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Delivery of BUD/FM via pMDI is not indicated for MART minocin 50mg with visa. Two trials compared BUD/FM for 98-100 discount 50 mg minocin fast delivery, 103, 105 maintenance and relief to BUD/FM for maintenance with a SABA for relief; three trials compared BUD/FM for maintenance and relief to the combination of fluticasone and 98, 100, 104, 106 salmeterol (FP/SM) for maintenance with a SABA for relief. Several of the trials included in this section significantly reduced the total ICS doses for many of the subjects upon randomization (some studies averaged a 75% dose reduction). Overall, results from large trials up to twelve months in duration found statistically significantly lower odds of exacerbations requiring medical intervention for those treated with BUD/FM for maintenance and relief than for those treated with ICS/LABA for maintenance and a SABA for relief (moderate strength of evidence, Appendix H, Table H-6). A separate meta-analysis of exacerbations resulting in emergency department visits or hospital admissions revealed similar findings; the odds ratio for MART was 0. MART was also associated with fewer nocturnal awakenings, compared with 2 ICS/LABA + SABA (SMD = -0. I values for each of those meta-analyses were < 25%, indicating low heterogeneity, and sensitivity analysis results did not change our conclusions in either case. None of the individual trials found a significant difference in symptoms. Our meta-analyses found no statistically significant differences in symptom-free days (SMD = 0. Sensitivity analyses for each of these comparisons did not reveal anything that would change our conclusions. Detailed Assessment Description of Studies Of the four RCTs we included (Table 13), two compared BUD/FM MART to BUD/FM for 98-100, 103, 105 maintenance and SABA for relief, and three compared BUD/FM MART to FP/SM for maintenance and SABA for relief. All trials administered the ICS/LABA combinations in a 98, 100, 104 103, 105, 106 single inhaler. Controller medications for asthma 68 of 369 Final Update 1 Report Drug Effectiveness Review Project Total daily maintenance ICS components of the BUD/FM MART groups varied. One study compared low starting and mean ex-mouthpiece doses of BUD (in the MART arm) with 103, 105 low fixed-dose BUD (fixed-dose BUD/FM arm), one compared low mean daily dose of 98-100 BUD (MART arm) with medium and high doses of non-adjustable combinations, one 106 compared medium dose with medium dose, and one compared medium dose BUD (MART 104 arm) with high fixed-dose FP (FP/SM + SABA arm). In two studies, the mean total daily dose of ICS administered ex-mouthpiece in the BUD/FM MART group was less than the total daily 98-100, 104 dose in the ICS/LABA with a SABA for relief group. Several of the trials significantly reduced the total ICS doses for many of the subjects upon randomization. Some studies reduced the starting ICS doses to levels that could be considered inadequate compared to the subjects’ previous dose requirements. In three studies all medications were delivered via DPIs; one study 98-100 compared BUD/FM DPI with FP/SM pMDI. Study Populations The four head-to-head RCTs included a total of 10,547 subjects. Three studies were conducted in 105 adolescent and/or adult populations. One study included children and adults, and one 103 publication further described the subset of children four to 11 years of age from that study. All enrolled subjects that were not adequately controlled on 103-105 current therapy. Two were conducted in subjects with mild to moderate persistent asthma 98-100, 106 and two did not report asthma severity classification. Two trials did not report smoking 98-100, 104 rates and two allowed some smokers. Trials enrolling smokers reported that 4% to 7% of subjects in each group were current smokers. Sponsorship Of the four head-to-head trials, all four (100%) were funded by pharmaceutical companies. BUD/FM MART compared with ICS/LABA for maintenance and SABA for relief The results of the four RCTs contributing five comparisons (one study compared BUD/FM MART with BUD/FM maintenance and SABA relief and with FP/SM maintenance and SABA relief) are described below under the appropriate drug comparisons. Overall, all five comparisons reported statistically significantly lower rates of exacerbations for those treated with BUD/FM MART, but no differences in symptoms. We conducted meta-analyses for seven outcomes that were reported with sufficient data in multiple trials (Appendix I). These included symptom-free days, symptom scores, nocturnal awakenings, exacerbations requiring medical intervention, exacerbations resulting in emergency visit or hospital admission, rescue-free days, and rescue medicine use (puffs/day). Our meta-analysis for exacerbations requiring medical intervention shows an odds ratio of 0. A separate meta-analysis of exacerbations resulting in emergency department visits or hospital admissions revealed similar findings; the odds ratio for MART was 0. MART was also associated with fewer nocturnal awakenings, compared with ICS/LABA + SABA (SMD = - 2 0. We found no statistically significant differences in symptom-free days (SMD = 0. Of note, the comparisons that administered scheduled maintenance ICS doses that were lower in the BUD/FM MART group all found statistically significantly lower exacerbation rates 98-100, 104 for those treated with BUD/FM MART. In addition, the BUD/FM MART group had a lower mean daily steroid dose (maintenance plus relief) than the ICS/LABA for maintenance 98-100, 104, 106 with SABA relief in three of the five trials. Thus, it does not appear that delivering a higher total ICS dose explains the better exacerbations outcomes in the BUD/FM MART group.

