Sleep EEG signatures in mouse models of 15q11.2-13.1 duplication (Dup15q) syndrome.

BACKGROUND: Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABAAR) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABAARs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls. METHODS: We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student's t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05. RESULTS: Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation. CONCLUSIONS: Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations.

Hydrogen-rich water improves sleep consolidation and enhances forebrain neuronal activation in mice.

Study Objectives: Sleep loss contributes to various health issues and impairs neurological function. Molecular hydrogen has recently gained popularity as a nontoxic ergogenic and health promoter. The effect of molecular hydrogen on sleep and sleep-related neural systems remains unexplored. This study investigates the impact of hydrogen-rich water (HRW) on sleep behavior and neuronal activation in sleep-deprived mice. Methods: Adult C57BL/6J mice were implanted with electroencephalography (EEG) and electromyography (EMG) recording electrodes and given HRW (0.7-1.4 mM) or regular water for 7 days ad libitum. Sleep-wake cycles were recorded under baseline conditions and after acute sleep loss. Neuronal activation in sleep- and wake-related regions was assessed using cFos immunostaining. Results: HRW increased sleep consolidation in undisturbed mice and increased non-rapid-eye movement and rapid-eye-movement sleep amount in sleep-deprived mice. HRW also decreased the average amount of time for mice to fall asleep after light onset. Neuronal activation in the lateral septum, medial septum, ventrolateral preoptic area, and median preoptic area was significantly altered in all mice treated with HRW. Conclusions: HRW improves sleep consolidation and increases neuronal activation in sleep-related brain regions. It may serve as a simple, effective treatment to improve recovery after sleep loss.

The Effects of Liposomal Bupivacaine on Long-term Outcomes and Decreasing Immediate Postoperative Opioid Use Following One-level and Two-level Posterior Lumbar Fusions.

STUDY DESIGN: This is a retrospective observational study. OBJECTIVE: This study aims to determine the efficacy of liposomal bupivacaine in postoperative analgesia and long-term outcomes in patients undergoing one-level and two-level posterior lumbar fusion. SUMMARY OF BACKGROUND DATA: Multiple studies have investigated the use of liposomal bupivacaine in spine surgery with varying results. The potential benefits of its use include decreasing postoperative opioid use, improved pain control, and a shorter hospital stay. Several studies have supported its use in spine surgery with others showing minimal to no benefit. No studies have investigated its possible impact on long-term outcomes. MATERIALS AND METHODS: A total of 42 patients (22 one-level, 20 two-level) received liposomal bupivacaine injection just before surgical closure and were compared with a historical control group of 42 patients (27 one-level, 15 two-level) that did not receive liposomal bupivacaine. Daily opioid consumption was collected and converted to oral morphine equivalents. Length of stay and daily average pain scores using the visual analog scale were also recorded. In addition, SF-36 bodily pain and physical function outcome measures were collected preoperatively and at 6 months, 1 year and 2 years postoperatively. RESULTS: The liposomal bupivacaine group was found to have a significantly lower total opioid consumption compared with the control group ( P =0.001). The liposomal bupivacaine group was also found to use significantly fewer opioids on the day of surgery compared with the control group ( P <0.0001). There was no significant difference shown in the average visual analog scale pain scores, length of stay, or long-term outcomes between the 2 groups. CONCLUSIONS: The use of liposomal bupivacaine in one-level and two-level posterior lumbar fusions shows promise as an adjuvant for postoperative analgesia by decreasing postoperative opioid consumption. With the varying results demonstrated with the utilization of liposomal bupivacaine in spine surgery, further investigation is warranted, namely a larger prospective randomized control study. LEVEL OF EVIDENCE: Level III.

Association of Preoperative Patient Frailty and Operative Stress With Postoperative Mortality.

