Differences in Susceptibility to SARS-CoV-2 Infection Among Transgenic hACE2-Hamster Founder Lines.

Animal models that are susceptible to SARS-CoV-2 infection and develop clinical signs like human COVID-19 are desired to understand viral pathogenesis and develop effective medical countermeasures. The golden Syrian hamster is important for the study of SARS-CoV-2 since hamsters are naturally susceptible to SARS-CoV-2. However, infected hamsters show only limited clinical disease and resolve infection quickly.

Discovery of SARS-CoV-2 papain-like protease (PL) inhibitors with efficacy in a murine infection model.

Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PL) is one of the two essential cysteine proteases involved in viral replication.

A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19.

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883.

A Health Economic Analysis Exploring the Cost Consequence of Using a Surgical Site Infection Prevention Bundle for Hip and Knee Arthroplasty in Germany.

Background: According to the European Centre for Disease Prevention and Control, surgical site infections (SSIs) constitute over 50% of all hospital-acquired infections. Reducing SSIs can enhance healthcare efficiency.

Objective: This study explores the cost consequences of implementing an SSI prevention bundle (SPB) in total hip and knee arthroplasty (THKA).

An Economic Model to Establish the Costs Associated With Routes to Presentation for Patients With Multiple Myeloma in the United Kingdom.

Objectives: Patients with myeloma often face significant diagnostic delay, with up to one-third of UK patients diagnosed after an emergency presentation (EP). Compared with other routes, patients presenting as an emergency have more advanced disease, increased complications, and poorer prognosis.

Methods: An economic model was developed using a decision-tree framework and lifetime time horizon to estimate costs related to different presentation routes (EP, general practitioner [GP] 2-week wait, GP urgent, GP routine, and consultant to consultant) for UK patients diagnosed as having myeloma.

Human IVIG treatment in a neurological disease model for Enterovirus A71 infection in 28-day-old AG129 mice.

Enterovirus A71 can cause serious neurological disease in young children. Animal models for EV-A71 are needed to evaluate potential antiviral therapies. Existing models have limitations, including lack of lethality or crucial disease signs.

Programmable antivirals targeting critical conserved viral RNA secondary structures from influenza A virus and SARS-CoV-2.

Influenza A virus's (IAV's) frequent genetic changes challenge vaccine strategies and engender resistance to current drugs. We sought to identify conserved and essential RNA secondary structures within IAV's genome that are predicted to have greater constraints on mutation in response to therapeutic targeting. We identified and genetically validated an RNA structure (packaging stem-loop 2 (PSL2)) that mediates in vitro packaging and in vivo disease and is conserved across all known IAV isolates.

Economic and clinical impact of a novel, light-based, at-home antiviral treatment on mild-to-moderate COVID-19.

Objectives: Antiviral treatments for early intervention in patients with mild-to-moderate COVID-19 are needed as a complement to vaccination. We sought to estimate the impact on COVID-19 cases, deaths, and direct healthcare costs over 12 months following introduction of a novel, antiviral treatment, RD-X19, a light-based, at-home intervention designed for the treatment of mild-to-moderate COVID-19 infection.

Methods: A time-dependent, state transition (semi-Markov) cohort model was developed to simulate infection progression in individuals with COVID-19 in 3 US states with varying levels of vaccine uptake (Alabama, North Carolina, and Massachusetts) and at the national level between 1 June 2020 and 31 May 2021.

Stress Factors in Primary Packaging, Transportation and Handling of Protein Drug Products and Their Impact on Product Quality.

Protein-based biologic drugs encounter a variety of stress factors during drug substance (DS) and drug product (DP) manufacturing, and the subsequent steps that result in clinical administration by the end user. This article is the third in a series of commentaries on these stress factors and their effects on biotherapeutics. It focuses on assessing the potential negative impact from primary packaging, transportation, and handling on the quality of the DP.

How Much Are Borrowers Willing to Pay to Remove Uncertainty Surrounding Mortgage Defaults?

Using a large, non-student sample, we assess and differentiate between borrowers' Risk Aversion and Ambiguity Aversion levels and their willingness to pay to resolve a mortgage default settlement negotiation. Ambiguity Aversion is found to be negatively associated with willingness to pay for borrowers with high financial literacy in both the gain and loss domains, whereas personality traits matter more for borrowers with low financial literacy. This finding is important to policymakers in that they should adopt differential resolution strategies for defaulting borrowers based on these intervening variables.

An oral SARS-CoV-2 M inhibitor clinical candidate for the treatment of COVID-19.

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles.

Evaluating the Waste Prevention Potential of a Multi- versus Single-Use Surgical Stapler.

Purpose: Within the hospital, surgery is recognized as a resource-intensive activity that disproportionately generates large volumes of healthcare waste. Single-use, disposable medical supplies contribute substantially to this problem, and more broadly to the depletion of scarce resources. Given that many surgical procedures utilize surgical stapling techniques, this study uses surgical stapling systems as functional units for evaluating the waste prevention potential of switching from single-use systems (SUSs) to multi-use systems (MUSs).

A Fiber Optic Interface Coupled to Nanosensors: Applications to Protein Aggregation and Organic Molecule Quantification.

Fluorescent nanosensors hold promise to address analytical challenges in the biopharmaceutical industry. The monitoring of therapeutic protein critical quality attributes such as aggregation is a long-standing challenge requiring low detection limits and multiplexing of different product parameters. However, general approaches for interfacing nanosensors to the biopharmaceutical process remain minimally explored to date.

Characterization of Protein Aggregation Using Hydrogel-Encapsulated nIR Fluorescent Nanoparticle Sensors.

The monitoring of biopharmaceutical critical quality attributes in-process, at both the process development and manufacturing stages, is necessary for the implementation of process analytical technology and quality-by-design principles. Among these attributes, it is important to monitor and control protein aggregation during the manufacturing of biological therapeutics to prevent adverse immunogenic responses and minimize negative impacts on drug deliverability. In this work, we explore hydrogel-encapsulated, label-free fluorescent nanosensors for the characterization of protein aggregation.

The validity and reliability of ultrasound on identifying supraspinatus tears during passive external rotation from 0° to 30°: a pilot project.

Background: Controversy exists regarding how much external rotation should be allowed following rotator cuff repair. Clinicians may use ultrasound imaging (USI) to visualize the supraspinatus (SSp) tendon during passive external rotation. However, the validity and reliability of USI used to assess supraspinatus tendon gap formation during external rotation needs to be established prior to using this technique in patient cohorts.

Maximizing capture of gene co-expression relationships through pre-clustering of input expression samples: an Arabidopsis case study.

Background: In genomics, highly relevant gene interaction (co-expression) networks have been constructed by finding significant pair-wise correlations between genes in expression datasets. These networks are then mined to elucidate biological function at the polygenic level. In some cases networks may be constructed from input samples that measure gene expression under a variety of different conditions, such as for different genotypes, environments, disease states and tissues.

Massive-scale gene co-expression network construction and robustness testing using random matrix theory.

The study of gene relationships and their effect on biological function and phenotype is a focal point in systems biology. Gene co-expression networks built using microarray expression profiles are one technique for discovering and interpreting gene relationships. A knowledge-independent thresholding technique, such as Random Matrix Theory (RMT), is useful for identifying meaningful relationships.

Exploring emergency physician-hospitalist handoff interactions: development of the Handoff Communication Assessment.

Study Objective: We develop and evaluate the Handoff Communication Assessment, using actual handoffs of patient transfers from emergency department to inpatient care.

Methods: This was an observational qualitative study. We derived a Handoff Communication Assessment tool, using categories from discourse coding described in physician-patient communication, previous handoff research in medicine, health communication, and health systems engineering and pilot data from 3 physician-hospitalist handoffs.

Communicating in the "gray zone": perceptions about emergency physician hospitalist handoffs and patient safety.

Objectives: To identify the perceptions of emergency physicians (EPs) and hospitalists regarding interservice handoff communication as patients are transferred from the emergency department to the inpatient setting.

Methods: Investigators conducted individual interviews with 12 physicians (six EPs and six hospitalists). Data evaluation consisted of using the steps of constant comparative, thematic analysis.

Phototoxicity of a core-modified porphyrin and induction of apoptosis.

A core-modified porphyrin, 5-phenyl-10,15-bis(carboxylatomethoxyphenyl)-20-(2-thienyl)-21,23-dithiaporphyrin (IY69) was studied in vitro for photodynamic activity under a variety of experimental protocols. Variables included the cell line (the rodent mammary tumor cell line R3230AC or the human breast cancer cell line MCF-7), light fluence, time of exposure of the cell cultures to IY69, and the time post-irradiation for cell counting. The length of time cell cultures were exposed to IY69 impacted cellular accumulation and cellular localization, phototoxicity, and the apparent mode of cell death - apoptosis vs.

Gialpha and Gbeta subunits both define selectivity of G protein activation by alpha2-adrenergic receptors.

Previous studies of the specificity of receptor interactions with G protein subunits in living cells have relied on measurements of second messengers or other downstream responses. We have examined the selectivity of interactions between alpha2-adrenergic receptors (alpha2R) and various combinations of Gialpha and Gbeta subunit isoforms by measuring changes in FRET between Gialpha-yellow fluorescent protein and cyan fluorescent protein-Gbeta chimeras in HeLa cells. All combinations of Gialpha1, -2, or -3 with Gbeta1, -2, or -4 were activated to some degree by endogenous alpha2Rs as judged by agonist-dependent decreases in FRET.

Tooth movement and cytokines in gingival crevicular fluid and whole blood in growing and adult subjects.

Introduction: Tooth movement has been studied largely with respect to the force required for tipping when pressure distribution varies along the length of the periodontal ligament. But important factors for effective canine translation include the nature and magnitude of applied stress and the patient's cell biology. The purpose of this research was to test 3 hypotheses: (1) the velocity of tooth translation (v(t)) is related to applied stress and growth status, (2) a threshold of stress accounts for the lag phase, and (3) v(t) is correlated with the ratio (AI) of 2 cytokines (IL-1beta, IL-1RA) measured in gingival crevicular fluid (GCF) and stimulated whole blood (SWB).