Publications by authors named "Edward Yang"

150 Publications

Targeting neurological abnormalities in lysosomal storage diseases.

Trends Pharmacol Sci 2021 Nov 27. Epub 2021 Nov 27.

Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA. Electronic address:

Central nervous system (CNS) abnormalities and corresponding neurological and psychiatric symptoms are frequently observed in lysosomal storage disorders (LSDs). The genetic background of individual LSDs is indeed unique to each illness. However, resulting defective lysosomal function within the CNS can transition normal cellular processes (i.e., autophagy) into aberrant mechanisms, facilitating overlapping downstream consequences including neurocircuitry dysfunction, neurodegeneration as well as sensory, motor, cognitive, and psychological symptoms. Here, the neurological and biobehavioral phenotypes of major classes of LSDs are discussed alongside therapeutic strategies in development that aim to tackle neuropathology among other disease elements. Finally, focused ultrasound blood-brain barrier opening is proposed to enhance therapeutic delivery thereby overcoming the key hurdle of central distribution of disease modifying therapies in LSDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tips.2021.11.005DOI Listing
November 2021

Abdominal free fluid in acute pancreatitis predicts necrotizing pancreatitis and organ failure.

Ann Gastroenterol 2021 Nov-Dec;34(6):872-878. Epub 2021 Sep 14.

Division of Gastroenterology, Department of Medicine, UC San Diego, La Jolla, California, USA.

Background: Abdominal free fluid is frequently encountered on cross-sectional imaging for acute pancreatitis and may be a sign of increased severity and complications. This study examines the ability of free fluid to predict necrotizing pancreatitis and other adverse outcomes.

Methods: We conducted a single-center retrospective study of patients with acute pancreatitis and multiple cross-sectional imaging studies. Patients were divided into those who demonstrated free fluid on initial imaging and those without free fluid. The primary outcome was developing necrotizing pancreatitis. Logistic regression analysis assessed the performance of several predictors.

Results: A total of 245 acute pancreatitis patients were included. Pancreatic necrosis occurred more frequently in the free fluid group (31.3 vs. 1.3%, P<0.001). The free fluid group also had higher rates of transient organ failure (17.7 vs. 3.4%, P<0.001), persistent organ failure (17.7 vs. 2.0%, P<0.001), in-hospital mortality (7.3 vs. 1.3%, P=0.016), length of stay (16.2 vs. 5.5 days, P<0.001), and intensive care unit admission (30.2 vs. 4.7%, P<0.001). On multivariate logistic regression, free fluid was the strongest predictor (adjusted odds ratio 17.11, 95% confidence interval 3.68-79.65; P<0.001) for necrotizing pancreatitis, with an excellent performance (area under the curve 0.92). When neither fluid on initial imaging nor persistent systemic inflammatory response syndrome was present, the negative predictive value for developing pancreatic necrosis was 100%.

Conclusions: Free fluid in acute pancreatitis is a strong predictor for necrotizing pancreatitis, organ failure and mortality, and outperformed current predictors. Patients who lacked both free fluid on imaging and persistent systemic inflammatory response syndrome are at low risk for adverse outcomes and may be considered for early discharge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.20524/aog.2021.0666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596223PMC
September 2021

Differences in standardized neonatal encephalopathy exam criteria may impact therapeutic hypothermia eligibility.

Pediatr Res 2021 Nov 9. Epub 2021 Nov 9.

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Background: Therapeutic hypothermia (TH) is routinely provided to those with moderate or severe neonatal encephalopathy (NE). Subtle differences exist in the standardized exams used to define NE severity. We aimed to assess if an infant's TH eligibility status differed if they were evaluated using either the NICHD/Neonatal Research Network's (NICHD-NRN) or TOBY/British Association of Perinatal Medicine's (TOBY-BAPM) neurological exam.

Methods: Encephalopathic infants ≥36 weeks with evidence of perinatal asphyxia and complete documentation of the neurological exam <6 h of age were included. TH eligibility using the NICHD-NRN and TOBY-BAPM criteria was determined based upon the documented exams.

Results: Ninety-one encephalopathic infants were included. Despite good agreement between the two exams (κ = 0.715, p < 0.001), TH eligibility differed between them (p < 0.001). A total of 47 infants were deemed eligible by at least one method-46 using NICHD-NRN and 35 using TOBY-BAPM. Of the 12 infants eligible per NICHD-NRN, but ineligible per TOBY-BAPM, two developed electrographic seizures and seven demonstrated hypoxic-ischemic cerebral injury.

Conclusions: Both the NICHD-NRN and TOBY-BAPM exams are evidence-based. Despite this, there is a significant difference in the number of infants eligible for TH depending on which exam is used. The NICHD-NRN exam identifies a greater proportion as eligible.

