Citations

Abstract Introduction Down-sized inflatable penile prosthesis (IPP) cylinders are used in challenging penile fibrosis scenarios, such as after priapism or prior implant infection. Their role in primary penile prosthesis surgery, however, is not well studied. Objective This study aims to identify factors associated with the use of down-sized cylinders in men undergoing primary IPP placement. Methods We conducted a multicenter, retrospective study on men undergoing primary IPP surgery, categorizing them into a down-sized cylinder group (AMS 700 CXR and Coloplast NB) and a standard cylinder group (AMS 700 CX, AMS 700 LGX, and Coloplast Titan). We collected demographic, intraoperative, and postoperative variables and performed a multivariable analysis. Results 4,389 men were included in the study with a mean age of 62.3±10.3 years. Overall, 1,485 (34%) men had diabetes, and 2,131 (49%) had hypertension. Down-sized cylinders were placed in 406 men (174 CXRs, 232 NBs), while standard cylinders were placed in 3,983. Multivariable analysis indicated that down-sized cylinders were more commonly used in men with diabetes (OR 2.6 [1.9, 3.7], p<0.001) and less frequently in men with hypertension (OR 0.5 [0.4, 0.7], p<0.001). A history of priapism did not significantly impact the use of down-sized cylinders (p≥0.152). Sequential dilation was performed more often with the use of down-sized cylinders (OR 4.0 [2.8, 5.7], p<0.001). Down-sized cylinders were associated with an increased rate of non-infectious complications (OR 1.9 [1.3, 2.9], p<0.001), however, there was no significant association with implant infection (OR 2.1 [0.9, 4.6], p=0.07). Non-infectious complications occurred in 44 (25%) men with down-sized cylinders. In the down-sized group, hematomas occurred in 10 (2.5%) men and wound-related complications occurred in 7 (1.7%) men (Table 1). Cylinder-related complications occurred in 7 (1.7%) men with down-sized cylinders. Device-related malfunctions were seen in 8 (2%) men. Conclusions This study demonstrates that down-sized cylinders are more frequently used in men with diabetes and surgeons should be prepared to place down-sized cylinders in these men. Prosthetic urologists are also more likely to use down-sized cylinders in men requiring sequential dilation likely due to fibrosis or more challenging dilations. Down-sized cylinders are associated with a low overall complication rate. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Intuitive Surgical, Fidelis, Urofill, Boston Scientific, Coloplast, Cynosure, Antares Pharma, Clarus Pharmaceuticals, Acerus Pharma; Endo Pharma.

Abstract Background Common genetic variation has been linked to an increased risk of developing dilated cardiomyopathy (DCM) in case-control studies. However, the phenotypic profile and biological mechanisms by which genetic background may predispose individuals to DCM and outcomes in the general population remain unclear. Aim The primary objectives of this study were twofold: (1) to validate a DCM polygenic score (PRS-1) based on a prior meta-analysis of case–control genetic association studies [Tadros R et al. Nat Genet (2021)]; and (2) To apply this PRS, along with two recently developed PRSs for DCM [PRS-2 from Zheng SL et al. Nat Genet (2024) and PRS-3 from Jurgens SJ et al. Nat Genet (2024)] to a general population that underwent comprehensive longitudinal phenotypic assessments and had long-term outcomes available. Methods While the PRS-1 was derived from only 13 SNPs, PRS-2 and PRS-3 were generated from 709,534 and 1,072,247 SNPs, respectively with significant overlap between them. These DCM-PRSs were applied to an unselected community-based cohort (n=1897) aged >45 years, who underwent a physical examination, echocardiogram, and blood sample at baseline. Subsequent clinical outcomes were collected over a median 16 year follow-up (IQR: 15-17). Results No significant differences between the quartiles were present in terms of age, sex (48% male), and cardiovascular risk factors (CV-RF) (such as hypertension, diabetes, and coronary artery disease). However, linear regression models demonstrated a significant correlation between all DCM-PRSs and left ventricular (LV) parameters, including LV ejection fraction, LV end-systolic diameter, and LV end-diastolic diameter (Table). Multivariable regression analysis confirmed that these correlations were independent of age, sex, CV-RF, and population stratification (adjusted for the first 10 principal components [PCs]). During follow-up, 47 individuals developed DCM. A logistic regression analysis, using a 3:1 matched cohort of non-DCM vs. DCM individuals based on age and sex and adjusted for the same 10 PCs, found a significant correlation between DCM development and both PRS-1 [OR=2.27 (1.06–4.85), p=0.03] and PRS-3 [OR=2.63 (1.20–5.75), p=0.02], while PRS-2 did not show a significant association [OR=1.85 (0.84–4.06), p=0.12]. No association was found between the DCM-PRSs and heart failure (HF) biomarkers (aldosterone, natriuretic peptides, ST2, Galectin-3) or HF outcomes (all-cause mortality/HF hospitalization). Conclusion PRS-1 for DCM despite being derived from only 13 risk alleles, performs at least as well as the newer and more extensive PRSs, in its correlation with LV function, dimensions, and DCM development (except for PRS-2) in a general population. The absence of correlation between these DCM-PRSs and the renin-angiotensin-aldosterone system or natriuretic peptides suggests that genetic background influences LV traits through mechanisms independent of these biological pathways.

The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well‐structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of the more detailed information and links available at the www.guidetopharmacology.org website, the printed guide serves as a permanent, citable, point‐in‐time record, that remains stable despite ongoing updates to the online database. The full contents of this publication can be found at https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70233 . The Concise Guides provide expert‐curated recommendations of ‘Gold Standard’ selective pharmacological tools, available either commercially or as donations, which enable the identification of individual drug targets or families of drug targets. While the Concise Guide offers a more streamlined overview, more comprehensive information, including detailed pharmacological profiles and links to multiple online databases, is available through the Guide to Pharmacology website. The 2025/26 edition of the Concise Guide is based on material current as of mid‐2025, and supersedes all previous editions, including the 2023/24 Guide, and earlier Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), and as such provides official IUPHAR classification and nomenclature for human drug targets, where applicable. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. Each section includes nomenclature guidance, concise summaries, information of the best available pharmacological tools, key references, and suggestions for further reading.

Although CNP (C‐type natriuretic peptide) was first identified in brain tissue, its systemic expression and release is mainly located to the endothelial lining of the vasculature. As such, CNP should not be viewed as a classic blood‐borne hormone but rather as a local factor that supports the integrity of vascular function. Albeit CNP is structurally related to both ANP and BNP (A‐ and B‐type natriuretic peptide), the main signaling pathway is through a specific membrane‐bound receptor without crosstalk from endocrine ANP and BNP. CNP expression and CNP‐mediated effects can thus be uniquely targeted without interference from the related cardiac NPs. In this perspective, we present the CNP system as a largely overlooked target for potential intervention in cardiometabolic disease, hypertension, and diabetes before onset of complications and overt heart failure. To fully unleash this potential, with this perspective, we hope to fuel renewed interest with a focus on use of human in vitro and ex vivo systems as well as experimental medical approaches and human cohort data.

Abstract Introduction Down-sized inflatable penile prosthesis (IPP) cylinders are useful in cases with substantial penile fibrosis such as history of priapism or prior infection. Although down-sized IPP cylinders have a clear role in fibrotic corpora, their role in primary implant cases is unclear. Objective To identify factors associated with the use of down-sized cylinders in men undergoing primary IPP placement. Methods We conducted a retrospective analysis of 4,389 patients undergoing primary IPP placement from our multicenter database. Patients were categorized by down-sized (AMS 700 CXR, Coloplast NB) vs. standard sized cylinders (AMS 700 CX, AMS 700 LGX, Coloplast Titan). We collected demographic, intraoperative, and postoperative data. A multivariable analysis was performed to identify factors associated with use of down-sized cylinders Results A total of 4,389 men undergoing primary inflatable penile prosthesis (IPP) placement were included in the study, with a mean age of 62.3 ± 10.3 years. Among them, 1,485 (34%) had diabetes and 2,131 (49%) had hypertension. A total of 406 down-sized cylinders and 3,983 standard cylinders were implanted. Non-infectious complications occurred more frequently with the use of down-sized cylinders (odds ratio [OR] = 2.0, p < 0.001). Specifically, non-infectious complications were reported in 44 out of 185 men (23.8%) with down-sized cylinders, compared to 192 out of 2,727 men (10.9%) with standard cylinders. Cylinder complications constituted 13.9% and 13.0% of the non-infectious complications in the down-sized and standard cylinder groups, respectively. Conclusions The rate of cylinder-related complications were similar between the down-sized cylinder and standard cylinder groups. Urologists should be prepared to place down-sized cylinders during IPP placement in diabetic men and in men requiring serial dilation due to fibrosis. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Intuitive Surgical, Fidelis, Urofill, Boston Scientific, Coloplast, Cynosure, Antares Pharma, Clarus Pharmaceuticals, Acerus Pharma; Endo Pharma.

Background: The cardiac hormone atrial natriuretic peptide is the endogenous ligand for the guanylyl cyclase A (GC-A) receptor. The ANP/GC-A/cGMP pathway is a key regulator of cardiorenal and metabolic homeostasis. Beyond its classical natriuretic and vasodilatory roles, emerging evidence reveals that ANP via GC-A stimulates lipolysis in human adipocytes and modulates insulin secretion. Notably, the ANP gene variant rs5068, which enhances ANP production, is associated with reduced risk of obesity and metabolic syndrome in humans. We recently engineered CRRL191, a novel best-in-class GC-A agonist, with superior receptor activation and greater resistance to degradation by neprilysin and insulin degrading enzyme resulting in greater blood pressure lowering and natriuretic effects than ANP. Given the metabolic properties of GC-A signaling, we investigated CRRL191’s metabolic effects on lipolysis and insulin secretion in pancreatic, including its interaction with GLP-1. Hypothesis: CRRL191 exerts potent lipolytic and insulinotropic effects and synergizes with GLP-1 to enhance insulin secretion. Methods: Human visceral adipocytes were treated with CRRL191 (10 -8 -10 -6 M) for 6 hrs. Lipolysis was assessed by measuring glycerol and non-esterified fatty acids (NEFA) in supernatants. Rat pancreatic beta cells (INS-1) were stimulated treated with CRRL191 (10 -10 -10 -6 M), GLP-1 (10 -10 -10 -6 M) alone or their combination for 1 hr. Insulin secretion was quantified by ELISA. Results: CRRL191 stimulated lipolysis in human visceral adipocytes (10 -8 -10 -6 M), increasing glycerol and NEFA release. CRRL191 induced greater glycerol release than GLP-1 across all tested doses, with low dose CRRL191 (10 -10 M) notably enhancing NEFA production. In INS-1 cells, CRRL191 dose dependently increased insulin secretion under hyperglycemic conditions, demonstrating superior potency at lower concentrations (10 -10 and 10 -8 M) compared to GLP-1. Remarkably, co-administration of CRRL191 with GLP-1 amplified insulin release beyond levels achieved by either peptide alone. Conclusion: CRRL191 is a potent GC-A agonist that robustly stimulates lipolysis in visceral adipocytes and enhances insulin secretion in pancreatic beta cells. Its synergistic interaction with GLP-1 highlights a novel therapeutic avenue targeting the GC-A/cGMP pathway for integrated treatment of cardiometabolic diseases. These findings support further evaluation of CRRL191 as a promising candidate for cardiometabolic drug development.

Background: Heart failure (HF) is a complex syndrome marked by adverse cardiac remodeling and natriuretic peptide (NP) deficiency, which drives disease progression despite current therapies. NPs exert cardioprotective effects via particulate guanylate cyclase receptors GC-A and GC-B, which generate cGMP. Activation of GC-A by ANP or BNP induces arteriodilation, natriuresis, antihypertrophic effects, and inhibits the renin-angiotensin-aldosterone system, while GC-B activation by CNP mediates antifibrotic, lusitropic, venodilatory, and anti-inflammatory actions. Existing drugs target either GC-A or GC-B, but none target both. We developed RT-A1, a unimolecular peptide activating both GC-A and GC-B, hypothesizing it will attenuate myocardial remodeling in a preclinical model of HF with preserved systolic function. Methods: RT-A1 was engineered by rational drug design. HEK293 cells expressing human GC-A or GC-B, human cardiac myocytes (CMs) and fibroblasts (CFs) were treated with RT-A1 (10-100nM) and cGMP was measured. In vivo, mice underwent mild transverse aortic constriction (TAC) or sham surgery. After 3 weeks, LV hypertrophy (LVH) was confirmed by echo. TAC mice were then randomized to vehicle (Veh) or RT-A1 (50pmol/kg/min) via subcutaneous osmotic pumps for 3 weeks. Endpoints included LV/body weight ratio, myocyte cross-sectional area (CSA), plasma cGMP, and RNA-seq. Data are mean±SEM. P<0.05 was significant. Results: RT-A1 dose-dependently increased cGMP in HEK293 cells expressing GC-A or GC-B, confirming dual activation, and elevated cGMP in human CMs and CFs. TAC induced significant LV wall thickening with preserved systolic function versus sham. After three weeks, RT-A1 normalized LV/body weight (3.14±0.14 vs. 3.82±0.29, P=0.03) and reduced myocyte CSA (348±16 vs. 506±17, P=0.0005) compared to Veh. Plasma cGMP was higher in TAC+RT-A1 versus TAC+Veh (85±8 vs 54±8 pmol/ml, P=0.01), confirming target engagement. RNA-seq showed reduced LV BNP expression and downregulation of hypertrophy, fibrosis, and inflammation pathways with RT-A1 treatment vs. Veh following TAC. Conclusions: RT-A1 is a novel dual GC-A/GC-B peptide activator that elevates plasma cGMP and reduces adverse cardiac remodeling in experimental HF by downregulating hypertrophy, fibrosis, and inflammation pathways. Dual GC-A/GC-B activation via RT-A1 represents a promising anti-remodeling therapeutic strategy for HF with preserved systolic function warranting further study.