be administered at a different anatomic site. If >2 injections must be administered in a single limb, the thigh is usually the preferred site because of the greater muscle mass; the injections should be sufficiently separated (i.e., >1 inch) so that any local reactions can be differentiated (55,63). For older children and adults, the deltoid muscle can be used for multiple intramuscular injections, if necessary. The location of each injection should documented in the person's medical record. # Jet Injection Jet injectors (JIs) are needle-free devices that drive liquid medication through a nozzle orifice, creating a narrow stream under high pressure that penetrates skin to deliver a drug or vaccine into intradermal, subcutaneous, or intramuscular tis-sues (64,65). Increasing attention to JI technology as an alternative to conventional needle injection has resulted from recent efforts to reduce the frequency of needle-stick injuries to health-care workers (66) and to overcome the improper reuse and other drawbacks of needles and syringes in economically developing countries (67)(68)(69). JIs have been reported safe and effective in administering different live and inactivated vaccines for viral and bacterial diseases (69). The immune responses generated are usually equivalent to, and occasionally greater than, those induced by needle injection. However, local reactions or injury (e.g., redness, induration, pain, blood, and ecchymosis at the injection site) can be more frequent for vaccines delivered by JIs compared with needle injection (65,69). Certain JIs were developed for situations in which substantial numbers of persons must be vaccinated rapidly, but personnel or supplies are insufficient to do so with conventional needle injection. Such high-workload devices vaccinate consecutive patients from the same nozzle orifice, fluid pathway, and dose chamber, which is refilled automatically from attached vials containing <50 doses each. Since the 1950s, these devices have been used extensively among military recruits and for mass vaccination campaigns for disease control and eradication (64). An outbreak of hepatitis B among patients receiving injections from a multiple-use-nozzle JI was documented (70,71), and subsequent laboratory, field, and animal studies demonstrated that such devices could become contaminated with blood (69,72,73). No U.S.-licensed, high-workload vaccination devices of unquestioned safety are available to vaccination programs. Efforts are under way for the research and development of new high-workload JIs using disposable-cartridge technology that avoids reuse of any unsterilized components having contact with the medication fluid pathway or patient's blood. Until such devices become licensed and available, the use of existing multiple-use-nozzle JIs should be limited. Use can be considered when the theoretical risk for bloodborne disease transmission is outweighed by the benefits of rapid vaccination with limited personnel in responding to serious disease threats (e.g., pandemic influenza or bioterrorism event), and by any competing risks of iatrogenic or occupational infections resulting from conventional needles and syringes. Before such emergency use of multiple-use-nozzle JIs, health-care workers should consult with local, state, national, or international health agencies or organizations that have experience in their use. In the 1990s, a new generation of low-workload JIs were introduced with disposable cartridges serving as dose chambers and nozzle (69). With the provision of a new sterile cartridge for each patient and other correct use, these devices avoid the safety concerns described previously for multiple-use-nozzle devices. They can be used in accordance with their labeling for intradermal, subcutaneous, or intramuscular administration. # Methods for Alleviating Discomfort and Pain Associated with Vaccination Comfort measures and distraction techniques (e.g., playing music or pretending to blow away the pain) might help children cope with the discomfort associated with vaccination. Pretreatment (30-60 minutes before injection) with 5% topical lidocaine-prilocaine emulsion (EMLA ® cream or disk ) can decrease the pain of vaccination among infants by causing superficial anesthesia (74,75). Preliminary evidence indicates that this cream does not interfere with the immune response to MMR (76). Topical lidocaine-prilocaine emulsion should not be used on infants aged <12 months who are receiving treatment with methemoglobin-inducing agents because of the possible development of methemoglobinemia (77). Acetaminophen has been used among children to reduce the discomfort and fever associated with vaccination (78). However, acetaminophen can cause formation of methemoglobin and, thus, might interact with lidocaine-prilocaine cream, if used concurrently (77). Ibuprofen or other nonaspirin analgesic can be used, if necessary. Use of a topical refrigerant (vapocoolant) spray can reduce the shortterm pain associated with injections and can be as effective as lidocaine-prilocaine cream (79). Administering sweettasting fluid orally immediately before injection can result in a calming or analgesic effect among certain infants. # Nonstandard Vaccination Practices Recommendations regarding route, site, and dosage of immunobiologics are derived from data from clinical trials, from practical experience, and from theoretical considerations. ACIP strongly discourages variations from the recommended route, site, volume, or number of doses of any vaccine. Variation from the recommended route and site can result in inadequate protection. The immunogenicity of hepatitis B vaccine and rabies vaccine is substantially lower when the gluteal rather than the deltoid site is used for administration (53,59). Hepatitis B vaccine administered intradermally can result in a lower seroconversion rate and final titer of hepatitis B surface antibody than when administered by the deltoid intramuscular route (80,81). Doses of rabies vaccine administered in the gluteal site should not be counted as valid doses and should be repeated. Hepatitis B vaccine administered by any route or site other than intramuscularly in the anterolateral thigh or deltoid muscle should not be counted as valid and should be repeated, unless serologic testing indicates that an adequate response has been achieved. Live attenuated parenteral vaccines (e.g., MMR, varicella, or yellow fever) and certain inactivated vaccines (e.g., IPV, pneumococcal polysaccharide, and anthrax) are recommended by the manufacturers to be administered by subcutaneous injection. Pneumococcal polysaccharide and IPV are approved for either intramuscular or subcutaneous administration. Response to these vaccines probably will not be affected if the vaccines are administered by the intramuscular rather then subcutaneous route. Repeating doses of vaccine administered by the intramuscular route rather than by the subcutaneous route is unnecessary. Administering volumes smaller than those recommended (e.g., split doses) can result in inadequate protection. Using larger than the recommended dose can be hazardous because of excessive local or systemic concentrations of antigens or other vaccine constituents. Using multiple reduced doses that together equal a full immunizing dose or using smaller divided doses is not endorsed or recommended. Any vaccination using less than the standard dose should not be counted, and the person should be revaccinated according to age, unless serologic testing indicates that an adequate response has been achieved. # Preventing Adverse Reactions Vaccines are intended to produce active immunity to specific antigens. An adverse reaction is an untoward effect that occurs after a vaccination that is extraneous to the vaccine's primary purpose of producing immunity. Adverse reactions also are called vaccine side effects. All vaccines might cause adverse reactions (82). Vaccine adverse reactions are classified by three general categories: local, systemic, and allergic. Local reactions are usually the least severe and most frequent. Systemic reactions (e.g., fever) occur less frequently than local reactions. Serious allergic reactions (e.g., anaphylaxis) are the most severe and least frequent. Severe adverse reactions are rare. The key to preventing the majority of serious adverse reactions is screening. Every person who administers vaccines should screen patients for contraindications and precautions to the vaccine before it is administered (Table 5). Standardized screening questionnaires have been developed and are available from certain state immunization programs and other sources (e.g., the Immunization Action Coalition at ). Severe allergic reactions after vaccination are rare. However, all physicians and other health-care providers who administer vaccines should have procedures in place for the emergency management of a person who experiences an anaphylactic reaction. All vaccine providers should be familiar with the office emergency plan and be certified in cardiopulmonary resuscitation. Syncope (vasovagal or vasodepressor reaction) can occur after vaccination, most commonly among adolescents and young adults. During 1990-August 2001, a total of 2,269 reports to the Vaccine Adverse Event Reporting system were coded as syncope. Forty percent of these episodes were reported among persons aged 10-18 years (CDC, unpublished data, 2001). Approximately 12% of reported syncopal episodes resulted in hospitalization because of injury or medical evaluation. Serious injury, including skull fractures and cerebral bleeding, have been reported to result from syncopal episodes after vaccination. A published review of syncope after vaccination reported that 63% of syncopal episodes occurred <5 minutes after vaccination, and 89% occurred within 15 minutes after vaccination (83). Although syncopal episodes are uncommon and serious allergic reactions are rare, certain vaccination specialists recommend that persons be observed for 15-20 minutes after being vaccinated, if possible (84). If syncope develops, patients should be observed until the symptoms resolve. # Managing Acute Vaccine Reactions Although rare after vaccination, the immediate onset and life-threatening nature of an anaphylactic reaction require that personnel and facilities providing vaccinations be capable of providing initial care for suspected anaphylaxis. Epinephrine and equipment for maintaining an airway should be available for immediate use. Anaphylaxis usually begins within minutes of vaccine administration. Rapidly recognizing and initiating treatment are required to prevent possible progression to cardiovascular collapse. If flushing, facial edema, urticaria, itching, swelling of the mouth or throat, wheezing, difficulty breathing, or other signs of anaphylaxis occur, the patient should be placed in a recumbent position with the legs elevated. Aqueous epinephrine (1:1000) should be administered and can be repeated within 10-20 minutes (84). A dose of diphenhydramine hydrochloride might shorten the reaction, but it will have little immediate effect. Maintenance of an airway and oxygen administration might be necessary. Arrangements should be made for immediate transfer to an emergency facility for further evaluation and treatment. # Occupational Safety Regulations Bloodborne diseases (e.g., hepatitis B and C and human immunodeficiency virus ) are occupational hazards for health-care workers. In November 2000, to reduce the incidence of needle-stick injuries among health-care workers and the consequent risk for bloodborne diseases acquired from patients, the Needlestick Safety and Prevention Act was signed into law. The act directed the Occupational Safety and Health Administration (OSHA) to strengthen its existing bloodborne pathogen standards. Those standards were revised and became effective in April 2001 (66). These federal regulations require that safer injection devices (e.g., needle-shielding syringes or needle-free injectors) be used for parenteral vaccination in all clinical settings when such devices are appropriate, commercially available, and capable of achieving the intended clinical purpose. The rules also require that records be kept documenting the incidence of injuries caused by medical sharps (except in workplaces with <10 employees) and that nonmanagerial employees be involved in the evaluation and selection of safer devices to be procured. Needle-shielding or needle-free devices that might satisfy the occupational safety regulations for administering parenteral injections are available in the United States and are listed at multiple websites (69,85-87). ¶ Additional information regarding implementation and enforcement of these regulations is available at the OSHA website at / needlesticks (accessed October 31, 2001). # Storage and Handling of Immunobiologics Failure to adhere to recommended specifications for storage and handling of immunobiologics can reduce potency, resulting in an inadequate immune response in the recipient. Recommendations included in a product's package insert, including reconstitution of the vaccine, should be followed carefully. Vaccine quality is the shared responsibility of all parties from the time the vaccine is manufactured until administration. All vaccines should be inspected upon delivery and monitored during storage to ensure that the cold chain has been maintained. Vaccines should continue to be stored at recommended temperatures immediately upon receipt. Certain vaccines (e.g., MMR, varicella, and yellow fever) are sensitive to increased temperature. All other vaccines are sensitive to freezing. Mishandled vaccine usually is not distinguishable from potent vaccine. When in doubt regarding the appropriate handling of a vaccine, vaccination providers should contact the manufacturer. Vaccines that have been mishandled (e.g., inactivated vaccines and toxoids that have been exposed to freezing temperatures) or that are beyond their expiration date