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Tracy Marien, Mustafa Kadihasanoglu, Nicole L Miller Department of Urology, Vanderbilt Medical Center, Nashville, TN, USA Background: Multiple endoscopic surgical options exist to treat benign prostatic hyperplasia (BPH), including holmium laser enucleation of the prostate (HoLEP). HoLEP alleviates obstructive prostatic tissue via enucleation, both bluntly with a resectoscope and by cutting tissue with the holmium laser, and removal of adenoma via morcellation. This article reviews patient selection for HoLEP in order to optimize outcomes, costs, and patient satisfaction.Methods: A literature review of all studies on HoLEP was conducted. Studies that focused on outcomes in regard to patient and procedural factors were closely reviewed and discussed.Results: Various studies found that men with large or small prostates, on antithrombotic therapy, in urinary retention, with bladder hypocontractility, with prostate cancer, undergoing retreatment for BPH, or in need of concomitant surgery for bladder stones and other pathologies do well with HoLEP, as demonstrated by excellent functional and symptomatic outcomes as well as low complication rates. There is a 74–78% rate of retrograde ejaculation following HoLEP. Techniques to preserve ejaculatory function following enucleative techniques have not been able to demonstrate a significant improvement.Conclusion: Patient selection for HoLEP can include most men with bothersome BPH who have evidence of bladder outlet obstruction and are healthy enough to undergo surgery. The ability to safely perform concomitant surgery with HoLEP benefits the patient by sparing them an additional anesthetic and also decreases costs. Patients should be made aware of the risk of retrograde ejaculation following HoLEP and counseled on treatment alternatives if maintaining ejaculatory function is desired. Keywords: holmium laser nucleation of the prostate, HoLEP, benign prostatic hyperplasia, prostate size, urinary retention, patient selection

© 2015. American Geophysical Union. All Rights Reserved. Increasing computational efficiency and the need for improved accuracy are currently driving the development of "hyper-resolution" land-surface models that can be implemented at continental scales with resolutions of 1 km or finer. Here we report research incorporating fine-scale grid resolutions into the NCAR Community Land Model (CLM v4.0) for simulations at 1, 25, and 100 km resolution using 1 km soil and topographic information. Multiyear model runs were performed over the Southwestern U.S., including the entire state of California and the Colorado River basin. The results show changes in the total amount of CLM-modeled water storage, and changes in the spatial and tempo ral distributions of water in snow and soil reservoirs, as well as changes in surface fluxes and the energy balance. To inform future model progress and continued development needs and weaknesses, we compare simulation outputs to station and gridded observations of model fields. Although the higher grid-resolution model is not driven by high-resolution forcing, grid resolution changes alone yield significant improvement (reduction in error) between model outputs and observations, where the RMSE decreases by more than 35%, 36%, 34%, and 12% for soil moisture, terrestrial water storage anomaly, sensible heat, and snow water equivalent, respectively. As an additional exercise, we performed a 100 m resolution simulation over a spatial subdomain. Those results indicate that parameters such as drainage, runoff, and infiltration are significantly impacted when hillslope scales of ∼100 m or finer are considered, and we show the ways in which limitations of the current model physics, including no lateral flow between grid cells, may affect model simulation accuracy. Key Points: CLM4.0 simulations are compared across multiple grid resolutions Changing grid resolution significantly affects the terrestrial water balance Outputs compared to observations show improvement with resolution

Rationale: Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein. Objectives: To evaluate ataluren activity, safety, and pharmacokinetics in children with nonsense mutation CF. Methods: Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients took ataluren three times per day (morning, midday, and evening) with randomization to the order of receiving a lower dose (4, 4, and 8 mg/kg) and a higher dose (10, 10, and 20 mg/kg) in the two cycles. Measurements and Main Results: The study enrolled 30 patients (16 male and 14 female, ages 6 through 18 yr) with a nonsense mutation in at least one allele of the CFTR gene, a classical CF phenotype, and abnormal baseline nasal epithelial chloride transport. Ataluren induced a nasal chloride transport response (at least a -5-mV improvement) or hyperpolarization (value more electrically negative than -5 mV) in 50% and 47% of patients, respectively, with more hyperpolarizations at the higher dose. Improvements were seen in seven of nine nonsense mutation genotypes represented. Ataluren significantly increased the proportion of nasal epithelial cells expressing apical full-length CFTR protein. Adverse events and laboratory abnormalities were infrequent and usually mild. Ataluren pharmacokinetics were similar to those in adults. Conclusions: In children with nonsense mutation CF, ataluren can induce functional CFTR production and is well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00458341). [ABSTRACT FROM AUTHOR]

This study examined the moderating influences of psychosocial functioning on the relation between perceived neighborhood risk and alcohol, cigarette, and marijuana use in a sample of inner-city, ethnic minority youths. Perceived neighborhood risk assessed gang activity, fighting, and neighborhood toughness. Measures of psychosocial functioning assessed intrapersonal and interpersonal skills implicated as correlates and predictors of early-stage drug use. Neighborhood risk uniquely predicted alcohol, cigarette, and marijuana use; however, some relations were qualified by level of psychosocial functioning. Negative affect, peer relations, and social concern moderated the effects of neighborhood risk on alcohol use. Negative affect moderated the relations between neighborhood risk and cigarette use. Risk-taking and family relations moderated the relations between neighborhood risk and marijuana use. Overall, the size of these effects was small and underscores the need to include a wider range of conceptually relevant measures. Longitudinally, neighborhood risk was uniquely associated with less protection and greater polydrug use, controlling for early levels of psychosocial risk and protection. Net of prediction, both risk and protection were associated equivalently with neighborhood risk. Findings indicate a need to develop a more complete understanding of the precise manner in which environmental risk increases susceptibility to early-stage drug use. [ABSTRACT FROM AUTHOR]