Impact: There are subtle differences in the NICHD-NRN and TOBY-BAPM's encephalopathy exams used to determine eligibility for TH. This results in a significant difference in the proportion of infants determined to be eligible for TH depending on which encephalopathy exam is used. The NICHD-NRN encephalopathy exam identifies more infants as being eligible for TH than the TOBY-BAPM encephalopathy exam. This may result in different rates of cooling depending on which evidence-based neurological exam for evaluation of encephalopathy a center uses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41390-021-01834-7DOI Listing
November 2021

High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegia.

Brain Commun 2021 25;3(4):fcab221. Epub 2021 Sep 25.

Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Adaptor protein complex 4-associated hereditary spastic paraplegia is caused by biallelic loss-of-function variants in , , or , which constitute the four subunits of this obligate complex. While the diagnosis of adaptor protein complex 4-associated hereditary spastic paraplegia relies on molecular testing, the interpretation of novel missense variants remains challenging. Here, we address this diagnostic gap by using patient-derived fibroblasts to establish a functional assay that measures the subcellular localization of ATG9A, a transmembrane protein that is sorted by adaptor protein complex 4. Using automated high-throughput microscopy, we determine the ratio of the ATG9A fluorescence in the trans-Golgi-network versus cytoplasm and ascertain that this metric meets standards for screening assays (Z'-factor robust >0.3, strictly standardized mean difference >3). The 'ATG9A ratio' is increased in fibroblasts of 18 well-characterized adaptor protein complex 4-associated hereditary spastic paraplegia patients [mean: 1.54 ± 0.13 versus 1.21 ± 0.05 (standard deviation) in controls] and receiver-operating characteristic analysis demonstrates robust diagnostic power (area under the curve: 0.85, 95% confidence interval: 0.849-0.852). Using fibroblasts from two individuals with atypical clinical features and novel biallelic missense variants of unknown significance in , we show that our assay can reliably detect adaptor protein complex 4 function. Our findings establish the 'ATG9A ratio' as a diagnostic marker of adaptor protein complex 4-associated hereditary spastic paraplegia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/braincomms/fcab221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557665PMC
September 2021

Value of cranial ultrasound at initiation of therapeutic hypothermia for neonatal encephalopathy.

J Perinatol 2021 Oct 18. Epub 2021 Oct 18.

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Objective: There is variation in the clinical practice for the use of cranial ultrasound (cUS) at the time of initiation of therapeutic hypothermia (TH) for neonatal encephalopathy. The role of cUS in selecting patients who may benefit from TH or excluding those where TH may impose risk is unknown.

Study Design: A retrospective study was conducted on infants who received TH at a single tertiary center. Findings from cUS at initiation of TH were compared to findings from MRI following the completion of TH.

Results: One hundred and eight infants were studied. Of the 55 with abnormalities on early cUS, 50 did not have corresponding MRI abnormalities. In contrast, 16 infants had some degree of intracranial hemorrhage detected on their MRI that was not noted on earlier cUS.

Conclusions: This study challenges whether cUS is an essential universal screening tool prior to the commencement of TH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41372-021-01233-0DOI Listing
October 2021

Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia.

Neurology 2021 Nov 20;97(19):e1942-e1954. Epub 2021 Sep 20.

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.

Background And Objectives: AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radioclinical correlations.

Methods: We performed a systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity.

Results: We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor ("ears of the grizzly sign"), and (4) periventricular white matter abnormalities. The presence of 2 or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP; the combination of all 4 is found in ∼45% of cases. Compared to other HSPs with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis identified a subset of patients with polymicrogyria, underscoring the role of AP-4 in early brain development. These patients displayed a higher prevalence of seizures and status epilepticus, many at a young age.

Discussion: Our findings define the MRI spectrum of AP-4-HSP, providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000012836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601212PMC
November 2021

Comparison of numerical and standard sarnat grading using the NICHD and SIBEN methods.

J Perinatol 2021 Aug 14. Epub 2021 Aug 14.

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, USA.

Objective: The NICHD and SIBEN assessments are adapted from the Sarnat grade, and used to determine severity of neonatal encephalopathy (NE). We compare NICHD and SIBEN methods, and their ability to define a minimum threshold associated with significant cerebral injury.

Study Design: Between 2016 and 2019, 145 infants with NE (77-mild; 65-moderate; 3-severe) were included. NICHD and SIBEN grade and numerical scores were assigned. Kappa scores described agreement between methods, and ROC curves their ability to predict MR injury.

Results: Good agreement existed between grading systems (K = 0.86). SIBEN defined more infants as moderate, and less as mild, than NICHD (p < 0.001). Both numerical scores were superior to standard grades in predicting MR injury.

