Enhancing anti-CTLA-4 antibody delivery to the brain using focused ultrasound and microbubbles

Introduction Gliomas, particularly glioblastomas, are characterised by their poor prognosis and low patient survival rate. Cytotoxic T lymphocyte-associated antigen-4 antibodies, a type of immune checkpoint inhibitors, have shown promise as an effective treatment strategy against the most aggressive tumour cells within the microenvironment of gliomas. However, their delivery to the brain is hindered by the impermeable blood-brain barrier, which is leaky in a heterogenous way, leading to uneven drug distribution across the tumours. Focused ultrasound, combined with intravenously administered microbubbles, is a technique that can non-invasively, safely, and reversibly increase the permeability of the blood-brain barrier in a targeted area, promoting the delivery of therapeutics, such as immune checkpoint inhibitors, to inaccessible tumour areas, to prevent tumour relapse. Methods We applied two different types of focused ultrasound sequences (long pulses vs rapid short-pulses) with microbubbles to the left hippocampus of wild-type female C57BL/6 mice before administering a fluorescently labelled cytotoxic T lymphocyte-associated antigen-4 antibody. Results We determined that the targeted brain region had a significant (p < 0.0001) increase in antibody delivery following ultrasound treatment with both pulse sequences. A more uniform delivery was achieved when treating with rapid short-pulse sequences, where bursts of short 5 µs pulses of focused ultrasound were emitted at a fast repetition frequency (1.25 kHz). We observed a significant increase in anti-tumour immune cells in long-pulse treated brains. Conclusion These results provide a proof-of-principle for how focused ultrasound with microbubbles can promote homogenous anti-tumour drug delivery and modulate the immune microenvironment

Seismological characterization of northern Hikurangi margin slow slip regions associated with normal faults, seamounts and seeps

At the northern Hikurangi margin, Aotearoa New Zealand, slow slip events (SSEs) recur every 6–24 months to ∼30 km depth. Although shallow SSEs (0–10 km) are well-studied offshore, the deeper portion (10–30 km) remains poorly understood, limiting insight into SSE initiation. Here we investigate this deeper region and examine relationships between newly resolved SSEs and seismicity. Using time-dependent inversions, we resolve two small SSEs (MW 6.2 and 6.4), including one that extends from 15 to 30 km depth. Using data from a dense onshore seismograph network deployed directly above this deeper portion from December 2017 to October 2018, we construct a catalog of 3,071 high-quality earthquakes with hypocentral uncertainties ≤5 km, located with a 3-D velocity model and a new 1-D model. Earthquake magnitudes range from -0.84 to 4.40, with a completeness magnitude of 1.7 and a b-value of 1.06. Focal mechanisms reveal numerous normal-faulting earthquakes, including some within the slab mantle. Vertically-aligned seismicity and normal-faulting earthquakes outline pathways linking the slab mantle to surface seeps of mantle-derived fluids. We infer that normal faults form due to slab bending and localized uplift of subducting seamounts, which roughen the plate interface, damage the upper plate, and promote fluid migration. Land-ward of ∼100 km from the trench, both surface seeps and normal-faulting mechanisms ceasecoinciding with the downdip limit of shallow SSEs. Together, these results suggest that the Hikurangi margin’s rough subducting plate interface exerts strong control on forearc dewatering and SSE genesis

The magnetic signature of stress in rocks

Magnetic signatures preserved in rocks have long provided insight into Earth’s evolution, revealing processes from plate tectonics to the habitability of Earth. While large impacts are known to impose extreme stresses (>1 GPa) and heat that fundamentally alters magnetic records, lower stresses typical of earthquakes have been considered magnetically undetectable. 2We show that magnetic responses to sub-GPa stresses can be precisely calibrated, enabling three-dimensional paleostress reconstructions in rocks – even stresses of just a few MPa can fully reset magnetic signals without heat or deformation. This newly revealed magnetic sensitivity to stress opens a powerful, non-destructive pathway to detecting paleostress fields in the elastic crust, offering new opportunities for improving seismic hazard assessment, interpreting impact processes, and re-evaluating magnetic records across Earth and Planetary sciences

Lung capacity is a determinant of cardiovascular disease and myocardial infarction

Introduction: There is growing evidence suggesting that lung capacity is associated with risk of cardiometabolic disease. However, most studies rely on spirometric measures of lung capacity and self-reported cardiometabolic disease. We aimed to investigate the association of total lung capacity (TLC) with cardiometabolic disease defined using ICD-10 codes. Methods: Data from adult patients referred to Cambridge University Hospitals between 2016 and 2024 were used if spirometry, single breath gas transfer, and body plethysmography were performed in the same session. GLI reference equations were used to generate z-scores for lung function measures. ICD-10 codes for cardiovascular disease, hypertension, and diabetes were extracted from medical records. We used multi-level (mixed-effects) Cox regression analysis to investigate the association between lung function measurements and incident cardiometabolic disease. Results: 5628 patients were included, 51% were female, with a median age of 62 (IQR 50-70) years. 60% reported a smoking history. Mean follow-up time was 5.7 (SD 2.3) years, during which time 5% received a cardiovascular disease code, 7% a hypertension code, and 3% a diabetes code. A 1-unit increment in TLC z-score was associated with a 12% lower risk of cardiovascular disease (HR: 0.88, 95%CI 0.80-0.97) later in life. The same was seen for FVC (HR: 0.88, 95%CI 0.77-0.99) but not FEV1/FVC or DLCO. A larger TLC was also associated with lower risk of myocardial infarction. We found no association of lung function measures with incident hypertension or diabetes. Conclusion: Lung capacity is a determinant for cardiovascular disease and myocardial infarction, with larger lungs being protective. TLC and FVC should be considered by clinicians along with other factors, when evaluating a person’s risk of cardiovascular disease

Multidisciplinary team–guided management of severe aortic stenosis: five-year outcomes following TAVI versus conservative treatment

Objective: Multidisciplinary team (MDT) meetings are central to treatment decisions in aortic stenosis (AS), particularly for borderline or high-risk patients. This study evaluates long-term, real-world outcomes according to MDT selected management strategy within routine clinical practice in this clinically important patient group. Methods: We conducted a retrospective cohort study of all patients with severe AS discussed at a TAVI MDT at a tertiary UK centre between January 2014 and December 2016. Patients were categorised as TAVI or non-TAVI (conservatively managed). Demographic, clinical, and frailty data were collected, including Charlson Comorbidity Index (CCI), Clinical Frailty Scale (CFS), and number of prescribed medications. Survival was analysed using Kaplan–Meier estimates and Cox proportional hazards modelling adjusted for age, sex, frailty, comorbidity burden, and medication count. Results: A total of 373 patients were included (TAVI = 178; non-TAVI = 195). Patients undergoing TAVI were younger (81.3 vs 83.5 years; p = 0.01) and less frail (CFS 3.9 vs 4.9; p < 0.01). Survival at one, two, and five years was significantly higher following TAVI (87.6%, 74.7%, 44.9%) compared with conservative management (60.8%, 44.2%, 12.1%; p <0.001). Median survival was 53 months after TAVI versus 20 months without intervention. On multivariable analysis, TAVI was independently associated with reduced mortality (HR 0.38, 95% CI 0.28–0.50; p <0.001). Conclusions: In patients with severe AS discussed at MDT, TAVI was associated with a substantial and durable survival advantage compared with conservative management. These findings highlight the poor prognosis of untreated severe AS and support systematic inclusion of conservatively managed patients in interventional registries to better inform MDT deliberation and shared decision-making

Integrated electrical connections in deployable composite tube flexures

This study extends the functionality of ultra-thin carbon fibre composite tube flexures by interleaving a multi-layered conductive film along the laminate’s midline to enable data and power transmission across the structural joint. Conductive tracks, created by silver nanoparticle deposition onto a polymide substrate, are encapsulated by a thermoplastic film to prevent short-circuits with the carbon fibres. The paper first establishes the mechanical stability of the integrated struc ture through analysis and testing, then investigates the electrical signal integrity and the feasibility of thermal actuation for a shape-memory use-case. Repeated moment-rotation tests showed a progressive reduction in locking moment. The conductive track remained functional, without showing an appreciable degra dation in signal quality or electrical resistance. Resistive heating tests reaching higher temperatures caused adhesive failure between the thermoplastic film and the tracks in the stowed state, leading to local delamination and catastrophic failure of the laminate. These findings demonstrate that novel inkjet-printed conductive interleaves are a viable solution for digital signal and low-power transfers in laboratory conditions, raising the challenge of extending testing to space-like environments and improving the bond strength of the silver tracks for enhanced thermal durability. This methodology represents a significant step forward in terms of structural power integration, enabling ultra-lightweight harnesses to be directly integrated within highly strained deployable members with applications on small and large satellites, as well as next generation space structures, such as space-based solar power stations

Coupled thermo-chemo-mechanical phase field-based modelling of hydrogen-assisted cracking in girth welds

A new computational framework is presented to predict the structural integrity of welds in hydrogen transmission pipelines. The framework combines: (i) a thermo-mechanical weld process model, and (ii) a coupled deformation-diffusion-fracture phase field-based model that accounts for plasticity and hydrogen trapping, considering multiple trap types, with stationary and evolving trap densities. This enables capturing, for the first time, the interplay between residual stresses, trap creation, hydrogen transport, and fracture. The computational framework is particularised and applied to the study of weld integrity in X80 pipeline steel. The focus is on girth welds, as they are more complex due to their multi-pass nature. The weld process model enables identifying the dimensions and characteristics of the three weld regions: base metal, heat-affected zone, and weld metal, and these are treated distinctively. This is followed by virtual fracture experiments, which reveal a very good agreement with laboratory studies. Then, weld pipeline integrity is assessed, estimating critical failure pressures for a wide range of scenarios. Of particular interest is to assess the structural integrity implications of welding defects present in existing natural gas pipelines under consideration for hydrogen transport: pores, lack of penetration, imperfections, lack of fusion, root contraction, and undercutting. The results obtained in hydrogen-containing environments reveal an important role of the weld microstructure and the detrimental effect of weld defects that are likely to be present in existing natural gas pipelines, as they are considered safe in gas pipeline standards

