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ABSTRACT Aims Common genetic variants have been linked to an increased risk of non-ischaemic cardiomyopathy (NICM). The primary objective of this study was to evaluate the significance of these variants in a general population. Methods and results Thirteen NICM risk alleles, previously validated by meta-analyses of case-control genetic association studies, were used to determine genetic risk (GR) in a large, unselected cohort (n = 1897) of Olmsted County residents aged >45 years. Clinical and echocardiographic data, with biomarkers, were correlated with this NICM-GR over a median of 16 years of follow-up (interquartile range [IQR] 15–17). There were no significant differences between the study population quartiles, based on NICM-GR, in terms of age (median 61.6 [IQR 53.6–70.4]), sex (48% male), and cardiovascular risk factors. A significant correlation was detected by specific linear-regression models between NICM-GR and left ventricular (LV) ejection-fraction (beta [standard error]: −2.68 [0.68], p < 0.001), LV end-systolic-diameter (0.22 [0.06], p < 0.001), and LV end-diastolic-diameter (0.14 [0.06], p = 0.01). During follow-up, 46 subjects developed NICM. Using a 3:1 matched-cohort of non-NICM versus NICM patients, linear-regression analysis found a significant correlation between NICM-GR and NICM development (odds ratio 2.27, 95% confidence interval 1.06–4.85, p = 0.03). There was no significant association between these variants and heart failure biomarkers (aldosterone, natriuretic peptides, ST2, galectin-3). Conclusions The NICM-GR correlates with LV function and dimension, and subsequent development of NICM in the general population. The lack of correlation of these variants with cardiovascular risk factors and the renin–angiotensin–aldosterone axis or natriuretic peptides suggest different biological mechanisms involved. These findings support the need to explore newer pathophysiologic pathways in the development of NICM.

Abstract Background: Rectosigmoid endometriosis (RSE) presents with a diverse array of MRI findings that impact surgical planning. No standardized reporting and data system has been established for RSE. Purpose: We propose a novel MRI scoring system designed to predict the likelihood of muscularis propria (MP) involvement in RSE, which would, in turn, influence surgical planning. Material and Methods: The records of patients with bowel endometriosis treated surgically from May 2018 to June 2022 were retrieved. Surgery was classified as partial thickness discoid, full thickness discoid, or segmental resection. Each pre-treatment MRI was scored based on the mutual agreement of two abdominal radiologists (reference score). The MRI score was defined as (1) score 0: no evidence of RSE, (2) score 1: minimal tethering involving the serosal surface without MP involvement, (3) score 2: intermediate soft tissue thickening involving the rectosigmoid colon with indeterminate MP involvement, or (4) score 3: definite mushroom cap sign or definite MP involvement. In the reader study, two radiologists independently scored each exam. The area under the curve (AUC) was evaluated for predicting the need for segmental or full thickness discoid resection. Results: The cohort consisted of 95 patients (median age: 36 years); 16, 14, 30, and 35 patients had MRI score 0, 1, 2, and 3, respectively. Patients with MRI scores 3 and 2 underwent partial thickness discoid (6% vs 50%), full thickness discoid (6% vs 17%), and segmental resection (89% vs 33%), respectively. All patients with MRI scores 1 or 0 either underwent partial thickness discoid resection or did not undergo rectosigmoid surgery. The AUCs were 92.2%, 84.5% and 93.9% for MRI scores of the reference, reader 1, and 2, respectively. Conclusion: Our MRI scoring system based on suspected depth of bowel invasion showed good diagnostic performance to predict the type of surgical intervention needed. Summary Statement This novel MRI scoring system for rectosigmoid endometriosis is a concise and qualitative scale based on suspected depth of bowel wall invasion to best guide operative planning.

This Viewpoint discusses clinicians as legal petitioners of extreme risk protection orders to promote the safety and well-being of patients and communities.

BACKGROUND: Cardiomyocyte oxidative stress significantly contributes to the progression of hypertension-induced heart failure, highlighting the need for targeted therapies. We developed a novel peptide, NPA7, that coactivates the GC-A (guanylyl cyclase A)/cGMP and MasR (Mas receptor)/cAMP pathway. This study aimed to test NPA7’s ability to inhibit oxidative stress by modulating the p62 (Sequestosome 1)-KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (nuclear factor erythroid 2-related factor 2) pathway in human cardiomyocytes (HCMs) and a rat model of hypertension. METHODS: Oxidative stress was induced in HCMs using H 2 O 2 with phosphate-buffered saline or NPA7 treatment. Intracellular reactive oxygen species levels were assessed via dihydroethidium staining. Western blotting analysis measured p62, KEAP1, and NRF2 protein levels, while GSH/GSSG (glutathione/glutathione disulfide) ratios and antioxidant gene expression were analyzed. HCMs were transfected with small interfering RNA targeting GC-A, MasR, or p62 before NPA7 and H 2 O 2 treatment. In vivo, spontaneously hypertensive rats received saline or NPA7, with normotensive Wistar Kyoto rats as control and cardiac oxidative stress, KEAP1 protein levels, NOX2 (NADPH oxidase 2), and p67 (NADPH oxidase subunit p67-phox) mRNA levels were measured. RESULTS: NPA7 reduced H 2 O 2 -induced reactive oxygen species levels and increased GSH/GSSG ratio in HCMs. Silencing GC-A (guanylyl cyclase A receptor) and MasR (Mas receptor) reversed NPA7’s effects. NPA7 activated the KEAP1-NRF2 pathway, enhancing NRF2’s antioxidant target gene expression. In p62 knockdown HCMs, NPA7-induced KEAP1 degradation and NRF2 activation were diminished. Reactive oxygen species levels were elevated in spontaneously hypertensive rat versusWistar Kyoto rats’ hearts, however, NPA7 treatment reduced myocardial reactive oxygen species, suppressed KEAP1 protein, and decreased NOX2 and p67 mRNA levels. CONCLUSIONS: NPA7 exhibits antioxidant properties in HCMs and spontaneously hypertensive rat hearts by targeting GC-A and MasR through the p62-KEAP1-NRF2 pathway, supporting a novel therapeutic approach against cardiovascular disease–related oxidative stress.

Abstract Introduction Obesity, defined as an elevated Body Mass Index (BMI) >30, is a prevalent public health concern with far-reaching implications for various medical procedures and outcomes. In the context of inflatable penile prosthesis placement (IPP), where patient well-being and surgical success are of paramount importance, the impact of obesity on postoperative and intraoperative complications warrants thorough investigation. Objective We aimed to investigate the impact of BMI on both postoperative and intraoperative complications in an international, multi-institutional cohort of patients who underwent IPP placement. Methods We performed a retrospective chart review of 4,398 cases. These cases were divided into two distinct groups based on BMI: less than 30 (n = 2,260) and greater than or equal to 30 (n = 2,138). The study assessed various surgical factors as well as complications, including overall complications, corporal scarring, incontinence, intraoperative complications, proximal perforation, distal perforation, proximal crossover, distal crossover, and urethral injury. Results Our analysis revealed that there were no statistically significant differences in intraoperative or postoperative complications between the two BMI categories. Notably, proximal corporal measurement was significantly higher for >30 BMI group with 1858 (86.9%) compared to 1919 (84.9%) for <30 BMI group, (p = < 0.001). The incidence rates for overall complications (30.2% vs. 28.7%; p = 0.164), corporal scarring (18.2% vs. 16.7%; p = 0.36), incontinence (3.53% vs. 3.13%; p = 0.076), intraoperative complications (1.94% vs. 1.68%; p = 0.253), and specific complications all exhibited no significant differences. Similarly, post-operative complications, including both non-infectious (6.99% vs. 6.22%; p = 0.215) and infectious (2.61% vs. 1.87%; p = 0.165) complications, did not significantly vary between BMI categories. Conclusions Our findings indicate that BMI does not exert a statistically significant influence on postoperative and intraoperative complications in the context of high-volume prosthetic urology. In the absence of any other differences between patients of differing BMIs, the IPP industry may need to consider device specific alterations with pump tubing length in obese patients. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast, Clarus Therapeutics, Antares Pharma, Acerus.

Abstract Introduction Inflatable penile prosthesis (IPP) surgery is a well-established treatment for erectile dysfunction (ED). There is little information in the literature regarding the utilization of perioperative antimicrobial prophylaxis in primary and revision IPP surgeries. Objective We investigated the patterns of perioperative antimicrobial prophylaxis among a large multinational cohort of primary and revision IPP surgeries. Methods We conducted a retrospective analysis of 5,400 patients (4,187 primary IPP patients and 849 revision IPP patients) from our Prosthetic Urology Multi-Institutional Partnership (PUMP) institutions. Usage data for intravenous (IV), preoperative oral, and postoperative oral antimicrobials were analyzed. We specifically assessed patient profiles, antimicrobial selection, and antimicrobial duration. Multivariate statistical analyses were conducted to identify significant variations between primary and revision surgeries. Results For patients undergoing primary IPP placement, 81.9% received IV antibiotics for <24 hours whereas 18.1% received IV antibiotics for >24 hours. Preoperative oral antimicrobials were used in 59.4% of patients and 99.4% received postoperative oral antimicrobials. The overall infection rate for primary implants was 2%. Notably, quinolone administration shows a higher postoperative infection rate (11.4%) compared to gentamicin (1.9%), cephalosporin (0%), and vancomycin (1.0%). Multivariable regression analysis identifies factors such as a history of infection, diabetes, and priapism as predictors for postoperative infections. Furthermore, the study finds that perioperative antifungal use is associated with a decreased risk of infection. Conclusions This study provides valuable insights into the patterns of perioperative antimicrobial prophylaxis. Duration, type, and route of antibiotics given preoperatively or postoperatively do not affect postoperative infection rates among high volume prosthetic urologists. Giving IV antibiotics for more than 24 hours does not affect postoperative infection. Perioperative antifungals are a protective factor. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast, Clarus Therapeutics, Antares Pharma, Acerus.

Objectives To evaluate the pre‐ and intraoperative variables that impact the integrity of the corporal bodies over time after inflatable penile prosthesis (IPP) placement, as predictors of intraoperative corporal perforation and delayed cylinder complications have not been well characterized. Patients and Methods We retrospectively reviewed a 16‐centre multi‐institutional database of IPP surgeries performed by experienced implanters from 2016 to 2021. Poor corporal integrity (PCI) was defined as intraoperative (iPCI) corporal complications or postoperative (pPCI) corporal complications. Multivariable analysis was performed to identify independent predictors of PCI, iPCI, and pPCI. Primary outcomes included intra‐ and postoperative corporal complications. Results We identified 5153 patients for analysis from 5406 IPP cases, finding 152 (2.95%) cases of PCI. On multivariable analysis, predictors of PCI included revision IPP surgery (odds ratio [OR] 8.16, 95% confidence interval [CI] 5.15–12.92; P < 0.001), sequential dilatation (OR 2.12, 95% CI 1.32–3.39; P = 0.002), coronary artery disease (CAD)/peripheral vascular disease (PVD) (OR 1.81, 95% CI 1.18–2.77; P = 0.006), older age (OR 1.02, 95% CI 1.01–1.04; P = 0.013), and corporal scarring (OR 1.58, 95% CI 1.0–2.5; P = 0.049). Predictors of iPCI included revision IPP surgery (OR 7.34, 95% CI 4.18–12.88; P < 0.001), corporal scarring (OR 2.77, 95% CI 1.64–4.69; P < 0.001), radiation therapy (OR 2.25, 95% CI 1.0–5.04; P = 0.049), and older age (OR 1.03, 95% CI 1.0–1.05; P = 0.025). Revision IPP surgery (OR 7.92, 95% CI 3.69–17.01; P < 0.001), sequential dilatation (OR 3.4, 95% CI 1.61–7.19; P = 0.001), CAD/PVD (OR 2.98, 95% CI 1.56–5.72; P = 0.001), and history of priapism (OR 3.59, 95% CI 1.08–11.99; P = 0.038) were predictive of pPCI. Conclusion Coronary artery disease/PVD, being of older age, having corporal scarring, undergoing IPP revision surgery and sequential dilatation were predictive risk factors for complications associated with PCI. Identifying patients who are at risk of having PCI may improve patient‐specific counselling, consideration of referral to more experienced implanters, and surgical planning to potentially promote longer‐term device viability.

