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Aims: The incidence of lung infections is increasing worldwide in individuals suffering from cystic fibrosis and chronic obstructive pulmonary disease. Mycobacterium abscessus is associated with chronic lung deterioration in these populations. The intrinsic resistance of M. abscessus to most conventional antibiotics jeopardizes treatment success rates. To date, no single drug has been developed targeting M. abscessus specifically. The objective of this study was to characterize VOMG, a pyrithione-core drug-like small molecule, as a new compound active against M. abscessus and other pathogens., Methods: A multi-disciplinary approach including microbiological, chemical, biochemical and transcriptomics procedures was used to validate VOMG as a promising anti-M. abscessus drug candidate., Results: To the authors' knowledge, this is the first study to report the in-vitro and in-vivo bactericidal activity of VOMG against M. abscessus and other pathogens. Besides being active against M. abscessus biofilm, the compound showed a favourable pharmacological (ADME-Tox) profile. Frequency of resistance studies were unable to isolate resistant mutants. VOMG inhibits cell division, particularly the FtsZ enzyme., Conclusions: VOMG is a new drug-like molecule active against M. abscessus, inhibiting cell division with broad-spectrum activity against other microbial pathogens., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Patients with cystic fibrosis (CF) are prone to developing life-threatening lung infections with a variety of pathogens that are difficult to eradicate, such as Burkholderia cepacia complex (Bcc) , Hemophilus influenzae , Mycobacterium abscessus ( Mab ), Pseudomonas aeruginosa , and Staphylococcus aureus . These infections still remain an important issue, despite the therapy for CF having considerably improved in recent years. Moreover, prolonged exposure to antibiotics in combination favors the development and spread of multi-resistant bacteria; thus, the development of alternative strategies is crucial to counter antimicrobial resistance. In this context, phage therapy, i.e., the use of phages, viruses that specifically infect bacteria, has become a promising strategy. In this review, we aim to address the current status of phage therapy in the management of multidrug-resistant infections, from compassionate use cases to ongoing clinical trials, as well as the challenges this approach presents in the particular context of CF patients.

Blocking iron uptake and metabolism has been emerging as a promising therapeutic strategy for the development of novel antimicrobial compounds. Like all mycobacteria, M. abscessus (Mab) has evolved several countermeasures to scavenge iron from host carrier proteins, including the production of siderophores, which play a crucial role in these processes. In this study, we solved, for the first time, the crystal structure of Mab-SaS, the first enzyme involved in the biosynthesis of siderophores. Moreover, we screened a small, focused library and identified a compound exhibiting a potent inhibitory effect against Mab-SaS (IC 50  ≈ 2 μM). Its binding mode was investigated by means of Induced Fit Docking simulations, performed on the crystal structure presented herein. Furthermore, cytotoxicity data and pharmacokinetic predictions revealed the safety and drug-likeness of this class of compounds. Finally, the crystallographic data were used to optimize the model for future virtual screening campaigns. Taken together, the findings of our study pave the way for the identification of potent Mab-SaS inhibitors, based on both established and unexplored chemotypes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laurent R. Chiarelli reports financial support was provided by Italian Cystic Fibrosis Research Foundation (FFC Ricerca). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A series of novel benzothiozinone (BTZ) derivatives were designed, prepared and evaluated for antituberculosis activity. Specifically, the BTZ pharmacophore is retained and the previous heterocyclic ring linker is replaced by alkynyl or vinyl linker, the resulting compounds displayed about 5-fold improved antimycobacterial activity. We further revealed that the linker attached tail group affects the compound metabolic stability, potency and other drug like properties. This work led to the discovery of two compounds (A1 and A11) with acceptable low MICs and improved metabolic stability. The representative compound A11 demonstrated bactericidal efficacy in an acute TB infection mouse model., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chunhua Qiao reports financial support was provided by Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD). Chunhua Qiao has patent Preparation of benzothiazinone derivatives and application thereof pending to WO 2023065182 A1. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Human neutrophil elastase (HNE) is involved in SARS-CoV-2 virulence and plays a pivotal role in lung infection of patients infected by COVID-19. In healthy individuals, HNE activity is balanced by α1-antitrypsin (AAT). This is a 52 kDa glycoprotein, mainly produced and secreted by hepatocytes, that specifically inhibits HNE by blocking its activity through the formation of a stable complex (HNE-AAT) in which the two proteins are covalently bound. The lack of this complex, together with the detection of HNE activity in BALf/plasma samples of COVID-19 patients, leads us to hypothesize that potential functional deficiencies should necessarily be attributed to possible structural modifications of AAT. These could greatly diminish its ability to inhibit neutrophil elastase, thus reducing lung protection. The aim of this work was to explore the oxidation state of AAT in BALf/plasma samples from these patients so as to understand whether the deficient inhibitory activity of AAT was somehow related to possible conformational changes caused by the presence of abnormally oxidized residues.

