By R. Bufford. Saint Thomas Aquinas College. 2019.

The WHI Study of Cognitive Aging (WHISCA) was an ancillary study to the WHI and 206 WHIMS and started 3 years after WHI randomization alli 60mg lowest price. CEE/MPA appeared to have different effects on various cognitive domains in older women after 4 purchase alli 60mg. There were no significant differences between treatment and placebo for other cognitive domains, depressive symptoms, and affect. In the CEE-only study of the WHI, the incidence of probable dementia was not significantly increased at mean follow-up of 5. Rates of mild cognitive impairment 207 were also not significantly increased. Similar to patterns in the CEE/MPA trial, global cognitive function increased for the first 4 years, then decreased, with no significant differences 204 between treatment groups. Subjects with lower baseline scores in cognitive function had the 204 greatest decline in cognitive function (p<0. The largest declines in scores occurred more frequently in CEE than in placebo, and the relative risk of decline of 10 units in the Mini Mental 204 State exam with CEE compared to placebo was 1. Cholecystitis HERS/HERS II reported increased risks for biliary tract surgery among estrogen users 194 with long-term use (mean follow-up of 6. The Nurse’s Hormone therapy Page 55 of 110 Final Report Update 3 Drug Effectiveness Review Project 209 Health Study also reported an increased risk with long-term use (RR=2. Data from this study also suggests that risk for cholecystitis increases with duration of estrogen use. The HERS/HERS II trial reported increased risks for biliary tract surgery among estrogen 194 users early in the study (RR 1. This outcome is supported by results of the Nurse’s Health Study, a large prospective observational study of estrogen users 209 compared to nonusers (RR 1. Ovarian cancer and endometrial cancer The WHI and HERS/HERS II reported no increase in ovarian or endometrial cancer 4, 194 with CEE and MPA. Other studies of unopposed estrogen have indicated increased 210 endometrial cancer for a woman with a uterus. Observational studies of estrogen imply an 211, 212 213 increased risk for ovarian cancer while others do not. Systematic review A recent Cochrane systematic review assessed the effect of long-term hormone therapy on mortality, heart disease, venous thromboembolism, stroke, transient ischemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive 214 function, dementia, fractures, and quality of life. Fifteen randomized controlled trials were included, but the WHI and HERS, the largest trials, contributed most of the data. This review concluded that combined continuous hormone therapy significantly increased the risk of both venous thromboembolism and coronary events after one year, stroke after 3 years, breast cancer after 5 years, and gallbladder disease. In women over age 65, the incidence of dementia was also increased. In younger women (age 50 to 59 years) taking either combined regimens or estrogen-only hormone therapy, there was an increased risk of venous thromboembolism, but the absolute risk was low. Are there subgroups of patients for which one medication or preparation is more effective or associated with fewer adverse effects? Age groups Trials of estrogen and menopausal symptoms were usually conducted among women ranging in age from 40 to 60 years old with the mean age in the early 50’s. Data was not stratified by age and direct within-study comparisons cannot be made. Generally, women with the most symptoms had the most benefit. Trials of estrogen and bone density and fractures were conducted predominantly in older women in order to detect significant treatment effects because the prevalence of low bone density and fractures is higher among older women. The most comprehensive trials of adverse effects (WHI and HERS/HERS II) enrolled older women with mean ages of 63 and 67 at baseline respectively. Data were not stratified by 149 age in HERS/HERS II. In the WHI, there was no evidence that the effect of CEE in reducing fracture risk differed by age or time since menopause. It is not clear how well the findings of these trials relate to younger women using estrogen for short-term relief of symptoms. Younger post-menopausal women (50-54 years of age) who reported moderate-to-severe vasomotor 85 symptoms at baseline were examined in the WHI CEE/MPA study and there was a positive Hormone therapy Page 56 of 110 Final Report Update 3 Drug Effectiveness Review Project effect on sleep disturbance, but no effect on other HRQL measures, despite significant improvement in vasomotor symptoms. These data were consistent with results in older women For Update #3, several studies examined older women and results were similar to studies among younger women. A study of oral estradiol compared to placebo in women over 70 years with an intact uterus did not report significant changes in a “SF-36 score” or in cognitive 26 function. In a study of community-dwelling women 65 years of age and older, Greenspan and 31 colleagues reported no significant difference between treatment with CEE 0. The ULTRA study examined the use of low-dose transdermal estradiol in women 60 to 80 years and found that active treatment did not improve menopausal symptoms, urinary incontinence, or 30, 39, 78 cognitive function at 2 years.

