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Comparison of laparoscopic cholecystectomy in children at paediatric centres and adult centres: a systematic review and meta-analysis
No full textINTRODUCTION: Paediatric laparoscopic cholecystectomy (LC) is performed by both paediatric and adult surgeons. The aim of this review was to compare outcomes at paediatric centres (PCs) and adult centres (ACs). METHODS: A literature search was conducted, in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines, for papers published between January 2000 and December 2020. Statistical analysis was performed using Stata(®) version 16 (StataCorp, College Station, TX, US). RESULTS: A total of 92 studies involving 74,852 paediatric LCs met the inclusion criteria. Over half (59%) of the LCs were performed at ACs. No significant differences were noted in the male-to-female ratio, mean age or mean body mass index between PCs and ACs. The main indications were cholelithiasis (34.1% vs 34.4% respectively, p=0.83) and biliary dyskinesia (17.0% vs 23.5% respectively, p<0.01). There was no significant difference in the median inpatient stay (2.52 vs 2.44 days respectively, p=0.89). Bile duct injury was a major complication (0.80% vs 0.37% respectively, p<0.01). Reoperation rates (2.37% vs 0.74% respectively, p<0.01) and conversion to open surgery (1.97% vs 4.74% respectively, p<0.01) were also significantly different. Meta-analysis showed no significant difference in overall complications (p=0.92). CONCLUSIONS: The number of LCs performed, intraoperative cholangiography use and conversion rates were higher at ACs whereas bile duct injury and reoperation rates were higher at PCs. Despite a higher incidence of bile duct injury at PCs, the incidence at both PCs and ACs was <1%. In complex cases, a joint operation by both paediatric and adult surgeons might be a better approach to further improve outcomes. Overall, LC was found to be a safe operation with comparable outcomes at PCs and ACs.Not permittedThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality by disrupting mitochondrial pathways
No full textDissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.UnknownUnpublished eprin
Outcomes of definite vs probable/presumed cardiac sarcoidosis: a systematic review and meta-analysis
No full textBACKGROUND: Diagnosing cardiac sarcoidosis (CS), which can be associated with arrhythmias and heart failure, remains challenging despite multiple advances over time. The 2014 Heart Rhythm Society (HRS) consensus statement recommends an endomyocardial biopsy (EMB) to establish a definite diagnosis of CS. In the absence of a positive EMB, a diagnosis of probable or presumed CS is made on the basis of clinical and imaging criteria. OBJECTIVE: To investigate whether there is any difference in outcomes between definite vs probable/presumed CS. METHODS: PubMed/MEDLINE, Embase, and the Cochrane Library databases were searched for relevant studies published after 2014. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using the random effects model and presented in forest plots. RESULTS: 6 studies involving 2,103 patients were identified. The cohort had a mean age of 56.8 years (SD:±13.6 years). The median duration of follow-up was 40.5 months. No statistically significant difference was observed between definite and probable/presumed CS for reduced risk of the composite endpoint (RR: 1.06, 95% CI: 0.66 to 1.72), all-cause death (RR: 1.03, 95% CI: 0.73 to 1.46), sudden cardiac death (RR: 1.59, 95% CI: 0.99 to 2.56), arrhythmias (RR: 0.80, 95% CI: 0.60 to 1.07), and HF-related hospitalizations (RR: 0.91, 95% CI: 0.59 to 1.38). CONCLUSION: This meta-analysis demonstrated the equivalence of clinical course and prognosis between definite and probable/presumed CS. This highlights the importance of a multi-disciplinary approach to CS care and emphasizes that histological confirmation should not be a prerequisite to diagnose or manage this condition.Published version, accepted version (12 month embargo), submitted versionNot hel
Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study
No full textEstimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.Published version, accepted version (12 month embargo), submitted versionJournal 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
Accessing mechanical thrombectomy treatment for stroke in England, Wales and Northern Ireland: the importance of the emergency pathway
No full textPublished version, accepted version, submitted versionRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
The Roles of GDF-9, BMP-15, BMP-4 and EMMPRIN in Folliculogenesis and In Vitro Fertilization
No full textGrowth differentiation factor 9 (GDF-9) contributes to early ovarian development and oocyte survival. Higher concentrations of GDF-9 in follicular fluid (FF) are associated with oocyte nuclear maturation and optimal embryo development. In in vitro fertilization (IVF), GDF-9 affects the ability of the oocyte to fertilize and subsequent embryonic development. Bone morphogenetic protein 15 (BMP-15) is involved in the regulation of ovarian function and affects oocyte development. During IVF, BMP-15 contributes to the formation of competent blastocysts. BMP-15 may play a role in embryo implantation by affecting endometrial receptivity. Bone morphogenetic protein 4 (BMP-4) is involved in the regulation of follicle growth and development and affects granulosa cell (GC) differentiation. In relation to IVF, BMP-4 is important for embryonic development, influences cell fate and differentiation, and plays a role in facilitating embryo-endometrial interactions during the implantation process. Extracellular matrix metalloproteinase inducer (EMMPRIN) is associated with ovulation and follicle rupture, promotes the release of mature eggs, and affects the modification of the extracellular matrix of the follicular environment. In IVF, EMMPRIN is involved in embryo implantation by modulating the adhesive properties of endometrial cells and promotes trophoblastic invasion, which is essential for pregnancy to occur. The purpose of the current article is to review the studies and recent findings of GDF-9, BMP-15, BMP-4 and EMMPRIN as fundamental factors in normal follicular development and in vitro fertilization.Published version, accepted version, submitted versionJournal 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
Optimised human stool sample collection for multi-omic microbiota analysis
No full textTo accurately define the role of the gut microbiota in health and disease pathogenesis, the preservation of stool sample integrity, in terms of microbial community composition and metabolic function, is critical. This presents a challenge for any studies which rely on participants self-collecting and returning stool samples as this introduces variability and uncertainty of sample storage/handling. Here, we tested the performance of three stool sample collection/preservation buffers when storing human stool samples at different temperatures (room temperature [20 °C], 4 °C and - 80 °C) for up to three days. We compared and quantified differences in 16S rRNA sequencing composition and short-chain fatty acid profiles compared against immediately snap-frozen stool. We found that the choice of preservation buffer had the largest effect on the resulting microbial community and metabolomic profiles. Collectively analysis confirmed that PSP and RNAlater buffered samples most closely recapitulated the microbial diversity profile of the original (immediately - 80 °C frozen) sample and should be prioritised for human stool microbiome studies.Published version, accepted version, submitted versionJournal 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
The evolving genetic landscape of telomere biology disorder dyskeratosis congenita
No full textDyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.UnknownRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Digital innovation for cancer risk assessment allows large-scale service redevelopment of regional cancer genetics service delivery
No full textFamily-history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention and Early Detection (SPED). The online patient-facing cancer Family History Questionnaire Service (cFHQS) is a digitalised, resource efficient tool for family history data capture to facilitate this. The capturing of digital data from cFHQS allows for data interrogation of patients referred to Clinical Genetics for the purposes of service improvement. Digital data from 4,044 cFHQS respondents over a three-year period was collected and interrogated with respect to the number and type of familial tumour diagnoses to enable service improvement and streamlining of referral pathways. 81% of colorectal and 71% of breast screening assessments were population- or moderate-risk. Most patients who completed cFHQS reported more than one diagnosis of cancer/tumour/polyps in their family. 2.5% of family history assessment patients had a second indication that required assessment that would have been missed if single tumour type assessment was undertaken. Implementation of an innovative, digital family history data collection pathway has allowed large scale interrogation of referral patterns and assessment outcomes to enable service development. The high volume of inappropriate referrals to Clinical Genetics for population and moderate risk patients highlighted the need for dedicated secondary care pathway provision for these patients. The use of cFHQS streamlined family history assessment allows for redistribution of resources to improve equity and access to genetic cancer risk assessment.Unknown1 year embargo from time of publicatio
Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK
No full textINTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.Published version, accepted version, submitted versionJournal 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