Energy expenditure was measured over 10 d using the doubly-labelled water (DLW) and activity diary methods in summer and winter in subjects with 'light' occupations but leisure activities which ranged from 'non-active' to 'very active'. The basal metabolic rate (BMR) and the energy cost of activities were determined by indirect calorimetry. The Department of Health (1991) predicted BMR for the group (689 (SD 0.30) MJ/d; n 18) was not sigdcantly different from the measured value (7.17 (SD 0.70) MJ/d; n 18). The range of DLW-derived expenditure values within the group was BMR x 1.41 to 2.41. The largest seasonal change within individuals was BMR x 0.5. The energy expenditure of the group as a whole was lower in winter (BMR x 1.88; SD 0.33; n 9) than summer (BMR x 201; SD 0.30; n 9) though the difference was not statistically significant. The average summer and winter DLW-derived expenditure was BMR x 1.96 (SD 0.31; n 17). The activity diary estimate of expenditure was BMR x 1.79 (SD 0.32; n 17). In a subset of the group who were representative of the most active 26% of all adult males in the UK, the DLW-derived expenditure was BMR x 2-08 (SD 024; n 11). This is higher than the highest Department of Health (1991) estimate of BMR x 1.6 for individuals in light occupations. The measured energy costs of low-intensity activities were similar to those presented in the Department of Health (1991) report but the value determined for running (BMR x 1308; SD 2-4; n 6) was higher than the highest value in the report (BMR x 6 to 8). The results indicate that the recent Department of Health (1991) reference values for energy may underestimate the expenditure of a significant proportion of the UK population largely because the energy costs of activity used in the report to calculate expenditure do not accurately reflect those achieved during active leisure in individuals who take regular exercise.Energy expenditure : Exercise : Doubly-labelled water : Season As opportunities for physical activity in the workplace are reduced by mechanization, leisure activity becomes increasingly important in determining overall activity levels (Allied Dunbar National Fitness Survey, 1992). One of the most popular reasons for participating in exercise during leisure time is to control or lose weight by increasing energy expenditure (Allied Dunbar National Fitness Survey, 1992). However, the recently published Department of Health (1991) reference values for the energy requirements of adults in the UK suggest that the potential of leisure activity to influence energy expenditure is extremely limited. For example, calculations based on the Department of Health (1991) report indicate that the difference in energy expenditure between the lowest and highest leisure activity categories for a typical 70 kg man with a light occupation would be 1.4 MJ/d; t h s is less than the energy content of some popular chocolate bars. Furthermore, these new estimates are lower than previous values (Department of Health and Social Security, 1979) and their accura...

Free-living energy expenditure was estimated by doubly-labelled water (DLW) and continuous heart-rate (HR) monitoring over nine consecutive days in nine healthy men with sedentary occupations but different levels of leisure-time physical activity. Individual calibrations of the HRenergy expenditure (EE) relationship were obtained for each subject using 30 min average values of HR and EE obtained during 24 h whole-body calorimetry with a defined exercise protocol, and additional data points for individual leisure activities measured with an Oxylog portable O2 consumption meter. The HR data were processed to remove spurious values and insert missing data before the calculation of EE from second-order polynomial equations relating EE to HR. After data processing, the HR-derived EE for this group of subjects was on average 0.8 (SEM 0.6) MJ/d, or 6.0 (SEM 4.2) 'YO higher than that estimated by DLW. The diary-respirometer method, used over the same 9 d, gave values which were 1.9 (SEM 0.7) MJ/d, or -12.1 (SEM 4.0) 'YO lower than the DLW method. The results suggest that HR monitoring can provide a better estimate of 24 h EE of groups than the diary-respirometer method, but show that both methods can introduce errors of 20 'YO or more in individuals.Energy expenditure: Doubly-labelled water: Heart-rate monitoringThe possibility that heart-rate (HR) monitoring may provide an alternative to whole-body calorimetry or doubly-labelled water (DLW) as a measure of 24 h energy expenditure (EE) is an attractive one due to the low cost of the HR monitors and the acceptability of HR monitoring for a wide range of subjects. The development of monitors which store minuteby-minute HR data for periods of 24 h or more has renewed interest in the method as it is now possible to estimate EE on a minute-by-minute basis rather than deriving a single value based on a mean daily HR. However, initial hopes that the relationship between HR and EE could be established for groups of subjects have not been realized, and the need for individual calibration of HR-EE relationships has been clearly established (Bradfield et al. 1970;Kalkwarf et al. 1989;Li et al. 1993). This requirement increased the complexity of the method, although the cost remains much less than that of DLW. Investigators differ in the mathematical model used to predict EE from HR, although it is generally agreed that an approach which takes account of the difference in the gradient of the relationship between HR and EE at low-and high-intensity activity is needed.

