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Postoperative outcomes in older patients living with frailty and multimorbidity in the UK: SNAP-3, a snapshot observational study
No full textBACKGROUND: Older surgical patients experience longer hospital stays and a higher risk of morbidity and mortality than their younger counterparts. Frailty (19.6% of cohort) and multimorbidity (63.1% of cohort) increase these risks. The 3(rd) Sprint National Anaesthesia Project (SNAP-3) describes the impact of frailty and multimorbidity on postoperative outcomes. METHODS: We conducted a prospective observational cohort study over 5 days in 2022 aiming to recruit all UK patients aged ≥60 yr undergoing surgery (excluding minor procedures). Data included patient characteristics, clinical variables, Clinical Frailty Scale (CFS), multimorbidity (two or more comorbidities), length of stay (LOS), postoperative delirium, morbidity, and mortality. Quantile regression and mixed effects logistic regression were used to analyse relationships. RESULTS: We recruited 7129 patients from 214 hospitals. Increasing frailty was associated with longer LOS, higher odds of delirium, morbidity, and mortality ≥1 yr, with a clear increase noted from CFS of 4 (19.0% of cohort). Amongst those without multimorbidity, individuals with CFS score of 4 had longer admissions than non-frail individuals (median LOS 0.75 days longer, 95% confidence interval [CI] 0.34-1.16), increasing to 2.69 days longer for CFS 5 (95% CI 0.76-4.62). Multimorbidity increased the odds of postoperative morbidity by 46% (adjusted odds ratio 1.46, 95% CI 1.24-1.73), but there was no evidence for multimorbidity impacting LOS, delirium, or mortality. CONCLUSIONS: SNAP-3 highlights the impact of frailty on postoperative outcomes. Multimorbidity had less impact, with an effect on postoperative morbidity the only one to have strong statistical evidence. The impact of these conditions must be discussed with older patients considering surgical intervention.CC BY‑NC‑ND 4.0 (open access
Supporting the bereaved child in the adult ICU: let's take the first step! Author's reply
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The 2025 British Society for Rheumatology guideline for the treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs
No full textCC BY‑NC‑ND 4.0 (open access
Interleukin-1β Stimulates Matrix Metalloproteinase 10 Secretion: A Possible Mechanism in Trophoblast-Dependent Spiral Artery Remodeling
No full textMaternal uterine spiral arteries (SpA) undergo significant structural changes in early pregnancy, resulting in increased blood flow to the developing fetus. Endothelial cells (EC) and vascular smooth muscle cells (VSMC) are lost from the SpA wall and are replaced by trophoblasts. We have previously shown that matrix metalloproteinase 10 (MMP-10) and Heparin binding-EGF like growth factor (HB-EGF) gene expression is increased in a 3D EC/VSMC co-culture system in response to trophoblast secreted factors. This study investigated trophoblast mediated MMP-10 and HB-EGF expression and determined if there was a relationship between the secretion of MMP-10 and the release of soluble HB-EGF (sHB-EGF) from EC. MMP-10 was widely expressed in first trimester decidual tissue including trophoblast, and EC, but not VSMC. MMP-10 expression was significantly lower in decidual tissue from pregnancies at increased risk of developing pre-eclampsia compared to low-risk pregnancies. In vitro, SGHEC-7 cells, a human EC line, but not SGHVMC-9, a human VSMC cell line, secreted MMP-10 in response to trophoblast conditioned medium (TCM). TCM contains several growth factors and cytokines, but only interleukin-1β (IL1β) significantly stimulated MMP-10 secretion by SGHEC-7 cells. Interleukin-1 receptor antagonist (IL-1Ra) significantly inhibited TCM-induced MMP-10 secretion. Interrogation of intracellular pathways established the involvement of MEK and JNK in TCM and IL-1β stimulated MMP-10 secretion. Although IL-1β also significantly increased sHB-EGF, inhibition of MMP-10 activity using a broad spectrum MMP inhibitor had no effect on sHB-EGF. Western blot analysis indicated that MMP-10 secreted by EC in response to IL-1β stimulation was the enzymatically inactive pro form.CC BY 4.0 (Creative Commons Attribution
Informant accuracy of IQCODE, AD8 and GPCOGi for diagnosis of dementia: does your friend know best?
