Cooperation between bHLH transcription factors and histones for DNA access.

The basic helix-loop-helix (bHLH) family of transcription factors recognizes DNA motifs known as E-boxes (CANNTG) and includes 108 members1. Here we investigate how chromatinized E-boxes are engaged by two structurally diverse bHLH proteins: the proto-oncogene MYC-MAX and the circadian transcription factor CLOCK-BMAL1 (refs. 2,3). Both transcription factors bind to E-boxes preferentially near the nucleosomal entry-exit sites. Structural studies with engineered or native nucleosome sequences show that MYC-MAX or CLOCK-BMAL1 triggers the release of DNA from histones to gain access. Atop the H2A-H2B acidic patch4, the CLOCK-BMAL1 Per-Arnt-Sim (PAS) dimerization domains engage the histone octamer disc. Binding of tandem E-boxes5-7 at endogenous DNA sequences occurs through direct interactions between two CLOCK-BMAL1 protomers and histones and is important for circadian cycling. At internal E-boxes, the MYC-MAX leucine zipper can also interact with histones H2B and H3, and its binding is indirectly enhanced by OCT4 elsewhere on the nucleosome. The nucleosomal E-box position and the type of bHLH dimerization domain jointly determine the histone contact, the affinity and the degree of competition and cooperativity with other nucleosome-bound factors.

Impact of an Acute Care Urology Service on Timelines and Quality of Care in the Management of Nephrolithiasis.

Background: The acute care surgery model has led to improved outcomes for emergent surgical conditions, but similar models of care have not been implemented in urology. Our department implemented an acute care urology (ACU) service in 2015, and the service evolved in 2018. We aimed to evaluate the impact of the ACU model on the management of nephrolithiasis. Materials and Methods: We conducted a retrospective review of all patients with urology consults in the emergency department for nephrolithiasis, who required surgical intervention from 2013 to 2019. Patients were divided into three cohorts based on date of consultation: Pre-ACU (2013-2014), Phase 1 (2015-2017), and Phase 2 (2018-2019). Results: We identified 733 patients with nephrolithiasis requiring intervention (162 pre-ACU, 334 Phase 1, and 237 Phase 2). Before ACU implementation, median time from consult to definitive intervention was 36 days. After ACU implementation, median time to intervention decreased to 22 days in Phase 1 (p < 0.001) and 15 days in Phase 2 (p < 0.001). On multivariable Cox regression, the hazard of definitive intervention improved in Phase 1 (hazard ratio [HR] 1.90, p < 0.001) and in Phase 2 (HR 1.80, p < 0.001). Rates of primary definitive intervention without initial decompression and loss to follow-up were also significantly improved, compared to the pre-ACU cohort. Conclusions: Implementation of a structured ACU service was associated with improved time to treatment for patients with acute nephrolithiasis, as well as increased primary definitive intervention and improved follow-up care. This model of care has potential to improve patient outcomes for nephrolithiasis and other acute urological conditions.

Silicone injection-induced granuloma formation, hypercalcemia and nephrolithiasis: a case report.

Hypercalcemia and nephrolithiasis have been associated with various etiologies, including dysregulation of the parathyroid glands, malignancies, or sarcoidosis. Other causes of hypercalcemia, such as granulomatous disease resulting from silicone-based cosmetic injections, have been reported but without specific emphasis on nephrolithiasis. Herein, we report an unusual case of simultaneous bilateral obstructing ureteral calculi (SBUC) triggered by recalcitrant hypercalcemia and granulomatous disease due to silicone-based cosmetic injections. A careful surgical history, physical exam, and imaging identified the underlying etiology, which was confirmed by final histopathology. Using a multidisciplinary approach, the patient's condition was successfully managed with endoscopic procedures and concurrent corticosteroid therapy.

Circadian Synchrony: Sleep, Nutrition, and Physical Activity.

The circadian clock in mammals regulates the sleep/wake cycle and many associated behavioral and physiological processes. The cellular clock mechanism involves a transcriptional negative feedback loop that gives rise to circadian rhythms in gene expression with an approximately 24-h periodicity. To maintain system robustness, clocks throughout the body must be synchronized and their functions coordinated. In mammals, the master clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is entrained to the light/dark cycle through photic signal transduction and subsequent induction of core clock gene expression. The SCN in turn relays the time-of-day information to clocks in peripheral tissues. While the SCN is highly responsive to photic cues, peripheral clocks are more sensitive to non-photic resetting cues such as nutrients, body temperature, and neuroendocrine hormones. For example, feeding/fasting and physical activity can entrain peripheral clocks through signaling pathways and subsequent regulation of core clock genes and proteins. As such, timing of food intake and physical activity matters. In an ideal world, the sleep/wake and feeding/fasting cycles are synchronized to the light/dark cycle. However, asynchronous environmental cues, such as those experienced by shift workers and frequent travelers, often lead to misalignment between the master and peripheral clocks. Emerging evidence suggests that the resulting circadian disruption is associated with various diseases and chronic conditions that cause further circadian desynchrony and accelerate disease progression. In this review, we discuss how sleep, nutrition, and physical activity synchronize circadian clocks and how chronomedicine may offer novel strategies for disease intervention.

