Medicine (Austin & Northern Health) - Research Publications

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    Multiscale bone quality analysis in osteoarthritic knee joints reveal a role of the mechanosensory osteocyte network in osteophytes
    Rabelo, GD ; vom Scheidt, A ; Klebig, F ; Hemmatian, H ; Citak, M ; Amling, M ; Busse, B ; Jaehn, K (NATURE RESEARCH, 2020-01-20)
    Osteophytes - bony outgrowths on joint structures - are found in healthy individuals but are specifically present in late osteoarthritis (OA). Osteophyte development and function is not well understood, yet biomechanical stimuli are thought to be critical. Bone adapts to mechanical forces via the cellular network of osteocytes. The involvement of osteocytes in osteophyte formation and maturation has not been unravelled. Forty-three osteophytes from tibias of 23 OA patients (65 ± 9 years) were analysed. The trabecular bone structure of osteophytes presented with fewer trabeculae of lower bone mineral density compared to subchondral bone. We identified 40% early stage and 60% late stage osteophytes that significantly differed in their trabecular bone characteristics. Osteophyte bone revealed a higher number of osteocytes and a lower number of empty osteocyte lacunae per bone area than the subchondral bone. We found that OA osteophytes consist of younger bone material comprised of woven and lamellar bone with the capacity to develop into a late stage osteophyte potentially via the involvement of the osteocyte network. Our analysis of OA osteophytes implies a transition from woven to lamellar bone as in physiological bone growth within a pathological joint. Therefore, osteophyte development and growth present a valuable research subject when aiming to investigate the osteogenic signalling cascade.
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    Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
    Motelow, JE ; Povysil, G ; Dhindsa, RS ; Stanley, KE ; Allen, AS ; Feng, Y-CA ; Howrigan, DP ; Abbott, LE ; Tashman, K ; Cerrato, F ; Cusick, C ; Singh, T ; Heyne, H ; Byrnes, AE ; Churchhouse, C ; Watts, N ; Solomonson, M ; Lal, D ; Gupta, N ; Neale, BM ; Cavalleri, GL ; Cossette, P ; Cotsapas, C ; De Jonghe, P ; Dixon-Salazar, T ; Guerrini, R ; Hakonarson, H ; Heinzen, EL ; Helbig, I ; Kwan, P ; Marson, AG ; Petrovski, S ; Kamalakaran, S ; Sisodiya, SM ; Stewart, R ; Weckhuysen, S ; Depondt, C ; Dlugos, DJ ; Scheffer, IE ; Striano, P ; Freyer, C ; Krause, R ; May, P ; McKenna, K ; Regan, BM ; Bennett, CA ; Leu, C ; Leech, SL ; O'Brien, TJ ; Todaro, M ; Stamberger, H ; Andrade, DM ; Ali, QZ ; Sadoway, TR ; Krestel, H ; Schaller, A ; Papacostas, SS ; Kousiappa, I ; Tanteles, GA ; Christou, Y ; Sterbova, K ; Vlckova, M ; Sedlackova, L ; Lassuthova, P ; Klein, KM ; Rosenow, F ; Reif, PS ; Knake, S ; Neubauer, BA ; Zimprich, F ; Feucht, M ; Reinthaler, EM ; Kunz, WS ; Zsurka, G ; Surges, R ; Baumgartner, T ; von Wrede, R ; Pendziwiat, M ; Muhle, H ; Rademacher, A ; van Baalen, A ; von Spiczak, S ; Stephani, U ; Afawi, Z ; Korczyn, AD ; Kanaan, M ; Canavati, C ; Kurlemann, G ; Muller-Schluter, K ; Kluger, G ; Haeusler, M ; Blatt, I ; Lemke, JR ; Krey, I ; Weber, YG ; Wolking, S ; Becker, F ; Lauxmann, S ; Bosselmann, C ; Kegele, J ; Hengsbach, C ; Rau, S ; Steinhoff, BJ ; Schulze-Bonhage, A ; Borggraefe, I ; Schankin, CJ ; Schubert-Bast, S ; Schreiber, H ; Mayer, T ; Korinthenberg, R ; Brockmann, K ; Wolff, M ; Dennig, D ; Madeleyn, R ; Kalviainen, R ; Saarela, A ; Timonen, O ; Linnankivi, T ; Lehesjoki, A-E ; Rheims, S ; Lesca, G ; Ryvlin, P ; Maillard, L ; Valton, L ; Derambure, P ; Bartolomei, F ; Hirsch, E ; Michel, V ; Chassoux, F ; Rees, M ; Chung, S-K ; Pickrell, WO ; Powell, R ; Baker, MD ; Fonferko-Shadrach, B ; Lawthom, C ; Anderson, J ; Schneider, N ; Balestrini, S ; Zagaglia, S ; Braatz, V ; Johnson, MR ; Auce, P ; Sills, GJ ; Baum, LW ; Sham, PC ; Cherny, SS ; Lui, CHT ; Delanty, N ; Doherty, CP ; Shukralla, A ; El-Naggar, H ; Widdess-Walsh, P ; Barisi, N ; Canafoglia, L ; Franceschetti, S ; Castellotti, B ; Granata, T ; Ragona, F ; Zara, F ; Iacomino, M ; Riva, A ; Madia, F ; Vari, MS ; Salpietro, V ; Scala, M ; Mancardi, MM ; Nobili, L ; Amadori, E ; Giacomini, T ; Bisulli, F ; Pippucci, T ; Licchetta, L ; Minardi, R ; Tinuper, P ; Muccioli, L ; Mostacci, B ; Gambardella, A ; Labate, A ; Annesi, G ; Manna, L ; Gagliardi, M ; Parrini, E ; Mei, D ; Vetro, A ; Bianchini, C ; Montomoli, M ; Doccini, V ; Barba, C ; Hirose, S ; Ishii, A ; Suzuki, T ; Inoue, Y ; Yamakawa, K ; Beydoun, A ; Nasreddine, W ; Zgheib, NK ; Tumiene, B ; Utkus, A ; Sadleir, LG ; King, C ; Caglayan, SH ; Arslan, M ; Yapici, Z ; Topaloglu, P ; Kara, B ; Yis, U ; Turkdogan, D ; Gundogdu-Eken, A ; Bebek, N ; Tsai, M-H ; Ho, C-J ; Lin, C-H ; Lin, K-L ; Chou, I-J ; Poduri, A ; Shiedley, BR ; Shain, C ; Noebels, JL ; Goldman, A ; Busch, RM ; Jehi, L ; Najm, IM ; Ferguson, L ; Khoury, J ; Glauser, TA ; Clark, PO ; Buono, RJ ; Ferraro, TN ; Sperling, MR ; Lo, W ; Privitera, M ; French, JA ; Schachter, S ; Kuzniecky, R ; Devinsky, O ; Hegde, M ; Greenberg, DA ; Ellis, CA ; Goldberg, E ; Helbig, KL ; Cosico, M ; Vaidiswaran, P ; Fitch, E ; Berkovic, SF ; Lerche, H ; Lowenstein, DH ; Goldstein, DB (CELL PRESS, 2021-06-03)
    Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
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    Add-on cannabidiol in patients with Dravet syndrome: Results of a long-term open-label extension trial
    Scheffer, IE ; Halford, JJ ; Miller, I ; Nabbout, R ; Sanchez-Carpintero, R ; Shiloh-Malawsky, Y ; Wong, M ; Zolnowska, M ; Checketts, D ; Dunayevich, E ; Devinsky, O (WILEY, 2021-08-18)
    OBJECTIVE: Add-on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double-blind, placebo-controlled trials: GWPCARE1 Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or GWPCARE2, were enrolled in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. METHODS: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/ml), titrated from 2.5 to 20 mg/kg/day over a 2-week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30 mg/kg/day. RESULTS: Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open-label extension. Median treatment duration was 444 days (range = 18-1535), with a mean modal dose of 22 mg/kg/day; patients received a median of three concomitant antiseizure medications. Adverse events (AEs) occurred in 97% patients (mild, 23%; moderate, 50%; severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixty-nine (22%) patients had liver transaminase elevations >3 × upper limit of normal; 84% were on concomitant valproic acid. In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45%-74% for convulsive seizures and 49%-84% for total seizures. Across all visit windows, ≥83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition. SIGNIFICANCE: We show that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.
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    Cutting edge approaches to detecting brain mosaicism associated with common focal epilepsies: implications for diagnosis and potential therapies
    Ye, Z ; Bennett, MF ; Bahlo, M ; Scheffer, IE ; Berkovic, SF ; Perucca, P ; Hildebrand, MS (TAYLOR & FRANCIS LTD, 2021-09-24)
    INTRODUCTION: Mosaic variants arising in brain tissue are increasingly being recognized as a hidden cause of focal epilepsy. This knowledge gain has been driven by new, highly sensitive genetic technologies and genome-wide analysis of brain tissue from surgical resection or autopsy in a small proportion of patients with focal epilepsy. Recently reported novel strategies to detect mosaic variants limited to brain have exploited trace brain DNA obtained from cerebrospinal fluid liquid biopsies or stereo-electroencephalography electrodes. AREAS COVERED: The authors review the data on these innovative approaches published in PubMed before 12 June 2021, discuss the challenges associated with their application, and describe how they are likely to improve detection of mosaic variants to provide new molecular diagnoses and therapeutic targets for focal epilepsy, with potential utility in other nonmalignant neurological disorders. EXPERT OPINION: These cutting-edge approaches may reveal the hidden genetic etiology of focal epilepsies and provide guidance for precision medicine.
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    Natural History Studies and Clinical Trial Readiness for Genetic Developmental and Epileptic Encephalopathies
    Palmer, EE ; Howell, K ; Scheffer, IE (SPRINGER, 2021-10-27)
    The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies. They usually begin in infancy or childhood with drug-resistant seizures, epileptiform EEG patterns, developmental slowing or regression, and cognitive impairment. DEEs have a high mortality and profound morbidity; comorbidities are common including autism spectrum disorders. With advances in genetic sequencing, over 400 genes have been implicated in DEEs, with a genetic cause now identified in over 50% patients. Each genetic DEE typically has a broad genotypic-phenotypic spectrum, based on the underlying pathophysiology. There is a pressing need to improve health outcomes by developing novel targeted therapies for specific genetic DEE phenotypes that not only improve seizure control, but also developmental outcomes and comorbidities. Clinical trial readiness relies firstly on a deep understanding of phenotype-genotype correlation and evolution of a condition over time, in order to select appropriate patients for clinical trials. Understanding the natural history of the disorder informs assessment of treatment efficacy in terms of both clinical outcome and biomarker utility. Natural history studies (NHS) provide a high quality, integrated, comprehensive approach to understanding a complex disease and underpin clinical trial design for novel therapies. NHS are pre-planned observational studies designed to track the course of a disease and identify demographic, genetic, environmental, and other variables, including biomarkers, that correlate with the disease's evolution and outcomes. Due to the rarity of individual genetic DEEs, appropriately funded high-quality DEE NHS will be required, with sustainable frameworks and equitable access to affected individuals globally.
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    Epidemiology of Treated Epilepsy in New Zealand Children A Focus on Ethnicity
    Ali, S ; Stanley, J ; Davis, S ; Keenan, N ; Scheffer, IE ; Sadleir, LG (LIPPINCOTT WILLIAMS & WILKINS, 2021-11-09)
    BACKGROUND AND OBJECTIVES: To determine the period prevalence and incidence of treated epilepsy in a New Zealand pediatric cohort with a focus on ethnicity and socioeconomic status. METHODS: This was a retrospective cohort study. The New Zealand Pharmaceutical Collection database was searched for individuals ≤18 years of age dispensed an antiseizure medication (ASM) in 2015 from areas capturing 48% of the New Zealand pediatric population. Medical records of identified cases were reviewed to ascertain the indication for the ASM prescription. Population data were derived from the New Zealand 2013 Census. RESULTS: A total of 3,557 ASMs were prescribed during 2015 in 2,594 children, of whom 1,717 (66%) children had epilepsy. An indication for prescription was ascertained for 3,332/3,557 (94%) ASMs. The period prevalence of treated epilepsy was 3.4 per 1,000 children. Children in the most deprived areas had 1.9 times the rate of treated epilepsy (95% confidence interval [CI] 1.6-2.2) as those from the least deprived areas. Prevalence was similar for most ethnic groups (European/other: 3.7, 95% CI 3.4-3.9; Pacific Peoples: 3.6, 95% CI 3.2-4.1; Māori: 3.4, 95% CI 3.1-3.8) apart from Asians, who had a lower prevalence of 2.3 per 1,000 (95% CI 2.0-2.6). However, when adjusted for socioeconomic deprivation, the prevalence of epilepsy was highest in European and similar in Māori, Pacific, and Asian children. DISCUSSION: This is the largest pediatric epidemiology epilepsy study where diagnosis of epilepsy was confirmed by case review. This is the first study to provide epidemiologic information for pediatric epilepsy in Māori and Pacific children.
