Elevated Ratio of Urinary Metabolites of Thromboxane and Prostacyclin Is Associated with Adverse Cardiovascular Events in ADAPT

Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B2 (Tx-M) to 2′3-donor–6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F2-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F2-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F2-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older

Recombination-mediated remodelling of host-pathogen interactions during Staphylococcus aureus niche adaptation

Large-scale recombination events have led to the emergence of epidemic clones of several major bacterial pathogens. However, the functional impact of the recombination on clonal success is not understood. Here, we identified a novel widespread hybrid clone (ST71) of livestock-associated Staphylococcus aureus that evolved from an ancestor belonging to the major bovine lineage CC97, through multiple large-scale recombination events with other S. aureus lineages occupying the same ruminant niche. The recombination events, affecting a 329 kb region of the chromosome spanning the origin of replication, resulted in allele replacement and loss or gain of an array of genes influencing host–pathogen interactions. Of note, molecular functional analyses revealed that the ST71 hybrid clone has acquired multiple novel pathogenic traits associated with acquired and innate immune evasion and bovine extracellular matrix adherence. These findings provide a paradigm for the impact of large-scale recombination events on the rapid evolution of bacterial pathogens within defined ecological niches

Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible

A single natural nucleotide mutation alters bacterial pathogen host tropism

The capacity of microbial pathogens to alter their host tropism leading to epidemics in distinct host species populations is a global public and veterinary health concern. To investigate the molecular basis of a bacterial host-switching event in a tractable host species, we traced the evolutionary trajectory of the common rabbit clone of Staphylococcus aureus. We report that it evolved through a likely human-to-rabbit host jump over 40 years ago and that only a single naturally occurring nucleotide mutation was required and sufficient to convert a human-specific S. aureus strain into one that could infect rabbits. Related mutations were identified at the same locus in other rabbit strains of distinct clonal origin, consistent with convergent evolution. This first report of a single mutation that was sufficient to alter the host tropism of a microorganism during its evolution highlights the capacity of some pathogens to readily expand into new host species populations

Implementation of the evidence for the improvement of nursing care to the critical patient's family: a participatory action research

Background: There are many descriptive studies regarding the needs of the family, as well as those regarding nursing care aimed directly at family members. However, there is no widespread application of such evidence in clinical practice. There has also been no analysis made of the evolution of patterns of knowing during the act of improving clinical practice. Therefore, the purpose of the study is to understand the change process aimed at improving care to critical patient's families, and to explore the evolution of patterns of knowing that nurses use in this process. Methods: Qualitative study with a Participatory Action Research method, in accordance with the Kemmis and McTaggart model. In this model, nurses can observe their practice, reflect upon it and compare it with scientific evidence, as well as define, deploy and evaluate improvement strategies adapted to the context. Simultaneously, the process of empowerment derived from the Participatory Action Research allows for the identification of patterns of knowing and their development over time. The research will take place in the Intensive Care Units of a tertiary hospital. The participants will be nurses who are part of the regular workforce of these units, with more than five years of experience in critical patients, and who are motivated to consider and critique their practice. Data collection will take place through participant observation, multi-level discussion group meetings and documentary analysis. A content analysis will be carried out, following a process of codification and categorisation, with the help of Nvivo10. The approval date and the beginning of the funding were December 2012 and 2013, respectively. Discussion: The definition, introduction and evaluation of care strategies for family members will allow for their real and immediate implementation in practice. The study of the patterns of knowing in the Participatory Action Research will be part of the theoretical and practical feedback process of a professional discipline. Also, the identification of the construction and evolution of knowledge will provide decision elements to managers and academics when choosing strategies for increased quality

Implications of serial measurements of natriuretic peptides in heart failure: insights from BIOSTAT‐CHF

No abstract available

Arrhythmia and death following percutaneous revascularization in ischemic left ventricular dysfunction: Prespecified analyses from the REVIVED-BCIS2 trial

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82–1.30]; P =0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920048

Cheer* in health care practice: what it excludes and why it matters

Clinicians’ positive demeanor and “strengths based” focus can include working to create a cheerful atmosphere in health care environments, cheering for improvements in assessment outcomes, and cheering up clients in situations of decline. Drawing from philosopher Karen Barad’s theories of inclusions and exclusions, we investigated what comes to matter (and what is excluded from mattering) when there is cheerfulness, cheering, and so forth (cheer*) in the day-to-day practices of a neuromuscular clinic. We worked collaboratively with clinicians, young people with Duchenne muscular dystrophy, and their families to co-examine the clinic in three iterative exploratory method spaces: (a) group “dialogues” with clinicians; (b) consultative interviews with children, families, and clinicians; and (c) transdisciplinary research team analysis sessions. Cheer* made some things matter in the clinic (“normal” physical function, “positive” emotions, test scores, compliance); and excluded others (grief and loss, “non-normative” bodies and lives, alternative practices, embodied knowledge). We discuss implications across health care settings

Enhancing the human dimensions of children’s neuromuscular care: piloting a methodology for fostering team reflexivity

For those with chronic, progressive conditions, high quality clinical care requires attention to the human dimensions of illness—emotional, social, and moral aspects—which co-exist with biophysical dimensions of disease. Reflexivity brings historical, institutional, and socio-cultural influences on clinical activities to the fore, enabling consideration of new possibilities. Continuing education methodologies that encourage reflexivity may improve clinical practice and trainee learning, but are rare. We piloted a dialogical methodology with a children’s rehabilitation team to foster reflexivity (patient population: young people with Duchenne’s or Becker’s muscular dystrophy). The methodology involved three facilitated, interactive dialogues with the clinical team. Each dialogue involved clinicians learning to apply a social theory (Mol’s The Logic of Care) to ethnographic fieldnotes of clinical appointments, to make routine practice less familiar and thus open to examination. Discourse analyses that preserve group dynamics were completed to evaluate the extent to which the dialogues spurred reflexive dialogue within the team. Overall, imagining impacts of clinical care on people’s lives—emphasized in the social theory applied to fieldnotes—showed promise, shifting how clinicians interpreted routine practices and spurring many plans for change. However, this reflexive orientation was not sustained throughout, particularly when examining entrenched assumptions regarding ‘best practices’. Clinicians defended institutional practices by co-constructing the metaphor of balancing logics in care delivery. When invoked, the balance metaphor deflected attention from emotional, social, and moral impacts of clinical care on patients and their families. Emergent findings highlight the value of analysing reflexivity-oriented dialogues using discourse analysis methods