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Valentina Perrone,1 Dario Cattaneo,1 Sonia Radice,1 Diego Sangiorgi,2 Augusto B Federici,3 Maria Rita Gismondo,4 Massimo Medaglia,5 Valeria Micheli,4 Stefania Vimercati,5 Enza Pallone,6 Luca Degli Esposti,2 Emilio Clementi1,71Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, L Sacco University Hospital, University of Milan, Milan, 2CliCon Srl, Health, Economics and Outcomes Research, Ravenna, 3Hematology and Transfusion Medicine, Department of Clinical Sciences and Community Health, 4Clinical Microbiology Virology and Diagnosis of Bioemergency, 5Pharmaceutical Department, 6Quality Clinical Risk and Accreditation Unit, L Sacco University Hospital, Milan, 7Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, ItalyBackground: Highly active antiretroviral therapy (HAART) has reduced morbidity and mortality in patients infected with human immunodeficiency virus (HIV). Studies have documented high interindividual variability in the pharmacokinetics of antiretroviral drugs, which may impair the success of HAART if not managed properly. Therapeutic drug monitoring (TDM) is a useful diagnostic tool that helps clinicians to optimize drug doses so that drug concentrations associated with the highest therapeutic efficacy are obtained with a reduced risk of concentration-dependent adverse effects. The aim of this study was to assess whether use of TDM improves clinical outcomes and cost of illness.Methods: A retrospective cohort study was conducted at L Sacco University Hospital in Milan, Italy, in HIV-infected patients aged ≥18 years with at least one prescription of antiretroviral drugs for which TDM was applied. The inclusion period was from January 2010 to December 2011, with a follow-up period of up to 12 months. Laboratory and administrative databases were analyzed and matched with each other.Results: The cohort consisted of 5,347 patients (3,861 males and 1,486 females) of mean age 43.9±12.5 years. We found that TDM had been used in 143 of these patients, among whom adherence with therapy was significantly higher than among those in whom TDM had not been used (94% versus 78%). In TDM-controlled patients, the mean length of HIV-related hospitalization stay and mean cost of hospitalization were significantly reduced with respect to those observed in the group in which TDM had not been used (7.21 days versus 29.47 days and €293 versus €688, respectively).Conclusion: Inclusion of TDM as part of routine clinical optimization of drug dosing in HIV-infected patients is associated with higher adherence to therapy, reduced length of hospitalization stay, and reduced cost of illness.Keywords: human immunodeficiency virus, therapeutic drug monitoring, health care costs

Giorgio L Colombo,1,2 Sergio Di Matteo,2 Andrea Antinori,3 Massimo Medaglia,4 Silvia Murachelli,3 Giuliano Rizzardini51Department of Drug Sciences, University of Pavia, Pavia, Italy; 2SAVE – Studi Analisi Valutazioni Economiche, Milan, Italy; 3National Institute for Infectious Diseases L Spallanzani, IRCCS, Rome, Italy; 4Pharmaceutical Department, L. Sacco Hospital, Milan, Italy; 5First Division of Infectious Disease, L. Sacco Hospital, Milan, Italy Introduction: Highly active antiretroviral therapy (HAART) has allowed many HIV-infected patients to enjoy longer survival and a better quality of life. We performed an economic analysis to estimate the cost-effectiveness of HAART regimens in Italy for managing HIV-naïve infected patients with a viral load below 100,000 copies/mL.Patients and methods: The population considered in the model consisted of adult subjects with an HIV viral load below 100,000 copies/mL who received antiretroviral HAART treatment for the first time, according to the Italian National Guidelines with recommendation grade A1. The incremental cost-effectiveness analysis of quality-adjusted life years (QALYs) was carried out by means of a Markov model. Both the outcomes (QALYs) and the costs were discounted by 3.5%. The time horizon adopted in the model was 10 years. The point of view of the analysis was that of the Italian national health service.Results: The tenofovir (TDF)/emtricitabine (FTC)/rilpivirine (RPV) single-tablet regimen (STR) (€7,417.00) revealed the lowest mean treatment cost. TDF/FTC + raltegravir (RAL) showed a better quality of life (0.906 QALY/year), followed by TDF/FTC/RPV (STR; 0.900 QALY/year), TDF/FTC + RPV (multipill regimen) (0.889 QALY/year), and TDF/FTC + atazanavir (ATV/r) (0.886 QALY/year). TDF/FTC/RPV (STR) appeared to be the most cost-effective therapeutic choice (€13,655.00), followed by TDF/FTC + RPV (multipill regimen) (€15,803.00), and TDF/FTC + efavirenz (EFV) (€16,181.00). The sensitivity analysis on the main variables confirmed the validity of the base case scenario.Conclusion: STR (TDF/FTC/RPV) is the most cost-effective treatment strategy compared with the other therapeutic regimens recommended by the Italian guidelines for the treatment of naïve patients with a viral load