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The tendon of tibialis posterior lies above the sustentaculum tali • The common peroneal nerve winds superficially around the neck of and the tendon of flexor hallucis longus winds beneath it buy alli 60 mg low cost. Footdrop can • The dorsalis pedis pulse is located on the dorsum of the foot be- result from fibular neck fractures where damage to this nerve has tween the tendons of extensor hallucis longus and extensor digitorum buy 60 mg alli fast delivery. Surface landmarks around the knee • The dorsal venous arch is visible on the dorsum of the foot. The • The patella and ligamentum patellae are easily palpable with the small saphenous vein drains the lateral end of the arch and passes pos- limb extended and relaxed. The ligamentum patellae can be traced to its terior to the lateral malleolus to ascend the calf and drain into the attachment at the tibial tuberosity. The great saphenous vein passes anterior to the medial • The adductor tubercle can be felt on the medial aspect of the femur malleolus to ascend the length of the lower limb and drain into the above the medial condyle. This vein can be accessed consistently by ‘cutting down’ • The femoral and tibial condyles are prominent landmarks. With the anterior to, and above, the medial malleolus following local anaesthe- knee in flexion the joint line, and outer edges of the menisci within, are sia. This is used in emergency situations when intravenous access is palpable. The medial and lateral collateral ligaments are palpable on difficult but required urgently. Surface anatomy of the lower limb 119 53 The autonomic nervous system Visible Sympathetic Parasympathetic Sympathetic ganglion Cranial outflow 3, 7, 9, 10/11 Parasympathetic T1 Spinal cord Microscopic ganglion Fig. Preganglionic fibres: red Postganglionic fibres: green Sacral outflow S 2, 3, 4 Cauda equina Fig. The former initiates the ‘fight or flight’ reac- ramus and are then distributed with the branches of that nerve. B They may pass to adjacent arteries to form a plexus around them Both systems have synapses in peripheral ganglia but those of the sym- and are then distributed with the branches of the arteries. Other pathetic system are, for the most part, close to the spinal cord in the gan- fibres leave branches of the spinal nerves later to pass to the arter- glia of the sympathetic trunk whereas those of the parasympathetic ies more distally. Thus the sympathetic preganglionic fibres are re- vical ganglia. If the sympathetic trunk is divided above T1 or below L2, the head • Sympathetic outflow (Fig. The fibres leave these spinal nerves as the white rami Loss of the supply to the head and neck will produce Horner’s syn- communicantes and synapse in the ganglia of the sympathetic trunk. There will be loss of sweating (anhidrosis), drooping of the • Parasympathetic outflow: this comprises: upper eyelid (ptosis) and constriction of the pupil (myosis) on that side. The parasympathetic system The sympathetic system • The cranial outflow: • The sympathetic trunk: from the base of the skull to the tip of the III The oculomotor nerve carries parasympathetic fibres to the coccyx where the two trunks join to form the ganglion impar. The trunk constrictor pupillae and the ciliary muscle, synapsing in the ciliary continues upwards into the carotid canal as the internal carotid nerve. IX The glossopharyngeal nerve carries fibres for the parotid gland It may be fused with the ganglion of T1 to form the stellate ganglion. For courses of the pre- and postganglionic fibres see Fig. X/XI The vagus and cranial root of the accessory carry fibres for the • Preganglionic fibres: when the white (myelinated) rami reach the thoracic and abdominal viscera down as far as the proximal two-thirds sympathetic trunk they may follow one of three different routes: of the transverse colon, where supply is taken over by the sacral out- 1 They may synapse with a nerve cell in the corresponding ganglion. Synapses occur in minute ganglia in the cardiac and pulmonary 2 They may pass straight through the corresponding ganglion and travel plexuses and in the walls of the viscera. One exceptional group of