ZMIZ1 enhances ERα-dependent expression of E2F2 in breast cancer.

The estrogen receptor-α (ER) drives 75% of breast cancers. On activation, the ER recruits and assembles a 1-2 MDa transcriptionally active complex. These complexes can modulate tumour growth, and understanding the roles of individual proteins within these complexes can help identify new therapeutic targets. Here, we present the discovery of ER and ZMIZ1 within the same multi-protein assembly by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating a significant decrease in the proliferation of ER-positive cancer cell lines. To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 h. Gene set enrichment analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell cycle genes. Integration of ENCODE data with our RNA-seq results identified that ER and ZMIZ1 both bind the promoter of E2F2. We therefore propose that ER and ZMIZ1 interact to enable the efficient estrogenic response at subset of cell cycle genes via a novel ZMIZ1-ER-E2F2 signalling axis. Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA and METABRIC, and the proteins are co-localised within the nuclei of tumour cell in patient biopsies. In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER-ZMIZ1 interaction in ER-positive patient tumours, supporting potential clinical relevance.

Artificial Intelligence for Urology Research: The Holy Grail of Data Science or Pandora's Box of Misinformation?

Introduction: Artificial intelligence tools such as the large language models (LLMs) Bard and ChatGPT have generated significant research interest. Utilization of these LLMs to study the epidemiology of a target population could benefit urologists. We investigated whether Bard and ChatGPT can perform a large-scale calculation of the incidence and prevalence of kidney stone disease. Materials and Methods: We obtained reference values from two published studies, which used the National Health and Nutrition Examination Survey (NHANES) database to calculate the prevalence and incidence of kidney stone disease. We then tested the capability of Bard and ChatGPT to perform similar calculations using two different methods. First, we instructed the LLMs to access the data sets and independently perform the calculation. Second, we instructed the interfaces to generate a customized computer code, which could perform the calculation on downloaded data sets. Results: While ChatGPT denied the ability to access and perform calculations on the NHANES database, Bard intermittently claimed the ability to do so. Bard provided either accurate results or inaccurate and inconsistent results. For example, Bard's "calculations" for the incidence of kidney stones from 2015 to 2018 were 2.1% (95% CI 1.5-2.7), 1.75% (95% CI 1.6-1.9), and 0.8% (95% CI 0.7-0.9), while the published number was 2.1% (95% CI 1.5-2.7). Bard provided discrete mathematical details of its calculations, however, when prompted further, admitted to having obtained the numbers from online sources, including our chosen reference articles, rather than from a de novo calculation. Both LLMs were able to produce a code (Python) to use on the downloaded NHANES data sets, however, these would not readily execute. Conclusions: ChatGPT and Bard are currently incapable of performing epidemiologic calculations and lack transparency and accountability. Caution should be used, particularly with Bard, as claims of its capabilities were convincingly misleading, and results were inconsistent.

Treatment of bilateral encrusted ureteral stents, large volume renal stones, and ureteral stricture in a complex pediatric patient: a surgical video and case review.

Myotonic dystrophy is a debilitating genetic disease that carries a predilection for a variety of comorbidities. Kidney stone disease in this population can present a variety of unique challenges related to patient age, comorbidities, and social factors. We present a video review case of a 13-year-old girl with myotonic dystrophy who was treated surgically for large bilateral stone burden, bilateral retained ureteral stents with nephrostomy tubes, and right ureteral stricture. The patient had multiple prior urologic procedures and recurrent admissions for infection prior to presentation. Preoperative planning included non-contrast CT imaging, admission to an intensive care unit, and multidisciplinary discussion of treatment and goals. Through combined antegrade and retrograde approaches, the patient's stone burden was cleared, right ureteral stricture was treated, and all tubes were able to be removed in two major procedures and one minor cystoscopy with stent removal under anesthesia. Early referral to tertiary care centers and involvement of multiple specialist teams may help reduce perioperative risk and minimize the number of surgeries. Additionally, patients at high anesthesia risk may benefit from concurrent percutaneous nephrolithotomy with endopyelotomy.

Drivers of calcium oxalate stone formation in the octogenarian population.

INTRODUCTION: American Urological Association (AUA) guidelines suggest metabolic testing via 24-h urine studies in high-risk, interested first-time stone formers, and recurrent stone formers. If metabolic testing is not available or otherwise not feasible, clinicians may need to utilize empiric therapy. Debility and social barriers, particularly in the elderly population, may limit the practicality of metabolic testing, and therefore, empiric therapy is of particular importance. The aim of this study is to identify whether unique urinary metabolic abnormality profiles exist for octogenarians with calcium oxalate kidney stones, as this may guide empiric stone prevention therapy more precisely in this population. MATERIALS AND METHODS: Patients with calcium oxalate stones from a single academic kidney stone center in New York, NY, were retrospectively identified in our prospectively managed database. Patient data, including demographic, clinical information, and baseline 24-h urine studies, were collected before initiating any treatment. Subjects were stratified by age (≤ 40, 41-59, 60-79, and ≥ 80 years) to compare the metabolic urinary abnormality profiles between octogenarians and other age groups. Subgroup analyses were also performed to compare results by gender and by the presence of underlying kidney dysfunction. Comparative statistical analysis was carried out using Chi-square tests, Mann-Whitney U tests, and t-tests where appropriate. RESULTS: Hypocitraturia, low urine pH, and low urine volume were most common in older patients, particularly in octogenarians. Hypercalciuria, hypernatriuria, and hyperuricosuria were more apparent in younger groups. CONCLUSION: With increasing age, hypocitraturia, low urine pH, and low urine volume were more prevalent on 24-h urine metabolic testing. We hypothesize increased comorbidity, including medical renal disease, polypharmacy, and dehydration are possible factors contributing to this unique profile. We suggest that empiric therapy targeted towards this profile is important in very elderly stone formers in whom 24-h urine testing may not be possible. Increased hydration, increased fruit and vegetable intake, and low-dose alkali therapy are easy measures to accomplish this.

Opioid-free percutaneous nephrolithotomy: an initial experience.

INTRODUCTION: The opioid epidemic in the United States is an ongoing public health crisis that is in part fueled by excessive prescribing by physicians. Percutaneous nephrolithotomy (PCNL) is a procedure that conventionally involves opioid prescriptions for adequate post-operative pain control. We aimed to evaluate the feasibility of a non-opioid pain regimen by evaluating post-operative outcomes in PCNL patients discharged without opioids. MATERIALS AND METHODS: As a quality improvement measure to reduce opioid consumption our department began routinely prescribing oral ketorolac instead of oxycodone-acetaminophen for pain control after PCNL. We retrospectively compared patients undergoing PCNL who had received ketorolac prescriptions (NSAID) to those who received oxycodone-acetaminophen prescriptions (NARC). Demographic, operative, and post-operative factors were obtained and compared in both groups. Peri-operative factors and demographics were compared using either Chi-squared tests, Mann-Whitney U tests. Surgical outcomes were compared between the two groups using Chi-squared tests and Fisher's exact tests. Multivariate logistic regression analysis was performed to determine whether ketorolac use was an independent predictor of post-surgical pain-related encounters. Primary outcome was unplanned pain-related healthcare encounters inclusive of office phone calls, unscheduled office visits, and emergency department (ED) visits. Secondary outcome measures were non-pain-related healthcare encounters, hospital readmissions, pain-related rescue medications prescribed, and post-op complications. RESULTS: There were similar demographics and peri-operative characteristics amongst patients in both cohorts. There was no significant difference identified between NSAID and NARC regarding unplanned pain-related encounters (8/70, 11.4% vs. 10/70, 14.3%, p = 0.614). However, NARC experienced more unplanned phone calls (42, 60% vs. 24, 34.3%, p = 0.004). Multivariate analysis revealed only prior stone surgery was predictive of pain-related encounters after PCNL (p = 0.035). CONCLUSION: Our results show that there were no significant differences in pain-related encounters between those who received ketorolac and oxycodone-acetaminophen following PCNL. A non-opioid pathway may mitigate the potential risk associated with opioid prescription without compromising analgesia. Prospective comparative studies are warranted to confirm feasibility.

Association of Life's Simple 7 and ideal cardiovascular health in American Indians/Alaska Natives.

OBJECTIVE: American Indians and Alaska Natives (AI/ANs) are an understudied population at high risk for cardiovascular diseases (CVDs); little is known about contextual factors contributing to CVDs in AI/ANs. This study examined the association of Life's Simple 7 (LS7) factors and social determinants of health (SDH) with CVD outcomes in a nationally representative sample of AI/ANs. METHODS: We conducted a cross-sectional study of 8497 AI/ANs using 2017 Behavioural Risk Factor Surveillance Survey data. Individual LS7 factors were summarised as ideal and poor levels. Coronary heart disease, myocardial infarction and stroke were defined as CVD outcomes. Healthcare access measures represented SDH. Logistic regression analyses examined associations of LS7 factors and SDH with CVD outcomes. Population attributable fractions (PAFs) quantified individual contributions of LS7 factors to CVD outcomes. RESULTS: N=1,297 (15%) participants with CVD outcomes were identified. Smoking, physical inactivity, diabetes, hypertension and hyperlipidaemia were LS7 factors associated with CVD outcomes. Hypertension was the largest contributor to CVD (aPAF 42%; 95% CI 37% to 51%), followed by hyperlipidaemia (aPAF 27%; 95% CI 17% to 36%) and diabetes (aPAF 18%; 95% CI 7% to 23%). Compared with individuals with poor LS7 levels, participants with ideal levels showed 80% lower odds of CVD outcomes (aOR 0.20; 95% CI 0.16 to 0.25). Access to health insurance (aOR 1.43, 95% CI 1.08 to 1.89) and a regular care provider (aOR 1.47, 95% CI 1.24 to 1.76) were associated with CVD outcomes. CONCLUSIONS: Effective interventions are needed to address SDH and attain ideal LS7 factors to improve cardiovascular health among AI/ANs.

