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A 20-year-old male patient with a history of celiac disease came to medical attention after developing profound fatigue and pancytopenia. Evaluation demonstrated pan-hypogammaglobulinemia. There was no history of significant clinical infections. Bone marrow biopsy confirmed hypocellular marrow consistent with aplastic anemia. Oncologic and hematologic evaluations were unremarkable for iron deficiency, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndromes, T-cell clonality, and leukemia. A next generation genetic sequencing immunodeficiency panel revealed a heterozygous variant of uncertain significance in CTLA4 c.385T >A, p.Cys129Ser (C129S). Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor important in maintaining immunologic homeostasis. To determine the functional significance of the C129S variant, additional testing was pursued to assess for diminished protein expression, as described in other pathogenic CTLA4 variants. The results demonstrated severely impaired CTLA-4 expression and CD80 transendocytosis, consistent with other variants causing CTLA-4 haploinsufficiency. He was initially treated with IVIG and cyclosporine, and became transfusion independent for few months, but relapsed. Treatment with CTLA-4-Ig fusion protein (abatacept) was considered, however the patient opted for definitive therapy through reduced-intensity haploidentical hematopoietic stem cell transplant, which was curative.

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Cervical sympathetic chain schwannomas are uncommon benign tumors that usually develop in the retrostyloid compartment of the parapharyngeal space. Differentiating cervical sympathetic chain schwannomas from other lesions of the retrostyloid parapharyngeal space can be very difficult. We present a case of a major ingrowth of a cervical lesion, covering the larynx and obstructing the airway beyond the midline. The imaging revealed an extensive parapharyngeal lesion with significant cystic degeneration, which complicated the radiological diagnosis. Severe cystic degeneration of a cervical schwannoma is associated with fast expansion, and near-fully cystic schwannomas have been described in the literature.

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BACKGROUND: Patients with high grade hydronephrosis (HN) and non-obstructive drainage on mercaptoacetyltriglycine (MAG-3) diuretic renography (renal scans) can pose a dilemma for clinicians. Some patients may progress and require pyeloplasty; however, more clarity is needed on outcomes among these patients. OBJECTIVE: Our primary objective was to predict which patients with high-grade HN and non-obstructive renal scan, (defined as T ½ time <20 min) would experience resolution of HN. Our secondary objective was to determine predictors for surgical intervention. STUDY DESIGN: Patients with prenatally detected HN were prospectively enrolled from 7 centers from 2007 to 2022. Included patients had a renal scan with T ½<20 min and Society for Fetal Urology (SFU) grade 3 or 4 at last ultrasound (RBUS) prior to renal scan. Primary outcome was resolution of HN defined as SFU grade 1 and anterior posterior diameter of the renal pelvis (APD) < 10 mm on follow-up RBUS. Secondary outcome was pyeloplasty, comparing patients undergoing pyeloplasty with patients followed with serial imaging without resolution. Multivariable logistic regression was used for analysis. RESULTS: Of the total 2228 patients, 1311 had isolated HN, 338 patients had a renal scan and 129 met inclusion criteria. Median age at renal scan was 3.1 months, 77% were male and median follow-up was 35 months (IQR 20-49). We found that 22% (29/129) resolved, 42% of patients had pyeloplasty (54/129) and 36% had persistent HN that required follow-up (46/129). Univariate predictors of resolution were age≥3 months at time of renal scan (p = 0.05), T ½ time≤5 min (p = 0.09), SFU grade 3 (p = 0.0009), and APD<20 mm (p = 0.005). Upon multivariable analysis, SFU grade 3 (OR = 4.14, 95% CI: 1.30-13.4, p = 0.02) and APD<20 mm (OR = 6.62, 95% CI: 1.41-31.0, p = 0.02) were significant predictors of resolution. In the analysis of decision for pyeloplasty, SFU grade 4 (OR = 2.40, 95% CI: 1.01-5.71, p = 0.04) and T ½ time on subsequent renal scan of ≥20 min (OR = 5.14, 95% CI: 1.54-17.1, p = 0.008) were the significant predictors. CONCLUSIONS: Patients with high grade HN and reassuring renal scan can pose a significant challenge to clinical management. Our results help identify a specific candidate for observation with little risk for progression: the patient with SFU grade 3, APD under 20 mm, T ½ of 5 min or less who was 3 months or older at the time of renal scan. However, many patients may progress to surgery or do not fully resolve and require continued follow-up.

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PURPOSE: With recent advances in artificial intelligence (AI), it has become crucial to thoroughly evaluate its applicability in healthcare. This study aimed to assess the accuracy of ChatGPT in diagnosing ear, nose, and throat (ENT) pathology, and comparing its performance to that of medical experts. METHODS: We conducted a cross-sectional comparative study where 32 ENT cases were presented to ChatGPT 3.5, ENT physicians, ENT residents, family medicine (FM) specialists, second-year medical students (Med2), and third-year medical students (Med3). Each participant provided three differential diagnoses. The study analyzed diagnostic accuracy rates and inter-rater agreement within and between participant groups and ChatGPT. RESULTS: The accuracy rate of ChatGPT was 70.8%, being not significantly different from ENT physicians or ENT residents. However, a significant difference in correctness rate existed between ChatGPT and FM specialists (49.8%, p < 0.001), and between ChatGPT and medical students (Med2 47.5%, p < 0.001; Med3 47%, p < 0.001). Inter-rater agreement for the differential diagnosis between ChatGPT and each participant group was either poor or fair. In 68.75% of cases, ChatGPT failed to mention the most critical diagnosis. CONCLUSIONS: ChatGPT demonstrated accuracy comparable to that of ENT physicians and ENT residents in diagnosing ENT pathology, outperforming FM specialists, Med2 and Med3. However, it showed limitations in identifying the most critical diagnosis.

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A 36 year old woman with history of heart failure and left ventricular assist device (LVAD) implantation, with subsequent explantation after myocardial recovery, presented for management of preconception counseling and subsequent pregnancy. To our knowledge, this case represents the first documented successful pregnancy after LVAD explantation. Management details are provided, and relevant literature is reviewed.

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INTRODUCTION AND OBJECTIVE: Ureteral reimplantation of the dilated ureter in infants is challenging; however, some patients with primary obstructive megaureter (POM) in this age group require intervention due to clinical or radiological progression. We sought to determine if high pressure balloon dilation (HPBD) can serve as a definitive treatment for POM in children under one year of age, or as a temporizing measure until later reimplantation. MATERIALS AND METHODS: All patients from a single institution who underwent HPBD between October 2009 and May 2022 were retrospectively reviewed. Patients were excluded if older than 12 months or diagnosed with neurogenic bladder, posterior urethral valves, or obstructed refluxing megaureter. Patients with prior surgical intervention at the ureterovesical junction were excluded. Indications for surgery included progressive hydroureteronephrosis or urinary tract infection (UTI). Balloon dilation was performed via cystoscopy with fluoroscopic guidance, followed by placement of two temporary ureteral stents. Primary outcomes were improvement or resolution of megaureter and rates of subsequent reimplantation. Secondary outcomes included total number of anesthetics and postoperative UTIs. RESULTS: Fifteen infants with median age of 7.6 months (IQR 3.8-9.7) underwent HPBD. Twelve (80%) patients were detected prenatally and 3 (20%) after a UTI. Indication for surgery was progressive hydroureteronephrosis in 10 patients (67%) and UTI in five (33%). All had SFU grade 3 or 4 hydronephrosis on preoperative ultrasound and median distal ureteral diameter was 13 mm. Median follow up was 2.9 years. Twelve (80%) succeeded with endoscopic treatment: 7 patients had an undetectable distal ureter on ultrasound at last follow-up, 5 were improved with median distal ureteral diameter of 7 mm. Three patients (20%) required ureteral reimplantation due to progressive dilation, all with grade 4 hydronephrosis and distal ureteral diameters were 11, 15, and 21 mm. Six patients (40%) required two anesthetics to complete endoscopic treatment. Among those, 4 patients required initial stent placement for passive dilation followed by a second anesthetic for HPBD weeks later. Two patients underwent repeat HPBD following postoperative proximal migration of the ureteral stents. All 15 patients had an additional anesthetic for removal of stents. Five patients (33%) were treated for a symptomatic UTI (4 febrile, 1 afebrile) with the stents indwelling but there were no UTIs in the group following stent removal. CONCLUSION: Balloon dilation is a practical option for treatment of POM in infants, and in most cases (80%) avoids subsequent open surgery (over median 2.9 years of follow-up).

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Herein, we study the influences of the laser-exposed volume and the irradiation position on the nonphotochemical laser-induced nucleation (NPLIN) of supersaturated potassium chloride solutions in water. The effect of the exposed volume on the NPLIN probability was studied by exposing distinct milliliter-scale volumes of aqueous potassium chloride solutions stored in vials at two different supersaturations (1.034 and 1.050) and laser intensities (10 and 23 MW/cm2). Higher NPLIN probabilities were observed with increasing laser-exposed volume as well as with increasing supersaturation and laser intensity. The measured NPLIN probabilities at different exposed volumes are questioned in the context of the dielectric polarization mechanism and classical nucleation theory. No significant change in the NPLIN probability was observed when samples were irradiated at the bottom, top, or middle of the vial. However, a significant increase in the nucleation probability was observed upon irradiation through the solution meniscus. We discuss these results in terms of mechanisms proposed for NPLIN.

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OBJECTIVE: To compare the surgical outcomes and complications of boys who underwent double-face onlay-tube-onlay transverse preputial island flap (DFOTO) one-stage repair vs. two-stage repair for proximal hypospadias. STUDY DESIGN: Males with proximal hypospadias who underwent DFOTO or two-stage repair at a single institution from 2008 to 2021 were identified. Patients who had prior hypospadias surgery were excluded. Outcomes were surgical complications, number of surgical procedures, operative time, and post-operative uroflowmetry results. RESULTS: Fifty-three males who underwent DFOTO and 39 who underwent two-stage repair were included. Median age at surgery was 1.1 years (IQR 0.83-1.6) and median follow-up was 3.0 years (IQR 1.2-6.8). Although not statistically significant, the DFOTO group had higher rates of urethrocutaneous fistula (30% vs. 15%, p = 0.10), urethral stricture (15% vs. 3%, p = 0.07) and urethral diverticulum (8% vs. 3%, p = 0.39). Although the unplanned re-operation rate was higher in DFOTO (58% vs. 33%, p = 0.02), the mean number of procedures and median total surgical time were lower in DFOTO (1.8 ± 0.9 vs. 2.4 ± 0.8, p = 0.0004; 337 min [IQR 278-460] vs. 468 min [IQR 400-563], p = 0.008). There were no significant differences between groups for mean peak flow rates and post void residuals. CONCLUSIONS: In males who underwent DFOTO, 42% achieved completion of their proximal hypospadias repair with one operation, while the remainder had largely minor complications. Accounting for reoperation rates, the mean number of procedures per patient was lower in the DFOTO group. Comparable results can be achieved with both techniques; the risks of higher unplanned operation rates in the DFOTO group should be considered with the benefit of fewer total procedures.

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Non-photochemical laser-induced nucleation (NPLIN) has emerged as a promising primary nucleation control technique offering spatiotemporal control over crystallization with potential for polymorph control. So far, NPLIN was mostly investigated in milliliter vials, through laborious manual counting of the crystallized vials by visual inspection. Microfluidics represents an alternative to acquiring automated and statistically reliable data. Thus we designed a droplet-based microfluidic platform capable of identifying the droplets with crystals emerging upon Nd:YAG laser irradiation using the deep learning method. In our experiments, we used supersaturated solutions of KCl in water, and the effect of laser intensity, wavelength (1064, 532, and 355 nm), solution supersaturation (S), solution filtration, and intentional doping with nanoparticles on the nucleation probability is quantified and compared to control cooling crystallization experiments. Ability of dielectric polarization and the nanoparticle heating mechanisms proposed for NPLIN to explain the acquired results is tested. Solutions with lower supersaturation (S = 1.05) exhibit significantly higher NPLIN probabilities than those in the control experiments for all laser wavelengths above a threshold intensity (50 MW/cm2). At higher supersaturation studied (S = 1.10), irradiation was already effective at lower laser intensities (10 MW/cm2). No significant wavelength effect was observed besides irradiation with 355 nm light at higher laser intensities (≥50 MW/cm2). Solution filtration and intentional doping experiments showed that nanoimpurities might play a significant role in explaining NPLIN phenomena.

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The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα-TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN-pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1.

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Long-term adult outcomes of children diagnosed with urinary tract dilatation (UTD) and vesicoureteral reflux (VUR) are not clearly documented in the literature. Likewise, follow-up protocols for these patients as they transition through adolescence and into adulthood vary with institution and cultures. Several studies have shown that individuals diagnosed with VUR in childhood are at higher risk of urinary tract infection (UTI) throughout their lives, even in the setting of prior VUR resolution or surgical correction. This is particularly relevant in patients with renal scarring, who are at higher risk of UTIs, hypertension and renal function deterioration in pregnancy. The risk of adverse maternal and fetal outcomes in pregnancy are higher for women with significant chronic kidney disease (CKD). Patients who underwent endoscopic injection or reimplantation should be counselled on the long-term particular risks associated with each intervention, including calcification of ureteric injection mounds, and the potential challenges of future endoscopic procedures following reimplantation. Although there is no evidence for the direct correlation between conservatively managed UTD in childhood, and symptomatic UTD diagnosed in adulthood, all patients should be aware of the long-term risks of persistent upper tract dilatation. Lastly, bladder-bowel dysfunction (BBD) management in adolescence can be more challenging and may contribute to symptomatic recurrence in this age group.

