Miconazole and phenothiazine hinder the quorum sensing regulated virulence in Pseudomonas aeruginosa.

Antibiotic resistance is a major health problem worldwide. Pseudomonas aeruginosa is a Gram-negative pathogen with an arsenal of virulence factors and elevated antimicrobial resistance. It is a leading cause of nosocomial infections with high morbidity and mortality. The significant time and effort required to develop new antibiotics can be circumvented using alternative therapeutic strategies, including anti-virulence targets. This study aimed to investigate the anti-virulence activity of the FDA-approved drugs miconazole and phenothiazine against P. aeruginosa. The phenotypic effect of sub-inhibitory concentrations of miconazole and phenothiazine on biofilm, pyocyanin, protease, rhamnolipid and hemolysin activities in PAO1 strain was examined. qRT-PCR was used to assess the effect of drugs on quorum-sensing genes that regulate virulence. Further, the anti-virulence potential of miconazole and phenothiazine was evaluated in silico and in vivo. Miconazole showed significant inhibition of Pseudomonas virulence by reducing biofilm-formation approximately 45-48%, hemolytic-activity by 59%, pyocyanin-production by 47-49%, rhamnolipid-activity by approximately 42-47% and protease activity by 36-40%. While, phenothiazine showed lower anti-virulence activity, it inhibited biofilm (31-35%), pyocyanin (37-39%), protease (32-40%), rhamnolipid (35-40%) and hemolytic activity (47-56%). Similarly, there was significantly reduced expression of RhlR, PqsR, LasI and LasR following treatment with miconazole, but less so with phenothiazine. In-silico analysis revealed that miconazole had higher binding affinity than phenothiazine to LasR, RhlR, and PqsR QS-proteins. Furthermore, there was 100% survival in mice injected with PAO1 treated with miconazole. In conclusion, miconazole and phenothiazine are promising anti-virulence agents for P. aeruginosa.

Current applications of ex-vivo fluorescent confocal microscope in urological practice: a systematic review of literature.

BACKGROUND: Histopathological examination, a cornerstone in diagnosing cancer, faces challenges due to its time-consuming nature. This review explores the potential of ex-vivo fluorescent confocal microscopy (FCM) in urology, addressing the need for real-time pathological assessment, particularly in prostate cancer. This systematic review aims to assess the applications of FCM in urology, including its role in prostate cancer diagnosis, surgical margin assessment, and other urological fields. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a systematic search of PubMed and SCOPUS was conducted, focusing on English written original articles published after January 1, 2018, discussing the use of FCM in urological practice. The search included keywords related to FCM and urological terms. The risk of bias assessment was performed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. RESULTS: A total of 17 relevant studies were included in the review that focuses on three main urological issues: prostate cancer (15 articles), bladder cancer (1 article), and renal biopsy (1 article). FCM exhibited significant promise in diagnosing prostate cancer. These studies reported an accuracy range of 85.33% to 95.1% in distinguishing between cancerous and non-cancerous prostate tissues. Moreover, FCM proved valuable for assessing surgical margins in real-time during radical prostatectomy, reducing the need for frozen section analysis. In some investigations, researchers explored the integration of artificial intelligence (AI) with FCM to automate diagnostic processes. Concerning bladder cancer, FCM played a beneficial role in evaluating urethral and ureteral margins during radical cystectomy. Notably, it showed substantial agreement with conventional histopathology and frozen section examination. In the context of renal biopsy, FCM demonstrated the potential to differentiate normal renal parenchyma from cancerous tissue, although the available evidence is limited in this area. The main limitation of the current study is the scarcity of data regarding the topic of interest. CONCLUSIONS: Ex-vivo FCM holds promise in urology, particularly in prostate cancer diagnosis and surgical margin assessment. Its real-time capabilities may reduce diagnostic delays and patient stress. However, most studies remain experimental, requiring further research to validate clinical utility.

Outcomes of Ventral Onlay Buccal Mucosal Graft Urethroplasty in Bulbomembranous Urethral Strictures Post-transurethral Resection of the Prostate.

