Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ear balance organs.

Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.

Effectiveness of an early operating room start time in managing pediatric trauma.

BACKGROUND: The timing of operative treatment for pediatric supracondylar humerus fractures (SCHF) and femoral shaft fractures (FSF) remains controversial. Many fractures previously considered to be surgical emergencies, such as SCHF and open fractures, are now commonly being treated the following day. When presented with an urgent fracture overnight needing operative treatment, the on-call surgeon must choose whether to mobilize resources for a late-night case or to add the case to an elective schedule of the following day. AIM: To describe the effect of a program allowing an early operating room (OR) start for uncomplicated trauma prior to an elective day of surgery to decrease wait times for surgery for urgent fractures admitted overnight. METHODS: Starting in October 2017, patients were eligible for the early slot in the OR at the discretion of the surgeon if they were admitted after 21:00 the previous night and before 05:00. We compared demographics and timing of treatment of SCHF and FSF treated one year before and after implementation as well as the survey responses from the surgical team. RESULTS: Of the 44 SCHF meeting inclusion criteria, 16 received treatment before implementation while 28 were treated after. After implementation, the mean wait time for surgery decreased by 4.8 h or 35.4% (13.4 h vs 8.7 h; P = 0.001). There were no significant differences in the operative duration, time in the post anesthesia care unit, and wait time for discharge. Survey results demonstrated decreased popularity of the program among nurses and anesthesiologists relative to surgeons. Whereas 57% of the surgeons believed that the program was effective, only 9% of anesthesiologists and 16% of nurses agreed. The program was ultimately discontinued given the dissatisfaction. CONCLUSION: Our findings demonstrate significantly reduced wait times for surgery for uncomplicated SCHF presenting overnight while discussing the importance of shared decision-making with the stakeholders. Although the program produced promising results, it also created new conflicts within the OR staff that led to its discontinuation at our institution. Future implementations of such programs should involve stakeholders early in the planning process to better address the needs of the OR staff.

Pediatric meniscus morphology varies with age: a cadaveric study.

PURPOSE: In adolescent patients, meniscal tear injury can occur either in isolation (e.g., discoid lateral meniscus tears) or in association with other traumatic injuries including tibial eminence fracture or ACL tear. Damage to meniscal integrity has been shown to increase contact pressure in articular cartilage, increasing risk of early onset osteoarthritis. In symptomatic patients failing conservative management, surgical intervention via meniscus repair or meniscus transplant is indicated. The purpose of this study was to evaluate the radial dimensions of pediatric menisci throughout development. The hypothesis was that the average radial meniscus dimensions will increase as specimen age increases, and mean medial and lateral region measurements will increase at a linear rate. METHODS: Seventy-eight skeletally immature knee cadaver specimens under age 12 years were included in this study. The meniscal specimens were photographed in the axial view with ruler in the plane of the tibial plateau and analyzed using computer-aided design (CAD) software (Autodesk Fusion 360). Measurements were taken from inner to outer meniscus rims at five 45 degree intervals using the clockface as a reference (12:00, 1:30, 3:00, 4:30, 6:00), and total area of meniscus and tibial plateau was recorded. Generalized linear models were used to evaluate the associations of radial width measurements with age, tibial coverage, and lateral vs. medial meniscus widths. RESULTS: All radial width measurements increased significantly with specimen age (p ≤ 0.002), and all lateral-medial meniscal widths increased (p < 0.001). The anterior zones of the meniscus were found to increase at the slowest rate compared to other regions. Tibial plateau coverage was found to not significantly vary with age. CONCLUSIONS: Meniscus radial width and lateral-medial meniscus width are related to age. The anterior width of the meniscus varied least with age. Improved anatomic understanding may help surgeons more effectively plan for meniscus repair, discoid resection/saucerization/repair, and also support appropriate selection of meniscus allograft for transplantation.

Opioid Represcriptions After ACL Reconstruction in Adolescents Are Associated With Subsequent Opioid Use Disorder.

