Prediction of human pharmacokinetics from chemical structure: combining mechanistic modeling with machine learning.

Pharmacokinetics (PK) is the result of a complex interplay between compound properties and physiology, and a detailed characterization of a molecule's PK during preclinical research is key to understanding the relationship between applied dose, exposure, and pharmacological effect. Predictions of human PK based on the chemical structure of a compound are highly desirable to avoid advancing compounds with unfavorable properties early on and to reduce animal testing, but data to train such models are scarce. To address this problem, we combine well-established physiologically based pharmacokinetic models with Deep Learning models for molecular property prediction into a hybrid model to predict PK parameters for small molecules directly from chemical structure.

A deep neural network: mechanistic hybrid model to predict pharmacokinetics in rat.

An important aspect in the development of small molecules as drugs or agrochemicals is their systemic availability after intravenous and oral administration. The prediction of the systemic availability from the chemical structure of a potential candidate is highly desirable, as it allows to focus the drug or agrochemical development on compounds with a favorable kinetic profile. However, such predictions are challenging as the availability is the result of the complex interplay between molecular properties, biology and physiology and training data is rare.

Wetting Characteristics of Laser-Ablated Hierarchical Textures Replicated by Micro Injection Molding.

Texturing can be used to functionalize the surface of plastic parts and, in particular, to modify the interaction with fluids. Wetting functionalization can be used for microfluidics, medical devices, scaffolds, and more. In this research, hierarchical textures were generated on steel mold inserts using femtosecond laser ablation to transfer on plastic parts surface via injection molding.

Care When It Counts: Establishing Trauma-Sensitive Care as a Preventative Approach for 0-3-Year-Old Children Suffering from Trauma and Chronic Stress.

Adverse childhood experiences are an important societal concern. Children aged 0-3 are particularly vulnerable to unpredictable chronic stress due to the critical period for brain development and attachment. Trauma-sensitive care is a preventative approach to reduce the burden of stressful experiences by committing to positive relationships.

The Development of a Screening Tool for Childcare Professionals to Detect and Refer Infant and Toddler Maltreatment and Trauma: A Tale of Four Countries.

Unlabelled: Child maltreatment is considered a pressing social question, compromising the present and future mental and physical health of one in four children in Europe. While children younger than three years of age are especially vulnerable, few screening instruments are available for the detection of risk in this age group. The purpose of this research was to develop a screening tool for childcare professionals working in public and private daycare settings to support them in the early identification and referral of infants and toddlers exposed to emotional and physical abuse and neglect by primary caregivers, to be used in different settings across four European countries: Belgium, Italy, Latvia, and Hungary.

Hepatic arterial infusion of irinotecan and EmboCept S results in high tumor concentration of SN-38 in a rat model of colorectal liver metastases.

Intraarterial chemotherapy for colorectal liver metastases (CRLM) can be applied alone or together with embolization particles. It remains unclear whether different types of embolization particles lead to higher intratumoral drug concentration. Herein, we quantified the concentrations of CPT-11 and its active metabolite SN-38 in plasma, liver and tumor tissue after hepatic arterial infusion (HAI) of irinotecan, with or without further application of embolization particles, in a rat model of CRLM.

Monitoring of erlotinib in pancreatic cancer patients during long-time administration and comparison to a physiologically based pharmacokinetic model.

Purpose: In this study, a therapeutic drug monitoring (TDM) of erlotinib in pancreatic cancer patients was performed over 50 weeks to reveal possible alterations in erlotinib plasma concentrations. Additionally, a physiologically based pharmacokinetic (PBPK) model was created to assess such variations in silico.

Methods: Patients with advanced pancreatic cancer received a chemotherapeutic combination of 100 mg erlotinib q.

Inotropic effect of NCX inhibition depends on the relative activity of the reverse NCX assessed by a novel inhibitor ORM-10962 on canine ventricular myocytes.

Na/Ca exchanger (NCX) is the main Ca transporter in cardiac myocytes. Its inhibition could be expected to exert positive inotropic action by accumulation of cytosolic Ca ([Ca]). However, we have observed only a marginal positive inotropic effect upon selective inhibition of NCX, which was enhanced when forward activity was facilitated.

Comparison of pulmonary vascular permeability index PVPI and global ejection fraction GEF derived from jugular and femoral indicator injection using the PiCCO-2 device: A prospective observational study.

Background: Transpulmonary thermodilution (TPTD) is used to derive cardiac output CO, global end-diastolic volume GEDV and extravascular lung water EVLW. To facilitate interpretation of these data, several ratios have been developed, including pulmonary vascular permeability index (defined as EVLW/(0.25*GEDV)) and global ejection fraction ((4*stroke volume)/GEDV).

Complex partial cluster seizures in cats with orofacial involvement.

Seventeen cats were presented with acute onset of complex partial seizures with orofacial involvement (salivation, facial twitching, lip smacking, chewing, licking or swallowing), motor arrest (motionless starring) and behavioural changes. In 11 cats hippocampal necrosis (HN) was confirmed by histopathology. In a further six cats hippocampal changes were suggested by magnetic resonance imaging.

Diagnostic markers for encephalitozoonosis in pet rabbits.

Encephalitozoonosis is a common disease in pet rabbits, routinely diagnosed in vivo by serological examination or post mortem by histopathology. Recently molecular techniques have become increasingly important as diagnostic tools. The application of different diagnostic markers for in vivo and post mortem determination of E.

Encephalitozoonosis in pet rabbits (Oryctolagus cuniculus): pathohistological findings in animals with latent infection versus clinical manifestation.

Encephalitozoon cuniculi is a common infectious agent of rabbits. The aim of this study was to determine the distribution and extent of histological lesions in the brain and in the kidney of naturally infected pet rabbits with or without clinical encephalitozoonosis. In 71 animals (33 with symptoms) which died or were euthanised, histopathological examination including staining of spores (Ziehl-Neelsen, acid-fast trichrome) was performed and changes were described quantitatively.

Clinical symptoms and diagnosis of encephalitozoonosis in pet rabbits.

Infections with Encephalitozoon cuniculi in rabbits are observed at increasing frequency and are known as opportunistic infections in immunocompromised humans. 191 pet rabbits with suspected encephalitozoonosis, presented at the Animal Hospital of the Veterinary University of Vienna (Austria), were included in this study. Rabbits were serologically examined for antibodies against E.

Poxvirus infection in a great tit (Parus major).

Four great tits (Parus major) with nodular lesions suggestive of poxvirus infections were observed in a garden in Vienna, Austria. One of the birds was submitted for examination. Because of its poor condition, the bird had to be euthanatized and was subsequently necropsied.

Malignant B-cell lymphoma of the Harder's gland in a rabbit.

A 22-month-old, female rabbit was presented with a 1-day history of acute unilateral exophthalmos. Ultrasonography and computed tomography (CT) of the orbit revealed an orbital mass. Retrobulbar lymphoma was diagnosed following fine-needle aspiration biopsy (FNAB).