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Electroencephalogram (EEG) discontinuity can occur at high concentrations of anesthetic drugs, reflecting suppression of electrocortical activity. This EEG pattern has been reported in children and reflects a deep state of anesthesia. Isoelectric events on the EEG, a more extreme degree of voltage suppression, have been shown to be associated with worse long-term neurologic outcomes in neonates undergoing cardiac surgery. However, the clinical significance of EEG discontinuities during pediatric anesthesia for noncardiac surgery is not yet known and merits further research. In this study, we assessed the incidence of EEG discontinuity during anesthesia induction in neurologically normal infants and the clinical factors associated with its development. We hypothesized that EEG discontinuity would be associated with sevoflurane-induced alpha (8-12 Hz) power during the period of anesthesia induction in infants.We prospectively recorded 26 channels of EEG during anesthesia induction in an observational cohort of 54 infants (median age, 7.6 months; interquartile range [IQR] [4.9-9.8 months]). We identified EEG discontinuity, defined as voltage amplitude25 microvolts for2 seconds, and assessed its association with sevoflurane-induced alpha power using spectral analysis and multivariable logistic regression adjusting for clinically important variables.EEG discontinuity was observed in 20 of 54 subjects (37%), with a total of 25 discrete events. Sevoflurane-induced alpha power in the posterior regions of the head (eg, parietal or occipital regions) was significantly lower in the EEG discontinuity group (midline parietal channel on the electroencephalogram, International 10-20 System [Pz]; 8.3 vs 11.2 decibels [dBs]; P = .004), and this association remained after multivariable adjustment (adjusted odds ratio [aOR] = 0.51 per dB increase in alpha power [95% CI, 0.30-0.89]; P = .02). There were no differences in the baseline (unanesthetized) EEG between groups in alpha power or power in any other frequency band.We demonstrate that EEG discontinuity is common during anesthesia induction and is related to the level of sevoflurane-induced posterior alpha power, a putative marker of cortical-thalamic circuit development in the first year of life. This association persisted even after adjusting for age and propofol coadministration. The fact that this difference was only observed during anesthesia and not in the baseline EEG suggests that otherwise hidden brain circuit properties are unmasked by general anesthesia. These neurophysiologic markers observed during anesthesia may be useful in identifying patients who may have a greater chance of developing discontinuity.

A retrospective review.The objective of this study was to determine whether fusing to touched vertebra (TV) on prone x-rays (XRs) with minimal rotation (Gd 0/1) allow for shorter fusion with optimal correction.Previous studies have shown risk of "adding on" when TV is not selected as lowest instrumented vertebra (LIV). Fusion proximal to TV leads to suboptimal results but fusing to TV on standing XRs can result in longer fusions. On lying down XRs, TV moves proximally, and its rotation decreases by a grade.TV patients with minimal rotation were selected on prone (TVP) or standing XRs (TVS). Patients fused to rotated (Gd 2+) TV on standing or prone XRs were considered touched vertebra rotated (TVR). In the non-TV (NTV) group, LIV was fused proximal to TV. Disk wedging ≥5° determined risk of "adding-on." To compare patients fused to minimally rotated TV, to those that were not, patients in group A (TVP + TVS) were compared with group B (TVR + NTV).In part II: TVP, TVS, TVR, and NTV patients were compared. Subanalysis compared levels saved as the difference between predicted and real LIV in TVP and TVS patients. Another subanalysis was carried out for Lenke 1+2 and Lenke 3, 4, 5.In part III: XRs of nonoperative adolescents idiopathic scoliosis patients with Cobb30 and Risser 4/5 were analyzed to determine "acceptable" end vertebra tilt and disc wedging and served as controls.There were a significantly greater number of patients in group B patients(TVR + NTV) with final disk wedging ≥5°, final LIV translation ≥1 and ≥2 cm ( P0.001).Utilizing prone XRs in TVP saved average 1 level, and 1.2 levels in TVS patients. TVP patients also had similar LIV tilt, disk wedging and coronal balance( P0.05) to controls.Choosing minimally rotated (Gd 0/1) TV on prone XR saves levels without sacrificing radiographic outcomes.

Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability,RB1andTP53have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) ofRb1andTrp53within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2complex. In addition, SKP2 plays a central role in regulating the cell cycle by ubiquitinating and promoting the degradation of p27. We previously reported the DKOAA transgenic model, which harbored a knock-in mutation in p27 that impaired its binding to SKP2. Here, we generated a novelp53-Rb1-SKP2triple-knockout model (TKO) to examine SKP2 function and its potential as a therapeutic target in OS. First, we observed that OS tumorigenesis was significantly delayed in TKO mice and their overall survival was markedly improved. In addition, the loss ofSKP2also promoted an apoptotic microenvironment and reduced the stemness of DKO tumors. Furthermore, we found that small-molecule inhibitors of SKP2 exhibited anti-tumor activities in vivo and in OS organoids as well as synergistic effects when combined with a standard chemotherapeutic agent. Taken together, our results suggest that SKP2 inhibitors may reduce the stemness plasticity of OS and should be leveraged as next-generation adjuvants in this cancer.