should not be administered. If mishandled or expired vaccines are administered inadvertently, they should not be counted as valid doses and should be repeated, unless serologic testing indicates a response to the vaccine. Live attenuated virus vaccines should be administered promptly after reconstitution. Varicella vaccine must be administered <30 minutes after reconstitution. Yellow fever vaccine must be used <1 hour after reconstitution. MMR vaccine must be administered <8 hours after reconstitution. If not administered within these prescribed time periods after reconstitution, the vaccine must be discarded. The majority of vaccines have a similar appearance after being drawn into a syringe. Instances in which the wrong vaccine inadvertently was administered are attributable to the practice of prefilling syringes or drawing doses of a vaccine into multiple syringes before their immediate need. ACIP discourages the routine practice of prefilling syringes because of the potential for such administration errors. To prevent errors, vaccine doses should not be drawn into a syringe until immediately before administration. In certain circumstances where a single vaccine type is being used (e.g., in advance of a community influenza vaccination campaign), filling multiple syringes before their immediate use can be considered. Care should be taken to ensure that the cold chain is maintained until the vaccine is administered. When the syringes are filled, the type of vaccine, lot number, and date of filling must be carefully labeled on each syringe, and the doses should be administered as soon as possible after filling. Certain vaccines are distributed in multidose vials. When opened, the remaining doses from partially used multidose vials can be administered until the expiration date printed on the vial or vaccine packaging, provided that the vial has been stored correctly and that the vaccine is not visibly contaminated. ¶ Internet sites with device listings are identified for information purposes only. CDC, the U.S. Public Health Service, and the Department of Health and Human Services do not endorse any specific device or imply that the devices listed would all satisfy the needle-stick prevention regulations. # MMWR February 8, 2002 # Special Situations # Concurrently Administering Antimicrobial Agents and Vaccines With limited exceptions, using an antibiotic is not a contraindication to vaccination. Antimicrobial agents have no effect on the response to live attenuated vaccines, except live oral Ty21a typhoid vaccine, and have no effect on inactivated, recombinant subunit, or polysaccharide vaccines or toxoids. Ty21a typhoid vaccine should not be administered to persons receiving antimicrobial agents until >24 hours after any antibiotic dose (18). Antiviral drugs used for treatment or prophylaxis of influenza virus infections have no effect on the response to inactivated influenza vaccine (88). Antiviral drugs active against herpesviruses (e.g., acyclovir or valacyclovir) might reduce the efficacy of live attenuated varicella vaccine. These drugs should be discontinued >24 hours before administration of varicella vaccine, if possible. The antimalarial drug mefloquine (Lariam ® ) could affect the immune response to oral Ty21a typhoid vaccine if both are taken simultaneously (89,90). To minimize this effect, administering Ty21a typhoid vaccine >24 hours before or after a dose of mefloquine is prudent. # Tuberculosis Screening and Skin Test Reactivity Measles illness, severe acute or chronic infections, HIV infection, and malnutrition can create an anergic state during which the tuberculin skin test (usually known as purified protein derivative skin test) might give a false negative reaction (91)(92)(93). Although any live attenuated measles vaccine can theoretically suppress PPD reactivity, the degree of suppression is probably less than that occurring from acute infection from wild measles virus. Although routine PPD screening of all children is no longer recommended, PPD screening is sometimes needed at the same time as administering a measles-containing vaccine (e.g., for well-child care, school entrance, or for employee health reasons), and the following options should be considered: - PPD and measles-containing vaccine can be administered at the same visit (preferred option). Simultaneously administering PPD and measles-containing vaccine does not interfere with reading the PPD result at 48-72 hours and ensures that the person has received measles vaccine. - If the measles-containing vaccine has been administered recently, PPD screening should be delayed >4 weeks after vaccination. A delay in performing PPD will re-move the concern of any theoretical but transient suppression of PPD reactivity from the vaccine. - PPD screening can be performed and read before administering the measles-containing vaccine. This option is the least favored because it will delay receipt of the measles-containing vaccine. No data exist for the potential degree of PPD suppression that might be associated with other parenteral live attenuated virus vaccines (e.g., varicella or yellow fever). Nevertheless, in the absence of data, following guidelines for measlescontaining vaccine when scheduling PPD screening and administering other parenteral live attenuated virus vaccines is prudent. If a risk exists that the opportunity to vaccinate might be missed, vaccination should not be delayed only because of these theoretical considerations. Mucosally administered live attenuated virus vaccines (e.g., OPV and intranasally administered influenza vaccine) are unlikely to affect the response to PPD. No evidence has been reported that inactivated vaccines, polysaccharide vaccines, recombinant, or subunit vaccines, or toxoids interfere with response to PPD. PPD reactivity in the absence of tuberculosis disease is not a contraindication to administration of any vaccine, including parenteral live attenuated virus vaccines. Tuberculosis disease is not a contraindication to vaccination, unless the person is moderately or severely ill. Although no studies have reported the effect of MMR vaccine on persons with untreated tuberculosis, a theoretical basis exists for concern that measles vaccine might exacerbate tuberculosis (6). Consequently, before administering MMR to persons with untreated active tuberculosis, initiating antituberculosis therapy is advisable (6). Ruling out concurrent immunosuppression (e.g., immunosuppression caused by HIV infection) before administering live attenuated vaccines is also prudent. # Severe Allergy to Vaccine Components Vaccine components can cause allergic reactions among certain recipients. These reactions can be local or systemic and can include mild to severe anaphylaxis or anaphylactic-like responses (e.g., generalized urticaria or hives, wheezing, swelling of the mouth and throat, difficulty breathing, hypotension, and shock). Allergic reactions might be caused by the vaccine antigen, residual animal protein, antimicrobial agents, preservatives, stabilizers, or other vaccine components (94). An extensive listing of vaccine components, their use, and the vaccines that contain each component has been published (95) and is also available from CDC's National Immunization Program website at (accessed October 31,2001). The most common animal protein allergen is egg protein, which is found in vaccines prepared by using embryonated chicken eggs (influenza and yellow fever vaccines). Ordinarily, persons who are able to eat eggs or egg products safely can receive these vaccines; persons with histories of anaphylactic or anaphylactic-like allergy to eggs or egg proteins should not be administered these vaccines. Asking persons if they can eat eggs without adverse effects is a reasonable way to determine who might be at risk for allergic reactions from receiving yellow fever and influenza vaccines. A regimen for administering influenza vaccine to children with egg hypersensitivity and severe asthma has been developed (96). Measles and mumps vaccine viruses are grown in chick embryo fibroblast tissue culture. Persons with a serious egg allergy can receive measles-or mumps-containing vaccines without skin testing or desensitization to egg protein (6). Rubella and varicella vaccines are grown in human diploid cell cultures and can safely be administered to persons with histories of severe allergy to eggs or egg proteins. The rare serious allergic reaction after measles or mumps vaccination or MMR are not believed to be caused by egg antigens, but to other components of the vaccine (e.g., gelatin) (97-100). MMR, its component vaccines, and other vaccines contain hydrolyzed gelatin as a stabilizer. Extreme caution should be exercised when administering vaccines that contain gelatin to persons who have a history of an anaphylactic reaction to gelatin or gelatincontaining products. Before administering gelatincontaining vaccines to such persons, skin testing for sensitivity to gelatin can be considered. However, no specific protocols for this approach have been published. Certain vaccines contain trace amounts of antibiotics or other preservatives (e.g., neomycin or thimerosal) to which patients might be severely allergic. The information provided in the vaccine package insert should be reviewed carefully before deciding if the rare patient with such allergies should receive the vaccine. No licensed vaccine contains penicillin or penicillin derivatives. Certain vaccines contain trace amounts of neomycin. Persons who have experienced anaphylactic reactions to neomycin should not receive these vaccines. Most often, neomycin allergy is a contact dermatitis, a manifestation of a delayed type (cell-mediated) immune response, rather than anaphylaxis (101,102). A history of delayed type reactions to neomycin is not a contraindication for administration of these vaccines. Thimerosal is an organic mercurial compound in use since the 1930s and added to certain immunobiologic products as a preservative. A joint statement issued by the U.S. Public Health Service and the American Academy of Pediatrics (AAP) in 1999 (103) and agreed to by the American Academy of Family Physicians (AAFP) later in 1999, established the goal of removing thimerosal as soon as possible from vaccines routinely recommended for infants. Although no evidence exists of any harm caused by low levels of thimerosal in vaccines and the risk was only theoretical (104), this goal was established as a precautionary measure. The public is concerned about the health effects of mercury exposure of any type, and the elimination of mercury from vaccines was judged a feasible means of reducing an infant's total exposure to mercury in a world where other environmental sources of exposure are more difficult or impossible to eliminate (e.g., certain foods). Since mid-2001, vaccines routinely recommended for children have been manufactured without thimerosal as a preservative and contain either no thimerosal or only trace amounts. Thimerosal as a preservative is present in certain other vaccines (e.g., Td, DT, one of two adult hepatitis B vaccines, and influenza vaccine). A trace thimerosal formulation of one brand of influenza vaccine was licensed by FDA in September 2001. Receiving thimerosal-containing vaccines has been believed to lead to induction of allergy. However, limited scientific basis exists for this assertion (94). Hypersensitivity to thimerosal usually consists of local delayed type hypersensitivity reactions (105)(106)(107). Thimerosal elicits positive delayed type hypersensitivity patch tests in 1%-18% of persons tested, but these tests have limited or no clinical relevance (108,109). The majority of patients do not experience reactions to thimerosal administered as a component of vaccines even when patch or intradermal tests for thimerosal indicate hypersensitivity (109). A localized or delayed type hypersensitivity reaction to thimerosal is not a contraindication to receipt of a vaccine that contains thimerosal. # Latex Allergy Latex is liquid sap from the commercial rubber tree. Latex contains naturally occurring impurities (e.g., plant proteins and peptides), which are believed to be responsible for allergic reactions. Latex is processed to form natural rubber latex and dry natural rubber. Dry natural rubber and natural rubber latex might contain the same plant impurities as latex but in lesser amounts. Natural rubber latex is used to produce medical gloves, catheters, and other products. Dry natural rubber is used in syringe plungers, vial stoppers, and injection ports on intravascular tubing. Synthetic rubber and synthetic latex also are used in medical gloves, syringe plungers, and vial stoppers. Synthetic rubber and synthetic latex do not contain natural rubber or natural latex, and therefore, do not contain the impurities linked to allergic reactions. The most common type of latex sensitivity is contacttype (type 4) allergy, usually as a result of prolonged contact with latex-containing gloves (110). However, injectionprocedure-associated latex allergies among patients with diabetes have been described (111)(112)(113). Allergic reactions (including anaphylaxis) after vaccination procedures are rare. Only one report of an allergic reaction after administering hepatitis B vaccine in a patient with known severe allergy (anaphylaxis) to latex has been published (114). If a person reports a severe (anaphylactic) allergy to latex, vaccines supplied in vials or syringes that contain natural rubber should not be administered, unless the benefit of vaccination outweighs the risk of an allergic reaction to the vaccine. For latex allergies other than anaphylactic allergies (e.g., a history of contact allergy to latex gloves), vaccines supplied in vials or syringes that contain dry natural rubber or natural rubber latex can be administered. # Vaccination of Premature Infants In the majority of cases, infants born prematurely, regardless of birth weight, should be vaccinated at