Creation of an Age-Adjusted, Dual-Energy X-ray Absorptiometry-Derived Trabecular Bone Score Curve for the Lumbar Spine in Non-Hispanic US White Women.

The trabecular bone score (TBS, Med-Imaps, Pessac, France) is an index of bone microarchitecture texture extracted from anteroposterior dual-energy X-ray absorptiometry images of the spine. Previous studies have documented the ability of TBS of the spine to differentiate between women with and without fractures among age- and areal bone mineral density (aBMD)-matched controls, as well as to predict future fractures. In this cross-sectional analysis of data collected from 3 geographically dispersed facilities in the United States, we investigated age-related changes in the microarchitecture of lumbar vertebrae as assessed by TBS in a cohort of non-Hispanic US white American women. All subjects were 30 yr of age and older and had an L1-L4aBMDZ-score within ±2 SD of the population mean. Individuals were excluded if they had fractures, were on any osteoporosis treatment, or had any illness that would be expected to impact bone metabolism. All data were extracted from Prodigy dual-energy X-ray absorptiometry devices (GE-Lunar, Madison, WI). Cross-calibrations between the 3 participating centers were performed for TBS and aBMD. aBMD and TBS were evaluated for spine L1-L4 but also for all other possible vertebral combinations. To validate the cohort, a comparison between the aBMD normative data of our cohort and US non-Hispanic white Lunar data provided by the manufacturer was performed. A database of 619 non-Hispanic US white women, ages 30-90 yr, was created. aBMD normative data obtained from this cohort were not statistically different from the non-Hispanic US white Lunar normative data provided by the manufacturer (p = 0.30). This outcome thereby indirectly validates our cohort. TBS values at L1-L4 were weakly inversely correlated with body mass index (r = -0.17) and weight (r = -0.16) and not correlated with height. TBS values for all lumbar vertebral combinations decreased significantly with age. There was a linear decrease of 16.0% (-2.47 T-score) in TBS at L1-L4 between 45 and 90 yr of age (vs. -2.34 for aBMD). Microarchitectural loss rate increased after age 65 by 50% (-0.004 to -0.006). Similar results were obtained for other combinations of lumbar vertebra. TBS, an index of bone microarchitectural texture, decreases with advancing age in non-Hispanic US white women. Little change in TBS is observed between ages 30 and 45. Thereafter, a progressive decrease is observed with advancing age. The changes we observed in these American women are similar to that previously reported for a French population of white women (r(2) > 0.99). This reference database will facilitate the use of TBS to assess bone microarchitectural deterioration in clinical practice.

Reducing the learning curve for the treatment of morphoeic (sclerosing) basal cell carcinoma of the face.

The treatment of morphoeic (or sclerosing) basal cell carcinoma (mBCC) of the face is associated with high rates of incomplete excision and recurrence. A principal risk factor for incomplete resection is the grade of surgeon. We did a prospective, randomised study of 40 consecutive patients with mBCC of the face. The extent of the tumour was assessed under standard conditions by consultant surgeons and compared with assessments by resident surgeons with the help of the Varioscope, a combination of microscope and loupe glasses with strong illumination and a maximal magnification of 7x. The data from a former retrospective study of all excisions of mBCC of the face during a five-year period at the hospital served as control. Residents with the support of the Varioscope achieved a rate of incomplete excisions similar to that of consultants under standard conditions. There was a significant reduction of the rate of incomplete resections by resident surgeons thanks to high magnification and good lighting (p=0.02). High magnification and good lighting were useful in learning how to recognise skin changes associated with mBCC of the face and achieving a low rate of incomplete excisions.

Constraints on the upper Permian to upper Triassic marine carbon isotope curve : case studies from the Tethys

Secular variations of the seawater carbon isotopic composition provide evidence for paleoceanographic and paleoclimatic changes and may serve for chemiostratigraphic correlations. The present study aimed to improve the current knowledge on the Upper Permian and Triassic segment of the Phanerozoic marine carbon isotope curve, whose Triassic part was poorly constrained by previous studies. Profiles of inorganic carbon isotopes are provided for sections from Himalaya (Salt Range, Kashmir, Spiti and Nepal), Oman and North Dobrogea (Romania) on the basis of whole-rock carbonate analysis. The data acquired, together with a literature compilation confirmed that most of the Upper Permian is characterized by high δ13C values (averaging +40/00) but failed to detect a positive excursion as suggested by recent compilations. In the light of these observations, the large drop in δ13C values associated with the end-Permian mass extinction appears to be driven by a sudden transfer of previously stocked 13C depleted carbon, rather than by the overturn of a Late Permian stratified ocean. The Triassic data-set outlines significant secular variations. The best documented is a carbon isotope positive excursion just across the Lower-Middle Triassic boundary, globally developed since it was detected in various paleogeographic settings. It is interpreted to reflect variations in surface ocean chemistry, possibly related to increased primary productivity, at times when the biotic recovery after the end-Permian mass-extinction began to accelerate significantly and when a sharp rise in seawater δ34S values occurred globally. Strontium isotope data obtained from well preserved biogenic phosphates allow a refinement of the Middle Triassic segment of the seawater strontium isotope curve and show a major inflexion point of the seawater strontium isotope curve also near the Lower Triassic - Middle Triassic boundary. These facts suggest that the transition from the Early to the Middle Triassic was a time of revolutionary global change which represented an important step in the evolution of Mesozoic marine environments. A tentative carbon isotope curve for the Upper Permian to Upper Triassic time interval is proposed. Its major features are: ? high but constant δ13C values during the Late Permian ? a sharp drop in δ13C values in the latest Permian ? subsequent recovery of δ13C values ? a short-lived positive excursion across the Early-Middle Triassic boundary ? a gradual rise in δ13C values starting in the Late Ladinian or in the Early Carnian It is foreseen that these fluctuations of the carbon isotope curve may serve as chronostratigraphic markers and further assist in the correlation of Permian and Triassic carbonate deposits.

