Machine-Learning Assisted Screening of Correlated Covariates: Application to Clinical Data of Desipramine.

Stepwise covariate modeling (SCM) has a high computational burden and can select the wrong covariates. Machine learning (ML) has been proposed as a screening tool to improve the efficiency of covariate selection, but little is known about how to apply ML on actual clinical data. First, we simulated datasets based on clinical data to compare the performance of various ML and traditional pharmacometrics (PMX) techniques with and without accounting for highly-correlated covariates. This simulation step identified the ML algorithm and the number of top covariates to select when using the actual clinical data. A previously developed desipramine population-pharmacokinetic model was used to simulate virtual subjects. Fifteen covariates were considered with four having an effect included. Based on the F1 score (an accuracy measure), ridge regression was the most accurate ML technique on 200 simulated datasets (F1 score = 0.475 ± 0.231), a performance which almost doubled when highly-correlated covariates were accounted for (F1 score = 0.860 ± 0.158). These performances were better than forwards selection with SCM (F1 score = 0.251 ± 0.274 and 0.499 ± 0.381 without/with correlations respectively). In terms of computational cost, ridge regression (0.42 ± 0.07 seconds/simulated dataset, 1 thread) was ~20,000 times faster than SCM (2.30 ± 2.29 hours, 15 threads). On the clinical dataset, prescreening with the selected ML algorithm reduced SCM runtime by 42.86% (from 1.75 to 1.00 days) and produced the same final model as SCM only. In conclusion, we have demonstrated that accounting for highly-correlated covariates improves ML prescreening accuracy. The choice of ML method and the proportion of important covariates (unknown a priori) can be guided by simulations.

Duet playing in dementia care: a new therapeutic music technology.

PURPOSE: Supporting the relational worlds of people living with dementia, especially the spousal dyad, is a growing focus in dementia care as is advancing the therapeutic use of music in dementia care. This paper describes a mixed-methods, multi-phase, iterative research study designed to develop the Music Memory Makers (MMM) Duet System, a novel therapeutic music technology, that allows non-musicians to play a personalized repertoire of songs arranged as duets. METHODS: Following a pilot phase to iteratively assess and refine the MMM Duet System for recreational and therapeutic purposes, multiple sources of data were used to investigate five older spousal dyads' experiences with the system, two couples living with dementia and three who were not. We assessed perceptions of task difficulty, joint agency, and enjoyment as well as therapeutic benefits associated with enhancing the spousal relationship and sense of couplehood. RESULTS: Findings suggest playing meaningful songs together is an enjoyable interactive activity that prompts musical reminiscence, involves joint agency, and supports relationship continuity within a relational, positive approach to dementia care. All couples mastered the task, none evaluated it as "very challenging," and positive couple interactions were evoked, commonly before and after playing the duets. CONCLUSIONS: The MMM Duet System is recommended for further research and development as an innovative way to support couples living with dementia with commercial implications, and as a new music technology suitable for use as a research tool.

Implications For RehabilitationMusic making is an engaging, rewarding activity promoting social bonding and wellbeing that with technology innovation, can be extended to non-musicians and people with differing skills, abilities, and preferences.The MMM Duet System is a promising new music technology that supports the relationship of people living with dementia and their spousal caregivers by encouraging relationship continuity and sense of couplehood. Supporting caregivers enables people with dementia to remain longer in their homes and communities.Practical suggestions are offered to develop music technology suitable for use by older adults and people living with dementia, e.g., involving participants who live with dementia, assembling interdisciplinary research teams, adopting iterative, participant-focused approach.

Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy.

