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By I. Farmon. Metropolitan State College of Denver. 2018.

Weight loss remains an independent risk factor for mortality cleocin gel 20gm visa, even in the HAART era cleocin gel 20gm sale, and every patient should be weighed regularly cheap cleocin gel 20gm on line. In one large study, mortality risk in patients with a loss greater than 10% of body weight was more than four to six times higher than that of patients with stable body weight (Tang 2002). Patients with classic wasting syndrome are often extremely weak and the risk for opportunistic infections is significantly elevated (Dworkin 2003). There is also cognitive impairment in these patients (Dolan 2003). Diagnosis The causes of wasting syndrome are complex. First, it is necessary to exclude or treat opportunistic infections (TB, MAC, cryptosporidiosis and microsporidiosis). If none are found, then several reasons remain that may contribute, even in combination, to wasting syndrome. These include: metabolic disorders, hypogonadism, poor nutri- tion and malabsorption syndrome (Overview: Grinspoon 2003). Consequently, a thorough patient history is extremely beneficial. Distinction from antiretroviral- induced lipoatrophy (d4T/ddI) is often difficult. Significant weight loss also occurs frequently on interferon (Garcia-Benayas 2002), but rapidly resolves after finishing treatment. In addition, hypogonadism should be ruled out with the measurement of testosterone. While there are several simple tests for malabsorption syndromes, it is prudent to start with testing albumin as well as TSH and cholesterol levels. Further tests such as D-xylose absorption or biopsies of the small intestine should only be initiated after consulting with a gastroenterologist. Other tests, such as DEXA, densitometry, bioelectrical impedance analysis, etc, should be conducted in centers experienced with AIDS wasting syndrome to determine the patient’s body compo- sition. Therapy Wasting syndrome always requires competent diet counseling. Supportive parenteral nutri- tion only helps if there are problems with absorption (Kotler 1990, Melchior 1996). Effective ART, ideally without drugs that cause lipoatrophy such as d4T or ddI, and possibly even omitting nucleoside analogs completely, is ideal. Severe lipoatrophy may require complete omission of nucleoside analogs (see Chapter on Nuke-sparing). Beyond this, many kinds of drug treatment have been attempted. However, these have limited success and are often problematic. Megestrol acetate, a synthetic gestagenic hormone, shows some benefit as an appetite stimulant in wasting syndrome, as demonstrated in some studies (Von Roenn 1994, 400 AIDS Mulligan 2006). Its side effects are those typically associated with steroids, includ- ing induced hypogonadism, which should always be avoided, especially in cases of wasting syndrome. As a result, it is not widely nor currently recommended that this drug be used. Dronabinol, the main active ingredient in marijuana, has been licensed in the US since 1985 as Marinol, and may be prescribed for pharmacy formulation as drops or hard gel capsules. This drug is certainly attractive for many patients and some- times actively demanded. Prescription should be carefully considered, particularly in view of the significant cost associated with the medication. In some European countries, dronabinol costs approximately 600 euros per month for the usual dose of 5 mg TID. Without a clear diagnosis of wasting syndrome, communication with the insurance company may minimize substantial payment problems. Some health insurances and other payors reject the request. The effect on wasting syndrome is moderate at best, if detectable at all (Beal 1995). It tends to be even weaker than megestrol acetate (Timpone 1997). Hypogonadism, a frequent condition of patients with wasting syndrome, calls for the measurement of testosterone levels. If the age-dependent levels are low, then testosterone substitution has proven itselfuseful, both for weight gain and quality of life (Grinspoon 1998). A dose of 250 mg testosterone is given IM every 3-4 weeks, and there are a variety of less expensive generic names. The effect is sustained, even with long-term use (Grinspoon 1999). If testosterone levels are normal, substitution is not indicated. In women, one should exercise caution when administering andro- genic hormones.

