The Expression and Secretion Profile of TRAP5 Isoforms in Gaucher Disease.

BACKGROUND: Gaucher disease (GD) is caused by glucocerebrosidase (GCase) enzyme deficiency, leading to glycosylceramide (Gb-1) and glucosylsphingosine (Lyso-Gb-1) accumulation. The pathological hallmark for GD is an accumulation of large macrophages called Gaucher cells (GCs) in the liver, spleen, and bone marrow, which are associated with chronic organ enlargement, bone manifestations, and inflammation. Tartrate-resistant acid phosphatase type 5 (TRAP5 protein, ACP5 gene) has long been a nonspecific biomarker of macrophage/GCs activation; however, the discovery of two isoforms of TRAP5 has expanded its significance. The discovery of TRAP5's two isoforms revealed that it is more than just a biomarker of macrophage activity. While TRAP5a is highly expressed in macrophages, TRAP5b is secreted by osteoclasts. Recently, we have shown that the elevation of TRAP5b in plasma is associated with osteoporosis in GD. However, the role of TRAP isoforms in GD and how the accumulation of Gb-1 and Lyso-Gb-1 affects TRAP expression is unknown. METHODS: 39 patients with GD were categorized into cohorts based on bone mineral density (BMD). TRAP5a and TRAP5b plasma levels were quantified by ELISA. ACP5 mRNA was estimated using RT-PCR. RESULTS: An increase in TRAP5b was associated with reduced BMD and correlated with Lyso-Gb-1 and immune activator chemokine ligand 18 (CCL18). In contrast, the elevation of TRAP5a correlated with chitotriosidase activity in GD. Lyso-Gb-1 and plasma seemed to influence the expression of ACP5 in macrophages. CONCLUSIONS: As an early indicator of BMD alteration, measurement of circulating TRAP5b is a valuable tool for assessing osteopenia-osteoporosis in GD, while TRAP5a serves as a biomarker of macrophage activation in GD. Understanding the distinct expression pattern of TRAP5 isoforms offers valuable insight into both bone disease and the broader implications for immune system activation in GD.

ModE-RA: a global monthly paleo-reanalysis of the modern era 1421 to 2008.

The Modern Era Reanalysis (ModE-RA) is a global monthly paleo-reanalysis covering the period between 1421 and 2008. To reconstruct past climate fields an offline data assimilation approach is used, blending together information from an ensemble of transient atmospheric model simulations and observations. In the early period, ModE-RA utilizes natural proxies and documentary data, while from the 17th century onward instrumental measurements are also assimilated. The impact of each observation on the reconstruction is stored in the observation feedback archive, which provides additional information on the input data such as preprocessing steps and the regression-based forward models. The monthly resolved reconstructions include estimates of the most important climate fields. Furthermore, we provide a reconstruction, ModE-RAclim, which together with ModE-RA and the model simulations allows to disentangle the role of observations and model forcings. ModE-RA is best suited to study intra-annual to multi-decadal climate variability and to analyze the causes and mechanisms of past extreme climate events.

Monthly multidisciplinary complex spine conference: a cost-analysis utilizing time-driven activity-based costing.

PURPOSE: To understand costs and provide an initial framework associated with conference implementation as it pertains to complication prevention. METHODS: Team members' time spent on conference preparation, presentation, and follow-up tasks was recorded and averaged to determine the time required to prepare and present one patient. Using 2022 hourly wage rates based on our urban hospital setting, wage values were calculated for each personnel type and applied to their time spent. The total cost of the conference was annualized and calculated from the time spent in the three phases of the conference multiplied by the wage rate. Published data on complication rates and associated costs before and after conference implementation were used to calculate total cost reduction. RESULTS: With 3 active spine surgeons and 108 patients per year, the total time investment was 104.04 min per patient, costing $21,791 annually. Total RN equivalent value per patient was 5.25 for all three phases. Using a historical model, this multidisciplinary approach for adult spinal deformity reduced complications by 51% at 30 days, resulting in cost savings of $418,518 per year. Thus, the model demonstrates that implementation of this approach resulted in a potential total savings of $396,726/year. CONCLUSION: Implementing a cost-saving tool for managing complex spinal disorders is a responsibility of the spine team, who should lead a multidisciplinary conference. The combination of TDABC and lean methodology can effectively demonstrate the variable costs associated with this multidisciplinary effort and models provide evidence of potential cost-savings when applied to a multidisciplinary adult spinal deformity conference. These findings should encourage clinicians and administrators to allocate resources to improve patient care by reducing complications and costs.

