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Teaching Mathematics with Lean: Interactive Theorem Provers in the Classroom
No full textIn September 2018, I* (Paola) received an email from a mathematician at Imperial College London whom I had met a couple of years previously at a meeting. He asked me whether I was interested in studying the impact of introducing Lean, an Interactive Theorem Prover (ITP), on students’ understanding of proof in his transition to proof course. I did not know at that time what an Interactive Theorem Prover was, but it sounded interesting as it was linked to proof writing and mathematical reasoning—one of my research interests—so I agreed to meet and discuss the course. The mathematician was Kevin Buzzard and eventually I and Athina Thoma‡ designed and carried out that study. Since then we have collaborated with mathematicians in Europe and the United States to study the impact that interacting with Lean (https://leanprover-community.github.io) has on students’ understanding of mathematics, the development of their mathematics epistemology, and the way in which students and, more recently, teachers use this tool.One of the mathematicians we collaborated with is Gihan Marasingha,† who let us into his classroom for one of our projects. In this article, we discuss in turn our research findings and Gihan’s experience with using Lean for teaching to outline some of the potential of this tool for learning mathematics at the undergraduate level
One model to rule them all:unification of voltage-gated potassium channel models via deep non-linear mixed effects modelling
No full textIon channels are essential for signal processing and propagation in neural cells. Voltage-gated ion channels permeable to potassium (Kv) form one of the most prominent channel families. Techniques used to model the voltage-dependent gating of Kv channels date back to Hodgkin and Huxley (1952). Different Kv types can display radically different kinetic properties, requiring different mathematical models. However, the construction of Hodgkin-Huxley-like (HH-like) models is generally complex and time consuming due to the number of parameters, their tuning and having to choose functional forms to model gating. In addition to the between-Kv type heterogeneity, there can be significant within-Kv type kinetic heterogeneity between different cells with genetically identical channels. Since HH-like models do not account for such variability, extensions to it are necessary. We use scientific machine learning (SciML), the integration of machine learning methodologies with existing scientific models, and non-linear mixed effects (NLME) modelling to bypass the limitations of HH-like modelling. NLME is a modelling methodology that takes into account both within- and between-subject variability. These tools allowed us to complement the HH-like modelling and construct a unified SciML HH-like model that fits the recordings from 20 different Kv types. The unified SciML HH-like model produced closer fits to the data compared to a set of seven previous HH-like models and was able to represent the highly heterogeneous data from different cells. Our model may be the first step in producing a SciML foundation model for ion channels that would be capable of modelling the gating kinetics of any ion channel type
Cross-national risk factors for childbirth-related PTSD:Findings from the INTERSECT study
No full textBACKGROUND: Childbirth-related post-traumatic stress disorder (CB-PTSD) is an underrecognized condition with consequences for mothers and infants. This study aimed to determine risk factors for CB-PTSD symptoms across countries within a stress-diathesis framework, focusing on antenatal, birth-related, and postpartum predictors.METHODS: The INTERSECT cross-sectional survey (April 2021-January 2024) included 11,302 women at 6-12 weeks postpartum. The study was carried out across maternity services in 31 countries. Outcomes were CB-PTSD diagnosis, symptom severity, and perceived traumatic birth, assessed with the City Birth Trauma Scale. Multiple risk factors were assessed, including preexisting vulnerability, pregnancy, birth, and infant-related factors. All models were adjusted for country-level variation as a random effect.RESULTS: Models explained substantial variance across all outcomes (conditional R 2 = 0.53-0.58). Negative birth experience was the strongest predictor (e.g. odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.80-0.84 for diagnosis). Ongoing maternal complications predicted both CB-PTSD diagnosis and symptoms (e.g. OR = 1.61, 95% CI = 1.41-1.84), and major infant complications were associated with CB-PTSD diagnosis (OR = 1.63, 95% CI = 1.29-2.07). Reports of perceived danger to self or infant (criterion A) were linked to higher CB-PTSD symptoms and traumatic birth ratings (e.g., β =0.25, 95% CI = 0.21-0.29). Other predictors reached significance but showed small effects. CONCLUSIONS: Findings support a stress-diathesis framework, showing that while pre-existing vulnerabilities contribute, birth-related stressors exert the strongest influence. Trauma-informed maternity care should prioritize these factors, with attention to women's appraisals of birth.</p
Characterisation of lmx1b paralogues in zebrafish reveals divergent roles in skeletal, kidney and muscle development