the same chronological age and according to the same schedule and precautions as full-term infants and children. Birth weight and size are not factors in deciding whether to postpone routine vaccination of a clinically stable premature infant (115)(116)(117), except for hepatitis B vaccine. The full recommended dose of each vaccine should be used. Divided or reduced doses are not recommended (118). Studies demonstrate that decreased seroconversion rates might occur among certain premature infants with low birth weights (i.e., <2,000 grams) after administration of hepatitis B vaccine at birth (119). However, by chronological age 1 month, all premature infants, regardless of initial birth weight or gestational age are as likely to respond as adequately as older and larger infants (120)(121)(122). A premature infant born to HBsAg-positive mothers and mothers with unknown HBsAg status must receive immunoprophylaxis with hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) <12 hours after birth. If these infants weigh <2,000 grams at birth, the initial vaccine dose should not be counted towards completion of the hepatitis B vaccine series, and three additional doses of hepatitis B vaccine should be administered, beginning when the infant is age 1 month. The optimal timing of the first dose of hepatitis B vaccine for premature infants of HBsAg-negative mothers with a birth weight of <2,000 grams has not been determined. However, these infants can receive the first dose of the hepatitis B vaccine series at chronological age 1 month. Premature infants discharged from the hospital before chronological age 1 month can also be administered hepatitis B vaccine at discharge, if they are medically stable and have gained weight consistently. # Breast-Feeding and Vaccination Neither inactivated nor live vaccines administered to a lactating woman affect the safety of breast-feeding for mothers or infants. Breast-feeding does not adversely affect immunization and is not a contraindication for any vaccine. Limited data indicate that breast-feeding can enhance the response to certain vaccine antigens (123). Breast-fed infants should be vaccinated according to routine recommended schedules (124)(125)(126). Although live vaccines multiply within the mother's body, the majority have not been demonstrated to be excreted in human milk. Although rubella vaccine virus might be excreted in human milk, the virus usually does not infect the infant. If infection does occur, it is well-tolerated because the viruses are attenuated (127). Inactivated, recombinant, subunit, polysaccharide, conjugate vaccines and toxoids pose no risk for mothers who are breast-feeding or for their infants. # Vaccination During Pregnancy Risk to a developing fetus from vaccination of the mother during pregnancy is primarily theoretical. No evidence exists of risk from vaccinating pregnant women with inactivated virus or bacterial vaccines or toxoids (128,129). Benefits of vaccinating pregnant women usually outweigh potential risks when the likelihood of disease exposure is high, when infection would pose a risk to the mother or fetus, and when the vaccine is unlikely to cause harm. Td toxoid is indicated routinely for pregnant women. Previously vaccinated pregnant women who have not received a Td vaccination within the last 10 years should receive a booster dose. Pregnant women who are not immunized or only partially immunized against tetanus should complete the primary series (130). Depending on when a woman seeks prenatal care and the required interval between doses, one or two doses of Td can be administered before delivery. Women for whom the vaccine is indicated, but who have not completed the recommended three-dose series during pregnancy, should receive follow-up after delivery to ensure the series is completed. Women in the second and third trimesters of pregnancy have been demonstrated to be at increased risk for hospitalization from influenza (131). Therefore, routine influenza vaccina-tion is recommended for healthy women who will be beyond the first trimester of pregnancy (i.e., >14 weeks of gestation) during influenza season (usually December-March in the United States) (88). Women who have medical conditions that increase their risk for complications of influenza should be vaccinated before the influenza season, regardless of the stage of pregnancy. IPV can be administered to pregnant women who are at risk for exposure to wild-type poliovirus infection (4). Hepatitis B vaccine is recommended for pregnant women at risk for hepatitis B virus infection (132). Hepatitis A, pneumococcal polysaccharide, and meningococcal polysaccharide vaccines should be considered for women at increased risk for those infections (43,133,134). Pregnant women who must travel to areas where the risk for yellow fever is high should receive yellow fever vaccine, because the limited theoretical risk from vaccination is substantially outweighed by the risk for yellow fever infection (22,135). Pregnancy is a contraindication for measles, mumps, rubella, and varicella vaccines. Although of theoretical concern, no cases of congenital rubella or varicella syndrome or abnormalities attributable to fetal infection have been observed among infants born to susceptible women who received rubella or varicella vaccines during pregnancy (6,136). Because of the importance of protecting women of childbearing age against rubella, reasonable practices in any immunization program include asking women if they are pregnant or intend to become pregnant in the next 4 weeks, not vaccinating women who state that they are pregnant, explaining the potential risk for the fetus to women who state that they are not pregnant, and counseling women who are vaccinated not to become pregnant during the 4 weeks after MMR vaccination (6,35,137). Routine pregnancy testing of women of childbearing age before administering a live-virus vaccine is not recommended (6). If a pregnant woman is inadvertently vaccinated or if she becomes pregnant within 4 weeks after MMR or varicella vaccination, she should be counseled regarding the theoretical basis of concern for the fetus; however, MMR or varicella vaccination during pregnancy should not ordinarily be a reason to terminate pregnancy (6,8). Persons who receive MMR vaccine do not transmit the vaccine viruses to contacts (6). Transmission of varicella vaccine virus to contacts is rare (138). MMR and varicella vaccines should be administered when indicated to the children and other household contacts of pregnant women (6,8). All pregnant women should be evaluated for immunity to rubella and be tested for the presence of HBsAg (6,35,132). Women susceptible to rubella should be vaccinated immedi-ately after delivery. A woman known to be HBsAg-positive should be followed carefully to ensure that the infant receives HBIG and begins the hepatitis B vaccine series <12 hours after birth and that the infant completes the recommended hepatitis B vaccine series (132). No known risk exists for the fetus from passive immunization of pregnant women with immune globulin preparations. # Vaccination of Internationally Adopted Children The ability of a clinician to determine that a person is protected on the basis of their country of origin and their records alone is limited. Internationally adopted children should receive vaccines according to recommended schedules for children in the United States. Only written documentation should be accepted as evidence of prior vaccination. Written records are more likely to predict protection if the vaccines, dates of administration, intervals between doses, and the child's age at the time of immunization are comparable to the current U.S. recommendations. Although vaccines with inadequate potency have been produced in other countries (139,140), the majority of vaccines used worldwide are produced with adequate quality control standards and are potent. The number of American families adopting children from outside the United States has increased substantially in recent years (141). Adopted children's birth countries often have immunization schedules that differ from the recommended childhood immunization schedule in the United States. Differences in the U.S. immunization schedule and those used in other countries include the vaccines administered, the recommended ages of administration, and the number and timing of doses. Data are inconclusive regarding the extent to which an internationally adopted child's immunization record reflects the child's protection. A child's record might indicate administration of MMR vaccine when only single-antigen measles vaccine was administered. A study of children adopted from the People's Republic of China, Russia, and Eastern Europe determined that only 39% (range: 17%-88% by country) of children with documentation of >3 doses of DTP before adoption had protective levels of diphtheria and tetanus antitoxin (142). However, antibody testing was performed by using a hemagglutination assay, which tends to underestimate protection and cannot directly be compared with antibody concentration (143). Another study measured antibody to diphtheria and tetanus toxins among 51 children who had records of having received >2 doses of DTP. The majority of the children were from Russia, Eastern Europe, and Asian countries, and 78% had re-ceived all their vaccine doses in an orphanage. Overall, 94% had evidence of protection against diphtheria (EIA > 0.1 IU/mL). A total of 84% had protection against tetanus (enzyme-linked immunosorbent assay > 0.5 IU/mL). Among children without protective tetanus antitoxin concentration, all except one had records of >3 doses of vaccine, and the majority of nonprotective concentrations were categorized as indeterminate (ELISA = 0.05-0.49 IU/mL) (144). Reasons for the discrepant findings in these two studies probably relate to different laboratory methodologies; the study using a hemagglutination assay might have underestimated the number of children who were protected. Additional studies using standardized methodologies are needed. Data are likely to remain limited for countries other than the People's Republic of China, Russia, and Eastern Europe because of the limited number of adoptees from other countries. Physicians and other health-care providers can follow one of multiple approaches if a question exists regarding whether vaccines administered to an international adoptee were im-munogenic. Repeating the vaccinations is an acceptable option. Doing so is usually safe and avoids the need to obtain and interpret serologic tests. If avoiding unnecessary injections is desired, judicious use of serologic testing might be helpful in determining which immunizations are needed. This report provides guidance on possible approaches to evaluation and revaccination for each vaccine recommended universally for children in the United States (see Table 6 and the following sections). # MMR Vaccine The simplest approach to resolving concerns regarding MMR immunization among internationally adopted children is to revaccinate with one or two doses of MMR vaccine, depending on the child's age. Serious adverse events after MMR vaccinations are rare (6). No evidence indicates that administering MMR vaccine increases the risk for adverse reactions among persons who are already immune to measles, mumps, or rubella as a result of previous vaccination or natural disease. Doses of measles-containing vaccine Serologic testing for neutralizing antibody to poliovirus types 1, 2, and 3 (limited availability), or administer single dose of IPV, followed by serologic testing for neutralizing antibody to poliovirus types 1, 2, and 3 Children whose records indicate receipt of >3 doses: serologic testing for specific IgG antibody to diphtheria and tetanus toxins before administering additional doses (see text), or administer a single booster dose of DTaP, followed by serological testing after 1 month for specific IgG antibody to diphtheria and tetanus toxins with revaccination as appropriate (see text) -- # TABLE 6. Approaches to the evaluation and vaccination of internationally adopted children # Vaccine Recommended approach Alternative approach administered before the first birthday should not be counted as part of the series (6). Alternatively, serologic testing for immunoglobulin G (IgG) antibody to vaccine viruses indicated on the vaccination record can be considered. Serologic testing is widely available for measles and rubella IgG antibody. A child whose record indicates receipt of monovalent measles or measles-rubella vaccine at age >1 year and who has protective antibody against measles and rubella should receive a single dose of MMR as age-appropriate to ensure protection against mumps (and rubella if measles vaccine alone had been used). If a child whose record indicates receipt of MMR at age >12 months has a protective concentration of antibody to measles, no additional vaccination is needed unless required for school entry. # Hib Vaccine Serologic correlates of protection for children vaccinated >2 months previously might be difficult to interpret. Because the number of vaccinations needed for protection decreases with age and adverse events are rare (24), ageappropriate vaccination should be provided. Hib vaccination is not recommended routinely for children aged >5 years. # Hepatitis B Vaccine Serologic testing for HBsAg is recommended for international adoptees, and children determined to be HBsAgpositive should be monitored for the development of liver disease. Household members of HBsAg-positive children should be vaccinated. A child whose records indicate receipt of >3 doses of vaccine can be considered protected, and additional doses are not needed if >1 doses were administered at age >6 months. Children who received their last hepatitis B vaccine dose at age 6 months. Those who have received <3 doses should complete the series at the recommended intervals and ages (Table 1). # Poliovirus Vaccine The simplest