Conclusion: Despite good agreement between methods, SIBEN defines more infants as moderate NE. Both numerical scores were superior to standard grade, and comparable to each other, in defining a minimum threshold for cerebral injury. Further assessment contrasting their predictive ability for long-term outcome is required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41372-021-01180-wDOI Listing
August 2021

Blood gas measures as predictors for neonatal encephalopathy severity.

J Perinatol 2021 09 24;41(9):2261-2269. Epub 2021 Jun 24.

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: To correlate arterial umbilical cord gas (aUCG) and infant blood gas with severity of neurological injury.

Study Design: Retrospective single-site study of infants evaluated for therapeutic hypothermia. Clinical neurological examination and a validated MRI scoring system were used to assess injury severity.

Results: Sixty-eight infants were included. aUCG base deficit (BD) and lactate correlated with infant blood gas counterparts (r = 0.43 and r = 0.56, respectively). aUCG and infant pH did not correlate. Infant blood gas lactate (R = 0.40), infant BD (R = 0.26), infant pH (R = 0.17), aUCG base deficit (R = 0.08), and aUCG lactate (R = 0.11) were associated with clinical neurological examination severity. aUCG and infant blood gas measures were not correlated with MRI score.

Conclusion: Metabolic measures from initial infant blood gases were most associated with the clinical neurological examination severity and can be used to evaluate hypoxic-ischemic cerebral injury risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41372-021-01075-wDOI Listing
September 2021

Convolutional neural networks to identify malformations of cortical development: A feasibility study.

Seizure 2021 Oct 31;91:81-90. Epub 2021 May 31.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA USA.

Objective: To develop and test a deep learning model to automatically detect malformations of cortical development (MCD).

Methods: We trained a deep learning model to distinguish between diffuse cortical malformation (CM), periventricular nodular heterotopia (PVNH), and normal magnetic resonance imaging (MRI). We trained 4 different convolutional neural network (CNN) architectures. We used batch normalization, global average pooling, dropout layers, transfer learning, and data augmentation to minimize overfitting.

Results: There were 45 subjects (866 images) with a normal MRI, 52 subjects (790 images) with CM, and 32 subjects (750 images) with PVNH. There was no subject overlap between the training, validation, and test sets. The InceptionResNetV2 architecture performed best in the validation set in all models and was evaluated in the test set with the following results: 1) the model distinguishing between CM and normal MRI yielded an area under the curve (AUC) of 0.89 and accuracy of 0.81; 2) the model distinguishing between PVNH and normal MRI yielded an AUC of 0.90 and accuracy of 0.84; 3) the model distinguishing between the three classes (CM, PVNH, and normal MRI) yielded an AUC of 0.88 and accuracy of 0.74. Visualization with gradient-weighted class activation maps and saliency maps showed that the deep learning models classified images based on relevant areas within each image.

Significance: This study showed that CNNs can detect MCD at a clinically useful performance level with a fully automated workflow without image feature selection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.seizure.2021.05.023DOI Listing
October 2021

Intracranial Traumatic Hematoma Detection in Children Using a Portable Near-infrared Spectroscopy Device.

West J Emerg Med 2021 Mar 24;22(3):782-791. Epub 2021 Mar 24.

Alpert Medical School of Brown University, Departments of Emergency Medicine and Pediatrics, Providence, Rhode Island.

Introduction: We sought to validate a handheld, near-infrared spectroscopy (NIRS) device for detecting intracranial hematomas in children with head injury.

Methods: Eligible patients were those <18 years old who were admitted to the emergency department at three academic children's hospitals with head trauma and who received a clinically indicated head computed tomography (HCT). Measurements were obtained by a blinded operator in bilateral frontal, temporal, parietal, and occipital regions. Qualifying hematomas were a priori determined to be within the brain scanner's detection limits of >3.5 milliliters in volume and <2.5 centimeters from the surface of the brain. The device's measurements were positive if the difference in optical density between hemispheres was >0.2 on three successive scans. We calculated diagnostic performance measures with corresponding exact two-sided 95% Clopper-Pearson confidence intervals (CI). Hypothesis test evaluated whether predictive performance exceeded chance agreement (predictive Youden's index > 0).

Results: A total of 464 patients were enrolled and 344 met inclusion for primary data analysis: 10.5% (36/344) had evidence of a hematoma on HCT, and 4.7% (16/344) had qualifying hematomas. The handheld brain scanner demonstrated a sensitivity of 58.3% (21/36) and specificity of 67.9% (209/308) for hematomas of any size. For qualifying hematomas the scanner was designed to detect, sensitivity was 81% (13/16) and specificity was 67.4% (221/328). Predictive performance exceeded chance agreement with a predictive Youden's index of 0.11 (95% CI, 0.10 - 0.15; P < 0.001) for all hematomas, and 0.09 (95% CI, 0.08 - 0.12; P < 0.001) for qualifying hematomas.

