Previous studies have showed that reading fluency is strongly associated with cognitive skills, including rapid automatized naming, phonological awareness, orthographical awareness, and so on. However, these studies are largely based on alphabetic languages, and it remains unclear which cognitive factors contribute to the development of reading fluency in logographic Chinese, a language in which the graphic forms map onto morphemes (meaning) rather than phonemes. In Study 1, we tested 179 Chinese children aged 6 to 9 on a set of cognitive tasks as well as for word reading accuracy and sentence reading fluency. The results showed that rapid naming, writing fluency, and phonological awareness significantly predicted reading fluency in both beginning and intermediate readers. In addition, while the contribution of rapid naming and writing fluency increased with grades, the effect of phonological awareness decreased. In Study 2, we examined the role of visual crowding in reading fluency in a subgroup of 86 children and found that visual crowding accounted for the unique variance of individual differences in reading fluency. The findings reflect both universal and language-specific cognitive correlates of reading fluency and provide important implications for potentially effective treatment for individuals suffering from Chinese reading disabilities, particularly in terms of reading fluency. Reading fluency, the ability to read rapidly and automatically, is considered a key to good reading comprehension . DiffereRapid automatized naming involves naming a series of familiar items  presented repeatedly in random order as quickly as possible. The important role of RAN in reading fluency may be due to the cognitive components that it shares with reading fluency, such as general processing speed, eye saccades, phonological process, and so on. In addition, the automaticity that supports RAN is also an important characteristic of fluent reading . Savage Phonological awareness (PA) refers to awareness of the phonological structure or sound structure of language . It is en = 1491), Relative to RAN and PA, fewer studies have examined the role of orthographic awareness in reading fluency. Orthographic awareness refers to the ability to form, store, and access printed words and the general attributes of writing systems , which are mainly obtained implicitly . There aFurthermore, previous studies have demonstrated that the cognitive skills contributed differently to reading fluency in languages with different degrees of orthographic transparency . TranspaMoreover, the verbal efficiency model proposed by In the present study, we investigated what cognitive skills contribute to the development of reading fluency in Chinese children. Written Chinese has an extremely opaque orthography, and it provides an important window for understanding the universal and writing system-specific cognitive processes that underlie the development of reading fluency . Accordi,/du/, to read) that corresponds to a specific phoneme  in the syllable. Chinese characters are salient visual units, formed with intricate strokes within square configurations, which is in contrast to the linear structure of alphabetic words. Chinese characters can be categorized into simple characters and compound characters. Simple characters are formed with stroke patterns that cannot be decomposed . The vast majority of characters are compound characters, which are formed with two or more identifiable components. About 85% of Chinese characters are phonetic compounds that contain a semantic radical and a phonetic radical, which, respectively, provide the semantic and phonological information of the characters. For example, in the character  , the semantic radical  suggests that it is related to wood, and the phonetic radical  suggests its pronunciation/feng1/.Chinese is a morpho-syllabic system, in which the graphic forms (characters) map onto morphemes (meaning) rather than phonemes . This mePrevious studies on the development of reading fluency in Chinese mainly focused on cognitive factors including RAN, PA, orthographic awareness, and morphological awareness. For example, Although some previous studies have emphasized the importance of writing ability in reading development , the rolIn addition, due to the salient visual-orthographic property, it has been long proposed that reading of Chinese words is more prone to the influence of visual factors . As for n = 86) in Study 1.In Study 1, we used a cross-sectional design to examine the contributions of a set of cognitive skills to reading fluency in 179 first- to fourth-year primary school students. The cognitive factors included measures of RAN, PA and orthographic awareness, writing fluency, verbal working memory, and executive control. In Study 2, we further investigated whether the effect of visual crowding accounted for unique variance in Chinese reading fluency in a subgroup of children , and the intermediate readers were 3rd and 4th graders   . All theD = 0.7) .A battery of tests was administrated, including RAN, PA, orthographic awareness, writing fluency, verbal working memory, Stroop task, and non-verbal intelligence. The standardized Chinese version of Raven’s Standard Progressive Matrices was used as a non-verbal intelligence test. The reading performance was assessed with a word reading test and a sentence reading fluency test. All tests were conducted by trained experimenters. Written consent was obtained from the children’s parents before the tests. The non-verbal intelligence test, lasting about 40 min, was administered on a group basis, and the other tests were tested individually, taking about 40 min in total.The RAN tasks examined children’s ability to name letters, symbols, words, or objects in a quick and automatic manner. Previous research suggested that the contribution of RAN to reading development seemed to be dependent on the RAN tasks employed in the studies e.g., . Hence, An oddity test was used to examine children’s phonological awareness of onsets and rimes. The children were given four practice items and twenty testing items, among which ten items tested onset awareness and ten tested rime awareness. We obtained a score for PA by adding the number of correct items for onset awareness and rime awareness. In each item, the children were required to carefully listen to four monosyllabic words. One of the four syllables was the odd one out by virtue of lacking an initial or final sound shared by the other three syllables. The subjects were asked to identify the odd one out. For example,/sha1/was the odd one out in the set/chu3/,/sha1/,/pu2/,/lu3/(the numbers indicate the tone of the syllables) in terms of the final sound. The score was the total number of items answered correctly. The maximum score for this task was 20.SD = 3.17), and the average frequency of the characters was 227.61 per million (SD = 108.99)1. The children were presented with a series of Chinese characters arranged in a 10 × 10 matrix, and they were asked to circle the characters containing a designated component  as correctly and rapidly as possible within 2 min. The score was the number of correct answers.We used a component search task to test children’s awareness of the internal structure of Chinese characters. This task was similar to the orthographic processing test used in previous studies of Chinese reading development e.g.,  and was SD = 2.59). The characters were of high frequency, with an average frequency of 346.26 per million (SD = 799.58). There were two simple characters and eighty-two compound characters, and 76% of the compound characters were phonetic compounds. They were arranged in nine rows and ten columns according to grade from lowest to highest. The number of characters written correctly was taken as the score for writing skill.In the writing fluency task, the children were asked to copy Chinese written characters from samples as correctly and rapidly as possible within 3 min. Eighty-four Chinese characters were selected from the textbooks of grades 1 to 6, fourteen characters from each grade. The average number of strokes of the selected characters was 9.6 ” printed in yellow ink], whereas facilitation arose in the congruent condition when the ink color and the word meaning were congruent . In the neutral condition, squares were used, and the subjects were asked to name the ink color of the squares . Each condition involved 30 printed items presented in six rows and five columns. The children were required to name the stimuli as correctly and rapidly as possible. Before each task began, there was a practice test with nine example stimuli to ensure that the children understood the task and could accurately name the colors. Time (in milliseconds) and accuracy of naming the ink color were recorded, but only the time taken for naming was analyzed. The interfering effect was determined by comparing the reaction times (RTs) in the incongruent and neutral conditions.The color-word Stroop task was used to examine children’s ability to inhibit interfering information. During the test, children were required to name the color of the ink and inhibit reading the word. The task demanded executive function and speed of processing, which might be related to the development of reading fluency . Three cSD = 3.08) characters per sentence. The average frequency of the characters was 2385.85 per million (SD = 983.11). The children were asked to judge the correctness of the sentences, for example, ” (winter is a season), in 3 min as correctly and rapidly as possible. The score was the number of sentences that were correctly judged. To ensure that the children understood the task, two sample sentences were used for instruction and four sentences for practice before the test.A reading fluency task was used to examine children’s ability to integrate word meanings into sentence comprehension on the basis of fast decoding. Relative to word reading fluency, which is often measured as the number of words correctly read within a time limit , the sentence reading fluency used in our study could better measure the multifaceted performance of both reading speed and comprehension of the text. The sentence reading fluency test was designed based on the reading fluency subtest in Woodcock-Johnson III - Tests of Achievement  and was SD = 243.24), and the average frequency of the additional 60 low-frequency words was 0.96 per million (SD = 3.28). There were five simple characters and 355 compound characters, and 84% of the compound characters were phonetic compounds. These characters were presented in a sequence increasing in difficulty. The 300 characters from the textbooks were presented in sequence from the lowest to the highest grades, which were followed by the 60 low-frequency words. The children were asked to read the words aloud to the experimenters as accurately as possible. The test stopped if the children made five consecutive mistakes. The score was the number of words correctly read. The purpose of including the word reading task was to examine whether there were cognitive skills that were specifically correlated to reading fluency, as compared with their correlations with word reading accuracy.A Chinese word reading test was used to assess word reading accuracy. There were 360 single-character words, of which 300 characters were selected from the textbooks of grades 1 to 6 (50 words for each grade) and 60 low-frequency words from the dictionary. The average frequency of the characters selected from textbooks was 96.12 per million , word reading accuracy , RAN-D , RAN-O , RAN-C , PA , forward digit span , backward digit span , Chinese component search , and writing fluency , with intermediate readers showing better performance than beginning readers. There was no significant difference in inhibition effect in the Stroop task  or in non-verbal IQ  between the two groups.The means and standard deviations of the test scores are shown in r = 0.751, p < 0.001) and intermediate readers . r = −0.405, p < 0.001; intermediate readers: r = −0.436, p < 0.001), RAN-C , PA , and writing fluency . In addition, intermediate readers’ performance was also significantly correlated with RAN-O . For the word reading accuracy test, beginning readers’ performance were significantly correlated with RAN-D  and PA , while intermediate readers’ performance of word reading was significantly correlated with RAN-D , RAN-O , RAN-C , and forward digit span . Thus, these results indicated that RAN-D correlated with both reading fluency and word reading in both age groups, whereas RAN-O and RAN-C had larger correlations with reading performance in intermediate readers than in beginning readers. The correlations between PA and reading performance (both reading fluency and word reading accuracy) decreased from beginning readers to intermediate readers. Moreover, writing fluency was more specifically correlated with reading fluency but not word reading accuracy across age groups.There were strong correlations between reading fluency and word reading in both beginning readers ], RAN-C [2.3% of variance ], PA [6.5% of variance ], and writing [7.2% of variance ] were the significant predicters for reading fluency. For intermediate readers, RAN-D [13.3% of variance ], RAN-O [14% of variance ], RAN-C [9.3% of variance ], PA [4.6% of variance ], and writing [9.3% of variance ] were the significant predictors for reading fluency. The results indicated that the predictive power of RAN and writing fluency increased from beginning to intermediate readers, whereas the predictive power of PA diminished.To determine the relative power of these cognitive factors for predicting sentence reading fluency and word reading accuracy, we carried out a series of fixed order hierarchical multiple regression analyses. The results are shown in F = 8.991, p < 0.01) of the variance, whereas writing accounted for 3.2%  of the variance. In the intermediate readers, PA and writing did not account for additional variance in reading performance. The results suggested that in the beginning readers, PA and writing contributed to reading fluency even after the effect of RAN was partialled out, but in the intermediate readers, PA and writing did not account for additional variance in reading fluency.As revealed in the above regression analyses, RAN, PA, and writing fluency were the three most powerful predictors of reading fluency. Among these three factors, RAN and PA may share common variance of phonological process , whereasF = 4.983, p = 0.028)] in reading fluency after the effects of RAN and writing were controlled, but the effect of writing was not significant after the effects of RAN and PA were controlled. In contrast, in the intermediate readers, writing explained 2.6%  of the variance in reading fluency after the effect of RAN and PA were controlled, but PA did not account for the additional variance of reading fluency. We then entered subtests of RAN as step 5 in the model after the effects of PA and writing were controlled ] and RAN-C  explained significant proportions of variance in reading fluency in beginning readers, and RAN-D , RAN-O , and RAN-C  explained significant proportions of variance in intermediate readers, suggesting that RAN made a unique contribution to reading fluency that cannot be explained by PA or writing fluency. The results indicated that, among the three most powerful predictors of reading fluency , RAN made a unique contribution to reading fluency that cannot be explained by PA or writing fluency in both beginning and intermediate readers and that the predictive power of RAN increased as age increased. In contrast, PA accounted for unique variance in reading fluency only in beginning readers. The effect of writing fluency on reading fluency was strong in both age groups, but it seemed to share considerable common variance with RAN.Second, to further estimate the unique predictive power of PA and writing for reading fluency, we entered PA or writing as step 7 in the model after entering all the other related factors . We founntrolled . We founF = 12.502, p ≤ 0.01) and 7.4% of variance , respectively. For intermediate readers, RAN-D [10.1% of variance ], RAN-O [11.4% of variance ], RAN-C [5.4% of variance ], and forward digit span [3.7% of variance ] were the significant predictors for word reading ability  of the variance, whereas forward digit span did not account for additional variance in word reading performance. In intermediate readers, PA and forward digit span did not account for additional variance in word reading performance. The results suggested that PA played a more important role in word reading accuracy in the beginning readers than in the intermediate readers.To determine the contribution of PA  after the effect of RAN was controlled, we performed fixed-order multiple regression analyses with children’s age and IQ being again entered into the model as steps 1 and 2, and RAN being entered as steps 3–5. PA or forward digit span was then entered as step 6 . In begiF = 9.765, p < 0.01) to the variance in word reading in beginning readers. In addition, only RAN-D explained 3.6%  of variance in word reading for beginning readers. For intermediate readers, RAN-D [5.5% of variance ], RAN-O [7.1% of variance ], and RAN-C [3.4% of variance ] explained significant proportions of variance in word reading. The results suggested that there were strong effects of RAN on word reading accuracy across beginning and intermediate readers, and the findings were consistent with those in reading fluency.To evaluate the unique predictive power of PA and RAN for word reading accuracy, we entered PA or RAN as the last step in the model after entering all of the other factors . We founIn summary, we identified cognitive factors that contributed significantly to reading fluency, including RAN (particularly rapid naming of digits), PA, and writing fluency. We found that rapid naming of digits consistently accounted for the unique variance both of reading fluency and word reading accuracy and across age groups, indicating that rapid digit naming may play a more important role in reading development than rapid naming of objects or colors. The results were consistent with previous findings. For example, The multiple