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Altered chaperone-nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome.
The osteo-oto-hepato-enteric (O2HE) syndrome is a severe autosomal recessive disease ascribed to loss-of-function mutations in the Unc-45 myosin chaperone A (UNC45A) gene. The clinical spectrum includes bone fragility, hearing loss, cholestasis, and life-threatening diarrhea associated with microvillus inclusion disease-like enteropathy. Here, we present molecular and functional analysis of the UNC45A c.710T>C (p.Leu237Pro) missense variant, which revealed a unique pathogenicity compared with other genetic variants causing UNC45A deficiency. The UNC45A p.Leu237Pro mutant retained chaperone activity, prevented myosin aggregation, and supported proper nonmuscle myosin II (NMII) filament formation in patient fibroblasts and human osteosarcoma (U2OS) cells. However, the mutant formed atypically stable oligomers and prevented chaperone-myosin complex dissociation, thereby inhibiting NMII functions. Similar to biallelic UNC45A deficiency, this resulted in impaired intracellular trafficking, defective recycling, and abnormal retention of transferrin at various endocytic sites. In particular, coexpression of wild-type protein attenuated the pathogenic effects of the variant by inhibiting excessive oligomer formation. Our results elucidate the pathogenic mechanisms and recessive characteristics of this variant and may aid in the development of targeted therapies.
Mid-term outcomes of the fixed-bearing lateral Oxford unicompartmental knee arthroplasty.
AIMS: Mixed clinical results have been reported following the use of lateral unicompartmental knee arthroplasty (UKA) in patients with isolated lateral compartment osteoarthritis (OA) of the knee. Although this procedure may be appropriate for use in about 10% of knees needing arthroplasty, it is only used in about 1%. The aim of this study was to determine the medium-term results for the Fixed Lateral Oxford (FLO) UKA. METHODS: We report the clinical results and survival for 305 consecutive FLO UKAs implanted in 279 patients between July 2015 and August 2022. A total of 283 knees (93%) satisfied the recommended surgical indications. The mean age of the patients was 70.8 years (SD 11), their mean BMI was 28.4 kg/m2 (SD 5.4), and 219 (72%) were female. Isolated lateral compartment OA was the indication for 298 operations (98%). The mean follow-up was 4.3 years (1 to 8). The Oxford Knee Score (OKS) was recorded pre- and postoperatively. The revision status of all knees was known. RESULTS: There were four revisions (1%): two were conversions to a total knee arthroplasty (TKA) for instability and progressive OA and two had the addition of a medial UKA for medial compartment OA. Three other UKAs required a reoperation. At the last follow-up, the mean OKS was 40.9 (SD 7.8), a mean increase of 20 points from the preoperative score. The cumulative rate of survival with any reoperation, including revision, as the endpoint, at seven years, was 96% (95% CI 91 to 100), with revision as the endpoint was 98% (95% CI 94 to 100) and with revision to a TKA as the endpoint was 99% (95% CI 96 to 100). No revisions required revision TKA components. When those who underwent surgery for indications which were outside the recommended indications were excluded, there were only two revisions, both with the addition of a medial UKA for progressive OA, resulting in a seven-year cumulative survival with revision as the endpoint of 99% (95% CI 93 to 100). CONCLUSION: This study involved the largest published cohort of fixed-bearing lateral UKAs. The good clinical outcomes and medium-term survival of the FLO UKA, particularly in patients satisfying the recommended indications, suggest that it is an excellent alternative to TKA for the treatment of patients with isolated OA of the lateral compartment of the knee.
Diffusion-weighted imaging to predict longer-term response in Crohn's disease patients commencing biological therapy: results from the MOTILITY trial.
ObjectivesPredicting longer-term response to biological therapy for small bowel Crohn's disease (SBCD) is an unmet clinical need. Diffusion-weighted magnetic resonance (MR) imaging (DWI) may indicate disease activity, but its predictive ability, if any, is unknown. We investigated the prognostic value of DWI for 1 year response or remission (RoR) in SBCD patients commencing biologic therapy, including incremental value over C-reactive protein (CRP) and faecal calprotectin (FC).MethodsA subset of participants in a prospective, multicentre study investigating the predictive ability of motility MRI for 1-year RoR in patients starting biologic therapy for active SBCD, underwent additional DWI at baseline and post-induction (12-30 weeks). CRP and FC were collected in a subgroup. RoR at 1 year was evaluated using clinical and morphological MR enterography (MRE) parameters. We calculated sensitivity and specificity to predict RoR and quality of life (QoL) at 1 year, comparing apparent diffusion coefficient (ADC) value, Clermont score, and CRP using multivariable logistic regression.ResultsA total of 25 participants were included (mean 36.9 years, 32% female). ADC changes and Clermont score had poor sensitivity (30.0% [95% CI, 6.7-65.2] and 40.0% [95% CI, 12.2-73.8], respectively) and poor-to-modest specificity (50.0 [95% CI, 27.2-72.8] and 65.0% [95% CI, 40.8-84.6]) for RoR. None of Clermont score, CRP, or FC predicted QoL.ConclusionsDWI has inadequate sensitivity and specificity for RoR at 1 year. There is no significant incremental prognostic value of DWI over CRP and FC to predict RoR and/or QoL at 1 year.Advances in knowledgeEarly post-induction DWI has no prognostic value for RoR at 1 year.