Conclusion: The handheld brain scanner can non-invasively detect a subset of intracranial hematomas in children and may serve an adjunctive role to head-injury neuroimaging decision rules that predict the risk of clinically significant intracranial pathology after head trauma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5811/westjem.2020.11.47251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203002PMC
March 2021

Magnetic Resonance Imaging (MRI) and Spectroscopy in Succinic Semialdehyde Dehydrogenase Deficiency.

J Child Neurol 2021 Feb 9:883073821991295. Epub 2021 Feb 9.

Contributing authors and affiliations are listed at the end of the article.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of γ-aminobutyric acid (GABA) degradation, resulting in elevations of brain GABA and γ-hydroxybutyric acid (GHB). Previous magnetic resonance (MR) spectroscopy studies have shown increased levels of Glx in SSADH deficiency patients. Here in this work, we measure brain GABA in a large cohort of SSADH deficiency patients using advanced MR spectroscopy techniques that allow separation of GABA from overlapping metabolite peaks. We observed significant increases in GABA concentrations in SSADH deficiency patients for all 3 brain regions that were evaluated. Although GABA levels were higher in all 3 regions, each region had different patterns in terms of GABA changes with respect to age. We also report results from structural magnetic resonance imaging (MRI) of the same cohort compared with age-matched controls. We consistently observed signal hyperintensities in globus pallidus and cerebellar dentate nucleus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0883073821991295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349937PMC
February 2021

A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features.

Genet Med 2021 06 2;23(6):1158-1162. Epub 2021 Feb 2.

Centogene AG, Rostock, Germany.

Purpose: The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10.

Methods: Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry.

Results: A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein.

Conclusion: We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01097-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187145PMC
June 2021

Association between cerebral oxygen saturation and brain injury in neonates receiving therapeutic hypothermia for neonatal encephalopathy.

J Perinatol 2021 02 18;41(2):269-277. Epub 2021 Jan 18.

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: To assess the association of cerebral oxygen saturation (CrSO) collected by near infrared spectroscopy (NIRS) during therapeutic hypothermia (TH) and rewarming with evidence of brain injury on post-rewarming MRI.

Study Design: This retrospective cohort study included 49 infants, who received TH for mild to severe neonatal encephalopathy. Of those, 26 presented with brain injury assessed by a novel MRI grading system, whereas 23 had normal MRI scans.

Results: CrSO increased significantly from the first to the second day of TH in infants with brain injury, whereas it remained stable in patients with normal MRI. Increasing mean CrSO values during rewarming was associated with brain injury (aOR 1.14; 95% CI 1.00-1.28), specifically with gray matter (GM) injury (aOR 1.23; 95% CI 1.02-1.49). The area under the ROC curve showed an excellent discrimination for GM involvement.

Conclusion: Clinically applied NIRS during TH and rewarming can assist in identifying the risk for brain injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41372-020-00910-wDOI Listing
February 2021

Hippocampal Involvement With Vigabatrin-Related MRI Signal Abnormalities in Patients With Infantile Spasms: A Novel Finding.

J Child Neurol 2021 06 12;36(7):575-582. Epub 2021 Jan 12.

Neuroradiology Division, Department of Radiology, 1862Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Background: In a subset of infants exhibiting typical vigabatrin-related magnetic resonance imaging (MRI) changes, the authors observed additional hippocampal signal abnormalities. The authors investigated occurrence and significance of additional signal abnormalities.

Methods: A retrospective review of infantile spasms patients with typical vigabatrin-related MRI abnormalities was performed. Atypical features included signal changes unilaterally or at previously unreported sites. Comparisons were made between patients with and without atypical features.

Results: In all, 26/55 (47%) exhibited typical vigabatrin-related MRI changes, with additional signal abnormalities in the hippocampi in 6 of 26. On follow-up, evolution of hippocampal signal changes paralleled changes at typical locations in 4 patients. Two patients, clinically well, without follow-up MRI. Patients with and without additional hippocampal signal changes did not differ with respect to clinical factors, including seizure status. One patient had unilateral thalamic/cerebral peduncle signal abnormality along with typical vigabatrin changes.

Conclusions: Hippocampal changes seen in subset of patients with typical vigabatrin-related changes may be attributable to vigabatrin exposure in the appropriate circumstance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0883073820985395DOI Listing
June 2021

The N-terminus of varicella-zoster virus glycoprotein B has a functional role in fusion.

PLoS Pathog 2021 01 7;17(1):e1008961. Epub 2021 Jan 7.

Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.

