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Introduction: Multiple sclerosis (MS) is a highly symptomatic disease, with a wide range of disabilities affecting many bodily functions, even in younger persons with a short disease history. The availability of a cannabinoid oromucosal spray (Sativex) for the management of treatment-resistant MS spasticity has provided a new opportunity for many patients. Objective: Our study aimed to assess the cost effectiveness of Sativex in Italian patients with treatment-resistant MS spasticity. The analysis was based on the real-world data of a large registry of Italian patients. Methods: A cost-utility analysis was conducted using data collected prospectively from an electronic registry of all patients who began to use Sativex for MS-resistant spasticity between January 2014 and February 2015 in 30 specialized MS units across Italy and were followed up for ≤ 6months. Data on drug consumption and spasticity/utility were used to estimate the incremental cost-effectiveness ratio (ICER) of Sativex, as compared with no intervention. No costs or spasticity/utility changes were assumed for no treatment intervention. The ICER was expressed as quality-adjusted life-years (QALYs) gained, using the Italian NHS perspective and a 6-month time horizon. Results: Sativex effectiveness and consumption was estimated analyzing data of 1350 patients from the registry. These patients reported a mean (SD) utility increment of 0.087 (0.069) after 1month of treatment, 0.118 (0.073) after 3months’ treatment and 0.127 (0.080) after 6months’ treatment. The 6-month cost of treating the entire population with Sativex was €1,361,266, with a €1008 cost and 0.0284 QALYs gained per patient. The estimated ICER was €35,516 per QALY gained, with little variability around the central estimate of cost-effectiveness, as shown by the cost-effectiveness acceptability curve. Conclusion: The use of Sativex could improve the quality of life of patients with a reasonable incremental cost resulting as a cost-effective option for patients with MS-resistant spasticity. These results could help clinicians and decision makers to develop improved management strategies for spasticity in patients with MS, optimizing the use of available resources.

Background: Spasticity is a frequent multifactorial manifestation of multiple sclerosis (MS), affecting mostly the chronic courses of the disease. Its impact on patient functioning and quality of life is profound. Treatment of spasticity includes oral and intrathecal anti-spastic drugs, muscle injections with relaxant agents, physical therapy, electrical and magnetic stimulation and peripheral nerve stimulation, alone or in various combinations. Methods: This Italian consensus on the treatment of spasticity in MS was produced by a large group of Italian MS experts in collaboration with neurophysiologists, experts in the production of guidelines and patients’ representatives operating under the umbrella of the Italian Neurological Society, the Associazione Italiana Sclerosi Multipla and the European Charcot Foundation. This guideline was developed in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A total of 11 questions were formulated following the PICO framework (patients, intervention, comparator, outcome). Controlled studies only were included in the analysis. Results: Despite some consistent limitations due to the poor methodological quality of most studies, there was a consensus on a strong recommendation for the use of intrathecal baclofen, oromucosal spray of nabiximols and intramuscular injection of botulinum toxin. The level of recommendation was weak for oral baclofen, tizanidine, gabapentin, benzodiazepines and transcranial magnetic stimulation. Conclusions: There is a clear need for new larger multicentre well-designed clinical trials with a duration that allows the persistence of the effects and the long-term safety of the interventions to be evaluated.

Green plants (Viridiplantae) include around 450,000–500,000 species1,2 of great diversity and have important roles in terrestrial and aquatic ecosystems. Here, as part of the One Thousand Plant Transcriptomes Initiative, we sequenced the vegetative transcriptomes of 1,124 species that span the diversity of plants in a broad sense (Archaeplastida), including green plants (Viridiplantae), glaucophytes (Glaucophyta) and red algae (Rhodophyta). Our analysis provides a robust phylogenomic framework for examining the evolution of green plants. Most inferred species relationships are well supported across multiple species tree and supermatrix analyses, but discordance among plastid and nuclear gene trees at a few important nodes highlights the complexity of plant genome evolution, including polyploidy, periods of rapid speciation, and extinction. Incomplete sorting of ancestral variation, polyploidization and massive expansions of gene families punctuate the evolutionary history of green plants. Notably, we find that large expansions of gene families preceded the origins of green plants, land plants and vascular plants, whereas whole-genome duplications are inferred to have occurred repeatedly throughout the evolution of flowering plants and ferns. The increasing availability of high-quality plant genome sequences and advances in functional genomics are enabling research on genome evolution across the green tree of life., The One Thousand Plant Transcriptomes Initiative provides a robust phylogenomic framework for examining green plant evolution that comprises the transcriptomes and genomes of diverse species of green plants.

