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Disease detection through gas analysis has long been the topic of many studies because of its potential as a rapid diagnostic technique. In particular, the pathogens that cause urinary tract infection (UTI) have been shown to generate different profiles of volatile organic compounds, thus enabling the discrimination of causative agents using an electronic nose. While past studies have performed data collection on either agar culture or jellified urine culture, this study measures the headspace volume of liquid urine culture samples. Evaporation of the liquid and the presence of background compounds during electronic nose (e-nose) device operation could introduce variability to the collected data. Therefore, a headspace gas chromatography-mass spectrometry method was developed and validated for quantitating ethanol in the headspace of the urine samples. By leveraging the new method to characterize the sample stability during e-nose measurement, it was revealed that ethanol concentration dropped more than 15% after only three measurement cycles, which equal 30 minutes for this study. It was further shown that by using only data within the first three cycles, better accuracies for between-day classification were achieved, which was 73.7% and 97.0%, compared to using data from within the first nine cycles, which resulted in 65.0% and 81.1% accuracies. Therefore, the newly developed method provides better quality control for data collection, paving ways for the future establishment of a training data library for UTI.

Here, we report a pathomimetic Leaky Gut Chip that recapitulates increased epithelial permeability and intestinal inflammation to assess probiotic intervention as live biotherapeutics. We leveraged a mechanodynamic human gut-on-a-chip (Gut Chip) that recreates three-dimensional epithelial layers in a controlled oxygen gradient and biomechanical cues, where the addition of a cocktail of pro-inflammatory cytokines, TNF-α and IL-1β, reproducibly induced impaired epithelial barrier followed by intestinal inflammation. This inflamed leaky epithelium was not recovered for up to 3 days, although the cytokine treatment ceased. However, when probiotic bacteria, either Lactobacillus rhamnosus GG or a multi-species mixture (VSL#3), were respectively administered on the leaky epithelium, bacterial cells colonized mucosal surface and significantly improved barrier function, enhanced the localization of tight junction proteins such as ZO-1 and occludin, and elevated mucus production. In addition, inflammatory markers, including p65, pSTAT3, and MYD88, that were highly expressed in the germ-free control were significantly reduced when probiotic bacteria were co-cultured in a Leaky Gut Chip. Probiotic treatment also significantly reduced the production of secretory pro-inflammatory cytokines. Hence, our pathomimetic Leaky Gut Chip may offer a translational strategy to dissect the therapeutic mechanism of live biotherapeutic products and validate their clinical potential by incorporating patient-derived organoids.

The human microbiome orchestrates a variety of metabolic, immunological and regulatory functions in health and disease. However, experimentally dissecting host–microbiome interactions remains challenging. In this Review, we discuss how human organ-on-a-chip platforms can be designed to study fundamental microbiome mechanisms, investigate microbiome-related disease pathophysiology and provide preclinical drug screening platforms, as an alternative to conventional cell cultures or animal models. We outline key design parameters, including spatial configurations, microfluidic setups, mechanical deformation and oxygen gradients, that allow the longitudinal co-culture of aerobic and anaerobic microorganisms with human cells. Such organ-on-a-chip platforms have been explored for the preclinical modelling of microbiome-associated diseases, including infectious and reproductive organ diseases. Moreover, organ-on-a-chip platforms can be engineered to test microbiome-assisted therapeutics, for pharmacomicrobiomics and culturomics investigations, and to model microbiome-mediated multi-organ interactions. Finally, we provide a translational outlook, discussing clinical challenges, regulatory hurdles and precision interventions.The human microbiome plays a central role in health and disease. This Review discusses the design of human organ-on-a-chip platforms to model host–microbiome interactions in vitro and investigate microbiome-associated diseases as well as microbiome-mediated interventions.

Disease detection through gas analysis has long been the topic of many studies because of its potential as a rapid diagnostic technique. In particular, the pathogens that cause urinary tract infection (UTI) have been shown to generate different profiles of volatile organic compounds, thus enabling the discrimination of causative agents using an electronic nose. While past studies have performed data collection on either agar culture or jellified urine culture, this study measures the headspace volume of liquid urine culture samples. Evaporation of the liquid and the presence of background compounds during electronic nose (e-nose) device operation could introduce variability to the collected data. Therefore, a headspace gas chromatography-mass spectrometry method was developed and validated for quantitating ethanol in the headspace of the urine samples. By leveraging the new method to characterize the sample stability during e-nose measurement, it was revealed that ethanol concentration dropped more than 15% after only three measurement cycles, which equal 30 minutes for this study. It was further shown that by using only data within the first three cycles, better accuracies for between-day classification were achieved, which was 73.7% and 97.0%, compared to using data from within the first nine cycles, which resulted in 65.0% and 81.1% accuracies. Therefore, the newly developed method provides better quality control for data collection, paving ways for the future establishment of a training data library for UTI.