OBJECTIVE: To evaluate the outcomes of ventral onlay buccal mucosal graft urethroplasty (VOBMGU) in bulbomembranous urethral strictures after transurethral resection of the prostate. METHODS: After approval of the institutional ethical committee, we retrospectively examined the database of patients diagnosed with post-TURP urethral stricture (PTS) and treated by VOBMGU from January 2020 to January 2022. The patients were evaluated by retrograde urethrogram and voiding cystourethrogram. Follow-up evaluation included assessment of lower urinary tract symptoms, physical examination, uroflowmetry (Q-max and International Prostate Symptom Score) 3, 6, and 12months of follow-up. RESULTS: A total of 30 patients underwent VOBMGU for bulbomembranous PTS were included. The median age of the patients was 63.5 (11.25). The median stricture length was 3.5 (1.5) cm. During follow-up, the mean Q-max significantly increased to 21.1 ± 5.5 mL/s (P < .0001), 20.1 ± 5.4 mL/s (P < .001), and 19.1 ± 5.3 mL/s (P < .003) at 3, 6, and 12months, respectively. IPSS significantly decreased to 8.93 ± 6.37 at the 12-month follow-up mark (P < .0001). Three patients developed stricture recurrence and two patients developed postoperative urinary incontinence. CONCLUSION: VOBMGU in cases of bulbomembranous urethral PTS offered excellent functional outcomes with low stricture recurrence and minimal risk of incontinence. Further prospective studies are warranted to confirm the results.

Applicability and feasibility of robot-assisted cystectomy and intracorporeal urinary diversion in a patient with right renal pelvic ectopia.

BACKGROUND: The ectopic pelvic kidney, a common renal anomaly, is often smaller and malformed, with a shorter and sometimes tortuous ureter (1). Muscle-invasive bladder cancer (MIBC), constituting 15-25% of bladder cancer cases (2), mandates radical cystectomy with a 50% 5-year survival rate (2). Despite the growing use of robot-assisted radical cystectomy (RARC) (3, 4), there is limited data on its application in ectopic kidneys. Only one RARC case has been reported (5), in contrast to numerous open radical cystectomies (1, 6) involving an ectopic kidney. PATIENT AND METHODS: After being diagnosed with T2 high-grade urothelial carcinoma, the 66-year-old patient, previously treated with multiple transurethral resections and adjuvant BCG therapy, received neoadjuvant chemotherapy. Preoperative staging CT revealed a 2.6 x 2.2 cm bladder neoformation and an ectopic right pelvic kidney. RESULTS: Using the da Vinci Surgical System, radical cystectomy with ileal conduit (sec Wallace II) and lymphadenectomy were performed. During the demolition phase, the shorter right ureter was dissected with care to avoid damage to the renal pedicle. The reconstructive phase included intracorporeal urinary diversion (ICUD) and uretero-ileal anastomosis, facilitated by the favorable position of the kidney. The 8-hour console surgery resulted in minimal blood loss. Discharged on day 16 due to COVID-19, the patient exhibited positive outcomes. A 2-month CT follow-up revealed no cancer recurrence, metastasis, hydronephrosis, and complete regression of the lymphocele. Imaging follow-up continues without postoperative adjuvant chemotherapy. CONCLUSION: Robotic surgery with intracorporeal urinary diversion holds potential for right-sided pelvic kidney cases, but additional studies are necessary for validation.

Cytotoxic evaluation of new polyhydroxylated steroids from the Red Sea soft coral Litophyton mollis (Macfadyen, 1936).

