Propofol for treatment resistant depression: A randomized controlled trial.

Background: Anesthetic agents including ketamine and nitrous oxide have shown antidepressant properties when appropriately dosed. Our recent open-label trial of propofol, an intravenous anesthetic known to elicit transient positive mood effects, suggested that it may also produce robust and durable antidepressant effects when administered at a high dose that elicits an electroencephalographic (EEG) burst-suppression state. Here we report findings from a randomized controlled trial ( NCT03684447 ) that compared two doses of propofol. We hypothesized greater improvement with a high dose that evoked burst suppression versus a low dose that did not. Methods: Participants with moderate-to-severe, treatment-resistant depression were randomized to a series of 6 treatments at low versus high dose (n=12 per group). Propofol infusions were guided by real-time processed frontal EEG to achieve predetermined pharmacodynamic criteria. The primary and secondary depression outcome measures were the 24-item Hamilton Depression Rating Scale (HDRS-24) and the Patient Health Questionnaire (PHQ-9), respectively. Secondary scales measured suicidal ideation, anxiety, functional impairment, and quality of life. Results: Treatments were well tolerated and blinding procedures were effective. The mean [95%-CI] change in HDRS-24 score was -5.3 [-10.3, -0.2] for the low-dose group and -9.3 [-12.9, -5.6] for the high-dose group (17% versus 33% reduction). The between-group effect size (standardized mean difference) was -0.56 [-1.39, 0.28]. The group difference was not statistically significant (p=0.24, linear model). The mean change in PHQ-9 score was -2.0 [-3.9, -0.1] for the low dose and -4.8 [-7.7, -2.0] for the high dose. The between-group effect size was -0.73 [-1.59, 0.14] (p=0.09). Secondary outcomes favored the high dose (effect sizes magnitudes 0.1 - 0.9) but did not generally reach statistical significance (p>0.05). Conclusions: The medium-sized effects observed between doses in this small, controlled, clinical trial suggest that propofol may have dose-dependent antidepressant effects. The findings also provide guidance for subsequent trials. A larger sample size and additional treatments in series are likely to enhance the ability to detect dose-dependent effects. Future work is warranted to investigate potential antidepressant mechanisms and dose optimization.

Implementing Digital-Waveform Technology for Extended m/z Range Operation on a Native Dual-Quadrupole FT-IM-Orbitrap Mass Spectrometer.

Here, we describe a digital-waveform dual-quadrupole mass spectrometer that enhances the performance of our drift tube FT-IMS high-resolution Orbitrap mass spectrometer (MS). The dual-quadrupole analyzer enhances the instrument capabilities for studies of large protein and protein complexes. The first quadrupole (q) provides a means for performing low-energy collisional activation of ions to reduce or eliminate noncovalent adducts, viz., salts, buffers, detergents, and/or endogenous ligands. The second quadrupole (Q) is used to mass-select ions of interest for further interrogation by ion mobility spectrometry and/or collision-induced dissociation (CID). Q is operated using digital-waveform technology (DWT) to improve the mass selection compared to that achieved using traditional sinusoidal waveforms at floated DC potentials (>500 V DC). DWT allows for increased precision of the waveform for a fraction of the cost of conventional RF drivers and with readily programmable operation and precision (Hoffman, N. M. . A comparison-based digital-waveform generator for high-resolution duty cycle. Review of Scientific Instruments 2018, 89, 084101).

A comparison based digital waveform generator for high resolution duty cycle.

A comparison-based digital waveform generator has been developed that directly enables purely duty cycle controlled digital mass filters. This waveform generator operates by the comparison of a periodic waveform and a DC level to produce a digital waveform. The improved duty cycle realized by this method of waveform generation is demonstrated by producing a mass spectrum of electrosprayed lysozyme by varying the duty cycle of a digital waveform applied to a quadrupole rod set. Operation and control of the waveform generator using an inexpensive open-source microcontroller is discussed.

Using Digital Waveforms to Mitigate Solvent Clustering During Mass Filter Analysis of Proteins.

