Lane Medical Library

Evaluation of racial disparities in pediatric optic pathway glioma incidence: Results from the Surveillance, Epidemiology, and End Results Program, 2000-2014.

Cancer Epidemiol. 2018 Apr 20;54:90-94

Authors: Peckham-Gregory EC, Montenegro RE, Stevenson DA, Viskochil DH, Scheurer ME, Lupo PJ, Schiffman JD

Abstract
BACKGROUND: Racial predilection to pediatric cancer exists; however optic pathway glioma (OPG) risk differences by race/ethnicity are undefined. We estimated differences in OPG incidence across racial/ethnic groups in a multi-state cancer surveillance registry in the United States.
METHODS: OPG data were obtained from the Surveillance, Epidemiology, and End Results (SEER-18) Program, 2000-2014. Race/ethnicity was categorized as: White; Black; Asian; Other; and Latino/a ("Spanish-Hispanic-Latino"). Latino/a included all races, while all other categories excluded those identified as Latino/a. Age-adjusted incidence rates and rate ratios (IRR) with 95% confidence intervals (CIs) were generated in SEER-STAT (v8.3.4).
RESULTS: Data on 709 OPG cases ages 0-19 were abstracted from SEER-18. Minority children experienced lower age-adjusted OPG incidence rates compared to White children (IRRBlack = 0.38, 95% CI: 0.28-0.50; IRRAsian = 0.41, 95% CI: 0.29-0.58; and IRRLatino/a = 0.39, 95% CI: 0.32-0.48). In subgroup analyses among the highest risk age categories (0-4, 5-9), minority children experienced lower incidence rates compared to White children. Specific patterns for Latinos/as also emerged. Latino/a children ages 0-4 experienced the lowest incidence rates of all racial/ethnic groups compared to Whites (0.24 per 100,000 person-years versus 0.66 per 100,000 person-years, respectively), whereas among those ages 5-9, Black and Asian children experienced the lowest incidence rates (0.08 per 100,000 person-years each).
CONCLUSIONS: Incidence of OPGs was highest among White children. This study represents one of the largest to assess differences in OPG susceptibility by race/ethnicity. These findings may inform future studies that seek to evaluate modifying factors for this pediatric tumor including tumorigenesis, treatment, outcome, and long-term late effects.

PMID: 29684801 [PubMed - as supplied by publisher]

Bilateral automatized intermittent bolus erector spinae plane analgesic blocks for sternotomy in a cardiac patient who underwent cardiopulmonary bypass: A new era of Cardiac Regional Anesthesia.

J Clin Anesth. 2018 Apr 19;48:9-10

Authors: Tsui BCH, Navaratnam M, Boltz G, Maeda K, Caruso TJ

PMID: 29684728 [PubMed - as supplied by publisher]

Cryoballoon Best Practices II: Practical Guide to Procedural Monitoring and Dosing During Atrial Fibrillation Ablation From the Perspective of Experienced Users.

Heart Rhythm. 2018 Apr 20;:

Authors: Su W, Aryana A, Passman R, Singh G, Hokanson R, Kowalski M, Andrade J, Wang P

Abstract
Since cryoballoon was evaluated in STOP-AF, over 350,000 patients with AF have been treated. Several studies have reported improved outcomes using the second-generation cryoballoon, and recent publications have evaluated modifications, refinements, and improvements to procedural techniques. Here, peer-reviewed manuscripts published since the first cryoballoon best practices review were summarized against the technical practices of physicians with a high-level of experience with the cryoballoon (average ≥6 years of experience in ≥900 cases). This summary includes a comprehensive literature review along with practical usage guidance from physicians using the cryoballoon to facilitate safe, efficient, and effective outcomes for patients with AF.

PMID: 29684571 [PubMed - as supplied by publisher]

Effects of exercise on brown and beige adipocytes.

Biochim Biophys Acta. 2018 Apr 20;:

Authors: Dewal RS, Stanford KI

Abstract
Physical exercise leads to beneficial effects in numerous tissues and organ systems and offers protection against obesity and type 2 diabetes. Recent studies have investigated the role of exercise on brown adipose tissue (BAT) and white adipose tissue (WAT), and have indicated marked adaptations to each tissue with exercise. Studies investigating the effects of exercise on BAT have produced conflicting results, with some showing an increase in the thermogenic activity of BAT and some demonstrating a decrease in the thermogenic activity of BAT. Human studies have observed a down-regulation of BAT activity (measured by a reduction in glucose uptake) in response to exercise. In WAT, exercise decreases adipocyte size, alters gene expression, and increases mitochondrial activity. Transplantation of exercise-trained subcutaneous WAT (scWAT) improves whole-body metabolic health. In rodents, exercise also results in a beiging of scWAT. Thus, exercise-induced changes to adipose tissue may be part of the mechanism by which exercise improves metabolic health.

PMID: 29684558 [PubMed - as supplied by publisher]

The Rodent Tibia Fracture Model: A Critical Review and Comparison with the Complex Regional Pain Syndrome Literature.

J Pain. 2018 Apr 20;:

Authors: Birklein F, Ibrahim A, Schlereth T, Kingery WS

Abstract
Distal limb fracture is the most common cause of complex regional pain syndrome (CRPS), thus the rodent tibia fracture model (TFM) was developed to study CRPS pathogenesis. This comprehensive review summarizes the published TFM research and compares these experimental results with the CRPS literature. The TFM generated spontaneous and evoked pain behaviors, inflammatory symptoms (edema, warmth) and trophic changes (skin thickening, osteoporosis) resembling symptoms in early CRPS. Neuropeptides, inflammatory cytokines, and nerve growth factor (NGF) have been linked to pain behaviors, inflammation, and trophic changes in the TFM model and proliferating keratinocytes were identified as the primary source of cutaneous cytokines and NGF. Tibia fracture also activated spinal glia and up regulated spinal neuropeptide, cytokine, and NGF expression, and in the brain it changed dendritic architecture. B cell expressed IgM antibodies also contributed to pain behavior, indicating a role for adaptive immunity. These results modeled many findings in early CRPS, but significant differences were also noted.
PERSPECTIVE: Multiple neuroimmune signaling mechanisms contribute to the pain, inflammation, and trophic changes observed in the injured limb of the rodent tibia fracture model (TFM). This model replicates many of the symptoms, signs, and pathophysiology of early CRPS, but most post fracture changes resolve within 5 months and may not contribute to perpetuating chronic CRPS.

PMID: 29684510 [PubMed - as supplied by publisher]

Repair of Ductus or Hemi-Truncus to One Lung and Major Aortopulmonary Collaterals to the Other Lung.

Ann Thorac Surg. 2018 Apr 20;:

Authors: Mainwaring RD, Rosenblatt TR, Patrick WL, Ma M, Peng L, Hanley FL

Abstract
BACKGROUND: There are patients born with pulmonary atresia and a ductus arteriosus or hemi-truncus to one lung and major aortopulmonary collateral arteries (MAPCAs) to the contralateral lung. The purpose of this study was to review our surgical results for this relatively rare subset of patients.
METHODS: This was a retrospective review of 35 patients with ductus/hemi-truncus in association with pulmonary atresia with ventricular septal defect and MAPCAs. Our surgical algorithm is bifurcated into two strategies: 1) patients with "favorable" MAPCAs are candidates for single stage complete repair, and 2) patients with "unfavorable" MAPCAs undergo a staged approach. The median age at surgery was 3 months (range 1-7 months), and the mean number of MAPCAs was 3.1 ± 1.3.
RESULTS: Twenty patients underwent a single stage complete repair. All 20 of these patients are alive with a right ventricle to aortic pressure ratio of 0.34 ± 0.07. The distribution of pulmonary blood flow by lung perfusion scan was 44% to the right and 56% to the left lung. Fifteen patients underwent a staged approach, including unifocalization of the MAPCAs to a central shunt. There were two interim deaths. Twelve patients have undergone complete repair with a right ventricle to aortic pressure ratio of 0.38 ± 0.07. There was one late death after complete repair. The distribution of pulmonary blood flow was 39% to the right and 61% to the left lung.
CONCLUSIONS: The data demonstrate that 32 of 35 patients with ductus/hemi-truncus and MAPCAs ultimately achieved complete repair with relatively low pulmonary artery pressures.

PMID: 29684371 [PubMed - as supplied by publisher]

Editorial Comment.

J Urol. 2018 Apr 20;:

Authors: Wang NN, Sonn GA

PMID: 29684305 [PubMed - as supplied by publisher]

The Problem with "Magnitude-Based Inference".

Med Sci Sports Exerc. 2018 Apr 21;:

Authors: Sainani KL

Abstract
PURPOSE: A statistical method called "Magnitude-Based Inference" (MBI) has gained a following in the sports science literature, despite concerns voiced by statisticians. Its proponents have claimed that MBI exhibits superior Type I and Type II error rates compared with standard null hypothesis testing for most cases. I have performed a re-analysis to evaluate this claim.
METHODS: Using simulation code provided by MBI's proponents, I estimated Type I and Type II error rates for clinical and non-clinical MBI for a range of effect sizes, sample sizes, and smallest important effects. I plotted these results in a way that makes transparent the empirical behavior of MBI. I also re-ran the simulations after correcting mistakes in the definitions of Type I and Type II error provided by MBI's proponents. Finally, I confirmed the findings mathematically; and I provide general equations for calculating MBI's error rates without the need for simulation.
RESULTS: Contrary to what MBI's proponents have claimed, MBI does not exhibit "superior" Type I and Type II error rates to standard null hypothesis testing. As expected, there is a tradeoff between Type I and Type II error. At precisely the small-to-moderate sample sizes that MBI's proponents deem "optimal," MBI reduces the Type II error rate at the cost of greatly inflating the Type I error rate-to two to six times that of standard hypothesis testing.
CONCLUSIONS: MBI exhibits worrisome empirical behavior. In contrast to standard null hypothesis testing, which has predictable Type I error rates, the Type I error rates for MBI vary widely depending on the sample size and choice of smallest important effect, and are often unacceptably high. MBI should not be used.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

PMID: 29683920 [PubMed - as supplied by publisher]

Fetal sex determination in twin pregnancies using cell free fetal DNA analysis.

Prenat Diagn. 2018 Apr 23;:

Authors: Milan M, Mateu E, Blesa D, Clemente-Ciscar M, Simon C

Abstract
OBJECTIVE(S): We sought to develop an accurate sex classification method in twin pregnancies using data obtained from a standard commercial non-invasive prenatal test.
STUDY DESIGN: A total of 706 twin pregnancies were included in this retrospective analytical data study. Normalized chromosome values for chromosomes X and Y were used and adapted into a sex-score to predict fetal sex in each fetus and results were compared to the clinical outcome at birth.
RESULTS: Outcome information at birth for sex chromosomes was available for 232 twin pregnancies. From these, a total of 173 twin pregnancies with a Y chromosome identified in non-invasive pregnancy testing were used for the development of a predictive model. Global accuracy for sex classification in the testing set with 51 samples was 0.98 (95% confidence interval [0.90,0.99]), with a specificity and sensitivity of 1 (95% confidence interval [0.82,1.00]) and 0.97 (95% confidence interval [0.84,0.99]), respectively.
CONCLUSION: While non-invasive prenatal testing is a screening method and confirmatory results must be obtained by ultrasound or genetic diagnosis, the sex-score determination presented herein offers an accurate and useful approach to characterizing fetus sex in twin pregnancies in a non-invasive manner early on in pregnancy.

PMID: 29683524 [PubMed - as supplied by publisher]

Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis.

Mult Scler. 2018 Apr 01;:1352458518770019

Authors: Creary LE, Mallempati KC, Gangavarapu S, Caillier SJ, Oksenberg JR, Fernández-Viňa MA

Abstract
BACKGROUND: The association between HLA-DRB1*15:01 with multiple sclerosis (MS) susceptibility is well established, but the contribution of the tightly associated HLA-DRB5*01:01 allele has not yet been completely ascertained. Similarly, the effects of HLA-DRB1*04:01 alleles and haplotypes, defined at the full-gene resolution level with MS risk remains to be elucidated.
OBJECTIVES: To characterize the molecular architecture of class II HLA-DR15 and HLA-DR4 haplotypes associated with MS.
METHODS: Next-generation sequencing was used to determine HLA-DQB1, HLA-DQA1, and HLA-DRB1/4/5 alleles in 1403 unrelated European-American patients and 1425 healthy unrelated controls. Effect sizes of HLA alleles and haplotypes on MS risk were measured by odds ratio (OR) with 95% confidence intervals.
RESULTS: HLA-DRB1*15:01:01:01SG (OR = 3.20, p < 2.2E-16), HLA-DRB5*01:01:01 (OR = 2.96, p < 2.2E-16), and HLA-DRB5*01:01:01v1_STR1 (OR = 8.18, p = 4.3E-05) alleles all occurred at significantly higher frequencies in MS patients compared to controls. The most significant predis-posing haplotypes were HLA-DQB1*06:02:01~ HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01 and HLA-DQB1*06:02:01~HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01v1_STR1 (OR = 3.19, p < 2.2E-16; OR = 9.30, p = 9.7E-05, respectively). Analyses of the HLA-DRB1*04 cohort in the absence of HLA-DRB1*15:01 haplotypes revealed that the HLA-DQB1*03:01:01:01~HLA-DQA1*03:03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was protective (OR = 0.64, p = 0.028), whereas the HLA-DQB1*03:02:01~HLA-DQA1*03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was associated with MS susceptibility (OR = 1.66, p = 4.9E-03).
CONCLUSION: HLA-DR15 haplotypes, including genomic variants of HLA-DRB5, and HLA-DR4 haplotypes affect MS risk.

