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Article: Searching the Dark Genome for Alzheimer's Disease Risk Variants.

Raybould, Rachel / Sims, Rebecca

2021 Volume 11, Issue 3

Abstract: Sporadic Alzheimer's disease (AD) is a complex genetic disease, and the leading cause of dementia worldwide. Over the past 3 decades, extensive pioneering research has discovered more than 70 common and rare genetic risk variants. These discoveries have ... ...

Abstract	Sporadic Alzheimer's disease (AD) is a complex genetic disease, and the leading cause of dementia worldwide. Over the past 3 decades, extensive pioneering research has discovered more than 70 common and rare genetic risk variants. These discoveries have contributed massively to our understanding of the pathogenesis of AD but approximately half of the heritability for AD remains unaccounted for. There are regions of the genome that are not assayed by mainstream genotype and sequencing technology. These regions, known as the Dark Genome, often harbour large structural DNA variants that are likely relevant to disease risk. Here, we describe the dark genome and review current technological and bioinformatics advances that will enable researchers to shed light on these hidden regions of the genome. We highlight the potential importance of the hidden genome in complex disease and how these strategies will assist in identifying the missing heritability of AD. Identification of novel protein-coding structural variation that increases risk of AD will open new avenues for translational research and new drug targets that have the potential for clinical benefit to delay or even prevent clinical symptoms of disease.
Language	English
Publishing date	2021-03-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci11030332
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Article: Quantifying the psychological and behavioural consequences of a diagnostic label for non-cancer conditions: systematic review.

Sims, Rebecca / Michaleff, Zoe A / Glasziou, Paul / Jones, Mark / Thomas, Rae

BJPsych open

2023 Volume 9, Issue 3, Page(s) e73

Abstract: Background: Screening for asymptomatic health conditions is perceived as mostly beneficial, with possible harms receiving little attention.: Aims: To quantify proximal and longer-term consequences for individuals receiving a diagnostic label ... ...

Abstract	Background: Screening for asymptomatic health conditions is perceived as mostly beneficial, with possible harms receiving little attention. Aims: To quantify proximal and longer-term consequences for individuals receiving a diagnostic label following screening for an asymptomatic, non-cancer health condition. Method: Five electronic databases were searched (inception to November 2022) for studies that recruited asymptomatic screened individuals who received or did not receive a diagnostic label. Eligible studies reported psychological, psychosocial and/or behavioural outcomes before and after screening results. Independent reviewers screened titles and abstracts, extracted data from included studies, and assessed risk of bias (Risk of Bias in Non-Randomised Studies of Interventions). Results were meta-analysed or descriptively reported. Results: Sixteen studies were included. Twelve studies addressed psychological outcomes, four studies examined behavioural outcomes and none reported psychosocial outcomes. Risk of bias was judged as low ( Conclusions: The impacts of screening asymptomatic, non-cancer health conditions are not universally positive. Limited research exists regarding longer-term impacts. Well-designed, high-quality studies further investigating these impacts are required to assist development of protocols that minimise psychological distress following diagnosis.
Language	English
Publishing date	2023-04-19
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2829557-2
ISSN	2056-4724
ISSN	2056-4724
DOI	10.1192/bjo.2023.49
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Article ; Online: Women's experiences of a diagnosis of gestational diabetes mellitus: a systematic review.

Craig, Louise / Sims, Rebecca / Glasziou, Paul / Thomas, Rae

BMC pregnancy and childbirth

2020 Volume 20, Issue 1, Page(s) 76

Abstract: Background: Gestational diabetes mellitus (GDM) - a transitory form of diabetes induced by pregnancy - has potentially important short and long-term health consequences for both the mother and her baby. There is no globally agreed definition of GDM, but ...

