Abstract Context Robot-assisted radical prostatectomy (RARP) was proposed to improve functional outcomes in comparison with retropubic radical prostatectomy (RRP) or laparoscopic radical ...prostatectomy (LRP). In the initial RARP series, 12-mo urinary continence recovery rates ranged from 84% to 97%. However, the few available studies comparing RARP with RRP or LRP published before 2008 did not permit any definitive conclusions about the superiority of any one of these techniques in terms of urinary continence recovery. Objective The aims of this systematic review were (1) to evaluate the prevalence and risk factors for urinary incontinence after RARP, (2) to identify surgical techniques able to improve urinary continence recovery after RARP, and (3) to perform a cumulative analysis of all available studies comparing RARP versus RRP or LRP in terms of the urinary continence recovery rate. Evidence acquisition A literature search was performed in August 2011 using the Medline, Embase, and Web of Science databases. The Medline search included only a free-text protocol using the term radical prostatectomy across the title and abstract fields of the records. The following limits were used: humans; gender (male); and publication date from January 1, 2008. Searches of the Embase and Web of Science databases used the same free-text protocol, keywords, and search period. Only comparative studies or clinical series including >100 cases reporting urinary continence outcomes were included in this review. Cumulative analysis was conducted using the Review Manager v.4.2 software designed for composing Cochrane Reviews (Cochrane Collaboration, Oxford, UK). Evidence synthesis We analyzed 51 articles reporting urinary continence rates after RARP: 17 case series, 17 studies comparing different techniques in the context of RARP, 9 studies comparing RARP with RRP, and 8 studies comparing RARP with LRP. The 12-mo urinary incontinence rates ranged from 4% to 31%, with a mean value of 16% using a no pad definition. Considering a no pad or safety pad definition, the incidence ranged from 8% to 11%, with a mean value of 9%. Age, body mass index, comorbidity index, lower urinary tract symptoms, and prostate volume were the most relevant preoperative predictors of urinary incontinence after RARP. Only a few comparative studies evaluated the impact of different surgical techniques on urinary continence recovery after RARP. Posterior musculofascial reconstruction with or without anterior reconstruction was associated with a small advantage in urinary continence recovery 1 mo after RARP. Only complete reconstruction was associated with a significant advantage in urinary continence 3 mo after RARP (odds ratio OR: 0.76; p = 0.04). Cumulative analyses showed a better 12-mo urinary continence recovery after RARP in comparison with RRP (OR: 1.53; p = 0.03) or LRP (OR: 2.39; p = 0.006). Conclusions The prevalence of urinary incontinence after RARP is influenced by preoperative patient characteristics, surgeon experience, surgical technique, and methods used to collect and report data. Posterior musculofascial reconstruction seems to offer a slight advantage in terms of 1-mo urinary continence recovery. Update of a previous systematic review of literature shows, for the first time, a statistically significant advantage in favor of RARP in comparison with both RRP and LRP in terms of 12-mo urinary continence recovery.
G protein-coupled receptors (GPCRs) are targeted by ∼30-40% of marketed drugs, and their key roles in normal physiology and in disease demonstrate that an understanding of their structure and ...function is valuable to researchers in both basic science and drug discovery. However, until recently, detailed structural information on this protein family was limited by challenges in X-ray crystallographic analysis of such membrane proteins. The GPCR Network was created in 2010 with the goal of structurally characterizing 15-25 representative human GPCRs within 5 years, based on an active outreach programme addressing an interdisciplinary community of scientists interested in GPCR structure, chemistry and biology. Here, we provide an overview of how this collaborative effort has enabled the structural determination and characterization of eight human GPCRs so far, and discuss some of the challenges that remain in gaining more detailed insights into structure-function relationships in this receptor superfamily.
