Bile Salt Hydrolase Activity-Based Probes for Monitoring Gut Microbial Bile Acid Metabolism.

Bile acids are bioactive metabolites that are biotransformed into secondary bile acids by the gut microbiota, a vast consortium of microbes that inhabit the intestines. The first step in intestinal secondary bile acid metabolism is carried out by a critical enzyme, bile salt hydrolase (BSH), that catalyzes the gateway reaction that precedes all subsequent microbial metabolism of these important metabolites. As gut microbial metabolic activity is difficult to probe due to the complex nature of the gut microbiome, approaches are needed to profile gut microbiota-associated enzymes such as BSH. Here, we develop a panel of BSH activity-based probes (ABPs) to determine how changes in diurnal rhythmicity of gut microbiota-associated metabolism affects BSH activity and substrate preference. This panel of covalent probes enables determination of BSH activity and substrate specificity from multiple gut anerobic bacteria derived from the human and mouse gut microbiome. We found that both gut microbiota-associated BSH activity and substrate preference is rhythmic, likely due to feeding patterns of the mice. These results indicate that this ABP-based approach can be used to profile changes in BSH activity in physiological and disease states that are regulated by circadian rhythms.

Re: Pentosan polysulfate and a pigmentary maculopathy: causation versus correlation?

How should a conscientious physician advise patients with Interstitial Cystitis /Bladder Pain Syndrome (IC/BPS) when they want to know if taking Pentosan Polysulfate Sodium (PPS) will lead to loss of vision? Ever since the initial report from Pearce et al in 2018 suggesting that PPS usage can lead to the development of pigmented maculopathy (PM), my patients have been inundated with solicitations from attorneys looking to sign up clients for class action lawsuits.1 While there have been additional reports suggesting a relationship between PPS exposure and the development of PM, Ludwig et al found that there was no difference in the rate of macular disease between patients with documented IC/BPS who had taken PPS and those with IC/BPS with no history of PPS use.2 The large size of Ludwig's study certainly suggests that PPS may not cause PM to develop, and if the rate of PM in the IC population is higher than in controls, it may be due to the disease itself and not from the medication. In this manuscript, Proctor clearly describes the immune inflammatory response that is responsible for the development of the bladder damage seen with IC/BPS. Also, he describes how inflammatory mediators can enter the blood stream and might be a potential cause for the development of PM.3 This is a thought-provoking hypothesis that demands further evaluation. I have prescribed PPS since its approval and have many patients who feel it is an essential part of their IC treatment regimen. There is no other prescription medication that functions in the same fashion. I require them to follow the FDA recommendations for annual eye exams to look for PM development. I also advise patients that as they improve, we will discuss dose reduction and even discontinuation if their IC symptoms have abated. By following these suggestions, one should be able to continue to prescribe PPS for appropriate patients while carefully monitoring them for PM. I found this article extremely informative and will refer to it when counseling patients about IC/BPS and PPS.

Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270-360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90-18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).

Safety and economics of an enhanced recovery after surgery protocol in pelvic reconstructive surgery.

INTRODUCTION AND HYPOTHESIS: We hypothesized that an enhanced recovery after surgery (ERAS) protocol for patients undergoing female pelvic reconstructive surgery would conserve hospital resources without compromising patient safety. METHODS: In June 2020, an ERAS protocol designed to promote same-day discharge was initiated that included pre-operative hydration, a urinary anesthetic, non-narcotic analgesia, perineal ice, a bowel regimen, enrollment of the family to assist with care, and communication regarding planned same-day discharge. We compared demographic, operative, hospital stay, complications, and cost data in patients undergoing pelvic organ prolapse or incontinence surgery over 4 sequential months pre (PRE; N = 82) and post (POST; N = 91) ERAS implementation using univariate statistics. RESULTS: There were no differences in demographics, operative details, or complications (p > 0.05). There were no significant differences in overall revenues or expenses (p > 0.05), but bed unit cost was significantly lower in the POST group ($210 vs $533, p < 0.0001). There was a trend toward an increased operating margin in POST patients ($4,554 vs $2,151, p = 0.1163). Significantly more POST surgeries were performed in an ambulatory setting (73.6% vs 48.8%, p = 0.0008) and resulted in same-day discharge (80.2% vs 50.0%, p = 0.0003). There were no differences in the rates of emergency room or unexpected clinic visits (p > 0.05). Prescribed post-operative opiate dose was significantly reduced in POST patients (p < 0.0001). CONCLUSIONS: In patients undergoing female pelvic reconstructive surgery, an ERAS protocol facilitated transfer of procedures to an ambulatory surgical site and permitted same-day discharge without increasing complications, clinic visits, or emergency room visits. It also reduced bed unit cost and may improve operating margins.

