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Islet autoantibodies as precision diagnostic tools to characterize heterogeneity in type 1 diabetes: a systematic review
No full textBACKGROUND: Islet autoantibodies form the foundation for type 1 diabetes (T1D) diagnosis and staging, but heterogeneity exists in T1D development and presentation. We hypothesized that autoantibodies can identify heterogeneity before, at, and after T1D diagnosis, and in response to disease-modifying therapies. METHODS: We systematically reviewed PubMed and EMBASE databases (6/14/2022) assessing 10 years of original research examining relationships between autoantibodies and heterogeneity before, at, after diagnosis, and in response to disease-modifying therapies in individuals at-risk or within 1 year of T1D diagnosis. A critical appraisal checklist tool for cohort studies was modified and used for risk of bias assessment. RESULTS: Here we show that 152 studies that met extraction criteria most commonly characterized heterogeneity before diagnosis (91/152). Autoantibody type/target was most frequently examined, followed by autoantibody number. Recurring themes included correlations of autoantibody number, type, and titers with progression, differing phenotypes based on order of autoantibody seroconversion, and interactions with age and genetics. Only 44% specifically described autoantibody assay standardization program participation. CONCLUSIONS: Current evidence most strongly supports the application of autoantibody features to more precisely define T1D before diagnosis. Our findings support continued use of pre-clinical staging paradigms based on autoantibody number and suggest that additional autoantibody features, particularly in relation to age and genetic risk, could offer more precise stratification. To improve reproducibility and applicability of autoantibody-based precision medicine in T1D, we propose a methods checklist for islet autoantibody-based manuscripts which includes use of precision medicine MeSH terms and participation in autoantibody standardization workshops.
Islet autoantibodies are markers found in the blood when insulin-producing cells in the pancreas become damaged and can be used to predict future development of type 1 diabetes. We evaluated published literature to determine whether characteristics of islet antibodies (type, levels, numbers) could improve prediction and help understand differences in how individuals with type 1 diabetes respond to treatments. We found existing evidence shows that islet autoantibody type and number are most useful to predict disease progression before diagnosis. In addition, the age when islet autoantibodies first appear strongly influences rate of progression. These findings provide important information for patients and care providers on how islet autoantibodies can be used to understand future type 1 diabetes development and to identify individuals who have the potential to benefit from intervention or prevention therapy.
eng MJH Life Sciences and as a consultant for DRI Healthcare. C.E.M. reported serving on advisory boards for Provention Bio, Isla Technologies, MaiCell Technologies, Avotres, DiogenyX, and Neurodon; receiving in-kind research support from Bristol Myers Squibb and Nimbus Pharmaceuticals; and receiving investigator initiated grants from Lilly Pharmaceuticals and Astellas Pharmaceuticals. L.A.D. reports research support to institution from Dompe, Lilly, Mannkind, Provention, Zealand and consulting relationships with Abata and Vertex. R.A.O. had a UK MRC Confidence in concept grant to develop a T1D GRS biochip with Randox Ltd, and has ongoing research funding from Randox R&D. No other authors report any relevant conflicts of interest.Published 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
Air Pollution and Myocardial Infarction-A New Smoker's Paradox?