Generation and validation of a normative, age-specific reference curve for lumbar spine trabecular bone score (TBS) in French women.

Age-related changes in lumbar vertebral microarchitecture are evaluated, as assessed by trabecular bone score (TBS), in a cohort of 5,942 French women. The magnitude of TBS decline between 45 and 85 years of age is piecewise linear in the spine and averaged 14.5 %. TBS decline rate increases after 65 years by 50 %. INTRODUCTION: This study aimed to evaluate age-related changes in lumbar vertebral microarchitecture, as assessed by TBS, in a cohort of French women aged 45-85 years. METHODS: An all-comers cohort of French Caucasian women was selected from two clinical centers. Data obtained from these centers were cross-calibrated for TBS and bone mineral density (BMD). BMD and TBS were evaluated at L1-L4 and for all lumbar vertebrae combined using GE-Lunar Prodigy densitometer images. Weight, height, and body mass index (BMI) also were determined. To validate our all-comers cohort, the BMD normative data of our cohort and French Prodigy data were compared. RESULTS: A cohort of 5,942 French women aged 45 to 85 years was created. Dual-energy X-ray absorptiometry normative data obtained for BMD from this cohort were not significantly different from French prodigy normative data (p = 0.15). TBS values at L1-L4 were poorly correlated with BMI (r = -0.17) and weight (r = -0.14) and not correlated with height. TBS values obtained for all lumbar vertebra combined (L1, L2, L3, L4) decreased with age. The magnitude of TBS decline at L1-L4 between 45 and 85 years of age was piecewise linear in the spine and averaged 14.5 %, but this rate increased after 65 years by 50 %. Similar results were obtained for other region of interest in the lumbar spine. As opposed to BMD, TBS was not affected by spinal osteoarthrosis. CONCLUSION: The age-specific reference curve for TBS generated here could therefore be used to help clinicians to improve osteoporosis patient management and to monitor microarchitectural changes related to treatment or other diseases in routine clinical practice.

Decision curve analysis revisited: overall net benefit, relationships to ROC curve analysis, and application to case-control studies.

ABSTRACT: BACKGROUND: Decision curve analysis has been introduced as a method to evaluate prediction models in terms of their clinical consequences if used for a binary classification of subjects into a group who should and into a group who should not be treated. The key concept for this type of evaluation is the "net benefit", a concept borrowed from utility theory. METHODS: We recall the foundations of decision curve analysis and discuss some new aspects. First, we stress the formal distinction between the net benefit for the treated and for the untreated and define the concept of the "overall net benefit". Next, we revisit the important distinction between the concept of accuracy, as typically assessed using the Youden index and a receiver operating characteristic (ROC) analysis, and the concept of utility of a prediction model, as assessed using decision curve analysis. Finally, we provide an explicit implementation of decision curve analysis to be applied in the context of case-control studies. RESULTS: We show that the overall net benefit, which combines the net benefit for the treated and the untreated, is a natural alternative to the benefit achieved by a model, being invariant with respect to the coding of the outcome, and conveying a more comprehensive picture of the situation. Further, within the framework of decision curve analysis, we illustrate the important difference between the accuracy and the utility of a model, demonstrating how poor an accurate model may be in terms of its net benefit. Eventually, we expose that the application of decision curve analysis to case-control studies, where an accurate estimate of the true prevalence of a disease cannot be obtained from the data, is achieved with a few modifications to the original calculation procedure. CONCLUSIONS: We present several interrelated extensions to decision curve analysis that will both facilitate its interpretation and broaden its potential area of application.

Stimulus-response curve of human motor nerves: multicenter assessment of various indexes.

The value of various indexes to characterize the stimulus-response curve of human motor nerves was assessed in 40 healthy subjects recruited from four European centers of investigation (Créteil, Lausanne, Liège, Marseille). Stimulus-response curves were established by stimulating the right median and ulnar motor nerves at the wrist, with stimulus durations of 0.05 and 0.5 ms. The following parameters were studied: the threshold intensity of stimulation to obtain 10% (I 10), 50% (I 50), and 90% (I 90) of the maximal compound muscle action potential, the ratios I 10/I 50, I 90/I 50, (I 90 - I 10)/I 10, (I 90-I 50)/I 50, and (I 50 - I 10)/I 10, and the slopes of the stimulus-response curves with or without normalization to I 50. For each parameter, within-center variability and reproducibility (in a test-retest study) were assessed and between-center comparisons were made. For most of the parameters, the results varied significantly within and between the centers. Within the centers, only the ratios I 10/I 50 and I 90/I 50 were found constant and reproducible. Between the centers, the absolute intensity thresholds (I 10, I 50, I 90) and the ratio I 90/I 50 did not show significant differences at stimulus duration of 0.5 ms, whatever the stimulated nerve. The reduced variability and good reproducibility of the ratios I 10/I 50 and I 90/I 50 open perspectives in neurophysiological practice for the use of these indexes of the stimulus-response curve, a rapid and noninvasive test.

The role of smoking in changes in the survival curve: an empirical study in 10 European countries.

PURPOSE: We examined the role of smoking in the two dimensions behind the time trends in adult mortality in European countries, that is, rectangularization of the survival curve (mortality compression) and longevity extension (increase in the age-at-death). METHODS: Using data on national sex-specific populations aged 50 years and older from Denmark, Finland, France, West Germany, Italy, the Netherlands, Norway, Sweden, Switzerland, and the United Kingdom, we studied trends in life expectancy, rectangularity, and longevity from 1950 to 2009 for both all-cause and nonsmoking-related mortality and correlated them with trends in lifetime smoking prevalence. RESULTS: For all-cause mortality, rectangularization accelerated around 1980 among men in all the countries studied, and more recently among women in Denmark and the United Kingdom. Trends in lifetime smoking prevalence correlated negatively with both rectangularization and longevity extension, but more negatively with rectangularization. For nonsmoking-related mortality, rectangularization among men did not accelerate around 1980. Among women, the differences between all-cause mortality and nonsmoking-related mortality were small, but larger for rectangularization than for longevity extension. Rectangularization contributed less to the increase in life expectancy than longevity extension, especially for nonsmoking-related mortality among men. CONCLUSIONS: Smoking affects rectangularization more than longevity extension, both among men and women.

A mathematical model to describe fat oxidation kinetics during graded exercise.

PURPOSE: The purpose of this study was to develop a mathematical model (sine model, SIN) to describe fat oxidation kinetics as a function of the relative exercise intensity [% of maximal oxygen uptake (%VO2max)] during graded exercise and to determine the exercise intensity (Fatmax) that elicits maximal fat oxidation (MFO) and the intensity at which the fat oxidation becomes negligible (Fatmin). This model included three independent variables (dilatation, symmetry, and translation) that incorporated primary expected modulations of the curve because of training level or body composition. METHODS: Thirty-two healthy volunteers (17 women and 15 men) performed a graded exercise test on a cycle ergometer, with 3-min stages and 20-W increments. Substrate oxidation rates were determined using indirect calorimetry. SIN was compared with measured values (MV) and with other methods currently used [i.e., the RER method (MRER) and third polynomial curves (P3)]. RESULTS: There was no significant difference in the fitting accuracy between SIN and P3 (P = 0.157), whereas MRER was less precise than SIN (P < 0.001). Fatmax (44 +/- 10% VO2max) and MFO (0.37 +/- 0.16 g x min(-1)) determined using SIN were significantly correlated with MV, P3, and MRER (P < 0.001). The variable of dilatation was correlated with Fatmax, Fatmin, and MFO (r = 0.79, r = 0.67, and r = 0.60, respectively, P < 0.001). CONCLUSIONS: The SIN model presents the same precision as other methods currently used in the determination of Fatmax and MFO but in addition allows calculation of Fatmin. Moreover, the three independent variables are directly related to the main expected modulations of the fat oxidation curve. SIN, therefore, seems to be an appropriate tool in analyzing fat oxidation kinetics obtained during graded exercise.

Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers.

Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of the UGT1A1 genotype are unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Nineteen healthy volunteers, age 24 to 51 years, took raltegravir 400 mg twice daily (arm A) and 400 mg plus atazanavir 400 mg once daily (arm B), separated by ?3 days, in a crossover design. After 1 week on each regimen, raltegravir and raltegravir-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 h (arm A) or 24 h (arm B) and analyzed by noncompartmental methods. UGT1A1 promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir C(tau), or concentration at the end of the dosing interval, for arm B (24 h) versus arm A (12 h). The arm B-to-arm A geometric mean ratios (95% confidence interval, P value) for plasma raltegravir C(tau), area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and raltegravir-glucuronide/raltegravir AUC(0-12) were 0.38 (0.22 to 0.65, 0.001), 1.32 (0.62 to 2.81, 0.45), and 0.47 (0.38 to 0.59, <0.001), respectively. Nine volunteers were heterozygous and one was homozygous for a UGT1A1 reduction-of-function allele, but these were not associated with metabolite formation. Although atazanavir significantly reduced the formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render the C(tau) with a once-daily raltegravir dose of 400 mg similar to the C(tau) with the standard twice-daily dose. UGT1A1 promoter variants did not significantly influence this interaction.