An efficient column chromatography of the CH2Cl2/MeOH crude extract from the soft coral Litophyton mollis (Macfadyen, 1936) yielded seven steroids, including five 4α-methylated steroids (1-5) and two 19-oxygenated steroids (6-7). Notably, both compounds 3 and 7 are new, identified as (22E)-4α,24-dimethyl-5α-cholesta-22,24(28)-dien-3ß,8ß-diol (3) and (22E,24R)-7ß-acetoxy-24-methyl-cholesta-5,22-dien-3ß,19-diol (7). The chemical structures and relative configurations were elucidated through comprehensive spectroscopic analyses, including 1D and 2D NMR, as well as HRESIMS analysis. The cytotoxicity of metabolites 1-7 was evaluated against three cancer cell lines: MCF-7, HepG2, and NCI-1299. Remarkably, metabolites 6 and 7 exhibited strong cytotoxic activity against MCF-7, with IC50 values of 8.6 and 8.4 µM, respectively, while also showing moderate effects against NCI-1299, with IC50 values of 15.7 and 15.1 µM, respectively. Additionally, steroids 4 and 5 displayed weak cytotoxicity against all three cell lines, with IC50 values in the ranges of 34.7-37.5 and 30.8-46.3 µM, respectively.

Effects of algerian nettle (Urtica dioica L.) on benign prostatic hyperplasia and their mechanism of action elucidation: in vivo and in silico approaches.

This study investigated the effect of Urtica dioica roots etheric extract (UDEE) on oxidative stress, and urine obstruction with histopathological examinations of prostatic and renal tissues,and suggests computational methods as a complementary method, to make a hypothesis on the overall effect of UDEE in the treatment of benign prostatic hyperplasia (BPH).Gas chromatography/mass spectrometry was utilised to characterise UDEE.BPH was induced in rats through daily subcutaneous injections of testosterone propionate. Rats were also orally administered UDEE or a vehicle. After four weeks, prostate weight, urine output, and biochemical markers were evaluated. UDEE treatment demonstrated significant regression of prostatic enlargement, improved biochemical and histopathological characteristics, and regulation of antioxidant activity levels. Phytosteroids stand out, act by inhibiting 5α-reductase and aromatase. This study provides an insight into treatment of BPH, demonstrating safety of this compound towards the kidney compared to finasteride without severe side effects.

Artificial Intelligence in Surgical Training for Kidney Cancer: A Systematic Review of the Literature.

The prevalence of renal cell carcinoma (RCC) is increasing due to advanced imaging techniques. Surgical resection is the standard treatment, involving complex radical and partial nephrectomy procedures that demand extensive training and planning. Furthermore, artificial intelligence (AI) can potentially aid the training process in the field of kidney cancer. This review explores how artificial intelligence (AI) can create a framework for kidney cancer surgery to address training difficulties. Following PRISMA 2020 criteria, an exhaustive search of PubMed and SCOPUS databases was conducted without any filters or restrictions. Inclusion criteria encompassed original English articles focusing on AI's role in kidney cancer surgical training. On the other hand, all non-original articles and articles published in any language other than English were excluded. Two independent reviewers assessed the articles, with a third party settling any disagreement. Study specifics, AI tools, methodologies, endpoints, and outcomes were extracted by the same authors. The Oxford Center for Evidence-Based Medicine's evidence levels were employed to assess the studies. Out of 468 identified records, 14 eligible studies were selected. Potential AI applications in kidney cancer surgical training include analyzing surgical workflow, annotating instruments, identifying tissues, and 3D reconstruction. AI is capable of appraising surgical skills, including the identification of procedural steps and instrument tracking. While AI and augmented reality (AR) enhance training, challenges persist in real-time tracking and registration. The utilization of AI-driven 3D reconstruction proves beneficial for intraoperative guidance and preoperative preparation. Artificial intelligence (AI) shows potential for advancing surgical training by providing unbiased evaluations, personalized feedback, and enhanced learning processes. Yet challenges such as consistent metric measurement, ethical concerns, and data privacy must be addressed. The integration of AI into kidney cancer surgical training offers solutions to training difficulties and a boost to surgical education. However, to fully harness its potential, additional studies are imperative.

Three-Dimensional Customized Imaging Reconstruction for Urological Surgery: Diffusion and Role in Real-Life Practice from an International Survey.

