Interstitial fluid streaming in deep tissue induced by ultrasound momentum transfer for accelerating nanoagent transport and controlling its distribution.

This study aims to theoretically investigate the dynamics of ultrasound-induced interstitial fluid streaming and tissue recovery after ultrasound exposure for potentially accelerating nanoagent transport and controlling its distribution in tissue.Starting from fundamental equations, the dynamics of ultrasound-induced interstitial fluid streaming and tissue relaxation after an ultrasound exposure were modeled, derived and simulated. Also, both ultrasound-induced mechanical and thermal effects were considered in the models.

Sustained inhibition of NPY/AgRP neuronal activity by FGF1.

In rodent models of type 2 diabetes (T2D), central administration of FGF1 normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons and, if so, whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1.

A Randomized Controlled Trial of Mobile Health Intervention in Patients With Heart Failure and Diabetes.

Background: Mobile health (mHealth) platforms can affect health behaviors but have not been rigorously tested in randomized trials.

Objectives: We sought to evaluate the effectiveness of a pragmatic mHealth intervention in patients with heart failure (HF) and diabetes (DM).

Methods: We conducted a multicenter randomized trial in 187 patients with both HF and DM to assess an mHealth intervention to improve physical activity and medication adherence compared to usual care.

Development of entrustable professional activities for regional anesthesia and pain medicine fellowship training.

Introduction: The Accreditation Council for Graduate Medical Education (ACGME) offers descriptions of competencies and milestones but does not provide standardized assessments to track trainee competency. Entrustable professional activities (EPAs) and special assessments (SAs) are emerging methods to assess the level of competency obtained by regional anesthesiology and acute pain medicine (RAAPM) fellows.

Methods: A panel of RAAPM physicians with experience in education and competency assessment and one medical student were recruited to participate in a modified Delphi method with iterative rounds to reach consensus on: a list of EPAs, SAs, and procedural skills; detailed definitions for each EPA and SA; a mapping of the EPAs and SAs to the ACGME milestones; and a target level of entrustment for graduating US RAAPM fellows for each EPA and procedural skill.

Inhibition of NLRP3-mediated crosstalk between hepatocytes and liver macrophages by geniposidic acid alleviates cholestatic liver inflammatory injury.

The excessive accumulation of bile acids (BA) in hepatocytes can trigger inflammatory response and recruit macrophages, thereby accelerating cholestatic liver injury. The crosstalk between hepatocytes and macrophages has been recently implicated in the pathogenesis of cholestasis; however, the underlying mechanisms remain unclear. Here, we demonstrated that BA initiate NLRP3 inflammasome activation in hepatocytes to release proinflammatory cytokines and promote the communication between hepatocytes and macrophages, thus enhancing liver inflammation in an NLRP3-dependent manner.

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention.

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells.

Clinical experience with the Bendit steerable microcatheter: a new paradigm for endovascular treatment.

Background: Vessel tortuosity poses a challenge during endovascular treatment of neurovascular lesions. Bendit Technologies (Petah Tikva, Israel) has developed flexible, steerable microcatheters designed with unique bending and torquing capabilities.

Objective: To describe our first-in-human trial of Bendit21.

Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis.

Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis.

Perinatal management: Lessons learned from the neonatal research network.

Recent contributions of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) regarding obstetrical perinatal interventions and neonatal delivery room practices include the following: the impact of multiple antepartum factors including maternal diabetes, hypertension, obesity and mode of delivery on outcomes of extremely preterm newborns, effects of delayed delivery interval for extremely preterm multiples, effects of antenatal steroids on preterm newborn outcomes and the impact of antenatal magnesium sulfate therapy on neurodevelopmental outcomes for extremely preterm infants. NRN studies also contribute important evidence for neonatal delivery room resuscitation guidelines including umbilical cord management and maintenance of euthermia immediately after birth. The updated NRN outcome calculator helps better counsel families regarding possible outcomes for the most immature newborns if resuscitation is attempted at birth.

Thermal Shift Assay for Small GTPase Stability Screening: Evaluation and Suitability.

Thermal unfolding methods are commonly used as a predictive technique by tracking the protein's physical properties. Inherent protein thermal stability and unfolding profiles of biotherapeutics can help to screen or study potential drugs and to find stabilizing or destabilizing conditions. Differential scanning calorimetry (DSC) is a 'Gold Standard' for thermal stability assays (TSA), but there are also a multitude of other methodologies, such as differential scanning fluorimetry (DSF).

Brown adipose tissue activation with ginsenoside compound K ameliorates polycystic ovary syndrome.

