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Understanding the role of KDM5B loss-of-function mutations in childhood disorders
No full textDevelopmental disorders (DDs) are a diverse group of chronic conditions that affect the physical, cognitive or behavioural development of a child. The heterogeneous nature of these disorders, and their diverse aetiology poses signifcant diagnostic and therapeutic challenges, where patients are often left with limited treatment options. Increasing evidence highlights the importance of genetic mutations in these disorders. Loss-of-function (LoF) of KDM5B leads to a recognisable disorder characterised by intellectual disability and physical deformities. KDM5B is predominately expressed during early development where it has a crucial role in neurodevelopment. However, despite its association with this disorder, its underlying mechanisms remain under-explored.This thesis aimed to elucidate the role of KDM5B in early neuronal differentiation, hypothesizing that KDM5B loss-of-function disrupts neuronal differentiation and contributes to pathogenesis of the neurodevelopmental disorder. CRISPR-Cas9 mediated KDM5B knockout models were generated in human neuroblastoma SH-SY5Y cells and induced pluripotent stem cells (iPSCs) to simulate key stages of neuronal development. It was observed that KDM5B LoF delayed the transition from pluripotent stem cell to neural progenitor cell. Conversely, at later stages of differentiation, KDM5B-KO cells exhibited enhanced neurite outgrowth and branching, suggesting a stage-dependent role of KDM5B. Transcriptomic and proteomic analyses further highlighted KDM5B’s involvement in proliferation, RNA splicing regulation, mitochondrial function and cell adhesion.These fndings increase our understanding of KDM5B’s essential functions in neurodevelopment and have implications for both KDM5B-associated developmental disorders and cancer biology. Future research into these pathways may uncover novel therapeutic targets and further elucidate the diverse roles of KDM5B in human development
"Enriching the golden time" - a study about time and goals, and their effects on depression in later life
No full textGoals play an important part in human development and are interrelated with future time perspective. What is less clear is whether a short future time perspective leads to poor mental wellbeing. This mixed methods study addressed the question of the relationship between goals, future time perspective and depression in later life. The first study strand (Study One) deployed an online- and paper questionnaire with a total of 76 older adults aged 65 and above from the United Kingdom. The survey contained questions about sociodemographic variables, Instrumental Activities of Daily Living (IADL), Geriatric Depression Scale (GDS) and the Motivational-Induction-Method (MIM) to measure and classify future time perspective and goals. Crosstabulations and Mann-Whitney U Tests were conducted to analyse the sample. The results show that depression in this sample does not increase in later life and that older adults with extended future time perspective (>1 year)have more goals than older adults with limited future time perspective. However, the hypothesis that having both limited future time perspective and fewer goals in later life led to subthreshold depression was not confirmed. The second study strand (Study Two) used a qualitative research design to explore how perceived future time perspective impacts older people’s views about their own goals. Using Thematic Analysis, four themes were created from the interviews with 18 older adults. The first two themes explored the impact health, ageing, and retirement have on goals and future time perspective, while the last two themes describe the adaptation strategies participants used to navigate the impacts they experienced. This study offers insights into how health, ageing, and retirement shape older adults' perceptions of their goals and future time perspective, while examining their adaptation to the changing circumstances of later life. Despite a limited future time perspective, participants showed a diverse range of goals. The findings reveal how older adults adjust their goals in response to health changes and retirement, employing different strategies to focus on meaningful goals. Although the hypothesis linking a limited future time perspective and fewer goals to subthreshold depression was not supported, the research underscores that experiences of losses are not necessarily associated with depressive symptoms. These findings highlight the importance of present-focused strategies in enabling older adults to navigate later life effectively, contributing to a better understanding of adaptation in later life
Influence of individual and social values on customer engagement in luxury thermal spa hotels: the mediating roles of perceived justice and brand experience