Pulmonary fibrosis is an often fatal lung disease. Immune cells such as macrophages were shown to accumulate in the fibrotic lung, but their contribution to the fibrosis development is unclear. To recapitulate the involvement of macrophages in the development of pulmonary fibrosis, we developed a fibrotic microtissue model with cocultured human macrophages and fibroblasts. We show that profibrotic macrophages seeded on topographically controlled stromal tissues became mechanically activated. The resulting co-alignment of macrophages, collagen fibers, and fibroblasts promoted widespread fibrogenesis in micro-engineered lung tissues. Anti-fibrosis treatment using pirfenidone disrupts the polarization and mechanical activation of profibrotic macrophages, leading to fibrosis inhibition. Pirfenidone inhibits the mechanical activation of macrophages by suppressing integrin αMß2 and Rho-associated kinase 2. These results demonstrate a potential pulmonary fibrogenesis mechanism at the tissue level contributed by macrophages. The cocultured microtissue model is a powerful tool to study the immune-stromal cell interactions and the anti-fibrosis drug mechanism.

Modeling Mechanical Activation of Macrophages During Pulmonary Fibrogenesis for Targeted Anti-Fibrosis Therapy.

Pulmonary fibrosis, as seen in idiopathic pulmonary fibrosis (IPF) and COVID-induced pulmonary fibrosis, is an often-fatal lung disease. Increased numbers of immune cells such as macrophages were shown to accumulate in the fibrotic lung, but it is unclear how they contribute to the development of fibrosis. To recapitulate the macrophage mechanical activation in the fibrotic lung tissue microenvironment, we developed a fibrotic microtissue model with cocultured human macrophages and fibroblasts. We show that profibrotic macrophages seeded on topographically controlled stromal tissue constructs become mechanically activated. The resulting co-alignment of macrophages, collagen fibers and fibroblasts promote widespread fibrogenesis in micro-engineered lung tissues. Anti-fibrosis treatment using pirfenidone disrupts the polarization and mechanical activation of profibrotic macrophages, leading to fibrosis inhibition. Pirfenidone inhibits the mechanical activation of macrophages by suppressing integrin αMß2 (CD11b/CD18) and Rho-associated kinase 2, which is a previously unknown mechanism of action of the drug. Together, these results demonstrate a potential pulmonary fibrogenesis mechanism at the tissue level contributed by mechanically activated macrophages. We propose the coculture, force-sensing microtissue model as a powerful tool to study the complex immune-stromal cell interactions and the mechanism of action of anti-fibrosis drugs.

Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases.

Extracellular vesicles (EVs) carry diverse bioactive components including nucleic acids, proteins, lipids and metabolites that play versatile roles in intercellular and interorgan communication. The capability to modulate their stability, tissue-specific targeting and cargo render EVs as promising nanotherapeutics for treating heart, lung, blood and sleep (HLBS) diseases. However, current limitations in large-scale manufacturing of therapeutic-grade EVs, and knowledge gaps in EV biogenesis and heterogeneity pose significant challenges in their clinical application as diagnostics or therapeutics for HLBS diseases. To address these challenges, a strategic workshop with multidisciplinary experts in EV biology and U.S. Food and Drug Administration (USFDA) officials was convened by the National Heart, Lung and Blood Institute. The presentations and discussions were focused on summarizing the current state of science and technology for engineering therapeutic EVs for HLBS diseases, identifying critical knowledge gaps and regulatory challenges and suggesting potential solutions to promulgate translation of therapeutic EVs to the clinic. Benchmarks to meet the critical quality attributes set by the USFDA for other cell-based therapeutics were discussed. Development of novel strategies and approaches for scaling-up EV production and the quality control/quality analysis (QC/QA) of EV-based therapeutics were recognized as the necessary milestones for future investigations.

"That was a tip from my physician"-Gender-specific pathways of patients and relatives to outpatient psychosocial cancer counselling centres-A qualitative study.

