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Abrocitinib, an oral, once-daily, Janus kinase (JAK) 1-selective inhibitor, is approved for the treatment of adults and adolescents with moderate-to-severe atopic dermatitis (AD). Abrocitinib has shown rapid and sustained efficacy in phase 3 trials and a consistent, manageable safety profile in long-term studies. Rapid itch relief and skin clearance are more likely to be achieved with a 200-mg daily dose of abrocitinib than with dupilumab. All oral JAK inhibitors are associated with adverse events of special interest and laboratory changes, and initial risk assessment and follow-up monitoring are important. Appropriate selection of patients and adequate monitoring are key for the safe use of JAK inhibitors. Here, we review the practical use of abrocitinib and discuss characteristics of patients who are candidates for abrocitinib therapy. In general, abrocitinib may be used in all appropriate patients with moderate-to-severe AD in need of systemic therapy, provided there are no contraindications, e.g., in patients with active serious systemic infections and those with severe hepatic impairment, as well as pregnant or breastfeeding women. For patients aged ≥ 65 years, current long-time or past long-time smokers, and those with risk factors for venous thromboembolism, major adverse cardiovascular events, or malignancies, a meticulous benefit-risk assessment is recommended, and it is advised to start with the 100-mg dose, when abrocitinib is the selected treatment option.

Abstract Background Topical corticosteroids (TCS) are efficacious treatments for inflammatory skin conditions, however, there is a risk of adverse effects; understanding how best to use these treatments is an unmet research priority shared by patients and healthcare professionals. Objectives To develop non‐invasive biomarkers of local adverse effects to facilitate the optimisation of topical therapy. Methods An observer‐blind randomised within‐subject controlled trial in atopic dermatitis patients was undertaken (NCT04194814) comparing betamethasone valerate 0.1% cream (BMV) to a non‐steroidal anti‐inflammatory treatment, crisaborole 2% ointment (CRB). Participants underwent 4 weeks twice‐daily treatment with CRB on one forearm and BMV on the other (left/right randomised). Skin properties were assessed on days 1, 15, 29 of treatment and again on day 57, including imaging of skin microstructure using Optical Coherence Tomography (OCT) and Attenuated Total Reflectance (ATR)‐Fourier Transform Infrared (FTIR) spectroscopic assessment of stratum corneum molecular structure. The primary outcome was the difference in the change in epidermal thickness from days 1 to 29. Results Thirty‐seven participants received the first dose, of which 32 completed the study (all 37 were included in the analysis). Pathologic epidermal thinning at day 29 was significantly greater (p

Abstract Pyoderma gangrenosum (PG) in Caucasians with Takayasu's arteritis (TA) is uncommon. We described a case of refractory PG in an 18‐year‐old Caucasian man with TA since the age of 10 and was treated with corticosteroids, methotrexate, anti‐TNF therapy (adalimumab), anti‐CD20 therapy (rituximab), cyclophosphamide and most latterly tocilizumab and leflunomide. He has vascular stenosis complicated with renovascular hypertension and is steroid‐dependent. He presented with a 6‐week history of a left cheek rapidly enlarging lesion associated with pain, bleeding and purulent discharge not responding to flucloxacillin. Incisional biopsy suggested PG. He later developed similar lesions on the volar aspect of the right hand and at venepuncture sites. Despite topical immunosuppressive medication and high‐dose pulsed intravenous methylprednisolone, the left cheek lesion continued to grow rapidly. These painful, unsightly ulcers caused significant psychosocial stress and limited his daily life. Following a multidisciplinary team (MDT) discussion, tocilizumab was switched to abrocitinib. While initial improvement of lesions was observed, he subsequently developed an acneiform eruption which evolved into PG and became superinfected with herpes zoster virus and Staphylococcus aureus, requiring hospitalisation for intravenous (IV) acyclovir and antibiotics. Following several MDT discussions, abrocitinib was discontinued and a new regimen consisting of ciclosporin, dapsone and enhanced frequency IV immunoglobulin (IVIg) every 2 weeks was initiated, effectively stabilising his PG. This case highlights the rare association of PG and TA in Caucasians, the complexities of managing PG complicated by severe infections and underlying immunodeficiency, and the significant psychosocial burden of PG.