Interferon ε (IFNε) is a unique type I IFN that has been implicated in host defense against sexually transmitted infections (STIs). Zika virus (ZIKV), an emerging pathogen, can infect the female reproductive tract (FRT) and cause devastating diseases, particularly in pregnant women. How IFNε contributes to protection against ZIKV infectionin vivois unknown. Here, we show that IFNε plays a critical role in host protection against vaginal ZIKV infection in mice. We found that IFNε was expressed not only by epithelial cells in the FRT, but also by certain immune and other cells at baseline or after exposure to viruses or specific TLR agonists. IFNε-deficient mice exhibited abnormalities in the epithelial border and underlying tissue in the cervicovaginal tract, and these defects were associated with increased susceptibility to vaginal, but not subcutaneous ZIKV infection. IFNε-deficiency resulted in an increase in magnitude, duration, and depth of ZIKV infection in the FRT. Critically, intravaginal administration of recombinant IFNε protectedIfnε-/-mice and highly susceptibleIfnar1-/-mice against vaginal ZIKV infection, indicating that IFNε was sufficient to provide protection even in the absence of signals from other type I IFNs and in an IFNAR1-independent manner. Our findings reveal a potentially critical role for IFNε in mediating protection against transmission of ZIKV in the context of sexual contact.SignificanceInterferon ε (IFNε), a unique Type I IFN that is highly expressed in the epithelium of the female reproductive tract (FRT), is thought to protect the host against sexually transmitted infections (STIs) but the mechanism of action is not defined. Zika virus (ZIKV), a causative agent for preterm birth and other severe diseases in pregnant women, can be spread through vaginal transmission. Here, we show that mice lacking theIfnεgene have abnormal epithelial development and tissue architecture in the cervicovaginal tract. The role of IFNε in protecting host against ZIKV is FRT-specific and is independent of IFNAR1 signaling. Our findings suggest potential preventive strategies based on harnessing mucosal immunity against STIs.

Retrospective review.The objective of this study was to evaluate and compare distribution of hospital and operating room charges and outcomes during posterior spinal fusion for adolescent idiopathic scoliosis (AIS) patients by high-volume (HV) and standard-volume (SV) surgeons at one institution and examine potential cost savings.Increased surgical volume has been associated with improved perioperative outcomes after spinal deformity correction. However, there is a lack of information on how this may affect hospital costs.Retrospective study of AIS patients undergoing posterior spinal fusion between 2013 and 2019. Demographic, x-ray, chart review and hospital costs were collected and compared between HV surgeons (≥50 AIS cases/y) and SV surgeons (50/y). Comparative analyses were computed using Wilcoxon rank-sum, Kruskal-Wallis, and the Fisher exact tests. Average values with corresponding minimum-maximum rages were reported.A total of 407 patients (HV: 232, SV: 175) operated by 4 surgeons (1 HV, 3 SV). Radiographic parameters were similar between the groups. HV surgeons had significantly lower estimated blood loss (385.3 vs. 655.6 mL, P0.001), fewer intraoperative transfusions (10.8% vs. 25.1%, P0.001), shorter surgery time (221.6 vs. 324.9 min, P0.001), and lower radiation from intraoperative fluoroscopy (4.4 vs. 6.4 mGy, P0.001). HV patients had a significantly lower length of stay (4.3 vs. 5.3, P0.001) and complication rate (0.4% vs. 4%, P =0.04).HV surgeons had significantly lower total costs ($61,716.24 vs. $72,745.93, P0.001). This included lower transfusion costs ( P0.001), operative time costs ( P0.001), screw costs ( P0.001), hospital stay costs ( P0.001), and costs associated with 30-day emergency department returns ( P0.001).HV surgeons had significantly lower operative times, lower estimated blood loss and transfusion rates and lower perioperative complications requiring readmission or return to emergency department resulting in lower health care costs.Level III.

Previous reports identified minority race/ethnicity to be an independent risk factor for prolonged length of stay (LOS); however, these cohorts consisted of predominantly White patients. This study sought to evaluate minority status as an independent risk factor for prolonged LOS after primary total knee arthroplasty (TKA) in a predominantly Hispanic and Black cohort.This was a retrospective study using an institutional database of patients who underwent primary TKA between the years 2016 and 2019. Demographic and socioeconomic data, smoking, body mass index (BMI), medical comorbidities, discharge disposition, and 30-day readmission rates were collected. Patients were first categorized into racial/ethnic groups (Hispanic, Black, or White). An univariate analysis was performed comparing patient characteristics between racial/ethnic groups using the Wilcoxon rank sum, chi-squared, and Fisher exact tests. We then categorized patients into two groups-normal LOS (discharged on postoperative day 1 to 2) and prolonged LOS (discharged after postoperative day 2). An univariate analysis was again performed comparing patient characteristics between LOS groups using Wilcoxon rank sum, chi-squared, and Fisher exact tests. After identifying risk factors markedly associated with LOS, a multivariate logistic regression analysis was performed to identify independent risk factors for prolonged LOS.A total of 3,093 patients were included-47.9% Hispanic and 38.3% Black. Mean LOS was 2.9 ± 1.6 days. An univariate analysis found race/ethnicity, age, low socioeconomic status (SES), discharge disposition, insurance type, weekday of surgery, BMI40, smoking, increased American Society of Anesthesiologists (ASA)/Charlson Comorbidity Index (CCI) and several medical comorbidities to be associated with prolonged LOS (P0.05). A multivariate logistic regression analysis found Black and Hispanic patients were less likely to have prolonged LOS after adjusting for associated risk factors. White race/ethnicity, nonhome discharge, low SES, weekday of surgery, smoking, BMI40, and increased ASA and CCI were identified as independent risk factors for prolonged LOS (P0.05). The overall 30-day readmission rate was 3.6%, with no notable difference between racial/ethnic and LOS groups (P = 0.98 and P = 0.78).In contrast to previous reports, our study found that after adjusting for associated risk factors, minority patients do not have prolonged LOS after primary TKA in an urban, socioeconomically disadvantaged, predominantly minority patient cohort. White race/ethnicity, nonhome discharge, low SES, weekday of surgery, smoking, BMI40, increased CCI, and ASA were all found to be independent risk factors for prolonged LOS. These findings highlight the need to further investigate the role of race/ethnicity on LOS after primary TKA using large-scale, randomized controlled trials with equally represented patient cohorts.

