WashU weekly Neuroscience publications

Perioperative gabapentin and post cesarean pain control: A systematic review and meta-analysis of randomized controlled trials
(2019) European Journal of Obstetrics Gynecology and Reproductive Biology, 233, pp. 98-106. 

Felder, L.^a , Saccone, G.^b , Scuotto, S.^c , Monks, D.T.^d , Carvalho, J.C.A.^e , Zullo, F.^b , Berghella, V.^f

^a Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, United States
^b Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
^c Department of Anesthesiology, School of Medicine, University of Siena, Siena, Italy
^d Department of Anesthesia, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Anesthesia and Pain Management, Mount Sinai Hospital, University of Toronto, Toronto, Canada
^f Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, United States

Abstract
Cesarean delivery occurs in roughly one third of pregnancies. Effective postoperative pain control is a goal for patients and physicians. Limiting opioid use in this period is important as some percentage of opioid naïve individuals will develop persistent use. Gabapentin is a non-opioid medication that has been used perioperatively to improve postoperative pain and limit opioid requirements. The goal of this study is to determine the efficacy of perioperative gabapentin in improving post cesarean delivery pain control. The following data sources were searched from their inception through October 2018: MEDLINE, Ovid, ClinicalTrials.gov, Sciencedirect, and the Cochrane Library at the CENTRAL Register of Controlled Trials. A systematic review of the literature was performed to include all randomized trials examining the effect of perioperative gabapentin on post cesarean delivery pain control and other postoperative outcomes. The primary outcome was analgesic effect of gabapentin on post cesarean delivery pain, measured by visual analog scale (VAS; 0–100) or Numerical Rating Scale (NRS; 0–10) on movement 24 h postoperative. These scores were directly compared by multiplying all NRS scores by a factor of 10. Meta-analysis was performed using the random effects model of DerSimonian and Laird, to produce summary treatment effects in terms of mean difference (MD) with 95% confidence interval (CI). Six placebo controlled trials (n = 645) were identified as relevant and included in the meta-analysis. All studies included only healthy pregnant women (American Society of Anesthesiologist (ASA) physical status I or II) undergoing spinal anesthesia for cesarean delivery at term. Participants were randomized to either 600 mg oral gabapentin or placebo preoperatively and in one study the medications were also continued postoperatively. Pooled data showed that women who received gabapentin prior to cesarean delivery had significantly lower VAS pain scores at 24 h after movement (MD -11.58, 95% CI -23.04 to -0.12). VAS pain scores at other time intervals at rest or after movement were not significantly different for those who received gabapentin and placebo although there was a general trend toward lower pain scores for women receiving gabapentin. There was no significant between-group difference in use of additional pain medications, supplemental opioids, and maternal or neonatal side effects. There was higher pain control satisfaction at 12 and 24 h in the gabapentin versus placebo groups. © 2018 Elsevier B.V.

Author Keywords
Cesarean delivery;  Gabapentin;  Postoperative pain control

Document Type: Review
Publication Stage: Final
Source: Scopus

Clinical and Psychosocial Characteristics of Young Children With Suicidal Ideation, Behaviors, and Nonsuicidal Self-Injurious Behaviors
(2019) Journal of the American Academy of Child and Adolescent Psychiatry, 58 (1), pp. 117-127. Cited 1 time.

Luby, J.L., Whalen, D., Tillman, R., Barch, D.M.

Washington University in St. LouisMO, United States

Abstract
Objective: Based on previous findings that suicidal ideation (SI) and behavior (SB) arose in depressed preschoolers and showed stability into school age, we sought to investigate whether unique clinical and psychosocial correlates of SI/SB and nonsuicidal self-injurious behaviors (NSSI) could be identified in young children recuited into a depression treatment study and healthy controls. Method: Data from 288 children 3.0 to 6.11 years of age who were recruited for participation in a psychotherapy treatment study of depression and 26 healthy control subjects (total N = 314) were used. At baseline, subjects received a comprehensive assessment of psychopathology and suicidal ideation/suicidal behavior. Multinominal logistic regressions were conducted comparing those with no SI/SB/NSSI to those with SI/SB or NSSI. Those with SI/SB who also had NSSI were placed in the SI/SB group. Results: In this sample of young children, the rates of NSSI, SI, and SB were 21.3%, 19.1%, and 3.5% respectively. Children with SI/SB or NSSI experienced a greater frequency of violent life events than children with no SI/SB/NSSI. Children with SI/SB had significantly more preoccupation with death compared to subjects with NSSI and subjects with no SI/SB/NSSI. Children with SI/SB had more vegetative signs of depression and greater depression severity, and those with NSSI were more irritable with higher depression severity than those with no SI/SB/NSSI. Conclusion: Distinct characteristics of SI/SB and NSSI in early childhood were identified, informing high risk subgroups. Findings suggest that clinicians should be aware of the potential for SI/SB and/or NSSI in young children and should directly address these symptoms in clinical interviews. Clinical trial registration information: A Randomized Controlled Trial of PCIT-ED for Preschool Depression. https://clinicaltrials.gov/; NCT02076425. © 2018 American Academy of Child and Adolescent Psychiatry

Author Keywords
depression;  risk;  suicidality;  young children

Document Type: Article
Publication Stage: Final
Source: Scopus

Exercise and Parkinson Disease: Comparing Tango, Treadmill, and Stretching
(2019) Journal of neurologic physical therapy : JNPT, 43 (1), pp. 26-32. 

Rawson, K.S., McNeely, M.E., Duncan, R.P., Pickett, K.A., Perlmutter, J.S., Earhart, G.M.

