A Curious Case of Weakness: Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Presenting With Muscle Weakness.

Disease manifestations of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a small vessel vasculitis with multisystemic effects, include respiratory, renal, nervous, gastrointestinal, and skin implications. Muscle weakness and inflammatory myopathy are rare manifestations of AAV. We report the case of a 77-year-old female with a medical history of hypothyroidism and osteoarthritis who presented with a two-month history of worsening muscle weakness (mainly proximal). She endorsed dysphagia, a 40-lb unintentional weight loss, and persistent sinusitis with middle ear effusions, requiring bilateral tympanostomy. The physical examination was notable for 2/5 muscle strength in her hip flexors and extensors, with 4/5 strength in other extremities. Lower extremity MRI showed diffuse intramuscular edema between fat planes and intramuscular septal regions. Erythrocyte sedimentation rate (70 mm/hr), C-reactive protein (141 mg/L), creatine kinase (690 U/L), and anti-myeloperoxidase (MPO) antibodies (>999 AU/mL) were elevated. A thigh biopsy revealed fibrinoid necrosis of small intramuscular arteries, confluent circumferential granulomatous vessel wall inflammation, and associated mild chronic inflammation, including occasional eosinophils and a few plasma cells. She was diagnosed with MPO-positive AAV. The patient was started on high-dose steroids (prednisone), with a taper on a disease-modifying agent, azathioprine, with significant improvement in symptoms over the next four months and complete resolution at 16-month follow-up. This patient's clinical presentation of predominant lower extremity weakness due to inflammatory myositis is an unusual manifestation of AAV. Clinicians should keep a broad differential diagnosis and consider the possibility of AAV, especially in cases of muscle weakness presenting as inflammatory myositis, in the absence of other clinical manifestations of systemic vasculitis or specific myositis serologies.

Rapid reconstitution of ubiquitinated nucleosome using a non-denatured histone octamer ubiquitylation approach.

BACKGROUND: Histone ubiquitination modification is emerging as a critical epigenetic mechanism involved in a range of biological processes. In vitro reconstitution of ubiquitinated nucleosomes is pivotal for elucidating the influence of histone ubiquitination on chromatin dynamics. RESULTS: In this study, we introduce a Non-Denatured Histone Octamer Ubiquitylation (NDHOU) approach for generating ubiquitin or ubiquitin-like modified histone octamers. The method entails the co-expression and purification of histone octamers, followed by their chemical cross-linking to ubiquitin using 1,3-dibromoacetone. We demonstrate that nucleosomes reconstituted with these octamers display a high degree of homogeneity, rendering them highly compatible with in vitro biochemical assays. These ubiquitinated nucleosomes mimic physiological substrates in function and structure. Additionally, we have extended this method to cross-linking various histone octamers and three types of ubiquitin-like proteins. CONCLUSIONS: Overall, our findings offer an efficient strategy for producing ubiquitinated nucleosomes, advancing biochemical and biophysical studies in the field of chromatin biology.

Understanding the Mechanisms of Cognitive Remediation on Recovery in People With Early Psychosis: A Mediation and Moderation Analysis.

BACKGROUND: To provide precision cognitive remediation therapy (CR) for schizophrenia, we need to understand whether the mechanism for improved functioning is via cognition improvements. This mechanism has not been rigorously tested for potential moderator effects. STUDY DESIGN: We used data (n = 377) from a randomized controlled trial using CIRCuiTS, a therapist-supported CR, with participants from first-episode psychosis services. We applied structured equation modeling to test whether: (1) CR hours explain the goal attainment functional outcome (GAS) at posttreatment, (2) global cognitive improvement mediates GAS, and if (3) total symptoms moderate the CR hours to cognitive improvement pathway, and/or negative symptoms moderate the cognition to functioning pathway, testing moderator effects via the mediator or directly on CR hours to functioning path. STUDY RESULTS: CR produced significant functioning benefit for each therapy hour (Coeff = 0.203, 95% CI 0.101-0.304, P < .001). The mediated path from CR hours to cognition and cognition to functioning was small and nonsignificant (Coeff = 0.014, 95% CI = -0.010, 0.037, P = .256). Total symptoms did not moderate the path to cognition (P = .211) or the direct path to outcome (P = .896). However, negative symptoms significantly moderated the effect of cognitive improvements on functioning (P = .015) with high negative symptoms reducing the functional gains of improved cognition. CONCLUSIONS: Although cognitive improvements were correlated with functioning benefit, they did not fully explain the positive effect of increased therapy hours on functioning, suggesting additional CR factors also contribute to therapy benefit. Negative symptoms interfere with the translation of cognitive improvements into functional gains so need consideration.