Abstract Background Although the initial robot-assisted radical prostatectomy (RARP) series showed 12-mo potency rates ranging from 70% to 80%, the few available comparative studies did not permit ...any definitive conclusion about the superiority of this technique when compared with retropubic radical prostatectomy (RRP) and laparoscopic radical prostatectomy (LRP). Objectives The aims of this systematic review were (1) to evaluate the current prevalence and the potential risk factors of erectile dysfunction after RARP, (2) to identify surgical techniques able to improve the rate of potency recovery after RARP, and (3) to perform a cumulative analysis of all available studies comparing RARP versus RRP or LRP. Evidence acquisition A literature search was performed in August 2011 using the Medline, Embase, and Web of Science databases. Only comparative studies or clinical series including >100 cases reporting potency recovery outcomes were included in this review. Cumulative analysis was conducted using Review Manager v.4.2 software designed for composing Cochrane Reviews (Cochrane Collaboration, Oxford, UK). Evidence synthesis We analyzed 15 case series, 6 studies comparing different techniques in the context of RARP, 6 studies comparing RARP with RRP, and 4 studies comparing RARP with LRP. The 12- and 24-mo potency rates ranged from 54% to 90% and from 63% to 94%, respectively. Age, baseline potency status, comorbidities index, and extension of the nerve-sparing procedure represent the most relevant preoperative and intraoperative predictors of potency recovery after RARP. Available data seem to support the use of cautery-free dissection or the use of pinpointed low-energy cauterization. Cumulative analyses showed better 12-mo potency rates after RARP in comparison with RRP (odds ratio OR: 2.84; 95% confidence interval CI: 1.46–5.43; p = 0.002). Only a nonstatistically significant trend in favor of RARP was reported after comparison with LRP (OR: 1.89; p = 0.21). Conclusions The incidence of potency recovery after RARP is influenced by numerous factors. Data coming from the present systematic review support the use of a cautery-free technique. This update of previous systematic reviews of the literature showed, for the first time, a significant advantage in favor of RARP in comparison with RRP in terms of 12-mo potency rates.
Abstract Context Despite the large diffusion of robot-assisted radical prostatectomy (RARP), literature and data on the oncologic outcome of RARP are limited. Objective Evaluate lymph node yield, ...positive surgical margins (PSMs), use of adjuvant therapy, and biochemical recurrence (BCR)–free survival following RARP and perform a cumulative analysis of all studies comparing the oncologic outcomes of RARP and retropubic radical prostatectomy (RRP) or laparoscopic radical prostatectomy (LRP). Evidence acquisition A systematic review of the literature was performed in August 2011, searching Medline, Embase, and Web of Science databases. A free-text protocol using the term radical prostatectomy was applied. The following limits were used: humans; gender (male); and publications dating from January 1, 2008. A cumulative analysis was conducted using Review Manager software v.4.2 (Cochrane Collaboration, Oxford, UK) and Stata 11.0 SE software (StataCorp, College Station, TX, USA). Evidence synthesis We retrieved 79 papers evaluating oncologic outcomes following RARP. The mean PSM rate was 15% in all comers and 9% in pathologically localized cancers, with some tumor characteristics being the most relevant predictors of PSMs. Several surgeon-related characteristics or procedure-related issues may play a major role in PSM rates. With regard to BCR, the very few papers with a follow-up duration >5 yr demonstrated 7-yr BCR-free survival estimates of approximately 80%. Finally, all the cumulative analyses comparing RARP with RRP and comparing RARP with LRP demonstrated similar overall PSM rates (RARP vs RRP: odds ratio OR: 1.21; p = 0.19; RARP vs LRP: OR: 1.12; p = 0.47), pT2 PSM rates (RARP vs RRP: OR: 1.25; p = 0.31; RARP vs LRP: OR: 0.99; p = 0.97), and BCR-free survival estimates (RARP vs RRP: hazard ratio HR: 0.9; p = 0.526; RARP vs LRP: HR: 0.5; p = 0.141), regardless of the surgical approach. Conclusions PSM rates are similar following RARP, RRP, and LRP. The few data available on BCR from high-volume centers are promising, but definitive comparisons with RRP or LRP are not currently possible. Finally, significant data on cancer-specific mortality are not currently available.
