Publications by authors named "William Gibson"

265 Publications

Considerations for multi-centre conditioned pain modulation (CPM) research; an investigation of the inter-rater reliability, level of agreement and confounders for the Achilles tendon and Triceps Surae.

Br J Pain 2021 Feb 17;15(1):91-101. Epub 2020 Apr 17.

La Trobe Sport and Exercise Medicine Research Centre, La Trobe University, Bundoora, VIC, Australia.

Objective: This study aimed to investigate the inter-rater reliability of the conditioned pain modulation (CPM) effect.

Methods: The reliability between two examiners assessing the CPM effect via pressure pain thresholds and induced using the cold pressor test of 28 healthy volunteers at the mid-portion Achilles tendon (AT) and Triceps Surae musculotendinous junction was performed. Reliability was calculated using intraclass correlation coefficient (ICC). Confounders were assessed using multivariable generalised estimating equations (GEEs). Bias in the level of agreement was assumed if the confidence intervals (CIs) of the mean difference in Bland-Altman plots did not cross the line of equality.

Results: The inter-rater reliability of the CPM effect was poor to moderate in the AT (ICC 95% CI = 0.00-0.66) and Triceps Surae (ICC 95% CI = 0.00-0.69). However, when accounting for confounders within the GEE, there were no differences between testers and Bland-Altman plots reported good agreement between testers. Habitual completion of running-related physical activity was a confounder for both the AT parallel-paradigm (p = 0.017) and sequential-paradigm (p = 0.029). Testing order was a confounder for the AT (p = 0.023) and Triceps Surae (p = 0.014) parallel-paradigm.

Conclusion: This study suggests the CPM effect may be site specific (i.e. differences between the AT and Triceps Surae exist). In addition, differences in the reliability between examiners are likely due to the influence of confounders and not examiner technique and therefore appropriate analysis should be used in research investigating the CPM effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2049463720912208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882768PMC
February 2021

Are you translating research into clinical practice? What to think about when it does not seem to be working.

Br J Sports Med 2021 Jan 11. Epub 2021 Jan 11.

La Trobe Sport and Exercise Medicine Research Centre, La Trobe University, Bundoora, Victoria, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bjsports-2020-102369DOI Listing
January 2021

Do Older Adults with Overactive Bladder Demonstrate Impaired Executive Function Compared to Their Peers Without OAB?

Can Geriatr J 2020 Dec 1;23(4):329-334. Epub 2020 Dec 1.

Division of Geriatric Medicine, University of Alberta, Edmonton, AB.

Background: Maintaining urinary continence is not an automatic process, but relies on continuous processing of sensory signals from the bladder and suppression of the desire to void. Urinary incontinence (UI) and lower urinary tract symptoms (LUTS), including urinary urgency, frequency, and nocturia are highly prevalent among the general population. This prevalence rises in association with increasing age, and this may be in part due to changes in the central nervous system rather than the urinary tract. The aim of this study was to assess if older adults with overactive bladder (OAB) had demonstrable impairment in executive function.

Methods: This was a cross-sectional study comparing the performance of adults aged 65 and over with and without OAB on two cognitive tests, the Trail Making Test B (TMT-B) and simple reaction time (SRT). OAB was defined as urgency, with at least weekly urgency incontinence and a daytime urinary frequency of 8 or more. The control group were defined as a Bladder control Self-Assessment Questionnaire (B-SAQ) score of ≤4.

Results: 56 participants were recruited, of whom 35 met criteria for OAB. The OAB group took significantly longer to complete the TMT-B than the control group (103s vs. 77s, = .003). There was no difference in the SRT.

Conclusions: In this sample of older adults, OAB was associated with measurable slower performance on the TMT-B, suggesting that impaired executive function is associated with OAB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5770/cgj.23.423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704076PMC
December 2020

Do people with unilateral mid-portion Achilles tendinopathy who participate in running-related physical activity exhibit a meaningful conditioned pain modulation (CPM) effect: a pilot study.

J Sci Med Sport 2021 May 4;24(5):441-447. Epub 2020 Nov 4.

School of Physiotherapy, The University of Notre Dame Australia, Fremantle, WA, Australia.