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 µM. The representative compound 37 displays improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model.

Reverse vaccinology is a powerful tool that was recently used to develop vaccines starting from a pathogen genome. Some bacterial infections have the necessity to be prevented then treated. For example, individuals with chronic pulmonary diseases, such as Cystic Fibrosis, are prone to develop infections and biofilms in the thick mucus that covers their lungs, mainly caused by Burkholderia cepacia complex, Haemophilus influenzae , Mycobacterium abscessus complex , Pseudomonas aeruginosa and Staphylococcus aureus. These infections are complicated to treat and prevention remains the best strategy. Despite the availability of vaccines against some strains of those pathogens, it is necessary to improve the immunization of people with Cystic Fibrosis against all of them. An effective approach is to develop a broad-spectrum vaccine to utilize proteins that are well conserved across different species. In this context, reverse vaccinology, a method based on computational analysis of the genome of various microorganisms, appears as one of the most promising tools for the identification of putative targets for broad-spectrum vaccine development. This review provides an overview of the vaccines that are under development by reverse vaccinology against the aforementioned pathogens, as well as the progress made so far.

Treatment against tuberculosis can lead to the selection of drug-resistant Mycobacterium tuberculosis strains. To tackle this serious threat, new targets from M. tuberculosis are needed to develop novel effective drugs. In this work, we aimed to provide a possible workflow to validate new targets and inhibitors by combining genetic, in silico , and enzymological approaches. CanB is one of the three M. tuberculosis β-carbonic anhydrases that catalyze the reversible reaction of CO 2 hydration to form HCO 3 - and H + . To this end, we precisely demonstrated that CanB is essential for the survival of the pathogen in vitro by constructing conditional mutants. In addition, to search for CanB inhibitors, conditional canB mutants were also constructed using the Pip-ON system. By molecular docking and minimum inhibitory concentration assays, we selected three molecules that inhibit the growth in vitro of M. tuberculosis wild-type strain and canB conditional mutants, thus implementing a target-to-drug approach. The lead compound also showed a bactericidal activity by the time-killing assay. We further studied the interactions of these molecules with CanB using enzymatic assays and differential scanning fluorimetry thermal shift analysis. In conclusion, the compounds identified by the in silico screening proved to have a high affinity as CanB ligands endowed with antitubercular activity., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections is one of the most crucial challenges currently faced by the scientific community. Developments in the fundamental understanding of their underlying mechanisms may open new perspectives in drug discovery. In this review, we conducted a systematic literature search in PubMed, Web of Science, and Scopus, to collect information on innovative strategies to hinder iron acquisition in bacteria. In detail, we discussed the most interesting targets from iron uptake and metabolism pathways, and examined the main chemical entities that exhibit anti-infective activities by interfering with their function. The mechanism of action of each drug candidate was also reviewed, together with its pharmacodynamic, pharmacokinetic, and toxicological properties. The comprehensive knowledge of such an impactful area of research will hopefully reflect in the discovery of newer antibiotics able to effectively tackle the antimicrobial resistance issue.

Mycobacterium abscessus is an opportunistic pathogen that mainly colonizes and infects cystic fibrosis patients' lungs. M. abscessus is naturally resistant to many antibiotics such as rifamycin, tetracyclines and β-lactams. The current therapeutic regimens are not very effective and are mostly based on repurposed drugs used against Mycobacterium tuberculosis infections. Thus, new approaches and novel strategies are urgently needed. This review aims to provide an overview of the latest ongoing findings to fight M. abscessus infections by analyzing emerging and alternative treatments, novel drug delivery strategies, and innovative molecules.