Importance: Patients with frailty have higher risk for postoperative mortality and complications; however, most research has focused on small groups of high-risk procedures. The associations among frailty, operative stress, and mortality are poorly understood. Objective: To assess the association between frailty and mortality at varying levels of operative stress as measured by the Operative Stress Score, a novel measure created for this study. Design, Setting, and Participants: This retrospective cohort study included veterans in the Veterans Administration Surgical Quality Improvement Program from April 1, 2010, through March 31, 2014, who underwent a noncardiac surgical procedure at Veterans Health Administration Hospitals and had information available on vital status (whether the patient was alive or deceased) at 1 year postoperatively. A Delphi consensus method was used to stratify surgical procedures into 5 categories of physiologic stress. Exposures: Frailty as measured by the Risk Analysis Index and operative stress as measured by the Operative Stress Score. Main Outcomes and Measures: Postoperative mortality at 30, 90, and 180 days. Results: Of 432 828 unique patients (401 453 males [92.8%]; mean (SD) age, 61.0 [12.9] years), 36 579 (8.5%) were frail and 9113 (2.1%) were very frail. The 30-day mortality rate among patients who were frail and underwent the lowest-stress surgical procedures (eg, cystoscopy) was 1.55% (95% CI, 1.20%-1.97%) and among patients with frailty who underwent the moderate-stress surgical procedures (eg, laparoscopic cholecystectomy) was 5.13% (95% CI, 4.79%-5.48%); these rates exceeded the 1% mortality rate often used to define high-risk surgery. Among patients who were very frail, 30-day mortality rates were higher after the lowest-stress surgical procedures (10.34%; 95% CI, 7.73%-13.48%) and after the moderate-stress surgical procedures (18.74%; 95% CI, 17.72%-19.80%). For patients who were frail and very frail, mortality continued to increase at 90 and 180 days, reaching 43.00% (95% CI, 41.69%-44.32%) for very frail patients at 180 days after moderate-stress surgical procedures. Conclusions and Relevance: We developed a novel operative stress score to quantify physiologic stress for surgical procedures. Patients who were frail and very frail had high rates of postoperative mortality across all levels of the Operative Stress Score. These findings suggest that frailty screening should be applied universally because low- and moderate-stress procedures may be high risk among patients who are frail.

The Unstable Spine: A Surgeon's Perspective.

Instability of the spine is a complex clinical entity that exists on a wide spectrum encompassing many aspects of spinal pathology including traumatic, neoplastic, infectious, and degenerative processes. The importance of determining stability is paramount in the decision-making process regarding the need for operative or nonoperative care. Defining clinical instability can be a challenging and requires careful attention to the pathology involved, findings of necessary imaging, and a thorough clinical exam. Several classification systems have been developed to aid in surgical decision making, but certain limitations exist. Various imaging modalities play a crucial role in the evaluation of suspected instability. Computed tomography is the initial imaging modality of choice in the traumatic setting. Magnetic resonance imaging is an important adjunct in the setting of suspected ligamentous injury and the modality of choice in suspected infectious and neoplastic processes. Upright radiographs can be particularly useful in the setting of acute or subacute instability to glean information about how the spine responds to gravity and weightbearing. The clinical exam is also of critical importance in the determination of stability. The presence of a neurologic deficit is highly suggestive of a potentially unstable spine and appropriate spinal precautions should be maintained until instability and injury has been ruled out. Certain clinical entities, such as ankylosing spondylitis and diffuse idiopathic skeletal hyperostosis, are at high risk for instability particularly in the traumatic setting. In these situations, the spine should be considered unstable until proven otherwise. Ultimately, the determination of spinal stability, and subsequent need for surgical treatment, should be based on the individual case. Combining information from the clinical exam and imaging findings, including upright radiographs when appropriate, allows for the appropriated determination of spinal stability.

A Prospective Multicenter Evaluation of the Value of the On-Call Orthopedic Resident.