factors that contributed to reading fluency in Chinese children have highlighted the components of phonology, speeded processing, visual-motor process, and so on. In Study 2, we focused on visual crowding and explored whether this visual factor accounted for the unique variance of Chinese reading fluency. Previous studies have shown that visual crowding, a key factor in how people visually recognize objects, can severely affect reading speed . IndividSD = 0.63). All subjects had normal or corrected-to-normal vision. Written consent was obtained from their parents before the tests. They were assessed with the following tests besides the visual crowding test: RAN-D , RAN-O , RAN-C , PA , forward digit span , backward digit span , Stroop task , Chinese component search , writing fluency , non-verbal IQ , Chinese word reading , and reading fluency test .Ninety children participated in this study. They were 2nd and 3rd graders from Study 1. Data for four participants were excluded because they failed to complete the visual crowding test. The final sample included 86 children  with a mean age of 8.5 years . Each run contained two conditions , and each condition included 60 trials. There were five practice trials before the formal test to make sure that the participants understood the task. In the uncrowded condition, a Chinese character or a grating (the target) appeared randomly to the left or right of the fixation point. The subjects were asked to choose the target from 10 Chinese characters or from two gratings. We only offered the children two options because it was difficult for the young children to identify subtle differences in the orientation of the grating if many options were provided. In the crowded condition, the target was surrounded by two other flankers horizontally, and the subjects were asked to ignore the two flankers and pay attention to the target . They wemean accuracy (MA) = 0.87, SD = 0.14], crowded VCC , uncrowded VCG , and crowded VCG . We first conducted a paired t-test between crowded and uncrowded conditions and found significant crowding effects for both word condition  and grating condition . We then calculated the visual crowding strength (VCS), which reflected the extent to which the subjects’ performance was affected by crowding, using the following equation (Performance accuracy has been shown to be a reliable behavior indicator of crowding . Therefoequation  (1):SD = 0.21) for Chinese characters (VCSC) and 0.05 (SD = 0.18) for gratings (VCSG).where the numerator is the difference in the accuracy between the uncrowded and crowded condition, and the denominator is the accuracy in the uncrowded condition, which serves as the baseline. The mean visual crowding strength was 0.17 ]. The greater impact of visual crowding on sentence reading fluency relative to word reading accuracy may be due to the fact that children’s reading fluency was tested with characters presented in closely spaced continuous lists  of variance in reading fluency. In addition, RAN-D, RAN-O, RAN-C, and writing fluency explained 15.0% , 3.3% , 3.9% , and 8.8%  of the variance, respectively. In contrast, PA could not explain a significant proportion of variance in reading fluency .To further examine the contribution of visual crowding to reading fluency relative to the other cognitive skills, we conducted a series of fixed-order hierarchical multiple regressions, with children’s age and IQ being entered into the model as steps 1 and 2, and other skills, including VCSC, RAN, PA, and writing, as step 3 . We compF = 8.369, p < 0.01) of variance  after the effects of VCSC, RAN, and PA were controlled. In addition, after VCSC, writing and PA were controlled, RAN-D and RAN-C were significant predictors, which contributed 7.5%  and 3.8%  of the variance in reading fluency, respectively. The results suggested that visual crowding of characters accounted for unique variance of reading fluency in children that could not be explained by RAN, PA, or writing fluency.Furthermore, we tested whether VCSC, RAN, and writing fluency accounted for the unique variance of reading fluency. The results showed that after the effects of RAN, PA, and writing were controlled, VCSC still accounted for 4.5%  in Chinese reading fluency than for cognitive capacities such as working memory and executive control. We further demonstrated in Study 2 that visual crowding accounted for unique variance in reading fluency and that the effect was much more pronounced for crowding caused by linguistic stimuli than for gratings. The impact of visual crowding may be related to the presentation format, in that the characters were presented in close-spaced continuous lists during reading.The results showed that children’s reading fluency was affected mainly by RAN, writing fluency, and PA but that the roles of these factors were different in beginning readers and intermediate readers. We found that RAN was a strong predictor of both reading fluency and word reading accuracy and that the predictive power was strong in both beginning readers and intermediate readers. In contrast, PA seemed to be more important for reading fluency and reading accuracy for beginning readers than for intermediate readers. Writing fluency predicted reading fluency but not word reading accuracy, and it played an increasingly important role during reading development. The effect of writing skill may reflect accommodation to the demands of learning to read Chinese.The importance of RAN in reading fluency has been well-established across alphabetic orthographies , and defPhonological awareness contributed to Chinese reading fluency in our study, but the effect diminished from beginning to intermediate readers. In addition, the predictive power of PA for word-level reading accuracy was significant in beginning readers but not in intermediate readers. The results were consistent with previous studies . For exaWhile there have been a great number of studies investigating RAN and reading fluency, studies examining the relationship between writing fluency and reading fluency are limited. Previous studies found that the effect of writing on reading was less robust and inconsistent in alphabetic systems, but research on Chinese had demonstrated writing to have a beneficial effect on reading development . For exaMoreover, we found that children who were more affected by visual crowding also performed worse in the reading fluency test. Visual crowding contributed unique variance to reading fluency of Chinese after the effects of RAN, PA, and writing fluency had been controlled. Despite crowding being well-known as an essential bottleneck to reading in the periphery, there has previously been a dearth of research into what the role of crowding is in reading development relative to other cognitive factors. During Chinese reading, it was found that there was both within-character (predominantly in complex characters) and between-characters crowding, with the latter being much stronger . The strOur findings have important implications for the potential treatment for individuals who suffer from reading disabilities, particularly in terms of reading fluency. Previous studies demonstrated that intensive instruction in phonological skills improved children’s decoding and word identification but provided only minimal gains in reading fluency , whereasFinally, there are some limitations to this study that are worth mentioning. First, in the Stroop task, we used squares instead of words that were unrelated to color in the neutral condition. The difference in visual complexity (squares vs. words) between the neutral and incongruent conditions may influence the differential time that we used as an index of the interference effect. Second, for the visual crowding test, different numbers of options were provided to the children in the VCC and VCG conditions. Although we did not directly compare between the two conditions and instead conducted correlational analyses between reading performance and crowding effect separately for the VCC and VCG conditions, this resulted in incomparable baseline accuracy for the VCC and VCG conditions and affected the values of visual crowding strength. Future studies are needed to overcome these limitations and to employ more sophisticated manipulation of the spatial and temporal relations between the targets and flankers to better characterize and understand the influence of the crowding effect on reading and particularly to identify at which stages of reading the crowding has its effect. Third, the data presented in our study were cross-sectional and correlational, so we could not make any causal assertions. Further studies using a longitudinal design are essential to further explore the causal effects of cognitive factors on reading fluency in Chinese children.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Institute of Psychology Chinese Academy of Sciences. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.JB, WL, YY, WH, and MX designed the research. JB, WL, WH, and MX performed the research and analyzed the data. All authors wrote 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.