Abstract Introduction Inflatable penile prosthesis (IPP) surgery is a well-established treatment for erectile dysfunction (ED). There is little information in the literature regarding the utilization of perioperative antimicrobial prophylaxis in primary and revision IPP surgeries. Objective We investigated the patterns of perioperative antimicrobial prophylaxis among a large multinational cohort of primary and revision IPP surgeries. Methods We conducted a retrospective analysis of 5400 patients (4187 primary IPP patients and 849 revision IPP patients) from our Prosthetic Urology Multi-Institutional Partnership (PUMP) institutions. Usage data for intravenous (IV), preoperative oral, and postoperative oral antimicrobials were analyzed. We specifically assessed patient profiles, antimicrobial selection, and antimicrobial duration. Multivariate statistical analyses were conducted to identify significant variations between primary and revision surgeries. Results For patients undergoing primary IPP placement, 81.9% received IV antibiotics for &lt;24 hours whereas 18.1% received IV antibiotics for &gt;24 hours. Preoperative oral antimicrobials were used in 59.4% of patients and 99.4% received postoperative oral antimicrobials. The overall infection rate for primary implants was 2%. Notably, quinolone administration shows a higher postoperative infection rate (11.4%) compared to gentamicin (1.9%), cephalosporin (0%), and vancomycin (1.0%). Multivariable regression analysis identifies factors such as a history of infection, diabetes, and priapism as predictors for postoperative infections. Furthermore, the study finds that perioperative antifungal use is associated with a decreased risk of infection. Conclusions This study provides valuable insights into the patterns of perioperative antimicrobial prophylaxis. Duration, type, and route of antibiotics given preoperatively or postoperatively do not affect postoperative infection rates among high volume prosthetic urologists. Giving IV antibiotics for more than 24 hours does not affect postoperative infection. Perioperative antifungals are a protective factor. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast, Clarus Therapeutics, Antares Pharma, Acerus.

Linked article: This Correspondence comments on Deslandes and Leonardi. Click here to view the article.

Background: Tyrosine kinase inhibitors (TKIs), such as sunitinib, are highly effective in treating cancers. However, they have severe cardiovascular (CV) side effects that include cardiotoxicity via cardiomyocyte injury and death resulting in myocardial dysfunction. There are no FDA-approved drugs to prevent or treat cardiotoxicity, which have been linked mechanistically to mitochondrial dysfunction and oxidative stress, highlighting the need for new therapeutics. Two recognized CV protective pathways are the particulate guanylyl cyclase A receptor (GC-A)/cGMP and the Mas receptor (MasR)/cAMP pathways. We recently engineered NPA7 a novel peptide that activates both pathways. Aim: Here we investigated NPA7’s ability to protect against sunitinib-induced cardiotoxicity in human cardiomyocytes (HCMs) and defined its role on mitochondrial function. Methods: HCMs were treated with DMSO or sunitinib (10 µM) together with PBS or NPA7 (10 µM). Intracellular reactive oxygen species (ROS) was assessed by DHE staining. CCK8 assay was performed to measure cell viability. TOM20 staining were performed by immunofluorescence and the mitochondrial length was analyzed. The protein levels of mitochondrial dynamics markers (fission: MFF, Fis1; fusion: OPA1 and MFN1) proteins were measured by western blot. Cell surface area was assessed by phalloidin staining with mRNA levels of hypertrophic gene markers (NPPA and MYH7) in HCMs using real-time PCR. Results: Sunitinib increased DHE staining and intracellular ROS in HCMs, which was decreased with NPA7 treatment. NPA7 enhanced HCM cell viability in the presence of sunitinib. TOM20 staining showed a marked reduction in mitochondrial length in sunitinib group, compared to DMSO group, whereas NPA7 treatment rescued mitochondria length (DMSO= 6.15 ± 0.94 μm, Sunitinib= 2.42 ± 0.63 μm, NPA7= 5.4 ± 1.19 μm; P < 0.05). Moreover, NPA7 inhibited mitochondrial fission protein levels (MFF and Fis1) and increased mitochondrial fusion protein levels (OPA1, MFN1) in HCMs treated with sunitinib. Sunitinib treatment notably increased HCM cell surface area and hypertrophic gene markers (NPPA and MYH7), whereas NPA7 abolished these markers of hypertrophy. Conclusions: We report, for the first time, that NPA7 protects against sunitinib induced oxidative stress, mitochondrial fragmentation, hypertrophy and cell death in HCMs. These data support a novel therapeutic approach against TKI-induced cardiotoxicity with NPA7 to which no therapies exist.