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Comparative Analysis of Fluorescence In Situ Hybridization and Next-Generation Sequencing in Sperm Evaluation: Implications for Preimplantation Genetic Testing and Male Infertility
No full textPre-implantation genetic testing (PGT) is a crucial process for selecting embryos created through assisted reproductive technology (ART). Couples with chromosomal rearrangements, infertility, recurrent miscarriages, advanced maternal age, known single-gene disorders, a family history of genetic conditions, previously affected pregnancies, poor embryo quality, or congenital anomalies may be candidates for PGT. Preimplantation genetic testing for aneuploidies (PGT-A) enables the selection and transfer of euploid embryos, significantly enhancing implantation rates in assisted reproduction. Fluorescence in situ hybridization (FISH) is the preferred method for analyzing biopsied cells to identify these abnormalities. While FISH is a well-established method for identifying sperm aneuploidy, NGS offers a more comprehensive assessment of genetic material, potentially enhancing our understanding of male infertility. Chromosomal abnormalities, arising during meiosis, can lead to aneuploid sperm, which may hinder embryo implantation and increase miscarriage rates. This review provides a comparative analysis of fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) in sperm evaluations, focusing on their implications for preimplantation genetic testing. This analysis explores the strengths and limitations of FISH and NGS, aiming to elucidate their roles in improving ART outcomes and reducing the risk of genetic disorders in offspring. Ultimately, the findings will inform best practices in sperm evaluations and preimplantation genetic testing strategies.Journal content freely available via Open Access. Some content may be unavailable due to publisher embarg
Classification of Variants of Reduced Penetrance in High Penetrance Cancer Susceptibility Genes: Framework for Genetics Clinicians and Clinical Scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)
No full textPURPOSE: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene (CSG) as though having equivalent penetrance, despite increasing evidence of inter-variant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants where reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance (VUS). We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network. METHODS: A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group (CStAG) working group. RESULTS: CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants where (A) Active evidence suggests a reduced penetrance effect size (e.g. from case-control or segregation data) (B) Reduced penetrance effect is inferred from weaker/potentially-inconsistent observed data. CONCLUSIONS: CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, whilst developed for CSGs, are potentially applicable to other clinical contexts.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
BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations
No full textAn increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11A's role in brain development.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
Accurate and cost-effective generation of a genetic risk score direct from blood lysates
No full textJournal 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
Reducing Time Taken to Gather Equipment for Venepuncture and Cannulation: A Quality Improvement Project
No full textTimely gathering of equipment for venepuncture or cannulation on hospital wards is important, particularly in emergency situations. Anecdotally several doctors working at a hospital in England expressed frustration at low equipment stock, layout, and discrepancies between wards leading to significant delays in this process. This quality improvement project therefore aimed to reduce the time taken to gather equipment for venepuncture or cannulation to 20 seconds by June 2023. Methods: Quality improvement methodology was used to define the problem, produce an aim statement, and design several interventions. A flow map was created to understand the equipment collection process, a root cause analysis identified problem areas, and a driver diagram highlighted potential change ideas. A new trolley layout was implemented as part of several plan-do-study-act cycles with the addition of several simple human interventions to maximise its usage. More widespread introduction of identical trolleys across the surgical wards was also achieved. Results: Initial qualitative surveys and the root cause analysis identified a lack of equipment availability, and discrepancies between wards being key barriers to rapid collection of equipment. Prior to any intervention, the average time taken to gather equipment for venepuncture and cannulation was 141 and 137.5 seconds respectively. After implementing a new trolley design and layout, with clear markings and human factor optimisation, the times were reduced to 18 seconds each. Subjective feedback during a cardiac arrest scenario following the intervention was positive. Widespread implementation of the trolleys around the hospital was started following this success although the efficacy of their introduction was not measured during the study period. Conclusion: This quality improvement project successfully reduced the time taken to gather equipment for venepuncture or cannulation on a hospital ward, with positive feedback in an emergency. The project used well-documented quality improvement methodology to achieve this and highlights the ability of empowered clinical staff in non-managerial or non-leadership positions to action change.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