Fabrication method of directional microstructure for high energy density, high power battery cathodes

Rechargeable batteries have attracted significant attention for electric transportation and storage of intermittent renewable energy. Conventional slurry coating makes random electrode microstructure with tortuous ion diffusion pathways that restrict capacity. We present a novel directional ice templating (DIT) method of making ultra-high mass loading (70 mg cm−2) LiNi0.8Mn0.1Co0.1O2 cathodes containing engineered electrode/electrolyte interface and aligned, fast ion diffusion channels to break the conventional energy-power trade-off. We investigated the effects of calendering to reduce electrode porosity while maintaining the interfacial vertical microstructure. Our results show a critical threshold of 30% calendering degree that exhibits the optimal combination of gravimetric and volumetric energy density, fast (dis)charging, and long-term cycling stability. The porosity of the calendered DIT cathode is compatible with that of the conventional slurry coated cathodes, but exhibits significantly higher energy densities of 367 Wh kg−1 and 779 Wh L−1 when the (dis)charge current is increased to 7 mA cm−2 vs. 102 Wh kg−1 and 215 Wh L−1 for the slurry coated electrodes in pouch cells. Further, we built an electrode processing instrument to demonstrate the scalability of the aqueous DIT method. The developments demonstrate the feasibility of extending the DIT approach toward industrial-scale sustainable electrode manufacturing for efficient energy storage

Rotating night shifts and physical well-being in nurses: cross-sectional associations consistent with a sleep-quality pathway

Background: Rotating and night-including shifts disrupt circadian alignment, impair sleep, and may reduce nurses’ physiological recovery. Objectives: This study aimed (1) to compare sleep quality and physical well-being across four shift schedules among hospital nurses; and (2) to examine whether the association between rotating shifts and physical well-being was statistically consistent with an indirect association via sleep quality. Methods: In this cross-sectional study, 173 nurses from a ter-tiary hospital in Zagreb, Croatia, completed validated measures of sleep quality and physical well-being. Four shift patterns were analyzed—fixed morning, morning–afternoon, extended 12-h, and rotating three-shift—using Welch ANOVA and regression models. A bootstrapped mediation analysis (10,000 resamples; BCa method), interpreted as a statistical decomposition, estimated an indirect association consistent with sleep quality. Results: Rotating-shift nurses reported the poorest sleep (PSQI = 10.2 ± 2.6; p = 0.003). Physical well-being did not differ significantly across shift types (p = 0.08), although rotating-shift nurses had the lowest mean physical scores (24.3 ± 4.4). The rotat-ing-shift subgroup was small (n = 16), limiting precision. The mediation analysis was statistically consistent with an indirect association between rotating shifts and physical well-being via sleep quality (ACME = −1.85, 95% CI −3.05 to −0.88; p < 0.001), while the proportion of the total association was imprecisely estimated. Conclusions: In this single-site cross-sectional sample, rotating night shifts were associated with poorer sleep and, on average, lower physical well-being; patterns were statistically consistent with an indirect association via sleep quality. Because exposure, mediator, and outcome were measured concurrently, these findings are hypothesis-generating and do not estab-lish causality

Greening Lean: overcoming barriers to integrating environmental practices in surgical Lean management projects: a scoping review

Background Surgical practices generate the largest share of hospital waste and significantly contribute to NHS carbon emissions, highlighting the need for sustainable interventions. Lean management, which optimises efficiency and reduces waste, offers a pathway to address these concerns. However, its application in surgical settings remains fragmented and under-researched. This review explores how Lean methodologies can improve environmental outcomes in surgery and identifies systemic barriers to their implementation. Methods A scoping review of five databases (MEDLINE, EMBASE, SCOPUS, EBSCO, and Cochrane) and grey literature, following PRISMA-P protocols, yielded 24 academic and 13 grey literature sources from 5,011 search results. Quality assessment was performed using validated tools, and thematic analysis was applied to synthesise data and identify key challenges and opportunities. Results The review found limited evidence quantifying environmental benefits of Lean practices, including waste reduction, lower carbon emissions, and decreased energy consumption. 11 articles demonstrated quantifiable environmental outcomes, primarily in hand surgery and anaesthesia. Potential environmental benefits included waste reduction, nitrous oxide cylinder turnover minimisation, decreased carbon footprint, and reduction in anaesthetic use. Overall, four primary barriers were identified: lack of responsibility ownership, overly hierarchical organisational structures, collaboration challenges, and limited education and awareness. Conclusion As healthcare systems progress toward Net Zero targets, Lean management offers potential for simultaneous environmental and operational improvements. However, their successful application is hindered by significant barriers. Targeted educational initiatives, interdepartmental collaboration with aligned sustainable goals, and strategic support are crucial for successfully embedding environmental sustainability within surgery