Digitalis for treatment of heart failure in patients in sinus rhythm

<b>Background</b><p></p> Digitalis glycosides have been in clinical use for the treatment of heart failure (HF) for longer than 200 years. In recent years, several trials have been conducted to address concerns about their efficacy and toxicity.<p></p> <b>Objectives</b><p></p> To examine the effectiveness of digitalis glycosides in treating HF in patients with normal sinus rhythm. To examine the effects of digitalis in patients taking diuretics and angiotensin-converting enzyme inhibitors; in patients with varying severity and duration of disease; in patients with prior exposure to digitalis versus no prior exposure; and in patients with "HF due to systolic dysfunction" versus "HF with preserved ejection fraction."<p></p> <b>Search methods</b><p></p> Searches on the following databases were updated in May 2013: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Dissertation Abstracts. Annual meeting abstracts of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology were searched from 1996 to March 2013. In addition, reference lists provided by the pharmaceutical industry (GlaxoSmithKline and Covis Pharma) were searched.<p></p> <b>Selection criteria</b><p></p> Included were randomized placebo-controlled trials of 20 or more adult participants of either sex with symptomatic HF who were studied for seven weeks or longer. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of HF such as acute ischemic heart disease or myocarditis was present.<p></p> <b>Data collection and analysis</b><p></p> Articles selected from the searches described above were evaluated in a joint effort of the review authors. The staff of the Cochrane Heart Group ran searches on the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE.<p></p> <b>Main results</b><p></p> No new studies were identified in the updated searches. Thirteen studies (7896 participants) are included, and major endpoints of mortality, hospitalization, and clinical status, based respectively on 8, 4, and 12 of these selected studies, were recorded and analyzed. The data show no evidence of a difference in mortality between treatment and control groups, whereas digitalis therapy is associated with lower rates of both hospitalization and clinical deterioration. The largest study, in which most participants were taking angiotensin-converting enzyme inhibitors, showed a significant rise in “other cardiac” deaths, possibly due to arrhythmias. However collectively, these findings were based on studies done before beta-blockers, as well as angiotensin receptor blockers and aldosterone antagonists, became widely used to treat HF.<p></p> <b>Authors' conclusions</b><p></p> The literature indicates that digitalis may have a useful role in the treatment of patients with HF who are in normal sinus rhythm. New trials are needed to elucidate the importance of the dosage of digitalis and its usefulness in the era of beta-blockers and other agents shown to be effective in treating HF.<p></p&gt

Aggregation in schistosomiasis: comparison of the relationships between prevalence and intensity in different endemic areas

Distributions of the intensities of helminth infections within their host populations are invariably aggregated. In the case of the intestinal nematodes, the degrees of aggregation have been shown to be species specific, and constant for any given species despite geographical variation in study sites. This species-specific aggregation can be quantified and used as a tool in planning control interventions. One practical application is that the prevalence of infection can be used to predict the prevalence of heavy infection and thus the risks of morbidity. This paper investigates the patterns of aggregation in schistosome egg counts in different endemic areas in Africa (data sets were obtained from Burundi, Cameroon, Tanzania, Zambia and Zaire). The analysis demonstrates that the degree of parasite aggregation, for both Schistosoma mansoni and S. haematobium, differs amongst the different study localities. This is probably due to area-specific differences in host exposure and immunity. This implies that for these schistosome species, it is not possible to predict egg count distributions or morbidity levels from prevalence data alon

Diurnal Variation in repeated sprint performance cannot be offset when rectal and muscle temperatures are at optimal levels (38.5 C)

The present study investigated whether increasing morning rectal temperatures (Trec) to evening levels, or increasing morning and evening Trec to an “optimal” level (38.5°C), resulting in increased muscle temperatures (Tm), would offset diurnal variation in repeated sprint (RS) performance in a causal manner. Twelve trained males underwent five sessions [age (mean ± SD) 21.0 ± 2.3 years, maximal oxygen consumption (V̇O2max) 60.0 ± 4.4 mL.kg–1 min–1, height 1.79 ± 0.06 m, body mass 78.2 ± 11.8 kg]. These included control morning (M, 07:30 h) and evening (E, 17:30 h) sessions (5-min warm-up), and three further sessions consisting of a warm-up morning trial (ME, in 39–40°C water) until Trec reached evening levels; two “optimal” trials in the morning and evening (M38.5 and E38.5, in 39–40°C water) respectively, until Trec reached 38.5°C. All sessions included 3 × 3-s task-specific warm-up sprints, thereafter 10 × 3-s RS with 30-s recoveries were performed a non-motorised treadmill. Trec and Tm measurements were taken at the start of the protocol and following the warm-up periods. Values for Trec and Tm at rest were higher in the evening compared to morning values (0.48°C and 0.69°C, p < 0.0005). RS performance was lower (7.8–8.3%) in the M for distance covered (DC; p = 0.002), average power (AP; p = 0.029) and average velocity (AV; p = 0.002). Increasing Trec in the morning to evening values or optimal values (38.5°C) did not increase RS performance to evening levels (p = 1.000). However, increasing Trec in the evening to “optimal” level through a passive warm-up significantly reduced DC (p = 0.008), AP (p < 0.0005) and AV (p = 0.007) to values found in the M condition (6.0–6.9%). Diurnal variation in Trec and Tm is not wholly accountable for time-of-day oscillations in RS performance on a non-motorised treadmill; the exact mechanism(s) for a causal link between central temperature and human performance are still unclear and require more research

Multivariable fractional polynomial interaction to investigate continuous effect modifiers in a meta-analysis on higher versus lower PEEP for patients with ARDS.