Varicella-zoster virus (VZV) is a medically important alphaherpesvirus that induces fusion of the virion envelope and the cell membrane during entry, and between cells to form polykaryocytes within infected tissues during pathogenesis. All members of the Herpesviridae, including VZV, have a conserved core fusion complex composed of glycoproteins, gB, gH and gL. The ectodomain of the primary fusogen, gB, has five domains, DI-V, of which DI contains the fusion loops needed for fusion function. We recently demonstrated that DIV is critical for fusion initiation, which was revealed by a 2.8Å structure of a VZV neutralizing mAb, 93k, bound to gB and mutagenesis of the gB-93k interface. To further assess the mechanism of mAb 93k neutralization, the binding site of a non-neutralizing mAb to gB, SG2, was compared to mAb 93k using single particle cryogenic electron microscopy (cryo-EM). The gB-SG2 interface partially overlapped with that of gB-93k but, unlike mAb 93k, mAb SG2 did not interact with the gB N-terminus, suggesting a potential role for the gB N-terminus in membrane fusion. The gB ectodomain structure in the absence of antibody was defined at near atomic resolution by single particle cryo-EM (3.9Å) of native, full-length gB purified from infected cells and by X-ray crystallography (2.4Å) of the transiently expressed ectodomain. Both structures revealed that the VZV gB N-terminus (aa72-114) was flexible based on the absence of visible structures in the cryo-EM or X-ray crystallography data but the presence of gB N-terminal peptides were confirmed by mass spectrometry. Notably, N-terminal residues 109KSQD112 were predicted to form a small α-helix and alanine substitution of these residues abolished cell-cell fusion in a virus-free assay. Importantly, transferring the 109AAAA112 mutation into the VZV genome significantly impaired viral propagation. These data establish a functional role for the gB N-terminus in membrane fusion broadly relevant to the Herpesviridae.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1008961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817050PMC
January 2021

Characterization of the GABRB2-Associated Neurodevelopmental Disorders.

Ann Neurol 2021 03 24;89(3):573-586. Epub 2020 Dec 24.

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA.

Objective: We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in the gene GABRB2, coding for the γ-aminobutyric acid type A (GABA ) receptor subunit β2.

Methods: We recruited and systematically evaluated 25 individuals with variants in GABRB2, 17 of whom are newly described and 8 previously reported with additional clinical data. Functional analysis was performed using a Xenopus laevis oocyte model system.

Results: Our cohort of 25 individuals from 22 families with variants in GABRB2 demonstrated a range of epilepsy phenotypes from genetic generalized epilepsy to developmental and epileptic encephalopathy. Fifty-eight percent of individuals had pharmacoresistant epilepsy; response to medications targeting the GABAergic pathway was inconsistent. Developmental disability (present in 84%) ranged from mild intellectual disability to severe global disability; movement disorders (present in 44%) included choreoathetosis, dystonia, and ataxia. Disease-associated variants cluster in the extracellular N-terminus and transmembrane domains 1-3, with more severe phenotypes seen in association with variants in transmembrane domains 1 and 2 and the allosteric binding site between transmembrane domains 2 and 3. Functional analysis of 4 variants in transmembrane domains 1 or 2 (p.Ile246Thr, p.Pro252Leu, p.Ile288Ser, p.Val282Ala) revealed strongly reduced amplitudes of GABA-evoked anionic currents.

Interpretation: GABRB2-related epilepsy ranges broadly in severity from genetic generalized epilepsy to developmental and epileptic encephalopathies. Developmental disability and movement disorder are key features. The phenotypic spectrum is comparable to other GABA receptor-encoding genes. Phenotypic severity varies by protein domain. Experimental evidence supports loss of GABAergic inhibition as the mechanism underlying GABRB2-associated neurodevelopmental disorders. ANN NEUROL 2021;89:573-586.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25985DOI Listing
March 2021

Fetal magnetic resonance imaging: supratentorial brain malformations.

Pediatr Radiol 2020 12 30;50(13):1934-1947. Epub 2020 Nov 30.

Department of Radiology, Boston Children's Hospital, 300 Longwood Ave., Boston, MA, 02115, USA.

Fetal MRI is the modality of choice to study supratentorial brain malformations. To accurately interpret the MRI, the radiologist needs to understand the normal sequence of events that occurs during prenatal brain development; this includes familiarity with the processes of hemispheric cleavage, formation of interhemispheric commissures, neuro-glial proliferation and migration, and cortical folding. Disruption of these processes results in malformations observed on fetal MRI including holoprosencephaly, callosal agenesis, heterotopic gray matter, lissencephaly and other malformations of cortical development (focal cortical dysplasia, polymicrogyria). The radiologist should also be familiar with findings that have high association with specific conditions affecting the central nervous system or other organ systems. This review summarizes and illustrates common patterns of supratentorial brain malformations and emphasizes aspects that are important to patient care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00247-020-04696-zDOI Listing
December 2020

Cholangitis Caused by a Migrated Pancreatic Duct Stent Into the Bile Duct After Pancreaticoduodenectomy.

