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Molecular docking has been successfully used in computer-aided molecular design projects for the identification of ligand poses within protein binding sites. However, relying on docking scores to rank different ligands with respect to their experimental affinities might not be sufficient. It is believed that the binding scores calculated using molecular mechanics combined with the Poisson-Boltzman surface area (MM-PBSA) or generalized Born surface area (MM-GBSA) can predict binding affinities more accurately. In this perspective, we decided to take part in Stage 2 of the Drug Design Data Resource (D3R) Grand Challenge 4 (GC4) to compare the performance of a quick scoring function, AutoDock4, to that of MM-GBSA in predicting the binding affinities of a set of [Formula: see text]-Amyloid Cleaving Enzyme 1 (BACE-1) ligands. Our results show that re-scoring docking poses using MM-GBSA did not improve the correlation with experimental affinities. We further did a retrospective analysis of the results and found that our MM-GBSA protocol is sensitive to details in the protein-ligand system: (i) neutral ligands are more adapted to MM-GBSA calculations than charged ligands, (ii) predicted binding affinities depend on the initial conformation of the BACE-1 receptor, (iii) protonating the aspartyl dyad of BACE-1 correctly results in more accurate binding affinity predictions.

The introduction of bio-based matrices in automotive applications would, in principle, increase their sustainability and, in case the use of secondary raw materials is also involved, even result in reduced resource depletion. The bio-based polymer composite matrix that has been mainly brought forward towards industrial application is poly(lactic acid) (PLA), which has often been proposed as the replacement for matrices based on polyolefins in fields such as packaging and short-term commodities since, in general, it matches the needs for conventional thermoplastic production processes. The passage to the automotive sector is not obvious, though: problems affecting durability, the relation with water and the environment, together with the requirement for outstanding mechanical and impact performance appear very stringent. On the other hand, PLA has obtained durable success in additive manufacturing as a competitor for acrylonitrile butadiene styrene (ABS). Also, the perspective for 3D and 4D printing does not appear to be confined to bare prototyping. These contrasting pieces of evidence indicate the necessity to provide more insight into the possible development of PLA use in the automotive industry, also considering the pressure for the combined use of more sustainable reinforcement types in automotive composites, such as natural fibers. [ABSTRACT FROM AUTHOR]

Recent pressure on scientists and industries to use renewable resources, as well as the need to produce environmentally friendly materials, has led researchers and manufacturers to use natural fibres as possible reinforcements for their composites. Although they seem to be "ideal" due to their low cost, light weight and interesting energy absorption properties, they cannot be compared to synthetic fibres. To solve this problem, hybridization techniques can be considered, since the combination of synthetic and natural fibres allows for good performances. The aim of this study was to characterize the delamination and in-plane crashworthiness behaviour of carbon, flax and hybrid composites from experimental and numerical points of view. Double Cantilever Beam and Four-Point End Notched Flexure tests were carried out to determine the interlaminar fracture modes. In-plane crashworthiness tests were then performed to investigate the delamination phenomenon and the energy absorption capacity considering two different geometries: flat and corrugated. Numerical models were created and validated on both geometries, comparing the obtained load–displacement curves with the experimental ones. Crush force efficiency and specific energy absorption were quantified to provide a proper comparison of the investigated materials. The good results achieved represent a promising starting point for the design of future and more complex structures. [ABSTRACT FROM AUTHOR]

Natural fibres, valued for their low density, cost-effectiveness, high strength-to-weight ratio, and efficient energy absorption, are increasingly emerging as alternatives to synthetic materials in green composites. Although they cannot fully replace synthetic counterparts, like carbon, in structural applications due to their inferior mechanical performance, combining them through hybridization presents a potential solution. This approach promotes a balance between environmental benefits and mechanical efficiency. Recently, the transportation sector has shifted its focus towards delivering lightweight and crashworthy composite structures to improve vehicle performance, address safety concerns, and minimise environmental impact through the use of eco-friendly materials. The crashworthiness of energy absorbers, typically thin-walled structures, is influenced by several factors, including their material and geometric design. This paper presents a comprehensive overview of recent studies focused on the crashworthiness of fibre-reinforced, thin-walled composites under axial crushing. It explores different aspects, such as their materials, cross-sections, stacking sequences, triggering or filling mechanisms, and the effect of loading rate speed. Emphasis is placed on natural-fibre-based materials, including a comparative analysis of synthetic ones and their hybridization. The primary objective is to review the progress of solutions using green composites as energy absorbers in the automotive industry, considering their lightweight design, crashworthiness, and environmental sustainability. [ABSTRACT FROM AUTHOR]

