Metabolomic Signatures Associated With Pulmonary Arterial Hypertension Outcomes.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a complex disease characterized by progressive right ventricular (RV) failure leading to significant morbidity and mortality. Investigating metabolic features and pathways associated with RV dilation, mortality, and measures of disease severity can provide insight into molecular mechanisms, identify subphenotypes, and suggest potential therapeutic targets. METHODS: We collected data from a prospective cohort of PAH participants and performed untargeted metabolomic profiling on 1045 metabolites from circulating blood. Analyses were intended to identify metabolomic differences across a range of common metrics in PAH (eg, dilated versus nondilated RV). Partial least squares discriminant analysis was first applied to assess the distinguishability of relevant outcomes. Significantly altered metabolites were then identified using linear regression, and Cox regression models (as appropriate for the specific outcome) with adjustments for age, sex, body mass index, and PAH cause. Models exploring RV maladaptation were further adjusted for pulmonary vascular resistance. Pathway enrichment analysis was performed to identify significantly dysregulated processes. RESULTS: A total of 117 participants with PAH were included. Partial least squares discriminant analysis showed cluster differentiation between participants with dilated versus nondilated RVs, survivors versus nonsurvivors, and across a range of NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, REVEAL 2.0 composite scores, and 6-minute-walk distances. Polyamine and histidine pathways were associated with differences in RV dilation, mortality, NT-proBNP, REVEAL score, and 6-minute walk distance. Acylcarnitine pathways were associated with NT-proBNP, REVEAL score, and 6-minute walk distance. Sphingomyelin pathways were associated with RV dilation and NT-proBNP after adjustment for pulmonary vascular resistance. CONCLUSIONS: Distinct plasma metabolomic profiles are associated with RV dilation, mortality, and measures of disease severity in PAH. Polyamine, histidine, and sphingomyelin metabolic pathways represent promising candidates for identifying patients at high risk for poor outcomes and investigation into their roles as markers or mediators of disease progression and RV adaptation.

Temporal gene signature of myofibroblast transformation in Peyronie's disease: first insights into the molecular mechanisms of irreversibility.

BACKGROUND: Transformation of resident fibroblasts to profibrotic myofibroblasts in the tunica albuginea is a critical step in the pathophysiology of Peyronie's disease (PD). We have previously shown that myofibroblasts do not revert to the fibroblast phenotype and we suggested that there is a point of no return at 36 hours after induction of the transformation. However, the molecular mechanisms that drive this proposed irreversibility are not known. AIM: Identify molecular pathways that drive the irreversibility of myofibroblast transformation by analyzing the expression of the genes involved in the process in a temporal fashion. METHODS: Human primary fibroblasts obtained from tunica albuginea of patients with Peyronie's disease were transformed to myofibroblasts using transforming growth factor beta 1 (TGF-ß1). The mRNA of the cells was collected at 0, 24, 36, 48, and 72 hours after stimulation with TGF-ß1 and then analyzed using a Nanostring nCounter Fibrosis panel. The gene expression results were analyzed using Reactome pathway analysis database and ANNi, a deep learning-based inference algorithm based on a swarm approach. OUTCOMES: The study outcome was the time course of changes in gene expression during transformation of PD-derived fibroblasts to myofibroblasts. RESULTS: The temporal analysis of the gene expression revealed that the majority of the changes at the gene expression level happened within the first 24 hours and remained so throughout the 72-hour period. At 36 hours, significant changes were observed in genes involved in MAPK-Hedgehog signaling pathways. CLINICAL TRANSLATION: This study highlights the importance of early intervention in clinical management of PD and the future potential of new drugs targeting the point of no return. STRENGTHS AND LIMITATIONS: The use of human primary cells and confirmation of results with further RNA analysis are the strengths of this study. The study was limited to 760 genes rather than the whole transcriptome. CONCLUSION: This study is to our knowledge the first analysis of temporal gene expression associated with the regulation of the transformation of resident fibroblasts to profibrotic myofibroblasts in PD. Further research is warranted to investigate the role of the MAPK-Hedgehog signaling pathways in reversibility of PD.

A single pedicled robotic peritoneal flap in penile inversion vaginoplasty augmentation.

