Non-concordance with medication remains a major public health problem that imposes a considerable financial burden on the health care system, and there is still a need for studies on correlates of non-concordance. Our first aim is to analyse whether any of the individual characteristics age, educational level, financial strain, self-rated health, social participation, and trust in the health care system are associated with primary non-concordance with medication. Our second aim is to investigate whether people living in the same area have similar probability of primary non-concordance with medication, that relates to area social participation.We analysed cross sectional data from 9 070 women and 6 795 men aged 18 to 79 years, living in 78 areas in central Sweden, who participated in the Life & Health year 2000 survey, with multilevel logistic regression .Younger age, financial strain, low self-rated health, and low trust in the health care system were associated with primary non-concordance with medication. However, area social participation was not related to primary non-concordance, and the variation in primary non-concordance between the areas was small.Our results indicate that people in central Sweden with younger age, financial difficulties, low self-rated health, and low trust in the health care system may have a higher probability of primary non-concordance with medication. However, the area of residence – as defined by administrative boundaries – seems to play a minor role for primary non-concordance. Patients' concordance with medication is a prerequisite for effective drug therapy. Non-concordance is a major public health problem that imposes a considerable financial burden on the health care system ,2. DespiThe term concordance implies agreement, trust, and harmony between patient and doctor regarding treatment, and acknowledges the patient as a decision maker, and a cornerstone is professional empathy ,5. The mPatient non-concordance with medication may be divided into primary non-concordance, where the patient does not redeem the prescription, and secondary non-concordance, where the patient does not take the medication as prescribed ,6. Most Individual characteristics, such as age, educational level, self-rated health, and social support have been discussed as correlates of concordance, however, the results are inconsistent -3,17,18.Individual social participation describes how actively a person takes part in activities, groups, and associations, and social participation has been associated with health-related behaviours, such as smoking cessation  and physThe area level of social participation has been considered as a structural component within the concept of social capital ,25, whicBecause of our contextual approach in this study, we used multilevel analysis, which handles information on both people and context simultaneously within the same model , and we The first aim of this study is to analyse whether any of the individual characteristics age, educational level, financial strain, self-rated health, social participation, and trust in the health care system are associated with primary non-concordance with medication. The second aim is to investigate whether people living in the same area have similar probability of primary non-concordance with medication, that relates to area social participation.We used data from the Life & Health year 2000 survey , a postaThe areas in this study correspond to municipalities, except for Uppsala, Västerås, and Örebro (the three largest cities in the sample region), which were divided into ten, eight, and five smaller urban areas, respectively. In total, there were 78 areas.Primary non-concordance with medication (dichotomous) was assessed by the question "During the last 3 months, have you received a prescription for medicine, but not redeemed the medicine?"The correlates of non-concordance were selected by reviewing the literature and grouped into a) social and economic factors and b) Health care system and area factors, as suggested by the World Health Organization (WHO) .Age was categorized into four groups: 18–34 years, 35–49 years, 50–64 years, and 65–79 years (used as reference category).Educational level was dichotomised into ≥9 years of education   and >9 years [>9 years .Financial strain was assessed by a negative answer to the question, "Would you manage to raise 18 000 SEK (about 1900 Euro) in 1 week?" (dichotomous).Self-rated health was assessed by the question "How do you rate your general health status?" and dichotomised into "neither good nor bad/bad/very bad health"  and "good/very good health" [ health" .Individual social participation was defined by active membership [mbership  in a labTrust in the health care system was assessed by the question "How much do you trust the following institutions in society?" and for "The health care system" indicating "not particularly high trust/no trust/have no opinion"  and "very high trust/fairly high trust" (dichotomous).Area low social participation was based on a larger sample from the Life & Health year 2000 survey (20 715 women and 18 190 men), and was estimated by the proportion of participants in the area who were classified as having low social participation [cipation ,30,37. AWe used multilevel logistic regression analysis  with indIn Model i (empty model), we did not include any explanatory variables. In Model ii, we included only the individual variables, i.e., age, education, financial strain, self-rated health, social participation, and trust in the health care system. In Model iii, we added area low social participation, because we wanted to investigate the influence of area low social participation on primary non-concordance with medication, after adjustment for the individual  variables.The results are shown as odds ratios (ORs) with 95 % confidence intervals (CIs).We examined whether the area of residence had a general contextual effect on individual primary non-concordance. In other words, we wanted to establish whether individuals living in the same area shared a similar probability of primary non-concordance, after adjusting for the individual characteristics studied. This hypothesized contextual phenomenon  was measThe IOR considers the magnitude of the difference between the areas regarding primary non-concordance when interpreting the influence of area variables. It has been suggested to report the IOR as an 80% interval, and also, the IOR is not an ordinary confidence interval. If the IOR contains 1, the remaining unexplained difference between the areas regarding primary non-concordance is large compared with the effect of the area variable. However, if the IOR does not contain 1, the effect of the area variable is large compared with the unexplained difference between the areas.The MLwiN software, version 2.0 , was useThe prevalence of primary non-concordance with medication was 7.6% (range across the 78 areas: 2%–14%) for women and 6.5% (range across the 78 areas: 0%–15%) for men in the study sample. Financial strain and low social participation were more frequent among women than among men  number of participants in the areas was 115 (102–126) women and 86 (72–94) men. Area low social participation ranged from 45% to 63%.women = 1.87 (95% CI 1.58–2.22) and ORmen = 2.24 (95% CI 1.82–2.75)). Also low self-rated health (ORwomen = 1.38 (95% CI 1.16–1.63) and ORmen = 1.58 (95% CI 1.28–1.95)) was associated with primary non-concordance. The lower DIC value in Model ii indicated a better fit than in Model i (the empty model).In Model ii, the association between age and primary non-concordance with medication was inversed table  and 3. Mwomen = 1.33 (95% CI 1.12–1.58) and ORmen = 1.37 (95% CI 1.11–1.69)) was related to primary non-concordance.In Model ii, low trust in the health care system  declare that they have no competing interests.KJ and JM developed the original idea, participated in the design of the study, performed the statistical analyses, and drafted the manuscript. ML and JS participated in the design of the study and revised the manuscript. CE participated in the design of the study, helped to collect the data, and revised the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Studies on the effects of (-)-hydroxycitric acid (HCA) in humans are controversial. As differences in the HCA preparations may contribute to this apparent discrepancy, the aim of the current study is to compare different HCA-containing preparations in adult Wistar rats.The effects of 3 different HCA-containing preparations  on food intake and body weight were studied in adult male Wistar rats. The efficacy was tested under 2 different experimental conditions: 1) after a single dose administration and 2) during repeated administration for 4 subsequent days.Regulator and Citrin K significantly reduced food intake in both experimental setups, while Super CitriMax HCA-600-SXS was less effective. When administered for 4 subsequent days Regulator and Citrin K diminished body weight gain.Regulator and Citrin K were shown to be potent inhibitors of food intake in rats, whereas Super CitriMax HCA-600-SXS showed only small and more inconsistent effects. The striking differences in efficacy between these 3 preparations indicate that low doses of a relatively low-effective HCA preparation may have contributed to the lack of efficacy as found in several human studies. However, studies on the effects of HCA in humans are controversial. Four placebo-controlled studies support the efficacy of HCA in man. In these studies, HCA administration led to increased loss of body weight and appetite reduction ,2, decreSeveral factors may contribute to these inconclusive results of the human studies on the efficacy of HCA. First, the doses used in the human studies are highly variable, typically ranging from 5 – 40 mg/kg HCA per day whereas in one trial a dose as high as 250 mg/kg was used . Second,To obtain some insight into the difference in efficacy of commercially available HCA preparations, we studied the effects of three different HCA