Over the past decade, there has been an increasing interest in the relationship between participation in collective gatherings and rituals and different important psychosocial variables and processes, such as social sharing of emotions, group cohesion, identity fusion, prosocial tendencies and behaviors, and well-being e.g., . These s In this part, we examine different conceptions of the emotional experience lived by respondents during their participation in a group gathering that could help to elaborate our construct. Perceived emotional synchrony (PES) is a proxy for the notion of intense shared emotional experience introduced by Other social psychologists observe that, in a collective gathering, emotional synchrony pulls humans fully but temporarily into the higher realm of the sacred, where the self disappears and collective interests predominate. The realm of the profane, in contrast, is the ordinary day-to-day world, where we live most of our lives, concerned about wealth, health, and reputation but nagged by the sense that there is, somewhere, something higher and nobler . From ouThe emotional experience during collective gatherings is influenced by a wide variety of variables, some of them being indispensable criteria for it to occur . For ins1.Perceived emotional synchrony is a process that occurs when there is a collective gathering, shared focused attention, and behavioral synchrony that potentially elicits a collective emotional state. PES is a subjective process or the shared perception of entrainment, coordination, and synchronization of the affective experience. It is the emergence of high arousal emotions and, at least in part, of strongly positive emotions  in the participants in a successful collective gathering , 2019. PItems appraise two main aspects of PES: emotional communion or intense sharing of emotions and feelings of unity see . ExploraFactor analysis of PES has consistently resulted in a unidimensional structure. This structure has emerged in exploratory factor analyses of multiple samples, and CFA of the scale scores have resulted in adequate fit to a unique-factor model .M = 42.75 years, SD = 13.98), most of them (89.2%) residents of San Sebastian (Spain) and the rest of the people living around there, volunteered to complete the study forms. The sample was composed of several social groups, 57% married, 53% have children, 73% employed, and 11% unemployed.We used a sample in the analysis of the structural validity of the PES. The group was Folk Festival-Tamborrada . A totalTown hall officials and coordinators of folkloric companies were contacted to recruit volunteers who would participate in the Tamborrada held on January 20, 2013. Longitudinal observations were analyzed in this study. Thus, encrypted personal e-mails were used to collect data online at three different measurement times .First, we computed reliability estimates, Cronbach’s alpha, and corrected item-total correlations using SPSS 21 and McDonald’s Omega using Omega, and we averaged these item-total correlations. We then created working scales containing the six items with the highest mean item-total correlations. A minimum alpha of 0.65 was desired; a previous work had referred to 0.65 alpha as satisfactory for a 5-item scale see .H values (>0.80) suggest a well-defined latent variable, which is more likely to be stable across studies. In our case, we obtained a highly H-latent value of 0.981 and H-observed of 0.932. H-latent assesses how well the factor can be identified by the continuous latent response variables that underlie the observed item scores, whereas H-observed assesses how well it can be identified from the observed item scores. Subsequently, driven by theory and previous analysis, we tested a unidimensional model of PES for both long and short versions by the mean of CFA (2 (100. N = 550) = 639.648, p < 0.001; CFI = 0.939; TLI = 0.927; RMSEA = 0.099 ; SRMR = 0.032]. The standardized estimates, i.e., factor loadings and factor correlation, are displayed in Parallel analysis (PA) based on principal component analysis  with 500n of CFA . In the 2 (100. N = 550) = 639.648, p < 0.001; CFI = 0.939; TLI = 0.927; RMSEA = 0.099 ; SRMR = 0.032]. The standardized estimates, i.e., factor loadings and factor correlation, are displayed in Several considerations guided the construction of the short form. As in the development of other measures, we sought to maximize the reliability and validity of the instrument. Reliability and content validity, however, are often in conflict during the construction of short forms. Therefore, in addition to considering item-total correlations, our decisions regarding inclusion of items were also based on thorough examination of the content of individual items and within-scale factor analysis of the original scales. We included three items of felt unity  and three of shared intense emotionality  that had the highest coefficients with the latent variable. Item nine has a high load, but the semantic content overlaps with items of the scale of fusion identity , and it In addition to its reliability and structural validity, incremental validity of the PES scale was tested because the usefulness of any test is questioned if it cannot account for additional variance in relevant criteria such as well-being. When testing the incremental validity of PES, the primary concern was whether it was incrementally valid beyond theoretical constructs that explain the effects of collective gatherings, such as social identification, arousal, and rumination . RecentlThis study was conducted around a patriotic paramilitary parade in Chile. On May 21, Iquique’s Naval Combat and the role of Arturo Prat are recalled through the organization of military civic parades between members of the Navy and students of various public and private schools. The school parades have pseudo-military characteristics because they imitate the instrumental and war bands of the Chilean armed forces. A territorial conflict was active in this year between Bolivia and Chile. A product of War of the Pacific (1879–1883), Bolivia was left without sovereign access to the sea, and an important part of its territory became part of Chile. Bolivians demanded a sovereign exit to the Pacific Ocean, and on the other side, Chile shows willingness to make commercial concessions but without territorial cession. Chile and Bolivia were in litigation in 2016 before the International Court of Justice of The Hague because Bolivia demands that the court force Chile to negotiate an exit to the sea. This patriotic parade is aimed to enhance nationalist and pro-war attitudes. This longitudinal study analyses if different mediators explain disposition to fight for the country and negative attitudes toward relevant national out-groups.M = 16.86, SD = 0.61) from a high school in Puchuncaví , who participated in the parade of the Naval Glories – also known as the 21st of May Parade. Participants completed self-reported measures at T1 (4 days prior the gathering), T2 (the day after participation), and T3 (4 days after the event). The students completed the questionnaires in the classrooms, in the computer room, and during the parade. The students did not gain any benefit from participating in the study.Participants were secondary school students belonging to the municipal education of a working class neighborhood. Data collection took place in May 2016. The sample was composed of 65 students .Out-group negative emotions . In a second step, we introduced the second mediator: identity fusion of T2. Finally, in the third step, PES-S scores were included.Results show that, for every analysis, baseline scores predict the criterion variables. In Step 2, when changes in Chilean identity and identity fusion was included, the last one explained every dependent variable – marginally in the case of negative emotions. Finally, at Step 3, the inclusion of PES-S was a significant predictor of defense of Chile, and fusion of identity was a significant predictor of negative emotions in the last step see .This study was conducted on the campus of the University of Louvain, addressing newcomer hazing, a costly ritual  frequently practiced in (a.o.) fraternities, sororities, military organizations, or athletic groups. To illustrate, participants may have to crawl through a muddy field while someone curses and yells at them. Such practices are worrisome due to their potential danger, whereas advocates stress social cohesion outcomes e.g., . DependiMage = 18.74, SD = 1.00, with an equal number of men and women) linked to different hazing committees, depending on their area of origin and type of study, participated in all three measurement times: (1) baseline levels of dependent variables assessed just before hazing, (2) potential mediators halfway through hazing, (3) dependent variables 3 days after the final hazing ceremony. Questionnaires were paired using a specific code for each participant.One hundred twenty freshmen .Emotional climate . We usedThe first mediator is a measure of change of social identification during the hazing. The second and third mediators, experience-elicited arousal and experience-related thoughts, constitute proxy measures for the high-arousal intrapersonal model of costly ritual. The fourth one, PES, aims at appraising the model based on the socially shared experience.2. An indicator of the change in identification in the period of hazing was then computed (T3–T1).Social identification . Three questions were used: “Overall, how much stress or trauma did you experience during the hazing?” “How intense was this experience for you?” “To what extent did you feel anxiety during this experience?” Ratings  were averaged in a single index, α = 0.72.Experience-elicited arousal (ad hoc). Three questions assessed respondents’ thinking of the ritual . “Since the event, to what extent has it occupied your mind?” “Do you ever experience thoughts, mental