OBJECTIVES: A recent individual patient data (IPD) meta-analysis suggested that patients with moderate or severe acute respiratory distress syndrome (ARDS) benefit from higher positive end-expiratory pressure (PEEP) ventilation strategies. However, thresholds for continuous variables (eg, hypoxaemia) are often arbitrary and linearity assumptions in regression approaches may not hold; the multivariable fractional polynomial interaction (MFPI) approach can address both problems. The objective of this study was to apply the MFPI approach to investigate interactions between four continuous patient baseline variables and higher versus lower PEEP on clinical outcomes. SETTING: Pooled data from three randomised trials in intensive care identified by a systematic review. PARTICIPANTS: 2299 patients with acute lung injury requiring mechanical ventilation. INTERVENTIONS: Higher (N=1136) versus lower PEEP (N=1163) ventilation strategy. OUTCOME MEASURES: Prespecified outcomes included mortality, time to death and time-to-unassisted breathing. We examined the following continuous baseline characteristics as potential effect modifiers using MFPI: PaO2/FiO2 (arterial partial oxygen pressure/ fraction of inspired oxygen), oxygenation index, respiratory system compliance (tidal volume/(inspiratory plateau pressure-PEEP)) and body mass index (BMI). RESULTS: We found that for patients with PaO2/FiO2 below 150 mm Hg, but above 100 mm Hg or an oxygenation index above 12 (moderate ARDS), higher PEEP reduces hospital mortality, but the beneficial effect appears to level off for patients with very severe ARDS. Patients with mild ARDS (PaO2/FiO2 above 200 mm Hg or an oxygenation index below 10) do not seem to benefit from higher PEEP and might even be harmed. For patients with a respiratory system compliance above 40 mL/cm H2O or patients with a BMI above 35 kg/m(2), we found a trend towards reduced mortality with higher PEEP, but there is very weak statistical confidence in these findings. CONCLUSIONS: MFPI analyses suggest a nonlinear effect modification of higher PEEP ventilation by PaO2/FiO2 and oxygenation index with reduced mortality for some patients suffering from moderate ARDS. STUDY REGISTRATION NUMBER: CRD42012003129

The Number of Patients and Events Required to Limit the Risk of Overestimation of Intervention Effects in Meta-Analysis—A Simulation Study

BACKGROUND: Meta-analyses including a limited number of patients and events are prone to yield overestimated intervention effect estimates. While many assume bias is the cause of overestimation, theoretical considerations suggest that random error may be an equal or more frequent cause. The independent impact of random error on meta-analyzed intervention effects has not previously been explored. It has been suggested that surpassing the optimal information size (i.e., the required meta-analysis sample size) provides sufficient protection against overestimation due to random error, but this claim has not yet been validated. METHODS: We simulated a comprehensive array of meta-analysis scenarios where no intervention effect existed (i.e., relative risk reduction (RRR) = 0%) or where a small but possibly unimportant effect existed (RRR = 10%). We constructed different scenarios by varying the control group risk, the degree of heterogeneity, and the distribution of trial sample sizes. For each scenario, we calculated the probability of observing overestimates of RRR>20% and RRR>30% for each cumulative 500 patients and 50 events. We calculated the cumulative number of patients and events required to reduce the probability of overestimation of intervention effect to 10%, 5%, and 1%. We calculated the optimal information size for each of the simulated scenarios and explored whether meta-analyses that surpassed their optimal information size had sufficient protection against overestimation of intervention effects due to random error. RESULTS: The risk of overestimation of intervention effects was usually high when the number of patients and events was small and this risk decreased exponentially over time as the number of patients and events increased. The number of patients and events required to limit the risk of overestimation depended considerably on the underlying simulation settings. Surpassing the optimal information size generally provided sufficient protection against overestimation. CONCLUSIONS: Random errors are a frequent cause of overestimation of intervention effects in meta-analyses. Surpassing the optimal information size will provide sufficient protection against overestimation

Growth differentiation factor-15 predicts mortality and morbidity after cardiac resynchronization therapy

The aim of this study was to determine whether growth differentiation factor-15 (GDF-15) predicts mortality and morbidity after cardiac resynchronization therapy (CRT). Growth differentiation factor-15, a transforming growth factor-beta-related cytokine which is up-regulated in cardiomyocytes via multiple stress pathways, predicts mortality in patients with heart failure treated pharmacologically

Performative Work: Bridging Performativity and Institutional Theory in the Responsible Investment Field

Callon’s performativity thesis has illuminated how economic theories and calculative devices shape markets, but has been challenged for its neglect of the organizational, institutional and political context. Our seven-year qualitative study of a large financial data company found that the company’s initial attempt to change the responsible investment field through a performative approach failed because of the constraints posed by field practices and organizational norms on the design of the calculative device. However, the company was subsequently able to put in place another form of performativity by attending to the normative and regulative associations of the device. We theorize this route to performativity by proposing the concept of performative work, which designates the necessary institutional work to enable translation and the subsequent adoption of the device. We conclude by considering the implications of performative work for the performativity and the institutional work literatures

Users' guides to the medical literature: how to use an article about mortality in a humanitarian emergency

The accurate interpretation of mortality surveys in humanitarian crises is useful for both public health responses and security responses. Recent examples suggest that few medical personnel and researchers can accurately interpret the validity of a mortality survey in these settings. Using an example of a mortality survey from the Democratic Republic of Congo (DRC), we demonstrate important methodological considerations that readers should keep in mind when reading a mortality survey to determine the validity of the study and the applicability of the findings to their settings