The impact of ventral oral graft bulbar urethroplasty on sexual life

Objective: To evaluate the pre- and postoperative aspects of sexual life (SL) in patients with bulbar urethral stricture who underwent ventral oral graft urethroplasty. Methods: Between 2009 and 2010, 52 men (mean age 36 years) were enrolled in our prospective study to ascertain sexual disorders before and after surgery. The validated Male Sexual Health Questionnaire-Long Form (MSHQ-LF) was completed pre- and postoperatively; the unvalidated but adapted Post-Urethroplasty Sexual Questionnaire (PUSQ) was completed postoperatively. Data were compared using the non parametric Wilcoxon test. Results: Before urethroplasty, most of the patients reported sexual disorders, in particular reduced ejaculatory stream (85%); many of them (35%) feared the risk of a postoperative worsening in the quality of SL. After urethroplasty, nobody reported a worsened erection, while most of the patients noticed a significant improvement in erection, ejaculation, relationship with their partner, sexual activity, and desire. Modifications in the scrotoperineal sensitivity were reported by 42% and 15% noticed esthetic changes without impact on SL. All patients reported an improvement in quality of life (QOL) and were satisfied with the outcome of urethroplasty. Conclusion: Urethral stricture disease may be responsible for sexual disorders that have a significant impact upon SL. Patients confessed a marked anxiety tackling urethroplasty and declared that one of their deepest fears regarded a potential further deterioration in the quality of SL. At short-term follow-up, the minimally invasive ventral graft urethroplasty does not cause sexual complications, apart from the post-ejaculation dribbling. On the contrary, this technique showed to restore SL in all its aspects

Discovery of new diketopiperazines inhibiting Burkholderia cenocepacia quorum sensing in vitro and in vivo

Burkholderia cenocepacia, an opportunistic respiratory pathogen particularly relevant for cystic fibrosis patients, is difficult to eradicate due to its high level of resistance to most clinically relevant antimicrobials. Consequently, the discovery of new antimicrobials as well as molecules capable of inhibiting its virulence is mandatory. In this regard quorum sensing (QS) represents a good target for anti-virulence therapies, as it has been linked to biofilm formation and is important for the production of several virulence factors, including proteases and siderophores. Here, we report the discovery of new diketopiperazine inhibitors of the B. cenocepacia acyl homoserine lactone synthase CepI, and report their anti-virulence properties. Out of ten different compounds assayed against recombinant CepI, four were effective inhibitors, with IC50 values in the micromolar range. The best compounds interfered with protease and siderophore production, as well as with biofilm formation, and showed good in vivo activity in a Caenorhabditis elegans infection model. These molecules were also tested in human cells and showed very low toxicity. Therefore, they could be considered for in vivo combined treatments with established or novel antimicrobials, to improve the current therapeutic strategies against B. cenocepacia

Development and Validation of a Novel Skills Training Model for PCNL, an ESUT project

Background and aim: The aim of this study is to validate a totally non biologic training model that combines the use of ultrasound and X ray to train Urologists and Residents in Urology in PerCutaneous NephroLithotripsy (PCNL). Methods: The training pathway was divided into three modules: Module 1, related to the acquisition of basic UltraSound (US) skill on the kidney; Module 2, consisting of correct Nephrostomy placement; and Module 3, in which a complete PCNL was performed on the model. Trainees practiced on the model first on Module 1, than in 2 and in 3. The pathway was repeated at least three times. Afterward, they rated the performance of the model and the improvement gained using a global rating score questionnaire. Results: A total of 150 Urologists took part in this study. Questionnaire outcomes on this training model showed a mean 4.21 (range 1-5) of positive outcome overall. Individual constructive validity showed statistical significance between the first and the last time that trainees practiced on the PCNL model among the three different modules. Statistical significance was also found between residents, fellows and experts scores. Trainees increased their skills during the training modules. Conclusion: This PCNL training model allows for the acquisition of technical knowledge and skills as US basic skill, Nephrostomy placement and entire PCNL procedure. Its structured use could allow a better and safer training pathway to increase the skill in performing a PCNL

Characterization of the dispirotripiperazine derivative PDSTP as antibiotic adjuvant and antivirulence compound against Pseudomonas aeruginosa

Pseudomonas aeruginosa is a major human pathogen, able to establish difficult-to-treat infections in immunocompromised and people with cystic fibrosis (CF). The high rate of antibiotic treatment failure is due to its notorious drug resistance, often mediated by the formation of persistent biofilms. Alternative strategies, capable of overcoming P. aeruginosa resistance, include antivirulence compounds which impair bacterial pathogenesis without exerting a strong selective pressure, and the use of antimicrobial adjuvants that can resensitize drug-resistant bacteria to specific antibiotics. In this work, the dispirotripiperazine derivative PDSTP, already studied as antiviral, was characterized for its activity against P. aeruginosa adhesion to epithelial cells, its antibiotic adjuvant ability and its biofilm inhibitory potential. PDSTP was effective in impairing the adhesion of P. aeruginosa to various immortalized cell lines. Moreover, the combination of clinically relevant antibiotics with the compound led to a remarkable enhancement of the antibiotic efficacy towards multidrug-resistant CF clinical strains. PDSTP-ceftazidime combination maintained its efficacy in vivo in a Galleria mellonella infection model. Finally, the compound showed a promising biofilm inhibitory activity at low concentrations when tested both in vitro and using an ex vivo pig lung model. Altogether, these results validate PDSTP as a promising compound, combining the ability to decrease P. aeruginosa virulence by impairing its adhesion and biofilm formation, with the capability to increase antibiotic efficacy against antibiotic resistant strains

International alliance of Urolithiasis (IAU) guideline on percutaneous nephrolithotomy

The International Alliance of Urolithiasis (IAU) would like to release the latest guideline on percutaneous nephrolithotomy (PCNL) and to provide a clinical framework for surgeons performing PCNL. These recommendations were collected and appraised from a systematic review and assessment of the literature covering all aspects of PCNLs from the PubMed database between January 1, 1976, and July 31, 2021. Each generated recommendation was graded using a modified GRADE methodology. The quality of the evidence was graded using a classification system modified from the Oxford Center for Evidence-Based Medicine Levels of Evidence. Forty-seven recommendations were summarized and graded, which covered the following issues, indications and contraindications, stone complexity evaluation, preoperative imaging, antibiotic strategy, management of antithrombotic therapy, anesthesia, position, puncture, tracts, dilation, lithotripsy, intraoperative evaluation of residual stones, exit strategy, postoperative imaging and stone-free status evaluation, complications. The present guideline on PCNL was the first in the IAU series of urolithiasis management guidelines. The recommendations, tips and tricks across the PCNL procedures would provide adequate guidance for urologists performing PCNLs to ensure safety and efficiency in PCNLs

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery