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A tumour-derived organoid biobank defines a functional map of gene dependencies
No full textCancer cell lines remain foundational for research and drug discovery, yet they incompletely capture tumour diversity, lack linked patient context, and have undergone
adaptation to culture. Tumour organoids are three-dimensional cultures derived from patient tissue, offering a powerful complement to cell lines. Here we derived and characterised 256 clinically annotated tumour organoids directly from colorectal, oesophageal, ovarian, pancreatic, and gastric cancers as renewable, genetically stable models. Extensive characterisation of each model and matched patient tumour sample included whole-genome and transcriptome sequencing, while genome-wide CRISPR–Cas9 screens across 164 organoids mapped gene dependencies. Integrative analyses revealed genomic and clinical markers of dependency across common and rare
subtypes, identified organoid-specific essential genes, and illuminated targetable vulnerabilities following tumour evolution in paired pre- and post-treatment samples. In colorectal cancer, functional and pharmacological interrogation of the EGFR–RAS–MAPK axis uncovered differential effects of KRAS variant alleles. This new open,
publicly available resource provides the first systematic map of gene dependencies in patient-derived organoids, expanding the model diversity and mechanistic insight needed to advance precision oncology
Climate change and its impact on the Antarctic Peninsula
No full textThe Antarctic Peninsula, part of the British Antarctic Territory, is a global biodiversity hotspot, and a focus of tourism, scientific and fishing operations. The region is warming rapidly, at up to two times the global rate of 0.27°C per decade.
This Policy Brief presents the key findings of research into the threats posed to the Peninsula under three global warming scenarios. It provides a vital update to research published in 2019 that examined the impacts of warming limited to 1.5°C, a scenario that is now unachievable
Development of the antimicrobial resistance burden score through a modified eDelphi
No full textCurrent antimicrobial resistance (AMR) surveillance relies on fragmented indicators that fail to capture institutional AMR burden complexity. To develop the AMR Burden Score, a three-round modified eDelphi study engaged interdisciplinary experts (Round 1: n=17, Rounds 2 and 3: n=7) including clinicians, microbiologists, pharmacists, health economists, and public health specialists. The AMR Burden Score comprises six weighted domains: Resistance (25%), Effectiveness (30%), Monitoring (30%), Adoption (5%), Processes (5%), and Systems (5%). Strong consensus emerged for core indicators including incidence of resistant infections (unanimous Round 3 agreement, median 8.0), pathogen-specific resistance rates (median 7.0), and staff training programs (median 8.0). The AMR Burden Score provides a structured framework for institutional AMR assessment, though implementation requires context-specific adaptation and further validation
Prednisolone once daily vs hydrocortisone thrice daily in hypoadrenalism: a randomized controlled trial
No full textImportance: Adrenal insufficiency (AI) is conventionally treated with daily multiple-dose hydrocortisone. Once-daily low-dose prednisolone is an alternative for glucocorticoid replacement. This is the first ever clinical trial comparing once daily low-dose prednisolone with thrice-daily hydrocortisone.
Objective: We investigate differences in metabolism and bone turnover with this comparative study of hydrocortisone versus prednisolone.
Design, Setting and Participants: This double-blind randomised crossover trial of multiple-dose daily hydrocortisone versus once-daily low-dose prednisolone (2-5 mg), between September 2019 and December 2023, involved adults with AI. Anthropometrics, biochemical data for cardiometabolic and bone health, and subjective health survey data were collected at Day 1, 30 and 120 of each study period, on both medications.
Intervention: Individuals were randomised to four months of once-daily prednisolone in the morning (placebos at noon and afternoon), or hydrocortisone at the same times. All participants were crossed over to the alternative treatment for a further four months.
Main Outcome and Measures: The primary outcome was assessment of bone turnover, detected by change in carboxylated and under-carboxylated osteocalcin between Day 1 and Day 120 in each treatment period.
Results: Forty-seven participants were randomised, 24 receiving prednisolone first and 23 for hydrocortisone first. Body weight fell by -1.04 kg [95%-CI -1.88 to -0.21] on prednisolone compared to an increase of 0.83 kg [-0.01 to 1.66] with hydrocortisone (treatment difference -1.87 kg, p=0.002). Waist circumference fell by -1.1 cm [95%-CI -2.4 to 0.1] on prednisolone and rose by 1.1 cm [95%-CI -0.1 to 2.4] on hydrocortisone (treatment difference -2.26 cm, p=0.01). HbA1c fell by -0.7 mmol/mol [95%-CI -1.2 to -0.2] on prednisolone and increased by 0.6 mmol/mol [95%-CI 0.1 to 1.1] on hydrocortisone (treatment difference -1.23 mmol/mol; p=0.001). Bone formation and resorption markers including osteocalcin, P1NP and urinary NTX were significantly lower on prednisolone compared to hydrocortisone. There were no differences in safety measures, or subjective health outcomes, including all SF36 domains and Addi-QoL questionnaire.