Doing research in non-specialist mental health services for children and young people: lessons learnt from a process evaluation of the ICALM (Interpersonal Counselling for Adolescent Low Mood) feasibility randomised controlled trial.

BACKGROUND: The rising prevalence of adolescent mild depression in the UK and the paucity of evidence-based interventions in non-specialist sectors where most cases present, creates an urgent need for early psychological interventions. Randomised controlled trials (RCTs) are considered the gold standard for obtaining unbiased estimates of intervention effectiveness. However, the complexity of mental health settings poses great challenges for effectiveness evaluations. This paper reports learning from an embedded process evaluation of the ICALM RCT which tested the feasibility of delivering Interpersonal Counselling for Adolescents (IPC-A) plus Treatment as Usual (TAU) versus TAU only for adolescent (age 12-18) mild depression by non-qualified mental health professionals in non-specialist sectors. METHODS: A qualitative mixed methods process evaluation, drawing on Bronfenbrenner's socioecological model to investigate key influences on trial delivery across macro-(e.g. policy), meso-(e.g. service characteristics) and micro-(e.g. on-site trial processes) contextual levels. Data collection methods included 9 site questionnaires, 4 observations of team meetings, policy documents, and 18 interviews with stakeholders including therapists, heads of service and managers. Thematic analysis focused on understanding how contextual features shaped trial implementation. RESULTS: The ICALM trial concluded in 2022 having only randomised 14 out of the target 60 young people. At a macro-level, trial delivery was impacted by the COVID-19 pandemic, with services reporting a sharp increase in cases of (social) anxiety over low mood, and backlogs at central referral points which prolonged waiting times for mild cases (e.g. low mood). An interaction between high demand and lack of capacity at a meso-service level led to low prioritisation of trial activities at a micro-level. Unfamiliarity with research processes (e.g. randomisation) and variation in TAU support also accentuated the complexities of conducting an RCT in this setting. CONCLUSIONS: Conducting a RCT of IPC-A in non-specialist services is not feasible in the current context. Failure to conduct effectiveness trials in this setting has clinical implications, potentially resulting in escalation of mild mental health problems. Research done in this setting should adopt pragmatic and innovative recruitment and engagement approaches (e.g. creating new referral pathways) and consider alternative trial designs, e.g. cluster, stepped-wedge or non-controlled studies using complex systems approaches to embrace contextual complexity. TRIAL REGISTRATION: ISRCTN registry, ISRCTN82180413. Registered on 31 December 2019.

Exoskeletal solutions to enable mobility with a lower leg fracture in austere environments.

The treatment and evacuation of people with lower limb fractures in austere environments presents unique challenges that assistive exoskeletal devices could address. In these dangerous situations, independent mobility for the injured can preserve their vital capabilities so that they can safely evacuate and minimize the need for additional personnel to help. This expert view article discusses how different exoskeleton archetypes could provide independent mobility while satisfying the requisite needs for portability, maintainability, durability, and adaptability to be available and useful within austere environments. The authors also discuss areas of development that would enable exoskeletons to operate more effectively in these scenarios as well as preserve the health of the injured limb so that definitive treatment after evacuation will produce better outcomes.