This study examined personal life events and neighborhood stress as determinants of alcohol use among urban, minority youth. Personal events included disruptive and beneficial life experiences, whereas neighborhood stress assessed gang involvement and perceived neighborhood toughness. Analyses were constructed to examine the ability of several key measures of psychosocial functioning to moderate relations between life events, neighborhood stress, and alcohol use. Positive outcomes (e.g., family communication) and internal health locus of control buffered the effects of negative life events on alcohol use. High levels of absenteeism exacerbated the effects of neighborhood stress on alcohol use. Both positive and negative life events and neighborhood stress uniquely predicted alcohol use controlling for risk, gender, and ethnicity. Findings are discussed in terms of extending current etiology models to include stressful life events and contextual factors as predictors of early-stage alcohol use. [ABSTRACT FROM AUTHOR]

Introduction: Guidelines for benign prostate hyperplasia (BPH) interventions are volume based. The degree to which different imaging modalities actually correlate to treated volume is not known for BPH. The present study compares the accuracy of preoperative ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and MRI-transitional zone (TZ) to BPH enucleation weight. Methods: A retrospective review of patients who underwent enucleation for BPH and had preoperative transrectal ultrasound (TRUS), CT, and/or MRI was performed. Total prostate volumes were measured for CT, MRI, and TRUS; MRI-TZ volume was also measured. The primary outcome was difference between enucleated pathology weight in grams and preoperative imaging volume. Differences between enucleation and imaging volume for each modality were calculated with one-way analysis of variance, with Tukey's honest significance test to determine pairwise significance (RStudio V1.2). Results: From January to October 2020, there were 114 preoperative imaging studies available for 95 patients. Thirty-four (30%) of the studies were TRUS, 46 (40%) were CT, and 34 (30%) were MRI. MRI-TZ most accurately predicted enucleation volume on multivariate analysis (F-statistic p -value < 0.001). Preoperative imaging was greater than enucleation volume by a median of 46 cc for TRUS, 51 cc for CT, 53 cc for MRI, and 14 cc for MRI-TZ. Pairwise significance was reached for MRI-TZ over CT ( p -adj < 0.001), MRI-TZ over MRI ( p -adj < 0.001) and MRI-TZ over US ( p -adj = 0.03). Conclusions: Enucleation volume for BPH was most accurately predicted by TZ volume on MRI compared with total prostate volume on CT, TRUS, and MRI. MRI total volume was not superior to CT total volume. Focusing on MRI-TZ volume rather than total prostate volume may more accurately stratify patients for BPH treatment. In experienced hands, median enucleation volume is within 14 cc of MRI-TZ volume.

Background: The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis., Method: Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis., Results: Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM., Conclusions: Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS., (© 2024 Wiley Periodicals LLC.)

Introduction: New opioid dependency after urologic surgery is a serious adverse outcome that is well-described in the literature. Patients with stone disease often require multiple procedures because of recurrence of disease and hence are at greater risk for repeat opioid exposures. Despite this, opioid prescribing after urologic surgery remains highly variable and in an emergency setting, opioids are still used commonly in management of acute renal colic. Methods: Two literature searches were performed using PubMed. First, we searched available literature concerning opioid-sparing pathways in acute renal colic. Second, we searched available literature for opioid-sparing pathways in ureteroscopy and percutaneous nephrolithotomy (PCNL). Abstracts were reviewed for inclusion in our narrative review. Results: In the setting of acute renal colic, multiple randomized control trials have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) attain greater reduction in pain scores, decreased need for rescue medications, and decreased vomiting events in comparison with opioids. NSAIDs also form a core component in management of postureteroscopy pain and have been demonstrated in randomized trials to have equivalent to improved pain control outcomes compared with opioids. Multiple opioid-free pathways have been described for postureteroscopy analgesia with need for rescue narcotics falling under 20% in most studies, including in patients with ureteral stents. Enhanced Recovery After Surgery protocols after percutaneous nephrolithotomy are less well described but have yielded a reduction in postoperative opioid requirements. Conclusions: In select patients, both acute renal colic and after kidney stone surgery, adequate pain management can usually be obtained with minimal or no opioid medication. NSAIDs form the core of most described opioid-sparing pathways for both ureteroscopy and PCNL, with the contribution of other components to postoperative pain outcomes limited because of lack of head-to-head comparisons. However, medications aimed specifically at targeting stent-related discomfort form a key component of most multimodal postsurgical pain management pathways. Further investigation is needed to develop pathways in patients unable to tolerate NSAIDs.

Acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE) is a rare cause of exertional acute kidney injury. The proposed mechanism of injury in ALPE is renovascular spasm, in the setting of oxidative stress and muscular damage, which creates a characteristic wedge-shaped infarction pattern on delayed imaging. Patients present with nausea, vomiting, loin or abdominal pain, and fatigue within 1-2 days of anaerobic exercise, associated with an acute rise in serum creatinine, which generally plateaus within 3 days. This process is likely exacerbated by dehydration, analgesic usage, and lower baseline fitness levels. This disease process is distinct from rhabdomyolysis, in that creatine kinase levels are not significantly elevated, myoglobinuria is not seen, and aggressive fluid resuscitation is not beneficial. We present three cases of ALPE following participation in the Marine Combat Fitness Test (CFT), an anaerobic evolution. Medical workup demonstrated no additional etiology for acute renal failure. The average peak creatinine in these patients was 2.9 mg/dL, and all demonstrated return to normal renal function, without hemodialysis. One patient experienced recurrent ALPE, after short-interval CFT participation. Military medical providers should be aware of this diagnosis when evaluating service members with acute renal injury after exercise. The clinical course is benign, and affected service members are at increased risk of recurrence, with subsequent intense exercise. Service members should engage in a graduated exercise program, before intense exercise activities, and should be monitored closely for recurrent renal injury., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Introduction: Holmium laser lithotripsy is a standard energy source used for treatment of kidney stones during flexible ureteroscopy. Efficiency of laser surgery may be affected by patient and operator characteristics or perioperative management. Here, we sought to examine intraoperative data from patients undergoing high frequency dusting with high-powered holmium laser lithotripsy to evaluate surgical and demographic factors associated with lasing efficiency (LE). Methods: A total of 82 intraoperative reports were analyzed from an ongoing laser lithotripsy clinical trial evaluating the Lumenis Pulse™ 120H holmium laser with renal stones up to 20 mm in diameter with and without Moses 2.0 technology. For each case, the total pause time between lasing activations was corrected to remove lengthy pauses and divided by the total lasing time to calculate an efficiency percentage. This was then compared with patient demographics, anesthesia administration, stone burden, postoperative complications, and stone-free rates using both univariate and multivariate analyses. Results: Of the 82 included patients, 36 received endotracheal tube (ETT) intubation and 46 had a laryngeal mask airway (LMA). Patients with ETT had significantly higher LE (78.7%) compared to those with an LMA (73.3%) in our univariate analysis ( p  < 0.01) as well as in the multivariate model that adjusted for maximum stone size, number of stones, stone density, and patient body mass index ( p  < 0.05). There was also significantly higher mean LE in patients with no postoperative complications (76.3%) compared to those with any grade (I-V) Clavien-Dindo complication within 30 days after surgery (70.0%) ( p  < 0.05). Conclusions: Flexible ureteroscopy and laser lithotripsy cases with higher LE are associated with lower rates of postoperative complications. The data also support the use of ETT over LMA to improve overall LE; however, this remains one consideration among many for choosing anesthesia administration. Clinical Trial Registration number: NCT04505956.

