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To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up.
Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo.
Community settings and care homes in 26 UK centers.
People with probable or possible Alzheimer’s disease and agitation.
Primary outcome included incremental cost of participants’ health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants’ and unpaid carers’ gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives.
One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment.
On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.
Only a limited number of patients with major depressive disorder (MDD) respond to a first course of antidepressant medication (ADM). We investigated the feasibility of creating a baseline model to determine which of these would be among patients beginning ADM treatment in the US Veterans Health Administration (VHA).
A 2018–2020 national sample of n = 660 VHA patients receiving ADM treatment for MDD completed an extensive baseline self-report assessment near the beginning of treatment and a 3-month self-report follow-up assessment. Using baseline self-report data along with administrative and geospatial data, an ensemble machine learning method was used to develop a model for 3-month treatment response defined by the Quick Inventory of Depression Symptomatology Self-Report and a modified Sheehan Disability Scale. The model was developed in a 70% training sample and tested in the remaining 30% test sample.
In total, 35.7% of patients responded to treatment. The prediction model had an area under the ROC curve (s.e.) of 0.66 (0.04) in the test sample. A strong gradient in probability (s.e.) of treatment response was found across three subsamples of the test sample using training sample thresholds for high [45.6% (5.5)], intermediate [34.5% (7.6)], and low [11.1% (4.9)] probabilities of response. Baseline symptom severity, comorbidity, treatment characteristics (expectations, history, and aspects of current treatment), and protective/resilience factors were the most important predictors.
Although these results are promising, parallel models to predict response to alternative treatments based on data collected before initiating treatment would be needed for such models to help guide treatment selection.
Fewer than half of patients with major depressive disorder (MDD) respond to psychotherapy. Pre-emptively informing patients of their likelihood of responding could be useful as part of a patient-centered treatment decision-support plan.
This prospective observational study examined a national sample of 807 patients beginning psychotherapy for MDD at the Veterans Health Administration. Patients completed a self-report survey at baseline and 3-months follow-up (data collected 2018–2020). We developed a machine learning (ML) model to predict psychotherapy response at 3 months using baseline survey, administrative, and geospatial variables in a 70% training sample. Model performance was then evaluated in the 30% test sample.
32.0% of patients responded to treatment after 3 months. The best ML model had an AUC (SE) of 0.652 (0.038) in the test sample. Among the one-third of patients ranked by the model as most likely to respond, 50.0% in the test sample responded to psychotherapy. In comparison, among the remaining two-thirds of patients, <25% responded to psychotherapy. The model selected 43 predictors, of which nearly all were self-report variables.
Patients with MDD could pre-emptively be informed of their likelihood of responding to psychotherapy using a prediction tool based on self-report data. This tool could meaningfully help patients and providers in shared decision-making, although parallel information about the likelihood of responding to alternative treatments would be needed to inform decision-making across multiple treatments.
In 2006 the Bodleian Library acquired, thanks to the generosity of the Friends of the Bodleian, an autograph score of William Croft's concerted Latin ode ‘Laurus cruentas’ (1713). Croft set to music two texts by Oxford's first Professor of Poetry, Joseph Trapp (1679–1747) – one Latin, the other English – in celebration of the Peace of Utrecht; the Duke of Ormonde (chancellor of the university) duly recommended the composer for a doctorate, which was conferred on Monday 13 July at the end of a long weekend of celebrations.
The manuscript (GB-Ob, MS Mus. d.271) preserves the only surviving extensive autograph material for Croft's Utrecht music. No autograph score remains for the longer English ode, ‘With noise of cannon’, though we do have the remarkable score (US-Su, MS M782.8 C874t) copied by Croft's thirteen-yearold apprentice James Kent for presentation to John Dolben, and also the later engraved publication Musicus apparatus academicus (hereafter MAA) of 1720, both of which also contain the Latin ode. Thus Mus. d.271 offers a unique window onto Croft's creative processes in his secular vocal music, of which it is indeed the most significant surviving autograph. The manuscript reveals that, despite his overwhelming concentration on sacred music over his almost thirty-year career, Croft was intimately familiar with the creative strategies adopted by his teacher John Blow and other composers of secular music for the court and public performance, including royal welcome songs and new year and birthday odes as well as the closely related Cecilian odes such as Purcell's ‘Hail, bright Cecilia’ (1692).
If Croft's preservation of these methods reveals his indebtedness to his seventeenth-century predecessors, his pioneering production of prestigious retrospective compendia of his compositions, neatly engraved in score – most famously in the two volumes of Musica sacra (published by Walsh, 1724) – set a pattern for the proliferation of printed anthem collections by English musicians throughout the remainder of the century and into the next. Indeed, this applied equally – thanks to the views expressed in his preface, which amounts in part to a manifesto for the preservation of English sacred music in printed score – to the emergence slightly later of monumental collections of English sacred music extending back to the Reformation, chief among them William Boyce's Cathedral Music (vol. 1, 1760).