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Vulvovaginitis is a common complaint in examination (use a nasal speculum or a hystero- children and adolescents and can be caused by scope or cystoscope in young children) under several agents: general anesthetic 50 mg minocin with amex. On examination purchase 50 mg minocin mastercard, the labia majora quently seen in toddlers and small infants. You are erythematous, scaly and often rugose due can confirm the diagnosis by applying sticky to lichenification. The labia minora may be tape on the perianal region at night and examine involved with an increase in erythema and des- the sticky tape the next morning under a micro- quamation, giving the impression the child has scope (transfer the sticky tape on a microscope vaginal discharge. Recommenda- Treatment is mebendazole stat according to the tions to improve vaginal hygiene are: wear only weight of the child (also treat the family). If possible • Vaginal discharge in neonates is physiological and do not wear underwear at night. Wash the vulva caused by estrogens received from the mother with clean water without soap. It is odorless and stops after a few 297 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS (a) (b) Figure 5 Enterobius vermicularis in the anal region of a child (a) and eggs seen under the microscope after a Scotch tape test (b) and children wearing diapers. Treatment is miconazole ointment or vaginal capsule (Ovule). LICHEN SCLEROSUS IN CHILDREN AND ADOLESCENTS Lichen sclerosus is a chronic skin condition of un- known origin common in pre-pubertal girls (preva- lence approximately 1 in 900) and postmenopausal women (prevalence 1 in 300–1000). It is a chronic skin condition of the ano-genital region but can Figure 4 Vulvovaginitis in children: (a) redness and (b) also be present on other parts of the body. This Examination of the vulva shows the characteris- decrease in estrogens may cause vaginal blood tic appearance of a hour-glass-shaped lesion around loss since the endometrium may be shed4. There are often associated but is sometimes seen in children after a course areas of erosion, ulceration and purpura and, in of antibiotics, and in immunosuppressed children severe cases, hemorrhagic bullae. UNICEF states that sexual violence against children is a gross violation of children’s rights. Yet it is a global real- ity across all countries and social groups. It takes the form of sexual abuse, harassment, rape or sexual exploitation in prostitution or pornography. It can happen in homes, institutions, schools or work- places, in travel and tourism facilities, and within communities – both in development and emer- gency contexts (http://www. Child sexual abuse is outlawed nearly every- where in the world, generally with severe criminal penalties. The exact incidence of sexual abuse in children and adolescents is unknown, but in a South African study forced sexual initiation was re- ported by ‘almost a third’ of adolescent girls6. The number of children involved in child prostitution is unknown, but between 1 million and 10 million children are estimated to be involved. Source: http:// Sexual abuse and prostitution of children and www. Treatment is with physical abuse or with diseases like HIV). They can potent topical steroids, such as clobetasol propion- be damaged by it for the rest of their lives as they are ate 0. On physi- cal examination of an abused child you may find CONDYLOMATA ACUMINATA (GENITAL subtle signs and symptoms and you should be WARTS) familiar with normal children and adolescent anat- omy to appreciate these changes. One study reports Before the age of 3 years genital warts are trans- that in only 4% of the abused children are physical mitted via mother-to-child transmission and are signs visible. Findings after penetration are tearing not a sign of sexual abuse. They are caused by a or transection of the hymen fossa or Fourchette. In 50% the warts disappear without treat- ture) and/or anus (Neisseria gonorrhoeae, and deep ment. Podophyllotoxin is contraindicated in chil- lacerations to the anal sphincter are considered dren. Treatment in children is electrosurgical ‘diagnostic’ of penetration by an object). Healing of a vaginal/ SEXUAL ABUSE IN CHILDREN AND hymenal tear may be complete or result in hymenal ADOLESCENTS clefts or V-shaped notches that approach the floor Sexual abuse in children and adolescents can be of the vulva below 3–9 o’clock; 77% of experts defined as any activity with a child before the age judge this finding to be due to possible trauma or of legal consent that is for the sexual gratification of sexual contact5. They may present with inter- detection should be done during MCH, in schools mittent vaginal bleeding, sometimes associated and in out-patient departments. Diagnosis is made by should be given to children with developmental, examination under anesthesia and biopsy for behavioral, or medical problems, who may be at histological examination. Healthcare providers is a fast-growing aggressive malignancy of the should be aware of the fact that recognizing and submucosa of the vagina; 90% of the girls who reporting child sexual abuse, or tertiary prevention are affected are below the age of 5 years and (to prevent recurrent abuse in an already abused signs and symptoms are a mass protruding from child), is the most effective means of prevention of the vagina accompanied by bleeding. Several countries have policies on chil- should be performed by experienced oncolo- dren and adolescent abuse; please make yourself gists/pediatric surgeons/gynecologic oncologist familiar with them. PRE-PUBERTAL VAGINAL BLEEDING The incidence of pre-pubertal vaginal bleeding is MENORRHAGIA AROUND MENARCHE low; however, as serious causes can underlie the Menstrual disorders around menarche are common problem, it is important to examine the girl.

Negative (−) difference of mean differences were interpreted as suggesting that drug A is associated with a greater reduction in fibromyalgia symptoms than drug B buy minocin 50mg visa. Peer Review We requested and received peer review of the report from 4 content experts minocin 50mg online. Their comments were reviewed and, where possible, incorporated into the final document. All comments and the authors’ proposed actions were reviewed by representatives of the participating organizations of the Drug Effectiveness Review Project before finalization of the report. Names of peer reviewers for the Drug Effectiveness Review Project are listed at www. Public Comment This report was posted to the Drug Effectiveness Review Project website for public comment. We received comments from 3 persons, representing 2 pharmaceutical companies. RESULTS Overview Literature searches identified 1148 citations. We received dossiers from 2 pharmaceutical manufacturers: Eli Lilly and Company and Forest Laboratories Inc. By applying the eligibility and exclusion criteria to titles and abstracts of all identified citations, we obtained full-text copies of 119 citations. After re-applying the criteria for inclusion, we ultimately included 51publications. Five included studies were identified after expanding the population inclusion 38-42 criteria to include a broadened definition of fibromyalgia or fibrositis. See Appendix E for a list of excluded studies and reasons for exclusion at this stage. Drugs for fibromyalgia 17 of 86 Final Original Report Drug Effectiveness Review Project a Figure 1. Results of literature search 1121 records identified from 27 additional records identified database searches after through other sources removal of duplicates 1148 records screened 1029 records excluded at abstract level 68 full-text articles excluded 119 full-text articles assessed • 5 non-English language for eligibility • 7 ineligible outcome • 22 ineligible intervention • 9 ineligible population 51 publications included in • 9 ineligible publication type qualitative synthesis • 10 ineligible study design • 38 trials (+2 companion • 7 ineligible systematic review publications) • 3 systematic reviews • 8 others (include pooled analysis, post hoc analysis of trials etc). Trials included in quantitative synthesis (meta-analysis): • Pain = 16 • Fatigue = 9 • FIQ, PGIC = 10 • 30% and 50% response = 11 • SF-36 = 6 • Overall withdrawal = 16 • Overall adverse events = 13 • Withdrawals due to adverse events = 14 a 1 The Drug Effectiveness Review Project uses a modified PRISMA flow diagram. Drugs for fibromyalgia 18 of 86 Final Original Report Drug Effectiveness Review Project Key Question 1. For adults with fibromyalgia, what is the comparative effectiveness/efficacy of included interventions? Summary of Findings General  We found no eligible studies of treatment for fibromyalgia with desipramine, imipramine, desvenlafaxine, venlafaxine, escitalopram, fluvoxamine, sertraline, mirtazapine, bupropion, nefazodone, carbamazepine, divalproex, ethotoin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, tiagabine, topiramate, valproic acid, or zonisamide  We found no eligible studies of included interventions when used as adjunctive therapy. Direct evidence  There was low-strength evidence that immediate-release paroxetine is superior to amitriptyline in reducing pain (−28% compared with −1%; z= −5. Indirect evidence Pooled analysis  All trials included used the drugs as monotherapy and no trial evaluated the effectiveness of the drugs as adjunctive therapy  Pain, 50% response rate, Patient Global Impression of Change: Pooled analysis of placebo-controlled trials of amitriptyline, pregabalin, milnacipran, and duloxetine found that all drugs were superior to placebo  Fatigue: Pooled analysis of placebo-controlled trials of amitriptyline, pregabalin, and milnacipran found that these drugs were superior to placebo for short-term results, but not in longer-term trials of 24 to 28 weeks in duration. Indirect meta-analysis  Pain: Indirect meta-analysis of short-term trials (8-15 weeks) of amitriptyline, pregabalin, milnacipran, and duloxetine on measures of pain found that duloxetine was superior to milnacipran (mean difference, −0. Comparisons to placebo • Gabapentin significantly improved pain severity and response, overall impact of fibromyalgia, global status, and sleep, but not tender point pain threshold, depression or overall quality of life • Compared with placebo, a significant reduction in pain severity was only found with cyclobenzaprine in 1 of 3 trials • Among selective serotonin reuptake inhibitors, only fluoxetine, at a higher dose (45 mg), resulted in significantly greater improvements than placebo in pain, fatigue, and