Objectives: Our primary objective was to report the presence of a conditioned pain modulation (CPM) effect in people with localised mid-portion Achilles tendinopathy and whether changes occur over a 12-week period. Our secondary objectives were to quantify the proportion of participants who present for tendinopathy research with previous interventions or co-morbidities, which may impact the CPM-effect and investigate modulating factors.

Design: Prospective, observational cohort pilot study.

Method: 215 participants presented for this Achilles tendinopathy research and were screened for inclusion with nine being included. Included participants had the CPM-effect (cold-pressor test) assessed using pressure pain thresholds at the Achilles tendon and quantified as absolute, relative and meaningful change at baseline and 12-week follow-up.

Results: The most common reasons for exclusion were failure to meet a load-related diagnosis for Achilles tendinopathy (15.5%), presence of confounding other injury (14.1%) and previous injection therapy (13.6%). All participants had a meaningful CPM-effect at baseline and 12-week follow-up. The mean (SD, n) baseline relative CPM effect (reduction in PPTs) was -40.5 (32.7, 9) percent. Moderators of the CPM-effect as well as follow-up changes were not statistically analysed due to a small sample size.

Conclusion: Based on these data, we would suggest that a homogenous population of patients with chronic, unilateral mid-portion Achilles tendinopathy and no other co-morbidities are likely to exhibit a meaningful CPM-effect. Impairments to endogenous analgesic mechanisms seen in people presenting with mid-portion Achilles tendinopathy may be due to other confounding variables.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jsams.2020.10.015DOI Listing
May 2021

Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.

Am J Med Genet A 2021 01 24;185(1):119-133. Epub 2020 Oct 24.

Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61926DOI Listing
January 2021

Incontinence in frail elderly persons: Report of the 6th International Consultation on Incontinence.

Neurourol Urodyn 2021 01 21;40(1):38-54. Epub 2020 Oct 21.

Division of Geriatric Medicine, University of Alberta, Edmonton, Alberta, Canada.

Background: Evidence-based guidelines for the management of frail older persons with urinary incontinence are rare. Those produced by the International Consultation on Incontinence represent an authoritative set of recommendations spanning all aspects of management.

Aims: To summarize the available evidence relating to the management of urinary incontinence in frail older people published since the 5th International Consultation on Incontinence.

Materials And Methods: A series of systematic reviews and evidence updates were performed by members of the working group to update the 2012 recommendations.

Results: Along with the revision of the treatment algorithm and accompanying text, there have been significant advances in several areas of the management of lower urinary tract symptoms in frail older people.

Discussion: The committee continues to note the relative paucity of data concerning frail older persons and draw attention to knowledge gaps and research opportunities. Clinicians treating older people with lower urinary tract symptoms should use the available evidence from studies of older people combined with careful extrapolation of those data from younger subjects. Due consideration to an individual's frailty and wishes is crucial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nau.24549DOI Listing
January 2021

A Novel Framework for Characterizing Genomic Haplotype Diversity in the Human Immunoglobulin Heavy Chain Locus.

Front Immunol 2020 23;11:2136. Epub 2020 Sep 23.

Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, United States.

An incomplete ascertainment of genetic variation within the highly polymorphic immunoglobulin heavy chain locus (IGH) has hindered our ability to define genetic factors that influence antibody-mediated processes. Due to locus complexity, standard high-throughput approaches have failed to accurately and comprehensively capture IGH polymorphism. As a result, the locus has only been fully characterized two times, severely limiting our knowledge of human IGH diversity. Here, we combine targeted long-read sequencing with a novel bioinformatics tool, IGenotyper, to fully characterize IGH variation in a haplotype-specific manner. We apply this approach to eight human samples, including a haploid cell line and two mother-father-child trios, and demonstrate the ability to generate high-quality assemblies (>98% complete and >99% accurate), genotypes, and gene annotations, identifying 2 novel structural variants and 15 novel IGH alleles. We show multiplexing allows for scaling of the approach without impacting data quality, and that our genotype call sets are more accurate than short-read (>35% increase in true positives and >97% decrease in false-positives) and array/imputation-based datasets. This framework establishes a desperately needed foundation for leveraging IG genomic data to study population-level variation in antibody-mediated immunity, critical for bettering our understanding of disease risk, and responses to vaccines and therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.02136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539625PMC
September 2020

