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"Curtis, Sarah"
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E-therapy for substance abuse and co-morbidity
This brief provides an overview of the emerging field of Electronic Therapy, E-Therapy, with a specific focus on alcohol and substance abuse. Understanding barriers that prevent individuals from seeking necessary mental health treatment is at the center of the development and analysis of practice models of care. Geographic location, transportation, language barriers and other situations contribute to difficulties in obtaining adequate treatment for mental illness. E-Therapy eliminates these barriers by administering counseling and mental health services through audio or audiovisual means. This brief examines E-Therapy best practices as they apply to alcohol and substance abuse intervention and prevention.
Book
A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results
Randomized controlled trials (RCTs) are conducted under idealized and rigorously controlled conditions that may compromise their external validity. A literature review was conducted of published English language articles that reported the findings of studies assessing external validity by a comparison of the patient sample included in RCTs reporting on pharmaceutical interventions with patients from everyday clinical practice. The review focused on publications in the fields of cardiology, mental health, and oncology. A range of databases were interrogated (MEDLINE; EMBASE; Science Citation Index; Cochrane Methodology Register). Double-abstract review and data extraction were performed as per protocol specifications. Out of 5,456 de-duplicated abstracts, 52 studies met the inclusion criteria (cardiology, n = 20; mental health, n = 17; oncology, n = 15). Studies either performed an analysis of the baseline characteristics (demographic, socioeconomic, and clinical parameters) of RCT-enrolled patients compared with a real-world population, or assessed the proportion of real-world patients who would have been eligible for RCT inclusion following the application of RCT inclusion/exclusion criteria. Many of the included studies concluded that RCT samples are highly selected and have a lower risk profile than real-world populations, with the frequent exclusion of elderly patients and patients with co-morbidities. Calculation of ineligibility rates in individual studies showed that a high proportion of the general disease population was often excluded from trials. The majority of studies (n = 37 [71.2 %]) explicitly concluded that RCT samples were not broadly representative of real-world patients and that this may limit the external validity of the RCT. Authors made a number of recommendations to improve external validity. Findings from this review indicate that there is a need to improve the external validity of RCTs such that physicians treating patients in real-world settings have the appropriate evidence on which to base their clinical decisions. This goal could be achieved by trial design modification to include a more representative patient sample and by supplementing RCT evidence with data generated from observational studies. In general, a thoughtful approach to clinical evidence generation is required in which the trade-offs between internal and external validity are considered in a holistic and balanced manner.
Journal Article
Impact of extreme weather events and climate change for health and social care systems
This review, commissioned by the Research Councils UK Living With Environmental Change (LWEC) programme, concerns research on the impacts on health and social care systems in the United Kingdom of extreme weather events, under conditions of climate change. Extreme weather events considered include heatwaves, coldwaves and flooding. Using a structured review method, we consider evidence regarding the currently observed and anticipated future impacts of extreme weather on health and social care systems and the potential of preparedness and adaptation measures that may enhance resilience. We highlight a number of general conclusions which are likely to be of international relevance, although the review focussed on the situation in the UK. Extreme weather events impact the operation of health services through the effects on built, social and institutional infrastructures which support health and health care, and also because of changes in service demand as extreme weather impacts on human health. Strategic planning for extreme weather and impacts on the care system should be sensitive to within country variations. Adaptation will require changes to built infrastructure systems (including transport and utilities as well as individual care facilities) and also to institutional and social infrastructure supporting the health care system. Care sector organisations, communities and individuals need to adapt their practices to improve resilience of health and health care to extreme weather. Preparedness and emergency response strategies call for action extending beyond the emergency response services, to include health and social care providers more generally.
