SARS-CoV-2 omicron spike simulations: broad antibody escape, weakened ACE2 binding, and modest furin cleavage.

The recent emergence of the omicron variant of the SARS-CoV-2 virus with large numbers of mutations has raised concern about a potential new surge in infections. Here we use molecular dynamics to study the biophysics of the interface of the BA1 and BA2 omicron spike protein binding to (i) the ACE2 receptor protein, (ii) antibodies from all known binding regions, and (iii) the furin binding domain. Our simulations suggest that while there is a significant reduction of antibody (Ab) binding strength corresponding to escape, the omicron spikes pay a cost in terms of weaker receptor binding as measured by interfacial hydrogen bonds (H-bond). The furin cleavage domain (FCD) is the same or weaker binding than the delta variant, suggesting lower fusogenicity resulting in less viral load and disease intensity than the delta variant. IMPORTANCE The BA1 and BA2 and closely related BA2.12.2 and BA.5 omicron variants of SARS-CoV-2 dominate the current global infection landscape. Given the high number of mutations, particularly those which will lead to antibody escape, it is important to establish accurate methods that can guide developing health policy responses that identify at a fundamental level whether omicron and its variants are more threatening than its predecessors, especially delta. The importance of our work is to demonstrate that simple in silico simulations can predict biochemical binding details of the omicron spike protein that have epidemiological consequences, especially for binding to the cells and for fusing the viral membrane with the cells. In each case, we predicted weaker binding of the omicron spike, which agreed with subsequent experimental results. Future virology experiments will be needed to test these predictions further.

Treatment of Unstable Versus Stable Slipped Capital Femoral Epiphysis Using the Modified Dunn Procedure.

BACKGROUND: The modified Dunn procedure (open subcapital realignment via a surgical dislocation approach) has been shown to be a safe and effective way of treating acute, unstable slipped capital femoral epiphysis (SCFE). There is a paucity of literature comparing the modified Dunn procedure in stable SCFE. The purpose of this study was to compare acute, unstable versus chronic, stable SCFE managed with the modified Dunn procedure. METHODS: A retrospective chart review was performed on 44 skeletally immature patients who underwent the modified Dunn procedure for SCFE. Patients were divided into stable or unstable based on clinical presentation and intraoperative findings. Demographics, radiographic measurements, and complications were recorded and compared. χ and t tests were used to compare variables. RESULTS: In total, 31 consecutive hips (29 patients) with acute, unstable slips, and 17 consecutive hips (15 patients) with chronic, stable slips were reviewed. Average age was 12.5 and 13.8 years for acute and chronic, respectively (P=0.05). Mean follow-up was 27.9 months (unstable) and 35.5 months (stable). Average postoperative Southwick angle was 14.2 degrees; (unstable) and 25.3 degrees (stable) (P=0.001). Greater trochanteric height averaged 6.2 mm below the center of the femoral head in the acute group and 6.2 mm above center in the chronic group (P<0.001). Average femoral neck length measured 34.1 mm (unstable) and 27.1 mm (stable) (P<0.001). Two patients (6%) developed avascular necrosis (AVN) in the unstable group, with 5 patients (29.4%) in the stable group (P=0.027). All patients with hip instability (N=3) developed AVN. CONCLUSIONS: Although both acute, unstable and chronic, stable SCFE can be successfully treated with the modified Dunn procedure, the complication rate is statistically higher in patients with stable SCFE, specifically both AVN rate and postoperative instability. In addition, it is more difficult to establish normal anatomic indexes with regard to greater trochanteric height and femoral neck length. This procedure has great utility in the correction of the anatomic deformity associated with SCFE, but should be used with caution in patients with chronic, stable SCFE. LEVEL OF EVIDENCE: Level III-retrospective review.

Treatment of Unstable Slipped Capital Epiphysis Via the Modified Dunn Procedure.