OBJECTIVE: This study aims to identify pathways patients and their relatives take to outpatient psychosocial cancer counselling centres. We had a special interest in how access for men can be eased. METHODS: Cancer patients and relatives were purposively sampled in two regions in Germany. Participants were either outpatient cancer counselling centres (OCCCs) users or non-users and participated in qualitative face-to-face interviews. We used different guidelines for users and non-users. The interviews were analysed using content analysis. RESULTS: One hundred and three people participated in the study. Important pathways to outpatient psychosocial cancer counselling centres for both men and women were: information about the service and its content, easy access (obtaining appointments quickly and without bureaucracy, close to home), and recommendations from another person, in particular from their treating physician. Pathways especially important for men are positive and repeated recommendations from their treating physician and other people they trust, organisation by others on the men's behalf, the Internet, the possibility to talk to a male counsellor, making it a routine in the hospital to refer distressed patients to the counselling services, and the emphasis on information sharing. Women reported more often than men that they discovered and accessed OCCCs via information material. CONCLUSIONS: Men in particular need recommendations from others, especially from their treating physician, in order to make use of psychosocial cancer counselling. In addition, stressing the provision of information instead of exploring and expressing emotions can ease access for men to cancer counselling.

Factors affecting survival in 516 dogs that underwent cholecystectomy for the treatment of gallbladder mucocele.

Gallbladder mucocele (GBM) is a commonly diagnosed disease process in dogs that is associated with high morbidity and mortality if not recognized and appropriately managed. Although the exact mechanism of this disease process is not completely understood, previous studies in smaller populations of dogs have identified multiple factors that predispose to the development of GBM and affect survival. The purpose of this cross-sectional, retrospective study was to evaluate the effects of age, breed category, sex, preoperative antibiotic administration, gallbladder rupture, and a positive biliary culture in dogs that had a cholecystectomy performed for the treatment of GBM. The age (median: 11 years) and percentage of dogs that died within 14 days of cholecystectomy (16.7%) are similar to what have been reported in other studies. Gallbladder rupture and a positive biliary culture occurred in 20.4% and 12.5% of dogs, respectively. Dogs with a gallbladder rupture and positive biliary culture were 2.74 and 3.10 times more likely to die within 14 days of cholecystectomy, respectively. This contradicts a recent study that failed to find a significant association between survival and biliary culture result. Interestingly, younger age was associated with an increased occurrence of gallbladder rupture in that population. Because of the potential effect of gallbladder rupture and a biliary tract infection, abdominal imaging, biliary culture, and empirical preoperative antimicrobial therapy are recommended in dogs undergoing cholecystectomy for the treatment of GBM.

Facteurs affectant la survie chez 516 chiens ayant subi une cholécystectomie pour le traitement de la mucocèle de la vésicule biliaire. La mucocèle de la vésicule biliaire (GBM) est un processus pathologique couramment diagnostiqué chez les chiens qui est associé à une morbidité et une mortalité élevées s'il n'est pas reconnu et géré de manière appropriée. Bien que le mécanisme exact de ce processus pathologique ne soit pas complètement compris, des études antérieures sur de plus petites populations de chiens ont identifié de multiples facteurs qui prédisposent au développement du GBM et affectent la survie. Le but de cette étude rétrospective transversale était d'évaluer les effets de l'âge, de la catégorie de race, du sexe, de l'administration préopératoire d'antibiotiques, de la rupture de la vésicule biliaire et d'une culture biliaire positive chez les chiens ayant subi une cholécystectomie pour le traitement du GBM. L'âge (médiane : 11 ans) et le pourcentage de chiens décédés dans les 14 jours suivant la cholécystectomie (16,7 %) sont similaires à ceux rapportés dans d'autres études. Une rupture de la vésicule biliaire et une culture biliaire positive se sont produites chez 20,4 % et 12,5 % des chiens, respectivement. Les chiens présentant une rupture de la vésicule biliaire et une culture biliaire positive étaient respectivement 2,74 et 3,10 fois plus susceptibles de mourir dans les 14 jours suivant la cholécystectomie. Cela est en contradiction avec une étude récente qui n'a pas réussi à trouver une association significative entre la survie et le résultat de la culture biliaire. Fait intéressant, un âge plus jeune était associé à une fréquence accrue de rupture de la vésicule biliaire dans cette population. En raison de l'effet potentiel d'une rupture de la vésicule biliaire et d'une infection des voies biliaires, une imagerie abdominale, une culture biliaire et un traitement antimicrobien préopératoire empirique sont recommandés chez les chiens subissant une cholécystectomie pour le traitement du GBM.(Traduit par Dr Serge Messier).

