TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. Here, we found that TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in patients with GBM. TREM2 loss of function in human macrophages and mouse myeloid cells increased interferon-γ-induced immunoactivation, proinflammatory polarization, and tumoricidal capacity. In orthotopic mouse GBM models, mice with chronic and acute Trem2 loss of function exhibited decreased tumor growth and increased survival. Trem2 inhibition reprogrammed myeloid phenotypes and increased programmed cell death protein 1 (PD-1)+CD8+ T cells in the TME. Last, Trem2 deficiency enhanced the effectiveness of anti-PD-1 treatment, which may represent a therapeutic strategy for patients with GBM.

Sinusitis complicated by intracranial abscess in 3 patients with coronavirus disease 2019: illustrative cases.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) can be associated with various neurological manifestations, including cerebrovascular disease, seizures, peripheral nerve disease, and encephalitis. Intracranial abscess related to COVID-19 is rare but illustrates a serious complication in the studied cases. OBSERVATIONS: The authors report 3 cases of patients presenting with COVID-19 complicated by sinusitis with associated intracranial abscesses. Each patient underwent craniotomy with washout and sinus debridement during their hospital stay. All 3 patients improved to their baseline following treatment. Similar outcomes have been observed in other cases of intracranial abscess associated with COVID-19 infections. LESSONS: Patients achieved significant improvement following evacuation of the abscess and intravenous antibiotics. Further investigation is needed to determine treatment in relation to COVID-19, and the authors recommend following the standard treatment of intracranial abscess at this time.

CDC20 regulates sensitivity to chemotherapy and radiation in glioblastoma stem cells.

Glioblastoma stem cells (GSCs) are an important subpopulation in glioblastoma, implicated in tumor growth, tumor recurrence, and radiation resistance. Understanding the cellular mechanisms for chemo- and radiation resistance could lead to the development of new therapeutic strategies. Here, we demonstrate that CDC20 promotes resistance to chemotherapy and radiation therapy. CDC20 knockdown does not increase TMZ- and radiation-induced DNA damage, or alter DNA damage repair, but rather promotes cell death through accumulation of the pro-apoptotic protein, Bim. Our results identify a CDC20 signaling pathway that regulates chemo- and radiosensitivity in GSCs, with the potential for CDC20-targeted therapeutic strategies in the treatment of glioblastoma.

Patient Reported Quality of Life Outcomes After Definitive Radiation Therapy With Absorbable Spacer Hydrogel for Prostate Cancer.

PURPOSE: SpaceOAR is a device approved for conventional radiation in prostate cancer. We sought to observe prospectively how SpaceOAR Hydrogel effected quality of life and dosimetry to organs at risk at our institution. METHODS AND MATERIALS: We prospectively enrolled patients with low risk or favorable-intermediate risk localized prostate cancer. Baseline Expanded Prostate Cancer Index Composite (EPIC-26) scores along with baseline American Urology Association Symptom Index (AUA-SI) scores were collected. SpaceOAR was placed for all patients who then received stereotactic body radiation therapy, low dose rate brachytherapy, conventionally fractionated radiation therapy, or moderately hypofractionated radiation therapy. We evaluated postimplant dosimetry to critical structures, and prospectively collected follow-up EPIC-26 and AUA-SI scores. We performed a repeated measures analysis of variance to compare patient-specific responses and correlated survey data with dosimetric metrics by generating linear regression models. RESULTS: We enrolled 59 patients in this study with a median follow-up of 366 days (interquartile range, 507). At final follow-up, the "?>prostate-specific antigen had a significant decline compared with baseline (P < .0001). There were no grade 3 toxicities on treatment. There were no significant changes in the AUA-SI score (P = .69) at final follow-up compared with baseline, nor was there any change in EPIC-26 domain scores (P = .19) during the course of the study period. There were no significant associations between AUA scores and EPIC-26 scores and the dose to the rectum, bladder, or urethra with the exception being dose to the 2 mL rectum correlated with decline in EPIC-26 rectal score (ß, -0.002; P = .006). Patient-reported declines in bowel domains were less than previously reported data. CONCLUSIONS: Use of SpaceOAR results in favorable dosimetry to the organs at risk and portends excellent short-term quality of life as measured by the association with the patient reported outcome measures. Longer-term follow-up is ongoing and necessary to assess the long-term effect and association of the hydrogel.

Neuromodulation Approaches in Parkinson's Disease Using Deep Brain Stimulation and Transcranial Magnetic Stimulation.