Indwelling ureteric stents: Patterns of use and nomenclature.

Objectives: To evaluate ureteric stenting practice patterns amongst a range of academic and community urologists, and to examine the nomenclature used to identify an indwelling ureteric stent from both our questionnaire and from a review of the literature. Subjects and methods: A 16-question, peer-reviewed online survey was distributed to members of the Mid-Atlantic American Urological Association. Responses were collected over a 1-month period. Questions included demographics, ureteric stenting practice patterns, and utilization of stenting nomenclature. Inappropriate use of nomenclature was defined as a mismatch between the visually depicted stents and the written description amongst urologists. Trends in ureteric stenting and nomenclature usage were tabulated and analyzed. Results: Of 863 members, 105 (12.2%) responded to the survey. There was a wide variety of practice settings, with the single-specialty group (44.2%) and academic/university (27.9%) being the two most common. Most providers used both cystoscopy and fluoroscopy to place stents (87.5%) as compared to fluoroscopy alone (12.5%). Most urologists (63.5%) removed stents with cystoscopy as compared to using a stent string (36.5%). While about half (51.0%) of the respondents left stents in situ for ≤3 months, many respondents (43.3%) felt comfortable with maximum dwell times of up to 6 months. The most commonly placed stent was the double pigtail stent (80.8%). However, most respondents inappropriately described this stent design as a Double J stent (72.1%). In the recent literature, 80% of articles clearly defined as using double pigtail stents, incorrectly identified their stent as a 'Double J'. Conclusions: Variations in ureteric stenting practice patterns exist amongst community and academic urologists. Although most urologists utilize double pigtail ureteric stents, the majority inaccurately identified this stent design as a Double J. We propose use of the term 'indwelling ureteric stent' (IUS) unless describing any specific stent design.

Long term outcomes of ureteroscopic management of upper tract urothelial carcinoma.

OBJECTIVES: Upper tract urothelial carcinoma (UTUC) is relatively rare. While nephroureterectomy is considered the gold standard for treatment, endoscopic nephron- sparing techniques have emerged for select cases with equivalent cancer specific survival (CSS). We present the largest series with longest follow-up to date of retrograde ureteroscopy as the primary treatment of UTUC. METHODS: A retrospective review was performed of 258 patients diagnosed with UTUC who were initially evaluated and managed by a single surgeon. Patients were followed from 1994 to 2017. Clinical records were evaluated for patient and tumor characteristics, operative parameters and outcomes. Statistical analysis was performed to identify risk of recurrence, progression, cancer and overall survival. RESULTS: Following exclusion criteria, 168 patients were evaluated. Average tumor size on initial excision was 16.8mm. Mean age of the cohort was 70 years, with mean follow-up of 5.53 years. The 5-year overall survival was 80.9%, but CSS was 92.6%. Recurrence free survival was 30% with average tumor size on recurrence of 6.39mm. Progression free survival was 75% with a renal preservation rate of 71.4%. CONCLUSIONS: Ureteroscopic management of UTUC is a successful alternative to nephroureterectomy in select cases of UTUC. With strict surveillance protocols to manage frequent local recurrence rates, it is possible to achieve high renal preservation rates with acceptable CSS, even in the long-term.

Bladder Preservation for Patients With Bladder Paragangliomas: Case Series and Review of the Literature.

Bladder paragangliomas are rare tumors, with no prospective studies or guidelines on the management of this disease. We present a case series of 6 patients managed with bladder preservation over a median follow-up period of 124 months. We also present a review of the recent literature on bladder paragangliomas. We aim to provide a timely synthesis of the recent evidence on bladder paragangliomas as changing paradigms necessitate individualized treatment.

Diagnosis, management, and follow-up of upper tract urothelial carcinoma: an interdisciplinary collaboration between urology and radiology.

