Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1.

Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation.

Comment on "Strength of shock-loaded single-crystal tantalum [100] determined using in situ broadband X-Ray Laue diffraction".

A Comment on the Letter by A. J. Comley et al., Phys. Rev. Lett. 110, 115501 (2013). The authors of the Letter offer a Reply.

The environmental consequences of oral healthcare provision by the dental team.

OBJECTIVES: To undertake a comparative ecological impact (Total lifetime carbon footprint and single use plastics (SUP) waste generation) derived from the provision of professional oral healthcare (Dentists and hygienist) to five different patient categories up to the age of 50 years, representative of different levels of progressive dental disease and treatment experience. METHOD: CO2e and SUP waste generated was calculated for five patient categories with common preventable diseases; that are representative of different levels of progressive dental disease and treatment experience. The assessment is based on the average restorative care levels for 50-year-olds in the UK. The number of appointments for each procedure was calculated using current evidence-based guidelines. The total lifetime carbon and the SUP waste analysis was calculated using published peer-reviewed data. RESULTS: The total carbon footprint follows a progression with low impacts for individual persons with very low disease and treatment experience (285 KgCO2e), escalating to very high impacts (approximately 2,170 KgCO2e) for people with high levels of disease and treatment experience. SUP waste follows a similar linear rise across the different cohorts of dental experience over a lifetime (6-50 years), from 1,382 items and 4.6 Kg for patients in a the very low dental experience, to 12,200 items and 33.8 Kg for patients in the cohort of very high dental experience. CONCLUSIONS: The provision of all oral healthcare carries an environmental impact in the form of carbon footprint and SUP waste. The cumulative lifetime environmental impact of oral healthcare is proportional to the disease and treatment experience of the individual person for these preventable diseases; with a x8 difference between the two extremes of experience. CLINICAL SIGNIFICANCE: All forms of oral healthcare have an environmental impact. The most effective way to mitigate these impacts is through the promotion and provision of effective evidence-based preventive oral healthcare.

Intergranular fracture, grain-boundary structure, and dislocation-density interactions in FCC bicrystals.

A dislocation-density based crystalline plasticity (DCP) and nonlinear finite element (FE) analysis were used to predict, and fundamentally understand how and why fracture nucleation and propagation are related to the interrelated microstructural mechanisms of dislocation-density pileups, GB structure, orientation, and total and partial dislocation density interactions within and adjacent for a random low angle grain boundary (LAGB) and a random high angle GB (HAGB). The GB orientations and structures were obtained from micropillar experiments, such that LAGBs and the HAGBs can be accurately represented and used for the modeling predictions. The normal stress, density of pileups, and dislocation-density accumulation along and within the GB were higher for the low angle GB bicrystal. These interrelated phenomena delineate how fracture for high angle GBs nucleate and propagate at lower nominal strains than the lower angle GB bicrystal case. These predictions underscore how fundamental mechanisms can be identified and used to understand how failure nucleates and propagates for different GB structures and orientations.

Worldwide Distribution and Extracutaneous Manifestations of Henoch-Schönlein Purpura in Adults: Narrative Review.

BACKGROUND: Henoch-Schönlein purpura (HSP), a leukocytoclastic small vessel vasculitis, exhibits both cutaneous and systemic manifestations. While predominantly observed in childhood, it may manifest in adults with more pronounced systemic involvement. Furthermore, HSP is a global phenomenon showcasing epidemiological and systemic variances. OBJECTIVE: This study aims to scrutinize extracutaneous manifestations in adults with HSP, discerning distinctions according to geographical regions on a worldwide scale. METHODS: A comprehensive search encompassing PubMed, Embase, Cochrane Library, and Web of Science was executed, covering papers published from January 1, 1970, to December 1, 2019. Keywords used included "Henoch-Schönlein purpura," "henoch schonlein purpura+adult," "IgA vasculitis+adult," "HSP+adult," and "IgAV." A total of 995 publications were identified, from which 42 studies encompassing 4064 patients were selected, with a predominant focus on cases reported in Asia, Europe, and the Americas. RESULTS: Among adults afflicted with HSP, European patients exhibited a higher propensity for male predominance (P<.001), gastrointestinal involvement (P<.001), and musculoskeletal complications (P<.001). Conversely, patients from the Americas were least likely to experience genitourinary involvement (P<.001). CONCLUSIONS: HSP demonstrates a variance in distribution and extracutaneous manifestations within distinct geographical boundaries. In the adult population, European patients exhibited a higher prevalence of male gender and gastrointestinal and musculoskeletal involvement. Asian patients were more predisposed to genitourinary involvement when compared to their American counterparts. The establishment of prospective studies using standardized reporting measures is imperative to validate the relationships unveiled in this investigation.

