DNA mismatch and damage patterns revealed by single-molecule sequencing.

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other diseases1,2. Most mutations begin as nucleotide mismatches or damage in one of the two strands of the DNA before becoming double-strand mutations if unrepaired or misrepaired3,4. However, current DNA-sequencing technologies cannot accurately resolve these initial single-strand events. Here we develop a single-molecule, long-read sequencing method (Hairpin Duplex Enhanced Fidelity sequencing (HiDEF-seq)) that achieves single-molecule fidelity for base substitutions when present in either one or both DNA strands. HiDEF-seq also detects cytosine deamination-a common type of DNA damage-with single-molecule fidelity. We profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes, and derive from them single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumours deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples that are deficient in only polymerase proofreading. We also define a single-strand damage signature for APOBEC3A. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. As double-strand DNA mutations are only the end point of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable studies of how mutations arise in a variety of contexts, especially in cancer and ageing.

Antibiotic Use in Hospital Urinary Tract Infections After FDA Regulation.

BACKGROUND: The FDA issued a "black box" warning regarding risks of fluoroquinolones in 2008 with updates in 2011, 2013, and 2016. OBJECTIVE: To examine antimicrobial use in hospital-treated UTIs from 2000 to 2020. DESIGN: Cross-sectional study with interrupted time series analysis. PARTICIPANTS: Patient encounters with a diagnosis of UTI from January 2000 to March 2020, excluding diagnoses of renal abscess, chronic cystitis, and infection of the gastrointestinal tract, lungs, or prostate. MAIN MEASURES: Monthly use of fluoroquinolone and non-fluoroquinolone antibiotics were assessed. Fluoroquinolone resistance was assessed in available cultures. Interrupted time series analysis examined level and trend changes of antimicrobial use with each FDA label change. KEY RESULTS: A total of 9,950,790 patient encounters were included. From July 2008 to March 2020, fluoroquinolone use declined from 61.7% to 11.7%, with similar negative trends observed in inpatients and outpatients, age ≥ 60 and < 60 years, males and females, patients with and without pyelonephritis, and across physician specialties. Ceftriaxone use increased from 26.4% encounters in July 2008 to 63.6% of encounters in March 2020. Among encounters with available culture data, fluoroquinolone resistance declined by 28.9% from 2009 to 2020. On interrupted time series analysis, the July 2008 FDA warning was associated with a trend change (-0.32%, < 0.001) and level change (-5.02%, p < 0.001) in monthly fluoroquinolone use. CONCLUSIONS: During this era of "black box" warnings, there was a decline in fluoroquinolone use for hospital-treated UTI with a concomitant decline in fluoroquinolone resistance and rise in ceftriaxone use. Efforts to restrict use of a medication class may lead to compensatory increases in use of a single alternative agent with changes in antimicrobial resistance profiles.

Hypogonadism, frailty, and postoperative outcomes among men undergoing radical nephrectomy.

BACKGROUND AND OBJECTIVE: Hypogonadism and frailty may impact postoperative outcomes for men undergoing radical nephrectomy (RN). We aimed to determine the prevalence of hypogonadism in men undergoing RN and whether hypogonadism and frailty are associated with adverse postoperative outcomes. METHODS: We identified men undergoing RN between 2012 and 2021 using the IBM Marketscan database. Frailty was determined using the Hospital Frailty Risk Score (HFRS). Patients were considered to have hypogonadism if diagnosed <5 years before RN. Length of stay (LOS), complications, emergency department (ED) visits, and readmissions were evaluated between men with and without hypogonadism at the time of surgery. Subgroup analysis of men with hypogonadism was performed to determine the effect of testosterone replacement therapy (TRT) on clinical outcomes. RESULTS: Among 13 598 men who underwent RN, 972 (7.1%) had hypogonadism. Men with hypogonadism were more frail compared to men without hypogonadism (HFRS: median: 8.2, interquartile range [IQR]: 5.2-11.7 vs. median: 7.0, IQR: 4.3-10.7, p < 0.001) and had increased incidence of postoperative ileus (13.0% vs. 10.8%, p = 0.045), acute kidney injury (25.5% vs. 21.6% p = 0.005), and cardiac arrest (1.2% vs. 0.6%, p = 0.034). Hypogonadism was not associated with LOS, 90-day ED visit or readmission. However, high-risk frailty was associated with increased risk of 90-day ED visit (hazard ratio [HR]: 2.1, 95% confidence interval [95% CI]: 1.9-2.4, p < 0.001) and 90-day inpatient readmission (HR: 2.6, 95% CI: 2.2-3.1, p < 0.001), compared to low-risk frailty patients. Among men with hypogonadism, TRT was not associated with any postoperative outcomes. CONCLUSIONS: Hypogonadism and frailty should be considered in the preoperative evaluation for men undergoing RN as risk factors for adverse postoperative outcomes.