This study comprehensively examines recent developments in bio-epoxy resins and their applications in composites. Despite the reliability of traditional epoxy systems, the increasing demand for sustainability has driven researchers and industries to explore new bio-based alternatives. Additionally, natural fibers have the potential to serve as environmentally friendly substitutes for synthetic ones, contributing to the production of lightweight and biodegradable composites. Enhancing the mechanical properties of these bio-composites also involves improving the compatibility between the matrix and fibers. The use of bio-epoxy resins facilitates better adhesion of natural composite constituents, addressing sustainability and environmental concerns. The principles and methods proposed for both available commercial and especially non-commercial bio-epoxy solutions are investigated, with a focus on promising renewable sources like wood, food waste, and vegetable oils. Bio-epoxy systems with a minimum bio-content of 20% are analyzed from a thermomechanical perspective. This review also discusses the effect of incorporating synthetic and natural fibers into bio-epoxy resins both on their own and in hybrid form. A comparative analysis is conducted against traditional epoxy-based references, with the aim of emphasizing viable alternatives. The focus is on addressing their benefits and challenges in applications fields such as aviation and the automotive industry. [ABSTRACT FROM AUTHOR]

We propose two optimal representations for the elements of trace zero subgroups of twisted Edwards curves. For both representations, we provide efficient compression and decompression algorithms. The efficiency of the algorithm is compared with the efficiency of similar algorithms on elliptic curves in Weierstrass form.

An axial-flux permanent-magnet machine (AFPM) topology with coreless winding is proposed for generator units required aboard ships, aircraft, or hybrid electric vehicles. In the proposed AFPM configuration, the winding consists of rhomboidal-shaped coils encapsulated in fiber-reinforced epoxy resin. The coils have a double-layer arrangement to leave space for a cooling water duct being used to remove heat directly from the interior surface of the winding. The overall machine structure has high compactness and lightness and, due to the lack of the iron core, generator operation with power output at 400 Hz can be accomplished with high efficiency and acceptable voltage regulation. This paper discusses the basic design and construction of AFPM generators with coreless winding and experimental results taken from a 16-pole machine prototype rated 230 N-m, 3000 r/min are finally reported. Index Terms - Aerospace power generation, on-board electric generators, permanent-magnet machines.

Targeted covalent inhibitors are currently showing great promise for systems that are normally difficult to target with small molecule therapies. This renewed interest has spurred the refinement of existing computational methods as well as the design of new ones, expanding the toolbox for discovery and optimization of selective and effective covalent inhibitors. Commonly applied approaches are covalent docking methods that predict the conformation of the covalent complex with known residues. More recently, a new predictive method, reactive docking, was developed, building on the growing corpus of data generated by large proteomics experiments. This method was successfully used in several 'inverse drug discovery' programs that use high-throughput techniques to isolate effective compounds based on screening of entire compound libraries based on desired phenotypes. Molecular modeling is widely applied in drug discovery, with a number of successful approaches. Only recently have there been applications to the characterization of covalent inhibitors. Several methods have been proposed, but a number of challenges arise from the modeling of the warhead reactivity, prediction of residue propensity to react, and, ultimately, the prediction of reaction outcome. The recent resurgence of interest in covalent inhibitors is generating large amounts of experimental data that can be used to train computational models and improve the accuracy of predictive methods. In order to be useful in drug discovery campaigns, computational methods need to achieve an ideal balance between accuracy and speed, in order to reduce experimental resources required to identify new hits while being applicable in high-throughput fashion. [ABSTRACT FROM AUTHOR]

The pathogenesis of diverticular disease and acute diverticulitis is still unclear and many different hypotheses have been formulated. Seemingly, there are several related factors such as chronic inflammation, gut microbiome, obesity and the immunogenic properties of fat tissue and diet. Inflammation plays a pivotal role in diverticular disease and acute diverticulitis. The aim of the present review is to investigate the role of inflammation in diverticular disease as well as in mild and complicated acute diverticulitis with a focus on current research and treatment perspectives. [ABSTRACT FROM AUTHOR]

In the continuous effort to identify new HIV-1 inhibitors endowed with innovative mechanisms, the dual inhibition of different viral functions would provide a significant advantage against drug-resistant variants. The HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) is the only viral-encoded enzymatic activity that still lacks an efficient inhibitor. We synthesized a library of 3,5-diamino-N-aryl-1H-pyrazole-4-carbothioamide and 4-amino-5-benzoyl-N-phenyl-2-(substituted-amino)-1H-pyrrole-3-carbothioamide derivatives and tested them against RNase H activity. We identified the pyrazolecarbothioamide derivative A15, able to inhibit viral replication and both RNase H and RNA-dependent DNA polymerase (RDDP) RT-associated activities in the low micromolar range. Docking simulations hypothesized its binding to two RT pockets. Site-directed mutagenesis experiments showed that, with respect to wt RT, V108A substitution strongly reduced A15 IC50 values (12.6-fold for RNase H inhibition and 4.7-fold for RDDP), while substitution A502F caused a 9.0-fold increase in its IC50 value for RNase H, not affecting the RDDP inhibition, reinforcing the hypothesis of a dual-site inhibition. Moreover, A15 retained good inhibition potency against three non-nucleoside RT inhibitor (NNRTI)-resistant enzymes, confirming a mode of action unrelated to NNRTIs and suggesting its potential as a lead compound for development of new HIV-1 RT dual inhibitors active against drug-resistant viruses. [ABSTRACT FROM AUTHOR]

