Fatigue Analysis of a Jacket-Supported Offshore Wind Turbine at Block Island Wind Farm.

Offshore wind-turbine (OWT) support structures are subjected to cyclic dynamic loads with variations in loadings from wind and waves as well as the rotation of blades throughout their lifetime. The magnitude and extent of the cyclic loading can create a fatigue limit state controlling the design of support structures. In this paper, the remaining fatigue life of the support structure for a GE Haliade 6 MW fixed-bottom jacket offshore wind turbine within the Block Island Wind Farm (BIWF) is assessed. The fatigue damage to the tower and the jacket support structure using stress time histories at instrumented and non-instrumented locations are processed. Two validated finite-element models are utilized for assessing the stress cycles. The modal expansion method and a simplified approach using static calculations of the responses are employed to estimate the stress at the non-instrumented locations-known as virtual sensors. It is found that the hotspots at the base of the tower have longer service lives than the jacket. The fatigue damage to the jacket leg joints is less than 20% and 40% of its fatigue capacity during the 25-year design lifetime of the BIWF OWT, using the modal expansion method and the simplified static approach, respectively.

In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury.

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ injury including testicular inflammation, reduced testosterone, and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells, however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury could be initiated by direct virus infection or exposure to systemic inflammatory mediators or viral antigens. We characterized SARS-CoV-2 infection in different human testicular 2D and 3D culture systems including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not productively infect any testicular cell type. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma decreased cell viability and resulted in the death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 Envelope protein caused inflammatory response and cytopathic effects dependent on TLR2, while Spike 1 or Nucleocapsid proteins did not. A similar trend was observed in the K18-hACE2 transgenic mice which demonstrated a disrupted tissue architecture with no evidence of virus replication in the testis that correlated with peak lung inflammation. Virus antigens including Spike 1 and Envelope proteins were also detected in the serum during the acute stage of the disease. Collectively, these data strongly suggest that testicular injury associated with SARS-CoV-2 infection is likely an indirect effect of exposure to systemic inflammation and/or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.

Examining potential mechanisms of testicular fibrosis in Klinefelter Syndrome: A review of current understanding.

BACKGROUND: Men with Klinefelter Syndrome develop some degree of seminiferous tubule degeneration, hyalinization, and fibrosis by adulthood. However, the pathophysiology surrounding testicular fibrosis in Klinefelter Syndrome patients remains incompletely understood. OBJECTIVES: To perform a systematic review of literature studying the mechanisms of fibrosis initiation or propagation in Klinefelter Syndrome testes. MATERIALS/METHODS: PubMed was searched systematically for articles specific to Klinefelter Syndrome and the process of fibrosis. Articles that did not contain original data or specifically addressed the target material were excluded. Additional references were extracted when pertinent from the reference lists of included studies. RESULTS: Primary search yielded 139 articles for abstract review, which was narrowed to 16 for full-text review. Following full-text review, eight contained original data and met topic criteria, with one paper added from reference review for a total of nine papers. DISCUSSION: The date range for included papers was 1992-2022. The proposed mechanisms of fibrosis mainly were centered around the impact of altered Sertoli cells on germ cells, the hormonal impact on Leydig cells, the inflammation mediated by mast cells, or the fibrous extracellular matrix deposition by peritubular myoid cells. Additionally, discussions of the role of the altered microvasculature and the specific proteins involved in the blood-testis barrier or the seminiferous tubule architecture are reviewed. Recent papers have incorporated advanced sequencing and offer future directions for targeted gene expression analysis. Still, much of the published data consists solely of immunohistological assessment by age range, creating difficulties in extrapolating causality. CONCLUSION: The specific initiating factors of fibrosis of the seminiferous tubules and the propagation mechanisms unique to Klinefelter Syndrome remain incompletely understood with a relative paucity of data. Nonetheless, academic interest is increasing in this field as it may further elucidate the pathophysiology behind Klinefelter syndrome.

Morphometric and immunohistochemical analysis as a method to identify undifferentiated spermatogonial cells in adult subjects with Klinefelter syndrome: a cohort study.

