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With increasing computational capabilities, the implementation of statistical approaches to quantify and propagate input uncertainties through hydrodynamic models has become increasingly feasible and crucial to capture the full range of output scenarios. However, full robust uncertainty quantification remains computationally expensive and out of reach for general purposes. In this study, we demonstrate that by utilizing advanced response surface surrogate modeling techniques, specifically Gaussian Process Regression (GPR) and Polynomial Chaos Expansion (PCE), we have developed efficient and high‐fidelity emulators for capturing the uncertainty in flood extents of realistic fluvial flood scenarios. With proper tuning, both emulators requiring only 9 model evaluations, provide near‐perfect estimates where we have two uncertain flow magnitudes being modeled. In the more complex three‐inputs scenario, where a time lag between river flow peaks is introduced, accurate flood extent emulation becomes more challenging. The computational cost required to build one surrogate for acceptable estimation accuracy increases to 27 full model runs for GPR and PCE‐Regression methods. The largest R2${R}^{2}$of 0.66 was obtained by the PCE‐Regression method with a Halton quasi‐sampling experimental design. GPR outperforms PCE in capturing lower extreme flood extents due to its ability to model uncertainty and fine‐tune variance across the input space. Our findings highlight the effectiveness of both GPR and PCE in capturing broad trends and extremes within response surfaces, offering substantial computational savings compared to the exponentially more expensive FMC simulations. However, when the hydrodynamic response becomes more complex, we have identified significant challenges in constructing high‐fidelity emulators.

Despite recent progress in our understanding of the association between the gut microbiome and inflammatory bowel disease (IBD), the role of microbiome biomarkers in IBD diagnosis remains underexplored. Here we developed a microbiome-based diagnostic test for IBD. By utilization of metagenomic data from 5,979 fecal samples with and without IBD from different geographies and ethnicities, we identified microbiota alterations in IBD and selected ten and nine bacterial species for construction of diagnostic models for ulcerative colitis and Crohn’s disease, respectively. These diagnostic models achieved areas under the curve >0.90 for distinguishing IBD from controls in the discovery cohort, and maintained satisfactory performance in transethnic validation cohorts from eight populations. We further developed a multiplex droplet digital polymerase chain reaction test targeting selected IBD-associated bacterial species, and models based on this test showed numerically higher performance than fecal calprotectin in discriminating ulcerative colitis and Crohn’s disease from controls. Here we discovered universal IBD-associated bacteria and show the potential applicability of a multibacteria biomarker panel as a noninvasive tool for IBD diagnosis. Using ethnically and geographically diverse metagenomic data, the authors identify microbiota alterations associated with inflammatory bowel disease (IBD). They discover universal IBD-associated bacteria, which serve as the basis for a multibacteria biomarker panel that could support a noninvasive tool for IBD diagnosis.

(1) Background: Developing countries have experienced a rapid recent rise in Inflammatory Bowel Disease (IBD) incidence and emerging evidence suggests processed foods and food additives may predispose one to the development and perpetuation of Crohn’s disease (CD). The aim of this study was to evaluate processed food and food additive intake in CD patients and controls, in Australia (high CD incidence), Hong Kong (intermediate incidence) and mainland China (emerging incidence). (2) Methods: In 274 CD patients (CD), 82 first-degree relatives (FDR), 83 household members (HM) and 92 healthy unrelated controls (HC) from Australia (n = 180), Hong Kong (HK) (n = 160) and mainland China (n = 191) we estimated early life (0–18 years), recent (12 months), and current processed and food additive intake, using validated questionnaires and a 3-day-food diary. (3) Results: Early life processed food intake: Combining all regions, CD were more likely to have consumed soft drinks and fast foods than HM, more likely to have consumed processed fruit and snacks than their FDR, and more likely to have consumed a range of processed foods than HC. HK and China CD patients were more likely to have consumed a range of processed foods than HC. Recent food-additive intake (12-months): Combining all regions, CD patients had significantly higher intakes of aspartame and sucralose, and polysorbate-80, than HC, and more total emulsifiers, artificial sweeteners, and titanium dioxide than FDR and HC. HK and China CD patients had a higher intake of almost all food additives than all controls. Current additive intake (3-days): Australian and HK CD patients had higher total food-additive intake than FDR, and HK CD patients had a higher intake of total food-additives and emulsifiers than HM. (4) Conclusions: CD patients have been exposed to more processed food and food additives than control groups, which may predispose them to CD development and ongoing inflammation.