preparations on voluntary food intake and body weight in conscious rats. The product names of these preparations were: Regulator, Citrin K and Super CitriMax HCA-600-SXS (abbreviated as CitriMax), respectively.ad libitum unless mentioned otherwise.All experimental protocols were approved by the Animal Experiments Ethical Committee DEC-Consult, Bilthoven, the Netherlands. Male Wistar rats  aged 3 months and weighing 290–320 gram at arrival were used. The rats were kept at 20 ± 1°C, with lights on from 23.00 h (ZT 0.00) until 11.00 h (ZT 12.00), and with water and RMH-B standard lab chow, containing (w/w) 24% protein, 52% carbohydrates and 6% fat  The rats received a permanent silicone cannula  in the stomach under Isoflurane/oxygen/nitrogen oxide anesthesia according to the method described by Strubbe et al. . This waGarcinia cambogia, which contains 50% HCA , with potassium as its primary mineral (28 g/100 g) and (3) Super CitriMax HCA-600-SXS (abbreviated as CitriMax), an extract of Garcinia cambogia, which contains 60% HCA , containing K+ (15 g/100 g) and Ca2+ (11 g/100 g). To test whether the effects are specific to HCA, its structural analogue (4) tri-potassium citrate  was used for comparison.The following preparations were used: (1) Regulator, a synthetic produced product, which contains 97% of a tri-potassium salt of HCA , (2) Citrin K, an extract of At a concentration of 75 mg HCA/ml demineralized water, the osmotic values of all preparations were 0.545 mOsm/l for Regulator, 0.507 mOsm/l for Citrin K, 0.265 mOsm/l for CitriMax and 0.490 mOsm/l for an equimolar solution of tri-potassium citrate in demineralized water.Two types of experiments were performed to study the potential differences in efficacy between the different HCA preparations. The first series of experiments focused on the effect of one single administration of each preparation on food and water intake for the following 46 hrs in a 4 days placebo-controlled crossover experiment. In the second series of experiments, HCA was given twice a day for 4 days to study effects of repeated doses of the component on food and water intake. In both studies, rats were housed individually in cages in which food and water intake was monitored online .4 groups of 6 animals were used; within each group 2 single experiments were done. Each single experiment lasted for 4 days (96 hours). On day 1, food was removed 2 hours before dark onset (ZT 10.00). At ZT 11.30 randomly assigned rats received either a single bolus of the test component  or a single bolus of isovolumic amount of water alone through the gastric cannula. At ZT 12.00 food was returned, and food and drink intake were monitored at 1, 2, 3, 4, 5, 6, 12, 24 and 46 hrs after administration. This period of 46 hrs was a washout period at the same time. On day 3 the protocol of day 1 was repeated. The rats that received the component on day 1 now receive vehicle and vice versa. Body weight was registered daily. In this way each dose of each HCA preparation was tested with regard to it's own vehicle treatment in a crossover experiment.Each HCA preparation was tested, in a group of 6 animals, at two doses corresponding to 150 and 300 mg HCA/kg body weight. Thus, three groups of 6 animals were used to test Regulator at doses of 155 and 310 mg/kg, Citrin K at 300 and 600 mg/kg and CitriMax at 250 and 500 mg/kg, respectively. In the fourth group of 6 animals tri-potassium citrate, first, was tested at a dose of 475 mg per kg body weight (corresponding to the molarity of 300 mg/kg HCA) in comparison with vehicle treatment. Second, tri-potassium citrate (475 mg/kg) was tested in comparison with Regulator (310 mg/kg).To study the effects of long-term administration of the different HCA preparations, HCA or vehicle was administered intragastric twice daily for 4 subsequent days (at ZT 11.30 and ZT 17.00). Body weight and food intake were monitored during the 4 days of ig HCA-administration and the 3 days thereafter at ZT 10.00.For logistic reasons, the long term studies were performed in two subsequent series of experiments. In the first set of experiments  vehicle, Regulator and CitriMax and in the second set  vehicle, Regulator and Citrin K were tested. All tested doses corresponded to the dose of 300 mg HCA/kg body weight.In the single administration experiments, food intake were analyzed for the crossover experiments by a four-way ANOVA test with the factors, group of treatment order, animals within group, period and type of vehicle treatment, all per HCA preparation. First, the difference between time period and beginning was analyzed to test the possibility of a carryover effect. Because of the absence of a carryover effect, the type of vehicle treatment effects can be tested in the crossover experiment.To compare the food intake results of the different HCA preparations in the single administration experiments, the delta (= difference) between treatment and vehicle on t = 24 hrs was calculated. To make comparisons between the HCA preparations, these deltas were analyzed using a two independent sample t-test with equal variances.In the single administration experiments, bodyweight and water intake were also analyzed for the crossover experiments by a four-way ANOVA test, per HCA preparation.In the repeated-administration experiments, the effects of HCA treatment on food intake, water intake and body weight were analyzed by a one-way ANOVA test. P values less than 0.05 were regarded significant. Data are presented as mean ± SEM.Cumulative food intake was significantly reduced after intragastric administration of 310 mg/kg Regulator figure . CitriMaTo enable comparison between the effects of the different HCA treatments, the difference between 24 hrs cumulative food intake after component treatment and after vehicle treatment was calculated for each HCA source .The effects of repeated administration of the high doses of the three preparations on food intake were comparable to the data of the single bolus experiments. Both Regulator and Citrin K significantly reduced cumulative food intake at days 1–4, whereas CitriMax did not reduce food intake figure  and 6. TRegulator resulted in a significantly lower gain of body weight compared to vehicle at day 2 and 4. Citrin K significantly reduced gain of body weight compared to vehicle at day 1, 2 and 4 (data not shown).This study shows that three commercially available HCA preparations exert striking differences in efficacy in inhibiting voluntary food intake in rats. Regulator and Citrin K were potent suppressants of food intake, both after a single bolus and after repeated administration, whereas CitriMax exerted much smaller effects on food intake. Accordingly, repeated administration of Regulator and Citrin K, but not CitriMax, reduced gain of body weight. Many of the peer-reviewed human studies on HCA, which report a lack of efficacy, used a CitriMax preparation as their source ,10,12 atThe results of the current study are in line with earlier observations that HCA reduces food intake in rats -22. MostThe cause of the differences in efficacy between the various HCA preparations remains speculative. In this study, it cannot simply be explained by differences in the relative HCA content of the used preparations. Regulator (97% pure for HCA) was equally effective as Citrin K (50% pure for HCA). Citrin K was more effective than CitriMax (60% pure for HCA). It cannot be excluded that the 40% non-HCA content of CitriMax contains component(s) that interfered with the suppressive effect of HCA on food intake. Alternatively, the extraction method may have resulted in an increased formation of (-)-HCA lactones, which are less potent inhibitors of the citrate cleavage enzyme .It has been suggested that minerals play an important role in regulating the stability, bio-availability or solubility of HCA. In contrast to the two other more effective HCA sources, CitriMax has relatively a high calcium and relatively a low potassium content. Regulator and Citrin K contain negligible amounts of calcium and a relatively high content of potassium. If, as has been suggested, calcium reduces solubility and hinders bio-availability ,24, the The osmolarity of the CitriMax solution was considerably lower than the osmolarity of the more effective Regulator and Citrin K solutions. It has been suggested that osmolarity plays an important role in the regulation of satiety. Ingestion of hypertonic solutions decreased subsequent food intake in pigs . In humaIt should be noted, however, that a decrease in food intake as a result of induction of malaise or discomfort by any of the used HCA sources cannot be excluded. Still, previous studies on the occurrence of conditioned taste aversion after HCA administration concluded that the food intake reducing effects of HCA cannot be solely explained by the induction of discomfort . AccordiIn summary, this study shows that different commercially available HCA preparations show differences in their potency: Regulator and Citrin K are potent inhibitors of food intake in rats, whereas similar doses of CitriMax hardly showed any effect on food intake. As most of the (ineffective) human studies used low dose CitriMax preparations, the present study may indicate that low doses of a relatively low-effective HCA preparation may have contributed to the lack of efficacy in several human studies.The author(s) declare that they have no competing interests.JL: has made substantial contributions to conception and design, acquisition, analysis and interpretation of data and drafted the manuscript.PW: has made substantial contributions to conception and design, acquisition, analysis and interpretation of data and has been involved in revising the article critically.AS: has made substantial contributions to conception and design and has been involved in revising the article critically.AN: has made substantial contributions to conception and design, has been involved in drafting the article and gave final approval of the version to be published.All authors read and approved the final manuscript.


Diseases of the circulatory system (DCS) are the major cause of death inBrazil and worldwide.To correlate the compensated and adjusted mortality rates due to DCS in theRio de Janeiro State municipalities between 1979 and 2010 with the HumanDevelopment Index (HDI) from 1970 onwards.Population and death data were obtained in DATASUS/MS database. Mortalityrates due to ischemic heart diseases (IHD), cerebrovascular diseases (CBVD)and DCS adjusted by using the direct method and compensated for ill-definedcauses. The HDI data were obtained at the Brazilian Institute of AppliedResearch in Economics. The mortality rates and HDI values were correlated byestimating Pearson linear coefficients. The correlation coefficients betweenthe mortality rates of census years 1991, 2000 and 2010 and HDI data ofcensus years 1970, 1980 and 1991 were calculated with discrepancy of twodemographic censuses. The linear regression coefficients were estimated withdisease as the dependent variable and HDI as the independent variable.In recent decades, there was a reduction in mortality due to DCS in all Riode Janeiro State municipalities, mainly because of the decline in mortalitydue to CBVD, which was preceded by an elevation in HDI. There was a strongcorrelation between the socioeconomic indicator and mortality rates.The HDI progression showed a strong correlation with the decline in mortalitydue to DCS, signaling to the relevance of improvements in lifeconditions. That indicator was calculated as the geometric meanof its three components. From 2009 on, there have been changes: the 'education'component began being measured as the mean years of schooling and expected years ofschooling, and the 'economic' component began being measured as per capitaincome.3The Human Development Index (HDI), a measure of long and healthy life, access toeducation and standard of living, comprises three main pillars, health, educationand income. The HDI was developed in 1990 by two economists, the Pakistani Mahbub ulHaq and the Indian Amartya Sen, aimed at being a general and concise measure ofhuman development.4 In 2003 and2013, new reports were published with data from the 2000 and 2010 censuses,respectively. That indicator comprises the Atlas of Brazilian HumanDevelopment,5 organized andmade available by three institutions, the United Nations Development Programme(UNDP),1 the BrazilianInstitute of Applied Research in Economics (IPEA),6 and the João Pinheiro Foundation.7In Brazil, the HDI data of the municipalities were first published in 1998retrospectively based on data of the 1970, 1980 and 1991 demographiccensuses.8 The healthconditions of the populations are determined in a complex way by social components,such as income distribution, wealth and level of knowledge.9According to data from 1979 on, the mortality rates due to diseases of thecirculatory system (DCS) and their major subgroups, cerebrovascular diseases (CBVD)and ischemic heart diseases (IHD), showed a progressive reduction in Rio de JaneiroState municipalities.This study aimed at correlating the mortality rates due to DCS, CBVD and IHD with theevolution of HDI in Rio de Janeiro State municipalities.Data on HDI and mortality in Rio de Janeiro State municipalities were collected. TheRio de Janeiro State municipalities were constituted according to the geopoliticalstructure of 1950, grouping together emancipated municipalities from that date onwith their original headquarters. Those aggregations of municipalities implicated ina reduction in the total number of municipalities existing in 2010 in the Rio deJaneiro State, passing from 92 to 56 aggregates for the purpose of this studyanalysis.10In addition, those aggregations of municipalities were grouped into regions proposedby the Rio de Janeiro State Health Secretariat with the dismemberment of themetropolitan region into the Metropolitan Belt, comprising all municipalities in theregion, except for the municipalities of Rio de Janeiro and Niterói, whichbegan constituting two other autonomous regions. The other regions,Middle-Paraíba, Mountain, Northern, Seaside, Northwestern, Southern-Centraland Baía da Ilha Grande are those same defined by the Rio de Janeiro StateHealth Secretariat.6 for the years of the 1970, 1980 and 1991 demographiccensuses. To estimate the HDI of the headquarter municipalities, respecting the Riode Janeiro State geopolitical structure in 1950, arithmetic means weighted bypopulation size of each emancipated municipality were estimated. This can beexemplified as follows: headquarter-municipality HDI = [ + ] /. The population data were retrieved from the Brazilian Institute of Geography andStatistics4 for the yearsof general census  and by counting, and were obtained in theDATASUS-MS site.11The HDI data were obtained from the IPEA site11 Such data were discriminated in the fractions ofmajor interest of the study: DCS, corresponding to the codes listed in chapter VIIof the International Statistical Classification of Diseases and Related HealthProblems, ninth revision (ICD-9), 12 or in chapter IX of ICD-10;13 IHD, corresponding to the codes 410-414 of ICD-9 or I20-I25of ICD-10; CBVD, corresponding to the codes 430-438 of ICD-9 or I60-I69 of ICD-10.In addition, ill-defined causes (IDC) of death were assessed, contemplated inchapter XVI of ICD-9 and chapter XVIII of ICD-10, as was the total number of deathsdue to all causes. The ICD-9 was in effect up to 1995, and ICD-10 has been in effectsince 1996. Raw and adjusted, for sex and age, mortality rates per 100,000inhabitants were calculated by using the direct method.14 Because the mortality rates due to IDC in Rio deJaneiro State have increased significantly since 1990,15 we chose to use compensation, which consisted inadding to the number of declared deaths due to a specific cause a certain number ofdeaths due to IDC, which corresponds to the proportion of specific deaths inrelation to the total of deaths. For example, if 30% of the specified deaths are dueto DCS, 30% of deaths due to IDC are added to those due to DCS. Compensation wasperformed for all years in the series. For the deaths due to DCS, IHD and CBVD, partof the deaths due to IDC were added, corresponding to the fractions observed in thedefined deaths, that is, excluding those due to IDC. After compensating deaths dueto DCS, IHD and CBVD for IDC, mortality rates adjusted for sex and age wereestimated. The standard population for the adjustments was that of Rio de JaneiroState counted in the 2000 census, stratified into seven age groups  for each sex. Such rates were denominated compensated and adjusted. Themortality rates for the 1991 and 2000 census years were calculated by use of 3-yearmoving means and 2-year moving means for the year 2010.The mortality rates derived from the analysis of the death data of adults aged atleast 20 years and were obtained in the DATASUS-MS site.16 of DCS, CBVDor IHD with HDI figures with discrepancy of two demographic censuses was calculated.In addition, we estimated the linear regression coefficients and R2 ofthe linear regression models with DCS, CBVD or IHD as dependent variables and HDI asindependent variable, the latter with 0.1 units. We chose to consider thediscrepancy of two demographic censuses based on the results of a previous study, inwhich mortality rates were correlated with pcGDP, and the optimal temporaldiscrepancy between the mortality rates and the socioeconomic indicator was, onaverage, close to 20 years; therefore, a similar discrepancy was adopted for thisstudy.Dispersion graphs were built with the mortality rates due to DCS, IHD and CBVD asordinates, and the HDI figures as abscissae, with discrepancy of two demographiccensuses. The mortality rates of the years 1991, 2000 and 2010 were related to theHDI figures of the years 1970, 1980 and 1991, respectively. In addition, the Pearsoncorrelation17 and STATA18 programs.Quantitative procedures were performed with Excel-MicrosoftAll municipalities had a reduction in the mortality rates due to DCS, CBVD and IHDwhen comparing the initial rates (1991) with those in 2010 , 2 and 32 value, which explains how much of thevariability of mortality can be caused by the HDI, was higher for CBVD (0.20),followed by DCS (0.15) and IHD (0.05). In addition, There is a negative correlation of mortality rates with HDI figures, the HDI increaserelating to a reduction in the mortality rates due to those three causes analyzed.The correlation coefficient between the mortality rates and HDI, when calculatedwith the total set of municipalities , was cloThis study showed that the reduction in the mortality rates due to DCS, CBVD and IHDin the Rio de Janeiro State in the past decades was preceded by an increase in HDI,with significant numbers, because a 0.1 increment in HDI correlated with thefollowing reductions in the number of deaths per 100,000 inhabitants: 53.5 for DCS;30.2 for CBVD; and 10.0 for IHD.Although the values of the correlation coefficients were not very close to theminimum extreme limit, in the individualized analysis of the municipalities, andregarding DCS, 47 municipalities showed correlation coefficient with HDI lower than-0.7, and only 9 municipalities had it higher than -0.7: Bom Jardim, Itaocara, SantaMaria Madalena, Sumidouro, São Fidélis, São João daBarra, São Sebastião do Alto, Trajano de Morais and Três Rios.Regarding CBVD, 11 of the 56 municipalities had correlation coefficients with HDIhigher than -0.7: Bom Jardim, Cambuci, Itaocara, Santa Maria Madalena, Sapucaia,Sumidouro, São Fidelis, São João da Barra, SãoSebastião do Alto, Trajano de Morais and Três Rios. Regarding IHD, 10municipalities had correlation coefficients with HDI higher than -0.7: Bom Jardim,Itaocara, Miracema, Porciúncula, Santa Maria Madalena, Sumidouro, SãoFidélis, São Sebastião do Alto, Trajano de Morais andTrês Rios. Of the total, only 8 municipalities  had correlation coefficients higherthan -0.7 for the three groups of causes of death .All municipalities with correlation coefficients between mortality rates and HDIgreater than -0.7 have small populations, less than 40,000 inhabitants in 2000,except for São João da Barra and Três Rios, which had less than100,000 inhabitants. Together, their population does not add up to 10% of that ofthe Rio de Janeiro State.20 mainly areduction in the deaths due to DCS.21During the 20th century, mainly after World War II, all developed countries, and alittle later, the developing countries, showed improvement in their socioeconomicindicators, followed by a decline in mortality rates,23 infectious diseases24 and CBVD,25 or even HDI to be a predictor forother indicators, such as child and maternal mortalities.26 Thus, HDI elevations are related to a reduction inthe number of deaths due to several causes. Even general mortality relates directlyto HDI, because, one component of that indicator is life expectancy at birth, thus,if there is a reduction in the number of deaths due to any cause, there is HDIincrease.Several studies have shown an inverse correlation of HDI with mortality due toneoplasms,21 The Rio deJaneiro State municipalities have heterogeneous HDI figures: in 1970, somemunicipalities, such as Duas Barras, Parati, Rio Claro and Silva Jardim, had HDIclose to 0.4, comparable to that of Ethiopia and Mozambique. Other municipalities,such as Rio de Janeiro, Niterói and Resende, had much higher HDI, closer tothat of Scandinavian countries.2Several municipalities that began the series with low HDI figures showed HDIelevations in the following years of census, and a progressive reduction incardiovascular mortality, showing that not only HDI figures, but its progressiveimprovement, relate to a reduction in mortality rates.Socioeconomic improvements preceded the decline in mortality due to cardiovasculardiseases, which account for almost half of the deaths due to endogenous causes inadults.3 This study used only the HDI valuescalculated for the 1970, 1980 and 1991 census years, because such figures werehomogeneous regarding the calculation method. From the year 2000 onwards, othercalculation methods began to be used for the estimations, with changes in the HDIcomponents; therefore, they were not used in this study. Other limitation relates tothe fact that some municipalities had small populations, less than 40,000inhabitants, being subject to significant oscillations regarding the annualoccurrence of any low-frequency event, such as death. In an attempt to minimize thatoccurrence, the mortality rates were calculated by using 3-year moving means for allaggregations of municipalities. Other limitations derive from the use of mortalitydata subject to the influence of factors such as improper completion of deathcertificates and the compensation maneuver for IDC, which might have underestimatedor overestimated the deaths due to defined causes.The main limitation of this study relates to the availability of HDI figures formunicipalities only from the census years of 1970 onward. That is compounded by thefact that those figures were calculated retrospectively for all years, and there wasa change in the calculation method from the year 2009 onward.In recent decades, there was a significant reduction in the mortality rates of Rio deJaneiro State municipalities due to DCS, especially CBVD, and that reduction waspreceded by periods of elevation in HDI. This shows the important correlation of HDIwith the reduction in those mortality rates, signaling to the relevance ofimprovements in life conditions.