OBJECTIVE: To study the prevalence of spermatogonia in adult subjects with Klinefelter syndrome (KS) using MAGE-A4 and UCHL1 (PGP9.5) immunohistochemistry as markers for undifferentiated spermatogonial cells. We aimed to compare this method to the gold standard of hematoxylin and eosin (H & E) staining with histologic analysis in the largest reported cohort of adult subjects with KS. DESIGN: A retrospective cohort study. SETTING: Infertility Clinic and Institute for Regenerative Medicine. PATIENT(S): This study consisted of 79 adult subjects with KS and 12 adult control subjects. INTERVENTION(S): The subjects with KS (n = 79) underwent bilateral testicular biopsy in an initial effort to recover spermatozoa for in vitro fertilization and intracytoplasmic sperm injection. The institutional review board approved the use of a portion of the archived diagnostic pathology paraffin blocks for the study. The samples were superimposed onto microscopic slides and labeled with the PGP9.5 and MAGE-A4 antibodies. Subjects (n = 12) who had previously consented to be organ donors via the National Disease Research Interchange were selected as controls. Dedicated genitourinary pathologists examined the H & E-, PGP9.5-, and MAGE-A4-stained tissue for presence of undifferentiated spermatogonia and spermatozoa with the use of a virtual microscopy software. MAIN OUTCOME MEASURE(S): The primary outcome was the presence of MAGE-A4-positive or UCHL1-positive tubules that indicate undifferentiated spermatogonia. Supportive outcomes include assessing the biopsy specimen for the following: total surface area; total seminiferous tubule surface area; total interstitium surface area; the total number of seminiferous tubules; and MAGE-A4- negative or UCHL1-negative tubules. Additionally, clinical information, such as age, karyotype, height, weight, mean testicle size, and hormonal panel (luteinizing hormone, follicle-stimulating hormone, and testosterone), was obtained and used in a single and multivariable analysis with linear regression to determine predictive factors for the number of UCHL1-positive tubules. RESULT(S): The mean age of the subjects in the KS group was 32.9 ± 0.7 years (range, 16-48). UCHL1 (PGP9.5) and MAGE-A4 staining showed that 74.7% (n = 59) and 40.5% (n = 32) of the subjects with KS, respectively, were positive for undifferentiated spermatogonia compared with 100% (n = 12) of the control subjects who were positive for both the markers. Hematoxylin and eosin with microscopic analysis showed that only 10.1% (n = 8) of the subjects were positive for spermatogonia. The mean number of positive tubules per subject with KS was 11.8 ± 1.8 for UCHL1 and 3.7 ± 1.0 for MAGE-A4. Secondary analysis showed 7 (8.9%) adult subjects with KS as positive for spermatozoa on biopsy. The population having negative testicular sperm extraction results (n = 72) showed a spermatogonia-positive rate of 1.4%, (n = 1), 72.2% (n = 52), and 34.7% (n = 25) using H & E, UCHL1, and MAGE-A4, respectively. Further analysis showed that 54 (75.0%) subjects were either positive for UCHL1 or MAGE-A4. Twenty (27.8%) subjects were positive for both UCHL1 and MAGE-A4. Multivariate analysis with linear regression showed no significant correlation between clinical variables and the number of UCHL1-positive tubules found on biopsy specimens. CONCLUSION(S): We report a cohort of adult subjects with KS undergoing analysis for the presence of undifferentiated spermatogonia. UCHL1 and MAGE-A4 immunostaining appear to be an effective way of identifying undifferentiated spermatogonia in testicular biopsy specimens of subjects with KS. Despite observing deterioration in the testicular architecture, many patients remain positive for undifferentiated spermatogonia, which could be harvested and potentially used for infertility therapy in a patient with KS who is azoospermic and has negative testicular sperm extraction results.

In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury.

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ failure including testicular injury and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury can likely result either from direct virus infection of resident cells or by exposure to systemic inflammatory mediators or virus antigens. We here characterized SARS-CoV-2 infection in different human testicular 2D and 3D models including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not establish a productive infection in any testicular cell types. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma depicted a significant decrease in cell viability and death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 envelope protein, but not Spike or nucleocapsid proteins led to cytopathic effects on testicular cells that was dependent on the TLR2 receptor. A similar trend was observed in the K18h-ACE2 mouse model which revealed gross pathology in the absence of virus replication in the testis. Collectively, data strongly indicates that the testicular injury is not due to direct infection of SARS-CoV-2 but more likely an indirect effect of exposure to systemic inflammation or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.

Impact of Metastasectomy on Cancer Specific and Overall Survival in Metastatic Renal Cell Carcinoma: Analysis of the REMARCC Registry.

