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EVC protein regulates Sonic hedgehog signaling during human intervertebral disc development and degeneration
Get PDFNotochord-derived cells (NCs) in the developing nucleus pulposus (NP) of the intervertebral disc maintain its hydrated extracellular matrix and their aging-associated loss initiates intervertebral disc degeneration, contributing to back pain. To better understand the molecular regulators of NC function, we profiled the proteome of human fetal NP cells and identified Ellis-van Creveld (EVC) protein as highly enriched in NCs. Using mouse models and CRISPR-engineered human NP cells, we show that EVC facilitates Shh signaling, supports NP cell phenotype, and limits fibrotic matrix changes. Loss of EVC reduced Gli3 processing, impaired Shh pathway activity, and altered extracellular matrix organization, while TGF-β signaling suppressed EVC expression indicating crosstalk between these pathways. These findings establish EVC as a key modulator of developmental and homeostatic signaling in the disc and suggest potential therapeutic targets for disc degeneration and fibrosis, providing strategies for preserving NP function and informing regenerative approaches.</p
Effect of rotational forces on the durability of dental materials:Implications in biology and anthropology
Get PDFBoth natural and synthetic prosthetic teeth undergo mechanical degradation, impacting their durability. Experimental studies typically simulate dental contacts using simple configurations involving normal and lateral forces. While often necessary due to the constraints of apparatus set-ups and mathematical models, these assumptions oversimplify the complex conditions during mastication and ignore poorly understood but potentially important rotational forces, which occur when teeth are compressed into the alveolar bone. We investigate the influence of rotational forces on contact damage/wear in synthetic dental materials using advanced equipment with decoupled biaxial actuators. Cyclic contact loads combining compression (50 N) and rotation (30°) are applied to zirconia (Z), composite (CP), feldspathic (F) and lithium silicate based (ZLS) glass-ceramics. After 10 5 cycles, Z exhibits the greatest wear resistance (wear volume 4.16 × 10 -4 mm 3), followed by F (5.83 × 10 -3 mm 3), CP (9.17 × 10 -3 mm 3) and ZLS (1.64 × 10 -2 mm 3), with p-values 0.004 (Z-F), 0.631 (F-CP), 0.012 (F-ZLS) and 0.009 (CP-ZLS). Abrasion is the primary wear mode, with specific mechanisms such as plastic deformation and microfracture varying with material microstructure. Contact mechanics analysis indicates that rotational forces induce lower wear than non-rotational sliding. Potential implications in dentistry, biology and anthropology are discussed, including the design of culturally and behaviourally informed dental prosthetics.</p
Patient experience and preference while waiting for elective cardiac surgery:a mixed-methods cross-sectional survey across four major National Health Service hospitals in London
No full textOBJECTIVES: Waiting for cardiac surgery is a stressful life event for most patients. Exploring what people experience while waiting and understanding their preferences and views on how waiting time could be improved will help to inform new strategies for more efficacious waiting list management. In this study, we explored experiences and views of people waiting for elective cardiac surgery across four major London hospitals.DESIGN: Mixed-methods cross-sectional survey, with explanatory concurrent design.SETTING: Four cardiac surgery services across two National Health Service Trusts in London.PARTICIPANTS: Patients on waiting lists for elective cardiac surgery at Royal Brompton, Harefield, St Thomas and King's College hospitals between October 2023 and March 2024.OUTCOME MEASURES: Experience of waiting for surgery, and preferences about how waiting time could be improved.RESULTS: 554 out of 1041 invited participants agreed to participate (recruitment rate 53.2%). Among them, 274 fully completed the survey (completion rate 49.5%). Most participants (from 52.2% to 70.9%) reported their daily and social activities were impacted by their cardiac condition, and worrying was an ubiquitous feeling (reported by 86%). Psychological distress was reported differently across women and men (higher in women). Eight themes were identified: worrying, daily activities, family/friends and social activities, sexual life, waiting list experience and feelings, communication, most important factors for surgery and suggested improvements. Communication with the surgeon and clinical team, and regular updates on waiting list progress are suggested as crucial factors to alleviate stress, thus potentially improving the experience of waiting for the surgery.CONCLUSIONS: This study highlights the importance of emotional support, clear communication, regular updates on waiting list progress and building trust with the clinical team to improve patient-centred care while waiting for elective cardiac surgery. This finding can offer valuable insights for managing waiting lists in other surgery waiting list contexts.TRIAL REGISTRATION: NCT05996640.</p
Human-Centered Quantum Software Engineering:A Research Agenda