No full textLMX1B, a LIM-homeodomain family transcription factor, plays critical roles in the development of multiple tissues, including limbs, eyes, kidneys, brain, and spinal cord. Mutations in the human LMX1B gene cause the rare autosomal-dominant disorder Nail-patella syndrome, which affects development of limbs, eyes, brain, and kidneys. In zebrafish, lmx1b has two paralogues: lmx1ba and lmx1bb. While lmx1b morpholino data exists, stable mutants were previously lacking. Here, we describe the characterisation of lmx1b stable mutant lines, with a focus on development of tissues that are affected in Nail-patella syndrome. We demonstrate that the lmx1b paralogues have divergent developmental roles in zebrafish, with lmx1ba affecting skeletal and neuronal development, and lmx1bb affecting renal development. The double mutant, representing loss of both paralogues (lmx1b dKO) showed a stronger phenotype, which included additional defects to trunk muscle patterning, and a failure to fully inflate the notochord leading to a dramatic reduction in body length. Overall, these mutant lines demonstrate the utility of zebrafish for modelling Nail-patella syndrome and describe a previously undescribed role for lmx1b in notochord cell inflation
A novel cause of type 1 von Willebrand disease:impaired exocytosis of Weibel-Palade bodies due to biallelic MADD variants
No full textThe regulated secretion of von Willebrand factor (VWF) from Weibel-Palade bodies (WPBs) in endothelial cells is fundamental to hemostasis. This process relies on recruiting Rab GTPases and their effectors to the WPB membrane, with the guanine nucleotide exchange factor MAPK-activating death domain (MADD) playing a central role. Biallelic variants in MADD lead to a pleiotropic neurological and developmental disorder that can include bleeding abnormalities. This study investigates the impact of pathogenic MADD variants on VWF secretion using patient-derived endothelial cells. We isolated endothelial colony-forming cells (ECFCs) from 3 pediatric patients with biallelic MADD variants and unaffected heterozygous family members. All patients exhibited low VWF plasma levels (22-30 IU/dL). Proteomic analysis of patient-derived ECFCs revealed an absence of MADD peptides, reduced VWF, and downregulation of proteins involved in the exocytotic machinery, including Rab3D and the Rab3/27 effector Slp4-a. Functional assays demonstrated diminished Rab27A and Rab3D activity and their failure to localize to WPBs in patient cells. Biochemical and live-imaging studies showed that histamine-induced VWF and VWF propeptide secretion were significantly reduced in patient cells due to delayed and reduced degranulation of WPBs. Our findings demonstrate the critical role of MADD in maintaining the secretion competence of WPBs and the magnitude of VWF secretion by regulating the recruitment of the endothelial exocytotic machinery. This study highlights the in vivo significance of WPB exocytosis in maintaining plasma VWF levels and establishes MADD as the first causal gene for quantitative von Willebrand disease in patients without pathogenic VWF variants.</p
Small Interfering RNA Therapy Targeting the Long Noncoding RNA SMILR for Therapeutic Intervention in Coronary Artery Bypass Graft Failure
No full textCoronary artery bypass graft (CABG) surgery remains the gold standard of care to prevent myocardial ischemia in patients with advanced atherosclerosis; however, poor long-term graft patency remains a considerable and long-standing problem. Excessive vascular smooth muscle cell (SMC) proliferation in the grafted tissue is recognized as central to late CABG failure. We previously identified SMILR, a human-specific SMC-enriched long noncoding RNA that drives SMC proliferation, suggesting that targeting SMILR expression could be a novel way to prevent neointima formation, and thus CABG failure. Here, we sought to identify a lead siRNA for clinical development. We describe the design and synthesis of a library of 76 chemically enhanced SMILR-targeting siRNA. From this library, we identify a lead siRNA, BHF7, which demonstrates potent and reproducible silencing of SMILR expression, and which robustly blocks vascular smooth muscle cell proliferation, both in vitro and in the ex vivo human saphenous vein model. We further demonstrate using RNA-sequencing that BHF7 down-regulates the expression of genes associated with proliferation and does not induce the expression of interferon or apoptosis genes, suggesting it has a favorable safety profile, both on- and off-target. Finally, we performed TUNEL staining on BHF7-treated tissues and measured the levels of cleaved caspase-3 by enzyme-linked immunosorbent assay after BHF7 treatment. This demonstrated that BHF7 does not induce a cytotoxic response either in vitro or ex vivo. Collectively, these data represent a preclinical package into the function and specificity of BHF7 which warrants further investigation into the possibility of utilizing BHF7 as a novel, ex vivo RNA therapeutic for the prevention of CABG failure in humans
Rationale and design of the REMBRANDT trial: A phase 3 study to evaluate the effect of obicetrapib/ezetimibe on coronary plaque characteristics