Circulated TGF-ß1 and VEGF-A as Biomarkers for Fabry Disease-Associated Cardiomyopathy.

Fabry disease (FD) is a lysosomal disorder caused by α-galactosidase A deficiency, resulting in the accumulation of globotriaosylceramide (Gb-3) and its metabolite globotriaosylsphingosine (Lyso-Gb-3). Cardiovascular complications and hypertrophic cardiomyopathy (HCM) are the most frequent manifestations of FD. While an echocardiogram and cardiac MRI are clinical tools to assess cardiac involvement, hypertrophic pattern variations and fibrosis make it crucial to identify biomarkers to predict early cardiac outcomes. This study aims to investigate potential biomarkers associated with HCM in FD: transforming growth factor-ß1 (TGF-ß1), TGF-ß active form (a-TGF-ß), vascular endothelial growth factor (VEGF-A), and fibroblast growth factor (FGF2) in 45 patients with FD, categorized into cohorts based on the HCM severity. TGF-ß1, a-TGF-ß, FGF2, and VEGF-A were elevated in FD. While the association of TGF-ß1 with HCM was not gender-related, VEGF was elevated in males with FD and HCM. Female patients with abnormal electrocardiograms but without overt HCM also have elevated TGF-ß1. Lyso-Gb3 is correlated with TGF-ß1, VEGF-A, and a-TGF-ß1. Elevation of TGF-ß1 provides evidence of the chronic inflammatory state as a cause of myocardial fibrosis in FD patients; thus, it is a potential marker of early cardiac fibrosis detected even prior to hypertrophy. TGF-ß1 and VEGF biomarkers may be prognostic indicators of adverse cardiovascular events in FD.

Clinical Guidelines for the Evaluation and Treatment of Lumbar Disc Herniations: How Accurate is the Internet?

OBJECTIVE: To compare information online regarding lumbar disc herniation (LDH) on commonly searched websites and compare those findings with the evidence-based recommendations listed in the North American Spine Society (NASS) clinical practice guidelines. METHODS: NASS Clinical Practice Guidelines, Internet searches were performed utilizing three common search engines (Google, Bing, Yahoo) and keywords associated with LDH. The top 20 websites from each search were selected. The content regarding diagnosis and treatment of LDH was compared to the NASS clinical practice guidelines. RESULTS: On average, websites mentioned only 59% of recommendations supported by Level I evidence. Websites included an average of 3 recommendations not discussed in the NASS guidelines out of an average of 12 total recommendations. Muscle and sensory testing and physical therapy were the most frequent recommendations, appearing on over 80% of websites. Websites were equally likely to contain recommendations backed by high-quality evidence as recommendations not included in NASS guidelines. CONCLUSIONS: This study demonstrates that websites regarding LDH contain a mix of information, with only a fraction of recommendations aligning with NASS clinical guidelines. Patients who use these websites are presented with unsubstantiated information, conceivably impacting their understanding, expectations and decision-making in physician offices.

Metasurface-Enabled Holographic Lithography for Impact-Absorbing Nanoarchitected Sheets.

Nanoarchitected materials represent a class of structural meta-materials that utilze nanoscale features to achieve unconventional material properties such as ultralow density and high energy absorption. A dearth of fabrication methods capable of producing architected materials with sub-micrometer resolution over large areas in a scalable manner exists. A fabrication technique is presented that employs holographic patterns generated by laser exposure of phase metasurface masks in negative-tone photoresists to produce 30-40 µm-thick nanoarchitected sheets with 2.1 × 2.4 cm2 lateral dimensions and ≈500 nm-wide struts organized in layered 3D brick-and-mortar-like patterns to result in ≈50-70% porosity. Nanoindentation arrays over the entire sample area reveal the out-of-plane elastic modulus to vary between 300 MPa and 4 GPa, with irrecoverable post-elastic material deformation commencing via individual nanostrut buckling, densification within layers, shearing along perturbation perimeter, and tensile cracking. Laser induced particle impact tests (LIPIT) indicate specific inelastic energy dissipation of 0.51-2.61 MJ kg-1 , which is comparable to other high impact energy absorbing composites and nanomaterials, such as Kevlar/poly(vinyl butyral) (PVB) composite, polystyrene, and pyrolized carbon nanolattices with 23% relative density. These results demonstrate that holographic lithography offers a promising platform for scalable manufacturing of nanoarchitected materials with impact resistant capabilities.