IntroductionThe enteric microbiota drives inflammation in Crohn’s disease. Yet, there are no placebo controlled trials evaluating the efficacy and safety of faecal microbiota transplantation (FMT) in inducing and maintaining remission in patients with active Crohn’s disease. The Microbial Restoration (MIRO) study aims to establish this evidence.Methods and analysisAt two specialist inflammatory bowel disease centres, 120 enrolled patients will have a 3-week period of diet optimisation (removal of ultra-processed foods) together with a 7-day course of antibiotics (to facilitate subsequent FMT engraftment). Patients will then be stratified to upper gut (for disease proximal to the splenic flexure) or lower gut (distal to the splenic flexure) disease. Patients will then be randomised in a 2:1 ratio to receive anaerobically prepared stool or placebo for 8 weeks either by gastroscopy, or colonoscopy and enemas. Clinical response at 8 weeks (Crohn’s Disease Activity Index (CDAI) reduction ≥100 points or to <150 points) is the primary outcome measure. Non-responders to placebo and partial responders to FMT (CDAI decrease <100 but >70) receive FMT for weeks 8–16.Patients achieving clinical response from FMT after 8 or 16 weeks will be randomised in a 1:1 ratio to either a 44-week maintenance phase of FMT or placebo. Patients will receive FMT from one donor throughout the study.The MIRO study will establish whether FMT is an effective and safe therapy to induce and maintain remission in patients with active Crohn’s disease.Ethics and disseminationEthical approval has been received by the St Vincent’s Hospital Melbourne Human Research Ethics Committee (HREC-A 084/21). The results will be disseminated in peer-reviewed journals and presented at international conferences.Trial registration numberClinicalTrials.gov: NCT04970446; Registered on 20 July 2021.

Background Despite the ongoing promotion of physical activity, the rates of physical inactivity remain high. Drawing on established methods of analysing consumer behaviour, this study seeks to understand how physical activity competes for finite time in a day – how Exercise and Sport compete with other everyday behaviours, and how engagement in physical activity is shared across Exercise and Sport activities. As targeted efforts are common in physical activity intervention and promotion, the existence of segmentation is also explored. Methods Time-use recall data ( n  = 2307 adults) is analysed using the Duplication of Behaviour Law, and tested against expected values, to document what proportion of the population that engage in one activity, also engage in another competing activity. Additionally, a Mean Absolute Deviation approach is used to test for segmentation. Results The Duplication of Behaviour Law is evident for everyday activities, and Exercise and Sport activities – all activities ‘compete’ with each other, and the prevalence of the competing activity determines the extent of competition. However, some activities compete more or less than expected, suggesting the combinations of activities that should be used or avoided in promotion efforts. Competition between everyday activities is predictable, and there are no specific activities that are sacrificed to engage in Exercise and Sport. How people share their physical activity across different Exercise and Sport activities is less predictable – Males and younger people (under 20 years) are more likely to engage in Exercise and Sport, and those who engage in Exercise and Sport are slightly more likely to Work and Study. High competition between Team Sports and Non-Team Sports suggests strong preferences for sports of different varieties. Finally, gender and age-based segmentation does not exist for Exercise and Sport relative to other everyday activities; however, segmentation does exist for Team Sports, Games, Active Play and Dance. Conclusions The Duplication of Behaviour Law demonstrates that population-level patterns of behaviour can yield insight into the competition between different activities, and how engagement in physical activity is shared across different Exercise and Sport activities. Such insights can be used to describe and predict physical activity behaviour and may be used to inform and evaluate promotion and intervention.

(1) Background: The Food Agricultural Organization/World Health Organization (FAO/WHO) International Food Standards Codex Alimentarius CXS 192e International Food Standards (hereafter, CODEX) declares additives non-toxic, but they have been associated with changes to the microbiota changes and thinning of the mucus layer of the gut. Their widespread use has occurred in parallel with increased inflammatory bowel disease (IBD) incidence. This paper reports on the development and validation of surveys to estimate additive intake. (2) Methods: Dietitians created a food-additive database, with a focus on additives that have been associated with IBD. For each additive, information on the CODEX food-category they are permitted in and the associated maximum permissible levels (mg/kg) was recorded. Based on the database, questions to assess early life (part 1) and recent (part 2) additive intake were written. Forward–backward translation from English to Chinese was undertaken. Thirty-one individuals were evaluated to assess understandability. A further fifty-seven individuals completed the tool on two occasions, a fortnight apart; agreement was assessed using Cohen’s kappa coefficient or the intra-class correlation coefficient (ICC). (3) Results: The participants reported that it was difficult to remember food intake and estimate portion sizes. The participants also noted confusion around the term ‘home-grown’. Instructions and definitions were added; after this, respondents judged the questionnaires as clear. The average kappa coefficient for part 1 and part 2 questions were 0.61 and 0.67, respectively. The average ICC ranged from 0.30 to 0.94; three food lists were removed due to low reliability. (4) Conclusions: Two tools have been created and validated, in two languages, that reliably assess remote and recent food additive intake.

Britain's power system has shifted towards a major contribution from wind energy. However, wind is highly variable, and exceptionally low wind events can simultaneously occur with cold conditions, which increase demand. These conditions can pose a threat for the security of energy supply. Here we use bias‐corrected wind supply data and the estimated temperature‐related part of demand to analyse events of potential weather‐related energy shortfall based on the historic meteorological record. We conduct sensitivity studies with varying scenarios of Britain's total wind energy capacity and the temperature sensitivity of national demand. These scenarios are estimates for present‐day conditions as well as potential future changes of the power system. We apply a new methodology to estimate the potential severity of an event for the power system, and analyse the atmospheric conditions associated with the most severe events. We find that events of potentially severe shortfall are relatively rare and short‐lived, and often occur with an atmospheric pattern broadly resembling a negative North Atlantic Oscillation. This broad tendency emerges from a wide range of individual daily weather patterns that cause cold and still conditions. With an increase in wind capacity, it is likely that severe events will become rarer, although the most severe days of the record are relatively insensitive to changes in wind supply and temperature sensitivity of demand under our assumptions. Compound events of exceptionally low wind and cold temperature can pose a threat for the security of energy supply in a wind‐dominated power system. We estimate wind supply and temperature‐related demand to analyse severe events for different scenarios of the British power system and show that negative North Atlantic Oscillation‐like atmospheric conditions favour the occurrence of severe weather events. We show that the risk reduces for potential future power systems, although the most severe events are largely unaffected by the energy system scenario.

The treatment of ovarian cancer has not significantly changed in decades and it remains one of the most lethal malignancies in women. The serine protease dipeptidyl peptidase 4 (DPP4) plays key roles in metabolism and immunity, and its expression has been associated with either pro- or anti-tumour effects in multiple tumour types. In this study, we provide the first evidence that DPP4 expression and enzyme activity are uncoupled under hypoxic conditions in ovarian cancer cells. Whilst we identified strong up-regulation of DPP4 mRNA expression under hypoxic growth, the specific activity of secreted DPP4 was paradoxically decreased. Further investigation revealed matrix metalloproteinases (MMP)-dependent inactivation and proteolytic shedding of DPP4 from the cell surface, mediated by at least MMP10 and MMP13. This is the first report of uncoupled DPP4 expression and activity in ovarian cancer cells, and suggests a previously unrecognized, cell- and tissue-type-dependent mechanism for the regulation of DPP4 in solid tumours. Further studies are necessary to identify the functional consequences of DPP4 processing and its potential prognostic or therapeutic value.

Background Leader cells are a subset of cancer cells that coordinate the complex cell-cell and cell-matrix interactions required for ovarian cancer migration, invasion, tumour deposition and are negatively associated with progression-free survival and response to therapy. Emerging evidence suggests leader cells may be enriched in response to chemotherapy, underlying disease recurrence following treatment. Methods CRISPR was used to insert a bicistronic T2A-GFP cassette under the native KRT14 (leader cell) promoter. 2D and 3D drug screens were completed in the presence of chemotherapies used in ovarian cancer management. Leader cell; proliferative (Ki67); and apoptotic status (Cleaved Caspase 3) were defined by live cell imaging and flow cytometry. Quantitative real-time PCR defined “stemness” profiles. Proliferation was assessed on the xCELLigence real time cell analyser. Statistical Analysis was performed using unpaired non-parametric t-tests or one-way ANOVA and Tukey’s multiple comparison post hoc. Results Leader cells represent a transcriptionally plastic subpopulation of ovarian cancer cells that arise independently of cell division or DNA replication, and exhibit a “stemness” profile that does not correlate with epithelial-to-mesenchymal transition. Chemotherapeutics increased apoptosis-resistant leader cells in vitro, who retained motility and expressed known chemo-resistance markers including ALDH1 , Twist and CD44v6 . Functional impairment of leader cells restored chemosensitivity, with leader cell-deficient lines failing to recover following chemotherapeutic intervention. Conclusions Our data demonstrate that ovarian cancer leader cells are resistant to a diverse array of chemotherapeutic agents, and are likely to play a critical role in the recurrence of chemo-resistant disease as drivers of poor treatment outcomes.