No full textBackground/Objectives: Ambient air pollution is a significant public health concern, known to affect cardiovascular health adversely. Research has identified both long-term and short-term cardiovascular risks associated with various air pollutants, including those linked to acute coronary syndromes. However, the observed effects are rather small, with most data sourced from highly polluted regions. Methods: This study utilized a prospective registry database, documenting 12,581 myocardial infarction (MI) events in Styria, Austria from January 2007 to December 2015. Pollutants analyzed included particulate matter (PM(2.5), PM(10)) and gases, such as NO(2), CO, SO(2), O(3) and NOx. We employed generalized linear models to examine the interaction of each of these pollutants on the daily incidence of MI. Additionally, we conducted separate analyses for patients with specific comorbidities: diabetes mellitus (DM), arterial hypertension (HTN), heart failure with reduced ejection fraction (HFrEF), chronic obstructive pulmonary disease (COPD) and current smokers. Results: No significant associations were identified between any of the pollutants and MI incidence, both in the overall cohort and in patient subgroups with DM, HTN, HFrEF or COPD. However, among active smokers, we observed a decreased relative risk of MI associated with elevated levels of NO(2), CO, SO(2) and NOx on the day of MI (p < 0.01 for all pollutants). Conversely, an increased MI risk was associated with rising ozone levels (p = 0.0027). This counterintuitive finding aligns with previously published data and may suggest a new dimension to the smoker's paradox". Conclusions: In regions with low pollution levels, air pollutants pose only minor or insignificant short-term risks for myocardial infarction. Active smokers exhibit an altered response to ambient air pollution."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
Defunctioning loop ileostomies - making better decisions
No full textAccepted version (12 month embargo)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
Genetic modifiers of rare variants in monogenic developmental disorder loci
No full textRare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DDs) and have also been shown to cause milder subclinical phenotypes in population cohorts. Here, we show that carrying multiple (2-5) rare damaging variants across 599 dominant DD genes has an additive adverse effect on numerous cognitive and socioeconomic traits in UK Biobank, which can be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS). Phenotypic deviators from expected EA-PGS could be partly explained by the enrichment or depletion of rare DD variants. Among carriers of rare DD variants, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without a clinical diagnosis. Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may then influence whether an individual reaches the threshold for clinical disease.Accepted version (6 months 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
Revision of metal-on-metal hip replacements with dual-mobility bearings and acetabular component retention
No full textAIMS: In metal-on-metal (MoM) hip arthroplasties and resurfacings, mechanically induced corrosion can lead to elevated serum metal ions, a local inflammatory response, and formation of pseudotumours, ultimately requiring revision. The size and diametral clearance of anatomical (ADM) and modular (MDM) dual-mobility polyethylene bearings match those of Birmingham hip MoM components. If the acetabular component is satisfactorily positioned, well integrated into the bone, and has no surface damage, this presents the opportunity for revision with exchange of the metal head for ADM/MDM polyethylene bearings without removal of the acetabular component. METHODS: Between 2012 and 2020, across two centres, 94 patients underwent revision of Birmingham MoM hip arthroplasties or resurfacings. Mean age was 65.5 years (33 to 87). In 53 patients (56.4%), the acetabular component was retained and dual-mobility bearings were used (DM); in 41 (43.6%) the acetabulum was revised (AR). Patients underwent follow-up of minimum two-years (mean 4.6 (2.1 to 8.5) years). RESULTS: In the DM group, two (3.8%) patients underwent further surgery: one (1.9%) for dislocation and one (1.9%) for infection. In the AR group, four (9.8%) underwent further procedures: two (4.9%) for loosening of the acetabular component and two (4.9%) following dislocations. There were no other dislocations in either group. In the DM group, operating time (68.4 vs 101.5 mins, p < 0.001), postoperative drop in haemoglobin (16.6 vs 27.8 g/L, p < 0.001), and length of stay (1.8 vs 2.4 days, p < 0.001) were significantly lower. There was a significant reduction in serum metal ions postoperatively in both groups (p < 0.001), although there was no difference between groups for this reduction (p = 0.674 (cobalt); p = 0.186 (chromium)). CONCLUSION: In selected patients with Birmingham MoM hips, where the acetabular component is well-fixed and in a satisfactory position with no surface damage, the metal head can be exchanged for polyethylene ADM/MDM bearings with retention of the acetabular prosthesis. This presents significant benefits, with a shorter procedure and a lower risk of complications.Published 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
Multidisciplinary Management of Phyllodes Tumours and Breast Sarcoma: A Cross-sectional Survey of Clinical Practice across the UK and Ireland
No full textAIMS: Phyllodes tumours and breast sarcomas are uncommon tumours and their rarity poses significant challenges in diagnosis and management. This cross-sectional study was conducted to evaluate the multidisciplinary clinical practice for these tumours across the UK and Ireland, with the aim of identifying gaps in knowledge and providing direction for establishing national guidelines. MATERIALS AND METHODS: An international survey was adapted and circulated to breast and/or sarcoma surgeons and oncologists in the UK and Ireland through national organisations. Multidisciplinary team (MDT) responses were analysed anonymously. RESULTS: Twenty-eight MDTs participated in this study, predominately from high-volume units (85.5%). Although only 43% of the surveyed units were part of a trust that holds a sarcoma MDT, 68% of units managed malignant phyllodes and angiosarcoma, whereas 64.5% managed soft-tissue sarcoma of the breast. Across all subtypes, axillary surgery was recommended by 14-21% of the MDTs and the most recommended resection margins for breast surgery were 'no tumour on ink' in benign phyllodes (39%) and 10 mm in the remaining subtypes (25-29%). Immediate breast reconstruction was supported by 11-18% of MDTs for breast sarcoma subtypes, whereas 36% and 32% advocated this approach in benign and borderline phyllodes tumours, respectively. Adjuvant radiotherapy and chemotherapy were recommended by up to 29% and 11% of the MDTs, respectively. CONCLUSION: The results of this study demonstrate a wide variation in clinical practice across the surveyed MDTs. As only 28 MDTs participated in our study, with under-representation from low-volume units, our results might be an underestimation of the variability in practice across the UK and Ireland. This multi-institutional study sheds light on controversial aspects in the management of phyllodes tumours and breast sarcoma, identifies the need for national guidelines to inform best practice, and calls for the centralisation of the management of breast sarcoma within specialist centres.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
A de novo TLR7 gain-of-function mutation causing severe monogenic lupus in an infant
No full textNot 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
Comparative Analysis of Cellulite Treatment Modalities: A Systematic Review
No full textBACKGROUND: Cellulite is a highly prevalent and aesthetically distressing skin condition. Whilst there are a variety of treatment modalities, none are definitively established. OBJECTIVE: This systematic review aims to assess invasive and noninvasive treatment modalities for cellulite management. METHODS: The review protocol was published and registered a priori (PROSPERO CRD42022359334). A comprehensive electronic search for relevant randomised controlled trials, (RCTs) was performed in CENTRAL, MEDLINE, Embase and Web of Science databases. Study quality and risk of bias were assessed using Cochrane's risk of bias tool, respectively. RESULTS: Overall, 753 studies were initially identified, of which 24 randomised controlled trials (RCTs) satisfied the eligibility criteria with a total of 2084 patients with a mean follow-up of 3.33 ± 13.4 weeks. Evaluated interventions included mechanical stimulation, topical therapy, shock wave therapy (SWT), laser and light-based devices, radiofrequency therapy, subcutaneous injectables, and ultrasound. SWT emerged as a standout intervention, demonstrating a consistent cellulite reduction score of 2.07 ± 0.39 across four studies. Radiofrequency therapy exhibited a statistically significant reduction of thigh circumference (- 2.09 cm, p < 0.001) and subcutaneous tissue thickness (- 2.23 cm, p < 0.001). Subcutaneous injectables, specifically collagenase Clostridium histolyticum-aaes, demonstrated a statistically significant improvement in the clinician-reported photonumeric cellulite severity scale (17.0%) and patient-reported photonumeric cellulite severity scale (25.7%) (p < 0.001). The overall quality of the studies using the grading of recommendations, assessment, development and evaluation approach was moderate. CONCLUSION: This is the first methodologically robust systematic review evaluating interventions for cellulite. SWT, radiofrequency therapy, and subcutaneous injectables have shown promising findings in cellulite treatment. LEVEL OF EVIDENCE I: The journal asks authors to assign a level of evidence to each article. For a complete description of Evidence-Based Medicine ratings, see the Table of Contents or the online Instructions for Authors at www.springer.com/00266 .1 year embargo from time of publicatio
Choosing the best shoulder replacement
No full textUnknownRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Widening the phenotypic spectrum caused by pathogenic PDX1 variants in individuals with neonatal diabetes
No full textINTRODUCTION: Biallelic PDX1 variants are a rare cause of isolated pancreatic agenesis and neonatal diabetes (NDM) without exocrine pancreatic insufficiency, with 17 cases reported in the literature. RESEARCH DESIGN AND METHODS: To determine the phenotypic variability caused by this rare genetic aetiology, we investigated 19 individuals with NDM resulting from biallelic disease-causing PDX1 variants. RESULTS: Of the 19 individuals, 8 (42%) were confirmed to have exocrine insufficiency requiring replacement therapy. Twelve individuals (63.2%) had extrapancreatic features, including 8 (42%) with conditions affecting the duodenum and/or hepatobiliary tract. Defects in duodenum development are consistent with previous Pdx1 ablation studies in mice which showed abnormal rostral duodenum development. CONCLUSIONS: Our findings show that recessive PDX1 variants can cause a syndromic form of NDM, highlighting the need for clinical assessment of extrapancreatic features in individuals with NDM caused by PDX1 variants.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