An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): Protocol for a randomized controlled trial

Background

Organ dysfunction consequent to infection (‘severe sepsis’) is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients.

This is a multicenter, randomized, double-blind, parallel group, placebo-controlled trial. Adults fulfilling the criteria for systemic inflammatory response syndrome due to infection, and requiring vasopressor therapy, will be eligible for inclusion in the trial. Within 24 hours of meeting these inclusion criteria, patients will be randomized in a 1:1 ratio stratified by the ICU to receive either levosimendan (0.05 to 0.2 μg.kg^-1.min^-1 or placebo for 24 hours in addition to standard care. The primary outcome measure is the mean Sequential Organ Failure Assessment (SOFA) score while in the ICU. Secondary outcomes include: central venous oxygen saturations and cardiac output; incidence and severity of renal failure using the Acute Kidney Injury Network criteria; duration of renal replacement therapy; serum bilirubin; time to liberation from mechanical ventilation; 28-day, hospital, 3 and 6 month survival; ICU and hospital length-of-stay; and days free from catecholamine therapy. Blood and urine samples will be collected on the day of inclusion, at 24 hours, and on days 4 and 6 post-inclusion for investigation of the mechanisms by which levosimendan might improve organ function. Eighty patients will have additional blood samples taken to measure levels of levosimendan and its active metabolites OR-1896 and OR-1855. A total of 516 patients will be recruited from approximately 25 ICUs in the United Kingdom.

This trial will test the efficacy of levosimendan to reduce acute organ dysfunction in adult patients who have septic shock and evaluate its biological mechanisms of action.

THE SAAF STUDY: evaluation of the Safeguarding Children Assessment and Analysis Framework (SAAF), compared with management as usual, for improving outcomes for children and young people who have experienced, or are at risk of, maltreatment: study protocol for a randomised controlled trial

Background: Serious case reviews and research studies have indicated weaknesses in risk assessments conducted by child protection social workers. Social workers are adept at gathering information but struggle with analysis and assessment of risk. The Department for Education wants to know if the use of a structured decision-making tool can improve child protection assessments of risk.

Methods/design: This multi-site, cluster-randomised trial will assess the effectiveness of the Safeguarding Children Assessment and Analysis Framework (SAAF). This structured decision-making tool aims to improve social workers' assessments of harm, of future risk and parents' capacity to change. The comparison is management as usual.

Inclusion criteria: Children's Services Departments (CSDs) in England willing to make relevant teams available to be randomised, and willing to meet the trial's training and data collection requirements.

Exclusion criteria: CSDs where there were concerns about performance; where a major organisational restructuring was planned or under way; or where other risk assessment tools were in use.

Six CSDs are participating in this study. Social workers in the experimental arm will receive 2 days training in SAAF together with a range of support materials, and access to limited telephone consultation post-training. The primary outcome is child maltreatment. This will be assessed using data collected nationally on two key performance indicators: the first is the number of children in a year who have been subject to a second Child Protection Plan (CPP); the second is the number of re-referrals of children because of related concerns about maltreatment. Secondary outcomes are: i) the quality of assessments judged against a schedule of quality criteria and ii) the relationship between the three assessments required by the structured decision-making tool (level of harm, risk of (re) abuse and prospects for successful intervention).

Discussion: This is the first study to examine the effectiveness of SAAF. It will contribute to a very limited literature on the contribution that structured decision-making tools can make to improving risk assessment and case planning in child protection and on what is involved in their effective implementation.

'A Land Beyond the Wave': Transnational Perspectives on Easter 1916

Despite the appeal and significance of nationalism as a near universal political force, Irish historians – in common with the historians of most nationalist movements – have struggled to analyse nationalism from beyond the perspective of the nation state. The reasons for this are varied, arising both from practical aspects, such as the availability and accessibility of sources, to more conceptual issues such as the resilience of the national perspective in the framing of historiographical narratives. This paper considers the Easter Rising as a case study in assessing how a transnational framework complicates traditional historiographical perspectives. Accounts of the Easter Rising generally interpret the rebellion within local, national, or international (particularly Anglo-Irish or imperial) frameworks. Interpretations that adopt a broader framework have tended to focus on international rather than transnational dimensions: the First World War context, revolutionary links with Germany, and the role of the United States. This paper assesses the potential of a transnational approach by analysing four aspects of the Rising: the significance of the transnational movement of people prior to the event; the influence of the transnational circulation of political ideas; the impact of transnational cultural currents in shaping the framing of revolutionary ideals; and the impact of the Rising on Irish nationalist communities beyond Ireland.

Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603 838 individuals

Background: Long working hours might increase the risk of cardiovascular disease, but prospective evidence is scarce, imprecise, and mostly limited to coronary heart disease. We aimed to assess long working hours as a risk factor for incident coronary heart disease and stroke. 

Methods We identified published studies through a systematic review of PubMed and Embase from inception to Aug 20, 2014. We obtained unpublished data for 20 cohort studies from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium and open-access data archives. We used cumulative random-effects meta-analysis to combine effect estimates from published and unpublished data. 