Parkinson's Disease (PD) is the second most common neurodegenerative disease, characterized by progressive motor (such as resting tremor, hypokinesia, postural instability) and non-motor symptoms (such as neuropsychiatric decline and autonomic dysfunction). Since its introduction in the late 1980s, deep brain stimulation (DBS) has revolutionized the treatment of PD. Initially used in patients' with advanced PD with either medically refractory motor symptoms or medication intolerance, DBS typically provides excellent improvement in motor symptoms. Indications for DBS have continued to expand, with demonstrated efficacy in early PD and essential tremor, and promising preliminary results in the treatment of epilepsy, psychiatric disease, and depression. Advancements in DBS hardware, programming, neuroimaging, and surgical techniques have led to progressive improvement in efficacy and safety profiles. Thanks to ongoing research into remote programming, adaptive DBS, new targets, and alternative interventions, such as transcranial magnetic stimulation, the opportunities for further improvements in DBS and neuromodulation are bright.

Emerging and Historical Contaminants Detected in Desert Rodents Collected Near a Low-Level Radioactive Waste Site.

In an effort to determine contaminant presence, concentrations, and movement from a low-level radioactive waste (LLRW) burial disposal site to ecosystems in the surrounding area, a study was developed to assess concentrations of per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), and tritium. To complete this assessment small mammals, vegetation, soil, and insect samples were collected from areas within and adjacent to the Beatty, Nevada, LLRW site and from a reference area located approximately 3 km south of the LLRW site. Samples underwent analysis via liquid chromatography tandem mass spectrometry, gas chromatography mass spectrometry, or scintillation spectroscopy depending on the analyte of interest. Small mammal tissues showed maximum concentrations of over 1700 ng/g for PFAS, 1600 ng/g for PCBs, and 10 000 Bq/kg for tritium. The primary contaminants found in soil samples were PCBs, with maximum concentrations exceeding 25 ng/g. Trace amounts of PFAS were also detected in soils and insects. Only qualitative data were obtained from vegetation samples because of the complex matrix of the dominant plant species (creosote bush; Larrea tridentata [Sessé & Moc. ex DC.] Coville). Overall, these data indicate the presence of various anthropogenic contaminants in the ecosystem surrounding the LLRW area, but additional analyses are necessary to confirm the sources and migration pathways of PFAS and PCBs in this hyperarid environment. Environ Toxicol Chem 2021;40:727-734. © 2020 SETAC.

Spontaneous closure of myelomeningocele.

Fetal repair of myelomeningocele has been increasingly offered to mothers of children with myelomeningocele after the seminal Management of Myelomeningocele (MOMs) trial, which demonstrated decreased reliance on ventriculoperitoneal shunt following fetal closure. We present the case of a fetus diagnosed with a lumbar myelomeningocele in utero whose mother refused in utero closure and who was subsequently born with a skin-covered defect. A fetal MRI was obtained on a mother with a male fetus diagnosed with open neural tube defect at 20 weeks of gestation. The child demonstrated spinal dysraphism extending from L2 to L5 and associated Chiari II malformation with lateral and third ventriculomegaly. Based on our institutional criteria and the criteria of the MOMs trial, the parents were offered fetal repair of the myelomeningocele; however, they declined because of concerns about risks to the mother. At birth, the patient was found to have a skin-covered meningocele. He underwent elective repair of his occult meningocele and detethering of his spinal cord. Intraoperative findings demonstrated spinal nerve roots attached to the arachnoid within the defect, and a closed, tubularized neural placode. This represents a unique case in which a fetus with a clinical picture consistent with open spinal defect was found to have a lesion more consistent with meningocele on postnatal operative interrogation. Knowledge that this can occur should be taken into consideration when discussing fetal closure, although the frequency of this occurrence is not known. Additionally, identification of this case sheds light on the mechanism by which occult myelomeningoceles form.

Evolving Treatment Paradigms for Oropharyngeal Squamous Cell Carcinoma.

Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence in the United States and in many countries worldwide primarily as a result of increasing rates of human papillomavirus (HPV) infection. HPV-positive OPSCC represents a distinct disease entity from head and neck squamous cell carcinoma caused by traditional risk factors such as tobacco and alcohol, with different epidemiology, patterns of failure, and expected outcomes. Because patients with HPV-positive OPSCC have a younger median age and superior prognosis compared with their HPV-negative counterparts, they live longer with the morbidity of treatment, which can be severe. Therefore, efforts are under way to de-escalate therapy in favorable-risk patients while maintaining treatment efficacy. Additional work is being undertaken to discover new therapies that may benefit both HPV-positive and HPV-negative patient subsets. Herein, we will review the available data for the evolving treatment paradigms in OPSCC as well as discuss ongoing clinical trials.

