IL11 is elevated in systemic sclerosis and IL11-dependent ERK signalling underlies TGFß-mediated activation of dermal fibroblasts.

OBJECTIVES: Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with activation of human dermal fibroblasts (HDFs) from patients with SSc or controls. METHODS: We measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping. RESULTS: In patients with SSc, serum IL11 levels are elevated as compared with healthy controls. All transforming growth factor beta (TGFß) isoforms induced IL11 secretion from HDFs, which highly express IL11 receptor α-subunit and the glycoprotein 130 (gp130) co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFß upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signalling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFß-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacological inhibition of ERK. CONCLUSIONS: These data reveal that autocrine IL11-dependent ERK activity alone or downstream of TGFß stimulation promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc.

Rationale and design of the randomized prospective ATLAS study: Avoid Transvenous Leads in Appropriate Subjects.

BACKGROUND: The defibrillator lead is the weakest part of the transvenous (TV) implantable cardioverter defibrillation (ICD) system and a frequent cause of morbidity. Lead dislodgement, cardiac perforation, insertion-related trauma including pneumothorax and vascular injury, are common early complications of TV-ICD implantation. Venous occlusion, tricuspid valve dysfunction, lead fracture and lead insulation failure are additional, later complications. The introduction of a totally sub-cutaneous ICD (S-ICD) may reduce these lead-related issues, patient morbidity, hospitalizations and costs. However, such benefits compared to the TV-ICD have not been demonstrated in a randomized trial. DESIGN: ATLAS (Avoid Transvenous Leads in Appropriate Subjects) is a multi-centered, randomized, open-label, parallel group trial. Patients younger than 60 years are eligible. If older than 60 years, patients are eligible if they have an inherited heart rhythm disease, or risk factors for ICD-related complication, such as hemodialysis, a history of ICD or pacemaker infection, heart valve replacement, or severe pulmonary disease. This study will determine if using an S-ICD compared to a TV-ICD reduces a primary composite outcome of perioperative complications including pulmonary or pericardial perforation, lead dislodgement or dysfunction, tricuspid regurgitation and ipsilateral venous thrombosis. Five hundred patients will be enrolled from 14 Canadian hospitals, and data collected to both early- (at 6 months) and mid-term complications (at 24 months) as well as mortality and ICD shock efficacy. SUMMARY: The ATLAS randomized trial is comparing early- and mid-term vascular and lead-related complications among S-ICD versus TV-ICD recipients who are younger or at higher risk of ICD-related complications.

Could it have been predicted? A retrospective analysis of the last year of life for people who died whilst in an intermediate care centre.

Objectives: Intermediate care centres (ICCs) exist in the UK to bridge between acute hospital and home for those with rehabilitation needs. A national study shows 25% of ICC in-patients died within a year of admission. High quality end-of-life care includes early conversations with a person and their loved ones about what matters to them; timely identification of those who are likely to be nearing the end of their life is key. Methods: This retrospective quantitative review of 98 patient notes reviewed deaths in one NHS trust, comparing 50 deaths in the acute hospital and 48 in the ICC. Data included frailty score, previous hospital admissions, specialist palliative input and conversations between professionals, patients and their loved ones. Supportive and Palliative Care Indicators Tool (SPICT) scores were used to identify those likely to have a poor prognosis. Results: Results showed statistically significant differences between the groups. The ICC cohort were older with higher clinical frailty scores. They were less likely to have previous hospital admissions but more likely to have poor prognostic features on final admission. Despite this, the possibility of deterioration was discussed them less frequently than the acute hospital cohort, and fewer saw the Palliative care team. Conclusion: This data suggests support is needed in ICCs to recognise those likely to be nearing end-of-life. One challenge is patients are more likely to be seen as 'well' in a rehabilitation focused environment. This paper suggests a 'proactive approach' trial using SPICT for ongoing assessment of ICC in-patients supporting identification of a deteriorating person and avoid missed opportunities for key conversations.

Dual carbon sequestration with photosynthetic living materials.

Natural ecosystems offer efficient pathways for carbon sequestration, serving as a resilient approach to remove CO2 from the atmosphere with minimal environmental impact. However, the control of living systems outside of their native environments is often challenging. Here, we engineered a photosynthetic living material for dual CO2 sequestration by immobilizing photosynthetic microorganisms within a printable polymeric network. The carbon concentrating mechanism of the cyanobacteria enabled accumulation of CO2 within the cell, resulting in biomass production. Additionally, the metabolic production of OH- ions in the surrounding medium created an environment for the formation of insoluble carbonates via microbially-induced calcium carbonate precipitation (MICP). Digital design and fabrication of the living material ensured sufficient access to light and nutrient transport of the encapsulated cyanobacteria, which were essential for long-term viability (more than one year) as well as efficient photosynthesis and carbon sequestration. The photosynthetic living materials sequestered approximately 2.5 mg of CO2 per gram of hydrogel material over 30 days via dual carbon sequestration, with 2.2 ± 0.9 mg stored as insoluble carbonates. Over an extended incubation period of 400 days, the living materials sequestered 26 ± 7 mg of CO2 per gram of hydrogel material in the form of stable minerals. These findings highlight the potential of photosynthetic living materials for scalable carbon sequestration, carbon-neutral infrastructure, and green building materials. The simplicity of maintenance, coupled with its scalability nature, suggests broad applications of photosynthetic living materials as a complementary strategy to mitigate CO2 emissions.

Diagnostic accuracy and yield of screening tests for atrial fibrillation in the family practice setting: a multicentre cohort study.

BACKGROUND: Detection of undiagnosed or undertreated ("actionable") atrial fibrillation could increase the use of appropriate oral anticoagulant therapy and reduce the risk of stroke. We sought to compare newer screening technologies with a pulse-check for the detection of atrial fibrillation and to determine whether the detection of actionable atrial fibrillation increases the use of oral anticoagulant agents. METHODS: This prospective multicentre cohort study involved 22 primary care clinics. We recruited participants aged 65 years and older who were attending routine appointments. Each participant underwent 3 methods of screening: a 30-second radial pulse-check; single-lead electrocardiogram; and screening by blood pressure machine with atrial fibrillation detection algorithms. Participants who received a positive result on 1 or more test underwent 12-lead electrocardiogram with or withour 24-hour Holter. Screening tests were compared using the McNemar test. Participants with confirmed atrial fibrillation received follow-up at 90 days. RESULTS: The mean age of participants was 73.7 (± 6.9) years, and 53.4% of participants were female. Of 2171 patients, we had data from all 3 screening tests for 2054 patients. Both single-lead electrocardiogram and the blood pressure device showed superior specificity compared with pulse-check (p < 0.001 for each). Fifty-six patients (2.7%) had confirmed atrial fibrillation: 12 patients had newly detected atrial fibrillation (none of the patients were using anticoagulation agents), and 44 patients had previously diagnosed atrial fibrillation (42 patients were receiving anticoagulant therapy, 2 were not). Thus, 14 patients had actionable atrial fibrillation (0.7%). By 90 days, 77% of patients with actionable atrial fibrillation had started anticoagulant therapy. INTERPRETATION: Newer screening technologies showed superior specificity compared with a pulse-check. Screening detected undiagnosed or undertreated atrial fibrillation in 0.7% of participants, and 77% started appropriate anticoagulant therapy. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT02262351.

B-cell targeted therapy with rituximab for thyroid eye disease: closer to the clinic.

The management of thyroid eye disease (TED) remains a therapeutic challenge. The current established therapies are unsatisfactory in one-third of the patients and have many limitations. Rituximab (RTX) is a CD20+ B-cell-depleting monoclonal antibody approved for the treatment of non-Hodgkin lymphomas, chronic lymphocytic leukemia, and rheumatoid arthritis. The early experience with RTX suggests that it is a promising alternative therapy for TED. Rituximab may compare favorably to the conventional glucocorticoid therapy and causes less collateral damage than retrobulbar orbital radiation and decompression surgery. In addition, the preliminary studies on RTX's proposed mechanism of action have revealed new insights into the pathogenic role of B-cells in TED. We summarize the current literature on the clinical application of RTX in TED and discuss its putative mechanisms of action.