Development of a behaviour change intervention to increase the delivery of upper limb constraint-induced movement therapy programs to people with stroke and traumatic brain injury.

Purpose: Constraint-induced movement therapy (CIMT) is a recommended intervention for arm recovery after acquired brain injury but is underutilised in practice. The purpose of this study is to describe the development of a behaviour change intervention targeted at therapists, to increase delivery of CIMT.Methods: A theoretically-informed approach for designing behaviour change interventions was used including identification of which behaviours needed to change (Step 1), barriers and enablers that needed to be addressed (Step 2), and intervention components to target those barriers and enablers (Step 3). Data collection methods included file audits and therapist interviews. Quantitative data (file audits) were analysed using descriptive statistics. Qualitative data analysis (interviews) was informed by the Theoretical Domains Framework (TDF) and Behaviour Change Wheel.Results: Fifty two occupational therapists, physiotherapists and allied health assistants participated in focus groups (n = 7) or individual interviews (n = 6). Key barriers (n = 20) and enablers (n = 10) were identified across 11 domains of the TDF and perceived to influence CIMT implementation. The subsequent behaviour change intervention included training workshops, nominated team champions, community of practice meetings, three-monthly file audit feedback cycles, poster reminders and drop-in support during CIMT.Conclusion: This study describes the development of a behaviour change intervention to increase CIMT delivery by clinicians.Trial registration: Australian New Zealand Clinical Trials Registry, Trial ID: ACTRN12617001147370.

Constraint induced movement therapy (CIMT) is a highly effective intervention for arm recovery after acquired brain injury, recommended in multiple clinical practice guidelines, yet delivery of CIMT is often not part of routine practice.The Behaviour Change Wheel, COM-B (capability, opportunity, motivation- behaviour) system and Theoretical Domains Framework (TDF) helped identify barriers and enablers to CIMT delivery by therapists, and design a theoretically-informed behaviour change intervention.The effect of the behaviour change intervention on therapists practice can now be evaluated to determine if it increases the delivery of CIMT more routinely in practice.

Adult experiences of constraint-induced movement therapy programmes: a qualitative study using the Theoretical Domains Framework and Capability, Opportunity, Motivation - Behaviour system.

AIM: To explore the experiences of adults who completed a constraint-induced movement therapy (CIMT) programme, and the barriers and enablers to their participation. METHODS: Qualitative design using semi-structured interviews. Stroke and brain injury survivors (n = 45) who had completed CIMT as part of their usual rehabilitation were interviewed 1 month post-CIMT. Interviews were audio-recorded, transcribed and imported into Nvivo for analysis. Inductive coding was used to identify initial themes. Themes were then deductively mapped to the Capability, Opportunity, Motivation - Behaviour system, a behaviour change model, to identify barriers and enablers to CIMT programme adherence and engagement. RESULTS: Enablers influencing participation included being provided with education about the programme (Capability - psychological), seeing improvements in arm function (Motivation - reflective), being committed to the programme (Motivation - reflective) and having strong social support from staff, family and allied health students (Opportunity - social). The structured programme was a motivator and offered a way to fill the time, particularly during inpatient rehabilitation (Opportunity - physical). Barriers to participation included experiencing physical and mental fatigue (Capability - physical) and frustration early in the CIMT programme (Motivation - automatic), and finding exercises boring and repetitive (Motivation - automatic). CONCLUSION: Therapist provision of educational supports for CIMT participants and their families is important to maximise CIMT programme uptake. During CIMT delivery, we recommend the provision of positive feedback and coaching in alignment with CIMT principles, and the inclusion of social supports such as group-based programmes to enhance participant adherence.