Pulsed electromagnetic field (PEMF) as an adjunct therapy for pain management in interstitial cystitis/bladder pain syndrome.

INTRODUCTION AND HYPOTHESIS: Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often experience chronic pelvic and even systemic pain that can be difficult to clinically manage. Pulsed electromagnetic field (PEMF) therapy, a non-invasive strategy that has shown significant efficacy for pain reduction in other chronic pain conditions, may provide benefit for pain management in patients with IC/BPS. METHODS: PEMF delivery to patients occurs via a bio-electromagnetic-energy device which consists of a flexible mat (180 × 50 cm) that the patient lies on for systemic, full-body delivery and/or a flexible pad (50 × 15 cm) for targeted delivery to a specific body region (e.g., pelvic area). The duration of individual sessions, number of sessions per day, total number of sessions, and follow-up observation period vary between previously published studies. Positive outcomes are typically reported as a significant reduction in visual analog scale (VAS) pain score and functional improvement assessed using validated questionnaires specific to the condition under study. RESULTS AND CONCLUSIONS: The use of PEMF has been evaluated as a therapeutic strategy for pain management in several clinical scenarios. Randomized, double-blinded, placebo-controlled trials have reported positive efficacy and safety profiles when PEMF was used to treat non-specific low back pain, patellofemoral pain syndrome, chronic post-operative pain, osteoarthritis-related pain, rheumatoid arthritis-related pain, and fibromyalgia-related pain. Based on these positive outcomes in a variety of pain conditions, clinical trials to evaluate whether PEMF can provide a safe, non-invasive therapeutic approach to improve symptoms of chronic pain and fatigue in patients with IC/BPS are warranted.

Hydrodistention does not alter bladder gene expression profiles in patients with non-Hunner lesion interstitial cystitis/bladder pain syndrome.

AIMS: Gene expression profiling of bladder biopsies in patients with interstitial cystitis/bladder pain syndrome (IC/BPS), typically obtained following therapeutic bladder hydrodistention (HOD), is used to improve our understanding of molecular phenotypes. The objective of this study was to determine if the HOD procedure itself impacts the biopsy gene expression profile and, by extension, whether biopsies from non-HOD bladders are appropriate controls. METHODS: Bladder biopsies were obtained just before HOD and immediately following HOD from 10 consecutively recruited IC/BPS patients undergoing therapeutic HOD. Biopsies were also obtained from four non-IC/BPS patients who did not undergo HOD (controls). Total RNA was isolated from each of the 24 samples and used to query whole-genome microarrays. Differential gene expression analysis was performed to compare expression profiles of IC/BPS biopsies before and after HOD, and between IC/BPS and control biopsies. RESULTS: Principal component analysis revealed complete separation between gene expression profiles from IC/BPS and control samples (q ≤ 0.05) and while IC/BPS samples before and after HOD showed no significant differences in expressed genes, 68 transcripts were found to be significantly different between IC/BPS and control samples (q ≤ 0.05). CONCLUSIONS: The bladder HOD procedure itself does not significantly change gene expression within the IC/BPS patient bladder, a finding that provides evidence to support the use of biopsies from non-IC/BPS patients that have not undergone HOD as controls for gene expression studies.

Specialty-Specific Trends in Surgery for Apical Pelvic Organ Prolapse Post Vaginal Mesh.