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

Authors:
Félixe Pelletier Stefanie Perrier Ferdy K Cayami Amytice Mirchi Stephan Saikali Luan T Tran Nicole Ulrick Kether Guerrero Emmanouil Rampakakis Rosalina M L van Spaendonk Sakkubai Naidu Daniela Pohl William T Gibson Michelle Demos Cyril Goizet Ingrid Tejera-Martin Ana Potic Brent L Fogel Bernard Brais Michel Sylvain Guillaume Sébire Charles Marques Lourenço Joshua L Bonkowsky Coriene Catsman-Berrevoets Pedro S Pinto Sandya Tirupathi Petter Strømme Ton de Grauw Dorota Gieruszczak-Bialek Ingeborg Krägeloh-Mann Hanna Mierzewska Heike Philippi Julia Rankin Tahir Atik Brenda Banwell William S Benko Astrid Blaschek Annette Bley Eugen Boltshauser Drago Bratkovic Klara Brozova Icíar Cimas Christopher Clough Bernard Corenblum Argirios Dinopoulos Gail Dolan Flavio Faletra Raymond Fernandez Janice Fletcher Maria Eugenia Garcia Garcia Paolo Gasparini Janina Gburek-Augustat Dolores Gonzalez Moron Aline Hamati Inga Harting Christoph Hertzberg Alan Hill Grace M Hobson A Micheil Innes Marcelo Kauffman Susan M Kirwin Gerhard Kluger Petra Kolditz Urania Kotzaeridou Roberta La Piana Eriskay Liston William McClintock Meriel McEntagart Fiona McKenzie Serge Melançon Anjum Misbahuddin Mohnish Suri Fernando I Monton Sebastien Moutton Raymond P J Murphy Miriam Nickel Hüseyin Onay Simona Orcesi Ferda Özkınay Steffi Patzer Helio Pedro Sandra Pekic Mercedes Pineda Marfa Amy Pizzino Barbara Plecko Bwee Tien Poll-The Vera Popovic Dietz Rating Marie-France Rioux Norberto Rodriguez Espinosa Anne Ronan John R Ostergaard Elsa Rossignol Rocio Sanchez-Carpintero Anna Schossig Nesrin Senbil Laura K Sønderberg Roos Cathy A Stevens Matthis Synofzik László Sztriha Daniel Tibussek Dagmar Timmann Davide Tonduti Bart P van de Warrenburg Maria Vázquez-López Sunita Venkateswaran Pontus Wasling Evangeline Wassmer Richard I Webster Gert Wiegand Grace Yoon Joost Rotteveel Raphael Schiffmann Marjo S van der Knaap Adeline Vanderver Gabriel Á Martos-Moreno Constantin Polychronakos Nicole I Wolf Geneviève Bernard

J Clin Endocrinol Metab 2021 Jan;106(2):e660-e674

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823228PMC
January 2021

Reciprocal skeletal phenotypes of PRC2-related overgrowth and Rubinstein-Taybi syndromes: potential role of H3K27 modifications.

Cold Spring Harb Mol Case Stud 2020 08 25;6(4). Epub 2020 Aug 25.

BC Children's Hospital Research Institute, Vancouver, British Columbia V5Z 4H4, Canada.

Within histone H3, lysine 27 (H3K27) is one of the residues that functions as a molecular switch, by virtue of being subject to mutually exclusive post-translational modifications that have reciprocal effects on gene expression. Whereas acetylation of H3K27 is associated with transcriptional activation, methylation at this residue causes transcriptional silencing; these two modifications are mutually exclusive. Establishment of these epigenetic marks is important in defining cellular identity and for maintaining normal cell function, as evidenced by rare genetic disorders of epigenetic writers involved in H3K27 post-translational modification. Polycomb repressive complex (PRC2)-related overgrowth and Rubinstein-Taybi syndrome (RSTS) are respectively associated with impaired H3K27 methylation and acetylation. Whereas these syndromes share commonalities like intellectual disability and susceptibility to cancers, they are generally divergent in their skeletal growth phenotypes, potentially through dysregulation of their opposing H3K27 writer functions. In this review, we discuss the requirement of H3K27 modifications for successful embryogenesis, highlighting data from relevant mouse knockout studies. Although such gene ablation studies are integral for defining fundamental biological roles of methyl- and acetyltransferase function in vivo, studies of partial loss-of-function models are likely to yield more meaningful translational insight into progression of PRC2-related overgrowth or RSTS. Thus, modeling of rare human PRC2-related overgrowth and RSTS variants in mice is needed to fully understand the causative role of aberrant H3K27 modification in the pathophysiology of these syndromes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a005058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476411PMC
August 2020

-associated neurodevelopmental disorder.