BACKGROUND: The modified Dunn procedure has been shown to be safe and effective in treating unstable slipped capital femoral epiphysis (SCFE). We present a consecutive series of unstable SCFE managed by a single surgeon with a focus on timing of surgical intervention, postoperative complications, and radiographic results. METHODS: Thirty-one consecutive unstable SCFEs were treated. Demographics, presentation time to time of operation, surgical times, and complications were recorded. Bilateral hip radiographs at latest follow-up were utilized to record slip angle, α angle, greater trochanteric height, and femoral neck length. RESULTS: Thirty-one consecutive hips in 30 patients were reviewed: 15 males (50%) and 15 females (50%), average age 12.37 years (range, 8.75 to 14.8 y), 20 left hips (65%) and 11 right hips (35%). Mean follow-up was 27.9 months (range, 1 to 82 mo). Time from presentation to intervention averaged 13.9 hours (range, 2.17 to 23.4 h). Two patients (6%) developed avascular necrosis at average 19 weeks postoperative. Three patients (10%) developed mild heterotopic ossification requiring no treatment. Two patients (6%) required removal of symptomatic hardware. One patient had hardware failure and in no patients was nonunion, delayed union, or postoperative hip subluxation/dislocation seen. Three patients (10%) presented with bilateral, stable SCFE requiring contralateral in situ pinning. Five patients (16%) had sequential SCFE requiring treatment with 1 patient having an acute, unstable SCFE 10 months after the previous realignment. Mean postoperative slip angle measured 2.5 degrees (range, +19 to -9.4 degrees) (SD, 7.2), α angle 47.43 degrees (range, 34 to 64 degrees) (SD, 7.49), greater trochanteric height averaged 3.5 mm below the center of femoral head (-17.5 to +25 mm), and mean femoral neck length difference measured -7.75 mm (range, -1.8 to -18.6 mm). CONCLUSIONS: A single surgeon series of unstable SCFEs treated by a modified Dunn procedure showed a 6% incidence of avascular necrosis and low complication rates at latest follow-up. Radiographs showed restoration of the slip angle, α angle, femoral neck length, and greater trochanteric height. This series reveals the safety and effectiveness of the modified Dunn procedure for unstable SCFE. LEVEL OF EVIDENCE: Level III-retrospective review.

Randomized Prospective Trial Comparing the Use of Intravenous versus Oral Acetaminophen in Total Joint Arthroplasty.

BACKGROUND: Multimodal pain management has had a significant effect on improving total joint arthroplasty recovery and patient satisfaction. There is literature supporting that intravenous (IV) acetaminophen reduces postoperative pain and narcotic use in the total joint population. However, there are no studies comparing the effectiveness of IV vs oral (PO) acetaminophen as part of a standard multimodal perioperative pain regimen. METHODS: One hundred twenty patients undergoing hip and knee arthroplasty surgeries performed by one joint arthroplasty surgeon were prospectively randomized into 2 groups. Group 1 (63 patients) received IV and group 2 (57 patients) received PO acetaminophen in addition to a standard multimodal perioperative pain regimen. Each group received 1 gram of acetaminophen preoperatively and then every 6 hours for 24 hours. Total narcotic use and visual analog scale (VAS) scores were collected every 4 hours postoperatively. RESULTS: The 24-hour average hydromorphone equivalents given were not different between groups (3.71 vs 3.48) at 24 hours (P = .76), or at any of the individual 4-hour intervals. The 24-hour average visual analog scale scores in group 1 (IV) was 3.00 and in group 2 (PO) was 3.40 (P = .06). None of the 4-hour intervals were significantly different except the first interval (0-4 hour postoperatively), which favored the IV group (P = .03). CONCLUSION: The use of IV acetaminophen may have a role when given intraoperatively to reduce the immediate pain after surgery. Following that, it does not provide a significant benefit in reducing pain or narcotic use when compared with the much less expensive PO form.

The influence of central review on outcome in malignant gliomas of the spinal cord: the CCG-945 experience.

OBJECT The impact of central pathology review on outcome has been described in pediatric patients with high-grade glioma (HGG). The objective of this report was to analyze the impact of the central pathology review on outcome in the subgroup of patients with institutional diagnosis of HGG of the spinal cord enrolled in the Children's Cancer Group 945 cooperative study. METHODS Five neuropathologists centrally reviewed the pathology of the 18 patients with HGG of the spinal cord who were enrolled in the study. These reviews were independent, and reviewers were blinded to clinical history and outcomes. A consensus diagnosis was established for each patient, based on the outcome of the review. RESULTS Of 18 patients, only 10 were confirmed to have HGG on central review. At a median follow-up of 12 years, event-free and overall survival for all 18 patients was 43.2% ± 13.3% and 50% ± 13.4%, respectively. After central review, 10-year event-free and overall survival for confirmed HGGs and discordant diagnoses was 30% ± 12.5% versus 58.3% ± 18.8% (p = 0.108) and 30% ± 12.5% versus 75% ± 14.2% (p = 0.0757), respectively. CONCLUSIONS The level of discordant diagnoses in children and adolescents with institutional diagnosis of HGG of the spinal cord was 44% in this experience. However, there was no significant difference in outcome between patients with confirmed and discordant diagnosis. This group of tumor deserves a specific attention in future trials.