The Rotator Cable Does Not Stress Shield the Crescent Area During Shoulder Abduction.

BACKGROUND: It is accepted by the orthopaedic community that the rotator cable (RCa) acts as a suspension bridge that stress shields the crescent area (CA). The goal of this study was to determine if the RCa does stress shield the CA during shoulder abduction. METHODS: The principal strain magnitude and direction in the RCa and CA and shoulder abduction force were measured in 20 cadaveric specimens. Ten specimens underwent a release of the anterior cable insertion followed by a posterior release. In the other 10, a release of the posterior cable insertion was followed by an anterior release. Testing was performed for the native, single-release, and full-release conditions. The thicknesses of the RCa and CA were measured. RESULTS: Neither the principal strain magnitude nor the strain direction in either the RCa or the CA changed with single or full RCa release (p ≥ 0.493). There were no changes in abduction force after single or full RCa release (p ≥ 0.180). The RCa and CA thicknesses did not differ from one another at any location (p ≥ 0.195). CONCLUSIONS: The RCa does not act as a suspension bridge and does not stress shield the CA. The CA primarily transfers shoulder abduction force to the greater tuberosity. CLINICAL RELEVANCE: The CA is important in force transmission during shoulder abduction, and efforts should be made to restore its continuity with a repair or reconstruction.

Humeral offset as a predictor of outcomes after reverse shoulder arthroplasty.

INTRODUCTION: The Grammont-style reverse shoulder arthroplasty (RSA) relies on medialization and distalization of the shoulder center of rotation. Lateralized designs have recently gained popularity. The amount of lateralization, however, remains a controversial topic. The purpose of this study was to correlate the change in humeral offset (HO) with outcomes and complications following RSA. We hypothesized that a lateralized HO following RSA would be associated with improved range of motion (ROM), better patient-reported outcomes (PROs), and fewer complications. MATERIALS AND METHODS: A consecutive series of 104 patients (109 shoulders) was retrospectively evaluated. All patients underwent primary RSA by 2 shoulder and elbow fellowship-trained orthopedic surgeons at 2 different centers. Inclusion criteria was a primary RSA with at least 1-year follow-up. All patients had the HO measured on a preoperative and a postoperative Grashey radiograph, and the change in HO was calculated (ΔHO = PostHO-PreHO). A negative value was defined as a medialized HO and a positive value as a lateralized HO. ROM and primary outcomes, including forward elevation (FE), external rotation (ER), internal rotation (IR), Subjective Shoulder Value (SSV), and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score, were collected. Complications and revisions were also reported. RESULTS: The mean age was 72 years with a mean follow-up of 22.3 months. The average FE (92° vs. 148°), ER (34° vs. 44°), SSV (35% vs. 87%), and ASES score (37.2 vs. 81.2) increased significantly (all P < .01) compared with preoperative values. The HO was medialized postoperatively in 63 shoulders and lateralized in 46 shoulders. No statistically significant differences in the mean values for postoperative FE (147° vs. 146°, P = .892), ER (43° vs. 45°, P = .582), IR (L3 vs. L3, P = .852), SSV (88% vs. 85%, P = .476), and ASES score (81.3 vs. 81.1, P = .961) were found between the groups. However, there was significantly more improvement in ER in the lateralized HO cohort than the medialized cohort (16° vs. 7°, P = .033). Six shoulders, 5 medialized and 1 lateralized HO, demonstrated scapular notching and remained asymptomatic. Five shoulders, 4 medialized and 1 lateralized HO, experienced at least 1 instability incident, and 2 shoulders with medialized HO had an acromion/scapular spine fracture. Overall, 2 shoulders with medialized HO underwent revision surgery because of instability. CONCLUSIONS: Although RSA provides significant improvement in ROM and PROs regardless of postoperative HO, restoring baseline HO or lateralization beyond baseline may be favorable for improving ER and decreasing complications following RSA.