Long-term Outcomes after Salvage Stereotactic Radiosurgery (SRS) following In-Field Failure of Initial SRS for Brain Metastases.

PURPOSE: The optimal treatment strategy following local recurrence after stereotactic radiosurgery (SRS) remains unclear. While upfront SRS has been extensively studied, few reports focus on outcomes after retreatment. Here, we report the results following a second course of SRS for local recurrence of brain metastases previously treated with SRS. METHODS: Using institutional database, patients who received salvage SRS (SRS2) following in-field failure of initial SRS (SRS1) for brain metastases were identified. Radionecrosis and local failure were defined radiographically by MRI following SRS2. The primary endpoint was defined as the time from SRS2 to the date of all-cause death or last follow-up [overall survival (OS)]. The secondary endpoints included local failure-free survival (LFFS) and radionecrosis-free survival, defined as the time from SRS2 to the date of local failure or radionecrosis, or last follow-up, respectively. RESULTS: Twenty-eight patients with 32 brain metastases were evaluated between years 2004 and 2015. The median interval between SRS1 and SRS2 was 9.7 months. Median OS was 22.0 months. Median LFFS time after SRS2 was 13.6 months. The overall local control rate following SRS2 was 84.4%. The 1- and 2-year local control rates are 88.3% (95% CI, 76.7-100%) and 80.3% (95% CI, 63.5-100%), respectively. The overall rate of radionecrosis following SRS2 was 18.8%. On univariate analysis, higher prescribed isodose line (p = 0.033) and higher gross tumor volume (p = 0.015) at SRS1 were associated with radionecrosis. Although not statistically significant, there was a trend toward lower risk of radionecrosis with interval surgical resection, fractionated SRS, lower total EQD2 (<50 Gy), and lack of concurrent systemic therapy at SRS2. CONCLUSION: In select patients, repeat LINAC-based SRS following recurrence remains a reasonable option leading to long-term survival and local control. Radionecrosis approaches 20% for high risk individuals and parallels historic values.

Postoperative Fractionated Stereotactic Radiosurgery to the Tumor Bed for Surgically Resected Brain Metastases.

Introduction Stereotactic radiosurgery (SRS) is increasingly used as an alternative to whole brain radiotherapy (WBRT) following surgical resection of brain metastases. We analyzed the outcomes of postoperative frameless fractionated stereotactic radiosurgery (fSRS) cases for surgically resected brain metastases at our institution. Materials and Methods We performed a retrospective review of 85 patients who underwent fSRS to 87 resection beds from 2006 - 2014 with a median follow-up of 6.4 months. Clinically relevant outcomes were assessed with analysis to determine predictors of these outcomes. Results The median target volume was 9.8 cm-3 (1.1 - 43.1 cm-3). The most frequently used fractionation scheme was 3,000 cGy in five fractions. The rates of local control (LC), distant brain failure (DBF), and overall survival (OS) at one-year were 87%, 52%, and 52%, respectively. Five patients (5.9%) experienced Grade >2 toxicity related to fSRS, including seizures (two), symptomatic radionecrosis (two), and potential treatment-related death (one). A multivariable analysis revealed that tumor volume (p < 0.001) and number of fractions (p < 0.001) were associated with LC, while recursive partitioning analysis (RPA) class (p < .0001), tumor volume (p = .0181), and the number of fractions (p = .0181) were associated with OS. Conclusions Postoperative fSRS for surgically resected brain metastases is well-tolerated and achieves durable LC. Further studies are needed to determine the optimal dose and fractionation for fSRS as well as to compare outcomes with WBRT.

Fluorescence in situ hybridization (FISH) in the diagnosis of bladder and upper tract urothelial carcinoma: the largest single-institution experience to date.