Repeat Manipulation Under Anesthesia For Persistent Stiffness After Total Knee Arthroplasty Achieves Functional Range of Motion.

Poor range of motion may decrease a patient's ability to participate in activities of daily living after total knee arthroplasty. Manipulation under anesthesia has been shown to improve range of motion; however, some patients have persistent stiffness even after manipulation. The goal of this study was to evaluate the outcomes and complications of patients who underwent a second manipulation under anesthesia for persistent stiffness after total knee arthroplasty. The review of surgical records of two joint arthroplasty surgeons identified 226 knees in 210 patients who underwent a manipulation under anesthesia for poor range of motion after total knee arthroplasty. Of these patients, 16 patients underwent a second manipulation under anesthesia. For patients undergoing two manipulations under anesthesia procedures, at latest follow up (mean 539 days), mean extension improved from 10.50° to 2.50° (p=0.001) and mean flexion improved from 87.50° to 112.69° (p=0.001) respectively. SF-12 scores were available for 12 of 16 knees with a mean score of 34.42. Two of 16 patients (12.5%) experienced a complication. Three of 16 (18.8%) patients who underwent a second manipulation required a revision arthroplasty procedure. In conclusion, a second manipulation under anesthesia can achieve functional range of motion that is sustained after total knee arthroplasty.

Retrograde Versus Antegrade Femoral Bone Graft Harvesting Using the Reamer-Irrigator-Aspirator.

OBJECTIVES: To compare retrograde versus antegrade femoral bone graft harvesting using the reamer-irrigator-aspirator system to determine whether there was any difference in intraoperative, postoperative, or patient outcome variables. DESIGN: Retrospective cohort study. SETTING: Urban Level I Trauma Center. PATIENTS/PARTICIPANTS: Ninety-four (62 antegrade and 32 retrograde procedures) consecutive adult patients who underwent femoral autologous bone graft harvesting using the Synthes reamer-irrigator-aspirator system between April 2008 and March 2013. MAIN OUTCOME MEASUREMENTS: Amount of bone graft, perioperative fractures or other complications, and postoperative hip and/or knee pain. RESULTS: There was no significant difference between demographic or medical comorbidities between the groups. There was no significant difference in the side of the graft harvest, graft volume, hospital length of stay, or the ability to ambulate on postoperative day 1. There was a significantly increased incidence of iatrogenic fracture or prophylactic nailing with antegrade reaming (4 vs. 0, P = 0.01). Average length of follow-up was 500 (range, 20-1477) days for the antegrade group and 378 (range, 19-706) days for the retrograde group. The antegrade group had a nonsignificant increased incidence of hip pain (8.1% vs. 3.1%, P = 0.66), and the retrograde group had a significantly higher incidence of knee pain (15.6% vs. 1.6%, P = 0.02) at 6-month follow-up. Neither hip nor knee complaints were present at final follow-up. No cases of delayed femur fracture, infection, or abductor and/or antalgic gait involving the donor extremity were seen at final follow-up. CONCLUSIONS: This study provides support to the safety of femoral bone graft harvesting using both antegrade and retrograde techniques. Both techniques provide reliable, high-volume, nonstructural autologous bone graft with minimal associated morbidity. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children's Cancer Group high-grade glioma study CCG-945.

Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children's Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG.

Anterior Tibial Artery Injury Following Tibiotalocalcaneal Retrograde Intramedullary Nailing: A Case Report.

CASE: We report the case of a patient who sustained injury to the anterior tibial artery during tibiotalocalcaneal retrograde nailing and developed an acutely ischemic foot. CONCLUSION: Vascular injury during tibiotalocalcaneal arthrodesis with retrograde nailing is a rare but serious complication. While retrograde tibiotalocalcaneal arthrodesis nailing for end-stage ankle and subtalar arthritis has shown encouraging results, a high index of suspicion for postoperative complications is necessary in patients with risk factors for poor posterior collateral circulation.

PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.

Parkinson's disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson's and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson's disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson's disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson's disease identifies PGC-1α as a potential therapeutic target for early intervention.