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There is an ongoing forensic and security need for rapid, on-scene, easy-to-use, non-invasive chemical identification of intact energetic materials at pre-explosion crime scenes. Recent technological advances in instrument miniaturization, wireless transfer and cloud storage of digital data, and multivariate data analysis have created new and very promising options for the use of near-infrared (NIR) spectroscopy in forensic science. This study shows that in addition to drugs of abuse, portable NIR spectroscopy with multivariate data analysis also offers excellent opportunities to identify intact energetic materials and mixtures. NIR is able to characterize a broad range of chemicals of interest in forensic explosive investigations, covering both organic and inorganic compounds. NIR characterization of actual forensic casework samples convincingly shows that this technique can handle the chemical diversity encountered in forensic explosive investigations. The detailed chemical information contained in the 1350-2550 nm NIR reflectance spectrum allows for correct compound identification within a given class of energetic materials, including nitro-aromatics, nitro-amines, nitrate esters, and peroxides. In addition, the detailed characterization of mixtures of energetic materials, such as plastic formulations containing PETN (pentaerythritol tetranitrate) and RDX (trinitro triazinane), is feasible. The results presented illustrate that the NIR spectra of energetic compounds and mixtures are sufficiently selective to prevent false-positive results for a broad range of food-related products, household chemicals, raw materials used for the production of home-made explosives, drugs of abuse, and products that are sometimes used to create hoax improvised explosive devices. However, for frequently encountered pyrotechnic mixtures, such as black powder, flash powder, and smokeless powder, and some basic inorganic raw materials, the application of NIR spectroscopy remains challenging. Another challenge is presented by casework samples of contaminated, aged, and degraded energetic materials or poor-quality HMEs (home-made explosives), for which the spectral signature deviates significantly from the reference spectra, potentially leading to false-negative outcomes.

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BACKGROUND: Although hypospadias outcomes studies typically report a level or type of repair performed, these studies often lack applicability to each surgical practice due to technical variability that is not fully delineated. An example is the tubularized incised plate (TIP) urethroplasty procedure, for which modifications have been associated with significantly decreased complication rates in single center series. However, many studies fail to report specificity in techniques utilized, thereby limiting comparison between series. OBJECTIVE: With the goal of developing a surgical atlas of hypospadias repair techniques, this study examined 1) current techniques used by surgeons in our network for recording operative notes and 2) operative technical details by surgeon for two common procedures, tubularized incised plate (TIP) distal and proximal hypospadias repairs across a multi-institutional surgical network. STUDY DESIGN: A two-part study was completed. First, a survey was distributed to the network to assess surgeon volume and methods of recording hypospadias repair operative notes. Subsequently, an operative template or a representative de-identified operative note describing a TIP and/or proximal repair with urethroplasty was obtained from participating surgeons. Each was analyzed by at least two individuals for natural language that signified specified portions of the procedure. Procedural details from each note were tabulated and confirmed with each surgeon, clarifying that the recorded findings reflected their current practice techniques and instrumentation. RESULTS: Twenty-five surgeons from 12 institutions completed the survey. The number of primary distal hypospadias repairs performed per surgeon in the past year ranged from 1-10 to >50, with 40% performing 1-20. Primary proximal hypospadias repairs performed in the past year ranged from 1-30, with 60% performing 1-10. 96% of surgeons maintain operative notes within an electronic health record. Of these, 66.7% edited a template as their primary method of note entry; 76.5% of these surgeons reported that the template captures their operative techniques very or moderately well. Operative notes or templates from 16 surgeons at 10 institutions were analyzed. In 7 proximal and 14 distal repairs, parameters for chordee correction, urethroplasty suture selection and technique, tissue utilized, and catheter selection varied widely across surgeons. CONCLUSION: Wide variability in technical surgical details of categorically similar hypospadias repairs was demonstrated across a large surgical network. Surgeon-specific modifications of commonly described procedures are common, and further evaluation of short- and long-term outcomes accounting for these technical variations is needed to determine their relative influence.

