Actigraphy Study Endpoints to Reduce Sample Size and Facilitate Drug Development for Pediatric Pulmonary Arterial Hypertension.

Objective: To investigate the feasibility of using actigraphy to measure physical activity (pA) and heart rate variability (HRV) as study endpoints in pediatric pulmonary arterial hypertension (PAH) and to compare their performance to 6-minute-walk distance (6MWD), a common primary endpoint used in PAH clinical trials in adults and children who can walk and understand the test process.

Study Design: We conducted a prospective, multicenter, noninterventional study in pediatric PAH patients and healthy children. Actiheart and Fitbit Charge 2 recorded pA and heart rate data.

Neuropilin-2-expressing breast cancer cells mitigate radiation-induced oxidative stress through nitric oxide signaling.

The high rate of recurrence after radiation therapy in triple-negative breast cancer (TNBC) indicates that novel approaches and targets are needed to enhance radiosensitivity. Here, we report that neuropilin-2 (NRP2), a receptor for vascular endothelial growth factor (VEGF) that is enriched on subpopulations of TNBC cells with stem cell properties, is an effective therapeutic target for sensitizing TNBC to radiotherapy. Specifically, VEGF/NRP2 signaling induces nitric oxide synthase 2 (NOS2) transcription by a mechanism dependent on Gli1.

Do Specific Ion Effects on Collective Relaxation Arise from Perturbation of Hydrogen-Bonding Network Structure?

The change in the transport properties (i.e., water diffusivity, shear viscosity, etc.

Improving Intravenous and Subcutaneous Insulin Overlap During Treatment of Diabetic Ketoacidosis: A Quality Improvement Project.

Objective: To reduce the frequency of insufficient overlap of intravenous (IV) and subcutaneous (SC) insulin during the treatment of diabetic ketoacidosis (DKA) as a quality improvement project.

Patients And Methods: Rates of insufficient IV and SC insulin overlap (< 2-hour overlap, SC insulin given after IV insulin discontinuation, or no SC insulin given after IV insulin discontinuation) were assessed in adults with DKA treated with IV insulin at a large tertiary care referral center in Rochester, Minnesota, from July 1, 2021, to March 15, 2023. After a preintervention analysis period, an electronic medical record-based best practice advisory was introduced to notify hospital providers discontinuing IV insulin if SC long-acting insulin had not been given in the previous 2-6 hours.

TRIP12 governs DNA Polymerase β involvement in DNA damage response and repair.

The multitude of DNA lesion types, and the nuclear dynamic context in which they occur, present a challenge for genome integrity maintenance as this requires the engagement of different DNA repair pathways. Specific 'repair controllers' that facilitate DNA repair pathway crosstalk between double strand break (DSB) repair and base excision repair (BER), and regulate BER protein trafficking at lesion sites, have yet to be identified. We find that DNA polymerase β (Polβ), crucial for BER, is ubiquitylated in a BER complex-dependent manner by TRIP12, an E3 ligase that partners with UBR5 and restrains DSB repair signaling.

Nasolacrimal duct obstruction prevalence is 0.3% among alpacas evaluated with ophthalmic disease at a veterinary teaching hospital between 2000 and 2023.

Objective: To examine the prevalence of nasolacrimal duct (NLD) obstruction in hospital populations and assess signalment, diagnostics, and clinical approaches for alpacas and llamas diagnosed with NLD atresia or obstruction.

Animals: 29 alpacas and 2 llamas.

Clinical Presentation: Medical records were reviewed to identify camelids with NLD evaluated between 2000 and 2023.

Dielectric Characterization of HO and CO Uptake by Polyethylenimine Films.

The absorption of CO by polyethylenimine polymer (PEI) materials is of great interest in connection with proposed carbon capture technologies, and the successful development of this technology requires testing methods quantifying the amount of CO, HO, and reaction byproducts under operating conditions. We anticipate that dielectric measurements have the potential for quantifying both the extent of CO and HO absorption within the PEI matrix material as well as insights into subsequent reaction byproducts that can be expected to occur in the presence of moisture. The complexity of the chemistry involved in this reactive binding process clearly points to the need for the use of additional spectroscopic techniques to better resolve the multiple components involved and to validate the model-dependent findings from the dielectric measurements.

Deep Few-view High-resolution Photon-counting Extremity CT at Halved Dose for a Clinical Trial.

The latest X-ray photon-counting computed tomography (PCCT) for extremity allows multi-energy high-resolution (HR) imaging for tissue characterization and material decomposition. However, both radiation dose and imaging speed need improvement for contrast-enhanced and other studies. Despite the success of deep learning methods for 2D few-view reconstruction, applying them to HR volumetric reconstruction of extremity scans for clinical diagnosis has been limited due to GPU memory constraints, training data scarcity, and domain gap issues.