Gadolinium released from MR contrast agents is deposited in brain tumors: in situ demonstration using scanning electron microscopy with energy dispersive X-ray spectroscopy.

BACKGROUND: gadolinium (Gd)-containing MRI contrast agents (GdCA) are widely used in studies of brain tumors, and a number of reports suggest that under certain conditions, such as renal failure, Gd may be released from GdCA into patient's tissues. Whether this may happen in abnormal tissues in the absence of renal failure has not been studied. PURPOSE: to test the hypothesis that the local retention of GdCA resulting from brain tumor-associated alterations in the blood-brain barrier (BBB) may result in the deposition of Gd released from the GdCA, depending on stability. MATERIAL AND METHODS: in this retrospective study, 30 selected brain tumor biopsies from 28 patients (taken before and after an institutional switch from a less stable to an intermediate stable GdCA) were searched for Gd-containing deposits using scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDS). Relevant histories and laboratory results were obtained through institutional electronic records. Associations between the presence of deposits and other variables were tested for statistical significance using the two-tailed Fisher's exact test. RESULTS: insoluble deposits containing Gd associated with phosphorus and calcium were found in seven biopsies from five patients. These deposits were found in patients with estimated GFRs above 53 ml/min, and were detected more often in those receiving GdCA before the switch from a less stable to an intermediate stable GdCA (P = 0.04), and may be more frequent in patients receiving more than one contrast-enhanced MR scan (P = 0.15). CONCLUSION: Gd-containing deposits are present in brain tumors following contrast-enhanced MR scans in patients without severe renal disease. Further studies are needed to assess the clinical importance of the deposits we observed and to determine whether they are also found in other conditions that alter the integrity of the BBB.

Applying the principles of adult learning to the teaching of psychopharmacology: audience response systems.

Medical presentations can be enhanced by systematically collecting audience feedback. This is readily accomplished with polling systems, called audience response systems. Several systems are now available that are small, inexpensive, and can be readily integrated into standard powerpoint presentations without the need for a technician. Use of audience response systems has several advantages. These include improving attentiveness, increasing learning, polling anonymously, tracking individual and group responses, gauging audience understanding, adding interactivity and fun, and evaluating both participant learning and instructor teaching. Tips for how to write questions for audience response systems are also included.

Lanthanum deposition in a dialysis patient.

Lanthanum carbonate (LaCO(3)) is an oral phosphate binder widely used in end-stage renal disease (ESRD). Preclinical animal studies reported the highest La concentrations outside the gut to be in mesenteric lymph nodes. We observed previously unreported La deposition visible by light microscopy and confirmed by scanning electron microscopy with energy dispersive x-ray spectroscopy in a mesenteric lymph node at autopsy of a 38-year-old female ESRD patient 3 years following LaCO(3) administration. Although LaCO(3) is generally thought to be minimally absorbed, this demonstration suggests the need for further investigation of the extent and potential effects of such absorption.

Applying the principles of adult learning to the teaching of psychopharmacology: overview and finding the focus.

Medical education in psychopharmacology can be designed according to modern principles of adult learning. The goal is to go beyond merely exposing learners to novel content, to the documentation that learning has occurred and that behaviors have changed, namely the upgrading of skills in clinical practice. The many aspects of this approach to medical education are discussed in overview here. Future installments of "Trends in Psychopharmacology" will periodically deal with specific aspects of the best practices for medical educators outlined here only in brief. This article considers whether the focus of medical education instructors should be the medical content they present, the medical educator that does the presenting, or the learner. The perspective here is that the focus of medical education should be the learner, and that the content should be structured and executed in a manner that facilitates learning instead of inhibiting it.

A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease, seizures and cotton wool plaques, but not spastic paraparesis.

Over 100 mutations in the presenilin-1 gene (PSEN1) have been shown to result in familial early onset Alzheimer disease (EOAD), but only a relatively few give rise to plaques with an appearance like cotton wool (CWP) and/or spastic paraparesis (SP). A family with EOAD, seizures and CWP was investigated by neuropathological study and DNA sequencing of the PSEN1 gene. Abeta was identified in leptomeningeal vessels and in cerebral plaques. A single point mutation, p.L420R (g.1508T > G) that gives rise to a missense mutation in the eighth transmembrane (TM8) domain of PS1 was identified in two affected members of the family. p.L420R (g.1508T > G) is the mutation responsible for EOAD, seizures and CWP without SP in this family.