PMID: 29683085 [PubMed - as supplied by publisher]

Molecular Cancer Imaging in the Second Near-Infrared Window Using a Renal-Excreted NIR-II Fluorophore-Peptide Probe.

Adv Mater. 2018 Apr 23;:e1800106

Authors: Wang W, Ma Z, Zhu S, Wan H, Yue J, Ma H, Ma R, Yang Q, Wang Z, Li Q, Qian Y, Yue C, Wang Y, Fan L, Zhong Y, Zhou Y, Gao H, Ruan J, Hu Z, Liang Y, Dai H

Abstract
In vivo molecular imaging of tumors targeting a specific cancer cell marker is a promising strategy for cancer diagnosis and imaging guided surgery and therapy. While targeted imaging often relies on antibody-modified probes, peptides can afford targeting probes with small sizes, high penetrating ability, and rapid excretion. Recently, in vivo fluorescence imaging in the second near-infrared window (NIR-II, 1000-1700 nm) shows promise in reaching sub-centimeter depth with microscale resolution. Here, a novel peptide (named CP) conjugated NIR-II fluorescent probe is reported for molecular tumor imaging targeting a tumor stem cell biomarker CD133. The click chemistry derived peptide-dye (CP-IRT dye) probe afforded efficient in vivo tumor targeting in mice with a high tumor-to-normal tissue signal ratio (T/NT > 8). Importantly, the CP-IRT probes are rapidly renal excreted (≈87% excretion within 6 h), in stark contrast to accumulation in the liver for typical antibody-dye probes. Further, with NIR-II emitting CP-IRT probes, urethra of mice can be imaged fluorescently for the first time noninvasively through intact tissue. The NIR-II fluorescent, CD133 targeting imaging probes are potentially useful for human use in the clinic for cancer diagnosis and therapy.

PMID: 29682821 [PubMed - as supplied by publisher]

Dynamic Hyaluronan Hydrogels with Temporally Modulated High Injectability and Stability Using a Biocompatible Catalyst.

Adv Mater. 2018 Apr 23;:e1705215

Authors: Lou J, Liu F, Lindsay CD, Chaudhuri O, Heilshorn SC, Xia Y

Abstract
Injectable and biocompatible hydrogels have become increasingly important for cell transplantation to provide mechanical protection of cells during injection and a stable scaffold for cell adhesion post-injection. Injectable hydrogels need to be easily pushed through a syringe needle and quickly recover to a gel state, thus generally requiring noncovalent or dynamic cross-linking. However, a dilemma exists in the design of dynamic hydrogels: hydrogels with fast exchange of cross-links are easier to eject using less force, but lack long-term stability; in contrast, slow exchange of cross-links improves stability, but compromises injectability and thus the ability to protect cells under flow. A new concept to resolve this dilemma using a biocompatible catalyst to modulate the dynamic properties of hydrogels at different time points of application to have both high injectability and high stability is presented. Hyaluronic acid based hydrogels are formed through dynamic covalent hydrazone cross-linking in the presence of a biocompatible benzimidazole-based catalyst. The catalyst accelerates the formation and exchange of hydrazone bonds, enhancing injectability, but rapidly diffuses away from the hydrogel after injection to retard the exchange and improve the long-term stability for cell culture.

PMID: 29682801 [PubMed - as supplied by publisher]

Patellar Instability in the Skeletally Immature.

Curr Rev Musculoskelet Med. 2018 Apr 23;:

Authors: Popkin CA, Bayomy AF, Trupia EP, Chan CM, Redler LH

Abstract
PURPOSE OF REVIEW: This review will focus on the evaluation and management of patellar instability in the developing patient.
RECENT FINDINGS: A large number of surgical techniques have been described to prevent recurrent patellofemoral instability in the pediatric population, including both proximal and distal realignment procedures. The wide variety of treatment options highlights the lack of agreement as to the best surgical approach. However, when a comprehensive exam and workup are paired with a surgical plan to address each of the identified abnormalities, outcomes are predictably good. Patellar instability is a common knee disorder in the skeletally immature patient that presents a unique set of challenges. Rates of re-dislocation in pediatric and adolescent patients are higher than in their adult counterparts. Careful consideration of the physeal and apophyseal anatomy is essential in these patients. While the majority of primary patellar instability events can be treated conservatively, multiple events often require surgical intervention.

PMID: 29682681 [PubMed - as supplied by publisher]

The Hair Follicle: An Underutilized Source of Cells and Materials for Regenerative Medicine.

ACS Biomater Sci Eng. 2018 Apr 09;4(4):1193-1207

Authors: Kiani MT, Higgins CA, Almquist BD

Abstract
The hair follicle is one of only two structures within the adult body that selectively degenerates and regenerates, making it an intriguing organ to study and use for regenerative medicine. Hair follicles have been shown to influence wound healing, angiogenesis, neurogenesis, and harbor distinct populations of stem cells; this has led to cells from the follicle being used in clinical trials for tendinosis and chronic ulcers. In addition, keratin produced by the follicle in the form of a hair fiber provides an abundant source of biomaterials for regenerative medicine. In this review, we provide an overview of the structure of a hair follicle, explain the role of the follicle in regulating the microenvironment of skin and the impact on wound healing, explore individual cell types of interest for regenerative medicine, and cover several applications of keratin-based biomaterials.

PMID: 29682604 [PubMed]

Anger Modulates Influence Hierarchies Within and Between Emotional Reactivity and Regulation Networks.

Front Behav Neurosci. 2018;12:60

Authors: Jacob Y, Gilam G, Lin T, Raz G, Hendler T

Abstract
Emotion regulation is hypothesized to be mediated by the interactions between emotional reactivity and regulation networks during the dynamic unfolding of the emotional episode. Yet, it remains unclear how to delineate the effective relationships between these networks. In this study, we examined the aforementioned networks' information flow hierarchy during viewing of an anger provoking movie excerpt. Anger regulation is particularly essential for averting individuals from aggression and violence, thus improving prosocial behavior. Using subjective ratings of anger intensity we differentiated between low and high anger periods of the film. We then applied the Dependency Network Analysis (DEPNA), a newly developed graph theory method to quantify networks' node importance during the two anger periods. The DEPNA analysis revealed that the impact of the ventromedial prefrontal cortex (vmPFC) was higher in the high anger condition, particularly within the regulation network and on the connections between the reactivity and regulation networks. We further showed that higher levels of vmPFC impact on the regulation network were associated with lower subjective anger intensity during the high-anger cinematic period, and lower trait anger levels. Supporting and replicating previous findings, these results emphasize the previously acknowledged central role of vmPFC in modulating negative affect. We further show that the impact of the vmPFC relies on its correlational influence on the connectivity between reactivity and regulation networks. More importantly, the hierarchy network analysis revealed a link between connectivity patterns of the vmPFC and individual differences in anger reactivity and trait, suggesting its potential therapeutic role.

PMID: 29681803 [PubMed]

Tilted Light Sheet Microscopy with 3D Point Spread Functions for Single-Molecule Super-Resolution Imaging in Mammalian Cells.

Proc SPIE Int Soc Opt Eng. 2018 Feb;10500:

Authors: Gustavsson AK, Petrov PN, Lee MY, Shechtman Y, Moerner WE

Abstract
To obtain a complete picture of subcellular nanostructures, cells must be imaged with high resolution in all three dimensions (3D). Here, we present tilted light sheet microscopy with 3D point spread functions (TILT3D), an imaging platform that combines a novel, tilted light sheet illumination strategy with engineered long axial range point spread functions (PSFs) for low-background, 3D super localization of single molecules as well as 3D super-resolution imaging in thick cells. TILT3D is built upon a standard inverted microscope and has minimal custom parts. The axial positions of the single molecules are encoded in the shape of the PSF rather than in the position or thickness of the light sheet, and the light sheet can therefore be formed using simple optics. The result is flexible and user-friendly 3D super-resolution imaging with tens of nm localization precision throughout thick mammalian cells. We validated TILT3D for 3D super-resolution imaging in mammalian cells by imaging mitochondria and the full nuclear lamina using the double-helix PSF for single-molecule detection and the recently developed Tetrapod PSF for fiducial bead tracking and live axial drift correction. We envision TILT3D to become an important tool not only for 3D super-resolution imaging, but also for live whole-cell single-particle and single-molecule tracking.

PMID: 29681676 [PubMed]

A Task-Optimized Neural Network Replicates Human Auditory Behavior, Predicts Brain Responses, and Reveals a Cortical Processing Hierarchy.

Neuron. 2018 Apr 17;:

Authors: Kell AJE, Yamins DLK, Shook EN, Norman-Haignere SV, McDermott JH

Abstract
A core goal of auditory neuroscience is to build quantitative models that predict cortical responses to natural sounds. Reasoning that a complete model of auditory cortex must solve ecologically relevant tasks, we optimized hierarchical neural networks for speech and music recognition. The best-performing network contained separate music and speech pathways following early shared processing, potentially replicating human cortical organization. The network performed both tasks as well as humans and exhibited human-like errors despite not being optimized to do so, suggesting common constraints on network and human performance. The network predicted fMRI voxel responses substantially better than traditional spectrotemporal filter models throughout auditory cortex. It also provided a quantitative signature of cortical representational hierarchy-primary and non-primary responses were best predicted by intermediate and late network layers, respectively. The results suggest that task optimization provides a powerful set of tools for modeling sensory systems.

PMID: 29681533 [PubMed - as supplied by publisher]

Phasic Dopamine Signals in the Nucleus Accumbens that Cause Active Avoidance Require Endocannabinoid Mobilization in the Midbrain.

Curr Biol. 2018 Apr 16;:

Authors: Wenzel JM, Oleson EB, Gove WN, Cole AB, Gyawali U, Dantrassy HM, Bluett RJ, Dryanovski DI, Stuber GD, Deisseroth K, Mathur BN, Patel S, Lupica CR, Cheer JF

Abstract
Phasic dopamine (DA) release accompanies approach toward appetitive cues. However, a role for DA in the active avoidance of negative events remains undetermined. Warning signals informing footshock avoidance are associated with accumbal DA release, whereas depression of DA is observed with unavoidable footshock. Here, we reveal a causal role of phasic DA in active avoidance learning; specifically, optogenetic activation of DA neurons facilitates avoidance, whereas optical inhibition of these cells attenuates it. Furthermore, stimulation of DA neurons during presentation of a fear-conditioned cue accelerates the extinction of a passive defensive behavior (i.e., freezing). Dopaminergic control of avoidance requires endocannabinoids (eCBs), as perturbing eCB signaling in the midbrain disrupts avoidance, which is rescued by optical stimulation of DA neurons. Interestingly, once the avoidance task is learned, neither DA nor eCB manipulations affect performance, suggesting that once acquisition occurs, expression of this behavior is subserved by other anatomical frameworks. Our findings establish an instrumental role for DA release in learning active responses to aversive stimuli and its control by eCB signaling.

PMID: 29681476 [PubMed - as supplied by publisher]

KREMEN1 Is a Host Entry Receptor for a Major Group of Enteroviruses.

Cell Host Microbe. 2018 Apr 18;:

Authors: Staring J, van den Hengel LG, Raaben M, Blomen VA, Carette JE, Brummelkamp TR

Abstract
Human type A Enteroviruses (EV-As) cause diseases ranging from hand-foot-and-mouth disease to poliomyelitis-like disease. Although cellular receptors are identified for some EV-As, they remain elusive for the majority of EV-As. We identify the cell surface molecule KREMEN1 as an entry receptor for coxsackievirus A10 (CV-A10). Whereas loss of KREMEN1 renders cells resistant to CV-A10 infection, KREMEN1 overexpression enhances CV-A10 binding to the cell surface and increases susceptibility to infection, indicating that KREMEN1 is a rate-limiting factor for CV-A10 infection. Furthermore, the extracellular domain of KREMEN1 binds CV-A10 and functions as a neutralizing agent during infection. Kremen-deficient mice are resistant to CV-A10-induced lethal paralysis, emphasizing the relevance of Kremen for infection in vivo. KREMEN1 is also essential for infection by a phylogenetic and pathogenic related group of EV-As. Collectively these findings highlight the importance of KREMEN1 for these emerging pathogens and its potential as an antiviral therapeutic target.