supply the pelvic viscera, synapsing in minute ganglia in the walls of fibres even pass through the coeliac ganglion and do not synapse the viscera themselves. Some fibres climb out of the pelvis around the until they reach the suprarenal medulla. Region Origin of connector fibres Site of synapse Sympathetic Head and neck T1–T5 Cervical ganglia Upper limb T2–T6 Inferior cervical and 1st thoracic ganglia Lower limb T10–L2 Lumbar and sacral ganglia Heart T1–T5 Cervical and upper thoracic ganglia Lungs T2–T4 Upper thoracic ganglia Abdominal and pelvic T6–L2 Coeliac and subsidiary ganglia viscera Parasympathetic Head and neck Cranial nerves 3, 7, 9, 10 Various parasympathetic macroscopic ganglia Heart Cranial nerve 10 Ganglia in vicinity of heart Lungs Cranial nerve 10 Ganglia in hila of lungs Abdominal and pelvic Cranial nerve 10 Microscopic ganglia in walls of viscera viscera (down to transverse colon) S2, 3, 4 Microscopic ganglia in walls of viscera The autonomic nervous system 121 54 The skull I Coronal suture Parietal Squamous Frontal temporal Sphenoid, greater wing Ethmoid Lambda Lacrimal Metopic suture (uncommon) Occipital Supraorbital foramen Nasal Position of frontal air sinus Zygomatic Maxilla Frontal External Ethmoid auditory meatus Lacrimal Orbital plate External occipital of frontal Styloid Optic canal Sphenoid, protuberance process Superior lesser wing Fig. The bones are the frontal, parietal, occipital, squamous temporal and the greater wing of the sphenoid. The frontal The bones of the cranium air sinuses are in the frontal bone just above the orbit. The bones are The vault of the skull separated by sutures which hold the bones firmly together in the mature • The vault of the skull comprises a number of flat bones, each of skull (Figs 54. Occasionally the frontal bone may be separated which consists of two layers of compact bone separated by a layer of into two halves by a midline metopic suture. The anterior, middle and posterior cranial fossae are coloured green, red and blue respectively • There are a number of emissary foramina which transmit emissary • Foramen rotundum (Maxillary branch of trigeminal nerve) veins.

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Triamcinolone acetonide and fluticasone propionate nasal sprays provide comparable relief of seasonal allergic rhinitis symptoms regardless of disease severity 60 mg alli. Comparative efficacy discount 60mg alli overnight delivery, safety, and effect on quality of life of triamcinolone acetonide and fluticasone propionate aqueous nasal sprays in patients with fall seasonal allergic rhinitis. Annals of Allergy, Asthma, & Immunology 2002;89(1):56-62. Comparative tolerability of two formulations of Rhinalar (flunisolide) nasal spray in patients with seasonal allergic rhinitis. A placebo- and active-controlled randomized trial of prophylactic treatment of seasonal allergic rhinitis with mometasone furoate aqueous nasal spray. The Journal of allergy and clinical immunology 1996;98(4):724-31. A Comparison of Two Dosing Regimens of Beclomethasone Dipropionate Aqueous Nasal Spray and Flunisolide Nasal Spray in the Treatment of Acute Seasonal Rhinitis. Triamcinolone acetonide aqueous nasal spray and fluticasone propionate are equally effective for relief of nasal symptoms in patients with seasonal allergic rhinitis. Otolaryngology - Head & Neck Surgery 2003;129(1):16-23. Once-daily mometasone furoate aqueous nasal spray (Nasonex(TM)) in seasonal allergic rhinitis: An active- and placebo-controlled study. Allergy: European Journal of Allergy and Clinical Immunology 1996;51(8):569-576. Once-daily mometasone furoate aqueous nasal spray (Nasonex) in seasonal allergic rhinitis: an active- and placebo-controlled study. NCS Page 47 of 71 Final Report Update 1 Drug Effectiveness Review Project 31. Effectiveness of ciclesonide nasal spray in the treatment of seasonal allergic rhinitis. Annals of Allergy, Asthma, & Immunology 2006a;97(5):657-63. Efficacy and safety of ciclesonide nasal spray for the treatment of seasonal allergic rhinitis. Journal of Allergy & Clinical Immunology 2006b;118(5):1142- 8. The new topical steroid ciclesonide is effective in the treatment of allergic