Abstract Abnormal passive stiffness of the heart muscle (myocardium) is evident in the pathophysiology of several cardiovascular diseases, making it an important indicator of heart health. Recent advancements in cardiac imaging and biophysical modeling now enable more effective evaluation of this biomarker. Estimating passive myocardial stiffness can be accomplished through an MRI-based approach that requires comprehensive subject-specific input data. This includes the gross cardiac geometry (e.g. from conventional cine imaging), regional diastolic kinematics (e.g. from tagged MRI), microstructural configuration (e.g. from diffusion tensor imaging), and ventricular diastolic pressure, whether invasively measured or non-invasively estimated. Despite the progress in cardiac biomechanics simulations, developing a framework to integrate multiphase and multimodal cardiac MRI data for estimating passive myocardial stiffness has remained a challenge. Moreover, the sensitivity of estimated passive myocardial stiffness to input data has not been fully explored. This study aims to: (1) develop a framework for integrating subject-specific in vivo MRI data into in silico left ventricular finite element models to estimate passive myocardial stiffness, (2) apply the framework to estimate the passive myocardial stiffness of multiple healthy subjects under assumed filling pressure, and (3) assess the sensitivity of these estimates to loading conditions and myofiber orientations. This work contributes toward the establishment of a range of reference values for material parameters of passive myocardium in healthy human subjects. Notably, in this study, beat-to-beat variation in left ventricular end-diastolic pressure was found to have a greater influence on passive myocardial material parameter estimation than variation in fiber orientation.

Abstract Introduction Current mitral annuloplasty rings fail to restrict the anteroposterior distance while allowing dynamic mitral annular changes. We designed and manufactured a mitral annuloplasty ring that demonstrated axis-specific, selective flexibility to meet this clinical need. The objectives were to evaluate ex vivo biomechanics of this ring and to validate the annular dynamics and safety after ring implantation in vivo. Methods Healthy human mitral annuli (n = 3) were tracked, and motions were isolated. Using the imaging data, we designed and manufactured our axis-specific mitral annuloplasty ring. An ex vivo annular dilation model was used to compare hemodynamics and chordal forces after repair using the axis-specific, rigid, and flexible rings in five porcine mitral valves. In vivo, axis-specific (n = 6), rigid (n = 6), or flexible rings (n = 6) were implanted into male Dorset sheep for annular motion analyses. Five additional animals receiving axis-specific rings survived for up to 6 months. Results Here we show the axis-specific, rigid, and flexible rings reduced regurgitation fraction to 4.7 ± 2.7%, 2.4 ± 3.2%, and 17.8 ± 10.0%, respectively. The axis-specific ring demonstrated lower average forces compared to the rigid ring (p = 0.046). Five animals receiving axis-specific rings survived for up to 6 months, with mitral annular motion preserved in vivo. Mature neoendocardial tissue coverage over the device was found to be complete with full endothelialization in all animals. Conclusions The axis-specific mitral annuloplasty ring we designed demonstrates excellent capability to repair mitral regurgitation while facilitating dynamic mitral annular motion. This ring has tremendous potential for clinical translatability, representing a promising surgical solution for mitral regurgitation.

BACKGROUND: Patients with atopic dermatitis (AD), particularly infants and young children, are at greater risk of developing skin infections. In this study, we assessed infection rates in AD patients aged 6 months to 5 years treated with dupilumab. METHODS: In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled, phase III clinical trial, children aged 6 months to 5 years with moderate-to-severe AD were randomized 1:1 to subcutaneous dupilumab or placebo, with concomitant low-potency topical corticosteroids, every 4 weeks for 16 weeks. Exposure-adjusted infection rates were used to compare treatment groups. RESULTS: The analysis included 162 patients, of whom 83 received dupilumab and 79 received placebo. Total infection rates were not significantly different between the dupilumab and placebo groups (rate ratio [RR] 0.75, 95% CI 0.48-1.19; p = 0.223). Non-herpetic adjudicated skin infections and bacterial infections were significantly less frequent with dupilumab versus placebo (non-herpetic skin infections: RR 0.46, 95% CI 0.21-0.99; p = 0.047; bacterial infections: RR 0.09, 95% CI 0.01-0.67; p = 0.019), and the number of patients using systemic anti-infective medication was significantly lower in the dupilumab group (RR 0.52, 95% CI 0.30-0.89; p = 0.019). There were no significant differences in the number of herpetic infections between the dupilumab and placebo groups (RR 1.17, 95% CI 0.31-4.35; p = 0.817). The number of patients with two or more infection events was significantly higher in the placebo group (RR 0.29, 95% CI 0.12-0.68; p = 0.004), and no severe or serious infections (including eczema herpeticum) were observed among patients receiving dupilumab. CONCLUSIONS: These data suggest that dupilumab treatment in infants and children younger than 6 years with AD does not increase overall risk of infections and is associated with a reduced risk of bacterial and non-herpetic skin infections compared with placebo, resulting in a reduced need for anti-infective medication. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov with ID number NCT03346434 on November 17, 2017. INFOGRAPHIC.