With advances in the precision of digital electronics, waveform generation technology has progressed to a state that enables the creation of m/z filters that are purely digitally driven. These advances present new methods of performing mass analyses that provide information from a chemical system that are inherently difficult to achieve by other means. One notable characteristic of digitally driven mass filters is the capacity to transmit ions at m/z ratios that vastly exceed the capabilities of traditional resonant systems. However, the capacity to probe ion m/z ratios that span multiple orders of magnitudes across multiple orders of magnitude presents a new set of issues requiring a solution. In the present work, when probing multiply charged protein species beyond m/z 2000 using a gentle atmospheric pressure interface, the presence of solvent adducts and poorly resolved multimers can severely degrade spectral fidelity. Increasing energy imparted into a target ion population is one approach minimizing these clusters; however, the use of digital waveform technology provides an alternative that maximizes ion transport efficiency and simultaneously minimizes solvent clustering. In addition to the frequency of the applied waveform, digital manipulation also provides control over the duty cycle of the target waveform. This work examines the conditions and approach leading to optimal digital waveform operation to minimize solvent clustering. Graphical Abstract ᅟ.

Digital Waveform Technology and the Next Generation of Mass Spectrometers.

Ion traps and guides are integral parts of current commercial mass spectrometers. They are currently operated with sinusoidal waveform technology that has been developed over many years. Recently, digital waveform technology has begun to emerge and promises to supplant its older cousin because it presents new capabilities that result from the ability to instantaneously switch the frequency and duty cycle of the waveforms. This manuscript examines these capabilities and reveals their uses and effects on instrumentation. Graphical Abstract ᅟ.

Note: An inexpensive square waveform ion funnel driver.

An inexpensive frequency variable square waveform generator (WFG) was developed to use with existing sinusoidal waveform driven ion funnels. The developed WFG was constructed using readily available low voltage DC power supplies and discrete components placed in printed circuit boards. As applied to ion funnels, this WFG represents considerable cost savings over commercially available products without sacrificing performance. Operation of the constructed pulse generator has been demonstrated for a 1 nF ion funnel at an operating frequency of 1 MHz while switching 48 Vp-p.

Development of MS(n) in digitally operated linear ion guides.

This publication demonstrates the use of digital waveform manipulation in linear ion guides to trap isolated ions and fragment them before mass analysis by time-of-flight mass spectrometry (TOF-MS). Ion trapping and collection was performed by waveform duty cycle manipulation to create a negative axial potential between the rods and the end-cap electrodes. Ion isolation can be performed by duty cycle manipulation to narrow the range of stable masses while continuing to axially trap the ions. Further ion isolation can then be performed by jumping the quadrupole frequency to each side of the stability zone to eliminate ions above and below the isolated ion mass. Collision-induced dissociation was demonstrated by duty cycle manipulation to either axially or radially excite the ions. The methods for performing these types of excitations are discussed and demonstrated. These techniques can be combined or used separately for MS(n) analysis. The use of frequency and duty cycle manipulation of the applied waveforms simplifies the hardware while greatly increasing the capabilities of linear ion guides and quadrupole time-of-flight mass spectrometers (Q-TOF-MS). Linear quadrupoles can now be used as high efficiency ion traps for collection, isolation, and tandem mass spectrometry at any value of m/z when operated digitally.

Angiomyofibroblastoma-like tumors (cellular angiofibroma).

Angiomyofibroblastoma-like tumor (cellular angiofibroma) is a rare, circumscribed, slow-growing mesenchymal tumor that occurs predominantly in the vulva, perineum, and pelvis of women. We report two cases of this tumor in men arising as paratesticular masses of the scrotum, summarize the history of this tumor, and discuss why efforts should be made to differentiate it from aggressive angiomyxoma. Recommended treatment is complete surgical excision with long-term follow up exams, as local recurrence may occur many years after resection of the lesion.

Impact of heads-up display imaging on endoscopic task performance.

BACKGROUND AND PURPOSE: Heads-Up Imaging goggles provide ergonomic advantages to the endourologist. This study was designed to evaluate whether heads-up display impacts task performance for ureteroscopic stone retrieval. MATERIALS AND METHODS: The ability to capture a 5-mm calculus with a Cook N-Circle 2.2F stone basket from an inanimate caliceal model was tested by three experienced and three novice stone-basket operators. Visual display for initial testing for each operator was randomized to the OptiVu HD3 Heads-Up googles or a 20- inch Sony Triniton monitor (TV). Subsequent testing alternated between the two devices. Camera input was provided by the Storz telecam SL-NTSC. The HD3 was set up to align the direction of view with the operator's hands, while the TV was aligned at an angle 45 degrees lateral and 30 degrees superior to the operator's direction of view to approximate the traditional room set-up for an endourologic procedure. Each operator performed five basketing trials with each display set-up. RESULTS: Expert operators retrieved calculi more rapidly (9.2 +/- 5.9 seconds) than novice operators (50.7 +/- 48.9 seconds), irrespective of whether a TV monitor or goggle display was utilized as the imaging modality. No significant differences were noted in task performance between the two imaging modalities for the expert (P = b0.60), novice (P = 0.77), or overall (P = 0.91) groups. CONCLUSION: The Optiview Heads-Up goggle display system does not offer advantages in task performance with specific regard to the ability to capture stone fragments with baskets.