MRI assessment of body composition for prediction of therapeutic response to biologic agents in patients with Crohn's disease.
OBJECTIVES: Altered body fat and muscle mass in Crohn's disease (CD) have been linked to adverse disease course and outcomes. Prediction of treatment response or remission (RoR) of small bowel CD (SBCD) to biologic therapy remains challenging. We aimed to establish the prognostic value of body composition parameters measured using MR enterography (MRE) for RoR at 1 year in patients with SBCD commencing biologic therapy. METHODS: Participants were identified from those recruited to a prospective, multicentre study investigating the predictive ability of motility MRI for 1 year RoR in patients starting biologic therapy for active SBCD (MOTILITY trial). Myopenia, skeletal muscle:fat and visceral:subcutaneous fat were measured from baseline MRE. RoR at 1 year was judged using a composite of clinical and morphological MRE parameters. We compared the likelihood of RoR in patients with and without myopenia or low skeletal muscle:fat using logistic regression models. RESULTS: Ninety-six participants were included (mean age 38.2 years; 40 (42%) female). There were 34 (35%) responders. There was no significant difference in RoR at 1 year between those patients with and without skeletal muscle myopenia (OR: 0.85, 95% CI: 0.27, 2.66, p-value: 0.78), or those with or without low skeletal muscle:fat (OR: 0.71, 95% CI: 0.19, 2.71, p-value: 0.62). CONCLUSIONS: Body composition parameters demonstrated no value for predicting therapeutic RoR in patients commencing biologic therapy for SBCD. CRITICAL RELEVANCE STATEMENT: Prediction of response to biologic therapy in small bowel Crohn's disease (SBCD) remains challenging. Body composition parameters cannot predict biologic therapeutic response or remission for SBCD reliably. KEY POINTS: Altered body fat and muscle mass in Crohn's disease have been linked to adverse outcomes. Prediction of response to biologic therapy in small bowel CD (SBCD) would be useful for treatment optimisation. Body composition parameters measured using MRI cannot reliably predict biological therapeutic response or remission for SBCD.
Complement-mediated enhancement of SARS-CoV-2 antibody neutralisation potency in vaccinated individuals.
With the continued emergence of SARS-CoV-2 variants and concerns of waning immunity, there is a need for better defined correlates of protection to aid future vaccine and therapeutic developments. Whilst neutralising antibody titres are associated with protection, these are typically determined in the absence of the complement system, which has the potential to enhance neutralisation titres and strengthen correlates with protection in vivo. Here we show that replenishment of the complement system in neutralisation assays can significantly enhance neutralisation titres, with up to an ~83-fold increase in neutralisation of the BA.1.1.529 strain using cross-reactive sera from vaccination against the ancestral strain. The magnitude of enhancement significantly varies between individuals, viral strains (wild-type/VIC01 and Omicron/BA.1), and cell lines (Vero E6 and Calu-3), and is abrogated following heat-inactivation of the complement source. Utilising ACE2 competition assays, we show that the mechanism of action is partially mediated by reducing ACE2-spike interactions. Through the addition of compstatin (a C3 inhibitor) to live virus neutralisation assays, the complement protein C3 is shown to be required for maximum efficiency. These findings further our understanding of SARS-CoV-2 immunity and neutralisation, with implications for protection against emerging variants and assessing future vaccine and therapeutic developments.
Achilles tendinopathy.
Achilles tendon pathologies are prevalent, impacting ~6% of the general population and up to 50% of elite endurance runners over their lifetimes. These conditions substantially affect quality of life and work productivity, leading to substantial societal costs. Achilles tendinopathy (AT) is a condition marked by localized pain and functional impairment related to mechanical loading. AT can considerably impair participation and potentially also performance in sports and daily activities. The aetiology of AT is multifactorial and repetitive overloading of the tendon is often observed as the inciting factor by health professionals. However, AT can also be associated with adverse effects of certain medication, ageing and various comorbidities. Characteristic tendon changes include proteoglycan accumulation, fluid accumulation with swelling and hypervascularization. Tissue disorganization advances as pathological changes in matrix structure are driven by altered cellular function and makeup, often accompanied by persistent inflammation. Treatment strategies include various interventions, although these can be protracted and challenging for both patients and health-care providers, often with high failure rates. Current research focuses on understanding the pathological processes at the cellular and molecular levels to distinguish between disease categories and to investigate the role of inflammation, metabolic maladaptation and mechanical stress. Emerging therapeutic approaches need to be developed to address these underlying mechanisms. These approaches focus on optimizing rehabilitation protocols and advancing the development of adjunct therapies, such as advanced therapy medicinal products, alongside the integration of precision medicine to improve treatment outcomes.