ACG Case Rep J 2020 Nov 19;7(11):e00477. Epub 2020 Nov 19.

Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14309/crj.0000000000000477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678796PMC
November 2020

Regional Brain Growth Trajectories in Fetuses with Congenital Heart Disease.

Ann Neurol 2021 01 4;89(1):143-157. Epub 2020 Nov 4.

Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.

Objective: Congenital heart disease (CHD) is associated with abnormal brain development in utero. We applied innovative fetal magnetic resonance imaging (MRI) techniques to determine whether reduced fetal cerebral substrate delivery impacts the brain globally, or in a region-specific pattern. Our novel design included two control groups, one with and the other without a family history of CHD, to explore the contribution of shared genes and/or fetal environment to brain development.

Methods: From 2014 to 2018, we enrolled 179 pregnant women into 4 groups: "HLHS/TGA" fetuses with hypoplastic left heart syndrome (HLHS) or transposition of the great arteries (TGA), diagnoses with lowest fetal cerebral substrate delivery; "CHD-other," with other CHD diagnoses; "CHD-related," healthy with a CHD family history; and "optimal control," healthy without a family history. Two MRIs were obtained between 18 and 40 weeks gestation. Random effect regression models assessed group differences in brain volumes and relationships to hemodynamic variables.

Results: HLHS/TGA (n = 24), CHD-other (50), and CHD-related (34) groups each had generally smaller brain volumes than the optimal controls (71). Compared with CHD-related, the HLHS/TGA group had smaller subplate (-13.3% [standard error = 4.3%], p < 0.01) and intermediate (-13.7% [4.3%], p < 0.01) zones, with a similar trend in ventricular zone (-7.1% [1.9%], p = 0.07). These volumetric reductions were associated with lower cerebral substrate delivery.

Interpretation: Fetuses with CHD, especially those with lowest cerebral substrate delivery, show a region-specific pattern of small brain volumes and impaired brain growth before 32 weeks gestation. The brains of fetuses with CHD were more similar to those of CHD-related than optimal controls, suggesting genetic or environmental factors also contribute. ANN NEUROL 2021;89:143-157.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970443PMC
January 2021

Polymicrogyria is Associated With Pathogenic Variants in PTEN.

Ann Neurol 2020 12 8;88(6):1153-1164. Epub 2020 Oct 8.

Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.

Objective: Congenital structural brain malformations have been described in patients with pathogenic phosphatase and tensin homologue (PTEN) variants, but the frequency of cortical malformations in patients with PTEN variants and their impact on clinical phenotype are not well understood. Our goal was to systematically characterize brain malformations in patients with PTEN variants and assess the relevance of their brain malformations to clinical presentation.

Methods: We systematically searched a local radiology database for patients with PTEN variants who had available brain magnetic resonance imaging (MRI). The MRI scans were reviewed systematically for cortical abnormalities. We reviewed electroencephalogram (EEG) data and evaluated the electronic medical record for evidence of epilepsy and developmental delay.

Results: In total, we identified 22 patients with PTEN pathogenic variants for which brain MRIs were available (age range 0.4-17 years). Twelve among these 22 patients (54%) had polymicrogyria (PMG). Variants associated with PMG or atypical gyration encoded regions of the phosphatase or C2 domains of PTEN. Interestingly, epilepsy was present in only 2 of the 12 patients with PMG. We found a trend toward higher rates of global developmental delay (GDD), intellectual disability (ID), and motor delay in individuals with cortical abnormalities, although cohort size limited statistical significance.

Interpretation: Malformations of cortical development, PMG in particular, represent an under-recognized phenotype associated with PTEN pathogenic variants and may have an association with cognitive and motor delays. Epilepsy was infrequent compared to the previously reported high risk of epilepsy in patients with PMG. ANN NEUROL 2020;88:1153-1164.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877488PMC
December 2020

Publisher Correction: A glycoprotein B-neutralizing antibody structure at 2.8 Å uncovers a critical domain for herpesvirus fusion initiation.

Nat Commun 2020 08 28;11(1):4398. Epub 2020 Aug 28.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18385-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455691PMC
August 2020

A glycoprotein B-neutralizing antibody structure at 2.8 Å uncovers a critical domain for herpesvirus fusion initiation.