PI-RADS Upgrading Rules: Impact on Prostate Cancer Detection and Biopsy Avoidance of MRI-Directed Diagnostic Pathways.

BACKGROUND. PI-RADS incorporates rules by which ancillary sequence findings upgrade a dominant score to a higher final category. Evidence on the upgrading rules' impact on diagnostic pathways remains scarce. OBJECTIVE. The purpose of this article was to evaluate the clinical net benefit of the PI-RADS upgrading rules in MRI-directed diagnostic pathways. METHODS. This study was a retrospective analysis of a prospectively maintained clinical registry. The study included patients without known prostate cancer who underwent prostate MRI followed by prostate biopsy from January 2016 to May 2020. Clinically significant prostate cancer (csPCa) was defined as International Society of Urological Pathology (ISUP) grade group 2 and higher. csPCa detection was compared between dominant (i.e., no upgrade rule applied) and upgraded lesions. Decision-curve analysis was used to compare the net benefit, considering the trade-off of csPCa detection and biopsy avoidance, of MRI-directed pathways in scenarios considering and disregarding PI-RADS upgrading rules. These included a biopsy-all pathway, MRI-focused pathway (no biopsy for PI-RADS ≤ 2), and risk-based pathway (use of PSA density ≥ 0.15 ng/mL2 to select patients with PI-RADS ≤ 3 for biopsy). RESULTS. The sample comprised 716 patients (mean age, 64.9 years; 93 with a PI-RADS ≤ 2 examination, 623 with total of 780 PI-RADS ≥ 3 lesions). Frequencies of csPCa were not significantly different between dominant and upgraded PI-RADS 3 transition zone lesions (20% vs 19%, respectively), dominant and upgraded PI-RADS 4 transition zone lesions (33% vs 26%), and dominant and upgraded PI-RADS 4 peripheral zone lesions (58% vs 45%) (p > .05). In the biopsy-all, per-guideline MRI-focused, MRI-focused disregarding upgrading rules, per-guideline risk-based, and risk-based disregarding upgrading rules pathways, csPCa frequency was 53%, 52%, 51%, 52%, and 48% and biopsy avoidance was 0%, 13%, 16%, 19%, and 25%, respectively. Disregarding upgrading rules yielded 5.5 and 1.9 biopsies avoided per missed csPCa for MRI-focused and risk-based pathways, respectively. At probability thresholds for biopsy selection of 7.5-30.0%, net benefit was highest for the per-guideline risk-based pathway. CONCLUSION. Disregarding PI-RADS upgrading rules reduced net clinical bene fit of the risk-based MRI-directed diagnostic pathway when considering trade-offs between csPCa detection and biopsy avoidance. CLINICAL IMPACT. This study supports the application of PI-RADS upgrading rules to optimize biopsy selection, particularly in risk-based pathways.

Risk of postoperative mesh exposure following sacrocolpopexy with supracervical versus total concomitant laparoscopic hysterectomy.

