Opioid-related emergency admissions in people with opioid dependence/use disorder with and without sickle cell disease: An analysis of multi-state insurance claims
(2024) General Hospital Psychiatry, 91, pp. 83-88.
Liu, S.A.a , Brown, T.R.b c , King, A.A.d e , Lin, L.A.f g , Rehman, S.S.d , Grucza, R.A.h , Xu, K.Y.i
a Division of Hospital Medicine, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110
b Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, 760 Westwood Plaza, Los Angeles, CA 90024, United States
c Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, 760 Westwood Plaza, Los Angeles, CA 90024, United States
d Division of Hematology and Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110
e Division of Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110
f Department of Psychiatry, University of Michigan Medical School, 4250 Plymouth Rd, Ann Arbor, MI 48109, United States
g Center for Clinical Management Research (CCMR), Veteran Affairs Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105, United States
h Departments of Family and Community Medicine and Health and Outcomes Research, St. Louis University, 1008 S. Spring Avenue, St. Louis, MO 63110
i Health and Behavior Research Center, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110
Abstract
Objective: We estimated rates of opioid-related admissions in people with sickle cell disease (SCD) diagnosed with opioid-related disorders. Method: We analyzed ten years (1/2006–12/2016) of multi-state claims data from 191,638 people receiving treatment for opioid-related disorders in the U.S. We used multivariable cox regression to estimate the association between admissions for opioid-related adverse events after initiating treatment and SCD status (SCD[n = 320] vs no SCD[n = 191,318]) among people with opioid-related disorders, controlling for sociodemographic variables and comorbidities. In secondary analyses, we excluded events occurring simultaneously as vaso-occlusive crises (VOCs) and computed rates of admissions for non-opioid substance-related events (i.e., alcohol, cannabis). Results: Whereas 287(90 %) of the SCD cohort had >1 all-cause admission, of which 199 were for VOCs, only 78(20 %) experienced an opioid-related adverse event. The SCD cohort experienced higher rates of opioid-related admissions than the non-SCD cohort (aHR = 1.82[95 % CI = 1.51–2.19), a finding that remained robust even after excluding events that occurred at the same time as a VOC. SCD diagnoses were not associated with admissions for non-opioid substance-related events. Conclusions: Even though clinicians may perceive people with SCD as being at elevated risk for substance use disorders, opioid-related admissions made up only a small fraction of all-cause admissions among people with SCD diagnosed with opioid-related disorders, in contrast to VOCs that comprised the majority of admissions. Opioid-related admissions, while modestly higher among those with SCD than among peers without SCD, were relatively uncommon. © 2024 Elsevier Inc.
Document Type: Article
Publication Stage: Final
Source: Scopus
A microbiome-directed therapeutic food for children recovering from severe acute malnutrition
(2024) Science Translational Medicine, 16 (767), p. eadn2366.
Hartman, S.J.a b , Hibberd, M.C.a b c , Mostafa, I.d , Naila, N.N.d , Islam, M.M.d , Zaman, M.U.d , Huq, S.d , Mahfuz, M.d , Islam, M.T.e , Mukherji, K.e , Moghaddam, V.A.f , Chen, R.Y.a b , Province, M.A.f , Webber, D.M.a b c , Henrissat, S.a b , Henrissat, B.g , Terrapon, N.h , Rodionov, D.A.i , Osterman, A.L.i , Barratt, M.J.a b c , Ahmed, T.d , Gordon, J.I.a b c
a Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Newman Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
d International Centre for Diarrhoeal Disease ResearchDhaka 1212, Bangladesh
e Terre des Hommes Netherlands – Bangladesh Country OfficeDhaka 1209, Bangladesh
f Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Biotechnology and Biomedicine (DTU Bioengineering), Technical University of Denmark, Denmark
h Architecture et Fonction des Macromolécules Biologiques, CNRS, Aix-Marseille University, Marseille, F-13288, France
i Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, United States
Abstract
Globally, severe acute malnutrition (SAM), defined as a weight-for-length z-score more than three SDs below a reference mean (WLZ < -3), affects 14 million children under 5 years of age. Complete anthropometric recovery after standard, short-term interventions is rare, with children often left with moderate acute malnutrition (MAM; WLZ -2 to -3). We conducted a randomized controlled trial (RCT) involving 12- to 18-month-old Bangladeshi children from urban and rural sites, who, after initial hospital-based treatment for SAM, received a 3-month intervention with a microbiome-directed complementary food (MDCF-2) or a calorically more dense, standard ready-to-use supplementary food (RUSF). The rate of WLZ improvement was significantly greater in MDCF-2-treated children (P = 8.73 × 10-3), similar to our previous RCT of Bangladeshi children with MAM without antecedent SAM (P = 0.032). A correlated meta-analysis of plasma levels of 4520 proteins in both RCTs revealed 215 positively associated with WLZ (largely representing musculoskeletal and central nervous system development) and 44 negatively associated (primarily related to immune activation). Moreover, the positively associated proteins were significantly enriched by MDCF-2 (q = 1.1 × 10-6). Characterizing the abundances of 754 bacterial metagenome-assembled genomes in serially collected fecal samples disclosed the effects of acute rehabilitation for SAM on the microbiome and how, during treatment for MAM, specific strains of Prevotella copri function at the intersection between MDCF-2 glycan metabolism and anthropometric recovery. These results provide a rationale for further testing the generalizability of MDCF efficacy and for identifying biomarkers to define treatment responses.