3,5-Diaryl-4,5-dihydroisoxazoles were synthesized and evaluated as monoamine oxidase (MAO) enzyme inhibitors and iron chelators. All compounds exhibited selective inhibitory activity towards the B isoform of MAO in the nanomolar concentration range. The best performing compound was preliminarily evaluated for its ability to bind iron II and III cations, indicating that neither iron II nor iron III is coordinated. The best compounds racemic mixtures were separated and single enantiomers inhibitory activity evaluated. Furthermore, none of the synthesised compounds exhibited activity towards MAO A. Overall, these data support our hypothesis that 3,5-diaryl-4,5-dihydroisoxazoles are promising scaffolds for the design of neuroprotective agents. [ABSTRACT FROM AUTHOR]

A series of 3-3-{2-[2-3-methyl-4-phenyl-2,3-dihydro-1,3-thiazol-2-ylidene]hydrazin-1-ylidene-2,3-dihydro-1H-indol-2-one derivatives has been designed and synthesized to study their activity on both HIV-1 (Human Immunodeficiency Virus type 1) RT (Reverse Transcriptase) associated functions. These derivatives are analogs of previously reported series whose biological activity and mode of action have been investigated. In this work we investigated the influence of the introduction of a methyl group in the position 3 of the dihydrothiazole ring and of a chlorine atom in the position 5 of the isatin nucleus. The new synthesized compounds are active towards both DNA polymerase and ribonuclease H in the µM range. The nature of the aromatic group in the position 4 of the thiazole was relevant in determining the biological activity. [ABSTRACT FROM AUTHOR]

The isatin scaffold is the constitutive fragment of several natural and synthetic bioactive molecules. Albeit several benzene sulphonamide-based carbonic anhydrase inhibitors (CAIs) have been reported, only recently isatin benzene sulphonamides have been studied and proposed as CAIs. In this study we have designed, synthesised, and evaluated the biological activity of a series of differently substituted isatin-based benzene sulphonamides which have been designed for the inhibition of carbonic anhydrase isoforms. The activity of all the synthesised compounds was evaluated towards human carbonic anhydrase I, II, IX, and XII isozymes. Our results indicate that the nature and position of substituents on the isatin ring can modulate both activity and isozyme selectivity. [ABSTRACT FROM AUTHOR]

Cyclohexyliden- and 2-methylcyclohexyliden-hydrazo-4-arylthiazoles were synthesized and tested as antifungal agents. All compounds exhibited minimal inhibitory concentration (MIC) values comparable with those of fluconazole (FLC). Moreover, some compounds showed fungicidal activity at low concentration. Worth noting five out of nine compounds were active towardsCandida albicans25 FLC resistant isolated from clinical specimens. The cellular toxicity was evaluated and none of the compounds is toxic at the MIC. On the basis of our data we can conclude that these derivatives are promising agents for the treatment of resistantC. albicans. [ABSTRACT FROM PUBLISHER]

The DNA polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) are needed for the replication of the viral genome and are validated drug targets. However, there are no approved drugs inhibiting RNase H and the efficiency of DNA polymerase inhibitors can be diminished by the presence of drug resistance mutations. In this context, drugs inhibiting both activities could represent a significant advance towards better anti-HIV therapies. We report on the mechanisms of allosteric inhibition of a newly synthesized isatin-based compound designated as RMNC6 that showed IC50 values of 1.4 and 9.8 μM on HIV-1 RT-associated RNase H and polymerase activities, respectively. Blind docking studies predict that RMNC6 could bind two different pockets in the RT: one in the DNA polymerase domain (partially overlapping the non-nucleoside RT inhibitor [NNRTI] binding pocket), and a second one close to the RNase H active site. Enzymatic studies showed that RMNC6 interferes with efavirenz (an approved NNRTI) in its binding to the RT polymerase domain, although NNRTI resistance-associated mutations such as K103N, Y181C and Y188L had a minor impact on RT susceptibility to RMNC6. In addition, despite being naturally resistant to NNRTIs, the polymerase activity of HIV-1 group O RT was efficiently inhibited by RMNC6. The compound was also an inhibitor of the RNase H activity of wild-type HIV-1 group O RT, although we observed a 6.5-fold increase in the IC50 in comparison with the prototypic HIV-1 group M subtype B enzyme. Mutagenesis studies showed that RT RNase H domain residues Asn474 and Tyr501, and in a lesser extent Ala502 and Ala508, are critical for RMNC6 inhibition of the endonuclease activity of the RT, without affecting its DNA polymerization activity. Our results show that RMNC6 acts as a dual inhibitor with allosteric sites in the DNA polymerase and the RNase H domains of HIV-1 RT. [ABSTRACT FROM AUTHOR]