BACKGROUND: Treatment paradigms for management of metastatic renal cell carcinoma (mRCC) are evolving. We examined impact of surgical metastasectomy on survival across in mRCC stratified by risk-group. METHODS: Multicenter retrospective analysis from the Registry of Metastatic RCC database. The cohort was subdivided utilizing Motzer criteria (favorable-, intermediate-, high-risk). Primary outcome was all-cause mortality (ACM)/overall survival (OS); secondary outcome was cancer-specific mortality (CSM)/cancer-specific survival (CSS). Impact of metastasectomy was analyzed via Cox-Regression analysis adjusting for potential prognostic variables and Kaplan-Meier analysis (KMA) within each risk-group. RESULTS: Four hundred thirty-one patients (59 favorable-risk, 274 intermediate-risk, 98 high-risk; median follow-up 27.2 months) were analyzed. Metastasectomy was performed in 22 (37%), 66 (24%), and 32 (16%) of favorable-, intermediate- and high-risk groups (P = .012). Median number of metastases at diagnosis differed significantly (favorable-risk 2, intermediate-risk 3.4, high-risk 5.1, P < .001). On Cox-regression, high-risk (HR = 1.72, P = .002) was associated with worsened ACM, while metastasectomy was associated with improved ACM (HR = 0.56, P = .005). On KMA, median OS (months) was longer with metastasectomy in favorable- (92.7 vs. 25.8, P = .003) and intermediate-risk (26.3 vs. 20.1, P = .038), but not high-risk (P = .911) groups. Metastasectomy was associated with longer CSS in favorable- (76.1 vs. 32.8, P = .004) but not intermediate- (P = .06) and high-risk (P = .595) groups. CONCLUSIONS: Metastasectomy was independently associated with improved ACM and CSM, as well as improved CSS and OS in favorable- and intermediate-risk mRCC patients. Metastasectomy may be considered as component of multimodal management strategy in favorable and intermediate-risk subgroups. In high-risk patients, metastasectomy should be deferred except in select circumstances.

Disparities in Cancer Specific and Overall Survival Outcomes in African Americans With Renal Cell Carcinoma: Analysis From the International Marker Consortium for Renal Cancer (INMARC).

OBJECTIVE: To investigate association of African-American race and survival in Renal Cell Carcinoma (RCC). PATIENTS AND METHODS: We queried the International Marker Consortium for Renal Cancer database for patients who underwent partial or radical (RN) nephrectomy. The cohort was divided into African American (AA) and non-African American (NAA) patients. Primary outcome was all-cause mortality. Secondary outcome was cancer-specific mortality. Multivariable Analysis and Kaplan-Meier Analysis were used to elucidate predictive factors and survival outcomes. RESULTS: Three thousand eight hundred and ninety-three patients were analyzed (AA, n = 564/NAA, n = 3329). AA had greater Stage I (73.8% vs 63.9%, P <.001) and papillary RCC (29.8% vs 8.5%, P <.001). Multivariable Analysis revealed increasing age (HR = 1.03, P <.001), AA (HR = 1.24, P = .027), higher stage (HR = 1.30-3.19, P <.001), RN (HR = 2.45, P <.001), clear cell (HR = 1.23, P <.001), positive margin (HR = 1.34, P .004), and high-grade (HR = 1.58, P <.001) to be associated with worsened all-cause mortality. Increasing age (HR = 1.02, P <.001), AA (HR = 1.48, P = .025), RN (HR = 2.98, P <.001), high-grade (HR = 3.11, P <.001), and higher stage (HR = 3.03-13.2, P <.001) were predictive for cancer-specific mortality. Kaplan-Meier Analysis revealed worsened 5-year overall survival for AA in stage I (80% vs 88%, P = .001), stage III (26% vs 70%, P = .001), and stage IV (23% vs 44%, P = .009). Five-year cancer-specific survival was worse for AA in stage III (36% vs 81%, P <.001) and stage IV (30% vs 49%, P = .007). CONCLUSION: Despite presenting with more indolent histology and lower stage, African-Americans were at greater risk for diminished survival, faring worse in overall survival for all stages and cancer-specific survival in for stage III/IV RCC. Further investigation into factors associated with these disparities is warranted.

Extensive Anti-CoA Immunostaining in Alzheimer's Disease and Covalent Modification of Tau by a Key Cellular Metabolite Coenzyme A.

