Publications by authors named "David Spiegel"

453 Publications

Comment on a suite of mathematical solutions to describe ternary complex formation and their application to targeted protein degradation by heterobifunctional ligands.

J Biol Chem 2021 Mar 1;296:100331. Epub 2021 Mar 1.

Department of Chemistry, Yale University, New Haven, Connecticut, USA; Department of Pharmacology, Yale University, New Haven, Connecticut, USA.

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http://dx.doi.org/10.1016/j.jbc.2021.100331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949160PMC
March 2021

The Variability of Pelvic Obliquity Measurements in Patients with Neuromuscular Scoliosis.

JB JS Open Access 2021 Jan-Mar;6(1). Epub 2021 Mar 10.

Division of Orthopaedics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Pelvic obliquity (PO), or pelvic alignment in the coronal plane, is an important radiographic parameter to indicate fusion levels and judge success of scoliosis correction in patients with neuromuscular scoliosis. There are multiple commonly used techniques to measure PO that have good to excellent interrater and intrarater reliability, but these different methods yield inconsistent values when used on the same radiograph. This study evaluates the inconsistency in the magnitude of PO measurements for patients with neuromuscular scoliosis among 5 common measurement techniques.

Methods: Radiographs of 63 patients with neuromuscular scoliosis were evaluated by 5 raters. Each rater measured PO on each radiograph using the Osebold, O'Brien, Allen and Ferguson, Lindseth, and Maloney techniques. Patients were divided into 2 cohorts based on coronal balance or imbalance. Interrater and intrarater analyses were performed using a 2-way random effects model to calculate absolute agreement. The mean difference in PO between all possible pairs of the techniques was compared using a 2-tailed t test.

Results: The Maloney and Osebold techniques demonstrated excellent interrater reliability, and the Maloney, Osebold, and O'Brien techniques demonstrated excellent intrarater reliability. Significant differences in PO measurement were found in 6 of the 10 comparisons for the balanced spines and 8 of the 10 comparisons for the unbalanced spines. Variability in measurement was captured by best-fit lines, which demonstrated greater dispersion between the means for the Osebold and Maloney techniques in the unbalanced spines than in the balanced spines.

Conclusions: To our knowledge, this study is the first to evaluate mean differences in magnitude of PO among common measurement techniques while accounting for coronal imbalance. Although there is no gold standard for measuring PO, the Maloney and Osebold techniques are the most consistent. This study suggests that those 2 techniques can be used interchangeably when the spine is coronally balanced, but the Osebold technique becomes more inconsistent than the Maloney technique when coronal imbalance exceeds 2 cm.

Clinical Relevance: This information is relevant to surgeons using PO to plan fusion levels and striving for objective ways to judge correction intraoperatively as well as for researchers compiling PO data from multiple centers or studies.
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http://dx.doi.org/10.2106/JBJS.OA.20.00143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963507PMC
March 2021

Sirtuin 2 Regulates Protein LactoylLys Modifications.

Chembiochem 2021 Mar 16. Epub 2021 Mar 16.

Department of Pharmacology and Toxicology College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA.

Post-translational modifications (PTMs) play roles in both physiological and pathophysiological processes through the regulation of enzyme structure and function. We recently identified a novel PTM, lactoylLys, derived through a nonenzymatic mechanism from the glycolytic by-product, lactoylglutathione. Under physiologic scenarios, glyoxalase 2 prevents the accumulation of lactoylglutathione and thus lactoylLys modifications. What dictates the site-specificity and abundance of lactoylLys PTMs, however, remains unknown. Here, we report sirtuin 2 as a lactoylLys eraser. Using chemical biology and CRISPR-Cas9, we show that SIRT2 controls the abundance of this PTM both globally and on chromatin. These results address a major gap in our understanding of how nonenzymatic PTMs are regulated and controlled.
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http://dx.doi.org/10.1002/cbic.202000883DOI Listing
March 2021

Shared cognitive mechanisms of hypnotizability with executive functioning and information salience.

Sci Rep 2021 Mar 11;11(1):5704. Epub 2021 Mar 11.

Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.

In recent years, evidence linked hypnotizability to the executive control and information salience networks, brain structures that play a role in cognitive conflict resolution and perseveration (insisting on applying a previously learned logical rule on a new set). Despite the growing body of neuroimaging evidence, the cognitive phenotype of hypnotizability is not well understood. We hypothesized that higher hypnotizability would correspond to lower perseveration and set-shifting. Seventy-two healthy adults were tested for hypnotizability and executive functions (perseveration and set-shifting). Multiple regression analyses were performed to test the relationship between hypnotizability and perseveration and set-shifting. Higher hypnotizability was associated with lower perseveration after accounting for age and education. Hypnotizability significantly predicted perseveration but not set-shifting. Our results indicate an inverse relationship between trait hypnotizability and perseveration, an executive function that utilizes regions of both the executive control and the salience systems. This suggests that hypnotizability may share a common cognitive mechanism with error evaluation and implementation of logical rules.
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http://dx.doi.org/10.1038/s41598-021-84954-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970985PMC
March 2021

When Physicians Engage in Practices That Threaten the Nation's Health.