Background: Surgeons are expected to teach students, residents and colleagues about surgical skills. The critical assumption that a “first-learner” will default to teaching a “second-learner” what they were taught, in the way they were taught, was investigated. Methods: Thirty-six medical students without experience tying a locking, sliding knot were divided into 18 pairs of first- and second-learners. 4 pairs were assigned to the “traditional teaching” (T) protocol group, 5 pairs were assigned to the “operant-teaching” (O) group and 9 pairs were “informed of the importance of the operant teaching strategy” before instruction and assigned to the “operant-informed” (OI) group. First-learners were taught to tie the locking, sliding knot according to one teaching protocol (T, O, or OI). Successful first-learners were asked to teach a second-learner. For the first-learners, time from the start of their instruction to the first constructed knot, time to tie 10 consecutive knots, and accuracy of knots (number of incorrectly constructed knots) were recorded. For second-learners, time from start of instruction to the first constructed knot, time to tie 10 knots, and accuracy of knots were recorded. Results: All first-learners, in all groups, were able to accurately tie a locking, sliding knot. During self-practice, all T-group first-learners lost the ability to tie the knot. Between the 5 O- and 9 OI- first-learners, only one OI-group first-learner lost the ability to tie the knot. After instruction from the 16 successful first-learners, 16 second-learners were able to tie to the knot. The error rate for second learners was 93% for the T-group, 20% in O-group and 12.5% in OI-group. Time to tie the first knot were different between the three teaching groups for both the first and second-learners (p=0.007 and p=0.041, respectively). The average time to tie the 10 knots was similar between first-learner (p=0.336) and second-learner O- and OI-groups (p=0.788). Conclusion: Demonstration-based teaching results in incomplete skills which deteriorate. Contrary to the assumption that successful first-learners would teach the way they were taught, first-learners abandon the teaching strategy when tasked with teaching a second-learner. Our results emphasize the importance of incorporating teaching curriculums into surgical education.

Neaodjuvant chemotherapy is used to treat high risk triple-negative breast cancer (TNBC). Residual cancer burden (RCB) is used to predict risk of relapse after neoadjuvant chemotherapy (NAC); however, it cannot predict disease recurrence with certainty. EZH2 is a targetable oncogenic protein overexpressed in TNBC and associated with metastasis and stem cell expansion. We quantified EZH2 protein expression in TNBC before NAC to examine potential utility as a predictive and prognostic biomarker.We retrospectively identified 63 patients with localized TNBC treated with NAC. We quantified EZH2 nuclear expression in pretherapy biopsies using a score which included intensity and percent of positive cells at each intensity. EZH2 expression was evaluated as a continuous variable and dichotomized at a score of 210. Logistic regression analysis was used to determine association between EZH2 expression and RCB, tumor-infiltrating lymphocytes, clinicopathologic features and disease-free survival.There was no significant association between EZH2 score and posttreatment RCB class evaluated as a continuous variable (P=0.831) or dichotomized at 210 (P=0.546). On multivariable logistic regression, adjusted for covariates including RCB, EZH2210 was associated with development of metastasis (odds ratio=14.35, 95% confidence interval: 2.69-76.66; P=0.002). Logistic regression was run with EZH2 scores as a continuous variable and increased EZH2 score was associated with metastasis (odds ratio=1.10, 95% confidence interval: 1.00-1.03; P=0.047).In our study of TNBC treated with NAC, high EZH2 expression in pretherapy core biopsies was significantly associated with metastatic recurrence independent of RCB. The potential value of EZH2 as a biomarker to improve stratification of outcome after NAC should be explored further.

Retrospective cohort study.This study aims to identify differences in perioperative outcomes between ambulatory patients with neuromuscular scoliosis (ANMS) and adolescent idiopathic scoliosis (AIS) following spinal fusion.NMS patients have severe curves with more comorbidities and procedural complexity. These patients require extensive fusion levels, increased blood loss, and suffer increased periop complications. However, NMS patients have a variable severity spectrum, including ambulation status.Chart and radiographic review of NMS and AIS patients undergoing PSF from 2005 to 2018. NNMS included NMS patients who were completely dependent (GMFCS IV-V). ANMS consisted of community ambulators without significant reliance on wheeled assistive devices (GMFCS I-III). Subanalysis matched by age, sex, levels fused and preoperative Cobb angle was conducted as well. Wilcoxon Rank-Sum, Kruskal-Wallis, χ2, and Fisher exact tests were performed.There were 120 patients in the NNMS group, 54 in ANMS and 158 in the AIS group. EBL was significantly lower for ANMS and AIS patients (P 0.001). Complications within 30 days were similar between ANMS and AIS (P = 1.0), but significantly higher for NNMS (P 0.001). Two (1.3%) AIS patients, (1.7%) nonambulatory NMS patients, and one (1.9%) ANMS patient required revision surgery (P = 1.0). However, all NMS patients had increased fusion levels, fixation points, and surgery time (P 0.05). NNMS had significantly longer ICU (P 0.001), hospital stay (P 0.001), intraoperative transfusions (P 0.001), and fewer patients extubated in the OR (P 0.001) than ANMS and AIS patients. In the subanalysis, ANMS had similar radiographic measurements, EBL, transfusion, surgery time, extubation rate, and complication rate (P 0.05) to AIS.Our data show radiographic outcomes, infections, revisions, and overall complications for ANMS were similar to the AIS population. This suggests that NMS patients who ambulate primarily without assistance can expect surgical outcomes comparable to AIS patients with further room for improvement in length of ICU and hospital stay.Level of Evidence: 4.

Testosterone levels decline as men age. There is little consensus on what testosterone levels are normal for aging men. In this paper, we estimate age-specific prevalence of testosterone deficiency in men using nor- mal mixture models when no generally agreed on cut-off value for defining testosterone deficiency is available. The Box-Cox power transformation is used to determine which transformation is most appropriate for correcting skewness in data and best suits normal mixture distributions. Parametric bootstrap tests are used to determine the number of components in a normal mixture.

