pH-Dependent Protein Chemical Degradation as a Representation of Effective pH Around Proteins Within Polymer-Based Sustained Release Formulations.

Protein-based therapeutics are prone to pH-dependent intramolecular chemical degradation reactions. Knowledge of the pH around protein-based therapeutics inside sustained release (SR) formulations is necessary for assessing their suitability for sustained delivery applications. Herein, we have taken advantage of the pH-sensitive chemical reactions of a model antibody, mAb1, to infer the pH around proteins in two representative SR formulations: PLGA microspheres and hyaluronic acid hydrogel.

Use of structured handoff protocols for within-hospital unit transitions: a systematic review from Making Healthcare Safer IV.

Background: Handoffs are a weak link in the chain of clinical care of inpatients. Within-unit handoffs are increasing in frequency due to changes in duty hours. There are strong rationales for standardising the reporting of critical information between providers, and such practices have been adopted by other industries.

Prospective SARS-CoV-2 Booster Vaccination in Immunosuppressant-Treated Systemic Autoimmune Disease Patients in a Randomized Controlled Trial.

Background: Autoimmune disease patients on immunosuppressants exhibit reduced humoral responses to primary COVID-19 vaccination. Booster vaccine responses and the effects of holding immunosuppression around vaccination are less studied. We evaluated the efficacy and safety of additional vaccination in mycophenolate mofetil/mycophenolic acid (MMF/MPA)-, methotrexate (MTX)-, and B cell-depleting therapy (BCDT)-treated autoimmune disease patients, including the impact of withholding MMF/MPA and MTX.

In vitro Stability Study of a Panel of Commercial Antibodies at Physiological pH and Temperature as a Guide to Screen Biologic Candidate Molecules for the Potential Risk of In vivo Asparagine Deamidation and Activity Loss.

Objective: Biologic drug molecules such as antibodies are exposed to the physiological stress conditions of pH 7.4 and 37°C during their long circulation lifetime in vivo. The stress on biologic molecules in vivo is more severe compared to that under typical storage conditions of low pH formulation and cold temperature.

The Effects of the Pneumonia Lung Microenvironment on MSC Function.

Background: Despite promise in preclinical models of acute respiratory distress syndrome (ARDS), mesenchymal stem cells (MSC) have failed to translate to therapeutic benefit in clinical trials. The MSC is a live cell medicine and interacts with the patient's disease state. Here, we explored this interaction, seeking to devise strategies to enhance MSC therapeutic function.

Prevention in adults of transmission of infection with multidrug-resistant organisms: an updated systematic review from Making Healthcare Safer IV.

Background: Healthcare-associated infections due to multidrug-resistant organisms (MDROs) remain a high priority patient safety topic, despite broad acceptance as standard-of-care safety practices to prevent central line-associated bloodstream infection, catheter-associated urinary tract infection and ventilator-associated pneumonia. Prior editions of Making Healthcare Safer have mixed certainty evidence for various other patient safety practices.

Objectives: As part of Making Healthcare Safer IV, we performed an updated systematic review on the certainty of evidence for the following safety practices at reducing in-facility MDRO infections in adult patients: universal gloving, contact precautions, cohorting, environmental decontamination, patient decolonisation and the adverse effects of isolation.

Linker substitution influences succinimide ring hydrolysis equilibrium impacting the stability of attachment to antibody-drug conjugates.

Maleimide chemistry is widely used in antibody-drug conjugate (ADC) generation to connect drugs to antibodies through a succinimide linker. The resulting ADC is prone to payload loss a reverse Michael reaction, leading to premature drug release . Complete succinimide hydrolysis is an effective strategy to overcome the instability of ADC.

Aerosol Delivery of a Novel Recombinant Modified Superoxide Dismutase Protein Reduces Oxidant Injury and Attenuates Induced Lung Injury in Rats.

Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory failure syndrome with diverse etiologies characterized by increased permeability of alveolar-capillary membranes, pulmonary edema, and acute onset hypoxemia. During the ARDS acute phase, neutrophil infiltration into the alveolar space results in uncontrolled release of reactive oxygen species (ROS) and proteases, overwhelming antioxidant defenses and causing alveolar epithelial and lung endothelial injury. To investigate the therapeutic potential of a novel recombinant human Cu-Zn-superoxide dismutase (SOD) fusion protein in protecting against ROS injury and for aerosolized SOD delivery to treat induced ARDS.

Dupilumab-Induced Pancreatitis.

Drug-induced pancreatitis (DIP) is a rare cause of pancreatitis with an extensive and growing list of offending medications. Drawing a causative relationship between a medication and pancreatitis can be challenging, requiring a thorough workup to exclude other potential etiologies. By using scoring systems to identify DIP, we have identified another case of suspected DIP.

Delayed MSC therapy enhances resolution of organized pneumonia induced by antibiotic resistant infection.

Introduction: Mesenchymal stromal cells (MSC) are a promising therapeutic for pneumonia-induced sepsis. Here we sought to determine the efficacy of delayed administration of naïve and activated bone marrow (BM), adipose (AD), and umbilical cord (UC) derived MSCs in organized antibiotic resistant pneumosepsis.

Methods: Human BM-, AD-, and UC-MSCs were isolated and expanded and used either in the naïve state or following cytokine pre-activation.

Nebulized mesenchymal stem cell derived conditioned medium ameliorates induced pneumonia in a rat model.

Background: Mesenchymal stem cells (MSC) have shown immense therapeutic promise in a range of inflammatory diseases, including acute respiratory distress syndrome (ARDS), and are rapidly advancing through clinical trials. Among their multimodal mechanisms of action, MSCs exert strong immunomodulatory effects via their secretome, which contains cytokines, small molecules, extracellular vesicles, and a range of other factors. Recent studies have shown that the MSC secretome can recapitulate many of the beneficial effects of the MSC itself.

Nebulised mesenchymal stem cell derived extracellular vesicles ameliorate E. coli induced pneumonia in a rodent model.

Background: Mesenchymal stem cell (MSC) derived extracellular vesicles (EVs) have been proposed as an alternative to cell therapy, creating new possible delivery modalities such as nebulisation. We wished to investigate the therapeutic potential of directly nebulised MSC-EVs in the mitigation of Escherichia coli-induced pneumonia.

Methods: EV size, surface markers and miRNA content were assessed pre- and post-nebulisation.

Differential Effects of Cytokine Versus Hypoxic Preconditioning of Human Mesenchymal Stromal Cells in Pulmonary Sepsis Induced by Antimicrobial-Resistant .

: Pulmonary sepsis is a leading cause of hospital mortality, and sepses arising from antimicrobial-resistant (AMR) bacterial strains are particularly difficult to treat. Here we investigated the potential of mesenchymal stromal cells (MSCs) to combat established pneumosepsis and further evaluated MSC preconditioning and pre-activation methods. : The potential for naïve and preconditioned MSCs to enhance wound healing, reduce inflammation, preserve metabolic activity, and enhance bacterial killing was assessed in vitro.

Multiple Dosing and Preactivation of Mesenchymal Stromal Cells Enhance Efficacy in Established Pneumonia Induced by Antimicrobial-Resistant in Rodents.

Antimicrobial-resistant (AMR) bacteria, such as species, are an increasingly common cause of hospital-acquired pneumonia, resulting in high mortality and morbidity. Harnessing the host immune response to AMR bacterial infection using mesenchymal stem cells (MSCs) is a promising approach to bypass bacterial AMR mechanisms. The administration of single doses of naïve MSCs to ARDS clinical trial patient cohorts has been shown to be safe, although efficacy is unclear.

Aerosolized Pulmonary Delivery of mRNA Constructs Attenuates Severity of Pneumonia in the Rat.

Acute respiratory distress syndrome (ARDS), a rapid onset inflammatory lung disease with no effective specific therapy, typically has pathogenic etiology termed pneumonia. In previous studies nuclear factor-κB (NF-κB) inhibitor α super-repressor (IκBα-SR) and extracellular superoxide dismutase 3 (SOD3) reduced pneumonia severity when prophylactically delivered by viral vector. In this study, mRNA coding for green fluorescent protein, IκBα-SR, or SOD3 was complexed with cationic lipid, passed through a vibrating mesh nebulizer, and delivered to cell culture or directly to rats undergoing pneumonia.

Homogeneous Gold Catalysis Using Complexes Recovered from Waste Electronic Equipment.

Despite the greater awareness of elemental sustainability and the benefits of the circular economy concept, much waste electrical and electronic equipment (WEEE) is still destined for landfill. Effective methods for valorizing this waste within our society are therefore imperative. In this contribution, two gold(III) complexes obtained as recovery products from WEEE and their anion metathesis products were investigated as homogenous catalysts.

Attribute Analytics Performance Metrics from the MAM Consortium Interlaboratory Study.

The multi-attribute method (MAM) was conceived as a single assay to potentially replace multiple single-attribute assays that have long been used in process development and quality control (QC) for protein therapeutics. MAM is rooted in traditional peptide mapping methods; it leverages mass spectrometry (MS) detection for confident identification and quantitation of many types of protein attributes that may be targeted for monitoring. While MAM has been widely explored across the industry, it has yet to gain a strong foothold within QC laboratories as a replacement method for established orthogonal platforms.

Enhancement strategies for mesenchymal stem cells and related therapies.

Cell therapy, particularly mesenchymal stem/stromal (MSC) therapy, has been investigated for a wide variety of disease indications, particularly those with inflammatory pathologies. However, recently it has become evident that the MSC is far from a panacea. In this review we will look at current and future strategies that might overcome limitations in efficacy.

From Waste to Green Applications: The Use of Recovered Gold and Palladium in Catalysis.

The direct use in catalysis of precious metal recovery products from industrial and consumer waste is a very promising recent area of investigation. It represents a more sustainable, environmentally benign, and profitable way of managing the low abundance of precious metals, as well as encouraging new ways of exploiting their catalytic properties. This review demonstrates the feasibility and sustainability of this innovative approach, inspired by circular economy models, and aims to stimulate further research and industrial processes based on the valorisation of secondary resources of these raw materials.

A Highly Sensitive LC-MS/MS Method for Targeted Quantitation of Lipase Host Cell Proteins in Biotherapeutics.

Identification and accurate quantitation of host cell proteins (HCPs) in biotherapeutic drugs has become increasingly important due to the negative impact of certain HCPs on the safety, stability, and other product quality of biotherapeutics. Recently, several lipase HCPs have been identified to potentially cause the enzymatic degradation of polysorbate, a widely used excipient in the formulation of biotherapeutics, which can severely impact the stability and product quality of drug products. In this study, we identified three lipase HCPs that were frequently detected in Chinese hamster ovary (CHO) cell cultures using shotgun proteomics, including phospholipase B-like 2 (PLBL2), lipoprotein lipase (LPL), and lysosomal acid lipase (LIPA).

New Peak Detection Performance Metrics from the MAM Consortium Interlaboratory Study.

The Multi-Attribute Method (MAM) Consortium was initially formed as a venue to harmonize best practices, share experiences, and generate innovative methodologies to facilitate widespread integration of the MAM platform, which is an emerging ultra-high-performance liquid chromatography-mass spectrometry application. Successful implementation of MAM as a purity-indicating assay requires new peak detection (NPD) of potential process- and/or product-related impurities. The NPD interlaboratory study described herein was carried out by the MAM Consortium to report on the industry-wide performance of NPD using predigested samples of the NISTmAb Reference Material 8671.

Hypercapnia in the critically ill: insights from the bench to the bedside.

Carbon dioxide (CO) has long been considered, at best, a waste by-product of metabolism, and at worst, a toxic molecule with serious health consequences if physiological concentration is dysregulated. However, clinical observations have revealed that 'permissive' hypercapnia, the deliberate allowance of respiratory produced CO to remain in the patient, can have anti-inflammatory effects that may be beneficial in certain circumstances. In parallel, studies at the cell level have demonstrated the profound effect of CO on multiple diverse signalling pathways, be it the effect from CO itself specifically or from the associated acidosis it generates.