Responsiveness of hand-held dynamometry for measuring changes in trunk muscle strength in people with chronic low back pain.

Objective: To assess the responsiveness of a hand-held dynamometer (HHD) in evaluating changes in trunk isometric strength in people with chronic low back pain (LBP).

Background: Reduced trunk muscle strength has been associated with pain incidence and severity in people with chronic LBP. Trunk muscle strength is an important functional outcome that is measured in clinical practice and research.

The molecular reach of antibodies crucially underpins their viral neutralisation capacity.

Key functions of antibodies, such as viral neutralisation, depend on high-affinity binding. However, viral neutralisation poorly correlates with antigen affinity for reasons that have been unclear. Here, we use a new mechanistic model of bivalent binding to study  >45 patient-isolated IgG1 antibodies interacting with SARS-CoV-2 RBD surfaces.

Humatch - fast, gene-specific joint humanisation of antibody heavy and light chains.

Antibodies are a popular and powerful class of therapeutic due to their ability to exhibit high affinity and specificity to target proteins. However, the majority of antibody therapeutics are not genetically human, with initial therapeutic designs typically obtained from animal models. Humanization of these precursors is essential to reduce immunogenic risks when administered to humans.

p-IgGen: a paired antibody generative language model.

Summary: A key challenge in antibody drug discovery is designing novel sequences that are free from developability issues-such as aggregation, polyspecificity, poor expression, or low solubility. Here, we present p-IgGen, a protein language model for paired heavy-light chain antibody generation. The model generates diverse, antibody-like sequences with pairing properties found in natural antibodies.

A comparative study of the developability of full-length antibodies, fragments, and bispecific formats reveals higher stability risks for engineered constructs.

Engineered antibody formats, such as antibody fragments and bispecifics, have the potential to offer improved therapeutic efficacy compared to traditional full-length monoclonal antibodies (mAbs). However, the translation of these non-natural molecules into successful therapeutics can be hampered by developability challenges. Here, we systematically analyzed 64 different antibody constructs targeting Tumor Necrosis Factor (TNF) which cover 8 distinct molecular format families, encompassing full-length antibodies, various types of single chain variable fragments, and bispecifics.

A multicentre point prevalence study of nocturnal hours awake and enteral pharmacological sleep aids in patients admitted to Australian and New Zealand intensive care units.

Objective: Critically ill patients suffer disrupted sleep. Hypnotic medications may improve sleep; however, local epidemiological data regarding the amount of nocturnal time awake and the use of such medications is needed.

Design: Point prevalence study.

Airways Abnormalities in a Prospective Cohort of Patients With Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) affects roughly 1% of the population and commonly involves the lungs. Of lung involvement in RA, interstitial lung disease (ILD) is well known; however, airways disease in RA is relatively understudied.

Research Question: What are the baseline airways abnormalities in a prospective cohort of patients with RA based on pulmonary function testing (PFT) results, high-resolution CT (HRCT) scans, and computational imaging analysis and are there associations between these abnormalities and respiratory symptoms?

Study Design And Methods: In this single-center study, 188 patients with RA without a clinical diagnosis of ILD underwent HRCT imaging and PFT.

Responsiveness of the cervical joint position error test to detect changes in neck proprioception following four weeks of home-based proprioceptive training.

Introduction: People with chronic neck pain (CNP) commonly exhibit a range of physical impairments including cervical proprioceptive deficits. Assessing proprioception using a head mounted laser to assess joint position error (JPE) is a reliable and valid measure. However, the responsiveness of this measure has not been assessed.

In-person peer support for critical care survivors: The ICU REcovery Solutions cO-Led through surVivor Engagement (ICURESOLVE) pilot randomised controlled trial.

Background: Peer support is a promising intervention to mitigate post-ICU disability, however there is a paucity of rigorously designed studies.

Objectives: The objective of this study was to establish feasibility of an in-person, co-designed, peer-support model.

Methods: Prospective, randomised, adaptive, single-centre pilot trial with blinded outcome assessment, conducted at a university-affiliated hospital in Melbourne, Australia.

Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis.

Intrathecal synthesis of central nervous system (CNS)-reactive autoantibodies is observed across patients with autoimmune encephalitis (AE), who show multiple residual neurobehavioral deficits and relapses despite immunotherapies. We leveraged two common forms of AE, mediated by leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies, as human models to comprehensively reconstruct and profile cerebrospinal fluid (CSF) B cell receptor (BCR) characteristics. We hypothesized that the resultant observations would both inform the observed therapeutic gap and determine the contribution of intrathecal maturation to pathogenic B cell lineages.

Multifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis.

Molecular markers of autoimmunity, such as antibodies to citrullinated protein antigens (ACPA), are detectable prior to inflammatory arthritis (IA) in rheumatoid arthritis (RA) and may define a state that is 'at-risk' for future RA. Here we present a cross-sectional comparative analysis among three groups that include ACPA positive individuals without IA (At-Risk), ACPA negative individuals and individuals with early, ACPA positive clinical RA (Early RA). Differential methylation analysis among the groups identifies non-specific dysregulation in peripheral B, memory and naïve T cells in At-Risk participants, with more specific immunological pathway abnormalities in Early RA.

Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis.

Measurement properties of cervical joint position error in people with and without chronic neck pain.

Background: People with chronic neck pain (CNP) often present with impaired neck proprioception. The most widely used clinical test for assessing neck proprioception is cervical joint position sense which measures joint position error (JPE). This clinical test is typically performed using a laser pointer to examine the accuracy of returning to a neutral head position (NHP) or target head position (THP) following active neck movements.

Fragment Merging Using a Graph Database Samples Different Catalogue Space than Similarity Search.

Fragment merging is a promising approach to progressing fragments directly to on-scale potency: each designed compound incorporates the structural motifs of overlapping fragments in a way that ensures compounds recapitulate multiple high-quality interactions. Searching commercial catalogues provides one useful way to quickly and cheaply identify such merges and circumvents the challenge of synthetic accessibility, provided they can be readily identified. Here, we demonstrate that the Fragment Network, a graph database that provides a novel way to explore the chemical space surrounding fragment hits, is well-suited to this challenge.

Preclinical characterization of the Toll-like receptor 7/8 antagonist MHV370 for lupus therapy.

Genetic and in vivo evidence suggests that aberrant recognition of RNA-containing autoantigens by Toll-like receptors (TLRs) 7 and 8 drives autoimmune diseases. Here we report on the preclinical characterization of MHV370, a selective oral TLR7/8 inhibitor. In vitro, MHV370 inhibits TLR7/8-dependent production of cytokines in human and mouse cells, notably interferon-α, a clinically validated driver of autoimmune diseases.