A Multipronged Intervention to Reduce Readmissions and Readmission Intensity After Radical Cystectomy.

OBJECTIVE: To develop a multipronged, evidence-based protocol to reduce readmission risk and readmission intensity, as represented by the duration of the index readmission, after radical cystectomy. MATERIALS AND METHODS: A per-protocol study was performed. The protocol included preoperative nutritional supplementation, early stent removal, and a follow-up phone call within 4-5days of discharge. The preprotocol period was from February 1, 2020 to July 31, 2021 and the postprotocol period was from December 1, 2020 to November 31, 2021. Using multivariate regression models, we compared outcomes among patients treated with radical cystectomy before and after protocol initiation. RESULTS: We identified 70 preprotocol patients and 126 postprotocol patients. After adjusting for age, sex, BMI, and frailty score, there was a significant reduction in 90-day readmission intensity (7 vs 5days; P = .048) among postprotocol patients. CONCLUSION: After implementation of an evidence-based protocol for patients undergoing radical 90-day readmission intensity decreased significantly. This protocol may move the needle forward on reducing readmissions, but a larger randomized trial is needed.

Factors Associated With Restarting Androgenic Anabolic Steroids After Cessation in Men With Infertility: A Retrospective Analysis.

Introduction The use of androgenic anabolic steroids (AAS) negatively affects male fertility by disrupting hormone release and reducing testosterone levels. Despite this, many men using steroids are unaware of fertility-related consequences. We aimed to determine the factors associated with AAS resumption during fertility treatment, specifically focusing on the duration, age, and dosage of AAS use prior to treatment. Our study, the first of its kind, investigated risk factors for resuming AAS following fertility assessment. Methods We conducted a retrospective review of adult men diagnosed with infertility due to chronic AAS use between 2012 and 2022 at the University of Miami. The study included men with azoospermia or severe oligospermia who were instructed to stop using AAS. Excluded were those who underwent orchiectomy for benign or malignant conditions. We collected data on demographic characteristics, AAS route details, fertility treatments, and AAS resumption. We hypothesized that risk factors for restarting AAS would include duration of AAS use, type of AAS, pre-treatment testosterone levels, and increased age. Results We identified 94 men with infertility caused by AAS use. Among them, 31 (33.0%) resumed AAS therapy within eight months after cessation. The median age of men who restarted AAS was 40 years. Those who resumed AAS had used it for a longer duration prior to fertility assessment compared to those who did not (60 months vs. 17 months, respectively). However, we found no statistically significant differences in age, duration of AAS use, AAS administration details, or serum testosterone levels at the time of initial assessment. Conclusion In conclusion, most men seeking fertility assessment due to AAS abuse did not resume testosterone therapy. However, those who did restart AAS had a longer history of AAS use. Future high-quality prospective studies are needed to better understand the risk factors associated with resuming AAS in male infertility caused by anabolic steroids.

Catheter Free Day of Surgery Discharge vs Overnight Observation Following Artificial Urinary Sphincter Placement.

Introduction To confirm the safety and examine outcomes of a day of surgery discharge following artificial urinary sphincter implantation in a population discharged without a catheter. Methods We retrospectively identified 110 patients, 31 of whom were discharged on the day of surgery, from a single surgeon following artificial urinary sphincter implantation. After institutional board review approval, patient charts were reviewed capturing demographics as well as three, thirty, and ninety-day outcomes. Further outcomes specific to urinary retention were obtained. Results Patients who were discharged the same day were older (71 vs. 68), had shorter operative times (92 minutes vs 109 minutes), and were less likely to have been smokers (6% vs 31%). There were no differences in the proportion of patients who underwent prior radiation or prior implant surgery. There was no significant difference in the number of patients who had emergency department visits, urinary retention, office calls, office visits, or unplanned office visits at all time points following surgery. There was no significant difference in overall urinary retention (15% vs 5%), retention presenting after the initial surgical event (6% vs 5%), or need for a suprapubic tube (0% vs 5%). Conclusions Day of surgery discharge is a safe discharge strategy for patients who have undergone artificial urinary sphincter placement. Furthermore, catheter-free days of discharge surgery did not have a significantly greater risk of urinary retention, office calls, emergency department (ED) visits, or office visits compared to our overnight observation population. This approach should be considered for all patients undergoing artificial urinary sphincter (AUS) implantation.

