Are large randomised controlled trials in severe sepsis and septic shock statistically disadvantaged by repeated inadvertent underestimates of required sample size?

OBJECTIVES: We sought to understand why randomised controlled trials in septic shock have failed to demonstrate effectiveness in the face of improving overall outcomes for patients and seemingly promising results of early phase trials of interventions. DESIGN: We performed a retrospective analysis of large critical care trials of severe sepsis and septic shock. Data were collected from the primary trial manuscripts, prepublished statistical plans or by direct communication with corresponding authors. SETTING: Critical care randomised control trials in severe sepsis and septic shock. PARTICIPANTS: 14 619 patients randomised in 13 trials published between 2005 and 2015, enrolling greater than 500 patients and powered to a primary outcome of mortality. INTERVENTION: Multiple interventions including the evaluation of treatment strategies and novel therapeutics. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary outcome measure was the difference between the anticipated and actual control arm mortality. Secondary analysis examined the actual effect size and the anticipated effect size employed in sample size calculation. RESULTS: In this post hoc analysis of 13 trials with 14 619 patients randomised, we highlight a global tendency to overestimate control arm mortality in estimating sample size (absolute difference 9.8%, 95% CI -14.7% to -5.0%, p<0.001). When we compared anticipated and actual effect size of a treatment, there was also a substantial overestimation in proposed values (absolute difference 7.4%, 95% CI -9.0% to -5.8%, p<0.0001). CONCLUSIONS: An interpretation of our results is that trials are consistently underpowered in the planning phase by employing erroneous variables to calculate a satisfactory sample size. Our analysis cannot establish if, given a larger sample size, a trial would have had a positive result. It is disappointing so many promising phase II results have not translated into durable phase III outcomes. It is possible that our current framework has biased us towards discounting potentially life-saving treatments

Is Seladin-1 really a selective Alzheimer\u27s disease indicator?

Selective Alzheimer\u27s Disease Indicator-1 (Seladin-1) was originally identified by its down-regulation in the brains of Alzheimer\u27s disease (AD) patients. Here, we re-examine existing data and present new gene expression data that refutes its role as a selective AD indicator. Furthermore, we caution against the use of the name “Seladin-1” and instead recommend adoption of the approved nomenclature, 3β-hydroxysterol Δ24-reductase (or DHCR24), which describes its catalytic function in cholesterol synthesis. Further work is required to determine what link, if any, exists between DHCR24 and AD

THE EFFECTS OF ULTRA-FILTERED MILK CONSUMPTION ON STRENGTH AND PERFORMANCE FOLLOWING RESISTANCE TRAINING IN FEMALE COLLEGIATE ATHLETES

Resistance training is beneficial in the improvement of skeletal muscle functionality. Improvements in performance, increased resistance to injury, and great force production are associated with resistance training. Hypertrophy of skeletal muscle mass is important for improving fitness, decreasing body fat percentage, improvements in whole-body metabolism, and enhancements in quality of life. The ability to recovery properly following subsequent training sessions is critical for maximizing training adaptations. Nutrient supplementation has been previously studied. The supplementation of carbohydrates has been shown to replenish muscle glycogen stores. The consumption of carbohydrates following resistance training benefits muscle protein balance by attenuating muscle protein breakdown. Another commonly consumed supplement is amino acids/protein. Supplementation of protein has demonstrated improvements in body composition (i.e. increased fat free mass), increases in hypertrophy, and muscular strength. Two type of proteins used by individuals that resistance train are whey protein and casein protein. Whey protein is a fast digesting protein that leads to quick stimulation of protein synthesis. Casein protein is a slower digesting protein that also attenuates the breakdown of muscle protein. Milk is a natural product that contains carbohydrates, whey protein, and casein protein. Whole milk, low fat milk (i.e., 1-2%), and fat free milk have shown positive results in the ability to improve muscle protein synthesis, lean body mass, strength gains. Therefore, the purpose of the following dissertation is to compare the effects of higher protein, less sugar content chocolate milk to traditional low fat chocolate milk on adaptations to (1) strength and performance measures and (2) body composition following resistance training

Clinical and Immunomodulating Effects of Ketamine in Horses with Experimental Endotoxemia