J Med Genet 2021 Mar 16;58(3):196-204. Epub 2020 Jun 16.

Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada.

Background: Dysfunction of histone methyltransferases and chromatin modifiers has been implicated in complex neurodevelopmental syndromes and cancers. encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. Previous reports of patients with rare variants in describe a distinctive phenotype that includes seizures, global developmental delay and intellectual disability.

Methods: Two of the patients described herein were identified via genome-wide and exome-wide testing, with microarray and research-based exome, through the CAUSES (Clinical Assessment of the Utility of Sequencing and Evaluation as a Service) Research Clinic at the University of British Columbia. The third Vancouver patient had clinical trio exome sequencing through Blueprint Genetics. The fourth patient underwent singleton exome sequencing in Nantes, with subsequent recruitment to this cohort through GeneMatcher.

Results: Here we present clinical reports of four patients with rare coding variants in that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory. We include supporting evidence from next-generation sequencing among a cohort of paediatric patients with epilepsy.

Conclusion: Rare coding variants in can cause a diagnosable syndrome and could contribute as a risk factor for epilepsy, autism and other neurodevelopmental phenotypes. In the long term, some patients may also be at increased risk for cancers and other complex diseases. Thus, longitudinal studies are required to further elucidate the precise role of SETD1B in neurodevelopmental disorders and other systemic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2019-106756DOI Listing
March 2021

T reg-specific insulin receptor deletion prevents diet-induced and age-associated metabolic syndrome.

J Exp Med 2020 08;217(8)

Department of Surgery, University of British Columbia, Vancouver, Canada.

Adipose tissue (AT) regulatory T cells (T regs) control inflammation and metabolism. Diet-induced obesity causes hyperinsulinemia and diminishes visceral AT (VAT) T reg number and function, but whether these two phenomena were mechanistically linked was unknown. Using a T reg-specific insulin receptor (Insr) deletion model, we found that diet-induced T reg dysfunction is driven by T reg-intrinsic insulin signaling. Compared with Foxp3cre mice, after 13 wk of high-fat diet, Foxp3creInsrfl/fl mice exhibited improved glucose tolerance and insulin sensitivity, effects associated with lower AT inflammation and increased numbers of ST2+ T regs in brown AT, but not VAT. Similarly, Foxp3creInsrfl/fl mice were protected from the metabolic effects of aging, but surprisingly had reduced VAT T regs and increased VAT inflammation compared with Foxp3cre mice. Thus, in both diet- and aging-associated hyperinsulinemia, excessive Insr signaling in T regs leads to undesirable metabolic outcomes. Ablation of Insr signaling in T regs represents a novel approach to mitigate the detrimental effects of hyperinsulinemia on immunoregulation of metabolic syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20191542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398165PMC
August 2020

Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities.

Nat Commun 2020 05 20;11(1):2517. Epub 2020 May 20.

Departments of Cancer Biology, Boston, MA, USA.

Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of therapeutic targets. We hypothesized that monoallelic inactivation of the allele retained in tumors can selectively kill cancer cells but not somatic cells, which retain both alleles. We identified 5664 variants in 1278 essential genes that undergo LOH in cancer and evaluated the potential for each to be targeted using allele-specific gene-editing, RNAi, or small-molecule approaches. We further show that allele-specific inactivation of either of two essential genes (PRIM1 and EXOSC8) reduces growth of cells harboring that allele, while cells harboring the non-targeted allele remain intact. We conclude that LOH of essential genes represents a rich class of non-driver cancer vulnerabilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-16399-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239950PMC
May 2020

Mirabegron in the Treatment of Overactive Bladder: Safety and Efficacy in the Very Elderly Patient.

Clin Interv Aging 2020 23;15:575-581. Epub 2020 Apr 23.