Abstract	Background: Gestational diabetes mellitus (GDM) - a transitory form of diabetes induced by pregnancy - has potentially important short and long-term health consequences for both the mother and her baby. There is no globally agreed definition of GDM, but definition changes have increased the incidence in some countries in recent years, with some research suggesting minimal clinical improvement in outcomes. The aim of this qualitative systematic review was to identify the psychosocial experiences a diagnosis of GDM has on women during pregnancy and the postpartum period. Methods: We searched CINAHL, EMBASE, MEDLINE and PsycINFO databases for studies that provided qualitative data on the psychosocial experiences of a diagnosis of GDM on women across any stage of pregnancy and/or the postpartum period. We appraised the methodological quality of the included studies using the Critical Appraisal Skills Programme Checklist for Qualitative Studies and used thematic analysis to synthesis the data. Results: Of 840 studies identified, 41 studies of diverse populations met the selection criteria. The synthesis revealed eight key themes: initial psychological impact; communicating the diagnosis; knowledge of GDM; risk perception; management of GDM; burden of GDM; social support; and gaining control. The identified benefits of a GDM diagnosis were largely behavioural and included an opportunity to make healthy eating changes. The identified harms were emotional, financial and cultural. Women commented about the added responsibility (eating regimens, appointments), financial constraints (expensive food, medical bills) and conflicts with their cultural practices (alternative eating, lack of information about traditional food). Some women reported living in fear of risking the health of their baby and conducted extreme behaviours such as purging and starving themselves. Conclusion: A diagnosis of GDM has wide reaching consequences that are common to a diverse group of women. Threshold cut-offs for blood glucose levels have been determined using the risk of physiological harms to mother and baby. It may also be advantageous to consider the harms and benefits from a psychosocial and a physiological perspective. This may avoid unnecessary burden to an already vulnerable population.
MeSH term(s)	Communication ; Diabetes, Gestational/diagnosis ; Diabetes, Gestational/psychology ; Emotional Adjustment ; Female ; Health Knowledge, Attitudes, Practice ; Humans ; Life Style ; Postpartum Period/psychology ; Pregnancy ; Prenatal Care/psychology ; Social Support
Language	English
Publishing date	2020-02-07
Publishing country	England
Document type	Systematic Review
ISSN	1471-2393
ISSN (online)	1471-2393
DOI	10.1186/s12884-020-2745-1
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Article ; Online: The multiplex model of the genetics of Alzheimer's disease.

Sims, Rebecca / Hill, Matthew / Williams, Julie

Nature neuroscience

2020 Volume 23, Issue 3, Page(s) 311–322

Abstract: Genes play a strong role in Alzheimer's disease (AD), with late-onset AD showing heritability of 58-79% and early-onset AD showing over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. ...

Abstract	Genes play a strong role in Alzheimer's disease (AD), with late-onset AD showing heritability of 58-79% and early-onset AD showing over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 50 loci are now implicated for AD, suggesting that AD is a disease of multiple components, as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD heritability has been captured, allowing researchers to calculate the accumulation of AD genetic risk through polygenic risk scores. A polygenic risk score predicts disease with up to 90% accuracy and is an exciting tool in our research armory that could allow selection of those with high polygenic risk scores for clinical trials and precision medicine. It could also allow cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Animals ; Humans ; Models, Genetic ; Signal Transduction/genetics
Language	English
Publishing date	2020-02-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-020-0599-5
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Zs.A 4891: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 67: Show issues

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Article ; Online: Consequences of a Diagnostic Label: A Systematic Scoping Review and Thematic Framework.

Sims, Rebecca / Michaleff, Zoe A / Glasziou, Paul / Thomas, Rae

Frontiers in public health

2021 Volume 9, Page(s) 725877

Abstract: Objectives: ...

Abstract	Objectives:
MeSH term(s)	Delivery of Health Care ; Health Personnel ; Humans ; Qualitative Research
Language	English
Publishing date	2021-12-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review ; Systematic Review
ZDB-ID	2711781-9
ISSN	2296-2565 ; 2296-2565
ISSN (online)	2296-2565
ISSN	2296-2565
DOI	10.3389/fpubh.2021.725877
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Article ; Online: Defining functional variants associated with Alzheimer's disease in the induced immune response.

Harwood, Janet C / Leonenko, Ganna / Sims, Rebecca / Escott-Price, Valentina / Williams, Julie / Holmans, Peter

Brain communications

2021 Volume 3, Issue 2, Page(s) fcab083

Abstract: Defining the mechanisms involved in the aetiology of Alzheimer's disease from genome-wide association studies alone is challenging since Alzheimer's disease is polygenic and most genetic variants are non-coding. Non-coding Alzheimer's disease risk ... ...

Abstract	Defining the mechanisms involved in the aetiology of Alzheimer's disease from genome-wide association studies alone is challenging since Alzheimer's disease is polygenic and most genetic variants are non-coding. Non-coding Alzheimer's disease risk variants can influence gene expression by affecting miRNA binding and those located within enhancers and within CTCF sites may influence gene expression through alterations in chromatin states. In addition, their function can be cell-type specific. They can function specifically in microglial enhancers thus affecting gene expression in the brain. Hence, transcriptome-wide association studies have been applied to test the genetic association between disease risk and cell-/tissue-specific gene expression. Many Alzheimer's disease-associated loci are involved in the pathways of the innate immune system. Both microglia, the primary immune cells of the brain, and monocytes which can infiltrate the brain and differentiate into activated macrophages, have roles in neuroinflammation and β-amyloid clearance through phagocytosis. In monocytes the function of regulatory variants can be context-specific after immune stimulation. To dissect the variants associated with Alzheimer's disease in the context of monocytes, we utilized data from naïve monocytes and following immune stimulation
Language	English
Publishing date	2021-04-19
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcab083
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Article ; Online: Overdiagnosis of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Systematic Scoping Review.

