Urine interleukin-6 is an early biomarker of acute kidney injury in children undergoing cardiac surgery

Introduction  

Interleukin-6 (IL-6) is a proinflammatory cytokine that increases early in the serum of patients with acute kidney injury (AKI). The aim of this study was to determine whether urine IL-6 is an early biomarker of AKI and determine the source of urine IL-6. Numerous proteins, including cytokines, are filtered by the glomerulus and then endocytosed and metabolized by the proximal tubule. Since proximal tubule injury is a hallmark of AKI, we hypothesized that urine IL-6 would increase in AKI due to impaired proximal tubule metabolism of filtered IL-6.     

Effects of Tuberculosis,Race, and Human Gene SLCO1B1 Polymorphisms on Rifampin Concentrations

Rifampin has concentration-dependent activity against Mycobacterium tuberculosis. However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes SLCO1B1, SLCO1B3, and MDR1. Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC_0-24] of 40.2 versus 40.9 μg·h/ml; P = 0.9). However, in multivariable analyses, the rifampin AUC_0-24 was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the SLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC_0-24 was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC_0-24 was also 36% lower among participants with SLCO1B1 genotype c.463CA than that among participants with SLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 μg·h/ml; P = 0.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC_0-24 values was observed, but the mean values of the AUC_0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.Rifamycins have consistently demonstrated concentration-dependent activity against Mycobacterium tuberculosis in both in vitro and in vivo models (14, 17, 18, 24). There is marked intersubject variation of rifamycin concentrations among patients on standard tuberculosis therapy, and the basis for variation is not well characterized. Advanced HIV infection has been associated with low rifampin concentrations, but marked differences in rifampin concentrations are also found among tuberculosis patients without HIV infection and between patient groups (7, 21, 27, 29). Low rifamycin exposures can have clinical significance. In a treatment trial of rifabutin in patients with HIV-associated tuberculosis, low rifabutin exposure (area under the concentration-time curve [AUC]) was associated with treatment failure or relapse with acquired rifamycin-resistant M. tuberculosis (33). In treatments with intermittent rifamycin-containing regimens (with lower total rifamycin exposure per week), increases in relapse rates were observed (5, 20).Two recent Tuberculosis Trials Consortium (TBTC) clinical trials demonstrated a decreased initial response to therapy (by 2-month culture conversion) among patients enrolled at African sites rather than non-African sites (3, 9). Possible explanations for the decreased response include differences in severity of tuberculosis, morbidity due to HIV infection, differences in microbiologic techniques between sites, or the pharmacokinetics of antitubercular drugs, particularly rifampin.Our primary study objectives were the comparison of rifampin pharmacokinetics among patients with tuberculosis and healthy controls and between regions (Africa versus non-Africa) and races (black versus all other races). Different human phenotypes may result from alternative forms of a gene at the same physical location (called alleles), and gene polymorphisms are reported to vary among races. Because organic anion transporter peptides (OATP) play key roles in transport and disposition of xenobiotics in the gastrointestinal tract and liver, the secondary objectives of the study were to determine the relationships between rifampin pharmacokinetics and human genetic polymorphisms of drug influx and efflux transporter genes (anion-transporting polypeptides [SLCO1B1 and SLCO1B3] and P-glycoprotein [MDR1]).Rifampin pharmacokinetic data of healthy controls were previously described (32).(Some of the pharmacokinetic and pharmacogenetic data for patients with tuberculosis were previously reported at the Second International Workshop on Clinical Pharmacology of Tuberculosis Drugs in 2009 [30] and as abstract A791 at the American Thoracic Society International Conference in 2008 [31].)     

Error self-regulation following traumatic brain injury: A single case study evaluation of metacognitive skills training and behavioural practice interventions

The objective of the study was to evaluate the effects of metacognitive skills training (MST) and behavioural practice on error self-regulation during a naturalistic task after traumatic brain injury (TBI). A single-case study design was used and three participants (two males, one female) aged 26–43 years with severe TBI were included in the study. In the first study, after a four-session baseline of behavioural practice, two participants received eight MST sessions followed by four maintenance sessions. In the second study, a third participant received 16 sessions of behavioural practice to assess the extent to which error self-regulation improves through long-term task practice and therapist corrections. Participants prepared two different meals with a novel meal introduced later to examine skills generalisation. Behavioural outcomes included error frequency, checking and self-corrections. Data analysis involved a combination of visual analysis and two standard deviation (2-SD) band analysis. In the MST study, the two participants demonstrated a 38% and 76% reduction in error frequency (p < .05), a significant decrease in checks (p < .05), and a significant increase in self-corrections (p < .05) relative to baseline. In the behavioural practice study, the participant demonstrated reduced errors (25%), although this was not statistically significant, and a significant increase in checks (p < .05), but self-corrections did not significantly change (p > .05). This exploratory research suggests that, firstly, by targeting error self-regulation MST can potentially promote independence on complex everyday tasks; and secondly, although behavioural practice alone may facilitate some functional gains, it fails to promote more independent self-regulatory behaviours.     

