Crosstalk between purinergic receptor P2Y11 and chemokine receptor CXCR7 is regulated by CXCR4 in human macrophages.

P2Y11 is a G protein-coupled ATP receptor that activates IL-1 receptor (IL-1R) in a cyclic AMP dependent manner. In human macrophages, P2Y11/IL-1R crosstalk with CCL20 as a prime target is controlled by phosphodiesterase 4 (PDE4), which mediates breakdown of cyclic AMP. Here, we used gene expression analysis to identify activation of CXCR4 and CXCR7 as a hallmark of P2Y11 signaling. We found that PDE4 inhibition with rolipram boosts P2Y11/IL-1R-induced upregulation of CXCR7 expression and CCL20 production in an epidermal growth factor receptor dependent manner. Using an astrocytoma cell line, naturally expressing CXCR7 but lacking CXCR4, P2Y11/IL-1R activation effectively induced and CXCR7 agonist TC14012 enhanced CCL20 production even in the absence of PDE4 inhibition. Moreover, CXCR7 depletion by RNA interference suppressed CCL20 production. In macrophages, the simultaneous activation of P2Y11 and CXCR7 by their respective agonists was sufficient to induce CCL20 production with no need of PDE4 inhibition, as CXCR7 activation increased its own and eliminated CXCR4 expression. Finally, analysis of multiple CCL chemokines in the macrophage secretome revealed that CXCR4 inactivation and CXCR7 activation selectively enhanced P2Y11/IL-1R-mediated secretion of CCL20. Altogether, our data establish CXCR7 as an integral component of the P2Y11/IL-1R-initiated signaling cascade and CXCR4-associated PDE4 as a regulatory checkpoint.

Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives.

Mitochondrial diseases (MDs) are inherited genetic conditions characterized by pathogenic mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Current therapies are still far from being fully effective and from covering the broad spectrum of mutations in mtDNA. For example, unlike heteroplasmic conditions, MDs caused by homoplasmic mtDNA mutations do not yet benefit from advances in molecular approaches. An attractive method of providing dysfunctional cells and/or tissues with healthy mitochondria is mitochondrial transplantation. In this review, we discuss what is known about intercellular transfer of mitochondria and the methods used to transfer mitochondria both in vitro and in vivo, and we provide an outlook on future therapeutic applications. Overall, the transfer of healthy mitochondria containing wild-type mtDNA copies could induce a heteroplasmic shift even when homoplasmic mtDNA variants are present, with the aim of attenuating or preventing the progression of pathological clinical phenotypes. In summary, mitochondrial transplantation is a challenging but potentially ground-breaking option for the treatment of various mitochondrial pathologies, although several questions remain to be addressed before its application in mitochondrial medicine.

Proficiency-based progression training for robotic surgery skills training: a randomized clinical trial.

OBJECTIVE: To determine whether proficiency-based progression (PBP) training leads to better robotic surgical performance compared to traditional training (TT), given that the value of PBP training for learning robotic surgical skills is unclear. MATERIALS AND METHODS: The PROVESA trial is a multicentric, prospective, randomized and blinded clinical study comparing PBP training with TT for robotic suturing and knot-tying anastomosis skills. A total of 36 robotic surgery-naïve junior residents were recruited from 16 training sites and 12 residency training programmes. Participants were randomly allocated to metric-based PBP training or the current standard of care TT, and compared at the end of training. The primary outcome was percentage of participants reaching the predefined proficiency benchmark. Secondary outcomes were the numbers of procedure steps and errors made. RESULTS: Of the group that received TT, 3/18 reached the proficiency benchmark versus 12/18 of the PBP group (i.e. the PBP group were ~10 times as likely to demonstrate proficiency [P = 0.006]). The PBP group demonstrated a 51% reduction in number of performance errors from baseline to the final assessment (18.3 vs 8.9). The TT group demonstrated a marginal improvement (15.94 vs 15.44) in errors made. CONCLUSIONS: The PROVESA trial is the first prospective randomized controlled trial on basic skills training in robotic surgery. Implementation of a PBP training methodology resulted in superior surgical performance for robotic suturing and knot-tying anastomosis performance. Compared to TT, better surgical quality could be obtained by implementing PBP training for basic skills in robotic surgery.

Development and Validation of the Metric-Based Assessment of a Robotic Dissection Task on an Avian Model.