No full textThis study aims to examine how values (i.e., individual and social values) influence customer engagement after managing a service failure in the thermal spa hotel context, and the mediating roles of perceived justice and brand experience. The data was collected from a survey of guests of luxury thermal spa hotels in Portugal, and the research model was assessed using partial least squares structural equation modeling. The results show that individual values affect perceived justice and brand experience, which in turn contribute to a higher level of customer engagement. Brand experience is a better mediator of the relationship between individual values and customer engagement than perceived justice. The novelty of this study is highlighted by the mediating effects of perceived justice and brand experience on the relationship between individual values and customer engagement.</p
The ELECTRA Trial: approach to contemporary challenges in the development and implementation of double-blinded, randomised, controlled clinical trials in low-volume high-complexity surgical oncology
No full textBackground: achieving evidence-based practice change in surgery has always been challenging, with many aspects of common clinical practice evolving through lower-level studies that are susceptible to bias and confounding rather than high-quality evidence. This challenge is even more pronounced in the setting of low-volume, high-complexity surgical oncology. Additionally, when the costs of interventions or technologies are high, designing and developing such studies within financially constrained national healthcare systems becomes even more complicated, potentially widening perceived healthcare inequalities between private and publicly funded systems. However, this is precisely the area where a lack of evidence can either hinder the development of significant new clinical advances or lead to the adoption of expensive and ineffective treatments. Here, we describe the novel approaches adopted in the design, development, and implementation of the ELECTRA trial, a randomised, controlled, double-blinded feasibility study with a planned extension to a late-phase trial. Methods: the Cancer Research UK ELECTRA (NCT05877352) trial is a three-armed randomised, controlled clinical trial designed to evaluate the incremental benefit of adding intraoperative electron beam radiotherapy (IOERT) to pelvic exenteration surgery for locally advanced and locally recurrent rectal cancer. ELECTRA is double-blinded, with patients, surgeons, and oncologists unaware of whether IOERT is administered or not. The primary feasibility outcome focuses on the ability to successfully recruit and randomise participants, while the subsequent primary outcome assesses IOERT field local control. Results: we describe the collaborative process involved in developing the trial, including national and international consultations to determine the best study design and the most optimal outcome measures to evaluate. We outline the extensive patient participation and input into the study design. Given the complexity and evolving nature of the field, with no clear international standardisations, we outline the processes used to address internationally agreed definitions, radiological standardisation, surgical learning curves, quality assurance, and pathological standardisation, as well as the broader impact and benefits of these activities. Finally, we describe the novel design utilised to facilitate the involvement of national and international units with varying levels of equipoise regarding IOERT. Conclusions: historically, randomised clinical trials have not been the standard approach for evaluating surgical interventions due to their practical and methodological challenges, particularly in high-complexity, low-volume settings. Despite these difficulties, they remain the gold standard for evidence-based practice. The ELECTRA trial exemplifies a complex, innovative trial design that addresses an unmet need in a specialised area of high-complexity surgery. Using ELECTRA as an example, we highlight the genuine challenges in designing such complex trials and provide recommendations to facilitate the conduct of future well-designed surgical studies.</p
Dose-dense adjuvant chemotherapy for high-risk early breast cancer: its role in the era of personalised oncology
No full textAssessing impacts of hydropower development on downstream inundation using a hybrid modeling framework integrating satellite data-driven and process-based models