Get PDFQuantum computing, grounded in principles such as superpositionand entanglement, is revolutionising the design, testing, and understanding of software. While the community is working on its technical challenges, the human and collaborative aspects have received little attention. This vision paper outlines a research agenda for human-centred quantum software engineering (HC-QSE). Building on current QSE foundations, the agenda spans three interrelated themes: understanding practice, designing support, and embeddingresponsibility. The first calls for studying how interdisciplinaryteams construct and share mental models of quantum behaviour, collaborate across disciplinary boundaries, and reason under uncertainty inherent in probabilistic computation. The second focuses on creating tools, workflows, and learning environments that enhance comprehension, interpretability, and shared accountability among practitioners, educators, and learners. The third integrates ethical reflection and equity considerations into the design and governance of quantum software ecosystems. By centering human experience within QSE, this agenda encourages cooperative, reflective, and ethically grounded approaches to building quantum software
Triage and care for women with symptoms or diagnosis of pregnancy loss between 14 + 0 and 21 + 6 weeks' gestation
Get PDFMid-trimester pregnancy loss (MTL), defined as a pregnancy loss occurring between 14 + 0 and 21 + 6 weeks of gestation, causes significant physical and emotional distress to women and presents clinical challenges to healthcare professionals. It is acknowledged that in low-resource settings, this guideline might be applicable to births up to 28 weeks or babies weighing less than 1 kg. Risk factors for MTL include advanced maternal age, previous history of MTL, women of Black ethnicity, smoking, excessive alcohol consumption, obesity, and anatomical factors such as a short cervix, congenital uterine anomalies, and myomas. Medical risk factors include previous cervical trauma from loop electrosurgical excision procedure or Cesarean section in labor, placental dysfunction, infections, thrombophilias, endocrine disorders such as thyroid disease and polycystic ovary syndrome, and fetal chromosomal abnormalities. Early assessment and accurate diagnosis are fundamental to managing threatened and confirmed mid-trimester pregnancy loss. Our guideline emphasizes the importance of maternal vital signs monitoring, laboratory investigations, and ultrasound imaging to identify and manage those with threatened or confirmed mid-trimester pregnancy loss, as well as address potential maternal complications, including infection or hemorrhage. A multidisciplinary approach involving obstetricians, gynecologists, maternal-fetal medicine specialists, nurses, midwives, psychologists, and social workers is important for providing comprehensive care. The guideline advocates for personalized management plans tailored to individual women's preferences, medical history, and gestational age. Care for threatened MTL should be targeted to the likely cause and might include cervical cerclage, progesterone, and management of risk factors, for example antibiotics for urinary tract infections. Care for confirmed MTL might include expectant management, medical induction of labor, or surgical intervention such as dilation and evacuation. Acknowledging the profound emotional impact of mid-trimester pregnancy loss, our guideline underscores the importance of offering compassionate and culturally sensitive psychosocial support to women and their families. This includes providing access to bereavement care, counseling services, support groups, and resources for coping with grief and loss. Continued monitoring and follow-up care are essential components of managing mid-trimester pregnancy loss. Our guideline recommends regular postpartum assessments to evaluate physical recovery and emotional well-being and to address any ongoing medical or psychological concerns. Contraceptive counseling and future pregnancy planning should also be discussed as part of comprehensive care. It is important that, where possible, women receive continuity of care from healthcare professionals to help the coordination and provision of holistic and comprehensive care. Further research is needed to enhance our understanding of the etiology, risk factors, and optimal management strategies for threatened mid-trimester pregnancy loss. Additionally, education and training initiatives should be implemented to ensure healthcare professionals are equipped with the knowledge and skills necessary to deliver high-quality, woman-centered care to individuals and families experiencing this complication. Mid-trimester pregnancy loss represents a complex clinical scenario necessitating a holistic and compassionate approach to care. By adhering to the recommendations outlined in this clinical guideline, healthcare providers can strive to optimize outcomes and support individuals and their families through this challenging experience.</p
Artificial intelligence methods to detect heart failure with preserved ejection fraction within electronic health records:an equitable disease detection model
Get PDFAIMS: Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases, with high levels of morbidity and mortality. However, many patients who meet diagnostic criteria for HFpEF do not have a documented diagnosis, particularly in non-White populations where conventional risk scores may underestimate risk. Our aim was to develop and validate a diagnostic prediction model to detect HFpEF based on ESC criteria, AIM-HFpEF.METHODS AND RESULTS: We applied natural language processing (NLP) and machine learning methods to routinely collected electronic health record (EHR) data from a tertiary centre hospital trust in London, UK, to derive the AIM-HFpEF model. We then externally validated the model and performed benchmarking against existing HFpEF prediction models (H2FPEF and HFpEF-ABA) for diagnostic power on the entire external cohort and in patients of non-White ethnicity and patients from areas of increased socioeconomic deprivation. An XGBoost