Simple Summary: The results of this study showed a greater ability of the Comprehensive Complication Index if compared to the conventional Clavien–Dindo classification to predict hospital stay in colon cancer patients, particularly in patients with multiple postoperative complications. These results encourage the routine use of the Comprehensive Complication Index to grade postoperative complications in colonic surgery. (1) Introduction: To date, the sensitivity of the Comprehensive Complication Index (CCI) in a homogeneous cohort of colonic resections for oncologic purposes has not been reported. The present study aims to compare the CCI with the conventional Clavien–Dindo classification (CDC) in colon cancer patients. (2) Methods: The clinical data of patients submitted to an elective colectomy for adenocarcinoma were retrieved from a prospectively maintained database. Postoperative complications and length of stay were reviewed, and CDC and CCI scores were calculated for each patient. The association of the CCI and the CDC with the length of stay, prolongation of stay and readmission rate were assessed and compared. (3) Results: The overall postoperative morbidity was 26.9%. In particular, 157 (20.4%) patients had more than one complication. A strong correlation between the two scoring systems was observed (r = 99.4%; 95%CI: 99.3–99.5%). In multivariate analysis, CCI had a higher predictive ability for all endpoints. Regarding subgroup analysis, the difference between the CCI and CDC was progressively increased when evaluating outcome measures in complicated and multi-complicated patients. (4) Conclusion: Both scoring systems adequately report the overall burden of postoperative complications. The CCI showed a greater ability than the CDC to predict hospital stay, particularly in patients with multiple postoperative complications. [ABSTRACT FROM AUTHOR]

An abstract of the article "Site directed mutagenesis studies on HIV-1 reverse transcriptase (RT) shed light on the mechanism of action of a new Ribonuclease H/DNA polymerase RT dual inhibitor," by Angela Corona and colleagues is presented.

Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3,000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving the direct functional perturbation and/or degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells and point to electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders. • Chemical proteomics identifies cysteine reactivity changes in activated T cells • Chemical proteomics maps ligandable cysteines in diverse immune-relevant proteins • Cysteine-directed electrophilic compounds suppress T cells by distinct mechanisms • Electrophile-cysteine interactions promote the degradation of immune proteins Integrated chemical proteomics and phenotypic screening furnishes a global portrait of cysteine reactivity and ligandability in primary human T cells and enables the discovery of electrophilic small molecules that suppress T cell activation and promote the degradation of immunomodulatory proteins. [ABSTRACT FROM AUTHOR]

Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core "SuFExable" hubs-exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)-enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1 H -1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented β-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function - a key objective of click chemistry - of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase.

Background: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) Registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2019 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers., Methods: The Registry collects prospectively national PM and ICD implantation activity on the basis of European cards., Results: PM Registry: data about 22 889 PM implantations were collected (19 621 first implants and 3268 replacements). The number of collaborating centers was 173. Median age of treated patients was 81 years (75 quartile I; 87 quartile III). ECG indications included atrioventricular conduction disorders in 33.3% of first PM implants, sick sinus syndrome in 16.4%, atrial fibrillation plus bradycardia in 11.6%, other in 38.7%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (18.3% of first implants). Use of single-chamber PMs was reported in 25.5% of first implants, of dual-chamber PMs in 67.1%, of PMs with cardiac resynchronization therapy (CRT) in 1.5%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 5.8%. ICD Registry: data about 17 328 ICD implantations were collected (12 129 first implants and 5199 replacements). The number of collaborating centers was 425. Median age of treated patients was 71 years (62 quartile I; 77 quartile III). Primary prevention indication was reported in 83.1% of first implants, secondary prevention in 16.9% (cardiac arrest in 5.9%). A single-chamber ICD was used in 26.1% of first implants, dual-chamber ICD in 28.0% and biventricular ICD in 45.9%., Conclusions: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice. In order to increase and optimize the cooperation of Italian implanting centers, online data entry (https://www.aiac.it/riprid) should be adopted at large scale.