Introduction: Recent retrospective literature suggests that the quick sequential organ failure assessment (qSOFA) scoring tool is a potentially superior tool over use of the systemic inflammatory response syndrome (SIRS) criteria to predict septic shock after percutaneous nephrolithotomy (PCNL) surgery. Here we examine use of qSOFA and SIRS to predict septic shock within data series collected prospectively on PCNL patients as part of a greater study of infectious complications. Materials and Methods: We performed a secondary analysis of two prospective multicenter studies including PCNL patients across nine institutions. Clinical signs informing SIRS and qSOFA scores were collected no later than postoperative day 1. The primary outcome was sensitivity and specificity of SIRS and qSOFA (high-risk score of greater-or-equal to two points) in predicting admission to the intensive care unit (ICU) for vasopressor support. Results: A total of 218 cases at 9 institutions were analyzed. One patient required vasopressor support in the ICU. The sensitivity/specificity was 100%/72.4% (McNemar's test p  < 0.001) for SIRS and was 100%/90.8% (McNemar's test p  < 0.001) for qSOFA. Conclusion: Although positive predictive value for both qSOFA and SIRS in prediction of post-PCNL septic shock is low, prospectively collected data demonstrate use of qSOFA may offer greater specificity than SIRS criteria when predicting post-PCNL septic shock.

Background: Residual fragments (RFs) after percutaneous nephrolithotomy (PCNL) have a significant impact on patients' quality of life and clinical course. There is a paucity of studies that evaluate the natural history of RFs after PCNL. The objective of this study is to compare rates of reintervention, complications, stone growth, and passage in patients with RFs >4, ≤4, and ≤2 mm after PCNL. Methods: Sites from the Endourologic Disease Group for Excellence (EDGE) research consortium examined data of PCNL patients from 2015 to 2019 with at least 1-year follow-up. RF passage, regrowth, reintervention, and complications were recorded and RFs were stratified into >4 and ≤4 mm groups, as well as >2 and ≤2 mm groups. Potential predictors for stone-related events after PCNL were determined using multivariable logistic regression analysis. It was hypothesized that larger RF thresholds would result in lower passage rates, faster regrowth, and greater clinically significant events (complications and reinterventions) than smaller RF thresholds. Results: A total of 439 patients with RFs >1 mm on CT postoperative day 1 were included in this study. For RFs >4 mm, rates of reintervention were found to be significantly higher and Kaplan-Meier curve analysis showed significantly higher rates of stone-related events. Passage and RF regrowth were not found to be significantly different compared with RFs ≤4 mm. However, RFs ≤2 mm had significantly higher rates of passage, and significantly lower rates of fragment regrowth (>1 mm), complications, and reintervention compared with RFs >2 mm. On multivariable analysis, older age, body mass index, and RF size were found to be predictive of stone-related events. Conclusions: With the largest cohort to date, this study by the EDGE research consortium further confirms that clinically insignificant residual fragment is problematic for patients after PCNL, particularly in older more obese patients with larger RFs. Our study underscores the importance of complete stone clearance post-PCNL and challenges the use of Clinically insignificant residual fragment (CIFR).

