The appearance of large-conductance, calcium-activated potassium (BK) current is a hallmark of functional maturation in auditory hair cells. Acquisition of this fast-activating current enables high-frequency, graded receptor potentials in all vertebrates and an electrical tuning mechanism in nonmammals. The gene encoding BK α subunits is highly alternatively spliced, and the resulting variations in channel isoforms may contribute to functional diversity at the onset of hearing. We examined the tissue specificity of nine BK α alternative exons and investigated changes in expression during chick cochlear development using quantitative polymerase chain reaction (qPCR). Each alternative was widely expressed in several tissues except for an insert near the C-terminus Ca2+ sensing domain, which appeared brain-specific. The only alternative form in the membrane-bound core of the channel was expressed in brain and muscle but was undetected in cochlea. Of the remaining variants, three increased in expression prior to the onset of hearing and acquisition of BK currents. These three variants cause decreased Ca2+ sensitivity or increased intracellular retention, traits that would not easily explain the advent of calcium-sensitive currents at embryonic day (E)18–19. Expression levels of other variants were mature and stable by E15, days before currents were acquired. Surface expression of C-terminal isoforms was examined using patch-clamp electrophysiology and immunocytochemistry. C-terminal variants that exhibit robust surface expression appeared in the membrane at E18, even though transcripts were unchanged during development starting from E12. These results indicate that delays in protein synthesis and trafficking/scaffolding of channel subunits underlie the late acquisition of BK currents in cochlear hair cells.

Although early therapeutic research on psychedelics dates back to the 1940s, this field of investigation was met with many cultural and legal challenges in the 1970s. Over the past two decades, clinical trials using psychedelics have resumed. Therefore, the goal of this study was to (1) better characterize the recent uptrend in psychedelics in clinical trials and (2) identify areas where potentially new clinical trials could be initiated to help in the treatment of widely prevalent medical disorders. A systematic search was conducted on the clinicaltrials.gov database for all registered clinical trials examining the use of psychedelic drugs and was both qualitatively and quantitatively assessed. Analysis of recent studies registered in clinicaltrials.gov was performed using Pearson's correlation coefficient testing. Statistical analysis and visualization were performed using R software. In totality, 105 clinical trials met this study's inclusion criteria. The recent uptrend in registered clinical trials studying psychedelics (p = 0.002) was similar to the uptrend in total registered clinical trials in the registry (p < 0.001). All trials took place from 2007 to 2020, with 77.1% of studies starting in 2017 or later. A majority of clinical trials were in phase 1 (53.3%) or phase 2 (25.7%). Common disorders treated include substance addiction, post-traumatic stress disorder, and major depressive disorder. Potential research gaps include studying psychedelics as a potential option for symptomatic treatment during opioid tapering. There appears to be a recent uptrend in registered clinical trials studying psychedelics, which is similar to the recent increase in overall trials registered. Potentially, more studies could be performed to evaluate the potential of psychedelics for symptomatic treatment during opioid tapering and depression refractory to selective serotonin reuptake inhibitors.

Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABAA-Rs and/or GABAB-Rs). Treatment with GABA, which activates both GABAA-Rs and GABAB-Rs), and/or a GABAA-R-specific agonist inhibits disease progression in mouse models of type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and COVID-19. Little is known about the clinical potential of specifically modulating GABAB-Rs. Here, we tested lesogaberan, a peripherally restricted GABAB-R agonist, as an interventive therapy in diabetic NOD mice. Lesogaberan treatment temporarily restored normoglycemia in most newly diabetic NOD mice. Combined treatment with a suboptimal dose of lesogaberan and proinsulin/alum immunization in newly diabetic NOD mice or a low-dose anti-CD3 in severely hyperglycemic NOD mice greatly increased T1D remission rates relative to each monotherapy. Mice receiving combined lesogaberan and anti-CD3 displayed improved glucose tolerance and, unlike mice that received anti-CD3 alone, had some islets with many insulin+ cells, suggesting that lesogaberan helped to rapidly inhibit β-cell destruction. Hence, GABAB-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABAB-Rs and GABAA-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.