Alzheimer's disease (AD) is a neurodegenerative disorder, accounting for at least two-thirds of dementia cases. A combination of genetic, epigenetic and environmental triggers is widely accepted to be responsible for the onset and development of AD. Accumulating evidence shows that oxidative stress and dysregulation of energy metabolism play an important role in AD pathogenesis, leading to neuronal dysfunction and death. Redox-induced protein modifications have been reported in the brain of AD patients, indicating excessive oxidative damage. Coenzyme A (CoA) is essential for diverse metabolic pathways, regulation of gene expression and biosynthesis of neurotransmitters. Dysregulation of CoA biosynthesis in animal models and inborn mutations in human genes involved in the CoA biosynthetic pathway have been associated with neurodegeneration. Recent studies have uncovered the antioxidant function of CoA, involving covalent protein modification by this cofactor (CoAlation) in cellular response to oxidative or metabolic stress. Protein CoAlation has been shown to both modulate the activity of modified proteins and protect cysteine residues from irreversible overoxidation. In this study, immunohistochemistry analysis with highly specific anti-CoA monoclonal antibody was used to reveal protein CoAlation across numerous neurodegenerative diseases, which appeared particularly frequent in AD. Furthermore, protein CoAlation consistently co-localized with tau-positive neurofibrillary tangles, underpinning one of the key pathological hallmarks of AD. Double immunihistochemical staining with tau and CoA antibodies in AD brain tissue revealed co-localization of the two immunoreactive signals. Further, recombinant 2N3R and 2N4R tau isoforms were found to be CoAlated in vitro and the site of CoAlation mapped by mass spectrometry to conserved cysteine 322, located in the microtubule binding region. We also report the reversible H2O2-induced dimerization of recombinant 2N3R, which is inhibited by CoAlation. Moreover, CoAlation of transiently expressed 2N4R tau was observed in diamide-treated HEK293/Pank1ß cells. Taken together, this study demonstrates for the first time extensive anti-CoA immunoreactivity in AD brain samples, which occurs in structures resembling neurofibrillary tangles and neuropil threads. Covalent modification of recombinant tau at cysteine 322 suggests that CoAlation may play an important role in protecting redox-sensitive tau cysteine from irreversible overoxidation and may modulate its acetyltransferase activity and functional interactions.

The PINK1-Parkin mitophagy signalling pathway is not functional in peripheral blood mononuclear cells.

Mutations in the PINK1 and PRKN genes are the most common cause of early-onset familial Parkinson disease. These genes code for the PINK1 and Parkin proteins, respectively, which are involved in the degradation of dysfunctional mitochondria through mitophagy. An early step in PINK1 -Parkin mediated mitophagy is the ubiquitination of the mitofusin proteins MFN1 and -2. The ubiquitination of MFN1 and -2 in patient samples may therefore serve as a biomarker to determine the functional effects of PINK1 and PRKN mutations, and to screen idiopathic patients for potential mitophagy defects. We aimed to characterise the expression of the PINK1 -Parkin mitophagy machinery in peripheral blood mononuclear cells (PBMCs) and assess if these cells could serve as a platform to evaluate mitophagy via analysis of MFN1 and -2 ubiquitination. Mitophagy was induced through mitochondrial depolarisation by treatment with the protonophore CCCP and ubiquitinated MFN proteins were analysed by western blotting. In addition, PINK1 and PRKN mRNA and protein expression levels were characterised with reverse transcriptase quantitative PCR and western blotting, respectively. Whilst CCCP treatment led to MFN ubiquitination in primary fibroblasts, SH-SY5Y neuroblastoma cells and Jurkat leukaemic cells, treatment of PBMCs did not induce ubiquitination of MFN. PRKN mRNA and protein was readily detectable in PBMCs at comparable levels to those observed in Jurkat and fibroblast cells. In contrast, PINK1 protein was undetectable and PINK1 mRNA levels were remarkably low in control PBMCs. Our findings suggest that the PINK1 -Parkin mitophagy signalling pathway is not functional in PBMCs. Therefore, PBMCs are not a suitable biosample for analysis of mitophagy function in Parkinson disease patients.

A functional genomics screen identifying blood cell development genes in Drosophila by undergraduates participating in a course-based research experience.

Undergraduate students participating in the UCLA Undergraduate Research Consortium for Functional Genomics (URCFG) have conducted a two-phased screen using RNA interference (RNAi) in combination with fluorescent reporter proteins to identify genes important for hematopoiesis in Drosophila. This screen disrupted the function of approximately 3500 genes and identified 137 candidate genes for which loss of function leads to observable changes in the hematopoietic development. Targeting RNAi to maturing, progenitor, and regulatory cell types identified key subsets that either limit or promote blood cell maturation. Bioinformatic analysis reveals gene enrichment in several previously uncharacterized areas, including RNA processing and export and vesicular trafficking. Lastly, the participation of students in this course-based undergraduate research experience (CURE) correlated with increased learning gains across several areas, as well as increased STEM retention, indicating that authentic, student-driven research in the form of a CURE represents an impactful and enriching pedagogical approach.

