King's College London
  • London, United Kingdom
Recent publications
Atrial fibrillation (AF), impacting nearly 50 million individuals globally, is a major contributor to ischaemic strokes, predominantly originating from the left atrial appendage (LAA). Current clinical scores like CHA₂DS₂-VASc, while useful, provide limited insight into the pro-thrombotic mechanisms of Virchow's triad—blood stasis, endothelial damage, and hypercoagulability. This study leverages biophysical computational modelling to deepen our understanding of thrombogenesis in AF patients. Utilising high temporal resolution Cine magnetic resonance imaging (MRI), a 3D patient-specific modelling pipeline for simulating patient-specific flow in the left atrium was developed. This computational fluid dynamics (CFD) approach was coupled with reaction-diffusion-convection equations for key clotting proteins, leading to an innovative risk stratification score that combines clinical and modelling data. This approach categorises thrombogenic risk into low (A), moderate (B), and high (C) levels. Applied to a cohort of nine patients, pre- and post-catheter ablation therapy, this approach generates novel risk scores of thrombus formation, which are based of mechanistic characterisation of all aspects of the Virchow's triad. Currently, thrombogenesis mechanisms are not factored in widespread clinical risks scores based on demographic characteristics and co-morbidities. Notably, some patients with a CHA₂DS₂-VASc score of 0 (lowest clinical risk) exhibited much higher risks once the individual pathophysiology was accounted for. This discrepancy highlights the limitations of the CHA₂DS₂-VASc score in providing detailed mechanistic insights into patient-specific thrombogenic risk. This work introduces a comprehensive method for assessing thrombus formation risks in AF patients, emphasising the value of integrating biophysical modelling with clinical scores to enhance personalised stroke prevention strategies.
Ice nucleation and growth are critical in many fields, including atmospheric science, cryobiology, and aviation. However, understanding the detailed mechanisms of ice crystal growth remains challenging. In this work, crystallization at the ice/quasi-liquid layer (QLL) interface of the basal and primary prism (prism1) surfaces of hexagonal ice (Ih) was investigated using molecular dynamics simulations across a wide range of temperatures for the TIP4P/Ice model, with comparisons to the mW coarse-grained model. Together with elucidating the temperature-dependent mechanisms of crystallization, face-specific growth rates were systematically estimated. While the prism surface generally exhibits faster growth rates than the basal surface, a temperature-dependent crossover in growth rates between the basal and prism surfaces is observed in TIP4P/Ice simulations, which correlates with crossovers in QLL thickness and properties and with the well-known column to platelets transition in ice-crystal habits at low vapor pressure. This observation helps decode the complex dependence between crystal morphology and temperature in ice crystals.
Background: Post-viral issues following acute infection with coronavirus disease 2019 (COVID-19), referred to widely as long COVID, are associated with episodic, persistent, and disabling symptoms affecting quality of life and functional status. Evidence demonstrates a significant impairment and long disease course, but there remains limited empirical data to profile and determine the fluctuating symptom profile of long COVID. Methods: We devised a 16-week, multicentre prospective cohort observation study to profile changes in patient-reported outcomes, and biological, physiological, psychological, and cognitive parameters following diagnosis and/or referral to an established long COVID clinic. Following baseline assessments, participants completed four face-to-face visits interspersed with telephone consultations. Face-to-face visits included physiological assessment, patient-reported outcome measures (PROMs), functional status, and respiratory function. Telephone consultations involved PROMs and symptom profiling. Results: Patient-reported outcomes improved from baseline to week sixteen, but demonstrated between visit fluctuations in frequency and severity. Further findings highlight the severity and frequency of long COVID symptom profiles and the extent of quality of life and functional status impairment. Conclusions: The data presented here highlight the episodic and relapsing nature and should be used to help characterise long COVID disability. They can inform the development of long COVID-specific guidelines and support services that can adequately respond to the reductions in patient well-being.
Assessing and quantifying recruitability are important for characterizing ARDS severity and for reducing or preventing the atelectrauma caused by the cyclic opening and closing of pulmonary units. Over the years, several methods for recruitment assessment have been developed, grouped into three main approaches: 1) Quantitative CT Scanning: This method accurately measures the amount of atelectatic lung tissue that regains aeration; 2) Regional Gas Volume Measurement: Based on anatomical markers, this approach assesses gas volume within a specified lung region; 3) Compliance-Based Gas Volume Measurement: This technique compares actual gas volume at a given pressure to expected values, assuming respiratory system compliance is constant within the explored pressure range. Additional methods, such as lung ultrasonography and electrical impedance variation, have also been explored. This paper details the distribution of opening and closing pressures throughout the lung parenchyma, which underpin the concept of recruitability. The distribution of recruitable regions corresponds to atelectasis distribution, with the pressure needed for recruitment varying according to whether the atelectasis is "loose" or "sticky. " We also discuss the effects of different PEEP levels on preventing atelectrauma, the importance of keeping some lung areas closed throughout the respiratory cycle, and briefly cover the roles of sigh ventilation, prone positioning, and the closed lung approach.
As obesity rates rise globally, addressing modifiable lifestyle factors, such as sleep, presents an opportunity for public health interventions. This review explores the growing evidence linking sleep duration, quality, and timing with weight management and dietary behaviours throughout the life course. Observational studies associate short or irregular sleep with increased obesity risk, poor diet quality, and metabolic disturbances. Plausible mechanisms include decreased physical activity, heightened hedonic and/or emotional eating, dysregulated appetite signals, and circadian misalignment of metabolism, which contribute to a positive energy balance. Unravelling the bidirectional relationship between sleep and weight is challenging; poor sleep exacerbates weight gain, while obesity-related comorbidities such as obstructive sleep apnoea further impair sleep. Despite promising evidence from sleep restriction studies showing increased energy intake, long-term randomised controlled trials (RCTs) examining interventions designed to improve sleep with weight management as an outcome are lacking. A handful of short-term interventions suggest benefits in reducing energy intake or improving dietary quality, but their effects on weight loss remain inconclusive. This review calls for robust, well-powered RCTs that integrate sleep, diet, and physical activity interventions to evaluate the potential of sleep as a core component of obesity prevention and treatment strategies. Currently, there is insufficient evidence to support sleep-focused interventions as a mandatory element in clinical weight management programmes.
Synaptic degeneration has been linked to cognitive decline. The presynaptic protein, synaptosomal‐associated protein 25 kDA (SNAP‐25), is crucial for synaptic transmission and has been suggested as a biomarker in Alzheimer's disease (AD). In the current study, we investigated the ability of SNAP‐25 to differentiate between heterogenous dementia etiologies and whether SNAP‐25 could be a staging marker in AD. SNAP‐25 in the cerebrospinal fluid (CSF) from a retrospective ( n = 187) and a prospective ( n = 134) cohort was investigated with immunoprecipitation mass spectrometry (IP‐MS) and single‐molecule array (Simoa), respectively. Both cohorts consisted of healthy controls (HC) and patients with cognitive decline of different etiologies. CSF SNAP‐25 concentration was higher in AD and non‐neurodegenerative diseases (i.e., vascular dementia) compared with controls but did not differ between AD and non‐AD neurodegenerative diseases. We found a trend toward an association between SNAP‐25 and disease burden when comparing HC, mild cognitive impairment due to AD, and AD. CSF SNAP‐25 concentrations were strongly associated with CSF phosphorylated tau (p‐tau) concentrations, thus strengthening the link between synaptic dysfunction and tau pathophysiology in AD. Our initial findings suggest that SNAP‐25 may be a potential biomarker for differentiating AD from dementia due to other etiologies. However, due to the significant association between SNAP‐25 and p‐tau proteins, the clinical utility of SNAP‐25 as a diagnostic biomarker for AD may be limited, while SNAP‐25 may be useful for monitoring disease progression or treatment response.
Importance Advanced clear cell gynecological cancers (CCGCs) have a poor prognosis, with response rates to second-line chemotherapy less than 8%. Preliminary clinical activity with programmed cell death 1 protein (PD-1) inhibitors reported in CCGC merits further investigation. Objective To assess the clinical benefit of pembrolizumab in patients with previously treated advanced CCGC. Design, Setting, and Participants The PEACOCC trial is a single-arm multicenter phase 2 trial conducted at 5 UK centers investigating the clinical benefit and safety of pembrolizumab. PD-1 inhibitor–naive patients with histologically confirmed advanced CCGC, radiological disease progression following 1 or more prior courses of chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1 were included. Patients were enrolled from March 2019 to October 2021, with data collected until July 2024. Interventions Pembrolizumab, 200 mg, intravenously every 21 days up to 2 years until progression, discontinuation due to toxic effects, or patient/clinician decision. Up to 1 year of retreatment on diseases progression, if stable disease, partial response, or complete response at 2 years. Main Outcomes and Measures The primary end point was progression-free survival (PFS) rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 to detect a 12-week PFS rate of 33% or greater and exclude a PFS rate of less than 15%, with 90% power and 1-sided 5% significance level. Secondary end points included objective response rate, duration of response, PFS, overall survival, safety, and quality of life. Results A total of 48 patients were eligible. The median (range) age was 58.5 (32-77) years, and 26 (54%) had an ECOG PS score of 0 and 22 (46%) had an ECOG PS score of 1; 41 (85%) had ovarian, 6 (13%) had endometrial, and 1 (2%) had cervical advanced CCGC. The median (range) courses prior therapy was 3 (1-6); 19 patients (40%) received prior anti-angiogenic therapy, and 19 (40%) had a platinum-free interval of more than 12 months. Grade 3 treatment-related adverse events were observed in 9 patients (19%), and no patients had grade 4 or 5 adverse events. A total of 45 of 46 patients (98%) had mismatch repair–proficient tumors. The 12-week PFS rate was 42% (95% CI, 28-57), and the best objective response rate was 25% (95% CI, 14-40), with 12 partial responses. After a median follow-up of 46.9 months (95% CI, 43.4-55.0), the median PFS was 2.7 months (95% CI, 1.3-5.4), and the median overall survival was 14.8 months (95% CI, 6.7-28.2). Conclusions and Relevance The PEACOCC trial showed clinical benefit with pembrolizumab in patients with previously treated advanced CCGC, of whom all except 1 had MMR-proficient disease. Clinical outcomes were durable with an overall tolerable safety profile, justifying further evaluation of pembrolizumab monotherapy for advanced CCGC in a randomized clinical trial. Trial Registration ClinicalTrials.gov Identifier: NCT03425565
Cells are thought to adopt mechanistically distinct migration modes depending on cell-type and environmental factors. These modes are assumed to be driven by mutually exclusive actin cytoskeletal organizations, which are either lamellar (flat, branched network) or cortical (crosslinked to the plasma membrane). Here we exploit Drosophila macrophage (hemocyte) developmental dispersal to reveal that these cells maintain both a lamellar actin network at their cell front and a cortical actin network at the rear. Loss of classical actin cortex regulators, such as Moesin, perturb hemocyte morphology and cell migration. Furthermore, cortical and lamellipodial actin networks are interregulated. Upon phosphorylation and binding to the plasma membrane, Moesin is advected to the rear by lamellar actin flow. Simultaneously, the cortical actin network feeds back on the lamella to help regulate actin flow speed and leading-edge dynamics. These data reveal that hemocyte motility requires both lamellipodial and cortical actin architectures in homeostatic equilibrium.
Background Many digital interventions for unhealthy alcohol use are based on personalized normative feedback (PNF) and personalized feedback on risks for health (PFR). The hypothesis is that PNF and PFR affect drinkers’ perceptions of drinking norms and risks, resulting in changes in drinking behaviors. This study is a follow-up mediation analysis of the primary and secondary outcomes of a randomized controlled trial testing the effect of a smartphone-based intervention to reduce alcohol use. Objective This study aimed to investigate whether perceptions of drinking norms and risks mediated the effects of a smartphone-based intervention to reduce alcohol use. Methods A total of 1770 students from 4 higher education institutions in Switzerland (mean age 22.35, SD 3.07 years) who screened positive for unhealthy alcohol use were randomized to receive access to a smartphone app or to the no-intervention control condition. The smartphone app provided PNF and PFR. Outcomes were drinking volume (DV) in standard drinks per week and the number of heavy drinking days (HDDs) assessed at baseline and 6 months. Mediators were perceived drinking norms and perceived risks for health measured at baseline and 3 months. Parallel mediation analyses and moderated mediation analyses were conducted to test whether (1) the intervention effect was indirectly related to lower DV and HDDs at 6 months (adjusting for baseline values) through perceived drinking norms and perceived risks for health at 3 months (adjusting for baseline values) and (2) the indirect effects through perceived drinking norms differed between participants who overestimated or who did not overestimate other people’s drinking at baseline. Results The intervention’s total effects were significant (DV: b=–0.85, 95% bootstrap CI –1.49 to –0.25; HDD: b=–0.44, 95% bootstrap CI –0.72 to –0.16), indicating less drinking at 6 months in the intervention group than in the control group. The direct effects (ie, controlling for mediators) were significant though smaller (DV: b=–0.73, 95% bootstrap CI –1.33 to –0.16; HDD: b=–0.39, 95% bootstrap CI –0.66 to –0.12). For DV, the indirect effect was significant through perceived drinking norms (b=–0.12, 95% bootstrap CI –0.25 to –0.03). The indirect effects through perceived risk (for DV and HDD) and perceived drinking norms (for HDD) were not significant. Results of moderated mediation analyses showed that the indirect effects through perceived drinking norms were significant among participants overestimating other people’s drinking (DV: b=–0.17, 95% bootstrap CI –0.32 to –0.05; HDD: b=–0.08, 95% bootstrap CI –0.15 to –0.01) but not significant among those not overestimating. Conclusions Perceived drinking norms, but not perceived risks, partially mediated the intervention’s effect on alcohol use, confirming one of its hypothesized mechanisms of action. These findings lend support to using normative feedback interventions to discourage unhealthy alcohol use. Trial Registration ISRCTN Registry 10007691; https://doi.org/10.1186/ISRCTN10007691
Motivation High-throughput omics technologies have revolutionised the identification of associations between individual traits and underlying biological characteristics, but still use ‘one effect-size fits all’ approaches. While covariates are often used, their potential as effect modifiers often remains unexplored. Results We propose ESPClust, a novel unsupervised method designed to identify covariates that modify the effect size of associations between sets of omics variables and outcomes. By extending the concept of moderators to encompass multiple exposures, ESPClust analyses the effect size profile (ESP) to identify regions in covariate space with different ESP, enabling the discovery of subpopulations with distinct associations. Applying ESPClust to synthetic data, insulin resistance and COVID-19 symptom manifestation, we demonstrate its versatility and ability to uncover nuanced effect size modifications that traditional analyses may overlook. By integrating information from multiple exposures, ESPClust identifies effect size modifiers in datasets that are too small for traditional univariate stratified analyses. This method provides a robust framework for understanding complex omics data and holds promise for personalised medicine. Availability and Implementation The source code ESPClust is available at https://github.com/fjpreche/ESPClust.git. It can be installed via Python package repositories as `pip install ESPClust==1.1.0`. Supplementary information Supplementary data are available at Bioinformatics online.
BACKGROUND AND OBJECTIVES Despite growing interest in neuroendoscopy, endoscopic resection of intraventricular and paraventricular brain tumors is still hindered by a lack of appropriate instrumentation. The Söring ultrasonic aspirator holds significant promise but is limited because of its original design allowing sole use with the GAAB® endoscope. METHODS A simple modification of the ultrasonic aspirator which allows use down multiple endoscopes is described along with surgical outcomes in the context of the largest reported case series of 58 procedures in 52 patients, thus further expanding its applications and versatility. RESULTS Our modification enabled the use of the Söring ultrasonic aspirator with the MINOP® InVent neuroendoscope, facilitating tumor resection in 58 procedures of 52 patients between July 2015 and June 2022. Near-total to gross-total resection was achieved in 30.8% of cases, with no permanent neurological deficits observed. The modified aspirator proved effective and safe, with no adverse events related to its use. CONCLUSION The Söring ultrasonic aspirator represents a significant landmark in neuroendoscopic surgery. Our modification allowed greater versatility and compatibility with multiple endoscopes. This safe and effective modification will broaden its use and with time will have a considerable impact in the field of minimally invasive neurosurgery.
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Brooke Rogers
  • Department of War Studies
Mario F Juruena
  • Department of Psychological Medicine
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Prof Reba rezavi