De novo variants in KDM2A cause a syndromic neurodevelopmental disorder

Germline variants that disrupt components of the epigenetic machinery cause syndromic neurodevelopmental disorders. Using exome and genome sequencing, we identified de novo variants in KDM2A, a lysine demethylase crucial for embryonic development, in 18 individuals with developmental delays and/or intellectual disabilities. The severity ranged from learning disabilities to severe intellectual disability. Other core symptoms included feeding difficulties, growth issues such as intrauterine growth restriction, short stature and microcephaly as well as recurrent facial features like epicanthic folds, upslanted palpebral fissures, thin lips, and low-set ears. Expression of human disease-causing KDM2A variants in a Drosophila melanogaster model led to neural degeneration, motor defects, and reduced lifespan. Interestingly, pathogenic variants in KDM2A affected physiological attributes including subcellular distribution, expression and stability in human cells. Genetic epistasis experiments indicated that KDM2A variants likely exert their effects through a potential gain-of-function mechanism, as eliminating endogenous KDM2A in Drosophila did not produce noticeable neurodevelopmental phenotypes. Data from Enzymatic-Methylation sequencing supports the suggested gene-disease association by showing an aberrant methylome profiles in affected individuals' peripheral blood. Combining our genetic, phenotypic and functional findings, we establish de novo variants in KDM2A as causative for a syndromic neurodevelopmental disorder.CC BY 4.0 Internationa

Quantitative hypermorphic FAM111A alleles cause autosomal recessive Kenny-Caffey syndrome type 2 and osteocraniostenosis

Kenny-Caffey syndrome (KCS) is a rare genetic disorder characterized by extreme short stature, cortical thickening and medullary stenosis of tubular bones, facial dysmorphism, abnormal T-cell function, and hypoparathyroidism. Biallelic loss-of-function variants in TBCE cause autosomal recessive type 1 KCS (KCS1). By contrast, heterozygous missense variants in a restricted region of the FAM111A gene have been identified in autosomal dominant type 2 KCS (KCS2) and a more severe lethal phenotype, osteocraniostenosis (OCS) that have recently been shown to confer a gain-of-function. In this study, we describe two unrelated children with KCS and OCS who were homozygous for different FAM111A variant alleles that result in replacement of the same residue, Tyr414 (c.1241A>G, p.Y414C and c.1240T>A, p.Y414N), in the mature FAM111A protein. Their heterozygous relatives are asymptomatic. Functional studies of recombinant FAM111AY414C demonstrated normal dimerization and a mild gain-of-function effect. This study provides evidence that both biallelic and monoallelic variants of FAM111A with varying degrees of activation can lead to dominant or recessive KCS2 and OCS.Open 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

The role of molecular pathology in soft tissue tumor diagnosis: what the radiologist needs to know

For both general radiologists and those specializing in soft tissue sarcoma imaging, understanding the importance and basic concepts of molecular pathology is becoming increasingly relevant to current clinical practice. As molecular research identifies the most fundamental causes and markers of disease, diagnostic testing is increasingly focused on the cell nucleus and its genetic material. Identifying molecular abnormalities, such as mutations, deletions, and amplifications, has advanced our ability to diagnose genetic diseases, including a variety of cancers. Over the past two decades, molecular pathology has rapidly evolved, enhancing our understanding of sarcoma pathogenesis, diagnosis, and classification. This progress forms the foundation of the 2020 WHO classification of soft tissue and bone tumors. This article will highlight cases where molecular diagnostics are crucial for the definitive classification and diagnosis of select soft tissue tumors, with MRI correlation and key teaching points.All rights reserve

Dietary interventions for the management of type 2 diabetes mellitus in childhood and adolescence: A systematic review

AIMS: 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

A UK multicentre cohort study of clinical outcomes of proximal femoral replacement for nononcological conditions : the EndoProsthetic Replacement for nonOncological conditions (EPRO) study