approach is to revaccinate internationally adopted children with IPV according to the U.S. schedule. Adverse events after IPV are rare (4). Children appropriately vaccinated with three doses of OPV in economically developing countries might have suboptimal seroconversion, including to type 3 poliovirus (125). Serologic testing for neutralizing antibody to poliovirus types 1, 2, and 3 can be obtained commercially and at certain state health department laboratories. Children with protective titers against all three types do not need revaccination and should complete the schedule as age-appropriate. Alternately, because the booster response after a single dose of IPV is excellent among children who previously received OPV (3), a single dose of IPV can be administered initially with serologic testing performed 1 month later. # DTaP Vaccine Vaccination providers can revaccinate a child with DTaP vaccine without regard to recorded doses; however, one concern regarding this approach is that data indicate increased rates of local adverse reactions after the fourth and fifth doses of DTP or DTaP (42). If a revaccination approach is adopted and a severe local reaction occurs, serologic testing for specific IgG antibody to tetanus and diphtheria toxins can be measured before administering additional doses. Protective concentration indicates that further doses are unnecessary and subsequent vaccination should occur as ageappropriate. No established serologic correlates exist for protection against pertussis. For a child whose record indicates receipt of >3 doses of DTP or DTaP, serologic testing for specific IgG antibody to both diphtheria and tetanus toxin before additional doses is a reasonable approach. If a protective concentration is present, recorded doses can be considered valid, and the vaccination series should be completed as age-appropriate. Indeterminate antibody concentration might indicate immunologic memory but antibody waning; serology can be repeated after a booster dose if the vaccination provider wishes to avoid revaccination with a complete series. Alternately, for a child whose records indicate receipt of >3 doses, a single booster dose can be administered, followed by serologic testing after 1 month for specific IgG antibody to both diphtheria and tetanus toxins. If a protective concentration is obtained, the recorded doses can be considered valid and the vaccination series completed as age-appropriate. Children with indeterminate concentration after a booster dose should be revaccinated with a complete series. # Varicella Vaccine Varicella vaccine is not administered in the majority of countries. A child who lacks a reliable medical history regarding prior varicella disease should be vaccinated as ageappropriate (8). # Pneumococcal Vaccines Pneumococcal conjugate and pneumococcal polysaccharide vaccines are not administered in the majority of coun- tries and should be administered as age-appropriate or as indicated by the presence of underlying medical conditions (26,43). # Altered Immunocompetence ACIP's statement regarding vaccinating immunocompromised persons summarizes recommendations regarding the efficacy, safety, and use of specific vaccines and immune globulin preparations for immunocompromised persons (145). ACIP statements regarding individual vaccines or immune globulins contain additional information regarding those concerns. Severe immunosuppression can be the result of congenital immunodeficiency, HIV infection, leukemia, lymphoma, generalized malignancy or therapy with alkylating agents, antimetabolites, radiation, or a high dose, prolonged course of corticosteroids. The degree to which a person is immunocompromised should be determined by a physician. Severe complications have followed vaccination with live-virus vaccines and live bacterial vaccines among immunocompromised patients (146)(147)(148)(149)(150)(151)(152)(153). These patients should not receive live vaccines except in certain circumstances that are noted in the following paragraphs. MMR vaccine viruses are not transmitted to contacts, and transmission of varicella vaccine virus is rare (6,138). MMR and varicella vaccines should be administered to susceptible household and other close contacts of immunocompromised patients when indicated. Persons with HIV infection are at increased risk for severe complications if infected with measles. No severe or unusual adverse events have been reported after measles vaccination among HIV-infected persons who did not have evidence of severe immunosuppression (154)(155)(156)(157). As a result, MMR vaccination is recommended for all HIVinfected persons who do not have evidence of severe immunosuppression † † and for whom measles vaccination would otherwise be indicated. Children with HIV infection are at increased risk for complications of primary varicella and for herpes zoster, compared with immunocompetent children (138,158). Limited data among asymptomatic or mildly symptomatic HIVinfected children (CDC class N1 or A1, age-specific CD4 + lymphocyte percentages of >25%) indicate that varicella vaccine is immunogenic, effective, and safe (138,159). Varicella vaccine should be considered for asymptomatic or mildly symptomatic HIV-infected children in CDC class N1 or A1 with age-specific CD4 + T lymphocyte percentages of >25%. Eligible children should receive two doses of varicella vaccine with a 3-month interval between doses (138). HIV-infected persons who are receiving regular doses of IGIV might not respond to varicella vaccine or MMR or its individual component vaccines because of the continued presence of passively acquired antibody. However, because of the potential benefit, measles vaccination should be considered approximately 2 weeks before the next scheduled dose of IGIV (if not otherwise contraindicated), although an optimal immune response is unlikely to occur. Unless serologic testing indicates that specific antibodies have been produced, vaccination should be repeated (if not otherwise contraindicated) after the recommended interval (Table 4). An additional dose of IGIV should be considered for persons on maintenance IGIV therapy who are exposed to measles >3 weeks after administering a standard dose (100-400 mg/kg body weight) of IGIV. Persons with cellular immunodeficiency should not receive varicella vaccine. However, ACIP recommends that persons with impaired humoral immunity (e.g., hypogammaglobulinemia or dysgammaglobulinemia) should be vaccinated (138,160). Inactivated, recombinant, subunit, polysaccharide, and conjugate vaccines and toxoids can be administered to all immunocompromised patients, although response to such vaccines might be suboptimal. If indicated, all inactivated vaccines are recommended for immunocompromised persons in usual doses and schedules. In addition, pneumococcal, meningococcal, and Hib vaccines are recommended specifically for certain groups of immunocompromised patients, including those with functional or anatomic asplenia (145,161). Except for influenza vaccine, which should be administered annually (88), vaccination during chemotherapy or radiation therapy should be avoided because antibody response is suboptimal. Patients vaccinated while receiving immunosuppressive therapy or in the 2 weeks before starting therapy should be considered unimmunized and should be revaccinated >3 months after therapy is discontinued. Patients with leukemia in remission whose chemotherapy has been terminated for >3 months can receive live-virus vaccines. † † As defined by a low age-specific total CD4 + T lymphocyte count or a low CD4 + T lymphocyte count as a percentage of total lymphocytes. ACIP recommendations for using MMR vaccine contain additional details regarding the criteria for severe immunosuppression in persons with HIV infection (Source: CDC. Measles, mumps, and rubella -vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices . MMWR 1998;47:1-57). # Corticosteroids The exact amount of systemically absorbed corticosteroids and the duration of administration needed to suppress the immune system of an otherwise immunocompetent person are not well-defined. The majority of experts agree that corticosteroid therapy usually is not a contraindication to administering live-virus vaccine when it is shortterm (i.e., 2 mg/kg of body weight or a total of 20 mg/day of prednisone or equivalent for children who weigh >10 kg, when administered for >2 weeks as sufficiently immunosuppressive to raise concern regarding the safety of vaccination with live-virus vaccines (84,145). Corticosteroids used in greater than physiologic doses also can reduce the immune response to vaccines. Vaccination providers should wait >1 month after discontinuation of therapy before administering a live-virus vaccine to patients who have received high systemically absorbed doses of corticosteroids for >2 weeks. # Vaccination of Hematopoietic Stem Cell Transplant Recipients Hematopoietic stem cell transplant (HSCT) is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy and often radiation, both of which are usually bone marrow ablative. HSCT is used to treat a variety of neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders. HSCT recipients can receive either their own cells (i.e., autologous HSCT) or cells from a donor other than the transplant recipient (i.e., allogeneic HSCT). The source of the transplanted stem cells can be from either a donor's bone marrow or peripheral blood or harvested from the umbilical cord of a newborn infant (162). Antibody titers to vaccine-preventable diseases (e.g., tetanus, poliovirus, measles, mumps, rubella, and encapsulated bacteria) decline during the 1-4 years after allogeneic or autologous HSCT if the recipient is not revaccinated (163)(164)(165)(166)(167). HSCT recipients are at increased risk for certain vaccine-pre-ventable diseases, including those caused by encapsulated bacteria (i.e., pneumococcal and Hib infections). As a result, HSCT recipients should be routinely revaccinated after HSCT, regardless of the source of the transplanted stem cells. Revaccination with inactivated, recombinant, subunit, polysaccharide, and Hib vaccines should begin 12 months after HSCT (162). An exception to this recommendation is for influenza vaccine, which should be administered at >6 months after HSCT and annually for the life of the recipient thereafter. MMR vaccine should be administered 24 months after transplantation if the HSCT recipient is presumed to be immunocompetent. Varicella, meningococcal, and pneumococcal conjugate vaccines are not recommended for HSCT recipients because of insufficient experience using these vaccines among HSCT recipients (162). The household and other close contacts of HSCT recipients and health-care workers who care for HSCT recipients, should be appropriately vaccinated, including against influenza, measles, and varicella. Additional details of vaccination of HSCT recipients and their contacts can be found in a specific CDC report on this topic (162). # Vaccinating Persons with Bleeding Disorders and Persons Receiving Anticoagulant Therapy Persons with bleeding disorders (e.g., hemophilia) and persons receiving anticoagulant therapy have an increased risk for acquiring hepatitis B and at least the same risk as the general population of acquiring other vaccinepreventable diseases. However, because of the risk for hematoma formation after injections, intramuscular injections are often avoided among persons with bleeding disorders by using the subcutaneous or intradermal routes for vaccines that are administered normally by the intramuscular route. Hepatitis B vaccine administered intramuscularly to 153 persons with hemophilia by using a 23-gauge needle, followed by steady pressure to the site for 1-2 minutes, resulted in a 4% bruising rate with no patients requiring factor supplementation (168). Whether antigens that produce more local reactions (e.g., pertussis) would produce an equally low rate of bruising is unknown. When hepatitis B or any other intramuscular vaccine is indicated for a patient with a bleeding disorder or a person receiving anticoagulant therapy, the vaccine should be administered intramuscularly if, in the opinion of a physician familiar with the patient's bleeding risk, the vaccine can be administered with reasonable safety by this route. If the patient receives antihemophilia or similar therapy, intramuscular vaccinations can be scheduled shortly after such # Vaccination Records # Consent to Vaccinate The National Childhood Vaccine Injury Act of 1986 (42 U.S.C. § 300aa-26) requires that all health-care providers in the United States who administer any vaccine covered by the act § § must provide a copy of the relevant, current edition of the vaccine information materials that have been produced by CDC before administering each dose of the vaccine. The vaccine information material must be provided to the parent or legal representative of any child or to any adult to whom the physician or other health-care provider intends to administer the vaccine. The Act does not require that a signature be obtained, but documentation of consent is recommended or required by certain state or local authorities. # Provider Records Documentation of patient vaccinations helps ensure that persons in need of a vaccine receive it and that adequately vaccinated patients are not overimmunized, possibly increasing the risk for local adverse events (e.g., tetanus toxoid). Serologic test results for vaccine-preventable diseases (e.g., those for rubella screening) as well as documented episodes of adverse events also should be recorded in the permanent medical record of the vaccine recipient. Health-care providers who administer vaccines covered by the National Childhood Vaccine Injury Act are required to ensure that the permanent medical record of the recipient (or a permanent office log or file) indicates the date the vaccine was administered, the vaccine manufacturer, the vaccine lot number, and the name, address, and title