JAMA 2021 Feb;325(8):723-724

Department of Medicine, Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1001/jama.2021.0122DOI Listing
February 2021

The Hypnotic Induction Profile (HIP) in Clinical Practice and Research.

Int J Clin Exp Hypn 2021 Jan-Mar;69(1):72-82

Stanford University School of Medicine , Palo Alto, California, USA.

The Hypnotic Induction Profile (HIP) was developed as a brief, yet thorough, assessment of a person's level of trait hypnotizability and their potential to experience a hypnotic state. The HIP quantitatively and qualitatively measures hynotizability by evaluating biological and sensorimotor experiences designed to assess 3 fundamental observable and measurable components of hypnosis: absorption, dissociation, and suggestibility through a guided assessment that takes 5 to 10 minutes. From conception, the HIP has been utilized in clinical settings to assess appropriateness for the use of hypnosis in treatment planning and research protocols to stratify research participants. The brevity, accessibility, and reliability of the HIP have allowed it to adapt, not only across settings but through media platforms as technology and remote delivery become increasingly incorporated in the field of hypnosis.
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http://dx.doi.org/10.1080/00207144.2021.1836646DOI Listing
January 2021

Testing Hypnotizability by Phone: Development and Validation of the Remote Hypnotic Induction Profile (rHIP).

Int J Clin Exp Hypn 2021 Jan-Mar;69(1):94-111

PGSP-Stanford Psy.D. Consortium, Palo Alto University , California, USA.

Standard hypnotizability scales require physical contact or direct observation by tester and participant. The authors addressed this limitation by developing and testing the remote Hypnotic Induction Profile (rHIP), a hypnotizability test derived from the Hypnotic Induction Profile that is completed by telephone. To assess the validity of the rHIP, 56 volunteers naïve to hypnotizability testing completed both the HIP and the rHIP, with order of testing randomized. Results indicate a strong correlation between HIP and rHIP scores,  =.71(0.53-0.84), <.0001, and good concordance, difference =.03(-0.53, 0.59), =.91, independent of testing order. The rHIP had few complications. Possible advantages of using the rHIP include improving patient expectancy prior to scheduling a hypnosis session, increasing access to hypnotizability testing for remote interventions, and obviating resource-intensive in-person hypnotizability screening for trials that exclude subjects with certain scores.
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http://dx.doi.org/10.1080/00207144.2021.1827937DOI Listing
January 2021

Posthypnotic Amnesia in Hypnotizability Assessment: Validation of a New Scoring System for the Hypnotic Induction Profile.

Int J Clin Exp Hypn 2021 Jan-Mar;69(1):83-93

Department of Psychiatry and Behavioral Sciences, Stanford University , California, USA.

The Hypnotic Induction Profile (HIP) is a standardized assessment of hypnotizability featuring a validated 0-10 scoring system, that does not factor in posthypnotic amnesia. Using confirmatory factor analyses (CFA), we compared the 10-point scoring system with a new 12-point system that includes the posthypnotic amnesia item in independent samples of individuals with fibromyalgia ( = 98) and healthy adults ( = 97). Additionally, we explored associations of the two scoring systems with measures of hypnotic phenomena. CFA results indicate that the 12-point scoring system is a good fit for the 1-factor model of hypnotizability. Posthypnotic amnesia loaded highly on the model in the fibromyalgia sample, and moderately on the model in healthy adults. Furthermore, the 12-point scoring system correlated significantly with measures of hypnotic phenomena. We conclude that the 12-point scoring system is psychometrically equivalent yet conceptually more comprehensive than the 10-point scoring system.
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http://dx.doi.org/10.1080/00207144.2021.1834860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850173PMC
January 2022

Model studies of advanced glycation end product modification of heterograft biomaterials: The effects of in vitro glucose, glyoxal, and serum albumin on collagen structure and mechanical properties.

Acta Biomater 2021 03 11;123:275-285. Epub 2021 Jan 11.

Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States. Electronic address:

Glutaraldehyde cross-linked heterograft tissues, bovine pericardium (BP) or porcine aortic valves, are the leaflet materials in bioprosthetic heart valves (BHV) used in cardiac surgery for heart valve disease. BHV fail due to structural valve degeneration (SVD), often with calcification. Advanced glycation end products (AGE) are post-translational, non-enzymatic reaction products from sugars reducing proteins. AGE are present in SVD-BHV clinical explants and are not detectable in un-implanted BHV. Prior studies modeled BP-AGE formation in vitro with glyoxal, a glucose breakdown product, and serum albumin. However, glucose is the most abundant AGE precursor. Thus, the present studies investigated the hypothesis that BHV susceptibility to glucose related AGE, together with serum proteins, results in deterioration of collagen structure and mechanical properties. In vitro experiments studied AGE formation in BP and porcine collagen sponges (CS) comparing C-glucose and C-glyoxal with and without bovine serum albumin (BSA). Glucose incorporation occurred at a significantly lower level than glyoxal (p<0.02). BSA co-incubations demonstrated reduced glyoxal and glucose uptake by both BP and CS. BSA incubation caused a significant increase in BP mass, enhanced by glyoxal co-incubation. Two-photon microscopy of BP showed BSA induced disruption of collagen structure that was more severe with glucose or glyoxal co-incubation. Uniaxial testing of CS demonstrated that glucose or glyoxal together with BSA compared to controls, caused accelerated deterioration of viscoelastic relaxation, and increased stiffness over a 28-day time course. In conclusion, glucose, glyoxal and BSA uniquely contribute to AGE-mediated disruption of heterograft collagen structure and deterioration of mechanical properties.
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http://dx.doi.org/10.1016/j.actbio.2020.12.053DOI Listing
March 2021

International Prevalence and Correlates of Psychological Stress during the Global COVID-19 Pandemic.

Int J Environ Res Public Health 2020 12 10;17(24). Epub 2020 Dec 10.

Department of Psychiatry & Behavioral Sciences, Stanford School of Medicine, Stanford, CA 94305, USA.

This study reports perceived stress and associated sociodemographic factors from an international sample of adults, during the COVID-19 pandemic. The Perceived Stress Scale (PSS-10) along with socio-demographic questions were conducted between 8 April 2020 and 11 May 2020. The survey was translated from English into five languages. Recruitment was conducted worldwide using social media. A total of 1685 survey responses were collected across 57 countries with eleven countries (≥30 responses/country) included in the sub-analyses. Overall, the mean PSS-10 score was 19.08 (SD = 7.17), reflecting moderate stress compared to previously reported norms. Female gender was associated with a higher PSS score (3.03, < 0.05) as well as four-year degree holders (3.29, < 0.05), while adults over 75 years (-7.46, < 0.05) had lower PSS scores. Personal care composite score (including hours of sleep, exercise, and meditation) was associated with lower PSS scores (-0.39, < 0.01). Increases in personal care and changes in work expectations were associated with lower PSS scores (-1.30 ( < 0.05) and -0.38 ( < 0.01), respectively). Lower total PSS scores were reported in Germany (-4.82, < 0.01) compared to the global response sample mean. This information, collected during the initial period of global mitigation orders, provides insight into potential mental health risks and protective factors during crises.
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http://dx.doi.org/10.3390/ijerph17249248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763004PMC
December 2020

Hypnosis: The Most Effective Treatment You Have Yet to Prescribe.

Am J Med 2021 03 8;134(3):304-305. Epub 2020 Nov 8.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.

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http://dx.doi.org/10.1016/j.amjmed.2020.10.010DOI Listing
March 2021

The risk of medically uncontrolled secondary hyperparathyroidism depends on parathyroid hormone levels at haemodialysis initiation.

Nephrol Dial Transplant 2021 01;36(1):160-169

Arbor Research Collaborative for Health, Ann Arbor, MI, USA.

Background: Optimal parathyroid hormone (PTH) control during non-dialysis chronic kidney disease (ND-CKD) might decrease the subsequent risk of parathyroid hyperplasia and uncontrolled secondary hyperparathyroidism (SHPT) on dialysis. However, the evidence for recommending PTH targets and therapeutic strategies is weak for ND-CKD. We evaluated the patient characteristics, treatment patterns and PTH control over the first year of haemodialysis (HD) by PTH prior to HD initiation.

Methods: We studied 5683 incident HD patients from 21 countries in Dialysis Outcomes and Practice Patterns Study Phases 4-6 (2009-18). We stratified by PTH measured immediately prior to HD initiation and reported the monthly prescription prevalence of active vitamin D and calcimimetics over the first year of HD and risk of PTH >600 pg/mL after 9-12 months on HD.

Results: The 16% of patients with PTH >600 pg/mL prior to HD initiation were more likely to be prescribed active vitamin D and calcimimetics during the first year of HD. The prevalence of PTH >600 pg/mL 9-12 months after start of HD was greater for patients who initiated HD with PTH >600 (29%) versus 150-300 (7%) pg/mL (adjusted risk difference: 19%; 95% confidence interval : 15%, 23%). The patients with sustained PTH >600 pg/mL after 9-12 months on HD were younger, more likely to be black, and had higher serum phosphorus and estimated glomerular filtration rates at HD initiation.

