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Impact of haemoglobin variants on the diagnostic sensitivity of glycated haemoglobin (HbA1c) assay methodologies in sub-Saharan Africa: a laboratory-based method validation study
No full textINTRODUCTION: the utility of glycated haemoglobin (HbA1c) for the diagnosis and monitoring of diabetes in sub-Saharan Africa is uncertain due to limited data on the performance of the available HbA1c assay methods in this population, which has a high prevalence of haemoglobin variants. We aimed to compare the diagnostic accuracy of the major HbA1c methodologies (Boronate Affinity, Capillary Electrophoresis, High Performance Liquid Chromatography, Immunoassay) in an African population, and assess the impact of the common haemoglobin variant HbAS (sickle cell trait). METHODS: whole blood samples were obtained from 182 individuals living with type 2 diabetes in Uganda. HbA1c values for each method were compared to average glucose measured over 14 days by continuous glucose monitoring (CGM). To determine concordance, the three HbA1c assay methods were compared to the capillary electrophoresis method. RESULTS: there was a strong correlation between CGM average glucose levels and all four HbA1c methodologies (r=0.81-0.89) which did not differ in those with and without HbAS (present in 37/182 participants). The presence of HbAS did not alter the relationship between HbA1c and CGM glucose for any assay (p for interaction >0.2 for all methods). Diagnostic accuracy for CGM average glucose thresholds of 7 and 10mmol/L was similar across methods (area under the receiver operating characteristic curve 0.80-0.84 and 0.76-0.84 respectively). The maximum bias between the HbA1c assay methodologies was 2 mmol/mol (2.07%). CONCLUSION: all major HbA1c technologies offer accurate and comparable HbA1c measurement even in this population with high prevalence of haemoglobin variants.UnknownJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo
Reproductive Health in Women with Major β-Thalassemia: Evaluating Ovarian Reserve and Endocrine Complications
No full textThalassemia is an autosomal recessive hereditary chronic hemolytic anemia characterized by a partial or complete deficiency in the synthesis of alpha- or beta-globin chains, which are essential components of adult hemoglobin. Mutations in the globin genes lead to the production of unstable globin chains that precipitate within cells, causing hemolysis. This shortens the lifespan of mature red blood cells (RBCs) and results in the premature destruction of RBC precursors in the bone marrow. Regular red blood cell transfusions are the standard treatment for thalassemia. However, these transfusions can lead to increased iron overload, which can impair vital systems such as the liver, heart, ovaries, and endocrine system. Focusing on female reproductive endocrinology, recurrent blood transfusions can cause iron accumulation in the pituitary and hypothalamus, leading to hypogonadotropic hypogonadism (HH), the most common endocrinopathy in these patients, affecting 40-91% of women. Recurrent transfusions and the resulting iron overload can also lead to oxidative stress and ovarian damage in patients with beta-thalassemia major (BTM). Despite advancements in iron chelation therapy, hypothalamic-pituitary damage associated with HH contributes to subfertility and sexual dysfunction, often with little to no recovery. In women exposed to gonadotoxic drugs, particularly those with BTM, anti-Mullerian hormone (AMH)-a marker of ovarian reserve-is frequently used to assess ovarian damage. This review aims to explore the pathophysiology of β-thalassemia and its major clinical manifestations, with a focus on endocrine complications and their impact on ovarian reserve. It also investigates how metabolomics can provide insights into the disease's metabolic alterations and inform current and emerging therapeutic strategies to mitigate complications and optimize patient outcomes, potentially leading to more effective and personalized treatments.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo
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
Pulsed-field ablation of atrial fibrillation with a pentaspline catheter across National Health Service England centres
