Distinctive communication networks in inactive states of ß2 -adrenergic receptor: Mutual information and entropy transfer analysis.

Mutual information and entropy transfer analysis employed on two inactive states of human beta-2 adrenergic receptor (ß2 -AR) unraveled distinct communication pathways. Previously, a so-called "highly" inactive state of the receptor was observed during 1.5 microsecond long molecular dynamics simulation where the largest intracellular loop (ICL3) was swiftly packed onto the G-protein binding cavity, becoming entirely inaccessible. Mutual information quantifying the degree of correspondence between backbone-Cα fluctuations was mostly shared between intra- and extra-cellular loop regions in the original inactive state, but shifted to entirely different regions in this latest inactive state. Interestingly, the largest amount of mutual information was always shared among the mobile regions. Irrespective of the conformational state, polar residues always contributed more to mutual information than hydrophobic residues, and also the number of polar-polar residue pairs shared the highest degree of mutual information compared to those incorporating hydrophobic residues. Entropy transfer, quantifying the correspondence between backbone-Cα fluctuations at different timesteps, revealed a distinctive pathway directed from the extracellular site toward intracellular portions in this recently exposed inactive state for which the direction of information flow was the reverse of that observed in the original inactive state where the mobile ICL3 and its intracellular surroundings drove the future fluctuations of extracellular regions.

Intrinsic Dynamics and Causality in Correlated Motions Unraveled in Two Distinct Inactive States of Human ß2-Adrenergic Receptor.

The alternative inactive state of the human ß2-adrenergic receptor originally exposed in molecular dynamics simulations was investigated using various analysis tools to evaluate causality between correlated residue-pair fluctuations and suggest allosteric communication pathways. A major conformational shift observed in the third intracellular loop (ICL3) displayed a novel inactive state, featuring an inaccessible G protein binding site blocked by ICL3 and an expanded orthosteric ligand binding site. Residue-based mean-square fluctuation and stiffness calculations revealed a significant mobility decrease in ICL3, which induced a mobility increase in the remaining loop regions. This indicates conformational entropy loss in one mobile region being compensated by residual intermolecular motions in other mobile regions. Moreover, the extent of significantly correlated motions decreased, and correlations that once existed between transmembrane helices shifted toward regions with increased mobility. Conditional time-delayed cross-correlation analysis identified distinct driver-follower relationship profiles. Prior to its packing, freely moving ICL3 was markedly driven by transmembrane helix-8 whereas once packed, ICL3 controlled future fluctuations of nearby helices. Moreover, two transmembrane helices, (H5 and H6), started to control future fluctuations of a remote site, the extracellular loop, ECL2. This clearly suggests that allosteric coupling between extra- and intracellular parts intensified, in agreement with the receptor's well recognized feature, which is the inverse proportionality between activity and the degree of coupling.

Relative pelvic version: an individualized pelvic incidence-based proportional parameter that quantifies pelvic version more precisely than pelvic tilt.