Comparison of tipless and helical baskets in an in vitro ureteral model.

OBJECTIVES: To compare the rapidity of stone capture and removal by six tipless and four helical baskets in a ureteral model. Expeditious ureteral stone extraction is reliant on the basket size, configuration, and radial dilation force. METHODS: A 5-mm feline calculus was placed in a simulated model of the human ureter at a distance of 7.5 cm from the orifice, and saline irrigant instilled. A 6/7.5F Wolf semirigid ureteroscope was used for access and visualization of the stone. Operators were randomized to start stone extraction with 1 of 10 stone baskets, and three extraction attempts were conducted with each device. Six experienced operators tested each device. The tipless baskets tested were the ACMI Sur-Catch NT 3.0F, Bard Dimension 3.0F, Boston Scientific Zerotip 3.0F, Cook N-Circle 3.0F, Cook Delta 2.4F, and Sacred Heart Halo 1.9F. The helical baskets tested were the Cook N-Force 3.2F, Microvasive Gemini 3.0F, ACMI Sur-Catch Helical 3.0F, and Sacred Heart Hercules 3.0F. The time to extraction in seconds was recorded. RESULTS: No statistically significant difference was observed between the tipless (14 +/- 7 seconds) or helical (12.8 +/- 6.6 seconds, P = 0.21) basket groups. All baskets were able to retrieve the ureteral stones successfully. The most efficient basket was the Cook N-Circle with an average time of 8.7 seconds to stone extraction compared with the least efficient basket, the ACMI Sur-Catch NT, at 15.8 seconds. CONCLUSIONS: The Cook N-Circle basket provided the most expeditious means to stone extraction in a ureteral model.

Percutaneous renal stone extraction: in vitro study of retrieval devices.

PURPOSE: Traditionally, percutaneous stone extraction has relied on the use of 2-prong and 3-prong graspers, which are prone to causing trauma to the urothelium. We evaluate the efficiency of stone removal with a novel tipless stone basket designed specifically for percutaneous procedures. MATERIALS AND METHODS: A 3, 5 and 8 mm human calculus were placed in the calix of a percutaneous renal model. A 26Fr Storz nephroscope (27093B, Storz Medical AG, Kreuzlingen, Switzerland) was inserted through a 30Fr Amplatz sheath into the model with camera input from a Storz telecam SL-NTSC feeding to a 20-inch Sony Triniton monitor (Sony Corp of America, New York, New York). Operators were randomized to start stone extraction with a Storz 3-prong grasper (27090RB) or a Cook 12Fr Perc-NCircle (38 cm) (Cook Urological, Inc., Indianapolis, Indiana). Subsequent testing alternated between the 2 devices until 10 extraction attempts were conducted with each device. Time to extraction of all 3 calculi and number of inadvertent withdrawals of the sheath were recorded. Three experienced operators tested each device. RESULTS: Stone extraction times were shorter with the Cook Perc-NCircle than the 3-prong grasper for all operators. Mean time for stone extraction was 25.3 +/- 11.2 seconds for the Perc-NCircle compared to 35.1 +/- 18.5 seconds for the 3-prong grasper (p = 0.016). Loss of access by inadvertent removal of the Amplatz sheath occurred in 53% of the attempts with the 3-prong grasper compared to 7% of attempts with the Perc-NCircle. CONCLUSIONS: The Cook Perc-NCircle facilitates a more expeditious approach to percutaneous stone removal with less risk of sheath withdrawal.

Comparison of nitinol tipless stone baskets in an in vitro caliceal model.