Findings We included 25 studies from 24 cohorts in Europe, the USA, and Australia. The meta-analysis of coronary heart disease comprised data for 603 838 men and women who were free from coronary heart disease at baseline; the meta-analysis of stroke comprised data for 528 908 men and women who were free from stroke at baseline. Follow-up for coronary heart disease was 5·1 million person-years (mean 8·5 years), in which 4768 events were recorded, and for stroke was 3·8 million person-years (mean 7·2 years), in which 1722 events were recorded. In cumulative meta-analysis adjusted for age, sex, and socioeconomic status, compared with standard hours (35-40 h per week), working long hours (≥55 h per week) was associated with an increase in risk of incident coronary heart disease (relative risk [RR] 1·13, 95% CI 1·02-1·26; p=0·02) and incident stroke (1·33, 1·11-1·61; p=0·002). The excess risk of stroke remained unchanged in analyses that addressed reverse causation, multivariable adjustments for other risk factors, and different methods of stroke ascertainment (range of RR estimates 1·30-1·42). We recorded a dose-response association for stroke, with RR estimates of 1·10 (95% CI 0·94-1·28; p=0·24) for 41-48 working hours, 1·27 (1·03-1·56; p=0·03) for 49-54 working hours, and 1·33 (1·11-1·61; p=0·002) for 55 working hours or more per week compared with standard working hours (p_trend<0·0001).

Interpretation Employees who work long hours have a higher risk of stroke than those working standard hours; the association with coronary heart disease is weaker. These findings suggest that more attention should be paid to the management of vascular risk factors in individuals who work long hours. 

‘The Violence of History: Rosa Chacel’s Memorias de Leticia Valle’

Leticia Valle, the eleven-year-old narrator and protagonist of Rosa Chacel’s 1945 novel Memorias de Leticia Valle seduces and destroys her history teacher, Daniel. Here, I argue that Daniel represents traditionalist, right-wing interpretations of Spanish history while also recalling the importance of the colonial wars in Morocco in the build up to the Civil War, and the Nationalists’ use of Moroccan conscripts and recruits within the peninsula. Written at a time when history was being used to justify an armed rebellion, a civil war, and the imposition of a brutal dictatorship, Chacel’s novel depends on ellipses and absence to question historiographical principles. Furthermore, it combines continued reference to Spanish history with the use of violent and militant language. The most devastating conflict of all is between Leticia and Daniel: she silences and dehumanizes him, though she is not able to fully explain what happened. Writing from Switzerland, Chacel’s narrator takes possession of Spanish history at a time when dissent within Spain was being silenced by the Francoist regime.

Incentives and rewards: what do adult populations truly want? Insights from the physical activity loyalty (PAL) scheme

Background
Trials depend on good recruitment and retention, but efforts to improve these have had varying success. This may be due to inadequate understanding of what participants would value in return for taking part. An opportunity arose in one trial to investigate the incentives that might help recruit and retain participants to another.

Aim
To determine what adults value as an incentive for involvement in a trial.

Methods
In the PAL Scheme, employees used a ‘loyalty card’ to monitor their physical activity over 12 weeks. The incentive group (n=199) collected points and received rewards for physical activity (1 minute = 1 point, max: 30 pts/day). A comparator group (n=207) self-monitored their physical activity only. Points could be redeemed as retail vouchers. 17 different incentives were available, from 75 pts (£2.50, a sandwich) to 1800 pts (£60, 1 month gym membership).

Results
148 of the 199 intervention participants used their card at least once, earning a mean of 374 pts. 121 earned sufficient to collect a reward and 76 redeemed points for vouchers but only 48 exchanged the vouchers for rewards. The most popular reward was not that of highest monetary value: two cinema tickets (300 pts, £10).

Conclusions
The value that participants place on a reward might be more important than its monetary value. Some might appreciate receiving the voucher, without spending it. In choosing incentives to boost trial participation, it may help to allow people to choose from a variety of rewards, rather than reimbursing in money.

Expression of proteins associated with hypoxia and Wnt pathway activation is of prognostic significance in hepatocellular carcinoma

In the development and progression of hepatocellular carcinoma, tumor hypoxia plays an important role, as does activation of the Wnt pathway. The aim of this study was to characterize the expression and interrelationship between hypoxia and Wnt-pathway-associated proteins as prognostic factors for hepatocellular carcinoma. Expression of HIF-1α, CA-IX, E-cadherin, β-catenin, and Ki-67 was assessed by immunohistochemistry in 179 primary hepatocellular carcinoma cases. Univariate and multivariate analyses were performed to assess the relationship between the clinicopathological factors, protein expression, overall survival (OS), and recurrence-free survival (RFS). By univariate analysis, tumor stage, size, satellitosis, and vascular invasion were confirmed as prognostic factors for worse OS and RFS. High expression of HIF-1α, CA-IX, β-catenin, Ki-67, and E-cadherin was observed in 60, 15, 64, 8, and 64 % of tumors, respectively, and this was significantly associated with poor OS. CA-IX, HIF-1α, and E-cadherin were independent predictors of poor prognosis. We stratified 169 patients into four groups according to the expression level of hypoxia and Wnt pathway markers. The group with high expression of both hypoxia and Wnt-pathway-associated proteins showed worst OS. The poor survival of this group was also significant in patients with early stage disease and tumor size of less than 5 cm (p < 0.05). We identified a subgroup of hepatocellular carcinoma patients with high expression of both hypoxia and Wnt pathway proteins and found this predictive of poor survival. The therapeutic options for this group might need to be revisited.