Recommended approaches for integration of population pharmacokinetic modelling with precision dosing in clinical practice.

Current methods of dose determination have contributed to suboptimal and inequitable health outcomes in underrepresented patient populations. The persistent demand to individualise patient treatment, alongside increasing technological feasibility, is leading to a growing adoption of model-informed precision dosing (MIPD) at point of care. Population pharmacokinetic (popPK) modelling is a technique that supports treatment personalisation by characterising drug exposure in diverse patient groups.

Characterizing functional DNA damage and response caused by the combination of CHK1 and WEE1 inhibitors in ovarian and breast cancer models.

Background: We proposed to quantify reduction of functional DNA damage response (DDR) mechanisms caused by the combination of CHK1 and WEE1 inhibitors.

Methods: Survival of cells and tumor growth in-vitro and in-vivo caused by the combination of the CHK1 inhibitor SRA737 and the WEE1 inhibitor adavosertib was studied in OVCAR3 and MDA-MB 436 cells. Functional DNA damage was quantified using in vitro cell free DNA assays.

Liver proteomics identifies a disconnect between proteins associated with de novo lipogenesis and triglyceride storage.

De novo lipogenesis (DNL) has been implicated in the development and progression of liver steatosis. Hepatic DNL is strongly influenced by dietary macronutrient composition with diets high in carbohydrate increasing DNL while diets high in fat decrease DNL. The enzymes in the core DNL pathway have been well characterized; however, less is known about other liver proteins that play accessory or regulatory roles.

Distinct genetic origins of eumelanin levels and barring patterns in cichlid fishes.

Pigment patterns are incredibly diverse across vertebrates and are shaped by multiple selective pressures from predator avoidance to mate choice. A common pattern across fishes, but for which we know little about the underlying mechanisms, is repeated melanic vertical bars. To understand the genetic factors that modify the level or pattern of vertical barring, we generated a genetic cross of 322 F2 hybrids between two cichlid species with distinct barring patterns, Aulonocara koningsi and Metriaclima mbenjii.

Evaluation of pharmacokinetics of metoclopramide administered via subcutaneous bolus and intravenous constant rate infusion to adult horses.

Objective: To determine the pharmacokinetics (PK) of metoclopramide administered via intravenous continuous rate infusion (IV CRI) and subcutaneous (SC) bolus and evaluate for gastrointestinal motility and adverse side effects.

Study Design: Experimental study; randomized, crossover design.

Animals: Six healthy adult horses.

The Chest Wall Mass of Unknown Origin: A Rare Presentation of Esophageal Adenocarcinoma.

A chest wall mass can result from a diversity of underlying disease processes ranging from benign to a site of distant metastasis. The chest wall is a rare site for esophageal adenocarcinoma (EAC) metastasis. Delayed diagnosis can occur when presenting symptoms are not typical of esophageal pathology, and advanced-stage EAC has a high morbidity and low survival rates.

Maternal Diet High in Linoleic Acid Alters Renal Branching Morphogenesis and mTOR/AKT Signalling Genes in Rat Fetal Kidneys.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is obtained from the maternal diet during pregnancy, and is essential for normal fetal growth and development. A maternal high-LA (HLA) diet alters maternal and offspring fatty acids, maternal leptin and male/female ratio at embryonic (E) day 20 (E20). We investigated the effects of an HLA diet on embryonic offspring renal branching morphogenesis, leptin signalling, megalin signalling and angiogenesis gene expression.

Hepatic lipid droplet-associated proteome changes distinguish dietary-induced fatty liver from glucose tolerance in male mice.

Fatty liver is characterized by the expansion of lipid droplets (LDs) and is associated with the development of many metabolic diseases. We assessed the morphology of hepatic LDs and performed quantitative proteomics in lean, glucose-tolerant mice compared with high-fat diet (HFD) fed mice that displayed hepatic steatosis and glucose intolerance as well as high-starch diet (HStD) fed mice who exhibited similar levels of hepatic steatosis but remained glucose tolerant. Both HFD- and HStD-fed mice had more and larger LDs than Chow-fed animals.

Amyloid-β and caspase-1 are indicators of sepsis and organ injury.

Background: Sepsis is a life-threatening condition that results from a dysregulated host response to infection, leading to organ dysfunction. Despite the prevalence and associated socioeconomic costs, treatment of sepsis remains limited to antibiotics and supportive care, and a majority of intensive care unit (ICU) survivors develop long-term cognitive complications post-discharge. The present study identifies a novel regulatory relationship between amyloid-β (Aβ) and the inflammasome-caspase-1 axis as key innate immune mediators that define sepsis outcomes.

Tau and Aβ42 in lavage fluid of pneumonia patients are associated with end-organ dysfunction: A prospective exploratory study.

Background: Bacterial pneumonia and sepsis are both common causes of end-organ dysfunction, especially in immunocompromised and critically ill patients. Pre-clinical data demonstrate that bacterial pneumonia and sepsis elicit the production of cytotoxic tau and amyloids from pulmonary endothelial cells, which cause lung and brain injury in naïve animal subjects, independent of the primary infection. The contribution of infection-elicited cytotoxic tau and amyloids to end-organ dysfunction has not been examined in the clinical setting.

Erratum: Proteomic pathways to metabolic disease and type 2 diabetes in the pancreatic islet.

[This corrects the article DOI: 10.1016/j.isci.

Log D and plasma protein binding of synthetic cannabinoid receptor agonists and a comparison of experimental and predicted lipophilicity.

The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D ranging from 2.

A Rare Presentation of Lichen Sclerosus Involving the Vaginal Canal After Radiation Therapy: A Case Report and Review of the Literature.

Vaginal lichen sclerosus (LS) is an extremely rare entity. Classically, LS is referred to as a chronic, inflammatory skin disease with a distinct predilection for the anogenital skin that is observed in post-menopausal women and typically manifests clinically as white, atrophic plaques. Here, we report a case of a 61-year-old patient who presented for a follow-up visit three years after vaginal brachytherapy as an adjuvant treatment for endometrial adenocarcinoma.

Evaluation of urine drug screen falsification of results among patients with opioid use disorder receiving treatment in a telehealth model of care.

Introduction: As telehealth models for treatment of opioid use disorder (OUD) are expanding, the field does not know the reliability of urine drug screening (UDS) in this setting. The objective of this study is to determine the rate of falsification of UDS testing among patients with OUD in active treatment with buprenorphine via a telehealth provider.

Methods: This is a prospective cohort study of 899 randomly selected eligible patients, of which 392 participated in the final cohort that the study team used for analysis.

Changing trends in novel benzodiazepine use within Scottish prisons: detection, quantitation, prevalence, and modes of use.

Drug use within prisons is increasingly complex and unpredictable. Benzodiazepines are currently one of the most common drugs detected in individuals leaving Scottish prisons; however, understanding illicit benzodiazepine use within prisons and assessing the potential harm to individuals is challenging due to the lack of available analytical data on the substances circulating. Increasingly, materials, such as paper and clothing, infused with novel benzodiazepines have been identified as a smuggling route into Scottish prisons.

Distinct genetic origins of eumelanin intensity and barring patterns in cichlid fishes.

Pigment patterns are incredibly diverse across vertebrates and are shaped by multiple selective pressures from predator avoidance to mate choice. A common pattern across fishes, but for which we know little about the underlying mechanisms, is repeated melanic vertical bars. In order to understand genetic factors that modify the level or pattern of vertical barring, we generated a genetic cross of 322 F hybrids between two cichlid species with distinct barring patterns, and .

Genetic basis of ecologically relevant body shape variation among four genera of cichlid fishes.

Divergence in body shape is one of the most widespread and repeated patterns of morphological variation in fishes and is associated with habitat specification and swimming mechanics. Such ecological diversification is the first stage of the explosive adaptive radiation of cichlid fishes in the East African Rift Lakes. We use two hybrid crosses of cichlids (Metriaclima sp.

A Fracture From a Physical Exam: A Case Report of Osteogenesis Imperfecta and the Use of Fassier-Duval Rods.

Osteogenesis Imperfecta (OI) is a rare hereditary disorder that leads to fragile bone mineralization and is most often due to a genetic defect in type I collagen, the primary collagen subtype that comprises bone. Patients with OI suffer from a significant burden of fractures and bony deformities. It has been recognized in countries throughout the world and has a variable age and severity of presentation depending on the subtype of OI.

Nd isotope variation between the Earth-Moon system and enstatite chondrites.

Reconstructing the building blocks that made Earth and the Moon is critical to constrain their formation and compositional evolution to the present. Neodymium (Nd) isotopes identify these building blocks by fingerprinting nucleosynthetic components. In addition, the Sm-Nd and Sm-Nd decay systems, with half-lives of 103 million years and 108 billion years, respectively, track potential differences in their samarium (Sm)/Nd ratios.

Sex-specific effects of maternal dietary carbohydrate quality on fetal development and offspring metabolic phenotype in mice.

Objectives: glycemia is an important determinant of fetal growth. Women with gestational diabetes are more likely to deliver large-for-gestational age babies that are at increased risk for obesity. The maternal nutritional state modulates the development of offspring biological systems during the critical periods of gestation and lactation.

Neural crest cells as a source of microevolutionary variation.

Vertebrates have some of the most complex and diverse features in animals, from varied craniofacial morphologies to colorful pigmentation patterns and elaborate social behaviors. All of these traits have their developmental origins in a multipotent embryonic lineage of neural crest cells. This "fourth germ layer" is a vertebrate innovation and the source of a wide range of adult cell types.

Prenatal hypoxia alters the early ontogeny of dopamine neurons.

Dopaminergic (DA) dysfunction is a significant feature in the pathophysiology of schizophrenia. Established developmental risk factors for schizophrenia such as maternal immune activation (MIA) or developmental vitamin D (DVD) deficiency, when modelled in animals, reveal the differentiation of early DA neurons in foetal brains is delayed suggesting this may be a convergent aetiological pathway. Here we have assessed the effects of prenatal hypoxia, another well-known developmental risk factor for schizophrenia, on developing DA systems.