Background: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) Registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2018 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers., Methods: The Registry collects prospectively national PM and ICD implantation activity on the basis of European cards., Results: PM Registry: data about 23 912 PM implantations were collected (20 084 first implants and 3828 replacements). The number of collaborating centers was 180. Median age of treated patients was 81 years (75 quartile I; 86 quartile III). ECG indications included atrioventricular conduction disorders in 34.5% of first PM implants, sick sinus syndrome in 18.3%, atrial fibrillation plus bradycardia in 13.0%, other in 34.2%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (19.2% of first implants). Use of single-chamber PMs was reported in 24.9% of first implants, of dual-chamber PMs in 67.6%, of PMs with cardiac resynchronization therapy (CRT) in 1.6%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 5.9%. ICD Registry: data about 18 353 ICD implantations were collected (13 944 first implants and 4359 replacements). The number of collaborating centers was 433. Median age of treated patients was 71 years (63 quartile I; 78 quartile III). Primary prevention indication was reported in 84.3% of first implants, secondary prevention in 15.7% (cardiac arrest in 5.3%). A single-chamber ICD was used in 27.9% of first implants, dual-chamber ICD in 31.9% and biventricular ICD in 40.2%., Conclusions: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice. In order to increase and optimize the cooperation of Italian implanting centers, online data entry (http://www.aiac.it/riprid) should be adopted at large scale.

Background: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) Registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2017 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers., Methods: The Registry collects prospectively national PM and ICD implantation activity on the basis of European cards., Results: PM Registry: data about 23 457 PM implantations were collected (19 378 first implant and 4079 replacements). The number of collaborating centers was 185. Median age of treated patients was 81 years (75 quartile I; 86 quartile III). ECG indications included atrioventricular conduction disorders in 37.1% of first PM implants, sick sinus syndrome in 19.5%, atrial fibrillation plus bradycardia in 13.2%, other in 30.2%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (21.0% of first implants). Use of single-chamber PMs was reported in 25.6% of first implants, of dual-chamber PMs in 66.7%, of PMs with cardiac resynchronization therapy (CRT) in 1.4%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 6.3%. ICD Registry: data about 19 023 ICD implantations were collected (13 898 first implants and 5125 replacements). The number of collaborating centers was 437. Median age of treated patients was 71 years (63 quartile I; 78 quartile III). Primary prevention indication was reported in 81.8% of first implants, secondary prevention in 18.2% (cardiac arrest in 6.4%). A single-chamber ICD was used in 27.0% of first implants, dual-chamber in 33.6% and biventricular in 39.3%., Conclusions: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice. In order to increase and optimize the cooperation of Italian implanting centers, online data entry (http://www.aiac.it/riprid) should be adopted at large scale.

A novel series of of 4-[(3-phenyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides ( EMAC10111a-g ) was synthesized and assayed toward both human carbonic anhydrase isozymes I, II, IX, and XII and cyclooxygenase isoforms. The majority of these derivatives preferentially inhibit hCA isoforms II and XII and hCOX-2 isozyme, indicating that 2,3,4-trisubstituted 2,3-dihydrothiazoles are a promising scaffold for the inhibition of hCA isozymes and of hCOX-2 enzyme. The nature of the substituent at the dihydrothiazole ring position 4 influenced the activity and selectivity toward both enzyme families. EMAC10111g resulted as the best performing compound toward both enzyme families and exhibited preferential activity toward hCA XII and hCOX-2 isozymes., Competing Interests: The authors declare no competing financial interest.

A small library of psoralen carboxylic acids and their corresponding benzenesulfonamide derivatives were designed and synthesized to evaluate their activity and selectivity toward tumor associated human carbonic anhydrase (hCA) isoforms IX and XII. Both psoralen acids and sulfonamides exhibited potent inhibition of IX and XII isozymes in the nanomolar concentration range. However, psoralen acids resulted as the most selective in comparison with the corresponding benzenesulfonamide derivatives. Our data indicate that the psoralen scaffold is a promising starting point for the design of highly selective tumor associated hCA inhibitors., Competing Interests: The authors declare no competing financial interest.