of the person administering the vaccine. Additionally, the provider is required to record the edition date of the vaccine information materials distributed and the date those materials were provided. Regarding this Act, the term health-care provider is defined as any licensed health-care professional, organization, or institution, whether private or public (including federal, state, and local departments and agencies), under whose authority a specified vaccine is adminis-tered. ACIP recommends that this same information be kept for all vaccines, not just for those required by the National Childhood Vaccine Injury Act. # Patients' Personal Records Official immunization cards have been adopted by every state, territory, and the District of Columbia to encourage uniformity of records and to facilitate assessment of immunization status by schools and child care centers. The records also are key tools in immunization education programs aimed at increasing parental and patient awareness of the need for vaccines. A permanent immunization record card should be established for each newborn infant and maintained by the parent or guardian. In certain states, these cards are distributed to new mothers before discharge from the hospital. Using immunization record cards for adolescents and adults also is encouraged. # Registries Immunization registries are confidential, populationbased, computerized information systems that collect vaccination data for as many children as possible within a geographic area. Registries are a critical tool that can increase and sustain increased vaccination coverage by consolidating vaccination records of children from multiple providers, generating reminder and recall vaccination notices for each child, and providing official vaccination forms and vaccination coverage assessments (169). A fully operational immunization registry also can prevent duplicate vaccinations, limit missed appointments, reduce vaccine waste, and reduce staff time required to produce or locate immunization records or certificates. The National Vaccine Advisory Committee strongly encourages development of community-or state-based immunization registry systems and recommends that vaccination providers participate in these registries whenever possible (170,171). A 95% participation of children aged <6 years in fully operational population-based immunization registries is a national health objective for 2010 (172). # Reporting Adverse Events After Vaccination Modern vaccines are safe and effective; however, adverse events have been reported after administration of all vaccines (82). These events range from frequent, minor, local reactions to extremely rare, severe, systemic illness (e.g., encephalopathy). Establishing evidence for cause-and-effect relationships on the basis of case reports and case series alone is impos- § § As of January 2002, vaccines covered by the act include diphtheria, tetanus, pertussis, measles, mumps, rubella, poliovirus, hepatitis B, Hib, varicella, and pneumococcal conjugate. sible because temporal association alone does not necessarily indicate causation. Unless the syndrome that occurs after vaccination is clinically or pathologically distinctive, more detailed epidemiologic studies to compare the incidence of the event among vaccinees with the incidence among unvaccinated persons are often necessary. Reporting adverse events to public health authorities, including serious events, is a key stimulus to developing studies to confirm or refute a causal association with vaccination. More complete information regarding adverse reactions to a specific vaccine can be found in the ACIP recommendations for that vaccine and in a specific statement on vaccine adverse reactions (82). The National Childhood Vaccine Injury Act requires health-care providers to report selected events occurring after vaccination to the Vaccine Adverse Event Reporting System (VAERS). Events for which reporting is required appear in the Vaccine Injury Table . ¶ ¶ Persons other than healthcare workers also can report adverse events to VAERS. Adverse events other than those that must be reported or that occur after administration of vaccines not covered by the act, including events that are serious or unusual, also should be reported to VAERS, even if the physician or other healthcare provider is uncertain they are related causally. VAERS forms and instructions are available in the FDA Drug Bulletin, by calling the 24-hour VAERS Hotline at 800-822-7967, or from the VAERS website at (accessed November 7, 2001). # Vaccine Injury Compensation Program The National Vaccine Injury Compensation Program, established by the National Childhood Vaccine Injury Act, is a no-fault system in which persons thought to have suffered an injury or death as a result of administration of a covered vaccine can seek compensation. The program, which became operational on October 1, 1988, is intended as an alternative to civil litigation under the traditional tort system in that negligence need not be proven. Claims arising from covered vaccines must first be adjudicated through the program before civil litigation can be pursued. The program relies on a Vaccine Injury # Benefit and Risk Communication Parents, guardians, legal representatives, and adolescent and adult patients should be informed regarding the benefits and risks of vaccines in understandable language. Opportunity for questions should be provided before each vaccination. Discussion of the benefits and risks of vaccination is sound medical practice and is required by law. The National Childhood Vaccine Injury Act requires that vaccine information materials be developed for each vaccine covered by the Act. These materials, known as Vaccine Information Statements, must be provided by all public and private vaccination providers each time a vaccine is administered. a dialogue regarding the risks and benefits of certain vaccines. Having a basic understanding of how patients view vaccine risk and developing effective approaches in dealing with vaccine safety concerns when they arise is imperative for vaccination providers. Each person understands and reacts to vaccine information on the basis of different factors, including prior experience, education, personal values, method of data presentation, perceptions of the risk for disease, perceived ability to control those risks, and their risk preference. Increasingly, through the media and nonauthoritative Internet sites, decisions regarding risk are based on inaccurate information. Only through direct dialogue with parents and by using available resources, health-care professionals can prevent acceptance of media reports and information from nonauthoritative Internet sites as scientific fact. When a parent or patient initiates discussion regarding a vaccine controversy, the health-care professional should discuss the specific concerns and provide factual information, using language that is appropriate. Effective, empathetic vaccine risk communication is essential in responding to misinformation and concerns, although recognizing that for certain persons, risk assessment and decision-making is difficult and confusing. Certain vaccines might be acceptable to the resistant parent. Their concerns should then be addressed in the context of this information, using the Vaccine Information Statements and offering other resource materials (e.g., information available on the National Immunization Program website). Although a limited number of providers might choose to exclude from their practice those patients who question or refuse vaccination, the more effective public health strategy is to identify common ground and discuss measures that need to be followed if the patient's decision is to defer vaccination. Health-care providers can reinforce key points regarding each vaccine, including safety, and emphasize risks encountered by unimmunized children. Parents should be advised of state laws pertaining to school or child care entry, which might require that unimmunized children stay home from school during outbreaks. Documentation of these discussions in the patient's record, including the refusal to receive certain vaccines (i.e., informed refusal), might reduce any potential liability if a vaccine-preventable disease occurs in the unimmunized patient. # Vaccination Programs The best way to reduce vaccine-preventable diseases is to have a highly immune population. Universal vaccination is a critical part of quality health care and should be accomplished through routine and intensive vaccination programs implemented in physicians' offices and in public health clinics. Programs should be established and maintained in all communities to ensure vaccination of all children at the recommended age. In addition, appropriate vaccinations should be available for all adolescents and adults. Physicians and other pediatric vaccination providers should adhere to the standards for child and adolescent immunization practices (1). These standards define appropriate vaccination practices for both the public and private sectors. The standards provide guidance on practices that will result in eliminating barriers to vaccination. These include practices aimed at eliminating unnecessary prerequisites for receiving vaccinations, eliminating missed opportunities to vaccinate, improving procedures to assess vaccination needs, enhancing knowledge regarding vaccinations among parents and providers, and improving the management and reporting of adverse events. Additionally, the standards address the importance of recall and reminder systems and using assessments to monitor clinic or office vaccination coverage levels among patients. Standards of practice also have been published to increase vaccination coverage among adults (2). Persons aged >65 years and all adults with medical conditions that place them at risk for pneumococcal disease should receive >1 doses of pneumococcal polysaccharide vaccine. All persons aged >50 years and those with medical conditions that increase the risk for complications from influenza should receive annual influenza vaccination. All adults should complete a primary series of tetanus and diphtheria toxoids and receive a booster dose every 10 years. Adult vaccination programs also should provide MMR and varicella vaccines whenever possible to anyone susceptible to measles, mumps, rubella, or varicella. Persons born after 1956 who are attending college (or other posthigh school educational institutions), who are employed in environments that place them at increased risk for measles transmission (e.g., health-care facilities), or who are traveling to areas with endemic measles, should have documentation of having received two doses of MMR on or after their first birthday or other evidence of immunity (6,173). All other adults born after 1956 should have documentation of >1 doses of MMR vaccine on or after their first birthday or have other evidence of immunity. No evidence indicates that administering MMR vaccine increases the risk for adverse reactions among persons who are already immune to measles, mumps, or rubella as a result of previous vaccination or disease. Widespread use of hepatitis B vaccine is encouraged for all persons who might be at in-creased risk (e.g., adolescents and adults who are either in a group at high risk or reside in areas with increased rates of injection-drug use, teenage pregnancy, or sexually transmitted disease). Every visit to a physician or other health-care provider can be an opportunity to update a patient's immunization status with needed vaccinations. Official health agencies should take necessary steps, including developing and enforcing school immunization requirements, to ensure that students at all grade levels (including college) and those in child care centers are protected against vaccine-preventable diseases. Agencies also should encourage institutions (e.g., hospitals and long-term care facilities) to adopt policies regarding the appropriate vaccination of patients, residents, and employees (173). Dates of vaccination (day, month, and year) should be recorded on institutional immunization records (e.g., those kept in schools and child care centers). This record will facilitate assessments that a primary vaccination series has been completed according to an appropriate schedule and that needed booster doses have been administered at the appropriate time. The independent, nonfederal Task Force on Community Preventive Services (the Task Force) gives public health decision-makers recommendations on population-based in-terventions to promote health and prevent disease, injury, disability, and premature death. The recommendations are based on systematic reviews of the scientific literature regarding effectiveness and cost-effectiveness of these interventions. In addition, the Task Force identifies critical information regarding the other effects of these interventions, as well as the applicability to specific populations and settings and the potential barriers to implementation. This information is available through the Internet at (accessed November 7, 2001). Beginning in 1996, the Task Force systematically reviewed published evidence on the effectiveness and cost-effectiveness of population-based interventions to increase coverage of vaccines recommended for routine use among children, adolescents, and adults. A total of 197 articles were identified that evaluated a relevant intervention, met inclusion criteria, and were published during 1980-1997. Reviews of 17 specific interventions were published in 1999 (174)(175)(176). Using the results of their review, the Task Force made recommendations regarding the use of these interventions (177). A number of interventions were identified and recommended on the basis of published evidence. The interventions and the recommendations are summarized in this report (Table 7). able for intravenous use. Intravenous immune globulin is used primarily for replacement therapy in primary