The effect of obstructive sleep apnea (OSA) on 24-h urine parameters and resultant kidney stone risk is unknown. We sought to compare urinary lithogenic risk factors among patients with kidney stone disease with and without OSA. We performed a retrospective cohort study of adult patients with nephrolithiasis undergoing both polysomnography and 24-h urine analysis. Measures of acid load including gastrointestinal alkali absorption, urinary titratable acid, and net acid excretion were calculated from 24-h urine. We performed univariable comparisons of 24-h urine parameters between those with and without OSA and fit a multivariable linear regression model adjusting for age, sex, and BMI. Overall, there were 127 patients who underwent both polysomnography and a 24-h urine analysis from 2006 to 2018. There were 109 (86%) patients with OSA and 18 (14%) without. Patients with OSA were more commonly male, had greater BMI and had higher rates of hypertension. Patients with OSA had significantly higher levels of 24-h urinary oxalate, uric acid, sodium, potassium, phosphorous, chloride, and sulfate; higher supersaturation of uric acid; higher titratable acid, and net acid excretion; and lower urinary pH and supersaturation of calcium phosphate (p < 0.05). The difference in urinary pH and titratable acid, but not net acid excretion, remained significant when adjusting for BMI, age, and gender (both p = 0.02). OSA is associated with changes in urinary analytes that promote kidney stone formation, similar to those observed with obesity. After accounting for BMI, OSA is independently associated with lower urine pH and increased urinary titratable acid., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To compare rates of patient-reported kidney stone disease to Electronic Health Records (EHR) kidney stone diagnosis using a common dataset to evaluate for socio-demographic differences, including between those with and without active care., Methods: From the All of Us research database, we identified 21,687 adult participants with both patient-reported and EHR data. We compared differences in age, sex, race, education, employment status and healthcare access between patients with self-reported kidney stone history without EHR data to those with EHR-based diagnoses., Results: In this population, the self-reported prevalence of kidney stones was 8.6% overall (n = 1877), including 4.6% (n = 1004) who had self-reported diagnoses but no EHR data. Among those with self-reported kidney stone diagnoses only, the median age was 66. The EHR-based prevalence of kidney stones was 5.7% (n = 1231), median age 67. No differences were observed in age, sex, education, employment status, rural/urban status, or ability to afford healthcare between groups with EHR diagnosis or self-reported diagnosis only. Of patients who had a self-reported history of kidney stones, 24% reported actively seeing a provider for kidney stones., Conclusion: Kidney stone prevalence by self-report is higher than EHR-based prevalence in this national dataset. Using either method alone to estimate kidney stone prevalence may exclude some patients with the condition, although the demographic profile of both groups is similar. Approximately 1 in 4 patients report actively seeing a provider for stone disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Defining predictors of antigen-binding affinity of antibodies is valuable for engineering therapeutic antibodies with high binding affinity to their targets. However, this task is challenging owing to the huge diversity in the conformations of the complementarity determining regions of antibodies and the mode of engagement between antibody and antigen. In this study, we used the structural antibody database (SAbDab) to identify features that can discriminate high- and low-binding affinity across a 5-log scale. First, we abstracted features based on previously learned representations of protein-protein interactions to derive 'complex' feature sets, which include energetic, statistical, network-based, and machine-learned features. Second, we contrasted these complex feature sets with additional 'simple' feature sets based on counts of contacts between antibody and antigen. By investigating the predictive potential of 700 features contained in the eight complex and simple feature sets, we observed that simple feature sets perform comparably to complex feature sets in classification of binding affinity. Moreover, combining features from all eight feature-sets provided the best classification performance (median cross-validation AUROC and F1-score of 0.72). Of note, classification performance is substantially improved when several sources of data leakage (e.g., homologous antibodies) are not removed from the dataset, emphasizing a potential pitfall in this task. We additionally observe a classification performance plateau across diverse featurization approaches, highlighting the need for additional affinity-labeled antibody-antigen structural data. The findings from our present study set the stage for future studies aimed at multiple-log enhancement of antibody affinity through feature-guided engineering., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Miller, Clark, Raman and Sasisekharan.)

Purpose: Treatment of struvite kidney stones requires complete surgical stone removal combined with antibiotic therapy to eliminate urinary tract infections and preventive measures to reduce stone recurrence. The optimal duration of antibiotic therapy is unknown. We sought to determine if 2- or 12-weeks of antibiotics post percutaneous nephrolithotomy (PNL) for infection stones resulted in better outcomes for stone recurrence and positive urine cultures., Material and Methods: This multi-center, prospective randomized trial evaluated patients with the clinical diagnosis of infection stones. Patients were randomized to 2- or 12-weeks of postoperative oral antibiotics (nitrofurantoin or culture-specific antibiotic) and included if residual fragments were ≤4 mm on computed tomography imaging after PNL. Imaging and urine analyses were performed at 3-, 6-, and 12-months post-procedure., Results: Thirty-eight patients were enrolled and randomized to either 2-weeks (n = 20) or 12-weeks (n = 18) of antibiotic therapy post-PNL. Eleven patients were excluded due to residual fragments >4 mm, and 3 patients were lost to follow-up. The primary outcome was the stone-free rate (SFR) at 6 months post-PNL. At 3-, 6-, and 12-months follow-up, SFRs were 72.7% versus 80.0%, 70.0% versus 57.1%, 80.0% versus 57.1% (p = ns), between 2- and 12-week-groups, respectively. At 3-, 6-, and 12-months follow-up, positive urine cultures were 50.0% versus 37.5%, 50.0% versus 83.3%, and 37.5% versus 100% between 2- and 12-week groups, respectively (p = ns)., Conclusions: For patients with stone removal following PNL, neither 2-weeks nor 12-weeks of postoperative oral antibiotics is superior to prevent stones and recurrent positive urine cultures., (© 2022 The Japanese Urological Association.)

Background: The development of benign prostatic hyperplasia (BPH) and medication-refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS., Methods: Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching., Results: BPH patients on 5-α-reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone (DHT), increased levels of steroid 5-α-reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate-specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha-adrenergic receptor antagonists (α-blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching., Conclusions: After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI-induced pathway increased tissue levels of GC not seen in patients on α-blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI-induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth., (© 2022 Wiley Periodicals LLC.)

Proton pump inhibitors (PPIs) are widely prescribed medications that have effects on both enteric and urinary solute handling with an unknown effect on risk of nephrolithiasis. Our objectives were to examine the association between PPI exposure and incident nephrolithiasis and to determine its effect on 24H urine chemistry. We performed a single-center retrospective study on patients diagnosed with gastroesophageal reflux disease (GERD) without a history of kidney stones. Exposure to PPIs was abstracted, and then subsequent kidney stone diagnoses were identified. Multivariable Cox models with time-varying covariates were used to estimate the hazard of PPI use on incident nephrolithiasis. We used multivariable linear regression to analyze a subset of patients who went through 24-h urine analysis. We identified n = 55,765 PPI-naïve GERD patients without prior kidney stone diagnoses of whom 40,866 (73.2%) were exposed to PPI over a median of 3 year follow up. On multivariable analysis, PPI use was associated with higher risk of incident kidney stone diagnoses (HR 1.19, 95% CI 1.06-1.34). Among 593 patients with GERD with 24-H urine data, the PPI-exposed group (n = 307) had significantly lower mean urinary citrate (mean 3.0 vs 3.4 mmol, p = 0.029) and urinary magnesium (mean 3.6 vs 4.3 mmol, p < 0.001) on multivariable analyses. Exposure to PPIs is associated with an increased risk of kidney stones among patients with GERD. Hypomagnesemia and hypocitraturia associated with PPI exposure may contribute to kidney stone risk., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The dynamic interplay between virus and host plays out across many interacting surfaces as virus and host evolve continually in response to one another. In particular, epitope-paratope interactions (EPIs) between viral antigen and host antibodies drive much of this evolutionary race. In this review, we describe a series of recent studies examining aspects of epitope complexity that go beyond two interacting protein surfaces as EPIs are typically understood. To structure our discussion, we present a framework for understanding epitope complexity as a spectrum along a series of axes, focusing primarily on 1) epitope biochemical complexity (e.g., epitopes involving N-glycans) and 2) antigen conformational/dynamic complexity (e.g., epitopes with differential properties depending on antigen state or fold-axis). We highlight additional epitope complexity factors including epitope tertiary/quaternary structure, which contribute to epistatic relationships between epitope residues within- or adjacent-to a given epitope, as well as epitope overlap resulting from polyclonal antibody responses, which is relevant when assessing antigenic pressure against a given epitope. Finally, we discuss how these different forms of epitope complexity can limit EPI analyses and therapeutic antibody development, as well as recent efforts to overcome these limitations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miller, Raman, Clark and Sasisekharan.)

