The relationship of race, ethnicity, gender identity, sex assigned at birth, sexual orientation, parental education, financial hardship and comorbid mental disorders with quality of life in college students with anxiety, depression or eating disorders
(2024) Journal of Affective Disorders, 366, pp. 335-344.
Baik, S.Y.a , Shin, K.E.b , Fitzsimmons-Craft, E.E.c d , Eisenberg, D.e , Wilfley, D.E.c , Taylor, C.B.f g , Newman, M.G.a
a Department of Psychology, The Pennsylvania State University, University Park, PA, United States
b Department of Behavioral Sciences, Long Island University, Post Campus, Brookville, NY, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
e Department of Health Policy and Management, University of California-Los Angeles, Los Angeles, CA, United States
f Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
g Center for m2Health, Palo Alto University, 5150 El Camino Real, Los Altos, CA, United States
Abstract
Background: Previous studies showed that comorbidity and demographic factors added to burden on health-related quality of life (HRQoL). Only one study explored the relationship between HRQoL and comorbidity in college students with mental disorders, leaving generalizability of findings uncertain. Less is known about the association of demographics on HRQoL. This study investigated HRQoL based on demographics and comorbidity among college students with mental disorders. Methods: Participants were students (N = 5535) across 26 U.S. colleges and universities who met criteria for depression, generalized anxiety, panic, social anxiety, post-traumatic stress, or eating disorders based on self-report measures. ANOVA and linear regressions were conducted. Results: Overall, female, minoritized (gender, sexual orientation, race, or ethnicity), and lower socioeconomic status students reported lower HRQoL than male, heterosexual, White, non-Hispanic, and higher socioeconomic status peers. After accounting for comorbidity, differences in physical HRQoL based on sex assigned at birth and gender were no longer significant. For mental HRQoL, only gender and sexual orientation remained significant. A greater number of comorbidities was associated with lower HRQoL regardless of demographic group. Limitations: The non-experimental design limits causal inference. The study focused on univariable associations without examining potential interactions between demographic factors. Future research should explore structural factors like discrimination. Conclusion: Results suggested that increased comorbidities placed an additional burden on HRQoL and that certain demographic groups were more vulnerable to HRQoL impairment among students with mental disorders. Findings suggest the need for prevention of disorders and their comorbidity and implementing tailored interventions for specific student subgroups with increased vulnerability. © 2024
Author Keywords
College students; Comorbidity; Mental disorder; Mental health; Physical health; Quality of life
Document Type: Article
Publication Stage: Final
Source: Scopus
Histopathologic correlates of opioid-associated injury in CHANTER syndrome: first report of a post-mortem examination
(2024) Acta Neuropathologica, 148 (1), art. no. 33, .
Schwetye, K.E.a , Nair, L.R.b , Boyle, J.c , Barash, J.A.d
a Department of Pathology and Immunology, Washington University School of Medicine, C.B. 8118, 660 S. Euclid Ave, St. Louis, MO 63110, United States
b Department of Pathology and Lab Medicine, Children’s National Hospital, 111 Michigan Avenue Northwest, Washington, DC 20010, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
d Veterans’ Home, 91 Crest Avenue, Chelsea, MA 02150, United States
Abstract
Opioid-associated brain injury may involve selective regions, including the hippocampi alone, globi pallidi, and cerebellar hemispheres. Opioid-associated amnestic syndrome, for example, is one clinical correlate of hippocampal injury as manifest by MRI abnormality. When all three regions are involved in what may be a more fulminant injury, the syndrome is termed “cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER)”, initially described in 2019. Until now, to our knowledge, there have been no histopathologic correlates to the imaging findings specifically in CHANTER syndrome. Here, for the first time, we present histopathologic findings of the post-mortem brain from a patient who died from complications of CHANTER syndrome following fentanyl intoxication. These observations included microhemorrhage, reactive and necrotic vasculature, eosinophilic neuronal necrosis, axonal swelling and spheroids, and frank infarction. The findings support previous experimental models implicating both hypoxic–ischemic and cytotoxic mechanisms in the tissue damage associated with CHANTER syndrome, though further work is needed to better characterize the exact cellular pathways involved to develop targeted treatments. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Mind-wandering in daily life in depressed individuals: An experience sampling study
(2024) Journal of Affective Disorders, 366, pp. 244-253.
Welhaf, M.S.a , Mata, J.b , Jaeggi, S.M.c , Buschkuehl, M.d , Jonides, J.e , Gotlib, I.H.f , Thompson, R.J.a
a Department of Psychological & Brain Sciences, Washington University in St. Louis, United States
b School of Social Sciences, Health Psychology, University of Mannheim, Germany
c Center for Cognitive and Brain Health, Northeastern University, Boston, United States
d MIND Research Institute, United States
e University of Michigan, United States
f Department of Psychology, Stanford University, United States
Abstract
Background: A diagnostic criterion for Major Depressive Disorder (MDD) is difficulty concentrating and increased distractibility. One form of distraction that occurs in everyday life is mind-wandering. The current study aims to test how individuals with MDD and healthy controls differ in their mind-wandering in everyday life. Methods: Adults diagnosed with MDD (n = 53) and healthy controls (n = 53) completed a week of experience sampling, with prompts administered up to eight times per day. At each prompt, participants reported the occurrence and characteristics of their mind-wandering. They also reported levels of momentary negative affect (NA), positive affect (PA), and rumination. Results: MDD participants reported mind-wandering almost twice as often as healthy control participants. Compared to healthy participants, MDD participants rated their mind-wandering as more negative, but did not differ in terms of temporal orientation. Higher NA and lower PA predicted mind-wandering in the MDD group but not healthy controls, even after controlling for rumination. Time-lagged analyses revealed that current mind-wandering predicted future levels of PA in MDD participants but not in healthy controls; in contrast, current NA and PA did not predict future mind-wandering. Limitations: Limitations include our examination of specific forms of mind-wandering (i.e., we did not sample the full spectrum of this construct). Conclusions: Individuals with MDD frequently report engaging in mind-wandering in everyday life, and this appears to be coupled with affect. Mind-wandering may have maladaptive effects in MDD and could serve as a target for intervention. © 2024 The Authors
Author Keywords
Ecological momentary assessment; Major Depressive Disorder; Mind-wandering; Time-lagged analyses
Funding details
National Institute on AgingNIAAG000030-47
National Institute of Mental HealthNIMHR21MH129909, R01MH59259, R01AG070139, R37MH101495
Document Type: Article
Publication Stage: Final
Source: Scopus
Sleep disorder symptoms and suicidal urges among US Marines seeking suicide treatment: Findings from an intensive daily assessment study
(2024) Journal of Psychiatric Research, 178, pp. 388-396.
Brown, L.A.a , Zhu, Y.a b , Feler, B.a , Kautz, M.a , Taylor, D.J.c , Pruiksma, K.E.d , Baker, J.e , Young, J.e , Khazem, L.e , Bryan, C.J.e , Wiley, J.f
a Department of Psychiatry, University of Pennsylvania, United States
b Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
c Department of Psychology, University of Arizona, Tucson, AZ, United States
d Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
e Department of Psychiatry & Behavioral Health, The Ohio State University College of Medicine, Columbus, OH, United States
f Turner Institute for Brain & Mental Health, Monash University, United States
Abstract
Background: Rates of suicide in United States Marines are among the highest in the military, and sleep disorder symptoms are a known risk factor for suicide in the military. Intensive ecological momentary assessments (EMA) might improve the ability to detect periods that are characterized by increased suicidal ideation. Marines who were at high risk for suicide were intensively assessed for one month on sleep, suicidal urges, posttraumatic stress disorder (PTSD) and depression symptoms. Methods: U.S. Marines (N = 40) who had a past month suicide attempt or suicidal urges with intent were sent EMA for 28 days. Mixed effects models explored associations among daily sleep, suicidal urges, PTSD, and depression symptoms. Results: Worsened sleep indicators on a given night significantly predicted higher maximum values of suicide urges the following day. Worse sleep quality the prior night was moderately associated with more severe PTSD symptoms and depression symptoms. Greater severity of PTSD symptoms and depression symptoms were strongly associated with both the maximum value and the range of suicide urges. PTSD and depression symptoms mediated the relationship between sleep quality and suicidal urges. Participants reported that 0000–0300 had the greatest elevation in endorsement of highest suicide urges. Limitations: This study had a small sample size may not generalize beyond active duty Marines. Conclusions: Poor sleep quality and other sleep markers were an important risk factor for suicidal urges among U.S. Marines. This relationship was mediated by exacerbations in PTSD and depression symptoms. Interventions are needed to interrupt suicide risk during and following nights with poor sleep. © 2024
Author Keywords
Military; Posttraumatic stress disorder; Sleep; Suicidal ideation
Funding details
Penn Mental Health AIDS Research CenterPMHARC
Military Suicide Research ConsortiumMSRC
W81XWH-16- 2-0004
U.S. Department of DefenseDODW81XWH-18-2-002
National Institute of Mental HealthNIMH5P50MH127511, R01MH13274001A1
National Institutes of HealthNIHP30 MH 097488
Document Type: Article
Publication Stage: Final
Source: Scopus
Effect of vagus nerve stimulation on emergency department utilization in children with drug-resistant epilepsy: a retrospective cohort study
(2024) Journal of Neurosurgery: Pediatrics, 34 (3), pp. 260-267.
Muthiah, N.a b , Reecher, H.M.c , Abel, T.J.b d
a Department of Neurological Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
c 3Department of Neurological Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; and
d Department of Bioengineering, University of PittsburghPA, United States
Abstract
OBJECTIVE: Epilepsy affects approximately 470,000 children in the United States. The estimated median incidence is 50.4 cases per 100,000 persons per year. There are approximately 3.1 million seizure-related emergency department (ED) visits per year among children. Vagus nerve stimulation (VNS) is a treatment option for drug-resistant epilepsy (DRE). While its primary goal is to decrease seizure burden, VNS may decrease seizure intensity and improve quality of life. The authors assessed whether VNS decreased the number of seizure-related ED visits in a cohort of children with DRE. METHODS: The authors performed a retrospective chart review of pediatric patients (aged 0-21 years) who underwent implantation of a vagus nerve stimulator between January 2009 and January 2020 at the University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh. They used paired t-tests to assess differences in the number of ED visits 2 years before versus 2 years after VNS device implantation. Univariable linear regression analyses were used to test associations of preoperative characteristics with change in the number of ED visits following vagus nerve stimulator insertion. RESULTS: This study included 240 patients. Compared with patients without seizure-related ED visits before VNS, patients with ≥ 1 ED visits were younger in age at first VNS surgery (9.5 vs 10.8 years), had a shorter epilepsy duration before VNS surgery (5.8 vs 7.4 years), had a later year of device implantation (2014 vs 2012), and on average took more antiseizure medications (ASMs; 2.4 vs 2.1). There was no significant difference between the total number of seizure-related ED visits pre- versus post-VNS surgery (1.72 vs 1.59, p = 0.50), and no difference in status epilepticus-related visits (0.59 vs 0.46, p = 0.17). Univariable linear regression analyses revealed a mean change in ED visits of +0.3 for each year prior to 2022 and -0.5 for each additional ASM that patients took before vagus nerve stimulator insertion. CONCLUSIONS: This single-institution analysis demonstrated no significant change in the number of seizure-related ED visits within 2 years following VNS device implantation. Earlier VNS surgery was associated with more seizure-related ED visits after device insertion, suggesting that medical management and center experience may play a role in decreasing seizure-related ED visits. A greater number of ASMs was associated with fewer seizure-related ED visits after VNS device insertion, suggesting the role of medical management, patient baseline seizure threshold, and caregiver comfort with at-home seizure management.
