Thrombospondin-4 correlates with MRI measures of structural damage and pain sensitisation: a new biomarker in knee osteoarthritis

Background We hypothesised thrombospondin-4 (TSP-4), a molecule mediating pain sensitisation in peripheral nerve injury, is associated with pain sensitisation in OA. Methods A cross-sectional study of clinical, imaging and fluid biomarkers from knee OA participants was conducted. TSP-4 was assessed by immunohistochemistry (IHC) for OA tissue samples and by ELISA in serum samples. Type II collagen degradation products (CTX-II), linked to OA structural damage, was determined from urine samples. A general linear model (GLM) was used to: a) investigate how patient-reported WOMAC (Western Ontario and McMaster Universities OsteoArthritis Index) pain/stiffness subscales and pain sensitisation measured by painDETECT, related to the Hospital Anxiety and Depression Scale (HADS), structural damage quantified from MRI and X-rays, CTX-II and TSP-4; b) how TSP-4 related to structural damage. We used linear discriminant analysis (LDA) to determine a classifier for pain-sensitisation from clinical and wet-biomarkers. Results TSP-4 was expressed in cartilage, bone marrow lesion (BML) and synovial tissue from OA samples. Upregulated TSP-4 protein was observed in cartilage, synovial tissue and BMLs in a perivascular distribution and in fibrotic tissue. Serum TSP-4 was significantly higher (p = 0.001) in those with pain sensitisation (painDETECT level ≥19) compared with non-sensitised participants. Serum TSP-4 was significantly increased with Hoffa’s synovitis (p < 0.001) and number of BMLs (p < 0.001 to p < 0.05). LDA provided classification accuracy of 80 % for pain sensitisation using TSP-4, CTX-II and HADS, supporting the biopsychosocial model of pain in OA. Conclusion Our data suggests TSP-4 is associated with pain sensitisation in OA and is a biomarker stratifying for pain sensitisation

Preventable deaths related to haemorrhage in England and Wales, 2013–2022: A systematic case series of coroners’ reports

Objectives To identify preventable haemorrhage-related deaths, classify coroner concerns and explore organisational responses. Study design Retrospective systematic case series of coroners’ Prevention of Future Deaths (PFD) reports from 1st July 2013 to 16 November 2022, in England and Wales. Methods Reports were acquired from the Courts and Tribunals Judiciary website and screened for haemorrhage-related deaths using a reproducible automated computer code. Demographic information, coroners’ concerns, and organisational responses to PFDs were extracted and analysed, including risk factors predisposing to haemorrhage. Results 339 PFDs (8 % of all PFDs) involved a haemorrhage event contributing to death. The average age of death was 78 years, and 57 % were male. The majority of haemorrhages were intracranial (64 %). 31 % of haemorrhage-related PFDs reported the use of anticoagulation, most often warfarin. Coroners reported 942 concerns directly relevant to the haemorrhage event, including failures to follow protocols, guidelines, or risk assessments (17 %), failures in communication or handovers (14 %), and failures in providing appropriate care, including investigations and observations (13 %). Just under half (48 %) of PFDs did not have responses published on the Judiciary website. Of the organisations who responded, 85 % reported plans to initiate new changes to address these concerns. Improvements most frequently focused on improving protocols, pathways and guidance documents, as well as education and training. Conclusions Coroner PFDs offer unique insights into haemorrhage-related deaths, highlighting the systems and processes which fail in everyday practice. Improving awareness and dissemination of these reports to clinicians and policymakers nationally may improve patient safety and save lives

Defining the analytical characteristics of a novel high-sensitivity point-of-care troponin I assay in its intended clinical environment