OBJECTIVES/GOALS: Our preclinical data demonstrate that the principal effects of nilotinib, a multi-tyrosine kinase inhibitor, in models of neurodegeneration is clearance of misfolded proteins via autophagy. Here we aimed to evaluate the effects of nilotinib on microRNAs in the cerebrospinal fluid of Parkinson’s disease patients. METHODS/STUDY POPULATION: Cerebrospinal fluid (CSF) was collected as part of an open label phase I (NCT02281474) (n = 12, 300 mg nilotinib taken orally once daily for 6 months), and a phase II randomized, double-blind, placebo-controlled study (NCT02954978) (n = 75, randomized 1:1:1 into placebo, 150 mg or 300 mg nilotinib taken orally once daily for 12 months). RNA was isolated from CSF and Indexed sequencing libraries were prepared from total RNA plus miRNA. Next generation whole-genome sequencing (single-end 1x75 bp, 25 million raw reads per sample) was performed to identify miRNAs significantly differentially expressed (fold-change ≥ 2, Benjamini-Hochberg FDR p-value ≤ 0.05 or Empirical Bayes FDR ≤ 0.05) with treatment compared to baseline. RESULTS/ANTICIPATED RESULTS: Next generation whole-genome sequencing of microRNAs in the CSF demonstrated that nilotinib significantly increases microRNAs that specifically regulate expression of autophagy and ubiquitination genes in individuals with Parkinson’s disease. In the open label phase I, samples, 28 microRNAs found to regulate autophagy and ubiquitination genes, were significantly altered with treatment (Benjamini-Hochberg FDR p-value ≤ 0.05). In the phase II randomized, double-blind, placebo-controlled study samples, we verified several of those 28 candidate microRNAs had been significantly deferentially expressed with treatment (Empirical Bayes FDR p-value ≤ 0.05). DISCUSSION/SIGNIFICANCE OF IMPACT: Our data provide robust evidence that nilotinib’s effects on misfolded protein clearance is via autophagy and CSF miRNA sequencing is a valid biomarker of nilotinib’s effects in a definitive phase III study to investigate nilotinib in Parkinson’s and other neurodegenerative diseases. CONFLICT OF INTEREST DESCRIPTION: Charbel Moussa is listed as an inventor on several Georgetown University patents for the use of tyrosine kinase inhibitors as a treatment for neurodegenerative diseases
It has frequently been observed that the techniques that Purcell employed in his trio sonatas found a new outlet in his orchestral symphonies and overtures of the 1690s. Giovanni Battista Draghi’s 1687 Cecilian ode had shown how a large-scale work could begin with an Italianate orchestral sinfonia rather than the more conventional English take on the French overture, and in their odes and theatre music of the 1690s Purcell and Blow embraced this feature with enthusiasm. What is not often acknowledged is that, Draghi’s example aside, Purcell was effectively forced to invent this genre for himself, adapting the chamber sonata to the larger orchestral resources available at performances of court odes and in the theatre.
What was Purcell aiming to do when he wrote his Chaconne for two flutes in Act III of The Prophetess, or the History of Dioclesian (1690; see facing page)? Such questions are not always easy to answer, but in this particular case there are strong grounds for optimism. Even without the informative heading, it is quickly obvious how the piece is constructed. Neither the repetitive ground bass nor the canon at the unison between the recorder parts could plausibly have arisen fortuitously, so at least in the context of compositional technique we can disregard many of the usual caveats about intention: in this work, Purcell was seeking to compose a canon ‘Two in one upon a Ground’, with the second recorder following the first, two bars later, at the unison.
In recent years, the cultural background to Purcell’s interest in the trio sonata has become much better understood and far more accessible. Apart from the perennial issue of his likely Italian models, we now recognize a body of ‘Restoration Trio Sonatas’, including works both by English composers (notably John Blow) and by Europeans active in London (among them Giovanni Battista Draghi and the elder Nicola Matteis). The example of Robert King’s ‘Sonetta after the Italion Way’ apparently composed around 1680, even sits alongside Purcell’s sonatas as an example of an explicitly acknowledged attempt to emulate Italian stylistic features.
Having laid out in Part I some of the ways in which Purcell’s instrumental music can be better understood through a historically sensitive approach to analysis, learning from contemporary theoretical discussions – both their contents and their omissions – I turn in Part II of this study to a broader consideration of what the same methods can reveal about some of the best known of the composer’s later works, while at the same time developing tools where necessary to explain the phenomena to be found there.
Some of the most conspicuous moments of artifice in Purcell’s vocal music of the 1690s arise from the deployment of contrapuntal augmentation, or ‘fugeing per augmentation’ as Purcell calls it in ‘The Art of Descant’. This chapter examines this phenomenon largely by delving again into the case of transformative self-borrowing identified at the start of Chapter 6: the relationship between the setting of ‘World without end’ in the orchestral Jubilate of 1694 and its antecedent – in terms of materials and contrapuntal treatment – in the last section of Fantazia XI. The technical resources necessary to devise such sustained passages of imitation per augmentation are worthy of consideration in their own right, and provide a fresh avenue for inquiry into Purcell’s compositional choices.
At the climax of his last great choral work, the orchestral Te Deum and Jubilate in D major for the St Cecilia’s Day celebrations of 1694, Purcell dusted off a contrapuntal motif familiar from the end of his much earlier Fantazia XII (Ex. 6.1). Moreover, he also used exactly the same compositional conceit in his working of this motif – no doubt, in fact, his very choice of materials was motivated by the desire to select an idea suitable for subjection to the extreme contrapuntal augmentation of bars 201–8, an illustration of the words ‘world without end’.
One way we can get at the kinds of creative strategies Purcell employed in his most contrapuntally intricate music is to examine it alongside contemporary theoretical writings, including his own. This chapter, then, is principally concerned with the establishment of a methodological basis for the analysis that follows later. This basis is unfolded in three parallel strands: the examination of theoretical texts by Purcell and his immediate contemporaries, the situation of these within the wider context of Restoration cultural discourse, and the analysis of Purcell’s music in the light of the insights gained from both. It culminates in a more detailed study of the first part of one of Purcell’s most accomplished fantazias, with the aim of recovering the composer’s working methods through a careful analysis of his use of counterpoint, or fugeing, as he called it in ‘The Art of Descant’.