No full textDespite its energy benefits, hydropower dam development often causes ecological damages and social disruption, including downstream livelihood impacts, and biodiversity loss. Current methods for analyzing changes in downstream inundation extent due to dam operation typically rely on historical ground or satellite observations, or on coupled hydrological-hydrodynamic modeling. However, while the former fails to isolate hydropower impacts from climate variations, the latter suffers from extensive input data requirements and high computational burden. This study proposes a novel hybrid framework integrating satellite data-driven Forecasting Inundation Extents using REOF (Rotated Empirical Orthogonal Function) analysis (FIER), and the process-based Hydrological Predictions for the Environment (HYPE) model incorporating the Integrated Reservoir Operation Scheme (IROS). The framework enables the isolated assessment of long-term hydropower impacts on downstream inundation dynamics with computational efficiency and reduced ground data requirements, making it suitable for poorly gauged regions. Applying FIER-HYPE-IROS to the Lower Mekong River basin (LMB), a region significantly affected by dam proliferation impacting fisheries and agriculture, we found that dam operations decreased decadal-average wet season water levels by up to 5% and increased dry season levels by up to 11%. Wet season inundation occurrence decreased by 11 days and the inundated area by 6%, while dry season inundation occurrence extended by 6 days and the surface water area increased by 40%. Although the current framework does not explicitly assess the downstream hydrological modifications, it offers a cost-effective alternative for evaluating upstream alterations on inundation dynamics, such as dam operations, particularly in poorly gauged regions
Associations between skeletal muscle strength and chronic kidney disease in patients with MASLD
No full textBackground: A skeletal muscle strength (SMS) decline is associated with metabolic diseases, but whether SMS also declines with chronic kidney disease (CKD) in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) is uncertain. This study examined the associations between SMS and the risk of CKD in MASLD population. Method: We performed a large-scale study with four cohorts: PERSONS and NHANES 2011–2014 cohorts for the cross-sectional investigation, and TCLSIH and UK Biobank cohorts for the longitudinal investigation. A handgrip dynamometer measured handgrip strength as a proxy for overall SMS. Participants were stratified according to CKD status [non-CKD vs. CKD (stages 1–5) groups]. Results: In the PERSONS cohort, the CKD group has a lower handgrip strength than the non-CKD group (27.14 ± 9.19 vs. 33.59 ± 11.92 kg, P < 0.001). Higher handgrip strength is associated with lower odds of abnormal albuminuria or CKD (OR: 0.96, 95%CI:0.92-0.99 and OR:0.95, 95%CI: 0.91-0.99 respectively). The highest handgrip strength tertile is associated with the lowest risk of having abnormal albuminuria or CKD (compared with the lowest or middle tertile). Results are similar in NHANES cohort. Furthermore, the highest handgrip strength is independently associated with the lowest risk of incident CKD in MASLD (HR: 0.95, 95%CI: 0.92-0.99 and HR:0.99, 95%CI: 0.98-0.99 in TCLSIH and UK Biobank cohorts). In Kaplan-Meier curve analysis, the cumulative incidence of CKD is lowest in the highest handgrip strength tertile compared to the lowest or the middle tertile. Conclusions: Higher handgrip/muscle strength is independently associated with a lower risk of CKD and abnormal albuminuria in MASLD population.</p
A scoping review of the methods used to estimate health facility catchment populations for child health indicators in sub‑Saharan Africa
No full textBackground: evidence indicating persistent geographic inequalities in health outcomes signifies a need for routine subnational monitoring of health-related Sustainable Development Goal targets in sub-Saharan Africa. Health facilities may be an appropriate subnational unit for monitoring purposes, but a lack of suitable demographic data complicates the production of baseline facility-level population denominators against which progress can be reliably measured. This scoping review aimed to map the methods and data sources used to estimate health facility catchment areas and translate them to population denominators for child health indicators in the region.Methods: peer-reviewed research publications and grey literature reports were identified by searching bibliographic databases and relevant organisational websites. The inclusion criteria required that studies were conducted in sub-Saharan Africa since January 2000, described quantitative method(s) for estimating health facility catchment areas and/or population denominators, and focussed on children as the population of interest. Following title/abstract then full text screening of search results, relevant data were extracted using a standard form. Thematic analysis was undertaken to extract themes and present a narrative synthesis.Results: overall, 33 research publications and 3 grey literature reports were included. Of these, only 7 research studies and 1 technical guidance document outlined aims explicitly framed around methods development and/or evaluation. Studies increasingly estimated catchment areas using complex geostatistical or travel time-based modelling approaches rather than simpler proximity metrics, and