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Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.
Fibrinolysis is an acceptable treatment for acute ST-segment elevation myocardial infarction (STEMI) when primary percutaneous coronary intervention (PCI) cannot be performed within 120 minutes. The American Heart Association has recommended Emergency Medical Services (EMS) interventions such as prehospital fibrinolysis (PHF), prehospital electrocardiogram (ECG), and hospital bypass direct to PCI center. Nova Scotia, Canada has incorporated these interventions into a unique province-wide approach to STEMI care. A retrospective cohort analysis comparing the primary outcome of 30-day mortality for patients receiving either prehospital or emergency department (ED) fibrinolysis (EDF) to patients transported directly by EMS from community or regional ED for primary PCI was conducted.
This retrospective, population-based cohort study included all STEMI patients in Nova Scotia who survived to hospital admission from July 2011 through July 2013. Three provincial databases were used to collect demographic, 30-day mortality, hospital readmission, and rescue PCI data. The results were grouped and compared according to reperfusion strategy received: PHF, EDF, patients brought by ambulance via EMS direct to PCI (EMS to PCI), and ED to PCI (ED to PCI).
There were 1,071 STEMI patients included with 145 PHF, 606 EDF, 98 EMS to PCI, and 222 ED to PCI. There were no significant differences in 30-day mortality across groups (n, %): PHF 5(3); EDF 36(6); EHS to PCI <5(2); and ED to PCI 10(4); P = .28. There was no significant difference in patients receiving fibrinolysis who underwent rescue PCI.
Prehospital fibrinolysis incorporated into a province-wide approach to STEMI treatment is feasible with no observed difference in patient 30-day mortality outcomes observed.
Recent evidence suggests that quitline text messaging is an effective treatment for smoking cessation, but little is known about the relative effectiveness of the message content.
A pilot study of the effects of gain-framed (GF; focused on the benefits of quitting) versus loss-framed (LF; focused on the costs of continued smoking) text messages among smokers contacting a quitline.
Participants were randomized to receive LF (N = 300) or GF (N = 300) text messages for 30 weeks. Self-reported 7-day point prevalence abstinence and number of 24 h quit attempts were assessed at week 30. Intent-to-treat (ITT) and responder analyses for smoking cessation were conducted using logistic regression.
The ITT analysis showed 17% of the GF group quit smoking compared to 15% in the LF group (P = 0.508). The responder analysis showed 44% of the GF group quit smoking compared to 35% in the LF group (P = 0.154). More participants in the GF group reported making a 24 h quit attempt compared to the LF group (98% vs. 93%, P = 0.046).
Although there were no differences in abstinence rates between groups at the week 30 follow-up, participants in the GF group made more quit attempts than those in the LF group.
Lymphopenia is common in adults who have had a Fontan operation although its aetiology and clinical implications remain unknown. Previous work suggests an association between lymphopenia and both liver disease and splenomegaly. The objective of this study was to assess the prevalence of lymphopenia in adults with a Fontan circulation and evaluate its associations with risk factors and clinical outcomes. Using a retrospective cohort study design, we studied 73 adult Fontan patients (age 25.0 ± 8.4 years) who had a complete blood count and abdominal imaging performed. Patients with protein-losing enteropathy were excluded. Clinical data were extracted from hospital records. The mean white blood cell count was 6580 ± 220/ml with a mean lymphocyte count of 1223 ± 508/ml. Lymphopenia, defined as lymphocyte count <1000/ml, was present in 23 (32%) patients. Patients with lymphopenia had a lower total white blood cell count (5556 ± 2517 versus 7136 ± 1924/ml, p = 0.009) and a lower platelet count (162 ± 69 versus 208 ± 69 k/ml, p = 0.008). Lymphopenia was also associated with findings of portal hypertension, including splenomegaly (36 versus 14%, p = 0.04), varices (22 versus 6%, p = 0.04), and ascites (39 versus 14%, p = 0.02). Lymphopenia did not correlate with any cardiac imaging, haemodynamic or exercise testing variables. In conclusion, lymphopenia is common in adult Fontan patients and is associated with markers of portal hypertension. Larger studies are needed to better define the relationship between lymphopenia and clinical outcomes.