Selective breast/gynecologic pathology fellowship training in the United States: Experience of program directors.

Published data on combined breast and gynecologic [breast/gyn] surgical pathology fellowship training programs are limited. Our study aimed to survey the landscape of such fellowships in the United States (US), including specific information about their characteristics and the educational activities therein. Using web searches, we identified programs offering combined breast/gyn surgical pathology fellowship training.

A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1.

The ability to quickly discover reliable hits from screening and rapidly convert them into lead compounds, which can be verified in functional assays, is central to drug discovery. The expedited validation of novel targets and the identification of modulators to advance to preclinical studies can significantly increase drug development success. Our SaXPy ("SAR by X-ray Poses Quickly") platform, which is applicable to any X-ray crystallography-enabled drug target, couples the established methods of protein X-ray crystallography and fragment-based drug discovery (FBDD) with advanced computational and medicinal chemistry to deliver small molecule modulators or targeted protein degradation ligands in a short timeframe.

The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing.

Understanding the cell biological mechanisms that enable tumor cells to persist after therapy is necessary to improve the treatment of recurrent disease. Here, we demonstrate that transient receptor potential channel 6 (TRPC6), a channel that mediates calcium entry, contributes to the properties of breast cancer stem cells, including resistance to chemotherapy, and that tumor cells that persist after therapy are dependent on TRPC6. The mechanism involves the ability of TRPC6 to regulate integrin α6 mRNA splicing.

A smoking cessation intervention for rural veterans tailored to individual risk factors: A multicenter randomized clinical trial.

Introduction: Rates of cigarette use remain elevated among those living in rural areas. Depressive symptoms, risky alcohol use, and weight concerns frequently accompany cigarette smoking and may adversely affect quitting. Whether treatment for tobacco use that simultaneously addresses these issues affects cessation outcomes is uncertain.

Severe adverse reactions after cyanoacrylate endovenous ablation.

Hypersensitivity reactions after endovenous ablation with cyanoacrylate are relatively common, mild, and self-limited. However, rare cases of severe hypersensitivity reactions have occurred. To date and to the best of our knowledge, only two other cases requiring vein excision have been reported, and we present the third.

Starvation selection reduces and delays larval ecdysone production and signaling.

Previous studies have shown that selection for starvation resistance in Drosophila melanogaster results in delayed eclosion and increased adult fat stores. It is assumed that these traits are caused by the starvation selection pressure, but its mechanism is unknown. We found that our starvation-selected (SS) population stores more fat during larval development and has extended larval development and pupal development time.

Molecular Dynamics Simulation of the Influence of Temperature and Salt on the Dynamic Hydration Layer in a Model Polyzwitterionic Polymer PAEDAPS.

We investigate the hydration of poly(3-[2-(acrylamido) ethyldimethylammonio] propanesulfonate) over a range of temperatures in pure water and with the inclusion of 0.1 mol/L NaCl using atomistic molecular dynamics simulation. Drawing on concepts drawn from the field of glass-forming liquids, we use the Debye-Waller parameter (<>) for describing the water mobility gradient around the polybetaine backbone extending to an overall distance ≈18 Å.

Statistical methods for handling missing data to align with treatment policy strategy.

The International Council for Harmonization (ICH) E9(R1) addendum recommends choosing an appropriate estimand based on the study objectives in advance of trial design. One defining attribute of an estimand is the intercurrent event, specifically what is considered an intercurrent event and how it should be handled. The primary objective of a clinical study is usually to assess a product's effectiveness and safety based on the planned treatment regimen instead of the actual treatment received.

Bayesian Clinical Trials.

The following is an introduction from the guest editors for the Bayesian Clinical Trials series.

Kurdish Refugee Beliefs about Mental Health and Help-Seeking: A Community-Engaged Research Study in Tennessee.

Refugee populations exhibit high rates of PTSD, anxiety, depression, and psychological distress, but are less likely to receive care than the general population. Perceptions among the Kurdish refugee community about causes and consequences of mental illness symptoms and perceived barriers to help-seeking are understudied. This community-engaged research study conducted in-depth interviews with Kurdish refugees from Iraq to explore their beliefs about drivers of mental illness and seeking help for mental health.

Why are There not More Bayesian Clinical Trials? Ability to Interpret Bayesian and Conventional Statistics Among Medical Researchers.

Objective And Background: We assessed current understandings in interpretation of Bayesian and traditional statistical results within the clinical researcher (non-statistician) community.

Methods: Within a 22-question survey, including demographics and experience and comfort levels with Bayesian analyses, we included questions on how to interpret both Bayesian and traditional statistical outputs. We also assessed whether Bayesian or traditional interpretations are considered more useful.

Bayesian Methods in Human Drug and Biological Products Development in CDER and CBER.

The Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) have been leaders in protecting and promoting the U.