Upper tract urothelial carcinoma (UTUC) is a common and lethal malignancy. Patients diagnosed with this illness often face invasive workups, morbid therapies, and prolonged post-operative surveillance. UTUC represents approximately 5-10% of urothelial malignancies in the United States and affect 4600-7800 new patients annually. Various environmental exposures as well as smoking have been implicated in the development of UTUC. The diagnosis and workup of UTUC relies on heavily on imaging studies, a close working relationship between Urologists and Radiologists, and invasive procedures such as ureteroscopy. Treatments range from renal-sparing endoscopic surgery to radical extirpative surgery depending on the specific clinical situation. Follow-up is crucial as UTUC has a high recurrence rate. Here we review the epidemiology, diagnosis, management strategies, and follow-up of UTUC from an interdisciplinary perspective.

Emerging Mobile Platforms to Aid in Stone Management.

Nephrolithiasis is an increasingly common condition worldwide and mobile technology is revolutionizing how patients with kidney stone are being diagnosed and managed. Emerging platforms include software applications to increase adherence to stone prevention, mobile compatible hardware, online social media communities, and telemedicine. Applications and hardware specifically relevant to increasing hydration, diet modification, medication adherence, and rapid diagnosis (ie, mobile ultrasound and endoscopy) have the greatest potential to reduce stone recurrence and expedite treatment. Social media and online communities have also been rapidly adopted by patients and providers to promote education and support.

Ureteroscopic Management of Large ≥2 cm Upper Tract Urothelial Carcinoma: A Comprehensive 23-Year Experience.

OBJECTIVE: To evaluate the effectiveness of ureteroscopy (URS) with laser ablation as an alternative treatment for upper tract urothelial carcinoma (UTUC) lesions larger than 2 cm. Traditionally, patients with large UTUC are treated with radical nephroureterectomy (RNU). However, in patients with pre-existing renal disease, a solitary kidney, or those who decline RNU, management of UTUC may prove challenging METHODS: An institutional database review identified 80 patients with biopsy proven low-grade UTUC who had at least one lesion larger than 2 cm. We collected clinical data including demographics, operative parameters, and pathologic features. Follow-up for all patients was standardized and included cystoscopy and URS every 3 months until clear, every 6 months through the fifth year, and yearly thereafter. We calculated rates of recurrence, progression, and overall survival. RESULTS: In total, 86 unique lesions ≥2cm were identified in the 80 qualifying patients; mean tumor size was 3.04 cm. Median follow-up was 43.6 months. During follow-up of patients treated curatively, 90.5% of tumors had ipsilateral recurrence and 31.7% progressed in grade at a median of 26.3 months. RNU was performed in 16 patients (20%); mean time to surgery was 23.2 months. Overall survival was 75%, and cancer specific survival was 84% at 5-year follow-up. CONCLUSION: Under strict surveillance, ureteroscopic management of large (≥ 2cm) UTUC lesions is a viable treatment alternative to RNU. While recurrence is common, URS can potentially preserve renal units in patients with large lesions.

Simultaneous Bilateral Ureteral Calculi: A New Paradigm for Management.

OBJECTIVE: To define the need for emergent intervention between patients with simultaneous bilateral ureteral calculi (SBUC) compared to unilateral ureteral calculi (UUC). Patients with SBUC represent a potential urological emergency due to possible anuria or electrolyte imbalance. While conventional practice mandates immediate intervention in these patients, little data exist to define the rate of these events. METHODS: Records of all patients with ureteral stones treated ureteroscopically over an 11-year period were reviewed to identify those with SBUC. Patient presenting characteristics, time from diagnosis to intervention, and postoperative outcomes were noted. To determine the need for emergent intervention, we compared metabolic and infectious parameters between SBUC patients and age- and sex-matched patients with UUC. RESULTS: A total of 3800 patients presented with ureteral calculi including 42 (1.1%) with SBUC. Two-thirds of patients with SBUC had an established diagnosis of nephrolithiasis. Among the 42 patients with SBUC, 11 (26.2%) were considered emergent due to metabolic (5 of 11, 45.5%), infectious (1 of 11, 9.1%), or both metabolic and infectious indications (5 of 11, 45.5%). No patients required acute dialysis before surgical intervention. Compared to patients with UUC, those with SBUC were significantly more likely to require emergent management (P = .03, odds ratio 2.3). Univariate and multivariate analyses showed this to be due to anuria (P = .001) and acidosis (P = .003). CONCLUSION: SBUC is an uncommon condition and, in this series, only the minority of patients presented emergently. Therefore, patients with SBUC can often be managed electively if counseled on clinical signs warranting emergent medical attention. Appropriately selected patients have excellent outcomes following single stage bilateral ureteroscopy.