The arrival of potent directly acting antivirals (DAAs) for the treatment of chronic Hepatitis C virus (HCV) infection was a challenge for the regional health system of the Lombardia Region. Lombardia represents roughly 8% of the Italian territory but includes nearly 16% of the Italian population. In 2014, nearly 37,600 HCV patients were routinely followed-up in liver centers across the region; nearly 16,000 were classified as having advanced fibrosis or cirrhosis (Metavir F3-F4). The creation of a regional network was necessary to ensure uniformity in treatment access and treatment management. The first database analysis of the Lombardia Hepatitis Network was conducted in January 2016, and included data on 2432 patients who had received treatment from December 2014 to December 2015. The most prevalent HCV genotypes were HCV-1 found in 63% and HCV-3 found in 17%. Overall 90.4% patients achieved an SVR, SVR rates were 92.9% in HCV-1, 89.3% in HCV-2, 81.1% in HCV-3 and 88.9% in HCV-4. [ABSTRACT FROM AUTHOR]

Competing Interests: Conflict of interest: The Authors declare no potential conflict of interest with respect to the research, authorship and/or publication of this article. The authors declare the following competing interests: AMM, FC, GCo, AG, ML, MMed , MMel, SP, MP, FP, MZ declare no conflict of interest. WM reports holding a fiduciary role in FIMMG, EPCCS and Consulta. EA is an employee of Amgen and reports stock ownership in the company. MB is an employee of Sanofi. GB is an employee of Dephaforum. RC reported receiving consulting fees from MSD Italia, Eli Lilly Italy, Menarini Diagnostics, Roche Diabetes Care Italy, honoraria from Novo Nordisk, Sanofi, Abbott, Mundipharma Farmaceuticals, participation to an advisory boards supported by Boehringer Ingelheim. GCa reported receiving consulting fees from Novartis, Alexion, AstraZeneca, Abbvie, Astellas, Roche, Takeda, Jannsen and Biomarin. ACa reported receiving consulting fees from MSD Italia, Eli Lilly Italy, Menarini Diagnostics, Roche Diabetes Care Italy, honoraria from Novo Nordisk, Sanofi, Abbott, Mundipharma Farmaceuticals, participation to advisory boards supported by Boehringer Ingelheim. ACo reported receiving research grants by AstraZeneca, honoraria from Novo Nordisk, Eli Lilly, Merck Sharp & Dhome, participation on advisory boards supported by Novo Nordisk and Eli Lilly. GD reports stock ownership in Bristol Meyers Squibb. MDG is an employee of Sanofi and reports stock ownership in the company. EP is an employee or Gilead Sciences and reports stock ownership in the company. DS is an employee of Abbvie. VT reported receiving consulting fees from Biogen Italia and grants from FEEM Fondazione Eni Enrico Mattei. EC is an employee of Chiesi Italia.