No abstract

OBJECTIVE Spinal robotics for thoracolumbar procedures, predominantly employed for the insertion of pedicle screws, is currently an emerging topic in the literature. The use of robotics in instrumentation of the cervical spine has not been broadly explored. In this review, the authors aimed to coherently synthesize the existing literature of intraoperative robotic use in the cervical spine and explore considerations for future directions and developments in cervical spinal robotics. METHODS A literature search in the Web of Science, Scopus, and PubMed databases was performed for the purpose of retrieving all articles reporting on cervical spine surgery with the use of robotics. For the purposes of this study, randomized controlled trials, nonrandomized controlled trials, retrospective case series, and individual case reports were included. The Newcastle-Ottawa Scale was utilized to assess risk of bias of the studies included in the review. To present and synthesize results, data were extracted from the included articles and analyzed using the PyMARE library for effect-size meta-analysis. RESULTS On careful review, 6 articles published between 2016 and 2022 met the inclusion/exclusion criteria, including 1 randomized controlled trial, 1 nonrandomized controlled trial, 2 case series, and 2 case reports. These studies featured a total of 110 patients meeting the inclusion criteria (mean age 53.9 years, range 29–77 years; 64.5% males). A total of 482 cervical screws were placed with the use of a surgical robot, which yielded an average screw deviation of 0.95 mm. Cervical pedicle screws were the primary screw type used, at a rate of 78.6%. According to the Gertzbein-Robbins classification, 97.7% of screws in this review achieved a clinically acceptable grade. The average duration of surgery, blood loss, and postoperative length of stay were all decreased in minimally invasive robotic surgery relative to open procedures. Only 1 (0.9%) postoperative complication was reported, which was a surgical site infection, and the mean length of follow-up was 2.7 months. No mortality was reported. CONCLUSIONS Robot-assisted cervical screw placement is associated with acceptable rates of clinical grading, operative time, blood loss, and postoperative complications—all of which are equal to or improved relative to the metrics seen in the conventional use of fluoroscopy or computer-assisted navigation for cervical screw placement.

Clerkship grading is a core feature of evaluation for medical students’ skills as physicians and is considered by most residency program directors to be an indicator of future performance and success. With the transition of the U.S. Medical Licensing Examination Step 1 score to pass/fail, there will likely be even greater reliance on clerkship grades, which raises several important issues that need to be urgently addressed. This article details the current landscape of clerkship grading and the systemic discrepancies in assessment and allocation of honors. The authors examine not only objectivity and fairness in clerkship grading but also the reliability of clerkship grading in predicting residency performance and the potential benefits and drawbacks to adoption of a pass/fail clinical clerkship grading system. In the promotion of a more fair and equitable residency selection process, there must be standardization of grading systems with consideration of explicit grading criteria, grading committees, and/or structured education of evaluators and assessors regarding implicit bias. In addition, greater adherence and enforcement of transparency in grade distributions in the Medical Student Performance Evaluation is needed. These changes have the potential to level the playing field, foster equitable comparisons, and ultimately add more fairness to the residency selection process.

BACKGROUND Primary spinal infections (PSIs) are a group of uncommon but serious infectious diseases considered more prevalent and aggressive among patients with chronic immunocompromised states. Association of PSI and solid organ transplant has not been systematically analyzed. The authors performed a systematic review analyzing clinical presentation and mortality of patients with PSI in the setting of solid organ transplant. OBSERVATIONS PSIs in patients with immunosuppressive therapy, such as those with solid organ transplant, may behave differently in terms of epidemiology, clinical presentation, and outcomes compared with nonimmunosuppressed patients. Overall PSI in solid organ transplant patients is associated with a high rate of neurological compromise, postoperative complications, and mortality. LESSONS Accurate diagnosis and appropriate treatment of PSI require a multidisciplinary effort. Localized pain is the most frequently reported symptom associated with PSI. As opposed to PSI in patients without transplant, inflammatory and infectious markers such as white blood cells and C-reactive protein are often not elevated. Furthermore, the causative microorganism profile varies significantly when compared to pyogenic spinal infection in patients without transplant. Aspergillus species was responsible for spondylodiscitis in transplant patients in more than 50% of cases, and the incidence of Aspergillus infection is projected to rise in the coming years.

No abstract