Background:  Ketamine has immunomodulating effects both in vitro and in vivo during experimental endotoxemia in humans, rodents, and dogs. Hypothesis:  Subanesthetic doses of ketamine will attenuate the clinical and immunologic responses to experimental endotoxemia in horses. Animals:  Nineteen healthy mares of various breeds. Methods:  Experimental study. Horses were randomized into 2 groups: ketamine-treated horses (KET; n = 9) and saline-treated horses (SAL; n = 10). Both groups received 30 ng/kg of lipopolysaccharide (LPS, Escherichia coli, O55:B5) 1 hour after the start of a continuous rate infusion (CRI) of racemic ketamine (KET) or physiologic saline (SAL). Clinical and hematological responses were documented and plasma concentrations of tumor necrosis factor-α (TNF-α) and thromboxane B2 (TXB2) were quantified. Results:  All horses safely completed the study. The KET group exhibited transient excitation during the ketamine loading infusion (P \u3c .05) and 1 hour after discontinuation of administration (P \u3c .05). Neutrophilic leukocytosis was greater in the KET group 8 and 24 hours after administration of LPS (P \u3c .05). Minor perturbations of plasma biochemistry results were considered clinically insignificant. Plasma TNF-α and TXB2 production peaked 1.5 and 1 hours, respectively, after administration of LPS in both groups, but a significant difference between treatment groups was not demonstrated. Conclusions and Clinical Importance:  A subanesthetic ketamine CRI is well tolerated by horses. A significant effect on the clinical or immunologic response to LPS administration, as assessed by clinical observation, hematological parameters, and TNF-α and TXB2production, was not identified in healthy horses with the subanesthetic dose of racemic ketamine utilized in this study

Moringa oleifera Improves Skeletal Muscle Metabolism and Running Performance in Mice

Background: Recent estimates suggest that 7% of Americans use plant-derived nutritional supplements to treat a variety of complications and/or to improve athletic performance and skeletal muscle health. Unfortunately, these supplements are largely unregulated and understudied. For example, Moringa oleifera (M. oleifera) is a subtropical plant and is routinely used to treat inflammation, diabetes, obesity, cancer and HIV. However, the mechanism of action of M. oleifera has not been fully elucidated, thus the purpose of this study is to evaluate the role of M. oleifera as a novel ergogenic aid to improve exercise performance by driving peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-dependent signaling pathways implicated in mitochondrial biogenesis and oxidative metabolism in skeletal muscle tissue. Methods: Adult male C57BL/6 mice were treated with 1.0 g of M. oleifera (N = 20) per day or vehicle control (N = 20) for a total of 5 weeks. Following 3 weeks of supplementation, half of each group (RUN) was given access to running wheels every night for 2 weeks (Remaining half = SED), distances ran were recorded daily. After treatment protocols were complete, the gastrocnemius muscles were excised and assayed for known markers of mitochondrial biogenesis, angiogenesis, endurance capacity, and capillary density using immunohistochemistry and RT-PCR. Results: Our results showed a significant increase in average distance run in the M. oleifera + SED and M. oleifera + RUN groups. This physiological trend was consistent with the molecular profile of key metabolic markers, i.e., there was an increase in levels of PGC-1α, PPARγ, SDHB, SUCLG1, VEGF, PGAM-2, PGK1, and MYLPF in the M. oleifera treated groups compared to vehicle + SED. Moreover, M. oleifera also increased CSA and decreased markers of protein degradation. Conclusions: This data suggests that M. oleifera has the potential to be an ergogenic aid via enhancing energy metabolism in adult skeletal muscle by increasing the expression of key metabolic markers, including those involved in glycolysis, oxidative phosphorylation, mitochondrial biogenesis and angiogenesis

Impact of β-lactam antibiotic therapeutic drug monitoring on dose adjustments in critically ill patients undergoing continuous renal replacement therapy

The objective of this study was to describe the effect of therapeutic drug monitoring (TDM) and dose adjustments of β-lactam antibiotics administered to critically ill patients undergoing continuous renal replacement therapy (CRRT) in a 30-bed tertiary intensive care unit (ICU). β-Lactam TDM data in our tertiary referral ICU were retrospectively reviewed. Clinical, demographic and dosing data were collected for patients administered β-lactam antibiotics while undergoing CRRT. The target trough concentration range was 1–10× the minimum inhibitory concentration (MIC). A total of 111 TDM samples from 76 patients (46 male) with a mean ± standard deviation age of 56.6 ± 15.9 years and weight of 89.1 ± 25.8 kg were identified. The duration of antibiotic therapy was between 2 days and 42 days. TDM identified a need for dose modification of β-lactam antibiotics in 39 (35%) instances; in 27 (24%) samples, TDM values resulted in decreasing the prescribed dose of β-lactam antibiotic whereas an increase in the prescribed dose occurred in 12 (11%) cases. In patients treated for hospital-acquired pneumonia and primary or secondary bacteraemia, the dose was required to be decreased in 10/25 (40%) and 7/46 (15%) cases, respectively, to attain target concentrations. β-Lactam TDM is a useful tool for guiding drug dosing in complex patients such as those receiving CRRT. Although over one-third of patients manifested concentrations outside the therapeutic range, most of these CRRT patients had excessive β-lactam concentrations

Involving people with diabetes and the wider community in diabetes research: a realist review protocol.