Locating the rotator cable during subacromial arthroscopy: bursal- and articular-sided anatomy.

BACKGROUND: The rotator cable (RCa) is an important articular-sided structure of the cuff capsular complex that helps prevent suture pull out during rotator cuff repairs (RCRs) and plays a role in force transmission. Yet, the RCa cannot be located during bursal-sided RCRs. The purpose of this study is to develop a method to locate the RCa in the subacromial space and compare its bursal- and articular-sided dimensions. METHODS: In 20 fresh-frozen cadaveric specimens, the RCa was found from the articular side, outlined with stitches, and then evaluated from the bursal side using an easily identifiable reference point, the intersection of a line bisecting the supraspinatus (SS) tendon and posterior SS myotendinous junction (MTJ). Four bursal-sided lengths were measured on the SS-bisecting line as well as the RCa's outside anteroposterior base. For the articular-sided measurements, the rotator cuff capsular complex was detached from bone and optically scanned creating 3D solid models. Using the 3D models, 4 articular-sided lengths were made, including the RCa's inside and outside anteroposterior base. RESULTS: The RCa's medial arch was located 9.9 ± 5.6 mm from the reference point in 10 intact specimens and 4.1 ± 2.4 mm in 10 torn specimens (P = .007). The RCa's width was 10.9 ± 2.1 mm, and the distance from the lateral edge of the RCa to the lateral SS insertion was 13.9 ± 4.8 mm. The bursal- and articular-sided outside anteroposterior base measured 48.1 ± 6.4 mm and 49.6 ± 6.5 mm, respectively (P = .268). The average inside anteroposterior base measurement was 37.3 ± 5.9 mm. DISCUSSION: The medial arch of the RCa can be reliably located during subacromial arthroscopy using the reference point, analogous to the posterior SS MTJ. The RCa is located 10 mm in intact and 4 mm in torn tendons (P = .007) from the posterior SS MTJ. If the above 6-mm shift in location of the RCa is not taken into consideration during rotator cuff suture placement, it could negatively affect time zero repair strength. The inside anteroposterior base of the RCa measures on average 37 mm; therefore, rotator cuff tears measuring >37 mm are at risk of rupturing part or all of the RCa's 2 humeral attachments, which if not recognized and addressed could impact postoperative function.

Can spinal deformity patients maintain proper arm positions while undergoing full-body X-ray?

Obtaining proper lateral full-body X-rays is paramount in accurately and consistently evaluating sagittal spinal alignment. This study explored the patient compliance rate of maintaining standardized arm position (fingers on the clavicles with shoulders in 45° of forward elevation while the patient is in a free-standing posture) during full-body X-rays at a single institution. HYPOTHESIS: The compliance rate of arm positioning during full-body X-rays varies depending on operative status (preoperative vs postoperative), age, and diagnosis. DESIGN: Retrospective cohort. INTRODUCTION: Despite the importance of patients maintaining arms in the same position in preoperative and postoperative standing films, patients are known to have their arms in varying positions, confounding radiographic interpretation and making global sagittal and coronal spinal balance assessment variable and potentially less reliable. This study seeks to examine arm position compliance among adult and pediatric surgical spinal deformity patients undergoing total body X-rays over the course of 4 years (2015-2018). METHODS: A retrospective radiographic review was performed on 382 spinal deformity patients from July 2015 to July 2018. The study's dependent variable of interest was standardized arm position (fingers on the clavicles with shoulders in 45° of forward elevation while the patient is in a free-standing posture) observed during full-body X-rays obtained for spinal deformity evaluation. Deviations and compliance to the standard protocol for full-body X-ray arm positioning was recorded and analyzed across various independent factors, including year of surgery, pre- and postoperative periods, type of spine surgery, and patient age. Chi-square and Cochran-Armitage analyses were performed to study categorical and trends, respectively. RESULTS: The overall compliance rate for maintaining standardized arm position was 90% for all 370 patients (277 adult and 93 pediatric), in preoperative and postoperative setting. Adults were more likely to follow protocol than pediatric patients (92.9% vs. 82.4%, P value = 0.003). The postoperative setting observed a significantly lower overall compliance rate when compared to the preoperative period (67.8% vs. 87.0%, P value < 0.0001). Patients undergoing neuromuscular scoliosis (73.3%), vertebral column resection (VCR) (70%), and growing rod lengthening (GRL) (57.1%) had the lowest overall compliance rate in the preoperative setting. In the postoperative setting, patients with GRL, VCR, revision congenital scoliosis, congenital scoliosis, neuromuscular scoliosis, and pedicle subtraction osteotomy (PSO) surgeries were compliant less than or equal to 50% of the time. From 2015 to 2018, there was an overall statistically significant increase in compliance rate (61.1% to 90.6%). Over the study period, adult patients became significantly more compliant to protocol. This was not observed in the pediatric population. CONCLUSION: This study documented the patient compliance rate of maintaining standardized arm position during full-body X-rays of spinal deformity patients. The overall compliance rate was 90.0% for all patients in the preoperative and postoperative setting. Risk factors for lower compliance rates included patients that were pediatric, postoperative, neuromuscular, and those who underwent a complex vertebral osteotomy or GRL. There was a trend showing improved compliance rate throughout the 4-year study period, which highlights the importance of having an ancillary staff who is comfortable with a consistent standard of care protocol. These results should help other centers optimize arm positioning in their patients undergoing full-body X-rays in the future.