Insurance Type and Area Deprivation Are Associated With Worse Overall Mortality for Patients With Muscle-invasive Bladder Cancer.

OBJECTIVE: To examine the association of area-level socioeconomic status, rural-urban residence, and type of insurance with overall and cancer-specific mortality among patients with muscle-invasive bladder cancer. METHODS: Using the Pennsylvania Cancer Registry, which collects demographic, insurance, and clinical information on every patient with cancer within the state, we identified all patients diagnosed with non-metastatic muscle-invasive bladder cancer between 2010 and 2016 based on clinical and pathologic staging. We used the Area Deprivation Index (ADI) as a surrogate for socioeconomic status and Rural-Urban Commuting Area codes to classify urban, large town, and rural communities. ADI was reported in quartiles, with 4 representing the lowest socioeconomic status. We fit multivariable logistic regression and Cox models to assess the relationship of these social determinants with overall and cancer-specific survival adjusting for age, sex, race, stage, treatment, rural-urban classification, insurance and ADI. RESULTS: We identified 2597 patients with non-metastatic muscle-invasive bladder cancer. On multivariable analysis, Medicare (hazards ratio [HR] 1.15), Medicaid (HR 1.38), ADI 3 (HR 1.16) and ADI 4 (HR 1.21) were independent predictors of greater overall mortality (all P < 0.05). Female sex and receipt of non-standard treatment were associated with increased overall mortality and bladder cancer-specific mortality. There was no significant difference in both overall and cancer-specific survival between patients who were non-Hispanic White compared to non-White or between those from urban areas, large towns, or rural locations. CONCLUSION: Lower socioeconomic status and Medicare and Medicaid insurance were associated with a greater risk of overall mortality while rural residence was not a significant factor. Implementation of public health programs may help reduce the gap in mortality for low SES at-risk populations.

Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA.

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. SIGNIFICANCE: MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517.

Mosaicism in Tumor Suppressor Gene Syndromes: Prevalence, Diagnostic Strategies, and Transmission Risk.

A mosaic state arises when pathogenic variants are acquired in certain cell lineages during postzygotic development, and mosaic individuals may present with a generalized or localized phenotype. Here, we review the current state of knowledge regarding mosaicism for eight common tumor suppressor genes-NF1, NF2, TSC1, TSC2, PTEN, VHL, RB1, and TP53-and their related genetic syndromes/entities. We compare and discuss approaches for comprehensive diagnostic genetic testing, the spectrum of variant allele frequency, and disease severity. We also review affected individuals who have no mutation identified after conventional genetic analysis, as well as genotype-phenotype correlations and transmission risk for each tumor suppressor gene in full heterozygous and mosaic patients. This review provides new insight into similarities as well as marked differences regarding the appreciation of mosaicism in these tumor suppressor syndromes.

The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2.

PURPOSE: Postzygotic (somatic) variants in the mTOR pathway genes cause a spectrum of distinct developmental abnormalities. Accurate classification of somatic variants in this group of disorders is crucial for affected individuals and their families. METHODS: The ClinGen Brain Malformation Variant Curation Expert Panel was formed to curate somatic variants associated with developmental brain malformations. We selected the genes AKT3, MTOR, PIK3CA, and PIK3R2 as the first set of genes to provide additional specifications to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) sequence variant interpretation guidelines, which currently focus solely on germline variants. RESULTS: A total of 24 of the original 28 ACMG/AMP criteria required modification. Several modifications used could be applied to other genes and disorders in which somatic variants play a role: 1) using variant allele fraction differences as evidence that somatic mutagenesis occurred as a proxy for de novo variation, 2) incorporating both somatic and germline evidence, and 3) delineating phenotype on the basis of variable tissue expression. CONCLUSION: We have established a framework for rigorous interpretation of somatic mosaic variants, addressing issues unique to somatic variants that will be applicable to many genes and conditions.

Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels.

PURPOSE: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not. METHODS: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. RESULTS: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants. CONCLUSION: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.

Safety During Ureteroscopy: Radiation, Eyes, and Ergonomics.