AIMS: This study aims to determine the outcomes of proximal femoral replacement (PFR) for nononcological conditions. METHODS: This was a multicentre retrospective cohort study across six UK centres. The primary outcome was the local complication rate. Secondary outcomes were blood transfusions, critical care requirements, return to baseline mobility and residence status, systemic complications, reoperations, and mortality rates. Implant survival analysis was performed using Kaplan-Meier methodology with local complication as the endpoint, and was compared by surgical indication, stem length, and construct stem ratio (CSR). RESULTS: There were 230 PFRs in 226 patients with a median age of 76.0 years (IQR 66.9 to 83.7). Indications were periprosthetic femoral fracture (n = 62; 27%), infected revision arthroplasty (n = 55; 24%), chronic/failed trauma (n = 41; 18%), aseptic revision arthroplasty (n = 38; 17%), acute trauma (n = 33; 14%), and complex primary arthroplasty (n = 1; 0.5%). Median follow-up was 4.2 years (IQR 1.9 to 7.2). The local complication rate was 27% (n = 62). The most common local complications were dislocation (n = 27; 12%) and periprosthetic joint infection (n = 22; 10%). Blood transfusion was required in 86 patients (37%). Overall, 90 patients (39%) required critical care facilities. A return to baseline mobility and residence was observed in 127 (55%) and 200 (87%) patients, respectively. The six-month systemic complication rate was 9% (n = 21) and the reoperation rate was 21% (n = 48). The 30-day and one-year mortality rates were 2% (n = 4) and 8% (n = 19), respectively. The two-year implant survival rate was 78.0% (SE 2.8). Survival rates did not differ significantly by surgical indication, stem length, or CSR. CONCLUSION: This is the largest study of PFR for nononcological conditions. Due to high local complication and reoperation rates, it should be considered a salvage option for complex hip reconstruction and patients should be counselled appropriately.All rights reserve

Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial

Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m(2), weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials.CC BY 4.0 (Creative Commons Attribution

Improved Neurodevelopment Following In Utero Sulfonylurea Exposure in a Patient With KCNJ11 Permanent Neonatal Diabetes: Future Implications for Targeted Treatment During Pregnancy

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Evaluation of intestinal biopsy tissue preservation methods to facilitate large-scale mucosal microbiota research

BACKGROUND: 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

Time Below Range and Its Influence on Hypoglycemia Awareness and Severe Hypoglycemia: Insights From the Association of British Clinical Diabetologists Study

OBJECTIVE: This study aimed to explore the relationship between time below range (TBR), impaired awareness of hypoglycemia (IAH), and severe hypoglycemia (SH). RESEARCH DESIGN AND METHODS: This cross-sectional study analyzed data from individuals with diabetes using continuous glucose monitors (CGMs) in the Association of British Clinical Diabetologists audit. Hypoglycemia awareness was assessed via the Gold score (≥4 denoting IAH), and SH was defined as hypoglycemia requiring third-party assistance. Logistic regression was used to determine the association between TBR percentage (<70 mg/dL; 3.9 mmol/L) at first follow-up and follow-up Gold score and SH incidence. The Youden J index identified optimal TBR percentage cutoffs for detecting IAH and SH. RESULTS: The study included 15,777 participants, with follow-up TBR and SH data available for 5,029. The median TBR percentage was 4% (interquartile range 2-6.6%), with 42% meeting the recommended TBR of ≤4%. Adjusted for age, sex, and BMI, TBR was significantly associated with SH (P < 0.001) and IAH (P = 0.005). Optimal TBR cutoffs for identifying IAH and SH were 3.35% and 3.95%, yielding negative predictive value (NPV) values of 85% and 97%, respectively. CONCLUSIONS: Our findings support the international consensus recommending a TBR of <4% in type 1 diabetes, with high NPV values suggesting the utility of TBR in screening for SH.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.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

Heart Failure Masked as Pulmonary Embolism in Non-adherent Patient With Atrial Fibrillation: Case Report and Analytical Review of the Literature

BACKGROUND/AIM: Atrial fibrillation (AF) and heart failure (HF) commonly co-occur, significantly increasing morbidity and mortality. Poorly controlled AF can contribute to complications like HF and is associated with conditions, such as stroke and pulmonary embolism (PE). This report involves a man with AF who had persistent respiratory symptoms and left-sided chest pain, initially suspected to be PE, but eventually diagnosed as HF. CASE REPORT: A 43-year-old male experienced increasing breathlessness, cough, and fatigue. Initially suspected to have a respiratory infection, his persistent symptoms raised concern for PE. The patient had a history of AF, unsuccessful cardioversion, and long-term non-adherence to beta blockers. Initial assessment revealed persistent respiratory symptoms and elevated levels of C-reactive protein, D-dimer, N-terminal pro-B-type natriuretic peptide, and Troponin T. Chest X-ray showed pulmonary congestion, and echocardiogram confirmed a severely impaired ejection fraction (EF <20%). While the differential diagnosis included community-acquired pneumonia, PE, and HF, the final diagnosis was worsening AF and HF with reduced EF, not PE. CONCLUSION: PE symptoms can overlap with HF, making careful differential diagnosis essential, particularly in AF patients with elevated D-dimer levels, where false positives necessitate caution. This case underscores the importance of thorough differential diagnosis and clinical judgment before ordering tests to avoid misdiagnosis. Long-term non-adherence to beta blockers exacerbated the patient's symptoms, emphasising the critical role of consistent medication use in managing AF and preventing complications like HF. This case report also highlights the importance of thorough investigations, guideline-based treatments and multidisciplinary care in complex AF-HF cases.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