An evaluation of community placements for GP registrars in Yorkshire and the Humber: 'a home visit not to a patient but to the community'.

BACKGROUND: GP registrars are required to demonstrate capabilities in 'community orientation', reflecting skills in developing and working with services that respond to community needs. These skills have sometimes been seen as vague and difficult to obtain. In the Yorkshire and the Humber Deanery of Health Education England we developed a novel programme of community placements to overcome this. Registrars spent two half-days with a community organisation of their choosing, working in their practice area. AIM: To evaluate if and how community placements enabled registrars to develop capabilities in community orientation. METHODS: All registrars completing placements were invited to participate in the evaluation; 13 (7%) accepted. Semi-structured, face-to-face and telephone interviews explored registrars' perceptions and experiences of the programme. Interviews were audio-recorded, transcribed verbatim and analysed thematically. RESULTS: The majority of participants reported that placements enabled them to attain a range of capabilities in community orientation. Registrars described an improved understanding of their practice community and the social determinants of health. Placements impacted their clinical practice by stimulating a holistic approach to the assessment and management of health needs. Our analysis described five key mechanisms for this learning: building confidence, building communities and networks of practice, gaining novel perspectives, generating a hunger for general practice and experiential learning. CONCLUSION: Community placements enabled GP registrars to attain capabilities in community orientation. Further research is required to determine the transferability of our findings and further evaluate mechanisms of learning through placements outside of training and their role in the development of professional practice.

Effect of voluntary exercise upon the metabolic syndrome and gut microbiome composition in mice.

The metabolic syndrome is a cluster of conditions that increase an individual's risk of developing diseases. Being physically active throughout life is known to reduce the prevalence and onset of some aspects of the metabolic syndrome. Furthermore, previous studies have demonstrated that an individual's gut microbiome composition has a large influence on several aspects of the metabolic syndrome. However, the mechanism(s) by which physical activity may improve metabolic health are not well understood. We sought to determine if endurance exercise is sufficient to prevent or ameliorate the development of the metabolic syndrome and its associated diseases. We also analyzed the impact of physical activity under metabolic syndrome progression upon the gut microbiome composition. Utilizing whole-body low-density lipoprotein receptor (LDLR) knockout mice on a "Western Diet," we show that long-term exercise acts favorably upon glucose tolerance, adiposity, and liver lipids. Exercise increased mitochondrial abundance in skeletal muscle but did not reduce liver fibrosis, aortic lesion area, or plasma lipids. Lastly, we observed several changes in gut bacteria and their novel associations with metabolic parameters of clinical importance. Altogether, our results indicate that exercise can ameliorate some aspects of the metabolic syndrome progression and alter the gut microbiome composition.

Modified GAN Augmentation Algorithms for the MRI-Classification of Myocardial Scar Tissue in Ischemic Cardiomyopathy.

Contrast-enhanced cardiac magnetic resonance imaging (MRI) is routinely used to determine myocardial scar burden and make therapeutic decisions for coronary revascularization. Currently, there are no optimized deep-learning algorithms for the automated classification of scarred vs. normal myocardium. We report a modified Generative Adversarial Network (GAN) augmentation method to improve the binary classification of myocardial scar using both pre-clinical and clinical approaches. For the initial training of the MobileNetV2 platform, we used the images generated from a high-field (9.4T) cardiac MRI of a mouse model of acute myocardial infarction (MI). Once the system showed 100% accuracy for the classification of acute MI in mice, we tested the translational significance of this approach in 91 patients with an ischemic myocardial scar, and 31 control subjects without evidence of myocardial scarring. To obtain a comparable augmentation dataset, we rotated scar images 8-times and control images 72-times, generating a total of 6,684 scar images and 7,451 control images. In humans, the use of Progressive Growing GAN (PGGAN)-based augmentation showed 93% classification accuracy, which is far superior to conventional automated modules. The use of other attention modules in our CNN further improved the classification accuracy by up to 5%. These data are of high translational significance and warrant larger multicenter studies in the future to validate the clinical implications.