University of Alberta, Division of Geriatric Medicine, Edmonton, Alberta, Canada.

Lower urinary tract symptoms, including urgency, urgency incontinence, frequency, and nocturia, are highly prevalent in older adults and are associated with significant morbidity and impairment in quality of life. When conservative measures such as bladder training fail to improve symptoms, pharmacological management is recommended by national and international guidelines. Mirabegron, an agonist of the β3 adrenergic receptor, demonstrates similar efficacy to the anticholinergic drugs without the risk of anticholinergic effects, but experience and evidence in the very elderly population are limited. This narrative review examines the current evidence base for mirabegron in very elderly adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/CIA.S174402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185319PMC
September 2020

Transcutaneous electrical nerve stimulation (TENS) for chronic pain: the opportunity to begin again.

Cochrane Database Syst Rev 2020 04 22;4:ED000139. Epub 2020 Apr 22.

The University of Notre Dame Australia, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.ED000139DOI Listing
April 2020

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Am J Hum Genet 2020 05 2;106(5):596-610. Epub 2020 Apr 2.

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212265PMC
May 2020

Author Response to Cibulka.

Phys Ther 2020 Apr 2. Epub 2020 Apr 2.

School of Physiotherapy, The University of Notre Dame; and School of Physiotherapy and Exercise Science, Curtin University, Perth, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ptj/pzaa047DOI Listing
April 2020

The Influence of a Positive Empathetic Interaction on Conditioned Pain Modulation and Manipulation-induced Analgesia in People With Lateral Epicondylalgia.

Clin J Pain 2020 06;36(6):411-419

School of Physiotherapy and Exercise Science, Curtin University.

Objective: Conditioned pain modulation (CPM) and manipulation-induced analgesia (MIA) are 2 forms of endogenous analgesia. Many forms of analgesia can be influenced by the nature of the patient-clinician interaction. The aim of this study was to evaluate the influence of an empathetic and supportive interaction on CPM and MIA in people with lateral epicondylalgia (LE).

Material And Methods: In a double-blind, randomized, controlled trial, 68 participants with LE were assigned to 2 groups: the empathetic and neutral interaction groups. The interactions were carried out by a trained, professional role-play actor, playing the part of a research assistant. The research assistant actor spent 15 minutes before CPM and MIA assessment interacting with the participants in an empathetic or neutral manner. Immediately after the interaction, a blinded assessor measured pressure pain threshold at the symptomatic elbow and ipsilateral wrist during CPM and MIA testing. Linear mixed models were used to evaluate differences in CPM and MIA responses between the interaction groups.

Results: There was a significant difference in Consultation and Relational Empathy scores between the groups (P<0.001), indicating that the intervention group experienced a more empathic interaction. Both groups showed a significant increase in pressure pain threshold measures, indicative of a CPM and MIA analgesic response (P<0.001), however, the analgesic responses were greater in the group that had experienced a supportive, empathetic interaction (post CPM, wrist: P<0.001; elbow: P=0.001) (post MIA wrist: P<0.001; elbow: P=0.001).

Discussion: A single session of empathetic interaction positively influenced both CPM and MIA responses in people with LE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AJP.0000000000000822DOI Listing
June 2020

MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.

Brain 2020 01;143(1):55-68

Laboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962909PMC
January 2020

Is the strong desire to void a source of diverted attention in healthy adult volunteers?

Neurourol Urodyn 2020 01 29;39(1):324-330. Epub 2019 Nov 29.

Faculty of Nursing, University of Alberta, Edmonton, Alberta, Canada.

Aims: The strong desire to void (SDV) induces changes in both cognition and gait. This may be due to the sensation of urinary urge acting as a source of diverted attention. This exploratory study examined the influence of SDV and a standardized distracting task on the performance of two measures of cognition, a simple reaction time (SRT) test and the trail making B test (TMT-B).

Methods: 18 volunteers, 8 male and 10 female, without lower urinary tract symptoms (LUTS) (mean age: 20.5, range: 20-47), performed a test of SRT and the TMT-B under three conditions; undistracted with an empty bladder, while experiencing SDV, and when performing a simultaneous distracting task, the auditory n back test.