INTRODUCTION: We evaluated the UroVysion (Abbott Molecular, IL, USA) fluorescence in situ hybridization (FISH) assay for the diagnosis of urothelial cancer in patients diagnosed with or suspected to have bladder, upper tract urothelial carcinoma (UTUC), and combined upper and lower tract urothelial carcinoma (BC). MATERIALS AND METHODS: A single institution retrospective analysis comparing sensitivity, specificity, positive predictive value, and negative predictive values for FISH and urinary cytology. FISH within 6 months of endoscopic evaluation were obtained from outpatient voided urine samples. Our institutional pathology department confirmed pathologic disease from specimens obtained during endoscopic evaluations for lower tract disease. For upper tract disease, disease was confirmed by retrograde ureteroscopy, biopsies of visual lesions, and site-specific upper tract cytology. RESULTS: A total of 415 patients submitted FISH specimens. Overall, FISH was more sensitive than cytology 54.9% in comparison with cytology 42.2% (p = 0.01), specificity favored cytology 92.9% compared to 73.5% with FISH (p < 0.01). For BC only patients, the same significant finding of increased sensitivity and decreased specificity was identified, but for UTUC alone and combined UTUC and BC, there was no significant difference. Cytology had improved positive predictive value (PPV) over FISH, 76.9% in comparison to 64.6% (p = 0.02). Negative predictive value (NPV) also favored cytology 74.2% versus 64.9% (p = 0.02). When analyzing individual cohorts, cytology had improved PPV for BC alone patients. UTUC showed no difference for PPV and NPV. For both UTUC and BC, NPV was slightly favored for FISH over cytology 93.2% versus 91.2% (p = 0.03). CONCLUSIONS: Voided urine FISH testing does offer a higher detection of urothelial carcinoma for BC compared to voided cytology; however, specificity was worse. FISH does not appear to improve detection of urothelial carcinoma in patients with either UTUC only or both BC and UTUC.

"Awake" clipping of cerebral aneurysms: report of initial series.

OBJECTIVE Risk of ischemia during aneurysm surgery is significantly related to temporary clipping time and final clipping that might incorporate a perforator. In this study, the authors attempted to assess the potential added benefit to patient outcomes of "awake" neurological testing when compared with standard neurophysiological testing performed under general anesthesia. The procedure is performed after the induction of conscious sedation, and for the neurological testing, the patient is fully awake. METHODS The authors conducted an institutional review board-approved prospective study of clipping unruptured intracranial aneurysms (UIAs) in 30 consecutive adult patients who underwent awake clipping. The end points were the incidence of stroke/cerebrovascular accident (CVA), death, discharge to a long-term facility, length of stay, and 30-day modified Rankin Scale score. All clinical and neurophysiological intraoperative monitoring data were recorded. RESULTS The median patient age was 52 years (range 27-63 years); 19 (63%) female and 11 (37%) male patients were included. Twenty-seven (90%) aneurysms were anterior, and 3 (10%) were posterior circulation aneurysms. Five (17%) had been coiled previously, 3 (10%) had been clipped previously, 2 (7%) were partially calcified, and 2 (7%) were fusiform aneurysms. Three patients developed synchronous clinical neurological and neurophysiological changes during temporary clipping with consequent removal of the temporary clip and reversal of those clinical and neurophysiological changes. Three patients developed asynchronous clinical neurological and neurophysiological changes. These 3 patients developed hemiparesis without changes in neurophysiological monitoring results. One patient developed linked clinical neurological and neurophysiological changes during final clipping that were not reversed by reapplication of the clip, and the patient had a CVA. Four patients with internal carotid artery ophthalmic segment aneurysms underwent visual testing with final clipping, and 1 of these patients required repositioning of the clip. Three patients who required permanent occlusion of a vessel as part of their aneurysm treatment underwent a 10-minute intraoperative clinical respective-vessel test occlusion. The median length of stay was 3 days (range 1-5 days). The median modified Rankin Scale score was 1 (range 0-3). All of the patients were discharged to home from the hospital except for 1 who developed a CVA and was discharged to a rehabilitation facility. There were no deaths in this series. CONCLUSIONS The 3 patients who developed neurological deterioration without a concomitant neurophysiological finding during temporary clipping revealed a potential advantage of awake aneurysm surgery (i.e., in decreasing the risk of ischemic injury).

Superficial Dorsal Venous Rupture of the Penis: False Penile Fracture That Needs to be Treated as a True Urologic Emergency.

A 38-year-old man with history of repaired penile fracture presented with rapid detumescence, penile pain, and ecchymosis during vaginal sexual intercourse concerning for recurrent fracture. Surgical exploration revealed ruptured superficial dorsal vein of the penis, which was subsequently ligated. Patients with traumatic penile vascular injuries often present with clinical features indistinguishable from a true penile fracture. Gradual detumescence and an absence of characteristic popping sound may indicate a vascular injury but they cannot safely rule out a true penile fracture. Both true and false penile fractures require emergent surgical exploration and repair to prevent long-term complications.

Ureteral Avulsion Associated with Ureteroscopy: Insights from the MAUDE Database.