Kazda, Luise / Bell, Katy / Thomas, Rae / McGeechan, Kevin / Sims, Rebecca / Barratt, Alexandra

JAMA network open

2021 Volume 4, Issue 4, Page(s) e215335

Abstract: Importance: Reported increases in attention-deficit/hyperactivity disorder (ADHD) diagnoses are accompanied by growing debate about the underlying factors. Although overdiagnosis is often suggested, no comprehensive evaluation of evidence for or against ...

Abstract	Importance: Reported increases in attention-deficit/hyperactivity disorder (ADHD) diagnoses are accompanied by growing debate about the underlying factors. Although overdiagnosis is often suggested, no comprehensive evaluation of evidence for or against overdiagnosis has ever been undertaken and is urgently needed to enable evidence-based, patient-centered diagnosis and treatment of ADHD in contemporary health services. Objective: To systematically identify, appraise, and synthesize the evidence on overdiagnosis of ADHD in children and adolescents using a published 5-question framework for detecting overdiagnosis in noncancer conditions. Evidence review: This systematic scoping review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension for Scoping Reviews and Joanna Briggs Methodology, including the PRISMA-ScR Checklist. MEDLINE, Embase, PsychINFO, and the Cochrane Library databases were searched for studies published in English between January 1, 1979, and August 21, 2020. Studies of children and adolescents (aged ≤18 years) with ADHD that focused on overdiagnosis plus studies that could be mapped to 1 or more framework question were included. Two researchers independently reviewed all abstracts and full-text articles, and all included studies were assessed for quality. Findings: Of the 12 267 potentially relevant studies retrieved, 334 (2.7%) were included. Of the 334 studies, 61 (18.3%) were secondary and 273 (81.7%) were primary research articles. Substantial evidence of a reservoir of ADHD was found in 104 studies, providing a potential for diagnoses to increase (question 1). Evidence that actual ADHD diagnosis had increased was found in 45 studies (question 2). Twenty-five studies showed that these additional cases may be on the milder end of the ADHD spectrum (question 3), and 83 studies showed that pharmacological treatment of ADHD was increasing (question 4). A total of 151 studies reported on outcomes of diagnosis and pharmacological treatment (question 5). However, only 5 studies evaluated the critical issue of benefits and harms among the additional, milder cases. These studies supported a hypothesis of diminishing returns in which the harms may outweigh the benefits for youths with milder symptoms. Conclusions and relevance: This review found evidence of ADHD overdiagnosis and overtreatment in children and adolescents. Evidence gaps remain and future research is needed, in particular research on the long-term benefits and harms of diagnosing and treating ADHD in youths with milder symptoms; therefore, practitioners should be mindful of these knowledge gaps, especially when identifying these individuals and to ensure safe and equitable practice and policy.
MeSH term(s)	Adolescent ; Attention Deficit Disorder with Hyperactivity/diagnosis ; Attention Deficit Disorder with Hyperactivity/drug therapy ; Attention Deficit Disorder with Hyperactivity/epidemiology ; Child ; Humans ; Medical Overuse/statistics & numerical data ; Practice Patterns, Physicians'/statistics & numerical data ; Severity of Illness Index
Language	English
Publishing date	2021-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Systematic Review
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2021.5335
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Article ; Online: Genetic Insights into the Impact of Complement in Alzheimer's Disease.

Torvell, Megan / Carpanini, Sarah M / Daskoulidou, Nikoleta / Byrne, Robert A J / Sims, Rebecca / Morgan, B Paul

Genes

2021 Volume 12, Issue 12

Abstract: The presence of complement activation products at sites of pathology in post-mortem Alzheimer's disease (AD) brains is well known. Recent evidence from genome-wide association studies (GWAS), combined with the demonstration that complement activation is ... ...

Abstract	The presence of complement activation products at sites of pathology in post-mortem Alzheimer's disease (AD) brains is well known. Recent evidence from genome-wide association studies (GWAS), combined with the demonstration that complement activation is pivotal in synapse loss in AD, strongly implicates complement in disease aetiology. Genetic variations in complement genes are widespread. While most variants individually have only minor effects on complement homeostasis, the combined effects of variants in multiple complement genes, referred to as the "complotype", can have major effects. In some diseases, the complotype highlights specific parts of the complement pathway involved in disease, thereby pointing towards a mechanism; however, this is not the case with AD. Here we review the complement GWAS hits;
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/immunology ; Brain/pathology ; Clusterin/genetics ; Complement Activation/genetics ; Complement Activation/immunology ; Complement C1s/genetics ; Complement System Proteins/genetics ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study/methods ; Humans ; Polymorphism, Single Nucleotide/genetics ; Receptors, Complement 3b/genetics
Chemical Substances	CLU protein, human ; CR1 protein, human ; Clusterin ; Receptors, Complement 3b ; Complement System Proteins (9007-36-7) ; Complement C1s (EC 3.4.21.42)
Language	English
Publishing date	2021-12-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12121990
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Article ; Online: Apolipoprotein ε4 modifies obesity-related atrophy in the hippocampal formation of cognitively healthy adults.

