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Correction: HELLO: a protocol for a cluster randomized controlled trial to enhance interpersonal relationships and team cohesion among ICU healthcare professionals
No full textOpen 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
Genetic Discovery and Risk Prediction for Type 1 Diabetes in Individuals Without High-Risk HLA-DR3/DR4 Haplotypes
No full textOBJECTIVE: More than 10% of patients with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes with distinct clinical features, such as later onset and reduced insulin dependence. We aimed to identify genetic drivers of T1D in the absence of DR3/DR4 and improve prediction of T1D risk in these individuals. RESEARCH DESIGN AND METHODS: We performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Next, we performed heterogeneity tests to examine differences in T1D risk variants in individuals without versus those with DR3/DR4 haplotypes. We further assessed genome-wide differences in gene regulatory element and biological pathway enrichments between the non-DR3/DR4 and DR3/DR4 cohorts. Finally, we developed a genetic risk score (GRS) to predict T1D in individuals without DR3/DR4 and compared with an existing T1D GRS. RESULTS: A total of 18 T1D risk variants in non-DR3/DR4 samples were identified. Risk variants at the MHC and multiple other loci genome wide had heterogeneity in effects on T1D dependent on DR3/DR4 status, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-associated variants in non-DR3/DR4 were more enriched for regulatory elements and pathways involved in antigen presentation, innate immunity, and β-cells and depleted in T cells compared with DR3/DR4. A non-DR3/DR4 GRS outperformed an existing risk score GRS2 in discriminating non-DR3/DR4 T1D from no diabetes (area under the curve 0.867; P = 7.48 × 10-32) and type 2 diabetes (0.907; P = 4.94 × 10-44). CONCLUSIONS: In total, we identified heterogeneity in T1D genetic risk dependent on high-risk HLA-DR3/DR4 haplotype, which uncovers disease mechanisms and enables more accurate prediction of T1D across the HLA background.Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available atJournal 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
Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
No full textPURPOSE: ATM germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing ATM heterozygotes in clinical practice are limited. METHODS: An international workgroup developed a clinical practice resource to guide management of ATM heterozygotes using peer-reviewed publications and expert opinion. RESULTS: Although ATM is a moderate (intermediate) penetrance gene, cancer risks may be considered as a continuous variable, influenced by family history and other modifiers. ATM GPV heterozygotes should generally be offered enhanced breast surveillance according to their personalized risk estimate and country-specific guidelines and, generally, risk-reducing mastectomy is not recommended. Prostate cancer surveillance should be considered. Pancreatic cancer surveillance should be considered based on assessment of family history, ideally as part of a clinical trial, with existence of country-specific guidelines. For ATM GPV heterozygotes who develop cancer, radiation therapy decisions should not be influenced by the genetic result. Although poly-adenosine diphosphate ribose polymerase inhibitors are licensed for use in metastatic castration-resistant prostate cancer and ATM GPVs, the evidence-base is currently weak. CONCLUSION: Systematic prospective data collection is needed to establish the spectrum of ATM-associated cancer and determine the outlines of surveillance, response to cancer treatment, and survival.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Evaluation of intestinal biopsy tissue preservation methods to facilitate large-scale mucosal microbiota research
No full textBACKGROUND: Large-scale multicentre studies are needed to understand complex relationships between the gut microbiota, health and disease. Interrogating the mucosal microbiota may identify important biology not captured by stool analysis. Gold standard tissue cryopreservation ('flash freezing') limits large-scale study feasibility. We aimed to compare gut microbiota in gold standard and pragmatic mucosal biopsy storage conditions. METHODS: We collected endoscopic recto-sigmoid biopsies from 20 adults with inflammatory bowel disease. Biopsies were preserved using three methods: (i) flash freezing (most proximal and distal biopsy sites); (ii) nucleic acid preservative reagents (QIAGEN Allprotect®, Invitrogen RNAlater™, and Zymo DNA/RNA Shield™); and (iii) formalin fixation with paraffin embedding (FFPE), which is used to preserve tissue for clinical histopathology within healthcare settings. Microbiota were sequenced on the MiSeq platform (V4 region, 16S rRNA gene). FINDINGS: Tissue microbiota were consistent between most proximal and distal tissue suggesting any within-patient variation observed reflected storage condition, not biopsy location. There was no significant difference in alpha-diversity or microbial community profiles of reagent-preserved versus gold standard tissue. FFPE community structure was significantly dissimilar to other tissue samples, driven by differential relative abundance of obligate gut anaerobes; Faecalibacterium, Anaerostipes and Lachnospiraceae. Despite these differences, tissue microbiota grouped by participant regardless of preservation and storage conditions. INTERPRETATION: Preservative reagents offer a convenient alternative to flash freezing tissue in prospective large-scale mucosal microbiota studies. Whilst less comparable, FFPE provides potential for retrospective microbiota studies using historical samples. FUNDING: Medical Research Council (MR/T032162/1) and The Leona M. and Harry B. Helmsley Charitable Trust (G-2002-04255).This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).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