IMPORTANCE: Since transvaginal mesh (VM) kits for apical pelvic organ prolapse (APOP) were labeled "high-risk" in 2016 and subsequently banned in 2019 by the U.S. Food and Drug Administration, the most common remaining surgical options include abdominal mesh-augmented sacrocolpopexy (AS) and transvaginal native tissue suspension (VN). OBJECTIVE: The objective of this study was to determine temporal trends in APOP procedures for urologists and gynecologists. STUDY DESIGN: Between 2011 and 2020, the American College of Surgeons National Surgical Quality Improvement Program database was queried for AS, VM, and VN. RESULTS: There were 26,477 cases of APOP repair (32% AS, 6% VM, 62% VN) included, 9% by urologists. Urologists operated on older (65 vs 61 years) patients with more medical comorbidities. Urologists performed significantly higher proportion of AS (65% vs 29%) and VM (8% vs 6%) relative to VN (27% vs 65%) than gynecologists ( P < 0.0001). Transvaginal mesh utilization has decreased over time for both specialties ( P < 0.05); nonsignificant trends toward increasing AS ( P = 0.1646) in urologists and VN ( P = 0.0913) in gynecologists concurrently occurred. Significant independent predictors of the operating surgeon being a urologist were surgery being performed in the latter half of the cohort (2016-2020; odds ratio [OR], 1.22), non-White patient race (OR < 1 for all), a concomitant sling being placed (OR = 0.89), the surgery being VM (OR = 2.95) or AS (OR = 4.36), the patient being older (OR > 1 for each age range), and having a higher frailty index score (OR = 1.16). CONCLUSIONS: Significant differences in APOP repair choices exist between specialties. Urologists operate on older, more medically complex patients while demonstrating a strong preference for mesh-augmented compared with transvaginal native tissue repairs.

Chemoproteomic profiling of substrate specificity in gut microbiota-associated bile salt hydrolases.

The gut microbiome possesses numerous biochemical enzymes that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in bile acid metabolism is bile salt hydrolase (BSH), which controls the host's overall bile acid pool. Despite the critical role of these enzymes, the ability to profile their activities and substrate preferences remains challenging due to the complexity of the gut microbiota, whose metaproteome includes an immense diversity of protein classes. Using a systems biochemistry approach employing activity-based probes, we have identified gut microbiota-associated BSHs that exhibit distinct substrate preferences, revealing that different microbes contribute to the diversity of the host bile acid pool. We envision that this chemoproteomic approach will reveal how secondary bile acid metabolism controlled by BSHs contributes to the etiology of various inflammatory diseases.

Chemoproteomic profiling of substrate specificity in gut microbiota-associated bile salt hydrolases.

The gut microbiome possesses numerous biochemical enzymes that biosynthesize metabolites that impact human health. Bile acids comprise a diverse collection of metabolites that have important roles in metabolism and immunity. The gut microbiota-associated enzyme that is responsible for the gateway reaction in bile acid metabolism is bile salt hydrolase (BSH), which controls the host's overall bile acid pool. Despite the critical role of these enzymes, the ability to profile their activities and substrate preferences remains challenging due to the complexity of the gut microbiota, whose metaproteome includes an immense diversity of protein classes. Using a systems biochemistry approach employing activity-based probes, we have identified gut microbiota-associated BSHs that exhibit distinct substrate preferences, revealing that different microbes contribute to the diversity of the host bile acid pool. We envision that this chemoproteomic approach will reveal how secondary bile acid metabolism controlled by BSHs contributes to the etiology of various inflammatory diseases.

Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration.

The importance of ubiquitin E3 ligases in neurodegeneration is being increasingly recognized. The crucial role of NEDD4-1 in neural development is well appreciated; however, its role in neurodegeneration remains unexplored. Herein, we report increased NEDD4-1 expression in the degenerated tissues of several major neurodegenerative diseases. Moreover, its expression is upregulated in cultured neurons in response to various neurotoxins, including zinc and hydrogen superoxide, via transcriptional activation likely mediated by the reactive oxygen species (ROS)-responsive FOXM1B. Reduced protein levels of the insulin-like growth factor receptor (IGF-1Rß) were observed as a consequence of upregulated NEDD4-1 via the ubiquitin-proteasome system. Overexpression of a familial mutant form of superoxide dismutase 1 (SOD1) (G93A) in neuroblastoma cells resulted in a similar reduction of IGF-1Rß protein. This inverse correlation between NEDD4-1 and IGF-1Rß was also observed in the cortex and spinal cords of mutant (G93A) SOD1 transgenic mice at a presymptomatic age, which was similarly induced by in vivo-administered zinc in wild-type C57BL/6 mice. Furthermore, histochemistry reveals markedly increased NEDD4-1 immunoreactivity in the degenerating/degenerated motor neurons in the lumbar anterior horn of the spinal cord, suggesting a direct causative role for NEDD4-1 in neurodegeneration. Indeed, downregulation of NEDD4-1 by shRNA or overexpression of a catalytically inactive form rescued neurons from zinc-induced cell death. Similarly, neurons with a NEDD4-1 haplotype are more resistant to apoptosis, largely due to expression of higher levels of IGF-1Rß.Together, our work identifies a novel molecular mechanism for ROS-upregulated NEDD4-1 and the subsequently reduced IGF-1Rß signaling in neurodegeneration.

A Case Report on "Pearling": Removal of Infected Objects During Circumcision.

The insertion of foreign bodies underneath the skin of the penis is commonly referred to as "pearling." Although rare, there are case reports that describe acute complications such as infection and damage to surrounding penile neurovascular structures; however, there is a paucity of data describing long-term complications and surgical management of such cases. A 43-year-old male presented with a penile abscess secondary to "pearling" five years after insertion. His abscess was drained and selected foreign objects were subsequently removed during a simultaneous circumcision procedure. This report describes a case in which surgical removal of penile foreign bodies was performed during a circumcision without the need for additional incisions. The case is unique in that it details a complication five years after initial insertion with microbiological data to guide adequate treatment.

Patient Satisfaction, Provider Productivity, and Efficacy of a Standardized Preparatory Toolkit With Broad Telemedicine Adaptation in an Outpatient Urology Clinic.

IMPORTANCE: The COVID-19 pandemic prompted telemedicine adoption. In March 2020, we developed an implementation toolkit with a nursing protocol for patient preparation before tertiary care urology clinic visits. OBJECTIVES: Our primary objective was to determine patient satisfaction after implementation of a telemedicine toolkit. Our secondary objective was to assess downstream productivity generated from telehealth visits. STUDY DESIGN: We prospectively conducted a postvisit survey that included the Telehealth Usability Questionnaire, a validated survey assessing patient satisfaction, for all patients with documented completion of the nursing protocol to assess patient experience and satisfaction. We then performed a retrospective chart review of all telemedicine visits to determine downstream outcomes, including imaging and procedure scheduling. RESULTS: Between April and May 2020, 1,422 visits were completed, of which 265 had complete nursing protocol documentation. Eighteen of 265 (6.8%) reported setup assistance. Four (1.8%) were unsuccessful and converted to a nonvisual phone visit. Overall, 186 (70.1%) completed the Telehealth Usability Questionnaire with a mean score of 118.31 ± 23.44. High satisfaction was reported regardless of race, marital status, income, education, employment status, or travel distance. Younger age ( P = 0.017) and female sex ( P = 0.017) were associated with greater satisfaction. Of 1,422 total visits, imaging was ordered in 29%, office procedures scheduled in 14%, and surgery scheduled in 14%. New visits were more likely to result in procedure and surgery scheduling than returns ( P < 0.0001). CONCLUSIONS: Our telemedicine toolkit designed to maximize patient engagement was successful in achieving patient-provider connectivity in 98% of patients with high satisfaction. Telemedicine visits are effective to provide comprehensive urologic care with implications beyond the pandemic.

Small-Fiber Polyneuropathy Is Prevalent in Patients With Interstitial Cystitis/Bladder Pain Syndrome.

IMPORTANCE: The pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is imperfectly understood. Recent studies reported that small-fiber polyneuropathy (SFPN) is common in fibromyalgia, a condition commonly comorbid with IC/BPS. OBJECTIVE: The objective of this study was to determine the prevalence of SFPN in a large cohort of IC/BPS patients. METHODS: Adults diagnosed with IC/BPS scheduled to undergo either therapeutic hydrodistention (n = 97) or cystectomy with urinary diversion (n = 3) were prospectively recruited to this study. A skin biopsy obtained from the lower leg was used for intraepidermal nerve fiber density measurement. Small-fiber polyneuropathy (+/-) status was determined by comparing linear intraepidermal nerve fiber density (fibers/mm2) with normative reference values. Demographic information, medical history, and diagnoses for 14 conditions (both urologic and nonurologic) known to co-occur with IC/BPS were documented from self-report and electronic medical record. RESULTS: In this large cohort of patients with IC/BPS, 31% (31/100) were positive for SFPN. Intraepidermal nerve fiber density was below the median for age and sex in 81% (81/100) of patients. Approximately one-third (31%) of SFPN+ patients reported co-occurring chronic fatigue syndrome, compared with 10.6% of the SFPN- group (P = 0.034). Small-fiber polyneuropathy-positive patients reported significantly fewer allergies than SFPN- patients (37.9% vs 60.6%; P = 0.047). There were no significant differences in bladder capacity or Hunner lesion status between the SFPN+ and SFPN- subgroups. CONCLUSIONS: Small-fiber polyneuropathy is a common finding in patients with IC/BPS, and SFPN status is significantly correlated with co-occurring chronic fatigue syndrome and negatively correlated with the presence of allergies in this population.

