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Prenatal diagnosis of clinodactyly and its association with genetic syndromes: A case report
No full textA curvature of a finger that bends inwards relative to the other fingers is a common observation during prenatal screening. When the angulation exceeds 10 degrees, it is known as clinodactyly" and could suggest a variety of underlying issues. Even though it usually remains unnoticed during pregnancy, it may be a sign of serious fetal disease. We report the case of a fetus diagnosed with clinodactyly of the thumb accompanied by tachycardia, abnormal levels of maternal hormones in the first trimester and increased impedance to flow in the uterine arteries. Although non-invasive prenatal testing was normal, amniocentesis was carried out and two deviations at chromosome 20 were identified through molecular karyotyping. Our report aims to raise clinical suspicion regarding the potential association between genetic abnormalities and clinodactyly. A careful clinical and genetic consultation is required in order to achieve the most favorable outcome for both mother and child."Journal content freely available via Open Access. Some content may be unavailable due to publisher embarg
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
Comparison of Bayesian approaches for developing prediction models in rare disease: application to the identification of patients with Maturity-Onset Diabetes of the Young
No full textBACKGROUND: Clinical prediction models can help identify high-risk patients and facilitate timely interventions. However, developing such models for rare diseases presents challenges due to the scarcity of affected patients for developing and calibrating models. Methods that pool information from multiple sources can help with these challenges. METHODS: We compared three approaches for developing clinical prediction models for population screening based on an example of discriminating a rare form of diabetes (Maturity-Onset Diabetes of the Young - MODY) in insulin-treated patients from the more common Type 1 diabetes (T1D). Two datasets were used: a case-control dataset (278 T1D, 177 MODY) and a population-representative dataset (1418 patients, 96 MODY tested with biomarker testing, 7 MODY positive). To build a population-level prediction model, we compared three methods for recalibrating models developed in case-control data. These were prevalence adjustment (offset"), shrinkage recalibration in the population-level dataset ("recalibration"), and a refitting of the model to the population-level dataset ("re-estimation"). We then developed a Bayesian hierarchical mixture model combining shrinkage recalibration with additional informative biomarker information only available in the population-representative dataset. We developed a method for dealing with missing biomarker and outcome information using prior information from the literature and other data sources to ensure the clinical validity of predictions for certain biomarker combinations. RESULTS: The offset, re-estimation, and recalibration methods showed good calibration in the population-representative dataset. The offset and recalibration methods displayed the lowest predictive uncertainty due to borrowing information from the fitted case-control model. We demonstrate the potential of a mixture model for incorporating informative biomarkers, which significantly enhanced the model's predictive accuracy, reduced uncertainty, and showed higher stability in all ranges of predictive outcome probabilities. CONCLUSION: We have compared several approaches that could be used to develop prediction models for rare diseases. Our findings highlight the recalibration mixture model as the optimal strategy if a population-level dataset is available. This approach offers the flexibility to incorporate additional predictors and informed prior probabilities, contributing to enhanced prediction accuracy for rare diseases. It also allows predictions without these additional tests, providing additional information on whether a patient should undergo further biomarker testing before genetic testing."Published versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embarg
Autoantibodies to truncated GAD(96-585) antigen stratify risk of early insulin requirement in adult-onset diabetes
No full textWe investigated whether characterisation of full-length (f-)GADA responses could identify early insulin requirement in adult-onset diabetes. In 179 f-GADA positive participants diagnosed with type 2 diabetes, we assessed associations of truncated (t-)GADA positivity, f-GADA IgG subclasses, and f-GADA affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. t-GADA positivity was lower in f-GADA positive without early insulin in comparison to f-GADA positive type 2 diabetes requiring insulin within 5 years, and type 1 diabetes (75% vs. 91% and 95% respectively, p<0.0001). t-GADA positivity (in those f-GADA positive) identified a group with a higher type 1 diabetes genetic susceptibility (mean T1D GRS 0.248 vs. 0.225, p=0.003), lower C-peptide (1156 pmol/L vs. 4289 pmol/L, p=1x10-7), and increased IA-2A positivity (23% vs. 6%, p=0.03). In survival analysis, t-GADA positivity was associated with early insulin requirement compared with those only positive for f-GADA, independently from age of diagnosis, f-GADA titre and duration of diabetes [adjusted HR 5.7 (95% CI 1.4, 23.5), p=0.017]. The testing of t-GADA in f-GADA positive individuals with type 2 diabetes identifies those who have genetic and clinical characteristics comparable to type 1 diabetes and stratifies those at higher risk of early insulin requirement.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
Current and future genomic applications for surgeons
No full textGenomics is a crucial part of managing surgical disease. This review focuses on some of the genomic advances that are available now and looks to the future of their application in surgical practice. Whole-genome sequencing enables unbiased coverage across the entire human genome of approximately three billion base pairs. Newer technologies, such as those that permit long-read sequence analysis, provide additional information in longer phased fragment and base pair epigenomic (methylomic) data. Whole-genome sequencing is currently available in England for cancers in children, teenagers and young adults, central nervous system tumours, sarcoma and haematological malignancies. Circulating tumour DNA (ctDNA), immunotherapy and pharmacogenomics have emerged as groundbreaking approaches in the field of cancer treatment. These are now revolutionising the way oncologists and surgeons approach curative cancer surgery. Cancer vaccines offer an innovative approach to reducing recurrence after surgery by priming the immune system to trigger an immune response. The Cancer Vaccine Launch Pad project facilitates cancer vaccine studies in England. The BNT122-01 trial is recruiting patients with ctDNA-positive high-risk colorectal cancer after surgery to assess the impact of cancer vaccines. The evolving landscape of cancer treatment demands a dynamic and integrated approach from the surgical multidisciplinary team. Immunotherapy, ctDNA, pharmacogenomics, vaccines, mainstreaming and whole-genome sequencing are just some of the innovations that have the potential to redefine the standards of care. The continued exploration of these innovative diagnostics and therapies, the genomic pathway evolution and their application in diverse cancer types highlights the transformative impact of precision medicine in surgery.This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, reproduction, and adaptation in any medium, provided the original work is properly attributed.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
British Gynaecological Cancer Society (BGCS) ovarian, tubal and primary peritoneal cancer guidelines: Recommendations for practice update 2024
No full textUnknownJournal 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
British Gynaecological Cancer Society and British Menopause Society guidelines: Management of menopausal symptoms following treatment of gynaecological cancer
No full textThese guidelines have been developed jointly by the British Gynaecological Cancer Society and British Menopause Society to provide information for all healthcare professionals managing women treated for gynaecological cancer. Menopausal symptoms can have a significant impact on quality of life for women. Cancer therapies, including surgery, pelvic radiotherapy, chemotherapy and endocrine therapy, can all affect ovarian function. The benefits and risks of using hormone replacement therapy are considered by cancer type with guidance on the type of HRT and optimal time of commencement after cancer treatment. Vaginal estrogens can be very effective for improving urogenital symptoms and are safe for the majority of women, including those for whom systemic HRT is contraindicated with rare exceptions. Alternative options to HRT are reviewed including pharmacological and non-pharmacological approaches.Not hel
Impact of patient demographics on treatment outcomes in AML: a population-based registry in England, 2013-2020
No full textWe report 1- and 5-year survival after acute myeloid leukemia (AML) diagnosis and early mortality within 30 days of systemic anticancer therapy (SACT) treatments, using national cancer registry data in England. Patients aged 18 to 99 years diagnosed between 2013 and 2020 were included. Overall survival (OS) was calculated using Kaplan-Meier methodology, and adjusted hazard ratios (aHRs; adjusted for intensity of treatment, age at diagnosis, sex, ethnicity, socioeconomic deprivation, comorbidity, and year of diagnosis) using Cox proportional hazards regression. Odds of 30-day mortality (adjusted odds ratios [aORs], adjusted for aforementioned characteristics), along with performance status and body mass index, were calculated using logistic regression. Among 17 107 patients identified, older age and comorbidity were associated with worse survival. Asian and Black patients had better survival than White patients: 5-year OS of 34.6%, 29.7%, and 17.8%, respectively; aHR of 0.86; (95% confidence interval [CI], 0.77-0.96) Asian vs White, and 0.84 (95% CI, 0.73-0.96) Black vs White. Socioeconomic deprivation was associated with worse survival. Overall, 7906 (46.2%) patients were documented as having received SACT. Thirty-day mortality was lower for patients receiving intensive rather than nonintensive SACT. After adjustment for cofactors, the risk was higher in those treated intensively (aOR, 0.74; 95% CI, 0.60-0.92). We show that ethnicity and socioeconomic status affects outcomes in AML. Further work is needed to understand how these effects may differ in different health care settings, and whether this because of effects on disease biology, responsiveness to treatment, or drug toxicity. Selection of intensive vs nonintensive treatment should be based on individual patient factors, balancing improved long-term survival against higher early mortality.Not permittedJournal 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
Editor's choice: February 2024
No full textAccepted version (12 month embargo)RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Experiences of interventions to reduce hospital stay for older adults following elective treatment: Qualitative evidence-synthesis
No full textBACKGROUND AND OBJECTIVES: Hospitals streamline treatment pathways to reduce the length of time older adults admitted for planned procedures spend in hospital. However patient perspectives have been poorly evaluated. This systematic review aimed to understand the experiences of older patients, carers, families and staff of multi-component interventions intended to improve recovery following elective treatment. RESEARCH DESIGN AND METHODS: Bibliographic databases searched in June 2021 included MEDLINE ALL, HMIC, CENTRAL, CINAHL, AMED and ProQuest Dissertations and Theses. We conducted citation searching and examined reference lists of reviews. Two reviewers independently undertook screening and data extraction, resolving disagreements through discussion. We used an adapted Wallace checklist for quality appraisal and meta-ethnography to synthesise data. Clinician, carer and patient views were incorporated throughout the review. RESULTS: Thirty-five papers were included in the synthesis. Thirteen studies were conducted in the UK, with patient views the most frequently represented. We identified six overarching constructs: 'Home as preferred environment for recovery', 'Feeling safe', 'Individualisation of structured programme', 'Taking responsibility', 'Essential care at home' and 'Outcomes'. DISCUSSION AND IMPLICATIONS: Findings explore the support patients, families and carers need throughout hospital admission, and may inform commissioning of services to ensure patients and carers receive appropriate follow-up support after hospital discharge. The findings may help hospital and community-based health and social care staff provide person-centred care based upon assessments of emotional and physical wellbeing of patients and family/carers. Research is needed to establish a core-set of patient-reported outcome measures which capture aspects of recovery which are meaningful to patients.Published version, accepted version (12 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text