Within a Brownian diffusion Markovian framework, we provide a direct PDE characterization of the minimal initial endowment required so that the terminal wealth of a financial agent (possibly diminished by the payoff of a random claim) can match a set of constraints in probability. Such constraints should be interpreted as a rough description of a targeted profit and loss (P&L) distribution. This allows us to give a price to options under a P&L constraint, or to provide a description of the discrete P&L profiles that can be achieved given an initial capital. This approach provides an alternative to the standard utility indifference (or marginal) pricing rules that is better adapted to market practices. From the mathematical point of view, this is an extension of the stochastic target problem under controlled loss, studied in Bouchard, Touzi, and Elie [Bouchard B, Touzi N, Elie R (2009) Stochastic target problems with controlled loss. SIAM J. Control Optim. 48(5):3123-3150], to the case of multiple constraints. Although the associated Hamilton-Jacobi-Bellman operator is fully discontinuous, and the terminal condition is irregular, we are able to construct a numerical scheme that converges at any continuity points of the pricing function.

An electronic nose technology was developed that aimed at an in vitro classification of urinary samples infected with different strains of Escherichia coli to predict the causing agents of urinary tract infection. The predictive model was optimized by developing a culturing protocol to ensure consistent assay as well as utilizing a headspace GC/MS method to characterize ethanol content in the samples. By employing a robust artificial neural network, it was shown to be able to extract the unique patterns of VOCs of the samples and successfully differentiate between those classes. For datasets collected from multiple measurements, the prediction accuracy was improved by including training data from the appropriate first few measurement cycles, which were deemed quality data from a stability test with the GC/MS. Lastly, a passive cell separation technique called deterministic lateral displacement (DLD) was enhanced by applying gap size variation while keeping the row shift fraction unchanged. This novel approach, which increases separation resolution while maintaining the microsystem throughput, was found to be disjunctive from the conventional method for not being predictable by the standard critical size equation. Future research could explore the capability of the DLD system as a bacterial concentrator and the possibility of automation, which highlights its great potentials for incorporating into the e-nose system.

We provide an obstacle version of the Geometric Dynamic Programming Principle of Soner and Touzi (J. Eur. Math. Soc. 4:201–236, 2002 ) for stochastic target problems. This opens the doors to a wide range of applications, particularly in risk control in finance and insurance, in which a controlled stochastic process has to be maintained in a given set on a time interval [0, T ]. As an example of application, we show how it can be used to provide a viscosity characterization of the super-hedging cost of American options under portfolio constraints, without appealing to the standard dual formulation from mathematical finance. In particular, we allow for a degenerate volatility, a case which does not seem to have been studied so far in this context.

Biomechanical cues, including shear stress and mechanical strain, are key regulators of intestinal cellular behavior, yet their mechanostimulatory impact on fibroblasts responses during early fibrotic remodeling remains poorly understood. Using a bioengineered gut-on-a-chip model, we independently modulated flow and mechanical strain to assess fibroblast dynamics under intact or impaired epithelial barriers. Inflammation-associated fibroblasts resisted biomechanical stress, exhibiting myofibroblast-like phenotypes with hypertrophy and elevated α-smooth muscle actin aligned with stress fibers. In contrast, normal fibroblasts were highly susceptible to shear stress, undergoing matrix metalloproteinase-dependent apoptotic injury, while mechanical strain alone had minimal effect. Notably, an intact epithelial barrier was both necessary and sufficient to protect fibroblasts from shear-induced damage, suggesting that \"good fences make good neighbors\". Under barrier dysfunction, prolonged exposure to shear stress induced the formation of stiff fibroblast aggregates composed of mechanoadaptive myofibroblast-like cells. These findings identify mechanostimulatory cues, particularly shear stress, as critical drivers of early fibrotic remodeling in inflammatory bowel disease and underscore epithelial barrier integrity as an essential biomechanical safeguard against pathological fibroblast dysregulation.