images, memories about hazing?” “To what extent do these thoughts monopolize your attention?” An average thought score was established, α = 0.70.Experience-related thoughts  with a significant mate see .Overall, the incremental validity of PES-S was confirmed through two studies on partially negatively valenced rituals, including a negative or costly ritual. Our studies emphasize the relevance of emotional synchronization in collective gatherings conducive to strong forms of social identification, particularly the overlapping of the individual with the collective self. However, studies also show the relevance of emotional sharing and of positive emotions.The short form includes three items of felt unity and three of shared intense emotionality. As antecedents, we included an item on shared focalized attention and Another element that is emphasized in the experience of collective gatherings and demonstrations is the joy of being together or the positive valence of being together . We propTo assess the process of social identification with other participants in the collective gathering, we add three items used by SCT authors , and forHow do instances of collective gatherings as collective rituals, secular, and religious ceremonies, enhance well-being even in the case of a negatively valenced event? We propose that collective effervescence or PES is one of the main explanatory variables of this effect. PES is a process that occurs when there is a collective gathering, shared focused attention, and behavioral and emotional synchrony. It is the shared perception of entrainment, coordination, and synchronization of the affective experience. This group state of high emotional arousal related to intensification of emotions, irrespective of the content and form of the collective gathering, evokes unison and connection with others and empowers the individual.A short form of PES was described in this paper. Reliability and content validity, however, are often in conflict during the construction of short forms. When questionnaire items are chosen for inclusion in a short form based solely on high item-total correlations, the result is often a scale that measures only a narrow portion of the original construct, a phenomenon referred to as the “attenuation paradox” . In the Contact with sacred values and transcendent emotions or a collective identity process, like social identification or cognitive categorization as in-group members, or a more affectively loaded process of collective identity such as fusion of identity, were excluded as items and contents because they are potential outcomes or alternative explanatory variables.Our results clearly favor the inter-individual process of socially shared emotional experience over the intra-individual cognitive process such as social identification and rumination even regarding effects of relatively negatively valenced and costly rituals. More specifically, we showed that PES always significantly increases the explained variance of all but one dependent variable above and beyond other factors .When people are gathered together in a costly ritual, an out-group anger-related parade or a funerary ritual, group members communicate in the same thought and action, they share and synchronize emotion. A successfully conducted collective gathering that induces a middle to high level of PES helps in the creation of an emotional atmosphere or climate, which is the expression of how the majority of people feel regarding the group’s current situation  as was fr = 0.49 and r = 0.44 in section “STUDY 1” and section “STUDY 2,” respectively, and with fusion of identity r = 0.62 in section “STUDY 2”). Social identity, as an internalized sense of shared group membership, and an associated sense that one is part of a bigger “us” is related to low depression and well-being (Far from excluding other variables, our results suggest that PES adds some explanatory power to a multifactor mechanism. For instance, social identification is probably a necessary condition for fusion, and both processes are relevant as shown in other studies. In fact, the baseline level of social identification shows positive correlations with PES (ll-being .Fusion of identity plays a specific role by reinforcing negative emotions toward out-groups, confirming the affective load facet of this process . On the Nevertheless, in the present data, an interpersonal and group process like PES demonstrates its superiority in predicting the effects even of costly rituals. Our studies are not alone in reaching this conclusion. In conclusion, our review and empirical studies emphasize the relevance of emotional synchronization in collective gatherings conducive to strong forms of social identification, particularly the overlapping of the individual with the collective self. However, studies also show the relevance of emotional sharing and of positive emotions. Globally, our review of models and studies reaffirm the importance of shared emotional experiences during collective gatherings and rituals, justifying the evaluation and measurement of the construct of perceived emotion synchrony as a proxy indicator of these processes of collective effervescence.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethical Committee of the University of the Basque Country. The patients/participants provided their written informed consent to participate in this study.AW, LZ, PB, JP, and FH planned and collected the data. NB and BR were involved in planning and supervised the work. All authors processed the data, performed the analysis, drafted the manuscript, designed the figures, performed the calculations, discussed the results, and commented on 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.


Prevalence of hepatitis C virus (HCV) infection among people who inject drugs (PWID) in Iran is high. Since 2005, the Iranian government has implemented a harm reduction program to control HCV. We aimed to describe the prevalence of HCV antibody (Ab) in Iranian PWID before and after the implementation of harm reduction with cumulative meta-analysis.Following PRISMA guidelines, we conducted a systematic review and meta-analysis of studies published on the seroprevalence of HCV among PWID. We systematically reviewed the literature to identify eligible studies up to December 2018 in international and national databases. Pooled prevalence and 95% confidence intervals were calculated using Der Simonian and Laird method, taking into account conceptual heterogeneity. Subgroup analyses were performed by harm reduction implementation and studies’ characteristics to assess the sources of heterogeneity. We used Cochran–Armitage test for the linear trend of the prevalence of HCV Ab among PWID.P = 0.04). The cumulative meta-analysis showed a slight decline in the prevalence of HCV Ab between the years 2005 and 2018.We reviewed 5966 papers and reports and extracted data from 62 eligible records. The pooled HCV Ab prevalence among PWID in Iran was 46.5% . Overall, the Cochran–Armitage test for trend indicated a significant decreasing trend of HCV Ab prevalence (The HCV Ab prevalence among PWID in Iran is high, with a considerable geographical variation. The prevalence of HCV Ab among PWID in Iran slightly decreased after 2005 which could be, at least to some extent, related to the implementation of extensive harm reduction programs in the country. Hepatitis C virus (HCV) infection is the main global health concern. The global prevalence of viraemic HCV infection is estimated to be 1% in 2015, corresponding to 71.1 million 62.5–79.4) viraemic infections . No effe viraemicIn Iran, during the end of 1990s and early 2000s, drug injection was common and general knowledge of PWUD on blood-borne infections was low , 24. In Previously, a systematic review had been conducted on the HCV prevalence among PWID in Iran, and the included studies were conducted from 2000 through 2016 . The curAn extensive and comprehensive search was done in the international , regional (IMEMR), and national (Barakat Knowledge Network System) databases in December 2018. To access studies not yet published by that date, expert authors in this field were contacted. Moreover, the reference lists of the studies included in the final analysis as well as previous systematic reviews conducted in Iran were reviewed , 35. In A broad search was conducted using the MeSH terms and text words (and their combinations and truncated synonyms) of geographical location  and HCV in electronic data sources including PubMed, EMBASE, Education Resource Information Center, MEDLINE, MEDLINE in process, PsycINFO, Scopus, and Web of Science, Iranmedex, Google Scholar, Iranian Data Bank of Hepatitis Research, Scientific Information Database (SID), Magiran, and the Iran Blood Transfusion Journal. In our search strategy, we did not apply any limitations in the time of publication and language. Iranian databases were searched using the related keywords and the Persian equivalents of HCV, considering all possible combinations. We reviewed the titles and abstracts to select potentially relevant papers. If there was doubt about the suitability of the paper based on the abstract, the full text was reviewed. We manually searched the references and relevant articles for inclusion. We also looked at the electronic abstract list of congresses conducted in Iran and also at the electronic database of students’ thesis through universities’ electronic libraries and Web sites. Furthermore, we searched and identified studies that were not captured by our database by reviewing the previously published meta-analyses and the reference lists in retrieved articles , 35, 38.All records identified through our search were imported into an EndNote library where duplicate publications were identified and excluded Fig. . SimilarThe objective of screening was to identify the scientific documents with epidemiological evidence on the prevalence and/or incidence