produced denominators by intersecting catchment boundaries with gridded population surfaces rather than aggregating area-based administrative counts. Few studies used data produced by or describing health facilities to link estimation methods to service utilisation patterns, inter-facility competition or facility characteristics.Conclusion: there is a need for catchment population estimation methods that can be scaled to national-level facility networks and replicated across the region. This could be achieved by leveraging routinely collected health data and other readily available and nationally consistent data sources. Future methodological development should emphasise modern geostatistical approaches drawing upon the relative strengths of multiple data sources and capturing the range of spatial, supply-side, individual-level and environmental factors with potential to influence catchments’ extent, shape and demographic composition
Self-reported hypertension prevalence, risk factors, and knowledge among South Africans aged 24 to 40 years old
No full textAlthough hypertension is a significant public health burden in South Africa (SA), less is known about its prevalence, risk factors, and possible preventative strategies among young adults. We assessed the prevalence, possible risk factors, and knowledge associated with self-reported hypertension among young adults from SA. A cross-sectional online survey was conducted among 1000 young South African adults (24–40 years; 51.0% women). We administered a socio-demographic questionnaire and collected information on measures of socio-economic status (SES) (e.g. asset wealth index), self-reported medical history, and lifestyle risk factors. Furthermore, a modified version of the hypertension evaluation of lifestyle and management questionnaire was used to assess participants’ hypertension knowledge. The overall prevalence of self-reported hypertension was 24.0%, with significant differences between women and men (27.5% and 20.4% respectively, p = 0.033). Only 16.8% of the respondents had good hypertension knowledge. There was a positive association between good knowledge of hypertension and being hypertensive (OR = 1.43 CI:1.23–3.12), monthly blood pressure check-ups (OR = 2.03 CI:1.78–3.23), knowing the side effects of uncontrolled blood pressure (OR = 1.28 CI:1.07–1.89) and having a biological mother with hypertension (OR = 1.79 CI:1.53–2.21). Being employed full-time (OR = 0.74 CI:0.69–0.80), having a higher SES (wealth index 4 (OR = 0.70 CI:0.59–0.97) and 5 (OR = 0.65 CI:0.48–0.81)), exercising 6 to 7 days per week (OR = 0.83 CI:0.71–0.94), and not consuming alcohol at all (OR = 0.73 CI:0.67–0.89), were all found to be protective against hypertension. The high hypertension prevalence, lack of hypertension knowledge, and reported risk factors among this group highlight the need for early robust preventative strategies to mitigate hypertension risk among this population
Spatiotemporal prediction of offshore wind fields based on a hybrid deep learning model for maritime navigation
No full textAccurate wind speed prediction is crucial for offshore wind power generation, ship navigation, and the use of renewable energy, as it optimises energy production, enhance maritime safety. This study introduces GswinLSTM, a novel hyrid model that integrates Long Short-Term Memory (LSTM) neural networks with the Group Swin Transformer (Gswin Transformer) to address the limitations of existing prediction models and improve wind speed prediction accuracy. Compared to conventional approaches, GswinLSTM simultaneously captures temporal dependencies and spatial correlations in wind speed data, significantly improving forecasting accuracy and robustness. The model is validated using ERA5 reanalysis data, which accurately represents offshore climate conditions. Experimental results demonstrate that GswinLSTM outperforms state-of-the-art models, including Transformer, Residual U-Net (ResUnet), and Convolutional LSTM (ConvLSTM), across four evaluation metrics, particularly in long-term forecasting where conventional methods struggle with error accumulation. By effectively capturing spatiotemporal dependencies, GswinLSTM enhances both prediction stability and precision in extended forecasting horizons. With strong theoretical contributions and practical applicability, this model offers valuable insights for wind field operations, maritime navigation, and climate monitoring. The findings underscore GswinLSTM's potential to drive advancements in renewable energy forecasting and environmental risk assessment, making it a promising tool for future atmospheric and meteorological studies. Additionally, the model's strong predictive capability supports maritime navigation safety, offshore wind energy optimization, and provides actionable insights for coastal management policies, such as maritime spatial planning and carbon reduction strategies.</p
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