INTRODUCTION AND HYPOTHESIS: The primary objective was to compare rates of mesh exposure in women undergoing minimally invasive sacrocolpopexy with concurrent supracervical vs total hysterectomy. We hypothesized there would be a lower risk of mesh exposure for supracervical hysterectomy. METHODS: This was a retrospective cohort study using the Premier Healthcare Database. Women undergoing sacrocolpopexy with supracervical or total hysterectomy between 2010 and 2018 were identified using Current Procedural (CPT) codes. Complications were identified using CPT and diagnosis codes; reoperations were identified using CPT codes. Mesh exposures were measured over a 2-year period. A multivariable logistic regression was performed with a priori defined predictors of mesh exposure. RESULTS: This study includes 17,111 women who underwent minimally invasive sacrocolpopexy with concomitant supracervical or total hysterectomy (6708 (39%) vs 10,403 (61%)). Women who underwent supracervical hysterectomy were older (age 60 ± 11 vs 53 ± 13, p < 0.01) and less likely to be obese (4% vs 7%, p < 0.01). Postoperative mesh exposures within 2 years were similar (supracervical n = 47, 0.7% vs total n = 65, 0.62%, p = 0.61). On logistic regression, obesity significantly reduced the odds of mesh exposure (OR 0.2, 95% CI 0.01, 0.8); concomitant slings increased odds (OR 1.91, 95% CI 1.28, 2.83). Supracervical hysterectomy was associated with higher rates of port site hernias (1.3% vs 0.65%, p < 0.01), but lower surgical site infections within 3 months (0.81% vs 1.2%, p = 0.03). Reoperation for recurrent prolapse within 24 months was similar (supracervical n = 94, 1.4% vs total n = 150, 1.4%, p = 0.88). CONCLUSIONS: Postoperative mesh exposure rates do not significantly differ based on type of concomitant hysterectomy in this dataset.

Novel reference range values for serum testosterone: a cross-sectional study of 200,000 males.

PURPOSE: To better understand the effects of aging, metabolic syndrome, diurnal variation, and seasonal variation on serum testosterone levels in the context of current guideline statements on testosterone deficiency. METHODS: This cross-sectional study utilized the United Kingdom Biobank. Physical examination, anthropomorphic measurements, and laboratory evaluation were performed at the time of enrollment from 2006 to 2010. The primary outcomes were the effect of age, the presence of metabolic syndrome, the time of day, and the month of the year on serum testosterone levels. RESULTS: Among 197,883 included men, the 5th, 25th, 50th, 75th and 95th percentile testosterone levels in men without metabolic syndrome were significantly higher than those in men with metabolic syndrome at every decade of life (p < 0.001). The average testosterone level within each group (men without metabolic syndrome vs. men with) was clinically similar across decade of life (12.43 in 40's 12.29 in 50's 12.24 in 60's vs. 10.69 in 40's 10.56 in 50's 10.63 in 60's respectively). Average testosterone levels decreased with blood draws later in the day ranging from 10.91 to 12.74 nmol/L (p < 0.01). Similarly, there was seasonal variation in serum testosterone ranging from 11.86 to 12.18 nmol/L (p < 0.01). CONCLUSIONS: We found significant variation in serum testosterone according to the presence of metabolic syndrome and time of laboratory draw, but not according to age. These data challenge the prior dogma of age-related hypogonadism and favor an individualized approach towards serum testosterone measurement and interpretation. However, further studies are needed to correlate these population-based data with individuals' hypogonadal symptoms.

Prostate cancer genetic alterations in Hispanic men.

BACKGROUND: Differences in DNA alterations in prostate cancer among White, Black, and Asian men have been widely described. This is the first description of the frequency of DNA alterations in primary and metastatic prostate cancer samples of self-reported Hispanic men. METHODS: We utilized targeted next-generation sequencing tumor genomic profiles from prostate cancer tissues that underwent clinical sequencing at academic centers (GENIE 11th). We decided to restrict our analysis to the samples from Memorial Sloan Kettering Cancer Center as it was by far the main contributor of Hispanic samples. The numbers of men by self-reported ethnicity and racial categories were analyzed via Fisher's exact test between Hispanic-White versus non-Hispanic White. RESULTS AND LIMITATIONS: Our cohort consisted of 1412 primary and 818 metastatic adenocarcinomas. In primary adenocarcinomas, TMPRSS2 and ERG gene alterations were less common in non-Hispanic White men than Hispanic White (31.86% vs. 51.28%, p = 0.0007, odds ratio [OR] = 0.44 [0.27-0.72] and 25.34% vs. 42.31%, p = 0.002, OR = 0.46 [0.28-0.76]). In metastatic tumors, KRAS and CCNE1 alterations were less prevalent in non-Hispanic White men (1.03% vs. 7.50%, p = 0.014, OR = 0.13 [0.03, 0.78] and 1.29% vs. 10.00%, p = 0.003, OR = 0.12 [0.03, 0.54]). No significant differences were found in actionable alterations and androgen receptor mutations between the groups. Due to the lack of clinical characteristics and genetic ancestry in this dataset, correlation with these could not be explored. CONCLUSION: DNA alteration frequencies in primary and metastatic prostate cancer tumors differ among Hispanic-White and non-Hispanic White men. Notably, we found no significant differences in the prevalence of actionable genetic alterations between the groups, suggesting that a significant number of Hispanic men could benefit from the development of targeted therapies.