Annual case volume is a risk factor for 30-day unplanned readmission after open reduction and internal fixation of acetabular fractures.

BACKGROUND: Surgical fixation of acetabular fractures is technically challenging, and quality of reduction directly correlates to patient outcomes. Considering the difficulty of open reduction and internal fixation (ORIF), increased case volumes may improve patient outcomes. No studies have investigated case volume as a risk factor for readmission after acetabular fracture ORIF. The present study sought to answer the question of whether annual case volume is a risk factor for 30-day unplanned readmission after acetabular fracture ORIF, if there is an identifiable threshold number of cases most predictive of a readmission, and if differences exist between reasons for readmission between high and low-volume centers. HYPOTHESIS: Institutions with a lower annual case volume will have a higher incidence of 30-day unplanned readmissions. MATERIALS AND METHODS: The national readmissions database (NRD) was queried for acetabular fractures that underwent ORIF during 2016. Comorbid conditions were summed, and annual hospital case volume was identified. A receiver operating characteristic (ROC) curve was generated and the Youden index identified threshold case volume most predictive of a 30-day readmission. A multivariable logistic regression was performed with 30-day readmission as the dependent variable and case volume below the threshold an independent variable. RESULTS: A total of 3,407 cases were included with a median age of 43. The 30-day readmission for this cohort was 6.5% (220/3407). ROC curve analysis identified 22 annual cases as the threshold value most predictive of 30-day readmission. Multivariable logistic regression identified age (Odds Ratio (OR)=1.01, p=0.005), number of comorbidities (OR=1.35, p<0.0001), and ≤22 cases (OR=1.50, p=0.006) as statistically significant risk factors for 30-day readmission. The most common reason for readmission at both high and low-volume centers was surgical site infection. DISCUSSION: Annual case volume is a statistically significant predictor of 30-day readmission after acetabular fracture ORIF. Performing ≤22 acetabular ORIFs places patients at greater risk for a readmission. Patients at low-volume centers may be predisposed to readmission, and it is paramount to optimize patients prior to discharge, and have appropriate surgeon and hospital resources to treat these complex injuries. LEVEL OF EVIDENCE: III, Cross-sectional study.

The implications of baseline bone-health assessment at initiation of androgen-deprivation therapy for prostate cancer.

OBJECTIVES: To assess bone-density testing (BDT) use amongst prostate cancer survivors receiving androgen-deprivation therapy (ADT), and downstream implications for osteoporosis and fracture diagnoses, as well as pharmacological osteoporosis treatment in a national integrated delivery system. PATIENTS AND METHODS: We identified 17 017 men with prostate cancer who received any ADT between 2005 and 2014 using the Veterans Health Administration cancer registry and administrative data. We identified claims for BDT within a 3-year period of ADT initiation. We then used multivariable regression to examine the association between BDT use and incident osteoporosis, fracture, and use of pharmacological treatment. RESULTS: We found that a minority of patients received BDT (n = 2 502, 15%); however, the rate of testing increased to >20% by the end of the study period. Men receiving BDT were older at diagnosis and had higher-risk prostate cancer (both P < 0.001). Osteoporosis and fracture diagnoses, use of vitamin D ± calcium, and bisphosphonates were all more common in men who received BDT. After adjustment, BDT, and to a lesser degree ≥2 years of ADT, were both independently associated with incident osteoporosis, fracture, and osteoporosis treatment. CONCLUSIONS: BDT is rare amongst patients with prostate cancer treated with ADT in this integrated delivery system. However, BDT was associated with substantially increased treatment of osteoporosis indicating an underappreciated burden of osteoporosis amongst prostate cancer survivors initiating ADT. Optimising BDT use and osteoporosis management in this at-risk population appears warranted.