Development of a Novel Risk Score to Select the Optimal Candidate for Cytoreductive Nephrectomy Among Patients with Metastatic Renal Cell Carcinoma. Results from a Multi-institutional Registry (REMARCC).

BACKGROUND: Selection of patients for upfront cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) has to be improved. OBJECTIVE: To evaluate a new scoring system for the prediction of overall mortality (OM) in mRCC patients undergoing CN. DESIGN, SETTING, AND PARTICIPANTS: We identified a total of 519 patients with synchronous mRCC undergoing CN between 2005 and 2019 from a multi-institutional registry (Registry for Metastatic RCC [REMARCC]). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazard regression was used to test the main predictors of OM. Restricted mean survival time was estimated as a measure of the average overall survival time up to 36 mo of follow-up. The concordance index (C-index) was used to determine the model's discrimination. Decision curve analyses were used to compare the net benefit from the REMARCC model with International mRCC Database Consortium (IMDC) or Memorial Sloan Kettering Cancer Center (MSKCC) risk scores. RESULTS AND LIMITATIONS: The median follow-up period was 18 mo (interquartile range: 5.9-39.7). Our models showed lower mortality rates in obese patients (p = 0.007). Higher OM rates were recorded in those with bone (p = 0.010), liver (p = 0.002), and lung metastases (p < 0.001). Those with poor performance status (<80%) and those with more than three metastases had also higher OM rates (p = 0.026 and 0.040, respectively). The C-index of the REMARCC model was higher than that of the MSKCC and IMDC models (66.4% vs 60.4% vs 60.3%). After stratification, 113 (22.0%) patients were classified to have a favorable (no risk factors), 202 (39.5%) an intermediate (one or two risk factors), and 197 (38.5%) a poor (more than two risk factors) prognosis. Moreover, 72 (17.2%) and 51 (13.9%) patients classified as having an intermediate and a poor prognosis according to MSKCC and IMDC categories, respectively, would be reclassified as having a good prognosis according to the REMARCC score. CONCLUSIONS: Our findings confirm the relevance of tumor and patient features for the risk stratification of mRCC patients and clinical decision-making regarding CN. Further prospective external validations are required for the scoring system proposed herein. PATIENT SUMMARY: Current stratification systems for selecting patients for kidney removal when metastatic disease is shown are controversial. We suggest a system that includes tumor and patient features besides the systems already in use, which are based on blood tests.

Elevated preoperative C-reactive protein is associated with renal functional decline and non-cancer mortality in surgically treated renal cell carcinoma: analysis from the INternational Marker Consortium for Renal Cancer (INMARC).

OBJECTIVE: To investigate association of preoperative C-reactive protein (CRP) and non-cancer mortality (NCM) in a cohort of patients undergoing surgery for localised renal cell carcinoma (RCC). PATIENTS AND METHODS: Retrospective multicentre analysis of patients surgically treated for clinical Stage 1-2 RCC from 2006 to 2017, excluding all cases of cancer-specific mortality. Descriptive analyses were obtained between the pre-treatment normal-CRP (≤5 mg/L) and elevated-CRP (>5 mg/L) groups. The primary outcome was NCM. The secondary outcomes included progression to de novo chronic kidney disease Stages 3-4 (estimated glomerular filtration rate [eGFR] of <60, <45, and <30 mL/min/1.73 m2 ). Multivariable analyses (MVA) were performed to assess for risk factors associated with functional decline and NCM, and Kaplan-Meier analysis was used to obtain survival estimates for outcomes. RESULTS: A total of 1987 patients who underwent radical or partial nephrectomy were analysed (normal-CRP group, n = 963; elevated-CRP group, n = 1024). Groups were similar in age (59 vs 60 years, P = 0.079). An elevated CRP was more frequent in males (36.8% vs 27.8%, P < 0.001), African-Americans (22.6% vs 2.9%, P < 0.001), and in those with a higher median body mass index (30 vs 25 kg/m2 , P < 0.001) and larger median tumour size (4.5 vs 3.3 cm, P < 0.001). On MVA, an elevated CRP was independently associated with development of de novo eGFR of <60 mL/min/1.73 m2 (hazard ratio [HR] 1.32, P = 0.015), <45 mL/min/1.73 m2 (HR 1.41, P = 0.023) and <30 mL/min/1.73 m2 (odds ratio 2.23, P < 0.001). The MVA for factors associated with NCM demonstrated increasing age (HR 1.06, P < 0.001), preoperative elevated CRP (HR 2.18, P < 0.001) and an eGFR of <45 mL/min/1.73 m2 (HR 1.16; P = 0.021) as independent risk factors. Kaplan-Meier analysis revealed significantly higher 5-year NCM in the elevated-CRP group vs the normal-CRP group (98% vs 80%, P < 0.001). CONCLUSIONS: Pre-treatment elevated CRP was independently associated with both progressive renal functional decline and NCM in patients undergoing surgery for Stage 1-2 RCC. Patients with elevated CRP and Stage 1 and 2 RCC may be considered as having indication for nephron-sparing strategies, which may be prioritised if oncologically appropriate.