of HCV Ab among PWID. The following five eligibility criteria were used in the selection of relevant studies: document type, study design, disease area, geographical setting, and population.Concerning the document type, all scientific documents reporting original data , in the form of a peer-reviewed manuscript, progress report, abstract, technical report, or substantive scientific commentary, were included. Documents not reporting epidemiological data  and those not reporting original data , as well as documents lacking scientific and methodological details needed for the assessment of the validity of findings , were excluded. Documents that were self-described as “systematic reviews” or “meta-analyses”  were retained for hand searching of the references. All study designs reporting data on the prevalence and incidence of disease, including cross-sectional studies, cohort studies, population case–control studies, and even experimental studies  in which a biological survey was conducted to test for HCV before the introduction of the intervention (baseline) were included. Case reports, case series, and qualitative studies were excluded. For the disease area, studies with biological evidence on infection with HCV were included. Self-reported data on the diseases were excluded. The geographical scope was limited to studies conducted within Iran; the studies conducted among Iranian populations residing outside of Iran were not included. For the study population, studies conducted in human subjects who self-identified as current or former drug users were included. Studies on populations who were in short-term mandatory drug treatment and rehabilitation detention centers were included. Studies in non-human subjects, blood donors, dialysis patients, pregnant women, families or sexual partners of HCV/HBV patients, and populations with other chronic diseases  were excluded. No limits were set on study implementation or publication date.Two authors (AR and HSH) reviewed the retrieved studies independently, and the following information was extracted: name of the first author, year of publication, date of study, location of study, total sample size, the prevalence of HCV Ab, recruitment setting, and recruitment method. The third author (SMA) was determined as the arbiter to resolve any disagreements.Two independent investigators (AR and HSH) assessed the quality of the studies using the Critical Appraisal Skills Programme (CASP) tools for observational studies  and a cr2, Tau2, and X2 were applied to assess heterogeneity among studies. The “metaprop” command was used to calculate the pooled prevalence of HCV Ab and the prevalence in different subgroups, by available geographical locations and study settings. The pooled prevalence of HCV Ab before 2005  and during and after 2005  was presented in a forest plot, and the heterogeneity of studies conducted in each period was estimated. The Q test was applied to assess heterogeneity between periods. Furthermore, the presence and the effect of publication bias were investigated using a combination of the visual inspection of funnel plots and Begg’s and Egger’s tests. Moreover, a trim-and-fill analysis was performed to assess the stability of overall prevalence when the results suggested obvious publication bias. The prevalence of HCV Ab for each province was also calculated and depicted on the map, using the GIS software.The extracted data were entered into the Excel software. Then, Stata 16.0 was used for analysis. Pooled prevalence and 95% confidence intervals were calculated using Der Simonian and Laird method, taking into account conceptual heterogeneity, and ITo assess differences in the accumulation of evidence for HCV Ab prevalence in PWID in Iran, cumulative meta-analyses were conducted. The cumulative meta-analysis provides cumulative pooled estimates and 95% CIs. As studies are successively added, the overall prevalence and 95% CIs are recalculated providing evidence of the evolution of HCV Ab prevalence over time. To assess the sequential contributions of studies and evaluate changes in HCV Ab prevalence over time, studies were added alphabetically by years of implementation to a random-effects model using the “metacum” user-written command in Stata version 16.0. Besides, the sequential contributions of studies were evaluated before 2005 and during and after 2005 for HCV Ab prevalence over time by cumulative meta-analysis.For investigating the trend of HCV Ab prevalence over time, the pooled prevalence every 3 years was estimated and presented in a line graph because the number of studies conducted in each year was few. The Cochran–Armitage test for linear trend was used by Winpepi software to test the variation in the prevalence of HCV Ab.A total of 7550 documents were found through searching databases, and 300 were retrieved through other review articles. After removing the duplicates, the titles and abstracts of 5966 documents were screened, of which 5683 documents were excluded because of not meeting the study criteria. If the inclusion criteria were not clear from the abstract, the full text was assessed. In this stage, 221 documents were excluded for different reasons. Finally, data were extracted and subjected to a meta-analysis from the remaining 62 documents  , among PWID in Iran  and Chaharmahal Province , respectively. There were no data for 14 provinces  of Iran. In Tehran, the capital of Iran, and in Isfahan with the highest sample size, the pooled HCV Ab prevalence was 47.0% (95% CI 35.2–58.9%) and 40.6% (95% CI 31.9–49.3%), respectively.The prevalence of HCV Ab according to the provinces is presented in Fig. P value = 0.39)  and 44.6% (95% CI 37.6–51.6%), respectively . The Cochran–Armitage test for trend indicated a significant decreasing trend of HCV Ab in PWID in total .Figure P value = 0.17). However, trend analysis results indicated a statistically significant decrease in HCV Ab prevalence among PWID in the hospitals and healthcare centers  and DIC settings   and Egger’s regression intercept 1.43 . Trim-and-fill method for calibration of publication bias was performed. However, the missing study was not identified by the trim-and-fill method.When we plotted the prevalence estimates against their standard errors, there was no publication bias Fig. . FurtherP value = 0.08), study type as cross-sectional versus case–control study , sampling method as random sampling versus convenience sampling , recruitment setting as hospitals and healthcare centers versus prison , DIC versus prison , and community-based setting versus prison . Univariate meta-regression showed that the 8.81% of between-study variance is explained by date of study, 0.22% by study design, 0.0% by sampling method, and 21.88% by recruitment setting.The results of the univariate meta-regression analyses for investigation into the sources of heterogeneity showed that only the recruitment setting had a significant effect on HCV Ab prevalence: date of study . The regional differences, at least somewhat, might be as a result of variations in time of the study and recruitment settings. It might also be due to differences in socio-demographic characteristics, access conditions for study participants, and high-risk behaviors of PWID in provinces of Iran. In addition, the number of studies conducted in each province is different. In a study  conducteDespite the above-mentioned limitations, the results of this meta-analysis are valuable due to its large sample size, offering evidence to support the hypothesis that after the extensive implementation of harm reduction programs in Iran, the HCV epidemic among PWID has been controlled. We also performed a cumulative meta-analysis by the study date to investigate a trend of the HCV Ab prevalence, and the result indicated that our conclusion was robust when more new studies were added.There is a large burden of HCV infection among PWID in Iran. The prevalence of HCV Ab in PWID decreased after 2005, and although not significant, there seemed to be lower prevalence estimates in later years. There are great variations in the prevalence of HCV Ab between different provinces. However, there is no sufficient information available from many provinces. Overall, the results of our study supported the effectiveness of harm reduction program in reducing HCV transmission.


Previous studies only focused on different adverse reactions caused by various platinum drugs, but not on common immunotoxicity caused by the accumulation of elemental platinum. Here, we determined the serum platinum concentrations of cancer patients after a metabolism period of platinum drug chemotherapy, in addition to hematological indices and subsequent immune-related adverse reactions, then analyzed the correlations between platinum accumulation, immune cell levels, and immune-toxicity. We chose the day before the next round of chemotherapy as the specified time point for blood sampling. Samples were collected at five time points, separately in oxaliplatin and cisplatin groups. The median serum platinum concentrations in all patients was 294.8  μg/L, and was approximately two-fold greater in the cisplatin group than in the oxaliplatin group (429.3 vs. 211.7 μg/L). The platinum level of both groups peaked at the third time point, with the average of females being higher than males (383.9 vs. 266.5 μg/L), and was positively correlated with leukocyte and platelet counts, but negatively correlated with erythrocyte counts and concentration of hemoglobin. The risks of anemia and adverse reactions were individually increased by 0.002- and 0.007-fold for every μg/L increase of platinum concentration. To our knowledge, this is the first study on the relationship between platinum accumulation, immune cell levels and toxicity, showing that drug-induced platinum accumulation may interfere with immune cells and thus increase the risk of toxicity. Chronic lead nitrate exposure results in decreased