PMID: 29681460 [PubMed - as supplied by publisher]

Mindsets Matter: A New Framework for Harnessing the Placebo Effect in Modern Medicine.

Int Rev Neurobiol. 2018;138:137-160

Authors: Zion SR, Crum AJ

Abstract
The clinical utility of the placebo effect has long hinged on physicians deceptively administering an objective placebo treatment to their patients. However, the power of the placebo does not reside in the sham treatment itself; rather, it comes from the psychosocial forces that surround the patient and the treatment. To this end, we propose a new framework for understanding and leveraging the placebo effect in clinical care. In outlining this framework, we first present the placebo effect as a neurobiological effect that is evoked by psychological processes. Next, we argue that along with implicit learning and expectation formation, mindsets are a key psychological process involved in the placebo effect. Finally, we illustrate the critical role of the social environment and treatment context in shaping these psychological processes. In doing so, we offer a guide for how the placebo effect can be understood, harnessed, and leveraged in the practice of modern medicine.

PMID: 29681322 [PubMed - in process]

Failed umbilical artery catheterization and adverse outcomes in extremely low birth weight infants.

J Matern Fetal Neonatal Med. 2018 Apr 22;:1-11

Authors: Wallenstein MB, Shaw GM, Yang W, Stevenson DK

Abstract
PURPOSE: To determine whether successful catheterization of the umbilical artery is associated with a reduced risk of death or neurodevelopment impairment among critically ill extremely low birth weight (ELBW) infants.
STUDY DESIGN: A retrospective chart review was conducted between 2007 and 2014 at Stanford University for all ELBW infants that required intubation immediately after birth. The primary outcome was death or neurodevelopmental impairment at 18-22 months. We measured the association of successful umbilical artery catheterization with the primary outcome using multivariable logistic regression with adjustment for gestational age. Bayesian analysis was also performed due to small sample size.
RESULTS: Eighty-four ELBW infants met inclusion criteria. Successful umbilical artery catheterization occurred in 88% of infants and failed catheterization in 12%. Death or neurodevelopmental impairment occurred in 41% of infants with successful catheterization, compared to 60% of infants with failed catheterization of the umbilical artery, adjusted odds ratio 0.3, 95% confidence interval 0.1-1.3, p = 0.11. Bayesian analysis indicated a 92% posterior probability of reduced death or neurodevelopmental impairment with successful catheterization and a 68% posterior probability of reduced death or neurodevelopmental by absolute risk difference of 20% or more, adjusted relative risk 0.74, 95% confidence interval 0.45-1.14.

PMID: 29681181 [PubMed - as supplied by publisher]

Genetic variation in biotransformation enzymes, air pollution exposures, and risk of spina bifida.

Am J Med Genet A. 2018 May;176(5):1055-1090

Authors: Padula AM, Yang W, Schultz K, Lurmann F, Hammond SK, Shaw GM

Abstract
Spina bifida is a birth defect characterized by incomplete closure of the embryonic neural tube. Genetic factors as well as environmental factors have been observed to influence risks for spina bifida. Few studies have investigated possible gene-environment interactions that could contribute to spina bifida risk. The aim of this study is to examine the interaction between gene variants in biotransformation enzyme pathways and ambient air pollution exposures and risk of spina bifida. We evaluated the role of air pollution exposure during pregnancy and gene variants of biotransformation enzymes from bloodspots and buccal cells in a California population-based case-control (86 cases of spina bifida and 208 non-malformed controls) study. We considered race/ethnicity and folic acid vitamin use as potential effect modifiers and adjusted for those factors and smoking. We observed gene-environment interactions between each of the five pollutants and several gene variants: NO (ABCC2), NO2 (ABCC2, SLC01B1), PM10 (ABCC2, CYP1A1, CYP2B6, CYP2C19, CYP2D6, NAT2, SLC01B1, SLC01B3), PM2.5 (CYP1A1 and CYP1A2). These analyses show positive interactions between air pollution exposure during early pregnancy and gene variants associated with metabolizing enzymes. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of pollution.

PMID: 29681089 [PubMed - in process]

Large Q and S waves in lead III on the electrocardiogram distinguish patients with hypertrophic cardiomyopathy from athletes.

Heart. 2018 Apr 21;:

Authors: Chen AS, Bent RE, Wheeler M, Knowles JW, Haddad F, Froelicher V, Ashley E, Perez MV

Abstract
OBJECTIVE: To identify electrocardiographic findings, especially deep Q and S waves in lead III, that differentiate athletes from patients with hypertrophic cardiomyopathy (HCM).
METHODS: Digital ECGs of athletes and patients with HCM followed at the Stanford Center for Inherited Cardiovascular Disease were studied retrospectively. All patients with HCM had an echocardiogram performed. A multivariable logistic regression model was used to calculate ORs for various demographic and ECG characteristics. Linear regression was used to correlate ECG characteristics with echocardiogram findings.
RESULTS: We studied 1124 athletes and 240 patients with HCM. The average Q+S wave amplitude in lead III (IIIQ+S) was significantly higher in patients with HCM compared with athletes (0.71±0.69 mV vs 0.21±0.17 mV, p<0.001). In patients with HCM, IIIQ+S directly correlated with interventricular septal (IVS) thickness on echocardiography (ρ=0.45, p<0.001). In a multivariable analysis adjusted for demographic and ECG characteristics, higher IIIQ+S values remained independently associated with HCM compared with athletes (OR=4.2 per 0.5 mV, p<0.001). In subgroup analyses of young patients, African-American subjects and subjects without left axis deviation (LAD), IIIQ+S remained associated with HCM. The addition of IIIQ+S>1.0 mV as an abnormal finding to the International Criteria for athletic ECG interpretation improved sensitivity from 64.2% to 70.4%, with a minimal decrease in specificity.
CONCLUSION: Large Q and S waves in lead III distinguished athletes from patients with HCM, independent of axis and well-known ECG markers associated with HCM. The correlation between IVS thickness in patients with HCM and IIIQ+S suggests a partial explanation for this association.

PMID: 29680808 [PubMed - as supplied by publisher]

"A Man Walks Into a Bar…": Riddles in the Teaching of Medicine.

Am J Med. 2018 Apr 19;:

Authors: Hall ET, Weaver KW, Perino AC, Elder A, Verghese A

PMID: 29680486 [PubMed - as supplied by publisher]

Financial Stability of Level I Trauma Centers within Safety-Net Hospitals.

J Am Coll Surg. 2018 Apr 19;:

Authors: Knowlton LM, Morris AM, Tennakoon L, Spain DA, Staudenmayer KL

Abstract
BACKGROUND: Level I trauma centers often exist within Safety-Net Hospitals (SNHs), facilities servicing high proportions of low-income and uninsured patients. Given the current healthcare funding environment, trauma centers within SNHs may be at particular risk. Using California as a model, we hypothesized that SNHs with trauma centers vary in terms of financial stability.
STUDY DESIGN: A retrospective cohort study using data from publically-available financial disclosure reports from California's Office of Statewide Health Planning and Development. Safety-net hospitals were identified from the California Association of Public Hospitals and Health Systems. The primary outcome metric for financial performance was operating margin.
RESULTS: California hospitals with Level I Trauma Centers were analyzed (11 SNH sites, 2 non SNH). SNHs did not behave uniformly, and were clustered into county owned SNHs (36%, n=4) and non-profit owned SNHs (64%, n=7). Mean operating margins for county SNHs, non-profit SNHs and non SNHs were -16.5%, 8.4% and 9.5% respectively (p<0.001). From 2010 to 2015, operating margins improved for all hospitals, partly due to increases in the percent of insured patients and changes in payer mix. Non-profit SNHs had a payer mix similar to non SNHs, whereas county SNHs had the highest proportions of MediCal (California Medicaid) (45% vs. 36% vs. 12%, p<0.001) and uninsured patients (17% vs. 5% vs. 0%, p<0.001) compared to non-profit SNHs and non SNHs respectively.
CONCLUSIONS: The majority (85%) of Level I Trauma Centers are within SNHs, whose financial stability is highly variable. A group of SNHs rely upon on infusions of government funds and are therefore susceptible to changes in policy. These findings suggest deliberate funding efforts are critical to protect the health of the U.S. academic trauma system.

PMID: 29680414 [PubMed - as supplied by publisher]

Index of Microcirculatory Resistance and Infarct Size.

JACC Cardiovasc Imaging. 2018 Apr 14;:

Authors: Fearon WF, Dash R

PMID: 29680353 [PubMed - as supplied by publisher]

The Sigmoid Notch View for Distal Radius Fractures.

J Hand Surg Am. 2018 Apr 18;:

Authors: Kamal RN, Leversedge F, Ruch DS, Mithani SK, Cotterell IHF, Richard MJ

Abstract
PURPOSE: This study defines the sigmoid notch view of the distal radius. Specifically, we tested the null hypothesis that there is no relationship between the subchondral stripe of bone seen on a sigmoid notch view of the distal radius and the articular surface of the sigmoid notch.
METHODS: We used 44 wrist specimens for anatomic and fluoroscopic analysis. We measured the articular depth of the sigmoid notch from its deepest point and classified the shape of the sigmoid notch. We then placed a radiopaque marker at the nadir of the articular surface and quantified the fluoroscopic depth of the sigmoid notch. A sigmoid notch view, which was a tangential fluoroscopic view of the volar and dorsal lips of the sigmoid notch, was obtained. The relationship of the articular surface to the stripe of subchondral bone seen on this view, called the sigmoid stripe, was determined.
RESULTS: Anatomic analysis revealed sigmoid notch types with proportions similar to those in previous descriptions. The marker for the articular surface was superimposed or just ulnar to the sigmoid stripe in all specimens. In flat face and ski slope notches, this was coincident with the volar and dorsal lips of the sigmoid notch. In C- and S-type notches, there was a measurable distance from the articular surface marker to the edges of the bone of the volar and dorsal lips of the sigmoid.
CONCLUSIONS: The articular surface marker at the nadir of the sigmoid notch is always coincident or ulnar to the sigmoid stripe in the sigmoid notch view.
CLINICAL RELEVANCE: Surgeons can use the sigmoid notch view as a reliable method to (1) evaluate the integrity of the articular surface, (2) ensure hardware is not placed in the distal radioulnar joint, and (3) guide placement of volar locking plates in the coronal plane.

PMID: 29680335 [PubMed - as supplied by publisher]

Meta-analysis of Randomized Controlled Trials on Patent Foramen Ovale Closure Versus Medical Therapy for Secondary Prevention of Cryptogenic Stroke.

Am J Cardiol. 2018 Mar 02;:

Authors: Smer A, Salih M, Mahfood Haddad T, Guddeti R, Saadi A, Saurav A, Belbase R, Ayan M, Traina M, Alla V, Del Core M

Abstract
The optimal management of patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) remains controversial. We conducted a meta-analysis to assess the effect of PFO closure for secondary prevention of stroke on patients with CS. We searched the literature for randomized control trials assessing the recurrence of stroke after PFO closure compared with medical therapy (antiplatelet and/or anticoagulation). Five randomized control trials with a total of 3,440 patients were included. The mean age was 45.2 ± 9.7 years and follow-up duration ranged from 2.0 to 5.9 years. PFO closure significantly reduced the risk of stroke compared with the medical therapy (2.8% vs 5.8%; relative risk [RR] 0.48, confidence interval [CI] 0.27 to 0.87, p = 0.01, I2 = 56%). The number needed to treat for stroke prevention was 10.5. PFO closure was associated with an increased risk of atrial fibrillation compared with medical therapy (4.2% vs 0.7%; RR 4.55, CI 2.16 to 9.6, p = 0.0001, I2 = 25%). There was no significant difference in all-cause mortality (RR 1.33, CI 0.56 to 3.16, p = 0.52, I2 = 0%), as well as no difference in bleeding risk between the 2 groups (RR 0.94, CI 0.49 to 1.83, p = 0.86, I2 = 29%). In conclusion, our meta-analysis demonstrates that PFO closure is associated with significantly lower risk of recurrent stroke in patients with PFO and CS compared with medical therapy. However, atrial fibrillation was more common among closure patients.

PMID: 29680170 [PubMed - as supplied by publisher]

The fog of development: evaluating the Millennium Villages Project.

Lancet Glob Health. 2018 05;6(5):e470-e471

Authors: Bendavid E

PMID: 29653612 [PubMed - indexed for MEDLINE]

Trading Bankruptcy for Health: A Discrete-Choice Experiment.