Abstract Effective approaches are needed to conserve the planet's remaining wildlife and wilderness landscapes, especially concerning global biodiversity conservation targets. Here, we present a new software system called EarthRanger: an open‐source platform built to help monitor, research and manage ecosystems. EarthRanger consists of seven main components (Core Server, API, Storage, Gundi, Web App, Mobile App, Ecoscope) that provide functionality for data (i) aggregation & collection, (ii) storage & management, (iii) real‐time and post hoc analysis, (iv) visualisation and (v) dissemination. The mobile application provides field‐based data recording and visualisation tools. EarthRanger may be deployed for single project use or can aggregate across multiple geographies as a centralised hub. EarthRanger can be used to collect standardised tracking data (e.g. from wildlife collars, vehicles and ranger patrols) and configurable event information (e.g. a singular recording with associated user‐defined attribute information such as a wildlife sighting or encounter with a poacher). Since development began in 2015, the platform has (at the time of writing) been deployed at over 500 sites across 70 countries and with myriad configurations and objectives. EarthRanger has improved the ability to monitor data feeds and manage conservation‐related operations in real time. For instance, the deployment of EarthRanger by African Parks has led to the removal of over 50,000 snares, steady population growth of key species of concern and near cessation of poaching. In Liwonde's protected area, enhanced mitigation efforts supported by EarthRanger reduced the number of deaths from wildlife conflict by more than 91%. EarthRanger is also providing a platform to enhance standardisation, aggregation, transfer and long‐term storage of ecological information and promote collaboration between groups conducting protected area management and ecology and biodiversity research.

The educational benefit of the traditional didactic lecture to learners in Higher Education is hotly debated. Given increasing student numbers, existing technical set ups and many logistical concerns, lectures remain the norm in many Higher Education Institutions (HEIs). In this personal view piece, we discuss the benefits, opportunities, and challenges of incorporating dynamic teaching approaches, including "draw-alongs" and animations into undergraduate lectures, typically with large class sizes, to create more engaging and interactive lectures for learners.

BACKGROUND: For children aged 6-11 years with uncontrolled severe atopic dermatitis (AD), 16 weeks of treatment with dupilumab resulted in substantial clinical benefit compared with placebo with an acceptable safety profile. However, longer-term safety and efficacy data are important to inform longitudinal AD management. OBJECTIVES: This analysis of data from an open-label extension study (LIBERTY AD PED-OLE, NCT02612454) reports the long-term safety, efficacy, and pharmacokinetics of dupilumab in children with severe AD who had participated in the pivotal dupilumab LIBERTY AD PEDS study (NCT03345914). METHODS: Enrolled patients initially received subcutaneous dupilumab 300 mg every 4 weeks (q4w). The q4w regimen could be uptitrated to dupilumab dose regimens of 200 or 300 mg every 2 weeks (q2w; for body weight

ABSTRACT Group A Streptococcus (GAS) is a human-adapted pathogen responsible for a variety of diseases. The GAS M1UK lineage has contributed significantly to the recently reported increases in scarlet fever and invasive infections. However, the basis for its evolutionary success is not yet fully understood. During the transition to systemic disease, the M1 serotype is known to give rise to spontaneous mutations in the control of virulence two-component regulatory system (CovRS) that confer a fitness advantage during invasive infections. Mutations that inactivate CovS function result in the de-repression of key GAS virulence factors such as streptolysin O (SLO), a pore-forming toxin and major trigger of inflammasome/interleukin-1β-dependent inflammation. Conversely, expression of the streptococcal cysteine protease SpeB, which is required during initial stages of colonization and onset of invasive disease, is typically lost in such mutants. In this study, we identified and characterized a novel covS single nucleotide polymorphism detected in three separate invasive M1UK isolates. The resulting CovSAla318Val mutation caused a significant upregulation of SLO resulting in increased inflammasome activation in human THP-1 macrophages, indicating an enhanced inflammatory potential. Surprisingly, SpeB production was unaffected. Site-directed mutagenesis was performed to assess the impact of this mutation on virulence and global gene expression. We found that the CovSAla318Val mutation led to subtle, virulence-specific changes of the CovRS regulon compared to previously characterized covS mutations, highlighting an unappreciated level of complexity in CovRS-dependent gene regulation. Continued longitudinal surveillance is warranted to determine whether this novel covS mutation will expand in the M1UK lineage.IMPORTANCEThe M1UK lineage of GAS has contributed to a recent global upsurge in scarlet fever and invasive infections. Understanding how GAS can become more virulent is critical for infection control and identifying new treatment approaches. The two-component CovRS system, comprising the sensor kinase CovS and transcription factor CovR, is a central regulator of GAS virulence genes. In the M1 serotype, covRS mutations are associated with an invasive phenotype. Such mutations have not been fully characterized in the M1UK lineage. This study identified a novel covS mutation in invasive Australian M1UK isolates that resulted in a more nuanced virulence gene regulation compared to previously characterized covS mutations. A representative isolate displayed upregulated SLO production and triggered amplified interleukin-1β secretion in infected human macrophages, indicating an enhanced inflammatory potential. These findings underscore the need for comprehensive analyses of covRS mutants to fully elucidate their contribution to M1UK virulence and persistence.