No full textBACKGROUND: Increasing numbers of people require evaluation for possible dementia. However, research on the accuracy of informant questionnaires in primary care remains limited. METHODS: This study assessed the diagnostic accuracy of IQCODE, AD8, and GPCOGi based on the informant's relationship to the patient. We recruited 240 participants from 21 general practices in South West England. The reference standard for a diagnosis of dementia was made by a specialist clinician using ICD-10 criteria. A threshold of greater than 3.3 on IQCODE, greater or equal to 2 on AD8 and less than 5 on the informant component of GPCOG was used to indicate an abnormal test. RESULTS: Of 238 participants with informant data, 131 had dementia, 60 had CIND, and 47 had normal cognition. Median informant age was 70 years (IQR 60 years to 78 years). 71% of informants were female and 56% were spouses. On all three questionnaires, compared to spouses, adult descendants tended to score participants more cognitively impaired, whereas friends scored participants less cognitively impaired. However, there was little evidence of difference by informant type once fully adjusted. Sensitivity by informant type ranged from 91 to 100% for IQCODE, 94-100% for AD8 and 99% to100% for GPCOGi. There was no significant difference in sensitivity by informant type. Specificity by informant type ranged from 25 to 79% for IQCODE, 13-75% for AD8 and 17-38% for GPCOGi. Adult descendants tended to have the lowest specificity at 25% (95% CI 10-47%) for IQCODE, 13% (95% CI 3-32%) for AD8 and 17% (95% CI 5-37%) for GPCOGi. Friends tended to have the highest specificity at 79% (95% CI 49-95%) for IQCODE, 75% (95% CI 48-93%) for AD8 and 38% (95% CI 15-64%) for GPCOGi. CONCLUSIONS: An informant of any relationship type, using IQCODE, AD8 or GPCOGi may be useful for ruling out dementia but not for ruling it in. We found no evidence of difference between spouse or adult descendants but friends performed significantly better overall on IQCODE and AD8.CC BY 4.0 (Creative Commons Attribution
Distribution of age at natural menopause, age at menarche, menstrual cycle length, height and BMI in BRCA1 and BRCA2 pathogenic variant carriers and non-carriers: results from EMBRACE
No full textBACKGROUND: Carriers of germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are at higher risk of developing breast and ovarian cancer than the general population. It is unclear if these PVs influence other breast or ovarian cancer risk factors, including age at menopause (ANM), age at menarche (AAM), menstrual cycle length, BMI or height. There is a biological rationale for associations between BRCA1 and BRCA2 PVs and reproductive traits, for example involving DNA damage and repair mechanisms. The evidence for or against such associations is limited. METHODS: We used data on 3,046 BRCA1 and 3,264 BRCA2 PV carriers, and 2,857 non-carrier female relatives of PV carriers from the Epidemiological Study of Familial Breast Cancer (EMBRACE). Associations between ANM and PV carrier status was evaluated using linear regression models allowing for censoring. AAM, menstrual cycle length, BMI, and height in carriers and non-carriers were compared using linear and multinomial logistic regression. Analyses were adjusted for potential confounders, and weighted analyses carried out to account for non-random sampling with respect to cancer status. RESULTS: No statistically significant difference in ANM between carriers and non-carriers was observed in analyses accounting for censoring. Linear regression effect sizes for ANM were -0.002 (95%CI: -0.401, 0.397) and -0.172 (95%CI: -0.531, 0.188), for BRCA1 and BRCA2 PV carriers respectively, compared with non-carrier women. The distributions of AAM, menstrual cycle length and BMI were similar between PV carriers and non-carriers, but BRCA1 PV carriers were slightly taller on average than non-carriers (0.5 cm difference, p = 0.003). CONCLUSION: Information on the distribution of cancer risk factors in PV carriers is needed for incorporating these factors into multifactorial cancer risk prediction algorithms. Contrary to previous reports, we found no evidence that BRCA1 or BRCA2 PV are associated with hormonal or anthropometric factors, except for a weak association with height. We highlight methodological considerations and data limitations inherent in studies aiming to address this question.CC BY 4.0 Internationa
Quantitative hypermorphic FAM111A alleles cause autosomal recessive Kenny-Caffey syndrome type 2 and osteocraniostenosis
No full textKenny-Caffey syndrome (KCS) is a rare genetic disorder characterized by extreme short stature, cortical thickening and medullary stenosis of tubular bones, facial dysmorphism, abnormal T-cell function, and hypoparathyroidism. Biallelic loss-of-function variants in TBCE cause autosomal recessive type 1 KCS (KCS1). By contrast, heterozygous missense variants in a restricted region of the FAM111A gene have been identified in autosomal dominant type 2 KCS (KCS2) and a more severe lethal phenotype, osteocraniostenosis (OCS) that have recently been shown to confer a gain-of-function. In this study, we describe two unrelated children with KCS and OCS who were homozygous for different FAM111A variant alleles that result in replacement of the same residue, Tyr414 (c.1241A>G, p.Y414C and c.1240T>A, p.Y414N), in the mature FAM111A protein. Their heterozygous relatives are asymptomatic. Functional studies of recombinant FAM111AY414C demonstrated normal dimerization and a mild gain-of-function effect. This study provides evidence that both biallelic and monoallelic variants of FAM111A with varying degrees of activation can lead to dominant or recessive KCS2 and OCS.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome
No full textPathogenic heterozygous variants in CHD4 cause Sifrim-Hitz-Weiss syndrome, a neurodevelopmental disorder associated with brain anomalies, heart defects, macrocephaly, hypogonadism, and additional features with variable expressivity. Most individuals have non-recurrent missense variants, complicating variant interpretation. A few were reported with truncating variants, and their role in disease is unclear. DNA methylation episignatures have emerged as highly accurate diagnostic biomarkers in a growing number of rare diseases. We aimed to study evidence for the existence of a CHD4-related DNA methylation episignature. We collected blood DNA samples and/or clinical information from 39 individuals with CHD4 variants, including missense and truncating variants. Genomic DNA methylation analysis was performed on 28 samples. We identified a sensitive and specific DNA methylation episignature in samples with pathogenic missense variants within the ATPase/helicase domain. The same episignature was observed in a family with variable expressivity, a de novo variant near the PHD domain, variants of uncertain significance within the ATPase/helicase domain, and a sample with compound heterozygous variants. DNA methylation data revealed higher percentages of shared probes with BAFopathies, CHD8, and the terminal ADNP variants encoding a protein known to form the ChAHP complex with CHD4. Truncating variants, as well as a sample with a recurrent pathogenic missense variant, exhibited DNA methylation profiles distinct from the ATPase/helicase domain episignature. These DNA methylation differences, together with the distinct clinical features observed in those individuals, provide preliminary evidence for clinical and molecular sub-types in the CHD4-related disorder.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Assessing chatbots ability to produce leaflets on cataract surgery: Bing AI, chatGPT 3.5, chatGPT 4o, ChatSonic, Google Bard, Perplexity and Pi
No full textPURPOSE: This study aimed to evaluate leaflets on cataract surgery produced by seven common free chatbots. SETTING: Usage of conversational artificial intelligence services (chatbots) is becoming more prevalent in all aspects of life, including healthcare. Cataract surgery is the most commonly performed operation in the world, with numbers set to increase. Possible applications for chatbots include information giving and education, allowing clinicians to allocate their time more efficiently. DESIGN: Analysis of answers given by seven chatbots (Bing AI, chatGPT 3.5, chatGPT 4o, ChatSonic, Google Bard, Perplexity and Pi) were prompted to make a patient information leaflet on cataract surgery". METHODS: Answers were evaluated using the DISCERN instrument, Patient Education Materials Assessment Tool (PEMAT), presence of misinformation, the Flesch-Kincaid Grade Level readability score and material reliability. RESULTS: The highest overall scored response was from ChatSonic, followed by Bing AI and then Perplexity. The lowest scoring was ChatGPT 3.5.ChatSonic achieved the highest DISCERN and PEMAT scores, and had the highest Flesch-Kincaid Grade level. The lowest DISCERN and PEMAT scores were for Pi. Only ChatGPT 3.5 included some misinformation in its response. Bing AI, ChatSonic and Perplexity included reliable references; the other chatbots provided no references. CONCLUSIONS: This study demonstrates a range of answers given by chatbots creating a cataract surgery leaflet, suggesting variation in their development and reliability. ChatGPT 3.5 scored the most poorly. However, ChatSonic indicated promise in how technology may be used to assist information giving in ophthalmology."Not hel
Do patients with minimally displaced distal radial fractures need a plaster cast?
No full textTraditionally, patients with a fracture of the distal radius are treated in a cast if they do not require surgery. If the fracture requires manipulation, the cast is moulded to hold the reduction and maintain normal anatomical alignment during healing. However, is a cast necessary for patients whose fracture does not require manipulation? Removable splints are an alternative treatment option. Such splints have the advantage that they can be adjusted to improve fit around the wrist as swelling reduces, and can be removed and reapplied for the purpose of washing or, in some cases, exercise. However, evidence for their safety and effectiveness in the management of distal radius fractures is lacking. DRAFT3 is a multicentre randomized non-inferiority trial and economic analysis designed to determine the safety and effectiveness of removable splints as an alternative to casts in the treatment of distal radius fractures that do not require manipulation.Not hel