No full textINTRODUCTION: Pulsed-field ablation (PFA) is a novel modality for pulmonary vein isolation in patients with atrial fibrillation (AF). We describe the initial uptake and experience of PFA using a pentaspline catheter across selected National Health Service England (NHSE) centres. METHODS: Data collected by NHSE Specialised Services Development Programme regarding AF ablation procedures using a single-shot, pentaspline, multielectrode PFA catheter (FARAWAVE, Boston Scientific) between June 2022 and August 2024 were aggregated and analysed to examine procedural metrics, acute efficacy and safety outcomes over 3-month follow-up. RESULTS: 1034 procedures were submitted. The patients were 32.1% female, mean age 63.8±10.7 years, 53.1% paroxysmal AF and 89.7% first-time AF ablation. Procedures were performed by 48 consultant operators at nine NHSE centres, with a mean of 115 procedures per centre (range 25-264). 93.7% of procedures were performed under general anaesthesia. Median skin-to-skin procedure time was 74 min (IQR 55-96 min) and fluoroscopy time 20 min (IQR 15-27 min). Electroanatomical mapping was used in 15.3%. In first-time ablation cases, acute isolation of all pulmonary veins was achieved in 99.5% of patients. Left atrial (LA) posterior wall ablation using the PFA catheter was performed in 11.0% of cases; additional LA radiofrequency ablation was performed in 0.6%. The major and minor acute procedural complication rates were, respectively, 1.3% and 3.1%, with no reports of periprocedural death or atrio-oesophageal fistula. 63.8% of patients were discharged on the day of procedure. Follow-up data were available for 870 procedures (84.1%). In the 3 months following ablation, hospitalisation for arrhythmia occurred in 3.2%, with 0.9% rehospitalised for procedural-related complications. CONCLUSION: In this real-world, nationwide registry of a pentaspline PFA catheter, efficacy, safety and efficiency outcomes were comparable to those from previous PFA studies in patients with AF.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
TECPR2-related hereditary sensory and autonomic neuropathy in two siblings from Palestine
No full textDue to the majority of currently available genome data deriving from individuals of European ancestry, the clinical interpretation of genomic variants in individuals from diverse ethnic backgrounds remains a major diagnostic challenge. Here, we investigated the genetic cause of a complex neurodevelopmental phenotype in two Palestinian siblings. Whole exome sequencing identified a homozygous missense TECPR2 variant (Chr14(GRCh38):g.102425085G>A; NM_014844.5:c.745G>A, p.(Gly249Arg)) absent in gnomAD, segregating appropriately with the inheritance pattern in the family. Variant assessment with in silico pathogenicity prediction and protein modeling tools alongside population database frequencies led to classification as a variant of uncertain significance. As pathogenic TECPR2 variants are associated with hereditary sensory and autonomic neuropathy with intellectual disability, we reviewed previously published candidate TECPR2 missense variants to clarify clinical outcomes and variant classification using current approved guidelines, classifying a number of published variants as of uncertain significance. This work highlights genomic healthcare inequalities and the challenges in interpreting rare genetic variants in populations underrepresented in genomic databases. It also improves understanding of the clinical and genetic spectrum of TECPR2-related neuropathy and contributes to addressing genomic data disparity and inequalities of the genomic architecture in Palestinian populations.Published version, accepted version (12 month embargo)The article is available via Open Access. Click on the 'Additional link' above to access the full-text
Characterisation of the spatio-temporal localisation of a pan-Mucorales specific antigen during germination and immunohistochemistry
No full textBACKGROUND: Mucormycosis is an aggressive, invasive fungal infection caused by moulds in the order Mucorales. Early diagnosis is key to improving patient prognosis, yet relies on insensitive culture or non-specific histopathology. A pan-Mucorales specific monoclonal antibody (mAb), TG11, was recently developed. Here, we investigate the spatio-temporal localisation of the antigen and specificity of the mAb for immunohistochemistry. METHODS: We use immunofluorescence (IF) microscopy to assess antigen localisation in eleven Mucorales species of clinical importance and live imaging of Rhizopus arrhizus germination. Immunogold transmission electron microscopy (immunoTEM) reveals the sub-cellular location of mAb TG11 binding. Finally, we perform immunohistochemistry of R. arrhizus in an ex vivo murine lung infection model alongside lung infection by Aspergillus fumigatus. RESULTS: IF revealed TG11 antigen production at the emerging hyphal tip and along the length of growing hyphae in all Mucorales except Sakasenea. Timelapse imaging revealed early antigen exposure during spore germination and along the growing hypha. ImmunoTEM confirmed mAb TG11 binding to the hyphal cell wall only. The TG11 mAb specifically stained Mucorales but not Aspergillus hyphae in infected murine lung tissue. CONCLUSIONS: TG11 detects early hyphal growth and has valuable potential for diagnosing mucormycosis by enhancing discriminatory detection of Mucorales in tissue.UnknownNot hel