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This chapter primarily focuses on the pros knee replacement buy cleocin gel 20gm. Edoxaban and betrixaban are other oral factor Xa and cons of the NOACs for the various indications that have gained approval in the United States by the middle of 2013 generic cleocin gel 20gm overnight delivery, particularly inhibitors in development generic cleocin gel 20 gm online. Phase 3 trials comparing edoxaban to focusing on real-world concerns related to their effectiveness, warfarin for the prevention of stroke and systemic embolism in safety, and use. Betrixaban is being evaluated in a phase 3 trial versus enoxaparin for the prevention of VTE in medically ill patients Pharmacologic properties of warfarin and NOACs undergoing hospitalization. The pharmacologic properties of warfarin, dabigatran etexilate, rivaroxaban, and apixaban are summarized in Table 1. Its pharmacokinetics thereby facilitating fixed dosing in adults without the need for and pharmacodynamics are influenced by genetic polymorphisms laboratory monitoring or dose adjustments for body weight. In general, the results for the approved indications have been robust, with NOACs being either noninferior or Dabigatran etexilate is an oral prodrug that is converted to superior to standard treatment regimens. Despite the advantages dabigatran, a competitive direct thrombin inhibitor (Ki 4. Properties of warfarin and oral inhibitors of thrombin and factor Xa inhibitors approved for use in the United States Warfarin Dabigatran etexilate Rivaroxaban Apixaban Target Vitamin K epoxide reductase (VKORC1) Thrombin Factor Xa Factor Xa lowers levels of vitamin K–dependent coagulation factors Prodrug No Yes No No Bioavailability 95% 6. Dabigatran etexilate has relatively low oral bioavailability and not be prescribed to patients with moderate or severe liver disease. The capsules, however, must be ingested intact (ie, they pharmacy programs, but requires that all of their other medications cannot be crushed, broken before administration, or chewed) and be inputted. If there is a strong drug interaction, it is best not to the medication cannot be administered to patients receiving nutri- prescribe the NOAC rather than altering doses as suggested by the tion and oral medications via nasogastric, gastrostomy, or jejunos- label. As yet, there are neither assays available to measure drug tomy tubes. The capsules are hygroscopic and expire 4 months after levels on a routine basis nor evidence-based algorithms for adjust- the seal of the bottle is broken upon opening. Although warfarin has innumerable drug interactions, the has relatively few drug interactions, but p-glycoprotein transporter dose can be adjusted by monitoring the INR more frequently to inhibitors such as amiodarone, verapamil, or quinidine increase account for any concomitant interactions. The use of the drug with rifampin, a p-glycoprotein regarding NOAC absorption in patients who have undergone inducer, should be avoided because it reduces the drug’s anticoagu- gastric-bypass or lap band surgery for obesity or resection of large lant effect. In patients with moderate renal impairment (creatinine portions of the small bowel; NOACs should therefore not be clearance 30-50 mL/min) taking potent p-glycoprotein inhibitors prescribed to such patients until data or algorithms for adjusting (eg, ketoconazole or dronedarone), it is recommended that consider- dose become available. Some of the potential advantages and ation be given to reducing the dose of dabigatran etexilate to 75 mg disadvantages of oral direct thrombin or factor Xa inhibitors twice daily (BID). Efficacy and safety of the NOACs in atrial fibrillation Although both agents have high oral bioavailability, it is necessary The key findings of the randomized trials comparing dabigatran (RE-LY),11 rivaroxaban (ROCKET-AF),12 and apixaban (ARIS- to take higher doses of rivaroxaban (15 or 20 mg tablets) with food TOTLE)13 with warfarin for stroke prevention in atrial fibrillation were to ensure optimal drug absorption. Rivaroxaban is absorbed best in the stomach, whereas apixaban is absorbed throughout the gastroin- as follows. Rivaroxaban may be crushed and mixed and adminis- tered with food through a gastrostomy tube. Rivaroxaban has a dual NOACs are noninferior to warfarin for the prevention of stroke and mode of elimination; one-third is excreted unchanged by the kidney systemic embolism (see Table 3 for approved doses and schedules). All reduced mortality by 10% per year compared with tors)/inducers (carbamazepine, phenytoin, rifampin, St John’s wort) warfarin. Apixaban is also The rates of major bleeding for dabigatran at the 