Despite the arising interest in three-dimensional (3D) reconstruction models from 2D imaging, their diffusion and perception among urologists have been scarcely explored. The aim of the study is to report the results of an international survey investigating the use of such tools among urologists of different backgrounds and origins. Beyond demographics, the survey explored the degree to which 3D models are perceived to improve surgical outcomes, the procedures mostly making use of them, the settings in which those tools are mostly applied, the surgical steps benefiting from 3D reconstructions and future perspectives of improvement. One hundred responders fully completed the survey. All levels of expertise were allowed; more than half (53%) were first surgeons, and 59% had already completed their training. Their main application was partial nephrectomy (85%), followed by radical nephrectomy and radical prostatectomy. Three-dimensional models are mostly used for preoperative planning (75%), intraoperative consultation and tailoring. More than half recognized that 3D models may highly improve surgical outcomes. Despite their recognized usefulness, 77% of responders use 3D models in less than 25% of their major operations due to costs or the extra time taken to perform the reconstruction. Technical improvements and a higher availability of the 3D models will further increase their role in surgical and clinical daily practice.

Exploring Proteus mirabilis Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation.

Currently, the treatment of Proteus mirabilis infections is considered to be complicated as the organism has become resistant to numerous antibiotic classes. Therefore, new inhibitors should be developed, targeting bacterial molecular functions. Methionine tRNA synthetase (MetRS), a member of the aminoacyl-tRNA synthetase family, is essential for protein biosynthesis offering a promising target for novel antibiotics discovery. In the context of computer-aided drug design (CADD), the current research presents the construction and analysis of a comparative homology model for P. mirabilis MetRS, enabling development of novel inhibitors with greater selectivity. Molecular Operating Environment (MOE) software was used to build a homology model for P. mirabilis MetRS using Escherichia coli MetRS as a template. The model was evaluated, and the active site of the target protein predicted from its sequence using conservation analysis. Molecular dynamic simulations were performed to evaluate the stability of the modeled protein structure. In order to evaluate the predicted active site interactions, methionine (the natural substrate of MetRS) and several inhibitors of bacterial MetRS were docked into the constructed model using MOE. After validation of the model, pharmacophore-based virtual screening for a systemically prepared dataset of compounds was performed to prove the feasibility of the proposed model, identifying possible parent compounds for further development of MetRS inhibitors against P. mirabilis.

New Cytotoxic Monoalkyl Glycerol Ether from the Red Sea Soft Coral Nephthea mollis.

A new monoalkyl glycerol ether, 3-(n-henicosyloxy)propane-1,2-diol (1), was isolated from the CH2 Cl2 /MeOH crude extract of the Red Sea soft coral Nephthea mollis. Additionally, three known related analogs were identified: chimyl alcohol (2), batyl alcohol (3), and 3-(icosyloxy)propane-1,2-diol (4). The chemical structure of 3-(n-henicosyloxy)propane-1,2-diol was determined using advanced spectroscopic analyses, including 1D, 2D Nuclear Magnetic Resonance (NMR), Electron Ionization mass spectra (EI-MS), and High-Resolution Electron Spray Ionization mass spectra (HR-ESI-MS) analyses. Furthermore, the identification of chimyl alcohol, batyl alcohol and 3-(icosyloxy)propane-1,2-diol was achieved by studying their EI mass fragmentation analyses and comparing their mass data with those previously reported in the literature. The cytotoxic activity of the Nephthea mollis crude extract and 3-(n-henicosyloxy)propane-1,2-diol was evaluated against five human cancer cell lines: HepG2 (hepatocellular carcinoma), MCF-7 (breast carcinoma), NCI-1299 (lung carcinoma), HeLa (cervical cancer cell), and HT-29 (colon adenocarcinoma). Moreover, 3-(n-henicosyloxy)propane-1,2-diol revealed moderate cytotoxicity against the HeLa cell lines with an IC50 value of 24.1 µM, while showing inactivity against the remaining cell lines (IC50 >100 µM).

Cytotoxic and anti-bacterial evaluation of two new aromatic A-ring steroids isolated from the Red Sea soft coral Dendronephthya spp.