Targeting pathogenic mechanisms, rather than essential processes, represents a very attractive approach for the development of new antimycobacterial drugs. In this context, iron acquisition routes have recently emerged as potentially druggable pathways. However, the importance of siderophore biosynthesis in the virulence and pathogenicity of M. abscessus ( Mab ) is still poorly understood. In this study, we investigated the Salicylate Synthase (SaS) of Mab as an innovative molecular target for the development of inhibitors of siderophore production. Notably, Mab -SaS does not have any counterpart in human cells, making it an interesting candidate for drug discovery. Starting from the analysis of the binding of a series of furan-based derivatives, previously identified by our group as inhibitors of MbtI from M. tuberculosis ( Mtb ), we successfully selected the lead compound 1 , exhibiting a strong activity against Mab -SaS (IC 50 ≈ 5 µM). Computational studies characterized the key interactions between 1 and the enzyme, highlighting the important roles of Y387, G421, and K207, the latter being one of the residues involved in the first step of the catalytic reaction. These results support the hypothesis that 5-phenylfuran-2-carboxylic acids are also a promising class of Mab -SaS inhibitors, paving the way for the optimization and rational design of more potent derivatives.

Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. tuberculosis ( Mtb ) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid ( I ), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure-activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, 1f emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs.

Tuberculosis (TB) is one of the leading causes of death worldwide, due to a single pathogen, Mycobacterium tuberculosis. To eradicate TB, management of drug-resistant strains is fundamental, therefore, the identification and characterization of drug targets is pivotal. In this work we aim at describing the relationships with the well-known drug target DprE1 and DprE2, working in association for the biosynthesis of the arabinogalactan precursor, essential component of mycobacterial cell wall. We demonstrated that the enzymes behave as a stable heterodimeric complex, once co-expressed into the same system. This complex showed improved catalytic properties, compared to the singularly expressed enzymes, demonstrating that co-expression is fundamental to achieve the proper folding of the active sites. Our results represent an important step forward in deciphering the functional properties of these enzymes, and lay the foundations for structural studies, useful for development of more specific inhibitors helpful to contrast the spreading of drug-resistant strains., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mycobacterial resistance is a rapidly increasing phenomenon requiring the identification of new drugs effective against multidrug-resistant pathogens. The inhibition of protein tyrosine phosphatase B (MptpB), which interferes with host immune responses, may provide a new strategy to fight tuberculosis (TB), while preventing cross-resistance issues. On this basis, starting from a virtual screening (VS) campaign and subsequent structure elucidation studies guided by X-ray analyses, an unexpected γ-lactone derivative (compound 1) with a significant enzymatic activity against MptpB was identified. The structural characterization of compound 1 was described by means of NMR spectroscopy, HRMS, single crystal X-ray diffraction and Hirshfeld surface analysis, allowing a detailed conformational investigation. Notably, the HPLC separation of (±)-1 led to the isolation of the most active isomer, which emerged as a very promising MptpB inhibitor, with an IC 50 value of 31.1 μM. Overall, the new chemotype described herein might serve as a basis for the development of novel treatments against TB infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The 6-trifluoro substituted 8-nitrobenzothiazinones (BTZs) represent a novel type of antitubercular agents, and their high antimycobacterial activity is related to the inhibition of decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1), an enzyme essential for the biosynthesis of mycobacterial cell wall. While extraordinary whole-cell activity was reported for the clinically advanced compound PBTZ169, its poor aqueous solubility signals the potential low bioavailability. To ameliorate the BTZ physiochemical property, a series of 6-methanesulfonyl substituted compounds were designed and prepared, and their antitubercular activity and DprE1 inhibition ability were evaluated. Among these compounds, MsPBTZ169 and compounds 2 and 8 exhibited minimum inhibitory concentrations (MICs) of less than 40 nM; moreover, these compounds displayed increased aqueous solubility and acceptable metabolic stability. Taken together, this study suggested that the 6-methanesulfonyl substituted 8-nitrobenzothiazinone derivatives, in combination with side chain modification, might provide BTZ type antitubercular agents with improved drug-like properties., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Avermectins are macrocyclic lactones with anthelmintic activity. Recently, they were found to be effective against Mycobacterium tuberculosis , which accounts for one third of the worldwide deaths from antimicrobial resistance. However, their anti-mycobacterial mode of action remains to be elucidated. The activity of selamectin was determined against a panel of M. tuberculosis mutants. Two strains carrying mutations in DprE1, the decaprenylphosphoryl-β-D-ribose oxidase involved in the synthesis of mycobacterial arabinogalactan, were more susceptible to selamectin. Biochemical assays against the Mycobacterium smegmatis DprE1 protein confirmed this finding, and docking studies predicted a binding site in a loop that included Leu275. Sequence alignment revealed variants in this position among mycobacterial species, with the size and hydrophobicity of the residue correlating with their MIC values; M. smegmatis DprE1 variants carrying these point mutations validated the docking predictions. However, the correlation was not confirmed when M. smegmatis mutant strains were constructed and MIC phenotypic assays performed. Likewise, metabolic labeling of selamectin-treated M. smegmatis and M. tuberculosis cells with 14 C-labeled acetate did not reveal the expected lipid profile associated with DprE1 inhibition. Together, our results confirm the in vitro interactions of selamectin and DprE1 but suggest that selamectin could be a multi-target anti-mycobacterial compound.