White to brown/beige adipocytes conversion is a possible therapeutic strategy to tackle the current obesity epidemics. While mitochondria are key for energy dissipation in brown fat, it is unknown if they can drive adipocyte browning. Here, we show that the mitochondrial cristae biogenesis protein optic atrophy 1 (Opa1) facilitates cell-autonomous adipocyte browning. In two cohorts of patients with obesity, including weight discordant monozygotic twin pairs, adipose tissue OPA1 levels are reduced. In the mouse, Opa1 overexpression favours white adipose tissue expandability as well as browning, ultimately improving glucose tolerance and insulin sensitivity. Transcriptomics and metabolomics analyses identify the Jumanji family chromatin remodelling protein Kdm3a and urea cycle metabolites, including fumarate, as effectors of Opa1-dependent browning. Mechanistically, the higher cyclic adenosine monophosphate (cAMP) levels in Opa1 pre-adipocytes activate cAMP-responsive element binding protein (CREB), which transcribes urea cycle enzymes. Flux analyses in pre-adipocytes indicate that Opa1-dependent fumarate accumulation depends on the urea cycle. Conversely, adipocyte-specific Opa1 deletion curtails urea cycle and beige differentiation of pre-adipocytes, and is rescued by fumarate supplementation. Thus, the urea cycle links the mitochondrial dynamics protein Opa1 to white adipocyte browning., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

To analyze sex-related differences about AF prevalence, use of OAC and outcomes focusing on the older age classes. We used administrative data of the Lombardy Region, describing period prevalence, use of OAC and outcomes from 2002 to 2014 for all patients diagnosed with AF. AF prevalence over the 2002-2014 period was higher in males than in females (2.7% vs. 2.1%, p < 0.001), increasing with age. From 2003 to 2014, not treated AF patients decreased mostly in males (from 40.3 to 33.7% with respect to 43.7-39.8% in females). Age-stratified adjusted logistic regression analysis found that females were more likely treated with OAC when < 65 years in 2003 (OR 1.51, 95% CI 1.35-1.69) and in 2014 (OR 1.32, 95% CI 1.13-1.53); contrariwise, were less likely treated with OAC when age ≥ 75 years, in 2003 (OR 0.92, 95% CI 0.86-0.98) and in 2014 (OR 0.77, 95% CI 0.72-0.81).Adjusted Cox regression analysis confirmed that female AF patients had a higher risk of stroke (HR 1.18, 95% CI 1.14-1.21) and a lower risk of major bleeding (HR 0.83, 95% CI 0.80-0.86), while, had a lower risk for all-cause death (HR 0.82, 95% CI 0.80-0.83). AF prevalence was higher in male than in female patients, while thromboembolic risk was higher in female. Older female patients were under-treated with OAC particularly in recent years. Over long-term follow-up, female had a higher risk of stroke and a lower risk of major bleeding and all-cause death.

Recent epidemiological studies have reported an increase in central nervous system (CNS)-active drug abuse rates in paediatric settings, raising several public health concerns. No study to date has explored this issue worldwide. We performed an extensive analysis of drugs abuse/overdose reported for children in the last decade by using the largest pharmacovigilance database, i.e. the VigiBase, collecting adverse drug reaction reports that involved at least one suspect drug belonging to the Anatomical Therapeutic Chemical code "Nervous System" through the Standardised Medical Dictionary for Drug Regulatory Affairs Queries for Drug abuse. 8.682 reports matched our criteria. An increase in reporting activity was observed, starting from 2014; an intentional overdose was reported more frequently than an accidental one, with a difference between age groups. We retrieved 997 reports with death outcome. These referred more to adolescents (n = 538) than subjects of any other paediatric age group. Paracetamol and opioid analgesics were the most common suspect drugs in deaths across all age groups due to hypoxic-ischaemic encephalopathy, brain death, and cardio-respiratory arrest.Conclusion: The number of reports associated with drug abuse and overdose is increasing (for opioid and paracetamol-containing products) and a considerable number of adverse drug reactions are serious. Data on the patterns of use of such medicines from each country may help in implementing strategies of risk-minimisation and renewing healthcare recommendations worldwide. An increased clinical awareness of drug abuse and overdose is warranted, while continuing to provide effective treatments. What is Known: • The large increase in paediatric prescriptions for CNS-active drugs in the last 20 years has recently raised public health concerns about drug abuse and overdose. • No study to date has examined this issue in paediatric patients worldwide. What is New: • The number of paediatric reports associated with CNS drug abuse and intentional overdose is increasing, including those with fatal outcome; over 4 years; more than 35% of the reports was entered from European countries. • Opioid and paracetamol were most frequently suspected for ADRs with fatal outcome across all age groups, due to hypoxic-ischaemic encephalopathy and cardio-respiratory arrest, suggesting the need to implement strategies of risk-minimisation.