No full textBackgroundObicetrapib is a potent, selective cholesteryl ester transfer protein (CETP) inhibitor that significantly lowers low-density lipoprotein cholesterol (LDL-C). Additive reductions in LDL-C occur when obicetrapib is combined with ezetimibe. The impact of obicetrapib and ezetimibe fixed-dose combination (FDC) on coronary plaque burden is unknown. Favorable changes in noncalcified coronary atherosclerotic plaque volume (NCPV) may indicate a potential beneficial effect on atherosclerotic cardiovascular disease (ASCVD) events.MethodsREMBRANDT is a placebo-controlled, double-blind, randomized trial designed to assess the efficacy of obicetrapib and ezetimibe FDC on coronary plaque burden. Individuals aged 45 years or older with ASCVD (imaging evidence of vascular disease or clinically manifested ASCVD) and an LDL-C of ≥70 mg/dL despite maximally tolerated lipid-modifying therapy are eligible to participate. Eligible participants (N = 300) will be randomized in a 1:1 ratio to obicetrapib 10 mg and ezetimibe 10 mg FDC once daily or placebo tablet once daily. The primary efficacy outcome of REMBRANDT is percent change in total NCPV from baseline to 18 months as assessed by coronary computed tomographic angiography (CCTA). Secondary endpoints include absolute change in total NCPV, percent and absolute change in NCPV in the most diseased coronary segment, percent change in LDL-C, and change in perivascular fat attenuation index from baseline to 18 months.ConclusionThe REMBRANDT trial will determine whether the favorable effects of obicetrapib and ezetimibe FDC on LDL-C translate to a reduction in coronary plaque burden as a potential mechanism for ASCVD risk reduction.Clinical trial registrationNCT06305559
Reactive Crystallization in Unsaturated Porous Media
No full textCrystal nucleation and growth reshape the mechanical, transport and reactive properties in subsurface porous media. We visualize CO2 hydrate formation and growth in a microfluidic unsaturated porous medium and uncover novel multiscale dynamics: (a) hydrate crystals preferentially grow in narrower paths and seal low-permeability regions, despite lower surface energy in wider pathways; (b) explosive crystallization emerges at water-gas interface when growing crystals touch water pockets, that enables efficient hydrate propagation across disconnected water clusters. These observations are theoretically rationalized. We therefore provide an interpretation of field observations of early stage hydrate enrichment in low permeability zones, and discover a new nucleation propagation mechanism. The mechanism may also emerge in other reactive crystallization in unsaturated media
Adverse drug reactions, particularly liver disorders, drive interruptions in anti‐tuberculosis treatment: A retrospective cohort study
No full textAIMS: Adverse drug reactions (ADRs) are a key driver of missed doses of anti-tuberculosis (TB) therapy. We aimed to determine the relative burden of ADR-driven missed doses, the missed dose patterns associated with ADRs, and the association between specific ADRs and missed doses.METHODS: In this retrospective cohort study, adults (≥18 years) who began the standard 6-month drug-sensitive anti-TB regimen in an outpatient facility in Riga, Latvia (May 2015-September 2022) and missed at least one dose of treatment were included. Data were collected from medical records and observed therapy records. Missed doses were subdivided into early discontinuation or sporadically missed. Descriptive analyses and lasagne plots were used.RESULTS: Across 174 patients, 54 (31.0%, CI: 24.2-37.9%) missed doses due to ADRs. Of 31 320 doses, 4217 (13.5%, CI: 13.1-13.9%) were missed, 20.9% (880/4217, CI: 19.6-22.1%) were due to ADRs. Eighteen (10.3%) of the 174 patients discontinued treatment early, two of which (11.1%) were due to ADRs. Doses missed due to ADRs caused longer yet less frequent periods of sporadic missed doses: 56.4% (479/849) of sporadic missed doses were 1 day in length vs. only 9.1% (7/77) for ADR-related ones. Hepatobiliary disorders were the leading ADR group causing missed doses. Hepatobiliary ADRs caused long median durations of missed doses (median 15.0, CI: 13.0-22.0).CONCLUSION: Our study underscores the importance of ADRs as a cause of missed doses of treatment, particularly hepatobiliary disorders. Regimens that are less prone to ADRs and strong healthcare system support structures for patients with ADRs are required to minimize missed doses, reducing unfavourable outcomes.</p
Sonopsychology: integrating psychological awareness and patient-centered outcomes into ultrasound practice
No full textSonopsychology refers to the multidimensional psychological interactions occurring before, during, and after ultrasound examinations. While the psychological effects of radiological examinations are documented, the unique context of ultrasound, marked by real-time imaging and close examiner-patient interaction, has not received equivalent attention. This review explores the psychological dynamics in various contexts–radiology, oncology, and interventional ultrasound–highlighting key domains such as communication, emotional attunement, examiner self-awareness, and the influence of environmental and procedural factors. The concept of Sonopsychology emphasizes that ultrasound is not merely a diagnostic tool or processes but also a human encounter. By integrating emotional intelligence and relational competencies into routine practice, examiners can enhance patient satisfaction, trust, and even clinical outcomes. Ultimately, this integrative approach reframes performance assessment emphasizing patient-centered outcomes, moving beyond a solely technical evaluation
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