Autoantibodies and damage in patients with idiopathic inflammatory myopathies: A longitudinal multicenter study from the MYONET international network

ObjectiveTo study the trajectories of changes in damage over time and explore associations with autoantibody defined subgroups using a large international cohort of patients with idiopathic inflammatory myopathies (IIM).MethodsData from the MYONET registry, including patients who were tested for autoantibodies and had at least one assessment of damage using the Myositis Damage Index (MDI), were analyzed. Patients were sub-grouped according to their autoantibody profiles (myositis-specific, myositis-associated, or seronegative). The index date was defined as the time point for the first registered MDI assessment. The longitudinal trajectories of damage with autoantibody status as the main predictor were analyzed using linear mixed models.ResultsA total of 757 adult patients were included in this study. Each year of disease duration since diagnosis had an estimated MDI score increase of 0.16 units for the seronegative group (reference). Compared with the seronegative group as reference, patients with dermatomyositis-specific autoantibodies developed less damage per year of follow-up since diagnosis (average 0.08 less score, P = 0.04), whereas patients with anti-PM/Scl autoantibodies developed more damage per year of follow-up since diagnosis (average 0.28 higher score, P = 0.03) independent of sex and age at diagnosis. The seronegative subgroup and the immune-mediated necrotizing myopathy autoantibody subgroup had the strongest correlation between severity of muscle damage and HAQ-DI scores at five years of follow-up, rho=0.84, P < 0.001 and rho=0.72, P < 0.001, respectively.ConclusionOur study is the first to describe patterns and trajectories of change in damage over time in relation to autoantibody defined subgroups in a large international multicenter cohort of patients with IIM. Patients with anti-PM/Scl scored a greater extent of damage, whereas patients with dermatomyositis-specific antibodies had less damage than seronegative patients. Severity in muscle damage had moderate to strong correlation with functional disability among the IMNM and seronegative subgroups with lower correlations for the other subgroups. These findings suggest that autoantibodies may be useful predictors of long-term damage

Ouroboros:cross-linking protein expression perturbations and cancer histology imaging with generative-predictive modeling

SUMMARY: Imagine if we could simultaneously predict spatial protein expression in tissues from their routine Hematoxylin and Eosin (H&amp;E) stained images, and create tissue images given protein expression profiles thus enabling virtual simulations of how protein expression alterations impact histology in complex diseases like cancer. Such an approach could lead to more informed diagnostic and therapeutic decisions for precision medicine at lower costs and shorter turnaround times, more detailed insights into underlying disease pathology as well as improvement in predictive and generative performance. In this study, we investigate the intricate correlation between protein expressions obtained from Hyperion mass cytometry and histopathological microstructures in conventional H&amp;E stained glioblastoma (GBM) samples, unveiling morphological patterns and cellular-level spatial alterations associated with protein expression changes. To model these complex relationships, we propose a novel generative-predictive framework called Ouroboros for producing H&amp;E images from protein expressions and simultaneously predicting protein expressions from H&amp;E images. Our comprehensive sample-independent validation over 9920 tissue spots from 4 GBM samples encompassing visual image analysis, quantitative analysis, subspace alignment and perturbation experiments shows that the proposed generative-predictive approach offers significant improvements in predicting protein expression from images in comparison to baseline methods as well as accurate generation of virtual GBM sample images. This proof of concept study can contribute to advancing our understanding of histological responses to protein expression perturbations and lays the foundations for further developments in this area.AVAILABILITY AND IMPLEMENTATION: Implementation and associated data for the proposed approach are available at the URL: https://github.com/Srijay/Ouroboros.</p

The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK

Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6–6.1), and the median OS was 10.8 months (95% CI 9.0–12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8–11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = &lt;.001) and median OS (18.8 vs. 8.9 months; log-rank p value &lt;.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.</p