Document Type: Article
Publication Stage: Final
Source: Scopus
Comparing ventriculoatrial and ventriculopleural shunts in pediatric hydrocephalus: a Hydrocephalus Clinical Research Network study
(2024) Journal of Neurosurgery. Pediatrics, 34 (4), pp. 305-314.
Ravindra, V.M.a b c d , Riva-Cambrin, J.e , Jensen, H.f , Whitehead, W.E.g , Kulkarni, A.V.h , Limbrick, D.D.i , Wellons, J.C.j , Naftel, R.P.j , Rozzelle, C.J.k , Rocque, B.G.k , Pollack, I.F.l , McDowell, M.M.l , Tamber, M.S.m , Hauptman, J.S.n , Browd, S.R.n , Pindrik, J.o , Isaacs, A.M.o , McDonald, P.J.p , Hankinson, T.C.q , Jackson, E.M.r , Chu, J.s , Krieger, M.D.s , Simon, T.D.t , Strahle, J.M.u , Holubkov, R.f , Reeder, R.f , Kestle, J.R.W.a
a Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT, United States
b Department of Neurosurgery, University of California, San Diego, CA, United States
c 3Division of Pediatric Neurosurgery, Rady Children’s Hospital, San Diego, CA, United States
d Department of Neurosurgery, Naval Medical Center, San Diego, CA, United States
e Department of Clinical Neurosciences, University of CalgaryAB, Canada
f Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
g Department of Neurosurgery, Division of Pediatric Neurosurgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
h 8Division of Neurosurgery, Hospital for Sick Children, University of TorontoON, Canada
i Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
j 10Department of Neurological Surgery, Division of Pediatric Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, United States
k 11Division of Neurosurgery, Section of Pediatric Neurosurgery, Children’s Hospital of Alabama, University of Alabama-BirminghamAL, United States
l 12Division of Neurosurgery, Children’s Hospital of PittsburghPA, United States
m 13Department of Surgery, Division of Neurosurgery, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
n 14Department of Neurosurgery, University of Washington, Seattle Children’s Hospital, Seattle, WA, United States
o 15Department of Neurosurgery, Nationwide Children’s Hospital, Columbus, OH, United States
p 16Department of Surgery, Section of Neurosurgery, University of Manitoba, Winnipeg, MB, Canada
q 17Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Colorado School of Medicine, Aurora, CO, United States
r 18Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, Liberia
s 19Department of Neurosurgery, Division of Neurosurgery, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, United States
t 20Department of Pediatrics, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, California; and
u 21Department of Neurosurgery, St. Louis Children’s Hospital, Washington University in St. LouisMO, United States
Abstract
OBJECTIVE: When the peritoneal cavity cannot serve as the distal shunt terminus, nonperitoneal shunts, typically terminating in the atrium or pleural space, are used. The comparative effectiveness of these two terminus options has not been evaluated. The authors directly compared shunt survival and complication rates for ventriculoatrial (VA) and ventriculopleural (VPl) shunts in a pediatric cohort. METHODS: The Hydrocephalus Clinical Research Network Core Data Project was used to identify children ≤ 18 years of age who underwent either VA or VPl shunt insertion. The primary outcome was time to shunt failure. Secondary outcomes included distal site complications and frequency of shunt failure at 6, 12, and 24 months. RESULTS: The search criteria yielded 416 children from 14 centers with either a VA (n = 318) or VPl (n = 98) shunt, including those converted from ventriculoperitoneal shunts. Children with VA shunts had a lower median age at insertion (6.1 years vs 12.4 years, p < 0.001). Among those children with VA shunts, a hydrocephalus etiology of intraventricular hemorrhage (IVH) secondary to prematurity comprised a higher proportion (47.0% vs 31.2%) and myelomeningocele comprised a lower proportion (17.8% vs 27.3%) (p = 0.024) compared with those with VPl shunts. At 24 months, there was a higher cumulative number of revisions for VA shunts (48.6% vs 38.9%, p = 0.038). When stratified by patient age at shunt insertion, VA shunts in children < 6 years had the lowest shunt survival rate (p < 0.001, log-rank test). After controlling for age and etiology, multivariable analysis did not find that shunt type (VA vs VPl) was predictive of time to shunt failure. No differences were found in the cumulative frequency of complications (VA 6.0% vs VPl 9.2%, p = 0.257), but there was a higher rate of pneumothorax in the VPl cohort (3.1% vs 0%, p = 0.013). CONCLUSIONS: Shunt survival was similar between VA and VPl shunts, although VA shunts are used more often, particularly in younger patients. Children < 6 years with VA shunts appeared to have the shortest shunt survival, which may be a result of the VA group having more cases of IVH secondary to prematurity; however, when age and etiology were included in a multivariable model, shunt location (atrium vs pleural space) was not associated with time to failure. The baseline differences between children treated with a VA versus a VPl shunt likely explain current practice patterns.
Author Keywords
Hydrocephalus Clinical Research Network; outcomes; pediatric; shunt failure; ventriculoatrial shunt; ventriculopleural shunt
Document Type: Article
Publication Stage: Final
Source: Scopus
“Indications for cerebral revascularization for moyamoya syndrome in pediatric sickle cell disease determined by Delphi methodology” (2024) Journal of Neurosurgery: Pediatrics
Indications for cerebral revascularization for moyamoya syndrome in pediatric sickle cell disease determined by Delphi methodology
(2024) Journal of Neurosurgery: Pediatrics, 34 (4), pp. 402-413.
Robert, A.P.a , Hanel, R.A.b , Adelson, P.D.c , Lang, S.-S.d , Grabb, P.e , Greene, S.f , Johnston, J.M.g , Leonard, J.h , Magge, S.N.i , Marupudi, N.I.j k , Piatt, J.l , De Oliveira Sillero, R.m , Smith, E.R.n , Smith, J.o , Strahle, J.M.p , Vadivelu, S.q , Wellons, J.C., IIIr , Wrubel, D.s , Hatem, A.a , Moody, C.a , Han, S.H.t , Montaser, A.u , Millican, N.u , Pederson, J.M.v w , Dain, A.S.x , Beslow, L.A.y , Aldana, P.R.a
a Division of Pediatric Neurosurgery, University of Florida College of Medicine, Jacksonville and Wolfson Children’s Hospital, Jacksonville, FL, United States
b Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, FL, United States
c Department of Neurosurgery, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States
d Department of Neurosurgery and Pediatric Neurosurgery, University of Pennsylvania School of Medicine, Children’s Hospital of PhiladelphiaPA, United States
e Department of Neurosurgery, Children’s Mercy Hospital, Kansas City, MO, United States
f Department of Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
g Department of Neurosurgery, Children’s Hospital of Alabama, Birmingham, AL, United States
h Department of Neurosurgery, Nationwide Children’s Hospital, Columbus, OH, United States
i CHOC Neuroscience Institute, Children’s Health of Orange County, Orange, CA, United States
j Department of Pediatric Neurosurgery, Children’s Hospital of Michigan, Detroit, MI, United States
k Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States
l Division of Neurosurgery, Nemours Children’s Hospital Delaware, Wilmington, DE, United States
m Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, United States
n Department of Neurosurgery, Children’s Hospital Boston, Harvard Medical School, Boston, MA, United States
o Goodman Campbell Brain and Spine, Peyton Manning Children’s Hospital, Indianapolis, IN, United States
p Department of Neurosurgery, Washington University School of Medicine, Washington University in St. LouisMO, United States
q Division of Neurosurgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
r Department of Neurological Surgery, Division of Pediatric Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
s Department of Neurosurgery, Children’s Healthcare of Atlanta, Egleston Hospital, Atlanta, GA, United States
t University of Florida College of Medicine, Gainesville, FL, United States
u Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL, United States
v Superior Medical Experts, St. Paul, MN, United States
w Nested Knowledge, St. Paul, MN, United States
x Division of Hematology, Children’s Hospital of PhiladelphiaPA, United States
y Departments of Neurology and Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, United States
Abstract
OBJECTIVE Cerebral revascularization surgery (CRS) has been used to prevent stroke in children with sickle cell disease (SCD) and cerebral vasculopathy (e.g., moyamoya syndrome). While results suggest that it may be an effective treatment, surgical indications have not been well defined. This study sought to determine indications for offering revascularization surgery in centers with established sickle cell programs in the US. METHODS Three sequential surveys utilizing the Delphi methodology were administered to neurosurgeons participating in the Stroke in Sickle Cell Revascularization Surgery study. Respondents were presented with clinical scenarios of patients with SCD and varying degrees of ischemic presentation and vasculopathy, and the group’s agreement to offer surgical revascularization was measured. Consensus was defined as ≥ 75% similar responses. RESULTS The response rate to all 3 surveys was 100%. Seventeen neurosurgeons from 16 different centers participated. The presence of moyamoya collaterals (MMCs) and arterial stenosis matching an ischemic distribution yielded the strongest recommendations to offer surgery. There was consensus to offer revascularization in the presence of MMCs and at least 50% arterial stenosis matching an ischemic distribution. In contrast, there was no consensus to offer revascularization with 50%–70% stenosis not matching an ischemic presentation in the absence of MMCs. The presence of the ivy sign in the distribution of the stenotic artery also contributed to the consensus to offer surgery in certain scenarios. CONCLUSIONS There were several clinical scenarios that attained consensus to offer surgery; the strongest was moderate to severe arterial stenosis that matched the distribution of ischemic presentation in the presence of MMCs. Radiological findings of decreased cerebral flow or perfusion also facilitated attaining consensus to offer surgery. The findings of this study reflect expert opinion about questions that deserve prospective clinical research. Determination of indications for CRS can guide clinical practice and aid the design of prospective studies. © AANS 2024.
Author Keywords
cerebral revascularization surgery; Delphi consensus methodology; moyamoya disease; sickle cell disease; vascular disorders
Document Type: Article
Publication Stage: Final
Source: Scopus
Optimal hippocampal targeting in responsive neurostimulation for mesial temporal lobe epilepsy
(2024) Journal of Neurosurgery, 141 (4), pp. 1105-1114.
Skelton, H.M.a b , Bullinger, K.c , Isbaine, F.a , Lau, J.C.d , Willie, J.T.e , Gross, R.E.a f
a Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States
b Morehouse School of Medicine, Atlanta, GA, United States
c Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
d Department of Clinical Neurological Sciences, Western University, London, ON, Canada
e Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, United States
Abstract
OBJECTIVE The aim of this study was to identify features of responsive neurostimulation (RNS) lead configuration and contact placement associated with greater seizure reduction in mesial temporal lobe epilepsy (MTLE). METHODS A single-center series of patients with MTLE treated with RNS were retrospectively analyzed to assess the relationship between anatomical targeting and seizure reduction. Targeting was determined according to both the preoperatively conceived lead configuration and the actual placement of RNS contacts. Three lead configurations were used: 1) single bilateral, with 1 depth lead in each hippocampus; 2) single unilateral, with 1 hippocampal depth lead and another implant outside the mesial temporal lobe; and 3) dual unilateral, with 2 leads in 1 hippocampus. Contact placement on postoperative imaging was measured according to the number of hippocampal contacts per targeted hippocampus (contact density) and per patient (contact count), distribution throughout the hippocampus, and proximity to the anteromedial hippocampus. RESULTS Dual unilateral lead placement resulted in significantly higher hippocampal contact density compared with the single hippocampal approaches, but only showed a nonsignificant trend toward a higher rate of response. However, those patients with more than 4 contacts in a single hippocampus, achievable only with dual unilateral leads, had a significantly higher rate of response. The higher likelihood of response was poorly explained by more widespread hippocampal coverage, but well correlated with proximity to the anteromedial hippocampus. CONCLUSIONS Dual unilateral hippocampal implantation increased RNS contact density in patients with unilateral MTLE, which contributed to improved outcomes, not by stimulating more of the hippocampus, but instead by being more likely to stimulate a latent subtarget in the anterior hippocampus. It remains to be explored whether a single electrode targeted selectively to this region would also result in improved outcomes. ©AANS 2024, except where prohibited by US copyright law.