A successful column chromatography of a CHCl3/MeOH crude extract of Dendronephthya spp. soft coral led to the isolation of two new aromatic A-ring steroids (1-2), together with three known compounds (3-5). Both 1 and 2 are 19-norsteroids. The chemical structures were elucidated based on extensive 1D, 2D NMR, and EIMS analyses. In cytotoxic bioassays, compounds 1-5 were tested against three cancer cell lines: MCF-7, NCI-1299, and HepG2, with IC50 in the ranges of 22.1-85.4, 26.9-88.7, and 25.9-93.7 µM, respectively. Compounds 1, 2, and 5 showed moderate degrees of inhibition against Escherichia coli and Pseudomonas sp. at 100 and 150 µg/mL, while exhibiting weak inhibition against Bacillus cereus and Staphylococcus aureus at 150 µg/mL.

Design and synthesis of novel uracil-linked Schiff bases as dual histone deacetylase type II/topoisomerase type I inhibitors with apoptotic potential.

Aim: The previously reported dual histone deacetylase type II (HDAC II) / topoisomerase type I (Topo I) inhibitors suffer pharmacokinetic limitations because of their huge molecular weights. Materials & methods: We report the design and synthesis of a smarter novel set of uracil-linked Schiff bases (19-30) as dual HDAC II/Topo I inhibitors keeping the essential pharmacophoric features. Cytotoxicity of all compounds was assessed against three cancer cell lines. Studies of their effects on the apoptotic BAX and antiapoptotic BCL2 genes, molecular docking studies, and absorption, distribution, metabolism and excretion studies were conducted. Results: Compounds 22, 25 and 30 exhibited significant activities. The bromophenyl derivative 22 displayed the best selectivity index, with IC50 values against HDAC II and Topo I of 1.12 and 13.44 µM, respectively. Conclusion: Compound 22 could be considered a lead HDAC II/Topo I inhibitor.

Drug repositioning: doxazosin attenuates the virulence factors and biofilm formation in Gram-negative bacteria.

The resistance development is an increasing global health risk that needs innovative solutions. Repurposing drugs to serve as anti-virulence agents is suggested as an advantageous strategy to diminish bacterial resistance development. Bacterial virulence is controlled by quorum sensing (QS) system that orchestrates the expression of biofilm formation, motility, and virulence factors production as enzymes and virulent pigments. Interfering with QS could lead to bacterial virulence mitigation without affecting bacterial growth that does not result in bacterial resistance development. This study investigated the probable anti-virulence and anti-QS activities of α-adrenoreceptor blocker doxazosin against Proteus mirabilis and Pseudomonas aeruginosa. Besides in silico study, in vitro and in vivo investigations were conducted to assess the doxazosin anti-virulence actions. Doxazosin significantly diminished the biofilm formation and release of QS-controlled Chromobacterium violaceum pigment and virulence factors in P. aeruginosa and P. mirabilis, and downregulated the QS encoding genes in P. aeruginosa. Virtually, doxazosin interfered with QS proteins, and in vivo protected mice against P. mirabilis and P. aeruginosa. The role of the membranal sensors as QseC and PmrA was recognized in enhancing the Gram-negative virulence. Doxazosin downregulated the membranal sensors PmR and QseC encoding genes and could in silico interfere with them. In conclusion, this study preliminary documents the probable anti-QS and anti-virulence activities of doxazosin, which indicate its possible application as an alternative or in addition to antibiotics. However, extended toxicological and pharmacological investigations are essential to approve the feasible clinical application of doxazosin as novel efficient anti-virulence agent. KEY POINTS: • Anti-hypertensive doxazosin acquires anti-quorum sensing activities • Doxazosin diminishes the virulence of Proteus mirabilis and Pseudomonas aeruginosa • Doxazosin could dimmish the bacterial espionage.

Digital real-time microscopy of ex-vivo tissues: A novel strategy to control surgical accuracy.