rat erythrocytes, hemoglobin, lymphocytes, and monocytes, and mercury exposure results in release of ROS, which inhibits IL-2-dependent signal transduction and reduces proliferation and survival of T cells  in the Cancer Hospital of Shantou University Medical College. All patients were eligible for enrollment and exclusion conditions before medication shown in Oxaliplatin has a half-life of 46 h, whereas cisplatin has 72 h. In theory, both drugs should be cleared completely after 5.5 times the half-life, which would be 10.5 days for oxaliplatin and 16.5 days for cisplatin. The time interval of chemotherapy was set at three weeks between rounds, according to drug elimination and the clinical requirements of the NCCN. We chose the day before the next round of chemotherapy as the specified time point for blood sampling and collected samples at five time points for the corresponding courses. Finally, we obtained 187 cases after eliminating invalid samples, 89 for oxaliplatin and 97 for cisplatin, from January to December in 2018. The dosage of oxaliplatin and cisplatin was set by the oncologist according to body surface area and the NCCN, as shown in Whole blood was extracted by elbow venous in all cases. A total of 1 ml was extracted in a heparin anticoagulant tube for hematological index analysis, and 3 ml was centrifuged  to obtain serum for platinum measurement. Adverse reactions were simultaneously recorded. All protocols in this investigation were approved by the Human Ethics Committee of the Cancer Hospital of Shantou University Medical College, China (2015030907). All patients signed informed consent.Hematological indices were measured with an automatic blood analyzer  immediately after sample collection by the methods on impedance measurement and cyanated methemoglobin colorimetric procedure.A total of 100 μl serum sample and 900 μl 0.5% nitric acid  were mixed by vortexing and quantified by graphite furnace atomic absorption spectrophotometry . Parameters for the AAS-650 were a 265.9 nm wavelength, 0.2 nm slit width, 8 mA Pt-lamp current and the temperature program was shown in Adverse reactions were assessed and recorded by a clinical doctor at each time point, based on The Common Terminology Criteria for Adverse Events . We recorded the adverse reactions, including diarrhea, nausea, emesis and allergy, and classified them into five grades (from 0-no symptoms to 4-severe life-threatening).th–75th percentile, the comparison of rates was performed by the chi-square test, skewed data was compared by non-parametric testing (Mann Whitney U test), and correlation analysis was performed by Spearman rank correlation analysis. The concentration-response relationship was analyzed by binary logistic regression. All analyses were performed with SPSS 22.0  and GraphPad Prism 7.0  software. A P<0.05 was considered as statistically significant in all analyses.Nonparametric analysis was performed, using the Kolmogorov-Smirnov test, for frequency distribution; data with skewed distributions was represented by median and 25P>0.05, In this study, there were 89 patients who were treated with oxaliplatin and 97 with cisplatin, with a higher proportion of female patients and lower average age in the cisplatin-treated group. No significant differences were found in height, weight and BMI between the patients in both groups  μg/L in all subjects, with the cisplatin group being significantly higher than oxaliplatin, 429.3  vs. 211.7  μg/L,  for females and males, respectively.We grouped the serum platinum data by gender and found the median level was significantly higher in females than males, with median values being 383.9  vs. 266.5  μg/L (P<0.05). On the contrary, erythrocyte count and hemoglobin took higher levels in the low platinum group (P<0.01). There is no significant difference on platelet between the two groups.We divided the cases into low- and high-platinum groups by the mean of the natural logarithm of platinum concentration, compared the hematological index in the two groups . To determine the correlation between anemia and platinum, a binary logistic regression model was used with occurrence of anemia as a dependent variable  and platinum as an independent variable. The results showed that the risk of anemia increased 0.002-fold for every unit (μg/L) increase of serum platinum concentration .We recorded the adverse reactions related to immune toxicity of tumor patients and observed almost no serious events . In order to further analyze the concentration-response relationship between serum platinum and adverse reactions, a binary logistic regression model was used with the occurrence of adverse reaction as a dependent variable , serum platinum concentration as an independent variable, and following adjustment for gender and age. The results showed that the risk of adverse reactions was increased by 0.007 times for every unit (μg/L) increase of serum platinum concentration, after adjustment with gender, age, surgery, cancer types . It is the first time to compare platinum accumulation of these two drugs, although a study on cisplatin has been reported indicating its continued presence 20 years after therapy . The ori in vivo . Our fin in vivo . In addi in vivo , autopha in vivo , and acq in vivo . As a rein vivo and stimulate the immune response  result from toxicity to rapidly dividing cells , but morresponse .Heavy metals can interfere with inflammation mediated by leukocytes and their subsets. For instance, cadmium affects the telomere length of leukocytes and immune regulation , lead anOn the other hand, serum platinum may result in anemia, as shown by the negative correlation with erythrocytes and hemoglobin, and regression analysis showed the risk of increasing platinum on anemia, which is similar to other divalent metals due to a competitive inhibition of iron ion . ErythroIn all, we conducted a study on the relationship between platinum accumulation, immunocytes and subsequent adverse reactions. The results show significant correlations between all three, as well as differing toxicities in different genders. All results demonstrate that drug-induced platinum accumulation may stimulate the immune system, as is the case with other heavy metals, and further lead to immune toxicity. Influences on adverse reactions and anemia risk mediated by platinum accumulation suggests that quelation therapy and nourishment to enhance immune function for patients should be considered. The mechanism of platinum resistance is still not clear, but our study suggests that it may due to the platinum accumulation resulting from subsequent rounds of chemotherapy. More and intensive study on the mechanism of immune toxicity caused by platinum accumulation should be carried out in the future.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Human Ethics Committee of the Cancer Hospital of Shantou University Medical College, China (2015030907). The patients/participants provided their written informed consent to participate in this study.LF is the corresponding author of this manuscript. He conceptualized, analyzed the platinum-immune toxicity assessment, performed and wrote the statistical analysis described in this manuscript. YZ is the first author of this manuscript. She measured the concentrations of platinum and analyzed the relationships between the platinum and adverse reactions. JZ collected and stored the blood samples, and administered the questionnaires with patients in the hospital. YJ is the physician of medical oncology. He implemented the therapeutic regimen and assessed adverse reactions of patients. XH is the clinical laboratory doctor. He took responsibilities for the hematological index analysis. All authors reviewed the manuscript.This work was supported by the Science and Technology Plan of Shantou (2016-6) and the Youth Research Fund of the Cancer Hospital of Shantou University Medical College.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.


Plasmodium falciparum/Plasmodium spp P.f/pan) versus microscopic tests for the diagnosis and treatment of gestational malaria in Colombia.Gestational malaria is associated with negative outcomes in maternal and gestational health; timely diagnosis is crucial to avoid complications. However, the limited infrastructure, equipment, test reagents, and trained staff make it difficult to use thick blood smear tests in rural areas, where rapid testing could be a viable alternative. The purpose of this study was to estimate the cost-effectiveness of rapid tests type III  were estimated. The cost using thick blood smear tests was US$50,838 and 1,023 DALYs, for an incremental cost-effectiveness of US$ 101.2. The probabilistic sensitivity analysis of rapid diagnostic tests determined that they are highly cost-effective in 70% of the cases, even below the US$1,200 threshold; also, they showed an incremental net monetary benefit of $150,000 when payer’s willingness is US$1,000.The use of rapid diagnostic tests for timely diagnosis and treatment of gestational malaria is a highly cost-effective strategy in Colombia, with uncertainty analyses supporting the robustness of this conclusion and the increased net monetary benefit that the health system would obtain. This strategy may help in preventing the negative effects on maternal health and the neonate at a low cost. Malaria is a public health problem worldwide. In 2018, the World Health Organization (WHO) reported 228 million cases of the disease, more than 400,000 deaths, and Africa as the most affected region. In America, 21 countries are endemic with Brazil, Colombia, Guyana, Haiti, Peru, and Venezuela reporting more than 90% of cases . Other cThis situation, together with the high burden of PAM has led to increased research efforts aimed at reducing its negative effects, mainly in high-risk groups. Works published include meta-analyses showing the effectiveness of intermittent preventive treatment in pregnant women (IPTp) in