model combining demographic, clinical, and echocardiogram data showed strong diagnostic performance in the derivation dataset [ n = 3173, AUC = 0.88, (95% CI, 0.85-0.91)] and validation cohort [ n = 5383, AUC: 0.88 (95% CI, 0.86-0.90)]. Diagnostic performance was maintained in patients of non-White ethnicity [AUC = 0.89 (95% CI, 0.85-0.93)] and patients from areas of high socioeconomic deprivation [AUC = 0.90 (95% CI, 0.85-0.95)]. In contrast, AIM-HFpEF demonstrated favourable performance relative to the H2FPEF and HFpEF-ABA models. AIM-HFpEF model probabilities were associated with an increased risk of death, hospitalization, and stroke in the external validation cohort ( P < 0.001, P = 0.01, P < 0.001, respectively, for highest vs. middle tertile). CONCLUSION: AIM-HFpEF represents a validated equitable diagnostic model for HFpEF, which can be embedded within an EHR to allow for fully automated HFpEF detection.</p
Kuznets at 70:The enduring significance of a curve and a hypothesis
Get PDFSeven decades ago, Simon Kuznets put forward the hypothesis that as economies developed, national inequality would first increase and then decrease—an inverted U-shape. He provided preliminary evidence for the hypothesis on the basis of the limited data available at the time, and theorized the genesis of the curve as arising from the twin forces of structural transformation of the economy and political economy pressures. Seven decades on, the Kuznets curve still has a hold on the development discourse as new data is used to test the hypothesis, new theories are elaborated to explain the evolution of inequality, and the metaphor of an inverse U-shape is extended beyond its original realm of national inequality. With this rich history and background, the time is right to examine the Kuznets curve literature broadly construed. This overview takes stock of what has been learned and highlights emerging research and policy questions
Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism
Get PDFThe human developmental disorder 3MC syndrome (Malpuech, Michels, Mingarelli and Carnevale) features skeletal deformities associated with a deficiency of the pattern recognition molecule collectin-11 (CL-11), yet the underlying molecular and cellular mechanisms remain uncertain. Here, we demonstrate that CL-11 deletion alone does not produce skeletal abnormalities in mice; however, combined deficiencies of CL-11 with complement components MASP-2 (lectin pathway), CFB, or C3 (alternative pathway amplification) result in marked vertebral bone loss and spinal curvature by 12 weeks of age. Ex vivo osteoclast (OCL) differentiation from bone marrow-derived cells of these double-knockout (DKO) mice was profoundly impaired but was substantially restored by CL-11 supplementation. This dependence on CL-11 and complement was recapitulated in human OCLs derived from induced pluripotent stem cell (iPSC) lines. CL-11 and the membrane attack complex (MAC, C5b-9) co-localized to OCLs and their precursors in normal bone from embryonic development through to adulthood. Together, these findings identify CL-11 as a key regulator of osteoclastogenesis and bone homeostasis acting in concert with complement-mediated signalling, and they nominate CL-11 as a potential therapeutic target in conditions involving dysregulated osteoclast function and bone remodelling
Botulism Sequelae:A Systematic Review
Get PDFBACKGROUND: Botulism is a life-threatening neuroparalytic disease caused by botulinum neurotoxins. While its acute phase has been extensively studied, long-term sequelae following recovery remain insufficiently explored. This systematic review aims to comprehensively assess and synthesize available evidence on post-botulism sequelae to improve understanding and guide future research.METHODS: A systematic search was conducted in MEDLINE, EMBASE via Ovid, and Web of Science from inception to 24 June 2024. Eligible studies included observational studies, case series, and case reports describing post-recovery symptoms in individuals diagnosed with foodborne, wound, or infant botulism, excluding iatrogenic cases. The risk of bias was assessed using the Critical Appraisal Skills Programme (CASP) checklists.RESULTS: Out of 340 screened records, 9 studies met inclusion criteria, comprising 2 case-control studies (n = 230 botulism cases, n = 669 controls) and 7 cohort studies (n = 185 botulism cases). Most studies reported some short- and/or long-term consequences of botulism. Among 3 studies homogeneously reporting sequelae symptomatology, the most frequently reported long-term symptoms included fatigue (66.2%, range 47.9%-84.6%), limitations in vigorous activities (55.8%, range 47.6%-64.0%), general weakness (57.1%, range 43.1%-76.9%), and dyspnea (42.9%, range 18.0%-92.3%). In some patients, psychosocial dysfunction persisted longer than physical impairments, over the 6-year period post intoxication. Two studies provided comparative data with control groups, demonstrating significantly higher prevalence of fatigue, weakness, and impaired health perception in botulism survivors. Additionally, 14 case reports and case series (n = 43 individuals) reported similar patterns with dyspnea, fatigue, and autonomic dysfunction among the most reported sequelae.CONCLUSIONS: This systematic review highlights significant long-term sequelae among botulism survivors, particularly fatigue, respiratory impairment, and psychosocial dysfunction. While recovery trajectories suggest improvement over time, persistent symptoms may impact quality of life. Standardized outcome measures and longitudinal studies are needed to elucidate the burden of post-botulism sequelae further and inform clinical management strategies.</p