Value Health. 2018 01;21(1):95-104

Authors: Shrime MG, Weinstein MC, Hammitt JK, Cohen JL, Salomon JA

Abstract
BACKGROUND: Although nearly two-third of bankruptcy in the United States is medical in origin, a common assumption is that individuals facing a potentially lethal disease opt for cure at any cost. This assumption has never been tested, and knowledge of how the American population values a trade-off between cure and bankruptcy is unknown.
OBJECTIVES: To determine the relative importance among the general American population of improved health versus improved financial risk protection, and to determine the impact of demographics on these preferences.
METHODS: A discrete-choice experiment was performed with 2359 members of the US population. Respondents were asked to value treatments with varying chances of cure and bankruptcy in the presence of a lethal disease. Latent class analysis with concomitant variables was performed, weighted for national representativeness. Sensitivity analyses were undertaken to test the robustness of the results.
RESULTS: It was found that 31.3% of the American population values cure at all costs. Nevertheless, for 8.5% of the US population, financial solvency dominates concerns for health in medical decision making. Individuals who value cure at all costs are more likely to have had experience with serious disease and to be women. No demographic characteristics significantly predicted individuals who value solvency over cure.
CONCLUSIONS: Although the average American values cure more than financial solvency, a cure-at-all-costs rubric describes the preferences of a minority of the population, and 1 in 12 value financial protection over any chances of cure. This study provides empirical evidence for how the US population values a trade-off between avoiding adverse health outcomes and facing bankruptcy. These findings bring to the fore the decision making that individuals face in balancing the acute financial burden of health care access.

PMID: 29304947 [PubMed - indexed for MEDLINE]

Ethnicity and MCH outcomes: widening gaps across time and space.

Lancet Glob Health. 2018 01;6(1):e2-e3

Authors: Wang L, Rozelle S

PMID: 29153767 [PubMed - indexed for MEDLINE]

Short Daytime Naps Briefly Attenuate Objectively Measured Sleepiness Under Chronic Sleep Restriction.

Sleep. 2017 Sep 01;40(9):

Authors: Saletin JM, Hilditch CJ, Dement WC, Carskadon MA

Abstract
Study Objectives: Napping is a useful countermeasure to the negative effects of acute sleep loss on alertness. The efficacy of naps to recover from chronic sleep loss is less well understood.
Methods: Following 2 baseline nights (10 hours' time-in-bed), participants were restricted to 7 nights of 5-hour sleep opportunity. Ten adults participated in the No-Nap condition, and a further 9 were assigned to a Nap condition with a daily 45-minute nap opportunity at 1300 h. Sleepiness was assessed using the multiple sleep latency test and a visual analogue scale at 2-hour intervals. Both objective and subjective indexes of sleepiness were normalized within subject as a difference from those at baseline prior to sleep restriction. Mixed-effects models examined how the daytime nap opportunity altered sleepiness across the day and across the protocol.
Results: Short daytime naps attenuated sleepiness due to chronic sleep restriction for up to 6-8 hours after the nap. Benefits of the nap did not extend late into evening. Subjective sleepiness demonstrated a similar short-lived benefit that emerged later in the day when objective sleepiness already returned to pre-nap levels. Neither measure showed a benefit of the nap the following morning after the subsequent restriction night.
Conclusions: These data indicate a short daytime nap may attenuate sleepiness in chronic sleep restriction, yet subjective and objective benefits emerge at different time scales. Because neither measure showed a benefit the next day, the current study underscores the need for careful consideration before naps are used as routine countermeasures to chronic sleep loss.

PMID: 28934525 [PubMed - indexed for MEDLINE]

Choice as an engine of analytic thought.

J Exp Psychol Gen. 2017 Sep;146(9):1234-1246

Authors: Savani K, Stephens NM, Markus HR

Abstract
Choice is a behavioral act that has a variety of well-documented motivational consequences-it fosters independence by allowing people to simultaneously express themselves and influence the environment. Given the link between independence and analytic thinking, the current research tested whether choice also leads people to think in a more analytic rather than holistic manner. Four experiments demonstrate that making choices, recalling choices, and viewing others make choices leads people to think more analytically, as indicated by their attitudes, perceptual judgments, categorization, and patterns of attention allocation. People who made choices scored higher on a subjective self-report measure of analytic cognition compared to whose did not make a choice (pilot study). Using an objective task-based measure, people who recalled choices rather than actions were less influenced by changes in the background when making judgments about focal objects (Experiment 1). People who thought of others' behaviors as choices rather than actions were more likely to group objects based on categories rather than relationships (Experiment 2). People who recalled choices rather than actions subsequently allocated more visual attention to focal objects in a scene (Experiment 3). Together, these experiments demonstrate that choice has important yet previously unexamined consequences for basic psychological processes such as attention and cognition. (PsycINFO Database Record

PMID: 28846005 [PubMed - indexed for MEDLINE]

Influence of gender on inpatient treatment for bipolar disorder: An analysis of 60,607 hospitalisations.

J Affect Disord. 2018 Jan 01;225:104-107

Authors: Fellinger M, Waldhör T, Blüml V, Williams N, Vyssoki B

Abstract
BACKGROUND: The influence of gender on inpatient treatment patterns in bipolar patients is unclear. The aim of this study is to examine whether differences in length of stay and frequency of inpatient episodes, according to ICD-10 bipolar disorder (BD)-subgroups, exist between men and women.
METHODS: All episodes of a manic (F31.0-2), depressive (F31.3-5) or mixed (F31.6) subtype of BD during an inpatient stay in an Austrian hospital in the period of 2001-2014 were included in this study. Data on episodes was provided by the national statistics agency. Weekly admission rates per 100,000 people were calculated by directly age-standardized rates.
RESULTS: The database comprised 60,607 admissions (35.8% men). The number of inpatient episodes was significantly higher (p < 0.001) in women in all BD subgroups. Average length of stay in manic (p < 0.001) and depressive (p < 0.001) episodes was shorter in women compared to men. No difference could be found for mixed episodes.
LIMITATIONS: Only aggregated patient data and no single case histories were available for this study.
CONCLUSIONS: The current study reveals relevant gender differences regarding inpatient treatment patterns, as women were overrepresented in all BD-subgroups. Despite equal life time prevalence, severe mood episodes lead more often to hospitalisations in women. There is a high necessity to further research the underlying causes of these findings.

PMID: 28810176 [PubMed - indexed for MEDLINE]

Gender myths in global health - Authors' reply.

Lancet Glob Health. 2017 09;5(9):e872

Authors: Talib Z, Burke KS, Barry M

PMID: 28807186 [PubMed - indexed for MEDLINE]

Extended Interneuronal Network of the Dentate Gyrus.

Cell Rep. 2017 Aug 08;20(6):1262-1268

Authors: Szabo GG, Du X, Oijala M, Varga C, Parent JM, Soltesz I

Abstract
Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG) to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network.

PMID: 28793251 [PubMed - indexed for MEDLINE]

NCCN Guidelines Insights: Palliative Care, Version 2.2017.

J Natl Compr Canc Netw. 2017 Aug;15(8):989-997

Authors: Dans M, Smith T, Back A, Baker JN, Bauman JR, Beck AC, Block S, Campbell T, Case AA, Dalal S, Edwards H, Fitch TR, Kapo J, Kutner JS, Kvale E, Miller C, Misra S, Mitchell W, Portman DG, Spiegel D, Sutton L, Szmuilowicz E, Temel J, Tickoo R, Urba SG, Weinstein E, Zachariah F, Bergman MA, Scavone JL

Abstract
The NCCN Guidelines for Palliative Care provide interdisciplinary recommendations on palliative care for patients with cancer. These NCCN Guidelines Insights summarize and provide context for the updated guidelines recommendations regarding hospice and end-of-life (EOL) care. Updates for 2017 include revisions to and restructuring of the algorithms that address important EOL concerns. These recommendations were revised to provide clearer guidance for oncologists as they care for patients with cancer who are approaching the transition to EOL care. Recommendations for interventions and reassessment based on estimated life expectancy were streamlined and reprioritized to promote hospice referrals and improved EOL care.

PMID: 28784860 [PubMed - indexed for MEDLINE]

Combining hiPSCs and Human Genetics: Major Applications in Drug Development.

Cell Stem Cell. 2017 Aug 03;21(2):161-165

Authors: Zhang J, Li H, Trounson A, Wu JC, Nioi P

Abstract
Merging iPSC models and human genetic research has opened up new avenues in understanding disease mechanisms and target biology, which facilitate exciting translation of this research to many areas of drug development. We highlight recent applications of these combined disciplines and discuss remaining challenges and potential solutions.

PMID: 28777942 [PubMed - indexed for MEDLINE]

Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice.

Sci Transl Med. 2017 Aug 02;9(401):

Authors: Selimbeyoglu A, Kim CK, Inoue M, Lee SY, Hong ASO, Kauvar I, Ramakrishnan C, Fenno LE, Davidson TJ, Wright M, Deisseroth K

Abstract
Alterations in the balance between neuronal excitation and inhibition (E:I balance) have been implicated in the neural circuit activity-based processes that contribute to autism phenotypes. We investigated whether acutely reducing E:I balance in mouse brain could correct deficits in social behavior. We used mice lacking the CNTNAP2 gene, which has been implicated in autism, and achieved a temporally precise reduction in E:I balance in the medial prefrontal cortex (mPFC) either by optogenetically increasing the excitability of inhibitory parvalbumin (PV) neurons or decreasing the excitability of excitatory pyramidal neurons. Surprisingly, both of these distinct, real-time, and reversible optogenetic modulations acutely rescued deficits in social behavior and hyperactivity in adult mice lacking CNTNAP2 Using fiber photometry, we discovered that native mPFC PV neuronal activity differed between CNTNAP2 knockout and wild-type mice. During social interactions with other mice, PV neuron activity increased in wild-type mice compared to interactions with a novel object, whereas this difference was not observed in CNTNAP2 knockout mice. Together, these results suggest that real-time modulation of E:I balance in the mouse prefrontal cortex can rescue social behavior deficits reminiscent of autism phenotypes.

PMID: 28768803 [PubMed - indexed for MEDLINE]

Conception and Management of a Poorly Understood Spectrum of Dermatologic Neoplasms: Atypical Fibroxanthoma, Pleomorphic Dermal Sarcoma, and Undifferentiated Pleomorphic Sarcoma.

Curr Treat Options Oncol. 2017 Aug;18(8):50

Authors: Soleymani T, Tyler Hollmig S

Abstract
OPINION STATEMENT: Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) tumors share many clinical, etiologic, and histologic features and likely represent components of a tumor spectrum. In dermatologic oncology, differentiating between AFX and PDS is pivotal as tumors with histological features consistent with PDS are more likely to behave in a clinically aggressive manner. Importantly, the term "pleomorphic dermal sarcoma" (PDS) is a more appropriate designation than "undifferentiated pleomorphic sarcoma" (UPS) for describing deeper, more aggressive, histologically high-grade cutaneous tumors that otherwise resemble AFX. Surgery remains the gold standard for treatment. In the setting of AFX, excision with the Mohs micrographic technique appears to offer superior tumor control rates while maintaining greater tissue preservation over wide local excision and should be considered first line. In the setting of PDS, optimal management is less clear given the paucity of available data. However, due to its greater propensity to recur and metastasize, extirpation with complete tumor margin control appears paramount. The roles of imaging and SLNB in management and clinical outcomes of AFX and PDS are unclear given the lack of available data. In reality, these tools are unlikely to be helpful in most cases of AFX. However, in the setting of PDS, emerging literature indicates that these tumors are inherently higher risk, and thus, imaging and SLNB may be helpful in select cases. Additionally, radiation therapy may be of adjuvant benefit for these tumors when clear surgical margins cannot be obtained. While traditional chemotherapy has been largely ineffectual, the recent discovery of key oncogenetic mutations has allowed for the identification of several potential molecular drug targets that may have a therapeutic role with future study. In the unfortunate setting of metastatic disease, a multidisciplinary approach is optimal. Further studies are needed to establish definitive conclusions regarding risk stratification and best management practices.

PMID: 28762020 [PubMed - indexed for MEDLINE]

Why Gupta et al.'s critique of niche construction theory is off target.

J Genet. 2017 Jul;96(3):505-508

Authors: Feldman MW, Odling-Smee J, Laland KN

Abstract
Gupta et al., in their article in this issue ('Niche construction in evolutionary theory: the construction of an academic niche?'. doi:10.1007/s12041-017-0787-6), lament 'serious problems with the way science is being done' and suggest that 'niche construction theory exemplifies this state of affairs.' However, their aggressively confrontational but superficial critique of niche construction theory (NCT) only contributes to these problems by attacking claims that NCT does not make. This is unfortunate, as their poor scholarship has done a disservice to the evolutionary biology community through propagating misinformation.We correct Gupta et al.'s misunderstandings, stressing that NCT does not suggest that the fact that organisms engage in niche construction is neglected, nor does it make strong claims on the basis of its formal theory. Moreover, the treatment of niche construction as an evolutionary process has been highly productive, and is both theoretically and empirically well-validated.We end by reflecting on the potentially deleterious implications of their publication for evolutionary science.