Database study.The purpose of this study was to use a large, nationwide database to determine prevalence of pediatric spine fractures in the United States, associated injuries, mechanisms of injury (MOI), use of safety devices, and mortality rates.Spinal fractures account for 1% to 2% of pediatric injuries. However, they are associated with significant comorbidities and complications. Motor vehicle accidents (MVAs) are most responsible for increased incidence observed.Retrospective review of National Trauma Data Bank between 2009 and 2014 (analysis in 2019) for all vertebral fractures in patients under 18 years of age. Subanalysis included those in MVAs where protective device use data were available. Patient demographics, MOI, geographical and anatomical region of injury, concomitant musculoskeletal/organ injury, protective device usage, hospital length of stay, surgical procedures, and mortality were all analyzed.A total of 34,563 patients with 45,430 fractured vertebrae included. Median age was 15 years. Most fractures (63.1%) occurred in patients aged 15 to 17 years, most frequent MOI was MVA (66.8%), and most common geographic location was the South (38%). Males sustained more spine fractures than females, overall (58.4% vs. 41.6%; P 0.001) and in MVAs (54.4% vs. 45.6%; P 0.001). Those in MVAs wearing seatbelts had lower odds of cranial (29.6% vs. 70.4%; odds ratio [OR] = 0.85, 95% confidence interval [CI]: 0.82-0.89; P 0.001) and thoracic (30.1% vs. 69.9%; OR = 0.88, 95% CI: 0.84-0.91; P 0.001) organ injury, multivertebral (30% vs. 70%; OR = 0.78, 95% CI: 0.73-0.83; P 0.001) and concomitant nonvertebral fractures (30.9% vs. 69.1%; OR = 0.89, 95% CI:0.73-0.83; P 0.001), and 21% lower odds of mortality (29.3% vs. 70.7%; OR = 0.79, 95% CI: 0.66-0.94; P = 0.009). Over 70% of drivers were not restrained during MVA, with majority of seatbelt violations incurred by males, ages 15 to 17, in the South.Over 60% of pediatric spinal fractures occur in children aged 15 to 17 years, coinciding with the beginning of legal driving. MVA is the most common cause and has significant association with morbidity/mortality. Nearly two- thirds pediatric spinal fractures sustained in MVAs occurred without seatbelts. Absence of seatbelts associated with20% greater odds of mortality. Ensuring new drivers wear protective devices can greatly reduce morbidity/ mortality associated with MVA.Level of Evidence: 3.

Single-center retrospective chart review with minimum 2-year follow up.To determine incidence of pulmonary hypertension in adolescent idiopathic scoliosis patients and to determine the effect of scoliosis surgery on pulmonary hypertension.Spinal deformity in adolescent idiopathic scoliosis can increase right atrial and ventricular pressures secondary to restrictive lung disease. Pulmonary hypertension leading to cor pulmonale is the most feared outcome, however mild pulmonary hypertension in adolescent idiopathic scoliosis (AIS) patients has been reported. No study has previously examined changes in the improvement of right heart function following scoliosis surgery.Cobb angle, 2D-echo signs of structural heart disease, aortic root dimensions, tricuspid regurgitant jet velocity (TRV), pulmonary function tests (PFTs), arterial blood gas (ABG), and patient demographics reviewed. Right ventricular systolic pressure (RVSP) estimated using Bernoulli equation (4[TRV]2) and right atrial pressure. RVSP ≥36 mmHg is a surrogate marker for pulmonary hypertension. All echocardiograms were read by board certified Pediatric Cardiologists. Logistic regression used to assess for differences in TRV between groups.Mean preoperative RVSP was significantly elevated in AIS patients (26.9 ± 0.49; P 0.001) compared with controls (17.25 + 0.88). Only 47 (21%) Group 1 patients had elevated preoperative TRV (≥2.8 m/s) versus none in Group 2 (P 0.001). Additionally, logistic regression showed AIS patients have odds ratio of 3.29 for elevated TRV (P = 0.007)-an indirect measure of pulmonary hypertension. In all Group 3 patients, the cardiac function normalized postoperatively (mean TRV = 2.09 + 0.23; P 0.001). No association found between Cobb angle, aortic root parameters, or pulmonary function tests.This study found 13.9% of patients with adolescent idiopathic scoliosis had elevated TRV while controls had no TRV abnormalities. Additionally, RVSP measurements demonstrated mild pulmonary hypertension in AIS patients. These abnormal values normalized postoperatively, indicating the benefits of scoliosis surgery on cardiac function in adolescent idiopathic scoliosis.Level of Evidence: 3.

Context.— Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) testing is used for serosurveillance and will be important to evaluate vaccination status. Given the urgency to release coronavirus disease 2019 (COVID-19) serology tests, most manufacturers have developed qualitative tests. Objective.— To evaluate clinical performance of 6 different SARS-CoV-2 IgG assays and their quantitative results to better elucidate the clinical role of serology testing in COVID-19. Design.— Six SARS-CoV-2 IgG assays were tested using remnant specimens from 190 patients. Sensitivity and specificity were evaluated for each assay with the current manufacturer's cutoff and a lower cutoff. A numeric result analysis and discrepancy analysis were performed. Results.— Specificity was higher than 93% for all assays, and sensitivity was higher than 80% for all assays (≥7 days post–polymerase chain reaction testing). Inpatients with more severe disease had higher numeric values compared with health care workers with mild or moderate disease. Several discrepant serology results were those just below the manufacturers' cutoff. Conclusions.— Severe acute respiratory syndrome coronavirus 2 IgG antibody testing can aid in the diagnosis of COVID-19, especially with negative polymerase chain reaction. Quantitative COVID-19 IgG results are important to better understand the immunologic response and disease course of this novel virus and to assess immunity as part of future vaccination programs.

In the intestine, IgA antibody-secreting B cells (IgA-ASCs) and helper T cells coordinate to maintain local homeostasis while their dysregulation could lead to development of intestinal inflammatory diseases. However, mechanisms underlying the coordinated localization and function of the B and T cells into the intestine, particularly the colon, are poorly understood. We herein report the first evidence that the gut-homing chemokine receptor CCR10+ IgA-ASCs form conjugates with helper T cells, preferentially regulatory T cells, at their differentiation sites of gut-associated lymphoid organs for their coordinated co-localization into the colon to promote local homeostasis. In CCR10-knockout mice, defective migration of IgA-ASCs also resulted in defective T cell migration and homeostasis, and development of inflammatory symptoms in the colon. Antigen-specific interaction of CCR10+ IgA-ASCs and T cells is crucial for their homeostatic establishment in the colon. On the other hand, in IgA-knockout mice, preferential expansion of CCR10+ IgG1-ASCs with regulatory functions compensated for CCR10+ IgA-ASCs to help maintain colonic homeostasis. The preferential expansion of specific subclasses of CCR10+ IgG-ASCs with regulatory functions was also found in asymptomatic IgA-deficient patients. These findings suggest coordinated cell migration as a novel mechanism underlying localization and function of B and T cells in colonic homeostatic regulation.

Osteosarcoma is a highly aggressive malignancy for which treatment has remained essentially unchanged for years. Our previous studies found that the F-box protein SKP2 is overexpressed in osteosarcoma, acting as a protooncogene; p27(Kip1) (p27) is an inhibitor of cyclin-dependent kinases and a downstream substrate of SKP2-mediated ubiquitination. Overexpression of SKP2 and underexpression of p27 are common characteristics of cancer cells. The SCF(SKP2) E3 ligase ubiquitinates Thr187-phosphorylated p27 for proteasome degradation, which can be abolished by a Thr187Ala knock-in (p27(T187A) KI) mutation. RB1 and TP53 are two major tumor suppressors commonly coinactivated in osteosarcoma. We generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which developed osteosarcoma with full penetrance. When p27(T187A) KI mice were crossed on to the DKO background, p27(T187A) protein was found to accumulate in osteosarcoma tumor tissues. Furthermore, p27(T187A) promoted apoptosis in DKO tumors, slowed disease progression, and significantly prolonged overall survival. RNA sequencing analysis also linked the SCF(SKP2)–p27(T187A) axis to potentially reduced cancer stemness. Given that RB1 and TP53 loss or coinactivation is common in human osteosarcoma, our study suggests that inhibiting the SKP2–p27 axis may represent a desirable therapeutic strategy for this cancer.

There has been increasing interest in the use of stemless humeral implants for total shoulder arthroplasty when compared with both short-stem (SS) and standard-length implants. Although evidence for decreased surgical time and blood loss exists for stemless versus standard-length stems, far less literature exists comparing these clinical parameters for stemless versus SS implants.A retrospective review of consecutive anatomic total shoulder arthroplasty (aTSA) cases conducted by a single, fellowship-trained shoulder surgeon was undertaken from January 2016 through January 2022 with the exception of March 2020 through January 2021 secondary to the COVID-19 pandemic. Demographic patient and surgical data, including age, sex, body mass index, American Society of Anesthesiologists score, age-adjusted Charlson Comorbidity Index, prior ipsilateral shoulder arthroscopy, surgical time, use of a Hemovac drain and/or tranexamic acid, hospital length of stay (LOS), and both postoperative day #1 (POD 1) and discharge visual analog scores. The use of a stemless or SS implant was recorded. Intraoperative total blood volume loss (TBVL) was calculated, in addition to the need for either intraoperative or postoperative transfusions. Nonparametric analysis of covariance was used to examine effects of stemless versus SS aTSA on surgical time and intraoperative TBVL adjusted for demographic, clinical, and surgical variables.There were 47 SS and 83 stemless anatomic implants included, of which 74 patients (57%) overall were women. The median surgical time for the stemless cohort was 111 minutes (IQR 96-130) versus 137 minutes (IQR 113-169) for the SS cohort (P0.00001). The median intraoperative TBVL for the stemless cohort was 298.3 mL (IQR 212.6-402.8) versus 359.7 mL (IQR 253.9-415.0) for the SS cohort (P = 0.05). After multivariable regression analysis, use of stemless humeral implants was independently associated with both decreased surgical time and intraoperative blood loss (P0.001 and P = 0.005, respectively). There was a shorter median hospital LOS in the stemless group (2 days [IQR 1-2] versus 2 days [IQR 2-3], P = 0.03). The visual analog score pain score at discharge was lower among the stemless cohort (0 [IQR 0-3] versus 4 [IQR 2-6], P0.00001). Increased surgical time was associated with intraoperative TBVL (r = 0.340, P0.0001).Stemless aTSA is associated with a markedly decreased surgical time and intraoperative TBVL when compared with a SS aTSA. Furthermore, the use of a stemless implant results in a shorter hospital LOS and lower discharge pain scores.

