Usability and engagement with an online platform to support the self-management of symptoms and promote the wellbeing of people with cardiovascular disease (CVD)

Cardiovascular disease (CVD) is the leading cause of disability & mortality. Related conditions include: coronary heart disease, stroke, hypertension, diabetes, chronic kidney disease, peripheral arterial disease and vascular dementia. These are conditions that can be managed but not cured. Self-management is the core of effective treatment for CVDs, but can be compromised in the presence of co-morbid depression and anxiety, which has a greater prevalence in CVD patients than in the general population. Co-morbid depression and anxiety can also exacerbate the perceived severity of physical symptoms such as chest pain, breathlessness and fatigue; this commonly leads to increased primary care and emergency department attendance. Access to effective psychological treatment for depression and anxiety for people with CVD (such as cognitive behavioural therapy delivered by the government’s Improving Access to Psychological Therapy services) is limited, waiting lists can be a problem and patients may be unwilling or unable to attend. Online-delivered interventions are a low-cost and non-stigmatising way of delivering therapy and self-management support and are easily accessed

The space from heart disease intervention for people with cardiovascular disease and distress: a mixed-methods study

BACKGROUND: Poor self-management of symptoms and psychological distress leads to worse outcomes and excess health service use in cardiovascular disease (CVD). Online-delivered therapy is effective, but generic interventions lack relevance for people with specific long-term conditions, such as cardiovascular disease. OBJECTIVE: To develop a comprehensive online CVD-specific intervention to improve both self-management and well-being, and to test acceptability and feasibility. METHODS: Informed by the Medical Research Council (MRC) guidance for the development of complex interventions, we adapted an existing evidence-based generic intervention for depression and anxiety for people with CVD. Content was informed by a literature review of existing resources and trial evidence, and the findings of a focus group study. Think-aloud usability testing was conducted to identify improvements to design and content. Acceptability and feasibility were tested in a cross-sectional study. RESULTS: Focus group participants (n=10) agreed that no existing resource met all their needs. Improvements such as "collapse and expand" features were added based on findings that participants' information needs varied, and specific information, such as detecting heart attacks and when to seek help, was added. Think-aloud testing (n=2) led to changes in font size and design changes around navigation. All participants of the cross-sectional study (10/10, 100%) were able to access and use the intervention. Reported satisfaction was good, although the intervention was perceived to lack relevance for people without comorbid psychological distress. CONCLUSIONS: We have developed an evidence-based, theory-informed, user-led online intervention for improving self-management and well-being in CVD. The use of multiple evaluation tests informed improvements to content and usability. Preliminary acceptability and feasibility has been demonstrated. The Space from Heart Disease intervention is now ready to be tested for effectiveness. This work has also identified that people with CVD symptoms and comorbid distress would be the most appropriate sample for a future randomized controlled trial to evaluate its effectiveness

Internet-delivered self-management support for improving coronary heart disease and self-management–related outcomes: a systematic review

Introduction: Coronary heart disease (CHD) is associated with significant morbidity and mortality, including mental health comorbidity, which is associated with poor outcomes. Self-management is key, but there is limited access to self-management support. Internet-delivered interventions may increase access. Objective: The aim of this study was to conduct a systematic review to (1) determine the effectiveness of Internet-delivered CHD self-management support for improving CHD, mood, and self-management related outcomes and (2) identify and describe essential components for effectiveness. Method: Randomized controlled trials that met prespecified eligibility criteria were identified using a systematic search of 3 healthcare databases (Medline, PsychINFO, and Embase). Results: Seven trials, which included 1321 CHD patients, were eligible for inclusion. There was considerable heterogeneity between studies in terms of the intervention content, outcomes measured, and study quality. All 7 of the studies reported significant positive between-group effects, in particular for lifestyle-related outcomes. Personalization of interventions and provision of support to promote engagement may be associated with improved outcomes, although more data are required to confirm this. The theoretical basis of interventions was poorly developed though evidence-based behavior change interventions were used. Conclusion: More well-designed randomized controlled trials are needed. These should also explore how interventions work and how to improve participant retention and satisfaction and examine the role of personalization and support within interventions

Cleaning up the cosmological constant

We present a novel idea for screening the vacuum energy contribution to the overall value of the cosmological constant, thereby enabling us to choose the bare value of the vacuum curvature empirically, without any need to worry about the zero-point energy contributions of each particle. The trick is to couple matter to a metric that is really a composite of other fields, with the property that the square-root of its determinant is the integrand of a topological invariant, and/or a total derivative. This ensures that the vacuum energy contribution to the Lagrangian is non-dynamical. We then give an explicit example of a theory with this property that is free from Ostrogradski ghosts, and is consistent with solar system physics and cosmological tests.Comment: 8 pages, typos corrected and more text added, version accepted for publication in JHE