rhinitis. Once daily fluticasone furorate nasal spray is effective in seasonal allergic rhinitis caused by grass pollen. Fluticasone furoate nasal spray: a single treatment option for the symptoms of seasonal allergic rhinitis. Journal of Allergy & Clinical Immunology 2007;119(6):1430-7. Optimal dose selection of fluticasone furoate nasal spray for the treatment of seasonal allergic rhinitis in adults and adolescents. A dose-ranging study of mometasone furoate aqueous nasal spray in children with seasonal allergic rhinitis. The Journal of allergy and clinical immunology 1999;104(1):107-14. Intranasal fluticasone propionate is effective and well-tolerated in adolescents with seasonal allergic rhinitis. Pediatric Asthma, Allergy and Immunology 1994;8(1):39-46. Fluticasone propionate aqueous nasal spray is safe and effective for children with seasonal allergic rhinitis. Treatment of seasonal allergic rhinitis with once-daily intranasal fluticasone propionate therapy in children. Rhinitis in children: Efficacy and safety of a new intranasal corticosteroid. The efficacy and tolerability of fluticasone propionate aqueous nasal spray in children with seasonal allergic rhinitis. Placebo-controlled, double-blind study of the efficacy and safety of triamcinolone acetonide aerosol nasal inhaler in pediatric patients with seasonal allergic rhinitis. Triamcinolone acetonide aqueous nasal inhaler for the treatment of spring grass seasonal allergic rhinitis in children. Pediatric Asthma, Allergy and Immunology 1997;11(2):129-136. Intranasal topical flunisolide therapy in children with seasonal allergic rhinitis. Flunisolide nasal spray for the treatment of children with seasonal allergic rhinitis. NCS Page 48 of 71 Final Report Update 1 Drug Effectiveness Review Project 47. Beclomethasone dipropionate aqueous nasal spray for seasonal allergic rhinitis in children.

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Hydrofluoroalkane-beclomethasone dipropionate effectively improves airway eosinophilic inflammation including the distal airways of patients with mild to moderate persistent asthma as compared with fluticasone propionate in a randomized open double-cross study alli 60 mg with amex. Comparison of mometasone furoate dry powder inhaler and fluticasone propionate dry powder inhaler in patients with moderate to severe persistent asthma requiring high-dose inhaled corticosteroid therapy: findings from a noninferiority trial purchase alli 60mg on line. Comparative efficacy of once-daily ciclesonide and budesonide in the treatment of persistent asthma. A multinational, 12-week, randomized study comparing the efficacy and tolerability of ciclesonide and budesonide in patients with asthma. Ciclesonide is more effective than budesonide in the treatment of persistent asthma. Vermeulen JH, Gyurkovits K, Rauer H, Engelstatter R. Randomized comparison of the efficacy and safety of ciclesonide and budesonide in adolescents with severe asthma. Controller medications for asthma 192 of 369 Final Update 1 Report Drug Effectiveness Review Project 62. Comparison of the efficacy and safety of ciclesonide 160 microg once daily vs. Bateman ED, Linnhof AE, Homik L, Freudensprung U, Smau L, Engelstatter R. Comparison of twice-daily inhaled ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma. Boulet LP, Bateman ED, Voves R, Muller T, Wolf S, Engelstatter R. A randomized study comparing ciclesonide and fluticasone propionate in patients with moderate persistent asthma. Comparable efficacy of ciclesonide once daily versus fluticasone propionate twice daily in asthma. Comparison of a step-down dose of once-daily ciclesonide with a continued dose of twice-daily fluticasone propionate in maintaining control of asthma. Magnussen H, Hofman J, Staneta P, Lawo JP, Hellwig M, Engelstatter R. Similar efficacy of ciclesonide once daily versus fluticasone propionate twice daily in patients with persistent asthma. Efficacy and safety of ciclesonide once daily and fluticasone propionate twice daily in children with asthma. Pedersen S, Garcia Garcia ML, Manjra A, Theron I, Engelstatter R. A comparative study of inhaled ciclesonide 160 microg/day and fluticasone propionate 176 