Purpose: Diabetic macular edema (DME) is a leading cause of vision loss and blindness. The aim of this study was to evaluate the economic benefits of introducing additional alternative technologies (Dexamethasone intravitreal implant - DEX - and Aflibercept injections), compared with the historical scenario of Ranibizumab intravitreal injections., Methods: A 3-year budget impact model was developed, taking into consideration the perspective of the Lombardy Region Healthcare Service (LRHS). Total administration costs (real-life data retrieved from clinical practice at three Departments of Ophthalmology) as well as costs related to the management of potential adverse events (information collected from the literature) were analysed., Results: Over a 36-month horizon, the results showed that a higher consumption of DEX could lead to significant economic savings for the Regional Healthcare Service, ranging from a minimum of -4.35% (if DEX were used only in the second-line of treatment) to a maximum of -12.97% (if DEX were used in both the first-line and second-line), including the potential impact of adverse events. Therapy costs with Aflibercept and Ranibizumab were similar., Conclusions: This study demonstrates that concentrating all eligible patients within the Ranibizumab regimen is unlikely to represent a cost-effective strategy. Indeed, significant economic advantages would be achieved by introducing the other licensed alternatives, Dexamethasone implant and Aflibercept, thus optimising DME Italian healthcare expenditure. The results demonstrate DEX as an advantageous technological alternative for the target population affected by DME, both as a first- and second-line treatment option, reducing the economic burden of the pathology for the Regional/National Health Service., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Unlabelled: Psoriasis is a chronic immune-mediated inflammatory skin disease commonly categorized as mild, moderate, or severe. Moderate-to-severe psoriasis is associated with significant comorbidity and has been shown to severely impair quality of life. Moreover, psoriasis is associated with high costs, including those associated with treatment, which have increased recently with the inclusion of biological systemic agents (most recently secukinumab) as available treatment options. However, despite clear evidence of their value in the treatment of moderate-to-severe plaque psoriasis, in Italy access to the biological agents remains limited to dermatological centers originally involved in the Psocare network. The impact of secukinumab entry into the market in Italy is still to be determined, but we believe that it will be associated with significant changes in the way in which biological treatments for psoriasis are accessed and prescribed in Italy. It is noteworthy that in January 2015, the European Medicines Agency approved secukinumab as first-line systemic therapy in this indication., Funding: Novartis, Italy.

Background: The most serious criticisms leveled at bacteriophage therapy are as follows: phages induce neutralizing antibodies, phages are active only when administered shortly after bacterial infection, and phage-resistant bacteria emerge rapidly in the course of therapy., Methods: Phages lytic for several Salmonella enterica serovars were isolated by means of standard protocols from feces of patients with gastroenteritis. Growth of S. enterica serovar Paratyphi B (Salp572(phi1S)) in the presence of phage phi1 (selected from among 8 phages for its larger host range) provided a phage phi1-resistant bacterial strain (Salp572(phi1R)). The properties of the Salp572(phi1S) and Salp572(phi1R) strains and of phage phi1 were studied in a mouse model of experimental infection., Results: Phages induced nonneutralizing antibodies and were active 2 weeks after experimental infection of mice; phage-resistant bacteria were avirulent and short lived in vivo. More importantly, phage-resistant bacteria were excellent vaccines, protecting against lethal doses of heterologous S. enterica serovars., Conclusions: Phage therapy effectiveness has not yet been properly assessed.