Background The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. Methods We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0–10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. Results A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3–2.4 p

Objective:To examine retrospectively the effects of plasmapheresis (PLEX) on the survival and clinical outcomes of patients with multiple sclerosis (MS) and natalizumab (NTZ)–associated progressive multifocal leukoencephalopathy (PML).Methods:The medical literature was searched for the terms natalizumab and progressive multifocal leukoencephalopathy. A total of 193 international and 34 Italian NTZ-PML cases were included. Clinical outcome was determined by comparing the patients' clinical status at PML diagnosis with status after PML resolution. The effects on survival and clinical outcome of PLEX, sex, age, country, pre-PML Expanded Disability Status Scale score, NTZ infusion number, prior immunosuppressant exposure, PML symptoms, PML lesion location at diagnosis, CSF JC virus status and copies, additional PML treatments and steroids, and PML immune reconstitution inflammatory syndrome (IRIS) development were investigated with both univariate and multivariate analyses.Results:A total of 219 NTZ-PML cases were analyzed, and 184 (84%) underwent PLEX, which did not reduce the mortality risk or the likelihood of poor vs favorable outcomes. Country was predictive of mortality and poor outcome, while PML-IRIS development was predictive of poor outcome.Conclusions:PLEX did not improve the survival or clinical outcomes of Italian or international patients with MS and NTZ-PML, suggesting that this treatment should be performed cautiously in the future.Classification of evidence:This study provides Class III evidence that for patients with NTZ-PML, PLEX does not improve survival. The study lacks the statistical precision to exclude an important benefit or harm of PLEX.

Giuseppe Sommaruga è incline a quel senso dell’iperbolico, sovente ottenuto anche per contrasti dimensionali e studiati “fuori scala” pur in organismi contratti, che procede dalla semplificazione dei formulari storicisti fino al loro disinvolto accorpamento e all’omologazione figurale, con alquanti contrappunti ed eterodosse soluzioni di continuità, verso una visione monumentale persuasiva ma esente da enfasi didascaliche e, nel divenire, sempre più ruvida e arcaicizzante. Anzi l’iperbolico è, in fin dei conti, il “filo rosso” dei suoi modi architettonici fin dalla prima stagione eclettica, dal progetto per il Concorso del Parlamento del Regno d’Italia a quello per l’Ossario di Palestro, dai progetti per i concorsi dei palazzi istituzionali a Buenos Aires e a Montevideo a quelli per i cimiteri di Bergamo e di Mantova, dallo Chalet Theobroma all’Esposizione Nazionale d’Igiene di Milano del 1891 al complesso per le Esposizioni Riunite di Milano del 1894. Sempre l’iperbolico, che per soli contrasti affiora persino nella sua produzione professionale più convenzionale (in particolare quella compresa fra il 1895, a seguito del successo per il complesso delle Esposizioni Riunite, e il 1901 anno della svolta di Palazzo Castiglioni) , ne avrebbe, poi, sostanziato l’operare modernista, distinguendolo nel panorama italiano e proiettandone la poetica ben oltre la prevedibile influenza su altri progettisti del periodo Liberty (che anzi ne recepiscono in maniera squisitamente esornativa il messaggio, a differenza di personalità come Arata o, verosimilmente, come Sant’Elia). L’iperbolico compare come componente subliminale nel Palazzo Castiglioni (materico “non finito” e contaminazioni figurali nei prospetti e nelle finiture, anche polimateriche, e manipolazione della citazione garnieriana per lo scalone-fuclro); compare ancora quale additivo di contrasto nella strumentazione formale nel Palazzo Viviani-Giberti a Trieste del 1906-1907 o per caratterizzazione di contrappunto nelle milanesi redesidenze Comi del 1906, Salmoiraghi del 1906, Galimberti del 1908, Faccanoni (poi Romeo) del 1912-1914 e nelle ville Galimberti a Stresa del 1906 e Carosio a Baveno del 1908-1909. È con le opere per i Faccanoni a Sarnico (dal 1907 al 1912) che Sommaruga, oltre a sublimare quella mitologia peculiare delle società più evolute del modernismo europeo consistente nel binomio fra ethos del progettista animato da slanci liberatori e proiezione della committenza verso modi e segni di un ideale meliorista di progresso sentito come missione totalizzante (formula che in Italia ha pochi altri casi simili e fra questi il precedente dei Florio con Basile in una Palermo ancora, fino al 1910, rilevante quale polo economico e città con una società egemone cosmopolita), riformula i modi della sua progettazione fino ad allora solamente supportati dalla vocazione iperbolica; essa ora non è più uno strumento gregario del fare architettonico, non interviene più come qualificante correttivo, ma assume il ruolo di valenza della stessa logica progettuale contribuendo, anche dall’inibito contesto italiano, al superamento di quel “falso problema” della ricerca di nuovi codici architettonici che era stato l’innesco e, al tempo stesso, il limite della volontà di generale “riorganizzazione del visibile” propria dell’Art Nouveau.