Inclisiran and cardiovascular events: a patient-level analysis of phase III trials.

BACKGROUND: Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. METHODS AND RESULTS: Patient-level, pooled analysis of ORION-9, -10 and -11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58-0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50-1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41-1.81)]. CONCLUSION: This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.

Wnt signaling pathway inhibitors, sclerostin and DKK-1, correlate with pain and bone pathology in patients with Gaucher disease.

Patients with Gaucher disease (GD) have progressive bone involvement that clinically presents with debilitating bone pain, structural bone changes, bone marrow infiltration (BMI), Erlenmeyer (EM) flask deformity, and osteoporosis. Pain is referred by the majority of GD patients and continues to persist despite the type of therapy. The pain in GD is described as chronic deep penetrating pain; however, sometimes, patients experience severe acute pain. The source of bone pain is mainly debated as nociceptive pain secondary to bone pathology or neuropathic or inflammatory origins. Osteocytes constitute a significant source of secreted molecules that coordinate bone remodeling. Osteocyte markers, sclerostin (SOST) and Dickkopf-1 (DKK-1), inactivate the canonical Wnt signaling pathway and lead to the inhibition of bone formation. Thus, circulated sclerostin and DKK-1 are potential biomarkers of skeletal abnormalities. This study aimed to assess the circulating levels of sclerostin and DKK-1 in patients with GD and their correlation with clinical bone pathology parameters: pain, bone mineral density (BMD), and EM deformity. Thirty-nine patients with GD were classified into cohorts based on the presence and severity of bone manifestations. The serum levels of sclerostin and DKK-1 were quantified by enzyme-linked immunosorbent assays. The highest level of sclerostin was measured in GD patients with pain, BMI, and EM deformity. The multiparameter analysis demonstrated that 95% of GD patients with pain, BMI, and EM deformity had increased levels of sclerostin. The majority of patients with elevated sclerostin also have osteopenia or osteoporosis. Moreover, circulating sclerostin level increase with age, and GD patients have elevated sclerostin levels when compared with healthy control from the same age group. Pearson's linear correlation analysis showed a positive correlation between serum DKK-1 and sclerostin in healthy controls and GD patients with normal bone mineral density. However, the balance between sclerostin and DKK-1 waned in GD patients with osteopenia or osteoporosis. In conclusion, the osteocyte marker, sclerostin, when elevated, is associated with bone pain, BMI, and EM flask deformity in GD patients. The altered sclerostin/DKK-1 ratio correlates with the reduction of bone mineral density. These data confirm that the Wnt signaling pathway plays a role in GD-associated bone disease. Sclerostin and bone pain could be used as biomarkers to assess patients with a high risk of BMI and EM flask deformities.

Identification and Characterization of a Novel Species of Genus Akkermansia with Metabolic Health Effects in a Diet-Induced Obesity Mouse Model.

Akkermansia muciniphila is a well-known bacterium with the ability to degrade mucin. This metabolic capability is believed to play an important role in the colonization of this bacterium in the gut. In this study, we report the identification and characterization of a novel Akkermansia sp. DSM 33459 isolated from human feces of a healthy donor. Phylogenetic analysis based on the genome-wide average nucleotide identity indicated that the Akkermansia sp. DSM 33459 has only 87.5% similarity with the type strain A. muciniphila ATCC BAA-835. Akkermansia sp. DSM 33459 showed significant differences in its fatty acid profile and carbon utilization as compared to the type strain. The Akkermansia sp. DSM 33459 strain was tested in a preclinical obesity model to determine its effect on metabolic markers. Akkermansia sp. DSM 33459 showed significant improvement in body weight, total fat weight, and resistin and insulin levels. Interestingly, these effects were more pronounced with the live form as compared to a pasteurized form of the strain. The strain showed production of agmatine, suggesting a potential novel mechanism for supporting metabolic and cognitive health. Based on its phenotypic features and phylogenetic position, it is proposed that this isolate represents a novel species in the genus Akkermansia and a promising therapeutic candidate for the management of metabolic diseases.