150 mg BID dose metabolized by the liver (partially by CYP 3A4); 75% is eliminated and rivaroxaban were similar to warfarin. Apixaban demonstrated a in the feces and 25% by the kidneys. All 3 and it is recommended that the dose be reduced to 2. However, both dabigatran and Hematology 2013 465 Table 2. Potential advantages and disadvantages of oral direct thrombin and factor Xa inhibitors compared with vitamin K antagonists Advantages Disadvantages Rapid onset/offset of action eliminates need for initial treatment with Use is contraindicated or dose reduction is required in patients with a parenteral anticoagulant in patients with acute thrombosis; also severe chronic kidney disease; such patients also require longer reduces need for “bridging” patients at high risk of thrombosis periods off therapy prior to procedures with high risk of bleeding. Absence of food interactions, limited hepatic metabolism, and few Limited availability of assays for measuring drug levels and absence strong drug interactions. Wide therapeutic window enables fixed of validated monitoring strategies prevent dose titration or dosing in adults without need for laboratory monitoring. Greater convenience for patients and providers with potential for Potential for overuse (eg, long-term treatment of VTE patients at greater use than vitamin K antagonists, particularly in atrial low recurrence risk). May be more cost-effective than vitamin K antagonists (no routine Higher drug acquisition costs. Lower risk of intracranial hemorrhage and lower potential risk of Short half-life leads to rapid decline in anticoagulant/antithrombotic bleeding complications, thereby reducing need for an antidote. No specific antidote in case of major bleeding; also complicates urgent surgery or interventions. For dabigatran, this appears to be an age-related warfarin places patients at increased risk for adverse events (ie, phenomenon and is most relevant to those older than 85 years. The AVERROES trial compared apixaban with aspirin stroke. Stroke can result from the rapid dissipation of the antithrom- for stroke prevention in atrial fibrillation in such a study popula- botic effect of NOACs if patients do not take their medication as tion. In the phase 3 trials of rivaroxaban and bleeding was surprisingly no different from aspirin. The results of apixaban, there was a clustering of thrombotic events at the end of the AVERROES study suggest that aspirin should not have a role in the double-blind, double-dummy ROCKET-AF and ARISTOTLE the prevention of stroke in atrial fibrillation.

C1-INH indicates C1 esterase inhibitor; AT-INH buy cleocin gel 20 gm free shipping, 1-antitrypsin; CHD cleocin gel 20 gm with mastercard, coronary heart disease; and OCPs buy cleocin gel 20 gm,oralcontraceptivepills. Reevaluation of the reported cases16 ( 15% fXI:c)—has been reported to be protective against VTE. Conversely, elevated fXI antigen levels were been reported that a subset of antiphospholipid antibodies bind to found to be a risk factor for VTE in the LITE study, with an odds fXII and may lead to an acquired “pseudo fXII deficiency”18; these ratio (OR) for VTE with fXI levels in the top quintile of 1. Importantly, there was also no FXII variation in the risk across various severities of deficiency. In a nested case-control study Second Northwick Park Study (NPHS-II), lower levels of the from the Longitudinal Investigation of Thromboembolism (LITE) complex were a risk factor for stroke. The risk of VTE did not vary across the range of percentile) levels of the complex were associated with an increased quintiles, indicating that neither fXII deficiency nor excess was risk of stroke, with an OR of 2. However, when fXII:Ag levels were assayed in the same deficient (type I or type II HAE) or fails to inhibit a mutated patients and controls, no association with stroke risk was apparent, inactivation-resistant form of fXII (type III HAE). Therefore, the most logical conclu- ties (ARIC) Study, baseline fXII:c levels were measured in 89 sion from the available data is that, whereas fXII deficiency (or incident stroke cases (42% male, 24% African American) and 406 indeed, excess) may not predispose to VTE, it also fails to be random sample subjects. As with VTE, reexamination of 68 American Society of Hematology reported cases of fXII deficiency and thrombosis, as well as Swiss FXI families with fXII deficiency, concluded that there was no associa- In the Israeli fXI-deficient population, no protection from MI was tion with stroke. First, as with VTE and using a similar approach in the of MI was increased for each quintile of fXI:c compared with the Israeli population with fXI deficiency, Salomon et al