Background: Inactivation of the human type Ia regulatory subunit (RIa) of cyclic AMP dependent protein kinase (PKA) (PRKAR1A) leads to altered kinase activity, primary pigmented nodular adrenocortical disease (PPNAD), and sporadic adrenal and other tumours. Methods and results: A transgenic mouse carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline responsive promoter (the Tg(Prkar1a*x2as)1Stra, Tg(tTAhCMV)3Uh or tTA/X2AS line) developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia and other features reminiscent of PPNAD, including late onset weight gain, visceral adiposity, and nondexamethasone suppressible hypercorticosteronaemia, with histiocytic, epithelial hyperplasias, lymphomas, and other mesenchymal tumours. These lesions were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIb protein levels; the latter biochemical and protein changes were also documented in Carney complex tumours associated with PRKAR1A inactivating mutations and chromosome 17 PRKAR1A locus changes. Conclusion: We conclude that the tTA/X2AS mouse line with a downregulated Prkar1a gene replicates several of the findings in Carney complex patients and their affected tissues, supporting the role of RIa as a candidate tumour suppressor gene.

Objective To describe the publication productivity of academic urologists in the United States by gender. Materials and Methods Gender inequality is prevalent in most surgical subspecialties, including urology. Despite small numbers of women in academic positions, differences in scholarly impact by gender are relatively unknown. We assembled a list of 1922 academic urologists (1686 male (87.7%), 236 female (12.3%)) at 124 academic institutions throughout the United States as of February 2016. Scopus and Google Scholar were queried for bibliometric data on each individual, including h-index and m-quotient. We analyzed these metrics for both genders by educational background, subspecialty, NIH funding, and academic rank. Results Men had higher median h-indices than women overall (p<0.05), and by successive academic ranks (p<0.05). Proportionally fewer women attained senior academic ranking (professor/chair), (p<0.05). There was no difference in research productivity by successive rank after controlling for career duration (m-quotient). Women were more likely to choose a practice that specialized in pediatric urology or female urology/pelvic reconstructive surgery than their male counterparts (p<0.05). Conclusions and Relevance Women represent a growing proportion of academic urology faculty, but despite the recent increase in number entering the field, relatively few women occupy senior leadership positions. Improving psychosocial barriers to advancement such as lack of mentorship or discriminatory policies may help pioneering female urologists as they progress in their careers.

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Mutations of the human type I␣ regulatory subunit (RI␣) of cyclic AMP-dependent protein kinase (PKA; PRKAR1A) lead to altered kinase activity, primary pigmented nodular adrenocortical disease, and tumors of the thyroid and other tissues. To bypass the early embryonic lethality of Prkar1a ؊/؊ mice, we established transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracyclineresponsive promoter. Down-regulation of Prkar1a by up to 70% was achieved in transgenic mouse tissues and embryonic fibroblasts, with concomitant changes in kinase activity and increased cell proliferation, respectively. Mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, and other features reminiscent of primary pigmented nodular adrenocortical disease, histiocytic and epithelial hyperplasias, lymphomas, and other mesenchymal tumors. These were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RII␤ protein levels. This mouse provides a novel, useful tool for the investigation of cyclic AMP, RI␣, and PKA functions and confirms the critical role of Prkar1a in tumorigenesis in endocrine and other tissues.

Recurrent urinary tract infections (rUTIs) are extremely common, with ~ 25% of all women experiencing a recurrence within 1 year of their original infection. Escherichia coli ST131 is a globally dominant multidrug resistant clone associated with high rates of rUTI. Here, we show the dynamics of an ST131 population over a 5-year period from one elderly woman with rUTI since the 1970s. Using whole genome sequencing, we identify an indigenous clonal lineage (P1A) linked to rUTI and persistence in the fecal flora, providing compelling evidence of an intestinal reservoir of rUTI. We also show that the P1A lineage possesses substantial plasmid diversity, resulting in the coexistence of antibiotic resistant and sensitive intestinal isolates despite frequent treatment. Our longitudinal study provides a unique comprehensive genomic analysis of a clonal lineage within a single individual and suggests a population-wide resistance mechanism enabling rapid adaptation to fluctuating antibiotic exposure.