PMID: 28761013 [PubMed - indexed for MEDLINE]

Piecewise convexity of artificial neural networks.

Neural Netw. 2017 Oct;94:34-45

Authors: Rister B, Rubin DL

Abstract
Although artificial neural networks have shown great promise in applications including computer vision and speech recognition, there remains considerable practical and theoretical difficulty in optimizing their parameters. The seemingly unreasonable success of gradient descent methods in minimizing these non-convex functions remains poorly understood. In this work we offer some theoretical guarantees for networks with piecewise affine activation functions, which have in recent years become the norm. We prove three main results. First, that the network is piecewise convex as a function of the input data. Second, that the network, considered as a function of the parameters in a single layer, all others held constant, is again piecewise convex. Third, that the network as a function of all its parameters is piecewise multi-convex, a generalization of biconvexity. From here we characterize the local minima and stationary points of the training objective, showing that they minimize the objective on certain subsets of the parameter space. We then analyze the performance of two optimization algorithms on multi-convex problems: gradient descent, and a method which repeatedly solves a number of convex sub-problems. We prove necessary convergence conditions for the first algorithm and both necessary and sufficient conditions for the second, after introducing regularization to the objective. Finally, we remark on the remaining difficulty of the global optimization problem. Under the squared error objective, we show that by varying the training data, a single rectifier neuron admits local minima arbitrarily far apart, both in objective value and parameter space.

PMID: 28732233 [PubMed - indexed for MEDLINE]

DTI measures identify mild and moderate TBI cases among patients with complex health problems: A receiver operating characteristic analysis of U.S. veterans.

Neuroimage Clin. 2017;16:1-16

Authors: Main KL, Soman S, Pestilli F, Furst A, Noda A, Hernandez B, Kong J, Cheng J, Fairchild JK, Taylor J, Yesavage J, Wesson Ashford J, Kraemer H, Adamson MM

Abstract
Standard MRI methods are often inadequate for identifying mild traumatic brain injury (TBI). Advances in diffusion tensor imaging now provide potential biomarkers of TBI among white matter fascicles (tracts). However, it is still unclear which tracts are most pertinent to TBI diagnosis. This study ranked fiber tracts on their ability to discriminate patients with and without TBI. We acquired diffusion tensor imaging data from military veterans admitted to a polytrauma clinic (Overall n = 109; Age: M = 47.2, SD = 11.3; Male: 88%; TBI: 67%). TBI diagnosis was based on self-report and neurological examination. Fiber tractography analysis produced 20 fiber tracts per patient. Each tract yielded four clinically relevant measures (fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity). We applied receiver operating characteristic (ROC) analyses to identify the most diagnostic tract for each measure. The analyses produced an optimal cutpoint for each tract. We then used kappa coefficients to rate the agreement of each cutpoint with the neurologist's diagnosis. The tract with the highest kappa was most diagnostic. As a check on the ROC results, we performed a stepwise logistic regression on each measure using all 20 tracts as predictors. We also bootstrapped the ROC analyses to compute the 95% confidence intervals for sensitivity, specificity, and the highest kappa coefficients. The ROC analyses identified two fiber tracts as most diagnostic of TBI: the left cingulum (LCG) and the left inferior fronto-occipital fasciculus (LIF). Like ROC, logistic regression identified LCG as most predictive for the FA measure but identified the right anterior thalamic tract (RAT) for the MD, RD, and AD measures. These findings are potentially relevant to the development of TBI biomarkers. Our methods also demonstrate how ROC analysis may be used to identify clinically relevant variables in the TBI population.

PMID: 28725550 [PubMed - indexed for MEDLINE]

Electrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery.

Biomaterials. 2017 Oct;142:31-40

Authors: George PM, Bliss TM, Hua T, Lee A, Oh B, Levinson A, Mehta S, Sun G, Steinberg GK

Abstract
Exogenous human neural progenitor cells (hNPCs) are promising stroke therapeutics, but optimal delivery conditions and exact recovery mechanisms remain elusive. To further elucidate repair processes and improve stroke outcomes, we developed an electrically conductive, polymer scaffold for hNPC delivery. Electrical stimulation of hNPCs alters their transcriptome including changes to the VEGF-A pathway and genes involved in cell survival, inflammatory response, and synaptic remodeling. In our experiments, exogenous hNPCs were electrically stimulated (electrically preconditioned) via the scaffold 1 day prior to implantation. After in vitro stimulation, hNPCs on the scaffold are transplanted intracranially in a distal middle cerebral artery occlusion rat model. Electrically preconditioned hNPCs improved functional outcomes compared to unstimulated hNPCs or hNPCs where VEGF-A was blocked during in vitro electrical preconditioning. The ability to manipulate hNPCs via a conductive scaffold creates a new approach to optimize stem cell-based therapy and determine which factors (such as VEGF-A) are essential for stroke recovery.

PMID: 28719819 [PubMed - indexed for MEDLINE]

Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification.

Mol Ther. 2017 Aug 02;25(8):1974-1987

Authors: Agarwal S, Loder SJ, Breuler C, Li J, Cholok D, Brownley C, Peterson J, Hsieh HH, Drake J, Ranganathan K, Niknafs YS, Xiao W, Li S, Kumar R, Tompkins R, Longaker MT, Davis TA, Yu PB, Mishina Y, Levi B

Abstract
Trauma-induced heterotopic ossification (tHO) is a condition of pathologic wound healing, defined by the progressive formation of ectopic bone in soft tissue following severe burns or trauma. Because previous studies have shown that genetic variants of HO, such as fibrodysplasia ossificans progressiva (FOP), are caused by hyperactivating mutations of the type I bone morphogenetic protein receptor (T1-BMPR) ACVR1/ALK2, studies evaluating therapies for HO have been directed primarily toward drugs for this specific receptor. However, patients with tHO do not carry known T1-BMPR mutations. Here we show that, although BMP signaling is required for tHO, no single T1-BMPR (ACVR1/ALK2, BMPR1a/ALK3, or BMPR1b/ALK6) alone is necessary for this disease, suggesting that these receptors have functional redundancy in the setting of tHO. By utilizing two different classes of BMP signaling inhibitors, we developed a translational approach to treatment, integrating treatment choice with existing diagnostic options. Our treatment paradigm balances either immediate therapy with reduced risk for adverse effects (Alk3-Fc) or delayed therapy with improved patient selection but greater risk for adverse effects (LDN-212854).

PMID: 28716575 [PubMed - indexed for MEDLINE]

Perspective: Improving Nutritional Guidelines for Sustainable Health Policies: Current Status and Perspectives.

Adv Nutr. 2017 Jul;8(4):532-545

Authors: Magni P, Bier DM, Pecorelli S, Agostoni C, Astrup A, Brighenti F, Cook R, Folco E, Fontana L, Gibson RA, Guerra R, Guyatt GH, Ioannidis JP, Jackson AS, Klurfeld DM, Makrides M, Mathioudakis B, Monaco A, Patel CJ, Racagni G, Schünemann HJ, Shamir R, Zmora N, Peracino A

Abstract
A large body of evidence supports the notion that incorrect or insufficient nutrition contributes to disease development. A pivotal goal is thus to understand what exactly is appropriate and what is inappropriate in food ingestion and the consequent nutritional status and health. The effective application of these concepts requires the translation of scientific information into practical approaches that have a tangible and measurable impact at both individual and population levels. The agenda for the future is expected to support available methodology in nutrition research to personalize guideline recommendations, properly grading the quality of the available evidence, promoting adherence to the well-established evidence hierarchy in nutrition, and enhancing strategies for appropriate vetting and transparent reporting that will solidify the recommendations for health promotion. The final goal is to build a constructive coalition among scientists, policy makers, and communication professionals for sustainable health and nutritional policies. Currently, a strong rationale and available data support a personalized dietary approach according to personal variables, including sex and age, circulating metabolic biomarkers, food quality and intake frequency, lifestyle variables such as physical activity, and environmental variables including one's microbiome profile. There is a strong and urgent need to develop a successful commitment among all the stakeholders to define novel and sustainable approaches toward the management of the health value of nutrition at individual and population levels. Moving forward requires adherence to well-established principles of evidence evaluation as well as identification of effective tools to obtain better quality evidence. Much remains to be done in the near future.

PMID: 28710141 [PubMed - indexed for MEDLINE]

Social norm perception in groups with outliers.

J Exp Psychol Gen. 2017 Sep;146(9):1342-1359

Authors: Dannals JE, Miller DT

Abstract
Social outliers draw a lot of attention from those inside and outside their group and yet little is known about their impact on perceptions of their group as a whole. The present studies examine how outliers influence observers' summary perceptions of a group's behavior and inferences about the group's descriptive and prescriptive norms. Across 4 studies (N = 1,718) we examine how observers perceive descriptive and prescriptive social norms in groups containing outliers of varying degrees. We find consistent evidence that observers overweight outlying behavior when judging the descriptive and prescriptive norms, but overweight outliers less as they become more extreme, especially in perceptions of the prescriptive norm. We find this pattern across norms pertaining to punctuality (Studies 1-2 and 4) and clothing formality (Study 3) and for outliers who are both prescriptively and descriptively deviant (e.g., late arrivers), as well as for outliers who are only descriptive deviants (e.g., early arrivers). We further demonstrate that observers' perceptions of the group shift in the direction of moderate outliers. This occurs because observers anchor on the outlier's behavior and adjust their recollections of nonoutlying individuals, making their inferences about the group's average behavior more extreme. (PsycINFO Database Record

PMID: 28682092 [PubMed - indexed for MEDLINE]

Benign Gynecologic Conditions of the Uterus.

Magn Reson Imaging Clin N Am. 2017 Aug;25(3):577-600

Authors: Kassam Z, Petkovska I, Wang CL, Trinh AM, Kamaya A

Abstract
In this article, the authors review the anatomy, pathophysiology, MR imaging features, and diagnostic criteria for benign uterine conditions, including adenomyosis, uterine leiomyomas, retained products of conception, and uterine arteriovenous malformations. Pearls, pitfalls, and variants are discussed for each entity as well as important imaging features that can affect management decisions.

PMID: 28668161 [PubMed - indexed for MEDLINE]

MR Imaging-Pathologic Correlation in Ovarian Cancer.

Magn Reson Imaging Clin N Am. 2017 Aug;25(3):545-562

Authors: Stein EB, Wasnik AP, Sciallis AP, Kamaya A, Maturen KE

Abstract
There are many ovarian cancer subtypes, giving rise to a range of appearances at gross pathology and magnetic resonance (MR) imaging. Certain fundamental concepts at MR, arising from underlying tissue characteristics, can provide guidance to radiologists in suggesting a diagnosis. The ability of multiparametric MR to risk stratify ovarian masses can contribute substantially to clinical decision making and patient management.

PMID: 28668159 [PubMed - indexed for MEDLINE]

Animal Models of Zika Virus.

Comp Med. 2017 Jun 01;67(3):242-252

Authors: Bradley MP, Nagamine CM

Abstract
Zika virus has garnered great attention over the last several years, as outbreaks of the disease have emerged throughout the Western Hemisphere. Until quite recently Zika virus was considered a fairly benign virus, with limited clinical severity in both people and animals. The size and scope of the outbreak in the Western Hemisphere has allowed for the identification of severe clinical disease that is associated with Zika virus infection, most notably microcephaly among newborns, and an association with Guillian-Barré syndrome in adults. This recent association with severe clinical disease, of which further analysis strongly suggested causation by Zika virus, has resulted in a massive increase in the amount of both basic and applied research of this virus. Both small and large animal models are being used to uncover the pathogenesis of this emerging disease and to develop vaccine and therapeutic strategies. Here we review the animal-model-based Zika virus research that has been performed to date.

PMID: 28662753 [PubMed - indexed for MEDLINE]

Implementation science for ambulatory care safety: a novel method to develop context-sensitive interventions to reduce quality gaps in monitoring high-risk patients.

Implement Sci. 2017 Jun 24;12(1):79

Authors: McDonald KM, Su G, Lisker S, Patterson ES, Sarkar U

Abstract
BACKGROUND: Missed evidence-based monitoring in high-risk conditions (e.g., cancer) leads to delayed diagnosis. Current technological solutions fail to close this safety gap. In response, we aim to demonstrate a novel method to identify common vulnerabilities across clinics and generate attributes for context-flexible population-level monitoring solutions for widespread implementation to improve quality.
METHODS: Based on interviews with staff in otolaryngology, pulmonary, urology, breast, and gastroenterology clinics at a large urban publicly funded health system, we applied journey mapping to co-develop a visual representation of how patients are monitored for high-risk conditions. Using a National Academies framework and context-sensitivity theory, we identified common systems vulnerabilities and developed preliminary concepts for improving the robustness for monitoring patients with high-risk conditions ("design seeds" for potential solutions). Finally, we conducted a face validity and prioritization assessment of the design seeds with the original interviewees.
RESULTS: We identified five high-risk situations for potentially consequential diagnostic delays arising from suboptimal patient monitoring. All situations related to detection of cancer (head and neck, lung, prostate, breast, and colorectal). With clinic participants we created 5 journey maps, each representing specialty clinic workflow directed at evidence-based monitoring. System vulnerabilities common to the different clinics included challenges with: data systems, communications handoffs, population-level tracking, and patient activities. Clinic staff ranked 13 design seeds (e.g., keep patient list up to date, use triggered notifications) addressing these vulnerabilities. Each design seed has unique evaluation criteria for the usefulness of potential solutions developed from the seed.
CONCLUSIONS: We identified and ranked 13 design seeds that characterize situations that clinicians described 'wake them up at night', and thus could reduce their anxiety, save time, and improve monitoring of high-risk patients. We anticipate that the design seed approach promotes robust and context-sensitive solutions to safety and quality problems because it provides a human-centered link between the experienced problem and various solutions that can be tested for viability. The study also demonstrates a novel integration of industrial and human factors methods (journey mapping, process tracing and design seeds) linked to implementation theory for use in designing interventions that anticipate and reduce implementation challenges.

PMID: 28646886 [PubMed - indexed for MEDLINE]

Reconstruction of Disrupted Extensor Mechanism After Total Knee Arthroplasty.

J Arthroplasty. 2017 Oct;32(10):3134-3140

Authors: Lim CT, Amanatullah DF, Huddleston JI, Harris AHS, Hwang KL, Maloney WJ, Goodman SB

Abstract
BACKGROUND: Disruption of the extensor mechanism after total knee arthroplasty (TKA) is a debilitating complication that results in extension lag, limited range of motion, difficulty in walking, frequent falls, and chronic pain. This study presents the clinical and radiographic results of reconstruction after extensor mechanism disruption in TKA patients.
METHODS: Consecutive patients with allograft reconstruction of extensor mechanism after TKA were identified retrospectively from an academic tertiary center for revision TKA.
RESULTS: Sixteen patients with a mean age of 61 ± 14 years at extensor mechanism reconstruction with a minimum of 2-year follow-up were included. The mean follow-up was 3.3 ± 2.2 years. Knee Society score (KSS), before and at final follow-up extension lag, range of motion, and radiographic change in patellar height were reviewed. There were statistically significant improvements between preoperative and final follow-up KSS (P < .001; KSS for pain, preoperative 40 ± 14 points to final follow-up 67 ± 15 points [P < .001]; KSS for function, preoperative 26 ± 21 points to final follow-up 48 ± 25 points [P < .001]). The extension lag was also reduced from 35° ± 16° preoperatively to 14° ± 18° (P < .001) at final follow-up. There was an average proximal patellar migration of 8 ± 10 mm. Five (31%) cases had an extensor lag of >30° or revision surgery for repeat extensor mechanism reconstruction, infection, or arthrodesis.
CONCLUSION: Our 10-year experience using allografts during extensor mechanism reconstruction demonstrates reasonable outcomes, but failures are to be anticipated in approximately one-third of patients.

PMID: 28634096 [PubMed - indexed for MEDLINE]

A Phase I/II study of suberoylanilide hydroxamic acid (SAHA) in combination with trastuzumab (Herceptin) in patients with advanced metastatic and/or local chest wall recurrent HER2-amplified breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1104).

Breast Cancer Res Treat. 2017 Sep;165(2):375-382

Authors: Goldstein LJ, Zhao F, Wang M, Swaby RF, Sparano JA, Meropol NJ, Bhalla KN, Pellegrino CM, Katherine Alpaugh R, Falkson CI, Klein P, Sledge GW

Abstract
PURPOSE: Suberoylanilide hydroxamic acid (SAHA; vorinostat), a small molecule inhibitor of histone deacetylase, attenuates signaling pathways known to confer trastuzumab resistance. A combination of SAHA and trastuzumab may be a promising strategy to improve the efficacy of trastuzumab against breast cancer. In this Phase I/II study, we evaluated the toxicity and response rate after treatment with SAHA and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with trastuzumab-resistant progressive disease.
METHODS: In Phase I, the SAHA dose was modified in cohorts of 3-6 patients to find the dose level at which 0 or 1 patients experienced a dose-limiting toxicity (DLT) during the first cycle of therapy. In the Phase II study, response to the recommended dose identified in Phase I was based on the response evaluation criteria in solid tumors. Overall survival and time to progression were also evaluated.
RESULTS: The recommended dose was determined to be 200 mg twice a day on days 1-14 and IV trastuzumab 6 mg/kg on day 1 of a 21-day cycle (n = 6). The Phase II study (n = 10) was terminated when the pre-planned efficacy evaluation found that none of the patients in the primary analysis set responded to combination SAHA and trastuzumab treatment.
CONCLUSIONS: In patients with HER2-positive metastatic breast cancer who had relapsed or progressed during trastuzumab therapy, we observed no DLTs with SAHA 200 mg twice daily combined with trastuzumab; however, there was insufficient statistical evidence that adding SAHA reversed trastuzumab resistance in these patients.

PMID: 28623430 [PubMed - indexed for MEDLINE]

Integrating NOE and RDC using sum-of-squares relaxation for protein structure determination.

J Biomol NMR. 2017 Jul;68(3):163-185

Authors: Khoo Y, Singer A, Cowburn D

Abstract
We revisit the problem of protein structure determination from geometrical restraints from NMR, using convex optimization. It is well-known that the NP-hard distance geometry problem of determining atomic positions from pairwise distance restraints can be relaxed into a convex semidefinite program (SDP). However, often the NOE distance restraints are too imprecise and sparse for accurate structure determination. Residual dipolar coupling (RDC) measurements provide additional geometric information on the angles between atom-pair directions and axes of the principal-axis-frame. The optimization problem involving RDC is highly non-convex and requires a good initialization even within the simulated annealing framework. In this paper, we model the protein backbone as an articulated structure composed of rigid units. Determining the rotation of each rigid unit gives the full protein structure. We propose solving the non-convex optimization problems using the sum-of-squares (SOS) hierarchy, a hierarchy of convex relaxations with increasing complexity and approximation power. Unlike classical global optimization approaches, SOS optimization returns a certificate of optimality if the global optimum is found. Based on the SOS method, we proposed two algorithms-RDC-SOS and RDC-NOE-SOS, that have polynomial time complexity in the number of amino-acid residues and run efficiently on a standard desktop. In many instances, the proposed methods exactly recover the solution to the original non-convex optimization problem. To the best of our knowledge this is the first time SOS relaxation is introduced to solve non-convex optimization problems in structural biology. We further introduce a statistical tool, the Cramér-Rao bound (CRB), to provide an information theoretic bound on the highest resolution one can hope to achieve when determining protein structure from noisy measurements using any unbiased estimator. Our simulation results show that when the RDC measurements are corrupted by Gaussian noise of realistic variance, both SOS based algorithms attain the CRB. We successfully apply our method in a divide-and-conquer fashion to determine the structure of ubiquitin from experimental NOE and RDC measurements obtained in two alignment media, achieving more accurate and faster reconstructions compared to the current state of the art.

PMID: 28616711 [PubMed - indexed for MEDLINE]

Learned control of inter-hemispheric connectivity: Effects on bimanual motor performance.

Hum Brain Mapp. 2017 Sep;38(9):4353-4369

Authors: Kajal DS, Braun C, Mellinger J, Sacchet MD, Ruiz S, Fetz E, Birbaumer N, Sitaram R

Abstract
Bimanual movements involve the interactions between both primary motor cortices. These interactions are assumed to involve phase-locked oscillatory brain activity referred to as inter-hemispheric functional coupling. So far, inter-hemispheric functional coupling has been investigated as a function of motor performance. These studies report mostly a negative correlation between the performance in motor tasks and the strength of functional coupling. However, correlation might not reflect a causal relationship. To overcome this limitation, we opted for an alternative approach by manipulating the strength of inter-hemispheric functional coupling and assessing bimanual motor performance as a dependent variable. We hypothesize that an increase/decrease of functional coupling deteriorates/facilitates motor performance in an out-of-phase bimanual finger-tapping task. Healthy individuals were trained to volitionally regulate functional coupling in an operant conditioning paradigm using real-time magnetoencephalography neurofeedback. During operant conditioning, two discriminative stimuli were associated with upregulation and downregulation of functional coupling. Effects of training were assessed by comparing motor performance prior to (pre-test) and after the training (post-test). Participants receiving contingent feedback learned to upregulate and downregulate functional coupling. Comparing motor performance, as indexed by the ratio of tapping speed for upregulation versus downregulation trials, no change was found in the control group between pre- and post-test. In contrast, the group receiving contingent feedback evidenced a significant decrease of the ratio implicating lower tapping speed with stronger functional coupling. Results point toward a causal role of inter-hemispheric functional coupling for the performance in bimanual tasks. Hum Brain Mapp 38:4353-4369, 2017. © 2017 Wiley Periodicals, Inc.

PMID: 28580720 [PubMed - indexed for MEDLINE]

Trends in Utilization and Cost of Cervical Spine Surgery Using the National Inpatient Sample Database, 2001 to 2013.

Spine (Phila Pa 1976). 2017 Aug 01;42(15):E906-E913

Authors: Liu CY, Zygourakis CC, Yoon S, Kliot T, Moriates C, Ratliff J, Dudley RA, Gonzales R, Mummaneni PV, Ames CP

Abstract
STUDY DESIGN: A retrospective review.
OBJECTIVE: The aim of this study was to determine national rates of cervical spine surgery and to examine factors that underlie cost variation.
SUMMARY OF BACKGROUND DATA: There has been an increase in the rate and cost of spinal surgery over the past decades, but there is little understanding of the drivers of cost variation at the national level.
METHODS: We analyzed 419,830 patients who underwent cervical spine surgery (anterior cervical fusion, posterior cervical fusion, posterior cervical decompression, combined anterior/posterior cervical fusion) for degenerative conditions in the 2001 to 2013 NIS database. We determined the rates of surgery by time and geographic region, and then created univariate and multivariate models to evaluate the effect of these factors on total hospital costs: patient age, gender, race, insurance, income, county of residence, elective versus nonelective case, length of stay, risk of mortality, severity of illness, hospital bed size, wage index, hospital type, and geographic region.
RESULTS: The most common type of cervical spine surgery was anterior fusion (80.6% of all surgeries). The national rates of all cervical spine surgery decreased slightly from 2001 to 2013 (75.34 to 72.20 per 100,000 adults), while the mean inflation-adjusted cost increased 64%, from $11,799 to $19,379, during this time period. Multivariate analyses showed that older age, male gender, black/other race, private insurance, greater risk of mortality/severity of illness, and longer length of stay were associated with higher costs. The wage index was positively correlated with cost, and hospitals in the western U.S. were 27% more expensive than those in the Northeast.
CONCLUSION: The rate of cervical spine surgery decreased slightly, while the mean case cost increased at a rate double that of inflation from 2001 to 2013. Even after controlling for patient and hospital factors including wage index, there was significant geographic variation in the cost for cervical spine surgery.
LEVEL OF EVIDENCE: 3.

PMID: 28562473 [PubMed - indexed for MEDLINE]

Correlation of Body Composition and Low Back Pain Severity in a Cross-Section of US Veterans.

J Manipulative Physiol Ther. 2017 Jun;40(5):358-364

Authors: Okamoto CS, Dunn AS, Green BN, Formolo LR, Chicoine D

Abstract
OBJECTIVE: Back pain is more prevalent in the obese, but whether back pain severity is directly correlated to obesity in veterans is unknown. We sought to determine if there was a correlation between body composition and low back pain severity in a sample of veterans. The hypothesis was that veterans with higher body mass index values would report higher low back pain severity scores.
METHODS: This study was a retrospective chart review of 1768 veterans presenting to a Veterans Affairs chiropractic clinic with a chief complaint of low back pain between January 1, 2009 and December 31, 2014. Spearman's rho was used to test for correlation between body composition as measured by body mass index and low back pain severity as measured by the Back Bournemouth Questionnaire.
RESULTS: On average, the sample was predominantly male (91%), older than 50, and overweight (36.5%) or obese (48.9%). There was no correlation between body mass index and Back Bournemouth Questionnaire scores, r = .088, p < .001.
CONCLUSIONS: The majority of veterans with low back pain in this sample were either overweight or obese. There was no correlation between body composition and low back pain severity in this sample of veterans.