Conclusions: Increased PTH before HD start predicted a higher PTH level 9-12 months later, despite greater use of active vitamin D and calcimimetics. More targeted PTH control during ND-CKD may influence outcomes during HD, raising the need for PTH target guidelines in these patients.
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http://dx.doi.org/10.1093/ndt/gfaa195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771977PMC
January 2021

A Case of Peduncular Hallucinosis Due to Right Pontine and Cerebral Peduncle Cerebrovascular Accident Treated Successfully With Risperidone: Insights Into an Uncommon Cause of Visual Hallucinations.

Prim Care Companion CNS Disord 2020 Oct 15;22(5). Epub 2020 Oct 15.

Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, Virginia, USA.

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http://dx.doi.org/10.4088/PCC.19l02584DOI Listing
October 2020

A Case of Wernicke-Korsakoff Syndrome Initially Diagnosed as Autoimmune Limbic Encephalitis: Differential Diagnosis of Delirium and Short-Term Memory Deficits.

Prim Care Companion CNS Disord 2020 Oct 8;22(5). Epub 2020 Oct 8.

Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, Virginia, USA.

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http://dx.doi.org/10.4088/PCC.20l02693DOI Listing
October 2020

Outcomes After Surgical Fixation of Posterior Sternoclavicular Physeal Fractures and Dislocations in Children.

J Pediatr Orthop 2021 Jan;41(1):11-16

Division of Orthopedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA.

Background: Acute sternoclavicular fractures and dislocations (SCFDs) are a rare but important injury in pediatric patients. SCFDs are either true dislocations, or more commonly, physeal fractures in children. The reduction is advised given the proximity to surrounding vascular structures, and some authors advocate for routine fixation given rates of redisplacement after closed reduction. The purpose of the current study was to provide validated long-term functional outcome data following open reduction and surgical fixation of pediatric SCFDs, as well as provide injury and demographic information.

Methods: This is a retrospective observational study with a subset of patients reporting functional outcomes. Patients under the age of 18 that had surgically managed acute posterior SCFD from 1990 to 2018 were included. A retrospective chart review was performed to obtain demographic, clinical, and surgical details. Patients with a minimum of 6-month follow-up were contacted to assess outcomes. Functional outcomes of interest included QuickDash, Visual Analog Scale pain rating, Single Assessment Numeric Evaluation of shoulder function, and PROMIS Upper Extremity questionnaire. Statistical analysis included descriptive statistics.

Results: A total of 37 patients that sustained an acute posterior SCFD during the study period were included. The average age at the time of injury was 15.2±2.1 years and 89% were male. Patient-reported outcomes were obtained for 14 patients with a mean follow-up of 4.5 years. The mean QuickDash score was 5.1/100 with 0 being normal, and the mean Visual Analog Scale pain rating was 0.7/10. The mean Single Assessment Numeric Evaluation score was 96% with 100% being completely normal. The mean PROMIS score was 55 with 50 being the mean of the relevant reference population. Approximately 29% (4/14 patients) stated that their injury negatively affected their ability to participate in sports.

Conclusions: There is a paucity of literature on functional outcomes after surgical management of pediatric acute posterior SCFD. Functional outcomes after surgery were satisfactory in this cohort with most patients being able to perform major activities of daily living. Additional future studies with larger cohorts and comparative groups are needed to better understand outcomes in this population.

Level Of Evidence: Level IV.
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http://dx.doi.org/10.1097/BPO.0000000000001691DOI Listing
January 2021

Generation and Characterization of Anti-Glucosepane Antibodies Enabling Direct Detection of Glucosepane in Retinal Tissue.

ACS Chem Biol 2020 10 7;15(10):2655-2661. Epub 2020 Oct 7.

Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, United States.

Although there is ample evidence that the advanced glycation end-product (AGE) glucosepane contributes to age-related morbidities and diabetic complications, the impact of glucosepane modifications on proteins has not been extensively explored due to the lack of sufficient analytical tools. Here, we report the development of the first polyclonal anti-glucosepane antibodies using a synthetic immunogen that contains the core bicyclic ring structure of glucosepane. We investigate the recognition properties of these antibodies through ELISAs involving an array of synthetic AGE derivatives and determine them to be both high-affinity and selective in binding glucosepane. We then employ these antibodies to image glucosepane in aging mouse retinae via immunohistochemistry. Our studies demonstrate for the first time accumulation of glucosepane within the retinal pigment epithelium, Bruch's membrane, and choroid: all regions of the eye impacted by age-related macular degeneration. Co-localization studies further suggest that glucosepane colocalizes with lipofuscin, which has previously been associated with lysosomal dysfunction and has been implicated in the development of age-related macular degeneration, among other diseases. We believe that the anti-glucosepane antibodies described in this study will prove highly useful for examining the role of glycation in human health and disease.
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http://dx.doi.org/10.1021/acschembio.0c00093DOI Listing
October 2020

Glycation and Serum Albumin Infiltration Contribute to the Structural Degeneration of Bioprosthetic Heart Valves.

JACC Basic Transl Sci 2020 Aug 5;5(8):755-766. Epub 2020 Aug 5.

