Anchoring the genome

Specific attachment of chromosomal sites to the nuclear matrix is crucial to the control of transcription and DNA replication

Is it me? The impact of patient-physician interactions on lupus patients' psychological well-being, cognition and health-care-seeking behaviour

Objective. The aim was to explore the impact of patient-physician interactions, pre- and postdiagnosis, on lupus and UCTD patients' psychological well-being, cognition and health-care-seeking behaviour. Methods. Participants were purposively sampled from the 233 responses to a survey on patient experiences of medical support. Twenty-one semi-structured interviews were conducted and themes generated using thematic analysis. Results. The study identified six principal themes: (i) the impact of the diagnostic journey; (ii) the influence of key physician(s) on patient trust and security, with most participants reporting at least one positive medical relationship; (iii) disparities in patient-physician priorities, with patients desiring more support with quality-of-life concerns; (iv) persisting insecurity and distrust, which was prevalent and largely influenced by previous and anticipated disproportionate (often perceived as dismissive) physician responses to symptoms and experiences of widespread inadequate physician knowledge of systemic autoimmune diseases; (v) changes to health-care-seeking behaviours, such as curtailing help-seeking or under-reporting symptoms; and (vi) empowerment, including shared medical decisionmaking and knowledge acquisition, which can mitigate insecurity and improve care. Conclusion. Negative medical interactions pre- and post-diagnosis can cause a loss of selfconfidence and a loss of confidence and trust in the medical profession. This insecurity can persist even in subsequent positive medical relationships and should be addressed. Key physicians implementing empowering and security-inducing strategies, including being available in times of health crises and validating patient-reported symptoms, might lead to more trusting medical relationships and positive health-care-seeking behaviour

Will 'the feeling of abandonment' remain? Persisting impacts of the COVID-19 pandemic on rheumatology patients and clinicians.

OBJECTIVE: To better understand rheumatology patient and clinician pandemic-related experiences, medical relationships and behaviours in order to help identify the persisting impacts of the COVID-19 pandemic and inform efforts to ameliorate the negative impacts and build upon the positive ones. METHODS: Rheumatology patients and clinicians completed surveys (patients n = 1543, clinicians n = 111) and interviews (patients n = 41, clinicians n = 32) between April 2021 and August 2021. A cohort (n = 139) of systemic autoimmune rheumatic disease patients was also followed up from March 2020 to April 2021. Analyses used sequential mixed methods. Pre-specified outcome measures included the Warwick-Edinburgh Mental wellbeing score (WEMWBS), satisfaction with care and healthcare behaviours. RESULTS: We identified multiple ongoing pandemic-induced/increased barriers to receiving care. The percentage of patients agreeing they were medically supported reduced from 74.4% pre-pandemic to 39.7% during-pandemic. Ratings for medical support, medical security and trust were significantly (P <0.001) positively correlated with patient WEMWBS and healthcare behaviours, and decreased during the pandemic. Healthcare-seeking was reduced, potentially long-term, including from patients feeling 'abandoned' by clinicians, and a 'burden' from government messaging to protect the NHS. Blame and distrust were frequent, particularly between primary and secondary care, and towards the UK government, who <10% of clinicians felt had supported clinicians during the pandemic. Clinicians' efforts were reported to be impeded by inefficient administration systems and chronic understaffing, suggestive of the pandemic having exposed and exacerbated existing healthcare system weaknesses. CONCLUSION: Without concerted action-such as rebuilding trust, improved administrative systems and more support for clinicians-barriers to care and negative impacts of the pandemic on trust, medical relationships, medical security and patient help-seeking may persist in the longer term. TRIAL REGISTRATION: This study is part of a pre-registered longitudinal multi-stage trial, the LISTEN study (ISRCTN-14966097), with later COVID-related additions registered in March 2021, including a pre-registered statistical analysis plan

Rituximab in rheumatology: single-centre SARS-CoV-2 infection and COVID-19 prevalence.

We describe a coronavirus disease 2019 (COVID-19) prevalence of 20% in rheumatic disease patients treated with rituximab, with 10.3% of these (2% of the entire cohort) having died of COVID-19-related causes

Medication decision-making and adherence in lupus: Patient-physician discordance and the impact of previous ‘Adverse Medical Experiences’

OBJECTIVES: Medication adherence is critical in the successful management of lupus. There is very limited existing literature on reasons why non-adherence is not reported. This study explores the impact of current and previous medical experiences on patient satisfaction, adherence and reporting of non-adherence. METHODS: Mixed methodology involved thematic analysis of in-depth interviews (n = 23) to further explore the statistically analysed quantitative survey findings (n = 186). RESULTS: This study identified five themes: (i) physician-patient discordance and a 'hierarchy of evidence' in medication decisions; (ii) the association of adherence with satisfaction with care; (iii) the persisting impact of past adverse medical experiences (AMEs); (iv) the dynamic balance of patient-physician control; and (v) holistic care, beyond a purely medication-based focus. Improving quality of life (43% of participants) and a supportive medical relationship (24%) were the main reasons for adherence. Patient-priorities and self-reported symptoms were perceived as less important to physicians than organ-protection and blood results. Non-reporters of non-adherence, non-adherers and those with past AMEs (e.g. psychosomatic misdiagnoses) had statistically significant lower satisfaction with care. The importance of listening to patients was a key component of every theme, and associated with patient satisfaction and adherence. The mean rating for rheumatologist's listening skills was 2.88 for non-adherers compared with 3.53 for other participants (mean difference 0.65, P = 0.003). CONCLUSION: Patients would like more weight and discussion given to self-reported symptoms and quality of life in medication decisions. Greater understanding and interventions are required to alleviate the persisting impact of past AMEs on some patients' wellbeing, behaviour and current medical relationships