Author Keywords
epilepsy; healthcare utilization; seizures; vagus nerve stimulation; VNS
Document Type: Article
Publication Stage: Final
Source: Scopus
Neuropathic Pain With and Without Diabetic Peripheral Neuropathy in Type 1 Diabetes
(2024) Diabetes Care, 47 (9), pp. 1559-1567. Cited 1 time.
Braffett, B.H.a , El Ghormli, L.a , Albers, J.W.b , Feldman, E.L.b , Herman, W.H.b , Gubitosi-Klug, R.A.c , Martin, C.L.b , Orchard, T.J.d , White, N.H.e , Lachin, J.M.a , Perkins, B.A.f , Pop-Busui, R.b , for the DCCT/EDIC Research Groupg
a Biostatistics Center, The George Washington University, Rockville, MD, United States
b University of Michigan Medical School, Ann Arbor, MI, United States
c Case Western Reserve University, Rainbow Babies and Children’s Hospital, Cleveland, OH, United States
d Pitt Public Health, University of Pittsburgh, Pittsburgh, PA, United States
e Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
f Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, ON, Canada
Abstract
OBJECTIVE Diabetic peripheral neuropathy (DPN) is common; however, the features and burden of neuropathic pain (NP) in type 1 diabetes (T1D) are poorly understood. We evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for NP during long-term follow-up of participants with T1D. RESEARCH DESIGN AND METHODS The Michigan Neuropathy Screening Instrument (MNSI) was administered annually (1994–2020) for 1,324 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. NP with clinical signs of DPN (NP DPN+) was defined according to self-reported NP plus an examination score >2, while NP without clinical signs of DPN (NP DPN-) was defined according to self-reported NP and an examination score ≤2. RESULTS At EDIC year 1, median age for participants was 36 years (interquartile range 30, 41), diabetes duration 13 years (10, 18), and HbA1c 7.9% (7.2, 8.9). At year 26 (median diabetes duration 39 years), cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs. 46% NP DPN-). NP prevalence was 20% at 26 years (11% NP DPN+ and 9% NP DPN-), suggesting frequent remission. Annualized remission rates were similar regardless of pain medication use. In addition to HbA1c, female sex was associated with NP DPN-. CONCLUSIONS NP incidence in T1D was high and frequently occurred in the absence of clinical signs of neuropathy, as assessed with the MNSI. Pain remission was not explained by pain medication use. Effective clinical strategies for identification and management are needed. © 2024 by the American Diabetes Association.
Document Type: Article
Publication Stage: Final
Source: Scopus
Language and the Cerebellum: Structural Connectivity to the Eloquent Brain
(2024) Neurobiology of Language, 5 (3), pp. 652-675. Cited 1 time.
Jobson, K.R.a , Hoffman, L.J.a , Metoki, A.b , Popal, H.a , Dick, A.S.c , Reilly, J.a d , Olson, I.R.a
a Department of Psychology, Temple University, Philadelphia, PA, United States
b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychology, Florida International University, Miami, FL, United States
d Department of Speech and Language Sciences, Temple University, Philadelphia, PA, United States
Abstract
Neurobiological models of receptive language have focused on the left-hemisphere perisylvian cortex with the assumption that the cerebellum supports peri-linguistic cognitive processes such as verbal working memory. The goal of this study was to identify language-sensitive regions of the cerebellum then map the structural connectivity profile of these regions. Functional imaging data and diffusion-weighted imaging data from the Human Connectome Project (HCP) were analyzed. We found that (a) working memory, motor activity, and language comprehension activated partially overlapping but mostly unique subregions of the cerebellum; (b) the linguistic portion of the cerebello-thalamo-cortical circuit was more extensive than the linguistic portion of the cortico-ponto-cerebellar tract; (c) there was a frontal-lobe bias in the connectivity from the cerebellum to the cerebrum; (d) there was some degree of specificity; and (e) for some cerebellar tracts, individual differences in picture identification ability covaried with fractional anisotropy metrics. These findings yield insights into the structural connectivity of the cerebellum as relates to the uniquely human process of language comprehension. © 2022 Massachusetts Institute of Technology.
Author Keywords
cerebellum; diffusion imaging; frontal lobe; human connectome project; language; tractography; white matter
Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Army Research LaboratoryARLW911NF-16-2-0189
National Institutes of HealthNIHR21 HD098509
National Institute of Mental HealthNIMHMH091113
National Science FoundationNSF1625061
National Institute of Child Health and Human DevelopmentNICHDR01HD099165
Document Type: Article
Publication Stage: Final
Source: Scopus
Characterization and individual-level prediction of cognitive state in the first year after ‘mild’ stroke
(2024) PLoS ONE, 19 (8), art. no. e0308103, .