Defining the extracellular matrix in non-cartilage soft-tissues in osteoarthritis: a systematic review.
AIMS: Extracellular matrix (ECM) is a critical determinant of tissue mechanobiology, yet remains poorly characterized in joint tissues beyond cartilage in osteoarthritis (OA). This review aimed to define the composition and architecture of non-cartilage soft joint tissue structural ECM in human OA, and to compare the changes observed in humans with those seen in animal models of the disease. METHODS: A systematic search strategy, devised using relevant matrix, tissue, and disease nomenclature, was run through the MEDLINE, Embase, and Scopus databases. Demographic, clinical, and biological data were extracted from eligible studies. Bias analysis was performed. RESULTS: A total of 161 studies were included, which covered capsule, ligaments, meniscus, skeletal muscle, synovium, and tendon in both humans and animals, and fat pad and intervertebral disc in humans only. These studies covered a wide variety of ECM features, including individual ECM components (i.e. collagens, proteoglycans, and glycoproteins), ECM architecture (i.e. collagen fibre organization and diameter), and viscoelastic properties (i.e. elastic and compressive modulus). Some ECM changes, notably calcification and the loss of collagen fibre organization, have been extensively studied across osteoarthritic tissues. However, most ECM features were only studied by one or a few papers in each tissue. When comparisons were possible, the results from animal experiments largely concurred with those from human studies, although some findings were contradictory. CONCLUSION: Changes in ECM composition and architecture occur throughout non-cartilage soft tissues in the osteoarthritic joint, but most of these remain poorly defined due to the low number of studies and lack of healthy comparator groups.
Methodology for the international working group clinical practice guidelines on X-linked hypophosphatemia in children and adults.
The guideline panel, comprising international experts in X-linked hypophosphatemia (XLH), patient partners from the XLH patient population, and guideline methodologists, held 18 teleconferences between January 2023 and July 2024 to develop comprehensive guidelines for the diagnosis and management of XLH in children and adults. For a subset of our questions, we utilized the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, assessed the certainty of evidence and formulated GRADEd recommendations. For these questions, the panelists and methodologists collaboratively framed PICO (Population, Intervention, Control, and Outcomes) questions and conducted four systematic reviews assessing the impact of medical therapy-using either burosumab or phosphate and active vitamin D-on patient-important outcomes in the XLH population as well as the impact of medical intervention compared to no treatment. We assessed the risk of bias and transparently generated summary of findings tables using MAGICApp. The panel developed three GRADEd treatment recommendations for adults and two for children. Each GRADEd recommendation was linked to an underlying body of evidence, reflecting judgments on the certainty of evidence, recommendation strength, values, preferences, and considerations of costs, feasibility, acceptability, and equity. Due to the paucity of evidence, the panel developed very low-quality GRADEd recommendations on monitoring patients with XLH based on an expert clinical practice survey. Using a rigorous narrative literature review, the panel developed non-GRADEd recommendations including guidance for pregnant women, patients with dental complications, and other areas where evidence is limited. This article summarizes the methodology utilized for the development of both GRADEd and non-GRADEd recommendations for patients with XLH.
Current Practices in Monitoring Children and Adults with X-linked Hypophosphatemia: A Global Survey of Expert Experience.
This report provides recommendations for XLH monitoring based on current monitoring practices of experts in the management of XLH in children (<18 years) and adults. We surveyed 43 experts to determine their monitoring practices for children and adults with XLH, including pregnant and lactating women. In the initial evaluation of children and adults with XLH, experts consistently obtain family history, fracture history and history of dental infections. They measure height, weight, blood pressure and conduct DNA analysis of multiple genes including the PHEX gene. For children follow-up, experts arrange follow-up every 3-6 months assessing height, weight, blood pressure and examining for skeletal deformities. Laboratory tests for children include serum phosphorus, corrected total/ionized calcium, alkaline phosphatase, renal function, parathyroid hormone and spot morning urine for calcium, creatinine and phosphorus. For adult follow-up, experts assess patients every 6-12-months including a clinical examination for skeletal deformities and joint involvment. The laboratory profile is completed at least once a year. In the presence of bone pain, experts conduct X-rays both in children and adults to evaluate for fractures or joint damage. With respect to nephrocalcinosis, renal ultrasound is suggested on an annual basis or less frequently when monitoring children and adults with XLH. Experts conduct a dental assessment at baseline and then every 6-12 months for all patients with XLH. The findings of the survey inform practice for assessing new patients with XLH, monitoring existing patients and identifying areas for future research. All recommendations based on these practices are weak with very low-quality evidence.