antibody-deficiency disorders, for treatment of Kawasaki disease, immune thrombocytopenic purpura, hypogammaglobulinemia in chronic lymphocytic leukemia, and certain cases of human immunodeficiency virus infection (Table 2). Hyperimmune globulin (specific). Special preparations obtained from blood plasma from donor pools preselected for a high antibody content against a specific antigen (e.g., hepatitis B immune globulin, varicella-zoster immune globulin, rabies immune globulin, tetanus immune globulin, vaccinia immune globulin, cytomegalovirus immune globulin, respiratory syncytial virus immune globulin, botulism immune globulin). Monoclonal antibody. An antibody product prepared from a single lymphocyte clone, which contains only antibody against a single microorganism. Antitoxin. A solution of antibodies against a toxin. Antitoxin can be derived from either human (e.g., tetanus antitoxin) or animal (usually equine) sources (e.g., diphtheria and botulism antitoxin). Antitoxins are used to confer passive immunity and for treatment. Vaccination and Immunization. The terms vaccine and vaccination are derived from vacca, the Latin term for cow. Vaccine was the term used by Edward Jenner to describe material used (i.e., cowpox virus) to produce immunity to smallpox. The term vaccination was used by Louis Pasteur in the 19 th century to include the physical act of administering any vaccine or toxoid. Immunization is a more inclusive term, denoting the process of inducing or providing immunity by administering an immunobiologic. Immunization can be active or passive. Active immunization is the production of antibody or other immune responses through administration of a vaccine or toxoid. Passive immunization means the provision of temporary immunity by the administration of preformed antibodies. Four types of immunobiologics are administered for passive immunization: 1) pooled human immune globulin or intravenous immune globulin, 2) hyperimmune globulin (specific) preparations, 3) monoclonal antibody preparations, and 4) antitoxins from nonhuman sources. Although persons often use the terms vaccination and immunization interchangeably in reference to active immunization, the terms are not synonymous because the administration of an immunobiologic cannot be equated automatically with development of adequate immunity. # Vaccine Information Sources In addition to these general recommendations, other sources are available that contain specific and updated vaccine information. # National Immunization Information Hotline The National Immunization Information Hotline is supported by CDC's National Immunization Program and provides vaccination information for health-care providers and the public, 8:00 am-11:00 pm, Monday-Friday: Telephone (English): 800-232-2522 Telephone (Spanish): 800-232-0233 Telephone (TTY): 800-243-7889 Internet: (accessed November 7, 2001) # CDC's National Immunization Program CDC's National Immunization Program website provides direct access to immunization recommendations of the Advisory Committee on Immunization Practices (ACIP), vaccination schedules, vaccine safety information, publications, provider education and training, and links to other immunization-related websites. It is located at http:// www.cdc.gov/nip (accessed November 7, 2001). # Morbidity and Mortality Weekly Report ACIP recommendations regarding vaccine use, statements of vaccine policy as they are developed, and reports of specific disease activity are published by CDC in the Morbidity and Mortality Weekly Report (MMWR) series. Electronic subscriptions are free and available at / subscribe.html (accessed November 7, 2001 # American Academy of Family Physicians (AAFP) Information from the professional organization of family physicians is available at (accessed November 7, 2001). # Immunization Action Coalition This source provides extensive free provider and patient information, including translations of Vaccine Information Statements into multiple languages. The Internet address is (accessed November 7, 2001). # National Network for Immunization Information This information source is provided by the Infectious Diseases Society of America, Pediatric Infectious Diseases Society, AAP, American Nurses Association, and other professional organizations. It provides objective, science-based information regarding vaccines for the public and providers. The Internet site is (accessed November 7, 2001). # Vaccine Education Center Located at the Children's Hospital of Philadelphia, this source provides patient and provider information. The Internet address is (accessed November 7, 2001). # Institute for Vaccine Safety # Located at Johns Hopkins University School of Public Health, this source provides information regarding vaccine safety concerns and objective and timely information to healthcare providers and parents. It is available at http:// www.vaccinesafety.edu (accessed November 7, 2001). # National Partnership for Immunization This national organization encourages greater acceptance and use of vaccinations for all ages through partnerships with public and private organizations. Their Internet address is http:// www.partnersforimmunization.org (accessed November 7, 2001). # State and Local Health Departments State and local health departments provide technical advice through hotlines, electronic mail, and Internet sites, including printed information regarding vaccines and immunization schedules, posters, and other educational materials. nical errors in vaccine preparation, handling, or administration; 4) coincidental: associated temporally with vaccination by chance or caused by underlying illness. Special studies are needed to determine if an adverse event is a reaction or the result of another cause (Sources: Chen RT. Special methodological issues in pharmacoepidemiology studies of vaccine safety. In: Strom BL, ed. Pharmacoepidemiology. Adverse reaction. An undesirable medical condition that has been demonstrated to be caused by a vaccine. Evidence for the causal relationship is usually obtained through randomized clinical trials, controlled epidemiologic studies, isolation of the vaccine strain from the pathogenic site, or recurrence of the condition with repeated vaccination (i.e., rechallenge); synonyms include side effect and adverse effect). Immunobiologic. Antigenic substances (e.g., vaccines and toxoids) or antibody-containing preparations (e.g., globulins and antitoxins) from human or animal donors. These products are used for active or passive immunization or therapy. The following are examples of immunobiologics: Vaccine. A suspension of live (usually attenuated) or inactivated microorganisms (e.g., bacteria or viruses) or fractions thereof administered to induce immunity and prevent infectious disease or its sequelae. Some vaccines contain highly defined antigens (e.g., the polysaccharide of Haemophilus influenzae type b or the surface antigen of hepatitis B); others have antigens that are complex or incompletely defined (e.g., killed Bordetella pertussis or live attenuated viruses). Toxoid. A modified bacterial toxin that has been made nontoxic, but retains the ability to stimulate the formation of antibodies to the toxin. Immune globulin. A sterile solution containing antibodies, which are usually obtained from human blood. It is obtained by cold ethanol fractionation of large pools of blood plasma and contains 15%-18% protein. Intended for intramuscular administration, immune globulin is primarily indicated for routine maintenance of immunity among certain immunodeficient persons and for passive protection against measles and hepatitis A. Intravenous immune globulin. A product derived from blood plasma from a donor pool similar to the immune globulin pool, but prepared so that it is suit- # Abbreviations Used in This Publication # Definitions Used in This Report Adverse event. An untoward event that occurs after a vaccination that might be caused by the vaccine product or vaccination process. It includes events that are 1) vaccineinduced: caused by the intrinsic characteristic of the vaccine preparation and the individual response of the vaccinee; these events would not have occurred without vaccination (e.g., vaccine-associated paralytic poliomyelitis); 2) vaccinepotentiated: would have occurred anyway, but were precipitated by the vaccination (e.g., first febrile seizure in a predisposed child); 3) programmatic error: caused by tech- # What action is recommended if varicella vaccine is inadvertently administered 10 days after a dose of measles-mumps-rubella (MMR) vaccine? A. Repeat both vaccines >4 weeks after the varicella vaccine was administered. B. Repeat only the MMR vaccine >4 weeks after the varicella. C. Repeat only the varicella vaccine >4 weeks after the inadvertently administered dose of varicella vaccine. D. Repeat only the varicella vaccine >6 months after the inadvertently administered dose of varicella vaccine. E. No action is recommended; both doses are counted as valid. # Goal and Objectives This MMWR provides general guidelines on immunizations. These recommendations were developed by CDC staff, the Advisory Committee on Immunization Practices (ACIP), and the American Academy of Family Physicians (AAFP). The goal of this report is to improve vaccination practices in the United States. Upon completion of this activity, the reader should be able to a) identify valid contraindications and precautions for commonly used vaccines; b) locate the minimum age and minimum spacing between doses for vaccines routinely used in the United States; c) describe recommended methods for administration of vaccines; and d) list requirements for vaccination providers as specified by the National Childhood Vaccine Injury Act of 1986. To receive continuing education credit, please answer all of the following questions. # What action is recommended if the interval between doses of hepatitis B vaccine is longer than the recommended interval? A. Add one additional dose. B. Add two additional doses. C. Restart the series from the beginning. D. Perform a serologic test to determine if a response to the vaccine has been obtained. E. Continue the series, ignoring the prolonged interval.

Premature birth overview # Overview Premature birth (also known as preterm birth) is the birth of a baby before the standard period of pregnancy is completed. In most systems of human pregnancy, prematurity is considered to occur when the baby is born sooner than 37 weeks after the beginning of the last menstrual period (LMP). The opposite condition, postmature birth, is defined as birth more than 42 weeks after the LMP. The standard length of a human gestation is 266 days. However, for convenience most timing is based on the LMP, with conception being assumed to occur approximately 14 days after the LMP, making a standard term pregnancy 280 days or 40 weeks. Premature or preterm birth is defined medically as childbirth occurring earlier than 37 completed weeks of pregnancy. Approximately 12 percent of babies in the United States — or 1 in 8 — are born prematurely each year. In 2003, more than 490,000 babies in the U.S. were born prematurely. Worldwide rates of prematurity are more difficult to obtain as the lack of widespread professional obstetric care in developing regions makes determination of gestational age less reliable. The World Health Organization instead tracks rates of low birth weight, which occurred in 16.5 percent of births in less developed regions in 2000. It is estimated that one-third of these low birth weight deliveries are due to premature delivery. The shorter the term of pregnancy, the greater the risks of complications. Infants born prematurely have an increased risk of death in the first year of life (infant mortality), with most of that occurring in the first month of life (neonatal mortality). Worldwide, prematurity accounts for 10% of neonatal mortality, or around 500,000 deaths per year. In the U.S. where many infections and other causes of neonatal death have been markedly reduced, prematurity is the leading cause of neonatal mortality at 25%. Prematurely born infants are also at greater risk for developing serious health problems such as cerebral palsy, chronic lung disease, gastrointestinal problems, mental retardation, vision or hearing loss and are more susceptible to developing depression as teenagers. Although there are several known risk factors for prematurity (see below), nearly half of all premature births have no known cause. When conditions permit, doctors may attempt to stop premature labor, so that the pregnancy can have a chance to continue to full term, thereby increasing the baby's chances of health and survival. However, there is currently no reliable means to stop or prevent preterm labor in all cases. In fact, the rate of preterm births in the United States has increased 30% in the past two decades. In developed countries premature infants are usually cared for in a Neonatal Intensive Care Unit (NICU). The physicians who specialize in the care of very sick or premature babies are known as neonatologists. In the NICU, premature babies are kept under radiant warmers or in incubators (also called isolettes), which are bassinets enclosed in plastic with climate control equipment designed to keep them warm and limit their exposure to germs. Modern neonatal intensive care involves sophisticated measurement of temperature, respiration, cardiac function, oxygenation, and brain activity. Treatments may include fluids and nutrition through intravenous catheters, oxygen supplementation, mechanical ventilation support, and medications. In developing countries where advanced equipment and even electricity may not be available or reliable, simple measures such as kangaroo care (skin to skin warming), encouraging breastfeeding, and basic infection control measures can significantly reduce preterm morbidity and mortality. "Ex-premies" is the term given to preterm infants born before the normal 37 weeks gestation.