Program in Physical Therapy (K.S.R., M.E.M., R.P.D., J.S.P., G.M.E.), Department of Neurology (M.E.M., R.P.D., J.S.P., G.M.E.), Department of Neuroscience (J.S.P., G.M.E.), Department of Radiology (J.S.P.), and Program in Occupational Therapy (J.S.P.), Washington University School of Medicine in Saint Louis, Missouri; and Department of Kinesiology and Occupational Therapy Program, University of Wisconsin-Madison (K.A.P.)

Abstract
BACKGROUND AND PURPOSE: Impaired gait, balance, and motor function are common in Parkinson disease (PD) and may lead to falls and injuries. Different forms of exercise improve motor function in persons with PD, but determining which form of exercise is most effective requires a direct comparison of various approaches. In this prospective, controlled trial, we evaluated the impact of tango, treadmill walking, and stretching on gait, balance, motor function, and quality of life. We hypothesized tango and treadmill would improve forward walking and motor symptom severity, and tango would also improve backward walking, balance, and quality of life. METHODS: Ninety-six participants (age: 67.2 ± 8.9 years, 42% female) with mild to moderate idiopathic PD were serially assigned to tango, treadmill walking, or stretching (active control group) and attended 1-hour classes twice weekly for 12 weeks. Assessments occurred OFF anti-PD medication before and after the intervention and at follow-up 12 weeks after the intervention. RESULTS: Forward velocity and backward velocity improved for the treadmill group from baseline to posttest and improvements persisted at follow-up. Backward velocity and motor functioning improved for the stretching group from baseline to posttest, but results did not persist at follow-up. There were no significant changes in the tango group across time points. DISCUSSION AND CONCLUSIONS: Contrary to our hypotheses, only treadmill improved forward walking, while backward walking improved with treadmill and stretching. Future research should examine combinations of exercises with a focus on optimizing dosing and examining whether specific characteristics of people with PD correlate with different types of exercise.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A237).

Document Type: Article
Publication Stage: Final
Source: Scopus

Outcomes of children with severe traumatic brain injury
(2019) The Lancet. Child & adolescent health, 3 (1), pp. 3-4. 

Pineda, J.A.

Department of Pediatrics and Neurology, Washington University School of Medicine, St Louis, MO 63110, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

Evolving and Expanding the Roles of Mitophagy as a Homeostatic and Pathogenic Process
(2019) Physiological reviews, 99 (1), pp. 853-892. 

Gustafsson, ÅB., Dorn, G.W., 2nd

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego , La Jolla, California ; and Washington University School of Medicine, St. Louis, Missouri

Abstract
The central functions fulfilled by mitochondria as both energy generators essential for tissue homeostasis and gateways to programmed apoptotic and necrotic cell death mandate tight control over the quality and quantity of these ubiquitous endosymbiotic organelles. Mitophagy, the targeted engulfment and destruction of mitochondria by the cellular autophagy apparatus, has conventionally been considered as the mechanism primarily responsible for mitochondrial quality control. However, our understanding of how, why, and under what specific conditions mitophagy is activated has grown tremendously over the past decade. Evidence is accumulating that nonmitophagic mitochondrial quality control mechanisms are more important to maintaining normal tissue homeostasis whereas mitophagy is an acute tissue stress response. Moreover, previously unrecognized mitophagic regulation of mitochondrial quantity control, metabolic reprogramming, and cell differentiation suggests that the mechanisms linking genetic or acquired defects in mitophagy to neurodegenerative and cardiovascular diseases or cancer are more complex than simple failure of normal mitochondrial quality control. Here, we provide a comprehensive overview of mitophagy in cellular homeostasis and disease and examine the most revolutionary concepts in these areas. In this context, we discuss evidence that atypical mitophagy and nonmitophagic pathways play central roles in mitochondrial quality control, functioning that was previously considered to be the primary domain of mitophagy.

Document Type: Article
Publication Stage: Final
Source: Scopus

Pain Wars: A New Hope
(2018) Neuron, 100 (6), pp. 1280-1282. 

Parker, K.E.^a , Bruchas, M.R.^{a b}

^a Department of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St. Louis, MO, United States
^b Center for the Neurobiology of Addiction, Pain, and Emotion, Departments of Anesthesiology and Pain Medicine, Department of Pharmacology, University of Washington, Seattle, WA, United States

Abstract
Nociceptin opioid peptide receptor agonists interact with mu-opioid receptor agonists for pain relief. A new study by Ding et al. (2018) examines a bifunctional nociceptin- and mu-opioid receptor agonist, AT-121, that provides analgesia without physiological side effects or abuse liability, offering a promising new hope toward better analgesics. © 2018 Elsevier Inc.

Nociceptin opioid peptide receptor agonists interact with mu-opioid receptor agonists for pain relief. A new study by Ding et al. (2018) examines a bifunctional nociceptin- and mu-opioid receptor agonist, AT-121, that provides analgesia without physiological side effects or abuse liability, offering a promising new hope toward better analgesics. © 2018 Elsevier Inc.

Document Type: Short Survey
Publication Stage: Final
Source: Scopus

Using Patient-reported Outcomes Measurement Information System Measures to Understand the Relationship Between Improvement in Physical Function and Depressive Symptoms
(2018) The Journal of the American Academy of Orthopaedic Surgeons, 26 (24), pp. e511-e518. 

Beleckas, C.M., Guattery, J., Chamberlain, A.M., Khan, T., Kelly, M.P., Calfee, R.P.

From Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
INTRODUCTION: This investigation determined whether improved physical function and decreased pain would reduce depressive symptoms using the Patient-reported Outcomes Measurement Information System (PROMIS). METHODS: This cohort study analyzed PROMIS Depression, Physical Function, and Pain Interference CAT scores from 3,339 patients presenting to a tertiary orthopaedic center. Patients demonstrating at least a-five point (effect size, 0.5) improvement in PROMIS Physical Function between consecutive visits were eligible for inclusion. RESULTS: Patients presented, on average, with Physical Function and Pain Interference scores nearly one SD worse than population averages and Depression scores that approximated the normal population. Improved Physical Function and Pain Interference scores demonstrated no correlation with change in Depression scores (r = -0.13; r = 0.25). CONCLUSION: Substantial early improvement in PROMIS Physical Function scores is not associated with change in PROMIS Depression scores. PROMIS Depression scores likely reflect underlying mental health rather than situational depressive symptoms. LEVEL OF EVIDENCE: Prognostic, level III.

Document Type: Article
Publication Stage: Final
Source: Scopus

Clinical use of a home sleep apnea test: An updated American academy of sleep medicine position statement
(2018) Journal of Clinical Sleep Medicine, 14 (12), pp. 2075-2077. 

Rosen, I.M.^a , Kirsch, D.B.^b , Carden, K.A.^c , Malhotra, R.K.^d , Ramar, K.^e , Aurora, R.N.^f , Kristo, D.A.^g , Martin, J.L.^{h i} , Olson, E.J.^e , Rosen, C.L.^j , Rowley, J.A.^k , Shelgikar, A.V.^l

^a Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Penn Sleep Center, 3624 Market Street, Suite 205, Philadelphia, PA 19104, United States
^b Carolinas Healthcare Medical Group Sleep Services, Charlotte, NC, United States
^c Saint Thomas Medical Partners – Sleep Specialists, Nashville, TN, United States
^d Washington University Sleep Center, St. Louis, MO, United States
^e Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, MN, United States
^f Johns Hopkins University, School of Medicine, Baltimore, MD, United States
^g University of Pittsburgh, Pittsburgh, PA, United States
^h Veteran Affairs Greater Los Angeles Healthcare System, North Hills, CA, United States
ⁱ David Geffen School of Medicine, University of California, Los Angeles, CA, United States
^j Department of Pediatrics, Case Western Reserve University, University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
^k Wayne State University, Detroit, MI, United States
^l University of Michigan Sleep Disorders Center, University of Michigan, Ann Arbor, MI, United States

Abstract
The diagnosis and effective treatment of obstructive sleep apnea (OSA) in adults is an urgent health priority. It is the position of the American Academy of Sleep Medicine (AASM) that only a medical provider can diagnose medical conditions such as OSA and primary snoring. Throughout this statement, the term “medical provider” refers to a licensed physician and any other health care professional who is licensed to practice medicine in accordance with state licensing laws and regulations. A home sleep apnea test (HSAT) is an alternative to polysomnography for the diagnosis of OSA in uncomplicated adults presenting with signs and symptoms that indicate an increased risk of moderate to severe OSA. It is also the position of the AASM that: the need for, and appropriateness of, an HSAT must be based on the patient’s medical history and a face-to-face examination by a medical provider, either in person or via telemedicine; an HSAT is a medical assessment that must be ordered by a medical provider to diagnose OSA or evaluate treatment efficacy; an HSAT should not be used for general screening of asymptomatic populations; diagnosis, assessment of treatment efficacy, and treatment decisions must not be based solely on automatically scored HSAT data, which could lead to sub-optimal care that jeopardizes patient health and safety; and the raw data from the HSAT device must be reviewed and interpreted by a physician who is either board-certified in sleep medicine or overseen by a board-certified sleep medicine physician. © 2018 American Academy of Sleep Medicine. All rights reserved.

Author Keywords
Home sleep apnea test;  HSAT;  Obstructive sleep apnea;  OSA

Document Type: Article
Publication Stage: Final
Source: Scopus

Aberrant structural and functional connectivity and neurodevelopmental impairment in preterm children
(2018) Journal of Neurodevelopmental Disorders, 10 (1), art. no. 38, . Cited 1 time.

Rogers, C.E.^a , Lean, R.E.^b , Wheelock, M.D.^b , Smyser, C.D.^c

^a Departments of Psychiatry and Pediatrics, Washington University, School of Medicine, Campus Box 8504, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^b Departments of Psychiatry, Washington University, School of Medicine, Campus Box 8504, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^c Departments of Neurology, Pediatrics and Mallinckrodt Institute of Radiology, Washington University, School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Background: Despite advances in antenatal and neonatal care, preterm birth remains a leading cause of neurological disabilities in children. Infants born prematurely, particularly those delivered at the earliest gestational ages, commonly demonstrate increased rates of impairment across multiple neurodevelopmental domains. Indeed, the current literature establishes that preterm birth is a leading risk factor for cerebral palsy, is associated with executive function deficits, increases risk for impaired receptive and expressive language skills, and is linked with higher rates of co-occurring attention deficit hyperactivity disorder, anxiety, and autism spectrum disorders. These same infants also demonstrate elevated rates of aberrant cerebral structural and functional connectivity, with persistent changes evident across advanced magnetic resonance imaging modalities as early as the neonatal period. Emerging findings from cross-sectional and longitudinal investigations increasingly suggest that aberrant connectivity within key functional networks and white matter tracts may underlie the neurodevelopmental impairments common in this population. Main body: This review begins by highlighting the elevated rates of neurodevelopmental disorders across domains in this clinical population, describes the patterns of aberrant structural and functional connectivity common in prematurely-born infants and children, and then reviews the increasingly established body of literature delineating the relationship between these brain abnormalities and adverse neurodevelopmental outcomes. We also detail important, typically understudied, clinical, and social variables that may influence these relationships among preterm children, including heritability and psychosocial risks. Conclusion: Future work in this domain should continue to leverage longitudinal evaluations of preterm infants which include both neuroimaging and detailed serial neurodevelopmental assessments to further characterize relationships between imaging measures and impairment, information necessary for advancing our understanding of modifiable risk factors underlying these disorders and best practices for improving neurodevelopmental trajectories in this high-risk clinical population. © 2018 The Author(s).