National Adherence to Guidelines for Antimicrobial Prophylaxis for Patients Undergoing Radical Cystectomy.

PURPOSE: The sentinel reference for antibiotic prophylaxis for radical cystectomy with ileal conduit in the AUA Guidelines reports data from 2003-2013 and has not been updated in the interim. Here, we assess adherence to antibiotic prophylaxis guidelines among patients undergoing radical cystectomy with ileal conduit for bladder cancer using a large national database. As a secondary objective, we assess the association between antimicrobial use and postoperative infection during the index admission following cystectomy. MATERIALS AND METHODS: The Premier Healthcare Database was queried for all patients undergoing cystectomy with ileal conduit with diagnosis of bladder cancer between 2015 and 2020. Antibiotics used and the duration of use was determined by charge codes and grouped as guidelines-based or not according to 2019 AUA Guidelines. Association with infectious complications was assessed by logistic mixed effects regression models. RESULTS: Among 6,708 patients undergoing cystectomy with ileal conduit, only 28% (1,843/6,708) were given prophylaxis according to AUA guidelines; 1.8% (121/6,708) of patients received an antifungal and 37% (2,482/6,708) received extended duration prophylaxis beyond postoperative day 1. Patients who received guidelines-based prophylaxis were less likely to be diagnosed with a urinary tract infection (21% vs 24%, P = .04), pyelonephritis (5.1% vs 7.7%, P < .001), bacterial infection (24% vs 27%, P = .03), or pneumonia (12% vs 17%, P < .001). There was no statistically significant difference in clostridium difficile infection between guidelines-based and nonguidelines-based prophylaxis (3.2% vs 3.7%, P = .32). In a multivariable logistic regression adjusting for age, race, insurance, and hospital and provider characteristics, nonguideline antibiotic prophylaxis (OR 1.27 [1.12, 1.43], P < .001) was associated with an increased odds of infectious events, whereas a robotic approach (OR 0.82 [0.73, 0.92], P < .001) was associated with lower odds. CONCLUSIONS: Seventy-three percent of patients fail to receive guideline-based antibiotic prophylaxis when undergoing radical cystectomy with conduit, which was largely driven by extended duration antibiotic use. Despite the shorter duration of antibiotics, we found that guideline-based prophylaxis was associated with a 25% decrease in the odds of infectious complications. While residual confounding is possible, these data support current AUA guidelines and suggest a need for outreach to improve guideline adherence.

Variability of Prostate MRI Charges Among U.S. Hospital-Based Facilities.

The Premier Healthcare Database was used to assess charge variation for prostate MRI examinations in U.S. hospitals from January 2010 to March 2020. In 552 facilities performing 37,073 examinations, the median charge per examination was $4419 with 26-fold variation between the lowest ($593) and highest ($15,150) median facility charges. In multilevel linear regression analysis, interfacility variation explained 63.9% of charge variation. Patients may be charged vastly different prices for prostate MRI depending on the facility.

Trends over 20 years of antimicrobial prophylaxis for artificial urinary sphincter surgery.

INTRODUCTION AND OBJECTIVE: Perioperative antimicrobial prophylaxis is crucial for prevention of prosthesis and patient morbidity after artificial urinary sphincter (AUS) placement. While antibiotic guidelines exist for many urologic procedures, adoption patterns for AUS surgery are unclear. We aimed to assess trends in antibiotic prophylaxis for AUS and outcomes relative to American Urological Association (AUA) Best Practice guidelines. METHODS: The Premier Healthcare Database was queried from 2000 to 2020. Encounters involving AUS insertion, revision/removal, and associated complications were identified via ICD and CPT codes. Premier charge codes were used to identify antibiotics used during the insertion encounter. AUS-related complication events were found using patient hospital identifiers. Univariable analysis between hospital/patient characteristics and use of guideline-adherent antibiotics was done via chi-squared and Kruskal-Wallis tests. A multivariable logistic mixed effects model was used to assess factors related to the odds of complication, specifically the use of guideline-adherent versus nonadherent regimens. RESULTS: Of 9775 patients with primary AUS surgery, 4310 (44.1%) received guideline-adherent antibiotics. The odds of guideline-adherent regimen use increased 7.7% per year with 53.0% (830/1565) receiving guideline-adherent antibiotics by the end of the study period. Patients with guideline-adherent regimens had a decreased risk of any complication (odds ratio [OR]: 0.83, 95% confidence interval [CI]: 0.74-0.93) and surgical revision (OR: 0.85, 95% CI: 0.74-0.96) within 3 months; however, no significant difference in infection within was noted (OR: 0.89, 95% CI: 0.68-1.17) within 3 months. CONCLUSIONS: Adherence to AUA antimicrobial guidelines for AUS surgery appears to have increased over the last two decades. While guideline-adherent regimens were associated with decreased risk of any complication and surgical intervention, no significant association was found with risk of infection. Surgeons appear to be increasingly following AUA recommendations for antimicrobial prophylaxis for AUS surgery, however, further level 1 evidence should be obtained to demonstrate conclusive benefit of these regimens.

Complications following retropubic versus transobturator midurethral synthetic sling placement.

INTRODUCTION AND HYPOTHESIS: Transobturator slings (TOS) are inferior to retropubic slings (RPS) based on long-term outcomes; data on complications is critical for patient counseling. We hypothesized rates of urinary retention would be higher for RPS, while pain and repeat sling surgery would be higher for TOS. METHODS: Using the Premier healthcare database we identified encounters for patients undergoing a midurethral sling procedure between 2010 and 2020. Patients were stratified by sling type, either RPS or TOS. The primary outcome was the difference in the composite complication rate between groups within 12 months. Statistical analysis was performed using Kruskal Wallis test for continuous variables and χ2-test for categorical variables. Multivariable logistic regression was used to determine risk factors for complications and risk of specific complications after sling placement. RESULTS: 36,991 patients were included in the RPS group and 16,371 in the TOS group. 7,880 patients (14.8%) had at least one sling specific complication. On multivariable logistic regression, RPS patients were more likely to have urinary retention (OR 1.29, 95%CI 1.16-1.43), sling lysis/excision (OR 1.29, 95%CI 1.10-1.53), and hematoma/hemorrhage (OR 1.82, 95%CI 1.16-2.86); they were less likely to have a UTI (OR 0.88, 95%CI 0.82-0.96) or repeat sling (OR 0.60, 95%CI 0.46-0.78). In patients with urinary retention, RPS patients were more likely to undergo sling lysis than TOS (p = 0.012). CONCLUSIONS: Significant complications after midurethral synthetic sling are overall rare. RPS are associated with a higher rate of perioperative bleeding and sling lysis/excision due to urinary retention, but less likely to be associated with UTI and treatment failure.

Evaluation of gastrointestinal tract injury within 1 year of surgery for pelvic organ prolapse.

OBJECTIVE: To identify the incidence and risk factors of gastrointestinal injury (GITI) related to pelvic organ prolapse (POP) surgery. METHODS: Women who underwent POP surgery between 2000 and 2020 were identified in the Premier Healthcare Database. The primary outcome was GITI, defined as small or large bowel injury or repair, and fistula or fistula repair. Differences between patients with and without GITI were evaluated, and a multivariable regression was performed to determine independent predictors of GITI. RESULTS: We identified 563,661 index POP surgeries in female patients aged 18 years and older. Of these, 4582 (0.8%) had a bowel injury code within 1 year of index POP surgery. Patients who experienced GITI were more likely to be younger (49.9 ± 12.8 vs 50.9 ± 13.7), and receive surgery with a surgeon who performed less than 12 surgeries per year (48% vs 42%). Most GITI was diagnosed in the same month (73.4%) and same hospital encounter (54%) as index POP surgery. After adjusting for confounders, lysis of adhesions (aOR = 2.03, 95% CI: 1.48-2.72) and perioperative hematoma/hemorrhage (aOR = 2.87, 95%C I: 1.70-4.59) were strongly associated with GITI, while having surgery with a surgeon performing > 50 POP surgeries per year (aOR = 0.66, 95%C I: 0.59-0.75 and concomitant obliterative procedures (aOR = 0.48, 95% CI: 0.34-0.65) were associated with a lower probability of GITI. CONCLUSIONS: The rate of GITI after POP surgery is less than 1%, and injuries are commonly diagnosed and treated in the same month as index surgery. High-volume surgeons and obliterative procedures may be protective against GITI.

Incidence of Kidney Stones in the United States: The Continuous National Health and Nutrition Examination Survey.

PURPOSE: The incidence of kidney stones in the United States is currently unknown. Here, we assessed the incidence of kidney stones using recent, nationally representative data. MATERIALS AND METHODS: We used the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2018. During this time participants were asked, "Have you ever had a kidney stone?" and "In the past 12 months, have you passed a kidney stone?" Demographics analyzed include age, race, gender, body mass index, history of smoking, diabetes, hypertension, hypercholesterolemia and gout. Multivariable models were used to assess the independent impact of subject characteristics on kidney stone prevalence and incidence. RESULTS: Data were available on 10,521 participants older than age 20. The prevalence of kidney stones was 11.0% (95% CI 10.1-12.0). The 12-month incidence of kidney stones was 2.1% (95% CI 1.5-2.7), or 2,054 stones per 100,000 adults. We identified significant relationships between stone incidence and subject age, body mass index, race and history of hypertension. CONCLUSIONS: Here we find a substantially higher 12-month incidence of kidney stones than previous reports. We also validate known risk factors for stone prevalence as associated with incidence. The remarkable incidence and prevalence of stones is concerning and has implications for disease prevention and allocation of medical resources.

Impact of Left-Digit Age Bias in the Treatment of Localized Prostate Cancer.

PURPOSE: Left-digit bias is a phenomenon in which the leftmost digit of a number disproportionately influences decision making. We measured the effect of left-digit age bias on treatment recommendations for localized prostate cancer. MATERIALS AND METHODS: We included men with clinically localized prostate adenocarcinoma in Surveillance, Epidemiology, and End Results from 2004 to 2018 and the National Cancer Database from 2004 to 2016. Primary outcomes were recommendations for radiation therapy and radical prostatectomy. Regression discontinuity was used to assess whether age increase from 69 to 70 years was associated with disproportionate changes in treatment recommendations. RESULTS: In Surveillance, Epidemiology, and End Results, discontinuities were found in the proportion of patients recommended for radiation among the entire cohort (effect size 2.2%, P < .01) and among patients with Gleason 6 (1.6%, P < .01), Gleason 7 (2.5%, P < .01), and Gleason ≥8 (2.1%, P < .01) cancer, while the proportion recommended for prostatectomy decreased in the entire cohort (-1.4%, P < .01) and in patients with Gleason 7 cancer (-2.4%, P < .01). In the National Cancer Database, discontinuity from age 69 to 70 was found in recommendations for radiation in the entire cohort (effect size: 3.1%, P < .01) and in patients with Gleason 6 (2.2%, P < .01), Gleason 7 (4.0%, P < .01), and Gleason ≥8 (2.3%, P < .02) cancer, while the proportion recommended for prostatectomy decreased at this cutoff in the entire cohort (effect size: -2.7%, P < .01) and patients with Gleason 6 (-2.2%, P < .01) and Gleason 7 (-3.7%, P < .01) cancer. CONCLUSIONS: In patients with localized prostate cancer, left-digit age change from 69 to 70 was associated with disproportionately increased recommendations for radiation and decreased recommendations for prostatectomy.

Adoption, Safety, and Retreatment Rates of Prostatic Urethral Lift for Benign Prostatic Enlargement.

PURPOSE: Novel minimally invasive therapies like the prostatic urethral lift are among the many endoscopic options for the treatment of benign prostatic enlargement and lower urinary tract symptoms (BPE/LUTS). To further understand the relative uptake, complications and retreatment rates of contemporary endoscopic procedures for BPE/LUTS across diverse practice types, we performed a retrospective study of inpatient and ambulatory surgery encounters in the Premier Healthcare database. MATERIALS AND METHODS: We included men who underwent endoscopic procedures for BPE/LUTS between 2000 and 2018. We determined the utilization of endoscopic therapies for BPE/LUTS, 30-day and 90-day readmission rates, and retreatment rate. Multivariable logistic regression was used to assess the association of procedure type with outcomes for the 3 most commonly performed procedures. RESULTS: We identified 175,150 men treated with endoscopic surgery for BPE/LUTS. The annual percent utilization of the prostatic urethral lift increased from <1% in 2014 to 10.4% in 2018. Compared to transurethral resection of the prostate and prostate photovaporization, prostatic urethral lift was associated with a lower odds of readmission at 30 (OR 0.58, p <0.01) and 90 (OR 0.55, p <0.01) days and a higher odds of retreatment within 2 years of followup (OR 1.78, p <0.01). CONCLUSIONS: Providers have rapidly adopted prostatic urethral lift which accounted for more than 1 in 10 endoscopic procedures captured for BPE/LUTS in 2018. Men treated with prostatic urethral lift are readmitted less within 30 and 90 days but are more likely to be retreated within 2 years of their index procedure as compared to men treated with transurethral resection of the prostate or prostate photovaporization.

Increasing Utilization of MRI Before Prostate Biopsy in Black and Non-Black Men: An Analysis of the SEER-Medicare Cohort.

OBJECTIVE. The potential for significant disparities exists in the setting of increased adoption of prostate MRI. We sought to assess temporal trends in the utilization of MRI before prostate biopsy in a nationally representative sample. MATERIALS AND METHODS. Using the SEER-Medicare linked database, we identified men undergoing prostate biopsy who had an MRI within 6 months of diagnosis of prostate cancer. Men were stratified according to whether they were biopsy naive or had undergone a prior negative prostate biopsy. RESULTS. We identified 82,483 men undergoing prostate biopsy in SEER-Medicare from 2008 to 2015 of whom 78,253 were biopsy naive and 4230 had a known prior negative biopsy. We found that the percentage of patients who received an MRI before biopsy has increased from 2008 to 2015 in biopsy-naive men (0.5-8.2%; p < .001), men with a prior negative biopsy (1.4-25.5%; p < .001), and overall (0.5-9.2%; p < .001). On multivariable modeling, the odds ratio (OR) of a patient undergoing an MRI before biopsy for Black men (OR, 0.4; 95% CI, 0.3-0.5; p < .001) was half that of White men, and the OR of MRI before biopsy in men from the Northeast (OR, 3.4; 95% CI, 2.8-4.3; p < .001) was more than three times that of men from the West. CONCLUSION. The steady overall increase in the utilization of MRI before prostate biopsy since 2008 has been associated with significant racial and regional disparities in utilization.

PGC-1 coactivators regulate MITF and the tanning response.

The production of pigment by melanocytes tans the skin and protects against skin cancers. UV-exposed keratinocytes secrete α-MSH, which then activates melanin formation in melanocytes by inducing the microphthalmia-associated transcription factor (MITF). We show that PPAR-γ coactivator (PGC)-1α and PGC-1ß are critical components of this melanogenic system in melanocytes. α-MSH signaling strongly induces PGC-1α expression and stabilizes both PGC-1α and PGC-1ß proteins. The PGC-1s in turn activate the MITF promoter, and their expression correlates strongly with that of MITF in human melanoma cell lines and biopsy specimens. Inhibition of PGC-1α and PGC-1ß blocks the α-MSH-mediated induction of MITF and melanogenic genes. Conversely, overexpression of PGC-1α induces pigment formation in cell culture and transgenic animals. Finally, polymorphism studies reveal expression quantitative trait loci in the PGC-1ß gene that correlate with tanning ability and protection from melanoma in humans. These data identify PGC-1 coactivators as regulators of human tanning.

Practice patterns of vasal reconstruction in a large United States cohort.