Dietary and Pharmacologic Manipulations of Host Lipids and Their Interaction With the Gut Microbiome in Non-human Primates.

The gut microbiome influences nutrient processing as well as host physiology. Plasma lipid levels have been associated with the microbiome, although the underlying mechanisms are largely unknown, and the effects of dietary lipids on the gut microbiome in humans are not well-studied. We used a compilation of four studies utilizing non-human primates (Chlorocebus aethiops and Macaca fascicularis) with treatments that manipulated plasma lipid levels using dietary and pharmacological techniques, and characterized the microbiome using 16S rDNA. High-fat diets significantly reduced alpha diversity (Shannon) and the Firmicutes/Bacteroidetes ratio compared to chow diets, even when the diets had different compositions and were applied in different orders. When analyzed for differential abundance using DESeq2, Bulleidia, Clostridium, Ruminococcus, Eubacterium, Coprocacillus, Lachnospira, Blautia, Coprococcus, and Oscillospira were greater in both chow diets while Succinivibrio, Collinsella, Streptococcus, and Lactococcus were greater in both high-fat diets (oleic blend or lard fat source). Dietary cholesterol levels did not affect the microbiome and neither did alterations of plasma lipid levels through treatments of miR-33 antisense oligonucleotide (anti-miR-33), Niemann-Pick C1-Like 1 (NPC1L1) antisense oligonucleotide (ASO), and inducible degrader of LDLR (IDOL) ASO. However, a liver X receptor (LXR) agonist shifted the microbiome and decreased bile acid levels. Fifteen genera increased with the LXR agonist, while seven genera decreased. Pseudomonas increased on the LXR agonist and was negatively correlated to deoxycholic acid, cholic acid, and total bile acids while Ruminococcus was positively correlated with taurolithocholic acid and taurodeoxycholic acid. Seven of the nine bile acids identified in the feces significantly decreased due to the LXR agonist, and total bile acids (nmol/g) was reduced by 62%. These results indicate that plasma lipid levels have, at most, a modest effect on the microbiome, whereas bile acids, derived in part from plasma lipids, are likely responsible for the indirect relationship between lipid levels and the microbiome.

Neutrophils aid cellular therapeutics by enhancing glycoengineered stem cell recruitment and retention at sites of inflammation.

The efficacy of cell-based therapies relies on targeted payload delivery and enhanced cell retention. In vitro and in vivo studies suggest that the glycoengineering of mesenchymal and cardiosphere-derived cells (CDCs) may enhance such recruitment at sites of injury. We evaluated the role of blood cells in amplifying this recruitment. Thus, the human α(1,3)fucosyltransferase FUT7 was stably expressed in CDCs, sometimes with P-selectin glycoprotein ligand-1 (PSGL-1/CD162). Such FUT7 over-expression resulted in cell-surface sialyl Lewis-X (sLeX) expression, at levels comparable to blood neutrophils. Whereas FUT7 was sufficient for CDC recruitment on substrates bearing E-selectin under flow, PSGL-1 co-expression was necessary for P-/L-selectin binding. In both cone-plate viscometer and flow chamber studies, chemokine driven neutrophil activation promoted the adhesion of glycoengineered-CDCs to blood cells. Here, blood neutrophils activated upon contact with IL-1ß stimulated endothelial cells, amplified glycoengineered-CDC recruitment. In vivo, local inflammation in a mouse ear elicited both glycoengineered-CDC and peripheral blood neutrophil homing to the inflamed site. Glycoengineering CDCs also resulted in enhanced (~16%) cell retention at 24 h in a murine myocardial infarction model, with CDCs often co-localized with blood neutrophils. Overall, peripheral blood neutrophils, activated at sites of injury, may enhance recruitment of glycoengineered cellular therapeutics via secondary capture mechanisms.