Although numerous population-based studies have reported the prevalences and risk factors for pterygium, information regarding the incidence of pterygium is scarce. This population-based cohort study aimed to evaluate the South Korean incidence and prevalence of pterygium. We retrospectively obtained data from a nationally representative sample of 1,116,364 South Koreans in the Korea National Health Insurance Service National Sample Cohort (NHIS-NSC). The associated sociodemographic factors were evaluated using multivariable Cox regression analysis, and the hazard ratios and confidence intervals were calculated. Pterygium was defined based on the Korean Classification of Diseases code, and surgically removed pterygium was defined as cases that required surgical removal. We identified 21,465 pterygium cases and 8,338 surgically removed pterygium cases during the study period. The overall incidences were 2.1 per 1,000 person-years for pterygium and 0.8 per 1,000 person-years for surgically removed pterygium. Among subjects who were ≥40 years old, the incidences were 4.3 per 1,000 person-years for pterygium and 1.7 per 1,000 person-years for surgically removed pterygium. The overall prevalences were 1.9% for pterygium and 0.6% for surgically removed pterygium, and the prevalences increased to 3.8% for pterygium and 1.4% for surgically removed pterygium among subjects who were ≥40 years old. The incidences of pterygium decreased according to year. The incidence and prevalence of pterygium were highest among 60–79-year-old individuals. Increasing age, female sex, and living in a relatively rural area were associated with increased risks of pterygium and surgically removed pterygium in the multivariable Cox regression analysis. Our analyses of South Korean national insurance claims data revealed a decreasing trend in the incidence of pterygium during the study period. Pterygium is an abnormal overgrowth of the bulbar conjunctiva, and severe pterygium can cause astigmatism and visual disturbance , 2. PterThis study adhered to the tenets of the Declaration of Helsinki, and the requirement for written informed consent was waived because of the retrospective design. This study’s design was approved by the institutional review board of the NHIS Ilsan Hospital .A detailed profile of the NHIS-NSC 2002–2013 cohort has been previously published . A natioCases of pterygium were defined based on an ophthalmologist examination and claim by the Korean Classification of Diseases code for pterygium . Incident pterygium was defined based on the patient’s first diagnosis of pterygium, rather than a specific diagnosis involving the right and/or the left eye. Surgically removed pterygium was defined as patient cases with pterygium that required surgical removal more than once during the study period, based on the Korean Electronic Data Interchange codes (S5341 and S5342). The incident time of surgically removed pterygium was defined as the first diagnosis of pterygium.The sociodemographic factors included age , sex, residence , and household incomes. Korean citizens who are covered under NHIS are categorized as insured employees, insured self-employed individuals, and medical aid beneficiaries. Low-income individuals were defined as insured employees or insured self-employed individuals in the first to third income deciles, and medical aid beneficiaries. Middle-income individuals were defined as insured employees or insured self-employed individuals in the fourth to seventh income deciles, and high-income individuals were defined as insured employees or insured self-employed individuals in the eighth to tenth income deciles. All data were collected annually (e.g. a 49-year-old subject belonged to the 40–49 years age group in 2007 and to the 50–59 years age group in 2008).To exclude subjects with chronic pterygium from the incidence calculation, we excluded patients who were diagnosed with pterygium in 2002 and 2003, and we included only patients who were first diagnosed with pterygium after 2003. The first visit to an ophthalmologist for pterygium was defined as the incident time. The annual incidence was calculated as persons who developed pterygium, based on the total at-risk population on January 1 of each year. Individuals without pterygium were followed-up starting on January 1, 2004, and the follow-up ended on the last day that the individual was covered by NHIS. For individuals with pterygium (incident cases), person-years were counted until the incident time. In cases of surgically removed pterygium, the incident time was defined as the first diagnosis of pterygium that was followed by surgical removal during the study period.To include all subjects who had pterygium in the prevalence calculation, we included patients with chronic pterygium and calculated the prevalence from 2004. Annual prevalences were calculated based on the total NHIS-NSC population on January 1 of each year and all new cases that were diagnosed between January 1 and December 31.We calculated the incidences per 1,000 person-years and prevalences (%) per 100 persons with the 95% confidence intervals (CIs). Multivariable Cox proportional hazard regression analysis was performed to identify the risk factors that were associated with pterygium, and the results were expressed as hazard ratios (HRs) and 95% CIs. A two-sided p-value of <0.05 was considered statistically significant. All analyses were performed using Stata/MP software .In the multivariable Cox regression model, the risk factors for pterygium and surgically removed pterygium were increasing age, female sex, living in a relatively rural area, and the middle income level . Fig 1 sIn South Korea, the incidences of pterygium and surgically removed pterygium were 2.1 per 1,000 person-years and 0.8 per 1,000 person-years, respectively. In addition, the overall prevalences of pterygium and surgically removed pterygium were 1.9% and 0.6%, respectively, during 2004–2013. Although the incidences tended to decrease, the prevalences increased over time.Two previous studies have evaluated the incidence of pterygium. The Barbados Eye Study included a predominantly black African Caribbean population  in the West Indies, and revealed an incidence of 11.6% (n = 218) during the 9-year follow-up period [Our group previously reported that the prevalence of pterygium was 8.9% (95% CI: 6.1–7.3%) among Korean subjects who were ≥40 years old, based on a nationwide population-based cross-sectional study  , and a shttp://kostat.go.kr). Moreover, a national survey revealed that vitamin D deficiency was common among Korean wage workers, who were more likely to experience insufficient exposure to sunlight, and that study suggested that vitamin D management should be considered for Korean wage workers [Prevalences may vary according to the definition of pterygium, the use of a chart review or disease codes, and the population structure of the target country. Over the past century, decreasing fertility and mortality have led to the rapid aging of the South Korean population . Therefo workers . Thus, t workers . We alsoPterygium was associated with increasing age, female sex, and living in a relatively rural area. However, our previous cross-sectional study revealed that pterygium tends to occur among elderly men who live in rural areas and have a history of lengthy sun exposure and low education level . MoreoveThe present study’s greatest strength is its large sample size and prolonged follow-up . However, as this study used an insurance database, there are some inevitable limitations. The most important limitation is that pterygium cases were identified using the Korean Classification of Diseases code, which may be less accurate than a medical chart review or cross-sectional evaluation. We were also unable to access important information regarding behavioral risk factors, such as smoking status and sun exposure. In addition, an assessment of the severity and duration of pterygium was not possible. Nevertheless, it is unlikely that a diagnosis of pterygium would be missed if it causes acute visual impairment, as South Korean patients have relatively good access to medical care and tertiary treatment centers . TherefoIn conclusion, the present study evaluated the incidence of pterygium during a 10-year period using a nationwide claims database. Among the total population, the incidences of pterygium and surgically removed pterygium were 2.1 per 1,000 person-years and 0.8 per 1,000 person-years, respectively, and 4.3 per 1,000 person-years and 1.7 per 1,000 person-years among subjects who were ≥40 years old. We also observed a gradually decreasing trend in the incidence , despite the rapidly aging South Korean population. This information may provide insight regarding the incidence, prevalence, and future trends of pterygium in South Korea.S1 Table(PDF)Click here for additional data file.


To describe the clinicopathological characteristics of a series of head and neck rhabdomyosarcoma (RMS) and to review the literature.Cases diagnosed as RMS affecting the head and neck region were retrospectively retrieved from the files of two Brazilian institutions from January 2006 to January 2017. Data on clinical features , microscopic subtype, immunohistochemical results, treatment employed and follow-up status were obtained from the patient’s medical charts.During the period considered, 10 cases of RMS were identified. Females predominated (4M:6F), the mean age at diagnosis was 16.5 years-old and the orbit was the most affected site (4 cases). Microscopically, most cases were classified as embryonal RMS (6 cases) and the Desmin/Myogenin/Myo-D1 immunohistochemical positivity was useful to confirm the diagnosis. Chemotherapy and radiotherapy were applied to 9 and 8 patients respectively, whereas 2 patients were treated by surgery. Recurrences occurred in 3 patients and distant metastasis in 2 cases. Nine patients were alive in their last follow-up, 3 of them with disease, whereas 1 patient died due to the disease.Head and neck RMS is an aggressive malignant neoplasm which demands especial concern to achieve early diagnosis and successful treatment. Key words:Rhabdomyosarcoma, soft tissue tumors, head and neck, oral cavity, chemotherapy.  Rhabdomyosarcoma (RMS) is classified by the World Health Organization as a skeletal muscle tumor arising from undifferentiated skeletal tissue ,2, predoRMS are highly sensitive to chemotherapy and radiotherapy, as a consequence, over the last 30 years pediatric patients had a significant improvement in their prognosis, with the 5-year survival rates achieving 80% to 85% in some series ,8,9. NevIn this study we aim to describe the clinicopathological characteristics of a series of head and neck RMS.All cases diagnosed as RMS affecting the head and neck region were retrospectively retrieved from the files of the Oral Pathology Service of the João de Barros Barreto University Hospital (Belém/Brazil) and from the Pathology Department of the Sírio-Libanês Hospital (São Paulo/Brazil) from January 2006 to January 2017. Data on clinical features , microscopic subtype, immunohistochemical results, treatment employed and follow-up status were obtained from the patient’s medical charts and descriptively presented. This study was approved by the local Ethical Committee.During the 11-year period investigated, 10 cases diagnosed as RMS were identified. The clinical and pathological data of these patients are summarized in All cases were positive for desmin, myogenin and MyoD1 antigens. Pan-cytokeratin AE1/AE3) was expressed in two cases and Ki67 proliferative index was high in all tumors ranging from approximately 70 to over 90% , accounting for 60% of all cases, characterized by undifferentiated, small, round and hypercromatic cells with variable number of strap or tadpole-shaped, eosinophilic rhabdomyoblasts ,20. AlveOther less common variants include the pleomorphic RMS that only rarely occurs in the pediatric group and comprises about 5% of all cases diagnosed ,17; the Significant improvements were achieved in the treatment of RMS over the last decades and multimodality treatment has been established as the recommended therapy for these patients with a combination of chemotherapy, radiation, and surgery. In cases where anatomical location allows total tumor resection, surgery is indicated followed by radiotherapy and chemotherapy. Where free surgical margins are not possible to be obtained, chemotherapy and radiotherapy is applied,18. In oThe most common cause of death is tumor progression and involvement of adjacent structures ,10,12,19Primary location of the disease may significantly influence the patients’ outcome, since parameningeal areas, paranasal sinus, nasal cavity, mastoid area and infratemporal fossa tends to present a poorer prognosis than non-parameningeal cases, which may be consequence of the impossibility to achieve total resection of the neoplasms and due to their proximity to intracranial area ,10. The In conclusion, RMS is an aggressive malignant soft tissue neoplasm that usually affects the head and neck region, including the oral cavity. Recent improvements in the therapeutic approaches significantly increased survival rates, but an early diagnosis is mandatory to achieve the appropriate management of these patients.