Reducing the stigma surrounding opioid use disorder: evaluating an opioid overdose prevention training program applied to a diverse population.

BACKGROUND: The opioid epidemic is a rapidly growing public health concern in the USA, as the number of overdose deaths continues to increase each year. One strategy for combating the rising number of overdoses is through opioid overdose prevention programs (OOPPs). OBJECTIVE: To evaluate the effectiveness of an innovative OOPP, with changes in knowledge and attitudes serving as the primary outcome measures. METHODS: The OOPP was developed by a group of medical students under guidance from faculty advisors. Training sessions focused on understanding stigmatizing factors of opioid use disorder (OUD), as well as protocols for opioid overdose reversal through naloxone administration. Pre- and post-surveys were partially adapted from the opioid overdose attitudes and knowledge scales and administered to all participants. Paired t-tests were conducted to assess differences between pre- and post-surveys. RESULTS: A total of 440 individuals participated in the training; 381 completed all or the majority of the survey. Participants came from a diverse set of backgrounds, ages, and experiences. All three knowledge questions showed significant improvements. For attitude questions, significant improvements were found in all three questions evaluating confidence, two of three questions assessing attitudes towards overdose reversal, and four of five questions evaluating stigma and attitudes towards individuals with OUD. CONCLUSIONS: Our innovative OOPP was effective not only in increasing knowledge but also in improving attitudes towards overdose reversal and reducing stigma towards individuals with OUD. Given the strong improvements in attitudes towards those with OUD, efforts should be made to incorporate the unique focus on biopsychosocial and sociohistorical components into future OOPPs.

A Comparative Analysis of Online Versus in-Person Opioid Overdose Awareness and Reversal Training for First-Year Medical Students.

INTRODUCTION: Physicians trained in opioid use disorder (OUD) harm reduction can mitigate opioid overdose deaths by prescribing naloxone and educating patients about its use. Unfortunately, many physicians possess OUD stigma. Training during medical school presents an opportunity to reduce OUD stigma and improve opioid overdose reversal knowledge. This study assessed the efficacy of Opioid Overdose Awareness and Reversal Training (OOART) and evaluated the equivalency of the online and in-person OOART. Methods: Voluntary training was delivered to first-year medical (M1) students at one medical school. In 2018 and 2019, 29 and 68 M1 students, respectively, received in-person OOART training and completed pre- and post-training surveys. In 2020, 62 students participated in online OOART training, of which 53 completed both pre- and post-training surveys. Results: All three opioid overdose Knowledge questions showed significant improvements between pre- and post-training survey responses. For Attitude questions, six of eleven questions in 2019 and 2020 and four of eleven questions in 2018 had statistically significant improvements between pre- and post-training survey responses. There were no statistical differences between in-person and online post-training survey results for two out of the three Knowledge questions and all 11 Attitude questions. Conclusions: This study demonstrates that our OOART was effective in increasing opioid overdose reversal knowledge and reducing OUD stigma. There was no meaningful difference in outcomes between the training modalities. These results support the future expansion of online and in-person OOART to a larger population of medical students.

Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis.

BACKGROUND: Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin-kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing. OBJECTIVES: The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran. METHODS: Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C-lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed. RESULTS: A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was -50.7% (95% confidence interval: -52.9% to -48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was -50.5% (95% confidence interval: -52.1% to -48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups. CONCLUSIONS: These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents.

Isolation, Characterization and Structure Elucidation of a Novel Lantibiotic From Paenibacillus sp.

We have isolated and characterized a novel antibacterial peptide, CMB001, following an extensive screening effort of bacterial species isolated from diverse environmental sources. The bacterium that produces CMB001 is characterized as a Gram (+) bacillus sharing approximately 98.9% 16S rRNA sequence homology with its closest match, Paenibacillus kyungheensis. The molecule has been purified to homogeneity from its cell-free supernatant by a three-step preparative chromatography process. Based on its primary structure, CMB001 shares 81% identity with subtilin and 62% with nisin. CMB001 is active mainly against Gram-positive bacteria and Mycobacteriaceae but it is also active against certain Gram-negative bacteria, including multi-drug resistant Acinetobacter baumannii. It retains full antibacterial activity at neutral pH and displays a low propensity to select for resistance among targeted bacteria. Based on NMR and mass spectrometry, CMB001 forms a unique 3D-structure comprising of a compact backbone with one α-helix and two pseudo-α-helical regions. Screening the structure against the Protein Data Bank (PDB) revealed a partial match with nisin-lipid II (1WCO), but none of the lantibiotics with known structures showed significant structural similarity. Due to its unique structure, resistance profile, relatively broad spectrum and stability under physiological conditions, CMB001 is a promising drug candidate for evaluation in animal models of bacterial infection.

