Phase 1 Studies to Assess Inhaled Seralutinib as a Perpetrator or a Victim of Drug-Drug Interactions in Healthy Participants.

Seralutinib, an inhaled, small-molecule tyrosine kinase inhibitor in clinical development for the treatment of pulmonary arterial hypertension (PAH), was evaluated for its potential as a perpetrator or victim of a metabolic and transporter-based drug-drug interactions in 2 phase 1 studies. In study 1, 24 participants received a cocktail of probe substrates: caffeine (CYP1A2), montelukast (CYP2C8), flurbiprofen (CYP2C9), midazolam (CYP3A), and pravastatin (OATP1B1/1B3), plus digoxin (P-gp) with or without seralutinib. In study 2, 19 participants received seralutinib with/without itraconazole, a strong CYP3A inhibitor, or fosaprepitant, a weak CYP3A inhibitor.

GRK5 is required for adipocyte differentiation through ERK activation.

Previous studies have identified G protein-coupled receptor (GPCR) kinase 5 (GRK5) as a genetic factor contributing to obesity pathogenesis, but the underlying mechanism remains unclear. We demonstrate here that Grk5 mRNA is more abundant in stromal vascular fractions of mouse white adipose tissue, the fraction that contains adipose progenitor cells, or committed pre-adipocytes, than in adipocyte fractions. Thus, we generated a GRK5 knockout (KO) 3T3-L1 pre-adipocyte to further investigate the mechanistic role of GRK5 in regulating adipocyte differentiation.

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation.

One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing knockout mice that are deficient in synthesizing itaconate, we aimed to understand the metabolic role of itaconate in the liver and systemically during sepsis.

ABHD4 regulates adipocyte differentiation in vitro but does not affect adipose tissue lipid metabolism in mice.

Alpha/beta hydrolase domain-containing protein 4 (ABHD4) catalyzes the deacylation of N-acyl phosphatidyl-ethanolamine (NAPE) and lyso-NAPE to produce glycerophospho-N-acyl ethanolamine (GP-NAE). Through a variety of metabolic enzymes, NAPE, lyso-NAPE, and GP-NAE are ultimately converted into NAE, a group of bioactive lipids that control many physiological processes including inflammation, cognition, food intake, and lipolysis (i.e.

Assessment of inter-centre agreement across multidisciplinary team meetings for patients with retroperitoneal sarcoma.

Background: Decision-making in the management of patients with retroperitoneal sarcoma is complex and requires input from a number of different specialists. The aim of this study was to evaluate the levels of agreement in terms of resectability, treatment allocation, and organs proposed to be resected across different retroperitoneal sarcoma multidisciplinary team meetings.

Methods: The CT scans and clinical information of 21 anonymized retroperitoneal sarcoma patients were sent to all of the retroperitoneal sarcoma multidisciplinary team meetings in Great Britain, which were asked to give an opinion about resectability, treatment allocation, and organs proposed to be resected.

Production and Testing of RNA Origami Anticoagulants.

Nucleic acid nanotechnology provides the ability to create unprecedented nanostructures with diverse architectures and functions that can be utilized in myriad fields. A set of self-folding, single-stranded RNA origami structures bearing thrombin RNA aptamers have been demonstrated to act as anticoagulants. Here, we describe the detailed methods of producing and testing of such RNA origami anticoagulants.

Corrigendum: Genetic inactivation of inclusion membrane protein CT228 alters MYPT1 recruitment, extrusion production, and longevity of infection.

[This corrects the article DOI: 10.3389/fcimb.2018.

Optical coherence tomography-guided Nd:YAG laser treatment and follow-up of basal cell carcinoma.

Objectives: Basal cell carcinoma (BCC) is the most common skin tumor with an annually increasing incidence. Standard care requires several visits for diagnosis and treatment. Optical coherence tomography (OCT) as a diagnostic tool increases the sensitivity (95%) and specificity (77%) of the diagnosis of BCC.

Redox integration of signaling and metabolism in a head and neck cancer model of radiation resistance using COSM.