Author Keywords
hippocampus; mesial temporal lobe epilepsy; neuromodulation; responsive neurostimulation
Document Type: Article
Publication Stage: Final
Source: Scopus
Association of germinal matrix hemorrhage volume with neurodevelopment and hydrocephalus
(2024) Journal of Neurosurgery: Pediatrics, 34 (4), pp. 347-356.
Yang, P.H.a , Karuparti, S.f , Varagur, K.a , Alexopoulos, D.g , Reeder, R.W.h , Lean, R.E.b , Rogers, C.E.b d , Limbrick, D.D., Jr.a i , Smyser, C.D.c d e , Strahle, J.M.a
a Departments of Neurological Surgery, Washington University in St. LouisMO, United States
b Departments of Psychiatry, Washington University in St. LouisMO, United States
c Departments of Neurology, Washington University in St. LouisMO, United States
d Departments of Pediatrics, Washington University in St. LouisMO, United States
e Departments of Radiology, Washington University in St. LouisMO, United States
f University of Missouri School of Medicine, Columbia, MO, United States
g Division of Biostatistics, Washington University in St. LouisMO, United States
h Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, United States
i Department of Neurological Surgery, Virginia Commonwealth University, Richmond, VA, United States
Abstract
OBJECTIVE The objective of this study was to evaluate whether volumetric measurements on early cranial ultrasound (CUS) in high-grade germinal matrix hemorrhage–intraventricular hemorrhage (GMH-IVH) are associated with hydrocephalus and neurodevelopmental metrics. METHODS A retrospective case series analysis of infants with high-grade GMH-IVH admitted to the St. Louis Children’s Hospital neonatal intensive care unit between 2007 and 2015 who underwent neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III) at 2 years of corrected age was performed. GMH volume, periventricular hemorrhagic infarction volume, and frontotemporal horn ratio were obtained from direct review of neonatal CUS studies. Univariate and multivariable regression models were used to evaluate the association between hemorrhage volumes and hydrocephalus requiring permanent CSF diversion with ventricular shunt or endoscopic third ventriculostomy with or without choroid plexus cauterization and composite Bayley-III cognitive, language, and motor scores. RESULTS Forty-three infants (29 males, mean gestational age 25 weeks) met the inclusion criteria. The mean age at time of the CUS with the largest hemorrhage volume or first diagnosis of highest grade was 6.2 days. Nineteen patients underwent treatment for hydrocephalus with permanent CSF diversion. In multivariable analyses, larger GMH volume was associated with worse estimated Bayley-III cognitive (left-sided GMH volume: p = 0.048, total GMH volume: p = 0.023) and motor (left-sided GMH volume: p = 0.010; total GMH volume: p = 0.014) scores. Larger periventricular hemorrhagic infarction volume was associated with worse estimated Bayley-III motor scores (each side p < 0.04). Larger left-sided (OR 2.55, 95% CI 1.10–5.88; p = 0.028) and total (OR 1.35, 95% CI 1.01–1.79; p = 0.041) GMH volumes correlated with hydrocephalus. There was no relationship between early ventricular volume and hydrocephalus or neurodevelopmental outcomes. CONCLUSIONS Location-specific hemorrhage volume on early CUS may be prognostic for neurodevelopmental and hydrocephalus outcomes in high-grade GMH-IVH. ©AANS 2024.
Author Keywords
germinal matrix hemorrhage; hydrocephalus; neonatal; neurodevelopment; ultrasound
Document Type: Article
Publication Stage: Final
Source: Scopus
Three classes of propofol binding sites on GABAA receptors
(2024) Journal of Biological Chemistry, 300 (10), art. no. 107778, .
Chen, Z.-W.a b , Chintala, S.M.a , Bracamontes, J.a , Sugasawa, Y.a c , Pierce, S.R.a , Varga, B.R.a , Smith, E.H.d , Edge, C.J.d , Franks, N.P.d e , Cheng, W.W.L.a , Akk, G.a b , Evers, A.S.a b f
a Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
b The Taylor Family Institute for Innovative Psychiatric Research Washington University School of Medicine, St Louis, MO, United States
c Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, Tokyo, Japan
d Department of Life Sciences, Imperial College, London, United Kingdom
e UK Dementia Research Institute, Imperial College, London, United Kingdom
f Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, United States
Abstract
Propofol is a widely used anesthetic and sedative that acts as a positive allosteric modulator of gamma-aminobutyric acid type A (GABAA) receptors. Several potential propofol binding sites that may mediate this effect have been identified using propofol-analogue photoaffinity labeling. Ortho-propofol diazirine (o-PD) labels β-H267, a pore-lining residue, whereas AziPm labels residues β-M286, β-M227, and α-I239 in the two membrane-facing interfaces [β(+)/α(−) and α(+)/β(−)] between α and β subunits. This study used photoaffinity labeling of α1β3 GABAA receptors to reconcile the apparently conflicting results obtained with AziPm and o-PD labeling, focusing on whether β3-H267 identifies specific propofol binding site(s). The results show that propofol, but not AziPm protects β3-H267 from labeling by o-PD, whereas both propofol and o-PD protect against AziPm labeling of β3-M286, β3-M227, and α1I239. These data indicate that there are three distinct classes of propofol binding sites, with AziPm binding to two of the classes and o-PD to all three. Analysis of binding stoichiometry using native mass spectrometry in β3 homomeric receptors, demonstrated a minimum of five AziPm labeled residues and three o-PD labeled residues per pentamer, suggesting that there are two distinct propofol binding sites per β-subunit. The native mass spectrometry data, coupled with photolabeling performed in the presence of zinc, indicate that the binding site(s) identified by o-PD are adjacent to, but not within the channel pore, since the pore at the 17′ H267 residue can accommodate only one propofol molecule. These data validate the existence of three classes of specific propofol binding sites on α1β3 GABAA receptors. © 2024 The Authors
Author Keywords
fluorescence resonance energy transfer (FRET); gamma-amino butyric acid (GABA); ligand binding protein; mass spectrometry (MS); neurotransmitter receptor; steroid
Document Type: Article
Publication Stage: Final
Source: Scopus
Leveraging machine learning to study how temperament scores predict pre-term birth status
(2024) Global Pediatrics, 9, art. no. 100220, .
Seamon, E.a , Mattera, J.A.b , Keim, S.A.c , Leerkes, E.M.d , Rennels, J.L.e , Kayl, A.J.e , Kulhanek, K.M.e , Narvaez, D.f , Sanborn, S.M.g , Grandits, J.B.g , Schetter, C.D.h , Coussons-Read, M.i , Tarullo, A.R.j , Schoppe-Sullivan, S.J.k , Thomason, M.E.l , Braungart-Rieker, J.M.m , Lumeng, J.C.n , Lenze, S.N.o , Christian, L.M.p , Saxbe, D.E.q , Stroud, L.R.r , Rodriguez, C.M.s , Anzman-Frasca, S.t , Gartstein, M.A.b
a University of Idaho Department of Design and Environments, 875 Perimeter Drive MS 2481, Moscow, ID 83844-2481, United States
b Washington State University, Department of Psychology, P.O. Box 644820, Pullman, WA 99164-4820, United States
c Nationwide Children’s Hospital & The Ohio State University, Center for Biobehavioral Health, Abigail Wexner Research Institute 700 Children’s Drive, Columbus, OH 43205, United States
d University of North Carolina Greensboro, P.O. Box 26170, Greensboro, NC 27402-6170, United States
e University of Nevada, Las Vegas, 4505 S. Maryland Way, Las Vegas, NV 89154, United States
f University of Notre Dame, 390 Corbett, Notre Dame, IN 46556, United States
g Clemson University, College of Behavioral, Social and Health Sciences, 116 Edwards Hall, Clemson South Carolina, 29634, United States
h University of California, Los Angeles, Department of Psychology, 1285 Franz Hall, Box 951563, Los Angeles, CA 90095, United States
i University of Colorado-Colorado Springs Psychology Department, Columbine Hall, 1420 Austin Bluffs Pkwy, Colorado Springs, CO 80918, United States
j Boston University, Department of Psychological & Brain Sciences 64 Cummington Mall, Room 149 Boston, Massachusetts, 02215, United States
k The Ohio State University, 243 Psychology Building, 1835 Neil Ave, Columbus, OH 43210, United States
l New York University, Langone One Park Ave, New York, NY 10016, United States
m Colorado State University, Human Development and Family Studies, College of Health and Human Sciences, 1570 Campus Delivery, Fort Collins, CO 80523-1501, United States
n University of Michigan Medical School, Division of Developmental and Behavioral Pediatrics, 1600 Huron Parkway, Building 520, Ann Arbor, MI 48109, United States
o Washington University School of Medicine Institute for Public Health, 660 S. Euclid, MSC 8217-0094-02, St. Louis, MO 63110, United States
p The Ohio State University Wexner Medical Center, 460 Medical Center Drive, Columbus, OH 43210, United States
q University of Southern California, 3616 Trousdale Parkway, AHF 108, Los Angeles, CA 90089-0376, United States
r Department of Psychiatry and Human Behavior Warren Alpert Medical School, Brown University, Coro West, Suite 309, 164 Summit Avenue, Providence, RI 02906, United States
s Old Dominion University, 115 Hampton Blvd, Norfolk, VA 23529, United States
t University at Buffalo Jacobs School of Medicine and Biomedical Sciences Division of Behavioral Medicine, G56 Farber Hall, 3435 Main Street, Buffalo, NY 14214, United States
Abstract
Background: Preterm birth (birth at <37 completed weeks gestation) is a significant public heatlh concern worldwide. Important health, and developmental consequences of preterm birth include altered temperament development, with greater dysregulation and distress proneness. Aims: The present study leveraged advanced quantitative techniques, namely machine learning approaches, to discern the contribution of narrowly defined and broadband temperament dimensions to birth status classification (full-term vs. preterm). Along with contributing to the literature addressing temperament of infants born preterm, the present study serves as a methodological demonstration of these innovative statistical techniques. Study design: This study represents a metanalysis conducted with multiple samples (N = 19) including preterm (n = 201) children and (n = 402) born at term, with data combined across investigations to perform classification analyses. Subjects: Participants included infants born preterm and term-born comparison children, either matched on chronological age or age adjusted for prematurity. Outcome measures: Infant Behavior Questionnaire-Revised Very Short Form (IBQ-R VSF) was completed by mothers, with factor and item-level data considered herein. Results and conclusions: Accuracy estimates were generally similar regardless of the comparison groups. Results indicated a slightly higher accuracy and efficiency for IBQR-VSF item-based models vs. factor-level models. Divergent patterns of feature importance (i.e., the extent to which a factor/item contributed to classification) were observed for the two comparison groups (chronological age vs. adjusted age) using factor-level scores; however, itemized models indicated that the two most critical items were associated with effortful control and negative emotionality regardless of comparison group. © 2024
Author Keywords
Infancy; Preterm birth; Quantitative methodology; Temperament
Document Type: Article
Publication Stage: Final
Source: Scopus
Machine Learning-Driven Analysis of Individualized Treatment Effects Comparing Buprenorphine and Naltrexone in Opioid Use Disorder Relapse Prevention
(2024) Journal of Addiction Medicine, 18 (5), pp. 511-519.
