The mechanism by which newly synthesized sterols are transported from their site of synthesis, the endoplasmic reticulum (ER), to the sterol-enriched plasma membrane (PM) is not fully understood. Studies in mammalian cells suggest that newly synthesized cholesterol is transported to the PM in Golgi-bypassing vesicles and/or via a nonvesicular process. Using the yeast Saccharomyces cerevisiae as a model system, we now rule out an essential role for known vesicular transport pathways in transporting the major yeast sterol, ergosterol, from its site of synthesis to the PM. We use a cyclodextrin-based sterol capture assay to show that transport of newly synthesized ergosterol to the PM is unaltered in cells defective in Sec18p, a protein required for almost all intracellular vesicular trafficking events; we also show that transport is not blocked in cells that are defective in formation of transport vesicles at the ER or in vesicle fusion with the PM. Our data suggest instead that transport occurs by equilibration (t(1/2) approximately 10-15 min) of ER and PM ergosterol pools via a bidirectional, nonvesicular process that is saturated in wild-type exponentially growing yeast. To reconcile an equilibration process with the high ergosterol concentration of the PM relative to ER, we note that a large fraction of PM ergosterol is found condensed with sphingolipids in membrane rafts that coexist with free sterol. We propose that the concentration of free sterol is similar in the PM and ER and that only free (nonraft) sterol molecules have access to a nonvesicular transport pathway that connects the two organelles. This is the first description of biosynthetic sterol transport in yeast.

IMPORTANCE Sex-associated differences in immune response are known, but a meta-analysis suggested men, compared with women, derive greater value from immunotherapy for advanced solid-organ malignant neoplasms. However, methodologic concerns and subsequent trials have placed these results in doubt.OBJECTIVE To perform an updated, comprehensive meta-analysis that assesses the efficacy of immunotherapy in advanced cancers according to patient sex. DESIGN, SETTING, AND PARTICIPANTSA systematic review of studies (n = 23) indexed in MEDLINE (PubMed), Embase, and Scopus from inception of these databases to October 2, 2018, was conducted. Randomized clinical trials that compared immunotherapy with standard of care in the treatment of advanced solid-organ malignant neoplasms were included if overall survival was reported as an outcome and if data stratified by patient sex were available. Observational studies, editorials, commentaries, review articles, non-peer-reviewed publications, studies that compared various immunotherapy regimens, studies that reported other measures of oncologic response, and studies that reported subgroup analyses for 1 sex only were excluded. MAIN OUTCOMES AND MEASURESOverall survival, with a test for heterogeneity between women and men, to assess the null hypothesis that no difference in the survival advantage of immunotherapy exists by patient sex.RESULTS This meta-analysis included 23 randomized clinical trials that reported on 9322 men (67.9%) and 4399 women (32.1%); the age of most patients was in the 70s. An overall survival benefit of immunotherapy was found for both men (hazard ratio [HR], 0.75; 95% CI, 0.69-0.81; P < .001) and women (HR, 0.77; 95% CI, 0.67-0.88; P = .002). Random-effects meta-analysis of study-level differences in response to immunotherapy demonstrated no statistically significant difference between the sexes (I 2 = 38%; P = .60). Subgroup analyses according to disease site, line of therapy, class of immunotherapy, study methodology, and representation of women recapitulated these findings. CONCLUSIONS AND RELEVANCEStratified analyses demonstrated no statistically significant association of patient sex with the efficacy of immunotherapy in the treatment of advanced cancers using overall survival as the outcome.

Context: The coronavirus disease 2019 (COVID-19) pandemic is leading to delays in the treatment of many urologic cancers. Objective: To provide a contemporary picture of the risks from delayed treatment for urologic cancers to assist with triage. Evidence acquisition: A collaborative review using literature published as of April 2, 2020. Evidence synthesis: Patients with low-grade non-muscle-invasive bladder cancer are unlikely to suffer from a 3-6-month delay. Patients with muscle-invasive bladder cancer are at risk of disease progression, with radical cystectomy delays beyond 12 wk from diagnosis or completion of neoadjuvant chemotherapy. Prioritization of these patients for surgery or management with radiochemotherapy is encouraged. Active surveillance should be used for low-risk prostate cancer (PCa). Treatment of most patients with intermediate-and high-risk PCa can be deferred 3-6 mo without change in outcomes. The same may be true for cancers with the highest risk of progression. With radiotherapy, neoadjuvant androgen deprivation therapy (ADT) is the standard of care. For surgery, although the added value of neoadjuvant ADT is questionable, it may be considered if a patient is interested in such an approach. Intervention may be safely deferred for T1/T2 renal masses, while locally advanced renal tumors (!T3) should be treated expeditiously. Patients with metastatic renal cancer may consider vascular endothelial growth factor targeted therapy over immunotherapy. Risks for delay in the treatment of upper tract urothelial cancer depend on grade and stage. For patients with high-grade disease, delays of 12 wk in nephroureterectomy are not associated with adverse survival outcomes. Expert guidance recommends expedient local treatment of testis cancer. In penile

IMPORTANCE Surgeon sex is associated with differential postoperative outcomes, though the mechanism remains unclear. Sex concordance of surgeons and patients may represent a potential mechanism, given prior associations with physician-patient relationships.OBJECTIVE To examine the association between surgeon-patient sex discordance and postoperative outcomes. DESIGN, SETTING, AND PARTICIPANTSIn this population-based, retrospective cohort study, adult patients 18 years and older undergoing one of 21 common elective or emergent surgical procedures in Ontario, Canada, from 2007 to 2019 were analyzed. Data were analyzed from November 2020 to March 2021.EXPOSURES Surgeon-patient sex concordance (male surgeon with male patient, female surgeon with female patient) or discordance (male surgeon with female patient, female surgeon with male patient), operationalized as a binary (discordant vs concordant) and 4-level categorical variable. MAIN OUTCOMES AND MEASURESAdverse postoperative outcome, defined as death, readmission, or complication within 30-day following surgery. Secondary outcomes assessed each of these metrics individually. Generalized estimating equations with clustering at the level of the surgical procedure were used to account for differences between procedures, and subgroup analyses were performed according to procedure, patient, surgeon, and hospital characteristics.RESULTS Among 1 320 108 patients treated by 2937 surgeons, 602 560 patients were sex concordant with their surgeon (male surgeon with male patient, 509 634; female surgeon with female patient, 92 926) while 717 548 were sex discordant (male surgeon with female patient, 667 279; female surgeon with male patient, 50 269). A total of 189 390 patients (14.9%) experienced 1 or more adverse postoperative outcomes. Sex discordance between surgeon and patient was associated with a significant increased likelihood of composite adverse postoperative outcomes (adjusted odds ratio [aOR], 1.07; 95% CI, 1.04-1.09), as well as death (aOR, 1.07; 95% CI, 1.02-1.13), and complications (aOR, 1.09; 95% CI, 1.07-1.11) but not readmission (aOR, 1.02; 95% CI, 0.98-1.07). While associations were consistent across most subgroups, patient sex significantly modified this association, with worse outcomes for female patients treated by male surgeons (compared with female patients treated by female surgeons: aOR, 1.15; 95% CI, 1.10-1.20) but not male patients treated by female surgeons (compared with male patients treated by male surgeons: aOR, 0.99; 95% CI, 0.95-1.03) (P for interaction = .004). CONCLUSIONS AND RELEVANCEIn this study, sex discordance between surgeons and patients negatively affected outcomes following common procedures. Subgroup analyses demonstrate that this is driven by worse outcomes among female patients treated by male surgeons. Further work should seek to understand the underlying mechanism.

Benign prostatic hyperplasia (BPH) is one of the most common conditions affecting men. BPH can lead to a number of symptoms for patients commonly referred to as lower urinary tract symptoms (LUTS).Over the last decade, increased modifiable risk factors, such as metabolic disease and obesity, have resulted in an increased incidence of BPH. This increasing incidence has brought about a multitude of treatment modalities in the last two decades. With so many treatment modalities available, physicians are tasked with selecting the optimal therapy for their patients. Current therapies can first be divided into medical or surgical intervention. Medical therapy for BPH includes 5-alpha-reductase inhibitors and alpha-blockers, or a combination of both. Surgical interventions include a conventional transurethral resection of the prostate (TURP), as well as newer modalities such as bipolar TURP, holmium laser enucleation of the prostate (HoLEP), Greenlight and thulium laser, and prostatic urethral lift (PUL). Emerging therapies in this field must also be further investigated for safety and efficacy. This narrative review attempts to consolidate current and emerging treatment options for BPH and highlights the need for additional investigation on optimizing treatment selection.