Redox metabolism is increasingly investigated in cancer as driving regulator of tumor progression, response to therapies and long-term patients' quality of life. Well-established cancer therapies, such as radiotherapy, either directly impact redox metabolism or have redox-dependent mechanisms of action defining their clinical efficacy. However, the ability to integrate redox information across signaling and metabolic networks to facilitate discovery and broader investigation of redox-regulated pathways in cancer remains a key unmet need limiting the advancement of new cancer therapies.

Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults.

Background: Neurodegenerative diseases are devastating conditions that most commonly affect individuals 65 years and older. Currently there are no effective treatments or cures for neurodegenerative diseases, and therapeutics that selectively target the underlying causes of these diseases are needed. Epichaperomes play a major role in the maintenance and progression of neuronal pathology.

Genetic Mapping of Multiple Traits Identifies Novel Genes for Adiposity, Lipids, and Insulin Secretory Capacity in Outbred Rats.

Despite the successes of human genome-wide association studies, the causal genes underlying most metabolic traits remain unclear. We used outbred heterogeneous stock (HS) rats, coupled with expression data and mediation analysis, to identify quantitative trait loci (QTLs) and candidate gene mediators for adiposity, glucose tolerance, serum lipids, and other metabolic traits. Physiological traits were measured in 1,519 male HS rats, with liver and adipose transcriptomes measured in >410 rats.

Patients undergoing colorectal surgery at a Veterans Affairs Hospital do not experience racial disparity in length of stay either before or after implementing an enhanced recovery pathway.

Background: Enhanced Recovery Pathways (ERP) have been shown to reduce racial disparities following surgery. The objective of this study is to determine whether ERP implementation mitigates racial disparities at a Veterans Affairs Hospital.

Methods: A retrospective cohort study was conducted using data obtained from the Veterans Affairs Surgical Quality Improvement Program.

Journey to a new era: An innovative academic-practice partnership.

Successful academic-clinical partnerships are mutually beneficial for academic nursing and clinical organizations, supporting the long-term success of nursing programs while simultaneously improving patient outcomes. Advocated by the American Association of Colleges of Nursing in their 2016 report, Advancing Healthcare Transformation: New Era for Academic Nursing, this position paper provides six actions for transforming academic nursing. However, developing sustainable academic-practice models has proven challenging despite this roadmap, as research has not substantiated their benefits.

A phase I randomized, double-blind, single subcutaneous dose escalation study to determine the safety, tolerability, and pharmacokinetics of rezafungin in healthy adult subjects.

Rezafungin is a novel echinocandin being developed for the treatment and prevention of invasive fungal infections. The objectives of this randomized, double-blind study in healthy adults were to determine the safety, tolerability, and pharmacokinetics of rezafungin after subcutaneous (s.c.

Reducing infantile anemia: insight on patterns of process and outcome indicators by ethnicity and socioeconomic class during a 10-year intervention program and 5 years after.

Background: In 2005, Clalit Health Services (CHS), the largest health maintenance organization in Israel, initiated an intervention program aimed at reducing the prevalence rate of infantile anemia (IA). This study evaluated the progress made during the intervention (2005-2014) and its yield 5 years after it ended (2019).

Methods: The CHS database was retrospectively reviewed twice yearly from 2005 to 2014 for repetitive samples of children aged 9 to 18 months regarding the previous half-year interval, and a single sample in 2019.

Genetic variation in satiety signaling and hypothalamic inflammation: merging fields for the study of obesity.

Although obesity has been a longstanding health crisis, the genetic architecture of the disease remains poorly understood. Genome-wide association studies have identified many genomic loci associated with obesity, with genes being enriched in the brain, particularly in the hypothalamus. This points to the role of the central nervous system (CNS) in predisposition to obesity, and we emphasize here several key genes along the satiety signaling pathway involved in genetic susceptibility.

Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in pregnancy.