Afshar, M., Graham Linck, E.J., Spicer, A.B., Rotrosen, J., Salisbury-Afshar, E.M., Sinha, P., Semler, M.W., Churpek, M.M.
From the University of Wisconsin School of Medicine and Public Health, Madison, WI (MA, EJGL, ABS, EMS-A, MMC); New York University Grossman School of Medicine, New York, NY (JR); Washington University School of Medicine, Saint Louis, MO (PS); and Vanderbilt University Medical Center, Nashville, TN (MWS)
Abstract
OBJECTIVE: A trial comparing extended-release naltrexone and sublingual buprenorphine-naloxone demonstrated higher relapse rates in individuals randomized to extended-release naltrexone. The effectiveness of treatment might vary based on patient characteristics. We hypothesized that causal machine learning would identify individualized treatment effects for each medication. METHODS: This is a secondary analysis of a multicenter randomized trial that compared the effectiveness of extended-release naltrexone versus buprenorphine-naloxone for preventing relapse of opioid misuse. Three machine learning models were derived using all trial participants with 50% randomly selected for training (n = 285) and the remaining 50% for validation. Individualized treatment effect was measured by the Qini value and c-for-benefit, with the absence of relapse denoting treatment success. Patients were grouped into quartiles by predicted individualized treatment effect to examine differences in characteristics and the observed treatment effects. RESULTS: The best-performing model had a Qini value of 4.45 (95% confidence interval, 1.02-7.83) and a c-for-benefit of 0.63 (95% confidence interval, 0.53-0.68). The quartile most likely to benefit from buprenorphine-naloxone had a 35% absolute benefit from this treatment, and at study entry, they had a high median opioid withdrawal score ( P < 0.001), used cocaine on more days over the prior 30 days than other quartiles ( P < 0.001), and had highest proportions with alcohol and cocaine use disorder ( P ≤ 0.02). Quartile 4 individuals were predicted to be most likely to benefit from extended-release naltrexone, with the greatest proportion having heroin drug preference ( P = 0.02) and all experiencing homelessness ( P < 0.001). CONCLUSIONS: Causal machine learning identified differing individualized treatment effects between medications based on characteristics associated with preventing relapse. Copyright © 2024 American Society of Addiction Medicine.
Document Type: Article
Publication Stage: Final
Source: Scopus
The Impact of Tobacco Use on Weight Loss During a Peer-Led Healthy Lifestyle Intervention for People With Serious Mental Illness Living in Permanent Supportive Housing
(2024) Research on Social Work Practice, .
Hawes, M.R.a , Park, M.b , Cabassa, L.J.c d
a Center for Tobacco Control Research and Education (CTCRE) and the Benioff Homelessness and Housing Initiative, University of California, San Francisco, CA, United States
b School of Social Work at Rutgers, The State University of New Jersey, New Brunswick, NJ, United States
c Brown School of Social Work, Washington University, St. Louis, MO, United States
d Center for Mental Health Services Research, Washington University, St. Louis, MO, United States
Abstract
Purpose: Over 50% of people with serious mental illness (SMI) smoke cigarettes. This study evaluated whether tobacco use impacted weight loss outcomes during a peer-led healthy lifestyle intervention (PGLB) for people with SMI living in permanent supportive housing (PSH). Method: Data from an effectiveness trial of PGLB examined whether baseline tobacco use moderated the effectiveness of the intervention compared to usual care (UC) in helping participants lose weight. PGLB was conducted in three sites in two U.S. cities between 2015 and 2018. Results: 63% of participants were current cigarette smokers. Smoking did not moderate the effect of the intervention. However, baseline tobacco use predicted greater weight loss (b = −4.1, p =.022) over the course of the trial, regardless of treatment group. Discussion: Tobacco use was a significant driver of weight loss for study participants. Findings have implications for offering tobacco cessation treatment during healthy lifestyle interventions for people with SMI. © The Author(s) 2024.
Author Keywords
health disparities; healthy lifestyle interventions; permanent supportive housing; serious mental illness; tobacco use
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Considerations for widespread implementation of blood-based biomarkers of Alzheimer’s disease
(2024) Alzheimer’s and Dementia, .
Mielke, M.M.a , Anderson, M.b , Ashford, J.W.c d , Jeromin, A.e , Lin, P.-J.f , Rosen, A.g h , Tyrone, J.i , VandeVrede, L.j , Willis, D.k , Hansson, O.l m , Khachaturian, A.S.n , Schindler, S.E.o , Weiss, J.p , Batrla, R.q , Bozeat, S.r , Dwyer, J.R.s , Holzapfel, D.t u , Jones, D.R.q , Murray, J.F.u , Partrick, K.A.t , Scholler, E.t u , Vradenburg, G.t u , Young, D.v , Braunstein, J.B.w , Burnham, S.C.x , de Oliveira, F.F.y , Hu, Y.H.q , Mattke, S.z , Merali, Z.aa , Monane, M.w , Sabbagh, M.N.ab , Shobin, E.ac , Weiner, M.W.ad , Udeh-Momoh, C.T.a aa
a Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, United States
b Atrium Health, Charlotte, NC, United States
c Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
d War Related Illness and Injury Study Center, VA Palo Alto Health Care System, Palo Alto, CA, United States
e ALZpath, Carlsbad, CA, United States
f Center for the Evaluation of Value and Risk in Health Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, United States
g Palo Alto Veterans Affairs Medical Center, Palo Alto, CA, United States
h Stanford University School of Medicine, Stanford, CA, United States
i Patient Advocate, California, United States
j Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, United States
k Department of Family Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
l Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
m Memory Clinic, Skåne University Hospital, Malmö, Sweden
n The Campaign to Prevent Alzheimer’s Disease, Rockville, MD, United States
o Department of Neurology, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
p US Department of Health and Human Services, Health Resources and Services Administration, Bureau of Health Workforce, Rockville, MD, United States
q Eisai Inc., Nutley, NJ, United States
r F. Hoffman–La Roche AG, Basel, Switzerland
s Global Alzheimer’s Platform Foundation, Washington, District of Columbia, United States
t The Global CEO Initiative on Alzheimer’s Disease, Philadelphia, PA, United States
u Davos Alzheimer’s Collaborative, Philadelphia, PA, United States
v Guidehouse, McLean, VA, United States
w C2N Diagnostics, St. Louis, MO, United States
x Eli Lilly & Co., Indianapolis, IN, United States
y Federal University of São Paulo, São Paulo, Brazil
z The USC Brain Health Observatory, University of Southern California, Los Angeles, CA, United States
aa Brain and Mind Institute, Aga Khan University, Nairobi, Kenya
ab Barrow Neurological Institute, Phoenix, AZ, United States
ac Biogen, Cambridge, MA, United States
ad Departments of Radiology and Biomedical Imaging, Medicine, Psychiatry, and Neurology, University of California, San Francisco, CA, United States
Abstract
Diagnosing Alzheimer’s disease (AD) poses significant challenges to health care, often resulting in delayed or inadequate patient care. The clinical integration of blood-based biomarkers (BBMs) for AD holds promise in enabling early detection of pathology and timely intervention. However, several critical considerations, such as the lack of consistent guidelines for assessing cognition, limited understanding of BBM test characteristics, insufficient evidence on BBM performance across diverse populations, and the ethical management of test results, must be addressed for widespread clinical implementation of BBMs in the United States. The Global CEO Initiative on Alzheimer’s Disease BBM Workgroup convened to address these challenges and provide recommendations that underscore the importance of evidence-based guidelines, improved training for health-care professionals, patient empowerment through informed decision making, and the necessity of community-based studies to understand BBM performance in real-world populations. Multi-stakeholder engagement is essential to implement these recommendations and ensure credible guidance and education are accessible to all stakeholders. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; amyloid; biomarker; blood-based biomarkers; clinical implementation; clinical practice; cognitive impairment; disease-modifying treatment; ethics; patient journey; primary care; secondary care
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Kif1a and intact microtubules maintain synaptic-vesicle populations at ribbon synapses in zebrafish hair cells
(2024) Journal of Physiology, .
David, S.a b , Pinter, K.a , Nguyen, K.-K.c d , Lee, D.S.c , Lei, Z.a , Sokolova, Y.e , Sheets, L.c d , Kindt, K.S.a
a Section on Sensory Cell Development and Function, National Institute on Deafness and other Communication Disorders, Bethesda, MD, United States
b National Institutes of Health–Brown University Graduate Partnership Program, Bethesda, MD, United States
c Department of Otolaryngology, Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
e Advanced Imaging Core, National Institute on Deafness and other Communication Disorders, Bethesda, MD, United States
Abstract
Abstract: Sensory hair cells of the inner ear utilize specialized ribbon synapses to transmit sensory stimuli to the central nervous system. This transmission necessitates rapid and sustained neurotransmitter release, which depends on a large pool of synaptic vesicles at the hair-cell presynapse. While previous work in neurons has shown that kinesin motor proteins traffic synaptic material along microtubules to the presynapse, the mechanisms of this process in hair cells remain unclear. Our study demonstrates that the kinesin motor protein Kif1a, along with an intact microtubule network, is essential for enriching synaptic vesicles at the presynapse in hair cells. Through genetic and pharmacological approaches, we disrupt Kif1a function and impair microtubule networks in hair cells of the zebrafish lateral-line system. These manipulations led to a significant reduction in synaptic-vesicle populations at the presynapse in hair cells. Using electron microscopy, in vivo calcium imaging, and electrophysiology, we show that a diminished supply of synaptic vesicles adversely affects ribbon-synapse function. Kif1aa mutants exhibit dramatic reductions in spontaneous vesicle release and evoked postsynaptic calcium responses. Furthermore, kif1aa mutants exhibit impaired rheotaxis, a behaviour reliant on the ability of hair cells in the lateral line to respond to sustained flow stimuli. Overall, our results demonstrate that Kif1a-mediated microtubule transport is critical to enrich synaptic vesicles at the active zone, a process that is vital for proper ribbon-synapse function in hair cells. (Figure presented.). Key points: Kif1a mRNAs are present in zebrafish hair cells. Loss of Kif1a disrupts the enrichment of synaptic vesicles at ribbon synapses. Disruption of microtubules depletes synaptic vesicles at ribbon synapses. Kif1aa mutants have impaired ribbon-synapse and sensory-system function. © 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Author Keywords
hair cells; kinesins; ribbon synapses; sensory systems; synaptic vesicles; zebrafish
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Children born very preterm experience altered cortical expansion over the first decade of life
(2024) Brain Communications, 6 (5), art. no. fcae318, .