Complex glycans decorate viral surface proteins and play a critical role in virus-host interactions. Viral surface glycans shield vulnerable protein epitopes from host immunity yet can also present distinct "glycoepitopes" that can be targeted by host antibodies such as the potent anti-HIV antibody 2G12 that binds high-mannose glycans on gp120. Two recent publications demonstrate 2G12 binding to high mannose glycans on SARS-CoV-2 and select Influenza A (Flu) H3N2 viruses. Previously, our lab observed 2G12 binding and functional inhibition of a range of Flu viruses that include H3N2 and H1N1 lineages. In this manuscript, we present these data alongside structural analyses to offer an expanded picture of 2G12-Flu interactions. Further, based on the remarkable breadth of 2G12 N-glycan recognition and the structural factors promoting glycoprotein oligomannosylation, we hypothesize that 2G12 glycoepitopes can be defined from protein structure alone according to N-glycan site topology. We develop a model describing 2G12 glycoepitopes based on N-glycan site topology, and apply the model to identify viruses within the Protein Data Bank presenting putative 2G12 glycoepitopes for 2G12 repurposing toward analytical, diagnostic, and therapeutic applications., (© 2022. The Author(s).)

The Omicron variant features enhanced transmissibility and antibody escape. Here, we describe the Omicron receptor-binding domain (RBD) mutational landscape using amino acid interaction (AAI) networks, which are well suited for interrogating constellations of mutations that function in an epistatic manner. Using AAI, we map Omicron mutations directly and indirectly driving increased escape breadth and depth in class 1-4 antibody epitopes. Further, we present epitope networks for authorized therapeutic antibodies and assess perturbations to each antibody's epitope. Since our initial modeling following the identification of Omicron, these predictions have been realized by experimental findings of Omicron neutralization escape from therapeutic antibodies ADG20, AZD8895, and AZD1061. Importantly, the AAI predicted escape resulting from indirect epitope perturbations was not captured by previous sequence or point mutation analyses. Finally, for several Omicron RBD mutations, we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBD down -RBD down interface., Competing Interests: R.S. is a board member of Tychan, Singapore, which focuses on infectious diseases., (© 2022 The Author(s).)

The evolution of mutations in SARS-CoV-2 at antigenic sites that impact neutralizing antibody responses in humans poses a risk to immunity developed through vaccination and natural infection. The highly successful RNA-based vaccines have enabled rapid vaccine updates that incorporate mutations from current variants of concern (VOCs). It is therefore important to anticipate future antigenic mutations as the virus navigates the heterogeneous global landscape of host immunity. Toward this goal, we survey epitope-paratope interfaces of anti-SARS-CoV-2 antibodies to map an antigenic space that captures the role of each spike protein residue within the polyclonal antibody response directed against the ACE2-receptor binding domain (RBD) or the N-terminal domain (NTD). In particular, the antigenic space map builds on recently published epitope definitions by annotating epitope overlap and orthogonality at the residue level. We employ the antigenic space map as a framework to understand how mutations on nine major variants contribute to each variant's evasion of neutralizing antibodies. Further, we identify constellations of mutations that span the orthogonal epitope regions of the RBD and NTD on the variants with the greatest antibody escape. Finally, we apply the antigenic space map to predict which regions of antigenic space-should they mutate-may be most likely to complementarily augment antibody evasion for the most evasive and transmissible VOCs.