BACKGROUND: Flexible and semirigid ureteroscopy (URS) are widely performed for the treatment of upper tract calculi and tumors. Ureteral avulsion is a rare, but devastating complication of endoscopic stone removal having multiple possible etiologies. Awareness and avoidance of this rare complication depend on identifying responsible mechanisms. This study examines the situations in which ureteral avulsion occurs as described anonymously in the Manufacturer and User facility Device Experience (MAUDE) database. MATERIALS AND METHODS: The MAUDE database was systematically reviewed to account for all reported complications of flexible and semirigid URS. Keywords "ureteroscopy, injury, death, malfunction and other" were entered in the database and medical device reports were reviewed to capture any cases resulting in ureteral avulsion. Attention was paid to the type of ureteroscope involved and the mechanism for avulsion. RESULTS: A total of 104 entries were found detailing the reported complications of flexible and semirigid URS. Ureteral avulsion was clearly noted in six reports with flexible (2) and semirigid ureteroscopes (4). Potential mechanisms included locked deflection of a flexible ureteroscope (1), bunching of the distal bending rubber in a flexible ureteroscope (1), scabbard avulsion (3), and stone basketing (1). CONCLUSIONS: Although the incidence of ureteral avulsion cannot truly be determined from this study, some potentially novel mechanisms for this rare complication are observed. This may target future educational efforts to maximize awareness and avoidance of this complication.

Subunit composition of glutamate and gamma-aminobutyric acid receptors in status epilepticus.

PURPOSE: To describe the subunit composition of glutamate and gamma-aminobutyric acid (GABA) receptors in brain tissue from patients with different types of status epilepticus. PATIENTS AND METHODS: The subunit composition of glutamate and GABA receptors was analyzed in: (1) surgical brain samples from three patients with refractory convulsive status epilepticus, three patients with electrical status epilepticus in sleep, and six patients with refractory epilepsy, and (2) brain autopsy samples from four controls who died without neurological disorders. Subunit expression was quantified with Western blotting and messenger ribonucleic acid (mRNA) expression was quantified with reverse polymerase chain reaction. RESULTS: Western blot analysis demonstrated the following patterns (as compared to controls): (1) alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors: elevated GluA1/GluA2 ratio in electrical status epilepticus in sleep (465%±119) and refractory epilepsy (329%±125; p<0.01); (2) N-methyl-d-aspartate (NMDA) receptors: increased GluN2B/GluN2A ratio in electrical status epilepticus in sleep (3682%±1000) and refractory convulsive status epilepticus (3520%±751; p<0.05); (3) GABA receptors: elevated α2/α1 ratio in refractory epilepsy (321%±138; p<0.05) and refractory convulsive status epilepticus (346%±74; p<0.05); and (4) patients with underlying malformation of cortical development had increased ratios in GluA1/GluA2 (382%±149; p<0.01), GluN2B/GluN2A (3321%±1581; p<0.05) and α2/α1 (303%±86; p<0.01). Quantification of mRNA demonstrated an elevated GABRA2/GABRA1 ratio in refractory epilepsy (712; p<0.05) as compared to controls. CONCLUSIONS: The subunit composition of glutamate and GABA receptors in patients with status epilepticus mirrors that found in animal models of refractory status epilepticus and may promote self-sustaining seizures. Receptor subunit changes may provide additional targets for improved treatment.

Bumetanide enhances phenobarbital efficacy in a rat model of hypoxic neonatal seizures.

Neonatal seizures can be refractory to conventional anticonvulsants, and this may in part be due to a developmental increase in expression of the neuronal Na(+)-K(+)-2 Cl(-) cotransporter, NKCC1, and consequent paradoxical excitatory actions of GABAA receptors in the perinatal period. The most common cause of neonatal seizures is hypoxic encephalopathy, and here we show in an established model of neonatal hypoxia-induced seizures that the NKCC1 inhibitor, bumetanide, in combination with phenobarbital is significantly more effective than phenobarbital alone. A sensitive mass spectrometry assay revealed that bumetanide concentrations in serum and brain were dose-dependent, and the expression of NKCC1 protein transiently increased in cortex and hippocampus after hypoxic seizures. Importantly, the low doses of phenobarbital and bumetanide used in the study did not increase constitutive apoptosis, alone or in combination. Perforated patch clamp recordings from ex vivo hippocampal slices removed following seizures revealed that phenobarbital and bumetanide largely reversed seizure-induced changes in EGABA. Taken together, these data provide preclinical support for clinical trials of bumetanide in human neonates at risk for hypoxic encephalopathy and seizures.