It is known that urologic surgeons are at risk of work-place injury due to the physical requirements of operating and exposure to hazards. These hazards include radiation, exposure to body fluids, use of laser energy, and orthopedic injury due to the physical nature of operating. The risks that these hazards present can be mitigated by implementing several evidence-based safety measures. The methods to protect against radiation exposure include keeping radiation usage in the operating room as low as reasonably achievable, donning lead aprons, and wearing protective glasses. Additionally, protective glasses decrease the risk of eye injury from laser injury and exposure to body fluids. Finally, practicing sound surgical ergonomics is essential to minimize the risk of orthopedic injury and promote career longevity. The interventions discussed herein are simple and easy to implement in one's daily practice of urology.

Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Chromosomal microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism array, are widely applied in the diagnostic evaluation for both constitutional and neoplastic disorders. In a constitutional setting, this technology is accepted as the first-tier test for the evaluation of chromosomal imbalances associated with intellectual disability, autism, and/or multiple congenital anomalies. Furthermore, chromosomal microarray analysis is recommended for patients undergoing invasive prenatal diagnosis with one or more major fetal structural abnormalities identified by ultrasonographic examination, and in the evaluation of intrauterine fetal demise or stillbirth when further cytogenetic analysis is desired. This technology also provides important genomic data in the diagnosis, prognosis, and therapy of neoplastic disorders, including both hematologic malignancies and solid tumors. To assist clinical laboratories in the validation of chromosomal microarray methodologies for constitutional and neoplastic applications, the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee has developed these updated technical laboratory standards, which replace the ACMG technical standards and guidelines for microarray analysis in constitutional and neoplastic disorders previously published in 2013.

Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders.

BACKGROUND: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. METHODS: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. RESULTS: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. CONCLUSIONS: Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Clinical Syndromic Phenotypes and the Potential Role of Genetics in Pulmonary Vein Stenosis.

Pulmonary vein stenosis (PVS) is a rare, frequently lethal disease with heterogeneous phenotypes and an unclear etiology. Limited studies have reported associations between PVS and congenital heart disease (CHD), chronic lung disease (CLD), and/or prematurity; however, to date, there have been no studies that report detailed clinical syndromic phenotypes and the potential role of genetics in PVS. An existing registry of multivessel PVS patients seen at Boston Children's Hospital (BCH) was queried between August 2006 and January 2017 for all existing genetic testing data on these patients. PVS was defined as an intraluminal pulmonary venous obstruction in ≥2 vessels with mean pressure gradients > 4 mmHg. One-hundred-and-fifty-seven patients (46% female, with a median age at PVS diagnosis of 3 months) formed the cohort. Seventy-one (45%) patients had available genetic testing information. Of the 71 patients, a likely genetic diagnosis was found in 23 (32%) patients: 13 (57%) were diagnosed with Trisomy 21 (T21), five (22%) with Smith-Lemli-Opitz Syndrome, five (22%) had other pathologic genetic disease, and 24 (33%) had variants of unknown significance. The majority of 13 patients with T21 and PVS had common atrioventricular canal (CAVC) (10, 77%) and all had severe pulmonary hypertension (PHTN), which led to their PVS diagnosis. In our study, PVS was associated with T21, the majority of whom also had CAVC and PHTN. Therefore, complete assessment of the pulmonary veins should be considered for all T21 patients, especially those with CAVC presenting with PHTN. Furthermore, prospective standardized genetic testing with detailed clinical phenotyping may prove informative about potential genetic etiologies of PVS.

Minimizing radiation dose in management of stone disease: how to achieve 'ALARA'.

PURPOSE OF REVIEW: Exposure to radiation is known to have adverse effects such as secondary malignancies. Patients with nephrolithiasis are exposed to radiation in the workup and treatment of their condition. Furthermore, exposure to radiation is often repeated due to the high recurrence rate of nephrolithiasis. RECENT FINDINGS: We discuss practices inside and outside of the operating room to strive to keep radiation exposure as low as reasonably achievable (ALARA) for patients being treated for nephrolithiasis. These efforts include reduced dose computed tomography scans, fluoroless surgical techniques and new alternative technologies. SUMMARY: Maintaining radiation exposure ALARA for our patients is increasingly practical. The urologist must make every effort to adhere to ALARA principles to protect patients from the stochastic effects of radiation.