concluded that bottom quintile even after adjustment for cardiovascular risk factors 27 and fXII:c levels. In the ARIC study, elevated levels of fXI:c were associated with an increased were correlated, the opposite effects on risk for MI were also risk of IS (hazard ratio 1. To explain this seeming paradox, the percentile in a population 55 years of age were associated with an investigators suggested that any effect of fXII on risk of MI may not 28 be mediated via fXI, but rather through some other mechanism. Furthermore, fXI:c and fXI:Ag levels were reasonably well correlated (R 0. In the RATIO study, fXIa the NPHS-II study, plasma levels of factor XIa complexes (fXIa-C1- levels were measured by ELISA assays of the complexes of fXIa INH and fXIa-AT-INH) were not associated with a greater risk of coronary heart disease in middle-aged male participants. In these younger women, levels of fXIa-C1-INH and agreement with this conclusion, the RATIO study demonstrated that th elevated levels of fXIa complexes,25 fXI:c,31 and fXI:Ag34 were not fXIa-AT-INH complexes above the 90 percentile were associated with an elevated risk of stroke (OR 2. Whether this represents some unique difference in the coronary vasculature or in the role of the intrinsic pathway factors in MI remains to be established. MI FXII Conclusions In the NPHS-II study, higher baseline levels of fXIIa (measured by Although there is reasonable consistency in the data linking fXI an ELISA specific for fXIIa) were predictive of coronary heart deficiency or excess to hemostatic or thrombotic disorders, respec- disease in middle-aged men. It remains unclear how seen in the same study when fXIIa-C1-INH levels were measured. This information may only be obtained by carefully cally, the adjusted OR of MI for men in the highest quintile designed and monitored intervention studies in primates and in compared with those in the lowest quintile was 0. In a case-cohort sample from the ARIC study, fXII:c was measured in 368 incident cases and 412 random controls. No Acknowledgments association was observed between fXII levels and coronary heart This work was supported by National Institutes of Health grant disease events, defined as hospitalized MI, a definite CHD death, 33 UO1HL117659 (to N. It is evident from these studies that a firm conclusion on the role of Disclosures fXII as a risk factor for MI is not established. It is possible that the Conflict-of-interest disclosures: The author declares no competing discrepant results are explained by chance or other factors such as financial interests. However, the particular assay selected is also likely to be an important variable, with major Correspondence differences sometimes apparent in studies measuring zymogen Nigel S. Key, MB, ChB, FRCP, Department of Medicine, Division versus enzyme levels. Therefore, when measuring fXIIa or the of Hematology/Oncology, University of North Carolina at Chapel fXIIa-C1-INH complex, the extent and/or rate of fXII activation Hill, 303 Mary Ellen Jones Building, CB #7035, Chapel Hill, NC could be quite heterogeneous among subjects. Therefore, levels of 27516; Phone: (919)966-3311; Fax: (919)966-7639; e-mail: these complexes do not necessarily correlate with fXII:c or fXII:Ag nigel_key@med. New hemophilia-like disease the consequences of moderate and severe fXII deficiency may be caused by deficiency of a third plasma thromboplastin factor. Increased activity of coagulation factor on one-stage clotting tests; a presumptive test for hemophilia and factor XII (Hageman factor) causes hereditary angioedema type III. Salomon O, Steinberg DM, Zucker M, Varon D, Zivelin A, Seligsohn 3. Patients with severe factor XI deficiency have a reduced incidence of simple screening test for first stage plasma clotting factor deficiencies. Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. A familial hemorrhagic trait associated with a High levels of coagulation factor XI as a risk factor for venous deficiency of a clot-promoting fraction of plasma. Segregation kinin system and risk of cardiovascular disease in men. J Thromb of an hereditary hemorrhagic state from the heterogeneous group Haemost. Siegerink B, Govers-Riemslag JW, Rosendaal FR, Ten Cate H, Algra A. Intrinsic coagulation activation and the risk of arterial thrombosis in 6. An enzyme cascade in the blood clotting mechanism, 122(18):1854-1861. Suri MF, Yamagishi K, Aleksic N, Hannan PJ, Folsom AR. Factor XI activation in a revised model of blood hemostatic factor levels and risk of ischemic stroke: the Atherosclerosis coagulation. Salomon O, Steinberg DM, Koren-Morag N, Tanne D, Seligsohn U. Reduced incidence of ischemic stroke in patients with severe factor XI 10.