INTRODUCTION: The introduction of robot-assisted surgical devices requires the application of objective performance metrics to verify performance levels. OBJECTIVE: To develop and validate (face, content, response process, and construct) the performance metrics for a robotic dissection task using a chicken model. METHODS: In a procedure characterization, we developed the performance metrics (i.e., procedure steps, errors, and critical errors) for a robotic dissection task, using a chicken model. In a modified Delphi panel, 14 experts from four European Union countries agreed on the steps, errors, and critical errors (CEs) of the task. Six experienced surgeons and eight novice urology surgeons performed the robotic dissection task twice on the chicken model. In the Delphi meeting, 100% consensus was reached on five procedure steps, 15 errors and two CEs. Novice surgeons took 20 min to complete the task on trial 1 and 14 min during trial two, whereas experts took 8.2 min and 6.5 min. On average, the Expert Group completed the task 56% faster than the Novice Group and made 46% fewer performance errors. RESULTS: Sensitivity and specificity for procedure errors and time were excellent to good (i.e., 1.0-0.91) but poor (i.e., 0.5) for step metrics. The mean interrater reliability for the assessments by two robotic surgeons was 0.91 (Expert Group inter-rater reliability = 0.92 and Novice Group = 0.9). CONCLUSIONS: We report evidence which supports the demonstration of face, content, and construct validity for a standard and replicable basic robotic dissection task on the chicken model.

A Systematic Review and Meta-analysis on the Impact of Proficiency-based Progression Simulation Training on Performance Outcomes.

OBJECTIVE: To analyze all published prospective, randomized, and blinded clinical studies on the proficiency-based progression (PBP) training using objective performance metrics. BACKGROUND: The benefit of PBP methodology to learning clinical skills in comparison to conventional training is not settled. METHODS: Search of PubMed, Cochrane library's Central, EMBASE, MEDLINE, and Scopus databases, from inception to 1st March 2020. Two independent reviewers extracted the data. The Medical Education Research Study Quality Instrument (MERSQI) was used to assess the methodological quality of included studies. Results were pooled using biased corrected standardized mean difference and ratio-of-means. Summary effects were evaluated using a series of fixed and random effects models. The primary outcome was the number of procedural errors performed comparing PBP and non-PBP-based training pathways. Secondary outcomes were the number of procedural steps completed and the time to complete the task/procedure. RESULTS: From the initial pool of 468 studies, 12 randomized clinical studies with a total of 239 participants were included in the analysis. In comparison to the non-PBP training, ratio-of-means results showed that PBP training reduced the number of performance errors by 60% (P < 0.001) and procedural time by 15% (P = 0.003) and increased the number of steps performed by 47% (P < 0.001). CONCLUSIONS AND RELEVANCE: Our systematic review and meta-analysis confirms that PBP training in comparison to conventional or quality assured training improved trainees' performances, by decreasing procedural errors and procedural time, while increasing the number of correct steps taken when compared to standard simulation-based training.

Feasibility of a telementoring approach as a practical training for transurethral enucleation of the benign prostatic hyperplasia using bipolar energy: a pilot study.

INTRODUCTION: Telementoring is one of the applications of telemedicine capable of bringing highly experienced surgeons to areas lacking expertise. In the current study, we aimed to assess a novel telementoring application during the learning curve of transurethral enucleation of the prostate using bipolar energy (TUEB). MATERIAL AND METHODS: A telementoring system was developed by our engineering department. This application was used to mentor ten prospective cases of TUEB performed by an expert endourologist (novice to the TUEB). A questionnaire was filled by the operating surgeon and the mentor to provide subjective evaluation of the telementoring system. Finally, the outcomes of these patients were compared to a control group consisting of ten consecutive patients performed by the mentor. RESULTS: Ten consecutive TUEB were performed using this telementoring application. Delayed and interrupted connection were experienced in two and one patients, respectively; however, their effect was minor, and they did not compromise the safety of the procedure. None of the patients required conversion to conventional transurethral resection of the prostate. Only one patient in our series experienced grade IIIb complication. CONCLUSION: The telementoring application for TUEB is promising. It is a simple and low-cost tool that could be a feasible option to ensure patients' safety during the initial phase of the learning curve without time and locations constraints for both the mentor and the trainee; However, it should be mentioned that telementoring cannot yet replace the traditional surgical training with the mentor and trainee being in the operative room. Further studies are required to confirm the current results.

Development and validation of the objective assessment of robotic suturing and knot tying skills for chicken anastomotic model.