Hand hygiene represents the main way to prevent and/or at least reduce nosocomial infection incidence. In this paper we discuss this "hot topic" through both the analysis of CDC guide lines and the data resulting from a questionnaire survey sent to health care workers, eventually corroborated by their direct observation. From literature data and our survey result analyses, we are more than convinced that the winning strategies for a slow but progressive improvement of hand washing practice and compliance are (i). using a product able to decontaminate hands very quickly and without needing water; (ii). the health care worker awareness of hand hygiene and compliance feed-back importance. From our questionnaire survey as well as from our direct observation, we found a very low (5.6%) compliance of our hospital health care workers to CDC guidelines for hand washing. This may be justified above all by ward logistical and structural problems, as only 55% of sinks are located inside patient rooms, but also because there is a lacking of knowledge of new CDC suggested practices and decontaminating products. Health care worker specific training and the choice of an alcoholic antiseptic disinfectant, allowed us to significantly increase their compliance to proper practices in hand washing and hygiene, showing their interest in such an important and delicate matter.

The aim of this study was to evaluate resistance rates to ciprofloxacin and levofloxacin of Pseudomonas aeruginosa (n=1917 strains) isolated at Laboratory of Microbiology at L. Sacco Teaching Hospital in Milan, Italy in the period between January 1998 and October 2002. Twenty-five percent of tested strains were isolated from sputum, 18% from bronchial lavage, 10% from urine, 9% from ear, 4.5% from blood and 26% from other materials. Ciprofloxacin-resistant strains were 121/ 411 (29%) in 1998, 158/ 526 (30%) in 1999, 136/ 400 (34%) in 2000, 129/ 390 (33%) in 2001 and 53/ 190 (28%) in 2002. Resistance rates for levofloxacin were 132/472 (28%) in 1999, 104/ 400 (26%) in 2000, 101/ 390 (26 %) in 2001 and 47/ 190 (25%) in 2002. Our data highlight overall stability in resistance to ciprofloxacin and levofloxacin with minor variations for ciprofloxacin. Moreover, in contrast with international worldwide studies, resistance rates to ciprofloxacin remained higher than those related to levofloxacin throughout the period studied.

We have analyzed the binding of recombinant human immunodeficiency virus type 1 nucleocapsid protein (NC) to very short oligonucleotides by using surface plasmon resonance (SPR) technology. Our experiments, which were conducted at a moderate salt concentration (0.15 M NaCl), showed that NC binds more stably to runs of d(G) than to other DNA homopolymers. However, it exhibits far more stable binding with the alternating base sequence d(TG)n than with any homopolymeric oligodeoxyribonucleotide; thus, it shows a strong sequence preference under our experimental conditions. We found that the minimum length of an alternating d(TG) sequence required for stable binding was five nucleotides. Stable binding to the tetranucleotide d(TG)2 was observed only under conditions where two tetranucleotide molecules were held in close spatial proximity. The stable, sequence-specific binding to d(TG)n required that both zinc fingers be present, each in its proper position in the NC protein, and was quite salt resistant, indicating a large hydrophobic contribution to the binding. Limited tests with RNA oligonucleotides indicated that the preferential sequence-specific binding observed with DNA also occurs with RNA. Evidence was also obtained that NC can bind to nucleic acid molecules in at least two distinct modes. The biological significance of the specific binding we have detected is not known; it may reflect the specificity with which the parent Gag polyprotein packages genomic RNA or may relate to the functions of NC after cleavage of the polyprotein, including its role as a nucleic acid chaperone.

Because of the role major histocompatibility complex (MHC) class I b molecules may play during mouse embryonic development, we thought it would be interesting to search for additional MHC class I b molecules that might be expressed in preimplantation embryos, and in particular in the trophoblastic lineage. We therefore screened a mouse preimplantation blastocyst cDNA library for MHC class I sequences. This search led to the identification and characterization of a new MHC class I b gene, blastocyst MHC. Sequences identical to the exons and 3' untranslated region of this gene have been found in many laboratory mouse strains, as well as in the related mouse species Mus spreciligus. The presence of this gene in mouse strains of different MHC class I haplotypes argues that blastocyst MHC is a unique, newly-described gene rather than a new allele of a previously described mouse MHC class I gene. Blastocyst MHC has the structure of an MHC class I b gene, with the six exons characteristic of T-region genes. It is linked to H2-D. The amino acid sequence encoded by this gene maintains all the features of a functional antigen-presentation domain. The blastocyst MHC gene, like the human class I b gene HLA-G, is expressed at the blastocyst stage and in the placenta, and may be the mouse analog for HLA-G.