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Very high levels of industrial contaminants in St. Lawrence Estuary (SLE) beluga whales represent one of the major threats to this population classified as endangered under the Species at Risk Act in Canada. Elevated concentrations of short-chained chlorinated paraffins (SCCPs) were recently reported in blubber of adult male SLE belugas. Recent regulations for SCCPs in North America, combined with their replacement by medium- (MCCPs) and long-chained chlorinated paraffins (LCCPs), highlight the importance of tracking this toxic chemical class. The objectives of this study were to evaluate (1) levels and profiles of chlorinated paraffins (CPs) in samples obtained from carcasses of adult male, adult female, juvenile, newborn, and fetus beluga, and (2) trends in adult male belugas between 1997 and 2018. Factors potentially influencing CP temporal trends such as age, feeding ecology and sampling year were also explored. SCCPs dominated (64 to 100%) total CP concentrations across all age and sex classes, MCCPs accounted for the remaining proportion of total CPs, and LCCPs were not detected in any sample. The chlorinated paraffin homolog that dominated the most in beluga blubber was C12Cl8. Adult male SCCP concentrations from this study were considerably lower (> 2000-fold) than those recently reported in Simond et al. (2020), likely reflecting a previously erroneous overestimate due to the lack of a suitable analytical method for SCCPs at the time. Both SCCPs and total CPs declined over time in adult males in our study (rate of 1.67 and 1.33% per year, respectively), presumably due in part to the implementation of regulations in 2012. However, there is a need to better understand the possible contribution of a changing diet to contaminant exposure, as stable isotopic ratios of carbon also changed over time.

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Telemedicine has increased during the coronavirus disease 2019 pandemic. Our objective was to determine if patient satisfaction with telemedicine differed from in-person visits in an academic pediatric urology clinic. Following outpatient telemedicine and in-person pediatric urology visits, the validated NRC Health© Patient Survey was used to assess patient experience. Patient satisfaction was assessed on a 10-point scale with scores of 9-10 considered "satisfied" and 1-8 considered "not satisfied." Satisfaction scores between telemedicine and in-person groups were compared using McNemar's test, Wilcoxon signed rank test, and conditional logistic regression. Fifty-one patients had urology telemedicine visits during April-August 2020 and completed the NRC Health© Patient Survey. Propensity score matching was used to identify 102 in-person controls between January 2019 and March 2020. Ninety-two percent of telemedicine patients were satisfied compared to 87% of in-person patients (OR 1.7 95% CI [0.53-5.6]). Regression analysis adjusting for matching variables demonstrated that patient satisfaction was higher for telemedicine compared to in-person visits but was not statistically significant (OR 1.5 95% CI [0.43-5.6]). Patient satisfaction with telemedicine was similar to in-person visits in the pediatric urology clinic. Reduced waiting time and convenience associated with telemedicine visits provide an opportunity for telemedicine as a useful modality for pediatric urology.

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INTRODUCTION AND OBJECTIVE: Optimal means to correct ventral curvature (VC) is debated. Our preferred technique for curvature greater than 45° is corporoplasty using tunica vaginalis flap (TVF). We describe our complications with TVF for ventral lengthening. METHODS: Forty-four boys who underwent ventral lengthening with a corporoplasty with TVF were identified in a prospective database for proximal hypospadias repair by a single surgeon from 2008 to 2021. Corporotomy was performed by incising the tunica albuginea of the corpora cavernosa transversely at the point of maximum curvature. Harvested TVF was tailored to the size of the corporotomy and anastomosed to the edges of the tunica albuginea and on laid to the corporal defect with the mesothelial side of the TVF abutting the erectile tissue. RESULTS: Median age at surgery was 1.0 years (IQR 0.72-1.82). Median follow-up time was 4.9 years (IQR 2.6-8.0). Thirteen patients (27%) were older than 10 years of age at last follow up (median 13.3, range 10-20). Twenty-two boys (50%) received preoperative testosterone. The most common location of the meatus after degloving was penoscrotal (41%). Median VC after degloving was 90° (IQR 80-100). The urethral plate was transected in 43/44 (98%) of boys, improving median VC to 60° (IQR 40-60). After corporotomy, the median longitudinal distracted distance was 15 mm (IQR 12-17). Urethral reconstruction was most commonly achieved with the transverse island preputial flap technique or its modifications (39/44; 89%). Erections were reported in 42 boys (95%). None developed corporal diverticula, and two patients (4.5%) had ascended testis associated with TVF harvest. Seven percent of boys had recurrent ventral curvature (RVC; 3/44). Median RVC was 30° (IQR 30-45). One patient had RVC at the penoscrotal junction (not at site of prior corporoplasty) identified 11 years post operatively at age 15, and underwent dorsal plication. The other 2 patients were diagnosed less than 1 year post operatively. Both patients received testosterone due to small glans size, had double-face tubularized transverse island preputial flap as urethral and ventral skin coverage, and had endocrine and genetic consultation. Both had scarring of the preputial flap and of the corporoplasty. Scar excision and superficial transverse incisions on the tunica albuginea corrected RVC. CONCLUSIONS: The five-year outcome of ventral penile lengthening using TVF for corporoplasty is favorable with 7% of boys with RVC, and 4.5% with ascended testes associated with TVF harvest. None developed corporal diverticula.