Is there bias in the treatment of degenerative spine disease? Analysis of anonymous voting via a multidisciplinary conference.

Many institutions have developed shared decision-making conferences as a mechanism for reducing treatment costs and improving patient outcomes. Little is known about the process of shared decision-making that takes place in these conferences, and there is the possibility of bias among surgeons and nonsurgeons for treatment within their respective specialties. This study was conducted to determine who is contributing to the decision-making process in a multidisciplinary spine conference and to what extent treatment biases exist among the surgical and nonsurgical members of this conference. Voting data were collected during weekly multidisciplinary spine conferences. Descriptive statistics were calculated on the cases presented and the number and type of physicians voting for each case. The likelihood of a particular vote in the surgeon and nonsurgeon cohorts was evaluated using relative risk calculation and multinomial logistic regression. A total of 262 consecutive cases were analyzed. No significant differences in treatment recommendation were observed between surgery and nonsurgical management (relative risk, 1.1; 95% CI, 0.97-1.25) when comparing votes from the surgeon and nonsurgeon cohorts. Multinomial logistic regression showed the odds of nonsurgeons recommending nonsurgical management over surgery was 20% greater than receiving that recommendation from their surgeon colleagues. Individual surgeon and nonsurgeon voters were evenly distributed above and below the mean for treatment recommendation. Individual and group biases exist among surgeons and nonsurgeons treating degenerative spine diseases. Multidisciplinary conferences may or may not level these biases, depending on how they are conducted.

Team Approach: Safety and Value in the Practice of Complex Adult Spinal Surgery.

Surgical management of complex adult spinal deformities is of high risk, with a substantial risk of operative mortality. Current evidence shows that potential risk and morbidity resulting from surgery for complex spinal deformity may be minimized through risk-factor optimization. The multidisciplinary team care model includes neurosurgeons, orthopaedic surgeons, physiatrists, anesthesiologists, hospitalists, psychologists, physical therapists, specialized physician assistants, and nurses. The multidisciplinary care model mimics previously described integrated care pathways designed to offer a structured means of providing a comprehensive preoperative medical evaluation and evidence-based multimodal perioperative care. The role of each team member is illustrated in the case of a 66-year-old male patient with previous incomplete spinal cord injury, now presenting with Charcot spinal arthropathy and progressive vertebral-body destruction resulting in lumbar kyphosis.

Opioids: Pharmacology, Physiology, and Clinical Implications in Pain Medicine.

Opioid receptors and opioid agonists are widespread throughout nature. Endogenous opioids mediate complex functions in animals and in humans. The opioid system in humans plays a central role in pain control and is a key mediator of hedonic homeostasis, mood, and well-being. This system also regulates responses to stress and several peripheral physiologic functions, including respiratory, gastrointestinal, endocrine, and immune systems. This article provides an overview of the basic physiology of opioids, reviews opioid pharmacology, and attempts to address several issues of current importance in the management of patients with established long-term opioid therapy.

Helping spine surgeons detect pre-surgical psychological distress in complex spine patients: an observational pilot study.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: Analysis of a standardized, pre-surgical psychological evaluation program for complex spine surgery. Adult spinal deformity (ASD) patients have a high rate of comorbid mental health conditions. Although there is a body of literature demonstrating the impact of psychological factors, including anxiety and depression, on spine surgery outcome, it is estimated that spine surgeons utilize a psychological assessment only about one third of the time prior to a patient's spine surgery. At this time, there is not a widely reported pre-surgical psychological evaluation program for ASD patients. METHODS: 129 consecutive complex spine surgery candidates receiving a pre-surgical psychological evaluation were analyzed between January 1st 2014 and December 31st 2018. Based on the available literature and professional experience in our facility, a color code for patients was developed from Green (low psychological or psychosocial co-morbidity) to Red (high psychological or psychosocial co-morbidity). Univariate analysis was used to evaluate between color grades and demographics, mental health disorders and outcomes. RESULTS: 83% of complex spine patients had at least one psychological disorder or psychosocial barrier. Only 17% had a combination of realistic expectations for surgery, a good support plan, and were without a history of mental illness. The pre-surgical psychological color criteria were validated in showing higher rates of major depression, anxiety disorder, and bipolar disorder in moderate to severe color grades (p < .001) in addition to higher PHQ-9 and GAD-7 scores (p < .001). Patients having a more severe color grade had lower rates of a discharge home and were taking higher morphine equivalent dosages (MEDs) at their six-month follow-up, though both did not reach statistical significance (p = .07 and p = .08; respectively). CONCLUSION: A comprehensive pre-surgical psychological evaluation may be beneficial to risk stratify and counsel patients being evaluated for surgical reconstruction of adult spinal deformities. LEVEL OF EVIDENCE: 3.

Team-Based Medicine: Incorporating a Clinical Pharmacist into Pain and Opioid Practice Management.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) reports that death from opioids has increased by more than five times since 1999. In response, federal and state organizations have released guidelines recommending best practice standards to combat the opioid epidemic. OBJECTIVE: To evaluate the impact of a clinical pharmacist in a team-based care model on the adherence to best practice standards and access to care for management of patients prescribed chronic opioid therapy (COT). DESIGN: Retrospective chart review study. SETTING: An outpatient physical medicine and rehabilitation clinic in a tertiary hospital. PATIENTS: Three hundred eighty-three patients presenting to the clinic between January 2012 and August 2016 with chronic, noncancer pain. METHODS: Comparison of adherence to best practice standards-including changes in morphine equivalent dose (MED), compliance with urine drug screenings, documentation of medication agreements, initiation of nonopioid medications, and the impact of comorbidities-was analyzed before and after a clinical pharmacist was added to the team. Data were gathered from the electronic medical record and the Prescription Monitoring Program. A control group of patients who did not see the pharmacist and were managed only by the physician section head was also compared to the group of patients managed by a clinical pharmacist. OUTCOME MEASUREMENTS: The primary outcome measurement evaluates the change in MED values over time. Secondary outcome measurements are to review compliance with annual urine drug screening, documentation of the medication agreement, initiation of nonopioid medications by the pharmacist, and assessment of the access to care for patients with chronic opioid therapy needs. RESULTS: A clinically significant reduction in MED with an average decrease of 207 mg was seen after five or more visits with the pharmacist. The pharmacist initiated nonopioid medications at 209 unique patient visits (19.5%). The pharmacist completed 1197 visits during the study time frame, increasing physician access by at least two additional visits per patient per year. Completion of urine drug screens and medication agreement reviews improved over time (P < .001). There was an increase in MED for patients who did not complete this monitoring, whereas the MED remained stable in patients who did complete the monitoring. CONCLUSIONS: The addition of a clinical pharmacist to an interdisciplinary team managing COT patients resulted in a MED reduction after five or more visits with the pharmacist, improved adherence to best practice standards, optimization of opioid and nonopioid medication therapy, and increased patient access. Developing a role for advanced practitioners, such as clinical pharmacist providers, working with patients on COT can result in significant improvements in patient access to care, adherence to best practice standards, and patient safety. LEVEL OF EVIDENCE: III.

Cosmic Bell Test Using Random Measurement Settings from High-Redshift Quasars.

In this Letter, we present a cosmic Bell experiment with polarization-entangled photons, in which measurement settings were determined based on real-time measurements of the wavelength of photons from high-redshift quasars, whose light was emitted billions of years ago; the experiment simultaneously ensures locality. Assuming fair sampling for all detected photons and that the wavelength of the quasar photons had not been selectively altered or previewed between emission and detection, we observe statistically significant violation of Bell's inequality by 9.3 standard deviations, corresponding to an estimated p value of ≲7.4×10^{-21}. This experiment pushes back to at least ∼7.8 Gyr ago the most recent time by which any local-realist influences could have exploited the "freedom-of-choice" loophole to engineer the observed Bell violation, excluding any such mechanism from 96% of the space-time volume of the past light cone of our experiment, extending from the big bang to today.