The outcomes of congenital scoliosis (CS) patients undergoing hemivertebra (HV) resection surgery with a 2-level fusion versus a2-level fusion are unclear. We hypothesized that CS patients undergoing HV resection and a2-level fusion have decreased curve progression and reoperation rates compared with 2-level fusions.Retrospective review of prospectively collected data from a multicenter scoliosis database. Fifty-three CS patients (average age 4.5, range 1.2 to 10.9 y) at index surgery were included. Radiographic and surgical parameters, complications, as well as revision surgery rates were tracked at a minimum of 2-year follow-up.Twenty-six patients had a 2-level fusion while 27 patients had a2-level fusion with similar age and body mass index between groups. The HV was located in the lumbar spine for 69% (18/26) 2-level fusions and 30% (8/27)2-level fusions ( P =0.006). Segmental HV scoliosis curve was smaller in 2-level fusions compared to2-level fusions preoperatively (38 vs. 50 degrees, P =0.016) and at follow-up (25 vs. 34 degrees, P =0.038). Preoperative T2-T12 (28 vs. 41 degrees, P =0.013) and segmental kyphosis (11 vs. 23 degrees, P =0.046) were smaller in 2-level fusions, but did not differ significantly at postoperative follow-up (32 vs. 39 degrees, P =0.22; 13 vs. 11 degrees, P =0.64, respectively). Furthermore, the 2 groups did not significantly differ in terms of surgical complications (27% vs. 22%, P =0.69; 2-level fusion vs.2-level fusion, respectively), unplanned revision surgery rate (23% vs. 22%, 0.94), growing rod placement or extension of spinal fusion (15% vs. 15%, P =0.95), or health-related quality of life per the EOS-Questionnaire 24 (EOSQ-24). Comparison of patients with or without the need for growing rod placement or posterior spinal fusion revealed no significant differences in all parameters analyzed.Two-level and2-level fusions can control congenital curves successfully. No differences existed in curve correction, proximal junctional kyphosis or complications between short and long-level fusion after HV resection. Both short and long level fusions are viable options and generate similar risk of revision. The decision should be individualized by patient and surgeon.

Neoadjuvant endocrine therapy (NET) can be used to treat estrogen receptor positive (ER+) invasive breast cancer (IBC). Tumors with Ki67gt;10% after 2 to 4 weeks of NET are considered resistant to endocrine therapy. Enhancer of Zeste Homolog 2 (EZH2) is a targetable oncoprotein and overexpression in ER+ IBC has been linked to resistance to endocrine therapy. We examined whether EZH2 expression levels in ER+ IBC could be used to predict response to NET.We retrospectively identified 46 patients with localized ER+ HER2/neu negative IBC treated with a minimum of 4 weeks of NET. We quantified EZH2 nuclear expression in pretherapy core biopsies using a score that included intensity and percent of cells staining. Ki67 was evaluated in both pretherapy core biopsies and posttherapy tumor resections and scored according to the guidelines of the International Ki67 Working Groups, with a global weighted score. Ki67≤10% after NET was considered endocrine responsive. Logistic regression analysis was performed to determine the association between EZH2 expression and response to NET.We found significant associations of tumor grade ( P =0.011), pretherapy Ki67 ( P =0.003), and EZH2 ( Plt;0.001), with response to NET. On logistic regression adjusted for tumor grade and pretherapy Ki67, increased EZH2 scores were associated with decreased odds of endocrine responsiveness, defined as posttreatment Ki67≤10% (odds ratio=0.976, 95% CI, 0.956 to 0.997; P =0.026). In addition, with EZH2 score in the model, associations of tumor grade and pretreatment Ki67 with posttreatment Ki67≤10% response to NET became not significant.Our results suggest that EZH2 might be a useful biomarker to predict response to NET.

Short-term cancellation of elective ambulatory orthopaedic surgery can result in disruption to the process flow of the operating room, with resultant negative financial implications for the health system. The risk factors for patient-related short-term cancellations within 24 hours of the surgical date have not been well defined.A retrospective review of a single orthopaedic surgery electronic internal database was done to identify all cancellations from January 1, 2016, through December 31, 2019, which were made within 24 hours of the surgical date. Inclusion criteria included elective arthroscopic procedures canceled solely for patient-related issues. Any cancellation for surgeon-related or ambulatory center-related reasons was excluded. Demographic patient and surgical data, including insurance type, employment status, previous history of cancellation for the same surgery, socioeconomic status based on the Area Deprivation Index, and surgery type, were tabulated. Each cancellation was matched 1:2 with noncanceled cases based on the anatomic site of the arthroscopy scheduled. Multivariable logistic regression was used to examine associations of patient demographic and medical characteristics with surgical cancellation.There were 4,715 total arthroscopic procedures done during the study period, of which 126 (2.7%) were canceled within 24 hours of the surgery date. The mean age of the canceled cases was 44.9 ± 16.1 years (range, 14 to 77 years), with 46 females (43%) included. The presence of MRI of the involved joint within 6 months of surgery (adjusted odds ratio [aOR], 0.39, 95% confidence interval [CI], 0.17 to 0.91) and current employment (aOR, 0.56, 95% CI, 0.33-0.94) were independently predictive of noncancellation. Current smokers were more likely to cancel within 24 hours of surgery (aOR, 2.63, 95% CI, 1.4-4.9). Finally, having previously canceled the same surgery was significantly associated with a current surgical cancellation (P = 0.004).Identification of the factors associated with short-term patient-related cancellation of elective arthroscopy may serve as the basis for preoperative interventions aimed specifically at those more likely to cancel. In turn, these interventions can minimize preventable cancellations.

Rationale & Objective Community racial composition has been shown to be associated with mortality in patients receiving maintenenance dialysis. It is unclear whether living in communities with predominantly Black residents is also associated with risk for hospitalization among patients receiving hemodialysis. Study Design Retrospective analysis of prospectively collected data from a cohort of patients receiving hemodialysis. Setting & Participants 4,567 patients treated in 154 dialysis facilities located in 127 unique zip codes and enrolled in US Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 5 (2010-2015). Exposure Tertile of percentage of Black residents within zip code of patients’ dialysis facility, defined through a link to the American Community Survey. Outcome Rate of hospitalizations during the study period. Analytic Approach Associations of patient-, facility-, and community-level variables with community’s percentage of Black residents were assessed using analysis of variance, Kruskal-Wallis, or χ2/Fisher exact tests. Negative binomial regression was used to estimate the incidence rate ratio for hospitalizations between these communities, with and without adjustment for potential confounding variables. Results Mean age of study patients was 62.7 years. 53% were White, 27% were Black, and 45% were women. Median and threshold percentages of Black residents in zip codes in which dialysis facilities were located were 34.2% and ≥14.4% for tertile 3 and 1.0% and ≤1.8% for tertile 1, respectively. Compared with those in tertile 1 facilities, patients in tertile 3 facilities were more likely to be younger, be Black, live in urban communities with lower socioeconomic status, have a catheter as vascular access, and have fewer comorbid conditions. Patients dialyzing in communities with the highest tertile of Black residents experienced a higher adjusted rate of hospitalization (adjusted incidence rate ratio, 1.32; 95% CI, 1.12-1.56) compared with those treated in communities within the lowest tertile. Limitations Potential residual confounding. Conclusions The risk for hospitalization for patients receiving maintenance dialysis is higher among those treated in communities with a higher percentage of Black residents after adjustment for dialysis care, patient demographics, and comorbid conditions. Understanding the cause of this association should be a priority of future investigation.