A Golden Hour and Golden Opportunity for ß-Cell Preservation
No full textAccepted 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
HormoneBayes: A novel Bayesian framework for the analysis of pulsatile hormone dynamics
No full textThe hypothalamus is the central regulator of reproductive hormone secretion. Pulsatile secretion of gonadotropin releasing hormone (GnRH) is fundamental to physiological stimulation of the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Furthermore, GnRH pulsatility is altered in common reproductive disorders such as polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA). LH is measured routinely in clinical practice using an automated chemiluminescent immunoassay method and is the gold standard surrogate marker of GnRH. LH can be measured at frequent intervals (e.g., 10 minutely) to assess GnRH/LH pulsatility. However, this is rarely done in clinical practice because it is resource intensive, and there is no open-access, graphical interface software for computational analysis of the LH data available to clinicians. Here we present hormoneBayes, a novel open-access Bayesian framework that can be easily applied to reliably analyze serial LH measurements to assess LH pulsatility. The framework utilizes parsimonious models to simulate hypothalamic signals that drive LH dynamics, together with state-of-the-art (sequential) Monte-Carlo methods to infer key parameters and latent hypothalamic dynamics. We show that this method provides estimates for key pulse parameters including inter-pulse interval, secretion and clearance rates and identifies LH pulses in line with the widely used deconvolution method. We show that these parameters can distinguish LH pulsatility in different clinical contexts including in reproductive health and disease in men and women (e.g., healthy men, healthy women before and after menopause, women with HA or PCOS). A further advantage of hormoneBayes is that our mathematical approach provides a quantified estimation of uncertainty. Our framework will complement methods enabling real-time in-vivo hormone monitoring and therefore has the potential to assist translation of personalized, data-driven, clinical care of patients presenting with conditions of reproductive hormone dysfunction.Published version, accepted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Rare disease genomic testing in the UK and Ireland: promoting timely and equitable access
No full textPURPOSE AND SCOPE: The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times. METHODS OF STATEMENT DEVELOPMENT: A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute. RESULTS AND CONCLUSIONS: We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/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
Congenital hyperinsulinism and novel KDM6A duplications -resolving pathogenicity with genome and epigenetic analyses
No full textCONTEXT: Hyperinsulinemic hypoglycemia (HI) can be the presenting feature of Kabuki syndrome (KS), which is caused by loss-of-function variants in KMT2D or KDM6A. As these genes play a critical role in maintaining methylation status in chromatin, individuals with pathogenic variants have a disease-specific epigenomic profile -an episignature. OBJECTIVE: We evaluated the pathogenicity of three novel partial KDM6A duplications identified in three individuals presenting with neonatal-onset HI without typical features of KS at the time of genetic testing. METHODS: Three different partial KDM6A duplications were identified by routine targeted next generation sequencing for HI and initially classified as variants of uncertain significance (VUS) as their location, and hence their impact on the gene, was not known. Whole genome sequencing (WGS) was undertaken to map the breakpoints of the duplications with DNA methylation profiling performed in two individuals to investigate the presence of a KS-specific episignature. RESULTS: WGS confirmed the duplication in proband 1 as pathogenic as it caused a frameshift in the normal copy of the gene leading to a premature termination codon. The duplications identified in probands 2 and 3 did not alter the reading frame and therefore their significance remained uncertain after WGS. Subsequent DNA methylation profiling identified a KS-specific episignature in proband 2 but not in proband 3. CONCLUSIONS: Our findings confirm a role for KDM6A partial gene duplications in the etiology of KS and highlight the importance of performing in-depth molecular genetic analysis to properly assess the clinical significance of VUS's in the KDM6A gene.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