The Efficacy and Safety of In-Intensive Care Unit Leg-Cycle Ergometry in Critically Ill Adults. A Systematic Review and Meta-analysis.

Background: Survivors of critical illness may experience physical-function deficits after intensive care unit (ICU) discharge. In-ICU cycle ergometry may facilitate early mobilization and decrease functional impairment.Objective: We conducted a systematic review and meta-analysis to understand the effect of in-ICU leg-cycle ergometry on patient-important and clinically relevant outcomes.Data Sources: We searched eight electronic databases from inception until July 2019.Data Extraction: We included randomized controlled trials (RCTs) and nonrandomized studies of critically ill adults admitted to the ICU for ≥24 hours, comparing cycling interventions to control arms that did not receive cycling. Main outcomes included physical function, mechanical ventilation (MV) duration, length of stay (LOS), quality of life (QoL), mortality, and safety. We conducted independent duplicate-citation screening, data abstraction, and risk-of-bias assessments. We pooled RCTs using a random-effects model and calculated the risk ratio (RR), mean difference (MD), or standardized MD with 95% confidence intervals (CIs). We assessed certainty of outcomes using the Grading of Recommendations Assessment, Development, and Evaluation approach.Results: Of 6,531 citations, we included 12 RCTs and 2 nonrandomized studies (n = 926). Between the cycling and control groups, there were no differences in physical function at hospital discharge (3 RCTs; n = 225; standardized MD, 0.07 [95% CI, -0.38 to 0.53]; very low certainty), MV duration (9 RCTs; n = 676; MD, 0.01 [-1.04 to 1.07] days; moderate certainty), ICU LOS (10 RCTs; n = 511; MD, 0.23 [-1.44 to 1.89] days; moderate certainty), hospital LOS (7 RCTs; n = 393, MD -0.07 [-3.87 to 3.73] days; moderate certainty), QoL at 6 months after hospital discharge (2 RCTs; n = 103; MD, 9.13 [13.80 to 32.05] points higher; very low certainty), or hospital mortality (7 RCTs; n = 710; RR 1.09 [0.82 to 1.46]; moderate-certainty). The adverse event rate in cycling sessions was 0.16% across studies (10 studies; 5 of 3,117 sessions; very low certainty).Conclusions: Cycling initiated in the ICU is probably safe; however, we did not find any differences in physical function, MV duration, LOS, QoL, or mortality compared with those not receiving cycling. Rigorously designed RCTs are needed to improve precision and further investigate the effect of cycling on patient-important outcomes.

Downregulation of cytochrome P450 2C8 by 3-methylcholanthrene in human hepatocellular carcinoma cell lines.

The marked induction of cytochromes P450 such as CYP1A1 caused by polycyclic aromatic hydrocarbons (PAHs) like 3-methylcholanthrene (MC) is often accompanied by suppression of other hepatic P450s. The molecular mechanisms, functional consequences, and human relevance of P450 downregulation by PAHs are poorly understood. MC suppresses mRNA levels for CYP2C8, an important human P450, in cultured human hepatocytes. To avoid hepatocyte lot-to-lot variability, we assessed CYP2C8 regulation by MC in HepaRG cells, a terminally differentiated human hepatocellular carcinoma cell line that maintains high P450 expression. MC strongly induced CYP1A1 mRNA levels and markedly downregulated CYP2C8 mRNA levels in HepaRG cells. Although MC also suppressed CYP2C8 mRNA levels in the HepG2 human hepatocellular carcinoma cell line, basal CYP2C8 expression was extremely low. HepaRG cells appear to be an appropriate model system for studying the mechanisms and functional consequences of CYP2C8 downregulation by PAHs.

Identification of a novel mutation in GYS1 (muscle-specific glycogen synthase) resulting in sudden cardiac death, that is diagnosable from skin fibroblasts.

We report here the identification of a patient with muscle-specific glycogen synthase deficiency. The 8-year-old patient showed no prior signs of distress before collapsing during a bout of exercise, resulting in death. Initial post-mortem analysis of tissues suggested death was due to metabolic complications of mitochondrial myopathy, but upon further examination it was found that the anomalies were indicative of mitochondrial proliferation and oxidative compensation. A homozygous two base pair deletion was identified in exon 2 of GYS1, and the parents and sibling were confirmed as heterozygous carriers of the deletion. This case highlights the importance of differentiating between mitochondrial compensatory phenomena and true mitochondrial disease, and suggests that GYS1 deficiency could be a common cause of sudden cardiac death in children. Children with abnormal cardiac responses to increased workloads as well as those with defined myocardial disease should therefore be tested for GYS1 deficiency.