How to interprete subclinical thyroid dysfunction in the prevention and management of heart failure events? Individual participant data analysis from six prospective cohorts

Background: Guidelines of the Diagnosis and Management of Heart Failure (HF) recommend investigating exacerbating conditions, such as thyroid dysfunction, but without specifying impact of different TSH levels. Limited prospective data exist regarding the association between subclinical thyroid dysfunction and HF events. Methods: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of HF events. Individual data on 25,390 participants with 216,247 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH 0.45-4.49 mIU/L, subclinical hypothyroidism as TSH 4.5-19.9 mIU/L and subclinical hyperthyroidism as TSH <0.45 mIU/L, both with normal free thyroxine levels. HF events were defined as acute HF events, hospitalization or death related to HF events. Results: Among 25,390 participants, 2068 had subclinical hypothyroidism (8.1%) and 648 subclinical hyperthyroidism (2.6%). In age- and gender-adjusted analyses, risks of HF events were increased with both higher and lower TSH levels (P for quadratic pattern<0.01): hazard ratio (HR) was 1.01 (95% confidence interval [CI] 0.81-1.26) for TSH 4.5-6.9 mIU/L, 1.65 (CI 0.84-3.23) for TSH 7.0-9.9 mIU/L, 1.86 (CI 1.27-2.72) for TSH 10.0-19.9 mIUL/L (P for trend <0.01), and was 1.31 (CI 0.88-1.95) for TSH 0.10-0.44 mIU/L and 1.94 (CI 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. Conclusion: Risks of HF events were increased with both higher and lower TSH levels, particularly for TSH ≥10 mIU/L and for TSH <0.10 mIU/L. Our findings might help to interpret TSH levels in the prevention and investigation of HF.

Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data.

The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model=1.77; 95% confidence interval [CI]: 1.42-2.19; P=2.78 × 10(-7) ). This association was more pronounced in ALD (OR=2.20; 95% CI: 1.80-2.67; P=4.71 × 10(-15) ) than in CHC patients (OR=1.55; 95% CI: 1.03-2.34; P=3.52 × 10(-2) ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.

Différences induites par la définition des périodes diurnes et nocturnes sur la pression artérielle et le dipping lors d'une mesure ambulatoire de la pression artérielle [Effects of nighttime and daytime interval definition on blood pressure and dipping in patients referred for ambulatory blood pressure measurement].

Ambulatory blood pressure monitoring (ABPM) has become indispensable for the diagnosis and control of hypertension. However, no consensus exists on how daytime and nighttime periods should be defined. OBJECTIVE: To compare daytime and nighttime blood pressure (BP) defined by an actigraph and by body position with BP resulting from arbitrary daytime and nighttime periods. PATIENTS AND METHOD: ABPM, sleeping periods and body position were recorded simultaneously using an actigraph (SenseWear Armband(®)) in patients referred for ABPM. BP results obtained with the actigraph (sleep and position) were compared to the results obtained with fixed daytime (7a.m.-10p.m.) and nighttime (10p.m.-7a.m.) periods. RESULTS: Data from 103 participants were available. More than half of them were taking antihypertensive drugs. Nocturnal BP was lower (systolic BP: 2.08±4.50mmHg; diastolic BP: 1.84±2.99mmHg, P<0.05) and dipping was more marked (systolic BP: 1.54±3.76%; diastolic BP: 2.27±3.48%, P<0.05) when nighttime was defined with the actigraph. Standing BP was higher (systolic BP 1.07±2.81mmHg; diastolic BP: 1.34±2.50mmHg) than daytime BP defined by a fixed period. CONCLUSION: Diurnal BP, nocturnal BP and dipping are influenced by the definition of daytime and nighttime periods. Studies evaluating the prognostic value of each method are needed to clarify which definition should be used.

Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.

CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk. OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs). DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes. DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events. DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status. CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis.

OBJECTIVE: The objective was to determine the risk of stroke associated with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels. DATA EXTRACTION AND SYNTHESIS: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations. CONCLUSIONS: Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.