BACKGROUND: Patient and public involvement in diabetes research is now actively encouraged in different countries because it is believed that involving people with experience of the condition will improve the quality and relevance of the research. However, reviews of patient involvement have noted that inadequate resources, patients' and communities' lack of research knowledge, and researchers' lack of skills to involve patients and communities in research may present significant contextual barriers. Little is known about the extent of patient/community involvement in designing or delivering interventions for people with diabetes. A realist review of involvement will contribute to assessing when, how and why involvement works, or does not work, to produce better diabetes interventions. METHODS/DESIGN: This protocol outlines the process for conducting a realist review to map how patients and the public have been involved in diabetes research to date. The review questions ask the following: How have people with diabetes and the wider community been involved in diabetes research? What are the characteristics of the process that appear to explain the relative success or failure of involvement? How has involvement (or lack of involvement) in diabetes research influenced the development and conduct of diabetes research? The degree of support in the surrounding context will be assessed alongside the ways in which people interact in different settings to identify patterns of interaction between context, mechanisms and outcomes in different research projects. The level and extent of the involvement will be described for each stage of the research project. The descriptions will be critically reviewed by the people with diabetes on our review team. In addition, researchers and patients in diabetes research will be asked to comment. Information from researcher-patient experiences and documents will be compared to theories of involvement across a range of disciplines to create a mid-range theory describing how involvement (or lack of involvement) in diabetes research influences the development and conduct of diabetes research

Induction of stable human FOXP3⁺ Tregs by a parasite-derived TGF-β mimic

Immune homeostasis in the intestine is tightly controlled by FOXP3 + regulatory T cells (Tregs), defects of which are linked to the development of chronic conditions, such as inflammatory bowel disease (IBD). As a mechanism of immune evasion, several species of intestinal parasites boost Treg activity. The parasite Heligmosomoides polygyrus is known to secrete a molecule (Hp-TGM) that mimics the ability of TGF-β to induce FOXP3 expression in CD4 + T cells. The study aimed to investigate whether Hp-TGM could induce human FOXP3 + Tregs as a potential therapeutic approach for inflammatory diseases. CD4 + T cells from healthy volunteers were expanded in the presence of Hp-TGM or TGF-β. Treg induction was measured by flow cytometric detection of FOXP3 and other Treg markers, such as CD25 and CTLA-4. Epigenetic changes were detected using ChIP-Seq and pyrosequencing of FOXP3. Treg phenotype stability was assessed following inflammatory cytokine challenge and Treg function was evaluated by cellular co-culture suppression assays and cytometric bead arrays for secreted cytokines. Hp-TGM efficiently induced FOXP3 expression (&gt; 60%), in addition to CD25 and CTLA-4, and caused epigenetic modification of the FOXP3 locus to a greater extent than TGF-β. Hp-TGM-induced Tregs had superior suppressive function compared with TGF-β-induced Tregs, and retained their phenotype following exposure to inflammatory cytokines. Furthermore, Hp-TGM induced a Treg-like phenotype in in vivo differentiated Th1 and Th17 cells, indicating its potential to re-program memory cells to enhance immune tolerance. These data indicate Hp-TGM has potential to be used to generate stable human FOXP3 + Tregs to treat IBD and other inflammatory diseases. </p

Mitotic Recombination and Rapid Genome Evolution in the Invasive Forest Pathogen Phytophthora ramorum

Invasive alien species often have reduced genetic diversity and must adapt to new environments. Given the success of many invasions, this is sometimes called the genetic paradox of invasion. Phytophthora ramorum is invasive, limited to asexual reproduction within four lineages, and presumed clonal. It is responsible for sudden oak death in the United States, sudden larch death in Europe, and ramorum blight in North America and Europe. We sequenced the genomes of 107 isolates to determine how this pathogen can overcome the invasion paradox. Mitotic recombination (MR) associated with transposons and low gene density has generated runs of homozygosity (ROH) affecting 2,698 genes, resulting in novel genotypic diversity within the lineages. One ROH enriched in effectors was fixed in the NA1 lineage. An independent ROH affected the same scaffold in the EU1 lineage, suggesting an MR hot spot and a selection target. Differences in host infection between EU1 isolates with and without the ROH suggest that they may differ in aggressiveness. Non-core regions (not shared by all lineages) had signatures of accelerated evolution and were enriched in putative pathogenicity genes and transposons. There was a striking pattern of gene loss, including all effectors, in the non-core EU2 genome. Positive selection was observed in 8.0% of RxLR and 18.8% of Crinkler effector genes compared with 0.9% of the core eukaryotic gene set. We conclude that the P. ramorum lineages are diverging via a rapidly evolving non-core genome and that the invasive asexual lineages are not clonal, but display genotypic diversity caused by MR

How stakeholder participation can contribute to systematic reviews of complex interventions

Although patient and public involvement in research is a requirement for research funding in many countries, the knowledge base for how to effectively involve people—and evidence of the effectiveness of involvement—is weak. This article describes how methods used in participatory health research were used to involve patients, clients, providers and community health workers across all stages of a realist review. Sustained involvement enabled better identification of the components of the complex intervention of community-based peer support. It also challenged assumptions of how peer support is constructed, leading the review team to question whether the process of designing and implementing interventions has more influence on effectiveness than previously recognised in empirical studies. We conclude with a discussion on when sustained involvement should be used, and the challenges of incorporating it into the traditional researcher-led approach to systematic reviews