Anatomical variation of the thoracic splanchnic nerves is as diverse as any structure in the body. Thoracic splanchnic nerves are derived from medial branches of the lower seven thoracic sympathetic ganglia, with the greater splanchnic nerve comprising the more cranial contributions, the lesser the middle branches, and the least splanchnic nerve usually T11 and/or T12. Much of the early anatomical research of the thoracic splanchnic nerves revolved around elucidating the nerve root level contributing to each of these nerves. The celiac plexus is a major interchange for autonomic fibers, receiving many of the thoracic splanchnic nerve fibers as they course toward the organs of the abdomen. The location of the celiac ganglia are usually described in relation to surrounding structures, and also show variation in size and general morphology. Clinically, the thoracic splanchnic nerves and celiac ganglia play a major role in pain management for upper abdominal disorders, particularly chronic pancreatitis and pancreatic cancer. Splanchnicectomy has been a treatment option since Mallet-Guy became a major proponent of the procedure in the 1940s. Splanchnic nerve dissection and thermocoagulation are two common derivatives of splanchnicectomy that are commonly used today. Celiac plexus block is also a treatment option to compliment splanchnicectomy in pain management. Endoscopic ultrasonography (EUS)-guided celiac injection and percutaneous methods of celiac plexus block have been heavily studied and are two important methods used today. For both splanchnicectomies and celiac plexus block, the innovation of ultrasonographic imaging technology has improved efficacy and accuracy of these procedures and continues to make pain management for these diseases more successful.

BACKGROUND: Approximately 70% of all suicides in patients aged >60 years are attributed to physical illness, with higher rates noted in patients with cancer. The purpose of the current study was to characterize suicide rates among patients with genitourinary cancers and identify factors associated with suicide in this specific cohort. METHODS: Patients with prostate, bladder, kidney, testis, and penile cancer were identified in the Surveillance, Epidemiology, and End Results database . Standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated for each anatomic site. Multivariable logistic regression models generated odds ratios (ORs) for the identification of factors associated with suicide for each malignancy. RESULTS: There were 2268 suicides identified among 1,239,522 individuals with genitourinary malignancies observed for 7,307,377 person-years. The SMRs for patients with cancer were 1.37 for prostate cancer (95% CI, 0.99-1.86), 2.71 for bladder cancer (95% CI, 2.02-3.62), 1.86 for kidney cancer (95% CI, 1.32-2.62), 1.23 for testis cancer (95% CI, 0.88-1.73), and 0.95 for penile cancer (95% CI, 0.65-1.35). On multivariable analysis, male sex was found to be associated with odds of suicide among patients with bladder cancer (OR, 6.63) and kidney cancer (OR, 4.98). Increasing age was associated with suicide for patients with prostate, bladder, and testis cancer (OR range, 1.03-1.06). Distant disease was associated with suicide in patients with prostate, bladder, and kidney cancer (OR range,). Among patients with prostate, bladder, and kidney cancer, African American patients were less likely to commit suicide compared with white individuals (OR range, 0.26-0.46). CONCLUSIONS: Suicide in patients with genitourinary malignancies poses a public health dilemma, especially among men, the elderly, and those with aggressive disease. Clinicians should be aware of risk factors for suicide in these patients.

Thoracic outlet syndrome (TOS) is a condition arising from compression of the subclavian vessels and/or brachial plexus as the structures travel from the thoracic outlet to the axilla. Despite the significant pathology associated with TOS, there remains some general disagreement among experts on the specific anatomy, etiology, and pathophysiology of the condition, presumably because of the wide variation in symptoms that manifest in presenting patients, and because of lack of a definitive gold standard for diagnosis. Symptoms associated with TOS have traditionally been divided into vascular and neurogenic categories, a distinction based on the underlying structure(s) implicated. Of the two, neurogenic TOS (nTOS) is more common, and typically presents as compression of the brachial plexus; primarily, but not exclusively, involving its lower trunk. Vascular TOS (vTOS) usually involves compression of the vessel, most commonly the subclavian artery or vein, or is secondary to thrombus formation in the venous vasculature. Any anatomical anomaly in the thoracic outlet has the potential to predispose a patient to TOS. Common anomalies include variations in the insertion of the anterior scalene muscle (ASM) or scalenus minimus muscle, the presence of a cervical rib or of fibrous and muscular bands, variations in insertion of pectoralis minor, and the presence of neurovascular structures, which follow an atypical course. A common diagnostic technique for vTOS is duplex imaging, which has generally replaced more invasive angiographic techniques. In cases of suspected nTOS, electrophysiological nerve studies and ASM blocks provide guidance when screening for patients likely to benefit from surgical decompression of TOS. Surgeons generally agree that the transaxillary approach allows the greatest field of view for first rib excision to relieve compressed vessels. Alternatively, a supraclavicular approach is favored for scalenotomies when the ASM impinges on surrounding structures. A combined supraclavicular and infraclavicular approach is preferred when a larger field of view is required. The future of TOS management must emphasize the improvement of available diagnostic and treatment techniques, and the development of a consensus gold standard for diagnosis. Helical computed tomography offers a three-dimensional view of the thoracic outlet, and may be valuable in the detection of anatomical variations, which may predispose patients to TOS. This review summarizes the history of TOS, the pertinent clinical and anatomical presentations of TOS, and the commonly used diagnostic and treatment techniques for the condition.