Saa, J.P.a b , Tse, T.a , Koh, G.C.-H.c , Yap, P.d , Baum, C.M.e , Uribe-Rivera, D.E.f , Windecker, S.M.g , Ma, H.h , Davis, S.M.i , Donnan, G.A.i , Carey, L.M.a b j
a School of Allied Health, Human Services and Sport, College of Science Health and Engineering, La Trobe University, Melbourne, Australia
b The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia
c Saw-Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
d Khoo Teck Puat Hospital, Singapore, Singapore
e School of Public Health, Washington University School of Medicine, Saint Louis, MO, United States
f Commonwealth Scientific and Industrial Research Organisation (CSIRO) of Australia, Brisbane, QLD, Australia
g Telethon Kids Institute, Perth, Australia
h Department of Medicine, Monash Health, Monash University, Clayton, Australia
i Departments of Medicine and Neurology, Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia
j Care Economy Research Institute, La Trobe University, Bundoora, Australia
Abstract
Background Mild stroke affects more than half the stroke population, yet there is limited evidence characterizing cognition over time in this population, especially with predictive approaches applicable at the individual-level. We aimed to identify patterns of recovery and the best combination of demographic, clinical, and lifestyle factors predicting individual-level cognitive state at 3- and 12-months after mild stroke. Methods In this prospective cohort study, the Montreal Cognitive Assessment (MoCA) was administered at 3–7 days, 3- and 12-months post-stroke. Raw changes in MoCA and impairment rates (defined as MoCA<24 points) were compared between assessment time-points. Trajectory clusters were identified using variations of ≥1 point in MoCA scores. To further compare clusters, additional assessments administered at 3- and 12-months were included. Gamma and Quantile mixed-effects regression were used to predict individual MoCA scores over time, using baseline clinical and demographic variables. Model predictions were fitted for each stroke survivor and evaluated using model cross-validation to identify the overall best predictors of cognitive recovery. Results Participants’ (n = 119) MoCA scores improved from baseline to 3-months (p<0.001); and decreased from 3- to 12-months post-stroke (p = 0.010). Cognitive impairment rates decreased significantly from baseline to 3-months (p<0.001), but not between 3- and 12-months (p = 0.168). Nine distinct trajectory clusters were identified. Clinical characteristics between clusters at each time-point varied in cognitive outcomes but not in clinical and/or activity participation outcomes. Cognitive performance at 3- and 12-months was best predicted by younger age, higher physical activity levels, and left-hemisphere lesion side. Conclusion More than half of mild-stroke survivors are at risk of cognitive decline one year after stroke, even when preceded by a significantly improving pattern in the first 3-months of recovery. Physical activity was the only modifiable factor independently associated with cognitive recovery. Individual-level prediction methods may inform the timing and personalized application of future interventions to maximize cognitive recovery post-stroke. © 2024 Saa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Document Type: Article
Publication Stage: Final
Source: Scopus
Accumulation of alkyl-lysophosphatidylcholines in Niemann-Pick disease type C1
(2024) Journal of Lipid Research, 65 (8), art. no. 100600, .
Mishra, S.a , Kell, P.a , Scherrer, D.a , Dietzen, D.J.b , Vite, C.H.c , Berry-Kravis, E.d , Davidson, C.e , Cologna, S.M.f , Porter, F.D.e , Ory, D.S.g , Jiang, X.a
a Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Clinical Studies and Advanced Medicine, University of Pennsylvania School of Veterinary MedicinePA, United States
d Department of Pediatrics, Neurological Sciences and Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States
e Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD, United States
f Department of Chemistry, University of Illinois Chicago, Chicago, IL, United States
g Arbor Biotechnologies, Cambridge, MA, United States
Abstract
Lysosomal function is impaired in Niemann-Pick disease type C1 (NPC1), a rare and inherited neurodegenerative disorder, resulting in late endosomal/lysosomal accumulation of unesterified cholesterol. The precise pathogenic mechanism of NPC1 remains incompletely understood. In this study, we employed metabolomics to uncover secondary accumulated substances in NPC1. Our findings unveiled a substantial elevation in the levels of three alkyl-lysophosphatidylcholine [alkyl-LPC, also known as lyso-platelet activating factor (PAF)] species in NPC1 compared to controls across various tissues, including brain tissue from individuals with NPC1, liver, spleen, cerebrum, cerebellum, and brain stem from NPC1 mice, as well as in both brain and liver tissue from NPC1 cats. The three elevated alkyl-LPC species were as follows: LPC O-16:0, LPC O-18:1, and LPC O-18:0. However, the levels of PAF 16:0, PAF 18:1, and PAF 18:0 were not altered in NPC1. In the NPC1 feline model, the brain and liver alkyl-LPC levels were reduced following 2-hydroxypropyl-β-cyclo-dextrin (HPβCD) treatment, suggesting that alkyl-LPCs are secondary storage metabolites in NPC1 disease. Unexpectedly, cerebrospinal fluid (CSF) levels of LPC O-16:0 and LPC O-18:1 were decreased in individuals with NPC1 compared to age-appropriate comparison samples, and their levels were increased in 80% of participants 2 years after intrathecal HPβCD treatment. The fold increases in CSF LPC O-16:0 and LPC O-18:1 levels were more pronounced in responders compared to nonresponders. This study identified alkyl-LPC species as secondary storage metabolites in NPC1 and indicates that LPC O-16:0 and LPC O-18:1, in particular, could serve as potential biomarkers for tracking treatment response in NPC1 patients. © 2024 THE AUTHORS.
Author Keywords
alkyl-lysophosphatidylcholine; biomarker; mass spectrometry; Niemann-Pick disease type C; structural identification
Document Type: Article
Publication Stage: Final
Source: Scopus
Clinical Features and Disease Progression in Older Individuals with Rett Syndrome
(2024) Genes, 15 (8), art. no. 1107, .
Neul, J.L.a , Benke, T.A.b , Marsh, E.D.c , Suter, B.d , Fu, C.a , Ryther, R.C.e , Skinner, S.A.f , Lieberman, D.N.g , Feyma, T.h , Beisang, A.h , Heydemann, P.i , Peters, S.U.a , Ananth, A.j , Percy, A.K.j
a Department of Pediatrics, Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN 37232, United States
b Department of Pediatrics, Neurology and Pharmacology, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, CO 80045, United States
c Department of Neurology, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, United States
d Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States
e Department of Neurology, Washington University School of Medicine, St. LouisMO 63110, United States
f Greenwood Genetic Center, Greenwood, SC 29646, United States
g Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, United States
h Gillette Children’s Specialty Healthcare, St Paul, MN 55101, United States
i Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, United States
j Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, United States
Abstract
Although long-term survival in Rett syndrome (RTT) has been observed, limited information on older people with RTT exists. We hypothesized that increased longevity in RTT would be associated with genetic variants in MECP2 associated with milder severity, and that clinical features would not be static in older individuals. To address these hypotheses, we compared the distribution of MECP2 variants and clinical severity between younger individuals with Classic RTT (under 30 years old) and older individuals (over 30 years old). Contrary to expectation, enrichment of a severe MECP2 variant (R106W) was observed in the older cohort. Overall severity was not different between the cohorts, but specific clinical features varied between the cohorts. Overall severity from first to last visit increased in the younger cohort but not in the older cohort. While some specific clinical features in the older cohort were stable from the first to the last visit, others showed improvement or worsening. These data do not support the hypothesis that mild MECP2 variants or less overall severity leads to increased longevity in RTT but demonstrate that clinical features change with increasing age in adults with RTT. Additional work is needed to understand disease progression in adults with RTT. © 2024 by the authors.