Results: A statistically significant increase in SRT was found when experiencing SDV and when distracted compared with the undistracted, bladder empty condition. The time taken to compete the TMT-B significantly increased with distraction but was not affected by SDV.

Conclusion: SDV induced a similar but smaller change in reaction time when compared with a distracting task, suggesting that SDV may act as a source of diverted attention in continent, healthy volunteers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nau.24201DOI Listing
January 2020

Rare SUZ12 variants commonly cause an overgrowth phenotype.

Am J Med Genet C Semin Med Genet 2019 12 17;181(4):532-547. Epub 2019 Nov 17.

Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like phenotype with a rare coding SUZ12 variant-the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver-like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre- and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly-affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically-recognizable syndromes emerge from different variant subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.c.31748DOI Listing
December 2019

PRC2-complex related dysfunction in overgrowth syndromes: A review of EZH2, EED, and SUZ12 and their syndromic phenotypes.

Am J Med Genet C Semin Med Genet 2019 12 14;181(4):519-531. Epub 2019 Nov 14.

Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic "writer" with H3K27 methyltransferase activity, catalyzing the addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss-of-function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2-associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590). EED-associated overgrowth (Cohen-Gibson syndrome; OMIM #617561) is caused by germline heterozygous mutations in Embryonic Ectoderm Development (EED), and manifests overgrowth and intellectual disability (OGID), along with other features similar to Weaver syndrome. Most recently, rare coding variants in SUZ12 have also been described that present with clinical characteristics similar to the previous two syndromes. Here we review the PRC2 complex and clinical syndromes of OGID associated with core components EZH2, EED, and SUZ12.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.c.31754DOI Listing
December 2019

Complexity in unclassified auto-inflammatory disease: a case report illustrating the potential for disease arising from the allelic burden of multiple variants.

Pediatr Rheumatol Online J 2019 Oct 28;17(1):70. Epub 2019 Oct 28.

Department of Pediatrics, The University of British Columbia Faculty of Medicine, BC Children's Hospital, 4480 Oak Street, Vancouver, BC, V6H 3V4, Canada.

Background: Despite recent advances in the diagnosis and understanding of many autoinflammatory diseases, there are still a great number of patients with phenotypes that do not fit any clinically- and/or genetically-defined disorders.

Case Presentation: We describe a fourteen-year-old boy who presented at two and a half years of age with recurrent febrile episodes. Over the course of the disease, the episodes increased in frequency and severity, with new signs and symptoms continuing to appear. Most importantly, these included skin changes, splenomegaly and transaminitis. Only partial control of the disease was achieved with anti-IL-1 therapy. Extensive investigation showed generalized inflammation without immune deficiency, with increased levels of serum amyloid A and several pro-inflammatory cytokines including interferon-γ, as well as an increased type I interferon score. Exome sequence analysis identified P369S and R408Q variants in the MEFV innate immunity regulator, pyrin (MEFV) gene and T260 M and T320 M variants in the NLR family pyrin domain containing 12 (NLRP12) gene.

Conclusion: Patients with unclassified and/or unexplained autoinflammatory syndromes present diagnostic and therapeutic challenges and collectively form a substantial part of every cohort of patients with autoinflammatory diseases. Therefore, it is important to acquire their full genomic profile through whole exome and/or genome sequencing and present their cases to a broader audience, to facilitate characterization of similar patients. A critical mass of well-characterized cases will lead to improved diagnosis and informed treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12969-019-0374-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819641PMC
October 2019

Machine learning versus traditional risk stratification methods in acute coronary syndrome: a pooled randomized clinical trial analysis.

J Thromb Thrombolysis 2020 01;49(1):1-9

The Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 930 Commonwealth Avenue, Boston, MA, USA.