Objective: To describe the patterns of complementary and alternative medicine (CAM) among patients with kidney stones and analyze the alkali content of commonly used CAM therapies., Methods: We prospectively conducted structured interviews with patients who presented to a specialty stone clinic for the management of kidney stones. Open-ended questions were used to elicit information regarding CAM knowledge, formulation/dosing, and patterns of use. Several common CAM therapies were then analyzed for their alkali, organic anion, and sugar content., Results: Of 103 subjects, 82 (80%) patients reported knowledge of CAM and 52 (50%) reported using CAM. Patients with recurrent kidney stones were more likely to report using CAM than patients with first-time episodes (56% vs 26%, P = 0.04). Some respondents reported their condition decreased in severity or frequency since starting CAM therapy (17%) and improvements in pain (12%). Total alkali content per serving of the tested supplements was 0 mEq (Stonebreaker), 1.5 mEq (Ocean Spray Cranberry Juice Cocktail), 4.7 mEq (Lakewood Pure Cranberry Juice), 0.6 mEq (Braggs Apple Cider Vinegar), 11.9 mEq (LithoBalance), 9.5 mEq (Simply Grapefruit Juice), 19.8 mEq (KSP-Key Lime), and 20.2 mEq (KSP-Very Berry)., Conclusion: Patients with kidney stones may use CAM to alleviate symptoms or prevent recurrence. Commercially available CAM therapies may contain comparable alkali content to commonly prescribed citrate therapy. These data suggest that providers should be prepared to discuss the role of CAM with their patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Little is known about how benign prostatic hyperplasia (BPH) develops and why patients respond differently to medical therapy designed to reduce lower urinary tract symptoms (LUTS). The Medical Therapy of Prostatic Symptoms (MTOPS) trial randomized men with symptoms of BPH and followed response to medical therapy for up to 6 years. Treatment with a 5α-reductase inhibitor (5ARI) or an alpha-adrenergic receptor antagonist (α-blocker) reduced the risk of clinical progression, while men treated with combination therapy showed a 66% decrease in risk of progressive disease. However, medical therapies for BPH/LUTS are not effective in many patients. The reasons for nonresponse or loss of therapeutic response in the remaining patients over time are unknown. A better understanding of why patients fail to respond to medical therapy may have a major impact on developing new approaches for the medical treatment of BPH/LUTS. Prostaglandins (PG) act on G-protein-coupled receptors (GPCRs), where PGE 2 and PGF 2 elicit smooth muscle contraction. Therefore, we measured PG levels in the prostate tissue of BPH/LUTS patients to assess the possibility that this signaling pathway might explain the failure of medical therapy in BPH/LUTS patients., Method: Surgical BPH (S-BPH) was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy and underwent surgical intervention to relieve LUTS. Control tissue was termed Incidental BPH (I-BPH). I-BPH was TZ obtained from men undergoing radical prostatectomy for low-volume, low-grade prostatic adenocarcinoma (PCa, Gleason score ≤ 7) confined to the peripheral zone. All TZ tissue was confirmed to be cancer-free. S-BPH patients divided into four subgroups: patients on α-blockers alone, 5ARI alone, combination therapy (α-blockers plus 5ARI), or no medical therapy (none) before surgical resection. I-BPH tissue was subgrouped by prior therapy (either on α-blockers or without prior medical therapy before prostatectomy). We measured prostatic tissue levels of prostaglandins (PGF 2α , PGI 2 , PGE 2 , PGD 2 , and TxA 2 ), quantitative polymerase chain reaction levels of mRNAs encoding enzymes within the PG synthesis pathway, cellular distribution of COX1 (PTGS1) and COX2 (PTGS2), and tested the ability of PGs to contract bladder smooth muscle in an in vitro assay., Results: All PGs were significantly elevated in TZ tissues from S-BPH patients (n = 36) compared to I-BPH patients (n = 15), regardless of the treatment subgroups. In S-BPH versus I-BPH, mRNA for PG synthetic enzymes COX1 and COX2 were significantly elevated. In addition, mRNA for enzymes that convert the precursor PGH 2 to metabolite PGs were variable: PTGIS (which generates PGI 2 ) and PTGDS (PGD 2 ) were significantly elevated; nonsignificant increases were observed for PTGES (PGE 2 ), AKR1C3 (PGF 2α ), and TBxAS1 (TxA 2 ). Within the I-BPH group, men responding to α-blockers for symptoms of BPH but requiring prostatectomy for PCa did not show elevated levels of COX1, COX2, or PGs. By immunohistochemistry, COX1 was predominantly observed in the prostatic stroma while COX2 was present in scattered luminal cells of isolated prostatic glands in S-BPH. PGE 2 and PGF 2α induced contraction of bladder smooth muscle in an in vitro assay. Furthermore, using the smooth muscle assay, we demonstrated that α-blockers that inhibit alpha-adrenergic receptors do not appear to inhibit PG stimulation of GPCRs in bladder muscle. Only patients who required surgery to relieve BPH/LUTS symptoms showed significantly increased tissue levels of PGs and the PG synthetic enzymes., Conclusions: Treatment of BPH/LUTS by inhibition of alpha-adrenergic receptors with pharmaceutical α-blockers or inhibiting androgenesis with 5ARI may fail because of elevated paracrine signaling by prostatic PGs that can cause smooth muscle contraction. In contrast to patients who fail medical therapy for BPH/LUTS, control I-BPH patients do not show the same evidence of elevated PG pathway signaling. Elevation of the PG pathway may explain, in part, why the risk of clinical progression in the MTOPS study was only reduced by 34% with α-blocker treatment., (© 2021 Wiley Periodicals LLC.)

Purpose: Holmium laser enucleation of the prostate has proven to be efficacious and safe for the treatment of benign prostatic hyperplasia. New laser technologies, such as the MOSES™ pulse laser system, improve energy delivery and may improve operative times. We sought to prospectively evaluate holmium laser enucleation of the prostate using MOSES technology in a double-blind randomized controlled trial., Materials and Methods: This is a single-center, prospective, double-blind, randomized controlled trial comparing holmium laser enucleation of the prostate using MOSES technology to holmium laser enucleation of the prostate. Patients were randomized in a 1:1 fashion. The study was powered to evaluate for a difference in operative time. Secondary end points included enucleation, morcellation, and hemostasis times, as well as blood loss, functional outcomes and complications 6 weeks postoperatively., Results: A total of 60 patients were analyzed without difference in preoperative characteristics in either group (holmium laser enucleation of the prostate using MOSES technology: 30/60, 50%, holmium laser enucleation of the prostate: 30/60, 50%). Shorter total operative time was seen in the holmium laser enucleation of the prostate using MOSES technology group compared to the holmium laser enucleation of the prostate group (mean: 101 vs. 126 minutes, p <0.01). This difference remained significant on multiple linear regression. Additionally, the holmium laser enucleation of the prostate using MOSES technology group had shorter enucleation times (mean: 68 vs. 80 minutes, p=0.03), hemostasis time (mean: 18 vs. 29 minutes, p <0.01), and less blood loss (mean: -6.3 vs. -9.0%, p=0.03), measured by a smaller change in hematocrit postoperatively, compared to the traditional holmium laser enucleation of the prostate. There was no difference in functional or safety outcomes at followup., Conclusions: We report the results of a prospective, double-blind, randomized controlled trial comparing holmium laser enucleation of the prostate using MOSES technology to traditional holmium laser enucleation of the prostate. MOSES technology resulted in an improvement in operative time and a reduction in blood loss with comparable functional outcomes and complications compared to traditional holmium laser enucleation of the prostate.

