Identifying systems delays in assessment, diagnosis, and operative management for testicular torsion in a single-payer health-care system.

INTRODUCTION: Testicular torsion (TT) is a common pediatric urologic emergency. Management of TT is time sensitive and often confirmed on scrotal Doppler ultrasound (DUS). Acquiring DUS, however, can result in delays in the management of TT, affecting testicular salvage rates. OBJECTIVE: The objective of this study is to identify delays in the assessment and diagnosis for patients presenting with TT to a Canadian academic hospital using patient flow analysis. STUDY DESIGN: A retrospective review was performed for patients presenting to the emergency department (ED) who received a scrotal DUS to rule out possible TT between 2012 and 2017. The primary outcome measured cycle-time measurements (median time) between points along the clinical flow pathway for a patient with suspected TT. The secondary outcome assessed diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of standard scrotal DUS components (Doppler flow, arterial waveform, heterogeneous echotexture). RESULTS: A total of 609 patients presented with an acute scrotum warranting a scrotal DUS to rule out TT; of which, 46 underwent scrotal exploration. Testicular salvage rate was 82.6% in the series (38 testes salvaged, 8 required orchiectomy). Median time from symptom onset to ED presentation for patients with possible TT was 4 h. After triage, a median of 79.8 min was required for ED physician assessment and an additional 48 min for scrotal DUS to be performed. Absence of Doppler flow on scrotal DUS had a 97.4% PPV for diagnosing TT confirmed during scrotal exploration. DISCUSSION: Almost 4 h of in-ED time is required from triage to surgical intervention for potential TT at the institution. One area of delay is the time needed to conduct a scrotal DUS (48-128 min; Fig. 1). This represents an area of opportunity for patient flow optimization through the use of standardized clinical pathways and diagnostic adjuncts, such as point-of-care ultrasound. This study is limited in its retrospective nature and does not include patients with overt signs of TT who underwent surgical detorsion without need for scrotal DUS. CONCLUSION: Patient flow delays to surgical intervention for patients with TT represent a preventable cause of orchiectomy in young men. This study identifies intervention points in patient-care flow pathways where delays to surgical intervention can be potentially reduced by up to 2 h. The findings support the need for further studies into the optimization of patient flow and management protocols to reduce delays in the diagnosis and management of TT.

BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control.

BCL-6, a transcriptional repressor frequently translocated in lymphomas, regulates germinal center B cell differentiation and inflammation. DNA microarray screening identified genes repressed by BCL-6, including many lymphocyte activation genes, suggesting that BCL-6 modulates B cell receptor signals. BCL-6 repression of two chemokine genes, MIP-1alpha and IP-10, may also attenuate inflammatory responses. Blimp-1, another BCL-6 target, is important for plasmacytic differentiation. Since BCL-6 expression is silenced in plasma cells, repression of blimp-1 by BCL-6 may control plasmacytic differentiation. Indeed, inhibition of BCL-6 function initiated changes indicative of plasmacytic differentiation, including decreased expression of c-Myc and increased expression of the cell cycle inhibitor p27kip1. These data suggest that malignant transformation by BCL-6 involves inhibition of differentiation and enhanced proliferation.

Two independent domains of hDlg are sufficient for subcellular targeting: the PDZ1-2 conformational unit and an alternatively spliced domain.

hDlg, a human homologue of the Drosophila Dig tumor suppressor, contains two binding sites for protein 4.1, one within a domain containing three PSD-95/Dlg/ZO-1 (PDZ) repeats and another within the alternatively spliced I3 domain. Here, we further define the PDZ-protein 4.1 interaction in vitro and show the functional role of both 4.1 binding sites in situ. A single protease-resistant structure formed by the entirety of both PDZ repeats 1 and 2 (PDZ1-2) contains the protein 4.1-binding site. Both this PDZ1-2 site and the I3 domain associate with a 30-kD NH2-terminal domain of protein 4.1 that is conserved in ezrin/radixin/moesin (ERM) proteins. We show that both protein 4.1 and the ezrin ERM protein interact with the murine form of hDlg in a coprecipitating immune complex. In permeabilized cells and tissues, either the PDZ1-2 domain or the I3 domain alone are sufficient for proper subcellular targeting of exogenous hDlg. In situ, PDZ1-2-mediated targeting involves interactions with both 4.1/ERM proteins and proteins containing the COOH-terminal T/SXV motif. I3-mediated targeting depends exclusively on interactions with 4.1/ERM proteins. Our data elucidates the multivalent nature of membrane-associated guanylate kinase homologue (MAGUK) targeting, thus beginning to define those protein interactions that are critical in MAGUK function.