Abstract Context Perioperative complications are a major surgical outcome for radical prostatectomy (RP). Objective Evaluate complication rates following robot-assisted RP (RARP), risk factors for ...complications after RARP, and surgical techniques to improve complication rates after RARP. We also performed a cumulative analysis of all studies comparing RARP with retropubic RP (RRP) or laparoscopic RP (LRP) in terms of perioperative complications. Evidence acquisition A systematic review of the literature was performed in August 2011, searching Medline, Embase, and Web of Science databases. A free-text protocol using the term radical prostatectomy was applied. The following limits were used: humans; gender (male); and publications dating from January 1, 2008. A cumulative analysis was conducted using Review Manager software v.4.2 (Cochrane Collaboration, Oxford, UK). Evidence synthesis We retrieved 110 papers evaluating oncologic outcomes following RARP. Overall mean operative time is 152 min; mean blood loss is 166 ml; mean transfusion rate is 2%; mean catheterization time is 6.3 d; and mean in-hospital stay is 1.9 d. The mean complication rate was 9%, with most of the complications being of low grade. Lymphocele/lymphorrea (3.1%), urine leak (1.8%), and reoperation (1.6%) are the most prevalent surgical complications. Blood loss (weighted mean difference: 582.77; p < 0.00001) and transfusion rate (odds ratio OR: 7.55; p < 0.00001) were lower in RARP than in RRP, whereas only transfusion rate (OR: 2.56; p = 0.005) was lower in RARP than in LRP. All the other analyzed parameters were similar, regardless of the surgical approach. Conclusions RARP can be performed routinely with a relatively small risk of complications. Surgical experience, clinical patient characteristics, and cancer characteristics may affect the risk of complications. Cumulative analyses demonstrated that blood loss and transfusion rates were significantly lower with RARP than with RRP, and transfusion rates were lower with RARP than with LRP, although all other features were similar regardless of the surgical approach.
The sphingosine-1-phosphate (S1P) receptor signaling system has biological and medical importance and is the first lipid G protein-coupled receptor (GPCR) structure to be solved to 2.8-Å resolution. ...S1P binds to five high-affinity GPCRs generating multiple downstream signals that play essential roles in vascular development and endothelial integrity, control of cardiac rhythm, and routine oral treatment of multiple sclerosis. Genetics, chemistry, and now structural biology have advanced this integrated biochemical system. The S1P receptors have a novel N-terminal fold that occludes access to the binding pocket from the extracellular environment as well as orthosteric and bitopic ligands with very different physicochemical properties. S1P receptors and metabolizing enzymes have been deleted, inducibly deleted, and knocked in as tagged or altered receptors in mice. An array of genetic models allows analysis of integrated receptor function in vivo. We can now directly understand causal relationships among protein expression, signal, and control points in physiology and pathology.
The lyso-phospholipid sphingosine 1-phosphate modulates lymphocyte trafficking, endothelial development and integrity, heart rate, and vascular tone and maturation by activating G protein—coupled ...sphingosine 1-phosphate receptors. Here, we present the crystal structure of the sphingosine 1-phosphate receptor 1 fused to T4-lysozyme (S1P₁-T4L) in complex with an antagonist sphingolipid mimic. Extracellular access to the binding pocket is occluded by the amino terminus and extracellular loops of the receptor. Access is gained by ligands entering laterally between helices I and VII within the transmembrane region of the receptor. This structure, along with mutagenesis, agonist structure-activity relationship data, and modeling, provides a detailed view of the molecular recognition and requirement for hydrophobic volume that activates S1P₁, resulting in the modulation of immune and stremal cell responses.
