Increased cardiac contractility during fight-or-flight response is caused by β-adrenergic augmentation of Ca V 1.2 channels 1-4. In transgenic murine hearts expressing fully PKA phosphorylation-site-deficient mutant Ca V 1.2 α 1C and β subunits, this regulation persists, implying involvement of extra-channel factors. Here, we identify the mechanism by which β-adrenergic agonists stimulate voltage-gated Ca 2+ channels. We expressed α 1C or β 2B subunits conjugated to ascorbate-peroxidase 5 in mouse hearts and used multiplexed, quantitative proteomics 6,7 to track hundreds of proteins in proximity of Ca V 1.2. We observed that the Ca 2+ channel inhibitor Rad 8,9 , a monomeric G-protein, is enriched in the Ca V 1.2 micro-environment but is depleted during β-adrenergic stimulation. PKA-catalyzed phosphorylation of specific Ser residues on Rad decreases its affinity for auxiliary β-Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

OBJECTIVE Surgical correction of cervical deformity (CD) has been associated with superior alignment and functional outcomes. It has not yet been determined whether baseline or postoperative T1 slope (T1S) and C2 slope (C2S) correlate with health-related quality-of-life (HRQoL) metrics and radiographic complications, such as distal junctional kyphosis (DJK) and distal junctional failure (DJF). The objective of this study was to determine the impact of T1S and C2S deformity severity on HRQoL metrics and DJF development in patients with CD who underwent a cervical fusion procedure. METHODS All operative CD patients with upper instrumented vertebra above C7 and preoperative (baseline) and up to 2-year postoperative radiographic and HRQoL data were included. CD was defined as meeting at least one of the following radiographic parameters: C2–7 lordosis < −15°, TS1–cervical lordosis mismatch > 35°, segmental cervical kyphosis > 15° across any 3 vertebrae between C2 and T1, C2–7 sagittal vertical axis > 4 cm, McGregor’s slope > 20°, or chin-brow vertical angle > 25°. Spearman’s rank-order correlation and linear regression analysis assessed the impact of T1S and C2S on HRQoL metrics (Neck Disability Index [NDI], modified Japanese Orthopaedic Association [mJOA] scale, EuroQOL 5-Dimension Questionnaire [EQ-5D] visual analog scale [VAS] score, and numeric rating scale [NRS]–neck) and complications (DJK, DJF, reoperation). Logistic regression and a conditional inference tree (CIT) were used to determine radiographic thresholds for achieving optimal clinical outcome, defined as meeting good clinical outcome criteria (≥ 2 of the following: NDI < 20 or meeting minimal clinically important difference, mild myelopathy [mJOA score ≥ 14], and NRS-neck ≤ 5 or improved by ≥ 2 points), not undergoing reoperation, or developing DJF or mechanical complication by 2 years. RESULTS One hundred five patients with CD met inclusion criteria. By surgical approach, 14.7% underwent an anterior-only approach, 46.1% a posterior-only approach, and 39.2% combined anterior and posterior approaches. The mean baseline radiographic parameters were T1S 28.3° ± 14.5° and C2S 25.9° ± 17.5°. Significant associations were found between 3-month C2S and mJOA score (r = −0.248, p = 0.034), NDI (r = 0.399, p = 0.001), EQ-5D VAS (r = −0.532, p < 0.001), NRS-neck (r = 0.239, p = 0.040), and NRS-back (r = 0.264, p = 0.021), while significant correlation was also found between 3-month T1S and mJOA score (r = −0.314, p = 0.026), NDI (r = 0.445, p = 0.001), EQ-5D VAS (r = −0.347, p = 0.018), and NRS-neck (r = 0.269, p = 0.049). A significant correlation was also found between development of DJF and 3-month C2S (odds ratio [OR] 1.1, 95% confidence interval [CI] 1.01–1.1, p = 0.015) as well as for T1S (OR 1.1, 95% CI 1.01–1.1, p = 0.023). Logistic regression with CIT identified thresholds for optimal outcome by 2 years: optimal 3-month T1S < 26° (OR 5.6) and C2S < 10° (OR 10.4), severe 3-month T1S < 45.5° (OR 0.2) and C2S < 38.0° (no patient above this threshold achieved optimal outcome; all p < 0.05). Patients below both optimal thresholds achieved rates of 0% for DJK and DJF, and 100% met optimal outcome. CONCLUSIONS The severity of CD, defined by T1S and C2S at baseline and especially at 3 months, can be predictive of postoperative functional improvement and occurrence of worrisome complications in patients with CD, necessitating the use of thresholds in surgical planning to achieve optimal outcomes.

Purpose International uniformity of definition and classification are crucial for diagnosis and management of cauda equina syndrome (CES). They are also useful for clinicians when discussing CES with patients and relatives, and for medicolegal purposes. Methods We reviewed published literature using PubMed on definition and classification of cauda equina syndrome since 2000 (21 years). Using the search terms ‘cauda equina’ and ‘definition’ or ‘classification’, we found and reviewed 212 papers. Results There were 17 different definitions of CES used in the literature. There were three well-defined methods of classification of CES. The two-stage system of incomplete CES (CESI) versus CES with retention (CESR) is the most commonly used classification, and has prognostic value although the details of this continue to be debated. Conclusion We used the existing literature to propose a clear definition of CES. We also drew on peer-reviewed published literature that has helped to amplify and expand the CESI/CESR dichotomy, adding categories that are both less severe than CESI, and more severe than CESR, and we propose clear definitions in a table form to assist current and future discussion and management of CES.

Background Despite the increasing prevalence of type 2 diabetes, limited pharmacologic options are available for prevention. Cholesteryl ester transfer protein inhibitors (CETPi) have been studied primarily as a therapy to reduce cardiovascular disease, but have also been shown to reduce new-onset diabetes. As new trial data have become available, this meta-analysis examines the effect of CETP inhibitors on new-onset diabetes and related glycemic measures. Methods We searched MEDLINE, EMBASE, and Cochrane databases (all articles until March 4, 2021) for randomised controlled trials ≥one-year duration, with at least 500 participants, comparing CETPi to placebo, and that reported data on new-onset diabetes or related glycemic measures (haemoglobin A1C (HbA1C), fasting plasma glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)). A fixed effects meta-analysis model was applied to all eligible studies to quantify the effect of CETPi therapy on new-onset diabetes. Results Four RCTs (n = 75,102) were eligible for quantitative analysis of the effect of CETPi on new-onset diabetes. CETPi were found to significantly decrease the risk of new-onset diabetes by 16% (RR:0.84; 95%CI:0.78,0.91; p&lt;0.001), with low between-trial heterogeneity (I2 = 4.1%). Glycemic measures were also significantly improved or trended towards improvement in those with and without diabetes across most trials. Conclusions Although RCTs have shown mixed results regarding the impact of CETPi on cardiovascular disease, they have shown a consistent reduction in the risk of new-onset diabetes with CETPi therapy. Future trials of CETPi and potentially other HDL-raising agents should therefore specify new-onset diabetes and reversal of existing T2DM as secondary endpoints.