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.

"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.

Monocyte recruitment and fate specification after myocardial infarction.

Monocytes are critical mediators of the inflammatory response following myocardial infarction (MI) and ischemia-reperfusion injury. They are involved in both initiation and resolution of inflammation and play an integral role in cardiac repair. The antagonistic nature of their function is dependent on their subset heterogeneity and biphasic response following injury. New advancements in single-cell transcriptomics and mass cytometry have allowed us to identify smaller, transcriptionally distinct clusters that may have functional relevance in disease and homeostasis. Additionally, recent insights into the spatiotemporal dynamics of monocytes following ischemic injury and their subsequent interactions with the endothelium and other immune cells reveal a complex interplay between monocytes and the cardiac milieu. In this review, we highlight recent findings on monocyte functional heterogeneity, present new mechanistic insight into monocyte recruitment and fate specification following MI, and discuss promising therapeutic avenues targeting monocytes for the treatment of ischemic heart disease.

CDC-derived extracellular vesicles reprogram inflammatory macrophages to an arginase 1-dependent proangiogenic phenotype.

Macrophages play a pivotal role in tissue repair following myocardial infarction (MI). In response to injury, they exist along a spectrum of activation states tightly regulated by their microenvironment. Cardiosphere-derived cells (CDCs) have been shown to mediate cardioprotection via modulation of the macrophage response. Our study was designed to gain mechanistic insight into the role of CDC-derived extracellular vesicles (EVs) in modulating macrophage phenotypes and operant signaling pathways to better understand their potential contribution to immunomodulatory cardioprotection. We found that CDC-derived EVs alter the functional phenotype of macrophages, modifying levels of phagocytosis and efferocytosis without changing viability or proliferation. Interestingly, extracellular vesicles differentially regulate several M1/M2 genes dependent on macrophage activation before EV treatment but consistently upregulate arginase 1 regardless of macrophage origin or polarization state. CDC-derived EVs polarize M1 macrophages to a proangiogenic phenotype dependent on arginase 1 upregulation and independent of VEGF-A. In addition, EV-dependent arginase 1 upregulation downregulates nitric oxide (NO) secretion in activated macrophages. These data suggest a novel urea-cycle-dependent mechanism in macrophages that promotes angiogenesis and provides additional mechanistic insight into the potential contribution of CDC-derived extracellular vesicles in immunomodulatory cardioprotection.NEW & NOTEWORTHY We hypothesized that in the window of therapeutic extracellular vesicle (EV) administration, inflammatory M1 macrophages are likely the primary target of cardiosphere-derived cell (CDC)-derived EVs. The effect of CDC-EVs on this population, however, is currently unknown. In this study, we demonstrate that CDC-derived EVs polarize M1 macrophages to a proangiogenic phenotype dependent on arginase 1 upregulation. These results provide insight into an immunomodulatory mechanism of CDC-EVs in a more physiologically relevant model of post-myocardial infarction (post-MI) macrophage polarization.

Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to Fructose Consumption in Mice.