Journal Article
Gene expression dynamics of human and mouse craniofacial development at the single-cell level
Craniofacial development is a complex process that involves the specification of diverse and transient cell types. However, our understanding of these processes and the cell-types present during human craniofacial developmental remains limited. We address this gap in knowledge through single-nucleus RNA sequencing of human craniofacial development spanning 4 to 8 post-conception weeks. This resource identifies multiple subtypes of mesenchyme, epithelium, and cranial neural crest, among other functionally distinct cell types. Extensive comparisons to single-nucleus gene expression and spatial transcriptomics of comparable mouse developmental stages reveal functional conservation of most cell types and identification of anatomically distinct cell subtypes. We find distinct contributions of cellular subtypes to normal facial morphology and common risk factors for orofacial clefts. Additionally, we find specific ectodermal and epithelial subtypes whose gene expression networks are most significantly affected by rare de novo protein-altering variants from orofacial cleft patients. Together our data provide an extensive resource for understanding human craniofacial development at the cellular level.
This study profiles gene expression of individual cell types that are present during the formation of human and mouse faces. The authors identify specific cell types that play roles in facial shape differences and contribute to risk for craniofacial diseases like cleft lip and palate.
Journal Article
Prevalence and cardiometabolic correlates of ketohexokinase gene variants among UK Biobank participants
Essential fructosuria (EF) is a benign, asymptomatic, autosomal recessive condition caused by loss-of-function variants in the ketohexokinase gene and characterized by intermittent appearance of fructose in the urine. Despite a basic understanding of the genetic and molecular basis of EF, relatively little is known about the long-term clinical consequences of ketohexokinase gene variants. We examined the frequency of ketohexokinase variants in the UK Biobank sample and compared the cardiometabolic profiles of groups of individuals with and without these variants alone or in combination. Study cohorts consisted of groups of participants defined based on the presence of one or more of the five ketohexokinase gene variants tested for in the Affymetrix assays used by the UK Biobank. The rs2304681:G>A (p.Val49Ile) variant was present on more than one-third (36.8%) of chromosomes; other variant alleles were rare (<1%). No participants with the compound heterozygous genotype present in subjects exhibiting the EF phenotype in the literature (Gly40Arg/Ala43Thr) were identified. The rs2304681:G>A (p.Val49Ile), rs41288797 (p.Val188Met), and rs114353144 (p.Val264Ile) variants were more common in white versus non-white participants. Otherwise, few statistically or clinically significant differences were observed after adjustment for multiple comparisons. These findings reinforce the current understanding of EF as a rare, benign, autosomal recessive condition.
Journal Article
Contextualising disability and dentistry: challenging perceptions and removing barriers
This paper explores the contextualised relationship between disability and oral health, locating questions about the oral health and oral health care of disabled people within wider debates about the material, social and cultural barriers that disabled people face when accessing health care. Sociological and disability studies research is drawn on to highlight potential barriers to oral health for disabled people and outline alternative ways of looking at, thinking about and challenging these barriers. Starting with a brief look at definitions and understandings of disability and the impact of this on attitudes, research on the multi-level barriers faced by disabled people within oral health care is then highlighted. The article concludes with some thoughts on how research from other disciplinary traditions can be useful in helping to make dentistry more prepared to appropriately and successfully meet the needs of disabled people, both in a special care setting but also, more crucially, in a general dental setting.
Journal Article
Patient-centered assessment of treatment for alpha-1 antitrypsin deficiency: literature review to identify concepts and measures for people with alpha1-antitrypsin deficiency
Background
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that can result in a range of illnesses, with chronic obstructive pulmonary disease (COPD) being one of the most common. Although some people obtain genetic testing that identifies AATD, many people are unaware that they have AATD until they develop COPD, often at a younger age than is typical. Treatment for AATD consists primarily of augmentation with AAT, requiring weekly infusions of blood products for most patients. This treatment can slow disease progression and improve symptoms, but is burdensome; thus, people with AATD could benefit from additional or alternate treatments. However, to guide the development of new treatments, researchers need to identify which outcomes matter to people with AATD.
Methods
We conducted a scoping literature review to better understand patient experiences with AATD and its treatment and identify patient-reported outcome measures (PROMs) used to assess symptoms and impacts in studies of people with AATD.