Conclusions and Relevance:
In this randomized clinical trial, once-daily low-dose prednisolone was associated with improvements in cardiometabolic health markers, in comparison to multiple-dose hydrocortisone, without compromising well-being. Studies assessing longer term mortality and morbidity outcomes are needed
In-Situ Raman Measurements of Fuel Dilution of Lubricant Films in a Direct-Injection Spark-Ignition Engine
No full textTo measure the fuel proportion within the lubricant film, an in-situ Raman spectroscopy technique was employed in a specially modified single-cylinder direct-injection spark-ignition engine. The engine block was engineered for optical access with a fused silica window, enabling a focused laser beam to probe the lubricant film on the engine liner under motoring conditions. The lubricant used was GTL8 base oil with ZDDP additive, and iso-octane was injected as a model fuel to study fuel-lubricant mixing. A calibration curve was established by recording Raman spectra of known mixtures of GTL8 oil and iso-octane. The Raman intensity ratio of the iso-octane peak to the oil peak was used as a quantitative indicator of fuel concentration. During engine operation, Raman spectra were acquired in real time, on a cycle-by-cycle basis, through the optical window. Upon iso-octane injection, its characteristic Raman peak appeared in the spectrum, and the intensity ratio was referenced against the calibration curve to estimate the fuel proportion within the lubricant film. Experimental results demonstrated that the iso-octane signal could be detected during and after injection and this allowed for real-time monitoring of fuel dilution dynamics. The main challenge encountered was high fluorescence from oil, which sometimes obscured the Raman peaks and complicated quantification. Despite this, the technique successfully demonstrated the feasibility of direct, in-situ, and real-time quantification of fuel dilution in engine lubricant films, providing a valuable tool for studying fuel-lubricant interactions under operating engine conditions
Three-dimensional analysis of interbody cage-apophyseal ring contact to predict endplate subsidence following transforaminal interbody fusion
No full textBackground
There is a higher risk of subsidence following transforaminal lumbar interbody fusion (TLIF) relative to other approaches. Decreased subsidence risk is associated with anterior cage placement, speculated to be because of increased apophyseal ring contact. However, this hypothesis is largely based on in vitro evidence and, to date, has not been investigated in a clinical cohort.
Methods
Pre-operative and post-operative computed tomography (CT) images from 42 TLIF patients were used to segment the endplate and cages. The apophyseal ring boundary was manually landmarked for each endplate. The pre-operative endplates were rigidly registered with the post-operative cage position, and an iterative closest point approach was used to calculate the contact area between the cage, apophyseal ring, and endplate. Subsidence was categorised based on severity (No Subsidence: <2 mm; Moderate Subsidence: 2-4 mm; Severe Subsidence: ≥4 mm) from post-operative CT.
Findings
Apophyseal ring contact was significantly lower in both Moderate and Severe Subsidence, relative to No Subsidence (Moderate: −19.6 ± 7.0%; Severe: −21.5 ± 6.5%; P < 0.05), and negatively correlated with subsidence depth (P < 0.05). Injury risk analysis demonstrated that a 50% subsidence risk was associated with 45.7% (38.4–53.6%) apophyseal ring contact. Suprajacent endplate apophyseal ring contact, but not subjacent, was significantly predictive of subsidence at the respective endplate (P < 0.05).