Nat Commun 2020 08 18;11(1):4141. Epub 2020 Aug 18.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Members of the Herpesviridae, including the medically important alphaherpesvirus varicella-zoster virus (VZV), induce fusion of the virion envelope with cell membranes during entry, and between cells to form polykaryocytes in infected tissues. The conserved glycoproteins, gB, gH and gL, are the core functional proteins of the herpesvirus fusion complex. gB serves as the primary fusogen via its fusion loops, but functions for the remaining gB domains remain unexplained. As a pathway for biological discovery of domain function, our approach used structure-based analysis of the viral fusogen together with a neutralizing antibody. We report here a 2.8 Å cryogenic-electron microscopy structure of native gB recovered from VZV-infected cells, in complex with a human monoclonal antibody, 93k. This high-resolution structure guided targeted mutagenesis at the gB-93k interface, providing compelling evidence that a domain spatially distant from the gB fusion loops is critical for herpesvirus fusion, revealing a potential new target for antiviral therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17911-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435202PMC
August 2020

Success of Nonsedated Neuroradiologic MRI in Children 1-7 Years Old.

AJR Am J Roentgenol 2021 05 12;216(5):1370-1377. Epub 2020 Aug 12.

Department of Radiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02215.

MRI use and the need for monitored anesthesia care (MAC) in children have increased. However, MAC is associated with examination delays, increased cost, and safety concerns. The purpose of this study was to evaluate the success rate of nonsedated neuroradiologic MRI studies in children 1-7 years old and to investigate factors associated with success. We retrospectively reviewed data from our institutional nonsedated MRI program. Inclusion criteria were outpatient nonsedated MRI referral, age 1-7 years old, and neuroradiologic indication. Exclusion criteria were MRI examinations for ventricular checks and contrast material use. Success was determined by reviewing the clinical MRI report. We recorded patient age and sex, type of MRI examination (brain, spine, craniospinal, head and neck, and brain with MRA), protocol length, presence of child life specialist, video goggle use, and MRI appointment time (routine daytime appointment or evening appointment). We used descriptive statistics to summarize patient demographics and clinical data and logistic regression models to evaluate predictors of success in the entire sample. Subset analyses were performed for children from 1 to < 3 years old and 3 to 7 years old. We analyzed 217 patients who underwent nonsedated MRI examinations (median age, 5.1 years). Overall success rate was 82.0% ( = 178). The success rates were 81.4% ( = 127) for brain, 90.3% ( = 28) for spine, 71.4% ( = 10) for craniospinal, 66.7% ( = 6) for head and neck, and 100% ( = 7) for brain with MRA. Age was significantly associated with success (odds ratio [OR], 1.33; = .009). In children 1 to < 3 years old, none of the factors analyzed were significant predictors of success (all, > .48). In children 3-7 years old, protocol duration (OR, 0.96; 95% CI, 0.93-0.99; = .02) and video goggle use (OR, 6.38; 95% CI, 2.16-18.84; = .001) were significantly associated with success. A multidisciplinary approach with age-appropriate resources enables a high success rate for nonsedated neuroradiologic MRI in children 1-7 years old. Using age as the primary criterion to determine the need for MAC may lead to overuse of these services. Dissemination of information regarding nonsedated MRI practice could reduce the rate of sedated MRI in young children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2214/AJR.20.23654DOI Listing
May 2021

Letter: combination of biologics in inflammatory bowel diseases. Authors' reply.

Aliment Pharmacol Ther 2020 08;52(3):568-569

Division of Gastroenterology, Department of Medicine, UCSD Inflammatory Bowel Disease Center, La Jolla, CA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apt.15919DOI Listing
August 2020

Cardiopulmonary Ultrasonography for Severe Coronavirus Disease 2019 Patients in Prone Position.

Card Fail Rev 2020 Mar 14;6:e12. Epub 2020 May 14.

Department of Anesthesiology, Baylor College of Medicine Houston, TX, US.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15420/cfr.2020.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265100PMC
March 2020

Deep learning in rare disease. Detection of tubers in tuberous sclerosis complex.

PLoS One 2020 29;15(4):e0232376. Epub 2020 Apr 29.

Boston Children's Hospital, Harvard Medical School, Boston, MA, United States of America.

Objective: To develop and test a deep learning algorithm to automatically detect cortical tubers in magnetic resonance imaging (MRI), to explore the utility of deep learning in rare disorders with limited data, and to generate an open-access deep learning standalone application.

Methods: T2 and FLAIR axial images with and without tubers were extracted from MRIs of patients with tuberous sclerosis complex (TSC) and controls, respectively. We trained three different convolutional neural network (CNN) architectures on a training dataset and selected the one with the lowest binary cross-entropy loss in the validation dataset, which was evaluated on the testing dataset. We visualized image regions most relevant for classification with gradient-weighted class activation maps (Grad-CAM) and saliency maps.

