Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948.

Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies.

Treatment fidelity in clinical trials.

In the context of clinical trials, treatment fidelity (TF) has traditionally referred to the extent to which an intervention or treatment is implemented by the clinicians as intended by the researchers who designed the trial. Updated definitions of TF have included an appropriate design of the intervention that was performed in a way that is known to be therapeutically beneficial. This requires careful attention to three key components: (1) protocol and dosage adherence, (2) quality of delivery, and (3) participant adherence.

Model-Based Prediction of Irinotecan-Induced Grade 4 Neutropenia in Cancer Patients: Influence of Incorporating Germline Genetic Factors in the Model.

Neutropenia is the major dose-limiting toxicity of irinotecan-based therapy. The objective of this study was to assess whether inclusion of germline genetic variants into a population pharmacokinetic/pharmacodynamic model can improve prediction of irinotecan-induced grade 4 neutropenia and identify novel variants of clinical value. A semimechanistic population pharmacokinetic/pharmacodynamic model was used to predict neutrophil response over time in 197 patients receiving irinotecan.

Allograft Anterior Cruciate Ligament Reconstruction Fails at a Greater Rate in Patients Younger Than 34 Years.

Purpose: To characterize the secondary anterior cruciate ligament (ACL) injury rates after primary allograft anterior cruciate ligament reconstruction (ACLR) and to identify the age cut-score at which the risk of allograft failure decreases.

Methods: All patients who underwent primary ACLR within a single orthopaedic department between January 2005 and April 2020 were contacted at a minimum of 2 years post-ACLR to complete a survey regarding complications experienced post-surgery, activity level, and perceptions of knee health. Patients were excluded for incidence of previous ACLR (ipsilateral or contralateral) and/or age younger than 14 years.

Digital image analysis for biothreat detection rapid centrifugal microfluidic orthogonal flow immunocapture.

We report clear proof-of-principle for centrifugally-driven, multiplexed, paper-based orthogonal flow sandwich-style immunocapture (cOFI) and colorimetric detection of Zaire Ebola virus-like particles. Capture antibodies are immobilized onto nanoporous nitrocellulose membranes that are then laminated into polymeric microfluidic discs to yield ready-to-use analytical devices. Fluid flow is controlled solely by rotational speed, obviating the need for complex pneumatic pumping systems, and providing more precise flow control than with the capillary-driven flow used in traditional lateral flow immunoassays (LFIs).