Retrograde Ureteroscopic Management of Large Renal Calculi: A Single Institutional Experience and Concise Literature Review.

INTRODUCTION: Advances in flexible ureteroscope design and accessory instrumentation have allowed for more challenging cases to be treated ureteroscopically. Here, we evaluate our experience with ureteroscopy (URS) for the management of large renal calculi (≥2 cm) and provide a concise review of recent reports. METHODS: A retrospective review was undertaken of all URS cases between 2004 and 2014 performed by the endourologic team at a single academic tertiary care institution. We identified patients with at least one stone ≥2 cm managed with retrograde URS. Stone size was defined as the largest linear diameter of the index stone. Small diameter flexible ureteroscopes were used primarily with holmium laser. Patient demographics, intraoperative data, and postoperative outcomes were evaluated. RESULTS: We evaluated 167 consecutive patients who underwent URS for large renal stones ≥2 cm. The initial reason for choosing URS included patient preference (29.5%), failure of other therapies (8.2%), anatomic considerations/body habitus (30.3%), and comorbidities (28.8%). Mean patient age was 55.5 years (22-84). The mean stone size was 2.75 cm with mean number of procedures per patient of 1.65 (1-6). The single session stone-free rate was 57.1%, two-stage procedure stone-free rate was 90.2% and three-stage stone-free rate was 94.0%. Access sheaths were used in 47% of patients. An association was identified between stone size and patient outcomes; smaller stones correlated with decreased number of procedures. Postoperative complications were minor. CONCLUSIONS: Single or multi-stage retrograde ureteroscopic lithotripsy is a safe and effective mode of surgical management of large renal calculi. Total stone burden is a reliable predictor of the need for a staged procedure and of stone-free rate.

Metastatic pancreatic adenocarcinoma to the scrotum.

Metastatic cancer to the scrotum is a rare occurrence. We describe the first case of cutaneous scrotal lesions consistent with metastatic pancreatic adenocarcinoma. A brief discussion including epidemiologic factors and clinical presentation is presented.

Superficial Dorsal Venous Rupture of the Penis: False Penile Fracture That Needs to be Treated as a True Urologic Emergency.

A 38-year-old man with history of repaired penile fracture presented with rapid detumescence, penile pain, and ecchymosis during vaginal sexual intercourse concerning for recurrent fracture. Surgical exploration revealed ruptured superficial dorsal vein of the penis, which was subsequently ligated. Patients with traumatic penile vascular injuries often present with clinical features indistinguishable from a true penile fracture. Gradual detumescence and an absence of characteristic popping sound may indicate a vascular injury but they cannot safely rule out a true penile fracture. Both true and false penile fractures require emergent surgical exploration and repair to prevent long-term complications.

Incidental Lymphoma Discovered During Surveillance for Low-Grade Upper Tract Urothelial Carcinoma Treated Ureteroscopically: A Case Report Series.

Two cases of incidentally found follicular lymphoma during surveillance for ureteroscopically treated upper tract urothelial carcinoma with cross-sectional imaging are described. Multiple independent primary malignancies should be considered in this population.

Rotavirus vaccination and intussusception - Science, surveillance, and safety: A review of evidence and recommendations for future research priorities in low and middle income countries.

As of January 2016, 80 countries have introduced rotavirus vaccines into their national immunization programs. Many have documented significant declines in rotavirus-specific and all-cause diarrheal illnesses following vaccine introduction. Two globally licensed rotavirus vaccines have been associated with a low risk of intussusception in several studies. In July 2014, the Rotavirus Organization of Technical Allies Council convened a meeting of research and advocacy organizations, public health experts, funders, and vaccine manufacturers to discuss post-marketing intussusception surveillance and rotavirus vaccine impact data. Meeting objectives were to evaluate updated data, identify and prioritize research gaps, discuss best practices for intussusception monitoring in lower-income settings and risk communication, and provide insight to country-level stakeholders on best practices for intussusception monitoring and communication. Meeting participants agreed with statements from expert bodies that the benefits of vaccination with currently available rotavirus vaccines outweigh the low risk of vaccination-associated intussusception. However, further research is needed to better understand the relationship of intussusception to wild-type rotavirus and rotavirus vaccines and delineate potential etiologies and mechanisms of intussusception. Additionally, evidence from research and post-licensure evaluations should be presented with evidence of the benefits of vaccination to best inform policymakers deciding on vaccine introduction or vaccination program sustainability.