Comparison of renal functional outcomes of active surveillance and partial nephrectomy in the management of oncocytoma.

PURPOSE: To compare functional outcomes of partial nephrectomy (PN) and active surveillance (AS) in oncocytoma. METHODS: Multicenter retrospective analysis of patients with oncocytoma managed with PN or AS (biopsy-confirmed). Primary outcome development of de novo chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73m2). Cox regression Multivariable analysis (MVA) was carried out for predictors of de novo CKD. Linear regression was carried out for factors associated with increasing deltaGFR. Kaplan-Meier Analysis (KMA) was performed to analyze 5-year CKD-free survival. RESULTS: 295 patients were analyzed (224 PN/71 AS, median follow-up 37.4 months). No differences were noted for clinical tumor size (AS 2.6 vs. PN 2.9 cm, p = 0.108), and baseline eGFR (AS 79.6 vs. PN 77, p = 0.9670). Median change in tumor diameter for AS was 0.42 cm. Compared to PN, AS had deltaGFR (-15.3 vs. -6.4 mL/min/1.73m2, p < 0.001) and de novo CKD (28.2% vs. 12.1%, p = 0.002). AS patients who developed CKD had higher RENAL score (p = 0.005) and lower baseline eGFR (73 vs. 91.2 mL/min/1.73m2, p < 0.001) than AS patients who did not. MVA demonstrated increasing age (OR = 1.03, p = 0.025), tumor size (HR = 1.26, p = 0.032) and AS (HR = 4.91, p < 0.001) to be predictive for de novo CKD. Linear regression demonstrated AS was associated with larger decrease in deltaGFR (B = -0.219, p < 0.001). KMA revealed 5-year CKD survival was higher in PN (87%) vs. AS (62%, p < 0.001). CONCLUSION: AS was associated with greater functional decline than PN in oncocytoma. PN may be considered to optimalize renal functional preservation in select circumstances. Further investigation into mechanisms of functional decline in oncocytoma is requisite.

Impact of positive surgical margins on survival after partial nephrectomy in localized kidney cancer: analysis of the National Cancer Database.

BACKGROUND: The impact of positive surgical margins (PSM) on outcomes in partial nephrectomy (PN) is controversial. We investigated impact of PSM for patients undergoing PN on overall survival (OS) in different stages of renal cell carcinoma (RCC). METHODS: Retrospective analysis of patients from the US National Cancer Database who underwent PN for cT1a-cT2b N0M0 RCC between 2004-13. Patients were stratified by pathological stage (pT1a, pT1b, pT2a, pT2b, and pT3a [upstaged]) and analyzed by margin status. Cox Regression multivariable analysis (MVA) was performed to investigate associations of PSM and covariates on all-cause mortality (ACM). Kaplan-Meier analysis (KMA) of OS was performed for PSM versus negative margin (NSM) by pathological stage. Sub-analysis of Charlson Comorbidity Index 0 (CCI=0) subgroup was conducted to reduce bias from comorbidities. RESULTS: We analyzed 42,113 PN (pT1a: 33,341 [79.2%]; pT1a, pT1b: 6689 [15.9%]; pT2a: 757 [1.8%]; pT2b: 165 [0.4%]; and pT3a: upstaged 1161 [2.8%]). PSM occurred in 6.7% (2823) (pT1a: 6.5%, pT1b: 6.3%, pT2a: 5.9%, pT2b: 6.1%, pT3a: 14.1%, P<0.001). On MVA, PSM was associated with 31% increase in ACM (HR 1.31, P<0.001), which persisted in CCI=0 sub-analysis (HR: 1.25, P<0.001). KMA revealed negative impact of PSM vs. NSM on 5-year OS: pT1 (87.3% vs. 90.9%, P<0.001), pT2 (86.7% vs. 82.5%, P=0.48), and upstaged pT3a (69% vs. 84.2%, P<0.001). CONCLUSIONS: PSM after PN was independently associated with across-the-board decrement in OS, which worsened in pT3a disease and persisted in sub-analysis of patients with CCI=0. PSM should prompt more aggressive surveillance or definitive resection strategies.