Coad, Bethany M / Ghomroudi, Parisa A / Sims, Rebecca / Aggleton, John P / Vann, Seralynne D / Metzler-Baddeley, Claudia

Neurobiology of aging

2022 Volume 113, Page(s) 39–54

Abstract: Characterizing age- and risk-related hippocampal vulnerabilities may inform about the neural underpinnings of cognitive decline. We studied the impact of three risk-factors, Apolipoprotein (APOE)-ε4, a family history of dementia, and central obesity, on ... ...

Abstract	Characterizing age- and risk-related hippocampal vulnerabilities may inform about the neural underpinnings of cognitive decline. We studied the impact of three risk-factors, Apolipoprotein (APOE)-ε4, a family history of dementia, and central obesity, on the CA1, CA2/3, dentate gyrus and subiculum of 158 cognitively healthy adults (38-71 years). Subfields were labelled with the Automatic Segmentation of Hippocampal Subfields and FreeSurfer (version 6) protocols. Volumetric and microstructural measurements from quantitative magnetization transfer and Neurite Orientation Density and Dispersion Imaging were extracted for each subfield and reduced to three principal components capturing apparent myelin/neurite packing, size/complexity, and metabolism. Aging was associated with an inverse U-shaped curve on myelin/neurite packing and affected all subfields. Obesity led to reductions in myelin/neurite packing and size/complexity regardless of APOE and family history of dementia status. However, amongst individuals with a healthy Waist-Hip-Ratio, APOE ε4 carriers showed lower size/complexity than non-carriers. Segmentation protocol type did not affect this risk pattern. These findings reveal interactive effects between APOE and central obesity on the hippocampal formation of cognitively healthy adults.
MeSH term(s)	Apolipoprotein E4/genetics ; Apolipoproteins ; Atrophy/pathology ; Dementia/pathology ; Hippocampus/diagnostic imaging ; Hippocampus/pathology ; Humans ; Magnetic Resonance Imaging/methods ; Obesity/complications ; Obesity/genetics ; Obesity/pathology ; Obesity, Abdominal/pathology
Chemical Substances	Apolipoprotein E4 ; Apolipoproteins
Language	English
Publishing date	2022-02-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2022.02.004
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Zs.A 1685: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Comparison of Psychophysiological and Dual-Task Measures of Listening Effort.

Seeman, Scott / Sims, Rebecca

Journal of speech, language, and hearing research : JSLHR

2015 Volume 58, Issue 6, Page(s) 1781–1792

Abstract: Purpose: We wished to make a comparison of psychophysiological measures of listening effort with subjective and dual-task measures of listening effort for a diotic-dichotic-digits and a sentences-in-noise task.: Method: Three groups of young adults ( ... ...

Abstract	Purpose: We wished to make a comparison of psychophysiological measures of listening effort with subjective and dual-task measures of listening effort for a diotic-dichotic-digits and a sentences-in-noise task. Method: Three groups of young adults (18-38 years old) with normal hearing participated in three experiments: two psychophysiological studies for two different listening tasks and a dual-task measure for a sentences-in-noise task. Psychophysiological variables included skin conductance, heart-rate variability, and heart rate; the dual-task measure was a letter-identification task. Heart-rate variability was quantified with the difference from baseline for the normalized standard deviation of R to R. Results: Heart-rate variability differences from baseline were greater for increased task complexity and for poorer signal-to-noise ratios (SNRs). The dual-task measure of listening effort also increased for sentences presented at a +5 dB SNR compared with a +15 dB SNR. Skin conductance was elevated for greater task complexity only, and similar across noise conditions. None of these measures were significantly correlated with subjective measures of listening effort. Conclusions: Heart-rate variability appears to be a robust psychophysiological indicator of listening effort, sensitive to both task complexity and SNR. This sensitivity to SNR was similar to a dual-task measure of listening effort.
MeSH term(s)	Acoustic Stimulation ; Adolescent ; Adult ; Analysis of Variance ; Auditory Perception/physiology ; Female ; Galvanic Skin Response/physiology ; Heart Rate/physiology ; Humans ; Language Tests ; Male ; Physical Exertion/physiology ; Psychophysics/methods ; Reaction Time ; Visual Perception/physiology ; Young Adult
Language	English
Publishing date	2015-12
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	1364086-0
ISSN	1558-9102 ; 1092-4388
ISSN (online)	1558-9102
ISSN	1092-4388
DOI	10.1044/2015_JSLHR-H-14-0180
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