Hope Center Member Publications: October 13, 2024

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, 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., III^r , 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

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

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

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 investigators^r

^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