Cardiac amyloidosis overview # Overview Cardiac amyloidosis is a well-known progressive condition, which has been reported with varying incidence rates. It refers to extracellular deposition of light chains of some serum proteins, that assume a beta pleated structure. Myocardial involvement results in congestive heart failure and fatal arrhythmias and is the leading cause of death in patients with amyloidosis. Systemic amyloidosis of AL and TTR type is often associated with amyloid deposition in heart valves, in addition to blood vessels and myocardium. In this classical type of valvular amyloidosis, the deposits occur in previously unaltered valves. There is also another type of cardiac amyloidosis restricted entirely to the heart valves (surgically removed for chronic valvular disease) or only the atria (also called isolated atrial amyloidosis). This condition is heavily under-diagnosed because the thickening of ventricles from extracellular deposition of amyloid material in the heart is mostly attributed to chronic hypertension, which is also a feature of cardiac amyloidosis. Cardiac amyloidosis should be suspected in the following scenarios: - Congestive heart failure and an increase in left ventricular wall thickness (> 12 mm) in the absence of hypertension or other causes of increased left ventricular mass - Congestive heart failure and an increase in left ventricular wall thickness (> 12 mm) in the absence of hypertension or other causes of increased left ventricular mass in an African-American > 60 years old - Congestive heart failure with preserved left ventricular ejection fraction fraction (HFPEF) in an individual > 60 years old - Congestive heart failure in an individual (particularly an elderly male) with unexplained neuropathy, bilateral carpal tunnel syndrome without risk factors, atrial fibrillation - Signs or symptoms in an individual with a family history of amyloidosis - Individuals with hyperenhancement on Cardiac Magnetic Resonance (CMR) or echogenicity on echocardiography # Historical Perspective In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess, and splenomegaly and his report has been the first description of amyloidosis. There is no significant data regarding the historical perspective of amyloidosis throughout the 18th century. Rudolph Virchow and Weber are the prominent figures with substantial work on amyloidosis during the 19th century. In 1922, Bennhold introduced Congo Red staining of amyloid that remains the gold standard for diagnosis. # Classification Cardiac amyloidosis can be classified based on the type of amyloid that infiltrates the heart. The types of amyloid that commonly deposit in the heart are immunoglobulin light chain (AL) and transthyretin (ATTR). These two types of amyloid can result in cardiac AL amyloidosis and cardiac transthyretin amyloidosis. # Pathophysiology The characteristic feature of cardiac amyloidosis is abnormal deposition of abnormally folded light chains of several serum proteins, making them insoluble and leading to their accumulation in various organs. This abnormal folding of proteins is most commonly a result of genetic mutations or excessive formation. Involvement of cardiac muscle can lead to heart failure, arrhythmias, and advanced cardiac conduction disorders. # Causes The causes of cardiac amyloidosis vary based on the cause of the systemic amyloidosis. # Differentiating Cardiac Amyloidosis from other Diseases Cardiomyopathy with congestive heart failure is the most common presentation of cardiac amyloidosis. Other common causes of cardiomyopathy should be excluded, and cardiac amyloidosis should be considered in the absence of a history of myocaridal ischemia, myocardial infarction, or presence of coronary artery disease risk factors. Cardiac amyloidosis should be included in the differential diagnoses in patients with unexplained congestive heart failure who have no history of valvular heart disease, long-standing hypertension, or myocardial ischemia. # Epidemiology and Demographics The incidence rate increased from 18 to 55 per 100,000 person-years from 2000 to 2012. The prevalence rate increased from 8 to 17 per 100 000 person-years from 2000 to 2012. Cardiac amyloidosis commonly presents in adults more than 40 years old. The incidence and prevalence of cardiac amyloidosis have increased among blacks from 2000 to 2012. Over the years, both incidence and prevalence of cardiac amyloidosis have increased among men. # Risk Factors The most common risk factor for the development of cardiac amyloidosis is the presence of an underlying plasma cell dyscrasia. # Screening There is insufficient evidence to recommend routine screening for cardiac amyloidosis. # Natural History, Complications, and Prognosis The presence or absence of cardiac involvement with amyloid is the most important prognostic factor. Untreated cardiac amyloidosis is associated with a very poor prognosis and a high mortality rate. The most common cardiac complications include heart failure, sudden cardiac death due to electromechanical dissociation and pericardial effusion. # Diagnosis ## Diagnostic Study of Choice A cardiac biopsy that reveals amyloid, confirms the diagnosis. Biopsy of other tissues may also confirm the diagnosis of a systemic involvement. Amyloidosis is frequently confirmed by biopsy of abdominal fat, rectal submucosa, kidney, or bone marrow. ## History and Symptoms Amyloidosis is a multi-system disease involving many organs simultaneously. Approximately 50% of patients with cardiac amyloidosis present with right heart failure symptoms. The most common symptoms observed in patients with cardiac amyloidosis include fatigue, weight loss, and periorbital purpura. ## Physical Examination Cardiac amyloidosis is difficult to diagnose. More than 50% of the patients with cardiac amyloidosis present with signs and symptoms suggestive of right heart failure. Common physical exam findings include elevated jugular venous pressure, third heart sound and pedal edema. ## Laboratory Findings There is no single specific diagnostic test that can be used to diagnose amyloidosis and the diagnosis is based upon the totality of the data. Hence, awareness of the disease is necessary to identify patients with amyloidosis. ## Electrocardiogram The combination of low voltage electrocardiographic pattern and increased thickness of the left ventricular posterior wall and interventricular septum on echocardiogram is highly specific for cardiac amyloidosis. Conduction and rhythm disturbances are common in cardiac amyloidosis, however direct infiltration of the specialized conduction tissue of the heart by the amyloid does not account for the majority of these disturbances. ## Imaging ### Cardiac MRI Amyloidosis is an infiltrative disease resulting in deposition of amyloid in the extracellular spaces of the tissues. Amyloid infiltration of the heart leads to expansion of these extracellular spaces resulting in retainment of gadolinium dye during cardiac magnetic resonance imaging. This retainment of gadolinium leads to signal enhancement in the late washout phase during delayed enhanced cardiac imaging. ### Echocardiography Transthoracic echocardiography is most commonly used in the initial evaluation of cardiac amyloidosis. The most common echocardiographic finding is thickening of the left ventricle. Echocardiographic findings strongly correlate with the degree of cardiac dysfunction and disease progression with mildly or moderately increased wall thickness in the early asymptomatic phase and severe thickening and hypokinesia of the left ventricular posterior wall and interventricular septum in clinically apparent cardiac dysfunction. Echocardiographic findings have both diagnostic and prognostic importance. ### Other Imaging Findings Nuclear cardiac scans like MUGA and radionuclide ventriculography (RNV) are not used routinely early in the diagnosis of cardiac amyloidosis. However, when performed, these scans show increased uptake of technetium by the myocardium correlating well with the degree of involvement. ## Cardiac Biopsy A cardiac biopsy that reveals amyloid confirms the diagnosis. Biopsy of other tissues may also confirm the diagnosis. Amyloidosis is frequently confirmed by biopsy of abdominal fat, rectal submucosa, kidney, or bone marrow. # Treatment ## Medical Therapy Major cardiac manifestations of systemic amyloidosis include heart failure and fatal arrhythmias. Therefore treatment of cardiac amyloidosis includes treatment of heart failure and arrhythmias and treatment of the underlying disease. Treatment of heart failure associated with cardiac amyloidosis differs from therapy usually attempted in patients with systolic or diastolic dysfunction. ## Surgery When heart function is very poor, a heart transplant may be considered for some patients, but not those with AL type amyloidosis since their disease compromises many organs. In one type of secondary amyloidosis, liver transplantation is also required. ## Future or Investigational Therapies New therapies targeting the serum amyloid protein (SAP), which is an excellent immunogen and a universal component of all amyloid deposits, using monoclonal antibodies are currently being investigated.

Superficial parotid lymph nodes The superficial parotid lymph nodes are a group of lymph nodes anterior to the ear. Their afferent vessels drain the root of the nose, the eyelids, the frontotemporal region, the external acoustic meatus and the tympanic cavity, possibly also the posterior parts of the palate and the floor of the nasal cavity. The efferents of these glands pass to the superior deep cervical glands.

Cryptomonad # Overview The cryptomonads are a small group of flagellates, most of which have chloroplasts. They are common in freshwater, and also occur in marine and brackish habitats. Each cell is around 10-50 μm in size and flattened in shape, with an anterior groove or pocket. At the edge of the pocket there are typically two slightly unequal flagella. Cryptomonads distinguished by the presence of characteristic extrusomes called ejectisomes, which consist of two connected spiral ribbons held under tension. If the cells are irritated either by mechanical, chemical or light stress, they discharge, propelling the cell in a zig-zag course away from the disturbance. Large ejectisomes, visible under the light microscope, are associated with the pocket; smaller ones occur elsewhere on the cell. Cryptomonads have one or two chloroplasts, except for Chilomonas which has leucoplasts and Goniomonas which lacks plastids entirely. These contain chlorophylls a and c, together with phycobiliproteins and other pigments, and vary in color from brown to green. Each is surrounded by four membranes, and there is a reduced cell nucleus called a nucleomorph between the middle two. This indicates that the chloroplast was derived from a eukaryotic symbiont, shown by genetic studies to have been a red alga. A few cryptomonads, such as Cryptomonas, can form palmelloid stages, but readily escape the surrounding mucus to become free-living flagellates again. Cryptomonad flagella are inserted parallel to one another, and are covered by bipartite hairs called mastigonemes, formed within the endoplasmic reticulum and transported to the cell surface. Small scales may also be present on the flagella and cell body. The mitochondria have flate cristae, and mitosis is open; sexual reproduction has also been reported. Originally the cryptomonads were considered close relatives of the dinoflagellates because of their similar pigmentation. Later botanists treated them as a separate division, Cryptophyta, while zoologists treated them as the flagellate order Cryptomonadida. There is considerable evidence that cryptomonad chloroplasts are closely related to those of the heterokonts and haptophytes, and the three groups are sometimes united as the Chromista. However, the case that the organisms themselves are closely related is not very strong, and they may have acquired chloroplasts independently.

HLA-A31 HLA-A31 (A31) is an HLA-A serotype. The serotype identifies the more common HLA-A*31 gene products. A31 is a split antigen of the A19 broad antigen serotype group. It is similar to the antigens A29, 30, A32,A33, and A74. A31 is more common in Japan, Siberia and Indigenous Americans. It is also more frequent in NE Europe than SW Europe. # Serotype There is substantive cross reaction of A30 with A*3101, otherwise serological identification is good. # A*31 alleles ### A*310102 # A31-B Haplotypes Examination of A31 haplotypes reveal a probably connection across northern Eurasia during the prehistoric period. Frequencies of the more 'tale-tell' haplotypes (A31-B60, B61, and B62) fall from NE to SW Europe. Other haplotypes appears to have spread from the middle east (A31-B51 and A31-B35).

