Citations

AbstractQualified medical physicists (QMPs) are in a unique position to influence the creation and application of key performance indicators (KPIs) across diverse practices in health care. Developing KPIs requires the involvement of stakeholders in the area of interest. Fundamentally, KPIs should provide actionable information for the stakeholders using or viewing them. During development, it is important to strongly consider the underlying data collection for the KPI, making it automatic whenever possible. Once the KPI has been validated, it is important to setup a review cycle and be prepared to adjust the underlying data or action levels if the KPI is not performing as intended. Examples of specific KPIs for QMPs of common scopes of practice are provided to act as models to aid in implementation. KPIs are a useful tool for QMPs, regardless of the scope of practice or practice environment, to enhance the safety and quality of care being delivered.

Abstract Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.

Abstract SETDB1 is a key regulator of lineage-specific genes and endogenous retroviral elements (ERVs) through its deposition of repressive H3K9me3 mark. Apart from its H3K9me3 regulatory role, SETDB1 has seldom been studied in terms of its other potential regulatory roles. To investigate this, a genomic survey of SETDB1 binding in mouse embryonic stem cells across multiple libraries was conducted, leading to the unexpected discovery of regions bereft of common repressive histone marks (H3K9me3, H3K27me3). These regions were enriched with the CTCF motif that is often associated with the topological regulator Cohesin. Further profiling of these non-H3K9me3 regions led to the discovery of a cluster of non-repeat loci that were co-bound by SETDB1 and Cohesin. These regions, which we named DiSCs (domains involving SETDB1 and Cohesin) were seen to be proximal to the gene promoters involved in embryonic stem cell pluripotency and lineage development. Importantly, it was found that SETDB1-Cohesin co-regulate target gene expression and genome topology at these DiSCs. Depletion of SETDB1 led to localized dysregulation of Cohesin binding thereby locally disrupting topological structures. Dysregulated gene expression trends revealed the importance of this cluster in ES cell maintenance as well as at gene ‘islands’ that drive differentiation to other lineages. The ‘unearthing’ of the DiSCs thus unravels a unique topological and transcriptional axis of control regulated chiefly by SETDB1.

Introduction: Through degradation of the cardio- and renal-protective second messenger cyclic GMP, phosphodiesterase-9 (PDE9) excess may contribute to cardiomyocyte hypertrophy, fibrosis, and renal dysfunction, common features in heart failure with preserved ejection fraction (HFpEF) development and progression. Hypothesis: Selective PDE9 inhibition with IMR-687 mitigates an adverse cardiac and renal phenotype in mouse models of HFpEF. Methods: Cardiac and renal responses to IMR-687 (60 mg/kg, 100 mg/kg) compared with vehicle were examined over 6-8 weeks in 3 adult male mouse models of HFpEF (1.5 mg/kg/d angiotensin-II infusion [ang-II]; uninephrectomy + 0.30 ug/h d-aldosterone infusion + 1% NaCl drinking water [neph-aldo]; and db/db [db]). Phenotyping included wheat germ agglutinin staining for cardiomyocyte cross-sectional area (CSA); RT-PCR for myocardial PDE9, natriuretic peptide, inflammatory and fibrosis marker transcript abundances; ELISA for plasma natriuretic peptides; and urinary albumin to creatinine ratio (UACR). Results: IMR-687 reduced median cardiomyocyte size (CSA) by 54, 58, and 35% compared with vehicle in the ang-II, neph-aldo, and db models, respectively; p < 0.003 for all. Myocardial PDE9, NPPA, NPPB, COL3A1, and IL-1β expression were decreased by IMR-687 in all models (Table). Median plasma BNP levels (pg/mL) were lower in IMR-687 vs. vehicle treated mice in all models (ang-II: 2376 vs. 5757; neph-aldo: 1216 vs. 1860; db: 830 vs. 1216); p < 0.007 for all, with similar findings for ANP (Table). UACR was lower in IMR-687 compared with vehicle treated mice in all models (Table). Heart rate and blood pressure did not differ between IMR-687 and vehicle treated mice. Conclusion: Selective PDE9 inhibition with IMR-687 was effective for prevention and treatment of cardiac hypertrophy and renal dysfunction in 3 different preclinical models of HFpEF. IMR-687 may be a promising candidate therapy for testing in clinical trials of human HFpEF.