Author Keywords
clinical severity; disease progression; MECP2; old age; Rett syndrome
Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
International Rett Syndrome FoundationIRSF
National Institutes of HealthNIHU54HD061222, P50HD103537, UL1TR0030396
University of Alabama at BirminghamUABUL1TR002243
Document Type: Article
Publication Stage: Final
Source: Scopus
Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells
(2024) Nature Genetics, . Cited 1 time.
Jang, H.J.a b c , Shah, N.M.a b , Maeng, J.H.a b , Liang, Y.a b , Basri, N.L.a b , Ge, J.a b , Qu, X.a b , Mahlokozera, T.d , Tzeng, S.-C.e , Williams, R.B.e , Moore, M.J.a b , Annamalai, D.d , Chen, J.Y.a b , Lee, H.J.a b , DeSouza, P.A.d , Li, D.a b , Xing, X.a b , Kim, A.H.d f , Wang, T.a b g
a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, United States
d Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
e Donald Danforth Plant Science Center, St. Louis, MO, United States
f The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
g McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden. We treated patient-derived primary glioblastoma stem cell lines, an astrocyte cell line and primary fibroblast cell lines with epigenetic drugs, and identified treatment-induced, TE-derived transcripts that are preferentially expressed in cancer cells. We verified that these transcripts could produce human leukocyte antigen class I-presented antigens using liquid chromatography with tandem mass spectrometry pulldown experiments. Importantly, many TEs were also transcribed, even in proliferating nontumor cell lines, after epigenetic therapy, which suggests that targeted strategies like CRISPR-mediated activation could minimize potential side effects of activating unwanted genomic regions. The results highlight both the need for caution and the promise of future translational efforts in harnessing treatment-induced TE-derived antigens for targeted immunotherapy. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Evolution of Proton Radiation Therapy Brainstem Constraints on the Pediatric Proton/Photon Consortium Registry
(2024) Practical Radiation Oncology, .
Correia, D.a b c , Indelicato, D.J.d , Paulino, A.C.e , Ermoian, R.f , Mihalcik, S.g , Perkins, S.M.h , Hill-Kayser, C.i , Mangona, V.S.j , Lee, J.k , Chang, J.H.-C.l , Laack, N.N.m , Kwok, Y.n , Perentesis, J.o , Vatner, R.p , Dave, R.q r , Gallotto, S.L.a , Lawell, M.P.a , Bajaj, B.V.M.a , Allison, K.W.a , Perry, A.a , Yock, T.I.a
a Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
b Department of Radiation Oncology, Cantonal Hospital Aarau, Aargau, Aarau, Switzerland
c Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Switzerland
d Department of Radiation Oncology, University of Florida, Jacksonville, Florida, United States
e Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
f Department of Radiation Oncology, University of Washington, Seattle, WA, United States
g Northwestern Medicine Chicago Proton Center, Warrenville, IL, United States
h Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, United States
i Department of Radiation Oncology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States
j Department of Radiation Oncology, Texas Center for Proton Therapy, Irving, TX, United States
k Department of Radiation Oncology, ProCure Proton Therapy Center, Franklin Township, New Jersey, United States
l Department of Radiation Oncology, The Oklahoma Proton Center and University of Oklahoma Health Science Center, Oklahoma City, OK, United States
m Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, United States
n Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, Maryland, United States
o Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
p Department of Radiation Oncology, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
q Medical College of Georgia, Augusta University, Augusta, Georgia
r Department of Pediatrics, Emory University, Atlanta, Georgia
Abstract
Purpose: Increasing concern that brainstem toxicity incidence after proton radiation therapy might be higher than with photons led to a 2014 University of Florida (UF) landmark paper identifying its risk factors and proposing more conservative dose constraints. We evaluated how practice patterns changed among the Pediatric Proton/Photon Consortium Registry (PPCR). Material and Methods: This prospective multicenter cohort study gathered data from patients under the age of 22 years enrolled on the PPCR, treated between 2002 and 2019 for primary posterior fossa brain tumors. After standardizing brainstem contours, we garnered dosimetry data and correlated those meeting the 2014 proton-specific brainstem constraint guidelines by treatment era, histology, and extent of surgical resection. Results: A total of 467 patients with evaluable proton radiation therapy plans were reviewed. Median age was 7.1 years (range: <1-21.9), 63.0% (n = 296) were men, 76.0% (n = 357) were White, and predominant histology was medulloblastoma (55.0%, n = 256), followed by ependymoma (27.0%, n = 125). Extent of resection was mainly gross total resection (GTR) (67.0%, n = 312), followed by subtotal resection (STR) or biopsy (20.0%, n = 92), and near total resection (NTR) (9.2%, n = 43). The UF brainstem constraint metrics most often exceeded were the goal D50% of 52.4 gray relative biological equivalents (43.3%, n = 202) and maximal D50% of 54 gray relative biological equivalents (12.6%, n = 59). The compliance rate increased after the new guidelines (2002-2014: 64.0% vs 2015-2019: 74.6%, P =. 02), except for ependymoma (46.3% pre- vs 50.0% post-guidelines, P =. 86), presenting lower compliance (48.8%) in comparison to medulloblastoma/ primitive neuroectodermal tumors/pineoblastoma (77.7%), glioma (89.1%), and atypical teratoid/rhabdoid tumors (90.9%) (P <. 001). Degree of surgical resection did not affect compliance rates (GTR/NTR 71.0% vs STR/biopsy 72.8%, P =. 45), even within the ependymoma subset (GTR/NTR 50.5% vs STR/biopsy 38.1%, P =. 82). Conclusion: Since the publication of the UF guidelines, the pediatric proton community has implemented more conservative brainstem constraints in all patients except those with ependymoma, irrespective of residual disease after surgery. Future work will evaluate if this change in practice is associated with decreased rates of brainstem toxicity. © 2024
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy
(2024) Annals of Clinical and Translational Neurology, .