BACKGROUND CONTEXT: Pelvic tilt (PT) is used as an indicator of pelvic version with increased values indicating retroversion and disability. The concept of using PT solely as an absolute numerical value can be misleading, especially for the patients with pelvic incidence (PI) values near the upper and lower normal limits. Relative pelvic version (RPV) is a PI-based individualized measure of the pelvic version. Relative pelvic version indicates the individualized spatial orientation of the pelvis relative to the ideal sacral slope as defined by the magnitude of PI. PURPOSE: The aim of this study was to compare RPV and PT for their ability to predict mechanical complications and their correlations with health-related quality of Life (HRQoL) scores. STUDY DESIGN: A retrospective analysis of a prospectively collected data of adult spinal deformity patients was carried out. Mechanical complications (proximal junctional kyphosis or proximal junctional failure, distal junctional kyphosis or distal junctional failure, rod breakage, and implant-related complications) and HRQoL scores (Oswestry Disability Index [ODI], Core Outcome Measures Index [COMI], Short Form-36 Physical Component Summary [SF-36 PCS], and Scoliosis Research Society 22 Spinal Deformity Questionnaire [SRS-22]) were used as outcome measures. METHODS: Inclusion criteria were ≥4 levels fusion, and ≥2-year follow-up. Correlations between PT, RPV, PI, and HRQoL were analyzed using Pearson correlation coefficient. Pelvic incidence values and mechanical complication rates in RPV subgroups for each PT category were compared using one-way analysis of variance, Student t test, and chi-squared tests. Predictive models for mechanical complications with RPV and PT were analyzed using binomial logistic regressions. RESULTS: A total of 222 patients (168 women, 54 men) met the inclusion criteria. Mean age was 52.2±19.3 (18-84) years. Mean follow-up was 28.8±8.2 (24-62) months. There was a significant correlation between PT and PI (r=0.613, p<.001), threatening the use of PT to quantify pelvic version for different PI values. Relative pelvic version was not correlated with PI (r=-0.108, p>.05), being able to quantify pelvic version for all PI values. Compared with PT, RPV had stronger partial correlations with ODI, COMI, SF-36 PCS, and SRS-22 scores (p<.05). Discrimination performance assessed by area under the curve, percentage accuracy in classification, true positive rate, true negative rate, and positive and negative predictive values was better for the model with RPV than for PT. For average PI sizes, the agreement between RPV and PT were moderate (0.609, p<.001), whereas the agreement in small and large PI sizes were poor (0.189, p>.05; -0.098, p>.496, respectively). When analyzed by RPV, each PT "0," "+," and "++" category was further divided into two or three distinct subgroups of patients having different PI values (p=.000, p=.000, and p=.029, respectively). Relative pelvic version subgroups within the same PT category displayed different mechanical complication rates (p=.000, p=.020, and p=.019, respectively). CONCLUSIONS: Pelvic tilt may be insufficient or misleading in quantifying normoversion for the whole spectrum of PI values when used as an absolute numeric value in conjunction with previously reported population-based average thresholds of 20 and 30 degrees. Relative pelvic version offers an individualized quantification of ante-, normo-, and retroversion for all PI sizes. Schwab PT groups were found to constitute inhomogeneous subgroup of patients with different mean PI values and mechanical complication rates. Compared with PT, RPV showed a greater association with both mechanical complications and HRQoL.

Relative lumbar lordosis and lordosis distribution index: individualized pelvic incidence-based proportional parameters that quantify lumbar lordosis more precisely than the concept of pelvic incidence minus lumbar lordosis.

OBJECTIVE The subtraction of lumbar lordosis (LL) from the pelvic incidence (PI) offers an estimate of the LL required for a given PI value. Relative LL (RLL) and the lordosis distribution index (LDI) are PI-based individualized measures. RLL quantifies the magnitude of lordosis relative to the ideal lordosis as defined by the magnitude of PI. LDI defines the magnitude of lower arc lordosis in proportion to total lordosis. The aim of this study was to compare RLL and PI - LL for their ability to predict postoperative complications and their correlations with health-related quality of life (HRQOL) scores. METHODS Inclusion criteria were ≥ 4 levels of fusion and ≥ 2 years of follow-up. Mechanical complications were proximal junctional kyphosis/proximal junctional failure, distal junctional kyphosis/distal junctional failure, rod breakage, and implant-related complications. Correlations between PI - LL, RLL, PI, and HRQOL were analyzed using the Pearson correlation coefficient. Mechanical complication rates in PI - LL, RLL, LDI, RLL, and LDI interpreted together, and RLL subgroups for each PI - LL category were compared using chi-square tests and the exact test. Predictive models for mechanical complications with RLL and PI - LL were analyzed using binomial logistic regressions. RESULTS Two hundred twenty-two patients (168 women, 54 men) were included. The mean age was 52.2 ± 19.3 years (range 18-84 years). The mean follow-up was 28.8 ± 8.2 months (range 24-62 months). There was a significant correlation between PI - LL and PI (r = 0.441, p < 0.001), threatening the use of PI - LL to quantify spinopelvic mismatch for different PI values. RLL was not correlated with PI (r = -0.093, p > 0.05); therefore, it was able to quantify divergence from ideal lordosis for all PI values. Compared with PI - LL, RLL had stronger correlations with HRQOL scores (p < 0.05). Discrimination performance was better for the model with RLL than for PI - LL. The agreement between RLL and PI - LL was high (κ = 0.943, p < 0.001), moderate (κ = 0.455, p < 0.001), and poor (κ = -0.154, p = 0.343), respectively, for large, average, and small PI sizes. When analyzed by RLL, each PI - LL category was further divided into distinct groups of patients who had different mechanical complication rates (p < 0.001). CONCLUSIONS Using the formula of PI - LL may be insufficient to quantify normolordosis for the whole spectrum of PI values when applied as an absolute numeric value in conjunction with previously reported population-based average thresholds of 10° and 20°. Schwab PI - LL groups were found to constitute an inhomogeneous group of patients. RLL offers an individualized quantification of LL for all PI sizes. Compared with PI - LL, RLL showed a greater association with both mechanical complications and HRQOL. The use of RLL and LDI together, instead of PI - LL, for surgical planning may result in lower mechanical complication rates and better long-term HRQOL.