BackgroundNeurogenic bladder (NGB) dysfunction after spinal cord injury (SCI) is generally irreversible. Preliminary animal and human studies have suggested that initiation of sacral neuromodulation (SNM) immediately following SCI can prevent neurogenic detrusor overactivity and preserve bladder capacity and compliance. We designed a multicenter randomized clinical trial to evaluate the effectiveness of early SNM after acute SCI.Methods/DesignThe scientific protocol comprises a multi-site, randomized, non-blinded clinical trial. Sixty acute, acquired SCI patients (30 per arm) will be randomized within 12 weeks of injury. All participants will receive standard care for NGB including anticholinergic medications and usual bladder management strategies. Those randomized to intervention will undergo surgical implantation of the Medtronic PrimeAdvanced Surescan 97,702 Neurostimulator with bilateral tined leads along the S3 nerve root in a single-stage procedure. All patients will undergo fluoroscopic urodynamic testing at study enrollment, 3 months, and 1-year post randomization. The primary outcome will be changes in urodynamic maximum cystometric capacity at 1-year. After accounting for a 15% loss to follow-up, we expect 25 evaluable patients per arm (50 total), which will allow detection of a 38% treatment effect. This corresponds to an 84 mL difference in bladder capacity (80% power at a 5% significance level). Additional parameters will be assessed every 3 months with validated SCI-Quality of Life questionnaires and 3-day voiding diaries with pad-weight testing. Quantified secondary outcomes include: patient reported QoL, number of daily catheterizations, incontinence episodes, average catheterization volume, detrusor compliance, presence of urodynamic detrusor overactivity and important clinical outcomes including: hospitalizations, number of symptomatic urinary tract infections, need for further interventions, and bowel and erectile function.DiscussionThis research protocol is multi-centered, drawing participants from large referral centers for SCI and has the potential to increase options for bladder management after SCI and add to our knowledge about neuroplasticity in the acute SCI patient.Trial registrationClinicalTrials.gov #NCT03083366 1/27/2017.

Objective Clean intermittent catheterization (CIC) is a preferred method of bladder management for many patients with spinal cord injury (SCI), but long‐term adherence is low. The aim of this study is to identify factors associated with low urinary quality of life (QoL) in SCI adults performing CIC. Methods Over 1.5 years, 1479 adults with SCI were prospectively enrolled through the Neurogenic Bladder Research Group registry, and 753 on CIC with no prior surgeries were included. Injury characteristics, complications, hand function, and Neurogenic Bladder Symptom Score (NBSS) were analyzed. The NBSS QoL question (overall satisfaction with urinary function) was dichotomized to generate comparative groups (dissatisfied vs neutral/satisfied). Results The cohort was 32.9% female with a median age of 43.2 (18‐86) years, time since the injury of 9.8 (0‐48.2) years, and 69.0% had an injury at T1 or below. Overall 36.1% were dissatisfied with urinary QoL. On multivariable analysis, female gender (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.15‐2.31; P = 0.016), earlier injury (OR, 0.95 per year; 95% CI, 0.93‐0.97; P < 0.001), ≥4 urinary tract infections (UTIs) per year (OR, 2.36; 95% CI, 1.47‐3.81; P = 0.001), and severe bowel dysfunction (OR, 1.42; 95% CI, 1.02‐1.98; P = 0.035) predicted dissatisfaction. Level of injury, fine motor hand function, and caregiver dependence for CIC were not associated with dissatisfaction. Conclusions In a mature SCI cohort, physical disability does not predict dissatisfaction with urinary QoL but severe bowel dysfunction and recurrent UTIs have a significant negative impact. With time the rates of dissatisfaction decline but women continue to be highly dissatisfied on CIC and may benefit from early intervention to minimize the burden of CIC on urinary QoL.

Patient-Centered Outcomes Research Institute (PCORI) Award CER14092138.