BACKGROUND: It is unclear how high fructose consumption induces disparate metabolic responses in genetically diverse mouse strains. OBJECTIVE: We aimed to investigate whether the gut microbiota contributes to differential metabolic responses to fructose. METHODS: Eight-week-old male C57BL/6J (B6), DBA/2J (DBA), and FVB/NJ (FVB) mice were given 8% fructose solution or regular water (control) for 12 wk. The gut microbiota composition in cecum and feces was analyzed using 16S ribosomal DNA sequencing, and permutational multivariate ANOVA (PERMANOVA) was used to compare community across mouse strains, treatments, and time points. Microbiota abundance was correlated with metabolic phenotypes and host gene expression in hypothalamus, liver, and adipose tissues using Biweight midcorrelation. To test the causal role of the gut microbiota in determining fructose response, we conducted fecal transplants from B6 to DBA mice and vice versa for 4 wk, as well as gavaged antibiotic-treated DBA mice with Akkermansia for 9 wk, accompanied with or without fructose treatment. RESULTS: Compared with B6 and FVB, DBA mice had significantly higher Firmicutes to Bacteroidetes ratio and lower baseline abundance of Akkermansia and S24-7 (P < 0.05), accompanied by metabolic dysregulation after fructose consumption. Fructose altered specific microbial taxa in individual mouse strains, such as a 7.27-fold increase in Akkermansia in B6 and 0.374-fold change in Rikenellaceae in DBA (false discovery rate <5%), which demonstrated strain-specific correlations with host metabolic and transcriptomic phenotypes. Fecal transplant experiments indicated that B6 microbes conferred resistance to fructose-induced weight gain in DBA mice (F = 43.1, P < 0.001), and Akkermansia colonization abrogated the fructose-induced weight gain (F = 17.8, P < 0.001) and glycemic dysfunctions (F = 11.8, P = 0.004) in DBA mice. CONCLUSIONS: Our findings support that differential microbiota composition between mouse strains is partially responsible for host metabolic sensitivity to fructose, and that Akkermansia is a key bacterium that confers resistance to fructose-induced metabolic dysregulation.

Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential.

RATIONALE: Gut microbes influence cardiovascular disease and thrombosis risks through the production of trimethylamine N-oxide (TMAO). Microbiota-dependent generation of trimethylamine (TMA)-the precursor to TMAO-is rate limiting in the metaorganismal TMAO pathway in most humans and is catalyzed by several distinct microbial choline TMA-lyases, including the proteins encoded by the cutC/D (choline utilization C/D) genes in multiple human commensals. OBJECTIVE: Direct demonstration that the gut microbial cutC gene is sufficient to transmit enhanced platelet reactivity and thrombosis potential in a host via TMA/TMAO generation has not yet been reported. METHODS AND RESULTS: Herein, we use gnotobiotic mice and a series of microbial colonization studies to show that microbial cutC-dependent TMA/TMAO production is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host. Specifically, we examine in vivo thrombosis potential employing germ-free mice colonized with either high TMA-producing stable human fecal polymcrobial communities or a defined CutC-deficient background microbial community coupled with a CutC-expressing human commensal±genetic disruption of its cutC gene (ie, Clostridium sporogenes Δ cutC). CONCLUSIONS: Collectively, these studies point to the microbial choline TMA-lyase pathway as a rational molecular target for the treatment of atherothrombotic heart disease.

Evaluation of Nodular Splenic Lesions in 370 Small-Breed Dogs (<15 kg).

Three hundred seventy small-breed dogs (<15 kg) undergoing splenectomy for the presence of nodular splenic lesions were evaluated in a retrospective study to assess associations with breeds, malignancy, hemoperitoneum, and median survival time compared with previous studies. Data analyzed included signalment, histopathologic diagnosis, presence or absence of hemoperitoneum, breed associations, and survival times. In the current study, 44% (163/370) of dogs had nonneoplastic splenic lesions and 56% (207/370) had neoplastic lesions. Hemangiosarcoma was present in 27% (100/370) of splenic lesions. Hemoperitoneum was present in 31% (115/370) of dogs, and of this population, 66% (76/115) had malignant splenic lesions. The most common breeds were miniature schnauzers, dachshunds, and beagles, with beagles exhibiting a positive association with malignancy. The presence of hemoperitoneum was associated with malignancy. Distribution for nodular splenic lesions, correlation of hemoperitoneum to malignancy, and median survival time were similar to previous reports in large-breed dogs. Small-breed dogs who present with hemoperitoneum are 2.6 times more likely to have a diagnosis of a malignant splenic lesion. The most common small-breed dogs with nodular splenic lesions were miniature schnauzers, dachshunds, and beagles. Beagles and small-breed terriers were more likely to have malignant splenic lesions, and small-breed terriers were more likely to present with hemoperitoneum.

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.

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.

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.

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.

Does temporary chest wall closure with or without chest packing improve survival for trauma patients in shock after emergent thoracotomy?

