Flip it and reverse it: Reasonable changes in designated controls can flip synergisms to antagonisms.

Ecological systems are subjected to multiple stressors that can interact in complex ways resulting in "ecological surprises". We examine the pivotal role of 'control' assignment in the categorization of stressors into five classes: additive, +synergistic, -synergistic, +antagonistic, and -antagonistic. We demonstrate if an alternate treatment can reasonably be considered the experimental control, nonlinear interaction classifications change, both in sign (+/-) and in direction (synergistic/antagonistic). Further, switching of interaction classifications is not predictable as changing control can result in multiple possible alternate nonlinear classifications. To explore the magnitude of this problem, we evaluate publications gathered for a recent meta-analysis to 1) explore rationales for choice of controls and 2) quantify how frequently it is reasonable to reassign the control. We found controls were designated with a variety of implicit and explicit justifications, with two overall rationales: 1) controls based on 'natural' conditions (historic, current, or future); 2) controls based on direction of impact, such that stressors always have negative impacts. We reasoned that control re-assignment was justified if an alternate treatment met one of these rationales. Of the 844 interactions classified in the meta-analysis, we determined >95% could be reassigned. Based on these findings, we recommend a new approach to meta-analyses, where the 'control' is strictly and consistently defined by the authors of the meta-analysis. These controls should be based on their broader question, rather than following the common practice of defaulting to controls assigned by the authors of each study, as we found these rationales vary broadly based on the specific questions of each study. Consistent control designation within the ecological or toxicological framework of each meta-analysis may provide deeper and more consistent insight into the nature of interactive effects between multiple stressors. Gaining this insight is crucial because stressor interactions are certain to increase in the Anthropocene.

Compartment Syndrome: Evaluation of Skeletal Muscle Ischemia and Physiologic Biomarkers in Controlled Conditions Within Ex Vivo Isolated Muscle Bundles.

OBJECTIVES: To identify potential physiologic markers of muscle ischemia to serve as diagnostic indicators of compartment syndrome. We hypothesize that muscle bundles in hypoxic conditions will elicit decreases in potential hydrogen (pH) and increases in lactate and potassium that correlates with decreased muscle twitch forces. METHODS: We performed an ex vivo evaluation of individual skeletal muscle bundles obtained from a swine's diaphragm that were exposed to hypoxic conditions and compared with control groups. Over a 4-hour period, we evaluated the following parameters for each muscle bundle: muscle twitch forces and levels of potassium, lactate, and pH. Comparisons between the hypoxic and control groups were calculated at each time point using the 2-tailed Wilcoxon rank sum test for nonparametric data. Longitudinal associations between biomarkers and muscle twitch forces were tested using repeated measures analyses. RESULTS: The hypoxic group elicited more significant decreases in normalized muscle twitch forces than the control group at all time points (0.15 g vs. 0.55 g at 4 hours, P < 0.001). Repeated measures analyses of the hypoxic group demonstrated a statistically significant association between potassium, lactate, and normalized peak force over the course of time. Potassium demonstrated the strongest association with a 1 mmol/L unit increase in potassium associated with a 2.9 g decrease in normalized peak force (95% confidence interval -3.3 to -2.4, P < 0.001). The pH of all muscle baths increased over the course of time at similar rates between the study groups. CONCLUSIONS: This study used an ex vivo ischemic skeletal muscle model as a representation for pathophysiologic pathways associated with compartment syndrome. In this experimental approach we were unable to evaluate the pH of the muscle bundles due to continuous applied gassing. Our findings support further evaluations of potassium and lactate levels as potential diagnostic markers.

Diagnostic Immunization with Bacteriophage ΦX 174 in Patients with Common Variable Immunodeficiency/Hypogammaglobulinemia.

PURPOSE: Use of the T cell-dependent neoantigen bacteriophage ΦX 174 has been described since the 1960s as a method to assess specific antibody response in patients with primary immunodeficiencies. We reviewed a cohort of patients at Duke University Medical Center who received immunization with bacteriophage and report the clinical utility and safety of the immunization, as well as patient characteristics. METHODS: A retrospective chart review was performed of all Duke Immunology Clinic patients (pediatric and adult) who received immunizations with bacteriophage, from 1976 to 2012. Subjects were selected for inclusion if their diagnosis at the time of bacteriophage was either presumed or confirmed common variable immunodeficiency (CVID), hypogammaglobulinemia, transient hypogammaglobulinemia, or antibody deficiency unspecified. Follow up post-immunization was also recorded. RESULTS: One hundred twenty-six patients were identified, 36 adults and 90 pediatric patients. Diagnoses prior to bacteriophage were CVID (n = 100), hypogammaglobulinemia (n = 23), and antibody deficiency (n = 3). Post-immunization diagnoses were CVID (n = 65), hypogammaglobulinemia (n = 19), unknown (n = 23), no primary immune deficiency (n = 10), and other primary immunodeficiency (n = 9). Seventy-five patients had abnormal bacteriophage results, 37 were normal, and 14 were borderline. There were 257 recorded administrations of the immunization. Information was available on adverse reactions for 171 administrations. Fourteen immunizations were associated with minor adverse events. Nineteen patients stopped their immunoglobulin replacement therapy based on reported normal responses to immunization. CONCLUSION: Bacteriophage ΦX 174 immunization is a safe, well-tolerated, and clinically useful method to assess antibody response in patients with suspected antibody-mediated immunodeficiencies, particularly those who are on immunoglobulin replacement therapy at the time of immunization.

Heart rate recovery after exercise: a predictor of ventricular fibrillation susceptibility after myocardial infarction.

Heart rate recovery after exercise, thought to be related to cardiac parasympathetic tone, has been shown to be a prognostic tool for all-cause mortality. However, the relationship between this variable and confirmed susceptibility to ventricular fibrillation (VF) has not been established. Therefore, myocardial ischemia was induced with a 2-min occlusion of the left circumflex artery during the last minute of exercise in mongrel dogs with myocardial infarction (n = 105 dogs). VF was induced in 66 animals (susceptible), whereas the remaining 39 dogs had no arrhythmias (resistant). On a previous day, ECG was recorded and a time-series analysis of heart rate variability was measured 30, 60, and 120 s after submaximal exercise (treadmill running). The heart rate recovery was significantly greater in resistant dogs than in susceptible dogs at all three times, with the most dramatic difference at the 30-s mark (change from maximum: 48.1 +/- 3.6 beats/min, resistant dogs; 31.0 +/- 2.2 beats/min, susceptible dogs). Correspondingly, indexes of parasympathetic tone increased to a significantly greater extent in resistant dogs at 30 and 60 s after exercise. These differences were eliminated by atropine pretreatment. When considered together, these data suggest that resistant animals exhibit a more rapid recovery of vagal activity after exercise than those susceptible to VF. As such, postexercise heart rate recovery may help identify patients with a high risk for VF following myocardial infarction.