Extending the roughness of the data via transitive closures of similarity indexes

One main assumption in the theory of rough sets applied to information tables is that the elements that exhibit the same information are indiscernible (similar) and form blocks that can be understood as elementary granules of knowledge about the universe. We propose a variant of this concept defining a measure of similarity between the elements of the universe in order to consider that two objects can be indiscernible even though they do not share all the attribute values because the knowledge is partial or uncertain. The set of similarities define a matrix of a fuzzy relation satisfying reflexivity and symmetry but transitivity thus a partition of the universe is not attained. This problem can be solved calculating its transitive closure what ensure a partition for each level belonging to the unit interval [0,1]. This procedure allows generalizing the theory of rough sets depending on the minimum level of similarity accepted. This new point of view increases the rough character of the data because increases the set of indiscernible objects. Finally, we apply our results to a not real application to be capable to remark the differences and the improvements between this methodology and the classical one

Spatial statistics applied to soybean production data from Paraná State for 2003-04 to 2009-10 crop-years

In the current study, we performed a soybean production spatial distribution analysis in Paraná State. Seven crop-year data, from 2003-04 to 2009-10, obtained from the Paraná Department of Agriculture and Supply (SEAB) were used to develop a Boxmap for each crop-year, show soybean production throughout this time interval. Moran's index was used to measure spatial autocorrelation among municipalities at an aggregate level, while LISA index local correlation. For each index, different contiguity matrix and order were used and there was a significance level study. As a result, we have showed spatial relationship among cities regarding the production, which allowed the indication of high and low production clusters. Finally, identifying main soybean-producing cities, what may provide supply chain members with information to strengthen the crop production in Paraná.

Effects of continuous vs interval exercise training on oxygen uptake efficiency slope in patients with coronary artery disease

The oxygen uptake efficiency slope (OUES) is a submaximal index incorporating cardiovascular, peripheral, and pulmonary factors that determine the ventilatory response to exercise. The purpose of this study was to evaluate the effects of continuous exercise training and interval exercise training on the OUES in patients with coronary artery disease. Thirty-five patients (59.3±1.8 years old; 28 men, 7 women) with coronary artery disease were randomly divided into two groups: continuous exercise training (n=18) and interval exercise training (n=17). All patients performed graded exercise tests with respiratory gas analysis before and 3 months after the exercise-training program to determine ventilatory anaerobic threshold (VAT), respiratory compensation point, and peak oxygen consumption (peak VO2). The OUES was assessed based on data from the second minute of exercise until exhaustion by calculating the slope of the linear relation between oxygen uptake and the logarithm of total ventilation. After the interventions, both groups showed increased aerobic fitness (P<0.05). In addition, both the continuous exercise and interval exercise training groups demonstrated an increase in OUES (P<0.05). Significant associations were observed in both groups: 1) continuous exercise training (OUES and peak VO2 r=0.57; OUES and VO2 VAT r=0.57); 2) interval exercise training (OUES and peak VO2 r=0.80; OUES and VO2 VAT r=0.67). Continuous and interval exercise training resulted in a similar increase in OUES among patients with coronary artery disease. These findings suggest that improvements in OUES among CAD patients after aerobic exercise training may be dependent on peripheral and central mechanisms.

Multichannel Remote Data Acquisition and Analysing Systems For Fisheries / Environmental Investigations

Remote Data acquisition and analysing systems developed for fisheries and related environmental studies have been reported. It consists of three units. The first one namely multichannel remote data acquisition system is installed at the remote place powered by a rechargeable battery. It acquires and stores the 16 channel environmental data on a battery backed up RAM. The second unit called the Field data analyser is used for insitue display and analysis of the data stored in the backed up RAM. The third unit namely Laboratory data analyser is an IBM compatible PC based unit for detailed analysis and interpretation of the data after bringing the RAM unit to the laboratory. The data collected using the system has been analysed and presented in the form of a graph. The system timer operated at negligibly low current, switches on the power to the entire remote operated system at prefixed time interval of 2 hours.Data storage at remote site on low power battery backedupRAM and retrieval and analysis of data using PC are the special i ty of the system. The remote operated system takes about 7 seconds including the 5 second stabilization time to acquire and store data and is very ideal for remote operation on rechargeable bat tery. The system can store 16 channel data scanned at 2 hour interval for 10 days on 2K backed up RAM with memory expansion facility for 8K RAM.