A New Gold Rush: A Review of Current and Developing Diagnostic Tools for Urinary Tract Infections.

Urinary tract infections (UTIs) are one of the most common infections in the United States and consequently are responsible for significant healthcare expenditure. The standard urine culture is the current gold standard for diagnosing urinary tract infections, however there are limitations of the test that directly contribute to increased healthcare costs. As a result, new and innovative techniques have been developed to address the inefficiencies of the current standard-it remains to be seen whether these tests should be performed adjunctly to, or perhaps even replace the urine culture. This review aims to analyze the advantages and disadvantages of the newer and emerging diagnostic techniques such as PCR, expanded quantitative urine culture (EQUC), and next generation sequencing (NGS).

Decreasing the prospect of upper extremity neuropraxia during robotic assisted laparoscopic prostatectomy: a novel technique.

Risk of intraoperative neuropathic injury in minimally invasive surgery has been established as a leading complication. Continuous intraoperative neuromonitoring (IONM), such as upper extremity somatosensory evoked potentials (ueSSEPs), to decrease peripheral nerve injury due to positional stress has been described. Robotic-assisted laparoscopic prostatectomy (RALP) requires steep Trendelenberg, which may predispose patients to upper extremity neuropraxia. Subdermal stimulating electrodes were placed on the patients' bilateral wrists over the ulnar nerve and the nerve was stimulated. Realtime waveforms were compared to baseline data to prevent and detect injury to the ulnar nerve. Established intervention criteria, indicating risk for neuropathic damage necessitating intraoperative patient repositioning, was a 50% loss in amplitude or a 10% increase in latency. One hundred and forty three patients received RALP with IONM. 17 of 143 patients (11.8%) met ueSSEP intervention criteria. Only weight was significantly different between the two groups (p = 0.04). Mean reduction in amplitude was 79.9% (SE 4.1). Average amplitude loss duration was 22 min (SE 4.0). Weight and BMI were correlated to the degree of amplitude reduction (p = 0.03 and < 0.01), while operative time and DM approached significance (p = 0.09 and p = 0.14). This is the first study to use IONM to reduce the risk of nerve injury during genitourinary surgery. Realtime nerve monitoring using ueSSEP allowed for upper extremity intraoperative monitoring and repositioning. This may decrease the risk of upper extremity neuropraxia due to malpositioning during RALP. Weight and BMI were identified as risk factors for possible nerve injury. Further data collection and analysis to preoperatively stratify patients for application of IONM during RALP is currently ongoing.

Innovation, Royalties, and Introduction of the Patent Hirsch Index within U.S. Academic Neurosurgery.

BACKGROUND: Historically, practicing neurosurgeons have been key drivers of neurosurgical innovation. We sought to describe the patents held by U.S. academic neurosurgeons and to explore the relationship between patents and royalties received. METHODS: The Centers for Medicare and Medicaid CMS Open Payments Data was used to identify academic neurosurgeons who had received royalties and royalty amounts during a 5-year period (2013-2017). Online patent databases were used to gather patent details. Patent citations and 5-year individual and departmental patent Hirsch (h)-indexes were calculated. Royalties were correlated with the number of patents, patent citations, and patent h-index. RESULTS: We found that 119 academic neurosurgeons (7.8%) from 57 U.S. teaching programs (48.3%) had received royalty payments; 72 (60.5%) had published 648 patents. All surgeons were men, with approximately one half in the "late" stages of their career (45.3%) and subspecializing in spinal surgery (50.4%). The patented products or devices were most commonly used for spinal surgery (72.1%), with 2010-2019 the most productive period (n = 455; 70.2%). The median number of citations per patent was 32 (range, 0-620), with 33% having ≥100 citations. The highest individual and institutional patent h-index was 95; 25 (34.7%) neurosurgeons had a patent h-index of ≥5. The median total royalty payment per individual neurosurgeon was $111,011 (range, $58.05-$76,715,750.34). Royalties were correlated with the number of patents (Spearman r = 0.37; P ≤ 0.001), citations (Spearman r, 0.38; P ≤ 0.001), and inventor h-index (Spearman r = 0.38; P ≤ 0.001). CONCLUSIONS: Few U.S. academic neurosurgeons (7.8%) receive royalties and hold patents (4.7%), with an even smaller select group having a patent h-index of ≥5 (1.6%).