Summary Background Biologics directed against the T-helper (Th)-17 pathway have been approved for several inflammatory diseases. Interleukin (IL)-17 is involved in anti- Candida host defense, and clinical trials suggested increased candidiasis incidence during IL-17 inhibitor therapy. We describe the worldwide epidemiology of candidiasis during Th17 inhibitor therapy, and immunological mechanisms involved in candidiasis susceptibility. Methods A comprehensive analysis of multiple independent sources reporting Candida adverse events during biologics inhibiting the Th17 pathway was performed. Association between Th17 inhibitors and candidiasis was assessed using safety reports of (1) WHO and (2) EMA, (3) a population-based prescriptions registry, and (4) a psoriasis cohort. In a cohort of psoriasis patients experiencing candidiasis during Th17 inhibitors, Candida killing by immune cells and serum inflammatory proteome were analyzed. Findings A strong association between IL-17 inhibitors and candidiasis (ROR 10·20) was found in the WHO database, particularly for cutaneous (ROR 12·28), oropharyngeal (ROR 19·18), and esophageal candidiasis (ROR 21·20). Risk was higher relative to TNF-α inhibitors (4–10-fold, depending on candidiasis type), confirmed by EMA reports (16–33-fold), prescriptions registry (2–42-fold), and a psoriasis cohort (3–25-fold). After start of IL-17 inhibitors, patients’ risk of candidiasis requiring antifungals increased 2–16 fold. In the psoriasis cohort, 58% of IL-17 treatment episodes were associated with candidiasis. In Th17 inhibitor recipients, proteins involved in anti- Candida immunity and Candida killing by mononuclear leukocytes were impaired. Interpretation IL-17 inhibitors are associated with an increased risk of oropharyngeal, esophageal, and cutaneous candidiasis, posing a significant disease burden for IL-17 inhibitor recipients. Funding RadboudUMC.

Mitochondrial bioenergetics profiling, a measure of oxygen consumption rates, correlates with prognostic markers and can be used to assess response to therapy in chronic lymphocytic leukemia (CLL) cells. In this study, we measured mitochondrial respiration rates in primary CLL cells using respirometry to evaluate mitochondrial function. We found significant increases in mitochondrial respiration rates in CLL versus control B lymphocytes. We also observed amongst CLL patients that advanced age, female sex, zeta-chain-associated protein of 70 kD (ZAP-70+), cluster of differentiation 38 (CD38+), and elevated β2-microglobulin (β2-M) predicted increased maximal respiration rates. ZAP-70+ CLL cells exhibited significantly higher bioenergetics than B lymphocytes or ZAP-70− CLL cells and were more sensitive to the uncoupler, carbonyl cyanide-p-trifluoro-methoxyphenylhydrazone (FCCP). Univariable and multivariable linear regression analysis demonstrated that ZAP-70+ predicted increased maximal respiration. ZAP-70+ is a surrogate for B cell receptor (BCR) activation and can be targeted by ibrutinib, which is a clinically approved Bruton’s tyrosine kinase (BTK) inhibitor. Therefore, we evaluated the oxygen consumption rates (OCR) of CLL cells and plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4) levels from ibrutinib-treated patients and demonstrated decreased OCR similar to control B lymphocytes, suggesting that ibrutinib treatment resets the mitochondrial bioenergetics, while diminished CCL3/CCL4 levels indicate the down regulation of the BCR signaling pathway in CLL. Our data support evaluation of mitochondrial respiration as a preclinical tool for the response assessment of CLL cells.