PMID: 28554432 [PubMed - indexed for MEDLINE]

R-SCAN: Imaging for Pediatric Simple Febrile Seizures.

J Am Coll Radiol. 2017 Aug;14(8):1064-1066

Authors: Lee S, Fisher P, Grant GA, Porter B, Dannenberg B, Wintermark M

PMID: 28551342 [PubMed - indexed for MEDLINE]

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis.

Curr Opin Immunol. 2017 Jun;46:112-120

Authors: Weyand CM, Zeisbrich M, Goronzy JJ

Abstract
In most autoimmune diseases, a decade-long defect in self-tolerance eventually leads to clinically relevant, tissue-destructive inflammatory disease. The pathogenic potential of chronic persistent immune responses during the pre-clinical and clinical phase is ultimately linked to the bioenergetic fitness of innate and adaptive immune cells. Chronic immune cell stimulation, high cellular turn-over, structural damage to the host tissue and maladaptive wound healing, all require a reliable supply of nutrients, oxygen, and biosynthetic precursors. Here, we use the model system of rheumatoid arthritis (RA) to discuss immunometabolism from the vantage point of T-cells and macrophages that encounter fundamentally different metabolic stress scenarios in the RA host. We outline the general principle that both insufficient nutrient supply, as well as nutrient excess generate cellular stress responses and guide immune function. ATPlow, NADPHhigh, ROSlow T-cells hyperproliferate and are forced into premature senescence. ATPhigh, ROShigh macrophages dimerize the glycolytic enzyme pyruvate kinase to amplify STAT3-dependent inflammatory effector functions. A corollary of this model is that simple nutraceutical interventions will be insufficient to re-educate the immune system in RA. Instead, interference with cell-type-exclusive and differentiation-stage-dependent metabolic setpoints will be needed to reprogram arthritogenic pathways.

PMID: 28538163 [PubMed - indexed for MEDLINE]

Percentile categorization of QT interval as an approach for identifying adult patients at risk for cardiovascular death.

Heart Rhythm. 2017 Aug;14(8):1210-1216

Authors: Mohebi R, Jehan A, Grober A, Froelicher V

Abstract
BACKGROUND: The results from studies of the association of QT prolongation with cardiovascular death (CVD) have been inconsistent.
OBJECTIVE: The purpose of this study was to compare the major correction formulas to percentile values of QT for heart rate ranges as to their ability to remove the relationship of QT to heart rate and to predict CVD.
METHODS: Participants were 16,531 veterans who had an initial ECG at the Veterans Affairs Medical Center, Palo Alto, between March 31, 1987, and December 20, 1999, and were followed for CVD. The 4 major correction formulas (Bazett, Fridericia, Framingham, and Hodges) were used to correct QT interval. In addition, the percentiles for heart rate ranges as proposed by Schwartz were calculated.
RESULTS: During median follow-up of 17.8 years, 455 CVD events occurred. When compared to the other equations, QTc Bazett had the greatest dependence on heart rate (R2 = 0.18). The hazard ratio (95% confidence interval) for CVD was 2.08 (1.28-3.9) for the 98th percentile of QT interval by heart rate ranges, 2.05 (1.27-3.33) for QTc Bazett, 1.39 (0.44-4.34) for QTc Fridericia, 1.05 (0.26-4.24) for QTc Hodges, and 1.12 (0.28-4.52) for QTc Framingham. The hazard ratio of QTc Bazett was significantly higher than the other formulas except for the 98th percentile method.
CONCLUSION: The Framingham, Hodges, and Fridericia equations remove the effect of heart rate on QT interval significantly better than the Bazett equation. Using QT-interval percentiles based on heart rate provides a consistent approach both for identifying those whose QT intervals prolong due to drugs or other stressors and for assessing CVD risk.

PMID: 28495651 [PubMed - indexed for MEDLINE]

Reply to Lazaridis and Reich: Robust model-based inference of male-biased admixture during Bronze Age migration from the Pontic-Caspian Steppe.

Proc Natl Acad Sci U S A. 2017 05 16;114(20):E3875-E3877

Authors: Goldberg A, Günther T, Rosenberg NA, Jakobsson M

PMID: 28476765 [PubMed - indexed for MEDLINE]

Biocompatible and totally disintegrable semiconducting polymer for ultrathin and ultralightweight transient electronics.

Proc Natl Acad Sci U S A. 2017 05 16;114(20):5107-5112

Authors: Lei T, Guan M, Liu J, Lin HC, Pfattner R, Shaw L, McGuire AF, Huang TC, Shao L, Cheng KT, Tok JB, Bao Z

Abstract
Increasing performance demands and shorter use lifetimes of consumer electronics have resulted in the rapid growth of electronic waste. Currently, consumer electronics are typically made with nondecomposable, nonbiocompatible, and sometimes even toxic materials, leading to serious ecological challenges worldwide. Here, we report an example of totally disintegrable and biocompatible semiconducting polymers for thin-film transistors. The polymer consists of reversible imine bonds and building blocks that can be easily decomposed under mild acidic conditions. In addition, an ultrathin (800-nm) biodegradable cellulose substrate with high chemical and thermal stability is developed. Coupled with iron electrodes, we have successfully fabricated fully disintegrable and biocompatible polymer transistors. Furthermore, disintegrable and biocompatible pseudo-complementary metal-oxide-semiconductor (CMOS) flexible circuits are demonstrated. These flexible circuits are ultrathin (<1 μm) and ultralightweight (∼2 g/m2) with low operating voltage (4 V), yielding potential applications of these disintegrable semiconducting polymers in low-cost, biocompatible, and ultralightweight transient electronics.

PMID: 28461459 [PubMed - indexed for MEDLINE]

Maternal History of Child Abuse and Obesity Risk in Offspring: Mediation by Weight in Pregnancy.

Child Obes. 2017 Aug;13(4):259-266

Authors: Leonard SA, Petito LC, Rehkopf DH, Ritchie LD, Abrams B

Abstract
BACKGROUND: Women's experience of childhood adversity may contribute to their children's risk of obesity. Possible causal pathways include higher maternal weight and gestational weight gain, which have been associated with both maternal childhood adversity and obesity in offspring.
METHODS: This study included 6718 mother-child pairs from the National Longitudinal Survey of Youth 1979 in the United States (1979-2012). We applied multiple log-binomial regression models to estimate associations between three markers of childhood adversity (physical abuse, household alcoholism, and household mental illness) and offspring obesity in childhood. We estimated natural direct effects to evaluate mediation by prepregnancy BMI and gestational weight gain.
RESULTS: Among every 100 mothers who reported physical abuse in childhood, there were 3.7 (95% confidence interval: -0.1 to 7.5) excess cases of obesity in 2- to 5-year olds compared with mothers who did not report physical abuse. Differences in prepregnancy BMI, but not gestational weight gain, accounted for 25.7% of these excess cases. There was no evidence of a similar relationship for household alcoholism or mental illness or for obesity in older children.
CONCLUSIONS: In this national, prospective cohort study, prepregnancy BMI partially explained an association between maternal physical abuse in childhood and obesity in preschool-age children. These findings underscore the importance of life-course exposures in the etiology of child obesity and the potential multi-generational consequences of child abuse. Research is needed to determine whether screening for childhood abuse and treatment of its sequelae could strengthen efforts to prevent obesity in mothers and their children.

PMID: 28440693 [PubMed - indexed for MEDLINE]

Unifying mechanism for different fibrotic diseases.

Proc Natl Acad Sci U S A. 2017 05 02;114(18):4757-4762

Authors: Wernig G, Chen SY, Cui L, Van Neste C, Tsai JM, Kambham N, Vogel H, Natkunam Y, Gilliland DG, Nolan G, Weissman IL

Abstract
Fibrotic diseases are not well-understood. They represent a number of different diseases that are characterized by the development of severe organ fibrosis without any obvious cause, such as the devastating diseases idiopathic pulmonary fibrosis (IPF) and scleroderma. These diseases have a poor prognosis comparable with endstage cancer and are uncurable. Given the phenotypic differences, it was assumed that the different fibrotic diseases also have different pathomechanisms. Here, we demonstrate that many endstage fibrotic diseases, including IPF; scleroderma; myelofibrosis; kidney-, pancreas-, and heart-fibrosis; and nonalcoholic steatohepatosis converge in the activation of the AP1 transcription factor c-JUN in the pathologic fibroblasts. Expression of the related AP1 transcription factor FRA2 was restricted to pulmonary artery hypertension. Induction of c-Jun in mice was sufficient to induce severe fibrosis in multiple organs and steatohepatosis, which was dependent on sustained c-Jun expression. Single cell mass cytometry revealed that c-Jun activates multiple signaling pathways in mice, including pAkt and CD47, which were also induced in human disease. αCD47 antibody treatment and VEGF or PI3K inhibition reversed various organ c-Jun-mediated fibroses in vivo. These data suggest that c-JUN is a central molecular mediator of most fibrotic conditions.

PMID: 28424250 [PubMed - indexed for MEDLINE]

Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis.

Proc Natl Acad Sci U S A. 2017 05 02;114(18):E3709-E3718

Authors: Kulkarni S, Micci MA, Leser J, Shin C, Tang SC, Fu YY, Liu L, Li Q, Saha M, Li C, Enikolopov G, Becker L, Rakhilin N, Anderson M, Shen X, Dong X, Butte MJ, Song H, Southard-Smith EM, Kapur RP, Bogunovic M, Pasricha PJ

Abstract
According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.

PMID: 28420791 [PubMed - indexed for MEDLINE]

Neurophysiological dynamics of phrase-structure building during sentence processing.

Proc Natl Acad Sci U S A. 2017 05 02;114(18):E3669-E3678

Authors: Nelson MJ, El Karoui I, Giber K, Yang X, Cohen L, Koopman H, Cash SS, Naccache L, Hale JT, Pallier C, Dehaene S

Abstract
Although sentences unfold sequentially, one word at a time, most linguistic theories propose that their underlying syntactic structure involves a tree of nested phrases rather than a linear sequence of words. Whether and how the brain builds such structures, however, remains largely unknown. Here, we used human intracranial recordings and visual word-by-word presentation of sentences and word lists to investigate how left-hemispheric brain activity varies during the formation of phrase structures. In a broad set of language-related areas, comprising multiple superior temporal and inferior frontal sites, high-gamma power increased with each successive word in a sentence but decreased suddenly whenever words could be merged into a phrase. Regression analyses showed that each additional word or multiword phrase contributed a similar amount of additional brain activity, providing evidence for a merge operation that applies equally to linguistic objects of arbitrary complexity. More superficial models of language, based solely on sequential transition probability over lexical and syntactic categories, only captured activity in the posterior middle temporal gyrus. Formal model comparison indicated that the model of multiword phrase construction provided a better fit than probability-based models at most sites in superior temporal and inferior frontal cortices. Activity in those regions was consistent with a neural implementation of a bottom-up or left-corner parser of the incoming language stream. Our results provide initial intracranial evidence for the neurophysiological reality of the merge operation postulated by linguists and suggest that the brain compresses syntactically well-formed sequences of words into a hierarchy of nested phrases.

PMID: 28416691 [PubMed - indexed for MEDLINE]

Drebrin restricts rotavirus entry by inhibiting dynamin-mediated endocytosis.

Proc Natl Acad Sci U S A. 2017 05 02;114(18):E3642-E3651

Authors: Li B, Ding S, Feng N, Mooney N, Ooi YS, Ren L, Diep J, Kelly MR, Yasukawa LL, Patton JT, Yamazaki H, Shirao T, Jackson PK, Greenberg HB

Abstract
Despite the wide administration of several effective vaccines, rotavirus (RV) remains the single most important etiological agent of severe diarrhea in infants and young children worldwide, with an annual mortality of over 200,000 people. RV attachment and internalization into target cells is mediated by its outer capsid protein VP4. To better understand the molecular details of RV entry, we performed tandem affinity purification coupled with high-resolution mass spectrometry to map the host proteins that interact with VP4. We identified an actin-binding protein, drebrin (DBN1), that coprecipitates and colocalizes with VP4 during RV infection. Importantly, blocking DBN1 function by siRNA silencing, CRISPR knockout (KO), or chemical inhibition significantly increased host cell susceptibility to RV infection. Dbn1 KO mice exhibited higher incidence of diarrhea and more viral antigen shedding in their stool samples compared with the wild-type littermates. In addition, we found that uptake of other dynamin-dependent cargos, including transferrin, cholera toxin, and multiple viruses, was also enhanced in DBN1-deficient cells. Inhibition of cortactin or dynamin-2 abrogated the increased virus entry observed in DBN1-deficient cells, suggesting that DBN1 suppresses dynamin-mediated endocytosis via interaction with cortactin. Our study unveiled an unexpected role of DBN1 in restricting the entry of RV and other viruses into host cells and more broadly to function as a crucial negative regulator of diverse dynamin-dependent endocytic pathways.