Fibromyalgia Impact Questionnaire Total Score • Controlled-release paroxetine did not significantly decrease pain, disability, or depressiveness or increase the number of patients with a 50% or greater response, but did significantly decrease the Fibromyalgia Impact Questionnaire Total Score, fatigue, and improved global status • Citalopram did not significantly improve pain or fatigue and only reduced depression and improved sleep in 1 of 2 trials. Detailed Assessment Direct evidence Direct evidence regarding the comparative effectiveness among included interventions was limited and only available from 4 small randomized controlled trials that compared amitriptyline 43 44 45 to cyclobenzaprine (N=208), fluoxetine (N=31), nortriptyline (N=118), and immediate- 46 release paroxetine (N=68). All patients met the American College of Rheumatology 1990 criteria for classification of fibromyalgia. Three trials reported duration of fibromyalgia, which 46 43 ranged from 36 months to 101 months. Participants were 95% female with mean ages ranging 46 45 from 36 years to 53. Race was 100% Caucasian in the fluoxetine trial conducted in 44 45 Massachusetts, 62% Caucasian and 38% non-Caucasian in the Brazilian trial of nortriptyline, 43 and was not reported in the Canadian study of cyclobenzaprine or the Turkish study of 46 43, 45 immediate-release paroxetine. Trial settings included outpatient rheumatology clinics and a 44 46 tertiary referral center, but was not well described in the Turkish study. Trial durations ranged 44, 46 43 44, 45 46 from 6 weeks to 6 months. Mean dosages for the comparator drugs were 20 mg for cyclobenzaprine, 20 mg for fluoxetine, 20 mg for immediate-release paroxetine, and 25 mg for nortriptyline. The main limitation of the poor-quality trial was that its analyses excluded a large proportion of the data – Drugs for fibromyalgia 20 of 86 Final Original Report Drug Effectiveness Review Project over one-third; consequently, its results will not be discussed here, but can be found in Evidence 44 Tables 1 and 2. However, differences between immediate-release paroxetine and amitriptyline were not significant for change in fatigue (−9% compared with −5%; z=0.

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In summary order minocin 50 mg visa, although we have probably doubled the survival of elderly patients minocin 50 mg low cost, this group requires close monitoring and individualized, dose-modified regimens to improve tolerability and treatment efficacy while maintaining their quality of life. Introduction Can we go beyond complete response as a goal of Multiple myeloma (MM) is a fatal cell disease that accounts for 1% therapy? It primarily The introduction of new treatment options for non-transplantation- affects older individuals; the median age at diagnosis is 70 years and eligible patients has altered the goals of therapy. Prolongation of two-thirds of MM patients are more than 65 years of age when they disease-free survival and overall survival (OS) remains the ultimate are first diagnosed. The increased life expectancy of the general goal, but achieving prolonged treatment-free intervals and good population means that an increase in the number of elderly MM quality of life have also become important aims, especially for patients is expected over time. In the era of MP (melphalan plus prednisone), the cantly improved in the last decade because myeloma treatment is goal was to achieve partial response; in contrast, with the new developing rapidly. The role of CR has been evaluated in elderly followed by autologous stem cell transplantation (HDT-ASCT) patients. In a retrospective analysis of pooled data from 1175 up-front and the use of novel agents as rescue therapy, although only patients with newly diagnosed MM treated with novel agents and a marginal change was observed in patients older than 65 years. MP, achieving CR was associated with improved progression-free survival (PFS) and OS. Due to the increased life expectancy of the general analysis of elderly patients receiving novel agents showed that population and the improved survival arising from better antimy- achieving an immunophenotypic response translated into better PFS eloma drugs, the number of MM patients will increase substan- 4 compared with conventional CR or stringent CR. The role of novel therapies in patients with high-risk cytogenetic abnormalities and comorbidities for optimized disease control is Options for induction therapy also discussed. The ultimate objective is to provide an outline to Alkylator-containing induction regimens help physicians choose and optimize treatment strategies for this Melphalan was the first active alkylating agent used to treat MM patient population. Novel agent-based induction regimens as primary treatment in elderly patients Study Induction regimen N Maintenance regimen CR, % ORR, % PFS, mo Median OS, mo or % Alkylator-based induction regimens Melphalan-based combinations Palumbo et al6,27 MPT vs MP 129 T until DP 16 76 22 48 126 None 2. A meta-analysis of pooled data from 1682 patients Although it should no longer be considered the standard of care, from the aforementioned 6 MPT trials showed that the addition of MP has been the backbone for proteasome inhibitor and immuno- thalidomide to MP is associated with a significant improvement in modulatory drug combinations and is used as the comparator arm PFS (5. With to 76% versus 28% to 48% with MPT and MP, respectively, and respect to its toxicity, the median incidences of grade 3-4 peripheral PFS was 14 to 28 versus 10 to 19 months. In 3 of the 6 trials, the PFS neuropathy (PN) and venous thromboembolism (VTE) were 13% Hematology 2013 489 and 6%, respectively,13 meaning that antithrombotic prophylaxis is complications, PN, infection, and constipation than MP, indicating that required when using MPT. The same Lenalidomide instead of thalidomide in combination with MP and group is currently evaluating the same combination by replacing followed by maintenance with lenalidomide (MPR-R) has been thalidomide with lenalidomide in a phase 3 trial. It has structural similarities with treatment was associated with higher response rates (77% vs 50%) and alkylating agents and purine analogs and is currently approved in greater CR rates (18% vs 5%). The most significant adverse events Europe for the treatment of newly diagnosed MM patients who are (AEs) observed with this combination were neutropenia (36% grade not candidates for HDT-ASCT and who cannot receive thalidomide 4), thrombocytopenia (13% grade 4), and infections (15% grade 4). The rationale for the The median PFS did not differ significantly between the 2 induction approval was a randomized trial in which BP (bendamustine plus regimens and the benefit of this combination mainly accrued from prednisone) proved to be superior to MP with respect to CR rate maintenance therapy. The results of the primary comparison of this (32% vs 13%, P. Bendamustine plus compared the proteasome inhibitor bortezomib plus MP (VMP) prednisone in combination with bortezomib is currently being with MP. VMP was superior to MP in ORR (71% vs 35%, evaluated in several pilot clinical trials. Alkylating agents in combination with second-generation protea- From the first analysis with 16. However, the addition of bortezomib good partial response [VGPR] or better of 42%) with an acceptable to the MP regimen also increased the rate of grade 3 or 4 AEs toxicity profile and no grade 3-4 PN, providing the rationale for a associated with treatment, particularly PN (14%) and gastrointestinal randomized trial comparing CMP with VMP. Antiviral prophylaxis is required to prevent the reactivation carfilzomib plus cyclophosphamide and low-dose dexamethasone is of herpes virus. On the basis of these data, VMP has been recognized as being evaluated in a series of 53 newly diagnosed elderly MM a new standard of care for elderly untreated MM patients. No grade 3-4 PN was reported and tolerability was Despite the favorable clinical benefits of VMP, AEs are an good. Ixazomib (MLN9708), an oral second-generation proteasome important concern. The Spanish group investigated the VMP inhibitor, plus MP in a biweekly or weekly scheme is also currently regimen but in a reduced-intensity bortezomib schedule based on undergoing a phase 1/2 clinical trial to evaluate the efficacy and the weekly administration of bortezomib; patients received the first safety of this combination (Table 1). After 6 cycles, the incidence of Non-alkylating-agent–containing induction regimens grade 3 or 4 PN dropped to 7%, with an ORR of 80% (20% CR)18 Thalidomide and dexamethasone (TD) was approved in the United and, after maintenance therapy with VT or VP (see below), the PFS States in newly diagnosed MM patients on the basis of results from and OS were 37 and 60 months, respectively. TD was compared with MP in a cohort of obtained similar results in a randomized trial comparing VMP (9 elderly MM patients22; although it induced higher response rates cycles) with VMPT, followed by maintenance therapy with VT. The evident in patients more than 75 years of age (20 vs 41 months). The addition of the 4 drugs disease-related deaths observed in the TD group during the first to VMP (VMPT) plus maintenance with VT resulted in higher ORR year. Therefore, TD in elderly patients is not a good option, unless and CR rates than obtained with VMP (89% vs 81% ORR and 38% patients receive reduced doses of both drugs.