Mohan, S.a , McNulty, S.a , Thaxton, C.a , Elnagheeb, M.a , Owens, E.a , Flowers, M.a , Nunnery, T.a , Self, A.a , Palus, B.a , Gorokhova, S.b c , Kennedy, A.d , Niu, Z.e , Johari, M.f g , Maiga, A.B.h , Macalalad, K.i , Clause, A.R.i , Beckmann, J.S.j , Bronicki, L.k , Cooper, S.T.l m n , Ganesh, V.S.o p , Kang, P.B.q , Kesari, A.r , Lek, M.s , Levy, J.t , Rufibach, L.u , Savarese, M.g , Spencer, M.J.v , Straub, V.w , Tasca, G.w , Weihl, C.C.i
a Department of Genetics, University of North Carolina, Chapel Hill, NC, United States
b Aix Marseille Univ, INSERM, MMG, U 1251, Marseille, France
c Department of Medical Genetics, Timone Children’s Hospital, APHM, Marseille, France
d Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada
e Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
f Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia
g Folkhälsan Research Center, Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
h Department of Medicine, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali
i Department of Neurology, Washington University School of Medicine in St. Louis, St Louis, MO, United States
j Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
k Department of clinical genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
l Kids Neuroscience Centre, Children’s Hospital at Westmead, Westmead, NSW, Australia
m School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
n Functional Neuromics, Children’s Medical Research Institute, Westmead, NSW, Australia
o Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
p Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
q Greg Marzolf Jr. Muscular Dystrophy Center and Department of Neurology, University of Minnesota, Minneapolis, MN, United States
r Illumina Inc, San Diego, CA, United States
s Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
t Coalition to Cure Calpain 3, Westport, CT, United States
u Jain Foundation, Seattle, WA, United States
v Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
w John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trusts, Newcastle Upon Tyne, United Kingdom
Abstract
Objective: Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. Methods: The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene–disease relationships (GDR) using the ClinGen gene–disease clinical validity framework to evaluate 31 genes implicated in LGMD. Results: The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. Interpretation: The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations. © 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The Impact of Cultural and Institutional Race-Related Stress on Mental Health Outcomes Among Ethnic/Racially Minoritized Young Adults: Ethnic Identity as a Protective Factor
(2024) American Journal of Orthopsychiatry, .
Brown, K.L.a , Banks, D.E.b , Zapolski, T.C.B.c
a Department of Psychological Science, University of Missouri, St. Louis, United States
b Department of Psychiatry, Washington University, St. Louis, United States
c Department of Psychology, Indiana University Purdue University, Indianapolis, United States
Abstract
Racism is multidimensional with three main domains: individual, cultural, and institutional. Much of the research linking racism/race-related stress to negative health outcomes have focused on race-related stress based on full-scale scores or within the individual domain of racism. Far less research has examined the cultural and institutional domains. Thus, the present study examined whether (a) there is a direct positive effect of cultural and institutional race-related stress on anxiety and depressive symptoms among a sample of ethnic/racially minoritized (ERM) young adults and whether (b) ethnic identity affirmation, belongingness, and commitment (EI-ABC), which has been identified as a protective factor of racism, buffers the effect of cultural and institutional race-related stress on symptoms of anxiety and depression. A total of 515 ERM young adults (58.5% females, Mage = 23.94, SD = 5.86) completed an online study examining stress and health outcomes among ERM young adults. A series of multiple regression analyses were used to examine the relationship between racerelated stress and anxiety and depressive symptoms and the moderating role of EI-ABC. Cultural and institutional race-related stress were found to significantly predict symptoms of depression and anxiety. Further, EI-ABC significantly buffered the effect of cultural (but not institutional) race-related stress on anxiety symptoms. Interventions for cultural race-related stress among ERMs that target anxiety symptoms should include building high EI-ABC. Additional research should identify factors that may alleviate symptoms of anxiety or depression associated with experiencing cultural and institutional race-related stress among ERM young adults. © 2024 Global Alliance for Behavioral Health and Social Justice
Author Keywords
cultural race-related stress; distress; ethnic identity; ethnic/racial minorities; institutional race-related stress
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A single-center retrospective series of OCT and MRI findings in pediatric MOGAD optic neuritis patients
(2024) Canadian Journal of Ophthalmology, .
Guniganti, R.a , Rho, S.a , Morales-Leόn, J.F.b , Mar, S.c , Lee, A.a , Goyal, M.b , Reynolds, M.M.a , Van Stavern, G.P.a
a Department of Ophthalmology & Visual Sciences, Washington University in St Louis, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University in St Louis, St. Louis, MO, United States
c Division of Pediatric & Developmental Neurology, Department of Neurology, St Louis Children’s Hospital, St. Louis, MO, United States
Abstract
Background: Whether optical computed tomography (OCT) and magnetic resonance imaging (MRI) findings are associated with final visual acuity in children with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) optic neuritis is unclear. Methods: We retrospectively reviewed the charts of pediatric patients with MOGAD optic neuritis seen at St. Louis Children’s Hospital/Barnes Jewish Hospital since 2016. Results: In the 12 patients in this study, presenting visual acuity was worse in the optic neuritis-affected eyes but significantly improved from presentation to follow-up, such that, at last follow-up, there was no longer a statistical difference between the affected and unaffected eyes. The number of affected eyes with nerve enhancement and the amount of optic nerve affected, as well as thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and macula, decreased from presentation to follow-up. Ultimately, none of these variables were associated with final visual acuity. Conclusion: In this cohort, pediatric MOGAD optic neuritis patients had positive visual outcomes despite significant RNFL thinning and involvement of the optic nerve on MRI, leading to a lack of correlation between follow-up visual acuity and OCT and MRI measures of disease severity, respectively. © 2024 Canadian Ophthalmological Society
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Isoflurane conditioning improves functional outcomes after peripheral nerve injury in a sciatic cut repair murine model
(2024) Frontiers in Neurology, 15, art. no. 1406463, .