Traditional statistical models allow population based inferences and comparisons. Machine learning (ML) explores datasets to develop algorithms that do not assume linear relationships between variables and outcomes and that may account for higher order interactions to make individualized outcome predictions. To evaluate the performance of machine learning models compared to traditional risk stratification methods for the prediction of major adverse cardiovascular events (MACE) and bleeding in patients with acute coronary syndrome (ACS) that are treated with antithrombotic therapy. Data on 24,178 ACS patients were pooled from four randomized controlled trials. The super learner ensemble algorithm selected weights for 23 machine learning models and was compared to traditional models. The efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. The safety endpoint was a composite of TIMI major and minor bleeding or bleeding requiring medical attention. For the MACE outcome, the super learner model produced a higher c-statistic (0.734) than logistic regression (0.714), the TIMI risk score (0.489), and a new cardiovascular risk score developed in the dataset (0.644). For the bleeding outcome, the super learner demonstrated a similar c-statistic as the logistic regression model (0.670 vs. 0.671). The machine learning risk estimates were highly calibrated with observed efficacy and bleeding outcomes (Hosmer-Lemeshow p value = 0.692 and 0.970, respectively). The super learner algorithm was highly calibrated on both efficacy and safety outcomes and produced the highest c-statistic for prediction of MACE compared to traditional risk stratification methods. This analysis demonstrates a contemporary application of machine learning to guide patient-level antithrombotic therapy treatment decisions.Clinical Trial Registration ATLAS ACS-2 TIMI 46: https://clinicaltrials.gov/ct2/show/NCT00402597. Unique Identifier: NCT00402597. ATLAS ACS-2 TIMI 51: https://clinicaltrials.gov/ct2/show/NCT00809965. Unique Identifier: NCT00809965. GEMINI ACS-1: https://clinicaltrials.gov/ct2/show/NCT02293395. Unique Identifier: NCT02293395. PIONEER-AF PCI: https://clinicaltrials.gov/ct2/show/NCT01830543. Unique Identifier: NCT01830543.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11239-019-01940-8DOI Listing
January 2020

Toileting Disability in Older People Residing in Long-term Care or Assisted Living Facilities: A Scoping Review of the Literature.

J Wound Ostomy Continence Nurs 2019 Sep/Oct;46(5):424-433

Jasper Yeung, BSc, School of Public Health, University of Alberta, Edmonton, Alberta, Canada. Allyson Jones, PhD, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada. Gian S. Jhangri, MSc, School of Public Health, University of Alberta, Edmonton, Alberta, Canada. William Gibson, PhD, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Kathleen F. Hunter, PhD, Faculty of Nursing, University of Alberta, Edmonton, Alberta, Canada. Adrian Wagg, MB BS, FRCP(Lond), FRCP(Edin), FHEA (MD), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

For purposes of this review, we defined toileting disability as a result of practices, procedures, or conditions that result in an individual requiring assistance using the bathroom. This scoping review synthesizes existing knowledge of extrinsic and/or intrinsic factors that might lead to or be associated with toileting disability and identified knowledge gaps related to toileting disability in older adults residing in long-term care or assisted living facilities. A search of 9 electronic databases and the gray literature identified 3613 articles. After exclusions and screening of the full text of 71 articles, 7 remaining eligible articles mapped research activity and identified knowledge gaps in this area. Only 1 study used toileting disability as the primary outcome; it was present in 15% of older adults without dementia living in long term-care facilities (a subgroup that comprised 34% of all residents). The other 6 articles examined factors and treatment of overall activities of daily living (ADL) performance as their primary outcome; in these, toileting disability was added to other difficulties, yielding a summary ADL outcome score. No study reported the incidence, distribution, or factors that affect toileting disability in long-term care; findings of this scoping review suggest a rich research agenda for future investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/WON.0000000000000575DOI Listing
March 2020

A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild-derived and classical inbred mouse strains.

Immunol Cell Biol 2019 11 6;97(10):888-901. Epub 2019 Oct 6.

School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.

The genomes of classical inbred mouse strains include genes derived from all three major subspecies of the house mouse, Mus musculus. We recently posited that genetic diversity in the immunoglobulin heavy chain (IGH) gene loci of C57BL/6 and BALB/c mice reflects differences in subspecies origin. To investigate this hypothesis, we conducted high-throughput sequencing of IGH gene rearrangements to document IGH variable (IGHV), joining (IGHJ) and diversity (IGHD) genes in four inbred wild-derived mouse strains (CAST/EiJ, LEWES/EiJ, MSM/MsJ and PWD/PhJ) and a single disease model strain (NOD/ShiLtJ), collectively representing genetic backgrounds of several major mouse subspecies. A total of 341 germline IGHV sequences were inferred in the wild-derived strains, including 247 not curated in the international ImMunoGeneTics information system. By contrast, 83/84 inferred NOD IGHV genes had previously been observed in C57BL/6 mice. Variability among the strains examined was observed for only a single IGHJ gene, involving a description of a novel allele. By contrast, unexpected variation was found in the IGHD gene loci, with four previously unreported IGHD gene sequences being documented. Very few IGHV sequences of C57BL/6 and BALB/c mice were shared with strains representing major subspecies, suggesting that their IGH loci may be complex mosaics of genes of disparate origins. This suggests a similar level of diversity is likely present in the IGH loci of other classical inbred strains. This must now be documented if we are to properly understand interstrain variation in models of antibody-mediated disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imcb.12288DOI Listing
November 2019