ABSTRACT Introduction Covid-19 has helped drive all forms of medicine away from traditional brick and mortar medical interactions. Given the availability of online services to obtain treatments for ED, we developed a website to facilitate patient education, triage and men's health appointment scheduling. Objective We sought to assess characteristics of men who utilized a novel website to treat their ED. Methods We report on 50 patients who ultimately booked and attended appointments (video or in person) for erectile dysfunction. Patients found our website through our institution's main informational ED pages or through youtube links from our men's health video playlist library. Patients create an institutional account and are then asked a series of MD created questions designed to streamline patient triage and complete the majority of chart documentation ahead of the appointment. Patients are then sent videos relevant to their condition and future appointment options. Results 2300 users investigated the ED portion of the website with 1.8% of patients ultimately following through with an appointment. 13% of patients who explored the ED portion of the site created a user account that allows a questionnaire to be taken. 90% of men who began the ED questionnaire completed with a mean time of 11 minutes. 52% of men offered an appointment based on their responses completed the patient scheduling form. 71% of traffic was on mobile devices with 29% on desktop/tablet. Site use by time of day is shown in figure 1. Mean age of patients was 53. 92% of patients had ED that occurred &gt; 6 months. Mean SHIM score was 8.2 (IQR 4-12). 80% of participants had both desire and opportunity for sexual activity, 20% did not meet both criteria and thus SHIM scores were less valid for these men. Of the users 28% had never tried pde5s, 32% had partial success with pde5s, 24% could not tolerate or afford pde5s and 42% had unsatisfactory results with pde5s. PDE5 naïve patients were seen by an internal medicine MD specializing in men's health, 10 were seen by surgeons as they requested IPPs and the rest were seen by a combination of men's health APPS and urology attendings for second line treatments and penile doppler. Interestingly, 66% of men were interested in undergoing penile doppler to better understand the etiology of their ED. Hypertension (40%) and diabetes (22%) were the most common medical comorbidities. 36% of the cohort had a strong family history of cardiac disease. Conclusions Men with ED can be effectively triaged through a website application. Most men with pde5 refractory ED wish to pursue penile doppler. The majority of patients seen had watched educational video material ahead of time, facilitating a more sophisticated and streamlined patient interaction. Disclosure No

ABSTRACT Introduction The significant overlap of risk factors for erectile dysfunction and venous thromboembolism (VTE) may disproportionally increase the risk of VTE in men undergoing inflatable penile prosthesis (IPP) surgery. Owing to the absence of available literature, AUA and EAU perioperative VTE guidelines do not address VTE risk with IPP surgery and generally recommend against pharmacologic prophylaxis with outpatient surgery. The Caprini Score is a validated scoring system to estimate VTE risk in the perioperative period. Objective We sought to assess the risk of VTE by calculating Caprini Scores in men undergoing IPP surgery. Methods We retrospectively reviewed and calculated Caprini Scores for patients undergoing IPP surgery at our institution between July 2017 and June 2019. Results 215 patients undergoing IPP surgery were identified with a mean and median Caprini score of 5.96 (SD, 1.63) and 6 (IQR 5,7), respectively. 84% of the cohort was classified as high or highest risk for VTE (Figure 1). This is in part due to our cohort's mean age of 64, mean BMI of 31 and history of prostate cancer treatment as the cause of ED. Prior history of VTE (deep vein thrombosis(DVT) or pulmonary embolism (PE)was identified in 17 (8%) patients with 5 (2%) have a history of both DVT and PE. Conclusions Men undergoing IPP surgery are high risk for VTE based on Caprini score assessment. VTE prophylaxis should be considered in men undergoing penile implant surgery. Before widespread application, long-term data is necessary to assess safety and efficacy of VTE prophylaxis in the IPP surgery population. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Senior author consultant for Coloplast

ABSTRACT Introduction Chronic pelvic and/or genital pain is a disabling condition and commonly associated with poor quality of life, impaired sexual function and decreased productivity. Objective To examine treatment outcomes among a cohort of patients diagnosed with refractory pelvic and/or genital pain enrolled in a 3-week interdisciplinary pain rehabilitation program (IPRP). Methods A series of with-in subjects ANOVAs (corrected for multiple comparisons) were used to evaluate the effectiveness of IPRP on self-report (pain severity, interference, depressive symptoms, quality of life) and observer-rated outcome (5 minute walk) among 15 treated patients receiving care at the Mayo Clinic IPRP between 2016-2018. Results Fifteen patients (5 male, 10 female) were identified. Mean age was 47.0 (range: 24-78) and primary diagnoses were pelvic pain (n=13) and penile pain (n=2). Significant within-subject effects were detected for all self-report outcomes and the 5-minute walk test (see table 1). Six patients were on opioid therapy (MME = 49mg), and all but one successfully tapered off opioids. In the remaining patient, daily MME decreased from 150 mg to 30 mg. Conclusions Intensive outpatient IPRP significantly improves quality of life for patients with treatment-refractory chronic pelvic and/or genital pain. These results support multi-disciplinary treatment paradigms for refractory urogenital pain. Disclosure No

ABSTRACT Introduction Erectile dysfunction (ED) stems from a variety of etiologies and often requires a multidisciplinary approach to optimize patient care. Objective We sought to assess attitudes and confidence regarding the treatment of erectile dysfunction across different provider types. Methods Anonymous, email-based survey of physicians and advanced practice providers in the disciplines of urology, internal medicine, and family medicine. Responses were recorded using a five-point Likert scale. Descriptive statistical analysis of survey response data was performed. Results With 76 providers on this ongoing survey including 31 internists, 24 family physicians, and 21 urologists, 88% of providers believed there to be good options for erectile dysfunction after failing pills. Figure 1 shows attitudes of the modalities of “good” options and confidence in the ability to counsel about these options. Regarding if most patients report willingness to consider surgical intervention for ED when counseled about it an equal portion of providers had positive, neutral, and negative feedback. Figure 2 lists other specific attitudes and opinions about penile prosthesis (IPP) implants. Moreover, 78% emphasized the necessity of a multidisciplinary team-based approach to ED patients. However, only 30% of the participants were in agreement with referrals to specialists in sexual health including urologists. Conclusions This survey indicates a knowledge gap and low comfort level in 2nd and 3rd line ED treatments. Focused education on penile implant outcomes appears particularly helpful. Disclosure No