OBJECTIVES: To develop a surgical technique to achieve greater depth of the neovaginal cavity in transgender patients undergoing scrotovaginoplasty, and to propose a method for restoring neovaginal integrity in case of lack of genital skin or reduction of the depth due to scarring after infections or ischaemic processes. METHODS: Eight patients were selected to undergo scrotovaginoplasty with scrotal graft and peritoneal flap augmentation in one operating session as a modification of Zhao's original technique. The age of the patients ranged from 25 to 65 years. The first step of the procedure was standard penile inversion vaginoplasty, avoiding suturing of the superior side of the skin cylinder. The skin cylinder was pushed into the abdominal cavity through the perineal access. Afterwards a laparoscopic/robotic approach was used: a single peritoneal flap was harvested from the posterior bladder surface, incised, dissected, pedicled on the neovaginal dome, overturned and and sutured all-round to the neovagina. The sides were adapted to obtain a 'cul-de-sac'. RESULTS: The average operating time was 6 ± 1.5 h, and patients' hospitalization lasted 6 days. There were no intra- or postoperative complications. Postoperative management was the same as that usually reported in BJUI for patients undergoing standard scrotovaginoplasty. CONCLUSIONS: The use of this technique represents a good solution for increasing neovaginal depth by harvesting a large peritoneal vascularized flap, without significantly affecting postoperative management or increasing complications, as frequently observed using the colovaginoplasty technique.

Initial safety outcomes for the Rigicon Infla10® inflatable penile prosthesis.

OBJECTIVE: To analyse data from patient information forms (PIFs) submitted to the manufacturer of a new three-piece inflatable penile prosthesis (IPP), the Rigicon Infla10®, to summarize early outcomes. METHODS: A retrospective review of PIFs from 319 patients implanted with the IPP between 6 January 2019 and 31 December 2021 was performed to assess device durability and rates of reoperation for infection, mechanical failure or medical reasons. RESULTS: The mean ± sd (range) follow-up was 21.2 ± 11 (5-36) months and the mean ± sd patient age was 58.5 ± 8.7 years. Of the total, 4.4% of devices required removal or revision. Complications included mechanical failure (2.5%) and component migration (0.7%). No infections were observed in this series. One patient (0.4%) required revision for inadequate straightening of Peyronie's disease. Three patients (0.9%) requested device removal because of dissatisfaction. A total of 95.6% of the Rigicon Infla10 devices were free from explant or revision 21 months after the original implant date. Kaplan-Meier analysis showed the rates of cumulative survival of the device at 12, 24, 36 months were 95.6%, 94.7% and 93.7%, respectively. CONCLUSIONS: The vast majority of the early Rigicon Infla10 IPPs implanted prior to January 2022 were included in this retrospective analysis of volunteered PIFs. These early results demonstrate initial durability from reoperation equivalent to that of other contemporary devices.

Statins synergize with phosphodiesterase type 5 inhibitors but not with selective estrogen receptor modulators to prevent myofibroblast transformation in an in vitro model of Peyronie's disease.

BACKGROUND: Peyronie's disease (PD) is a fibrotic disorder characterized by plaque formation in the tunica albuginea (TA) of the penis, and we have previously shown that inhibition of transformation of TA-derived fibroblasts to myofibroblasts using a combination phosphodiesterase type 5 (PDE5) inhibitors and selective estrogen receptor modulators (SERMs) is effective in slowing the progression of early PD. AIM: The study sought to investigate whether combinations of statins with PDE5 inhibitors or SERMs would affect myofibroblast transformation in vitro. METHODS: Primary fibroblasts were isolated from TA of patients with PD and stimulated with transforming growth factor ß1 in the absence and presence of a range of concentrations of statins, PDE5 inhibitors, SERMs, and their combinations for 72 hours before quantifying α-smooth muscle actin using in-cell enzyme-linked immunosorbent assay. OUTCOMES: The prevention of transforming growth factor ß1-induced transformation of TA-derived fibroblasts to myofibroblasts was measured in vitro. RESULTS: Statins (simvastatin, lovastatin) inhibited myofibroblast transformation in a concentration-dependent manner with half maximal inhibitory concentration values of 0.77 ± 0.07 µM and 0.8 ± 0.13 µM, respectively. Simvastatin inhibited myofibroblast transformation in a synergistic fashion when combined with vardenafil (a PDE5 inhibitor; log alpha >0). Combination of tamoxifen (a SERM) and simvastatin did not show synergy (log alpha <0). When 3 drugs (simvastatin, vardenafil, and tamoxifen) were combined, the effect was not synergistic, but rather was additive. CLINICAL IMPLICATIONS: A combination of a statin with a PDE5 inhibitor might be useful in the clinic to slow the progression of the disease in patients with early PD; however, caution should be taken with such a combination because of the reported myopathy as a side effect. STRENGTHS AND LIMITATIONS: The use of primary human cells from patients with PD is a strength of this study. The mechanisms by which these drug classes exert synergy when used in combination was not investigated. CONCLUSION: This is the first demonstration of an antifibrotic synergy between statins and PDE5 inhibitors.

Lightweight macroporous mesh can be used for corporal reconstruction during penile prosthesis surgery.

BACKGROUND: Options to reinforce or reconstruct the corpora cavernosa during penile prosthesis surgery are limited. Synthetic grafts may confer a higher infection risk. Lightweight macroporous mesh is a promising alternative due to better integration and tissue ingrowth. AIM: The study sought to report the first experience of using lightweight mesh to reinforce or reconstruct the corpora. METHODS: The medical records of all patients undergoing insertion or revision of penile prosthesis between May 2016 and May 2021 were reviewed retrospectively. Patient characteristics, management, and outcomes were extracted in which mesh was used for corporal reconstruction. Poliglecaprone-25/polypropylene mesh (UltraPro) was used in all cases. The surgical technique and alternatives were summarized. OUTCOMES: The outcomes were infection rate, postoperative complications by Clavien-Dindo classification, and patient-reported outcomes. RESULTS: Mesh was required during penile prosthesis surgery in 21 men (median age 56 [range, 18-74] years). Reasons for reconstruction were severe corporal fibrosis (n = 6), impending erosion (n = 6), crossover/perforation (n = 6), congenital corporal agenesis (n = 2), and excision of Peyronie's plaque. All but 2 patients (with corporal agenesis) presented for revision penile prosthesis surgery with a median number of previous revision attempts of 2 (range, 1-5). Two (10%) patients required explant after a mean follow-up of 23 ± 8.7 months. One man developed infection of the device 2 years after surgery, translating to an infection rate of 5% despite a high prevalence of diabetes (25%) in this cohort. Another required explantation due to debilitating chronic pain after 3 months. Further revision surgery for stiction syndrome was required in a third patient. Finally, another man was not satisfied with the position of the pump within the scrotum or the axial rigidity of the device, despite a second opinion suggesting no issues with the device. All men were sexually active following surgery. CLINICAL IMPLICATIONS: A lightweight mesh can be considered to reinforce or reconstruct the corpora cavernosa in complex cases in which there are no alternative techniques available. STRENGTHS AND LIMITATIONS: This is the first study using a lightweight macroporous mesh for revision penile prosthesis surgery. This was a well-characterized cohort of patients. A larger cohort with 5-year follow-up would be preferable. CONCLUSION: These early results suggest that a lightweight macroporous mesh may be an acceptable synthetic graft for corporal reconstruction. Poliglecaprone-25/polypropylene mesh may be ideal because it is partially absorbable, easy to handle, and not bulky.

Three-dimensional printed hydrogel model vs cadaver: comparing inflatable penile prosthesis training and evaluation.

BACKGROUND: Penile prosthesis implantation offers a durable, safe, and effective treatment option for male erectile dysfunction; however, many urologists feel apprehensive and uncomfortable placing penile prostheses due to limited training, low surgical experience, and intra- and postoperative complication management. AIM: To compare a previously validated hydrogel inflatable penile prosthesis (IPP) training model with cadaver simulations across 4 main categories: anatomic replication and realism, procedural replication and realism, educational effectiveness, and efficacy and safety. METHODS: An overall 88 participants (15 attendings, 18 fellows, and 55 residents) performed guided IPP placements on a cadaver and a hydrogel model. Based on a 5-point Likert scale, postsurveys were used to assess the participants' opinions regarding anatomic replication and realism, procedural replication and realism, educational effectiveness, and safety between the hydrogel model and cadavers. OUTCOMES: A direct head-to-head scenario was created, allowing participants to fully utilize the hydrogel model and cadaver, which ensured the most accurate comparison possible. RESULTS: A total of 84% agreed that the hydrogel model replicates the relevant human cadaveric anatomy for the procedure, whereas 69% agreed that the hydrogel tissue resembles the appearance of cadaveric tissue. Regarding the pubic bone, outer skin, corporal bodies, dartos layer, and scrotum, 79%, 74%, 82%, 46%, and 30% respectively agreed that the hydrogel tissue resembled the texture/behavior of cadavers. Furthermore, 66% of participants agreed that the hydrogel model replicates all the procedural steps. Specifically, participants agreed that the model replicates the skin incision/dartos dissection (74%), placement of stay suture and corporotomy (92%), corporal dilation (81%), measurement of prosthetic size (98%), reservoir placement (43%), IPP placement (91%), scrotal pump placement (48%), and skin closure (51%). Finally, 86%, 93%, and 78% agreed that the hydrogel model is useful for improving technical skills, as a teaching/practicing tool, and as an evaluation tool, respectively. To conclude, 81% of participants stated that they would include the hydrogel model platform in their current training. CLINICAL IMPLICATIONS: By replicating the IPP procedure, the hydrogel model offers an additional high-fidelity training opportunity for urologists, allowing them to improve their skills and confidence in placing penile prostheses, with the goal of improving patient surgical outcomes. STRENGTHS AND LIMITATIONS: The hydrogel training model allows users to perform the entire IPP placement procedure with high anatomic realism and educational effectiveness, maintaining many of the high-fidelity benefits seen in cadavers while improving safety and accessibility. CONCLUSION: Ultimately, this high-fidelity nonbiohazardous training model can be used to supplement and bolster current IPP training curriculums.

A Rare Cause of Autoinflation after Penile Prosthesis Insertion: Case Series and Systematic Review.

BACKGROUND: In 2016, we reported the first case of high flow priapism and arteriocavernosal fistula caused by penile prosthesis insertion that mimicked device autoinflation. AIM: To raise awareness amongst implanters, we describe further cases from our institution and perform a systematic review of the literature to understand the rarity of this phenomenon. METHODS: Patient demographics, management and outcomes were extracted retrospectively. A systematic search of the EMBASE, PubMed and PubMed Central libraries for studies reporting arteriocavernosal fistula mimicking autoinflation since 1946 was performed. OUTCOMES: To identify and report all known cases of high flow priapism and arteriocavernosal fistula presenting as autoinflation of an inflatable penile prosthesis. RESULTS: Four patients in total (median age 56, range 46-60 years) were identified. Catastrophic bleeding (1.8L) occurred during revision surgery for presumed autoinflation in Patient 1 and subsequent ultrasound (US) confirmed a fistula which was embolized. Patient 2 redeveloped autoinflation following revision surgery. Ultrasound confirmed high flow priapism from an arteriocavernosal fistula. Patient 3 underwent penile magnetic resonance imaging (MRI) to investigate autoinflation and residual penile curvature. MRI showed a tumescent penis despite a deflated device and the fistula was embolized successfully. Patient 4 with sleep-related painful erections did not improve following insertion of penile prosthesis. Doppler US identified 2 fistulae that was embolized but with no resolution of symptoms. Subsequent embolization of both common penile arteries were done to control his symptoms. No other publications apart from the published abstract from 2016 reporting patient 1 was found. CLINICAL IMPLICATIONS: If considered prior to revision surgery, the fistula can be managed safely by minimally invasive percutaneous angioembolisation avoiding surgery which can potentially be associated with significant complications. STRENGTHS AND LIMITATIONS: The rarity of this phenomenon was supported by a systematic review. Our study however does present the findings from a small number of patients. CONCLUSION: Damage to the cavernosal artery during inflatable penile prosthesis insertion can create an arteriocavernosal fistula that mimics autoinflation, leading to catastrophic intra-operative bleeding or unnecessary surgery. Lee WG, Satchi M, Skrodzka M, et al. A Rare Cause of Autoinflation after Penile Prosthesis Insertion: Case Series and Systematic Review. J Sex Med 2022;19:879-886.

Associations of Angiopoietins With Heart Failure Incidence and Severity.

BACKGROUND: Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity. METHODS AND RESULTS: In a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort. CONCLUSIONS: Ang2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.

UK practice for penile prosthesis surgery: baseline analysis of the British Association of Urological Surgeons (BAUS) Penile Prosthesis Audit.

OBJECTIVES: To undertake a prospective multicentre national audit of penile prosthesis practice in the UK over a 3-year period. PATIENTS AND METHODS: Data were submitted by urological surgeons as part of the British Association of Urological Surgeons Penile Prosthesis National Audit. Patients receiving a penile prosthesis (inflatable or malleable) were included as part of a prospective registry over a 3-year period. Data were validated and then analysed using a software package (Tableau). RESULTS: A total of 1071 penile prosthesis procedures were included from 22 centres. The three commonest aetiological factors for erectile dysfunction were diabetes, prostate surgery and Peyronie's disease. Of the recorded data, inflatable penile prostheses were the commonest devices implanted, with 665 devices used (62.1%), whereas malleable prostheses accounted for 14.2% of the implants. Recorded intra-operative complications included urethral injury (0.7%, n = 7), corporal perforation (1.1%, n = 12) and cross-over (0.6%, n = 6). Known postoperative complications were recorded in 9.8% of patients (74/752), with the two most frequently reported being postoperative penile pain (n = 11) and scrotal haematoma (n = 14). CONCLUSION: This baseline analysis is the largest prospective registry of penile prostheses procedures to date. The data show that, over the 3-year collection period in the UK, there are now fewer surgeons performing the procedure, together with a reduction in the number of centres. Peri-operative complications were infrequent, and the rate of implant abortion (e.g. as a result of urethral injury) was very low. Further follow-up data will be required to publish long-term outcomes and patient satisfaction.

Non-invasive and surgical penile enhancement interventions for aesthetic or therapeutic purposes: a systematic review.

OBJECTIVE: To systematically review the literature in order to investigate the efficacy and safety of surgical and non-invasive penile enhancement procedures for aesthetic and therapeutic purposes. METHODS: A systematic search for papers investigating penile enhancement procedures was performed using the MEDLINE database. Articles published from January 2010 to December 2019, written in English, including >10 cases, and reporting objective length and/or girth outcomes, were included. Studies without primary data and conference abstracts were excluded. The main outcome measure was objective length and/or girth improvement. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Out of 220 unique records, a total of 57 were reviewed. Eighteen studies assessed interventions for penile enhancement in 1764 healthy men complaining of small penis. Thirty-nine studies investigated 2587 men with concomitant pathologies consisting mostly of Peyronie's disease and erectile dysfunction. Twenty-five studies evaluated non-invasive interventions and 32 studies assessed surgical interventions, for a total of 2192 and 2159 men, respectively. Non-invasive interventions, including traction therapies and injection of fillers, were safe and mostly efficacious, whereas surgical interventions were associated with minor complications and mostly increased penile dimensions and/or corrected penile curvature. Overall, the quality of studies was low, and standardized criteria to evaluate and report efficacy and safety of procedures, as well as patient satisfaction, were missing. CONCLUSION: The quality of the studies on penile enhancement procedures published in the last decade is still low. This prevents us from establishing recommendations based on scientific evidence regarding the efficacy and safety of interventions that are performed to increase the penis size for aesthetic or therapeutic indications.

Technological Advances in Penile Implant Surgery.

BACKGROUND: During the last century, surgical management of erectile dysfunction has evolved from an experimental concept to a core treatment modality with widespread use among the men's health community. Over time, innovations in materials, mechanical design elements, device coatings, and surgical technique have provided patients with low-risk, reliable, and reproducible erectile function with high satisfaction rates. AIM: To provide a foundation for future innovation by improving understanding of historical penile prosthetics and the rationale behind incremental technological improvements for the contemporary Men's Health physician. METHODS: Literature review was conducted to generate a comprehensive review of historical technological innovations in penile implant surgery. Companies with FDA approved penile prosthetics in use in the United States were contacted for information regarding technological innovations in the past and future devices in development. A separate literature review was performed to identify any significant future device design elements being tested, even in the ex vivo setting, which may have future clinical applications. OUTCOMES: Technological innovations in penile implant surgery were described. RESULTS: Current options for the prosthetic surgeon include malleable penile prostheses (MPP), self-contained (2-piece) inflatable penile prostheses, and multicomponent (3-piece) inflatable penile prostheses. Current MPPs consist of a synthetic coated solid core which allow for manipulation of the penis for concealability while maintaining sufficient axial rigidity to achieve penetration when desired. Multi-component (3-Piece) IPPs currently include the Coloplast Titan and Boston Scientific/AMS 700 which consist of a fluid reservoir, intrascrotal pump, and intracavernosal cylinders. The devices have undergone numerous design updates to the cylinders, pump, reservoir, tubing, and external coatings to increase reliability and decrease short- and long-term complications. CLINICAL IMPLICATIONS: Future innovations in penile prosthetic surgery seek to broaden the indications and applicability to the transgender community and improve both safety and functionality for patient and partner. STRENGTHS & LIMITATIONS: The review is limited primarily to penile prosthetics approved for current or historical clinical use in the United States and may not be representative of the global prosthetic environment. Additionally, the research and development of future innovations, particularly those provided by device manufacturers, is likely limited by non-disclosure to maintain a competitive advantage. CONCLUSIONS: Penile prosthetic surgery will undoubtedly remain integral to the treatment of erectile dysfunction, and education regarding the current state of technological innovation will empower the prosthetic surgeon and biomedical engineering community to improve contemporary patient care and drive the development of the next generation of implantable penile prosthetics. Barnard JT, Cakir OO, Ralph D, et al. Technological Advances in Penile Implant Surgery. J Sex Med 2021;18:1158-1166.

Rare Disorders of Painful Erection: A Cohort Study of the Investigation and Management of Stuttering Priapism and Sleep-Related Painful Erection.

BACKGROUND: A chief complaint of men with stuttering priapism (SP) and sleep-related painful erections (SRPE) is bothersome nocturnal erections that wake them up and result in poor sleep and daytime tiredness. SP and SRPE are rare entities that have similarities in their clinical features, but that require different treatment approaches. AIM: The aim of this study was to describe the clinical features, investigations, and effective management options for men with SP and SRPE. METHODS: Retrospective cohort study of 133 men with bothersome nocturnal painful erections that attended a tertiary andrology unit between 2004 and 2018. These men were divided into 3 groups. Group 1 (n = 62) contains men with sickle cell SP; group 2 (n = 40) has men with non-sickle cell SP and group 3 (n = 31) contains men with SRPE. OUTCOME: To determine the effectiveness of medical and surgical treatments for men with SP and SRPE. RESULTS: Hydroxyurea and automated exchange transfusion were the most effective treatment options in the sickle cell SP group. Hormonal manipulation and α-agonist therapies were effective in both SP cohorts (groups 1 and 2). Baclofen was the most effective therapy in men with SRPE. For men who failed medical management, implantation of a penile prosthesis resulted in complete resolution of the symptoms in men with SP (groups 1 and 2). Surgical management (penile prosthesis implantation and embolization) did not improve the patients' symptoms in the SRPE group. CLINICAL IMPLICATIONS: This study differentiates between sickle cell SP, non-sickle cell SP, and SRPE and describes effective treatment options for each group. STRENGTHS & LIMITATIONS: This is the largest cohort study for both SP and SRPE, respectively. Limitations include its retrospective nature and single-center experience. CONCLUSION: Managing men in these 3 groups differently and in accordance with the proposed treatment pathway provides a more structured approach to the management of these rare conditions. Johnson M, McNeillis S, Chiriaco G, et al. Rare Disorders of Painful Erection: A Cohort Study of the Investigation and Management of Stuttering Priapism and Sleep-Related Painful Erection. J Sex Med 2021;18:376-384.

Discriminative stimulus properties of the 5-HT1A receptor biased agonists NLX-101 and F13714, in rats trained to discriminate 8-OH-DPAT from saline.

NLX-101 and F13714 are selective, full efficacy, biased agonists of the serotonin (5-HT1A) receptor. NLX-101 preferentially activates cortical postsynaptic 5-HT1A receptors, whereas F13714 preferentially activates raphe nuclei presynaptic 5-HT1A receptors. We compared NLX-101 and F13714 for their efficacy and potency to substitute for the discriminative cue produced by the prototypical, nonbiased 5-HT1A receptor agonist 8-OH-DPAT (racemate). Male and female Sprague-Dawley rats were trained to discriminate 8-OH-DPAT (0.1 mg/kg i.p., 20 min pretreatment) from saline using a classical two-lever drug-discrimination procedure. 8-OH-DPAT (0.01 and 0.05 mg/kg i.p.) dose-dependently substituted for the training dose, with about 50% responding on the 8-OH-DPAT-associated lever at 0.05 mg/kg. F13714 fully and very potently substituted for the training dose of 8-OH-DPAT from 0.018 mg/kg i.p., whereas NLX-101 only achieved full substitution at 0.5 mg/kg i.p., a dose which is known to also activate presynaptic 5-HT1A receptors. The 5-HT1A receptor partial agonist, buspirone, partially substituted (~80%) at 1 and 2 mg/kg i.p., doses which also decreased response rates. F13714 decreased response rates at 0.05 mg/kg. The selective 5-HT1A receptor antagonist WAY-100 635 (1 mg/kg s.c., 40 min pretreatment) elicited almost no responding on the 8-OH-DPAT-associated lever by itself, but blocked the discriminative stimulus effects produced by administration (20 min pretreatment) of 8-OH-DPAT (0.1 mg/kg), F13714 (0.025 mg/kg), NLX-101 (0.5 mg/kg) or buspirone (1 mg/kg). These data suggest that the discriminative cue produced by 0.1 mg/kg i.p. 8-OH-DPAT results from activation of presynaptic 5-HT1A receptors. They also further demonstrate the distinct profiles in behavioral models of 5-HT1A receptor-biased agonists.

The Future of Penile Prosthetic Surgical Training Is Here: Design of a Hydrogel Model for Inflatable Penile Prosthetic Placement Using Modern Education Theory.

BACKGROUND: There is a significant need for a non-biohazardous, educational platform to equip and maintain the surgical skills required by urology trainees and low-volume implanters for inflatable penile prosthetic (IPP) placement. AIM: To design and develop an anatomic, hydrogel-based simulation platform for training and evaluate IPP placement using modern education theory. METHODS: The backward design concept was used as a framework in the design and development of an IPP simulation platform. Steps included delineating requirements from a physicians' perspective, translating requirements into engineering tasks (deliverables), developing a prototype, and pilot validation. Using a combination of 3-dimensional printing and hydrogel casting, a genitourinary tract model was constructed to replicate the appropriate steps of IPP placement guided by expert feedback. Full-immersion IPP simulations were performed through both infrapubic and penoscrotal approaches by 4 expert surgeons under operative conditions. Questionnaires evaluating the simulation's realism, value as a training tool, and further recommendations were completed. OUTCOMES: Using backward design educational pedagogy, a high-fidelity, full-procedural IPP simulation was fabricated and verified as an adequate educational tool for training and assessment. RESULTS: An expert consensus on the anatomic landmarks, steps and substeps, instruments, and errors to be included in the model was reached using a hierarchical task analysis and was successfully translated into a prototype hydrogel model. Experts performed all appropriate steps of IPP surgery and rated the simulation highly in terms of its realism and value as a training tool. On average, experts agreed that the model could function as a training tool, assessment tool, prerequisite for IPP accreditation, and requirement before live surgery. Experts stated they would have their trainees ideally complete an average of 1.75 models before live surgical training. All experts believed an operative checklist would be an ideal assessment tool. Witthaus MW, Saba P, Melnyk R, et al. The Future of Penile Prosthetic Surgical Training Is Here: Design of a Hydrogel Model for Inflatable Penile Prosthetic Placement Using Modern Education Theory. J Sex Med 2020;17:2299-2306.

Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease.

BACKGROUND: Myofibroblast transformation is a key step in the pathogenesis of Peyronie's disease (PD). Phosphodiesterase type 5 inhibitors (PDE5is) and selective estrogen receptor modulators (SERMs) can prevent the formation of fibrosis in in vitro and in vivo models of PD. However, it is unknown whether these drugs can also reverse established fibrosis. AIM: To investigate whether PDE5is and SERMs can reverse transforming growth factor beta 1 (TGF-ß1)-induced myofibroblast transformation and determine the point of no return. METHODS: In-Cell enzyme-linked immunosorbent assay was used to quantify TGF-ß1-induced myofibroblast transformation of human primary fibroblasts isolated from tunica albuginea (TA) of patients undergoing surgery for treatment of PD. Extracellular matrix production and collagen contraction assays were used as secondary assays. Reverse transcription-quantitative polymerase chain reaction and In-Cell enzyme-linked immunosorbent assay were used to measure drug target expression. PDE5i (vardenafil) and SERM (tamoxifen) were applied at various time points after TGF-ß1. OUTCOMES: Reversibility of myofibroblast transformation and drug target expression were investigated in a time-dependent manner in TA-derived fibroblasts. RESULTS: Vardenafil or tamoxifen could not reverse the myofibroblast traits of alpha-smooth muscle actin expression and extracellular matrix production, whereas only tamoxifen affected collagen contraction after 72 hours of TGF-ß1 treatment. Phosphodiesterase 5A and estrogen receptor (ER)-ß were downregulated after 72 hours, and estrogen receptor -α protein could not be quantified. Tamoxifen could prevent myofibroblast transformation until 36 hours after TGF-ß1 treatment, whereas vardenafil could prevent only 24 hours after TGF-ß1 treatment. This was mirrored by downregulation of drug targets on mRNA and protein level. Furthermore, antifibrotic signaling pathways, peroxisome proliferator-activated receptor gamma and betaglycan (TGFB receptor III), were significantly downregulated after 36 hours of TGF-ß1 exposure, as opposed to upregulation of profibrotic thrombospondin-1 at the same time point. CLINICAL TRANSLATION: This study suggests that using PDE5is and SERMs might only help for early-phase PD and further highlights the need to test drugs at the appropriate stage of the disease based on their mechanism of action. STRENGTHS & LIMITATIONS: The study uses primary human TA-derived fibroblasts that enhances translatability of the results. Limitations include that only 1 example of PDE5i- and SERM-type drug was tested. Time course experiments were only performed for marker expression experiments and not for functional assays. CONCLUSION: This is the first study to demonstrate that timing for administration of drugs affecting myofibroblast transformation appears to be vital in in vitro models of PD, where 36 hours of TGF-ß1 treatment can be suggested as a "point of no return" for myofibroblast transformation. Ilg MM, Stafford SJ, Mateus M, et al. Phosphodiesterase Type 5 Inhibitors and Selective Estrogen Receptor Modulators Can Prevent But Not Reverse Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2020;17:1848-1864.

[Penile prosthesis in the treatment of erectile dysfunction: updates in 2020]. / Place des implants péniens d'érection dans le traitement de la dysfonction érectile†: le point en 2020.

Penile erection implants are considered to be the «â€…Gold Standard ¼ for the treatment of erectile dysfunction with an organic component that escapes pharmacological and mechanical treatment. The place of preoperative information is fundamental. It is a simple and minimally invasive surgery. Penile Erection Implants are becoming more and more a full-fledged treatment line, which can be offered at the same time as other Erectile Dysfunction treatments. In this article, we will discuss the presentation of the different implants available, the elements underlying their indication, the place of preoperative information, the mains steps of the surgical procedure, the outcomes and satisfaction rates.

Les implants péniens d'érection (IPE) sont considérés comme le gold standard du traitement de la dysfonction érectile (DE) à composante organique échappant aux traitements pharmacologiques et au traitement mécanique. Ils sont très largement associés à des taux de satisfaction élevés, des taux de complication bas et à une fiabilité élevée. La place de l'information préopératoire est fondamentale. Il s'agit d'une chirurgie simple et peu invasive. Les IPE s'imposent de plus en plus comme une ligne de traitement à part entière. Dans cet article seront abordés la présentation des différents implants disponibles, les éléments sous-tendant leur indication, la place de l'information préopératoire, les grands principes de la chirurgie, les résultats postopératoires et les taux de satisfaction.

[Peyronie's Disease: update in 2020]. / Maladie de Lapeyronie†: le point en 2020.