BACKGROUND: To improve patient safety, there is an imperative to develop objective performance metrics for basic surgical skills training in robotic surgery. OBJECTIVE: To develop and validate (face, content, and construct) the performance metrics for robotic suturing and knot tying, using a chicken anastomotic model. DESIGN, SETTING AND PARTICIPANTS: Study 1: In a procedure characterization, we developed the performance metrics (i.e., procedure steps, errors, and critical errors) for robotic suturing and knot tying, using a chicken anastomotic model. In a modified Delphi panel of 13 experts from four EU countries, we achieved 100% consensus on the five steps, 18 errors and four critical errors (CE) of the task. Study 2: Ten experienced surgeons and nine novice urology surgeons performed the robotic suturing and knot tying chicken anastomotic task. The mean inter-rater reliability for the assessments by two experienced robotic surgeons was 0.92 (95% CI, 0.9-0.95). Novices took 18.5 min to complete the task and experts took 8.2 min. (p = 0.00001) and made 74% more objectively assessed performance errors than the experts (p = 0.000343). CONCLUSIONS: We demonstrated face, content, and construct validity for a standard and replicable basic anastomotic robotic suturing and knot tying task on a chicken model. Validated, objective, and transparent performance metrics of a robotic surgical suturing and knot tying tasks are imperative for effective and quality assured surgical training.

COVID-19 and urology: a comprehensive review of the literature.

OBJECTIVE: To discuss the impact of COVID-19 on global health, particularly on urological practice and to review some of the available recommendations reported in the literature. MATERIAL AND METHODS: In the current narrative review the PubMed database was searched to identify all the related reports discussing the impact of COVID-19 on the urological field. RESULTS: The COVID-19 pandemic is the latest and biggest global health threat. Medical and surgical priorities have changed dramatically to cope with the current challenge. These changes include postponements of all elective outpatient visits and surgical procedures to save facilities and resources for urgent cases and patients with COVID-19 patients. This review discuss some of the related changes in urology. CONCLUSIONS: Over the coming weeks, healthcare workers including urologists will be facing increasingly difficult challenges, and consequently, they should adopt triage strategy to avoid wasting of medical resources and they should endorse sufficient protection policies to guard against infection when dealing with COVID-19 patients.

Serum miRNAs in women affected by hyperandrogenic polycystic ovary syndrome: the potential role of miR-155 as a biomarker for monitoring the estroprogestinic treatment.

MicroRNAs can be used as very efficient circulating biomarkers. The role of microRNAs in polycystic ovary syndrome (PCOS) and the effects of antiandrogen therapy on microRNA expression is still not fully understood. A panel of serum microRNAs were retrotranscribed via looped reverse primer transcription specific for each miRNA and quantified via probe specific RT-PCR in 16 Caucasian hyperandrogenic PCOS women selected according to the Rotterdam criteria and in a subset of seven patients after four months of sequential reverse antiandrogenic therapy. All women recruited underwent an oral glucose tolerance test (OGTT) and a baseline total cholesterol, high density lipoproteins cholesterol, triglycerides, AST and ALT dosage. In the follicular phase women were evaluated for total testosterone, Δ4-androstenedione, DHEAS, 17OHpg, FSH, LH, and 17-ß-E2. The AUC2hglucose, ISI Matsuda, oral disposition index (DIo) and visceral adipose index (VAI) were also calculated. We suggest that miR-155 might have a role as biomarker in hyperandrogenic PCOS patients to monitor the effect of antiandrogen therapy.

6-tips diet: a simplified dietary approach in patients with chronic renal disease. A clinical randomized trial.

BACKGROUND: The beneficial effects of dietary restriction of proteins in chronic kidney disease are widely recognized; however, poor compliance to prescribed low-protein diets (LPD) may limit their effectiveness. To help patients to adhere to the dietary prescriptions, interventions as education programmes and dietary counselling are critical, but it is also important to develop simple and attractive approaches to the LPD, especially when dietitians are not available. Therefore, we elaborated a simplified and easy to manage dietary approach consisting of 6 tips (6-tip diet, 6-TD) which could replace the standard, non-individualized LPD in Nephrology Units where dietary counselling is not available; hence, our working hypothesis was to evaluate the effects of such diet vs a standard moderately protein-restricted diet on metabolic parameters and patients' adherence. METHODS: In this randomized trial, 57 CKD patients stage 3b-5 were randomly assigned (1:1) to receive the 6-TD (Group 6-TD) or a LPD containing 0.8 g/kg/day of proteins (Group LPD) for 6 months. The primary endpoint was to evaluate the effects of the two different diets on the main "metabolic" parameters and on patients' adherence (registration number NCT01865526). RESULTS: Both dietary regimens were associated with a progressive reduction in protein intake and urinary urea excretion compared to baseline, although the decrease was more pronounced in Group 6-TD. Effects on serum levels of urea nitrogen and urinary phosphate excretion were greater in Group 6-TD. Plasma levels of phosphate, bicarbonate and PTH, and urinary NaCl excretion remained stable in both groups throughout the study. 44 % of LPD patients were adherent to the dietary prescription vs 70 % of Group 6-TD. CONCLUSIONS: A simplified diet, consisting of 6 clear points easily managed by CKD patients, produced beneficial effects either on the metabolic profile of renal disease and on patients' adherence to the dietary plan, when compared to a standard LPD.