Publications by authors named "Roberto Benedetti"

13 Publications

  • Page 1 of 1

Spatial auto-correlation and auto-regressive models estimation from sample survey data.

Biom J 2020 10 14;62(6):1494-1507. Epub 2020 Apr 14.

Istat, Directorate for Methodology and Statistical Process Design, Rome, Italy.

Maximum likelihood estimation of the model parameters for a spatial population based on data collected from a survey sample is usually straightforward when sampling and non-response are both non-informative, since the model can then usually be fitted using the available sample data, and no allowance is necessary for the fact that only a part of the population has been observed. Although for many regression models this naive strategy yields consistent estimates, this is not the case for some models, such as spatial auto-regressive models. In this paper, we show that for a broad class of such models, a maximum marginal likelihood approach that uses both sample and population data leads to more efficient estimates since it uses spatial information from sampled as well as non-sampled units. Extensive simulation experiments based on two well-known data sets are used to assess the impact of the spatial sampling design, the auto-correlation parameter and the sample size on the performance of this approach. When compared to some widely used methods that use only sample data, the results from these experiments show that the maximum marginal likelihood approach is much more precise.
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http://dx.doi.org/10.1002/bimj.201800225DOI Listing
October 2020

[Comparison between erector spinal plane block and epidural block techniques for postoperative analgesia in open cholecystectomies: a randomized clinical trial].

Rev Bras Anestesiol 2020 Jan - Feb;70(1):22-27. Epub 2020 Feb 27.

Serviço de Anestesiologia SIANEST, Florianópolis, SC, Brasil; Universidade do Sul de Santa Catarina (UNISUL), Florianópolis, SC, Brazil; Hospital Florianópolis, Florianópolis, SC, Brasil; TSA Sociedade Brasileira de Anestesiologia (SBA), Rio de Janeiro, RJ, Brasil.

Introduction And Objectives: Blockade of the Erector Spinal Muscle (ESP block) is a relatively new block, initially described for chronic thoracic pain analgesia, but it has already been described for anesthesia and analgesia in thoracic surgical procedures and, more recently, for high abdominal surgeries. The aim of the study was to compare two techniques, ESP Block and Epidural block with morphine and local anesthetic for postoperative analgesia of open cholecystectomy surgeries.

Methods: Controlled single-blind randomized clinical trial with 31 patients (ESP block, n = 15; Epidural, n = 16), of both genders, ages between 27 and 77 years. The ESP block was performed at the T8 level with injection of 20 mL of 0.5% ropivacaine bilaterally. The epidural block was performed at the T8-T9 space with 20 mL of 0.5% ropivacaine and 1 mg of morphine.

Results: The ESP block group presented higher mean Numeric Pain Scale (NPS) values for pain in the up to 2 hour (p = 0.001) and in the 24 hour (p = 0.001) assessments. The ESP block group had a three-fold increased risk (43.7% vs. 13.3%) of rescue opioid use in the 24 postoperative hours when compared to the epidural group (RR = 3.72, 95% CI: 0.91 to 15.31, p = 0.046).

Conclusion: ESP block did not prove to be an effective technique for postoperative analgesia of open cholecystectomy, at the doses performed in this study, having required more use of rescue opioid, and without differences in NPS. More comprehensive studies are required to assess the efficacy of ESP block for the visceral and abdominal somatic component, considering the specific blockade level.
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http://dx.doi.org/10.1016/j.bjan.2019.12.009DOI Listing
February 2020

Patient pain during intravitreal injections under topical anesthesia: a systematic review.

Int J Retina Vitreous 2017 3;3:23. Epub 2017 Jul 3.

Department of Ophthalmology and Visual Sciences, Federal University of São Paulo, Rua Pastor William Richard Schisler 900/apto 1011, Florianópolis, SC 88034-100 Brazil.

Background: Intravitreal injection (IVI) is a very common vitreoretinal procedure, and multiple injections are often required per patient. This systematic review was conducted to evaluate the effectiveness of various local anesthetic techniques in reducing pain during injection.

Methods: A systematic review was conducted based on searches of Cochrane, LILACS, PubMed, Scopus, Web of Science, and the gray literature (Google Scholar). The end search date was February 19, 2016, across all databases. We classified pain by converting visual analog scale (VAS) scores (0-100 mm) into Jensen's classification levels: 0-4, no pain; 5-44, mild pain; 45-74, moderate pain; and 75-100, severe pain. An intervention was considered clinically significant when pain score change was >12 mm on a 100-mm scale.

Results: Eight studies out of 23 met the eligibility criteria. The total number of patients was 847. Most studies (5/8 [62.5%]) were at unclear risk of bias because of unclear randomization, thus providing only moderate evidence to this review. The anesthetic techniques included eye drops with proparacaine, tetracaine or cocaine, a lidocaine pledget or gel, and subconjunctival injection of 2% lidocaine or 0.75% levobupivacaine. No study comprised all of the techniques. Pain was mild (VAS scores, 5-44 mm) regardless of anesthetic technique. A clinically significant intervention (pain score change >12 mm) was found for only one study comparing proparacaine drops, lidocaine gel, and subconjunctival lidocaine; in that study, a subconjunctival injection of 2% lidocaine provided the greatest pain reduction. A meta-analysis was not possible due to study heterogeneity.

Conclusions: Patient pain during IVI under topical anesthesia is mild regardless of anesthetic technique. A subconjunctival injection of 2% lidocaine could be an option for highly sensitive patients. However, with moderate level of evidence, no single anesthetic technique could be defined as the best option for IVI.
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http://dx.doi.org/10.1186/s40942-017-0076-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494853PMC
July 2017

A spatially balanced design with probability function proportional to the within sample distance.

Biom J 2017 Sep 16;59(5):1067-1084. Epub 2017 May 16.

Istat, Directorate for Methodology and Statistical Process Design, Via Cesare Balbo 16, Rome, IT-00184, Italy.

The units observed in a biological, agricultural, and environmental survey are often randomly selected from a finite population whose main feature is to be geo-referenced thus its spatial distribution should be used as essential information in designing the sample. In particular our interest is focused on probability samples that are well spread over the population in every dimension which in recent literature are defined as spatially balanced samples. To approach the problem we used the within sample distance as the summary index of the spatial distribution of a random selection criterion. Moreover numerical comparisons are made between the relative efficiency, measured with respect to the simple random sampling, of the suggested design and some other classical solutions as the Generalized Random Tessellation Stratified (GRTS) design used by the US Environmental Protection Agency (EPA) and other balanced or spatially balanced selection procedures as the Spatially Correlated Poisson Sampling (SCPS), the balanced sampling (CUBE), and the Local Pivotal method (LPM). These experiments on real and simulated data show that the design based on the within sample distance selects samples with a better spatial balance thus gives estimates with a lower sampling error than those obtained by using the other methods. The suggested method is very flexible to the introduction of stratification and coordination of samples and, even if in its nature it is computationally intensive, it is shown to be a suitable solution even when dealing with high sampling rates and large population frames where the main problem arises from the size of the distance matrix.
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http://dx.doi.org/10.1002/bimj.201600194DOI Listing
September 2017

Ethical and legal duty of anesthesiologists regarding Jehovah's Witness patient: care protocol.

Braz J Anesthesiol 2016 Nov - Dec;66(6):637-641. Epub 2016 Sep 12.

CET Sianest SBA, Florianópolis, SC, Brazil; Hospital Florianópolis, Florianópolis, SC, Brazil.

Background And Objectives: Jehovah's Witnesses patients refuse blood transfusions for religious reasons. Anesthesiologists must master specific legal knowledge to provide care to these patients. Understanding how the Law and the Federal Council of Medicine treat this issue is critical to know how to act in this context. The aim of this paper was to establish a treatment protocol for the Jehovah's Witness patient with emphasis on ethical and legal duty of the anesthesiologist.

Content: The article analyzes the Constitution, Criminal Code, resolutions of the Federal Council of Medicine, opinions, and jurisprudence to understand the limits of the conflict between the autonomy of will of Jehovah's Witnesses to refuse transfusion and the physician's duty to provide the transfusion. Based on this evidence, a care protocol is suggested.

Conclusions: The Federal Council of Medicine resolution 1021/1980, the penal code Article 135, which classifies denial of care as a crime and the Supreme Court decision on the HC 268,459/SP process imposes on the physician the obligation of blood transfusion when life is threatened. The patient's or guardian's consent is not necessary, as the autonomy of will manifestation of the Jehovah's Witness patient refusing blood transfusion for himself and relatives, even in emergencies, is no not forbidden.
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http://dx.doi.org/10.1016/j.bjane.2015.03.012DOI Listing
April 2017

[Ethical and legal duty of anesthesiologists regarding Jehovah's Witness patient: care protocol].

Rev Bras Anestesiol 2016 Nov - Dec;66(6):637-641. Epub 2016 Mar 23.

CET Sianest SBA, Florianópolis, SC, Brasil; Hospital Florianópolis, Florianópolis, SC, Brasil.

Background And Objectives: Jehovah's Witnesses patients refuse blood transfusions for religious reasons. Anesthesiologists must master specific legal knowledge to provide care to these patients. Understanding how the Law and the Federal Council of Medicine treat this issue is critical to know how to act in this context. The aim of this paper was to establish a treatment protocol for the Jehovah's Witness patient with emphasis on ethical and legal duty of the anesthesiologist.

Content: The article analyzes the Constitution, Criminal Code, resolutions of the Federal Council of Medicine (FCM), opinions, and jurisprudence to understand the limits of the conflict between the autonomy of will of Jehovah's Witnesses to refuse transfusion and the physician's duty to provide the transfusion. Based on this evidence, a care protocol is suggested.

Conclusions: The FCM resolution 1021/1980, the penal code Article 135, which classifies denial of care as a crime and the Supreme Court decision on the HC 268,459/SP process imposes on the physician the obligation of blood transfusion when life is threatened. The patient's or guardian's consent is not necessary, as the autonomy of will manifestation of the Jehovah's Witness patient refusing blood transfusion for himself and relatives, even in emergencies, is no not forbidden.
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http://dx.doi.org/10.1016/j.bjan.2015.03.008DOI Listing
March 2016

A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons.

J Pharmacol Exp Ther 2015 Sep 17;354(3):251-60. Epub 2015 Jun 17.

Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.)

Kv3.1 and Kv3.2 high voltage-activated potassium channels, which display fast activation and deactivation kinetics, are known to make a crucial contribution to the fast-spiking phenotype of certain neurons. Pharmacological experiments show that the blockade of native Kv3 currents with low concentrations of tetraethylammonium or 4-aminopyridine impairs the expression of this firing phenotype. In particular, Kv3 channels are highly expressed by fast-spiking, parvalbumin-positive interneurons in corticolimbic brain circuits, which modulate the synchronization of cortical circuits and the generation of brain rhythms. Here, we describe a novel small molecule, (5R)-5-ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione (AUT1), which modulates Kv3.1 and Kv3.2 channels in human recombinant and rodent native neurons. AUT1 increased whole currents mediated by human Kv3.1b and Kv3.2a channels, with a concomitant leftward shift in the voltage dependence of activation. A less potent effect was observed on hKv3.3 currents. In mouse somatosensory cortex slices in vitro, AUT1 rescued the fast-spiking phenotype of parvalbumin-positive-fast-spiking interneurons following an impairment of their firing capacity by blocking a proportion of Kv3 channels with a low concentration of tetraethylammonium. Notably, AUT1 had no effect on interneuron firing when applied alone. Together, these data confirm the role played by Kv3 channels in the regulation of the firing phenotype of somatosensory interneurons and suggest that AUT1 and other Kv3 modulators could represent a new and promising therapeutic approach to the treatment of disorders associated with dysfunction of inhibitory feedback in corticolimbic circuits, such as schizophrenia.
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http://dx.doi.org/10.1124/jpet.115.225748DOI Listing
September 2015

6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: a new potent and selective triple reuptake inhibitor.

J Med Chem 2010 Jul;53(13):4989-5001

Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy.

A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.
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http://dx.doi.org/10.1021/jm100481dDOI Listing
July 2010

1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes: a new series of potent and selective triple reuptake inhibitors.

J Med Chem 2010 Mar;53(6):2534-51

Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy.

The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.
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http://dx.doi.org/10.1021/jm901818uDOI Listing
March 2010

Cyclopenta[d]pyrimidines and dihydropyrrolo[2,3-d]pyrimidines as potent and selective corticotropin-releasing factor 1 receptor antagonists.

ChemMedChem 2007 Apr;2(4):528-40

GlaxoSmithKline Medicines Center, Psychiatry CEDD, Via A. Fleming 4, 37135 Verona, Italy.

Two new classes of potent and selective CRF(1) receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF(1) antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF(1) antagonists, as exemplified by compound 4 fi (4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine), produced a dose-dependent "anxiolytic-like" effect when administered orally, decreasing the vocalization of rat pups.
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http://dx.doi.org/10.1002/cmdc.200600257DOI Listing
April 2007

3-Methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester: an exploration of the C-2 position. Part I.

Farmaco 2004 Mar;59(3):175-83

GlaxoSmithKline Medicine Research Centre, via Fleming 4, Verona 37135, Italy.

Following the recent disclosure of 3-methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester, a potent and selective mGluR1 non-competitive antagonist, we report here a detailed exploration of the C-2 position of this scaffold with the preparation of differently substituted amides. Great improvement of the pharmacokinetic properties has been achieved through this exercise.
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http://dx.doi.org/10.1016/j.farmac.2003.12.005DOI Listing
March 2004