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The Global Fund The Global Fund to Fight AIDS discount cleocin gel 20 gm free shipping, Tuberculosis and Malaria (GFATM) is an interna- tional financing institution that invests the world’s money to save lives cheap 20 gm cleocin gel free shipping. It supports large-scale prevention cheap cleocin gel 20 gm overnight delivery, treatment and care programs against the three diseases. Fiscal strategies were reviewed and redesigned in 2013 for accounting and forecast- ing. Risk management was updated in 2014 in finance, procurement and supply chain management. Total new grants for 2014 fell by close to 25%, to $2. There is almost ¾ of another billion USD signed but not committed to. From their 2014 Press Statement on Results, “Through the (new) funding model, the Global Fund is pursuing a differentiated approach to investing. It is weighing eco- nomic scenarios against epidemiological intelligence that points to diseases, espe- cially HIV and tuberculosis, becoming less generalized and more concentrated in certain locations and in key populations within a country. While certain middle- income countries and regions are making remarkable progress, others are falling back. Achieving control over these diseases calls for a diversified and differentiated approach, aligned with the Post-2015 development agenda. Ireland and Italy are in the “promised but not yet paid” column. UNAIDS UNAIDS provides technical support to countries, assisting them with expertise and planning for national AIDS programs, to help ‘make the money work’ for the people on the ground. UNAIDS tracks, evaluates and projects the financial resource require- ments at global, regional and country levels to generate reliable and timely infor- mation on the epidemic and the response. Based on these evaluations, UNAIDS pro- duces guidelines and progress reports. Much of the international data we juggle is set and approved by UNAIDS. They set out plans for “Getting to Zero” and other platitude-ridden slogans and programs. They are making a good effort on tackling major social issues like homophobia, financial sustainability and gender equality. The UN adopted a Political Declaration on HIV/AIDS in which member states agreed to increase investments for HIV to between $22–24 billion by 2015. A concerted effort by all countries is needed to meet the targets (slightly under $22B has been reached up until June 2015). Another promising approach would be to expand innovative mechanisms like indirect taxation (airline tickets, mobile phone usage, exchange rate transactions) to support global health initiatives, includ- ing HIV. The larger international community must continue to support and strengthen existing financial mechanisms, including the Global Fund and relevant UN organizations. The 15x15 program is a UNAIDS-sponsored program, as is the 90/90/90 idea, mentioned above and further on. The Bill and Melinda Gates Foundation The largest private philanthropic organization is located in Seattle, US, “focusing on improving people’s health and giving them the chance” to emerge from “hunger and extreme poverty. Much of these moneys are for non-AIDS-specific works, including development (reducing poverty and hunger). In health (58% of the total spending), they fight and prevent enteric and diarrheal diseases, malaria, pneumo- nia, TB, neglected and infectious diseases, working on integrated heath solutions, improving delivery of existing tools and supporting research and development in 6. Drugs available from whom and where FDA’s qualification of generics Generic drugs are important options that allow greater access to health care. They have the same high quality, strength, purity and stability as brand-name drugs. Generic manufacturing, packaging, and testing sites must pass the same quality stan- dards as those of brand name drugs. As of 2 July 2015, FDA had approved 187 generic drugs for use in the PEPFAR program that are approved in as short a time as six weeks. While quality, strength, purity and stability are guaranteed, adminis- tration, delivery and correct use is another issue. For example, the latest generic approved was another version of nevirapine. Generics companies copy what is easiest and cheap, not necessarily the most innovative, or the most optimal treatments (there are no integrase inhibitors yet). We must continue to try to remind the generics companies that what is best for the patient will continue selling for years, while less-than-optimal combinations will have limited life-times, and might do harm via side effects along the way. Although the WHO pulled d4T from its list of recommended products in 2009, the switch to more effective treat- ments like TDF took time (the latest was an EFV/FTC/TDF FDC in Feb 2015). Lopinavir/r and atazanavir/r are the only PIs approved. Sadly, Janssen under J&J never bothered to outlicense any of its products (darunavir, etravirine, rilpivirine). There are a handful of generics companies with an abacavir approval. As HLA testing for abacavir HSR is not easily available in the Global South, it is very important to train both the medical professional as well as users on diagnosis of HSR and what to do if it occurs, and the importance of never re-starting it once HSR is suspected, things that from an international regulatory agency would be hard to monitor.