Spectroscopic studies reveal details of substrate-induced conformational changes distant from the active site in isopenicillin N synthase

Isopenicillin N synthase (IPNS) catalyzes formation of the β-lactam and thiazolidine rings of isopenicillin N from its linear tripeptide l-δ-(α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) substrate in an iron- and dioxygen (O2)-dependent four-electron oxidation without precedent in current synthetic chemistry. Recent X-ray free-electron laser studies including time-resolved serial femtosecond crystallography show that binding of O2 to the IPNS–Fe(II)–ACV complex induces unexpected conformational changes in α-helices on the surface of IPNS, in particular in α3 and α10. However, how substrate binding leads to conformational changes away from the active site is unknown. Here, using detailed 19F NMR and electron paramagnetic resonance experiments with labeled IPNS variants, we investigated motions in α3 and α10 induced by binding of ferrous iron, ACV, and the O2 analog nitric oxide, using the less mobile α6 for comparison. 19F NMR studies were carried out on singly and doubly labeled α3, α6, and α10 variants at different temperatures. In addition, double electron–electron resonance electron paramagnetic resonance analysis was carried out on doubly spin-labeled variants. The combined spectroscopic and crystallographic results reveal that substantial conformational changes in regions of IPNS including α3 and α10 are induced by binding of ACV and nitric oxide. Since IPNS is a member of the structural superfamily of 2-oxoglutarate-dependent oxygenases and related enzymes, related conformational changes may be of general importance in nonheme oxygenase catalysis

Selective Inhibitors of the JMJD2 Histone Demethylases: Combined Nondenaturing Mass Spectrometric Screening and Crystallographic Approaches†

Ferrous ion and 2-oxoglutarate (2OG) oxygenases catalyze the demethylation of N(epsilon)-methylated lysine residues in histones. Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combinatorial chemistry coupled to MS, turnover assays, and crystallography. The results of initial binding and inhibition assays directed the production and analysis of a set of N-oxalyl-d-tyrosine derivatives to explore the extent of a subpocket at the JMJD2 active site. Some of the inhibitors were shown to be selective for JMJD2 over the hypoxia-inducible factor prolyl hydroxylase PHD2. A crystal structure of JMJD2A in complex with one of the potent inhibitors was obtained; modeling other inhibitors based on this structure predicts interactions that enable improved inhibition for some compounds

Concurrent pulmonary zygomycosis and Mycobacterium tuberculosis infection: a case report

A non-smoking 77-year old gentleman of Indian origin was admitted with a 4-month history of intermittent night sweats, haemoptysis and 6 kg of weight loss. CT scan of thorax demonstrated a 2.5 cm mass in the right middle lobe with multiple small nodules within the right lung and confirmed the presence of mediastinal and hilar lymph nodes

Ribosomal oxygenases are structurally conserved from prokaryotes to humans

2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components1,2 and in the hydroxylation of transcription factors3 and splicing factor proteins4. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA5,6,7 and ribosomal proteins8 have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy9,10,11,12. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans8 raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone Nε-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases

Early versus Later Rhythm Analysis in Patients with Out-of-Hospital Cardiac Arrest

Background In a departure from the previous strategy of immediate defibrillation, the 2005 resuscitation guidelines from the American Heart Association–International Liaison Committee on Resuscitation suggested that emergency medical service (EMS) personnel could provide 2 minutes of cardiopulmonary resuscitation (CPR) before the first analysis of cardiac rhythm. We compared the strategy of a brief period of CPR with early analysis of rhythm with the strategy of a longer period of CPR with delayed analysis of rhythm. Methods We conducted a cluster-randomized trial involving adults with out-of-hospital cardiac arrest at 10 Resuscitation Outcomes Consortium sites in the United States and Canada. Patients in the early-analysis group were assigned to receive 30 to 60 seconds of EMS-administered CPR and those in the later-analysis group were assigned to receive 180 seconds of CPR, before the initial electrocardiographic analysis. The primary outcome was survival to hospital discharge with satisfactory functional status (a modified Rankin scale score of ≤3, on a scale of 0 to 6, with higher scores indicating greater disability). Results We included 9933 patients, of whom 5290 were assigned to early analysis of cardiac rhythm and 4643 to later analysis. A total of 273 patients (5.9%) in the later-analysis group and 310 patients (5.9%) in the early-analysis group met the criteria for the primary outcome, with a cluster-adjusted difference of −0.2 percentage points (95% confidence interval, −1.1 to 0.7; P=0.59). Analyses of the data with adjustment for confounding factors, as well as subgroup analyses, also showed no survival benefit for either study group. Conclusions Among patients who had an out-of-hospital cardiac arrest, we found no difference in the outcomes with a brief period, as compared with a longer period, of EMS-administered CPR before the first analysis of cardiac rhythm. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.