Objectives To assess the imprecision and stability of the point-of-care troponin I assay in the Emergency Department and its correlation and bias to two central laboratory troponin I assays (Siemens Atellica and Abbott Alinity). Methods Imprecision and stability testing was performed on opportunistically selected samples using whole blood in the emergency department by non-laboratory trained personnel. Assay comparisons were undertaken on samples taken from participants of the Mersey Acute Coronary syndrome Rule Out Study. Results The coefficient of variation (95 % confidence interval), at the 99th percentile for the point-of-care assay, was 8.1 % (6.1–12.1 %) but with a wide confidence interval reflective of considerable scatter at values just below the 99th percentile. The 10 % limit of quantification was 7.5 ng/L (1.7–61.8 ng/L). All samples met the ≤2 ng/L stability criteria for a duration of 4 h and under. The point-of-care assay very strongly correlated and had a negative bias with the Siemens Atellica and Abbott Alinity assays, Pearson’s R=0.99 and 0.95, mean difference −29.7 ng/L and −13.3 ng/L respectively. Conclusions The Siemens VTLi point-of-care assay fulfils high-sensitivity criteria when operated by non-laboratory trained staff using whole blood in its intended environment. Lithium heparin samples are likely stable up to 4 h. Significant bias between the point-of-care and two central laboratory assays negates the use of these assays interchangeably

Surgical management of atypical femoral fracture non-unions - strategies and outcomes

OBJECTIVES: Atypical femoral fractures are associated with high rates of non-union and reoperation due to their complex pathogenesis. There is no consensus in literature on the optimal treatment strategy of these difficult cases. This study demonstrates a standardized management protocol for atypical femoral fracture non-unions, with surgical mechanical alignment of the non-union, without bone grafting or use of biological adjuncts, and with immediate unrestricted weight bearing post operatively. The study aimed to examine whether comparable union and complications rates can be achieved to those published in literature. METHODS: A retrospective analysis of a prospectively collected trauma database at a tertiary referral centre for non-union was conducted. Demographic data, serial radiographs, and clinical records were reviewed. The primary outcomes were union rate and time to union. RESULTS: 13 consecutively treated patients with atypical femoral fracture non-union were included with a union rate 92 % (12 out of 13). The single ongoing non-union was in a patient who died shortly post-operatively and once excluded, the union rate was 100 %. 1 of the 12 patients who achieved union required two procedures. The average time to union of the 11 patients who underwent a single procedure for non-union was 8.3 months. The revision fixation methods were reconstruction intramedullary nail (n = 4), a reconstruction type nail with adjuvant plate (n = 5), or a 95-degree blade plate (n = 4). No bone graft or any other biological adjuncts were used in any cases. CONCLUSIONS: This study demonstrated a comparable union rate for atypical femoral fracture non-unions to studies previously reported and achieved this without any form of bone grafting and no complications from immediate weight bearing. To our knowledge, this is the only case series where no bone grafting was used in the management of AFFNU

WHO defeating meningitis symposium, 3rd international symposium on Streptococcus agalactiae disease (ISSAD) in Rio de Janeiro, Brazil: State-of-the-art overview of S. agalactiae meningitis

A World Health Organization (WHO) Defeating Meningitis Symposium took place as part of the 3rd International Symposium on Streptococcus agalactiae disease (ISSAD) conference which was held in Rio de Janeiro, Brazil, from October 16–18, 2023. The symposium highlighted WHO's Defeating meningitis by 2030 global road map focusing on Group B Streptococcus (GBS) meningitis and provided an overview of the meningitis burden and main challenges faced to tackle the disease across the Americas, Africa, and Asia

Proliferation makes a substantive contribution to the maintenance of airway resident memory T-cell subsets in young pigs

Tissue-resident memory (TRM) T cells play an important role in protection against respiratory infection but whether this memory is maintained by long-lived or dividing cells remains controversial. To address the rate of division of lung TRM T cells, deuterium-enriched water was administered orally to young pigs to label dividing lymphocytes. T-cell subsets were separated from blood, lymph nodes, and airways [bronchoalveolar lavage (BAL)], the latter comprising almost exclusively TRM. We show that, as in other species, circulating memory T-cell subsets divide more rapidly than naïve T cells. Rates of labelling of memory subsets were similar in blood and lymph nodes, consistent with the rapid and free exchange. Strikingly, the fraction of label in BAL was similar to those in blood/lymph nodes after 5–21 days of labelling, suggesting replacement with recently divided cells, but this was preceded at Day 2 by a phase when labelling was lower in BAL than blood/lymph node in some memory subsets. Our data exclude long-lived TRM as the source of BAL memory cells leaving three possible hypotheses: blood/airway exchange, in situ proliferation, or proliferation in the lung interstitium followed by migration to BAL. When considered in the context of other information, we favour the latter interpretation. These results indicate the dynamic nature of memory in the lung and have implications for harnessing immune responses against respiratory pathogens

KDM2B variants in the CxxC domain impair its DNA-binding ability and cause a distinct neurodevelopmental syndrome

Rare variants affecting the epigenetic regulator KDM2B cause a recently delineated neurodevelopmental disorder. Interestingly, we previously identified both a general KDM2B-associated episignature and a subsignature specific to variants in the DNA-binding CxxC domain. In light of the existence of a distinct subsignature, we set out to determine if KDM2B CxxC variants are associated with a unique phenotype and disease mechanism. We recruited individuals with heterozygous CxxC variants and assessed the variants’ effect on protein expression and DNA-binding ability. We analyzed clinical data from 19 individuals, including ten previously undescribed individuals with seven novel CxxC variants. The core phenotype of the KDM2B-CxxC cohort is more extensive as compared to that of individuals with KDM2B haploinsufficiency. All individuals with CxxC variants presented with developmental delay, mainly in the speech and motor domain, in addition to variable intellectual disability and mild facial dysmorphism. Congenital heart defects were observed in up to 78% of individuals, with additional common findings including musculoskeletal, ophthalmological, and urogenital anomalies, as well as behavioral challenges and feeding difficulties. Functional assays revealed that while mutant KDM2B protein with CxxC variants can be expressed in vitro, its DNA-binding ability is significantly reduced compared to wildtype. This study shows that KDM2B CxxC variants cause a distinct neurodevelopmental syndrome, possibly through a molecular mechanism different from haploinsufficiency

Is parvovirus B19 infection upsurge in 2023–2024 associated with adverse pregnancy outcome?

Objective A surge in parvovirus B19 infections has been reported in 2023–2024 across Europe and the USA, raising concerns about the associated perinatal risks. The aim of this study was to compare perinatal outcomes following maternal parvovirus B19 infection during the 2023–2024 period with those from a pre‐2023 cohort. Methods This multicenter, retrospective cohort study compared perinatal outcomes in women with maternal parvovirus B19 infection according to whether infection occurred pre‐2023 (2012–2022) or between 2023 and 2024. Pregnant women with confirmed parvovirus B19 infection were eligible for inclusion. Cases were excluded if they had incomplete records, an ongoing pregnancy, coinfection with cytomegalovirus or Epstein–Barr virus, pre‐existing structural or genetic abnormality, immune fetal hydrops or a maternal serology result not indicative of parvovirus B19 infection. The primary outcome was perinatal mortality, which was defined as intrauterine fetal death ≥ 20 weeks' gestation or neonatal death ≤ 28 days after delivery. The secondary outcomes were persistent fetal anemia requiring more than one intrauterine transfusion (IUT) and a composite adverse perinatal outcome (CAPO), defined as the presence of one or more adverse outcomes, including perinatal mortality, pregnancy loss < 20 weeks, new‐onset structural anomaly and termination of pregnancy owing to parvovirus‐related morbidity. Differences between the two groups were assessed using standard statistical tests, and a generalized linear mixed model was used to identify predictors of perinatal mortality in the 2023–2024 cohort. Results Following exclusions, 140 cases from pre‐2023 and 175 cases from 2023–2024 were analyzed. The rate of fetal hydrops at presentation was similar across the two groups (22.9% in pre‐2023 vs 23.4% in 2023–2024; P = 0.905). The rates of perinatal mortality (6.4% in pre‐2023 vs 8.0% in 2023–2024; P = 0.294) and CAPO (17.9% in pre‐2023 vs 21.7% in 2023–2024; P = 0.395) were not significantly different between groups, but the proportion of fetuses with persistent fetal anemia requiring a second IUT was significantly higher in the 2023–2024 cohort (46.0% vs 19.4%; P = 0.011). For the 2023–2024 cohort, fetal hydrops at presentation was an independent predictor of perinatal mortality (adjusted odds ratio, 10.91 (95% CI, 1.89–63.07); P = 0.007). Conclusion In this multicenter collaboration, we report perinatal outcomes following maternal parvovirus B19 infection during the recent upsurge and compare them with those of a historical cohort. Although perinatal mortality and CAPO rates were similar between cohorts, cases in the recent surge (2023–2024) required more prenatal interventions, including the need for more than one IUT. Early identification and monitoring remain essential to mitigate adverse perinatal outcomes following maternal parvovirus B19 infection. © 2025 The Author(s). Ultrasound in Obstetrics &amp; Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology

Uptake rates of influenza vaccination in over 65s in Denmark: a comparison between Danish-born and migrant populations, 2015–21

WHO’s Immunization Agenda 2030 has placed renewed focus on life-course vaccination, including among migrants. Despite the availability of a seasonal vaccine, influenza remains a key contributor to winter excess mortality in Northern Europe, yet limited data on influenza vaccination uptake in migrants has been published. We analyzed Danish national registry data to determine influenza vaccine uptake across six flu seasons (2015/16–2020/21) among migrants (asylum-pathway and quota refugees, family reunified migrants) ≥65 years matched 1:6 on age and gender to Danish-born individuals. We used multivariate logistic regression models controlling for migrant status (immigration status, time in Denmark) and other sociodemographic variables (age, gender, nationality, urban/rural residence) to identify factors associated with influenza vaccination uptake. All analyses were done in R v4.2.1. Across all six seasons, overall flu vaccination uptake was 49.3% (Danish-born: 50.9%; migrant cohort: 39.4%). Migrants were less likely [odds ratio (OR): 0.66; 95% confidence interval (CI): 0.64–0.67] to receive an influenza vaccine across all seasons, with this gap widening from 2015/16 (OR: 0.78; 95% CI: 0.74–0.84) to the 2020/21 season (OR: 0.44; 95% CI: 0.42–0.46). Family-reunified migrants were less likely to receive an influenza vaccine across the study period than asylum-pathway and quota refugees and those from the Sub-Saharan Africa region had the lowest uptake in terms of area of origin. This large and unique dataset shows that migrant groups have lower uptake rates for influenza vaccination compared with Danish-born individuals, with the gap widening over time. Going forward, developing tailored interventions, co-developed in collaboration with communities themselves, will be key

Factors Associated With Retinal Vessel Traits in the Canadian Longitudinal Study on Aging

PURPOSE: To determine the factors cross-sectionally and longitudinally associated with retinal vessel diameter, total area, and tortuosity in the Canadian Longitudinal Study on Aging (CLSA). METHODS: Of the 30,097 adults between ages 45 and 85 years old in the CLSA Comprehensive Cohort, 26,076 had at least one retinal image gradable by QUARTZ, a deep-learning algorithm that automatically assessed image quality, distinguished between arterioles and venules, and estimated retinal vessel traits over the entire retina. Questions were asked about demographic, lifestyle, and medical factors. Blood pressure, cholesterol, and C-reactive protein were measured. Participants returned for follow-up 3 years later. Multiple linear regression was used to provide adjusted estimates. RESULTS: Current smoking was strongly associated with wider arteriolar and venular diameters and their widening over 3 years (P < 0.05). Current smoking was also associated with a larger arteriolar and venular area and a 3-year increase in venular area (P < 0.05). Obesity was positively associated with venular diameter, total venular area, 3-year change in total venular area, and venular tortuosity (P < 0.05). Diastolic blood pressure was negatively associated with both arteriolar and venular diameter, area, and tortuosity, both cross-sectionally and longitudinally (P < 0.05). Diabetes was associated with wider arteriolar diameters cross-sectionally, and type 1 diabetes was associated with 3-year widening of arteriolar diameters (P < 0.05). CONCLUSIONS: This work provides comprehensive information on the factors associated with retinal vessel traits and their change. Factors such as smoking, obesity, blood pressure, and diabetes were longitudinally related to retinal vessel traits, which play a role in the development of eye disease