Peyronie's disease (PD) is a relatively unknown cause of sexual dysfunction. Symptoms may include the appearance of an erectile deformity, pain in the penis and erectile dysfunction (ED). The etiology is most often unclear, and medical treatments are limited, although improvement is always possible. However, surgical treatment remains the only option when the disease has stabilized and in the event of significant erectile and sexual disability.

La maladie de Lapeyronie (MDL) est une cause relativement méconnue de dysfonction sexuelle. La symptomatologie peut associer l'apparition d'une déformation en érection, des douleurs de la verge et une dysfonction érectile (DE). L'étiologie est le plus souvent floue, et les traitements médicaux limités, même si une amélioration est toujours possible. Le traitement chirurgical reste cependant la seule solution lorsque la maladie est stabilisée et en cas de handicap érectile et sexuel important.

Repair of the penile suspensory ligament for congenital and acquired pathology.

OBJECTIVE: To review the mechanisms and patient outcomes for men presenting with abnormalities of the penile suspensory ligament (PSL) and their correction. PATIENTS AND METHODS: We conducted a retrospective review of a total of 118 patients who presented with a variety of PSL abnormalities that necessitated surgical repair from 1993 to 2018. The patients mean (range) age at presentation was 29 (12-60) years with a mean (range) follow up of 8 months (3 months-12 years). The diagnosis was made clinically, often with a history of penile instability, pain or curvature/torsion, which was confirmed on artificial erection testing. Nocturnal tumescent testing and magnetic resonance imaging were used where necessary. The surgical repair was performed by placing non-absorbable sutures between the tunica albuginea of the penis and the symphysis pubis. Postoperative outcomes were reported in the clinic by direct questioning and a repeat of the investigations above when patients were unsatisfied with the result. RESULTS: The aetiologies and surgical indications in the 118 patients included: abnormality subsequent to sexual trauma (n = 66); congenital curvature of penis and/or congenital absence/laxity of the ligament (n = 37); Peyronie's disease (n = 8); and venogenic erectile dysfunction (ED; n = 7). A good surgical result, as defined by stabilization and straightening of the penis and a return to normal sexual function, was achieved in 85% of the patients and 82% were very satisfied with the outcome. Complications included long-term ED in four patients. CONCLUSION: Abnormalities of the PSL are uncommon and often subtle, but with the appropriate diagnosis, a good cosmetic and functional result is usually achievable.

Penile length is preserved after implant surgery.

OBJECTIVE: To investigate if there is a correlation between penile size measured preoperatively and erect penis after penile implant surgery (PI). A common cause of patient dissatisfaction after PI is caused by patients complaining that surgery has shortened the penis. It has been suggested that stretched penile length preoperatively is almost the same after surgery when the prosthesis is in erect status. However, no comprehensive data supports this theory. This prospective study was done to investigate this theory. PATIENTS AND METHODS: Standardised measurements of stretched penile length and girth were performed in theatre before PI implantation then re-measured at the end of the procedure with the penis in the erect position. We recorded type of PI, cylinder lengths and malleable rod diameters. All patients had data recorded on body mass index (BMI), hypertension (HTN), glycated haemoglobin (HbA1c ), and Peyronie's disease (PD). RESULTS: In all, 133 patients were assessed; 88 (66.2%) had a malleable penile prosthesis (MPP) and 45 (33.8%) an inflatable penile prosthesis (IPP). The median age and BMI were 56 years and 30 kg/m2 , respectively. In all, 40 (30.1%) patients had HTN, 37 (27.8%) had PD, and 89 (66.9%) were diabetic. The mean (SD) pre-implant stretched length was 12.8 (1.8) cm. The mean (SD) flaccid girth was 10.3 (1.2) cm. Postoperatively, the mean (SD) erect length and girth were 13.1 (1.7) cm and 11.3 (1.3) cm, respectively. Overall, there was a significant (P < 0.05) increase in both the mean (SD) length at +0.36 (0.63) cm, and girth at +1.04 (1.02) cm. Patients who had an IPP, had a greater increase in both length (mean [SD] 0.62 [0.72] cm) and girth (mean [SD] 1.7 [1.0] cm) compared to those who had a MPP (mean [SD] 0.22 [0.53] cm and 0.7 [0.87] cm, respectively) (P < 0.05). We investigated correlations between pre- and postoperative outcomes related to BMI, HTN, diabetes, and PD. None of these variables affected outcome. CONCLUSIONS: PI surgery does not significantly decrease penile size compared to the preoperative assessment. The outcome was not affected by co-morbidities. The preoperative length and girth correlated well with the immediate postoperative erect penis, although girth was not necessarily comparable in this series of patients measured under anaesthesia. Recording penile dimensions in the clinic and agreeing these with patients' preoperatively may be a way of improving satisfaction levels with this surgery.