Xu, Y.a , Yan, Y.b , Zipfel, G.J.b c , MacEwan, M.b , Ray, W.Z.b d e , Athiraman, U.b f
a The Institute of Materials Science & Engineering, Washington University, St. Louis, MO, United States
b Department of Neurological Surgery, Washington University, St. Louis, MO, United States
c Department of Neurology, Washington University, St. Louis, MO, United States
d Department of Orthopedic Surgery, Washington University, St. Louis, MO, United States
e Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
f Department of Anesthesiology, Washington University, St. Louis, MO, United States
Abstract
Introduction: Anesthetic conditioning has been shown to provide neuroprotection in several neurological disorders. Whether anesthetic conditioning provides protection against peripheral nerve injuries remains unknown. The aim of our current study is to investigate the impact of isoflurane conditioning on the functional outcomes after peripheral nerve injury (PNI) in a rodent sciatic nerve injury model. Methods: Adult male Lewis rats underwent sciatic nerve cut and repair and exposed to none (Group 1, sham), single isoflurane exposure (Group 2), three-time isoflurane exposure (Group 3), and six-time isoflurane exposure (Group 4). Isoflurane conditioning was established by administration of 2% isoflurane for 1 hour, beginning 1-hour post sciatic nerve cut and repair. Groups 3 and 4 were exposed to isoflurane for 1 hour, 3 and 6 consecutive days respectively. Functional outcomes assessed included compound muscle action potential (CMAP), evoked muscle force (tetanic and specific tetanic force), wet muscle mass, and axonal counting. Results: We observed an increase in axons, myelin width and a decrease in G-ratio in the isoflurane conditioning groups (3- and 6-days). This correlated with a significant improvement in tetanic and specific tetanic forces, observed in both groups 3 and 4. Discussion: Isoflurane conditioning (3- and 6-day groups) resulted in improvement in functional outcomes at 12 weeks post peripheral nerve injury and repair in a murine model. Future experiments should be focused on identifying the therapeutic window of isoflurane conditioning and exploring the underlying molecular mechanisms responsible for isoflurane conditioning induced neuroprotection in PNI. Copyright © 2024 Xu, Yan, Zipfel, MacEwan, Ray and Athiraman.
Author Keywords
axonal regeneration; functional outcomes; isoflurane conditioning; myelin regeneration; neuroprotection; peripheral nerve injury
Document Type: Article
Publication Stage: Final
Source: Scopus
Body mass index is lower in asymptomatic C9orf72 expansion carriers but not in SOD1 pathogenic variant carriers compared to gene negatives
(2024) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, .
Lee, I.a , Garret, M.A.b , Wuu, J.c , Harrington, E.A.a , Berry, J.D.b , Miller, T.M.d , Harms, M.a , Benatar, M.c , Shneider, N.a
a Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
b Sean M. Healey & AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
c Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States
d Department of Neurology, Washington University, St. Louis, MO, United States
Abstract
Objective: To examine the relationship between body mass index (BMI) and genotype among pre-symptomatic carriers of different pathogenic variants associated with amyotrophic lateral sclerosis. Methods: C9orf72+ carriers, SOD1+ carriers, and pathogenic variant negative controls (Gene-Negatives) were included from 3 largely independent cohorts: ALS Families Project (ALS-Families); Dominantly inherited ALS (DIALS); and Pre-symptomatic Familial ALS (Pre-fALS). First reported (ALS-Families) or measured (DIALS and Pre-fALS) weight and height were used to calculate BMI. Age at weight measurement, self-reported sex (male vs. female), and highest education (high school or below vs. college education vs. graduate school or above) were extracted. The associations between BMI and genotype in each cohort were examined with multivariable linear regression models, adjusted for age, sex, and education. Results: A total of 223 C9orf72+ carriers, 135 SOD1+ carriers, and 191 Gene-Negatives were included, deriving from ALS-Families (n = 114, median age 46, 37% male), DIALS (n = 221, median age 46, 30% male), and Pre-fALS (n = 214, median age 44, 39% male). Adjusting for age, sex, and education, the mean BMI of C9orf72+ carriers was lower than Gene-Negatives by 2.4 units (95% confidence interval [CI] = 0.3–4.6, p = 0.02) in ALS-Families; 2.7 units (95% CI = 0.9–4.4, p = 0.003) in DIALS; and 1.9 units (95% CI = 0.5–4.2, p = 0.12) in Pre-fALS. There were no significant differences in BMI between SOD1+ carriers and Gene-Negatives in any of the 3 cohorts. Conclusions: Compared to Gene-Negatives, average BMI is lower in asymptomatic C9orf72+ carriers across 3 cohorts while no significant difference was found between Gene-Negatives and SOD1+ carriers. © 2024 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.
Author Keywords
Amyotrophic Lateral Sclerosis; Body mass index; C9orf72; Presymptomatic; SOD1
Funding details
Biogen
American Academy of NeurologyAAN
ALS Recovery Fund
Ionis Pharmaceuticals
ALS AssociationALSA
A. O. Smith Foundation
Muscular Dystrophy AssociationMDA
National Center for Advancing Translational SciencesNCATSU54NS092091
National Institute of Neurological Disorders and StrokeNINDSK23NS131586
American Brain FoundationABF2015, 172123, 4365
National Institutes of HealthNIHR01 NS105479
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Deletions in the CDKL5 5′ untranslated region lead to CDKL5 deficiency disorder
(2024) American Journal of Medical Genetics, Part A, .