BACKGROUND: Funding for graduate medical education is at risk despite the services provided by residents. OBJECTIVE: We quantified the potential monetary value of services provided by on-call orthopedic surgery residents. METHODS: We conducted a prospective, cross-sectional, multicenter cohort study design. Over a 90-day period in 2014, we collected data on consults by on-call orthopedic surgery residents at 4 tertiary academic medical centers in the United States. All inpatient and emergency department consults evaluated by first-call residents during the study period were eligible for inclusion. Based on their current procedural terminology codes, procedures and evaluations for each consult were assigned a relative value unit and converted into a monetary value to determine the value of services provided by residents. The primary outcome measures were the total dollar value of each consult and the percentage of resident salaries that could be funded by the generated value of the resident consult services. RESULTS: In total, 2644 consults seen by 33 residents from the 4 institutions were included for analysis. These yielded an average value of $81,868 per center for the 90-day study period, that is, $327,471 annually. With a median resident stipend of $53,992, the extrapolated average percentage of resident stipends that could be funded by these consult revenues was 73% of the stipends of the residents who took call or 36% of the stipends of the overall resident cohort. CONCLUSIONS: The potential monetary value generated by on-call orthopedic surgery residents is substantial.

The association of incomplete glenoid component seating and periprosthetic glenoid radiolucencies after total shoulder arthroplasty.

BACKGROUND: Radiolucent lines surrounding prosthetic glenoid components are commonly seen after unconstrained total shoulder arthroplasty and can be a harbinger of subsequent glenoid component failure. Whether less than 100% glenoid seating is associated with the development of radiolucent lines around glenoid prostheses is unknown. This study investigated the association between incomplete glenoid component seating and periprosthetic glenoid radiolucencies. METHODS: Thirty-six unconstrained total shoulder arthroplasties were performed in 29 patients for primary glenohumeral osteoarthritis with a minimum 2-year follow-up. All were implanted with a partially cemented all-polyethylene glenoid prosthesis. Patients were evaluated with standardized plain films preoperatively and postoperatively and with thin-cut computed tomography (CT) scans at the latest follow-up. The Lazarus and Yian classifications were used to assess radiolucency and seating on radiographs and CT scans. Ratings were calculated for intraobserver and interobserver reliability and given κ, the Kendall coefficient, and interclass correlation coefficient values. RESULTS: At a mean of 43 months (range 24-26 months) after surgery, neither Lazarus plain film radiolucency scores (P = .78) nor Yian CT radiolucency scores (P = .68) were associated with Lazarus plain film seating scores. Neither Lazarus plain film radiolucency scores (P = .25) nor Yian CT radiolucency scores (P = .91) were associated with modified Lazarus CT scan seating scores. CT allowed for better intraobserver and interobserver reliability in all categories. CONCLUSION: Radiolucencies around a partially cemented glenoid component were not associated with the degree of component seating. Complete seating of the glenoid component is not necessary to achieve radiographic implant stability at a mean follow-up of 43 months.

Bacterial Spine Infections in Adults: Evaluation and Management.

Bacterial spinal infections in adults can have notable adverse consequences, including pain, neurologic deficit, spinal instability and/or deformity, or death. Numerous factors can predispose a person to spinal infection, many of which affect the immune status of the patient. These infections are typically caused by direct seeding of the spine, contiguous spread, or hematogenous spread. Infections are generally grouped based on anatomic location; they are broadly categorized as vertebral osteomyelitis, discitis, and epidural abscess. In some cases, the diagnosis may not be elucidated early without a reasonable index of suspicion. Diagnosis is based on history and physical examination, laboratory data, proper imaging, and culture. Most infections can be treated with an appropriate course of antibiotics and bracing if needed. Surgical intervention is usually reserved for infections resistant to medical management, the need for open biopsy/culture, evolving spinal instability or deformity, and neurologic deficit or deterioration.

A flow-cytometric method for determination of yeast viability and cell number in a brewery.

A flow-cytometric assay, using the fluorescent dye, oxonol, for the simultaneous determination of yeast cell viability and cell number is described. The assay was optimised, and trialed at a brewery for 6 months. The flow-cytometry assay offered a substantially reduced error in viability determination, compared to methylene blue which is the industry standard for measuring viability. Further, by calculating yeast cell number at the same time, this assay provides a reliable method for determining pitching rate, allowing increased quality control of subsequent fermentations.