The bone marrow NK cell profile predicts MRD negativity in patients with multiple myeloma treated with daratumumab-based therapy.
Natural killer (NK) cells are important effector cells in antibody-based immune therapies for multiple myeloma (MM) through antibody-dependent cellular cytotoxicity. Here, we used single-cell transcriptomics, flow cytometry and functional assays to investigate the bone marrow NK cell compartment of MM patients at diagnosis and during treatment. We show reduced proportion of CD16+ cytotoxic NK cells in a subset of patients at diagnosis, which correlated with decreased cytokine production and NK cell degranulation against MM cells in the presence of the anti-CD38 antibody daratumumab. In line with these findings, a low proportion of CD16+ bone marrow NK cells at diagnosis was associated with a reduced likelihood of achieving MRD-negativity post-consolidation in patients treated with daratumumab, bortezomib, thalidomide and dexamethasone in conjunction with autologous stem cell transplantation in the CASSIOPEIA trial. In contrast, NK cell distribution did not predict MRD-negativity in patients treated in the control arm without daratumumab. These findings highlight the impact of the bone marrow NK cell compartment on therapeutic outcomes in MM patients receiving immunotherapy with CD38-targeting antibodies.
The Type 1 Diabetes Genetics Consortium (T1DGC).
Type 1 diabetes results from the autoimmune destruction of the insulin-producing beta cells. Genetic factors account for ∼50% of the risk for type 1 diabetes but, by the late 1990's, the genetic basis was limited. The Type 1 Diabetes Genetics Consortium (T1DGC) was formed in 2002 to accelerate discovery of genes contributing to type 1 diabetes risk through a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to assemble existing data and samples from affected sib-pair families and to establish new collections. In recognition of the 75th anniversary of the NIDDK, this manuscript highlights the contributions made by the T1DGC to understanding the genetic basis of type 1 diabetes using both family (for linkage) and case-control (for genome-wide association) designs. The T1DGC conducted large-scale genetic research and used fine mapping to define risk regions. The T1DGC data, results, and samples have been made available to the scientific community, leading to the discovery of over 100 loci associated with type 1 diabetes risk, many with small effects and relevant to autoimmune pathways. The T1DGC not only expanded the list of genes contributing to disease risk but also identified non-coding genetic variation in disease-relevant cell types that contributed to the etiology of type 1 diabetes. The success of the T1DGC and the NIDDK investment in the global consortium is highlighted in its continuing impact on mapping genetic variants to their function and identifying pathways that provide new targets for prediction, prevention and treatment of type 1 diabetes.
Type 1 interferons: A target for Immune-mediated inflammatory diseases (IMIDs)
The improved understanding of the molecular basis of innate immunity have led to the identification of type I interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of several Immune-mediated inflammatory diseases (IMIDs) such as systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis and Sjögren's syndrome. Here, we review the main data regarding the opportunity to target type I IFNs for the treatment of IMIDS. Type I IFNs and their downstream pathways can be targeted pharmacologically in several manners. One approach is to use monoclonal antibodies against IFNs or the IFN-receptors (IFNARs, such as with anifrolumab). The downstream signaling pathways of type I IFNs also contain several targets of interest in IMIDs, such as JAK1 and Tyk2. Of these, anifrolumab is licensed and JAK1/Tyk2 inhibitors are in phase III trials in SLE. Targeting IFN-Is for the treatment of SLE is already a reality and in the near future may prove useful in other IMIDs. IFN assays will find a role in routine clinical practice for the care of IMIDs as further validation work is completed and a greater range of targeted therapies becomes available.
The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms.
Endothelial cells respond to mechanical forces exerted by blood flow. Endothelial cell-cell junctions and the sites of endothelial adhesion to the matrix sense and transmit mechanical forces to the cellular cytoskeleton. Here we show that the scaffold protein AmotL2 connects junctional VE-cadherin and actin filaments to the nuclear lamina. AmotL2 is essential for the formation of radial actin filaments and the alignment of endothelial cells, and, in its absence, nuclear integrity and positioning are altered. Molecular analysis demonstrated that VE-cadherin binds to AmotL2 and actin, resulting in a cascade that transmits extracellular mechanical signals to the nuclear membrane. Furthermore, the endothelial deficit of AmotL2 in mice fed normal diet provoked a pro-inflammatory response and abdominal aortic aneurysms (AAAs). Transcriptome analysis of human AAA samples revealed a negative correlation between AmotL2 and inflammation of the aortic intima. These findings offer insight into the link between junctional mechanotransduction and vascular disease.