Reduced physiologically-based pharmacokinetic model of dabigatran etexilate-dabigatran and its application for prediction of intestinal P-gp-mediated drug-drug interactions.

BACKGROUND: Dabigatran etexilate (DABE) has been suggested as a clinical probe for intestinal P-glycoprotein (P-gp)-mediated drug-drug interaction (DDI) studies and, as an alternative to digoxin. Clinical DDI data with various P-gp inhibitors demonstrated a dose-dependent inhibition of P-gp with DABE. The aims of this study were to develop a joint DABE (prodrug)-dabigatran reduced physiologically-based-pharmacokinetic (PBPK) model and to evaluate its ability to predict differences in P-gp DDI magnitude between a microdose and a therapeutic dose of DABE. METHODS: A joint DABE-dabigatran PBPK model was developed with a mechanistic intestinal model accounting for the regional P-gp distribution in the gastrointestinal tract. Model input parameters were estimated using DABE and dabigatran pharmacokinetic (PK) clinical data obtained after administration of DABE alone or with a strong P-gp inhibitor, itraconazole, and over a wide range of DABE doses (from 375 µg to 400 mg). Subsequently, the model was used to predict extent of DDI with additional P-gp inhibitors and with different DABE doses. RESULTS: The reduced DABE-dabigatran PBPK model successfully described plasma concentrations of both prodrug and metabolite following administration of DABE at different dose levels and when co-administered with itraconazole. The model was able to capture the dose dependency in P-gp mediated DDI. Predicted magnitude of itraconazole P-gp DDI was higher at the microdose (predicted vs. observed median fold-increase in AUC+inh/AUCcontrol (min-max) = 5.88 (4.29-7.93) vs. 6.92 (4.96-9.66) ) compared to the therapeutic dose (predicted median fold-increase in AUC+inh/AUCcontrol = 3.48 (2.37-4.84) ). In addition, the reduced DABE-dabigatran PBPK model predicted successfully the extent of DDI with verapamil and clarithromycin as P-gp inhibitors. Model-based simulations of dose staggering predicted the maximum inhibition of P-gp when DABE microdose was concomitantly administered with itraconazole solution; simulations also highlighted dosing intervals required to minimise the DDI risk depending on the DABE dose administered (microdose vs. therapeutic). CONCLUSIONS: This study provides a modelling framework for the evaluation of P-gp inhibitory potential of new molecular entities using DABE as a clinical probe. Simulations of dose staggering and regional differences in the extent of intestinal P-gp inhibition for DABE microdose and therapeutic dose provide model-based guidance for design of prospective clinical P-gp DDI studies.

CBR3 V244M is associated with LVEF reduction in breast cancer patients treated with doxorubicin.

