Economic consequences of investing in anti-HCV antiviral treatment from the Italian NHS perspective : a real-world-based analysis of PITER data

OBJECTIVE: We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy. METHODS: A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered. RESULTS: The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively. CONCLUSIONS: This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV

Alnus glutinosa (L.) Gaertn. and Alnus cordata (Loisel) Duby as new sources of safe cosmetic and pharmacological anti-melanogenic agents

The genus Alnus (Betulaceae) comprises many species with a long history in traditional medicines. The crude extracts and isolated compounds from Alnus species exhibit a wide spectrum of in vitro and in vivo pharmacological activities (1). Phytochemical investigations revealed the presence of diarylheptanoids, a class of natural products typically found in Alnus genus with two aryl groups joined by a heptane chain in the main skeleton that have drawn attention due to their multiple biological properties and their therapeutic potential (2). A previous study reported that oregonin and other structurally analogous diarylheptanoids isolated from the bark of A. hirsuta showed inhibitory effects on melanogenesis in B16 melanoma cells.(3). Nowadays the discovery of new whitening agents from natural sources is increasing, due to the weak effectiveness and unwanted side effects of currently available compounds. In this context, the aim of this study was to evaluate the skin whitening capabilities of crude extracts (80% aqueous MeOH) obtained from the fresh bark of Alnus glutinosa (L.) Gaertn. and Alnus cordata (Loisel) Duby, an endemic species in the Mediterranean areas (4). As tyrosinase is the rate-limiting enzyme in melanin biosynthesis, the inhibitory effects of A. glutinosa and A. cordata extracts (AGE and ACE, respectively) on mushroom tyrosinase activity were preliminary evaluated. In addition, the anti-melanogenic ability of AGE and ACE was further investigated on the pigmentation of early stage zebrafish at 72 hours post fertilization (hpf) to find new skin whitening agents without cytotoxic concerns. Results of the enzymatic assay showed that ACE was capable to inhibit dose dependently L-DOPA oxidation catalyzed by tyrosinase (IC50 = 77.44 \ub1 0.54 \u3bcg/mL) as compared to the reference inhibitor kojic acid (2.24 \ub1 0.18 \u3bcg/mL). Unlike, AGE exhibited a lower anti-tyrosinase activity (100 \u3bcg/mL reached 28% of inhibition while higher doses showed pro-oxidative effects). Moreover, the zebrafish in vivo assay revealed that ACE (50 \u3bcg/mL) has equivalent inhibitory effects on the pigmentation (76.57%) to that of phenylthiourea (PTU, 30 \u3bcg/mL), used as the reference inhibitor (77.80%), as compared to control, while they did not affect the embryos development and survival. Conversely, the depigmenting effects of AGE were about 10 fold less than ACE (45.28% at 500 \u3bcg/mL). A mild anti-melanogenic activity was also evidenced for the diarylheptanoid oregonin (10% of inhibition at 20 \u3bcg/mL). A preliminary phytochemical screening evidenced that ACE and AGE have a high phenolic content (399.27 \ub1 14.30 and 534.17 \ub1 20.60 mg GAE/g of extract, respectively). However, despite AGE showed the highest phenolic content, the quali-quantitative RP-HPLC-DAD analysis highlighted as it is predominantly composed by oregonin (418.45 \u3bcg/mg of AGE vs 1.23 \u3bcg/mg of ACE) that exhibited a mild anti-melanogenic activity both in vitro and in vivo assays. Further phytochemical investigations are still in progress to identify the bioactive compounds of ACE as to be considered a potential candidate for the treatment of skin disorders due to its bleaching properties and favorable safety profiles

Body knowledge in brain-damaged children: a double-dissociation in self and other's body processing.

Bodies are important element for self-recognition. In this respect, in adults it has been recently shown a self vs other advantage when small parts of the subjects\u2019 body are visible. This advantage is lost following a right brain lesion underlying a role of the right hemisphere in self body-parts processing. In order to investigate the bodily-self processing in children and the development of its neuronal bases, 57 typically developing healthy subjects and 17 subjects with unilateral brain damage (5 right and 12 left sided), aged 4\u201317 years, were submitted to a matching-to-sample task. In this task, three stimuli vertically aligned were simultaneously presented at the centre of the computer screen. Subjects were required which of two stimuli (the upper or the lower one) matched the central target stimulus, half stimuli representing self and half stimuli representing other people\u2019s body-parts and face-parts. The results showed that corporeal self recognition is present since at least 4 years of age and that self and others\u2019 body parts processing are different and sustained by separate cerebral substrates. Indeed, a double dissociation was found: right brain damaged patients were impaired in self but not in other people\u2019s body parts, showing a self-disadvantage, whereas left brain damaged patients were impaired in others\u2019 but not in self body parts processing. Finally, since the double dissociation self/other was found for body-parts but not for face parts, the corporal self seems to be dissociated for body and face-parts. This opens the possibility of independent and lateralized functional modules for the processing of self and other body parts during development