Increasing researchers indicate that necroptosis is playing an important role in the regulation of systemic inflammatory response syndrome. The current study was to investigate the prognostic biomarker of the regulated proteins of necroptosis in sepsis patients.p < 0.05), and the RIPK3 levels had positive association with the Sequential Organ Failure Assessment (SOFA) score as well as procalcitonin (PCT) level . The RIPK3 level like the SOFA score and PCT level could be a prognostic biomarker of sepsis patients.One hundred and twenty-four patients were divided into three groups: 43 patients (34.68%) with sepsis, 39 patients (31.45%) with severe sepsis, and 42 patients (33.87%) with septic shock. The RIPK3 levels in the severe sepsis and septic shock groups were notably higher than those in sepsis group at various time points  and receptor interacting protein kinase 3 (RIPK3) levels were determined from measurements taken in a double-blinded fashion at 24, 48, 72, and 120 hours later.These results suggested that dynamic monitoring of RIPK3 levels can contribute to the prediction of outcome of sepsis and might be of particular value in identifying patients who would benefit from specific treatments. Sepsis is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. The incidence of sepsis has yet to be determined, however, it is the most cause of mortality worldwide. For the initial phases of sepsis, early detection, appropriate classification, and suitable treatment have shown to be associated with improved patient outcome in intensive care units (ICUs). Indeed, the optimum timing of intervention seems to be vital and indicates the major determinant of survival for patients with sepsis.In clinical practice, the “gold standard” for diagnosis of sepsis is blood culture. However, it usually has the results delay of about 3 to 7 days, and false negative results occur frequently. In addition, some scoring systems to commonly evaluate organ dysfunction or prognosis in patients with sepsis, such as the Sequential Organ Failure Assessment (SOFA) and the Acute Physiology and Chronic Health Evaluation (APACHE), have not provided sufficient information to determine their accuracy of the prognosis for the severity and mortality of sepsis –3.Recent studies demonstrated that some biomarkers have been investigated for diagnosing and monitoring sepsis, such as C-reactive protein (CRP) and procalcitonin (PCT), however, these biomarkers levels were also detected to be elevated in patients with many noninfectious conditions, for instance, malignant tumors, acute coronary syndromes, severe trauma, burns, rheumatic disorders, or post-surgery, etc. –7. ThereNecrosis has been considered an accidental mode of cell death in cells; however, it has recently been recognized that necroptosis, a programmable form of necrosis, may be regulated via defined signal transduction pathways . For exaThe usage of necroptosis regulated proteins in monitoring response to therapeutic interventions would guide development of novel treatment strategies to patients with sepsis. In the light of the clinical importance of the early treatment strategy for sepsis prior to the onset of clinical deterioration, the current study was to determine the prognostic biomarker of the regulated proteins of necroptosis in sepsis patients.n = 43, 34.7%), severe sepsis , and septic shock  groups.One hundred and thirty-one patients with sepsis, who were admitted to our medical ICU from January 2014 to May 2016, were enrolled. Seven patients were excluded due to receipt of platelet transfusion, acute gastrointestinal hemorrhage, and insufficient data. Finally 124 eligible patients were categorized by severity into sepsis , and trends were remarkably similar for SOFA scores, CRP levels, and PCT among these groups but not RIPK1 levels and WBC counts.At 24 hours after sepsis diagnosed, the plasma RIPK3 and RIPK1 levels were 7.9 (3.2–16.7) pg/mL and 7.1 (2.7–15.6) pg/mL for sepsis patients, 11.3 (1.2–19.2) pg/mL and 8.4 (1.8–14.5) pg/mL for severe sepsis patients, as well as 18.9 (3.6–32.5) pg/mL and 8.9 (2.4–25.1) pg/mL for septic shock patients. The RIPK3 levels in severe sepsis and septic shock group were markedly higher than those in sepsis group at various time points , CRP level , and PCT level . However, the correlation between the RIPK3 level and WBC count was not significant . Based on the collected data, the dynamic changes in these variables indicated that the plasma RIPK3 level was a reliable predictor for patient with sepsis.The correlations between the plasma RIPK3 level and other infection-associated biomarkers were determined. The analysis displayed that the RIPK3 level showed positive correlations with SOFA score  and non-survivor groups . The RIPK3 level, SOFA score, CRP level, and PCT level were assessed by receiver operative characteristic (ROC) curve analysis in the survivor and non-survivor groups. The areas under ROC curves (AUCs) for RIPK3 level, SOFA score, CRP level, and PCT level were 0.813, 0.824, 0.756, and 0.653, respectively. These results indicated that the RIPK3 level for prognostic biomarker of sepsis was similar to that of the SOFA score  and CRP level . However, the RIPK3 for prognostic biomarker was significantly superior to the PCT level , as shown in Table Based on survival on day 28, patients with sepsis were divided into survivor group , and the prognostic biomarker of the plasma RIPK3 level was comparable to that of common infection-related variables such as SOFA score and PCT level. Meanwhile, our study found that the concentration changes of plasma RIPK3 with time was similar to those of CRP levels, PCT levels, and SOFA score to monitor sepsis dynamically and then evaluate the severity of sepsis, which may be used for determining the prognosis of sepsis patients.As always, PCT has been the most studied and promising biomarker of sepsis. Though PCT is superior to CRP and other traditional biomarkers of sepsis in critical practice, it is inaccurate for clinicians to judge clinical conditions –7. Thus,Moreover, among all those patients, RIPK3 levels of non-survivors were remarkably higher than those of survivors. Additionally, plasma RIPK3 levels, APACHE II score, SOFA score, PCT level, and the number of organs exhibiting dysfunction were association with a poor prognosis in sepsis patients. Given the above, we assumed that the RIPK3 levels might be as a valuable factor for determining the prognosis of sepsis.In order to reduce the therapeutic bias, all enrolled patients received standard treatment according to the International Guidelines for Management of Severe Sepsis and Septic Shock . In receThe main limitation of this study was that the different patient populations had various causes of mortality for sepsis, which might have impacted the results. Second, the number of patients was relatively small, and they treated with heterogeneous treatment regimens. In conclusion, our results have some clinical insights that the plasma RIPK3 level may have promising value for the prognostic of sepsis, and its application could be matched by that of the SOFA score and PCT level. The plasma RIPK3 concentration is also helpful to monitor the development and prognosis of sepsis dynamically and accordingly, it has a great potential for therapeutic interventions in clinical practice. Therefore, clinical studies with larger samples sizes are further warranted to confirm the clinical value of RIP3 as a prognostic biomarker in sepsis patients.We prospectively recruited the eligible patients with sepsis, severe sepsis, or septic shock who were treated in our hospital from January 2014 to May 2016. All patients enrolled into study with written informed consent. The protocol of this study was approved by the independent ethics committees at our hospital and according to the ethical guidelines of the Declaration of Helsinki.The definitions of sepsis, severe sepsis, and septic shock were in accordance with the American College of Chest Physician/Society of Critical Care Medicine (ACCP/SCCM) guidelines –20. PatiWe collected peripheral blood samples from patients in different groups and then analyzed data within 24 hours start with the diagnosis of sepsis. Meanwhile, we determined the APACHE II score, SOFA score, CRP level, PCT level, creatinine level, white blood cell (WBC) count, platelet (PLT) count, prothrombin time (PT), RIPK3 level, and RIPK1 level. Besides, we recorded other clinical parameters of each patient as follow: sex, age, primary infection site, microorganism identified, the type of organ dysfunction, and the number of organs affected.All enrolled patients received standard medical care. The routinely included antibiotics treatment, best supportive care treatment, and prevention treatment complication . To evalThe starting time point was defined from the enrolled time of those patients in the study. Venous blood plasma was collected at 24, 48, 72, and 120 hours later in a double-blinded fashion. Plasma RIPK3 and RIPK1 levels were detected with an enzyme-linked immunosorbent assay kit in line with the manufacturer's instructions  as previously described –22.U-test, one-way analysis of variance, a Fisher's exact test, or Chi-squared test were used to compare the data. For the value of RIPK3, SOFA, CFR, and PCT, receiver operating characteristics curve (ROC) was plotted to calculate the area under the curve (AUC) and obtaining best cutoff values for calculating the sensitivities, specificities predictive values and likelihood ratios. A logistic regression model was used to assess the independent factors for the short-term survival rate, and the significant variables in a univariate analysis were included in a multivariate analysis. A p-values < 0.05 was considered to indicate statistical significance. Data were analyzed using the statistical software Intercooled Stata version 8.2 for Windows .All quantitative data were expressed as median and range or mean ± standard deviation (SD). The nonparametric Mann-Whitney