Endocrinology in aging

Aging is a time of reduced adaptability to metabolic perturbation. This is particularly true in endocrinology which, after all, is the science of chemically regulated biologic systems. There is no evidence that equilibrium concentrations of the principal hormones are altered with age. However, the systems utilized to reach those equilibria become progressively taxed, and new equilibria may be achieved reflecting that regulatory problem. Thus, with advancing age there are significant alterations in hormone production, metabolism, and action. Some of these changes may play a role in the pathophysiology of senescence, although the evidence for that is limited. The magnitude of age-related alterations is highly variable and sex dependent. Whereas only subtle changes occur in pituitary dynamics, adrenal gland physiology, and thyroid function, the changes in glucose homeostasis, reproductive function, and calcium metabolism are more apparent. In the elderly, the interpretation of endocrine tests should reflect the nutritional status of the patient and the presence of coexisting illnesses. In this review, we describe the principles of endocrinology in the geriatric population and elaborate on the changes in specific glandular functions with aging. We also define strategies of evaluation and management protocols appropriate for the elderly with suspected endocrine dysfunction.     

Endogenous opioids and the exercise-induced augmentation of natural killer cell activity

Based on prior observations that both beta-endorphin and exercise stimulate natural killer (NK) cell activity, we have examined the hypothesis that the release of endogenous opioids during the stress of acute exercise may mediate this NK cell augmentation. Eight healthy young women underwent a maximal bicycle ergometer exercise test with prior in vivo administration of a placebo and an opioid antagonist, naloxone (100 micrograms/kg), in a randomized, blind protocol. Exercise after the placebo injection was accompanied by a dramatic rise in NK activity, as well as an increase in the percentage of lymphocytes bearing the NK cell surface markers Leu 11a and Leu 19. Significant stimulation of NK activity was observed with beta-endorphin in vitro before exercise, but after exercise, beta-endorphin had a nonsignificant inhibitory effect. When these experiments were carried out in the presence of naloxone in vivo, the rise in NK activity after exercise was no longer significant. Naloxone did not significantly alter the rise in Leu 11a+ or Leu 19+ cell after exercise, as compared with the placebo. Finally, when naloxone was given to the subjects beforehand, exercise no longer completely blocked the in vitro beta-endorphin stimulation of NK cells. In conclusion, our observations that the exercise-induced augmentation of NK activity and the lack of effect of beta-endorphin in vitro on NK activity after exercise are both significantly attenuated by prior administration of naloxone suggest that the opioid system may play a major role in the modulation of NK cells during physiologic stress.     

A Review of the Role of Female Gender in Autism Spectrum Disorders

This paper reviews the literature exploring gender differences associated with the clinical presentation of autism spectrum disorders (ASD). The potentially mediating effect of comorbid psychopathology, biological and neurodevelopmental implications on these gender differences is also discussed. A vastly heterogeneous condition, while females on the lower-functioning end of the spectrum appear to be more severely affected, an altered clinical manifestation of the disorder among high-functioning females may consequently result in many being un or misdiagnosed. To date, there is strong bias in the literature towards the clinical presentation of ASD in males. It is imperative that future research explores gender differences across the autism spectrum, in order to improve researchers’, clinicians’ and the publics’ understanding of this debilitating disorder.     

Development of a universal thoracic enhanced recover after surgery protocol for implementation across a diverse multi-hospital health system

BackgroundImplementation of enhanced recovery after surgery (ERAS) pathways for patients undergoing anatomic lung resection have been reported at individual institutions. We hypothesized that an ERAS pathway can be successfully implemented across a large healthcare system including different types of hospital settings (academic, academic-affiliated, community).MethodsAn expert panel with representation from each hospital within a healthcare system was convened to establish a thoracic ERAS pathway for patients undergoing anatomic lung resection and to develop tools and analytics to ensure consistent application. The protocol was translated into an order set and pathway within the electronic health record (EHR). Iterative implementation was performed with recording of the processes involved. Barriers and facilitators to implementation were recorded.ResultsDevelopment and implementation of the protocol took 13 months from conception to rollout. Considerable change management was needed for consensus and incorporation into practice. Facilitators of change included peer accountability, incorporating ERAS care elements into the EHR, and conducting case reviews with timely feedback on protocol deviations. Barriers included institutional cultural differences, agreement in defining mindful deviation from the ERAS protocol, lack of access to specific coded data, and resource scarcity caused by the COVID-19 pandemic. Support from the hospital system’s executive leadership and institutional commitment to quality improvement helped overcome barriers and maintain momentum.ConclusionsDevelopment and implementation of a health-system wide thoracic ERAS protocol for anatomic lung resections across a six-hospital health system requires a multidisciplinary team approach. Barriers can be overcome though multidisciplinary team engagement and executive leadership support.