PMID: 28416666 [PubMed - indexed for MEDLINE]

Regarding 'Advances of optical coherence tomography in myopia and pathologic myopia'.

Eye (Lond). 2017 07;31(7):1114-1115

Authors: Wood EH, Powers MA, Sanislo SR, Gaynon MW

PMID: 28282059 [PubMed - indexed for MEDLINE]

Mechanism and bottlenecks in strand photodissociation of split green fluorescent proteins (GFPs).

Proc Natl Acad Sci U S A. 2017 03 14;114(11):E2146-E2155

Authors: Lin CY, Both J, Do K, Boxer SG

Abstract
Split GFPs have been widely applied for monitoring protein-protein interactions by expressing GFPs as two or more constituent parts linked to separate proteins that only fluoresce on complementing with one another. Although this complementation is typically irreversible, it has been shown previously that light accelerates dissociation of a noncovalently attached β-strand from a circularly permuted split GFP, allowing the interaction to be reversible. Reversible complementation is desirable, but photodissociation has too low of an efficiency (quantum yield <1%) to be useful as an optogenetic tool. Understanding the physical origins of this low efficiency can provide strategies to improve it. We elucidated the mechanism of strand photodissociation by measuring the dependence of its rate on light intensity and point mutations. The results show that strand photodissociation is a two-step process involving light-activated cis-trans isomerization of the chromophore followed by light-independent strand dissociation. The dependence of the rate on temperature was then used to establish a potential energy surface (PES) diagram along the photodissociation reaction coordinate. The resulting energetics-function model reveals the rate-limiting process to be the transition from the electronic excited-state to the ground-state PES accompanying cis-trans isomerization. Comparisons between split GFPs and other photosensory proteins, like photoactive yellow protein and rhodopsin, provide potential strategies for improving the photodissociation quantum yield.

PMID: 28242710 [PubMed - indexed for MEDLINE]

Long Noncoding RNAs: At the Intersection of Cancer and Chromatin Biology.

Cold Spring Harb Perspect Med. 2017 Jul 05;7(7):

Authors: Schmitt AM, Chang HY

Abstract
Although only 2% of the genome encodes protein, RNA is transcribed from the majority of the genetic sequence, suggesting a massive degree of cellular functionality is programmed in the noncoding genome. The mammalian genome contains tens of thousands of long noncoding RNAs (lncRNAs), many of which occur at disease-associated loci or are specifically expressed in cancer. Although the vast majority of lncRNAs have no known function, recurring molecular mechanisms for lncRNAs are now being observed in chromatin regulation and cancer pathways and emerging technologies are now providing tools to interrogate lncRNA molecular interactions and determine function of these abundant cellular macromolecules.

PMID: 28193769 [PubMed - indexed for MEDLINE]

Comparing Chalk With Cheese-The EGG Contact Quotient Is Only a Limited Surrogate of the Closed Quotient.

J Voice. 2017 Jul;31(4):401-409

Authors: Herbst CT, Schutte HK, Bowling DL, Svec JG

Abstract
The electroglottographic (EGG) contact quotient (CQegg), an estimate of the relative duration of vocal fold contact per vibratory cycle, is the most commonly used quantitative analysis parameter in EGG. The purpose of this study is to quantify the CQegg's relation to the closed quotient, a measure more directly related to glottal width changes during vocal fold vibration and the respective sound generation events. Thirteen singers (six females) phonated in four extreme phonation types while independently varying the degree of breathiness and vocal register. EGG recordings were complemented by simultaneous videokymographic (VKG) endoscopy, which allows for calculation of the VKG closed quotient (CQvkg). The CQegg was computed with five different algorithms, all used in previous research. All CQegg algorithms produced CQegg values that clearly differed from the respective CQvkg, with standard deviations around 20% of cycle duration. The difference between CQvkg and CQegg was generally greater for phonations with lower CQvkg. The largest differences were found for low-quality EGG signals with a signal-to-noise ratio below 10 dB, typically stemming from phonations with incomplete glottal closure. Disregarding those low-quality signals, we found the best match between CQegg and CQvkg for a CQegg algorithm operating on the first derivative of the EGG signal. These results show that the terms "closed quotient" and "contact quotient" should not be used interchangeably. They relate to different physiological phenomena. Phonations with incomplete glottal closure having an EGG signal-to-noise ratio below 10 dB are not suited for CQegg analysis.

PMID: 28017461 [PubMed - indexed for MEDLINE]

Endoscopic detection of cancer with lensless radioluminescence imaging and machine vision.

Sci Rep. 2016 08 01;6:30737

Authors: Türkcan S, Naczynski DJ, Nolley R, Sasportas LS, Peehl DM, Pratx G

Abstract
Complete removal of residual tumor tissue during surgical resection improves patient outcomes. However, it is often difficult for surgeons to delineate the tumor beyond its visible boundary. This has led to the development of intraoperative detectors that can image radiotracers accumulated within tumors, thus facilitating the removal of residual tumor tissue during surgical procedures. We introduce a beta imaging system that converts the beta radiation from the radiotracer into photons close to the decay origin through a CdWO4 scintillator and does not use any optical elements. The signal is relayed onto an EMCCD chip through a wound imaging fiber. The sensitivity of the device allows imaging of activity down to 100 nCi and the system has a resolution of at least 500 μm with a field of view of 4.80 × 6.51 mm. Advances in handheld beta cameras have focused on hardware improvements, but we apply machine vision to the recorded images to extract more information. We automatically classify sample regions in human renal cancer tissue ex-vivo into tumor or benign tissue based on image features. Machine vision boosts the ability of our system to distinguish tumor from healthy tissue by a factor of 9 ± 3 and can be applied to other beta imaging probes.

PMID: 27477912 [PubMed - indexed for MEDLINE]

Changing Polygenic Penetrance on Phenotypes in the 20(th) Century Among Adults in the US Population.

Sci Rep. 2016 07 26;6:30348

Authors: Conley D, Laidley TM, Boardman JD, Domingue BW

Abstract
This study evaluates changes in genetic penetrance-defined as the association between an additive polygenic score and its associated phenotype-across birth cohorts. Situating our analysis within recent historical trends in the U.S., we show that, while height and BMI show increasing genotypic penetrance over the course of 20(th) Century, education and heart disease show declining genotypic effects. Meanwhile, we find genotypic penetrance to be historically stable with respect to depression. Our findings help inform our understanding of how the genetic and environmental landscape of American society has changed over the past century, and have implications for research which models gene-environment (GxE) interactions, as well as polygenic score calculations in consortia studies that include multiple birth cohorts.

PMID: 27456657 [PubMed - indexed for MEDLINE]

I Carry Your Heart.

JAMA Cardiol. 2016 05 01;1(2):213-5

Authors: Verghese A

PMID: 27437895 [PubMed - indexed for MEDLINE]

Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial.

JAMA Cardiol. 2016 05 01;1(2):163-71

Authors: Hammond HK, Penny WF, Traverse JH, Henry TD, Watkins MW, Yancy CW, Sweis RN, Adler ED, Patel AN, Murray DR, Ross RS, Bhargava V, Maisel A, Barnard DD, Lai NC, Dalton ND, Lee ML, Narayan SM, Blanchard DG, Gao MH

Abstract
IMPORTANCE: Gene transfer has rarely been tested in randomized clinical trials.
OBJECTIVE: To evaluate the safety and efficacy of intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled, phase 2 clinical trial was conducted in US medical centers (randomization occurred from July 19, 2010, to October 30, 2014). Participants 18 to 80 years with symptomatic heart failure (ischemic and nonischemic) and an ejection fraction (EF) of 40% or less were screened; 86 individuals were enrolled, and 56 were randomized. Data analysis was of the intention-to-treat population. Participants underwent exercise testing and measurement of left ventricular EF (echocardiography) and then cardiac catheterization, where left ventricular pressure development (+dP/dt) and decline (-dP/dt) were recorded. Participants were randomized (3:1 ratio) to receive 1 of 5 doses of intracoronary Ad5.hAC6 or placebo. Participants underwent a second catheterization 4 weeks later for measurement of dP/dt. Exercise testing and EF were assessed 4 and 12 weeks after randomization.
INTERVENTIONS: Intracoronary administration of Ad5.hAC6 (3.2 × 109 to 1012 virus particles) or placebo.
MAIN OUTCOMES AND MEASURES: Primary end points included exercise duration and EF before and 4 and 12 weeks after randomization and peak rates of +dP/dt and -dP/dt before and 4 weeks after randomization. Fourteen placebo participants were compared (intention to treat) with 24 Ad5.hAC6 participants receiving the highest 2 doses (D4 + 5).
RESULTS: Fifty-six individuals were randomized and monitored for up to 1 year. Forty-two participants (75%) received Ad5.hAC6 (mean [SE] age, 63 [1] years; EF, 30% [1%]), and 14 individuals (25%) received placebo (age, 62 [1] years; EF, 30% [2%]). Exercise duration showed no significant group differences (4 weeks, P = .27; 12 weeks, P = .47, respectively). The D4 + 5 participants had increased EF at 4 weeks (+6.0 [1.7] EF units; n = 21; P < .004), but not 12 weeks (+3.0 [2.4] EF units; n = 21; P = .16). Placebo participants showed no increase in EF at 4 weeks or 12 weeks. Exercise duration showed no between-group differences (4-week change from baseline: placebo, 27 [36] seconds; D4 + 5, 44 [25] seconds; P = .27; 12-week change from baseline: placebo, 44 [28] seconds; D4 + 5, 58 [29 seconds, P = .47). AC6 gene transfer increased basal left ventricular peak -dP/dt (4-week change from baseline: placebo, +93 [51] mm Hg/s; D4 + 5, -39 [33] mm Hg/s; placebo [n = 21]; P < .03); AC6 did not increase arrhythmias. The admission rate for patients with heart failure was 9.5% (4 of 42) in the AC6 group and 28.6% (4 of 14) in the placebo group (relative risk, 0.33 [95% CI, 0.08-1.36]; P = .10).
CONCLUSIONS AND RELEVANCE: AC6 gene transfer safely increased LV function beyond standard heart failure therapy, attainable with one-time administration. Larger trials are warranted.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00787059.

PMID: 27437887 [PubMed - indexed for MEDLINE]

Multiplex giant magnetoresistive biosensor microarrays identify interferon-associated autoantibodies in systemic lupus erythematosus.

Sci Rep. 2016 06 09;6:27623

Authors: Lee JR, Haddon DJ, Wand HE, Price JV, Diep VK, Hall DA, Petri M, Baechler EC, Balboni IM, Utz PJ, Wang SX

Abstract
High titer, class-switched autoantibodies are a hallmark of systemic lupus erythematosus (SLE). Dysregulation of the interferon (IFN) pathway is observed in individuals with active SLE, although the association of specific autoantibodies with chemokine score, a combined measurement of three IFN-regulated chemokines, is not known. To identify autoantibodies associated with chemokine score, we developed giant magnetoresistive (GMR) biosensor microarrays, which allow the parallel measurement of multiple serum antibodies to autoantigens and peptides. We used the microarrays to analyze serum samples from SLE patients and found individuals with high chemokine scores had significantly greater reactivity to 13 autoantigens than individuals with low chemokine scores. Our findings demonstrate that multiple autoantibodies, including antibodies to U1-70K and modified histone H2B tails, are associated with IFN dysregulation in SLE. Further, they show the microarrays are capable of identifying autoantibodies associated with relevant clinical manifestations of SLE, with potential for use as biomarkers in clinical practice.

PMID: 27279139 [PubMed - indexed for MEDLINE]

Using Item Response Theory to Develop Measures of Acquisitive and Protective Self-Monitoring From the Original Self-Monitoring Scale.

Assessment. 2017 Jul;24(5):677-691

Authors: Wilmot MP, Kostal JW, Stillwell D, Kosinski M

Abstract
For the past 40 years, the conventional univariate model of self-monitoring has reigned as the dominant interpretative paradigm in the literature. However, recent findings associated with an alternative bivariate model challenge the conventional paradigm. In this study, item response theory is used to develop measures of the bivariate model of acquisitive and protective self-monitoring using original Self-Monitoring Scale (SMS) items, and data from two large, nonstudent samples ( Ns = 13,563 and 709). Results indicate that the new acquisitive (six-item) and protective (seven-item) self-monitoring scales are reliable, unbiased in terms of gender and age, and demonstrate theoretically consistent relations to measures of personality traits and cognitive ability. Additionally, by virtue of using original SMS items, previously collected responses can be reanalyzed in accordance with the alternative bivariate model. Recommendations for the reanalysis of archival SMS data, as well as directions for future research, are provided.

PMID: 26603117 [PubMed - indexed for MEDLINE]