To evaluate the effectiveness of the BNT162b2 messenger RNA vaccine in pregnant women, we conducted an observational cohort study of pregnant women aged 16 years or older, with no history of SARS-CoV-2, who were vaccinated between 20 December 2020 and 3 June 2021. A total of 10,861 vaccinated pregnant women were matched to 10,861 unvaccinated pregnant controls using demographic and clinical characteristics. Study outcomes included documented infection with SARS-CoV-2, symptomatic COVID-19, COVID-19-related hospitalization, severe illness and death.

Self-Assembling Nucleic Acid Nanostructures Functionalized with Aptamers.

Researchers have worked for many decades to master the rules of biomolecular design that would allow artificial biopolymer complexes to self-assemble and function similarly to the diverse biochemical constructs displayed in natural biological systems. The rules of nucleic acid assembly (dominated by Watson-Crick base-pairing) have been less difficult to understand and manipulate than the more complicated rules of protein folding. Therefore, nucleic acid nanotechnology has advanced more quickly than protein design, and recent years have seen amazing progress in DNA and RNA design.

Multivalent Aptamer-Functionalized Single-Strand RNA Origami as Effective, Target-Specific Anticoagulants with Corresponding Reversal Agents.

Anticoagulants are commonly utilized during surgeries and to treat thrombotic diseases like stroke and deep vein thrombosis. However, conventional anticoagulants have serious side-effects, narrow therapeutic windows, and lack safe reversal agents (antidotes). Here, an alternative RNA origami displaying RNA aptamers as target-specific anticoagulant is described.

Adipose Tissue Macrophage Polarization in Healthy and Unhealthy Obesity.

Over 650 million adults are obese (body mass index ≥ 30 kg/m) worldwide. Obesity is commonly associated with several comorbidities, including cardiovascular disease and type II diabetes. However, compiled estimates suggest that from 5 to 40% of obese individuals do not experience metabolic or cardiovascular complications.

Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction.

Metabolic reprogramming between resistance and tolerance occurs within the immune system in response to sepsis. While metabolic tissues such as the liver are subjected to damage during sepsis, how their metabolic and energy reprogramming ensures survival is unclear. Employing comprehensive metabolomic, lipidomic, and transcriptional profiling in a mouse model of sepsis, we show that hepatocyte lipid metabolism, mitochondrial tricarboxylic acid (TCA) energetics, and redox balance are significantly reprogrammed after cecal ligation and puncture (CLP).

Guideline deviation and its association with specific chronic diseases among patients with multimorbidity: a cross-sectional cohort study in a care management setting.

Objectives: To assess whether the extent of deviation from chronic disease guideline recommendations is more prominent for specific diseases compared with combined-care across multiple conditions among multimorbid patients, and to examine reasons for this deviation.

Design: A cross-sectional cohort.

Setting: Multimorbidity care management programme across 11 primary care clinics.

Mixed Methods Evaluation of Reasons Why Care Deviates From Clinical Guidelines Among Patients With Multimorbidity.

Reasons why care does not conform to single-disease guideline recommendations for multimorbid patients have not been systematically measured in practice. Using a mixed methods approach, we identified and quantified types of reasons why care deviates from nine sets of disease guideline recommendations for multimorbid patients. Utilizing a focus group concept mapping technique, we built on a categorization of reasons explaining guideline deviation, and surveyed treating nurses about these reasons for patients' specific care processes.

Global Research Alliance N O chamber methodology guidelines: Guidelines for gap-filling missing measurements.

Nitrous oxide (N O) is a potent greenhouse gas that is primarily emitted from agriculture. Sampling limitations have generally resulted in discontinuous N O observations over the course of any given year. The status quo for interpolating between sampling points has been to use a simple linear interpolation.

Long-term effectiveness of the Diabetes Conversation Map™ Program on health outcomes: A case-control retrospective cohort study.

Aim: To evaluate the clinical and health behavioural outcomes of a large sample of participants from the Diabetes Conversation Map™ Program.

Design: A matched-case-control study that was performed on a retrospective cohort study.

Methods: Participants were 11,053 Clalit Health Services members with type 2 diabetes who enrolled in the Diabetes Conversation Map™ Program between January 2010 - April 2016.