INTRODUCTION: Ex-vivo FCM is a novel digital optical technique that provides images of fresh tissues in a real-time fashion with magnification to subcellular details of a flattened unprocessed sample. Digital images are hematoxylin-eosin-like and can be shared and interpreted remotely. In urology, FCM has been successfully applied for prostate tissue interpretation, either during biopsy and radical prostatectomy. Possible applications of FCM may reflect those of frozen section analysis and can be extended to all fields in which the intra-operative microscopical control is advisable. MATERIALS AND METHODS: This is an investigative prospective case series that aims to explore FCM feasibility in novel surgical settings and provide a depiction of FCM digital images in those fields. The definite purpose is to check the accuracy of surgical specimen during the following interventions: (a) trans-urethral resection of bladder tumors, to confirm the presence of muscular layer; (b) biopsy of a retroperitoneal mass, to check for the location and quality of cores; (c) training in robotic radical prostatectomy, to control surgical margins after a nerve sparing performed by a trainee. To this aim, we collected FCM images during seven surgical procedures. FCM findings were compared to those from the final histopathological analysis and the agreement was assessed. RESULTS: In all cases, FCM digital images were obtained in the OR. FCM was able to confirm the presence of muscular layer in TURB specimen, the presence of lymphomatous tissue, surgical margins at prostate specimen. FCM intra-operative interpretation was consistent with final histopathology in all cases. CONCLUSIONS: Ex vivo FCM may represent a novel approach to control the quality of specimens, likely to tailor surgical strategy in a real-time fashion. Moreover, digitalization represents a step toward the implementation of telepathology in clinical practice.

Corrigendum to "Rectal Perforation During Pelvic Surgery" [Eur Urol Open Sci 44 (2022) 54-59].

[This corrects the article DOI: 10.1016/j.euros.2022.04.006.].

Translational and linguistic validation of the Arabic version of dysfunctional voiding symptom score questionnaire.

INTRODUCTION: Dysfunctional voiding is a multifactorial condition that encompasses a wide variety of symptoms rendering its diagnosis a challenging process. In this setting, several tools have been proposed to aid the diagnosis of this disease among which is the Dysfunctional Voiding Symptom Score (DVSS). The DVSS has been translated and validated to different languages including Japanese, Thai, Chinese, Serbian, and Portuguese. The aim of the current study is to translate and cross-culturally validate the DVSS into the Arabic language. MATERIAL AND METHODS: The DVSS was translated and culturally adapted to the Arabic language following the standards of the ISPOR for the translation and cultural adaptation process for patient-reported outcomes measures. Subsequently, the translated version underwent a pre-test on 15 patients with dysfunctional voiding. Afterwards, the translated version was filled by 82 pediatric patients and/or their parents with dysfunctional voiding and then the same questionnaire was refilled by the patients and their families one week later at home. Finally, a group of healthy children and/or their parents were recruited to fill the questionnaire as a control group. Cronbach's alpha, Pearson's correlation, and Interclass correlation were used to assess for internal consistency and reliability between test-retest of the Arabic version. RESULTS: The mean total score of DVSS for the case and control groups was 16.66 ± 6.07 and 6.11 ± 3.36, respectively (P < 0.001). The Arabic-DVSS showed excellent internal consistency (Cronbach's α > 0.9) for all the questions except Q1, Q3, Q6, and Q7 that showed good internal consistency. DISCUSSION: Translational and linguistic validation of the DVSS questionnaire into Arabic language is an important step toward its introduction in the clinical practice in Arabic countries; however, this step has also to consider the cultural variations between countries and not just linguistic translation. Generally, the Arabic-DVSS showed a satisfactory test-retest internal consistency and reliability with an excellent Cronbach's α (0.982) and ICC (0.962) for the total score of the Arabic-DVSS. Yet, the main limitation of this study was that it was only advocated for the translation and validation of the Arabic-DVSS and did not assess its value in patients' follow-up. CONCLUSION: The Arabic version of the DVSS is reliable and valid to help in the evaluation of DV in children of Arabic countries.

Pyridine based dual binding site aromatase (CYP19A1) inhibitors.

Aromatase (CYP19A1) inhibitors are the mainstay therapeutics for the treatment of hormone dependant breast cancer, which accounts for approximately 70% of all breast cancer cases. However, increased resistance to the clinically used aromatase inhibitors, including letrozole and anastrazole, and off target effects, necessitates the development of aromatase inhibitors with improved drug profiles. The development of extended 4th generation pyridine based aromatase inhibitors with dual binding (haem and access channel) is therefore of interest and here we describe the design, synthesis and computational studies. Cytotoxicity and selectivity studies identified the pyridine derivative (4-bromophenyl)(6-(but-2-yn-1-yloxy)benzofuran-2-yl)(pyridin-3-yl)methanol (10c) as optimal with CYP19A1 IC50 0.83 nM (c.f. letrozole IC50 0.70 nM), and an excellent cytotoxicity and selectivity profile. Interestingly, computational studies for the 6-O-butynyloxy (10) and 6-O-pentynyloxy (11) derivatives identified an alternative access channel lined by Phe221, Trp224, Gln225 and Leu477, providing further insight into the potential binding mode and interactions of the non-steroidal aromatase inhibitors.

External validation of yonsei nomogram predicting chronic kidney disease development after partial nephrectomy: An international, multicenter study.

OBJECTIVE: To externally validate Yonsei nomogram. METHODS: From 2000 through 2018, 3526 consecutive patients underwent on-clamp PN for cT1 renal masses at 23 centers were included. All patients had two kidneys, preoperative eGFR ≥60 ml/min/1.73 m2, and a minimum follow-up of 12 months. New-onset CKD was defined as upgrading from CKD stage I or II into CKD stage ≥III. We obtained the CKD-free progression probabilities at 1, 3, 5, and 10 years for all patients by applying the nomogram found at https://eservices.ksmc.med.sa/ckd/. Thereafter, external validation of Yonsei nomogram for estimating new-onset CKD stage ≥III was assessed by calibration and discrimination analysis. RESULTS AND LIMITATION: Median values of patients' age, tumor size, eGFR and follow-up period were 47 years (IQR: 47-62), 3.3 cm (IQR: 2.5-4.2), 90.5 ml/min/1.73 m2 (IQR: 82.8-98), and 47 months (IQR: 27-65), respectively. A total of 683 patients (19.4%) developed new-onset CKD. The 5-year CKD-free progression rate was 77.9%. Yonsei nomogram demonstrated an AUC of 0.69, 0.72, 0.77, and 0.78 for the prediction of CKD stage ≥III at 1, 3, 5, and 10 years, respectively. The calibration plots at 1, 3, 5, and 10 years showed that the model was well calibrated with calibration slope values of 0.77, 0.83, 0.76, and 0.75, respectively. Retrospective database collection is a limitation of our study. CONCLUSIONS: The largest external validation of Yonsei nomogram showed good calibration properties. The nomogram can provide an accurate estimate of the individual risk of CKD-free progression on long-term follow-up.

Characterization of the Anti-Biofilm and Anti-Quorum Sensing Activities of the ß-Adrenoreceptor Antagonist Atenolol against Gram-Negative Bacterial Pathogens.

The development of bacterial resistance to antibiotics is an increasing public health issue that worsens with the formation of biofilms. Quorum sensing (QS) orchestrates the bacterial virulence and controls the formation of biofilm. Targeting bacterial virulence is promising approach to overcome the resistance increment to antibiotics. In a previous detailed in silico study, the anti-QS activities of twenty-two ß-adrenoreceptor blockers were screened supposing atenolol as a promising candidate. The current study aims to evaluate the anti-QS, anti-biofilm and anti-virulence activities of the ß-adrenoreceptor blocker atenolol against Gram-negative bacteria Serratia marcescens, Pseudomonas aeruginosa, and Proteus mirabilis. An in silico study was conducted to evaluate the binding affinity of atenolol to S. marcescens SmaR QS receptor, P. aeruginosa QscR QS receptor, and P. mirabilis MrpH adhesin. The atenolol anti-virulence activity was evaluated against the tested strains in vitro and in vivo. The present finding shows considerable ability of atenolol to compete with QS proteins and significantly downregulated the expression of QS- and virulence-encoding genes. Atenolol showed significant reduction in the tested bacterial biofilm formation, virulence enzyme production, and motility. Furthermore, atenolol significantly diminished the bacterial capacity for killing and protected mice. In conclusion, atenolol has potential anti-QS and anti-virulence activities against S. marcescens, P. aeruginosa, and P. mirabilis and can be used as an adjuvant in treatment of aggressive bacterial infections.