COVID-19 and shielding: Experiences of UK patients with lupus and related diseases

Objective: The shielding guidance in the UK for the clinically extremely vulnerable (CEV) commenced on 23 March 2020 in response to the coronavirus disease 2019 (COVID-19) pandemic. The purpose of this study was to explore the impact of the pandemic and shielding on patients with lupus and related systemic autoimmune rheumatic diseases (SARDs).Methods: This was a mixed-methods cohort study (n = 111) including pre-lockdown baseline surveys (March 2020), follow-up surveys (June 2020) and in-depth interviews during July 2020 (n = 25).Results: Most participants had a high level of anxiety regarding their mortality risk from COVID-19 and supported the concept of shielding. Shielding allocations and communications were perceived as inconsistently applied and delivered. More than half of those not classified as CEV reported feeling abandoned, at increased risk and with no support. Shielding communications increased feelings of being ‘cared about’, but also increased fear, and the ‘vulnerable’ labelling was perceived by some to damage social and self-identity. More than 80% of those classified as CEV stated that the classification and subsequent communications had changed their social-mixing behaviour. Despite many negative impacts of COVID-19 and shielding/lockdown being identified, including isolation, fear and reduced medical care, the quantitative data during the pandemic showed increases in most measures of wellbeing (which was low at both time points) from pre-lockdown, including reductions in the impact of fatigue and pain (P-values < 0.001). Conclusion: Shielding classifications and communications were, in general, viewed positively, although they were perceived as inconsistently delivered and anxiety-provoking by some participants. More frequent positively framed communication and wellbeing support could benefit all SARD patients. Slower-paced lockdown lifestyles might confer health/wellbeing benefits for some people with chronic diseases

CTCF binds to sites in the major histocompatibility complex that are rapidly reconfigured in response to interferon-gamma

Activation of the major histocompatibility complex (MHC) by interferon-gamma (IFN−γ) is a fundamental step in the adaptive immune response to pathogens. Here, we show that reorganization of chromatin loop domains in the MHC is evident within the first 30 min of IFN−γ treatment of fibroblasts, and that further dynamic alterations occur up to 6 h. These very rapid changes occur at genomic sites which are occupied by CTCF and are close to IFN−γ-inducible MHC genes. Early responses to IFN−γ are thus initiated independently of CIITA, the master regulator of MHC class II genes and prepare the MHC for subsequent induction of transcription

Microbial-host co-metabolites are prodromal markers predicting phenotypic heterogeneity in behavior, obesity, and impaired glucose tolerance

The influence of the gut microbiome on metabolic and behavioral traits is widely accepted, though the microbiome-derived metabolites involved remain unclear. We carried out untargeted urine 1 H-NMR spectroscopy-based metabolic phenotyping in an isogenic C57BL/6J mouse population (n = 50) and show that microbial-host co-metabolites are prodromal (i.e., early) markers predicting future divergence in metabolic (obesity and glucose homeostasis) and behavioral (anxiety and activity) outcomes with 94%– 100% accuracy. Some of these metabolites also modulate disease phenotypes, best illustrated by trimethylamine-N-oxide (TMAO), a product of microbial-host co-metabolism predicting future obesity, impaired glucose tolerance (IGT), and behavior while reducing endoplasmic reticulum stress and lipogenesis in 3T3-L1 adipocytes. Chronic in vivo TMAO treatment limits IGT in HFD-fed mice and isolated pancreatic islets by increasing insulin secretion. We highlight the prodromal potential of microbial metabolites to predict disease outcomes and their potential in shaping mammalian phenotypic heterogeneity

Abnormal septal convexity into the left ventricle occurs in subclinical hypertrophic cardiomyopathy.

BACKGROUND: Sarcomeric gene mutations cause hypertrophic cardiomyopathy (HCM). In gene mutation carriers without left ventricular (LV) hypertrophy (G + LVH-), subclinical imaging biomarkers are recognized as predictors of overt HCM, consisting of anterior mitral valve leaflet elongation, myocardial crypts, hyperdynamic LV ejection fraction, and abnormal apical trabeculation. Reverse curvature of the interventricular septum (into the LV) is characteristic of overt HCM. We aimed to assess LV septal convexity in subclinical HCM. METHODS: Cardiovascular magnetic resonance was performed on 36 G + LVH- individuals (31 ± 14 years, 33 % males) with a pathogenic sarcomere mutation, and 36 sex and age-matched healthy controls (33 ± 12 years, 33 % males). Septal convexity (SCx) was measured in the apical four chamber view perpendicular to a reference line connecting the mid-septal wall at tricuspid valve insertion level and the apical right ventricular insertion point. RESULTS: Septal convexity was increased in G + LVH- compared to controls (maximal distance of endocardium to reference line: 5.0 ± 2.5 mm vs. 1.6 ± 2.4 mm, p ≤ 0.0001). Expected findings occurred in G + LVH- individuals: longer anterior mitral valve leaflet (23.5 ± 3.0 mm vs. 19.9 ± 3.1 mm, p ≤ 0.0001), higher relative wall thickness (0.31 ± 0.05 vs. 0.29 ± 0.04, p ≤ 0.05), higher LV ejection fraction (70.8 ± 4.3 % vs. 68.3 ± 4.4 %, p ≤ 0.05), and smaller LV end-systolic volume index (21.4 ± 4.4 ml/m(2) vs. 23.7 ± 5.8 ml/m(2), p ≤ 0.05). Other morphologic measurements (LV angles, sphericity index, and eccentricity index) were not different between G + LVH- and controls. CONCLUSIONS: Septal convexity is an additional previously undescribed feature of subclinical HCM

Mechanisms of Autoantibody-Induced Pathology

Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein