TGF-ß1 induces formation of TSG-6-enriched extracellular vesicles in fibroblasts which can prevent myofibroblast transformation by modulating Erk1/2 phosphorylation.

Extracellular vesicles have emerged as important mediators of cell-to-cell communication in the pathophysiology of fibrotic diseases. One such disease is Peyronie's disease (PD), a fibrotic disorder of the penis caused by uncontrolled transformation of resident fibroblasts to alpha-smooth muscle actin positive myofibroblasts. These cells produce large amounts of extracellular matrix, leading to formation of a plaque in the penile tunica albuginea (TA), causing pain, penile curvature, and erectile dysfunction. We have used primary fibroblasts derived from the TA of PD patients to explore the role of transforming growth factor beta 1 (TGF-ß1), a key signalling factor in this process. TGF-ß1 treatment elicited a range of responses from the myofibroblasts: (i) they secreted extracellular vesicles (EVs) that were more numerous and differed in size and shape from those secreted by fibroblasts, (ii) these EVs prevented TGF-ß1-induced transformation of fibroblasts in a manner that was dependent on vesicle uptake and (iii) they prevented phosphorylation of Erk1/2, a critical component in modulating fibrogenic phenotypic responses, but did not affect TGF-ß1-induced Smad-signalling. We posit that this effect could be linked to enrichment of TSG-6 in myofibroblast-derived EVs. The ability of myofibroblast-derived vesicles to prevent further myofibroblast transformation may establish them as part of an anti-fibrotic negative feedback loop, with potential to be exploited for future therapeutic approaches.

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.

Investigating the risk factors of penile arterial insufficiency and veno-occlusive dysfunction in patients with erectile dysfunction.

Objective: To investigate the risk factors for penile arterial insufficiency (PAI), which is a known cause of erectile dysfunction (ED). Methods: Patients who attended our urology clinic complaining of ED for more than 6 months were prospectively enrolled in this study over 1-year period. Patient consent was taken and ethical committee approval. Complete medical history and thorough general and local examination including body mass index (BMI), Peyronie's disease (PD) and penile size measurements (length and girth) were done for all of them. Laboratory tests included testosterone, lipid profile and glycated haemoglobin (HA1c). A penile duplex ultrasound study (PDU) was done for all patients after intracavernosal injection (ICI) with alprostadil. Peak systolic velocity (PSV) and end-diastolic velocity (EDV) were measured after 15 min. Statistical analysis was done using SPSS. Results: A total of 440 patients were enrolled in this analysis. The mean age was 48(23-81), and the mean BMI was 30 (18-51). Older patients had lower PSV (r = -0.361, P = 0.000) and higher EDV (r = 0.174, P = 0.001), and both correlations were highly statistically significant. Diabetics had lower PSV (r = -0.318, P = 0.000) and higher EDV (r = 0.139, P = 0.008), which were also highly statistically significant. Smokers had lower PSV (r = -0.140, P = 0.008) and higher EDV (r = 0.178, P = 0.001), which were highly statistically significant. Men with larger penises measured skin to tip had lower EDV (r = -0.119, P = 0.024), which was less significant. Interestingly, there was neither a significant correlation between BMI and PSV (0.16, P = 0.745) nor a significant correlation between testosterone and PSV (0.029, P = 0.552). Also, there was no correlation between PSV and both dyslipidaemia and penile PD. Conclusions: Ageing, tobacco consumption, DM and hypertension seem to have a negative impact on penile haemodynamics, which was statistically significant. In our patients, there was no statistically significant effect on penile haemodynamics in patients with increased BMI, low testosterone or PD or according to the size of the penis.

Therapeutic outcomes and analysis of Doppler findings in 25 patients with non-ischemic priapism.

Non-ischemic priapism (NiP) is painless partial tumescence caused by genital trauma and the formation of intracorporal arterio-venous fistula. This is a retrospective study of 25 men with NiP and reports the long-term erectile function and colour doppler ultrasound (CDUS) findings after treatment for NiP. Unstimulated CDUS was performed at diagnosis, 1 week and at last follow-up after treatment. CDUS traces were analysed: peak systolic velocity (PSV), end diastolic velocity (EDV), resistive index (RI) and mean velocity (MV) were calculated. Erectile function was assessed using the IIEF-EF questionnaire. At the last follow-up (median 24 months), 16 men had normal erectile function (64%): median IIEF-EF score 29 (IQR 28.5-30; σ2 2.78) and nine had erectile dysfunction (36%): median IIEF-EF score 17 (IQR 14-22; σ2 33.6). MV and EDV were statistically higher in those patients with erectile dysfunction at last follow-up compared to patients with normal erectile function: median MV 5.3 cm/s (IQR 2.4-10.5 cm/s; σ2 34) vs 2.95 cm/s (IQR 1.03-3.95; σ2 3.4) p < 0.002 and median EDV 4.0 cm/s (IQR 1.5-8.0; σ2 14.7) vs 0 cm/s (IQR 0-1.75; σ2 2.21) p < 0.004. Erectile dysfunction was observed in 36% of men treated for NiP and was associated with abnormal low resistance resting CDUS waveforms. Further investigation for persistent arteriovenous fistulation should be considered in these patients.

Role of adipose-derived stem cells in healing surgically induced trauma of the rat's tunica albuginea.

Background: Injection of adipose-derived stem cells (ADSCs) into the injured tunica albuginea (TA) may prevent fibrosis, restore the balance between pro- and antifibrotic pathways, and potentially mitigate erectile dysfunction caused by abnormal TA healing. Aim: To assess the potential role of ADSC injection on structural, ultrastructural, functional, and molecular changes in surgically induced trauma of the rat's TA. Methods: Forty adult male albino Wistar rats were divided into 5 groups of 8 rats each: group 1, sham; group 2, injury to TA without treatment; group 3, injury to TA and suture repair; group 4, injury to TA and injection of ADSCs without suture repair; group 5, injury to TA followed by injection of ADSCs and suture repair. Outcomes: After 6 weeks, all groups were subjected to functional, histologic, and ultrastructural examination and molecular expression of healing growth factors. Results: The intracavernous pressure (ICP; mean ± SD) was 114 ± 2, 32 ± 2, 65 ± 2, 68 ± 2, and 111 ± 2 mm Hg in groups 1 to 5, respectively. There were significant differences in ICP between each of groups 3 to 5 and group 2 (P < .05), and groups 3 and 4 each had significant differences with group 1 (P < .05). No significant difference in ICP occurred between groups 3 and 4 (P > .05). There were significant histologic and ultrastructural alterations in tunical tissues from group 2; however, these changes were markedly less in group 5 in terms of lower levels of fibrotic changes, elastosis, and superior overall neuroendothelial expression. Groups 3 and 4 showed improved structural and ultrastructural parameters when compared with group 2. Group 5 demonstrated lower levels of transforming growth factor ß1 and basic fibroblast growth factor expression. Clinical Implications: This experimental model may encourage administration of ADSCs to prevent the deleterious effects of trauma to the TA. Strengths and Limitations: Injecting ADSCs can improve the healing process and erectile dysfunction in a rat model following TA injury, and combining ADSC injection with surgical suturing resulted in superior outcomes. The main limitation was the absence of long-term ICP measurements and a longer follow-up period that may provide further insight into the chronic phase of the healing process. Conclusion: ADSC injection may prevent structural, ultrastructural, functional, and molecular alterations in surgically induced trauma of the rat's TA and enhance the effect of tunical suturing after trauma.

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.

Erectile device insertion following phalloplasty in transgender and non-binary individuals assigned female at birth: a narrative review.

Genital gender affirmation surgery (gGAS) for individuals assigned female at birth (AFAB) is complex and requires the staged insertion of an erectile device to permit penetrative intercourse. This final stage of gGAS is challenging, owing to the variable anatomy and lack of supportive structures within the neophallus when compared with erectile device insertion for individuals assigned male at birth. There is a paucity in the literature at present regarding erectile device insertion in trans-sex AFAB patients. Hence, a narrative review following a literature review and supplemented by expert opinion from a high-volume centre of expertise is presented. The choices available for erectile device in this patient cohort are discussed. Principle surgical steps required for this complex surgery is outlined along with the recommended postoperative management of the patient. Postoperative outcomes and complications are also summarised in this fast-developing surgical procedure.

Insertion of inflatable penile prosthesis in the neophallus of assigned female at birth individuals: a systematic review of surgical techniques, complications and outcomes.