We aimed to characterise diverse practice patterns for vasal reconstruction and to determine whether surgeon volume is associated with vasoepididymostomy performance at the time of reconstruction. We identified adult men who underwent vasal reconstruction from 2000 to 2020 in Premier Healthcare Database and determined patient, surgeon, cost and hospital characteristics for each procedure. We identified 3,494 men who underwent either vasovasostomy-alone (N = 2,595, 74.3%) or any-vasoepididymostomy (N = 899, 25.7%). The majority of providers (N = 487, 88.1%) performed only-vasovasostomy, 10 (1.8%) providers performed only-vasoepididymostomy and 56 (10.1%) providers performed both. Median total hospital charge of vasoepididymostomy was significantly higher than vasovasostomy ($39,163, interquartile range [IQR]$11,854-53,614 and $17,201, IQR$10,904-29,986, respectively). On multivariable regression, men who underwent procedures at nonacademic centres (OR 2.71, 95% CI 2.12-3.49) with higher volume surgeons (OR 11.60, 95% CI 8.65-16.00) were more likely to undergo vasoepididymostomy. Furthermore, men who underwent vasoepididymostomy were more likely to self-pay (OR 2.35, 95% CI 1.83-3.04, p < .001) and more likely had procedures in the Midwest or West region (OR 2.22, 95% CI 1.66-2.96 and OR 2.11, 95% CI 1.61-2.76, respectively; p < .001). High-volume providers have increased odds of performing vasoepididymostomy at the time of reconstruction but at a significantly higher cost. These data suggest possibly centralising reconstructive procedures among high-volume providers.

Impact of prebiopsy magnetic resonance imaging on biopsy and radical prostatectomy grade concordance.

BACKGROUND: Adoption of prostate magnetic resonance imaging (MRI) before biopsy is based on evidence demonstrating superior detection of clinically significant prostate cancer on biopsy. Whether this is due to the detection of otherwise occult higher grade cancers or preferential sampling of higher grade areas within an otherwise low-grade cancer is unknown. METHODS: To distinguish these two possibilities, this study examined the effect of prebiopsy MRI on the rate of pathologic upgrading and downgrading at prostatectomy in Surveillance, Epidemiology, and End Results-Medicare linked data from 2010 to 2015. Logistic regression was performed to assess the effect of MRI use on the Gleason grade change between biopsy and prostatectomy. RESULTS: Among biopsy-naive men, those who underwent prebiopsy MRI had higher odds of downgrading at prostatectomy (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.05-1.66). In contrast, the odds of upgrading were significantly lower for men who underwent prebiopsy MRI (OR, 0.78; 95% CI, 0.61-0.99). Limitations included a low overall rate of MRI-utilization prior to biopsy and an inability to distinguish between template, software-assisted and cognitive fusion biopsy. CONCLUSIONS: Prebiopsy MRI is associated with both oversampling of higher grade areas, which results in downgrading at prostatectomy, and the detection of otherwise occult higher grade lesions, which results in less upgrading at prostatectomy.

Variation in Magnetic Resonance Imaging-Ultrasound Fusion Targeted Biopsy Outcomes in Asian American Men: A Multicenter Study.

PURPOSE: Asian American men have distinctly different prostate cancer epidemiology than other men. To our knowledge the role of multiparametric magnetic resonance imaging and targeted biopsy for elevated prostate specific antigen in this population has not been assessed. We sought to define imaging and targeted biopsy outcomes in Asian American men compared to other men. MATERIALS AND METHODS: We accrued a multicenter, prospective cohort of men who underwent magnetic resonance imaging targeted and systematic biopsy for elevated prostate specific antigen. The outcome of interest was a diagnosis of clinically significant prostate cancer (Gleason Grade Group 2 or greater) stratified by the PI-RADS™ (Prostate Imaging-Reporting and Data System) score and a history of negative biopsy. Multivariable logistic regression was used to assess the effect of Asian American race on cancer detection. RESULTS: Of the 2,571 men 275 (11%) were Asian American. Clinically significant prostate cancer was detected in 37% of Asian American men compared to 48% of men of other races (p <0.001). Asian American men were also less likely to be diagnosed with Grade Group 1 cancer (12% vs 18%, p=0.007). Additionally, there was significantly lower detection of significant cancer using PI-RADS 3 in Asian American men vs men of other races (12% vs 21%, p=0.032). On adjusted analysis Asian American men were less likely to be diagnosed with significant cancer (OR 0.57, 95% CI 0.42-0.79, p <0.001) and Grade Group 1 cancer (OR 0.57, 95% CI 0.38-0.84, p=0.005) than nonAsian men. CONCLUSIONS: Asian American men are less likely to be diagnosed with clinically significant prostate cancer on targeted biopsy, illustrating the different performance of PI-RADS in this population. Conventional risk assessment tools should be modified when selecting Asian American men for biopsy.