Results: 114 patients with TSC and 114 controls were divided into a training set, a validation set, and a testing set. The InceptionV3 CNN architecture performed best in the validation set and was evaluated in the testing set with the following results: sensitivity: 0.95, specificity: 0.95, positive predictive value: 0.94, negative predictive value: 0.95, F1-score: 0.95, accuracy: 0.95, and area under the curve: 0.99. Grad-CAM and saliency maps showed that tubers resided in regions most relevant for image classification within each image. A stand-alone trained deep learning App was able to classify images using local computers with various operating systems.

Conclusion: This study shows that deep learning algorithms are able to detect tubers in selected MRI images, and deep learning can be prudently applied clinically to manually selected data in a rare neurological disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232376PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190137PMC
July 2020

Efficacy and safety of simultaneous treatment with two biologic medications in refractory Crohn's disease.

Aliment Pharmacol Ther 2020 06 24;51(11):1031-1038. Epub 2020 Apr 24.

UCSD Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, La Jolla, CA, USA.

Background: Biologic therapies in patients with Crohn's disease often yield low clinical and endoscopic remission rates. After multiple failed therapies, combining two biologic therapies is possibly the sole medical alternative to recurrent surgery. However, data on this approach are limited.

Aims: To assess the efficacy and safety of concomitant use of two biologic therapies in the largest cohort to date of refractory Crohn's disease patients.

Methods: Data were extracted from Crohn's disease patients started on dual biologic therapy at two referral centres. Biologics utilised include infliximab, adalimumab, vedolizumab, ustekinumab, certolizumab and golimumab. The primary outcome was endoscopic improvement (>50% reduction in Simplified Endoscopic Score-Crohn's disease [SES-CD] or explicitly stated). Endoscopic remission (SES-CD < 3 or stated), clinical response (Crohn's disease-patient-reported outcome-2 score [PRO2] reduced by 8), clinical remission (PRO2 < 8), and C-reactive protein (CRP) were also assessed.

Results: A total of 22 patients with 24 therapeutic trials of dual biologic therapy were identified. The majority of patients had prior surgical resections (91%), stricturing (59%) or penetrating (36%) phenotype, and perianal fistulas (50%). Median number of prior failed biologics was 4. Endoscopic improvement occurred in 43% of trials and 26% achieved endoscopic remission. Fifty per cent had clinical response and 41% achieved clinical remission. There were significant post-treatment reductions in median SES-CD (14.0 [12.0-17.5] to 6.0 [2.5-8.0], P = 0.0005], PRO-2 (24.1 [20.3-27.0] to 13.4 [4.6-21.8], P = 0.002] and CRP (17.0 [11.0-24.0] to 9.0 [4.0-14.0], P = 0.02). Presence of perianal fistulas decreased from 50% to 33%. Adverse events occurred in 13% of trials.

Conclusion: Dual biologic therapy was associated with clinical, biomarker and endoscopic improvements in selected patients with refractory Crohn's disease who failed multiple biologics. Further studies are needed to validate this approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apt.15719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032452PMC
June 2020

Patient Perception and Clinical Impact of Direct-to-Consumer Advertising in Inflammatory Bowel Disease.

Dig Dis Sci 2021 01 7;66(1):63-69. Epub 2020 Mar 7.

Division of Digestive and Liver Diseases, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.

Introduction: With an increasing number of available therapies for inflammatory bowel disease (IBD), little is known about patients' attitudes regarding IBD-related direct-to-consumer advertising (IBD-DTCA) and its impact on treatment decisions in clinical practice.

Methods: We administered a 58-item, mailed questionnaire to patients with IBD receiving Gastroenterology subspecialty care at a large academic health system. The survey assessed patient awareness and perception of IBD-DTCA and its effect on IBD treatment discussions and decisions. We used bivariate analysis to evaluate patient-level factors associated with awareness and favorable perception of IBD-DTCA.

Results: We achieved a response rate of 15.2% (n = 226 of 1486). Most patients (93.3%) reported awareness of IBD-DTCA, with adalimumab receiving the most exposure. A majority of respondents reported IBD-DTCA made them more aware of treatments they otherwise would not know about (53.6%), provided information in a balanced manner (63.5%), and taught them about new potential risks and side effects (64.5%). Patients without a college degree and those with a household income less than $75 k per year perceived IBD-DTCA more favorably. However, IBD-DTCA rarely changed IBD management, with only 7.6% of respondents having a discussion with their provider about the advertised drug and only two (0.9%) being initiated on the advertised drug.

Conclusion: IBD patients were aware of IBD-DTCA and perceived it favorably; however, IBD-DTCA rarely led to patient-provider discussions or changes in treatment regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-020-06180-yDOI Listing
January 2021

First report of childhood progressive cerebellar atrophy due to compound heterozygous MTFMT variants.

Clin Genet 2020 05 5;97(5):793-794. Epub 2020 Mar 5.

Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13708DOI Listing
May 2020
-->