Many interactions between microbes and their hosts are driven or influenced by glycans, whose heterogeneous and difficult to characterize structures have led to an underappreciation of their role in these interactions compared to protein-based interactions. Glycans decorate microbe glycoproteins to enhance attachment and fusion to host cells, provide stability, and evade the host immune system. Yet, the host immune system may also target these glycans as glycoepitopes. In this review, we provide a structural perspective on the role of glycans in host-microbe interactions, focusing primarily on viral glycoproteins and their interactions with host adaptive immunity. In particular, we discuss a class of topological glycoepitopes and their interactions with topological mAbs, using the anti-HIV mAb 2G12 as the archetypical example. We further offer our view that structure-based glycan targeting strategies are ready for application to viruses beyond HIV, and present our perspective on future development in this area., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Miller, Clark, Raman and Sasisekharan.)

Purpose: Postoperative infectious related complications are not uncommon after percutaneous nephrolithotomy. Previously, we noted that 7 days of antibiotics did not decrease sepsis rates compared to just perioperative antibiotics in a low risk percutaneous nephrolithotomy population. This study aimed to compare the same regimens in individuals at moderate to high risk for sepsis undergoing percutaneous nephrolithotomy., Materials and Methods: Patients were prospectively randomized in this multi-institutional study to either 2 days or 7 days of preoperative antibiotics. Enrolled patients had stones requiring percutaneous nephrolithotomy and had either a positive preoperative urine culture or existing indwelling urinary drainage tube. Primary outcome was difference in sepsis rates between the groups. Secondary outcomes included rate of nonseptic bacteriuria, stone-free rate and length of stay., Results: A total of 123 patients at 7 institutions were analyzed. There was no difference in sepsis rates between groups on univariate analysis. Similarly, there were no differences in nonseptic bacteriuria, stone-free rate and length of stay. On multivariate analysis, 2 days of antibiotics increased the risk of sepsis compared to 7 days of antibiotics (OR 3.1, 95% CI 1.1-8.9, p=0.031). Patients receiving antibiotics for 2 days had higher rates of staghorn calculus than the 7-day group (58% vs 32%, p=0.006) but post hoc subanalysis did not demonstrate increased sepsis in the staghorn only group., Conclusions: Giving 7 days of preoperative antibiotics vs 2 days decreases the risk of sepsis in moderate to high risk percutaneous nephrolithotomy patients. Future guidelines should consider infectious risk stratification for percutaneous nephrolithotomy antibiotic recommendations.

Introduction: Nephrolithiasis is a known risk factor for chronic kidney disease (CKD); however, it is unknown how CKD affects urinary parameters related to stone risk. The purpose of this study was to assess the relationship of diminishing glomerular filtration rate (GFR) and kidney stone-related 24-hour urine (24H urine) composition. Materials and Methods: A single-institution retrospective review of patients ( n  = 2057) who underwent 24H urine analysis was performed. The serum creatinine within 1 year of the first 24H urine was used to determine estimated GFR and stratify patients by CKD stage. We performed analysis of variance and multivariable linear regression to assess the relationship of GFR and urinary analytes. Results: Among all patients, there were 184 (8.9%), 1537 (74.7%), 245 (11.9%), 70 (3.4%), 17 (0.8%), and 4 (0.2%) in CKD stage I, II, IIIa, IIIb, IV, and V groups, respectively. On analysis of 24H urine composition, as CKD increased, changes in urinary parameters protective against crystallization included decreased calcium and uric acid (UA) ( P  < 0.001). In addition, parameters favoring crystallization included decreased citrate and magnesium ( P  = 0.002 and P  < 0.001, respectively). The net effect with increasing GFR was decreasing supersaturation of calcium oxalate and phosphate. On linear regression, urinary excretion of calcium, oxalate, citrate, UA, phosphate, and ammonia all decreased with decreasing GFR (all P  < 0.05). Conclusions: Higher CKD stage was associated with changes in urinary analytes that both promoted and inhibited stone formation, with the net effect of decreasing calcium oxalate and phosphate supersaturation. These patients may benefit from medical therapy that targets improving urinary citrate instead of lowering calcium or UA.

Nipah Virus (NiV) has been designated as a priority disease with an urgent need for therapeutic development by World Health Organization. The monoclonal antibody m102.4 binds to the immunodominant NiV receptor-binding glycoprotein (GP), and potently neutralizes NiV, indicating its potential as a therapeutic agent. Although the co-crystal structure of m102.3, an m102.4 derivative, in complex with the GP of the related Hendra Virus (HeV) has been solved, the structural interaction between m102.4 and NiV is uncharacterized. Herein, we used structure-guided alanine-scanning mutagenesis to map the functional epitope and paratope residues that govern the antigen-antibody interaction. Our results revealed that the binding of m102.4 is mediated predominantly by two residues in the HCDR3 region, which is unusually small for an antibody-antigen interaction. We performed computational docking to generate a structural model of m102.4-NiV interaction. Our model indicates that m102.4 targets the common hydrophobic central cavity and a hydrophilic rim on the GP, as observed for the m102.3-HeV co-crystal, albeit with Fv orientation differences. In summary, our study provides insight into the m102.4-NiV interaction, demonstrating that structure-guided alanine-scanning and computational modeling can serve as the starting point for additional antibody reengineering (e.g. affinity maturation) to generate potential therapeutic candidates.