Background: Hamstring diseases are one of the most widespread diseases in athletes, especially in runners, sprinters, and endurance athletes. Notwithstanding the importance of the problem, risk factors are still marginally known. This transversal study analyzes the correlation between hamstring tendinopathy and hamstring strains and age, gender, weight, height, number of marathons, and impact profile in athletes who took part in the 2019 Rome Marathon., Methods: At the 2019 Marathon of Rome, 700 runners (484 males and 216 females; mean age: 43.6 years, range 17-80 years) filled the VISA-H and FASH questionnaires. an adequately skilled orthopedic surgeon made a diagnosis of hamstring tendinopathy and hamstring strain injuries in line with clinical criteria., Results: A diagnosis of hamstring tendinopathy was made in 537 participants while in 624 of hamstring strains. There was evidence of a positive correlation statistically significant between age, weight and impact profile with hamstring strain injuries, while there was no association between sex and number of marathons and the hamstring strains. No statistically significant positive correlation was found between all of the parameters analyzed and VISA-H. The association between VISA-H score and FASH score has resulted statistically significant., Conclusions: In marathon athletes, there was not found evidence of a statistically significant correlation between gender, weight, height, number of marathons, impact profile and hamstring tendinopathy. Nonetheless, age, weight and impact profile were associated with hamstring strains, while sex and number of marathons had not shown statistically significant positive association with hamstring strain injuries.

The benzothiazinone (BTZ) scaffold compound PBTZ169 kills Mycobacterium tuberculosis by inhibiting the essential flavoenzyme DprE1, consequently blocking the synthesis of the cell wall component arabinans. While extraordinarily potent against M. tuberculosis with a minimum inhibitory concentration (MIC) less than 0.2 ng/mL, its low aqueous solubility and bioavailability issues need to be addressed. Here, we designed and synthesized a series of 6-methanesulfonyl substituted BTZ analogues; further exploration introduced five-member aromatic heterocycles as linkers to attach an aryl group as the side chain. Our work led to the discovery of a number of BTZ derived compounds with potent antitubercular activity. The optimized compounds 6 and 38 exhibited MIC 47 and 30 nM, respectively. Compared to PBTZ169, both compounds displayed increased aqueous solubility and higher stability in human liver microsomes. This study suggested that an alternative side-chain modification strategy could be implemented to improve the druglike properties of the BTZ-based compounds.

Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of Mycobacterium tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new antitubercular agents is the salicylate synthase MbtI, an essential enzyme for the mycobacterial siderophore biochemical machinery, absent in human cells. A set of analogues of I and II , two of the most potent MbtI inhibitors identified to date, was synthesized, characterized, and tested to elucidate the structural requirements for achieving an efficient MbtI inhibition and a potent antitubercular activity with this class of compounds. The structure-activity relationships (SAR) here discussed evidenced the importance of the furan as part of the pharmacophore and led to the preparation of six new compounds ( IV - IX ), which gave us the opportunity to examine a hitherto unexplored position of the phenyl ring. Among them emerged 5-(3-cyano-5-(trifluoromethyl)phenyl)furan-2-carboxylic acid ( IV ), endowed with comparable inhibitory properties to the previous leads, but a better antitubercular activity, which is a key issue in MbtI inhibitor research. Therefore, compound IV offers promising prospects for future studies on the development of novel agents against mycobacterial infections.