AIMS Tumour-infiltrating lymphocytes (TILs) are prognostic in invasive breast cancer; however, their prognostic significance in ductal carcinoma in situ (DCIS) has not been established. The Oncotype DX (ODX) Breast DCIS Score test is a genomic assay used to predict the local recurrence risk. The aims of this study were to quantify TILs in DCIS by the use of three methodologies, and correlate them with the ODX DCIS Score. METHODS AND RESULTS We studied 97 DCIS cases, all with an ODX DCIS Score. Cases with a low ODX DCIS Score were considered as one group, and those with an intermediate/high ODX Score were considered together. TILs were quantified on haematoxylin and eosin-stained slides. The methodologies used to quantify TILS included assessment of stromal TILs, assessment of touching TILs, and assessment of circumferential TILS. In cases with >5% stromal TILS, the percentage of stromal TILS was considered to be high. In cases with a mean number of more than five touching TILs per DCIS duct, TILs were considered to be present. The ODX DCIS Score was intermediate/high in 27 (28%) cases and low in 70 (72%) cases. There were >5% stromal TILs in 33 (34%) cases, and more than five touching TILs per DCIS duct in 15 (15%) cases; circumferential TILs were present in nine (9%) cases. In univariate analysis, a low ODX DCIS Score showed significant associations with absent touching TILS (P = 0.027), stromal TILs

Hypothermia-related deaths affect vulnerable populations and are preventable. They account for the vast majority of weather-related deaths in the United States. The postmortem diagnosis of hypothermia can be challenging, as there are no pathognomonic signs. The electronic databases of the New York City Office of Chief Medical Examiner and Harris County Institute of Forensic Sciences were searched for all fatalities where the primary cause of death included hypothermia, between January 2009 and July 2019. There were 139 hypothermia deaths in New York City (NYC) with an average annualized rate of 1.7 per million. During this same time, there were 50 hypothermia deaths in Houston with an average annualized rate of 2.4 per million. Males were more likely to die of hypothermia compared to females in both cities. The rate ratio (RR) in NYC was 3.55 (95% CI 2.40, 5.25), while the RR in Houston was 2.83 (95% CI 1.50, 5.32). Age- and sex-specific standardized hypothermia mortality rates were 18.2 (95% CI 15.1, 21.2) per million in NYC and 30.1 (95% CI 21.7, 38.6) per million in Houston. The comparative hypothermia death ratio was 1.66 (95% CI 1.19, 2.30), indicating hypothermia mortality in Houston was 66% higher than in NYC. There was no correlation between zip code poverty rates and hypothermia-related deaths. The most consistent autopsy finding was Wischnewski spots (56.6%), and ethanol was the most common toxicological finding (36.5%). Local agencies can use this data to target these higher-risk populations and offer appropriate interventions to try to prevent these deaths.

Rationale & Objective Group-based care provides an opportunity to increase patient access to providers without increasing physician time and is effective in the management of chronic diseases in the general population. This model of care has not been investigated in chronic kidney disease (CKD). Study Design Randomized controlled trial in adults (n = 50); observational study in adolescents (n = 10). Setting & Participants Adults and adolescents with CKD and hypertension in the Bronx, NY. Intervention Group-based care (monthly sessions over 6 months) versus usual care in adults. All adolescents received group-based care and were analyzed separately. Outcomes Participant attendance and satisfaction with group-based care were used to evaluate intervention feasibility. The primary clinical outcome was change in mean 24-hour ambulatory blood pressure. Secondary outcomes included physical activity, medication adherence, quality of life, and sodium intake as assessed by 24-hour urinary sodium excretion and food frequency questionnaires. Results Among adults randomly assigned to group-based care, attendance was high (77% of participants attended ≥3 sessions) and most reported higher satisfaction. Mean 24-hour ambulatory systolic blood pressure decreased by −4.2 (95% CI, −13.3 to 5.8) mm Hg in group-based care patients compared with usual care at 6 months but this was not statistically significant. Similarly, we did not detect significant differences in health-related behaviors (such as medication adherence, sodium intake, and physical activity) or quality-of-life measures between the 2 groups. Among the adolescents, attendance was very poor; self-reported satisfaction, although high, did not change from baseline compared with the 6-month follow-up. Limitations Small study size, missing data. Conclusions Group-based care is feasible and acceptable among adults with hypertension and CKD. However, a larger trial is needed to determine the effect on blood pressure and health-related behaviors. Patient participation may limit the effectiveness of group-based care models in adolescents. Funding National Institutes of Health R34 DK102174. Trial registration https://clinicaltrials.gov/show/NCT02467894., Graphical Abstract