INTRODUCTION: Postoperative opioid prescriptions may confer a risk for subsequent opioid use disorders (OUDs). For many children, postoperative analgesia is often the first opioid exposure. The rates of anterior cruciate ligament (ACL) reconstruction in pediatric populations are rising. Here, we use an administrative claims database to describe opioid prescription patterns after ACL reconstruction and their effect on subsequent risk of OUD. METHODS: Using International Classification of Diseases (ICD)-9, ICD-10, and CPT codes, we identified patients, with ages 10 to 18, undergoing primary ACL reconstruction between 2014 and 2016 with minimum 1 year follow-up in the Optum Clinformatics Data Mart, which is a nationally representative administrative claims database. Demographic variables and prescription patterns (in morphine milligram equivalents [MMEs]) were analyzed using univariate tests and multivariable logistic regression to determine any potential association with the appearance of anew an ICD-9 or ICD-10 code for OUD within 1 year of the initial procedure. RESULTS: A total of 4459 cases were included and 29 (0.7%) of these patients were diagnosed with an OUD within 1 year of surgery. Upon univariate analysis, opioid represcriptions within 6 weeks were significantly more common among patients with OUD; 27.6% vs. 9.7% of patients that did not develop a new diagnosis of OUD ( P =0.005). Multivariable logistic regression indicated an independent significant relationship between total MMEs initially prescribed and the odds of a subsequent OUD diagnosis: for each additional 100 MMEs prescribed in total, the odds of OUD increased by 13% ( P =0.002). Patients with a represcription within 6 weeks of surgery had an average increase in the odds of OUD by 161% ( P =0.027). CONCLUSIONS: In this cohort of patient ages 10 to 18 undergoing primary isolated ACL reconstruction, we found substantial variability in opiate prescribing patterns and higher initial opioid prescription volume, as well as opioid represcription within 6 weeks were predictive of the subsequent development of OUD. LEVEL OF EVIDENCE: Level III.

Small-Scale Perfusion Bioreactor of Red Blood Cells for Dynamic Studies of Cellular Pathways: Proof-of-Concept.

To date, the development of bioreactors for the study of red blood cells (RBCs, daily transfused in the case of disease or hemorrhage) has focused on hematopoietic stem cells. Despite the fact that mature RBCs are enucleated and do not expand, they possess complex cellular and metabolic pathways, as well as post-translation modification signaling and gas-exchange regulation. In order to dynamically study the behavior of RBCs and their signaling pathways under various conditions, a small-scale perfusion bioreactor has been developed. The most advanced design developed here consists of a fluidized bed of 7.6 mL containing 3·10(9) cells and perfused at 8.5 µL/min. Mimicking RBC storage conditions in transfusion medicine, as a proof-of-concept, we investigated the ex vivo aging of RBCs under both aerobic and anaerobic conditions. Hence, RBCs stored in saline-adenine-glucose-mannitol (SAGM) were injected in parallel into two bioreactors and perfused with a modified SAGM solution over 14 days at room temperature under air or argon. The formation of a fluidized bed enabled easy sampling of the extracellular medium over the storage period used for the quantitation of glucose consumption and lactate production. Hemolysis and microvesiculation increased during aging and were reduced under anaerobic (argon) conditions, which is consistent with previously reported findings. Glucose and lactate levels showed expected trends, i.e., decreased and increased during the 2-week period, respectively; whereas extracellular glucose consumption was higher under aerobic conditions. Metabolomics showed depletion of glycolsis and pentose phosphate pathway metabolites, and an accumulation of purine metabolite end-products. This novel approach, which takes advantage of a fluidized bed of cells in comparison to traditional closed bags or tubes, does not require agitation and limit shear stress, and constantly segragates extracellular medium from RBCs. It thus gives access to several difficult-to-obtain on- and off-line parameters in the extracellular medium. This dynamic bioreactor system does not only allow us to probe the behavior of RBCs under different storage conditions, but it also could be a powerful tool to study physiological or pathological RBCs exposed to various conditions and stimuli.