Risk for fatal pulmonary hemorrhage does not appear to be increased following dose escalation using stereotactic body radiotherapy (SBRT) in locally advanced non-small cell lung cancer (NSCLC).

PURPOSE: A prospective single institution study evaluating the feasibility of conventional chemoradiation (CRT) followed by SBRT as a means of dose escalation for patients with stage II-III NSCLC with residual disease recently completed accrual. Two patients enrolled developed unexpected fatal pulmonary hemorrhages. A post-hoc analysis was performed to evaluate for an association between protocol therapy and this grade 5 toxicity. METHODS AND MATERIALS: 17 patients enrolled on the protocol with medial tumors according to the RTOG 0813 definitions, were selected for analysis. Protocol therapy consisted of SBRT boost consisting of 10Gy times two or 6.5Gy times three fractions, after completing initial CRT. Chi-square and ANOVA associations were performed using patient-specific and dosimetric characteristics, particularly volume and point doses to mediastinal structures. RESULTS: After a median follow-up of 13 months, 2 patients developed a grade V pulmonary hemorrhage, in the setting of recurrent disease. Cumulative biological effective doses (BED3) were calculated using an α/ß 3.0 for the pulmonary vasculature and bronchial wall. No volumetric or point doses administered seemed to correlate with the risk for pulmonary hemorrhage, despite an average maximum pulmonary artery dose of 175 Gy BED3. The only significant association with fatal hemorrhage was local recurrence (p = 0.0441). CONCLUSION: SBRT boost does not appear to increase the risk for fatal pulmonary hemorrhage. A cumulative maximum BED3 to the pulmonary artery less than 175 Gy appears to be safe.

Hand problems among endourologists.

BACKGROUND AND PURPOSE: Endourology has evolved rapidly for the management of both benign and malignant disease of the upper urinary tract. Limited data exist, however, on the occupational hazards posed by complex endourologic procedures. The aim of this study was to determine the prevalence and possible causes of hand problems among endourologists who routinely perform flexible ureteroscopy compared with controls. MATERIALS AND METHODS: An online computer survey targeted members of the Endourological Society and psychiatrists in academic and community settings. A total of 600 endourologists and 578 psychiatrists were contacted by e-mail. Invited physicians were queried regarding their practice settings and symptoms of hand pain, neuropathy, and/or discomfort. RESULTS: Survey responses were obtained from 122 (20.3%) endourologists and 74 (12.8%) psychiatrists. Of endourologists, 61% were in an academic setting and 70% devoted their practice to endourology. Endourologists were in practice for a mean 13 years, performing 4.5 ureteroscopic cases per week with a mean operative time of 50 minutes. Hand/wrist problems were reported by 39 (32%) endourologists compared with 14 (19%) psychiatrists (P=0.0486, relative risk [RR]=1.69). Surgeons who preferred counterintuitive ureteroscope deflection were significantly more likely to have problems (56%) compared with intuitive users (27%) (RR 2.07, P=0.0139) or those with no preference (26%) (RR 2.15, P=0.0451). Overall, most respondents (85%) with hand/wrist problems needed either medical or surgical intervention. CONCLUSIONS: Hand and wrist problems are very common among endourologists. Future studies are needed to develop more ergonomic platforms and thereby reduce the endourologist's exposure to these occupational hazards.

Sensitive isotope dilution liquid chromatography/tandem mass spectrometry method for quantitative analysis of bumetanide in serum and brain tissue.

We have developed and validated a simple and sensitive stable isotope dilution liquid chromatography/tandem mass spectrometric (LC-MS/MS) method for the quantification of bumetanide in human serum. Samples were prepared with a simple acetonitrile based protein precipitation. The supernatant was then analyzed directly using LC-MS/MS. Chromatographic separation was achieved on a C18 reversed phase column using a methanol and water gradient. The detection was performed in selected reaction monitoring (SRM) mode via a positive electrospray ionization (ESI) interface. The method had a lower limit of quantification (LLOQ) of 1 ng/mL, linearity up to 1250 ng/mL, intra- and inter-day precision less than 10%, and accuracy within ±10%. This method was also demonstrated to be suitable for the analysis of bumetanide in rat serum and brain tissue. Bumetanide concentrations in rat serum and brain were determined for samples collected at several intervals following intraperitoneal (i.p.) injection of bumetanide, and were used to calculate bumetanide permeability through the blood-brain barrier.