Infertility considerations in klinefelter syndrome: From origin to management.

Klinefelter syndrome (KS) is defined as the presence of one or more extra "X" chromosome in a male patient. It affects approximately 1 in 600 newborn males and the most common chromosomal abnormality, leading to male hypogonadism and infertility. There is a lack of data supporting best practices for KS patients' care. In this paper we review controversial issues in KS research ranging from mechanisms of variation in KS phenotype to abnormalities resulting in reduced sperm production to successful sperm retrieval disparities after testicular sperm extraction (TESE). Translation to live birth and offspring health is also examined. Finally, medical therapies used to optimize the hormonal status and chances of fertility in KS patients are reviewed. We will also discuss the experimental spermatogonial stem cell (SSC) treatments, which are considered the future for TESE negative patients.

Nephrostomy tubes placed emergently prior to percutaneous renal stone surgery are practical for obtaining access. / La colocación de nefrostomía percutánea antes de la cirugía percutánea de la litiasis facilita la obtención del acceso.

OBJECTIVES: Renal access in percutaneous nephrolithotomy (PCNL) may be obtained via a pre-existing nephrostomy tube (NT) tract; however, emergent NTs are not always ideal for subsequent surgery. We sought to determine the rate of NT tract usability and assess factors related to the usability of emergently placed NTs. METHODS: A retrospective review was performed of UC San Diego subjects undergoing percutaneous renal surgery between January 2016 and October 2018. Demographics and peri-operative variables were collected. The primary outcome was the usability of NT tract for dilation and instrumentation. "Usable" indicated a tract in which PCNL could be completed; "unusable" indicated lack of dilation and the requirement of additional tract(s) for PCNL. RESULTS: 35 PCNL cases had previous emergently placed NT which were indwelling at time of percutaneous surgery. 51% of these NT tracts (18/35) were deemed usable and dilated for PCNL. No significant difference was seen between usable and unusable NT groups for number of dilated tracts during PCNL (p=0.13), or either the location of indwelling NT (p=0.96) or renal stones (p=0.95). In the usable NT tract cohort PCNL access was via the lower pole 56% of the time, where as when previous NT tracts were deemed unusable, a separate upper-pole access was obtained intra-operatively 53% of the time (p<0.01). CONCLUSIONS: Pre-existing, emergent NTs served a ssufficient PCNL access tracts in over half of recorded cases. Contrary to recently published reports, the utility of pre-existing NTs appears to vary among health systems. Other variables, including the desired location of PCNL appear to directly influence the like lihood of NT tract usability.

OBJETIVOS: El acceso renal en la nefrolitotomía percutánea puede obtenerse a través de una nefrostomía pre-existente, aunque las nefrostomías urgentes no siempre son ideales para la posterior cirugía. Nosotros intentamos determinar la tasa de uso del tracto de nefrostomía y los factores de acceso relacionados con el uso de la nefrostomía urgente.MÉTODOS: Una revisión retrospectiva se realizó en UC San Diego de los pacientes que habían recibido cirugía renal percutánea entre enero 2016 y octubre 2018. Las variables demográficas y perioperatorias fueron recolectadas. El objetivo primario fue el uso del trayecto de nefrostomía después de dilatación e instrumentación.¨Usable"  indicó un trayecto en el que la nefrolitotomía percutánea se completo. "No usable" indicó falta de dilatación y el requerimiento de un nuevo trayecto para la cirugía percutánea. RESULTADOS: 35 casos de nefrolitotomía percutánea tenían nefrostomías urgentes previamente y presentes al empezar la cirugía. 51% de estos trayectos (18/35) fueron usados y dilatados para la nefrolitotomía percutánea. No hubo diferencias significativas entre los trayectos usables y no usables en el numero de trayectos dilatados durante la cirugía percutánea (p=0,13), ni en la localización de la sonda de nefrostomía (p=0,96) o las litiasis renales (p=0,95). En el grupo de pacientes con nefrostomía usable, en el 56% la nefrostomía accedía por el polo inferior. Cuando el trayecto de nefrostomía se considero no usable, un nuevo acceso intraoperatorio por el polo superior fue obtenido en el 53% de lo scasos (p<0,01). CONCLUSIONES: El trayecto de nefrostomía pre-existente fue suficiente para el acceso percutáneo en la mitad de los casos. Contrario a lo publicado recientemente, la utilidad de la nefrostomía pre-existente parece variar según el Sistema sanitario. Otras variables, incluyendo la localización deseada para la nefrostomía influencia el uso del trayecto.