An experiment was conducted under controlled condition to analyse how nitrogen deposition affects the ecophysiological and biochemical traits, and to explore how the nitrogen-induced changes influence the response to O3. For both factors we selected realistic exposures , in order to elucidate the mechanisms implemented by the plants. Nitrogen addition resulted in higher nitrogen concentration at the leaf level in F. ornus, whereas a slight increase was detected in Q. ilex. Nitrogen enhanced the maximum rate of assimilation and ribulose 1,5-bisphosphate regeneration in both species, whereas it influenced the light harvesting complex only in the deciduous F. ornus that was also affected by O3 (reduced assimilation rate and accelerated senescence-related processes). Conversely, Q. ilex developed an avoidance mechanism to cope with O3, confirming a substantial O3 tolerance of this species. Nitrogen seemed to ameliorate the harmful effects of O3 in F. ornus: the hypothesized mechanism of action involved the production of nitrogen oxide as the first antioxidant barrier, followed by enzymatic antioxidant response. In Q. ilex, the interaction was not detected on gas exchange and photosystem functionality; however, in this species, nitrogen might stimulate an alternative antioxidant response such as the emission of volatile organic compounds. Antioxidant enzyme activity was lower in plants treated with both O3 and nitrogen even though reactive oxygen species production did not differ between the treatments.The effects of nitrogen (N) deposition, tropospheric ozone (O Cuvetteal. 1999 . The CO2analysis .L, CL, % dry mass) were determined using the Dumas micro-combustion technique  on the same dried leaf samples used for the calculation of sclerophylly degree . Samples were ground in liquid nitrogen, and five subsamples were weighed using a precision balance  before the analysis. photosynthetic nitrogen-use efficiency (PNUE) was calculated as the ratio of instantaneous PNmax to nitrogen on an area basis.The total leaf nitrogen and carbon concentrations  activity of leaves was assayed by monitoring the decrease in absorbance at 290 nm due to ascorbate oxidation [The superoxide dismutase (SOD) activity was determined using an SOD assay kit WST (Sigma–Aldrich) according to manufacturer’s instructions. The SOD activity (inhibition of activity) was calculated by measuring the decrease in the colour development at 440 nm. Catalase  activity was measured using a commercial CAT assay kit (Sigma–Aldrich) following manufacturer’s protocol. CAT activities were calculated and expressed as a decrease in absorbance at 240 nm due to Hxidation . The conxidation . Brieflyxidation .-2). After petiole exclusion, the leaf area was measured using Image Lab software (http://en.freedownloadman-ager.org/Windows-PC/Image-Lab.html), and after the samples were dried at 80°C to constant weight, the leaf dry weight (g) was measured.The degree of sclerophylly was estimated by assessing the leaf mass area  was analysed using repeated measurement ANOVA with nitrogen and O3 treatments as between-subjects factors. Two-way ANOVA, with nitrogen and O3 as fixed factors, with their interaction factor, was used to analyse the ecophysiological measurements during each sampling date , and to test the differences between treatments on the PN/Ci curve parameters and on the biochemical and structural measurements performed at the end of the experiment. Two-way ANOVA was followed by post hoc Student–Neuman–Keuls test at p < 0.05 when necessary. All analyses were performed using Statistica software, version 7.0 .The effect of time on ecophysiological measurements  affected all the gas exchanges parameters for both species, with the exception of WUE in as noted  for all F. ornus for each sampling date  on DOF 4, lasting with the same order of magnitude through DOF 7 to 10. The interaction significantly affected PN and gs for low or high O3 exposure ; the direction of the interaction remained the same, where the decrease of PN and gs relative to the control was less pronounced in O3N plants than in O3 alone.OQ. ilex nitrogen led to the increase in both PN and gs relative to those in C (from +5% to 15% depending on DOF); however, the variability in the data led to p > 0.05 at each DOF  because of stomatal limitation as indicated by Ci/Ca reduction. The interaction was present on DOF 1, for low O3 exposure (AOT40 254.22 ppb h) only for gs, where the reduction in O3N experimental set was higher than in the O3 set. At DOF 4 and DOF 10, the reduction of PN and gs in O3N was less pronounced than that in O3, even if the interaction effect was not significant , with nitrogen ameliorating the detrimental effect of O3 photosystem functionality , whereas IP-phase and PItot , their ratio, and LMA are shown in The parameters derived from PF. ornus, PNmax increased significantly after nitrogen addition , decreasing in response to O3 (p = 0.058). The main driver of photosynthesis was O3, leading to a reduction of PNmax, Vcmax and Jmax relative to those in C plants. The NL decreased because of O3 fumigation, entailing a significant change in the CL/NL ratio. The interaction between factors significantly affected Jmax: O3 limited the positive effect of nitrogen. In F. ornus, nitrogen did not affect the LMA, whereas this parameter was reduced by O3 . Nitrogen addition resulted in an increase of NL ; however, because of high variability in the data, no significant nitrogen effect (p > 0.05) was detected. However, CL significantly increased in the evergreen species.Interestingly, in 3 caused the reduction in PNUE, because of slight, but not significant (p > 0.05), reduction of PNmax and NL, and an increase in CL concentration. No interaction was detected. LMA decreased in Q. ilex after nitrogen addition, because leaf area increased (data not shown), influencing in the same direction as the LMA of the O3N experimental set.O2- and H2O2 scavenging  were upregulated in the O3N plants. Conversely, in Q. ilex, even if ROS were produced to the same extent as in O3 and O3N plants, SOD and CAT were lower in O3N than in O3. All the antioxidants related to ascorbate-glutathione cycle were higher in O3N than in O3 plants.In 3 on Mediterranean forests have been of increasing concern, and experimental data are needed to elucidate the mechanisms of action, or identify specific functional traits affected by interacting stress factors. Thus, the present study aimed to measure the effects of realistic exposure of nitrogen and O3 on a broad range of traits of two Mediterranean species with different leaf habits, to characterize their response. The study was performed under controlled condition in a medium-term experiment, in order to determine the traits that are first affected by nitrogen and how the potential nitrogen effects can influence the response to O3. Moreover, to our knowledge, this is the first study to compare F. ornus and Q. ilex directly after O3 exposure, with important implication for assessing the risk for these co-occurring species.The impacts of atmospheric nitrogen deposition and O-1, which was within the threshold load considered as critical for Mediterranean vegetation, nitrogen concentration at the leaf level did not increase in both species, and no adverse effect was detected on photosynthetic traits (data not shown). When nitrogen exposure exceeded this level, between 14 and 17 kg N ha yr-1 (DOF 1), assimilation rate measured under steady state conditions was adversely affected in F. ornus possibly because of the nitrogen-induced decrease in stomatal conductance, as documented in several species [s by changing the hydraulic conductivity [s could be mediated by NO signalling.An overview of available literature highlights that the results for the effects of nitrogen deposition at the leaf and plant levels are contradictory ,66. The  species ,68. Indeuctivity , or by iuctivity . In factuctivity . Since tNmax and Jmax increased because of nitrogen, whereas Vcmax did not change, namely, the electron transport driving RuBP regeneration was more affected than carboxylation. This result also explains why the assimilation rate measured under steady state condition, i.e. in the Rubisco-limited phase [a fluorescence measurement, indicate that, in Q. ilex, a higher fraction of nitrogen was allocated to components related to biochemical phase of assimilation process than to light-harvesting elements [F. ornus. In fact, in Q. ilex, nitrogen significantly affects only the parameters related to the functionality of the end acceptors (i.e. IP-phase and PItot); in contrast in F. ornus primary photochemistry (φPo and J-phase) was also enhanced by nitrogen, confirming that the partitioning pattern can differ depending on leaf habit [Interestingly, in both species, Ped phase , did notelements . This hyaf habit .F. ornus, nitrogen addition resulted in 25% higher NL relative to that in the control (p = 0.058), whereas in Q. ilex the variation was less pronounced (+ 14%). Notably in both species PNUE did not change because of nitrogen addition. PNUE is controlled by physiological  and structural traits  [F. ornus, nitrogen treatment decreased both leaf area and dry mass, resulting in no LMA variation. However, in Q. ilex, the LMA decreased because of nitrogen, since the leaf area increased; thus, the evergreen species did not invest resources in the cell wall to increase leaf toughness, as reported in other studies [In agreement with ecophysiological measurements, at the end of the experimental period, the concentration of nitrogen on mass basis increased to a different extent between the species. In ickness) , which c studies ,74.F. ornus, area-based leaf nitrogen was lower relative to the mass-based value (data not shown), whereas the two values remained similar in Q. ilex.These effects of nitrogen supply on leaf structural traits could influence the leaf nitrogen concentration when it is considered on area-basis ,75. In F3 cannot be identified based on the extent of leaf injury alone, because impairments to photosystem functionality and photochemistry occur before the appearance of visible injury [3 exposure , F. ornus seemed to be sensitive to this pollutant because it did not trigger an active physiological response to O3, such as avoidance mechanisms, activating instead an incoming injury. The gas exchange reduction occurred from the first day of fumigation , remaining around this order of magnitude for the entire fumigation period. Furthermore, in this species the PN reduction was not merely owing to stomatal limitation, since the PN/Ci response curves highlighted a decrease of PNmax and of both carboxylation efficiency (Vcmax) and maximum electron transport rate driving RuBP regeneration (Jmax). The reduction of nitrogen concentration can also be a good indicator of O3 injury, helping to define the scale of tolerance between species [F. ornus, O3 exposure accelerated the processes related to senescence as shown by the decrease of leaf nitrogen and dry matter i.e. decrease of LMA. Although the results from controlled conditions cannot be extended to natural ecosystems, the sensitivity found in this experiment should be considered for risk assessment of tree species in a Mediterranean climate. The response pattern of Q. ilex to O3 can be attributed to an avoidance mechanism, as shown by traits related to photochemistry, photosystems functionality or structural traits. The reduction of PN in O3-treated plants relative to controls was less pronounced in Q. ilex than in F. ornus, starting on DOF 4, and was related to stomatal limitation more than to biochemical impairments. Indeed, the parameters derived from PN/Ci curves did not indicate any detrimental effect on Rubisco activity because of O3, whereas the analysis of photosystem functionality highlighted a down-regulation mechanisms (i.e. reduction of end-acceptors activity). The differences in the response strategies implemented by the two species could be strictly associated with a different antioxidant potential [2O2 [Q. ilex. Moreover, the components involved in the ascorbate-glutathione cycle  showed high concentration or activity in Q. ilex relative to that in F. ornus, but these could be related to the higher stomatal conductance  in the former species. Furthermore, in both the species, the finding that, in O3-treated plants, the increase in DHA/ASA ratio was lower than the increases in APX activity, suggestings that recycling of DHA to ASA was not compromised by O3.Ozone effect was assessed using a wide range of traits to allow defining thoroughly the differences in the response patterns between the species. Plant sensitivity to Oe injury ,76. In o species . In F. ootential . Indeed,ial [2O2 , was hig3 have focused on the changes in community structure or species abundance in grasslands ecosystems [3 interaction on tree species [N and gs can remarkably change depending on the concentration of nitrogen and O3 exposure. In the present study, the interaction followed different patterns in the two species, confirming our hypothesis that leaf habit plays a crucial role in determining the way of interaction between the two factors. In particular, in F. ornus, the interaction was detectable on several traits indicating that nitrogen addition can ameliorate the detrimental effects owing to O3. Nitrogen had a positive effect on the processes related to photochemistry, resulting in enhanced carbon assimilation rate in the O3N experimental set relative to that in the O3 experimental set. The mechanisms involved in this type of response could be associated with the investment of available nitrogen to proteins that play a crucial role in enhancing the photosynthetic activity [3 could also be attributed to the upregulation of antioxidant response to O3 implemented by nitrogen addition [3N plants, the APX activity and ASA and DHA were higher compared to that after treatment with O3 alone. Moreover, in F. ornus, the O3N experimental set led to lower ROS production relative to that in O3 plants, that is, lower exposure to oxidative stress, even if the O3 fluxes remained almost the same. On average, during the entire experimental period, gs was about 96.9 ± 21.2 and 92.5 ± 12.3 in O3 and O3N, respectively. This could be because of NO synthesis. Plants can emit NO under a series of stresses [2O2 and O2−, thereby decreasing their concentrations. We argue that, in the presence of high nitrogen availability, F. ornus can cope with incoming oxidative stress via the production of NO, which owing to the rapid synthesis and prompt availability, allows prompt scavenging of free radicals and concomitantly increases the photosynthesis rate [F. ornus. In Q. ilex, a strong monoterpene emitter species [Information on the interactive effects of nitrogen deposition and ozone pollution on vegetation is still scarce . Many ofosystems ,31,78. H species ,38,43. Tactivity . We arguactivity . The posaddition . In partstresses , in partstresses . NO is isis rate . As show species , the res species  rather tF. ornus, in Q. ilex, the interaction between nitrogen and O3 was weak and appeared only on DOF 1, when nitrogen seemed to aggravate the stomatal limitation owing to O3. The gs of O3N plants recovered at the following sampling times to the level in the O3 experimental set.Unlike in 3. However, interestingly, enzymes such as SOD and CAT, which play a crucial role in determining a suitable level of ROS in different cell compartments [3N plants than in O3 plants, although the ROS production did not differ between the treatments. This evidence suggests that, in Q. ilex, nitrogen addition could enhance secondary metabolism and promote the production of VOCs that can directly quench O3 without activating an enzymatic antioxidant response. Conversely, similar to that in F. ornus, nitrogen upregulated the activity of the ascorbate-glutathione cycle in Q. ilex, indicating that nitrogen deposition can largely protect against oxidative stressors and to multi-stress condition experienced by Mediterranean vegetation.Photosystem functionality was not affected by the interaction, and Rubisco-related parameters did not show any nitrogen effect (positive or negative) when plants were exposed to Oartments , were lo-1 y-1 had been reached. Moreover, in both species, nitrogen enhanced the constitutive level of antioxidant activity, thus with a potential ameliorative effect on O3-related impacts. In F. ornus nitrogen was allocated to the light harvesting components as shown by chlorophyll a fluorescence measurements. The results suggest that F. ornus is an O3-sensitive species, as shown by biochemical limitation to photosynthesis and the acceleration of leaf senescence-related processes. In F. ornus, nitrogen ameliorated the detrimental effects that O3 had on the photosynthetic processes. The interaction between nitrogen and O3 had different mechanisms of action in the two species. In the deciduous species F. ornus, the lower ROS production in the interaction experimental set (O3N) might be related to the enhanced nitrogen oxide production, whereas, in Q. ilex, nitrogen might have upregulated the secondary metabolism, promoting high VOCs production. This hypothesis is based on the fact that, although no difference was noted in ROS production between O3 and O3N plants in this species, the activity of the first-level scavenging enzymes such SOD or CAT was lower in the interaction experimental set. These results indicate that nitrogen deposition could counteract the detrimental effect of O3, thus suggesting that nitrogen is an important factor for assessing the critical level of O3 for Mediterranean vegetation.In both species, photosynthetic traits such as photosystem functionality, maximum assimilation and maximum electron transport rate were enhanced by nitrogen at the end of the experiment, when 20 kg N ha


N = 4,169) five different procrastination scales – Decisional Procrastination Scale (DPS), Irrational Procrastination Scale (IPS), Pure Procrastination Scale (PPS), Adult Inventory of Procrastination Scale (AIP), and General Procrastination Scale (GPS), focusing on factor structures and item functioning using Confirmatory Factor Analysis and Item Response Theory. The results indicated that The PPS  measures different facets of procrastination even better than the three scales it is based on. An even shorter version of the PPS , corresponds well to the nine-item IPS. Both scales demonstrate good psychometric properties and appear to be superior measures of core procrastination attributes than alternative procrastination scales.Scales attempting to measure procrastination focus on different facets of the phenomenon, yet they share a common understanding of procrastination as an unnecessary, unwanted, and disadvantageous delay. The present paper examines in a global sample ( Measurement of self-reported procrastination in tests and questionnaires focuses on different areas in which unnecessary delay expresses itself. As per Goal Phase Theory , aside fr = 0.87 . A German study, testing the student version of the GPS, could not confirm an one-factorial structure and instead proposed a reduced version – GPS-K – consisting of items 1, 2, 7, 12, 14, 15, 18, 19, and 20  and GPS (15 items) are relatively comprehensive instruments. Because procrastination scales are often administered with scales measuring other constructs, shorter instruments with comparable or even better psychometric qualities compared to the full scales contribute to overall reduction of survey length and should be used if possible  and Item Response Theory (IRT), we compare the different scales, examine their factor structures, and suggest simplified scales to measure procrastination. We also assess measurement invariance over gender and age, internal reliability, as well as correlations between the instruments.Table 2 that the DPS focuses on decisional procrastination, whereas the AIP contains several items that focus on timeliness and lateness. As the PPS includes items from both these scales, we ask how these PPS items perform compared to the full scales. In effect, we pursue the possibility that the DPS and AIP could be reduced to fewer items, likely corresponding the PPS items, and in consequence that the PPS could replace the DPS, AIP, and the GPS scales.The first purpose of the present study was to examine the possibility that the PPS addresses three rather different facets of procrastination , and thaThe sample consisted of 4169 respondents (57.4% women) completing an online survey. Mean age was 37.4 years, the most frequent age group being 20–30 years (1200 respondents). Most participants were located in the United States (68.1%), 5.9% in Canada, 4.4% in the United Kingdom, 2.4% in Australia, 1.6% in Italy, with the rest distributed among a large number of countries worldwide with 1–40 respondents/country. Respondents were recruited to participate in a study on regret when visiting a procrastination-themed website.Table 2). Test-retest reliability of this scale is relatively high, r = 0.71, as is internal consistency, α = 0.86  at the University of Calgary.1.The item scores were first examined for skewness and kurtosis. Then multivariate normality was assessed for all scales, in particular multivariate kurtosis, which is important to parameter estimation in CFA . Non-norTable 3 along with the CFA fit indices for the present data. As is seen in the table, the three-factor model for the PPS – items 1–3 measuring decisional procrastination, items 4–8 measuring implemental delay, items 9–12 measuring timeliness, and promptness – was superior to the other suggested models. As the one-factor model and the suggested three-factor models are nested, a Δ Chi squared comparison between these models indicates whether one model demonstrates a better fit  has previously been argued to be conflated with the busyness construct and not procrastination per se  between factors with the average variance extracted (AVE) by the latent variables (An examination of modification indices of the three-factor solution indicated a path to be added between the PPS factor timeliness/delay and PPS item 1. This connection is reasonable because this item explicitly addresses timeliness/lateness (“I delay making decisions until it’s too late”). Adding this path improved fit, RMSEA = 0.065, CFI = 0.968, SRMS = 0.029.n per se  and recoariables . All AVEAddressing the PPS parts specifically, PPS items 4–8 should measure implemental delay satisfactorily. A CFA of these items indicated good fit, RMSEA = 0.064 (0.053), CFI = 0.991 (0.992), SRMR = 0.016. Regarding the IRT analysis of this construct, parameter a coefficients were > 2 for all items, item 7 demonstrating the lowest coefficient (2.15) and item 4 the highest (2.71). All items covered the range of the latent construct quite well, from -3 to +2, indicating that this short scale measures implemental procrastination well in individuals in the normal range of the latent trait. Note that the scale discriminates rather poorly in the higher end of the latent construct, speaking for cautious use in clinical settings. Test Information Function (TIF) and Item Information Functions (IFF) graphs are shown in Appendix. A corresponding examination of PPS items 9–12 (lateness/timeliness items from the AIP) indicated an excellent fit, RMSEA = 0.056 (0.049), CFI = 0.996 (0.997), SRMR = 0.011. The IRT demonstrated discrimination coefficients between 1.72 (item 12) and 3.50 (item 10). Examination of the TIF graph (Appendix) again indicated rather poor discrimination in the higher end of the latent construct. Finally, examination of the decisional part of PPS, items 1–3, demonstrated an excellent fit, RMSEA = 0.000, CFI = 1.00, SRMR = 0.000. The IRT discrimination coefficients ranged from 2.18 (PPS item 1) to 3.85 (item 2). Again, the TIF graph (Appendix) indicated less reliability in the higher end of the latent construct. In summary, the three-factor model of the PPS, as well as reduced models focusing on three unidimensional constructs, decisional, implemental delay, and lateness/timeliness, all appear to work well psychometrically.Table 4, a multigroup men vs. women CFA indicated configural as well as metric invariance, but not scalar invariance. Hence, comparisons of PPS means with gender is problematic. Also note that configural fit was improved for participants > 30 years of age. The results further indicated that gender differences appeared in the decisional and lateness parts of the PPS , but not in the implemental part . Hence, invariance tests of PPS items 4–8 demonstrated a similar pattern to that of the complete PPS, with the important exception that scalar equivalence was now observed for the age group > 30 (see Table 5). In summary, the PPS results indicate that the complete scale does not attain full invariance across gender, and furthermore the model fit was better for participants greater than 30 years of age. For the reduced PPS , gender differences were minimal and these items also demonstrated full measurement invariance for participants over 30 years, indicating that this part of the scale permits comparisons of means scores for adults.Given the basic configural model of the PPS, we tested invariance across gender and age groups. Both gender and age differences  have been discussed repeatedly in the literature e.g., , but as The IPS is hypothesized to measure a single construct, “irrational delay,” and the present data indicates that it does, RMSEA = 0.075 (0.066), CFI = 0.971 (0.973), SRMR = 0.032. In accordance with prior findings , modificTable 6, even in the older group scalar invariance did not appear, indicating that care should be taken in comparing mean IPS scores between genders and age groups.Testing IPS measurement invariance over gender and age groups indicated somewhat better fit for age over 30 years, but as is apparent from Table 7, this was the case, r = 0.83 vs. 071 and 0.76. Further, IPS and PPS item means 4–8 should be comparable, and for the present sample they were, at 3.62 in both cases. These results indicate that PPS items 4–8 and IPS address the same unidimensional construct, implemental delay.Given that items 4–8 of the PPS measure implemental or “irrational delay,” this part of PPS should correlate highly with IPS, whereas the two other factors of the PPS should demonstrate more moderate correlations. As is seen from delay and procrastination domains), and a German study, testing the student version of the GPS, proposed a reduced version – GPS-K – consisting of items 1, 2, 7, 12, 14, 15, 18, 19, and 20 , which in part may explain why this scale did not do well in the CFA analyses.As the other general procrastination scales discussed, the AIP is hypothesized to measure a single latent construct, procrastination, and The DPS demonstrated a poor fit for a one-factor solution, RMSEA = 0.259, CFI = 0.916, SRMS = 0.076. Modification indices suggested correlations between errors for items 4 and 5 (two items with quite similar wording), and then between items 1 and 2. This model indicated an excellent fit, RMSEA = 0.017, CFI = 1.000, SRMS = 0.002.Table 7 shows the Cronbach’s alphas, correlations and mean scores for the DPS, AIP, and GPS scales as well as for the IPS and PPS . SWLS is also included to evaluate divergent validity. Overall, good convergent validity was observed between the procrastination scales, and divergent validity to the SWLS was apparent for all instruments. Note that the complete PPS correlates highly with the GPS, AIP, and DPS , making the PPS a briefer alternative to these scales. Also note that the DPS total scale correlates very highly with the first factor of the PPS, r = 0.97, effectively making the DPS part of the PPS equivalent to the complete DP scale. Similarly, the complete AIP correlates highly with the PPS factor containing AIP items, r = 0.86, making these four items comparable to the complete AIP.Figure 2. The figure indicates a slight reduction of procrastination over age decades 40–70, supporting the view that procrastination decreases with age . This is shown in with age . For illdecisional procrastination, delay in implementation, and timeliness/lateness. The three PPS subscales enable this scale to measure three facets of procrastination in much the same way with 12 items as is achieved by three separate scales with 39 items. This is a substantial practical advantage as well as a psychometrically sounder solution, as the reduced set of items selected for the PPS were shown to demonstrate better CFA fit indices compared to the full set of items of the individual DPS, GPS, and AIP scales.The present study examined the psychometric properties of five prevalent procrastination scales, with a main focus on the PPS and IPS. All scales were assessed with CFA and – for scales/subscales measuring one-dimensional constructs – also with IRT. For the PPS, the results indicated that this scale conforms to a three-factor solution corresponding to the three different scales the PPS is based on, measuring impl) appears to measure irrational delay in much the same way as does the IPS, and thus represents an even “purer” version of the PPS in measuring irrational delay. Additionally, this part of PPS also correlates very highly with the complete GPS, suggesting that this 20-item scale might be reduced to a 5-item scale without loss of information. Collapsing the three facets of the PPS into one score also masks the substantial mean differences in scores between the implemental part of PPS (items 4–8) and the two other facets, the former being consistently higher compared to the two others . Finally, the lateness part of PPS (items 9–12) may be more sensitive to cultural differences compared to the two other facets . Neither of these scales demonstrated full scalar invariance. As scalar invariance is required for meaningful comparisons between population means, gender and age differences cannot be assessed unless a given instrument is demonstrated to satisfy measurement invariance requirements. However, note that the implemental part of the PPS (items 4–8) seems to perform better compared to items related to decisional procrastination (items 1–3) and timeliness/lateness (items 9–12), and full scalar invariance for the PPSimpl subscale (items 4–8) conforms well to recent findings in a German representative community study  rather than “In preparing for some deadline, I often waste time by doing other things” . In the present study, the latter item demonstrated excellent item properties (Appendix) and appears to be more appropriate as an item measuring procrastination in the general population. However, future studies should examine these scales, both in item-level analyses and in cross-cultural comparisons. At present, the implemental part of the PPS and the IPS seem to be the best available candidates for assessing procrastination over different languages and cultures.The present results are based on answers from many nations, albeit with English as a common language. Hence, we cannot unambiguously assess cultural or national differences. We believe, however, that the present results, especially regarding the PPS and IPS, are quite robust. Thus, the conclusions from the present paper regarding PPS and IPS factor structures are very similar to prior findings in a comparison of these scales in Finland, Germany, Italy, Norway, Poland, and Sweden , and thety study . That stty study  consistiThe scales examined in this study all differentiate procrastination well for low and medium ranges of the construct, but appear to measure less reliably in the higher end of the construct. This implies that measurement of high levels of procrastination, for example in clinical cases, is error prone. Hence, assessment of procrastination in clinical settings should be supplemented by other measures  to ensure sufficient validity and reliability. Another issue of importance for future research is to establish more objective and reliable measures that can supplement or even replace self-report measures . This isPS was responsible for data collection. FS wrote the draft and did the statistical analyses. Both authors did final editing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.