BACKGROUND: Many surgeons avoid the damage-control techniques of intrathoracic packing and temporary chest wall closure after thoracotomy for trauma because of concerns about packing's effects on intrathoracic pressure and infectious risks. We hypothesized that temporary chest closure with or without intrathoracic packing (TCC-P) as a method of thoracic damage control would yield higher than expected survival rates for trauma thoracotomy patients with metabolic exhaustion, whereas traditional definitive chest closure (DEF) would exhibit predicted survival rates. METHODS: This was a retrospective cohort study by two urban Level I trauma centers on patients who (1) underwent emergent thoracotomy for trauma, (2) received ≥10 units (U) packed red blood cells and/or sustained a cardiac arrest before starting chest closure, and (3) survived to intensive care unit arrival. Demographic/physiologic data, chest closure method, and thoracic complications were gathered. Trauma injury severity scores (TRISS) were used to calculate survival probability for TCC-P and DEF. Nonparametric statistics were used for all comparisons. All values are expressed as medians and interquartile ranges (IQR). RESULTS: Sixty-one patients met inclusion criteria. Both TCC-P (n = 17) and DEF (n = 44) were severely injured (ISS=35 [IQR, 25-42] vs. 29 [IQR 19-45] and packed red blood cells = 16.5 U [IQR, 12.3-25.5 U] vs. 15 U [IQR, 11-23 U], respectively; p=ns). Patient demographics were similar except for the findings that the TCC-P cohort had higher rates of cardiac arrest before starting chest closure (TCC-P 82% vs. DEF 48%, p=0.04), significantly more severe abdominal injuries, and less severe head injuries than the DEF group. No significant differences were observed in survival of the overall samples (TCC-P=47% vs. DEF=57%), nor for observed:expected (O:E) survival ratio in 13 patients with TCC-P and 30 with DEF meeting criteria for TRISS calculation (TCC-P O:E, 46%:39%; DEF O:E, 53%:57%). No significant differences were found for TCC-P and DEF thoracic infectious (24% vs. 25%) or hemorrhagic (18% vs. 14%) complications. Surprisingly, peak inspiratory pressures on intensive care unit arrival were markedly better after TCC-P (20 cm H2O [IQR, 18-31 cm H2O]) than after DEF (32.5 cm H2O [IQR, 28-37.5 cm H2O], p=0.003). CONCLUSION: Concerns about TCC-P are not borne out as thoracic infection rates are unaffected and peak pressures are actually lower, possibly due to greater pleural volume from an open chest wall and skin-only closure. However, no significant survival benefit was seen with TCC-P.

Elective and emergency surgical management of adrenal gland tumors: 60 cases (1999-2006).

Sixty-one adrenal gland tumors were surgically removed from 60 dogs. Fifty-two dogs underwent elective adrenalectomy and 8 dogs underwent emergency adrenalectomy for acute adrenal hemorrhage. Size of adrenal tumors ranged from 10 mm to 80 mm. Histopathology confirmed a diagnosis of adrenocortical tumor in 47 dogs, 26 of which were malignant. Pheochromocytoma was diagnosed in 11 dogs. Six dogs had tumor invasion of the caudal vena cava. Of the seven dogs that did not survive the perioperative period, four underwent emergency adrenalectomy. No dogs with tumor invasion of the caudal vena cava died perioperatively. Perioperative morality rates were 5.7% for dogs that underwent elective adrenalectomy and 50% for dogs that underwent emergency adrenalectomy for acute adrenal hemorrhage. Median survival time was 492 days for the 53 dogs that survived the perioperative period. Of the factors analyzed, only adrenal tumor size and the presence of acute adrenal hemorrhage had predictive values for perioperative mortality. Those dogs that survived the perioperative period had extended survival times of up to 1,590 days. The mortality rate associated with elective adrenalectomy in dogs may be lower than previously reported. Dogs with very large tumors or acute adrenal hemorrhage may have a more guarded prognosis.

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.

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.

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.