Abstract Background Despite widespread adoption of the six-item erectile function (EF) domain of the International Index of Erectile Function (IIEF) as a clinical trial end point, there are currently ...no objective data on what constitutes a minimal clinically important difference (MCID) in the EF domain. Objective Estimate the MCID for the IIEF EF domain. Design, setting, and participants Anchor-based MCIDs were estimated using data from 17 randomized, double-blind, placebo-controlled, parallel-group clinical trials of the phosphodiesterase type 5 inhibitor (PDE5-I) tadalafil for 3345 patients treated for 12 wk. Measurements The anchor for the MCID is the minimal improvement measure calculated using change from baseline to 12 wk on IIEF question 7: “Over the past 4 weeks, when you attempted sexual intercourse how often was it satisfactory for you?” MCIDs were developed using analysis of variance (ANOVA)– and receiver operating characteristic (ROC)–based methods in a subset of studies ( n = 11) by comparing patients with and without minimal improvement ( n = 863). MCIDs were validated in the remaining six studies ( n = 377). Results and limitations The ROC-based MCID for the EF domain was 4, with estimated sensitivity and specificity of 0.74 and 0.73, respectively. MCIDs varied significantly ( p < 0.0001) according to baseline ED severity (mild: 2; moderate: 5; severe: 7). MCIDs consistently distinguished between patients in the validation sample classified as no change or minimally improved overall and by geographic region, ED etiology, and age group. MCIDs did not differ by age group, geographic region, or ED etiology. Current analyses were based on 17 clinical trials of tadalafil. Results need to be replicated in studies using other PDE5-Is or in nonpharmacologic intervention studies. Conclusions The contextualization of treatment-related changes in terms of clinically relevant improvement is essential to understanding treatment efficacy, to interpreting results across studies, and to managing patients effectively. This analysis provides, for the first time, anchor-based estimates of MCIDs in the EF domain score of the IIEF.
Abstract Objectives This study evaluated the associated comorbidities and patient satisfaction with treatment options for premature ejaculation (PE), a common sexual dysfunction. Methods A ...comprehensive, Internet-based survey (the PE Prevalence and Attitudes PEPA survey) was conducted among men ages 18–70 in the United States, Germany, and Italy ( n = 12,133). Men were classified as having PE based on self-report of low or absent control over ejaculation, resulting in distress for them or their sexual partner or both. Results The prevalence of PE was 22.7% (24.0% in the United States, 20.3% in Germany, and 20.0% in Italy) and did not vary significantly with age among men over age 24 yr. Men with PE were more likely to self-report other sexual dysfunctions (e.g., anorgasmia, low libido, erectile dysfunction) and psychological disturbances (e.g., depression, anxiety, excessive stress) than men without PE ( p < 0.05 for all). Men with PE were most aware of (>70%) and most likely to have used (>50%) special positions during sex, interrupted stimulation, masturbation, and having intercourse more often than usual to manage their PE. Only 9.0% of men with PE reported having consulted a physician for the condition; 81.9% had to initiate the conversation about PE and 91.5% reported little or no improvement as a result of seeking treatment. Conclusion PE is a highly prevalent sexual problem, with significant sexual and psychological comorbidities. Most men with PE do not seek assistance from their physician, and most of those who do are not satisfied with the results.
Abstract Context Radical retropubic prostatectomy (RRP) has long been the most common surgical technique used to treat clinically localized prostate cancer (PCa). More recently, robot-assisted ...radical prostatectomy (RARP) has been gaining increasing acceptance among patients and urologists, and it has become the dominant technique in the United States despite a paucity of prospective studies or randomized trials supporting its superiority over RRP. Objective A 2-d consensus conference of 17 world leaders in prostate cancer and radical prostatectomy was organized in Pasadena, California, and at the City of Hope Cancer Center, Duarte, California, under the auspices of the European Association of Urology Robotic Urology Section to systematically review the currently available data on RARP, to critically assess current surgical techniques, and to generate best practice recommendations to guide clinicians and related medical personnel. No commercial support was obtained for the conference. Evidence acquisition A systematic review of the literature was performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Evidence synthesis The results of the systematic literature review were reviewed, discussed, and refined over the 2-d conference. Key recommendations were generated using a Delphi consensus approach. RARP is associated with less blood loss and transfusion rates compared with RRP, and there appear to be minimal differences between the two approaches in terms of overall postoperative complications. Positive surgical margin rates are at least equivalent with RARP, but firm conclusions about biochemical recurrence and other oncologic end points are difficult to draw because the follow-up in existing studies is relatively short and the overall experience with RARP in locally advanced PCa is still limited. RARP may offer advantages in postoperative recovery of urinary continence and erectile function, although there are methodological limitations in most studies to date and a need for well-controlled comparative outcomes studies of radical prostatectomy surgery following best practice guidelines. Surgeon experience and institutional volume of procedures strongly predict better outcomes in all relevant domains. Conclusions Available evidence suggests that RARP is a valuable therapeutic option for clinically localized PCa. Further research is needed to clarify the actual role of RARP in patients with locally advanced disease.
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