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Handen BL buy 20gm cleocin gel overnight delivery, Feldman H 20 gm cleocin gel visa, Gosling A cleocin gel 20 gm generic, Breaux AM, McAuliffe S. Adverse side effects of methylphenidate among mentally retarded children with ADHD. Journal of the American Academy of Child & Adolescent Psychiatry. Efficacy of methylphenidate among preschool children with developmental disabilities and ADHD. Journal of the American Academy of Child & Adolescent Psychiatry. Spencer TJ, Wilens TE, Biederman J, Weisler RH, Read SC, Pratt R. Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in the management of attention-deficit/hyperactivity disorder in adolescent patients: a 4-week, randomized, double-blind, placebo-controlled, parallel-group study. Atomoxetine treatment for pediatric patients with attention-deficit hyperactivity disorder with comorbid anxiety disorder. Journal of the American Academy of Child & Adolescent Psychiatry. Atomoxetine and adult attention- deficit/hyperactivity disorder: the effects of comorbidity. A replication study of diagnosis and drug treatment. Efficacy and safety of atomoxetine in adolescents with attention deficit hyperactivity disorder and major depression. Attention deficit hyperactivity disorder 149 of 200 Final Update 4 Report Drug Effectiveness Review Project 382. Lisdexamfetamine dimesylate for the treatment of attention deficit hyperactivity disorder in adults with a history of depression or history of substance use disorder. Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. Methylphenidate in the treatment of children and adolescents with bipolar disorder and attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry. Zeni CP, Tramontina S, Ketzer CR, Pheula GF, Rohde LA. Methylphenidate combined with aripiprazole in children and adolescents with bipolar disorder and attention- deficit/hyperactivity disorder: a randomized crossover trial. Gadow KD, Paolicelli LM, Nolan EE, Schwartz J, et al. Indirect effects of medication treatment on peer behavior. School observations of children with attention- deficit hyperactivity disorder and comorbid tic disorder: effects of methylphenidate treatment. Stimulant medication withdrawal during long-term therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder. Journal of the American Academy of Child & Adolescent Psychiatry. Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders. Gadow KD, Sverd J, Nolan EE, Sprafkin J, Schneider J. Immediate-release methylphenidate for ADHD in children with comorbid chronic multiple tic disorder. Journal of the American Academy of Child & Adolescent Psychiatry. Atomoxetine treatment of ADHD in children with comorbid Tourette syndrome. Methylphenidate and comorbid anxiety disorder in children with both chronic multiple Tic disorder and ADHD. Gadow KD, Sverd J, Sprafkin J, Nolan EE, Grossman S. Long-term methylphenidate therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder. Attention deficit hyperactivity disorder 150 of 200 Final Update 4 Report Drug Effectiveness Review Project 396. A randomized crossover clinical study showing that methylphenidate-SODAS improves attention-deficit/hyperactivity disorder symptoms in adolescents with substance use disorder. Thurstone C, Riggs PD, Salomonsen-Sautel S, Mikulich-Gilbertson SK. Randomized, controlled trial of atomoxetine for attention-deficit/hyperactivity disorder in adolescents with substance use disorder. Journal of the American Academy of Child & Adolescent Psychiatry. Atomoxetine treatment of adults with ADHD and comorbid alcohol use disorders. Williams RJ, Goodale LA, Shay-Fiddler MA, Gloster SP, Chang SY. Methylphenidate and dextroamphetamine abuse in substance-abusing adolescents. Table 4: Annual Estimates of the Population by Race Alone and Hispanic or Latino Origin for the United States and States: Population Division, U. Attention Deficit Hyperactivity Disorder: Effectiveness of Treatment in At-Risk Preschoolers; Long-Term Effectiveness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment.

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