First Evaluation of an Index of Low Vagally-Mediated Heart Rate Variability as a Marker of Health Risks in Human Adults: Proof of Concept.

Multiple studies have demonstrated low vagally-mediated heart rate variability (HRV) being associated with a range of risk factors for heart disease and stroke, including inflammation, hyperglycemia, hyperlipidemia, and hypertension. Yet, no cut point exists that indicates elevated risk. In the present study we sought to identify a cut point-value for HRV that is associated with elevated risk across a range of known risk factors. METHODS:A total of 9550 working adults from 19 study sites took part in a health assessment that included measures of inflammation, hyperglycemia, hyperlipidemia, and hypertension and vagally-mediated HRV (Root mean square of successive differences between normal heartbeats (RMSSD)). Multiple age and sex adjusted logistic regressions were calculated per risk factor (normal versus clinical range), with RMSSD being entered in binary at different cut points ranging from 15-39 msec with a 2 msec increment. RESULTS:For daytime RMSSD, values below 25 ± 4 indicated elevated risk (odds ratios (OR) 1.5-3.5 across risk factors). For nighttime RMSSD, values below 29 ± 4 indicated elevated risk (OR 1.2-2.0). CONCLUSION:These results provide the first evidence that a single value of RMSSD may be associated with elevated risk across a range of established cardiovascular risk factors and may present an easy to assess novel marker of cardiovascular risk

Daily commuting to work is not associated with variables of health

Background: Commuting to work is thought to have a negative impact on employee health. We tested the association of work commute and different variables of health in German industrial employees. Methods: Self-rated variables of an industrial cohort (n = 3805; 78.9 % male) including absenteeism, presenteeism and indices reflecting stress and well-being were assessed by a questionnaire. Fasting blood samples, heart-rate variability and anthropometric data were collected. Commuting was grouped into one of four categories: 0–19.9, 20–44.9, 45–59.9, ≥60 min travelling one way to work. Bivariate associations between commuting and all variables under study were calculated. Linear regression models tested this association further, controlling for potential confounders. Results: Commuting was positively correlated with waist circumference and inversely with triglycerides. These associations did not remain statistically significant in linear regression models controlling for age, gender, marital status, and shiftwork. No other association with variables of physical, psychological, or mental health and well-being could be found. Conclusions: The results indicate that commuting to work has no significant impact on well-being and health of German industrial employees

Experimental ordinary language philosophy: a cross-linguistic study of defeasible default inferences

This paper provides new tools for philosophical argument analysis and fresh empirical foundations for ‘critical’ ordinary language philosophy. Language comprehension routinely involves stereotypical inferences with contextual defeaters. J.L. Austin’s Sense and Sensibilia first mooted the idea that contextually inappropriate stereotypical inferences from verbal case-descriptions drive some philosophical paradoxes; these engender philosophical problems that can be resolved by exposing the underlying fallacies. We build on psycholinguistic research on salience effects to explain when and why even perfectly competent speakers cannot help making stereotypical inferences which are contextually inappropriate. We analyse a classical paradox about perception (‘argument from illusion’), suggest it relies on contextually inappropriate stereotypical inferences from appearance-verbs, and show that the conditions we identified as leading to contextually inappropriate stereotypical inferences are met in formulations of the paradox. Three experiments use a forced-choice plausibility-ranking task to document the predicted inappropriate inferences, in English, German, and Japanese. The cross-linguistic study allows us to assess the wider relevance of the proposed analysis. Our findings open up new perspectives for ‘evidential’ experimental philosophy

Within- and between-group regression for improving the robustness of causal claims in cross-sectional analysis

Background: A major objective of environmental epidemiology is to elucidate exposure-health outcome associations. To increase the variance of observed exposure concentrations, researchers recruit individuals from different geographic areas. The common analytical approach uses multilevel analysis to estimate individual-level associations adjusted for individual and area covariates. However, in cross-sectional data this approach does not differentiate between residual confounding at the individual level and at the area level. An approach allowing researchers to distinguish between within-group effects and between-group effects would improve the robustness of causal claims. Methods: We applied an extended multilevel approach to a large cross-sectional study aimed to elucidate the hypothesized link between drinking water pollution from perfluoroctanoic acid (PFOA) and plasma levels of C-reactive protein (CRP) or lymphocyte counts. Using within- and between-group regression of the individual PFOA serum concentrations, we partitioned the total effect into a within- and between-group effect by including the aggregated group average of the individual exposure concentrations as an additional predictor variable. Results: For both biomarkers, we observed a strong overall association with PFOA blood levels. However, for lymphocyte counts the extended multilevel approach revealed the absence of a between-group effect, suggesting that most of the observed total effect was due to individual level confounding. In contrast, for CRP we found consistent between- and within-group effects, which corroborates the causal claim for the association between PFOA blood levels and CRP. Conclusion: Between- and within-group regression modelling augments cross-sectional analysis of epidemiological data by supporting the unmasking of non-causal associations arising from hidden confounding at different levels. In the application example presented in this paper, the approach suggested individual confounding as a probable explanation for the first observed association and strengthened the robustness of the causal claim for the second one

G-CSF and IL-8 for early diagnosis of sepsis in neonates and critically ill children – safety and cost effectiveness of a new laboratory prediction model: study protocol of a randomized controlled trial [ISRCTN91123847]