Department of Surgery, Columbia University, New York, New York.

Valvular heart diseases are associated with significant cardiovascular morbidity and mortality, and often require surgical and/or percutaneous repair or replacement. Valve replacement is limited to mechanical and biological prostheses, the latter of which circumvent the need for lifelong anticoagulation but are subject to structural valve degeneration (SVD) and failure. Although calcification is heavily studied, noncalcific SVD, which represent roughly 30% of BHV failures, is relatively underinvestigated. This original work establishes 2 novel and interacting mechanisms-glycation and serum albumin incorporation-that occur in clinical valves and are sufficient to induce hallmarks of structural degeneration as well as functional deterioration.
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http://dx.doi.org/10.1016/j.jacbts.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452200PMC
August 2020

A Case Report of Cobalamin Deficiency-Induced Mania in a Patient With Total Gastrectomy Due to Gastric Adenocarcinoma: Further Insights Into the Pathogenesis of Mania.

Prim Care Companion CNS Disord 2020 Aug 20;22(4). Epub 2020 Aug 20.

Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, Virginia, USA.

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http://dx.doi.org/10.4088/PCC.19l02565DOI Listing
August 2020

The Frequency of Mediastinal Injury in Acute Posterior Sternoclavicular Dislocations: A Multicenter Study.

J Pediatr Orthop 2020 Nov/Dec;40(10):e927-e931

Department of Orthopaedic Surgery and Biomechanical Engineering, University of Tennessee-Campbell Clinic, Memphis, TN.

Background: Acute posterior sternoclavicular dislocations (APSCD) are rare injuries that historically have prompted concern for injury to the great vessels and other mediastinal structures from initial trauma or subsequent treatment, resulting in the recommendation that a thoracic or vascular surgeon be present or available during operative treatment. The objectives of the study were to characterize the demographic, clinical, and radiographic characteristics of a large series of APSCDs in skeletally immature patients and to describe the rate and nature of any vascular or mediastinal complications that occurred during treatment.

Methods: Following Institutional Review Board approval, records of consecutive patients under 25 years of age treated for APSCD were collected from each of 6 participating centers. Only acute injuries (sustained fewer than 10 days before presentation) were included. Patient demographics, injury mechanism, associated mediastinal injuries, and need for thoracic/vascular surgery were recorded. Mediastinal structures injured or compressed by mass effect were specifically characterized by review of preoperative computed tomography imaging.

Results: Review identified 125 patients with a mean age of 14.7 years; 88% were male. APSCD most commonly resulted from a sporting injury (74%) followed by falls from standing height (10%) and high-energy motor vehicle trauma (10%). The most common finding on cross-sectional imaging was compression without laceration of the ipsilateral brachiocephalic vein (50%). Eleven patients had successful closed reduction, and 114 (90%) had open reduction and internal fixation, with 25 failed or unstable closed reductions preceding open treatment. There were no vascular or mediastinal injuries during reduction or fixation that required intervention.

Conclusions: In this multicenter series of 125 APSCDs no injuries to the great vessels/mediastinal structures requiring intervention were identified. Although more than half of patients had evidence of extrinsic vascular compression at the time of injury, careful open reduction of acute injuries can be safely performed. Although vascular injuries following APSCD seem to be quite rare, vascular complications can be catastrophic. Treating providers should consider these data and their own institutional resources to maximize patient safety during the treatment of APSCD.

Level Of Evidence: Level III-therapeutic case control study.
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http://dx.doi.org/10.1097/BPO.0000000000001649DOI Listing
February 2021

Classically activated mouse macrophages produce methylglyoxal that induces a TLR4- and RAGE-independent proinflammatory response.

J Leukoc Biol 2021 03 17;109(3):605-619. Epub 2020 Jul 17.

Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA.

The highly reactive compound methylglyoxal (MG) can cause direct damage to cells and tissues by reacting with cellular macromolecules. MG has been identified as a biomarker associated with increased sepsis-induced mortality. Patients undergoing septic shock have significantly elevated circulating MG levels compared to postoperative patients and healthy controls. Furthermore, MG has been implicated in the development of type II diabetes mellitus and Alzheimer's disease. Because MG is generated during glycolysis, we hypothesized that MG may be produced by classically activated (M1) macrophages, possibly contributing to the inflammatory response. LPS and IFN-γ-treated macrophages acquired an M1 phenotype (as evidenced by M1 markers and enhanced glycolysis) and formed MG adducts, MG-H1, MG-H2, and MG-H3, which were detected using antibodies specific for MG-modified proteins (methylglyoxal 5-hydro-5-methylimidazolones). MG adducts were also increased in the lungs of LPS-treated mice. Macrophages treated with LPS and IFN-γ also exhibited decreased expression of glyoxalase 1 (Glo1), an enzyme that metabolizes MG. Concentrations of exogenous, purified MG > 0.5 mM were toxic to macrophages; however, a nontoxic dose of 0.3 mM induced TNF-α and IL-1β, albeit to a lesser extent than LPS stimulation. Despite prior evidence that MG adducts may signal through "receptor for advanced glycation endproducts" (RAGE), MG-mediated cell death and cytokine induction by exogenous MG was RAGE-independent in primary macrophages. Finally, RAGE-deficient mice did not exhibit a significant survival advantage following lethal LPS injection. Overall, our evidence suggests that MG may be produced by M1 macrophages during sepsis, following IFN-γ-dependent down-regulation of Glo1, contributing to over-exuberant inflammation.
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http://dx.doi.org/10.1002/JLB.3A0520-745RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855181PMC
March 2021

Identification With the Aggressor and Inward and Outward Aggression in Abuse Survivors.

J Interpers Violence 2020 Jul 13:886260520938516. Epub 2020 Jul 13.

Stanford University, CA, USA.

Childhood abuse survivors may display both inward and outward aggression manifested in self-injurious behavior (SIB) and violent acts toward others. Scrutinizing the literature reveals that the relational dynamics between victims and their perpetrators might be involved in these phenomena. Yet, research on this subject matter has been sparse. Filling this gap, this study investigated the contribution of the singular bonds between victims and their perpetrators, known as identification with the aggressor, in explaining survivors' aggression. The study was conducted among 306 Israeli college/university students who reported a history of childhood abuse. Results revealed that levels of adopting the perpetrator's experience, identifying with the perpetrator's aggression, and replacing one's agency with that of the perpetrator were significantly associated with survivors' inward and outward aggression. Moreover, profile type-that is, having high versus low levels of identification with the aggressor-was implicated in participants' SIBs, urge to harm others, and violent acts toward others, above and beyond the effects of gender and posttraumatic stress disorder (PTSD) symptoms. The present findings suggest that identification with the aggressor might make survivors prone to the re-enactment of past abusive dynamics, which, in turn, could eventuate in aggression toward themselves and others.
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http://dx.doi.org/10.1177/0886260520938516DOI Listing
July 2020

Brain and Physiological Markers of Autonomic Function Are Associated With Treatment-Related Improvements in Self-Reported Autonomic Dysfunction in Veterans With Gulf War Illness: An Exploratory Pilot Study.

Glob Adv Health Med 2020 30;9:2164956120922812. Epub 2020 Apr 30.

War Related Illness and Injury Study Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California.

Background: Gulf War Illness (GWI) is a poorly understood condition characterized by a constellation of mood, cognitive, and physical symptoms. A growing body of evidence demonstrates autonomic nervous system (ANS) dysfunction. Few published treatment studies exist for GWI.

Method: We recently completed a randomized controlled trial comparing a 10-week group yoga intervention to 10-week group cognitive behavioral therapy (CBT) for veterans with GWI. Here, we present exploratory data on ANS biomarkers of treatment response from a small pilot exploratory neurophysiological add-on study (n = 13) within that larger study.

Results: Findings suggest that veterans with GWI receiving either yoga or CBT for pain improved following treatment and that changes in biological ANS-especially for the yoga group-moved in the direction of healthy profiles: lower heart rate, higher square root of the mean squared differences between successive R-R intervals (RMSSD), greater parasympathetic activation/dominance (increased high-frequency heart rate variability [HF-HRV], decreased low-frequency/high-frequency [LF/HF] ratio), reduced right amygdala volume, and stronger amygdala-default mode/amygdala-salience network connectivity, both immediately posttreatment and at 6-month follow-up. Biological mechanisms of CBT appeared to underlie improvements in more psychologically loaded symptoms such as self-reported fatigue and energy. Higher tonic arousal and/or more sympathetic dominance (higher skin conductance, lower RMSSD, lower HF-HRV, higher LF/HF ratio) pretreatment predicted greater treatment-related improvements in self-reported ANS for both the yoga and CBT group.

Conclusion: These exploratory pilot data provide preliminary support for the suggestion that treatment (yoga, CBT) is associated with improvements in both biological and self-reported ANS dysfunctions in GWI. The major limitation for these findings is the small sample size. Larger and more controlled studies are needed to replicate these findings and directly compare biomarkers of yoga versus CBT.
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http://dx.doi.org/10.1177/2164956120922812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218338PMC
April 2020

Fluorescent stem peptide mimics: In situ probes for peptidoglycan crosslinking.

Methods Enzymol 2020 8;638:57-67. Epub 2020 Apr 8.

Yale University, Department of Chemistry, New Haven, CT, United States. Electronic address:

Understanding the mechanisms of bacterial cell wall synthesis is essential for microbiology and medicine alike. A key step in this process is peptidoglycan crosslinking, which confers mechanical strength to the cell wall and represents a target for numerous classes of antibiotics. However, the biology of crosslinking remains poorly understood due to a lack of tools for studying the reaction in vivo. Recently, we developed a class of synthetic probes called fluorescent stem peptide mimics (FSPMs) that meet this need, allowing quantification and localization of crosslinking activity in live bacteria. We have utilized FSPMs to describe novel aspects of peptidoglycan synthesis in the human pathogen, Staphylococcus aureus. To enable wider use of our methodology, we provide detailed protocols herein for the synthesis of FSPMs, labeling of live bacteria, and evaluation of crosslinking by flow cytometry and super-resolution microscopy. We believe that FSPMs, together with complementary biosynthetic probes and traditional bacteriologic methods, will help to advance our understanding of peptidoglycan biology and accelerate the search for new antibiotics.
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http://dx.doi.org/10.1016/bs.mie.2020.02.016DOI Listing
April 2020

BMI change following spinal fusion for neuromuscular scoliosis surgery.

Spine Deform 2020 10 11;8(5):1081-1087. Epub 2020 May 11.

Shriners Hospital for Children, Philadelphia, PA, USA.

Study Design: Retrospective descriptive, multi-center study.

Objectives: We hypothesize that a post-operative weight gain will result in patients who are underweight prior to surgery. Cachexia and low body mass index is common among children with cerebral palsy (CP). Many interventions are undertaken to assist the child in nourishment and to obtain a more normal body mass. Additionally, scoliosis is common among children with CP. In our practice we have noted weight gain post operatively in severely underweight children after spinal fusion.

Methods: We underwent a retrospective review of a CP cohort from a multicenter prospective registry. Percentiles on the CP specific growth chart for which each child belonged were plotted based on the patients' age, weight, gender, GMFCS level, and tube feeding status. We then assessed percentile change in patients between pre-op visit, 1 year, 2 years and for those with available data, 5 years follow up visits. Patients with under two years of follow up, patients with GMFCS III and below, and patients without weight data were excluded.

Results: We identified a total of 211 potentially eligible patients from a multicenter prospective registry. 109 had complete 2 years data to analyze and 37 patients had full 5 years data to analyze. We found that patients under the 50th percentile pre-operatively increased their percentile on the CP growth chart for weight 12.1 percentiles (95% CI 6.7, 17.5 p value < 0.001) whereas patients that began at the 50th percentile or above on average lost 2.2 percentiles (95% CI -6.8, 2.3) though the change was not statistically significant (p value 0.330). These changes appeared stable at 5 years. Although regression analysis showed that Cobb correction and pelvic obliquity correction, and hyperlordosis were not independent predictors of the change, we noted that patients with residual curves after surgery of 40° or more experienced 13.3 percentile less weight gain than those with better corrections.

Conclusions: Patients with CP are at risk for cachexia, malnutrition, reflux and other GI disorders. Data presented here suggests that corrective spinal surgery may improve weight percentile in patients who start out at 50th percentile and lower. Patients with 40° or greater of residual scoliosis may benefit less from spinal fusion than those with a better correction.

Level Of Evidence: II; Prognostic retrospective cohort study.
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http://dx.doi.org/10.1007/s43390-020-00109-1DOI Listing
October 2020

Age-related changes in the physical properties, cross-linking, and glycation of collagen from mouse tail tendon.

J Biol Chem 2020 07 7;295(31):10562-10571. Epub 2020 May 7.

Babraham Institute, Cambridge, United Kingdom

Collagen is a structural protein whose internal cross-linking critically determines the properties and functions of connective tissue. Knowing how the cross-linking of collagen changes with age is key to understanding why the mechanical properties of tissues change over a lifetime. The current scientific consensus is that collagen cross-linking increases with age and that this increase leads to tendon stiffening. Here, we show that this view should be reconsidered. Using MS-based analyses, we demonstrated that during aging of healthy C57BL/6 mice, the overall levels of collagen cross-linking in tail tendon decreased with age. However, the levels of lysine glycation in collagen, which is not considered a cross-link, increased dramatically with age. We found that in 16-week-old diabetic db/db mice, glycation reaches levels similar to those observed in 98-week-old C57BL/6 mice, while the other cross-links typical of tendon collagen either decreased or remained the same as those observed in 20-week-old WT mice. These results, combined with findings from mechanical testing of tendons from these mice, indicate that overall collagen cross-linking in mouse tendon decreases with age. Our findings also reveal that lysine glycation appears to be an important factor that contributes to tendon stiffening with age and in diabetes.
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http://dx.doi.org/10.1074/jbc.RA119.011031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397091PMC
July 2020

Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal.

Nat Immunol 2020 05 23;21(5):555-566. Epub 2020 Apr 23.

Institute of Molecular Immunology, School of Life Sciences, TUM, Munich, Germany.

Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8 T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8 T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.
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http://dx.doi.org/10.1038/s41590-020-0666-9DOI Listing
May 2020

Evening salivary cortisol as a single stress marker in women with metastatic breast cancer.