Global Alignment and Proportion (GAP) Score: Development and Validation of a New Method of Analyzing Spinopelvic Alignment to Predict Mechanical Complications After Adult Spinal Deformity Surgery.

BACKGROUND: The restoration of normal sagittal alignment is a critical goal in adult spinal deformity surgery to achieve favorable outcomes and prevent mechanical complications. Schwab sagittal modifiers have been accepted as targets for appropriate alignment, but addressing these targets does not always prevent high mechanical complication or revision rates. This may be because the linear absolute numerical parameters do not cover the whole pelvic incidence spectrum and the distribution of lordosis, pelvic anteversion, and negative malalignment are not considered as potential causes of failure. The aim of the present study was to develop and validate a score based on pelvic-incidence-based proportional parameters to better predict mechanical complications. METHODS: Two hundred and twenty-two patients (168 women and 54 men) followed for ≥2 years after posterior fusion at ≥4 levels were included in the study. The mean age (and standard deviation) was 52.2 ± 19.3 years (range, 18 to 84 years), and the mean duration of follow-up was 28.8 ± 8.2 months (range, 24 to 62 months). The global alignment and proportion (GAP) score was developed and validated in groups of patients randomly assigned to derivation (n = 148, 66.7%) and validation (n = 74, 33.3%) cohorts. GAP score parameters were relative pelvic version (the measured minus the ideal sacral slope), relative lumbar lordosis (the measured minus the ideal lumbar lordosis), lordosis distribution index (the L4-S1 lordosis divided by the L1-S1 lordosis multiplied by 100), relative spinopelvic alignment (the measured minus the ideal global tilt), and an age factor. Proximal and distal junctional kyphosis and/or failure, rod breakage, and other implant-related complications were considered mechanical complications. The predictive accuracy of the GAP score was analyzed using receiver operating characteristic (ROC) analyses. Associations between GAP categories and mechanical complications and revisions were analyzed using Cochran-Armitage tests. RESULTS: In the validation cohort, 32 patients (43%) experienced mechanical complications and 17 (23%) underwent mechanical revision. The area under curve for the GAP score predicting mechanical complications was 0.92 (standard error [SE] = 0.034, p < 0.001, 95% [confidence interval [CI] = 0.85 to 0.98). Postoperatively, patients with a proportioned spinopelvic state according to the GAP score had a mechanical complication rate of 6% while those with a moderately or severely disproportioned spinopelvic state had rates of 47% and 95%, respectively. CONCLUSIONS: The GAP score is a new pelvic-incidence-based proportional method of analyzing the sagittal plane that predicts mechanical complications in patients undergoing surgery for adult spinal deformity. Setting surgical goals according to the GAP score may decrease the prevalence of mechanical complications.