Background: Achilles and patellar tendinopathy are common in runners. Despite the relevance of the problem, causative factors remain poorly understood. This cross-sectional study evaluated the association between Achilles and patellar tendinopathy and age, sex, weight, height, number of marathons, and impact profile in runners who participated in the 2017 Marathon of Rome., Methods: At the 2017 Marathon of Rome, 350 athletes (256 men and 94 women; mean age: 44.8 years, range 12-80 years) filled in the VISA-A and VISA-P questionnaires. A fully trained orthopedic surgeon made a diagnosis of Achilles and patellar tendinopathy according to clinical criteria., Results: Ninety-five participants were diagnosed with Achilles tendinopathy and 96 with patellar tendinopathy. There was evidence of a statistically significant positive association between age and Achilles and patellar tendinopathy, with no effect of sex, weight, and height on the presence of Achilles tendinopathy. There was no evidence of a statistically significant positive association between the number of marathons and impact profile and VISA-A score. There was a statistically significant association between VISA-P score and impact profile. Finally, there was evidence of a statistically significant positive association between VISA-A score and VISA-P score (P = 0.007)., Conclusions: In marathon runners, there was no evidence of a statistically significant association between sex, weight, height, number of marathons, and Achilles and patellar tendinopathy. However, age was associated with Achilles and patellar tendinopathy, and impact profile was associated with patellar tendinopathy.

Purpose: Nowadays, surgical treatment of acute avulsions of the Achilles tendon represents a hard challenge. There is often the possibility that the calcaneus remains completely uncovered from the tendon, making the reinsertion of its distal stub complex. At the same time, the standard open surgical technique could cause difficult wound healing because of the weak blood supply, the increasing possibility of rupture, and the bacterial contamination. To overcome these risks, less invasive procedures should be considered. Methods: We developed an innovative minimally invasive procedure for fixation of acute avulsions of the Achilles tendon employing an integration of four longitudinal stab incisions and one distal semicircular Cincinnati incision. In this way, the distal Achilles tendon stub and the calcaneal insertion are exhibited. Results: We basted the tendon through percutaneous sutures performed across the four stab incisions with a Mayo needle threaded with Ultrabraid. The procedure is repeated with another loop of Ultrabraid. After having bruised the calcaneus bone insertion of the tendon, two sites for two suture anchors were prepared using a specific hole preparation device for the anchors' footprint. Finally, we placed two suture anchors to reinsert the tendon to the calcaneal insertion. Conclusion: Our new less invasive technique is a promising alternative optional procedure for the Achilles tendon (AT) avulsion repair allowing clear exposure of the Achilles tendon insertion, maintaining the longitudinal wholeness of the dermis, and minimizing possible associated complications.

The Mg 2+ -dependent Mycobacterium tuberculosis salicylate synthase (MbtI) is a key enzyme involved in the biosynthesis of siderophores. Because iron is essential for the survival and pathogenicity of the microorganism, this protein constitutes an attractive target for antitubercular therapy, also considering the absence of homologous enzymes in mammals. An extension of the structure-activity relationships of our furan-based candidates allowed us to disclose the most potent competitive inhibitor known to date ( 10 , K i = 4 μM), which also proved effective on mycobacterial cultures. By structural studies, we characterized its unexpected Mg 2+ -independent binding mode. We also investigated the role of the Mg 2+ cofactor in catalysis, analyzing the first crystal structure of the MbtI-Mg 2+ -salicylate ternary complex. Overall, these results pave the way for the development of novel antituberculars through the rational design of improved MbtI inhibitors.

The authors would like to correct the names and surnames of the following authors of their previous paper [...].

Background : This study intends to summarize the causes, clinical examination, and treatments of scapular dyskinesis (SD) and to briefly investigate whether alteration can be managed by a precision rehabilitation protocol planned on the basis of features derived from clinical tests. Methods : We performed a comprehensive search of PubMed, Cochrane, CINAHL and EMBASE databases using various combinations of the keywords "Rotator cuff", "Scapula", "Scapular Dyskinesis", "Shoulder", "Biomechanics" and "Arthroscopy". Results : SD incidence is growing in patients with shoulder pathologies, even if it is not a specific injury or directly related to a particular injury. SD can be caused by multiple factors or can be the trigger of shoulder-degenerative pathologies. In both cases, SD results in a protracted scapula with the arm at rest or in motion. Conclusions : A clinical evaluation of altered shoulder kinematics is still complicated. Limitations in observing scapular motion are mainly related to the anatomical position and function of the scapula itself and the absence of a tool for quantitative SD clinical assessment. High-quality clinical trials are needed to establish whether there is a possible correlation between SD patterns and the specific findings of shoulder pathologies with altered scapular kinematics.