Devices such as inflatable penile prostheses (IPP) can be used to achieve erectile rigidity after phalloplasty in assigned female at birth (AFAB) individuals. The approach to inserting an IPP in a neophallus is different and more challenging compared to that of an anatomical penis due to the absence of anatomical structures such as the corpora cavernosa, and the more tenuous blood supply of the neophallus and reconstructed urethra. In addition, the ideal surgical techniques and devices for use in the neophallus have not been defined. This review systematically summarises the literature on the insertion of IPP in the neophallus of individuals AFAB. In particular, the described techniques, types of devices used and peri-operative and patient-reported outcomes are emphasised. An initial search of the PubMed database was performed on 16 September 2022 and an updated search was performed on 26 May 2023. Overall, 185 articles were screened for eligibility and 15 studies fulfilled the inclusion criteria and were included in the analysis. Two studies reported outcomes on the zephyr surgical implant 475 FTM device and the others reported outcomes on the Boston Scientific AMS 600/700TM CX 3-piece inflatable, AMS AmbicorTM 2-piece inflatable, Coloplast Titan® or Dynaflex devices. Overall, 1106 IPPs were analysed. The infection rate was 4.2%-50%, with most studies reporting an infection rate of <30%. Mechanical failure or dysfunction occurred in 1.4%-36.4%, explantation was required in 3.3%-41.6%, and implant revision or replacement was performed in 6%-70%. Overall, 51.4%-90.6% of patients were satisfied and 77%-100% were engaging in sexual intercourse. An IPP in a neophallus is an acceptable option to achieve rigidity for sexual intercourse. However, this challenging procedure has good reports of patient and partner satisfaction despite significant risks of complications.

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.

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.

Complications and outcomes following injection of foreign material into the male external genitalia for augmentation: a single-centre experience and systematic review.

Injection of exogenous material into the penis and scrotum has been performed for augmentation purposes. Complications include cosmetic dissatisfaction, penile necrosis and lymphoedema. We report the complications and outcomes from a single centre with an updated systematic review of the literature. A retrospective review of all cases presenting with foreign substance injection into the genitalia, over a 10-year period was performed. Thirty-five patients with a mean (standard deviation (SD); range) age of 36.9 (±9.1; 22-61) years at presentation were included. The mean (SD; range) time between injection and presentation was 7.8 (±5.8; 1 day-20 years) years. The most common injected substance was silicone (n = 16, 45.7%) and liquid paraffin (n = 8, 22.9%). The penile shaft (94.3%) was the most injected site. The most common presentations were cosmetic dissatisfaction (57.1%) and pain and/or swelling (45.7%). Surgery was required in 32 (91.4%) cases. Primary procedures included local excision and primary closure (n = 19, 59.4%), circumcision (n = 5, 15.6%), excision with a split skin graft or a scrotal flap reconstruction (n = 5, 15.6%). Three (8.6%) patients presented with necrosis and required acute debridement. Overall, 18 patients had more than 1 procedure, and 8 patients required 3 or more procedures. A systematic search of the literature identified 887 articles of which 68 studies were included for analysis. The most common substance injected was paraffin (47.7%), followed by silicone (15.8%). The majority of patients (77.9%) presented with pain, swelling or penile deformity. 78.8% of the patients underwent surgical treatment, which included excision and primary closure with or without the use of skin grafts (85.1% of all procedures), the use of flaps (12.3%) and penile amputation (n = 2). Complications of foreign body injection into the male genitalia can be serious resulting in necrosis and autoamputation. Surgical intervention is often required to excise abnormal tissue to manage pain and improve cosmesis.

In vivo Assessment of the Impact of Molecular Weight on Constructs of 68Ga-DOTA-Manocept in a Syngeneic Mouse Tumor Model.

PURPOSE: Manocept™ constructs are mannosylated amine dextrans (MADs) that bind with high affinity to the mannose receptor, CD206. Tumor-associated macrophages (TAMs) are the most numerous immune cells in the tumor microenvironment and a recognized target for tumor imaging and cancer immunotherapies. Most TAMs express CD206, suggesting utility of MADs to deliver imaging moieties or therapeutics to TAMs. The liver Kupffer cells also express CD206, making them an off-target localization site when targeting CD206 on TAMs. We evaluated TAM targeting strategies using two novel MADs differing in molecular weight in a syngeneic mouse tumor model to determine how varying MAD molecular weights would impact tumor localization. Increased mass dose of the non-labeled construct or a higher molecular weight (HMW) construct were also used to block liver localization and enhance tumor to liver ratios. PROCEDURES: Two MADs, 8.7 kDa and 22.6 kDa modified with DOTA chelators, were synthesized and radiolabeled with 68Ga. A HMW MAD (300 kDa) was also synthesized as a competitive blocking agent for Kupffer cell localization. Balb/c mice, with and without CT26 tumors, underwent dynamic PET imaging for 90 min followed by biodistribution analyses in selected tissues. RESULTS: The new constructs were readily synthesized and labeled with 68Ga with ≥ 95% radiochemical purity in 15 min at 65 °C. When injected at doses of 0.57 nmol, the 8.7 kDa MAD provided 7-fold higher 68Ga tumor uptake compared to the 22.6 kDa MAD (2.87 ± 0.73%ID/g vs. 0.41 ± 0.02%ID/g). Studies with increased mass of unlabeled competitors showed reduced liver localization of the [68Ga]MAD-8.7 to varying degrees without significant reductions in tumor localization, resulting in enhanced tumor to liver signal ratios. CONCLUSION: Novel [68Ga]Manocept constructs were synthesized and studied in in vivo applications, showing that the smaller MAD localized to CT26 tumors more effectively than the larger MAD and that the unlabeled HMW construct could selectively block liver binding of [68Ga]MAD-8.7 without diminishing the localization to tumors. Promising results using the [68Ga]MAD-8.7 show a potential path to clinical applications.

Establishing a balloon pulmonary angioplasty program for chronic thromboembolic pulmonary hypertension: A United States single-center experience.

INTRODUCTION: Balloon pulmonary angioplasty (BPA) is a less invasive treatment alternative for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are unable to move forward with pulmonary thromboendarterectomy. This report describes a single-center experience with a nascent BPA program in the United States (US). METHODS: All patients who underwent BPA between August 2018-2021 were included in this retrospective, single-center observational cohort. Pre- and post-procedure clinical information was collected, along with procedural characteristics. RESULTS: Thirty patients began their BPA series during the study period. The majority of patients had segmental disease (n = 25, 83.3%). A total of 135 BPA procedures were performed on 417 segments. On average, patients completed 4.5 sessions and the majority of patients (n = 23, 76.7%) underwent more than 2. There were 24 episodes of hemoptysis and 20 procedural events that required treatment, typically with either heparin reversal or balloon tamponade. Of 26 participants with completed series, mean PA pressure (-6 mmHg, 95% CI -9 to -4 mmHg, p = 0.0001), PVR (-1.9 Wood units, 95% CI -2.9 to -1.0, p = 0.0002), and pulmonary compliance (-1.0 mL/mmHg, 95% CI -1.5 to -0.5, p = 0.0002) improved. Improvement was also seen in NYHA functional classification and walk distance (p = 0.01). Two deaths occurred, with one death peri-procedurally. CONCLUSION: This paper describes an early experience with BPA at a single US center. Improvement in non-invasive and invasive metrics were seen without adding a significant morbidity to an already high-risk patient population.

A Unique Case of Inflatable Penile Prosthesis (IPP) Implantation and Mesh Phalloplasty in a Patient Born with Congenital Fusiform Megalourethra.

We present the first case of a patient born with congenital fusiform megalourethra who underwent the successful placement of an inflatable penile prosthesis (IPP) and mesh phalloplasty due to primary erectile dysfunction (ED). After an extensive psychosexual assessment and a preoperative MRI scan, an IPP was successfully implanted. The procedure was carried out through a penoscrotal approach, which offered excellent exposure to the crura and the proximal ends of the corpora cavernosa. Following the incision and the dilatation of both corpora cavernosa, the penile cylinders were inserted and a mesh phalloplasty was performed, to replace the erectile tissues lacking in the distal corpora cavernosa. After reservoir and pump placement, the device was tested, and no mechanical issues were recorded. The postoperative course was uneventful, and, at the 2-year follow-up, the patient reported highly satisfactory results, with valid functional erections.

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.

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.