INTRODUCTION: Bacterial infection represents a serious risk in neonates and critically ill paediatric patients. Current clinical practice is characterized by frequent antibiotic treatment despite low incidence of true infection. However, some patients escape early diagnosis and progress to septic shock. Many new markers, including cytokines, have been suggested to improve decision making, but the clinical efficacy of these techniques remains uncertain. Therefore, we will test the clinical efficacy of a previously validated diagnostic strategy to reduce antibiotic usage and nosocomial infection related morbidity. METHODS: All patients admitted to the multidisciplinary neonatal and paediatric intensive care unit of a university children's hospital will be included. Patients will be allocated either to routine sepsis work up or to the intervention strategy with additional cytokine measurements. Physicians will be requested to estimate the pre-test probability of sepsis and pneumonia at initial suspicion. In the treatment arm, physicians will receive raw cytokine results, the likelihood ratio and the updated post-test probability. A high post-test probability will suggest that immediate initiation of antibiotic treatment is appropriate, whereas a low post-test probability will be supportive of watchful waiting or discontinuing prophylactic empirical therapy. Physicians may overrule the suggestions resulting from the post-test probability. CONCLUSION: This trial will ascertain the clinical efficacy of introducing new diagnostic strategies consisting of pre-test probability estimate, novel laboratory markers, and computer-generated post-test probability in infectious disease work up in critically ill newborns and children

Glucocorticoid sensitivity of circulating monocytes in essential hypertension

Background: Essential hypertension ranks among the strongest cardiovascular risk factors. Cytokine production by monocytes plays a key role in atherosclerosis development and acute coronary syndromes. We investigated whether stimulated monocyte cytokine release and its inhibition by glucocorticoids would differ between hypertensive and normotensive subjects. Methods: Study participants were 222 middle-aged male employees with industrial jobs. Following the criteria of the World Health Organization/International Society for Hypertension, 76 subjects were classified as being hypertensive (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg). In vitro monocyte tumor necrosis factor (TNF)-α release after lipopolysaccharide (LPS) stimulation was assessed with and without coincubation with incremental doses of dexamethasone. Monocyte glucocorticoid sensitivity was defined as the dexamethasone concentration inhibiting TNF-α release by 50%. Results: Hypertensive subjects showed 11% higher LPS-stimulated TNF-α release than normotensive subjects (F1,181= 5.21, P = .024). In hypertensive subjects, monocyte glucocorticoid sensitivity was 21% lower than in normotensive subjects (F1,178= 4.94, P = .027), indicating that dexamethasone inhibited relatively less TNF-α release in hypertensive subjects. Results held significance when a set of classic cardiovascular risk factors was controlled for. Conclusion: The findings suggest that proinflammatory activity of circulating monocytes is higher in hypertensive than in normotensive men, providing one potential pathway to explain the increased atherosclerotic risk with essential hypertension. Am J Hypertens 2004;17:489-494 © 2004 American Journal of Hypertension, Lt

Quantifying Uncertainty: Physicians' Estimates of Infection in Critically Ill Neonates and Children

To determine the diagnostic accuracy of physicians' prior probability estimates of serious infection in critically ill neonates and children, we conducted a prospective cohort study in 2 intensive care units. Using available clinical, laboratory, and radiographic information, 27 physicians provided 2567 probability estimates for 347 patients (follow-up rate, 92%). The median probability estimate of infection increased from 0% (i.e., no antibiotic treatment or diagnostic work-up for sepsis), to 2% on the day preceding initiation of antibiotic therapy, to 20% at initiation of antibiotic treatment (P < .001). At initiation of treatment, predictions discriminated well between episodes subsequently classified as proven infection and episodes ultimately judged unlikely to be infection (area under the curve, 0.88). Physicians also showed a good ability to predict blood culture-positive sepsis (area under the curve, 0.77). Treatment and testing thresholds were derived from the provided predictions and treatment rates. Physicians' prognoses regarding the presence of serious infection were remarkably precise. Studies investigating the value of new tests for diagnosis of sepsis should establish that they add incremental value to physicians' judgmen

Elevated HbA1c levels and the accumulation of differentiated T cells in CMV+ individuals

Aims/hypothesis Biological ageing of the immune system, or immunosenescence, predicts poor health and increased mortality. A hallmark of immunosenescence is the accumulation of differentiated cytotoxic T cells (CD27−CD45RA+/−; or dCTLs), partially driven by infection with the cytomegalovirus (CMV). Immune impairments reminiscent of immunosenescence are also observed in hyperglycaemia, and in vitro studies have illustrated mechanisms by which elevated glucose can lead to increased dCTLs. This study explored associations between glucose dysregulation and markers of immunosenescence in CMV+ and CMV− individuals. Methods A cross-sectional sample of participants from an occupational cohort study (n = 1,103, mean age 40 years, 88% male) were assessed for HbA1c and fasting glucose levels, diabetes, cardiovascular risk factors (e.g. lipids), numbers of circulating effector memory (EM; CD27−CD45RA−) and CD45RA re-expressing effector memory (EMRA; CD27−CD45RA+) T cells, and CMV infection status. Self-report and physical examination assessed anthropometric, sociodemographic and lifestyle factors. Results Among CMV+ individuals (n = 400), elevated HbA1c was associated with increased numbers of EM (B = 2.75, p \u3c 0.01) and EMRA (B = 2.90, p \u3c 0.01) T cells, which was robust to adjustment for age, sex, sociodemographic variables and lifestyle factors. Elevated EM T cells were also positively associated with total cholesterol (B = 0.04, p \u3c 0.05) after applying similar adjustments. No associations were observed in CMV− individuals. Conclusions/interpretation The present study identified consistent associations of unfavourable glucose and lipid profiles with accumulation of dCTLs in CMV+ individuals. These results provide evidence that the impact of metabolic risk factors on immunity and health can be co-determined by infectious factors, and provide a novel pathway linking metabolic risk factors with accelerated immunosenescence. Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3731-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users