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The phosphoinositide 3-kinase (PI3K) pathway represents the most hyperactivated oncogenic pathway in triple-negative breast cancer (TNBC), a highly aggressive tumor subtype encompassing ∼15% of breast cancers and which possesses no targeted therapeutics. Despite critical contributions of its signaling arms to disease pathogenesis, PI3K pathway inhibitors have not achieved expected clinical responses in TNBC, owing largely to a still-incomplete understanding of the compensatory cascades that operate downstream of PI3K. Here, we investigated the contributions of long noncoding RNAs (lncRNAs) to PI3K activities in clinical and experimental TNBC and discovered a prominent role for LINC01133 as a PI3K-AKT signaling effector. We found that LINC01133 exerted protumorigenic roles in TNBC and that it governed a previously undescribed mTOR Complex 2 (mTORC2)-dependent pathway that activated AKT in a PI3K-independent manner. Mechanistically, LINC01133 induced the expression of the mTORC2 component PROTOR1/PRR5 by competitively coupling away its negative messenger RNA (mRNA) regulator, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1). PROTOR1/PRR5 in turn was sufficient and necessary for LINC01133-triggered functions, casting previously unappreciated roles for this Rictor-binding protein in cellular signaling and growth. Notably, LINC01133 antagonism undermined cellular growth, and we show that the LINC01133-PROTOR1/PRR5 pathway was tightly associated with TNBC poor patient survival. Altogether, our findings uncovered a lncRNA-driven signaling shunt that acts as a critical determinant of malignancy downstream of the PI3K pathway and as a potential RNA therapeutic target in clinical TNBC management.

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As a high trophic-level species, ringed seals (Pusa hispida) and beluga whales (Delphinapterus leucas) are particularly vulnerable to elevated concentrations of biomagnifying contaminants, such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and mercury (Hg). These species also face climate-change-related impacts which are leading to alterations in their diet and associated contaminant exposure. The metabolomic profile of marine mammal tissues and how it changes to environmental stressors is poorly understood. This study characterizes the profiles of 235 metabolites across plasma, liver, and inner and outer blubber in adult ringed seals and beluga whales and assesses how these profiles change as a consequence of contaminants and dietary changes. In both species, inner and outer blubber were characterized by a greater proportion of lipid classes, whereas the dominant metabolites in liver and plasma were amino acids, carbohydrates, biogenic amines and lysophosphatidylcholines. Several metabolite profiles in ringed seal plasma correlated with δ13C, while metabolite profiles in blubber were affected by hexabromobenzene in ringed seals and PBDEs and Hg in belugas. This study provides insight into inter-matrix similarities and differences across tissues and suggests that plasma and liver are more suitable for studying changes in diet, whereas liver and blubber are more suitable for studying the impacts of contaminants.

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Mesenchymal stem/stromal cells (MSCs) encompass a heterogeneous population of fibroblastic progenitor cells that reside in multiple tissues around the body. They are endowed with capacities to differentiate into multiple connective tissue lineages, including chondrocytes, adipocytes, and osteoblasts, and are thought to function as trophic cells recruited to sites of injury and inflammation where they contribute to tissue regeneration. In keeping with these roles, MSCs also to home to sites of breast tumorigenesis, akin to their migration to wounds, and participate in tumor stroma formation. Mounting evidence over the past two decades has described the critical regulatory roles for tumor-associated MSCs in various aspects of breast tumor pathogenesis, be it tumor initiation, growth, angiogenesis, tumor microenvironment formation, immune evasion, cancer cell migration, invasion, survival, therapeutic resistance, dissemination, and metastatic colonization. In this review, we present a brief summary of the role of MSCs in breast tumor development and progression, highlight some of the molecular frameworks underlying their pro-malignant contributions, and present evidence of their promising utility in breast cancer therapy.

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