Effects of clinically relevant acute hypercapnic and metabolic acidosis on the cardiovascular system: an experimental porcine study

INTRODUCTION: Hypercapnic acidosis (HCA) that accompanies lung-protective ventilation may be considered permissive (a tolerable side effect), or it may be therapeutic by itself. Cardiovascular effects may contribute to, or limit, the potential therapeutic impact of HCA; therefore, a complex physiological study was performed in healthy pigs to evaluate the systemic and organ-specific circulatory effects of HCA, and to compare them with those of metabolic (eucapnic) acidosis (MAC). METHODS: In anesthetized, mechanically ventilated and instrumented pigs, HCA was induced by increasing the inspired fraction of CO(2) (n = 8) and MAC (n = 8) by the infusion of HCl, to reach an arterial plasma pH of 7.1. In the control group (n = 8), the normal plasma pH was maintained throughout the experiment. Hemodynamic parameters, including regional organ hemodynamics, blood gases, and electrocardiograms, were measured in vivo. Subsequently, isometric contractions and membrane potentials were recorded in vitro in the right ventricular trabeculae. RESULTS: HCA affected both the pulmonary (increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR)) and systemic (increase in mean arterial pressure (MAP), decrease in systemic vascular resistance (SVR)) circulations. Although the renal perfusion remained unaffected by any type of acidosis, HCA increased carotid, portal, and, hence, total liver blood flow. MAC influenced the pulmonary circulation only (increase in MPAP and PVR). Both MAC and HCA reduced the stroke volume, which was compensated for by an increase in heart rate to maintain (MAC), or even increase (HCA), the cardiac output. The right ventricular stroke work per minute was increased by both MAC and HCA; however, the left ventricular stroke work was increased by HCA only. In vitro, the trabeculae from the control pigs and pigs with acidosis showed similar contraction force and action-potential duration (APD). Perfusion with an acidic solution decreased the contraction force, whereas APD was not influenced. CONCLUSIONS: MAC preferentially affects the pulmonary circulation, whereas HCA affects the pulmonary, systemic, and regional circulations. The cardiac contractile function was reduced, but the cardiac output was maintained (MAC), or even increased (HCA). The increased ventricular stroke work per minute revealed an increased work demand placed by acidosis on the heart

Variation in global treatment for subaxial cervical spine isolated unilateral facet fractures.

PURPOSE To determine the variation in the global treatment practices for subaxial unilateral cervical spine facet fractures based on surgeon experience, practice setting, and surgical subspecialty. METHODS A survey was sent to 272 members of the AO Spine Subaxial Injury Classification System Validation Group worldwide. Questions surveyed surgeon preferences with regard to diagnostic work-up and treatment of fracture types F1-F3, according to the AO Spine Subaxial Cervical Spine Injury Classification System, with various associated neurologic injuries. RESULTS A total of 161 responses were received. Academic surgeons use the facet portion of the AO Spine classification system less frequently (61.6%) compared to hospital-employed and private practice surgeons (81.1% and 81.8%, respectively) (p = 0.029). The overall consensus was in favor of operative treatment for any facet fracture with radicular symptoms (N2) and for any fractures categorized as F2N2 and above. For F3N0 fractures, significantly less surgeons from Africa/Asia/Middle East (49%) and Europe (59.2%) chose operative treatment than from North/Latin/South America (74.1%) (p = 0.025). For F3N1 fractures, significantly less surgeons from Africa/Asia/Middle East (52%) and Europe (63.3%) recommended operative treatment than from North/Latin/South America (84.5%) (p = 0.001). More than 95% of surgeons included CT in their work-up of facet fractures, regardless of the type. No statistically significant differences were seen in the need for MRI to decide treatment. CONCLUSION Considerable agreement exists between surgeon preferences with regard to unilateral facet fracture management with few exceptions. F2N2 fracture subtypes and subtypes with radiculopathy (N2) appear to be the threshold for operative treatment

Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

The constitutive androstane receptor (CAR) is a nuclear receptor involved mainly in xenobiotic and endobiotic metabolism regulation. CAR is activated directly by its ligands via the ligand binding domain (LBD) or indirectly by inhibition of the epidermal growth factor (EGF) signaling. We found that leflunomide (LEF) and its main metabolite teriflunomide (TER), both used for autoimmune diseases treatment, induce the prototype CAR target gene CYP2B6 in primary human hepatocytes. As TER was discovered to be an EGF receptor antagonist, we sought to determine if TER is an indirect activator of CAR. In primary human hepatocytes and in differentiated HepaRG cells, we found that LEF and TER up-regulate CAR target genes CYP2B6 and CYP3A4 mRNAs and enzymatic activities. TER stimulated CAR+A mutant translocation into the nucleus but neither LEF nor TER activated the CAR LBD, CAR3 variant or pregnane X receptor (PXR) in gene reporter assays. Interestingly, TER significantly up-regulated CAR mRNA expression, a result which could be a consequence of both EGF receptor and ELK-1 transcription factor inhibition by TER or by TER-mediated activation of glucocorticoid receptor (GR), an upstream hormonal regulator of CAR. We can conclude that TER is a novel indirect CAR activator which through EGF inhibition and GR activation controls both detoxification and some intermediary metabolism genes

AO Spine Upper Cervical Injury Classification System: A Description and Reliability Study.

BACKGROUND CONTEXT Prior upper cervical spine injury classification systems have focused on injuries to the craniocervical junction (CCJ), atlas, and dens independently. However, no previous system has classified upper cervical spine injuries using a comprehensive system incorporating all injuries from the occiput to the C2-3 joint. PURPOSE To (1) determine the accuracy of experts at correctly classifying upper cervical spine injuries based on the recently proposed AO Spine Upper Cervical Injury Classification System (2) to determine their interobserver reliability and (3) identify the intraobserver reproducibility of the experts. STUDY DESIGN/SETTING International Multi-Center Survey PATIENT SAMPLE: A survey of international spine surgeons on 29 unique upper cervical spine injuries OUTCOME MEASURES: Classification accuracy, interobserver reliability, intraobserver reproducibility METHODS: Thirteen international AO Spine Knowledge Forum Trauma members participated in two live webinar-based classifications of 29 upper cervical spine injuries presented in random order, four weeks apart. Percent agreement with the gold-standard and kappa coefficients (ƙ) were calculated to determine the interobserver reliability and intraobserver reproducibility. RESULTS Raters demonstrated 80.8% and 82.7% accuracy with identification of the injury classification (combined location and type) on the first and second assessment, respectively. Injury classification intraobserver reproducibility was excellent (mean, [range] ƙ = 0.82 [0.58-1.00]). Excellent interobserver reliability was found for injury location (ƙ = 0.922 and ƙ= 0.912) on both assessments, while injury type was substantial (ƙ=0.689 and 0.699) on both assessments. This correlated to a substantial overall interobserver reliability (ƙ = 0.729 and 0.732). CONCLUSION Early phase validation demonstrated classification of upper cervical spine injuries using the AO Spine Upper Cervical Injury Classification System to be accurate, reliable, and reproducible. Greater than 80% accuracy was detected for injury classification. The intraobserver reproducibility was excellent, while the interobserver reliability was substantial

Psychometric properties of the parent-rated assessment scale of positive and negative parenting behavior (FPNE) in a German sample of school-aged children

Background: The aim of this study was to develop and psychometrically evaluate a parent-rated parenting assessment scale including positive and negative dimensions of parenting. Factorial validity, reliability, measurement invariance, latent mean differences and construct validity of the Assessment Scale of Positive and Negative Parenting Behavior (FPNE) were tested in a pooled sample of five studies of 1,879 school-aged children (6.00 to 12.11 years). Methods: Exploratory factor analysis (EFA) was performed on a first randomized split-half sample, and confirmatory factor analysis (CFA) and exploratory structural equation modeling (ESEM) were conducted in the second half of the sample. Measurement invariance tests were conducted to assess factor structure equivalence across gender and age. Results: The EFA results supported a two-factor structure and the CFA results revealed a model with two correlated factors (Positive Parenting, Negative Parenting), which included 23 items and showed acceptable model fit and good psychometric properties. ESEM did not yield a model with significantly better model fit. Internal consistencies were acceptable. Adequate concurrent validity was demonstrated by low to moderate correlations between the FPNE and similar constructs. The factor structure was invariant (configural, metric, scalar) across different age groups and gender. Tests of latent mean differences revealed that older children scored significantly higher on negative parenting than younger children, while boys showed lower levels of positive parenting and higher levels of negative parenting compared to girls. All effect sizes were small. Conclusions: The results suggest that the FPNE is a reliable and valid instrument for the assessment of parenting