Knee4Life: Empowering Knee Recovery After Total Knee Replacement Through Digital Health Protocol
No full textPain and knee stiffness are common problems following total knee replacement surgery, with 10-20% of patients reporting dissatisfaction following their procedure. A remote assessment of knee stiffness could improve outcomes through continuous monitoring, facilitating timely intervention. Using machine learning algorithms, computer vision can extract joint angles from video footage, offering a method to monitor knee range of motion in patients' homes. This study outlines a protocol to provide proof of concept and validate a computer vision-based approach for measuring knee range of motion in individuals who have undergone total knee replacement. The study also explores the feasibility of integrating this technology into clinical practice, enhancing post-operative care. The study is divided into three components: carrying out focus groups, validating the computer vision-based software, and home testing. The focus groups will involve five people who underwent total knee replacement and ten healthcare professionals or carers who will discuss the deployment of the software in clinical settings. For the validation phase, 60 participants, including 30 patients who underwent total knee replacement surgery five to nine weeks prior and 30 healthy controls, will be recruited. The participants will perform five tasks, including the sit-to-stand test, where knee range of motion will be measured using computer vision-based markerless motion capture software, marker-based motion capture, and physiotherapy assessments. The accuracy and reliability of the software will be evaluated against these established methods. Participants will perform the sit-to-stand task at home. This will allow for a comparison between home-recorded and lab-based data. The findings from this study have the potential to significantly enhance the monitoring of knee stiffness following total knee replacement. By providing accurate, remote measurements and enabling the early detection of issues, this technology could facilitate timely referrals to non-surgical treatments, ultimately reducing the need for costly and invasive procedures to improve knee range of motion.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
Type 1 diabetes genetic risk score variation across ancestries using whole genome sequencing and array-based approaches
No full textA Type 1 Diabetes Genetic Risk Score (T1DGRS) aids diagnosis and prediction of Type 1 Diabetes (T1D). While traditionally derived from imputed array genotypes, Whole Genome Sequencing (WGS) provides a more direct approach and is now increasingly used in clinical and research studies. We investigated the concordance between WGS-based and array-based T1DGRS across genetic ancestries in 149,265 UK Biobank participants using WGS, TOPMed-imputed, and 1000 Genomes-imputed array genotypes. In the overall cohort, WGS-based T1DGRS demonstrated strong correlation with TOPMed-imputed array-based score (r = 0.996, average WGS-based score 0.0028 standard deviations (SD) lower, p < 10(- 31)), while showing lower correlation with 1000 Genomes-imputed array-based scores (r = 0.981, 0.043 SD lower in WGS, p < 10(- 300)). Ancestry-stratified analyses between WGS-based and TOPMed-imputed array-based score showed the highest correlation with European ancestry (r = 0.996, 0.044 SD lower in WGS, p < 10(- 300)) followed by African ancestry (r = 0.989, 0.0193 SD lower in WGS, p < 10(- 14)) and South Asian ancestry (r = 0.986, 0.0129 SD lower in WGS, p < 10 (- 6)). These differences were more pronounced when comparing WGS based score with 1000 Genomes-imputed array-based scores (r = 0.982, 0.975, 0.957 for European, South Asian, African respectively). Population-level analysis using WGS-based T1DGRS revealed significant ancestry-based stratification, with European ancestry individuals showing the highest scores, followed by South Asian (average 0.28 SD lower than Europeans, p < 10(- 58)) and African ancestry individuals (average 0.89 SD lower than Europeans, p < 10(- 300)). Notably, when applying the European ancestry-derived 90(th) centile risk threshold, only 0.71% (95% CI 0.41-1.13) of African ancestry individuals and 6.4% (95% CI 5.6-7.2) of South Asian individuals were identified as high-risk, substantially below the expected 10%. In conclusion, while WGS is viable for generating T1DGRS, with TOPMed-imputed genotypes offering a cost-effective alternative, the persistence of ancestry-based variations in T1DGRS distribution even using whole genome sequencing emphasises the need for ancestry-specific or pan-ancestry standards in clinical practice.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
Core Outcome Domains for Elbow Replacement (CODER)
No full textAIMS: A review of the literature on elbow replacement found no consistency in the clinical outcome measures which are used to assess the effectiveness of interventions. The aim of this study was to define core outcome domains for elbow replacement. METHODS: A real-time Delphi survey was conducted over four weeks using outcomes from a scoping review of 362 studies on elbow replacement published between January 1990 and February 2021. A total of 583 outcome descriptors were rationalized to 139 unique outcomes. The survey consisted of 139 outcomes divided into 18 domains. The readability and clarity of the survey was determined by an advisory group including a patient representative. Participants were able to view aggregated responses from other participants in real time and to revisit their responses as many times as they wished during the study period. Participants were able to propose additional items for inclusion. A Patient and Public Inclusion and Engagement (PPIE) panel considered the consensus findings. RESULTS: A total of 45 respondents completed the survey. Nine core mandatory domains were identified: 'return to work or normal daily role'; delivery of care was measured in the domains 'patient satisfaction with the outcome of surgery' and 'would the patient have the same operation again'; 'pain'; 'revision'; 'elbow function'; 'independence in activities of daily living'; 'health-related quality of life'; and 'adverse events'. 'Elbow range of motion' was identified as important by consensus but was felt to be less relevant by the PPIE panel. The PPIE panel unanimously stated that pain should be used as the primary outcome domain. CONCLUSION: This study defined core domains for the clinical outcomes of elbow replacement obtained by consensus from patients, carers, and healthcare professionals. Pain may be used as the primary outcome in future studies, where appropriate. Further work is required to define the instruments that should be used.Not hel
False Positive Rate from Prospective Studies of PET-CT in Cutaneous Malignant Melanoma: A Systematic Review and Meta-Analysis
No full textBACKGROUND: Cutaneous malignant melanoma (CMM) is increasing in prevalence and possesses the highest mortality rate of any skin cancer. Positron Emission Tomography and Computed Tomography (PET-CT) may be utilised in either radiological staging or surveillance, primarily in stage III-IV disease. False positive (FP) results lead to patient distress, increased costs, and unnecessary follow-up. The FP rate in CMM literature varies widely, altering calculations of positive predictive value and has not undergone pooled meta-analytic. MATERIALS AND METHODS: A systematic review and meta-analysis of FP results in prospective studies of PET-CT in CMM was performed in accordance with PRISMA guidelines. RESULTS: The systematic review produced 14 trials for inclusion. Patient-based reporting had the lowest pooled proportion of FP results with 5.8 % (95 % CI = 3.3 % to 8.8 %), lesion-based was highest with 9.1 % (95 % CI = 3.4 % to 17.2 %) and combined was 6.1 % (95 % CI = 4.3 % to 8.1 %). Bias was low to unclear other than for FP reporting. Heterogeneity (I2) was variable across all analyses. FP findings were mainly lymphatic, dermatological, respiratory, or skeletal. Diagnostic information was not provided. CONCLUSIONS: This study was the first attempt to quantify the pooled proportion of FP results from PET-CT in CMM. A small number of studies (n = 14) were available due to the predominance of retrospective methodology. Due to inconsistent reporting the true proportion of FP results is unclear. Systemic distribution was expected but limited diagnostic information was provided. Repeat meta-analysis using retrospective work should be performed. Future work should be prospective with clearly documented FP proportion, distribution, diagnosis, and follow-up.Not hel
Carbon footprint of hospital laundry: a life-cycle assessment
No full textOBJECTIVES: To assess greenhouse gas (GHG) emissions from a regional hospital laundry unit, and model ways in which these can be reduced. DESIGN: A cradle to grave process-based attributional life-cycle assessment. SETTING: A large hospital laundry unit supplying hospitals in Southwest England. POPULATION: All laundry processed through the unit in 2020-21 and 2021-22 financial years. PRIMARY OUTCOME MEASURE: The mean carbon footprint of processing one laundry item, expressed as in terms of the global warming potential over 100 years, as carbon dioxide equivalents (CO(2)e). RESULTS: Average annual laundry unit GHG emissions were 2947 t CO(2)e. Average GHG emissions were 0.225 kg CO(2)e per item-use and 0.5080 kg CO(2)e/kg of laundry. Natural gas use contributed 75.7% of on-site GHG emissions. Boiler electrification using national grid electricity for 2020-2022 would have increased GHG emissions by 9.1%, however by 2030 this would reduce annual emissions by 31.9% based on the national grid decarbonisation trend. Per-item transport-related GHG emissions reduce substantially when heavy goods vehicles are filled at =50% payload capacity. Single-use laundry item alternatives cause significantly higher per-use GHG emissions, even if reusable laundry were transported long distances and incinerated at the end of its lifetime. CONCLUSIONS: The laundry unit has a large carbon footprint, however the per-item GHG emissions are modest and significantly lower than using single-use alternatives. Future electrification of boilers and optimal delivery vehicle loading can reduce the GHG emissions per laundry item.Published version, accepted version, submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text