Background: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2016 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers., Methods: The registry collects prospectively national PM and ICD implantation activity on the basis of European cards., Results: PM Registry: data about 23 496 PM implantations were collected (19 003 first implant and 4493 replacements). The number of collaborating centers was 204. Median age of treated patients was 81 years (75 quartile I; 86 quartile III). ECG indications included atrioventricular conduction disorders in 39.8% of first PM implants, sick sinus syndrome in 22.1%, atrial fibrillation plus bradycardia in 14.1%, other in 24.0%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (22.18% of first implants). Use of single-chamber PMs was reported in 26.9% of first implants, of dual-chamber PMs in 65.0%, of PMs with cardiac resynchronization therapy (CRT) in 1.5%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 6.6%. ICD Registry: data about 20 350 ICD implantations were collected (14 763 first implants and 5587 replacements). The number of collaborating centers was 430. Median age of treated patients was 72 years (63 quartile I; 78 quartile III]. Primary prevention indication was reported in 79.0% of first implants, secondary prevention in 21.0% (cardiac arrest in 7.9%). A single-chamber ICD was used in 32.2% of first implants, dual-chamber in 31.1% and biventricular in 36.7%., Conclusions: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice.

Background: Our intention in this study was to evaluate the effectiveness of a new open mesh hernia repair procedure, the "All in One Mesh Hernioplasty", for the treatment of primary inguinal hernias in adults., Methods: Between February 2014 and February 2016, we performed the All In One Mesh Hernioplasty procedure on 400 patient suffering from primary unilateral inguinal hernia at our Institution. The prosthesis was placed on the floor of the inguinal canal, as described in the original technique, and later covered by the fibrocremasteric sheath. Followup visits with the evaluation of postoperative pain using Numerical Rating Scale, and of short and long-term complications were performed after 1, 6, and 24 months., Results: All patients were discharged within three hours after surgery. The majority of patients reported only slight pain at discharge and 31,7% of them were completely painless . One week after surgery 83% of patients reported no pain and no other symptoms. 91 % of patients returned to their normal daily activities within 2-3 days after surgery. We didn't record any case of postoperative neuralgia or recurrence after a 24 months follow up., Key Words: All In One Mesh Hernioplasty, Neuralgia post-hernioplasty, Tension free hernia repair.

Anal stenosis is a fibrous narrowing of the anal channel. It develops, in most cases, in the aftermath of proctologic surgical procedures with extensive anoderm excision or in the presence of chronic anal inflammation in patients with Crohn Disease. However rare, this condition is thoroughly debilitating for the patients. Symptoms include constipation, pain and bleeding with defecation and a reduction of the caliber of stools. Diagnosis is essentially clinical. Prevention of postsurgical stenosis is based on a scrupulous surgical technique and on an extensive and carefully- planned follow up. Treatment is based on an initially conservative approach with regularization of stool transit through hydration, dietary fibers and bulk-forming laxatives. The role of mechanical dilatation in the treatment of AS is still debated. For severe cases and cases that are not responsive to conservative treatment we must resort to surgery. Surgical approach is tailored on the severity, position and extension. The most severe cases require anoplasty procedures with mucosal or anal flaps. KEY WORDS: Anal stenosis, Anal stricture,Proctology.

Introduction: The actual high hospitalization costs have encouraged a growing attention towards reducing hospital stay. Nowadays, many simple surgical procedures are carried out in a one-day surgery regimen . A shorter hospital stay brings many advantages for the patients: lesser inconvenience, a lower risk of hospital infection and an earlier return to work. In proctology, day surgery polices are still uncommon because surgeons fear possible complications. In this paper we sum up our 15 years experience, stressing the possibility to perform even complex procedures in local-regional anesthesia and in a day-surgery context., Materials and Methods: In our experience, to be candidate to one-day surgery proctological procdures, patients should be classed as ASA I or II., Results: Between 2005 and 2015 our operative unit executed a total of 2688 proctological procedures in a one-day surgery. 1062 procedures have been completed under local anesthesia exclusively and all patients have been discharged between two and three hours after the procedure without significant complications. In the other 1626 patients perineal posterior block was performed in 932 cases (57.3%) and provided an optimal pain control in 51,6% of cases (301 patients) while in 5,7% of cases there was the need for an intravenous administration of Fentanil., Discussion and Conclusion: Day-surgery is nowadays a concrete reality, made possible by an attentive selection of patients, an accurate surgical technique, an attentive patient monitoring in the postoperative period and a continuous monitoring of the effectiveness of pain medications. Over the last decades our surgical team has developed modified techniques of loco-regional anesthesia that allow us to perform even complex procedures and discharge the patient within 24 hours., Key Words: Day-surgery, Haemorrhoids, Proctological procedures.

Hemorrhoidal disease is a very common condition requiring surgical management in approximately 10% of cases. Despite its long history and high prevalence, we are still trying to identify the best treatment. Earlier surgical approaches were soon abandoned and now only detain an historic significance. For long, proctologists have given their preference to hemorrhoidectomy that was gradually perfected through the years. The true innovation came in 1937, with the famous Milligan-Morgan hemorrhoidectomy, still one of the leading interventions for treatment of hemorrhoids. Less fortune encountered alternative techniques, such as the Whitehead hemorrhoidectomy, and closed and semi-closed techniques. Later on, the advent of a new concept of the pathogenesis of hemorrhoidal disease has brought to the development of stapled prolassectomy techniques. This approach has encountered both supporters and detractors between the experts in this field and has received a strong impulse by the emerging trend towards "day-surgery". Today the search for the best surgical technique for hemorrhoidal disease is far from being over and witnesses the introduction of new techniques for hemorrhoidal dissection. The choice of the best strategy remains in the hands of the clinician in the modern conception of tailored surgery., Key Word: Hemorrhoidal disease, Hemorrhoidectomy, Milligan-Morgan hemorrhoidectomy.

Background: Desmoid tumor is a rare soft tissues neoplasia characterized by local invasiveness and by a tendency towards local recurrence although not towards metastasization., Discussion: Etiology is not clear. Desmoid tumors originate from the monoclonal proliferation of one mesenchymal cell and develop in the context of fascial, muscular and aponeurotic tissue. They are free of capsule and do not usually metastatize, although they do present a high risk of local recurrence CONCLUSION: In the absence of a systematic data collection and of a clear distinction, in the existing databases, between primitive and recurrent lesions and between lesions of different sites, there are no standard guidelines for a correct management of desmoids., Key Words: Aggressive fibromatos Desmoid tumor, Soft tissue neoplasia.

The dichloromethane extract of the leaves of Bupleurum fruticosum was found to inhibit the replication of human rhinovirus (HRV) serotypes 14 and 39. Bioassay-guided fractionation led to the isolation of seven phenylpropenol derivatives (3-9), two polyacetylenes (1 and 2), and one monoterpene (10). Compounds 1 and 10 were identified as previously undescribed secondary metabolites after extensive 1D and 2D NMR experiments as well as high-resolution mass spectrometry. Compounds 2, 4, and 5 showed a selective inhibition of viral replication against HRV39 serotype, with 2 and 4 being the most active, with EC 50 values of 1.8 ± 0.02 and 2.4 ± 0.04 μM. Mechanism of action studies indicated that 4 behaves not only as a capsid binder, interfering with the early phases of virus replication, but also as a late-phase replication inhibitor. Docking experiments were performed to confirm the ability of the antiviral phenylpropenoids to selectively fit into the hydrophobic pocket of VP1-HRV39.

A series of N -acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids ( EMAC8000a-m ) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racemic mixture led to the isolation of the levorotatory eutomer exhibiting an increase of hCA XII inhibition potency and selectivity with respect to hCA II. Computational studies corroborated these data. Overall our data indicate that both substitution pattern and stereochemistry of dihydro-1,3,4-oxadiazole could be considered as key factors to determine activity and selectivity toward hCA isozymes. These results can provide further indication for the design and optimization of selective hCA inhibitors.

Background: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) Registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2015 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers., Methods: The Registry collects prospectively national PM and ICD implantation activity on the basis of European cards., Results: PM Registry: data about 24 285 PM implantations were collected (19 194 first implant and 5091 replacements). The number of collaborating centers was 218. Median age of treated patients was 81 years (75 quartile I; 86 quartile III). ECG indications included atrioventricular conduction disorders in 42.8% of first PM implants, sick sinus syndrome in 22.9%, atrial fibrillation plus bradycardia in 15.1%, other in 19.2%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (23.8% of first implants). Use of single-chamber PMs was reported in 26.9% of first implants, of dual-chamber PMs in 63.4%, of PMs with cardiac resynchronization therapy (CRT) in 1.8%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 7.9%. ICD Registry: data about 15 363 ICD implantations were collected (11 453 first implants and 3910 replacements). The number of collaborating centers was 434. Median age of treated patients was 71 years (63 quartile I; 78 quartile III]. Primary prevention indication was reported in 77.3% of first implants, secondary prevention in 22.7% (cardiac arrest in 8.0%). A single-chamber ICD was used in 29.3% of first implants, dual-chamber in 34.6% and biventricular in 36.1%., Conclusions: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice.

Background: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) Registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2014 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers., Methods: The Registry collects prospectively national PM and ICD implantation activity on the basis of European cards., Results: PM Registry: data about 24 680 PM implantations were collected (19 480 first implant and 5200 replacements). The number of collaborating centers was 208. Median age of treated patients was 81 years (75 quartile I; 86 quartile III). ECG indications included atrioventricular conduction disorders in 45.3% of first PM implants, sick sinus syndrome in 23.1%, atrial fibrillation plus bradycardia in 11.7%, other in 19.9%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (22.7% of first implants). Use of single-chamber PMs was reported in 26.9% of first implants, of dual-chamber PMs in 63.6%, of PMs with cardiac resynchronization therapy (CRT) in 1.7%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 7.8%. ICD Registry: data about 17 116 ICD implantations were collected (11 274 first implants and 5842 replacements). The number of collaborating centers was 424. Median age of treated patients was 71 years (62 quartile I; 77 quartile III). Primary prevention indication was reported in 72.3% of first implants, secondary prevention in 27.7% (cardiac arrest in 10.1%). A single-chamber ICD was used in 32.2% of first implants, dual-chamber in 37.1% and biventricular in 30.7%., Conclusions: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a large use of prophylactic and biventricular ICD, reflecting a favorable adherence to trials and guidelines in clinical practice.

Aim: To evaluate the impact of mesalamine administration on inflammatory response in acute uncomplicated diverticulitis., Methods: We conducted a single centre retrospective cohort study on patients admitted to our surgical department between January 2012 and May 2014 with a computed tomography -confirmed diagnosis of acute uncomplicated diverticulitis. A total of 50 patients were included in the analysis, 20 (study group) had received 3.2 g/d of mesalamine starting from the day of admission in addition to the usual standard treatment, 30 (control group) had received standard therapy alone. Data was retrieved from a prospective database. Our primary study endpoints were: C reactive protein mean levels over time and their variation from baseline (ΔCRP) over the first three days of treatment. Secondary end points included: mean white blood cell and neutrophile count over time, time before regaining of regular bowel movements (passing of stools), time before reintroduction of food intake, intensity of lower abdominal pain over time, analgesic consumption and length of hospital stay., Results: Patients characteristics and inflammatory parameters were similar at baseline in the two groups. The evaluation of CRP levels over time showed, in treated patients, a distinct trend towards a faster decrease compared to controls. This difference approached statistical significance on day 2 (mean CRP 6.0 +/- 4.2 mg/dL and 10.0 +/- 6.7 mg/dL respectively in study group vs controls, P = 0.055). ΔCRP evaluation evidenced a significantly greater increment of this inflammatory marker in the control group on day 1 (P = 0.03). A similar trend towards a faster resolution of inflammation was observed evaluating the total white blood cell count. Neutrophile levels were significantly lower in treated patients on day 2 and on day 3 (P < 0.05 for both comparisons). Mesalamine administration was also associated with an earlier reintroduction of food intake (median 1.5 d and 3 d, study group vs controls respectively, P < 0.001) and with a shorter hospital stay (median 5 d and 5.5 d, study group vs controls respectively, P = 0.03)., Conclusion: Despite its limitations, this study suggests that mesalamine may allow for a faster recovery and for a reduction of inflammatory response in acute uncomplicated diverticulitis.

Background: The pacemaker (PM) and implantable cardioverter-defibrillator (ICD) Registry of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) monitors the main epidemiological data in real-world practice. The survey for the 2013 activity collects information about demographics, clinical characteristics, main indications for PM/ICD therapy and device types from the Italian collaborating centers., Methods: The Registry collects prospectively national PM and ICD implantation activity on the basis of European cards., Results: PM Registry: data about 25 419 PM implantations were collected (19 134 first implant and 6285 replacements). The number of collaborating centers was 275. Median age of treated patients was 80 years (74 quartile I; 86 quartile III). ECG indications included atrioventricular conduction disorders in 43.6% of first PM implants, sick sinus syndrome in 24.7%, atrial fibrillation plus bradycardia in 12.9%, other in 18.8%. Among atrioventricular conduction defects, third-degree atrioventricular block was the most common type (23.2% of first implants). Use of single-chamber PMs was reported in 27.2% of first implants, of dual-chamber PMs in 62.6%, of PMs with cardiac resynchronization therapy (CRT) in 1.8%, and of single lead atrial-synchronized ventricular stimulation (VDD/R PMs) in 8.4%. ICD Registry: data about 16 519 ICD implantations were collected (11 474 first implants and 5045 replacements). The number of collaborating centers was 430. Median age of treated patients was 71 years (63 quartile I; 77 quartile III). Primary prevention indication was reported in 76% of first implants, secondary prevention in 24.0% (cardiac arrest in 7.8%). A single-chamber ICD was used in 27.2% of first implants, dual-chamber in 35.9% and biventricular in 36.8%., Conclusions: The PM and ICD Registry appears fundamental for monitoring PM and ICD utilization on a large national scale with rigorous examination of demographics and clinical indications. The PM Registry showed stable electrocardiographic and symptom indications, with an important prevalence of dual-chamber pacing. The use of CRT-PM regards a very limited number of patients. The ICD Registry documented a constant increase in prophylactic and biventricular ICD use, reflecting a favorable adherence to trials and guidelines in clinical practice.