microg/day in children with asthma. A 24-week comparison of low-dose ciclesonide and fluticasone propionate in mild to moderate asthma. Wardlaw A, Larivee P, Eller J, Cockcroft DW, Ghaly L, Harris AG. Efficacy and safety of mometasone furoate dry powder inhaler vs fluticasone propionate metered-dose inhaler in asthma subjects previously using fluticasone propionate. Effect of the two different leukotriene receptor antagonists, montelukast and zafirlukast, on quality of life: a 12- week randomized study. Campbell LM, Anderson TJ, Parashchak MR, Burke CM, Watson SA, Turbitt ML. A comparison of the efficacy of long-acting beta 2-agonists: eformoterol via Turbohaler and salmeterol via pressurized metered dose inhaler or Accuhaler, in mild to moderate asthmatics. Eformoterol Turbohaler compared with salmeterol by dry powder inhaler in asthmatic children not controlled on inhaled corticosteroids. A 6-month comparison between formoterol and salmeterol in patients with reversible obstructive airways disease. Cost-effectiveness analysis of formoterol versus salmeterol in patients with asthma. Controller medications for asthma 193 of 369 Final Update 1 Report Drug Effectiveness Review Project 77. Comparison of the efficacy of formoterol and salmeterol in patients with reversible obstructive airway disease: a multicenter, randomized, open-label trial. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. Omalizumab improves asthma-related quality of life in patients with severe allergic asthma. Lanier BQ, Corren J, Lumry W, Liu J, Fowler-Taylor A, Gupta N. Omalizumab is effective in the long-term control of severe allergic asthma. Efficacy and safety of a recombinant anti- immunoglobulin E antibody (omalizumab) in severe allergic asthma. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE.

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After a follow-up of 3 years purchase alli 60mg line, patients in the low-hematocrit group cheap alli 60mg mastercard, compared with 10. Therefore, the CYTO PV study reduced the risk of the combined primary end point of nonfatal strongly supports control of the hematocrit to at least 0. The use of low-dose aspirin also reduced the 24,25 reduction in thrombosis. There is no evidence to support a risk of the second combined end point to a statistically significant targeting the hematocrit 0. The incidence of major bleeding episodes was not related but unanswered dilemma that arises in clinical practice is significantly increased in the low-dose aspirin group (relative risk, whether to control the hematocrit of a patient with a diagnosis of ET 1. Interestingly, neither who has the JAK2V617F mutation and whose hematocrit is above overall mortality nor cardiovascular mortality was significantly 0. Masked PV should reduced; the trial was probably not adequately powered to address 13 certainly be excluded in these patients. In ET, the use of aspirin has never been addressed in distinction would include use of RBC mass, but because this test is a randomized controlled trial. Some studies, such as PT-1, included not widely available, other factors need to be considered. Such aspirin for all high-risk ET patients, whereas other more recent 15,16 additional factors would include: careful review of BM histology, studies, such as ANAHYDRET, did not. This reflects a di- replenishment of iron stores, review of erythropoietin level, and chotomy of opinion in the field. These include concerns that testing for endogenous erythroid colonies; sometimes, careful bleeding is a particular risk for patients with very high platelet observation until more obvious signs appear has to suffice. Regarding treatment targets, the European LeukemiaNet used a standard consensus approach to produce criteria for response; these For “low-risk” ET, a retrospective analysis from a group of Spanish criteria are designed primarily for clinical trials and also include investigators suggests variable benefits for low-dose aspirin. Interna- treated with antiplatelet drugs (mainly aspirin) as monotherapy tional practice varies widely, as demonstrated in the ongoing (n 198) or followed with careful observation (n 102). Fol- EXELS study with a recently