PURPOSE: Tipless stone baskets facilitate caliceal calculi extraction during flexible ureteroscopy. We evaluated the stone capture rate of 9 commercially available tipless stone baskets in an in vitro model using novice and expert operators. MATERIALS AND METHODS: The Microvasive Zerotip (2.4Fr, 3.0Fr), Cook N-Circle (2.2Fr, 3.0Fr, 3.2Fr), Bard Dimension (3.0Fr, Sacred Heart Medical Halo (1.9Fr), Vantage (1.9Fr) and Circon-ACMI Sur-Catch-NT (3.0Fr) were tested by 3 novice and 3 experienced basket operators. Each operator performed stone extraction of 2, 5 and 8 mm calculi (size determined by digital caliper with 3 repetitions of each basket. The time to extraction of the calculus from a convex based test tube caliceal model was recorded. Statistical analysis was performed using repeated measures ANOVA and Fisher's pairwise comparisons. RESULTS: After a learning curve of 27 basket retrievals, there was no significant difference in stone capture times between novice (38 +/- 54 seconds) and expert operators (32 +/- 49 seconds, p = 0.174). For total stone capture (all sizes) the Sacred Heart Halo resulted in the most rapid stone extraction (17 +/- 14 seconds) by novices and experts, while the Sur-Catch NT resulted in the slowest stone extraction (78 +/- 90, seconds, p = 0.001). The Halo (14 +/- 9 seconds) and Vantage (19 +/- 12 seconds) baskets were significantly faster for 2 mm calculi than the N-Circle (73 +/- 60 seconds, p = 0.006), Sur-Catch (169 +/- 85 seconds, p = 0.0005) and Dimension (73 +/- 70 seconds, p = 0.017). The Zerotip functioned well for 2 mm calculi in the hands of expert operators (15 +/- 9 seconds) but not novice operators (94 +/- 95 seconds). The Sur-Catch NT was significantly slower for 2 mm calculi than the N-Circle (p = 0.01), Dimension (p =.03), Halo (p =.0005), Vantage (p =.001) and Zerotip (p =.002). For 5 mm calculi the Halo was superior (12 +/- 8 seconds), while the Zerotip were superior for 8 mm calculi (8 +/- 3 seconds) compared to the N-Circle (23 +/- 28 seconds, p = 0.026), Halo (26 +/- 18 seconds, p = 0.021) and Vantage (23 +/- 15 seconds, p = 0.006). CONCLUSIONS: The Sacred Heart Halo and Vantage baskets resulted in the most expeditious stone extraction, especially for 2 to 5 mm calculi while the Microvasive Zerotip was optimal for 8 mm calculi. The Sur-Catch NT had the slowest stone capture rate for all stone sizes. Caliceal models of stone basketing may be useful to train novice urology residents and nursing assistants.

Ephedrine- and guaifenesin-induced nephrolithiasis.

OBJECTIVES: Ephedrine and guaifenesin are herbal supplements that have experienced increased use over the past decade. Ephedrine has been used as a stimulant and weight-loss product, guaifenesin as an expectorant and cough suppressant; both are found in combination in many antitussives and expectorants. This paper reviews the reported cases of ephedrine- and guaifenesin-induced nephrolithiasis, as well as the diagnostic techniques and treatments that have been successfully used for these stones. DESIGN: A systematic review of the literature pertaining to nephrolithiasis and the compounds ephedrine and guaifenesin was conducted. RESULTS: Ephedrine and guaifenesin use results in over 35% of urinary stones that are related to pharmaceutical metabolites, and collectively are present in 0.1% of all urinary stones. These calculi are radiolucent, requiring the use of computerized tomography (CT scan) for diagnosis. Alkalinization therapy offers an alternative to surgical intervention and may have a role in prevention of recurrence. CONCLUSIONS: Ephedrine and guaifenesin have been shown to cause nephrolithiasis in cases of abuse when taken individually or in combination. It is important for the clinician to be aware of the potential for these compounds to cause nephrolithiasis.

Resolution of ephedrine stones with dissolution therapy.

A patient with a history of ingesting large quantities of an over-the-counter stimulant developed renal calculi that on further analysis, after stone passage, revealed increased amounts of ephedrine. Over the course of 7 months, all of the patient's ephedrine stones were managed successfully by alkalinization. Similar to previously reported ephedrine calculi, these stones were radiolucent on x-ray imaging, but their course was monitored on serial nonenhanced computed tomography scans. We believe this to be the first reported use of alkaline therapy for the dissolution of renal stones containing ephedrine.