Author Keywords
Functional connectivity;  Magnetic resonance imaging;  Neurodevelopmental disorders;  Prematurity;  Structural connectivity

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Tau monomer encodes strains
(2018) eLife, 7, . 

Sharma, A.M.^{a b} , Thomas, T.L.^a , Woodard, D.R.^a , Kashmer, O.M.^a , Diamond, M.I.^a

^a Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States
^b Graduate Program in Biochemistry, Division of Biology and Biomedical Sciences, Washington University in St Louis, St. Louis, United States

Abstract
Tauopathies have diverse presentation, progression, and neuropathology. They are linked to tau prion strains, self-replicating assemblies of unique quaternary conformation, whose origin is unknown. Strains can be propagated indefinitely in cultured cells, and induce unique patterns of transmissible neuropathology upon inoculation into mice. DS9 and DS10 cell lines propagate different synthetic strains that derive from recombinant tau. We previously observed that tau monomer adopts two conformational states: one that is inert (Mi) and one that is seed-competent (Ms) (Mirbaha et al., 2018). We have now found that Ms itself is comprised of multiple stable ensembles that encode unique strains. DS9 monomer inoculated into naive cells encoded only DS9, whereas DS10 monomer encoded multiple sub-strains. Sub-strains each induced distinct pathology upon inoculation into a tauopathy mouse model (PS19). Ms purified from an Alzeimer’s disease brain encoded a single strain. Conversely, Ms from a corticobasal degeneration brain encoded three sub-strains, in which monomer from any one re-established all three upon inoculation into cells. Seed competent tau monomer thus adopts multiple, stable seed-competent conformations, each of which encodes a limited number of strains. This provides insight into the emergence of distinct tauopathies, and may improve diagnosis and therapy. © 2018, Sharma et al.

Author Keywords
biochemistry;  biosensor cell;  chemical biology;  mouse;  neuroscience;  prion;  strain;  Tau

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Inflammatory bowel disease and risk of Parkinson’s disease in medicare beneficiaries
(2018) Parkinsonism and Related Disorders, 57, p. 77. 

Camacho-Soto, A.^a , Searles Nielsen, S.^a , Racette, B.A.^{a b}

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Author Keywords
Inflammatory bowel disease;  Parkinson’s disease

Document Type: Letter
Publication Stage: Final
Source: Scopus

GAP junctions and NCA cation channels are critical for developmentally timed sleep and arousal in caenorhabditis elegans
(2018) Genetics, 210 (4), pp. 1369-1381. 

Huang, H.^{a f} , Hayden, D.J.^{a g} , Zhu, C.-T.^{b h} , Bennett, H.L.^{a c i} , Venkatachalam, V.^{d e j} , Skuja, L.L.^a , Hart, A.C.^a

^a Department of Neuroscience, Robert J. and Nancy D, Carney Institute for Brain Science, Brown University, Providence, RI 02912, United States
^b Department of Ecology and Evolution, Brown University, Providence, RI 02912, United States
^c Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, United States
^d Department of Physics, Harvard University, Cambridge, MA 02138, United States
^e Center for Brain Science, Harvard University, Cambridge, MA 02138, United States
^f Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
^g Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
^h Global Breeding, Bayer Crop Science, Chesterfield, MO 63017, United States
ⁱ Department of Biology, Reem-Kayden Center for Science and Computation, Bard College, Annandale-on-Hudson, NY 12504, United States
^j Department of Physics, Northeastern University, Boston, MA 02115, United States

Abstract
An essential characteristic of sleep is heightened arousal threshold, with decreased behavioral response to external stimuli. The molecular and cellular mechanisms underlying arousal threshold changes during sleep are not fully understood. We report that loss of UNC-7 or UNC-9 innexin function dramatically reduced sleep and decreased arousal threshold during developmentally timed sleep in Caenorhabditis elegans. UNC-7 function was required in premotor interneurons and UNC-9 function was required in motor neurons in this paradigm. Simultaneous transient overexpression of UNC-7 and UNC-9 was sufficient to induce anachronistic sleep in adult animals. Moreover, loss of UNC-7 or UNC-9 suppressed the increased sleep of EGL-4 gain-of-function animals, which have increased cyclic-GMP–dependent protein kinase activity. These results suggest C. elegans gap junctions may act downstream of previously identified sleep regulators. In other paradigms, the NCA cation channels act upstream of gap junctions. Consistent with this, diminished NCA channel activity in C. elegans robustly increased arousal thresholds during sleep bouts in L4-to-adult developmentally timed sleep. Total time in sleep bouts was only modestly increased in animals lacking NCA channel auxiliary subunit UNC-79, whereas increased channel activity dramatically decreased sleep. Loss of EGL-4 or innexin proteins suppressed UNC-79 loss-of-function sleep and arousal defects. In Drosophila, the ion channel narrow abdomen, an ortholog of the C. elegans NCA channels, drive the pigment dispersing factor (PDF) neuropeptide release, regulating circadian behavior. However, in C. elegans, we found that loss of the PDF receptor PDFR-1 did not suppress gain-of-function sleep defects, suggesting an alternative downstream pathway. This study emphasizes the conservation and importance of neuronal activity modulation during sleep, and unequivocally demonstrates that gap junction function is critical for normal sleep. © 2018 by the Genetics Society of America.

Author Keywords
Caenorhabditis elegans sleep;  CGMP-dependent kinase;  Gap junction;  NCA channel

Document Type: Article
Publication Stage: Final
Source: Scopus

Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks
(2018) Nature Communications, 9 (1), art. no. 5342, . 

Meister-Broekema, M.^a , Freilich, R.^b , Jagadeesan, C.^{a j} , Rauch, J.N.^b , Bengoechea, R.^c , Motley, W.W.^d , Kuiper, E.F.E.^a , Minoia, M.^a , Furtado, G.V.^{a e} , van Waarde, M.A.W.H.^a , Bird, S.J.^f , Rebelo, A.^g , Zuchner, S.^g , Pytel, P.^h , Scherer, S.S.^f , Morelli, F.F.ⁱ , Carra, S.^{a i} , Weihl, C.C.^c , Bergink, S.^a , Gestwicki, J.E.^b , Kampinga, H.H.^a

^a University Medical Center Groningen, University of Groningen, Department of Biomedical Sciences of Cell & Systems, Groningen, AV 9791, Netherlands
^b Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
^e Programa de Pós-Graduação em Genética e Biologia Molecular, Department of Genetics, Universidade Federal do Rio Grande do SulPorto Alegre, Porto Alegre, 15053, Brazil
^f Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^g Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136, United States
^h Department of Neuropathology, University of Chicago Pritzker School of Medicine, Chicago, IL 60637, United States
ⁱ Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Nanotechnology, University of Modena and Reggio Emilia Modena, Modena, 41125, Italy
^j Max Planck Institute of Biochemistry, Martinsried/Munich, 82152, Germany

Abstract
BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain. Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery. © 2018, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Distress in oncology: Not just a psychosocial phenomenon
(2018) Journal of Oncology Practice, 14 (12), pp. 699-700. 

Howrey, H.L., Vanderlan, J.R., Deshields, T.L.

Washington University School of Medicine Siteman Cancer Center at Barnes-Jewish Hospital, St Louis, MO; and Helen F Graham Cancer Center and Research Institute, Christiana Care Health System, Newark, DE, United States

Document Type: Editorial
Publication Stage: Final
Source: Scopus

Muscle atrophy in mechanically-ventilated critically ill children
(2018) PLoS ONE, 13 (12), art. no. e0207720, . 

Johnson, R.W.^a , Ng, K.W.P.^{b c} , Dietz, A.R.^{b d} , Hartman, M.E.^a , Baty, J.D.^e , Hasan, N.^f , Zaidman, C.M.^b , Shoykhet, M.^{a g}

^a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Medicine, National University, Singapore
^d Blue Sky Neurology, Englewood, CO, United States
^e Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^f St. Louis Children’s Hospital, St. Louis, MO, United States
^g Children’s Research Institute, Children’s National Medical Center, Washington, District of Columbia, United States

Abstract
Importance ICU-acquired muscle atrophy occurs commonly and worsens outcomes in adults. The incidence and severity of muscle atrophy in critically ill children are poorly characterized. Objective To determine incidence, severity and risk factors for muscle atrophy in critically ill children. Design, setting and participants A single-center, prospective cohort study of 34 children receiving invasive mechanical ventilation for 48 hours. Patients 1 week– 18 years old with respiratory failure and without preexisting neuromuscular disease or skeletal trauma were recruited from a tertiary Pediatric Intensive Care Unit (PICU) between June 2015 and May 2016. We used serial bedside ultrasound to assess thickness of the diaphragm, biceps brachii/brachialis, quadriceps femoris and tibialis anterior. Serial electrical impedance myography (EIM) was assessed in children >1 year old. Medical records were abstracted from an electronic database. Exposures Respiratory failure requiring endotracheal intubation for 48 hours. Main outcome and measures The primary outcome was percent change in muscle thickness. Secondary outcomes were changes in EIM-derived fat percentage and “quality”. Results Of 34 enrolled patients, 30 completed 2 ultrasound assessments with a median interval of 6 (IQR 6–7) days. Mean age was 5.42 years, with 12 infants <1 year (40%) and 18 children >1 year old (60%). In the entire cohort, diaphragm thickness decreased 11.1% (95%CI, -19.7% to -2.52%) between the first two assessments or 2.2%/day. Quadriceps thickness decreased 8.62% (95%CI, -15.7% to -1.54%) or 1.5%/day. Biceps (-1.71%; 95%CI, -8.15% to 4.73%) and tibialis (0.52%; 95%CI, -5.81% to 3.40%) thicknesses did not change. Among the entire cohort, 47% (14/30) experienced diaphragm atrophy (defined a priori as 10% decrease in thickness). Eighty three percent of patients (25/30) experienced atrophy in 1 muscle group, and 47% (14/30)—in 2 muscle groups. On multivariate linear regression, increasing age and traumatic brain injury (TBI) were associated with greater muscle loss. EIM revealed increased fat percentage and decreased muscle “quality”. Conclusions and relevance In children receiving invasive mechanical ventilation, diaphragm and other skeletal muscle atrophy is common and rapid. Increasing age and TBI may increase severity of limb muscle atrophy. Prospective studies are required to link muscle atrophy to functional outcomes in critically ill children. © 2018 Johnson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Variation in the management of isolated craniosynostosis: A survey of the Synostosis Research Group
(2018) Journal of Neurosurgery: Pediatrics, 22 (6), pp. 627-631. 

Kestle, J.R.W.^a , Lee, A.^b , Anderson, R.C.E.^c , Gociman, B.^d , Patel, K.B.^e , Smyth, M.D.^f , Birgfeld, C.^g , Pollack, I.F.^h , Goldstein, J.A.ⁱ , Tamber, M.^h , Imahiyerobo, T.^j , Siddiqi, F.A.^d , Synostosis Research Group^k

^a Department of Neurosurgery, Division of Pediatric Neurosurgery, Primary Children’s Hospital, University of Utah, Salt Lake City, UT, United States
^b Department of Neurological Surgery, Division of Plastic Surgery, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
^c Department of Neurological Surgery, Columbia University, Morgan Stanley Children’s Hospital of NewYork-Presbyterian, New York, NY, United States
^d Division of Plastic Surgery and Reconstructive Surgery, University of Utah, Salt Lake City, UT, United States
^e Division of Plastic and Reconstructive Surgery, Department of SurgeryMO, United States
^f Department of Neurosurgery, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Surgery, Division of Plastic Surgery, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
^h Department of Pediatric Neurosurgery, Children’s Hospital of Pittsburgh, UPMC, Pittsburgh, PA, United States
ⁱ Department of Plastic Surgery, Children’s Hospital of Pittsburgh, UPMC, Pittsburgh, PA, United States
^j Division of Plastic Surgery, Columbia University Medical Center, NewYork-Presbyterian Hospital, New York, NY, United States

Abstract
Objective: The authors created a collaborative network, the Synostosis Research Group (SynRG), to facilitate multicenter clinical research on craniosynostosis. To identify common and differing practice patterns within the network, they assessed the SynRG surgeons’ management preferences for sagittal synostosis. These results will be incorporated into planning cooperative studies. Methods: The SynRG consists of 12 surgeons at 5 clinical sites. An email survey was distributed to SynRG surgeons in late 2016, and responses were collected through early 2017. Responses were collated and analyzed descriptively. Results: All of the surgeons-7 plastic/craniofacial surgeons and 5 neurosurgeons-completed the survey. They varied in both experience (1-24 years) and sagittal synostosis case volume in the preceding year (5-45 cases). Three sites routinely perform preoperative CT scans. The preferred surgical technique for children younger than 3 months is strip craniectomy (10/12 surgeons), whereas children older than 6 months are all treated with open cranial vault surgery. Pre-incision cefazolin, preoperative complete blood count panels, and an arterial line were used by most surgeons, but tranexamic acid was used routinely at 3 sites and never at the other 2 sites. Among surgeons performing endoscopic strip craniectomy surgery (SCS), most create a 5-cm-wide craniectomy, whereas 2 surgeons create a 2-cm strip. Four surgeons routinely send endoscopic SCS patients to the intensive care unit after surgery. Two of the 5 sites routinely obtain a CT scan within the 1st year after surgery. Conclusions: The SynRG surgeons vary substantially in the use of imaging, the choice of surgical procedure and technique, and follow-up. A collaborative network will provide the opportunity to study different practice patterns, reduce variation, and contribute multicenter data on the management of children with craniosynostosis. © AANS 2018.

Author Keywords
Clinical research;  Cranial vault surgery;  Craniofacial;  Craniosynostosis;  Network;  Sagittal synostosis;  Strip craniectomy surgery;  Survey

Document Type: Review
Publication Stage: Final
Source: Scopus

Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP
(2018) Translational Psychiatry, 8 (1), art. no. 265, . 

Jiang, S.^{a b} , Wen, N.^{a b} , Li, Z.^{a b} , Dube, U.^{a b} , Del Aguila, J.^{a b} , Budde, J.^{a b} , Martinez, R.^{a b} , Hsu, S.^{a b} , Fernandez, M.V.^{a b} , Cairns, N.J.^c , Harari, O.^{a b} , Cruchaga, C.^{a b} , Karch, C.M.^{a b} , Dominantly Inherited Alzheimer Network (DIAN)^d , International FTD-Genomics Consortium (IFGC)^d

^a Department of Psychiatry, Washington University School of Medicine, 660S. Euclid Ave. Campus Box 8134, St. Louis, MO 63110, United States
^b Hope Center for Neurological Disorders, Washington University School of Medicine, 660S. Euclid Ave. Campus Box 8111, St. Louis, MO 63110, United States
^c Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, 660S. Euclid Ave, Campus Box 8118, Saint Louis, MO 63110, United States

Abstract
Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P &lt; 1 × 10−3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies. © 2018, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Epidemiology of lumbar punctures in hospitalized patients in the United States
(2018) PLoS ONE, 13 (12), art. no. e0208622, . 

Vickers, A.^a , Donnelly, J.P.^{b c} , Moore, J.X.^{b d} , Barnum, S.R.^e , Schein, T.N.^e , Wang, H.E.^{b f}

^a University of South Alabama, School of Medicine, Mobile, AL, United States
^b Department of Emergency Medicine, University of Alabama, School of Medicine, Birmingham, AL, United States
^c Department of Learning Health Sciences, University of Michigan Medical School, Ann Arbor, MI, United States
^d Department of Surgery, Washington University, School of Medicine, Saint Louis, MO, United States
^e CNine Biosolutions, LLC., Birmingham, AL, United States
^f Department of Emergency Medicine, University of Texas, Health Science Center at Houston, Houston, TX, United States

Abstract
Objectives Lumbar puncture (LP) is an important technique for assessing and treating neurological symptoms. The objective of this study was to describe the characteristics of diagnostic lumbar punctures performed on hospitalized patients in the United States. Methods We analyzed data from the 2010 National Inpatient Sample (NIS) and the National Emergency Department Survey (NEDS). We included patients treated in the Emergency Department (ED) as well as those admitted to an inpatient bed through the ED. We identified patients undergoing LPs from ICD-9 procedural code 03.31 and CPT code 62270. We generated nationally weighted estimates of the total number of LPs. We also assessed patient and hospital characteristics of cases undergoing LP. Results Of an estimated 135 million hospitalizations (ED + admission, or ED only), there were an estimated 362,718 LPs (331,248-394,188), including 273,612 (251,850-295,375) among adults and 89,106 (71,870-106,342) among children (<18 years old). Of the 362,718 LPs, 136,764 (122,117-151,410) were performed in the ED without admission. The most common conditions associated with LP among children were fever of unknown origin, meningitis, seizures and other perinatal conditions. The most common conditions associated with LP among adults were headache and meningitis. Conclusions Lumbar Puncture remains an important procedure for diagnostic and therapeutic uses in United States Hospitals. © 2018 Vickers et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Dopamine perturbation of gene co-expression networks reveals differential response in schizophrenia for translational machinery
(2018) Translational Psychiatry, 8 (1), art. no. 278, . 

Kos, M.Z.^a , Duan, J.^{b c} , Sanders, A.R.^{b c} , Blondell, L.^a , Drigalenko, E.I.^d , Carless, M.A.^d , Gejman, P.V.^{b c} , Göring, H.H.H.^a , Gejman, P.V.^f , Sanders, A.R.^f , Duan, J.^f , Levinson, D.F.^g , Shi, J.^h , Buccola, N.G.ⁱ , Mowry, B.J.^j , Freedman, R.^k , Olincy, A.^k , Amin, F.^l , Black, D.W.^m , Silverman, J.M.ⁿ , Byerley, W.F.^o , Cloninger, C.R.^p , Svrakic, D.M.^p , MGS^e

^a South Texas Diabetes and Obesity Institute, Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, San Antonio, TX, United States
^b Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, United States
^c Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
^d Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, United States
^e Molecular Genetics of Schizophrenia (MGS) Collaboration, San Antonio, TX, United States
^f NorthShore University HealthSystem, and University of Chicago, Chicago, IL, United States
^g Stanford University, Stanford, CA, United States
^h National Cancer Institute, Rockville, MD, United States
ⁱ Louisiana State University Health Sciences Center, New Orleans, LA, United States
^j Queensland Centre for Mental Health Research, Brisbane and Queensland Brain Institute, The University of Queensland, St Lucia, Australia
^k University of Colorado Denver, Denver, CO, United States
^l Atlanta Veterans Affairs Medical Center and Emory University, Atlanta, GA, United States
^m University of Iowa Carver College of Medicine, Iowa City, IA, United States
ⁿ Mount Sinai School of Medicine, New York, NY, United States
^o University of California at San Francisco, San Francisco, CA, United States
^p Washington University, St. Louis, MO, United States

Abstract
The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various oxidative species, and thus has important non-receptor-mediated effects, with empirical evidence of cellular toxicity and neurodegeneration. Here we examine non-receptor-mediated effects of DA on gene co-expression networks and its potential role in SZ pathology. Transcriptomic profiles were measured by RNA-seq in B-cell transformed lymphoblastoid cell lines from 514 SZ cases and 690 controls, both before and after exposure to DA ex vivo (100 μM). Gene co-expression modules were identified using Weighted Gene Co-expression Network Analysis for both baseline and DA-stimulated conditions, with each module characterized for biological function and tested for association with SZ status and SNPs from a genome-wide panel. We identified seven co-expression modules under baseline, of which six were preserved in DA-stimulated data. One module shows significantly increased association with SZ after DA perturbation (baseline: P = 0.023; DA-stimulated: P = 7.8 × 10-5; ΔAIC = −10.5) and is highly enriched for genes related to ribosomal proteins and translation (FDR = 4 × 10−141), mitochondrial oxidative phosphorylation, and neurodegeneration. SNP association testing revealed tentative QTLs underlying module co-expression, notably at FASTKD2 (top P = 2.8 × 10−6), a gene involved in mitochondrial translation. These results substantiate the role of translational machinery in SZ pathogenesis, providing insights into a possible dopaminergic mechanism disrupting mitochondrial function, and demonstrates the utility of disease-relevant functional perturbation in the study of complex genetic etiologies. © 2018, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Adolescent development of cortical oscillations: Power, phase, and support of cognitive maturation
(2018) PLoS biology, 16 (11), p. e2004188. 

Marek, S.^a , Tervo-Clemmens, B.^{b c} , Klein, N.^{d e} , Foran, W.^f , Ghuman, A.S.^g , Luna, B.^{b c f}

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, PA, United States
^c Department of Psychology, University of Pittsburgh, Pittsburgh, PA, United States
^d Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, United States
^e Machine Learning Department, Carnegie Mellon University, Pittsburgh, PA, United States
^f Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^g Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
During adolescence, the integration of specialized functional brain networks related to cognitive control continues to increase. Slow frequency oscillations (4-10 Hz) have been shown to support cognitive control processes, especially within prefrontal regions. However, it is unclear how neural oscillations contribute to functional brain network development and improvements in cognitive control during adolescence. To bridge this gap, we employed magnetoencephalography (MEG) to explore changes in oscillatory power and phase coupling across cortical networks in a sample of 68 adolescents and young adults. We found a redistribution of power from lower to higher frequencies throughout adolescence, such that delta band (1-3 Hz) power decreased, whereas beta band power (14-16 and 22-26 Hz) increased. Delta band power decreased with age most strongly in association networks within the frontal lobe and operculum. Conversely, beta band power increased throughout development, most strongly in processing networks and the posterior cingulate cortex, a hub of the default mode (DM) network. In terms of phase, theta band (5-9 Hz) phase-locking robustly decreased with development, following an anterior-to-posterior gradient, with the greatest decoupling occurring between association networks. Additionally, decreased slow frequency phase-locking between frontolimbic regions was related to decreased impulsivity with age. Thus, greater decoupling of slow frequency oscillations may afford functional networks greater flexibility during the resting state to instantiate control when required.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Freezing of Gait Boot Camp: feasibility, safety and preliminary efficacy of a community-based group intervention
(2018) Neurodegenerative disease management, 8 (5), pp. 307-314. 