Revisiting the compositional data. Some fundamental questions and new prospects in Archaeometry and Archaeology

In this paper we examine the problem of compositional data from a different starting point. Chemical compositional data, as used in provenance studies on archaeological materials, will be approached from the measurement theory. The results will show, in a very intuitive way that chemical data can only be treated by using the approach developed for compositional data. It will be shown that compositional data analysis is a particular case in projective geometry, when the projective coordinates are in the positive orthant, and they have the properties of logarithmic interval metrics. Moreover, it will be shown that this approach can be extended to a very large number of applications, including shape analysis. This will be exemplified with a case study in architecture of Early Christian churches dated back to the 5th-7th centuries AD

Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: Retrospective pooled analysis of trial data

Objectives To determine the effect of human papillomavirus (HPV) quadrivalent vaccine on the risk of developing subsequent disease after an excisional procedure for cervical intraepithelial neoplasia or diagnosis of genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia. Design Retrospective analysis of data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants Among 17 622 women aged 15–26 years who underwent 1:1 randomisation to vaccine or placebo, 2054 received cervical surgery or were diagnosed with genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia. Intervention Three doses of quadrivalent HPV vaccine or placebo at day 1, month 2, and month 6. Main outcome measures Incidence of HPV related disease from 60 days after treatment or diagnosis, expressed as the number of women with an end point per 100 person years at risk. Results A total of 587 vaccine and 763 placebo recipients underwent cervical surgery. The incidence of any subsequent HPV related disease was 6.6 and 12.2 in vaccine and placebo recipients respectively (46.2% reduction (95% confidence interval 22.5% to 63.2%) with vaccination). Vaccination was associated with a significant reduction in risk of any subsequent high grade disease of the cervix by 64.9% (20.1% to 86.3%). A total of 229 vaccine recipients and 475 placebo recipients were diagnosed with genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia, and the incidence of any subsequent HPV related disease was 20.1 and 31.0 in vaccine and placebo recipients respectively (35.2% reduction (13.8% to 51.8%)). Conclusions Previous vaccination with quadrivalent HPV vaccine among women who had surgical treatment for HPV related disease significantly reduced the incidence of subsequent HPV related disease, including high grade disease.

Variograms of ancillary data to aid sampling for soil surveys

To provide reliable estimates for mapping soil properties for precision agriculture requires intensive sampling and costly laboratory analyses. If the spatial structure of ancillary data, such as yield, digital information from aerial photographs, and soil electrical conductivity (EC) measurements, relates to that of soil properties they could be used to guide the sampling intensity for soil surveys. Variograins of permanent soil properties at two study sites on different parent materials were compared with each other and with those for ancillary data. The ranges of spatial dependence identified by the variograms of both sets of properties are of similar orders of magnitude for each study site, Maps of the ancillary data appear to show similar patterns of variation and these seem to relate to those of the permanent properties of the soil. Correlation analysis has confirmed these relations. Maps of kriged estimates from sub-sampled data and the original variograrns showed that the main patterns of variation were preserved when a sampling interval of less than half the average variogram range of ancillary data was used. Digital data from aerial photographs for different years and EC appear to show a more consistent relation with the soil properties than does yield. Aerial photographs, in particular those of bare soil, seem to be the most useful ancillary data and they are often cheaper to obtain than yield and EC data.

