Presence of an interferon signature in individuals who are anti-nuclear antibody positive lacking a systemic autoimmune rheumatic disease diagnosis

BACKGROUND: Elevated levels of type I interferons (IFNs) are a characteristic feature of the systemic autoimmune rheumatic diseases (SARDs) and are thought to play an important pathogenic role. However, it is unknown whether these elevations are seen in anti-nuclear antibody–positive (ANA(+)) individuals who lack sufficient criteria for a SARD diagnosis. We examined IFN-induced gene expression in asymptomatic ANA(+) individuals and patients with undifferentiated connective tissue disease (UCTD) to address this question. METHODS: Healthy ANA(−) control subjects and ANA(+) titre (≥1:160 by immunofluorescence) participants meeting no criteria, meeting at least one criterion (UCTD) or meeting SARD classification criteria were recruited. Whole peripheral blood IFN-induced and BAFF gene expression were quantified using NanoString technology. The normalized levels of five IFN-induced genes were summed to produce an IFN5 score. RESULTS: The mean IFN5 scores were increased in all ANA(+) participant subsets as compared with healthy control subjects. We found that 36.8% of asymptomatic ANA(+) and 50% of UCTD participants had IFN5 scores >2 SD above the mean for healthy control subjects. In all ANA(+) subsets, the IFN5 score correlated with the presence of anti-Ro/La antibodies. In the asymptomatic ANA(+) subset, this score also correlated with the ANA titre, whereas in the other ANA(+) subsets, it correlated with the number of different ANA specificities. Development of new SARD criteria was seen in individuals with normal and high IFN5 scores. CONCLUSIONS: An IFN signature is seen in a significant proportion of ANA(+) individuals and appears to be associated with ANA titre and type of autoantibodies, rather than with the presence or development of clinical SARD symptoms

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity

Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity

Protocol for the formative phase of a trial (SHE-CAN) to test co-designed implementation strategies for HPV-based cervical screening among vulnerable women in two diverse settings in India

BACKGROUND: In view of the WHO's call for the elimination of cervical cancer as a public health problem, and current low screening coverage, Indian policy makers need evidence on how to effectively implement cervical screening programmes, ensuring equity in access. Our study will follow the INSPIRE implementation framework to co-design and test HPV-based screening approaches in two states of India with different health system organisation, based on understanding the status of screening as currently implemented, readiness and challenges to transition to HPV-based screening, and preferences of key stakeholders. Here, we describe our protocol for the formative phase of the study (SHE-CAN). METHODS: The study population includes women from vulnerable populations, defined as residents of tribal areas, rural villages, and urban slums, in the states of Mizoram and Tamil Nadu. The baseline assessment will use mixed methods research, with desktop reviews, qualitative studies, and surveys. A capacity assessment survey of screening and treatment facilities will be done, followed by interviews with healthcare providers, programme managers, and community health workers. Interviews will be conducted with previously screened women and focus group discussions with under and never-screened women and community members. Stakeholder workshops will be held in each state to co-design the approaches to delivering HPV-based screening among 30-49-year-old women. DISCUSSION: The quality and outcomes of existing screening services, readiness to transition to HPV-based screening, challenges in providing and participating in the cervical cancer care continuum, and acceptability of screening and treatment approaches will be examined. The knowledge gained about the current system, as well as recognition of actions to be taken, will inform a stakeholder workshop to co-design and evaluate implementation approaches for HPV-based screening through a cluster randomised implementation trial