Gorham, L.S.a , Latham, A.R.b , Alexopoulos, D.b , Kenley, J.K.b , Iannopollo, E.b , Lean, R.E.a , Loseille, D.b , Smyser, T.A.a , Neil, J.J.b c d , Rogers, C.E.a c , Smyser, C.D.b c d , Garcia, K.e f
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Radiology & Imaging Sciences, Indiana University School of Medicine, Evansville, IN 46202, United States
f Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
The brain develops rapidly from the final trimester of gestation through childhood, with cortical surface area expanding greatly in the first decade of life. However, it is unclear exactly where and how cortical surface area changes after birth, or how prematurity affects these developmental trajectories. Fifty-two very preterm (gestational age at birth = 26 ± 1.6 weeks) and 41 full-term (gestational age at birth = 39 ± 1.2 weeks) infants were scanned using structural magnetic resonance imaging at term-equivalent age and again at 9/10 years of age. Individual cortical surface reconstructions were extracted for each scan. Infant and 9/10 cortical surfaces were aligned using anatomically constrained Multimodal Surface Matching (aMSM), a technique that allows calculation of local expansion gradients across the cortical surface for each individual subject. At the neonatal time point, very preterm infants had significantly smaller surface area than their full-term peers (P < 0.001), but at the age 9/10-year time point, very preterm and full-term children had comparable surface area (P > 0.05). Across all subjects, cortical expansion by age 9/10 years was most pronounced in frontal, temporal, and supramarginal/inferior parietal junction areas, which are key association cortices (PSpin < 0.001). Very preterm children showed greater cortical surface area expansion between term-equivalent age and age 9/10 compared to their full-term peers in the medial and lateral frontal areas, precuneus, and middle temporal/banks of the superior sulcus junction (P < 0.05). Furthermore, within the very preterm group, expansion was highly variable within the orbitofrontal cortex and posterior regions of the brain. By mapping these patterns across the cortex, we identify differences in association cortices that are known to be important for executive functioning, emotion processing, and social cognition. Additional longitudinal work will be needed to understand if increased expansion in very preterm children is adaptive, or if differences persist into adulthood. © The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.
Author Keywords
brain development; cortical expansion; prematurity; surface area
Document Type: Article
Publication Stage: Final
Source: Scopus
Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials
(2024) The Lancet Neurology, . Cited 1 time.
Montalban, X.a , Vermersch, P.b , Arnold, D.L.c d , Bar-Or, A.e , Cree, B.A.C.f , Cross, A.H.g , Kubala Havrdova, E.h , Kappos, L.i , Stuve, O.j , Wiendl, H.k , Wolinsky, J.S.l , Dahlke, F.m , Le Bolay, C.n , Shen Loo, L.o , Gopalakrishnan, S.p , Hyvert, Y.p , Javor, A.q , Guehring, H.p , Tenenbaum, N.o , Tomic, D.q , evolutionRMS investigatorsr
a Department of Neurology, Centre d’Esclerosi Múltiple de Catalunya, Hospital Universitario Vall d’Hebron, Barcelona, Spain
b University Lille, Inserm U1172 LilNCog, Centre Hospitalier Universitaire de Lille, Lille, France
c NeuroRx Research, Montreal, QC, Canada
d Montreal Neurological Institute, Montreal, QC, Canada
e Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
f Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, United States
g Section of Multiple Sclerosis and Neuroimmunology, Washington University School of Medicine, St Louis, MO, United States
h General University Hospital, Charles University, Prague, Czech Republic
i Departments of Headorgans, Spine and Neuromedicine, Clinical Research, and Biomedical Engineering, Research Center for Clinical Neuroimmunology and Neuroscience, University Hospital Basel, University of Basel, Basel, Switzerland
j Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States
k Department of Neurology with Institute of Translational Neurology, University Hospital, Münster, Germany
l Department of Neurology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, United States
m Impulze, Zürich, Switzerland
n Merck Santé, an affiliate of Merck KGaA, Lyon, France
o EMD Serono, an affiliate of Merck KGaA, Billerica, MA, United States
p Merck KGaA Healthcare, Darmstadt, Germany
q Ares Trading, an affiliate of Merck KGaA, Eysins, Switzerland
Abstract
Background: Evobrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis. Methods: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18–55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0–5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated). Findings: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12–0·18 with evobrutinib vs 0·14 [0·11–0·18] with teriflunomide (adjusted RR 1·02 [0·75–1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09–0·13 vs 0·11 [0·09–0·13]; adjusted RR 1·00 [0·74–1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy’s law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment. Interpretation: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis. Funding: Merck. © 2024 Elsevier Ltd
Document Type: Article
Publication Stage: Article in Press
Source: Scopus