BACKGROUND: The CBR3 V244M single nucleotide polymorphism has been linked to the risk of anthracycline-related cardiomyopathy in survivors of childhood cancer. There have been limited prospective studies examining the impact of CBR3 V244M on the risk for anthracycline-related cardiotoxicity in adult cohorts. OBJECTIVES: This study evaluated the presence of associations between CBR3 V244M genotype status and changes in echocardiographic parameters in breast cancer patients undergoing doxorubicin treatment. METHODS: We recruited 155 patients with breast cancer receiving treatment with doxorubicin (DOX) at Roswell Park Comprehensive Care Center (Buffalo, NY) to a prospective single arm observational pharmacogenetic study. Patients were genotyped for the CBR3 V244M variant. 92 patients received an echocardiogram at baseline (t0 month) and at 6 months (t6 months) of follow up after DOX treatment. Apical two-chamber and four-chamber echocardiographic images were used to calculate volumes and left ventricular ejection fraction (LVEF) using Simpson's biplane rule by investigators blinded to all patient data. Volumetric indices were evaluated by normalizing the cardiac volumes to the body surface area (BSA). RESULTS: Breast cancer patients with CBR3 GG and AG genotypes both experienced a statistically significant reduction in LVEF at 6 months following initiation of DOX treatment for breast cancer compared with their pre-DOX baseline study. Patients homozygous for the CBR3 V244M G allele (CBR3 V244) exhibited a further statistically significant decrease in LVEF at 6 months following DOX therapy in comparison with patients with heterozygous AG genotype. We found no differences in age, pre-existing cardiac diseases associated with myocardial injury, cumulative DOX dose, or concurrent use of cardioprotective medication between CBR3 genotype groups. CONCLUSIONS: CBR3 V244M genotype status is associated with changes in echocardiographic parameters suggestive of early anthracycline-related cardiomyopathy in subjects undergoing chemotherapy for breast cancer.

Machine Learning Reveals Time-Varying Microbial Predictors with Complex Effects on Glucose Regulation.

The incidence of type 2 diabetes (T2D) has been increasing globally, and a growing body of evidence links type 2 diabetes with altered microbiota composition. Type 2 diabetes is preceded by a long prediabetic state characterized by changes in various metabolic parameters. We tested whether the gut microbiome could have predictive potential for T2D development during the healthy and prediabetic disease stages. We used prospective data of 608 well-phenotyped Finnish men collected from the population-based Metabolic Syndrome in Men (METSIM) study to build machine learning models for predicting continuous glucose and insulin measures in a shorter (1.5 year) and longer (4 year) period. Our results show that the inclusion of the gut microbiome improves prediction accuracy for modeling T2D-associated parameters such as glycosylated hemoglobin and insulin measures. We identified novel microbial biomarkers and described their effects on the predictions using interpretable machine learning techniques, which revealed complex linear and nonlinear associations. Additionally, the modeling strategy carried out allowed us to compare the stability of model performance and biomarker selection, also revealing differences in short-term and long-term predictions. The identified microbiome biomarkers provide a predictive measure for various metabolic traits related to T2D, thus providing an additional parameter for personal risk assessment. Our work also highlights the need for robust modeling strategies and the value of interpretable machine learning.IMPORTANCE Recent studies have shown a clear link between gut microbiota and type 2 diabetes. However, current results are based on cross-sectional studies that aim to determine the microbial dysbiosis when the disease is already prevalent. In order to consider the microbiome as a factor in disease risk assessment, prospective studies are needed. Our study is the first study that assesses the gut microbiome as a predictive measure for several type 2 diabetes-associated parameters in a longitudinal study setting. Our results revealed a number of novel microbial biomarkers that can improve the prediction accuracy for continuous insulin measures and glycosylated hemoglobin levels. These results make the prospect of using the microbiome in personalized medicine promising.

Fast Stereolithography Printing of Large-Scale Biocompatible Hydrogel Models.

Large size cell-laden hydrogel models hold great promise for tissue repair and organ transplantation, but their fabrication using 3D bioprinting is limited by the slow printing speed that can affect the part quality and the biological activity of the encapsulated cells. Here a fast hydrogel stereolithography printing (FLOAT) method is presented that allows the creation of a centimeter-sized, multiscale solid hydrogel model within minutes. Through precisely controlling the photopolymerization condition, low suction force-driven, high-velocity flow of the hydrogel prepolymer is established that supports the continuous replenishment of the prepolymer solution below the curing part and the nonstop part growth. The rapid printing of centimeter-sized hydrogel models using FLOAT is shown to significantly reduce the part deformation and cellular injury caused by the prolonged exposure to the environmental stresses in conventional 3D printing methods. Embedded vessel networks fabricated through multiscale printing allows media perfusion needed to maintain the high cellular viability and metabolic functions in the deep core of the large-sized models. The endothelialization of this vessel network allows the establishment of barrier functions. Together, these studies demonstrate a rapid 3D hydrogel printing method and represent a first step toward the fabrication of large-sized engineered tissue models.