Gastrointestinal acute radiation syndrome (GI-ARS) poses a critical public health concern, necessitating the development of effective medical countermeasures (MCM). Here, we evaluated the therapeutic potential of a commercially available probiotic formulation using human gut-on-a-chip model that mimics physiodynamic intestinal microenvironment. Intestinal epithelial Caco-2 cells were subjected to 8 Gray gamma radiation, targeting the epithelial layer, the culture medium, or both. The irradiated epithelial cells challenged to the irradiated medium resulted in significant DNA damage quantified by the presence of 53BP1 foci, increased cellular injury, and disrupted epithelial morphology. While epithelial irradiation alone did not compromise structural integrity, longitudinal exposure to irradiated medium induced oxidative stress, leading to morphological damage. Administration of the probiotic formulation significantly suppressed reactive oxygen species production, reduced epithelial damage, and preserved microarchitecture, independent of direct modulation of DNA damage. These findings suggest that probiotics may serve as promising live biotherapeutic MCM for mitigating GI-ARS in high-risk radiological exposures.

Acute coronary syndrome and sudden cardiac death are often caused by rupture and thrombosis of lipid-rich atherosclerotic coronary plaques (known as vulnerable plaques), many of which are non-flow-limiting. The safety and effectiveness of focal preventive therapy with percutaneous coronary intervention of vulnerable plaques in reducing adverse cardiac events are unknown. We aimed to assess whether preventive percutaneous coronary intervention of non-flow-limiting vulnerable plaques improves clinical outcomes compared with optimal medical therapy alone. PREVENT was a multicentre, open-label, randomised controlled trial done at 15 research hospitals in four countries (South Korea, Japan, Taiwan, and New Zealand). Patients aged 18 years or older with non-flow-limiting (fractional flow reserve >0·80) vulnerable coronary plaques identified by intracoronary imaging were randomly assigned (1:1) to either percutaneous coronary intervention plus optimal medical therapy or optimal medical therapy alone, in block sizes of 4 or 6, stratified by diabetes status and the performance of percutaneous coronary intervention in a non-study target vessel. Follow-up continued annually in all enrolled patients until the last enrolled patient reached 2 years after randomisation. The primary outcome was a composite of death from cardiac causes, target-vessel myocardial infarction, ischaemia-driven target-vessel revascularisation, or hospitalisation for unstable or progressive angina, assessed in the intention-to-treat population at 2 years. Time-to-first-event estimates were calculated with the Kaplan–Meier method and were compared with the log-rank test. This report is the principal analysis from the trial and includes all long-term analysed data. The trial is registered at ClinicalTrials.gov, NCT02316886, and is complete. Between Sept 23, 2015, and Sept 29, 2021, 5627 patients were screened for eligibility, 1606 of whom were enrolled and randomly assigned to percutaneous coronary intervention (n=803) or optimal medical therapy alone (n=803). 1177 (73%) patients were men and 429 (27%) were women. 2-year follow-up for the primary outcome assessment was completed in 1556 (97%) patients (percutaneous coronary intervention group n=780; optimal medical therapy group n=776). At 2 years, the primary outcome occurred in three (0·4%) patients in the percutaneous coronary intervention group and in 27 (3·4%) patients in the medical therapy group (absolute difference –3·0 percentage points [95% CI –4·4 to –1·8]; p=0·0003). The effect of preventive percutaneous coronary intervention was directionally consistent for each component of the primary composite outcome. Serious clinical or adverse events did not differ between the percutaneous coronary intervention group and the medical therapy group: at 2 years, four (0·5%) versus ten (1·3%) patients died (absolute difference –0·8 percentage points [95% CI –1·7 to 0·2]) and nine (1·1%) versus 13 (1·7%) patients had myocardial infarction (absolute difference –0·5 percentage points [–1·7 to 0·6]). In patients with non-flow-limiting vulnerable coronary plaques, preventive percutaneous coronary intervention reduced major adverse cardiac events arising from high-risk vulnerable plaques, compared with optimal medical therapy alone. Given that PREVENT is the first large trial to show the potential effect of the focal treatment for vulnerable plaques, these findings support consideration to expand indications for percutaneous coronary intervention to include non-flow-limiting, high-risk vulnerable plaques. The CardioVascular Research Foundation, Abbott, Yuhan Corp, CAH-Cordis, Philips, and Infraredx, a Nipro company.