Background: The objective of the present study was to compare the efficacy between supervised and unsupervised rehabilitation after rotator-cuff (RC) repair in terms of clinical outcomes, visual-analog-scale (VAS) score, range of motion (ROM), and risk of retear., Material: a comprehensive search of Pubmed, CINAHL, Cochrane, EMBASE, Ovid, and Google Scholar databases through a combination of the following keywords with logical Boolean operators: "informed", "uninformed", "unsupervised", "supervised", "rehabilitation", "physical therapy", "physical therapies", "postoperative period", "physical-therapy techniques", "physical-therapy technique", "exercise", "exercise therapy", "rotator cuff", "rotator-cuff tear", and "rotator-cuff repair". For each article included in the study, the following data were extracted: authors, year, study design, sample size and demographic features, RC tear characteristics, clinical outcomes, ROM, VAS score, retear rate, and time of follow-up. Meta-analysis was performed in terms of VAS score., Results: Four randomized control trials with 132 patients were included. One study demonstrated significant improvement in VAS, active ROM, and the activity of the muscle's motor units at stop and during maximal effort in supervised patients. Another one showed lower retear rates in the supervised group. The remaining two randomized controlled trials did not reveal any significant differences between supervised and unsupervised rehabilitation in terms of clinical outcomes. Moreover, higher costs were described for supervised rehabilitation. The VAS was not significantly different in the two groups (9.9 compared with 8.25, p = 0.23)., Conclusions: although several publications address the problem of RC lacerations, there is a paucity of evidence in the literature regarding the effectiveness of supervised and unsupervised rehabilitation protocols. This systematic review and meta-analysis showed no significant differences between the two types of rehabilitation in terms of VAS scores, while outlining the pros and cons of each protocol.

Limited knowledge is accessible concerning the tendencies of hospitalization for skeletally immature patients with episodes of shoulder dislocation. Our research aim was to evaluate annual hospitalizations for shoulder dislocation in paediatric patients in Italy from 2001 to 2014, on the basis of the official data source as hospitalization reports. The second purpose was to investigate geographical diversification in hospitalization for shoulder dislocation in regions of Italy. The last aim was to make statistical predictions of the number of shoulder dislocation hospitalization volumes and rates in skeletally immature patients based on data from 2001 to 2014. An examination of the National Hospital Discharge records (SDO) kept at the Italian Ministry of Health regarding the 14 years of our study (2001 through 2014) was conducted. These data are anonymous and include patient's age, gender, domicile, region and time of hospitalization, and the kind of reimbursement (public or private). In the 14-year study time, 344 hospitalizations for shoulder dislocation of patients aged 0-14 years took place in Italy. The male/female hospitalization ratio varied from a maximum of 3.0 (2001) to a minimum of 1.1 (2013), with a mean average ratio in the 2001-2014 timespan of 2.0. Almost half of the hospitalizations (49.1%) were performed in the South. The mean incidence of hospitalizations in Italy for shoulder dislocation in patients with less than 14 years was 0.3 for every 100,000 inhabitants in the same class of age. The most common treatment was a closed reduction (60.8%), followed by open stabilization (16.6%) and arthroscopic procedures (13.7%). The present registry study shows a low incidence of hospitalization for shoulder dislocation in young patients. The most common treatment for a shoulder dislocation in paediatric patients is a closed shoulder reduction. Regions from the south and the centre of Italy are marked by an inferior number of operations and a higher number of hospitalization for closed shoulder reduction.

Tuberculosis is still an urgent global health problem, mainly due to the spread of multi-drug resistant M. tuberculosis strains, which lead to the need of new more efficient drugs. A strategy to overcome the problem of the resistance insurgence could be the polypharmacology approach, to develop single molecules that act on different targets. Polypharmacology could have features that make it an approach more effective than the classical polypharmacy, in which different drugs with high affinity for one target are taken together. Firstly, for a compound that has multiple targets, the probability of development of resistance should be considerably reduced. Moreover, such compounds should have higher efficacy, and could show synergic effects. Lastly, the use of a single molecule should be conceivably associated with a lower risk of side effects, and problems of drug-drug interaction. Indeed, the multitargeting approach for the development of novel antitubercular drugs have gained great interest in recent years. This review article aims to provide an overview of the most recent and promising multitargeting antitubercular drug candidates.

Starting from the analysis of the hypothetical binding mode of our previous furan-based hit (I), we successfully achieved our objective to replace the nitro moiety, leading to the disclosure of a new lead exhibiting a strong activity against MbtI. Our best candidate 1 h displayed a K i of 8.8 µM and its antimycobacterial activity (MIC 99  = 250 µM) is conceivably related to mycobactin biosynthesis inhibition. These results support the hypothesis that 5-phenylfuran-2-carboxylic derivatives are a promising class of MbtI inhibitors.

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (K i  = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC 99  = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)