Validation of the AO Spine CROST (Clinician Reported Outcome Spine Trauma) in the clinical setting

Purpose: To evaluate feasibility, internal consistency, inter-rater reliability, and prospective validity of AO Spine CROST (Clinician Reported Outcome Spine Trauma) in the clinical setting. Methods: Patients were included from four trauma centers. Two surgeons with substantial amount of experience in spine trauma care were included from each center. Two separate questionnaires were administered at baseline, 6-months and 1-year: one to surgeons (mainly CROST) and another to patients (AO Spine PROST—Patient Reported Outcome Spine Trauma). Descriptive statistics were used to analyze patient characteristics and feasibility, Cronbach’s α for internal consistency. Inter-rater reliability through exact agreement, Kappa statistics and Intraclass Correlation Coefficient (ICC). Prospective analysis, and relationships between CROST and PROST were explored through descriptive statistics and Spearman correlations. Results: In total, 92 patients were included. CROST showed excellent feasibility results. Internal consistency (α = 0.58–0.70) and reliability (ICC = 0.52 and 0.55) were moderate. Mean total scores between surgeons only differed 0.2–0.9 with exact agreement 48.9–57.6%. Exact agreement per CROST item showed good results (73.9–98.9%). Kappa statistics revealed moderate agreement for most CROST items. In the prospective analysis a trend was only seen when no concerns at all were expressed by the surgeon (CROST = 0), and moderate to strong positive Spearman correlations were found between CROST at baseline and the scores at follow-up (rs = 0.41–0.64). Comparing the CROST with PROST showed no specific association, nor any Spearman correlations (rs = −0.33–0.07). Conclusions: The AO Spine CROST showed moderate validity in a true clinical setting including patients from the daily clinical practice

The AO Spine Thoracolumbar Injury Classification System and Treatment Algorithm in Decision Making for Thoracolumbar Burst Fractures Without Neurologic Deficit

STUDY DESIGN: Prospective Observational Study. OBJECTIVE: To determine the alignment of the AO Spine Thoracolumbar Injury Classification system and treatment algorithm with contemporary surgical decision making. METHODS: 183 cases of thoracolumbar burst fractures were reviewed by 22 AO Spine Knowledge Forum Trauma experts. These experienced clinicians classified the fracture morphology, integrity of the posterior ligamentous complex and degree of comminution. Management recommendations were collected. RESULTS: There was a statistically significant stepwise increase in rates of operative management with escalating category of injury (P \u3c .001). An excellent correlation existed between recommended expert management and the actual treatment of each injury category: A0/A1/A2 (OR 1.09, 95% CI 0.70-1.69, P = .71), A3/4 (OR 1.62, 95% CI 0.98-2.66, P = .58) and B1/B2/C (1.00, 95% CI 0.87-1.14, P = .99). Thoracolumbar A4 fractures were more likely to be surgically stabilized than A3 fractures (68.2% vs 30.9%, P \u3c .001). A modifier indicating indeterminate ligamentous injury increased the rate of operative management when comparing type B and C injuries to type A3/A4 injuries (OR 39.19, 95% CI 20.84-73.69, P \u3c .01 vs OR 27.72, 95% CI 14.68-52.33, P \u3c .01). CONCLUSIONS: The AO Spine Thoracolumbar Injury Classification system introduces fracture morphology in a rational and hierarchical manner of escalating severity. Thoracolumbar A4 complete burst fractures were more likely to be operatively managed than A3 fractures. Flexion-distraction type B injuries and translational type C injuries were much more likely to have surgery recommended than type A fractures regardless of the M1 modifier. A suspected posterior ligamentous injury increased the likelihood of surgeons favoring surgical stabilization

Interobserver Reliability in the Classification of Thoracolumbar Fractures Using the AO Spine TL Injury Classification System Among 22 Clinical Experts in Spine Trauma Care