Determining nugget: sill ratios of standardized variograms from aerial photographs to krige sparse soil data

Maps of kriged soil properties for precision agriculture are often based on a variogram estimated from too few data because the costs of sampling and analysis are often prohibitive. If the variogram has been computed by the usual method of moments, it is likely to be unstable when there are fewer than 100 data. The scale of variation in soil properties should be investigated prior to sampling by computing a variogram from ancillary data, such as an aerial photograph of the bare soil. If the sampling interval suggested by this is large in relation to the size of the field there will be too few data to estimate a reliable variogram for kriging. Standardized variograms from aerial photographs can be used with standardized soil data that are sparse, provided the data are spatially structured and the nugget:sill ratio is similar to that of a reliable variogram of the property. The problem remains of how to set this ratio in the absence of an accurate variogram. Several methods of estimating the nugget:sill ratio for selected soil properties are proposed and evaluated. Standardized variograms with nugget:sill ratios set by these methods are more similar to those computed from intensive soil data than are variograms computed from sparse soil data. The results of cross-validation and mapping show that the standardized variograms provide more accurate estimates, and preserve the main patterns of variation better than those computed from sparse data.

Excess open solar magnetic flux from satellite data: 1. Analysis of the third perihelion Ulysses pass

We use the third perihelion pass by the Ulysses spacecraft to illustrate and investigate the “flux excess” effect, whereby open solar flux estimates from spacecraft increase with increasing heliocentric distance. We analyze the potential effects of small-scale structure in the heliospheric field (giving fluctuations in the radial component on timescales smaller than 1 h) and kinematic time-of-flight effects of longitudinal structure in the solar wind flow. We show that the flux excess is explained by neither very small-scale structure (timescales < 1 h) nor by the kinematic “bunching effect” on spacecraft sampling. The observed flux excesses is, however, well explained by the kinematic effect of larger-scale (>1 day) solar wind speed variations on the frozen-in heliospheric field. We show that averaging over an interval T (that is long enough to eliminate structure originating in the heliosphere yet small enough to avoid cancelling opposite polarity radial field that originates from genuine sector structure in the coronal source field) is only an approximately valid way of allowing for these effects and does not adequately explain or account for differences between the streamer belt and the polar coronal holes.

Donepezil for the symptomatic treatment of patients with mild to moderate Alzheimer's disease: a meta-analysis of individual patient data from randomised controlled trials

Background: The objective was to evaluate the efficacy and tolerability of donepezil (5 and 10 mg/day) compared with placebo in alleviating manifestations of mild to moderate Alzheimer's disease (AD). Method: A systematic review of individual patient data from Phase II and III double-blind, randomised, placebo-controlled studies of up to 24 weeks and completed by 20 December 1999. The main outcome measures were the ADAS-cog, the CIBIC-plus, and reports of adverse events. Results: A total of 2376 patients from ten trials were randomised to either donepezil 5 mg/day (n = 821), 10 mg/day (n = 662) or placebo (n = 893). Cognitive performance was better in patients receiving donepezil than in patients receiving placebo. At 12 weeks the differences in ADAS-cog scores were 5 mg/day-placebo: - 2.1 [95% confidence interval (CI), - 2.6 to - 1.6; p < 0.001], 10 mg/day-placebo: - 2.5 ( - 3.1 to - 2.0; p < 0.001). The corresponding results at 24 weeks were - 2.0 ( - 2.7 to - 1.3; p < 0.001) and - 3.1 ( - 3.9 to - 2.4; p < 0.001). The difference between the 5 and 10 mg/day doses was significant at 24 weeks (p = 0.005). The odds ratios (OR) of improvement on the CIBIC-plus at 12 weeks were: 5 mg/day-placebo 1.8 (1.5 to 2.1; p < 0.001), 10 mg/day-placebo 1.9 (1.5 to 2.4; p < 0.001). The corresponding values at 24 weeks were 1.9 (1.5 to 2.4; p = 0.001) and 2.1 (1.6 to 2.8; p < 0.001). Donepezil was well tolerated; adverse events were cholinergic in nature and generally of mild severity and brief in duration. Conclusion: Donepezil (5 and 10 mg/day) provides meaningful benefits in alleviating deficits in cognitive and clinician-rated global function in AD patients relative to placebo. Increased improvements in cognition were indicated for the higher dose. Copyright © 2004 John Wiley & Sons, Ltd.