STUDY DESIGN A retrospective chart review of prospectively collected data. OBJECTIVE The aim of this study was to determine whether back-to-back scoliosis surgeries can be performed safely without compromising outcomes and the reproducibility of the practice between institutions. SUMMARY OF BACKGROUND DATA During the summer, spinal surgeons will often book multiple cases in one day. The complexity and demands of spinal fusion surgery call into question the safety. Change of operating room staff including anesthesiologists, nurses, and neurologists may introduce new risks. METHODS From 2009 to 2018, index AIS surgeries were included. In Groups 1, 2, and 3, surgeries were performed by a single surgeon. In Group 4, they were performed by other institutional surgeons. Group 1: first surgery of the day, Group 2: second surgery of the day, Group 3: only surgery of the day, Group 4: only surgery of the day by different institutional surgeon. Additional analysis was done to determine reproducibility after a surgeon was moved from Institution 1 to Institution 2. RESULTS Five hundred sixty-seven AIS patients were analyzed. Group 1 patients had similar radiographic outcomes compared with Group 2 (P > 0.05). Surgical time was similar (P = 0.51), but significantly more levels fused (P = 0.01). Compared with Group 3, Group 2 had a smaller preoperative Cobb (P = 0.02), shorter surgeries (P

In this retrospective study of 319 children with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we assessed whether age, asthma, obesity, diabetes, and socioeconomic status were associated with hospitalization for coronavirus disease 2019 (COVID-19). Demographic and clinical characteristics were assessed using univariate statistics, excluding incidental or unrelated positives. There was a bimodal distribution of age among hospitalized children. Obesity ( P < .001) and a past medical history of diabetes ( P = .001) were significantly more prevalent in hospitalized children, including cases of new-onset diabetes and diabetic ketoacidosis. Neither a past medical history of asthma nor lower socioeconomic status was associated with hospitalization. Although limited to a single center, the findings in this study may have important clinical implications. Targeted, proactive health outreach to children with obesity and diabetes, with prioritization of preventative efforts such as vaccination, may be important in preventing worse SARS-CoV-2 infection in this vulnerable group.

Retrospective review.The objective of this study was to report on one institution's use of single bolus micro-dose intrathecal morphine as part of a rapid recovery pathway during posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) and its comparison to patients whose pain was controlled with patient-controlled analgesia (PCA).Narcotic substance addiction has risen across all patient populations, including pediatrics. Narcotics have been historically used in complex spine surgeries as a measure of pain control, predominantly provided as PCA and additional take-home medication.AIS patients undergoing PSF from 2015 to 2019 were reviewed. In 2018, we instituted a standardized rapid recovery pathway for scoliosis patients undergoing PSF utilizing micro-dose intrathecal morphine (ITM-RRP). Before this, traditional protocol with PCA was used for postoperative management. Perioperative data, morphine consumption and prescription refill requests were compared.There were 373 AIS patients total in this study, of which 250 patients were in the PCA group and 123 in the ITM-RRP Group. Preoperative Cobb angles (P = 0.195), as well as levels fused (P = 0.481) and body mass index (P = 0.075) were similar. 69.4% of ITM-RRP patients had a length of stay ≤3 days, significantly11.6% of PCA patients (P 0.001). ITM-RRP patients began ambulating significantly earlier with 84.6% patients out of bed by postoperative day 1 versus 8% PCA patients (P 0.001). Additionally, ITM-RRP patients had significantly lower VAS pain scores with activity and earlier initial bowel movements (P 0.001).Postoperative emesis was similar (P = 0.11). No patients had pruritus, respiratory depression, or required supplemental oxygenation.This is the first study to show that a rapid recovery protocol utilizing single micro-dose ITM with oral analgesics have adequate recovery, significantly better postoperative pain control and superior perioperative outcomes to traditional protocols using PCA in the AIS population following PSF.Level of Evidence: 3.

Multicenter retrospective review.This study aims to address major postoperative complications associated with Scheuermann kyphosis (SK) when compared with adolescent idiopathic scoliosis (AIS) in a large population matched by demographic characteristics, levels fused and operative technique.Prior studies have found that SK patients are 3.86 times more likely to experience major postoperative complications than in AIS. Historically, however, these studies have often had populations that were significantly different between the two groups in terms of disease severity, demographics, and small sample sizes.AIS patients were compared to SK patients between 2006 and 2018 contemporaneously. All surgeries were conducted by six surgeons among two institutions. Complications and revisions were calculated. A sub-analysis comparing SK and AIS patients by age, sex, and levels-fused in one-to-one matched pairs was performed as well as a sub-analysis matched by levels fused only in one-to-one matched pairs.One thousand three hundred twenty two patients were reviewed (1222 AIS; 100 SK). There were 52 (4.3%) complications in the AIS group compared with 20 (20%) complications in the SK group (P 0.001), with infections and revisions consisting of the majority of complication rates in both cohorts.When matched by age, sex, and levels fused, there were eight complications in the AIS group and 11 in the SK group (P = 0.63), with infection and revision rates being similar, (P = 0.29) and (P = 0.26) respectively.When matched by levels fused only, EBL, operative time and complication rates remained similar (P 0.05).Contrary to previously published literature, our analyses indicate that in a matched population, postoperative complication rates (i.e., infection and revision rates) are not significantly different between SK and AIS patients.Level of Evidence: 4.

STUDY DESIGN Retrospective review of prospective data from multicenter registry. OBJECTIVE Compare outcomes of posterior spinal fusion (PSF) versus magnetically controlled growing rods (MCGR) versus vertebral body tethers (VBT) in 8- to 11-year-old idiopathic early onset scoliosis (EOS) patients. SUMMARY OF BACKGROUND DATA In EOS, it is unclear at what age the benefit of growth-sparing strategies outweighs increased risks of surgical complications, compared with PSF. METHODS One hundred thirty idiopathic EOS patients, 81% female, aged 8-11 at index surgery (mean 10.5 yrs), underwent PSF, MCGR, or VBT. Scoliosis curve, kyphosis, thoracic and spinal height, complications, and Quality of Life (QoL) were assessed preoperatively and at most recent follow-up (prior to final fusion for VBT/MCGR). RESULTS Of 130 patients, 28.5% received VBT, 39.2% MCGR, and 32.3% PSF. The VBT cohort included more females (P