STUDY DESIGN: Reliability study utilizing 183 injury CT scans by 22 spine trauma experts with assessment of radiographic features, classification of injuries and treatment recommendations. OBJECTIVES: To assess the reliability of the AOSpine TL Injury Classification System (TLICS) including the categories within the classification and the M1 modifier. METHODS: Kappa and Intraclass correlation coefficients were produced. Associations of various imaging characteristics (comminution, PLC status) and treatment recommendations were analyzed through regression analysis. Multivariable logistic regression modeling was used for making predictive algorithms. RESULTS: Reliability of the AO Spine TLICS at differentiating A3 and A4 injuries (N = 71) (K = .466; 95% CI .458 – .474; P \u3c .001) demonstrated moderate agreement. Similarly, the average intraclass correlation coefficient (ICC) amongst A3 and A4 injuries was excellent (ICC = .934; 95% CI .919 – .947; P \u3c .001) and the ICC between individual measures was moderate (ICC = .403; 95% CI .351 – .461; P \u3c .001). The overall agreement on the utilization of the M1 modifier amongst A3 and A4 injuries was fair (K = .161; 95% CI .151 – .171; P \u3c .001). The ICC for PLC status in A3 and A4 injuries averaged across all measures was excellent (ICC = .936; 95% CI .922 – .949; P \u3c .001). The M1 modifier suggests respondents are nearly 40% more confident that the PLC is injured amongst all injuries. The M1 modifier was employed at a higher frequency as injuries were classified higher in the classification system. CONCLUSIONS: The reliability of surgeons differentiating between A3 and A4 injuries in the AOSpine TLICS is substantial and the utilization of the M1 modifier occurs more frequently with higher grades in the system

Expert Opinion, Real-World Classification, and Decision-Making in Thoracolumbar Burst Fractures Without Neurologic Deficits?

STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVES: To compare decision-making between an expert panel and real-world spine surgeons in thoracolumbar burst fractures (TLBFs) without neurological deficits and analyze which factors influence surgical decision-making. METHODS: This study is a sub-analysis of a prospective observational study in TL fractures. Twenty two experts were asked to review 183 CT scans and recommend treatment for each fracture. The expert recommendation was based on radiographic review. RESULTS: Overall agreement between the expert panel and real-world surgeons regarding surgery was 63.2%. In 36.8% of cases, the expert panel recommended surgery that was not performed in real-world scenarios. Conversely, in cases where the expert panel recommended non-surgical treatment, only 38.6% received non-surgical treatment, while 61.4% underwent surgery. A separate analysis of A3 and A4 fractures revealed that expert panel recommended surgery for 30% of A3 injuries and 68% of A4 injuries. However, 61% of patients with both A3 and A4 fractures received surgery in the real world. Multivariate analysis demonstrated that a 1% increase in certainty of PLC injury led to a 4% increase in surgery recommendation among the expert panel, while a .2% increase in the likelihood of receiving surgery in the real world. CONCLUSION: Surgical decision-making varied between the expert panel and real-world treating surgeons. Differences appear to be less evident in A3/A4 burst fractures making this specific group of fractures a real challenge independent of the level of expertise

Understanding Decision Making as It Influences Treatment in Thoracolumbar Burst Fractures Without Neurological Deficit: Conceptual Framework and Methodology

STUDY DESIGN: This paper presents a description of a conceptual framework and methodology that is applicable to the manuscripts that comprise this focus issue. OBJECTIVES: Our goal is to present a conceptual framework which is relied upon to better understand the processes through which surgeons make therapeutic decisions around how to treat thoracolumbar burst fractures (TL) fractures. METHODS: We will describe the methodology used in the AO Spine TL A3/4 Study prospective observational study and how the radiographs collected for this study were utilized to study the relationships between various variables that factor into surgeon decision making. RESULTS: With 22 expert spine trauma surgeons analyzing the acute CT scans of 183 patients with TL fractures we were able to perform pairwise analyses, look at reliability and correlations between responses and develop frequency tables, and regression models to assess the relationships and interactions between variables. We also used machine learning to develop decision trees. CONCLUSIONS: This paper outlines the overall methodological elements that are common to the subsequent papers in this focus issue