Purpose: Splenic injury is a rare complication after left-sided percutaneous nephrolithotomy (PCNL). Although initial observation is often espoused, the natural history of nonoperative conservative management is not well established and the implications of splenic injury are not fully defined in this context. We sought to describe outcomes of conservative management of splenic injury incurred at PCNL. Patients and Methods: We performed a multi-institutional retrospective review of individual patients who underwent PCNL complicated by trans-splenic nephrostomy access injury. Demographic info, intraoperative data, management strategies, and outcomes were reviewed. Results: Nine patients suffered splenic injury after left PCNL. All patients had supracostal upper pole access under fluoroscopic guidance. Splenic injury was identified by computed tomography (CT) in the eight of nine (89%) who had imaging on first postoperative day. All eight patients were managed conservatively with nephrostomy dwell time of 2-21 days, one of whom (11%) required blood transfusion. The remaining patient (11%)-who had tubeless PCNL without postoperative imaging presented 5 days postoperatively with a delayed bleed and underwent emergent splenectomy. Seven of the nine (78%) were managed nonoperatively and without need for transfusion or embolization. Conclusion: The majority of patients incurring splenic injury during PCNL can be managed conservatively with maintenance of nephrostomy tube for ≥2 days. Consequences of unrecognized splenic injury may include splenic bleed and may prompt transfusion and/or splenectomy, underscoring role of routine postoperative CT to allow timely diagnosis, particularly in those undergoing upper pole supracostal left-sided percutaneous renal access.

Background: Male lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often uses LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a proinflammatory and profibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to proinflammatory stimuli and identified downstream targets of OPN in prostate stromal cells., Methods: Immunohistochemistry was performed on prostate sections obtained from the transition zone of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS (surgical BPH, S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging System and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot analysis. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by enzyme-linked immunosorbent assay. Quantitative polymerase chain reaction was used to measure gene expression changes in these cells in response to OPN., Results: OPN immunostaining and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with the highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2, and IL6 in BHPrS-1, but not in epithelial cell lines., Conclusions: OPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by proinflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of proinflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways., (© 2020 Wiley Periodicals, Inc.)

Purpose: A large part of the national opioid epidemic has been tied to prescription opioids, leading to a push to reduce or eliminate their use when feasible. The objective of this study was to evaluate outcomes of implementing an Enhanced Recovery After Surgery (ERAS) protocol for patients undergoing ureteroscopic stone treatment with stent placement geared toward minimizing opioid use. Materials and Methods: We performed a pre-post study concerning a process improvement project of consecutive patients undergoing ureteroscopic stone treatment with stent placement utilizing a novel ERAS protocol. A lead-in period with patients managed conventionally with opioids was performed before implementation of the ERAS protocol. Data regarding opioid utilization, postoperative outcomes, and patient-reported outcomes, including Patient-Reported Outcomes Measurement Information System (PROMIS), were compared between groups. Results: There were 28 pre-ERAS patients and 52 ERAS-managed patients. Patients discharged with an opioid prescription decreased from 93% to 0% ( p  < 0.05). Mean total morphine milligram equivalent decreased from 60.1 ± 41 to 7.7 ± 26 ( p  < 0.05). There was no significant difference noted for postoperative calls for pain in the pre-ERAS vs ERAS groups (25% vs 19%, p  = 0.9) or in unscheduled provider encounters (0% vs 4%, p  = 0.46). There were no clinically significant differences between groups on patient-reported measures. Conclusions: Implementation of an ERAS protocol for ureteroscopic stone treatment resulted in a significant reduction in perioperative opioids, a total reduction in discharge opioid prescriptions, and ∼90% reduction in total 30-day postoperative opioid prescribing with no adverse effects on recovery or increase in postoperative clinical encounters.

Purpose: Nerve transfers for peripheral nerve injuries can result in variable outcomes. We investigated the neuroprotective effect of epineurial lidocaine injection in the donor nerve prior to transection, with the hypothesis that proximal axon loss would be decreased with consequent increased neuroregeneration and functional recovery., Methods: A rat sciatic nerve model was used with 4 intervention groups: (1) lidocaine; (2) lidocaine/calcium gluconate (CG); (3) CG; or (4) saline (control). Behavioral testing and qualitative and quantitative histological evaluation was performed at 8 and 12 weeks. Histological assays included transmission electron microscopy, retrograde fluorogold labeling, and whole mount immunostaining., Results: Functional assessments through the sciatic functional index and Basso, Beattie, and Bresnahan scale showed a statistically significant increase in recovery at 8 and 12 weeks with lidocaine treatment. Significantly higher axonal counts were obtained in the lidocaine-treated groups. Fragmentation and increased myelin damage was present in the CG and saline groups. Retrograde fluorogold labeling showed a statistically significant increase in the number of L4-6 dorsal root ganglion neurons in the lidocaine-treated groups. Whole mount immunostaining identified extension of the axonal growth cone past the nerve coaptation site in lidocaine-treated groups, but not in CG and saline groups., Conclusions: Our results suggest that epineurial lidocaine injection prior to donor nerve transection for nerve transfer has a neuroprotective effect, resulting in increased proximal axon counts and improved functional recovery., Clinical Relevance: These findings may have direct clinical application because epineurial lidocaine can be used in surgery as a simple and inexpensive intervention for promoting improved clinical outcomes after nerve transfer., (Copyright © 2019 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Failure to precisely distinguish malignant from healthy tissue has severe implications for breast cancer surgical outcomes. Clinical prognoses depend on precisely distinguishing healthy from malignant tissue during surgery. Laser Raman spectroscopy (LRS) has been previously shown to differentiate benign from malignant tissue in real time. However, the cost, assembly effort, and technical expertise needed for construction and implementation of the technique have prohibited widespread adoption. Recently, Raman spectrometers have been developed for non-medical uses and have become commercially available and affordable. Here we demonstrate that this current generation of Raman spectrometers can readily identify cancer in breast surgical specimens. We evaluated two commercially available, portable, near-infrared Raman systems operating at excitation wavelengths of either 785 nm or 1064 nm, collecting a total of 164 Raman spectra from cancerous, benign, and transitional regions of resected breast tissue from six patients undergoing mastectomy. The spectra were classified using standard multivariate statistical techniques. We identified a minimal set of spectral bands sufficient to reliably distinguish between healthy and malignant tissue using either the 1064 nm or 785 nm system. Our results indicate that current generation Raman spectrometers can be used as a rapid diagnostic technique distinguishing benign from malignant tissue during surgery.