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logistical challenges, including: settling on the type of HPV screening test to be used; ascertaining appropriate screening ages and intervals; defining triage and management policies for HPV-positive women; and ensuring quality of and adherence to revised policies.

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Sandra D Isidean, *Eduardo L Franco Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada H3A 1A2; and Department of Oncology, McGill University, Montreal, QC, Canada H2W 1S6 [email protected] ELF has served as a consultant or advisory board member for companies involved in HPV vaccination (Merck, GlaxoSmithKline), HPV diagnostics (Roche, Qiagen, Gen-Probe), and cytology (Cytyc, Ikonisys). McGill University has received grants from Merck to support investigator-initiated research by ELF. SDI declares that she has no conflicts of interest. 1

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Arbyn M, Ronco G, Anttila A, et al. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine 2012; 30 (suppl 5): F88–99. Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screening for cervical cancer in rural India. N Engl J Med 2009; 360: 1385–94. Canadian Task Force on Preventive Health Care. Recommendations on screening for cervical cancer. CMAJ 2013; 185: 35–45.

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Arbyn M, Anttila A, Jordan J, et al. European guidelines for quality assurance in cervical cancer screening: 2nd edn—summary document. Ann Oncol 2010; 21: 448–58. Ronco G, Dillner J, Elfström KM, et al, and the International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2013; published online Nov 3. http://dx.doi.org/10.1016/S01406736(13)62218-7. Naucler P, Ryd W, Tornberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 2007; 357: 1589–97. Bulkmans NWJ, Berkhof J, Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007; 370: 1764–72. Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol 2012; 13: 78–88. Kitchener HC, Almonte M, Thomson C, et al. HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial. Lancet Oncol 2009; 10: 672–82. Ronco G, Giorgi-Rossi P, Carozzi F, et al, and the New Technologies for Cervical Cancer screening (NTCC) Working Group. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol 2010; 11: 249–57. Franco EL, Mahmud SM, Tota J, Ferenczy A, Coutlee F. The expected impact of HPV vaccination on the accuracy of cervical cancer screening: the need for a paradigm change. Arch Med Res 2009; 40: 478–85.

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Pimavanserin as treatment for Parkinson’s disease psychosis

Published Online November 1, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62157-1 See Articles page 533

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Parkinson’s disease psychosis is common and causes substantial caregiver burden, resulting in a high rate of visits to emergency rooms and admission to nursing homes. The symptoms typically consist of illusions, hallucinations, and more bothersome and distressing paranoid delusions.1 Management includes exclusion of medical causes of delirium (especially infection), modification of drug treatment that might be the trigger of psychosis, and use of specific antipsychotic drugs. Notably, treatment of patients with Parkinson’s disease with classic dopamine antagonists is not recommended because of a propensity to worsen Parkinson’s disease motor symptoms; moreover, this drug class can be life-threatening in individuals with associated dementia (eg, Lewy body dementia). Present reviews of evidence-based medicine suggest that low doses of the atypical antipsychotic clozapine can provide benefit without worsening of Parkinson’s disease motor symptoms.2 However, concerns remain about use of antipsychotics in this susceptible population3 and clozapine use requires mandatory blood monitoring. The alternative atypical antipsychotic quetiapine is more widely used because of its ease of use, but this drug has

no convincing support for efficacy from randomised controlled trials.2 In The Lancet, Jeffrey Cummings and colleagues4 present a randomised, double-blind, placebocontrolled trial showing benefit and safety of the nondopaminergic drug pimavanserin for the treatment of psychosis in patients with Parkinson’s disease. Pimavanserin might offer an alternative therapy for patients with Parkinson’s disease psychosis without worsening motor symptoms. Pimavanserin is a 5-HT2A receptor inverse agonist.5 5-HT2A receptors are constitutively active, in that they are active even in the absence of the agonist 5-HT and an inverse agonist is able to inhibit such a receptor more effectively than is an antagonist. Atypical antipsychotics are 5-HT2A inverse agonists and this property was targeted in high throughput drug discovery screens, which led to the development of pimavanserin.6 Pimavanserin has highest affinity for 5-HT2A receptors, with a lower affinity for the 5-HT2C receptor and, notably, negligible binding at dopamine D2 or histamine receptors.5 Thus the pharmacological profile predicts better efficacy without motor or sedative side-effects. www.thelancet.com Vol 383 February 8, 2014

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The study4 enrolled 199 patients with Parkinson’s disease (mean age 72 years); overall Parkinson’s disease duration was not stated but all participants had a unified Parkinson’s disease rating scale part III (UPDRS-III) score of more than 30, suggesting moderately advanced disease. Psychosis was present for nearly 3 years and was of mild-to-moderate severity according to the neuropsychiatric inventory (NPI). 15–19% of participants reported previous use of quetiapine or clozapine and about a third were on a cholinesterase inhibitor. Enrolled participants were randomly allocated to pimavanserin or placebo for 6 weeks. The study showed a significant benefit of pimavanserin on all endpoints, including reduced scale for assessment of positive symptoms in Parkinson’s disease (SAPS-PD) scores, clinical global impression of change scores, improved night-time sleep without daytime somnolence, and reduced caregiver burden. Importantly, no worsening of Parkinson’s disease motor symptoms occurred. No differences in outcomes were noted when participants were analysed according to age (75 years) or minimental state examination scores (

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