Psychoneuroendocrinology 2020 05 8;115:104648. Epub 2020 Mar 8.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road Stanford, CA 94305-5717, United States.

Background: Flattened diurnal salivary cortisol patterns predict shorter subsequent survival with breast, lung, and renal cell carcinomas. The underlying cause of this flattened slope is undetermined, though it has been hypothesized to be secondary to a deficit in the amplitude of the circadian clock. To gain greater insight into the portions of the diurnal salivary curve that are associated with cancer survival, we examined (1) which points in the diurnal curve are predictive of the slope of the curve and (2) whether elevated evening cortisol levels alone are associated with reduced HPA-axis feedback inhibition (i.e., decreased sensitivity to the dexamethasone suppression test).

Method: We examined study hypotheses on adult women with advanced breast cancer (age = 54.3 ± 9.58 years; n = 99) using non-parametric Wilcoxon's rank-sum tests, Spearman correlation coefficients and an accuracy formula based on a confusion matrix. Cortisol was sampled five times per day for three consecutive days, with dexamethasone administered late on the second day.

Results: Salivary cortisol concentrations did not vary between those with flat and steep slopes during the morning (p's > .05), but did vary in the evening (p's < 0.05). Furthermore, the concentration of the 2100h alone was 86% accurate in discriminating between individuals classified as having "flat" or "steep" slopes. Dexamethasone suppression was only associated with diurnal salivary cortisol slope (p = .0042).

Conclusions: Evening cortisol levels are a sensitive indicator flattened diurnal cortisol slope, suggesting evening cortisol may also be a useful predictor of breast cancer survival. Future research should focus on determining the causes of abnormally increased evening cortisol.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104648DOI Listing
May 2020

Association between Anterior Cingulate Neurochemical Concentration and Individual Differences in Hypnotizability.

Cereb Cortex 2020 May;30(6):3644-3654

Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.

Hypnosis is the oldest form of Western psychotherapy and a powerful evidence-based treatment for numerous disorders. Hypnotizability is variable between individuals; however, it is a stable trait throughout adulthood, suggesting that neurophysiological factors may underlie hypnotic responsiveness. One brain region of particular interest in functional neuroimaging studies of hypnotizability is the anterior cingulate cortex (ACC). Here, we examined the relationships between the neurochemicals, GABA, and glutamate, in the ACC and hypnotizability in healthy individuals. Participants underwent a magnetic resonance imaging (MRI) session, whereby T1-weighted anatomical and MEGA-PRESS spectroscopy scans were acquired. Voxel placement over the ACC was guided by a quantitative meta-analysis of functional neuroimaging studies of hypnosis. Hypnotizability was assessed using the Hypnotic Induction Profile (HIP), and self-report questionnaires to assess absorption (TAS), dissociation (DES), and negative affect were completed. ACC GABA concentration was positively associated with HIP scores such that the higher the GABA concentration, the more hypnotizable an individual. An exploratory analysis of questionnaire subscales revealed a negative relationship between glutamate and the absorption and imaginative involvement subscale of the DES. These results provide a putative neurobiological basis for individual differences in hypnotizability and can inform our understanding of treatment response to this growing psychotherapeutic tool.
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http://dx.doi.org/10.1093/cercor/bhz332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232991PMC
May 2020

A low glycemic diet protects disease-prone Nrf2-deficient mice against age-related macular degeneration.

Free Radic Biol Med 2020 04 14;150:75-86. Epub 2020 Feb 14.

Laboratory for Nutrition and Vision Research, JM-USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, 02111, USA; Friedman School of Nutrition and Science Policy, Tufts University, Boston, MA, 02111, USA; Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, 02111, USA. Electronic address:

Age-related macular degeneration (AMD) is a major blinding disease, affecting over 14% of the elderly. Risk for AMD is related to age, diet, environment, and genetics. Dietary modulation of AMD risk is a promising treatment modality, but requires appropriate animal models to demonstrate advantages of diet. Mice lacking the antioxidant transcription factor Nrf2 (Nfe2l2) develop age-related retinopathy relevant to human AMD. Here we evaluated the effect of consuming high glycemic (HG) or low glycemic (LG) diets until 18-months of age on development of features relevant to AMD in Nrf2-null mice. Nrf2-null mice that consumed HG diets developed atrophic AMD, characterized by photoreceptor degeneration, retinal pigment epithelium (RPE) atrophy and pigmentary abnormalities, basal laminar deposits, and loss of the choriocapillaris. In contrast, Nrf2-null-mice that consumed LG diets did not develop retinal disease phenotypes. Consumption of HG diets was associated with accumulation of advanced glycation end-products in the RPE and systemically, whereas consumption of the LG diet was associated with increased levels of anti-glycative and anti-oxidative detoxification machinery. Together our data indicate that the Nrf2-null HG mouse is a good model for atrophic AMD studies and that the LG diet can activate protective pathways to prevent AMD, even in a genetically predisposed animal.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747150PMC
April 2020