Results
The review identified 44 concepts related to symptoms and disease burden, grouped into six domains (symptoms, physical function, cognitive function, emotional function, psychosocial function, and treatment burden) and 24 PROMs that have been used in research on AATD. None of the identified measures were developed specifically for people with AATD. Research on patient-focused outcomes was limited, suggesting a significant gap in knowledge.
Conclusions
People with AATD experience a variety of disease-related burdens, but this study showed there is a lack of published, in-depth studies to support selection and evaluation of patient-centered outcomes among populations of people with AATD. A limited number of PROMs have been used in research on AATD or in clinical trials of treatment, including COPD-specific measures that assess symptoms and quality of life and measures of mood, sleep, and general physical and psychosocial functioning. The current study documented the available evidence and compiled a list of potential concepts of interest, but further qualitative and quantitative studies will be needed to understand the outcomes that matter to people with AATD and to evaluate the alignment between these outcomes and available measures.
Journal Article
Identification of functional non-coding variants associated with orofacial cleft
Oral facial cleft (OFC) comprises cleft lip with or without cleft palate (CL/P) or cleft palate only. Genome wide association studies (GWAS) of isolated OFC have identified common single nucleotide polymorphisms (SNPs) in many genomic loci where the presumed effector gene (for example,
IRF6
in the 1q32 locus) is expressed in embryonic oral epithelium. To identify candidates for functional SNPs at eight such loci we conduct a massively parallel reporter assay in a fetal oral epithelial cell line, revealing SNPs with allele-specific effects on enhancer activity. We filter these SNPs against chromatin-mark evidence of enhancers and test a subset in traditional reporter assays, which support the candidacy of SNPs at loci containing
FOXE1
,
IRF6
,
MAFB
,
TFAP2A
, and
TP63
. For two SNPs near
IRF6
and one near
FOXE1
, we engineer the genome of induced pluripotent stem cells, differentiate the cells into embryonic oral epithelium, and discover allele-specific effects on the levels of effector gene expression, and, in two cases, the binding affinity of transcription factors FOXE1 or ETS2. Conditional analyses of GWAS data suggest the two functional SNPs near
IRF6
account for the majority of risk for CL/P at this locus. This study connects genetic variation associated with OFC to mechanisms of pathogenesis.
Non-syndromic orofacial cleft is a relatively common congenital anomaly. Many non-coding genetic variants are associated with this disorder but only a subset is functional. Here the authors use reporter assays and stem cells to reveal members of this subset.
Journal Article
Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework
Researchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel treatment pathways and aid in drug repurposing/repositioning. The objective of this study was to determine whether treatment of patients with multiple sclerosis with dimethyl fumarate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, results in a change in incidence of type 2 diabetes and its complications. This retrospective cohort study used administrative claims data to derive four cohorts of adults with multiple sclerosis initiating dimethyl fumarate, teriflunomide, glatiramer acetate or fingolimod between January 2013 and December 2018. A causal inference frequentist model averaging framework based on machine learning was used to compare the time to first occurrence of a composite endpoint of type 2 diabetes, cardiovascular disease or chronic kidney disease, as well as each individual outcome, across the four treatment cohorts. There was a statistically significantly lower risk of incidence for dimethyl fumarate versus teriflunomide for the composite endpoint (restricted hazard ratio [95% confidence interval] 0.70 [0.55, 0.90]) and type 2 diabetes (0.65 [0.49, 0.98]), myocardial infarction (0.59 [0.35, 0.97]) and chronic kidney disease (0.52 [0.28, 0.86]). No differences for other individual outcomes or for dimethyl fumarate versus the other two cohorts were observed. This study effectively demonstrated the use of an innovative statistical methodology to test a clinical hypothesis using real-world data to perform early target validation for drug discovery. Although there was a trend among patients treated with dimethyl fumarate towards a decreased incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease relative to other disease-modifying therapies–which was statistically significant for the comparison with teriflunomide–this study did not definitively support the hypothesis that Nrf2 activation provided additional metabolic disease benefit in patients with multiple sclerosis.
Journal Article