IL CONTROLLO DEL DOLORE POST-OPERATORIO NELLA CHIRURGIA DELLA MALATTIA DI CROHN

Obiettivo. Scopo dello studio era il confronto delle principali metodiche antalgiche impiegate nel controllo del dolore postoperatorio, in pazienti con MC. Materiali e metodi. Lo studio, osservazionale e retrospettivo, \ue8 stato condotto su 133 pazienti affetti da Malattia di Crohn che, nel periodo compreso tra settembre 2011 e aprile 2012, sono stati trattati chirurgicamente presso i Reparti di Chirurgia Generale dei Professori G. Poggioli e M. Taffurelli e sono stati seguiti, nel decorso post-operatorio, dal Servizio di Terapia del Dolore acuto Peri-Operatorio dell\u2019Unit\ue0 Operativa di Anestesiologia e Terapia Intensiva (Direttore Prof. G.F. Di Nino). La valutazione del dolore \ue8 stata effettuata mediante l\u2019utilizzo della NRS, esaminando i pazienti tre volte al giorno in condizioni statiche e dinamiche. Le variabili indagate, oltre all\u2019intensit\ue0 del dolore, comprendevano anche il Protocollo di terapia antalgica applicata. Risultati. Tra gli N=133 pazienti inseriti nello studio, il 48,1% (n=64) era di sesso maschile e il 51,9% (n=69) di sesso femminile; l\u2019et\ue0 media era 38,2 ( \ub1 13,8). La maggioranza del campione (n=60) \ue8 stata trattata nelle prime 48h post-operatorie mediante somministrazione di analgesico endovenoso tramite pompa PCA (Protocollo C), oltre un terzo \ue8 stato trattato con analgesia endovenosa continua mediante elastomero (n=48, Protocollo B), n=20 pazienti sono stati trattati con analgesia peridurale (Protocollo D) e n=5 con analgesici endovenosi ad orari fissi (Protocollo A). Analizzando l\u2019andamento del dolore in condizioni statiche, la mediana dell\u2019NRSs era superiore in tutte le rilevazioni per i pazienti trattati con Protocollo D. Alla 16a e 40a ora post-operatoria l\u2019analgesia con Protocollo D era meno efficace sia rispetto al Protocollo B (p=0,04) sia al Protocollo C (p=0,011 e p=0,03); alla 24a ora l\u2019analgesia peridurale era meno efficace rispetto alla PCA (p=0,03) ma non rispetto all\u2019elastomero (p=0,07). Infine all\u20198a ora post-operatoria il trattamento con PCA era superiore rispetto ad entrambe le metodiche. L\u2019andamento della mediana dell\u2019NRSd risultava essere superiore in tutte le rilevazioni nei pazienti trattati con Protocollo D. Alla 8a, 24a, 32a e 40a ora, il trattamento con Protocollo D era meno efficace rispetto alla PCA (p<0,02); alla 16a e 48a ora l\u2019analgesia peridurale era meno efficace sia rispetto alla PCA che rispetto all\u2019elastomero endovenoso. Discussione e conclusioni. Il dolore post-operatorio nei pazienti con MC pu\uf2 essere complesso e di difficile gestione1. Nel nostro studio l\u2019analgesia con PCA era la metodica pi\uf9 efficace nel controllo del dolore post-operatorio, permettendo un\u2019analgesia di base mediante l\u2019infusione continua del farmaco e consentendo al paziente di autosomministrarsi un bolo aggiuntivo in caso di persistenza del dolore. Forniva inoltre al paziente un controllo sulla propria malattia, rafforzando il suo \u201cinternal pain locus of control\u201d. L\u2019analgesia endovenosa continua mediante elastomero era sovrapponibile alla PCA nel controllo del dolore post-operatorio. L\u2019analgesia peridurale era meno efficace rispetto alle precedenti metodiche analizzate. \uc8 plausibile che la limitata efficacia antalgica sia legata all\u2019estensione del taglio chirurgico, non compatibile con l\u2019analgesia locoregionale. Bibliografia 1. Cameron CA, Sawatzky JA. Postoperative pain management: the challenges of the patient with Crohn\u2019s disease. Medsurg Nurs 2008;17:85-91

Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution

Purpose: Autoimmune diseases are typically associated with immune checkpoints blockade. This study aims at assessing, in real-life clinical practice, the prevalence and impact of thyroid disorders induced by immune checkpoint inhibitors. Methods: 52 patients (30 F; age 61 \uc2\ub1 13 years) with advanced melanoma treated with ipilimumab (3 mg/kg i.v./3 weeks; 4 doses) were included. For disease progression, 29 (16 F) of them received nivolumab (3 mg/kg i.v./2 weeks) or pembrolizumab (2 mg/kg i.v./3 weeks). Thyroid function and autoimmunity were assessed before, after 6 weeks, at the end of ipilimumab, as well as before and every 3 months during nivolumab/pembrolizumab treatment. Results: During ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1 associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7 patients (3 F) developed hypothyroidism with severe manifestations in 6 of them; 3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean follow-up after anti-CTLA4 inhibitors treatment was 36 \uc2\ub1 28 months. Thyroid disorders occurred 45.1 \uc2\ub1 20.8 and 151 \uc2\ub1 67 days after the initiation of CTLA4 and PD1 inhibitors, respectively. Autoimmune disorders and BRAF mutation were associated with a better clinical response to CTLA4 followed by PD1 treatment. Conclusions: Immune checkpoint blockade is burdened by a high incidence of autoimmune thyroid dysfunction, which is often severe. Therefore, early and careful monitoring and, eventually, treatment are crucial to prevent the negative impact of thyroid dysfunction on the clinical outcome

Treatment of pain in Postherpetic neuralgia

Introduction: Postherpetic neuralgia (PHN) is a relevant issue both for patients and physicians. Severe neuropathic pain is a constant element of this condition along with a remarkable deterioration of patient\u2019s quality of life1. Aims: To retrospectively analyse our practice for PHN in order to evaluate its efficacy and to compare our outcomes with those reported in the literature. Materials and Methods : We analyzed N=151 consecutive patients with PHN in our outpatient pain centre. The investigated variables were: topographical location of PHN, clinical signs and symptoms, analgesic therapy, pain intensity and interference with daily activities and quality of life. Data was retrieved from BPI questionnaires routinely filled at each visit and stored at patients\u2019 charts. Results: Main topographical location were the back and the chest (39,9%). The most frequent symptoms were pain associated with paresthesias (78,1%) and mechanical allodynia (52,3%); thermal allodynia was less frequent (19,2%). Before the first visit, most frequently drugs used were anticonvulsants, weak opioids (tramadol) and NSAIDS which weren\u2019t adequate for pain control. During patients\u2019 first visit the prescription dose of anticonvulsants (gabapentin or pregabalin) was improved, and major opioids (oxycodone), triciclic antidepressants and vitamin B complex were introduced. NSAIDS were held off. With the new treatment, pain intensity was reduced in most patients. The interference with the daily activities was reduced and the quality of life improved. Discussion and Conclusion note: The prevalence of PHN topographical location and symptoms in our practice is in accordance with the literature1. PHN\u2019s pain is often underestimated at the primary care level2 and thus lead to inconclusive treatments. According to international guide-lines3, therapy must be based on the use of strong opioids, anticonvulsants and triciclic antidepressants with generous doses. There is no pathophysiological reason to use NSAIDS. Though patients\u2019 management is not simple, it does require constant clinical control and frequent quantitative and qualitative changes in therapy. Key words: PHN, Neuropathic Pain. Bibliography Kost RG, Straus SE. Postherpetic neuralgia--pathogenesis, treatment, and prevention. N.Engl.J.Med. 1996;335:32-42 1. Alper BS, Lewis PR. Treatment of postherpetic neuralgia: a systematic review of the literature. J.Fam.Pract. 2002;51:121-82. Dubinsky, R.M. et al. Practice parameter: treatment of Postherpetic Neuralgia: an evidence-based report of the Quality Standard Subcommittee of the American Academy of Neurology\u201d. Neurology 63.6 2004; 959-653