published analysis of treatment low-up was 802 and 848 person-years for antiplatelet therapy and patterns for high-risk ET across Europe,27 and there are many strong observation, respectively. Rates of thrombotic events were not opinions regarding whether HU or IFN should be the treatment of different at 21. IFN and HU form a mainstay of therapy and there is an therapy and observation, respectively (P. Subgroup analyses ongoing increase in interest in IFN, especially pegylated forms with suggested that JAK2V617F-positive patients not receiving antiplate- disease-moderating effects. Pioneering studies with IFN were let medication showed an increased risk of venous thrombosis reported by Silver in 1988. Major bleeding was observed in patients with platelet when started at low doses. This targeting of the JAK2V617F-mutated clone by this agent. In the remaining low-risk tion of IFN from AOP pharma is also of interest in this context, with ET patients, aspirin does not appear to be effective for primary provisional results approximately equivalent to that for other prophylaxis of thrombosis and observation may be an adequate formulations of IFN. Recommendations for therapy in ET and PV PV ET All patients All patients Assess and manage for cardiovascular risk factors Treat with low-dose aspirin (unless contraindicated) and screen for disease-related symptoms High-risk patients* Venesection to target hematocrit 0. Two such trials are currently ments at weeks 24 and 144, respectively. Clinically meaningful ongoing internationally: MPD RC112, a phase 3 randomized study improvements in pruritus, night sweats, and bone pain were of HU versus Pegasys in newly diagnosed high-risk ET and PV, and observed within 4 weeks of the initiation of therapy and were PROUD-PV, a phase 3 study with AOP IFN in PV. It is absolutely maintained with continued treatment. Thrombocytopenia and ane- critical that the field addresses the relative superiority of IFN and mia were the most common adverse events, thrombocytopenia of HU by completing the phase 3 trials because they will inform the grade 3 or anemia of grade 3 occurred in 9% of patients each (1 relative benefits, efficacy, and toxicities of these medications. The phenomenon of HU resistance or intolerance is important and Two large phase 3 commercially sponsored studies of ruxolitinib identifies a group of ET and PV patients with a poor prognosis32 are fully recruited; the results of one (RESPONSE) were reported at who require a change of treatment and for whom novel therapies the recent American Society of Clinical Oncology (ASCO) and may be attractive. Options for management in the face of HU European Haematology Association (EHA) meetings. Ruxolitinib resistance would include adjusting therapeutic targets (eg, to a 9 was superior to best-available therapy for the composite primary platelet count of 600 10 /L) or to switch to an alternative agent end point of 35% spleen size reduction and freedom from venesec- either alone or in combination. This trial studied a highly selected group of patients who were when used with or succeeded by agents such as busulfan, will intolerant or resistant to HU yet had splenomegaly and still required significantly increase long-term risks of leukemia. A confounding aspect is that 50% of the control arm nonleukemogenic agents such as IFN or anagrelide are more was treated with HU, perhaps reflecting limited options for these appropriate in this setting. Most interesting was the reduction in thrombosis for ance are the group of ET and PV patients for whom novel therapies are currently being evaluated. Three important Impact of JAK inhibitors and other novel therapies safety concerns have arisen with regard to JAK inhibition: a There are data supporting the ability of some JAK inhibitors to “withdrawal syndrome,” neurological toxicity, and risk of infec- control myeloproliferation in patients with PV and ET. An early report suggested a risk of severe inflammatory beyond this, aspects that are uncertain include whether they prevent syndrome after ruxolitinib withdrawal and that these patients had a thrombosis and if they affect the probability of accelerated-phase 37 poor outcome.