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    Frailty, MRI, and FDG-PET Measures in an Australian Memory Clinic Cohort.
    Jordan, N ; Gvalda, M ; Cody, R ; Galante, O ; Haywood, C ; Yates, P (Frontiers Media SA, 2020)
    Given that the global population is aging, the number of age-related syndromes, such as frailty, is expected to rise in conjunction. Frailty is characterized by the loss of homeostatic reserve, rendering the individual vulnerable to poor health outcomes. Many biological mechanisms have been proposed to contribute to frailty. However, few studies have assessed the associations between frailty and brain diseases or neuroimaging biomarkers. Aims: The aims of this study were to measure the prevalence of frailty in a memory clinic and to examine associations between frailty and brain changes found on magnetic resonance imaging (MRI) and 18-F deoxyglucose (FDG) positron emission tomography (PET) in memory clinic attendees. Methods: A 54-items Frailty Index was retrospectively assessed for all clinic attendees from 2014. Frailty was defined as FI > 0.25. MR images were analyzed for stroke, cerebral small vessel disease [CSVD, including cerebral microbleeds (CMBs), cortical superficial siderosis (CSS), and white matter hyperintensity (WMH)], and neurodegenerative changes [MRI: mesial temporal atrophy (MTA), FDG-PET: regional hypometabolism], blind to clinical findings. Results: There were 209 clinic attendees in 2014, of whom 121 had MRI performed. The prevalence of frailty (using FI) in the memory clinic in 2014 was 38.3% overall (patients without MRI: 43.2%, patients with MRI 34.7%, p = 0.25). Frailty was associated with presence of deep WMH, increased severity of periventricular WMH, and presence of CSS, but not neurodegeneration markers (MTA atrophy/FDG-PET hypometabolism). Conclusion: The findings support the idea that previously reported associations between frailty and imaging evidence of CSVD in other cohorts are also relevant to the Australian clinic setting. Given that a large proportion of memory clinic attendees are frail, there may be opportunities for interventions to reduce preventable adverse health outcomes, such as falls and fractures, and reduce the prevalence and impact of frailty in this cohort.
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    Rare variant contribution to human disease in 281,104 UK Biobank exomes
    Wang, Q ; Dhindsa, RS ; Carss, K ; Harper, AR ; Nag, A ; Tachmazidou, I ; Vitsios, D ; Deevi, SVV ; Mackay, A ; Muthas, D ; Huhn, M ; Monkley, S ; Olsson, H ; Wasilewski, S ; Smith, KR ; March, R ; Platt, A ; Haefliger, C ; Petrovski, S (NATURE PORTFOLIO, 2021-08-10)
    Genome-wide association studies have uncovered thousands of common variants associated with human disease, but the contribution of rare variants to common disease remains relatively unexplored. The UK Biobank contains detailed phenotypic data linked to medical records for approximately 500,000 participants, offering an unprecedented opportunity to evaluate the effect of rare variation on a broad collection of traits1,2. Here we study the relationships between rare protein-coding variants and 17,361 binary and 1,419 quantitative phenotypes using exome sequencing data from 269,171 UK Biobank participants of European ancestry. Gene-based collapsing analyses revealed 1,703 statistically significant gene-phenotype associations for binary traits, with a median odds ratio of 12.4. Furthermore, 83% of these associations were undetectable via single-variant association tests, emphasizing the power of gene-based collapsing analysis in the setting of high allelic heterogeneity. Gene-phenotype associations were also significantly enriched for loss-of-function-mediated traits and approved drug targets. Finally, we performed ancestry-specific and pan-ancestry collapsing analyses using exome sequencing data from 11,933 UK Biobank participants of African, East Asian or South Asian ancestry. Our results highlight a significant contribution of rare variants to common disease. Summary statistics are publicly available through an interactive portal ( http://azphewas.com/ ).
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    Ureaplasma urealyticum meningitis complicated by hydrocephalus in a preterm neonate
    Jepp, CK ; Foley, DA ; Chua, I-LJ ; Kwong, JC ; Payne, MS ; Davis, J ; Yeoh, DK (WILEY, 2021-05-18)