Intravascular Shockwave Lithotripsy for the Treatment of Severe Peripheral Arterial Disease: A Single-Centre Experience
No full textBackground Chronic limb-threatening ischemia (CLTI) is the most severe manifestation of peripheral arterial disease. Various revascularization techniques are employed to treat peripheral arterial disease. Intravascular shockwave lithotripsy (IVL) is a relatively new procedure for the treatment of calcific lower limb peripheral arterial diseases (PAD). Objectives To assess the effectiveness and safety of shockwave lithotripsy in patients with severe PAD through an evaluation of limb salvage rate and patient survival. Methods A retrospective study of all patients treated with shockwave lithotripsy between November 2019 and June 2024 was performed. The primary outcome was amputation-free survival and secondary outcomes were potential complications of IVL (thrombo-embolization, perforation, and restenosis). Patients were followed up in the clinic and assessed both clinically and with a duplex scan at three months. Results A total of 38 patients were included in the study. The median age was 71 years; 28 were males. Among the patients, 28 (73.68%) were diabetic, 4 patients (10.53%) were current smokers, 10 patients (26.32%) were ex-smokers, and 24 patients (63.16%) were non-smokers. According to the Rutherford classification of PAD, 33 of the 38 patients were in stages 4-6. Only five patients were stage 3. Total number of treated arteries was 47. Treated lesions were 49% in the superficial femoral artery (SFA), 36% in the popliteal artery, 8% in the common femoral artery (CFA), 4% received treatment of the iliac arteries, and 2% of the posterior tibial artery. All treated arteries showed improved angiographic results. Four patients (10.53%) developed distal embolization. No perforation was recorded, and no significant flow-limiting dissection was recorded to require treatment. At the three-month follow-up, imaging revealed improvement in 58% of patients while 5% showed no improvement. Notably, follow-up imaging was not conducted in 37% of patients due to evident clinical improvement such as ulcer healing, palpable pulses, and the presence of Doppler signals. Seven patients required reintervention within three months after the initial IVL operation and 4 patients got revascularized after this period resulting in 11 patients requiring revascularisation after the initial operation. Amputation-free survival was 79% (30 patients). Conclusion Shockwave lithotripsy is associated with a high limb salvage rate and low complication rate. Further research is needed into long-term effectiveness and the role of shockwave treatment as an adjuvant to traditional revascularization techniques of patients with CLTI and short-distance claudicants.This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Neoadjuvant chemotherapy before surgery versus surgery followed by chemotherapy for initial treatment in advanced epithelial ovarian cancer
No full textRATIONALE: Epithelial ovarian cancer (EOC) presents at an advanced stage in the majority of women. These women require a combination of surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. OBJECTIVES: To assess the advantages and disadvantages of treating women with advanced EOC with chemotherapy before cytoreductive surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows cytoreductive surgery (primary cytoreductive surgery (PCRS)). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 21 March 2024. We also checked the reference lists of relevant papers for further studies. We contacted the principal investigators of relevant trials for further information. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. OUTCOMES: We extracted data on overall (OS) and progression-free survival (PFS), adverse events, surgically related mortality and morbidity, and quality of life outcomes. RISK OF BIAS: We used the Cochrane RoB 1 tool to assess risk of bias in RCTs. SYNTHESIS METHODS: We conducted meta-analyses using random-effects models (due to heterogeneity between studies) to calculate hazard ratios (HR), risk ratios (RR), mean differences (MD), and 95% confidence intervals (CI) for all outcomes. We assessed the certainty of evidence according to the GRADE approach. INCLUDED STUDIES: We identified a further 1022 titles and abstracts through our searches in this update (958 unique records after further de-duplication), adding to the 2227 titles and abstracts identified in previous versions of this review. A total of five RCTs of varying quality and size met the inclusion criteria. We identified no new completed studies in this update, but we did include additional data from existing studies. The studies assessed a total of 1774 women with stage III/IV ovarian cancer randomised to NACT followed by interval cytoreductive surgery (ICRS) or PCRS followed by chemotherapy. We included data from four studies in the meta-analyses (1692 participants). SYNTHESIS OF RESULTS: Survival We found little or no difference between groups in OS (HR 0.96, 95% CI 0.86 to 1.08; P = 0.49; I(2) = 0%; 4 studies; 1692 women; high-certainty evidence) and likely little or no difference between groups in PFS (HR 0.98, 95% CI 0.88 to 1.08; P = 0.62; I(2) = 0%; 4 studies; 1692 women; moderate-certainty evidence). Adverse events Adverse events, surgical morbidity, and quality of life outcomes were variably and incompletely reported across studies. NACT reduces postoperative mortality (0.4% in the NACT group versus 3.3% in the PCRS group) (RR 0.18, 95% CI 0.06 to 0.52; P = 0.002; I(2) = 0%; 4 studies; 1542 women; high-certainty evidence). There are probably clinically meaningful differences in favour of NACT compared to PCRS in overall surgically related adverse effects (grade 3+ (G3+)) (6% in the NACT group versus 29% in the PCRS group) (RR 0.22, 95% CI 0.13 to 0.38; P < 0.001; I(2) = 0%; 2 studies; 435 women; moderate-certainty evidence). Organ resection NACT probably results in a large reduction in the need for stoma formation (5.8% in the NACT group versus 20.4% in the PCRS group) (RR 0.29, 95% CI 0.12 to 0.74; P = 0.009; I(2) = 70%; 2 studies; 632 women; moderate-certainty evidence) and probably reduces the risk of needing bowel resection at the time of surgery (13.0% in the NACT group versus 26.6% in the PCRS group) (RR 0.47, 95% CI 0.27 to 0.81; P = 0.007; I(2) = 84%; 4 studies; 1578 women; moderate-certainty evidence). Quality of life Global quality of life on the EORTC QLQ-C30 produced imprecise results in three studies, with high levels of heterogeneity (quality of life at six months: MD 6.62, 95% CI -2.89 to 16.13; P = 0.17; I(2) = 92%; 3 studies; 559 women; low-certainty evidence). Overall, functional and symptom scores may be slightly improved for NACT at 6 months, but similar by 12 months, although the differences might not be clinically meaningful. AUTHORS' CONCLUSIONS: The available high- to moderate-certainty evidence shows there is likely little or no difference in primary survival outcomes between PCRS and NACT for those with advanced EOC who are suitable for either treatment option. NACT reduces the risk of postoperative mortality and likely reduces the risk of serious adverse events, especially those around the time of surgery, and the need for stoma formation. These data should inform women and clinicians (involving specialist gynaecological multidisciplinary teams) and allow treatment to be tailored to the individual patient, taking into account surgical resectability, age, histology, stage, and performance status. Data from an unpublished study and ongoing studies are awaited. FUNDING: This Cochrane review update had no dedicated funding. REGISTRATION: Protocol (2005): DOI: 10.1002/14651858.CD005343 Original review (2007): DOI: 10.1002/14651858.CD005343.pub2 Review update (2012): DOI: 10.1002/14651858.CD005343.pub3 Review update (2019): DOI: 10.1002/14651858.CD005343.pub4 Review update (2021): DOI: 10.1002/14651858.CD005343.pub5 Review updated (2021a): DOI: 10.1002/14651858.CD005343.pub6.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
Assessment of frailty in patients with heart failure: A new Heart Failure Frailty Score developed by Delphi consensus
No full textAIMS: The Heart Failure Frailty Score (HFFS) is a novel, multidimensional tool to assess frailty in patients with heart failure (HF). It has been developed to overcome limitations of existing frailty assessment tools while being practical for clinical use. The HFFS reflects the concept of frailty as a multidimensional, dynamic and potentially reversible state, which increases vulnerability to stressors and risk of poor outcomes in patients with HF. METHODS AND RESULTS: The HFFS was developed through a Delphi consensus process involving 54 international experts. This approach involved iterative rounds of questionnaires and interviews, where a panel of experts provided their opinions on specific questions prepared by the Steering Committee. The experts were invited to vote and share their views anonymously, using a 5-point Likert scale over iterative rounds. An 80% threshold was set for agreement or disagreement for each statement. Twenty-two variables from four domains (clinical, functional, psycho-cognitive and social) have been selected for inclusion in the HFFS after the third round of the Delphi process. A shorter version (S-HFFS), including 10 variables, has also been developed for daily clinical use. CONCLUSIONS: The HFFS is a new multidimensional tool for the identification of frailty in patients with HF. It should also enables healthcare providers to identify potential 'red flags' for frailty in order to develop personalized care plans. The next step will be to validate the new score in patients with HF.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Transient Ischaemic Attack in a Patient With Conn Syndrome: A Case Report and Literature Review on the Importance of Identifying Secondary Hypertension
No full textBACKGROUND/AIM: Transient ischaemic attack (TIA) is characterised by a temporary neurological dysfunction resulting from focal ischaemia in the brain, spinal cord or retina without acute infarction. These episodes typically last less than 24 hours and are significant predictors of subsequent ischaemic strokes. Hypertension is a major risk factor for cerebrovascular events, and primary aldosteronism (PA) is recognised as a common cause of secondary hypertension. This case report presents a male patient with secondary hypertension due to Conn Syndrome, a form of PA, who experienced a TIA manifesting as left leg weakness, underscoring the heightened stroke risk associated with secondary hypertension. CASE REPORT: A 78-year-old male with secondary hypertension caused by Conn Syndrome presented with an episode of left leg weakness that resolved within 24 hours. After ruling out other potential causes such as metabolic disturbances, infections, and structural brain lesions, he was diagnosed with TIA and treated with dual antiplatelet therapy. A carotid ultrasound revealed significant stenosis, leading to a referral for carotid endarterectomy. Long-term management included clopidogrel monotherapy and optimising hypertension control. CONCLUSION: This case highlights the increased stroke risk in patients with Conn Syndrome-related hypertension, emphasising the importance of early recognition and optimising hypertension management in patients with secondary hypertension to prevent future cerebrovascular events.This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international licenseRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Higher hospital volume reduces early failure rates in single-stage revision TKR for infection: An analysis of the United Kingdom National Joint Registry and National Administrative Databases
No full textPURPOSE: Revision knee replacement (RevKR) for infection is rare but increasing. It is hypothesised that higher hospital volume reduces adverse outcomes. The aim was to estimate the association of surgical unit volume with outcomes following first, single-stage RevKR for infection. METHODS: This population-based cohort study merged data from the United Kingdom National Joint Registry, Hospital Episode Statistics, National Patient Reported Outcome Measures and the Civil Registrations of Death. Patients undergoing procedures between 1 January 2009 and 30 June 2019 were included. Early outcomes were chosen to reflect the quality of the surgical provision and included re-revision at 2 years, mortality, serious medical complications, length of stay and patient-reported outcome measures (PROMs). Adjusted fixed effect multivariable regression models were used to examine the association between surgical unit mean annual caseload and the risk of adverse outcomes. RESULTS: A total of 1477 patients underwent first-time single-stage RevKRs for infection across 267 surgical units and 716 surgeons. Following adjustment for age, gender, American Society of Anaesthesiologists grade, surgeon volume, year of surgery and operation funder and modelling surgical unit volume with restricted cubic spline, a greater mean annual volume was associated with a lower risk of re-revision at 2 years. The odds of re-revision in hospitals performing fewer than or equal to 12 cases per year was 2.53 (95% confidence interval = 1.50-4.31) times more likely than hospitals performing three to four cases per month. Annual variation in surgical unit volume was not associated with mortality and serious medical complications within 90 days. Only 99 out of 1477 (7%) of patients had linked PROMs which precluded subsequent analysis. CONCLUSION: Overall, higher volume surgical units had lower rates of early re-revision following the first RevKR for infection. We were unable to provide recommended specific volume thresholds for units; however, the probability of re-revision appears to be lowest in the highest volume units. LEVEL OF EVIDENCE: Level III, retrospective cohort study of prospectively collected data.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Dietary interventions for the management of type 2 diabetes mellitus in childhood and adolescence: A systematic review
No full textAIMS: Despite the alarming increasing incidence of type 2 diabetes mellitus (T2DM) in children and young People (CYP), and its associated morbidities and poor long-term prognosis, there remains uncertainty in its management. Dietary interventions have been shown to be effective in adults with T2DM, but little is known about their effectiveness in CYP. The aim of this systematic review is to provide up-to-date evidence regarding dietary interventions for T2DM in childhood and adolescence. METHODS: Five databases Embase, MEDLINE, CENTRAL, Web of Science and CINAHL were searched from January 2000 to May 2023 for all studies involving dietary interventions in CYP under 19 years with T2DM. The primary outcome was glycaemic control as measured by HbA1c. RESULTS: Of 8352 search results, five papers met inclusion criteria. No randomised controlled trials were identified. Two interventional studies (n = 28) found very low energy diets (VLED) were associated with reduced HbA1c (16 mmol/mol (3.6%) reduction after 8 weeks), decreased requirement for pharmacotherapy and weight loss. However, benefits to HbA1c were not sustained over 2 years. From the observational studies, the most frequent self-reported dietary strategies were limiting sweets and increasing fruit/vegetable intake, but efficacy was limited. Limiting fat intake was associated with improved HbA1c in women. CONCLUSIONS: There is limited evidence and a lack of robust clinical trials to support the effectiveness of dietary interventions for CYP-onset T2DM. With evidence of benefit in adulthood and encouraging initial results in the young, it is imperative that fully powered randomised trials with longer follow-up are undertaken to determine efficacy.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted