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Lifestyle intervention is more effective in high 1-hour post-load glucose than in prediabetes for restoring β-cell function, reducing ectopic fat, and preventing type 2 diabetes
Get PDFBackground High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glucose regulation (IGR) and is amendable to greater lifestyle intervention (LI) benefit. Methods In the Tübingen Lifestyle Intervention Program, 317 people with either NGR, IGR or isolated high 1 h-PG without IGR underwent LI for 9 months to achieve ≥5 % weight loss. Results Before LI initiation, insulin sensitivity and β-cell function declined progressively from NGR ( n = 106) to high 1 h-PG ( n = 96) and to IGR ( n = 115). Visceral adipose tissue (VAT) volume and liver fat content increased from NGT to high 1 h-PG and to IGR. LI improved insulin sensitivity and ß-cell function in the high 1 h-PG group to levels observed in NGR together with a marked reduction in hepatic fat content. Compared to the IGR group, T2D risk was reduced by 80 % (37–96 %, p = 0.005) in the high 1 h-PG group during a 12-year follow-up period. The odds of remission to complete normoglycemia were doubled in the high 1 h-PG group compared to the IGR group (2.18 [1.13–4.28], p = 0.021). Conclusion High 1 h-PG indicates an intermediate metabolic state with pathophysiological changes more severe than in NGR but milder than in IGR. In people with high 1 h-PG, LI significantly improved insulin sensitivity and β-cell function and reduced ectopic lipid deposition and the risk of developing T2D compared to IGR. These findings highlight the value of 1 h-PG as a clinically useful biomarker, providing a critical window for early intervention to reverse core metabolic defects driving prediabetes and T2D.</p
Markets and New Industrial Policy:Systemic Directionality or Polycentric Evolutionism
Get PDFProponents of “new industrial policy” claim that systemic directionality can be imparted to market economies in ways recognising the epistemic challenges of complexity and uncertainty. This paper evaluates these efforts to reformulate industrial policy on a more epistemically modest, evolutionary footing and argues that they fail. We contend that the focus on “systemic directionality” undercuts the emphasis placed on evolutionary learning and the epistemic limitations of centralised authority. Proper attention to these problems implies neither a laissez-faire/market fundamentalist position nor one that favours “systemic directionality.” Rather, it points towards a largely directionless environment where market-state entanglements arise through a polycentric evolutionism at multiple different scales
Marketing Education in the Age of Generative AI:Preparing Graduates for Human–AI Collaboration
Get PDFThis white paper provides strategic guidance for marketing educators and programme leaders navigating the integration of Generative AI in higher education. Drawing on survey evidence from marketing academics and contributions from international experts, it examines implications for curriculum design, pedagogy, assessment, employability, and institutional governance. The report argues for a shift from output-focused learning to judgement-led, accountable human–AI collaboration, offering evidence-informed priorities and practical frameworks to support ethical, inclusive, and professionally relevant marketing education
Sotrovimab versus usual care in patients admitted to hospital with COVID-19 (RECOVERY):a randomised, controlled, open-label, platform trial
Get PDFBackgroundSotrovimab is a neutralising monoclonal antibody targeting the SARS-CoV-2 spike protein. We aimed to evaluate the efficacy and safety of sotrovimab in the RECOVERY trial, an investigator-initiated, individually randomised, controlled, open-label, adaptive platform trial testing treatments for patients admitted to hospital with COVID-19.MethodsPatients admitted with COVID-19 pneumonia to 107 UK hospitals were randomly assigned (1:1) to either usual care alone or usual care plus a single 1 g infusion of sotrovimab, using web-based unstratified randomisation. Participants were eligible if they were aged at least 18 years, or aged 12–17 years if weighing at least 40kg, and had confirmed COVID-19 pneumonia with no medical history that would put them at significant risk if they participated in the trial. Participants were retrospectively categorised as having a high antigen level if baseline serum SARS-CoV-2 nucleocapsid antigen was above the median concentration (the prespecified primary efficacy population), otherwise they were categorised as having a low antigen level. The primary outcome was 28-day mortality assessed by intention to treat. Safety outcomes were assessed among all participants, regardless of antigen level. Recruitment closed on March 31, 2024, when funding ended. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).FindingsFrom Jan 4, 2022, to March 19, 2024, 1723 patients were enrolled in the RECOVERY sotrovimab comparison. Of these, 828 (48%) were assigned to usual care plus sotrovimab and 895 (52%) were assigned to usual care only. Mean patient age was 70·7 years (SD 14·8) and 1033 (60%) were male. 720 (42%) patients were classified as having a high antigen level, 717 (42%) as having a low antigen level, and 286 (17%) had unknown antigen status. 1389 (81%) patients were vaccinated, 1179 (82%) of 1438 patients with known serostatus had anti-spike antibodies at randomisation, and 1021 (>99%) of 1026 patients with sequenced samples were infected with omicron variants. Among patients with a high antigen level, 82 (23%) of 355 assigned to sotrovimab versus 106 (29%) of 365 assigned usual care died within 28 days (rate ratio 0·75, 95% CI 0·56–0·99; p=0·046). In an analysis of all randomly assigned patients (regardless of antigen status), 177 (21%) of 828 patients assigned to sotrovimab versus 201 (22%) of 895 assigned to usual care died within 28 days (0·95, 0·77–1·16; p=0·60). Infusion reactions were recorded in 12 (2%) of 781 patients receiving sotrovimab. We found no difference between groups in any other safety outcome.InterpretationIn patients admitted to hospital with COVID-19 pneumonia, sotrovimab was associated with reduced mortality in the primary analysis population who had a high serum SARS-CoV-2 antigen concentration at baseline, but not in the overall population. Treatment options for patients admitted to hospital are limited, and mortality in those receiving current standard of care was high. The emergence of high-level resistance to sotrovimab among subsequent SARS-CoV-2 variants restricts its current usefulness, but these results indicate that targeted neutralising antibody therapy could potentially still benefit some patients admitted to hospital who are at high risk of death in an era of widespread vaccination and omicron infection.FundingUK Research and Innovation (Medical Research Council) and National Institute for Health and Care Research.<br/
Novel fully human IgG1 targeting folate receptor α demonstrates antitumor efficacy driven by avidity rather than monovalent binding affinity
No full textFolate receptor alpha (FRα), a membrane protein involved in folate transport, is a promising therapeutic target for ovarian cancer and other malignancies. The murine Monoclonal antibody (MAb) MOv19, developed in our lab, has pioneered the development of chimeric antibody-drug conjugates currently approved or in clinical trials for the treatment of FRα-positive cancers. To further reduce antibody’s immunogenicity, we engineered and characterized a new fully human IgG1 antibody (AFRA hIgG1) to FRα starting from MOv19. AFRA hIgG1 was constructed and characterized for binding affinity, specificity to purified FRα and various FRα-expressing tumor cells and ability to recruit effector cells in vitro in comparison to the chimeric version of MOv19 (ChiMOv19). AFRA hIgG1 and ChiMOv19 have comparable functional affinities being 10−9 M and 10−10 M, respectively although AFRA hIgG1 has an intrinsic constant affinity 103 lower than that of ChiMOv19, 2.6 × 10−7 M vs. 3.5 × 10−10 M, respectively. Furthermore, AFRA hIgG1 demonstrated a better binding kinetic with an overall efficacy comparable to ChiMOv19 in recruiting effector cell functions. These findings highlight that functional affinity, rather than intrinsic affinity, is a key determinant of biological response. AFRA hIgG1 shows promise as a biologic agent for the treatment of FRα-positive cancers.</p
A novel inhibitor of soluble epoxide hydrolase that adducts C521 is cardioprotective
Get PDFThe lipid electrophile nitro-oleic acid (NO2-OA) and inhibitors of soluble epoxide hydrolase (sEH) limit injury during myocardial ischemia and reperfusion (IR). We investigated if cardioprotection by NO2-OA was mediated by inhibitory adduction of this electrophile to C521 of the hydrolase. Indeed, administering NO2-OA to wild type (WT) isolated perfused hearts prior to IR limited infarction, but this protection was absent in C521S sEH knock-in (KI) mice - demonstrating the critical importance of this cysteine. To identify more potent and selective inhibitors, we screened a library of electrophiles for their ability to inhibit sEH. A compound, we termed RLC14, had an IC50 of 6.8x10−9 M and protected WT, but not KI, isolated hearts from infarction during IR. Systemic administration of RLC14 decreased myocardial sEH activity and increased plasma EET/DHET ratio selectively in WT mice, consistent with inhibition of the hydrolase. In line with these findings, RLC14 protected WT, but not KI, mice from in vivo coronary artery ligation IR-induced infarction. Mass spectrometry analyses showed the novel electrophilic inhibitor, RLC14, which contains a disulfide, adducts to C521 in sEH to mediate its effects. This study identifies RLC14 as a potent cardioprotective agent that limits IR injury through C521-dependent hydrolase inhibition.</p
Rheumatologist and patient perspectives on axial spondyloarthritis management and treatment satisfaction in Europe
Get PDFObjective: To investigate the characteristics of axial spondyloarthritis (axSpA) and understand rheumatologists’ and patients’ experiences of axSpA management in a large real-world population using data from a cross-sectional survey. Methods: Rheumatologists recruited from France, Germany, Italy, Spain, and the UK completed surveys for their next eight consulting adult patients with axSpA. The same patients were asked to voluntarily complete a survey, allowing rheumatologist- and patient-reported responses to be matched and compared. Surveys covered clinical status, symptoms and treatment decisions, preferences, and satisfaction. Results: Between June 2023 and June 2024, 268 rheumatologists provided data on 2165 patients, 538 of whom completed the survey. At the time of the survey, patients continued to experience symptoms of axSpA (morning stiffness [35 %], inflammatory back, hip, or buttock pain [25 %], and fatigue [25 %]), despite 77 % having received disease-modifying advanced therapy. There was moderate agreement between patients and their rheumatologists on disease severity (86 % weighted agreement at the time of the survey, κ=0.515) and on their satisfaction with current treatment. The most common treatment target for rheumatologists was to achieve low disease activity (76 %), while the most common target for patients was to alleviate pain (61 %). Rheumatologists highlighted lack of efficacy, pain control, and flare control, and residual fatigue as reasons for treatment dissatisfaction. Conclusion: Patients and their rheumatologists were moderately aligned on their perception of disease severity and treatment satisfaction but differed in their expectations regarding treatment target. The study highlights the need for ongoing involvement of patients in discussions and decisions about axSpA management.</p