Genetic regulation of liver lipids in a mouse model of insulin resistance and hepatic steatosis.

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.

Impact of Hepatic CYP3A4 Ontogeny Functions on Drug-Drug Interaction Risk in Pediatric Physiologically-Based Pharmacokinetic/Pharmacodynamic Modeling: Critical Literature Review and Ivabradine Case Study.

Clinical assessment of drug-drug interactions (DDIs) in children is not a common practice in drug development. Therefore, physiologically-based pharmacokinetic (PBPK) modeling can be beneficial for informing drug labeling. Using ivabradine and its metabolite (both cytochrome P450 3A4 enzyme (CYP3A4) substrates), the objectives were (i) to scale ivabradine-metabolite adult PBPK/PD to pediatrics, (ii) to predict the DDIs with a strong CYP3A4 inhibitor, and (iii) to compare the sensitivity of children to DDIs using two CYP3A4 hepatic ontogeny functions: Salem and Upreti. A scaled parent-metabolite PBPK/PD model from adults to children satisfactorily predicted pharmacokinetics (PK) and pharmacodynamics (PD) in 74 children (0.5-18 years) regardless of CYP3A4 hepatic ontogeny function applied. However, using the Salem ontogeny, mean predicted parent and metabolite area under the concentration-time curve over 12 hours (AUC12h ) and heart rate change from baseline were 2-fold, 1.5-fold, and 1.4-fold higher in young children (0.5-3 years old) compared with Upreti ontogeny, respectively. Despite these differences, choice of appropriate hepatic CYP3A4 ontogeny was challenging due to sparse PK and PD data. Different sensitivity to ivabradine-ketoconazole DDIs was simulated in young children relative to adults depending on the choice of hepatic CYP3A4 ontogeny. Predicted ivabradine and metabolite AUCDDI /AUCcontrol were 2-fold lower in the youngest children (0.5-1 year old) compared with adults (Salem function). In contrast, the Upreti function predicted comparable ivabradine DDIs across all age groups, although predicted metabolite AUCDDI/ AUCcontrol was 1.3-fold higher between the youngest children and adults. In the case of PD, differences in predicted DDIs were minor across age groups and between both functions. Current work highlights the importance of careful consideration of hepatic CYP3A4 ontogeny function and implications on labeling recommendations in the pediatric population.

Systems toxicogenomics of prenatal low-dose BPA exposure on liver metabolic pathways, gut microbiota, and metabolic health in mice.

Bisphenol A (BPA) is an industrial plasticizer widely found in consumer products, and exposure to BPA during early development has been associated with the prevalence of various cardiometabolic diseases including obesity, metabolic syndrome, type 2 diabetes, and cardiovascular diseases. To elucidate the molecular perturbations underlying the connection of low-dose prenatal BPA exposure to cardiometabolic diseases, we conducted a multi-dimensional systems biology study assessing the liver transcriptome, gut microbial community, and diverse metabolic phenotypes in both male and female mouse offspring exposed to 5 µg/kg/day BPA during gestation. Prenatal exposure to low-dose BPA not only significantly affected liver genes involved in oxidative phosphorylation, PPAR signaling and fatty acid metabolism, but also affected the gut microbial composition in an age- and sex-dependent manner. Bacteria such as those belonging to the S24-7 and Lachnospiraceae families were correlated with offspring phenotypes, differentially expressed liver metabolic genes such as Acadl and Dgat1, and key drivers identified in our gene network modeling such as Malat1 and Apoa2. This multiomics study provides insight into the relationship between gut bacteria and host liver genes that could contribute to cardiometabolic disease risks upon low-dose BPA exposure.