Haviland, I.a b , Hector, R.D.c , Swanson, L.C.a b , Verran, A.S.d , Sherrill, E.d , Frazier, Z.a b , Denny, A.M.e , Lucash, J.a b , Zhang, B.a , Dubbs, H.A.f , Marsh, E.D.f , Weisenberg, J.L.g , Leonard, H.h , Crippa, M.i , Cogliati, F.i , Russo, S.i , Suter, B.j , Rajaraman, R.k , Percy, A.K.l , Schreiber, J.M.m , Demarest, S.n , Benke, T.A.o , Chopra, M.a b , Yu, T.W.a d , Olson, H.E.a p
a Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
b Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
c Simons Initiative for the Developing Brain & Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
d Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
e Division of Pediatric Neurology, University of Saskatchewan, Saskatoon, SK, Canada
f Division of Child Neurology, Children’s Hospital of Philadelphia, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
g Department of Pediatric Neurology, Washington University School of Medicine, St. Louis, MO, United States
h Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia
i Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy
j Division of Child Neurology, Texas Children’s Hospital, Departments of Neurology and Pediatrics, Baylor College of Medicine, Houston, TX, United States
k Division of Pediatric Neurology, UCLA Mattel Children’s Hospital, Los Angeles, CA, United States
l Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States
m Division of Epilepsy, Neurophysiology, and Critical Care Neurology, Children’s National Hospital, Washington, DC, United States
n Department of Pediatrics and Neurology, Precision Medicine Institute, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO, United States
o Department of Pediatrics, Pharmacology and Neurology, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO, United States
p Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Boston, MA, United States
Abstract
Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X-linked developmental and epileptic encephalopathy. Deletions affecting the 5′ untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a–e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5′ UTR. All individuals presented characteristic features of CDD, including medically refractory infantile-onset epilepsy, global developmental delay, and visual impairment. We performed RNA sequencing on fibroblast samples from three individuals with small deletions involving exons 1 and/or 1a/1b only. Results demonstrated reduced CDKL5 mRNA expression with no evidence of expression from alternatively spliced first exons. Our study broadens the genotypic spectrum for CDD by adding to existing evidence that deletions affecting the 5′ UTR of the CDKL5 gene are associated with the disorder. We propose that smaller 5′ UTR deletions may require additional molecular testing approaches such as RNA sequencing to determine pathogenicity. © 2024 Wiley Periodicals LLC.
Author Keywords
5′ UTR; alternatively spliced exons; CDKL5; developmental and epileptic encephalopathy; exon 1; genotypic spectrum
Funding details
International Foundation for CDKL5 ResearchIFCR
ACADIA PharmaceuticalsACADIA
Rett Syndrome Research TrustRSRT
Dravet Syndrome FoundationDSF
National Institutes of HealthNIH
International Foundation
LouLou Foundation
Marinus Pharmaceuticals
A-T Children’s ProjectATCP
Simons FoundationSF
International Rett Syndrome FoundationIRSF
1012595
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Poor Sleep is Common in Treatment-Resistant Late-life Depression and Associated With Poorer Antidepressant Response: Findings From the OPTIMUM Clinical Trial
(2024) American Journal of Geriatric Psychiatry, .
Mak, M.S.B.a b , Gebara, M.A.c , Lenze, E.J.d , Blumberger, D.M.a b , Brown, P.J.e , Cristancho, P.d , Flint, A.J.a g , Karp, J.F.i , Lavretsky, H.f , Miller, J.P.h , Reynolds, C.F., IIIc , Roose, S.P.e , Mulsant, B.H.a b , Stahl, S.T.c
a Department of Psychiatry (MSBM, DMB, AJF, BHM), Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
b Centre for Addiction and Mental Health (MSBM, DMB, BHM), Toronto, Canada
c Department of Psychiatry (MAG, CFR, STS), University of Pittsburgh School of Medicine, Toronto, Canada
d Department of Psychiatry (EJL, PC), Washington University School of Medicine in St. Louis, St. Louis, MO, United States
e Department of Psychiatry (PJB, SPR), Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, United States
f Department of Psychiatry and Biobehavioral Sciences (HL), University of California, Los Angeles, United States
g Centre for Mental Health (AJF), University Health Network, Toronto, Canada
h Data Science and Biostatistics (JPM), Washington University School of Medicine in St. Louis, Institute for Informatics, St. Louis, MO, United States
i Department of Psychiatry (JFK), College of Medicine, University of Arizona, Tucson, AZ, United States
Abstract
Background: Adults with treatment-resistant late-life depression (TRLLD) have high rates of sleep problems; however, little is known about the occurrence and change in sleep during pharmacotherapy of TRLLD. This analysis examined: (1) the occurrence of insufficient sleep among adults with TRLLD; (2) how sleep changed during pharmacotherapy; and (3) whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep. Methods: Secondary analysis of data from 634 participants age 60+ years in the OPTIMUM clinical trial for TRLLD. Sleep was assessed using the sleep item from the Montgomery-Asberg Depression Rating Scale at the beginning (week-0) and end (week-10) of treatment. The analyses examined whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep during depression treatment. Results: About half (51%, n = 323) of participants reported insufficient sleep at baseline. Both persistent insufficient sleep (25%, n = 158) and worsened sleep (10%, n = 62) during treatment were associated with antidepressant nonresponse. Participants who maintained sufficient sleep (26%, n = 164) or who improved their sleep (n = 25%, n = 158) were three times more likely to experience a depression response than those with persistent insufficient sleep or worsened sleep. Conclusion: Insufficient sleep is common in TRLLD and it is associated with poorer treatment response to antidepressants. © 2024 The Authors
Author Keywords
Aging; geriatric mental health; sleep; sleep disturbance
Document Type: Article
Publication Stage: Article in Press
Source: Scopus