Amoxicillin Blood Concentration in High-Dose Intravenous Discontinuous Amoxicillin: Look Beyond Numbers. Max-Amox Study.

Purpose: High doses of amoxicillin are recommended to treat severe infections such as endocarditis. Amoxicillin causes dose-dependent toxicities, in particular crystal nephropathy. Toxicity could be avoided by monitoring of amoxicillin trough plasma concentrations (ATPC).

Detection of Real-Time Changes in Direction of COVID-19 Transmission Using National- and State-Level Epidemic Trends Based on R Estimates - United States Overall and New Mexico, April-October 2024.

Public health practitioners rely on timely surveillance data for planning and decision-making; however, surveillance data are often subject to delays. Epidemic trend categories, based on time-varying effective reproductive number (R) estimates that use nowcasting methods, can mitigate reporting lags in surveillance data and detect changes in community transmission before reporting is completed. CDC analyzed the performance of epidemic trend categories for COVID-19 during summer 2024 in the United States and at the state level in New Mexico.

The challenge to identify sensitive safety biomarkers of peripheral neurotoxicity in the rat: A collaborative effort across industry and academia (IMI NeuroDeRisk project).

Peripheral nervous system (PNS) toxicity assessment in non-clinical safety studies is challenging and relies mostly on histopathological assessment. The present work aims to identify blood-based biomarkers that could detect peripheral neuropathy in rats upon exposure to neurotoxic compounds. Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han).

FT-4202, a selective pyruvate kinase R activator for sickle cell disease.

Anemia in patients with sickle cell disease (SCD) increases 2,3-diphosphoglycerate (2,3-DPG), decreasing hemoglobin-oxygen (HbO) affinity to improve oxygen offloading and promote hemoglobin polymerization (sickling) of red blood cells (RBCs). We report the discovery of FT-4202, an investigational, selective pyruvate kinase type-R (PKR) activator with a multimodal mechanism of action and potential to increase ATP and decrease 2,3-DPG, resulting in increased HbO affinity, decreased Hb polymerization, and improved RBC health. FT-4202 was identified via structure-enabled lead optimization medicinal chemistry using X-ray crystallography, molecular modeling, and thermal shift assays.

Functional genomics of human skeletal development and the patterning of height heritability.

Underlying variation in height are regulatory changes to chondrocytes, cartilage cells comprising long-bone growth plates. Currently, we lack knowledge on epigenetic regulation and gene expression of chondrocytes sampled across the human skeleton, and therefore we cannot understand basic regulatory mechanisms controlling height biology. We first rectify this issue by generating extensive epigenetic and transcriptomic maps from chondrocytes sampled from different growth plates across developing human skeletons, discovering novel regulatory networks shaping human bone/joint development.

Sec14 proteins in the apicomplexan parasites Plasmodium and Toxoplasma.

Sec14 domain proteins are broadly conserved in eukaryotes and play essential roles in numerous cellular processes. Limited data on Sec14 proteins of apicomplexan parasites suggest that they could be important for their survival. The development of fungi-specific Sec14 inhibitors raises the tantalizing possibility that their apicomplexan counterparts might also be targeted.

Synthesis and Evaluation of Fluorinated Piperazine-Hydroxyethylamine Analogues as Potential Antiplasmodial Candidates.

In this manuscript, twenty-one novel fluorinated piperazine-hydroxyethylamine analogues were synthesized and tested against Plasmodium falciparum (Pf). Among tested compounds, two 13 g and 14 g exhibited promising inhibitory activity on Pf3D7 with IC values of 0.28 and 0.

Sustained improvements in brain health and metabolic markers 24 months following bariatric surgery.

Obesity and its metabolic complications are associated with lower grey matter and white matter densities, whereas weight loss after bariatric surgery leads to an increase in both measures. These increases in grey and white matter density are significantly associated with post-operative weight loss and improvement of the metabolic/inflammatory profiles. While our recent studies demonstrated widespread increases in white matter density 4 and 12 months after bariatric surgery, it is not clear if these changes persist over time.

Efficacy and safety of selexipag in patients with inoperable or persistent/recurrent CTEPH (SELECT randomised trial).