Changing the Narrative in Diagnosis and Management of Pain in the Sacroiliac Joint Area.

Phys Ther 2019 11;99(11):1511-1519

School of Physiotherapy, The University of Notre Dame; and School of Physiotherapy and Exercise Science, Curtin University, Perth, Australia.

The sacroiliac joint (SIJ) is often considered to be involved when people present for care with low back pain where SIJ is located. However, determining why the pain has arisen can be challenging, especially in the absence of a specific cause such as pregnancy, disease, or trauma, when the SIJ might be identified as a source of symptoms with the help of manual clinical tests. Nonspecific SIJ-related pain is commonly suggested to be causally associated with movement problems in the SIJ(s)-a diagnosis traditionally derived from manual assessment of movements of the SIJ complex. Management choices often consist of patient education, manual treatment, and exercise. Although some elements of management are consistent with guidelines, this Perspective article argues that the assumptions on which these diagnoses and treatments are based are problematic, particularly if they reinforce unhelpful, pathoanatomical beliefs. This article reviews the evidence regarding the clinical detection and diagnosis of SIJ movement dysfunction. In particular, it questions the continued use of assessing movement dysfunction despite mounting evidence undermining the biological plausibility and subsequent treatment paradigms based on such diagnoses. Clinicians are encouraged to align their assessment methods and explanatory models with contemporary science to reduce the risk of their diagnoses and choice of intervention negatively affecting clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ptj/pzz108DOI Listing
November 2019

A model of amygdala function following plastic changes at specific synapses during extinction.

Neurobiol Stress 2019 Feb 1;10:100159. Epub 2019 Apr 1.

Sunshine Coast Mind and Neuroscience - Thompson Institute, University of the Sunshine Coast, Birtinya, QLD, Australia.

The synaptic networks in the amygdala have been the subject of intense interest in recent times, primarily because of the role of this structure in emotion. Fear and its extinction depend on the workings of these networks, with particular interest in extinction because of its potential to ameliorate adverse symptoms associated with post-traumatic stress disorder. Here we place emphasis on the extinction networks revealed by recent techniques, and on the probable plasticity properties of their synaptic connections. We use modules of neurons representing each of the principal components identified as involved in extinction. Each of these modules consists of neural networks, containing specific ratios of excitatory and specialized inhibitory neurons as well as synaptic plasticity mechanisms appropriate for the component of the amygdala they represent. While these models can produce dynamic output, here we concentrate on the equilibrium outputs and do not model the details of the plasticity mechanisms. Pavlovian fear conditioning generates a fear memory in the lateral amygdala module that leads to activation of neurons in the basal nucleus fear module but not in the basal nucleus extinction module. Extinction protocols excite infralimbic medial prefrontal cortex neurons (IL) which in turn excite so-called extinction neurons in the amygdala, leading to the release of endocannabinoids from them and an increase in efficacy of synapses formed by lateral amygdala neurons on them. The model simulations show how such a mechanism could explain experimental observations involving the role of IL as well as endocannabinoids in different temporal phases of extinction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ynstr.2019.100159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535631PMC
February 2019

RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit-successes and challenges.

Eur J Pediatr 2019 Aug 7;178(8):1207-1218. Epub 2019 Jun 7.

Division of Neonatology, Department of Paediatrics, University of British Columbia, Vancouver, Canada.

Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women's Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant's phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%.Conclusion: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis. Health service implementation challenges and successes are discussed. What is Known: • Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation. What is New: • This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES). • In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00431-019-03399-4DOI Listing
August 2019