Erythema nodosum # Overview Erythema nodosum (EN) (red nodules) is an inflammation of the fat cells under the skin (panniculitis). It causes tender, red nodules that are usually seen on both shins. EN is an immunologic response to a variety of different causes. # Historical Perspective - Disease name] was first discovered by , a , in during/following . - 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 . # Pathophysiology - It is considered as a hypersensitivity reaction to various antigens leading to deposition of immune complexes in subcutaneous fat venules. Evidence of immune complexes and complement in the early lesions is affirmative of the above hypothesis. - Alternative hypothesis involving type 4 hypersensitive reaction, expression of various adhesion and inflammatory markers like P-selectin, E-selectin, IL-6, IL-8 has also been proposed in the pathophysiology of erythema nodosum. (Springer) # Causes - In about 30-50% of cases, the cause of EN is unknown. Idiopathic is the most common cause. - EN may be associated with a wide variety of diseases including the following - Infections (e.g., Tuberculosis, Streptococcal, Mycoplasma pneumoniae, and Epstein-Barr virus) - Sarcoidosis - Inflammatory bowel disease - Autoimmune disorders (e.g., Behçet's disease) - Pregnancy - Medications (sulfonamides, clomiphene, oral contraceptives (Desogestrel and Ethinyl Estradiol), bromides, certolizumab pegol, dapsone), and cancer. # Differentiating Erythema nodosum from Other Diseases Erythema nodosum is indicative of an underlying infectious disease but a cause is not found in about half the cases. - Behcet's Syndrome - Brucellosis - Campylobacter - Cat-Scratch Fever - Chlamydia - Coccidioidomycosisimportant in the south-west USA - Corynebacterium diphtheria - Crohn's Disease - Dermatophytosis - Drugs such as sulphonylureas, gold and oral contraceptives - Francisella tularensis - Hepatitis - Herpes simplex - Histoplasmosis - Hodgkin's Lymphoma can precede the diagnosis - Hookworm infection - Infectious mononucleosis - Leprosymay closely resemble erythema nodosum but the histological findings are different - Leptospirosis - Leukemia - Milker's nodule - Mycobacterium - Mycoplasma pneumoniae - Neisseria Meningitidis - North American Blastomycosis - Postradiated pelvic cancer - Pregnancy usually in the second trimester. Often recurs during future pregnancies and may occur with oral contraceptive uses - Radiation therapy - Reiter's Disease - Salmonella - Sarcoidosis - Sporotrichosis - Streptococcal infections are one of the most common causes - Toxoplasmosis - Tuberculosis - Ulcerative colitis - Yersinia # Epidemiology and Demographics Erythema nodosum is the most common form of panniculitis (inflammation of the subcutaneous fat). The prevalence is 24 cases per 100,000 per year. The peak incidence of EN occurs between 20-30 years of age. Women are 3-6 times more commonly affected than men. ### Age: 20 to 30 ### Gender: Female > Male ( 6:1) ### Race: African americans ( AAFP) # Risk Factors # Natural History, Complications and Prognosis - The majority patients with Erythema Nodosum will recover completely in few weeks. - Common complications of include , , and . - Prognosis is generally excellent. . # Diagnosis ## Diagnostic Criteria Diagnosis is clinical. A deep punch biopsy or an incisional biopsy may be performed in cases where the diagnosis is unclear. Microscopic examination will reveal a septal panniculitis with acute and chronic inflammation in the fat and around blood vessels. Once EN is diagnosed, additional evaluation needs to be performed to determine the underlying cause. A complete blood count, erythrocyte sedimentation rate (ESR), antistreptolysin-O (ASO) titer, urinalysis, throat culture, intradermal tuberculin test, and chest x-ray is part of the initial examination. The ESR is initially very high, and falls as the nodules fade. The ASO titer is high in cases associated with a streptococcal throat infection. A chest X-ray should be performed to rule out pulmonary diseases. Hilar lymphadenopathy may be due to tuberculosis, sarcoidosis, or Löfgren syndrome (a form of acute sarcoidosis with erythema nodosum , parotid swelling and bilateral hilar adenopathy, often accompanied by joint symptoms). ## Symptoms Erythema nodosum occurs 3-6 weeks after an event, either internal or external to the body, that initiates a hypersensitivity reaction in subcutaneous fat . EN is frequently associated with fever, malaise, arthralgia, and joint pain and inflammation. It presents as tender red nodules on the shins that are smooth and shiny. The nodules may occur anywhere there is fat under the skin, including the thighs, arms, trunk, face, and neck . The nodules are 1-5 cm in diameter, and individual nodules may coalesce to form large areas of hardened skin. As the nodules age, they become bluish purple, brownish, yellowish, and finally green, similar to the color changes that occur in a resolving bruise. The nodules usually subside over a period of 2–6 weeks without ulceration or scarring. Dermatophytids are similar skin lesions that result from a fungus infection such as ringworm in another area of the body. ## Physical Examination ### Skin - Erythema Nodosum involving the lower extremity - Erythema Nodosum - .:Erythema nodosum Adapted from Dermatology Atlas. - .:Erythema nodosum Adapted from Dermatology Atlas. - .:Erythema nodosum Adapted from Dermatology Atlas. - .:Erythema nodosum Adapted from Dermatology Atlas. - .:Erythema nodosum Adapted from Dermatology Atlas. - .:Erythema nodosum Adapted from Dermatology Atlas. - Lesions begin as red, tender nodules. The borders are poorly defined and they are 2 to 6 cms in diameter - In the first week the lesions become tense, hard, and painful. In the second week, they may become fluctuant, rather like an abscess, but they do not suppurate or ulcerate. Individual lesions last around 2 weeks, but occasionally, new lesions continue to appear for 3 to 6 weeks. - Initially, in the first week the lesions are bright red but in the second week they assume a more blue or purple hue. - The lesions may eventually even turn yellow like a bruise which is resolving before they disappear in a several weeks. - Usually the rash appears on the extremities, but most frequently they occur on the anterior aspect of the lower leg. - When the underlying cause is an infection, the lesions usually heal in 6 to 8 weeks. - If the cause is idiopathic, 30% of cases last 6 months. ## Laboratory Findings ## Other Imaging Findings ## Other Diagnostic Studies # Treatment ## Medical Therapy Treatment should focus on the underlying cause. Symptoms can be treated with bedrest, leg elevation, compressive bandages, wet dressings, and nonsteroidal anti-inflammatory agents (NSAIDs). NSAIDS are usually more effective at the onset of EN versus with chronic disease. Steroids can be of benefit but may be contraindicated if infection is present. In erythema nodosum associated with leprosy, thalidomide may be helpful. Potassium iodide can be used for persistent lesions whose cause remains unknown. Corticosteroids and colchicine can be used in severe refractory cases (Yurdakul et al, 2001). ## Surgery ## Prevention

Interferon alfa-2a dosage and administration # Dosage And Administration Roferon-A recommended dosing regimens are different for each of the following indications as described below. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. Roferon-A is administered subcutaneously. ## Chronic Hepatitis C The recommended dosage of Roferon-A for the treatment of chronic hepatitis C is 3 MIU three times a week (tiw) administered subcutaneously for 12 months (48 to 52 weeks). As an alternative, patients may be treated with an induction dose of 6 MIU tiw for the first 3 months (12 weeks) followed by 3 MIU tiw for 9 months (36 weeks). Normalization of serum ALT generally occurs within a few weeks after initiation of treatment in responders. Approximately 90% of patients who respond to Roferon-A do so within the first 3 months of treatment; however, patients responding to Roferon-A with a reduction in ALT should complete 12 months of treatment. Patients who have no response to Roferon-A within the first 3 months of therapy are not likely to respond with continued treatment; treatment discontinuation should be considered in these patients. Patients who tolerate and partially or completely respond to therapy with Roferon-A but relapse following its discontinuation may be re-treated. Re-treatment with either 3 MIU tiw or with 6 MIU tiw for 6 to 12 months may be considered. Please see ADVERSE REACTIONS regarding the increased frequency of adverse reactions associated with treatment with higher doses. Temporary dose reduction by 50% is recommended in patients who do not tolerate the prescribed dose. If adverse events resolve, treatment with the original prescribed dose can be re-initiated. In patients who cannot tolerate the reduced dose, cessation of therapy, at least temporarily, is recommended. ## Chronic Myelogenous Leukemia For patients with Ph-positive CML in chronic phase: Prior to initiation of therapy, a diagnosis of Philadelphia chromosome positive CML in chronic phase by the appropriate peripheral blood, bone marrow and other diagnostic testing should be made. Monitoring of hematologic parameters should be done regularly (e.g., monthly). Since significant cytogenetic changes are not readily apparent until after hematologic response has occurred, and usually not until several months of therapy have elapsed, cytogenetic monitoring may be performed at less frequent intervals. Achievement of complete cytogenetic response has been observed up to 2 years following the start of Roferon-A treatment. The recommended initial dose of Roferon-A is 9 MIU daily administered as a subcutaneous injection. Based on clinical experience,3 short-term tolerance may be improved by gradually increasing the dose of Roferon-A over the first week of administration from 3 MIU daily for 3 days to 6 MIU daily for 3 days to the target dose of 9 MIU daily for the duration of the treatment period. The optimal dose and duration of therapy have not yet been determined. Even though the median time to achieve a complete hematologic response was 5 months in study MI400, hematologic responses have been observed up to 18 months after treatment start. Treatment should be continued until disease progression. If severe side effects occur, a treatment interruption or a reduction in either the dose or the frequency of injections may be necessary to achieve the individual maximally tolerated dose (seePRECAUTIONS). Limited data are available on the use of Roferon-A in children with CML. In one report of 15 children with Ph-positive, adult-type CML doses between 2.5 to 5 MIU/m2/day given intramuscularly were tolerated.8 In another study, severe adverse effects including deaths were noted in children with previously untreated, Ph-negative, juvenile CML, who received interferon doses of 30 MIU/m2/day. 12 ## Hairy Cell Leukemia Prior to initiation of therapy, tests should be performed to quantitate peripheral blood hemoglobin, platelets, granulocytes and hairy cells and bone marrow hairy cells. These parameters should be monitored periodically (e.g., monthly) during treatment to determine whether response to treatment has occurred. If a patient does not respond within 6 months, treatment should be discontinued. If a response to treatment does occur, treatment should be continued until no further improvement is observed and these laboratory parameters have been stable for about 3 months. Patients with hairy cell leukemia have been treated for up to 24 consecutive months. The optimal duration of treatment for this disease has not been determined. The induction dose of Roferon-A is 3 MIU daily for 16 to 24 weeks, administered as a subcutaneous injection. The recommended maintenance dose is 3 MIU, tiw. Dose reduction by one-half or withholding of individual doses may be needed when severe adverse reactions occur. The use of doses higher than 3 MIU is not recommended in hairy cell leukemia.