Nephrostomy tubes placed emergently prior to percutaneous renal stone surgery are practical for obtaining access / La colocación de nefrostomía percutánea antes de la cirugía percutánea de la litiasis facilita la obtención del acceso

OBJECTIVES: Renal access in percutaneous nephrolithotomy (PCNL) may be obtained via a pre-existing nephrostomy tube (NT) tract; however, emergent NTs are not always ideal for subsequent surgery. We sought to determine the rate of NT tract usability and assess factors related to the usability of emergently placed NTs. METHODS: A retrospective review was performed of UC San Diego subjects undergoing percutaneous renal surgery between January 2016 and October 2018. Demographics and peri-operative variables were collected. The primary outcome was the usability of NT tract for dilation and instrumentation. "Usable" indicated a tract in which PCNL could be completed; "unusable" indicated lack of dilation and the requirement of additional tract(s) for PCNL. RESULTS: 35 PCNL cases had previous emergently placed NT which were indwelling at time of percutaneous surgery. 51% of these NT tracts (18/35) were deemed usable and dilated for PCNL. No significant difference was seen between usable and unusable NT groups for number of dilated tracts during PCNL (p = 0.13), or either the location of indwelling NT (p = 0.96) or renal stones (p = 0.95). In the usable NT tract cohort PCNL access was via the lower pole 56% of the time, whereas when previous NT tracts were deemed unusable, a separate upper-pole access was obtained intra-operatively 53% of the time (p < 0.01). CONCLUSIONS: Pre-existing, emergent NTs served as sufficient PCNL access tracts in over half of recorded cases. Contrary to recently published reports, the utility of pre-existing NTs appears to vary among health systems. Other variables, including the desired location of PCNL appear to directly influence the likelihood of NT tract usability

OBJETIVOS: El acceso renal en la nefrolitotomía percutánea puede obtenerse a través de una nefrostomía pre-existente, aunque las nefrostomías urgentes no siempre son ideales para la posterior cirugía. Nosotros intentamos determinar la tasa de uso del tracto de nefrostomía y los factores de acceso relacionados con el uso de la nefrostomía urgente. MÉTODOS: Una revisión retrospectiva se realizó en UC San Diego de los pacientes que habían recibido cirugía renal percutánea entre enero 2016 y octubre 2018. Las variables demográficas y perioperatorias fueron recolectadas. El objetivo primario fue el uso del trayecto de nefrostomía después de dilatación e instrumentación. ¨Usable" indicó un trayecto en el que la nefrolitotomía percutánea se completó. "No usable" indicó falta de dilatación y el requerimiento de un nuevo trayecto para la cirugía percutánea. RESULTADOS: 35 casos de nefrolitotomía percutánea tenían nefrostomías urgentes previamente y presentes al empezar la cirugía. 51% de estos trayectos (18/35) fueron usados y dilatados para la nefrolitotomía percutánea. No hubo diferencias significativas entre los trayectos usables y no usables en el número de trayectos dilatados durante la cirugía percutánea (p = 0,13), ni en la localización de la sonda de nefrostomía (p = 0,96) o las litiasis renales (p = 0,95). En el grupo de pacientes con nefrostomía usable, en el 56% la nefrostomía accedía por el polo inferior. Cuando el trayecto de nefrostomía se consideró no usable, un nuevo acceso intraoperatorio por el polo superior fue obtenido en el 53% de los casos (p < 0,01). CONCLUSIONES: El trayecto de nefrostomía pre-existente fue suficiente para el acceso percutáneo en la mitad de los casos. Contrario a lo publicado recientemente, la utilidad de la nefrostomía pre-existente parece variar según el Sistema sanitario. Otras variables, incluyendo la localización deseada para la nefrostomía influencia el uso del trayecto