Background And Purpose: Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disease affecting women of reproductive age. Due to its complex aetiology, there is no currently effective cure for PCOS. Brown adipose tissue (BAT) activity is significantly decreased in PCOS patients, and BAT activation has beneficial effects in animal models of PCOS.

Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance.

Intratumoral Resolution of Driver Gene Mutation Heterogeneity in Renal Cancer Using Deep Learning.

Unlabelled: Intratumoral heterogeneity arising from tumor evolution poses significant challenges biologically and clinically. Dissecting this complexity may benefit from deep learning (DL) algorithms, which can infer molecular features from ubiquitous hematoxylin and eosin (H&E)-stained tissue sections. Although DL algorithms have been developed to predict some driver mutations from H&E images, the ability of these DL algorithms to resolve intratumoral mutation heterogeneity at subclonal spatial resolution is unexplored.

Safety and efficacy of elsubrutinib or upadacitinib alone or in combination (ABBV-599) in patients with rheumatoid arthritis and inadequate response or intolerance to biological therapies: a multicentre, double-blind, randomised, controlled, phase 2 trial.

Background: ABBV-599 is a novel fixed-dose combination of the Bruton's tyrosine kinase (BTK) inhibitor elsubrutinib and the Janus kinase (JAK) inhibitor upadacitinib under investigation for the treatment of autoimmune diseases. We aimed to determine whether ABBV-599 could increase the treatment response for patients with active rheumatoid arthritis compared with inhibiting either pathway alone, while maintaining an acceptable safety profile.

Methods: We conducted a multicentre, double-blind, parallel-group, dose-exploratory, randomised, controlled, phase 2 trial at 75 community sites in eight countries in Europe and North America.

Statin therapy for primary prevention in women: What is the role for coronary artery calcium?

By current guidelines, statin treatment decisions depend on multiple risk factor algorithms (e.g., pooled cohort equations [PCEs]).

Synthesis and Structure-Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold.

Cyclin-dependent kinases (CDK) are attractive targets for drug discovery due to their wide range of cellular functions. CDK11 is an understudied CDK with roles in transcription and splicing, cell cycle regulation, neuronal function, and apoptosis. In this study, we describe a medicinal chemistry campaign to identify a CDK11 inhibitor.

Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families.

Allosteric mechanisms are pervasive in nature, but human-designed allosteric perturbagens are rare. The history of KRAS inhibitor development suggests that covalent chemistry may be a key to expanding the armamentarium of allosteric inhibitors. In that effort, irreversible targeting of a cysteine converted a non-deal allosteric binding pocket and low affinity ligands into a tractable drugging strategy.

A sound-driven cortical phase-locking change in the Fmr1 KO mouse requires Fmr1 deletion in a subpopulation of brainstem neurons.

Background: Sensory impairments commonly occur in patients with autism or intellectual disability. Fragile X syndrome (FXS) is one form of intellectual disability that is often comorbid with autism. In electroencephalographic (EEG) recordings obtained from humans with FXS, the ability of cortical regions to consistently synchronize, or "phase-lock", to modulated auditory stimuli is reduced compared to that of typically developing individuals.

T618I mutated chronic myelomonocytic leukemia: A proliferative subtype with a distinct mutational profile.

Chronic myelomonocytic leukemia (CMML) is a clonal myeloid neoplasm characterized by sustained monocytosis and mutations in , and . We describe a rare case of T618I mutated CMML that has a proliferative phenotype, myelodysplasia, and additional mutations in and . Comparing the clinicopathologic features of this case to previously reported cases of T618I mutated CMML and non-T618I mutated CMML, T618I seems to define a unique proliferative subtype of CMML with a distinct mutational profile.

Pilot Study of Neurologic Pupil Index as A Predictor of External Ventricular Drain Clamp Trial Failure After Subarachnoid Hemorrhage.

Background: External ventricular drains (EVDs) provide a temporary egress for cerebrospinal fluid (CSF) in patients with symptomatic hydrocephalus following aneurysmal subarachnoid hemorrhage. Before EVD removal, a wean trial, which involves clamping the EVD, is typically attempted to ensure that CSF self-regulation is achieved. Automated infrared pupillometry (AIP) has been shown to detect early neurologic decline.

Decreasing waiting time for new patients at a community pain clinic.

Long waiting time to access pain medicine clinics poses a significant mental, physical, and socioeconomic burden on patients with chronic pain. This project aimed to develop interventions to reduce the waiting time for new referrals. We used the define, measure, analyze, improve, control (DMAIC) method.