Background: SELECT was the first global randomised controlled trial of selexipag with standard of care in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension.

Methods: SELECT was a multicentre, randomised, double-blind, placebo-controlled, parallel-group, group-sequential, phase 3 study (ClinicalTrials.gov: NCT03689244).

Melanoma of Unknown Primary With Metastasis to the Brain: A Case Report and Review of the Literature.

We present the case of a 72-year-old male found to have melanoma of unknown primary (MUP) in the lung with brain metastasis. The patient has a history of prostate cancer with radical proctectomy in 1999, hypertension with right-sided heart failure, and bilateral cataracts treated operatively. He presented to their home hospital after an unwitnessed fall, with a history of left-sided weakness.

Inhaled Ivermectin-Loaded Lipid Polymer Hybrid Nanoparticles: Development and Characterization.

Ivermectin (IVM), a drug originally used for treating parasitic infections, is being explored for its potential applications in cancer therapy. Despite the promising anti-cancer effects of IVM, its low water solubility limits its bioavailability and, consequently, its biological efficacy as an oral formulation. To overcome this challenge, our research focused on developing IVM-loaded lipid polymer hybrid nanoparticles (LPHNPs) designed for potential pulmonary administration.

Lipid polymer hybrid nanoparticles against lung cancer and their application as inhalable formulation.

Lung cancer is a leading cause of global cancer mortality, often treated with chemotherapeutic agents. However, conventional approaches such as oral or intravenous administration of drugs yield low bioavailability and adverse effects. Nanotechnology has unlocked new gateways for delivering medicine to their target sites.

The Paradigm Shift of Using Natural Molecules Extracted from Northern Canada to Combat Malaria.

Parasitic diseases, such as malaria, are an immense burden to many low- and middle-income countries. In 2022, 249 million cases and 608,000 deaths were reported by the World Health Organization for malaria alone. Climate change, conflict, humanitarian crises, resource constraints and diverse biological challenges threaten progress in the elimination of malaria.

Virulence phenotypes differ between toxigenic Vibrio parahaemolyticus isolated from western coasts of Europe.

Vibrio parahaemolyticus is the leading bacterial cause of gastroenteritis associated with seafood consumption worldwide. Not all members of the species are thought to be pathogenic, thus identification of virulent organisms is essential to protect public health and the seafood industry. Correlations of human disease and known genetic markers (e.

The expression and role of the Lem-D proteins Ankle2, Emerin, Lemd2, and TMPO in triple-negative breast cancer cell growth.

Background: Triple-negative breast cancer (TNBC) is a sub-classification of breast carcinomas, which leads to poor survival outcomes for patients. TNBCs do not possess the hormone receptors that are frequently targeted as a therapeutic in other cancer subtypes and, therefore, chemotherapy remains the standard treatment for TNBC. Nuclear envelope proteins are frequently dysregulated in cancer cells, supporting their potential as novel cancer therapy targets.

Sequence- and Structure-Dependent Cytotoxicity of Phosphorothioate and 2'--Methyl Modified Single-Stranded Oligonucleotides.

Single-stranded oligonucleotides (SSOs) are a rapidly expanding class of therapeutics that comprises antisense oligonucleotides, microRNAs, and aptamers, with ten clinically approved molecules. Chemical modifications such as the phosphorothioate backbone and the 2'--methyl ribose can improve the stability and pharmacokinetic properties of therapeutic SSOs, but they can also lead to toxicity and through nonspecific interactions with cellular proteins, gene expression changes, disturbed RNA processing, and changes in nuclear structures and protein distribution. In this study, we screened a mini library of 277 phosphorothioate and 2'--methyl-modified SSOs, with or without mRNA complementarity, for cytotoxic properties in two cancer cell lines.

Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study.

Background: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar.

Methods: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable.

Connecting microscopic and mesoscopic mechanics in model structural glasses.

We present a novel formalism to characterize elastic heterogeneities in amorphous solids. In particular, we derive high-order strain-energy expansions for pairwise energies under athermal quasistatic dynamics. We then use the presented formalism to study the statistical properties of pairwise expansion coefficients and their link with the statistics of soft, quasilocalized modes, for a wide range of formation histories in both two- and three-dimensional systems.