Interpretation
The risk of subsidence in TLIF patients can be mitigated by ensuring that at least half of the interbody cage surface area is in contact with the peripheral endplate rim, particularly at the endplate superior to the cage
The climate opportunities and risks of contrail avoidance
No full textNavigational contrail avoidance presents an opportunity for rapid reduction in aviation-attributable warming. Here, we use the Aviation Climate and Air Quality Impacts model to evaluate the global temperature changes associated with contrail avoidance towards 2050. If no avoidance is adopted, aviation is projected to contribute 0.040 K of CO2 warming and 0.054 K of contrail warming by 2050. The combined warming from aviation CO2 and contrails is 19% of the difference between current temperatures and the +2 °C limit above pre-Industrial levels, i.e. 19% of our remaining temperature budget. An avoidance strategy phased in over 2035-2045 may recover 9% of this budget, but a 10-year delay may reduce this to 2%. The warming due to additional CO2 emitted during avoidance is two orders of magnitude lower than the expected contrail warming reduction. For every year of delay, the world will be on average 0.003 K hotter in 2050. The most significant climate risk associated with contrail avoidance is therefore inaction
Representation learning for human sensing with WiFi channel state information
No full textHuman sensing with radio signals has emerged as a less-intrusive and environment-robust alternative to approaches based on on-body sensors or cameras, and WiFi signals further support device-free detection without the need for dedicated hardware. Specifically, Channel State Information (CSI) monitors WiFi signal variations caused by human interference and accordingly contains useful features for human sensing. Since useful features in CSI are not explicit and typically intertwine with excessive noise, considerable efforts have been devoted to representation learning for implicit human features from CSI. However, several practical challenges still undermine the representation learning with WiFi CSI, such as incomplete CSI samples, multi-user activity sensing, the scarcity of fine-grained labels, and cross-domain human sensing. To tackle incomplete CSI samples, this thesis proposes DiffAR, a temporal-augmented approach to augment CSI samples with diffusion models for advanced WiFi-based human sensing. Considering that most existing methods, including DiffAR, focus on single-user activity sensing due to the lack of multi-user datasets, this thesis constructs the first WiFi-based multi-user activity sensing dataset, WiMANS, posing new challenges while opening up opportunities for future research. According to experiments on WiMANS, the scarcity of fine-grained labels hampers representation learning in multi-user scenarios, and thus this thesis devises CrossAR, a WiFi-Vision approach that adopts unlabeled CSI and auxiliary labels from pre-trained vision models to extract informative features through cross-modal contrastive learning. Despite the above significant progress, cross-domain human sensing with WiFi CSI is still challenging, especially for human pose estimation of which the latest methods are limited to single domains and fall short in cross-subject/environment scenarios, owing to domain-specific confounders. To eliminate these confounders, this thesis presents GenHPE, which formulates generative counterfactuals for domain-independent representation learning with WiFi CSI. Overall, this thesis discusses and handles practical challenges in representation learning with CSI, contributing to more effective and efficient WiFi-based human sensing.Open Acces
Glacial meltwater impacts marine carbonate chemistry on Iceland's continental shelf
No full textIncreased meltwater runoff from glaciers may drive localized ocean acidification and impact carbon dioxide (CO2) uptake in the coastal ocean. However, the paucity of carbonate system observations from continental shelves receiving inputs from glaciers limits our understanding of cryosphere-ocean connectivity. Here, we contrast meltwater impacts on seawater carbonate chemistry and stable isotopes (δ13C-DIC) off marine- and land-terminating glacier outflows off Iceland. On the shelf outside a marine-terminating glacier, glacial meltwater reduced the seawater buffer capacity of receiving surface waters through dilution of total alkalinity, and increased CO2 uptake through salinity-driven drawdown of pCO2. Primary production acted as a counterbalance to the lowered [TA-DIC]. On the shelf area receiving meltwater from large glacial river deltas, CO2 uptake was almost halved and the saturation state of aragonite was 0.2 units lower than on the marine-terminating glacier shelf. Reduced net autotrophy due to higher turbidity and upwelling of low-pH deep waters off the delta-dominated shelf likely explain those differences. The diverging carbonate dynamics on the two shelves build on previous observations that land-terminating glaciers can reduce the buffer capacity as well as CO2 uptake potential of nearshore surface waters in comparison to marine-terminating glaciers. The future retreat of many marine-terminating glaciers onto land is likely to modify how meltwater will impact coastal seawater carbonate chemistry
Understanding congestion in airport surface operations using 3D fundamental diagrams
No full textOperational delays that arise when demand on the airport surface approaches or exceeds its capacity adversely impact passengers, airports, and the environment. To design effective interventions to manage airport surface congestion, airport operators require a robust understanding of the technology that drives congestion on the airport surface, that is, how delays on the airport surface vary over capacity utilization of its bottlenecks. Theoretical models of congestion technology (CT) exist, however, they are defined for ideal conditions, for instance, by assuming demand being independent of airport surface congestion, thus failing to characterize the realized airport surface operations. The availability of highly granular data on day-to-day surface operations facilitates the development of practically relevant models of congestion that are reproducible under wide-ranging operational scenarios. Nevertheless, obtaining empirical estimates of the CT from observed data on airport operations is challenging due to statistical biases that emerge via the complex interactions between air traffic operations and control at airports and in the wider airspace. In this study, we propose a novel causal statistical approach to model airport surface congestion, represented via delay versus runway and ground capacity utilization relationships, henceforth Three-Dimensional Fundamental Diagrams (3D-FDs). The proposed approach allows us to capture inherent non-linearities in the relationship while addressing the aforementioned confounding biases. Accordingly, we model the 3D-FDs of five major global airports and deliver key new insights into their surface-use efficiency, for instance, by locating their optimum operating point, that is, the point beyond which delays increase at an increasing rate with the intensity of use