Rawson, K.S.^a , Creel, P.^b , Templin, L.^b , Horin, A.P.^a , Duncan, R.P.^{a c} , Earhart, G.M.^{a c d}

^a Program in Physical Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO 631082, United States
^b Greater St. Louis Chapter, American Parkinson Disease Association, Chesterfield, MO 630173, United States
^c Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 631104, United States
^d Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States

Abstract
AIM: In this pilot study, we evaluated the feasibility, safety and preliminary efficacy of a 6-week, community-based group intervention designed to reduce freezing of gait (FOG) for people with Parkinson’s disease (PD). METHODS: Seven people with PD completed ‘FOG Boot Camp’ provided by the St. Louis Chapter of the American Parkinson Disease Association. We recorded attendance, participant’s acceptance of the intervention and adverse events during classes. Pre and post-tests included measures of freezing, balance, motor severity, quality-of-life and gait speed. RESULTS: No falls or injuries occurred and attendance was high. Participants had favorable feedback and showed reduced freezing and improvements in balance and gait. CONCLUSION: Preliminary data suggest the FOG boot camp was feasible, safe and effective.

Author Keywords
freezing of gait;  Parkinson’s disease;  pilot study

Document Type: Article
Publication Stage: Final
Source: Scopus

Initial psychometric evaluation of the Community Participation Activation Scale [Évaluation psychométrique initiale de la Community Participation Activation Scale]
(2018) Canadian Journal of Occupational Therapy, 85 (4), pp. 286-296. 

Lee, D.^a , Mallinson, T.^b , Baum, C.M.^c , Hammel, J.^d

^a Division of Occupational Therapy, Department of Rehabilitation Medicine, University of Washington, Seattle, WA, United States
^b School of Medicine and Health Science, George Washington University, Washington, DC, United States
^c Program in Occupational Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Department of Occupational Therapy, University of Illinois at Chicago, Chicago, IL, United States

Abstract
Background.: Current assessments do not capture the dynamic and complex process of managing different individual and environmental factors influencing community participation post-stroke. Purpose.: The purpose of this study was to examine the psychometric properties of the Community Participation Activation Scale (CPAS) in persons with stroke. Method.: Rating scale structure, unidimensionality, reliability and precision, construct validity, and differential item functioning of the CPAS were examined with 93 community-dwelling people with stroke. Findings.: The CPAS consists of 15 action items and 10 attitude items. Person separation reliabilities of the action and attitude domains were.75 and.72, respectively, and internal consistency reliabilities were good (>.80). The CPAS showed low to moderate correlation with community integration and enfranchisement constructs. Implications.: The CPAS may be used as an assessment to better understand an individual’s level of activation and to inform individually designed, participation-focused interventions, although it needs further improvement to be used as a clinical measure. © CAOT 2018.

Author Keywords
Occupational therapy;  Outcome assessment;  Rasch model;  Social participation;  Stroke

Document Type: Article
Publication Stage: Final
Source: Scopus

Treatment satisfaction significantly improves in patients with multiple sclerosis switching from interferon beta therapy to peginterferon beta-1a every 2 weeks
(2018) Patient Preference and Adherence, 12, pp. 1289-1297. 

Hendin, B.^a , Naismith, R.T.^b , Wray, S.E.^c , Huang, D.^d , Dong, Q.^e , Livingston, T.^f , Jones, D.L.^f , Watson, C.^g , Jhaveri, M.^f

^a Phoenix Neurological Associates, Phoenix, AZ, United States
^b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^c Hope Neurology MS Center, Knoxville, TN, United States
^d Mount Carmel Neuroscience and MDH Research, Westerville, OH, United States
^e Biostatistics, Biogen, Cambridge, MA, United States
^f US Medical, Biogen, Cambridge, MA, United States
^g Global Value and Access, Biogen, Cambridge, MA, United States

Abstract
Objectives: Posthoc analysis of treatment satisfaction in patients switching to subcutaneous (SC) peginterferon beta-1a in the ALLOW study. Patients and methods: Patients with relapsing multiple sclerosis treated with intramuscular interferon (IFN) beta-1a or SC IFN beta-1a or beta-1b remained on their current therapy for a 4-week run-in period, followed by a switch to SC peginterferon beta-1a 125 mcg every 2 weeks for 48 weeks. Treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM), which covers effectiveness, side effects, convenience, and global satisfaction. Patients completed the TSQM at baseline (prior to starting the 4-week run-in period) and 4, 12, 24, 36, and 48 weeks after switching, and scores were analyzed for the overall population and compared to baseline. Patients reported the severity of flu-like symptoms (FLS) at baseline and with each peginterferon beta-1a injection; clinicians evaluated the occurrence of injection-site reactions (ISRs) after the first dose of peginterferon beta-1a and every 12 weeks thereafter. TSQM scores were stratified by the presence of FLS or ISRs during the study period and by prior IFN therapy use. Results: For the overall population (n=194), convenience and global satisfaction scores significantly improved from baseline at all time points, and side effect satisfaction scores significantly improved up to week 36. Convenience scores significantly improved regardless of FLS, ISRs, or prior IFN therapy. Patients without FLS during the study period showed significant improvements in global satisfaction, but not side effect satisfaction, versus those with FLS. Patients switching from SC IFN therapies achieved greater improvements in treatment satisfaction than patients who switched from intramuscular IFN beta-1a. Conclusions: Switching relapsing multiple sclerosis patients to SC peginterferon beta-1a from other IFN therapies significantly improved treatment satisfaction and convenience. © 2018 Hendin et al.

Author Keywords
Interferon beta-1a;  Interferon beta-1b;  Patient-reported outcomes;  Peginterferon beta-1a;  Quality of life;  Relapsing multiple sclerosis;  Treatment satisfaction;  Treatment satisfaction questionnaire for medication;  TSQM

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access