Deep generative computed perfusion-deficit mapping of ischaemic stroke
Get PDFFocal deficits in ischaemic stroke arise primarily from impaired perfusion downstream of a critical vascular occlusion. Though the consequent parenchymal lesion is traditionally used to predict clinical deficits, the underlying pattern of disrupted perfusion provides information upstream of the lesion, potentially yielding earlier predictive and localising signals. We previously developed a technique to compute perfusion maps from routine CT and CT angiography (CTA), an imaging modality widely deployed in clinical practice and available at large data scales. Analysing computed perfusion maps (derived from CT and CTA) from 1393 CTA-imaged patients with confirmed acute ischaemic stroke, here we use deep generative perfusion-deficit inference to localise the neural substrates of NIHSS sub-scores, explicitly disentangling the distinct topologies of disrupted perfusion and neural dependence. We show that our approach replicates known lesion-deficit relations without knowledge of the lesion itself and reveals novel neural dependents. The high achieved anatomical fidelity suggests acute CTA-derived computed perfusion maps may be of substantial clinical and scientific value in rich phenotyping of acute stroke. By relying only on an imaging modality well-established in the hyperacute setting, deep generative perfusion-deficit inference could power highly expressive models of functional anatomical relations in ischaemic stroke within the critical pre-interventional window
Key performance indicators in Elite Male Blind and Partially Sighted Football
Get PDFMale footballers with vision impairment (VI) compete in two adapted forms of futsal: (1) blind football, where players wear eyeshades and, at best, can perceive light; (2) partially sighted football, where individuals use their remaining sight. Currently, the key performance indicators (KPI) for both formats are unknown. This study aimed to identify the KPIs for male blind and partially sighted football. A total of 54 matches involving male footballers with a VI were analysed; 39 matches were played in the blind football competition and 15 were played in the partially sighted competition; each was analysed separately. Match footage was uploaded to an online performance analysis platform, where each game was tracked to acquire notational match data. Variables that were significantly correlated with dependent variables (win ratio, goal scored and goals conceded) were retained for linear mixed models, which were built to identify KPIs. Male blind football: Passing efficiency (β=0.0046, p<0.001), offensive zone entries (β=0.0044, p<0.001) and possession (β=0.0032, p=0.0044) positively impacted a team’s win ratio. The number of VI players fielded was positively related to the number of goals scored (β=0.2058, p<0.001) and negatively related to goals conceded (β=-0.1447, p=0.001). A possession-based strategy with efficient passing contributed to better performance; this strategy likely creates challenging conditions for the opposition when attempting to orient and track the location of the ball. Partially sighted football: the number of VI players fielded significantly predicted win ratio (β=0.0353, p<0.001), goals scored (β=0.8127, p<0.001) and conceded (β=-0.5800, p<0.001). Goals scored were positively impacted by passing efficiency (β=0.1992, p<0.001) and negatively impacted by possession (β=-0.0963, p<0.001). This indicates that a counterattacking style is favourable, whilst highlighting the importance of quick transitions and direct offensive actions. Interestingly, different KPIs were highlighted for each version of the sport, evidencing unique technical and tactical demands
A Novel Non-Contact Failure Detection Method for Vehicle-Mounted HTS Bulks Based on Null-Flux Coils: Scheme, Theory, and Experiment
Get PDFHigh-temperature superconducting (HTS) pinning maglev technology is considered promising for high-speed transportation due to its self-stabilizing characteristics, and it has been widely studied worldwide. In high-speed engineering applications, safety is a primary concern, largely dependent on the reliable flux-pinning capability of the onboard superconductors. This paper proposes a non-contact, non-destructive, and easy-to-implement real-time monitoring method for assessing the flux-pinning state of HTS bulks onboard maglev vehicles, based on the anti-symmetric property of null-flux coils. The configuration, working principle, and mathematical model of the method are established, along with a coil geometry optimization strategy and a tailored low-frequency, narrow-band filtering circuit. An experimental setup is then built based on the optimized parameters, and a series of tests are performed to the method's feasibility. Furthermore, the effectiveness of the resonance-frequency-based filtering circuit in enhancing signal extraction is analyzed, and theoretical predictions of the relationship between the voltage signal and factors such as displacement, working height, and degradation level are validated experimentally. This study provides a comprehensive investigation from concept to validation and demonstrates strong potential for real-time safety monitoring in HTS maglev systems. It can also offer useful insights for other superconducting or maglev monitoring applications