Dissecting the Financial Relationship Between Industry and Academic Neurosurgery.

BACKGROUND: Established by the Centers for Medicare and Medicaid Services (CMS), the Open Payments Database (OPD) has reported industry payments to physicians since August 2013. OBJECTIVE: To evaluate the frequency, type, and value of payments received by academic neurosurgeons in the United States over a 5-yr period (2014-2018). METHODS: The OPD was queried for attending neurosurgeons from all neurosurgical training programs in the United States (n = 116). Information from the OPD was analyzed for the entire cohort as well as for comparative subgroup analyses, such as career stage, subspecialty, and geographic location. RESULTS: Of all identified neurosurgeons, 1509 (95.0%) received some payment from industry between 2014 and 2018 for a total of 106 171 payments totaling $266 407 458.33. A bimodal distribution was observed for payment number and total value: 0 to 9 (n = 438) vs > 50 (n = 563) and 0-$1000 (n = 418) vs >$10 000 (n = 653), respectively. Royalty/License was the most common type of payment overall (59.6%; $158 723 550.57). The median number (40) and value ($8958.95) of payments were highest for mid-career surgeons. The South-Central region received the most money ($117 970 036.39) while New England received the greatest number of payments (29 423). Spine surgeons had the greatest median number (60) and dollar value ($20 551.27) of payments, while pediatric neurosurgeons received the least (8; $1108.29). Male neurosurgeons received a greater number (31) and value ($6395.80) of payments than their female counterparts (11, $1643.72). CONCLUSION: From 2014 to 2018, payments to academic neurosurgeons have increased in number and value. Dollars received were dependent on geography, career stage, subspecialty and gender.

Retinoid X receptor-alpha mediates (R )-flurbiprofen's effect on the levels of Alzheimer's beta-amyloid.

Alzheimer's disease (AD) is characterized by the formation of extracellular senile plaques in the brain, whose major component is a small peptide called beta-amyloid (Abeta). Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been found beneficial for AD and several reports suggest that NSAIDs reduce the generation of Abeta, especially the more amyloidogenic form Abeta42. However, the exact mechanism underlying NSAIDs' effect on AD risk remains largely inconclusive and all clinical trials using NSAIDs for AD treatment show negative results so far. Recent studies have shown that some NSAIDs can bind to certain nuclear receptors, suggesting that nuclear receptors may be involved in NSAID's effect on AD risk. Here we find that (R)-flurbiprofen, the R-enantiomer of the racemate NSAID flurbiprofen, can significantly reduce Abeta secretion, but at the same time, increases the level of intracellular Abeta. In addition, we find that a nuclear receptor, retinoid X receptor alpha (RXRalpha), can regulate Abeta generation and that down-regulation of RXRalpha significantly increases Abeta secretion. We also show that (R)-flurbiprofen can interfere with the interaction between RXRalpha and 9-cis-retinoid acid, and that 9-cis-retinoid acid decreases (R)-flurbiprofen's reduction of Abeta secretion. Moreover, the modulation effect of (R)-flurbiprofen on Abeta is abolished upon RXRalpha down-regulation. Together, these results suggest that RXRalpha can regulate Abeta generation and is also required for (R)-flurbiprofen-mediated Abeta generation.

Highly sensitive LC-MS-MS analysis of a pharmaceutical compound in human plasma using monolithic phase-based on-line extraction.

Monolithic columns have been used in recent years for fast chromatographic separation due to their high permeability and low backpressure. We have explored the potential of monolithic material as sample preparation tool in bioanalytical applications. By taking advantage of monolithic columns' online concentration capability, we have developed a highly sensitive liquid chromatography-tandem mass spectrometry assay for quantitative determination of a pharmaceutical compound in human plasma. The assay was fully validated to satisfy the requirements of precision and accuracy, selectivity, matrix effect, and reproducibility. A linear dynamic range from 0.011 ng/mL to 12.3 ng/mL was established as the calibration standard. The percentage of bias for quality control samples was between -9.9% and -2.5%. Coefficient of variation, a measurement of precision, was within 9.9%. On-line extraction with monolithic support provided adequate sample cleanup and on-line concentration of the analyte. The assay exhibited good tolerance to matrix effect and has been applied successfully to a clinical study. The incurred sample analysis showed that original and repeat values were within +/-10.1% for all assay samples.