Preoperative Opioid Use Disorder is Associated with Longer Length of Stay, Infection Rate, and Healthcare Expenditure Following Primary Shoulder Arthroplasty.

Recent research efforts have focused on the complications and outcomes associated with opioid use disorder (OUD). However, there is a lack of evidence on the associated risks respective to each primary shoulder arthroplasty procedure. After separating patients by total shoulder arthroplasty (TSA) and reverse shoulder arthroplasty (RSA) and matching to controls, our study demonstrated significant association with longer LOS in both groups, higher risk of SSI and PJI in the TSA group, PJI in the RSA group, and higher costs regardless of procedure. Efforts to appropriately recognize OUD, optimize patients pre-operatively, and apply targeted surveillance postoperatively should be made. (Journal of Surgical Orthopaedic Advances 33(2):117-121, 2024).

Update on the assessment of resistance to antidepressant treatment: Rationale for the Antidepressant Treatment History Form: Short Form-2 (ATHF-SF2).

All definitions of treatment-resistant depression (TRD) require that patients have experienced insufficient benefit from one or more adequate antidepressant trials. Thus, identifying "failed, adequate trials" is key to the assessment of TRD. The Antidepressant Treatment History Form (ATHF) was one of the first and most widely used instruments that provided objective criteria in making these assessments. The original ATHF was updated in 2018 to the ATHF-SF, changing to a checklist format for scoring, and including specific pharmacotherapy, brain stimulation, and psychotherapy interventions as potentially adequate antidepressant treatments. The ATHF-SF2, presented here, is based on the consensus of the ATHF workgroup about the novel interventions introduced since the last revision and which should/should not be considered effective treatments for major depressive episodes. This document describes the rationale for these choices and, for each intervention, the minimal criteria for determining the adequacy of treatment administration. The Supplementary Material that accompanies this article provide the Scoring Checklist, Data Collection Forms (current episode and composite of previous episodes), and Instruction Manual for the ATHF-SF2.

Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report.

BACKGROUND: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. OBJECTIVE: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. METHODS: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). RESULTS: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. CONCLUSIONS: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03887715.

Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: II. Sensitivity to treatment effects.

OBJECTIVE: Characteristics of difficult-to-treat depression (DTD), including infrequent symptom remission and poor durability of benefit, compel reconsideration of the outcome metrics historically used to gauge the effectiveness of antidepressant interventions. METHODS: Self-report and clinician assessments of depression symptom severity were obtained regularly over a 2-year period in a difficult-to-treat depression registry sample receiving treatment as usual (TAU), with or without vagus nerve stimulation (VNS). Alternative outcome metrics for characterizing symptom change were compared in effect size and discriminating power in distinguishing the vagus nerve stimulation + treatment as usual and treatment as usual treatment groups. We expected metrics based on remission status to produce weaker between-group separation than those based on the classifications of partial response or response and metrics that integrate information over time to produce greater separation than those based on single endpoint assessment. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination in separating the treatment groups than metrics based on partial response or response classifications. Metrics that integrated information over the 2-year observation period had stronger performance characteristics than those based on symptom scores at single endpoint assessment. For both the clinician-rated and self-report depression ratings, the metrics with the strongest performance characteristics were the median percentage change in symptom scores over the observation period and the proportion of the observation period in partial response or better. CONCLUSION: In difficult-to-treat depression, integrative symptom severity-based and time-based measures are sensitive and informative outcomes for assessing between-group treatment effects, while metrics based on remission status are not.

Persistent Brain Connectivity Changes in Healthy Volunteers Following Nitrous Oxide Inhalation.

Background: Nitrous oxide holds promise in the treatment of major depressive disorder. Its psychotropic effects and NMDA receptor antagonism have led to comparisons with ketamine. Despite longstanding use, persistent effects of nitrous oxide on the brain have not been characterized. Methods: Sixteen healthy volunteers were recruited in a double-blind crossover study. In randomized order, individuals underwent a 1-hour inhalation of either 50% nitrous oxide/oxygen or air/oxygen mixtures. At least two 7.5-minute echo-planar resting-state functional magnetic resonance imaging scans were obtained before and at 2 and 24 hours after each inhalation (average 130 min/participant). Using the time series of preprocessed, motion artifact-scrubbed, and nuisance covariate-regressed imaging data, interregional signal correlations were measured and converted to T scores. Hierarchical clustering and linear mixed-effects models were employed. Results: Nitrous oxide inhalation produced changes in global brain connectivity that persisted in the occipital cortex at 2 and 24 hours postinhalation (p < .05, false discovery rate-corrected). Analysis of resting-state networks demonstrated robust strengthening of connectivity between regions of the visual network and those of the dorsal attention network, across 2 and 24 hours after inhalation (p < .05, false discovery rate-corrected). Weaker changes in connectivity were found between the visual cortex and regions of the frontoparietal and default mode networks. Parallel analyses following air/oxygen inhalation yielded no significant changes in functional connectivity. Conclusions: Nitrous oxide inhalation in healthy volunteers revealed persistent increases in global connectivity between regions of primary visual cortex and dorsal attention network. These findings suggest that nitrous oxide inhalation induces neurophysiological cortical changes that persist for at least 24 hours.

Discovery of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain.

Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-f][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1. The synthesis, structure-activity relationships (SAR), and in vivo evaluation of these AAK1 inhibitors is described.

The Careful Return of Sports Medicine Procedures in the United States During COVID-19: Comparison of Utilization, Patient Demographics, and Complications.

OBJECTIVES: Sports medicine procedures encompass some of the highest-volume elective surgeries performed annually. Elective surgery was suspended because of the severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic; therefore, the purpose was to compare temporal trends in procedural volume, patient demographics, and postoperative complications of elective sports medicine procedures in 2019 and 2020. METHODS: Using a multicenter, nationwide sample, a retrospective query of the 2019 to 2020 American College of Surgeon's National Surgery Quality Improvement Program database was conducted for all patients undergoing common elective sports medicine procedures. Temporal trends in utilization, demographics, and 30-day complications were compared pre-COVID (2019 and 2020Q1) with post-COVID (2020Q2-Q4). Linear regression was used to evaluate changes in procedural volume over time. A significance threshold of P < 0.05 was used. RESULTS: A total of 48,803 patients underwent elective surgery in 2019 (n = 27,883) and 2020 (n = 20,920), a 25.0% decline. Procedural utilization declined by 42.5% in 2020Q2 and never returned to prepandemic baseline in 2020Q3-Q4. The percentage decline in case volume from 2019 to 2020Q2 was greatest for meniscectomy (47.6%), rotator cuff repair (42.7%), labral repair (41.6%), biceps tenodesis (41.3%), and anterior cruciate ligament reconstruction (38.5%). Total complication rates were similar in 2019 (1.31%) versus 2020 (1.51%; P = 0.072). The 30-day readmission (0.74% versus 0.67%; P = 0.374), reoperation (0.35% versus 0.35%; P = 0.963), and mortality (0.01% versus 0.01%; P = 0.657) rates were similar between calendar years. CONCLUSIONS: Sports medicine procedures declined during the second quarter of 2020. Despite pandemic restrictions, patients who did undergo surgery did not experience increased complications. The present study may be used by surgeons, hospitals, and subspecialty societies to support the careful utilization of elective surgery during COVID-19. LEVEL OF EVIDENCE: III, prognostic study.

Alternative metrics for characterizing longer-term clinical outcomes in difficult-to-treat depression: I. Association with change in quality of life.

BACKGROUND: In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD. METHODS: Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in their association with continuous QoL scores. RESULTS: Metrics based on remission status had smaller effect size and poorer discrimination of the binary QoL outcome and weaker associations with the continuous end-point QoL scores than metrics based on partial response or response. The metrics with the strongest performance characteristics were the SEP measure of percentage change in symptom severity and the INT metric quantifying the proportion of the observation period in partial response or better. Both metrics contributed independent variance when predicting end-point QoL scores. CONCLUSIONS: Revision is needed in the metrics used to quantify symptomatic change in DTD with consideration of INT time-based measures as primary or secondary outcomes. Metrics based on remission status may not be useful.

How does sleep apnea impact outcomes following primary total hip arthroplasty for femoral neck fractures: a matched-control analysis.

BACKGROUND: Cross-sectional studies have demonstrated that the prevalence of sleep apnea (SA) to be increasing within the United States. While studies have shown the association of SA and its association on complications following elective orthopedic procedures, well-powered studies investigating its impact in a traumatic setting are limited. The purpose of this study was to determine whether SA patients undergoing primary total hip arthroplasty (THA) for femoral neck fractures have higher rates of: (1) hospital lengths of stay (LOS); (2) readmissions; (3) complications; and (4) healthcare expenditures. METHODS: The 100% Medicare Standard Analytical Files was queried from 2005 to 2014 for patients who sustained femoral neck fractures and were treated with primary THA. The study group consisted of patients with concomitant diagnoses of SA, whereas patients without SA served as controls. Study group patients were matched to controls in a 1:5 ratio by age, sex, and various comorbid conditions. Demographics of the cohorts were compared using Pearson's chi-squared analyses, and multivariate logistic regression analyses were used to calculate the odds (OR) of the effects of SA on postoperative outcomes. A p value less than 0.006 was considered to be statistically significant. RESULTS: The final query yielded 24,936 patients within the study (n = 4166) and control (n = 20,770) cohorts. SA patients had significantly longer in-hospital LOS (6 vs. 5 days, p < 0.0001) but similar readmission rates (24.12 vs. 20.50%; OR: 1.03, p = 0.476). SA patients had significantly higher frequency and odds of developing medical complications (72.66 vs. 43.85%; OR: 1.57, p < 0.0001), and higher healthcare costs ($22,743.79 vs. $21,572.89, p < 0.0001). CONCLUSION: SA is associated with longer in-hospital LOS, higher rates of complications and healthcare expenditures. This study is vital as it can allow orthopaedists to educate patients with SA on the potential complications which may occur following their procedure. LEVEL OF EVIDENCE: III.

Anemia Severity and the Risks of Postoperative Complications and Extended Length of Stay Following Primary Total Elbow Arthroplasty.

BACKGROUND: Anemia is a modifiable risk factor that may influence postoperative complications following orthopedic surgical procedures. The objective was to determine the influence of preoperative anemia severity on postoperative complications and length of stay (LOS) following total elbow arthroplasty (TEA). METHODS: The American College of Surgeons National Surgical Quality Improvement Program registry was queried from 2006 to 2019 for patients undergoing primary TEA. Using the World Health Organization definitions of anemia, patients undergoing TEA were stratified into 3 cohorts: nonanemia (hematocrit >36% for women, >39% for men), mild anemia (hematocrit 33%-36% for women, 33%-39% for men), and moderate-to-severe anemia (hematocrit <33% for both women and men). Patient demographics, surgical time, LOS, and postoperative complications were compared between the groups. A P value <.004 was considered significant. RESULTS: After exclusion, 589 patients, of whom 369 (62.6%) did not have anemia, 129 (21.9%) had mild anemia, and 91 (15.5%) had moderate/severe anemia, were included. Increasing severity of anemia was associated with an increased average hospital LOS (2.30 vs 2.81 vs 4.91 days, P < .001). There was a statistically significant increase in blood transfusions (1.08% vs 7.75% vs 17.58%, P < .001), major complications (9.21% vs 17.83% vs 34.07%, P < .001), any complications (11.11% vs 23.26% vs 36.26%, P < .001), and extended LOS ≥6 days (6.23% vs 6.98% vs 31.87%, P < .001) with increasing severity of anemia. Multivariate analysis identified moderate-to-severe anemia was significantly associated with major complications and extended LOS (P < .001). CONCLUSIONS: Preoperative anemia is a modifiable risk factor for medical and surgical complications within 30 days of TEA.

The 5-Item Modified Frailty Index for Risk Stratification of Patients Undergoing Total Elbow Arthroplasty.

BACKGROUND: Frailty, quantified using the 5-item modified frailty index (mFI-5), has been shown to predict adverse outcomes in orthopaedic surgery. The utility in total elbow arthroplasty (TEA) patients is unclear. We evaluated if increasing frailty would correlate with worse postoperative outcomes. METHODS: A retrospective assessment of patients in the American College of Surgeons National Surgery Quality Improvement Program undergoing primary TEA was performed. The mFI-5 was calculated by assigning 1 point for each comorbidity (diabetes, hypertension, congestive heart failure, chronic obstructive pulmonary disease, and functionally dependent health status). Poisson regression was used to evaluate mFI-5 scores on complications, length of stay (LOS), and adverse discharge. A significance threshold was at P < .05. RESULTS: In total, 609 patients were included; 34.5% (n = 210) were not frail (mFI = 0), 44.0% (n = 268) were slightly frail (mFI = 1), and 21.5% (n = 131) were frail (mFI ≥ 2). As mFI score increased from 0 to ≥ 2, the following rates increased: any complication (9.0%-19.8%), major complication (11.0%-20.6%), cardiac complication (0.0%-2.3%), hematologic complication (3.3%-9.2%), adverse discharge (2.9%-22.9%), and LOS from 2.08 to 3.97 days (all P < .048). Following adjustment, Poisson regression demonstrated patients with a mFI ≥ 2 had increased risk of major complication (risk ratio [RR]: 2.13; P = .029), any complication (RR: 2.49; P = .032), Clavien-Dindo IV complication (RR: 5.53; P = .041), and adverse discharge (RR: 5.72; P < .001). CONCLUSIONS: Frailty is not only associated with longer hospitalizations, but more major complications and non-home discharge. The mFI-5 is a useful risk stratification that may assist in decision-making for TEA.

The effects of the COVID-19 pandemic on elective unicompartmental knee arthroplasty in the USA: further evidence that outpatient arthroplasty is safe and effective.

PURPOSE: In response to COVID-19, elective surgeries including unicompartmental knee arthroplasties (UKA) decreased. We aimed to quantify and compare temporal trends in utilization and complications in the calendar year 2019 (pre-pandemic) to 2020 in the USA. METHODS: The 2019 to 2020 ACS-NSQIP database was queried for patients undergoing elective UKA. Patients prior to COVID-19 (2019 and 2020 Q1) were compared to those after (2020 Q2-Q4). Case volumes, patient demographics, complications, and lengths of stay (LOS) were compared between years. Pearson's chi-square test was used to compare patient demographics. Linear regression was conducted to evaluate the change in case volumes. P values less than 0.05 were significant. RESULTS: In total, 3361 patients underwent UKA: 1880 in 2019 and 1481 in 2020. The number of outpatient UKAs increased (56.4% vs. 65.6%; p < 0.001). There was no significant difference in the volume of cases in 2019Q1 through 2020Q1 (p = 0.424). Case volumes fell by 60% in 2020Q2 compared with the average quarterly volume in 2019. Comparing 2019 to 2020, there was no significant difference in rates of total complications (2.1% vs. 2.2%; p = 0.843), minor complications (1.2% vs. 0.9%; p = 0.529), major complications (1.1% vs. 1.4%; p = 0.447), infection complications (1.0% vs. 0.8%; p = 0.652), wound complications (0.1% vs. 0.1%; p = 1.0), cardiac complications (0.0% vs. 0.1%; p = 0.111), pulmonary complications (0.1% vs. 0.2%; p = 0.473), hematology complications (0.1% vs. 0.1%; p = 1.0), renal complications (0.1% vs. 0.0%; p = 1.0), and Clavien-Dindo IV complications (0.1% vs. 0.4%; p = 0.177). CONCLUSION: UKA case volumes declined during the second quarter of 2020. A significant proportion of surgeries were transitioned outpatient, despite no change in complication rates.

Risk factors for the development of a peri-prosthetic joint infection up to 2 Years following primary reverse shoulder arthroplasty.

Background: Reverse shoulder arthroplasty (RSA) has become commonly used to treat glenohumeral osteoarthritis (GHOA), of which complications such as peri-prosthetic joint infections (PJIs) may develop. The objective of this study was to compare patient demographics of those who did and did not develop PJIs within 2 years after primary RSA for GHOA and identify risk factors for this sequela. Methods: A nationwide database was queried from 2005 to 2014 for Medicare patients treated with primary RSA (International Classification of Disease (ICD-9) procedural code 81.88) for GHOA. Patients who developed PJIs within 2-years of primary RSA defined the study group, whereas those who were devoid of infections represented the comparison group. Our study consisted of 51,824 patients, of which 879 (1.69%) developed a PJI. Patient demographics comprising the Elixhauser comorbidity index (ECI) were compared using Chi-Square analyses. Multivariable logistic regression models were used to compute the odds-ratios (OR) of patient-specific factors associated with acquiring a PJI within 2 years after RSA. P values less than 0.002 were significant. Results: Patients developing a PJI had higher mean ECI (8 vs. 6; p < 0.0001). The greatest risk factors for developing PJIs within 2-years following RSA were male sex (OR: 2.10, 95%CI: 1.81-2.43, p < 0.0001), pathologic weight loss (OR: 1.78, 95%CI: 1.45-2.17, p < 0.0001), iron deficiency anemia (OR: 1.75, 95%CI: 1.49-2.06, p < 0.0001), morbid obesity (OR: 1.52, 95%CI: 1.21-1.88, p = 0.0001), rheumatoid arthritis (OR: 1.32, 95%CI: 1.13-1.54, p = 0.0003), arrhythmias (OR: 1.26, 95%CI 1.09-1.46, p = 0.001), and depressive disorders (OR: 1.23, 95%CI 1.06-1.43, p = 0.001). Conclusions: The greatest risk factors for PJIs within 2 years of primary RSA included male sex; additional modifiable risk factors included iron deficiency anemia, pathologic weight loss, and obesity. Preoperative screening can help to identify modifiable risk factors and alter management for high-risk patients to potentially minimize PJIs.

The Effect of the Coronavirus Disease 2019 (COVID-19) Pandemic on Elective Cervical Spine Surgery Utilization and Complications in the United States: A Nationwide Temporal Trends Analysis.

OBJECTIVES: As a result of the coronavirus disease 2019 (COVID-19) pandemic, elective surgeries nationwide were suspended. The objective was to compare temporal trends in patient demographics, case volumes, and postoperative complications of patients undergoing elective cervical spine surgery from pre-COVID-19 (2019-2020 Q1) to post-COVID-19 (2020 Q2-Q4). METHODS: The 2019 to 2020 American College of Surgeon's National Surgery Quality Improvement Program database was queried for common elective cervical spine surgeries. Patients pre-COVID-19 (2019-2020 Q1) were compared with those undergoing surgery during post-COVID-19 (2020 Q2-Q4) protocols. Procedural use, patient demographics, and complications were compared. Linear regression was used to evaluate case volume changes over time. P values less than 0.05 were significant. RESULTS: In total, 31,013 patients underwent elective cervical spine surgery in 2019 (N = 16,316) and 2020 (N = 14,697); an overall 10% decline. Compared with the calendar year 2019 through 2020 Q1 mean, elective surgery volume decreased by 21.6% in 2020 Q2 and never returned to prepandemic baseline. The percentage decline in case volume from 2019 to 2020 Q1 to 2020 Q2 was greatest for anterior cervical discectomy and fusion (23.3%), followed by cervical decompression (23.4%), posterior cervical fusion (15.0%), and cervical disc arthroplasty and vertebral corpectomy (13.7%). Patients undergoing surgery in 2020 Q2-Q4 had overall greater comorbidity burden (American Society of Anesthesiologists grade 3 and 4) (P < 0.001). From 2019-2020 Q1 versus 2020 Q2-Q4, there was a significant increase in total complication (5.5% vs. 6.8%, P < 0.001), reoperation (1.9% vs. 2.2%, P = 0.048), and mortality (0.25% vs. 0.37%, P = 0.049) rates. CONCLUSIONS: Elective surgery declined drastically during the second quarter of 2020. Patients undergoing surgery during the pandemic had an overall greater comorbidity burden, resulting in increased total complication and mortality rates over the study period.

Resident and Fellow Participation Does Not Affect Short-Term Postoperative Complications After Distal Radius Fracture Fixation.

Background Complications after open reduction internal fixation (ORIF) for distal radius fractures (DRF) are well documented, but the impact of trainee involvement on postoperative outcomes has not been studied. Questions Does trainee involvement affect postoperative complication rates and length of hospital stay? Methods The American College of Surgeons National Surgical Quality Improvement Program was queried from 2006 to 2012 for patients undergoing DRF ORIF. A 1:1 propensity score matched resident/fellow involved cases to attending-only cases. Demographics, length of stay, and postoperative complications were compared between the two groups. Logistic regression was used to evaluate independent predictors of adverse events and to evaluate cases with and without trainee involvement. Results Overall, 3,003 patients underwent DRF ORIF from 2006 to 2012. After matching, 1,150 cases (50% with resident/fellow involvement) were included. The overall rate of adverse events was 4.4% (46/1,050). There were no significant differences in the short-term complication rate in trainee-involved (2.3%) versus attending-only cases (3.9%) ( p = 0.461). For ORIF of DRF, there were no significant differences, between attending-only cases and resident/fellow-involved cases, with regard to short-term major complications ( p = 0.720) or minor complications ( p = 0.374). Length of hospital stay was similar between cohorts (1.22 vs. 0.98 days) ( p = 0.723). On multivariate analysis, trainee involvement was not an independent predictor of minor, major, or any complication after DRF fixation after controlling for multiple independent factors (all p > 0.364). Discussion Trainee participation in DRF ORIF is not associated with increased risk of short-term (30 days) medical or surgical postoperative complications. Level of Evidence This is a Level IV case-control study.

Nitrous Oxide, a Rapid Antidepressant, Has Ketamine-like Effects on Excitatory Transmission in the Adult Hippocampus.

BACKGROUND: Nitrous oxide (N2O) is a noncompetitive inhibitor of NMDA receptors that appears to have ketamine-like rapid antidepressant effects in patients with treatment-resistant major depression. In preclinical studies, ketamine enhances glutamate-mediated synaptic transmission in the hippocampus and prefrontal cortex. In this study, we examined the effects of N2O on glutamate transmission in the hippocampus and compared its effects to those of ketamine. METHODS: Glutamate-mediated synaptic transmission was studied in the CA1 region of hippocampal slices from adult albino rats using standard extracellular recording methods. Effects of N2O and ketamine at subanesthetic concentrations were evaluated by acute administration. RESULTS: Akin to 1 µM ketamine, 30% N2O administered for 15-20 minutes resulted in persistent enhancement of synaptic responses mediated by both AMPA receptors and NMDA receptors. Synaptic enhancement by both N2O and ketamine was blocked by co-administration of a competitive NMDA receptor antagonist at saturating concentration, but only ketamine was blocked by an AMPA receptor antagonist. Synaptic enhancement by both agents involved TrkB (tropomyosin receptor kinase B), mTOR (mechanistic target of rapamycin), and NOS (nitric oxide synthase) with some differences between N2O and ketamine. N2O potentiation occluded enhancement by ketamine, and in vivo N2O exposure occluded further potentiation by both N2O and ketamine. CONCLUSIONS: These results indicate that N2O has ketamine-like effects on hippocampal synaptic function at a subanesthetic, but therapeutically relevant concentration. These 2 rapid antidepressants have similar, but not identical mechanisms that result in persisting synaptic enhancement, possibly contributing to psychotropic actions.

The Effect of COVID-19 on Elective Total Knee Arthroplasty Utilization, Patient Comorbidity Burden, and Complications in the United States: A Nationwide Analysis.

INTRODUCTION: Total knee arthroplasty (TKA) is one of the highest volume elective procedures done nationwide. Elective surgery was suspended because of the COVID-19 pandemic. The utilization trends, comparison of patient demographics, and postoperative outcomes in 2020 have yet to be evaluated substantially. We compared temporal trends in procedural volume, patient demographics, and postoperative complications of elective TKA in 2019 and 2020. METHODS: Using a multicenter, nationwide representative sample, a retrospective query of the 2019 to 2020 American College of Surgeon's National Surgery Quality Improvement Program database was conducted for patients undergoing elective TKA. Temporal trends in utilization, demographics, and length of stay were compared pre-COVID-19 (2019 to 2020Q1) with post-COVID-19 (2020Q2 to Q4). Postoperative outcomes were compared by calendar year (2019 versus 2020). Linear regression was used to evaluate changes in procedural volume over time. A significance threshold of P < 0.05 was used. RESULTS: A total of 121,415 patients underwent elective TKA in 2019 (N = 72,002) and 2020 (N = 49,413), a 31.4% decline. The proportion of hospital-defined "outpatient" TKAs in 2020 was significantly greater than that in 2019 (41.5% versus 25.5%; P < 0.001). Elective TKA utilization declined by 65.1% in 2020Q2 and never returned to prepandemic baseline in 2020Q3 to Q4. The average length of stay was shorter in 2020 (1.56 versus 1.87 days; P < 0.001). The proportion of same-day discharge increased each quarter from 2019Q1 to Q4 (6.2% to 8.6%) to 2020Q1 to Q4 (8.7% to 17.1%). Total complication rates were similar in 2019 (4.84%) versus 2020 (4.75%); P = 0.430. The 30-day mortality (0.08% versus 0.07%; P = 0.858), revision surgery (1.0% versus 1.0%; P = 0.940), and readmission (2.8% versus 2.6%; P = 0.053) rates were no different between 2019 and 2020. CONCLUSION: Elective TKA declined during the second quarter of 2020. A large proportion of surgeries were transitioned to outpatient with rates of same-day discharge increasing over the study period, despite no change in complication, mortality, and readmission rates. Patient outcomes were not compromised despite pandemic restrictions for elective surgery. LEVEL OF EVIDENCE: Level III.