Neonates with CHD are at increased risk of developing necrotising enterocolitis due to mesenteric hypoperfusion. Necrotising enterocolitis results in repeated feed interruptions contributing to poor growth during the early post-operative phase. Poor weight gain and longer hospital stay are risk factors for death in neonates with CHD. Abdominal radiography is used as a diagnostic tool for necrotising enterocolitis; however, its utility is limited in the early stages of necrotising enterocolitis when pneumatosis intestinalis is absent. Calprotectin is a neutrophil activation biomarker, and elevated levels are evident in inflammatory diseases such as necrotising enterocolitis. The aim of this study was to determine whether there is a correlation between faecal calprotectin concentration and gut inflammation in neonates with CHD. This prospective single-centre study recruited newly diagnosed term patients with duct-dependent CHD between March 2018 and March 2019. Faecal calprotectin concentrations were measured in post-surgical patients using enzyme-linked immunosorbent assay methods. A total of 30 patients were included in the analysis. Calprotectin concentration for patients who developed necrotising enterocolitis was 3528 µg/g compared with 390 µg/g without, compared with 1339 µg/g in patients with suspected necrotising enterocolitis (p = 0.0001). Patients with suspected necrotising enterocolitis had a significantly longer length of hospital stay, on average 18 days longer compared to patients without necrotising enterocolitis (p = 0.03). Faecal calprotectin concentrations may reflect severity of gut inflammation in neonates with CHD. Suspected necrotising enterocolitis contributes to longer days nil by mouth and an increase in length of hospital stay.
Beginning with loose aggregations of dust particles coated with heterogeneous ices under vacuum at Kuiper Belt temperatures, moving to Jupiter/Saturn distances and eventually to low-perihelion orbit, we consider the likely development of the gaseous phase within a cometary nucleus over the course of its lifetime. From the perspective of physical chemistry, we consider limits on the spatial and temporal distribution and composition of this gaseous phase. The implications of the gaseous phase for heat transfer and for the possible spatial and temporal development of liquid phases are calculated. We conclude that the likely temperatures, pressures, and compositions beneath the outer crust of typical cometary nuclei are such that fluidised phases can exist at significant depths and that these reservoirs give a coherent explanation for the high-intensity outbursts observed from cometary nuclei at large distances from perihelion.
The Green et al., Paranoid Thoughts Scale (GPTS) – comprising two 16-item scales assessing ideas of reference (Part A) and ideas of persecution (Part B) – was developed over a decade ago. Our aim was to conduct the first large-scale psychometric evaluation.
In total, 10 551 individuals provided GPTS data. Four hundred and twenty-two patients with psychosis and 805 non-clinical individuals completed GPTS Parts A and B. An additional 1743 patients with psychosis and 7581 non-clinical individuals completed GPTS Part B. Factor analysis, item response theory, and receiver operating characteristic analyses were conducted.
The original two-factor structure of the GPTS had an inadequate model fit: Part A did not form a unidimensional scale and multiple items were locally dependant. A Revised-GPTS (R-GPTS) was formed, comprising eight-item ideas of reference and 10-item ideas of persecution subscales, which had an excellent model fit. All items in the new Reference (a = 2.09–3.67) and Persecution (a = 2.37–4.38) scales were strongly discriminative of shifts in paranoia and had high reliability across the spectrum of severity (a > 0.90). The R-GPTS score ranges are: average (Reference: 0–9; Persecution: 0–4); elevated (Reference: 10–15; Persecution: 5–10); moderately severe (Reference: 16–20; Persecution:11–17); severe (Reference: 21–24; Persecution: 18–27); and very severe (Reference: 25+; Persecution: 28+). Recommended cut-offs on the persecution scale are 11 to discriminate clinical levels of persecutory ideation and 18 for a likely persecutory delusion.
The psychometric evaluation indicated a need to improve the GPTS. The R-GPTS is a more precise measure, has excellent psychometric properties, and is recommended for future studies of paranoia.
To evaluate the association between novel pre- and post-operative biomarker levels and 30-day unplanned readmission or mortality after paediatric congenital heart surgery.
Children aged 18 years or younger undergoing congenital heart surgery (n = 162) at Johns Hopkins Hospital from 2010 to 2014 were enrolled in the prospective cohort. Collected novel pre- and post-operative biomarkers include soluble suppression of tumorgenicity 2, galectin-3, N-terminal prohormone of brain natriuretic peptide, and glial fibrillary acidic protein. A model based on clinical variables from the Society of Thoracic Surgery database was developed and evaluated against two augmented models.
Unplanned readmission or mortality within 30 days of cardiac surgery occurred among 21 (13%) children. The clinical model augmented with pre-operative biomarkers demonstrated a statistically significant improvement over the clinical model alone with a receiver-operating characteristics curve of 0.754 (95% confidence interval: 0.65–0.86) compared to 0.617 (95% confidence interval: 0.47–0.76; p-value: 0.012). The clinical model augmented with pre- and post-operative biomarkers demonstrated a significant improvement over the clinical model alone, with a receiver-operating characteristics curve of 0.802 (95% confidence interval: 0.72–0.89; p-value: 0.003).
Novel biomarkers add significant predictive value when assessing the likelihood of unplanned readmission or mortality after paediatric congenital heart surgery. Further exploration of the utility of these novel biomarkers during the pre- or post-operative period to identify early risk of mortality or readmission will aid in determining the clinical utility and application of these biomarkers into routine risk assessment.
We measure the cosmic star formation history out to z = 1.3 using a sample of 918 radio-selected star-forming galaxies within the 2-deg2 COSMOS field. To increase our sample size, we combine 1.4-GHz flux densities from the VLA-COSMOS catalogue with flux densities measured from the VLA-COSMOS radio continuum image at the positions of I < 26.5 galaxies, enabling us to detect 1.4-GHz sources as faint as 40 μJy. We find that radio measurements of the cosmic star formation history are highly dependent on sample completeness and models used to extrapolate the faint end of the radio luminosity function. For our preferred model of the luminosity function, we find the star formation rate density increases from 0.017 M⊙ yr−1 Mpc−3 at z ∼ 0.225 to 0.092 M⊙ yr−1 Mpc−3 at z ∼ 1.1, which agrees to within 40% of recent UV, IR and 3-GHz measurements of the cosmic star formation history.
Global multi-stakeholder initiatives (MSIs) are important instruments that have the potential to improve the social and environmental sustainability of global supply chains. However, they often fail to comprehensively address the needs and interests of various supply-chain participants. While voluntary in nature, MSIs have most often been implemented through coercive approaches, resulting in friction among their participants and in systemic problems with decoupling. Additionally, in those cases in which deliberation was constrained between and amongst participants, collaborative approaches have often failed to materialize. Our framework focuses on two key aspects of these breakdowns: assumptions about the orientation of MSI participants, and the deliberation processes that participants use to engage with each other to create these initiatives and sustain them over time. Drawing from stakeholder and deliberation theories, we revisit the concept of MSIs and show how their deliberative capacity may be enhanced in order to encourage participants to collaborate voluntarily.
Optimising short- and long-term outcomes for children and patients with CHD depends on continued scientific discovery and translation to clinical improvements in a coordinated effort by multiple stakeholders. Several challenges remain for clinicians, researchers, administrators, patients, and families seeking continuous scientific and clinical advancements in the field. We describe a new integrated research and improvement network – Cardiac Networks United – that seeks to build upon the experience and success achieved to-date to create a new infrastructure for research and quality improvement that will serve the needs of the paediatric and congenital heart community in the future. Existing gaps in data integration and barriers to improvement are described, along with the mission and vision, organisational structure, and early objectives of Cardiac Networks United. Finally, representatives of key stakeholder groups – heart centre executives, research leaders, learning health system experts, and parent advocates – offer their perspectives on the need for this new collaborative effort.
Clostridium difficile spores play an important role in transmission and can survive in the environment for several months. Optimal methods for measuring environmental C. difficile are unknown. We sought to determine whether increased sample surface area improved detection of C. difficile from environmental samples.
Samples were collected from 12 patient rooms in a tertiary-care hospital in Toronto, Canada.
Samples represented small surface-area and large surface-area floor and bedrail pairs from single-bed rooms of patients with low (without prior antibiotics), medium (with prior antibiotics), and high (C. difficile infected) shedding risk. Presence of C. difficile in samples was measured using quantitative polymerase chain reaction (qPCR) with targets on the 16S rRNA and toxin B genes and using enrichment culture.
Of the 48 samples, 64·6% were positive by 16S qPCR (geometric mean, 13·8 spores); 39·6% were positive by toxin B qPCR (geometric mean, 1·9 spores); and 43·8% were positive by enrichment culture. By 16S qPCR, each 10-fold increase in sample surface area yielded 6·6 times (95% CI, 3·2–13) more spores. Floor surfaces yielded 27 times (95% CI, 4·9–181) more spores than bedrails, and rooms of C. difficile–positive patients yielded 11 times (95% CI, 0·55–164) more spores than those of patients without prior antibiotics. Toxin B qPCR and enrichment culture returned analogous findings.
Clostridium difficile spores were identified in most floor and bedrail samples, and increased surface area improved detection. Future research aiming to understand the role of environmental C. difficile in transmission should prefer samples with large surface areas.
This article focuses on the doctrine of divine favour and instrumentality as viewed from the emperor's own perspective, in relation to the early development of the ‘Arian controversy’ as far as the Council of Nicaea. While modern writers have focused on explicit statements by Constantine to suggest that unity was the emperor's highest priority, this article reveals a pattern by which he sought to manage divine favour and argues that doing so effectively was of primary importance to him. Such a shift in understanding the emperor's priorities adds to the range of explanations for his later apparent inconsistencies as the actual achievement of unity continually eluded him.