Orthopaedic Trauma-Induced Pyoderma Gangrenosum: A Case Report.

CASE: We present a case of a 60-year-old polytraumatized man who developed postoperative pyoderma gangrenosum (PG) after his initial stabilization procedures, mimicking a postoperative infection. This caused a delay in diagnosis, leading to progression of his wounds and a delay in initiation of the appropriate treatment. Once his PG was appropriately treated, his clinical status and wounds improved. He underwent successful wound coverage by plastic surgery and has been recovering from his injuries. CONCLUSION: Prompt identification and initiation of treatment for postoperative PG is critical to avoid exacerbation of wounds and subsequent morbidity to the patient.

Quantifying Topological Uncertainty in Fractured Systems using Graph Theory and Machine Learning.

Fractured systems are ubiquitous in natural and engineered applications as diverse as hydraulic fracturing, underground nuclear test detection, corrosive damage in materials and brittle failure of metals and ceramics. Microstructural information (fracture size, orientation, etc.) plays a key role in governing the dominant physics for these systems but can only be known statistically. Current models either ignore or idealize microscale information at these larger scales because we lack a framework that efficiently utilizes it in its entirety to predict macroscale behavior in brittle materials. We propose a method that integrates computational physics, machine learning and graph theory to make a paradigm shift from computationally intensive high-fidelity models to coarse-scale graphs without loss of critical structural information. We exploit the underlying discrete structure of fracture networks in systems considering flow through fractures and fracture propagation. We demonstrate that compact graph representations require significantly fewer degrees of freedom (dof) to capture micro-fracture information and further accelerate these models with Machine Learning. Our method has been shown to improve accuracy of predictions with up to four orders of magnitude speedup.

HOBOE (Head-of-Bed Optimization of Elevation) Study: association of higher angle with reduced cerebral blood flow velocity in acute ischemic stroke.

BACKGROUND: Cerebral autoregulation can be impaired after ischemic stroke, with potential adverse effects on cerebral blood flow during early rehabilitation. OBJECTIVE: The objective of this study was to assess changes in cerebral blood flow velocity with orthostatic variation at 24 hours after stroke. DESIGN: This investigation was an observational study comparing mean flow velocities (MFVs) at 30, 15, and 0 degrees of elevation of the head of the bed (HOB). METHODS: Eight participants underwent bilateral middle cerebral artery (MCA) transcranial Doppler monitoring during orthostatic variation at 24 hours after ischemic stroke. Computed tomography angiography separated participants into recanalized (artery completely reopened) and incompletely recanalized groups. Friedman tests were used to determine MFVs at the various HOB angles. Mann-Whitney U tests were used to compare the change in MFV (from 30° to 0°) between groups and between hemispheres within groups. RESULTS: For stroke-affected MCAs in the incompletely recanalized group, MFVs differed at the various HOB angles (30°: median MFV=51.5 cm/s, interquartile range [IQR]=33.0 to 103.8; 15°: median MFV=55.5 cm/s, IQR=34.0 to 117.5; 0°: median MFV=85.0 cm/s, IQR=58.8 to 127.0); there were no significant differences for other MCAs. For stroke-affected MCAs in the incompletely recanalized group, MFVs increased with a change in the HOB angle from 30 degrees to 0 degrees by a median of 26.0 cm/s (IQR=21.3 to 35.3); there were no significant changes in the recanalized group (-3.5 cm/s, IQR=-12.3 to 0.8). The changes in MFV with a change in the HOB angle from 30 degrees to 0 degrees differed between hemispheres in the incompletely recanalized group but not in the recanalized group. LIMITATIONS: Generalizability was limited by sample size. CONCLUSIONS: The incompletely recanalized group showed changes in MFVs at various HOB angles, suggesting that cerebral blood flow in this group may be sensitive to orthostatic variation, whereas the recanalized group maintained stable blood flow velocities.