Is everyone traumatized?:Perspectives from an Indonesian convent

What if we took trauma to be a fundamental aspect of human existence? Prominent in some strands of popular psychology, this is also the stance taken by an eastern Indonesian order of Catholic nuns who “dig up” their hearts as part of a continual process of self-formation. Set against a backdrop of Christian theologies of discernment, state concerns for human development, and local resonances of ritual sacrifice, nuns learn to interpret their childhoods as harmed by emotional trauma sustained in the company of kin. Once excavated, this trauma must be addressed in the convent through conscious efforts of mutual care, making trauma a moral category that creates new forms of subjectivity. Through acts of acknowledgment and support, the idiom of trauma makes the company surrounding a nun directly responsible for her self-formation. This article is about the ways Indonesian Catholic nuns conceptualize trauma as something that all humans sustain, how it grounds self-becoming, and how its causes—and cures—are rooted in the company of other people. I suggest that their experiences highlight the sociality of trauma more broadly and argue that trauma is one articulation of how people become themselves in the company of others

Rapid Amplification of Cerebrospinal Fluid Pressure as a Possible Mechanism for Optic Nerve Sheath Bleeding in Infants with Non-Accidental Head Injury

Purpose Subdural haemorrhage along the optic nerve (ON) is a histopathological indicator of abusive head trauma (AHT) in infants. We sought to determine if this bleeding could be caused by an abrupt increase in intracranial pressure (ICP) transmitted to cerebrospinal fluid (CSF) at the optic foramen (OF). Methods A theoretical model is developed to simulate the effect of a pressure perturbation of maximal amplitude P applied at the OF for a short duration T on the CSF-filled ON subarachnoid space (ONSAS). The ONSAS is modelled as a fluid-filled channel with an elastic wall representing the flexible ONSAS-arachnoid/dura interface. A constitutive law describing the relationship between SF pressure and ONSAS deformation is inferred from published measurements. CSF pressure profiles along the ONSAS are systematically examined over a broad range of P and T. Results The pressure perturbation initiated at the OF produces a pressure wave that stretches the ONSAS. This wave propagates rapidly along the ONSAS towards the scleral end of the ON, where it is reflected back towards the brain. For sufficiently small T a shock wave with amplification up to six times larger than P over a timescale of tens of milliseconds is observed at the scleral end of the ON. Comparatively smaller amplifications are observed for slower perturbations. Conclusions A sudden increase in CSF pressure in the cranial cavity can cause a rapid expansion of the ONSAS, which may lead to rupture of the bridging blood vessels. Our study predicts a plausible mechanism for subdural haemorrhage that occurs in AHT in infants

European Respiratory Society guidelines for the Diagnosis and Management of Pulmonary Alveolar Proteinosis

Background Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by several distinct diseases leading to progressive dyspnoea, hypoxemia, risk of respiratory failure and early death due to accumulation of proteinaceous material in the lungs. Diagnostic strategies may include computed tomography (CT) of the lungs, bronchoalveolar lavage, evaluation of antibodies against granulocyte macrophage colony stimulating factor (GM-CSF), genetic testing, and, eventually, lung biopsy. The management options are focused at removing the proteinaceous material by whole lung lavage (WLL), augmentation therapy with GM-CSF, rituximab, plasmapheresis, and lung transplantation. The presented diagnostic and management guideline aim to provide guidance to physicians managing patients with PAP.Methods A European Respiratory Society Task Force committee composed of clinicians, methodologists, and patients with experience in PAP developed recommendations in accordance with the ERS Handbook for Clinical Practice Guidelines and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. This included a systematic review of the literature and application of the GRADE approach to assess the certainty of the evidence and strength of recommendations. The committee formulated five PICO (Patients, Intervention, Comparison, Outcomes) questions, and two narrative questions to develop specific evidence-based recommendations.Results The Task Force committee developed recommendations for five PICOs. These included management of PAP with WLL, GM-CSF augmentation therapy, rituximab, plasmapheresis, and lung transplantation. Also, the committee made recommendations regarding the use of GM-CSF antibody testing, diagnostic bronchoalveolar lavage (BAL) and biopsy based on narrative questions. In addition to the recommendations, the committee provided information on the hierarchy of diagnostic interventions and therapy. Conclusions The diagnosis of PAP is based on CT and BAL cytology or lung histology, whereas diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis. There are several therapies including WLL and augmentation therapy with GM-CSF available to treat PAP, but supporting evidence is still limited.Take home message: The diagnosis of PAP is based on CT and BAL cytology or histology, whereas the diagnosis of a specific PAP-causing disease requires GM-CSF antibody testing and/or genetic analysis. WLL is considered the main management for many, but not all, PAP-causing diseases, and inhaled GM-CSF appears to be a promising option for autoimmune PA