reducing the risk of maternal anaemia up to 40%, 39% of miscarriages and 19% of LBW, as well as the effectiveness of insecticide-treated bed nets, preventive treatment in HIV-positive pregnant women, and infant prophylaxis , and theGiven that the disease mainly affects poor countries, experts have recommended the inclusion of economic studies as a research priority, aimed at identifying effective, safe and cost-effective strategies that guarantee their provision by the government . In respThese findings show that economic evaluations are still limited, demonstrating a gap in the knowledge about the economic impact of PAM, that the evidence is concentrated in Africa, where the WHO recommends the use of bed nets and IPTp-sulfadoxine-pyrimethamine (SP) which has not been evaluated in America.Particularly in Colombia, to avoid the complications and the sequelae of PAM, new cases are actively detected using thick blood smears during prenatal control in endemic areas . HoweverPlasmodium spp. antigens through lateral flow immunochromatography devices, known as rapid tests, can be applied in the field, they do not require specialized personnel or equipment, they are easy to use, and have showed an adequate diagnostic performance when compared to PCR [Molecular testing has shown the best results in terms of PAM diagnosis, including sub-microscopic infections; however, its high costs, lack of infrastructure, equipment and trained personnel, make it unfeasible in endemic areas. Conversely, the detection of d to PCR , even sud to PCR . Certaind to PCR . These tPlasmodium falciparum/Plasmodium spp P.f/pan) in the diagnosis of gestational malaria, compared to microscopic tests, from an institutional perspective in Colombia.In Colombia, the cost-effectiveness of these tests is unknown. This study was conducted to estimate the cost-effectiveness of rapid tests type III , 3.5 million inhabitants from 241 endemic rural municipalities  without Plasmodium spp antigens. Histidine-rich protein II (HRP2) expressed by P. falciparum or parasite lactate-dehydrogenase (pLDH) metabolic enzyme, expressed by all species of Plasmodium spp. (Pf/pan) using lateral flow immunochromatography devices containing antigen-specific monoclonal antibodies from mice.Qualitative detection of P. falciparum-positive if 2 colour bands are observed in lines ‘P.f’ and C, or 3 colour bands in lines P.f, ‘Pan’ and C; the test is considered positive for another species of Plasmodium  if 2 colour bands are observed in lines Pan and C. A colour band should always be observed in line C, otherwise it is considered as an invalid result and the test must be repeated.After using a cotton swab to clean the fingertip with alcohol, it is pricked on one side using a sterile lancet. The first drop of capillary blood is discarded. Using a capillary tube (5 µL), the whole blood sample is collected until it reaches the black line and transferred to the cassette sample well. Four drops of diluent are added vertically for testing in the well. The result is read after 15–30 min. A result is considered negative if a colour band is observed in line ‘C’; it is Thick blood smear through conventional microscopic test.DALY, a combined measure that considers morbidity, mortality and disability, it was used to calculate and study the burden of the disease. It is equivalent to a year of healthy life lost due to illness, disability or premature death and allows for comparison between different pathologies or interventions, and it helps in decision making related to health and resource prioritization , 29.The following components were taken into account: (i) life expectancy taken from previous studies about the burden of the disease in Colombia; (ii) age weighting, which confers greater importance to the years of healthy life of young people due to their greater reproductive capacity; (iii) disability weighting, which reflects the relation between the specific disability during the disease’s duration and the time lost due to mortality within a range from 0 (zero), for perfect health, to 1 (one) for a health status leading to death; and, (iv) discount rate, which gives greater importance to current benefits compared to future ones . For theDALYs were calculated using the WHO Global Burden of Disease study project Excel spreadsheet by introducing the following data from SIVIGILA  and studies about malaria burden of disease in Colombia , 29–31:K = 0.5. Age weighting as a modulating factor .β = 0.04. Parameter for age weighting function.r = 0.03. Annual discount rates for life years in terms of time preference.C = 0.1658. Model constant, standard-age weighting.A: Age of death due to gestational malaria.L: Life expectancy of 80 years for men and 82.5 for women.D: Disability weight, 0.195 for cases in women under 15 years of age and 0.172. for women over 15 years of age, according to the WHO’s disability weights.As: Patient age at the onset of the disease, considering the percentage distribution of malaria cases in women from adolescence to 44 years of age, the average onset age in each group with five-year interval according to the WHO, and studies about the burden of the disease in Colombia.Ld: Duration of the event according to studies about the burden of disease in Colombia: 10.4, 23.3, and 36.5 for age groups between 5–14, 15–29, and 30–44 years, respectively , 29, 31.Less than one year, consistent with the duration of pregnancy and prenatal control that include screening for malaria in endemic areas .Standard costing was performed and validated by three experts using publications on PAM for the identification, measurement and assessment phases. The results were expressed per patient, in Colombian pesos (COP-2019). In the first phase, the cost-generating events described in the management guides and by the experts were identified, which included costs for sampling (laboratory assistant), diagnostic test execution and results reporting (reagents and bacteriologist), costs of treatment  and thick blood smears for follow-up of positive cases. In the measurement phase, the amount and frequency for each identified cost was determined. In the assessment phase, data from the Colombian tariff manuals, such as SOAT  and SISMED , were considered. Since the cost of rapid tests for malaria diagnosis is not included in tariff manuals, micro-costing was performed according to the prices quoted by test suppliers in Colombia.versus molecular diagnosis by PCR [versus molecular diagnosis by PCR [The number of occurred cases was calculated using records from the Colombian Health Situation Analysis (ASIS) and reported cases at endemic areas in SIVIGILA. The probabilities of true positives and false negatives were obtained from a meta-analysis on the performance of Type III (Pf/pan) rapid tests diagnostic performance studies s by PCR  conductes by PCR  was conss by PCR .Decision tree whose initial node shows both the alternatives compared. The stages evaluated correspond to the classification of cases as true positives or false negatives; in case of a positive diagnosis, the second stage includes receiving or not receiving treatment Fig. .Fig. 1DeDiagnostic test specificity shows a trend to 100%  , 33. WheThe average cost-effectiveness ratio was estimated as the cost of each DALY per type of diagnostic test, and incremental cost-effectiveness as the cost of each additional DALY after diagnosis with rapid tests compared to thick blood smears.The uncertainty of the decision model components was assessed through probabilistic sensitivity analysis with Monte Carlo simulations, including a microsimulation with 1,000 individuals, an acceptability curve for different thresholds or willingness to pay, and net monetary benefit (NMB) and expected value of perfect information (EVPI). Thresholds according to WHO  were incP. falciparum/P. vivax-specific test. In addition, the cost of a laboratory assistant (2 min), a bacteriologist (20 min) and aseptic management materials were included. Materials supplied by test providers were not considered. The cost of a thick blood smear, as it appears in the SOAT tariff manual, includes the entire procedure. The cost per species only differed in the cost of the drug, only an averaged value was considered given that the difference was close to US$1. The persistence of parasitic antigens limits their use for follow-up testing [Regarding rapid tests, a micro-costing methodology was used to assess 25 tests with an average cost of 116,400 COP, which could vary by 22% if additional payment is made for the The total cost of the procedure involving a rapid test was US$41.6 per patient, 6.8% of which was related to the diagnosis. The cost of the procedure using thick blood smears was US$42.4, with 8.6% for test performance. For both strategies, the largest proportion of the total cost was for treatment and follow-up (Table Average cost-effectiveness (ACE) of diagnosis and treatment with rapid tests was US$56.6, and with thick blood smear, US$49.7, per DALY. The incremental cost-effectiveness ratio (ICER) showed that each additional DALY, when diagnosis is obtained using rapid tests, equals US$101.2, compared to thick drop smear. High variability was observed in cost estimation for rapid tests, with a standard deviation of US$4,293 and a range between US$412 and US$95,039. For thick blood smear tests, standard deviation was US$3,818 with a range between US$443 and US$81,362. Likewise, standard deviation for effects was 546 DALYs with a range between 98 and 1,536 for rapid tests and 356 DALYs for thick blood smear tests, with a range between 82 and 1,290. Despite this variability, the sensitivity analysis showed that most simulated cases were in quadrants I and III of the incremental cost-effectiveness plane, demonstrating that rapid tests were highly cost-effective in 70% of cases, with a cost below US$1,200. Only 5% of cases showed dominance of rapid tests compared to thick blood smears  also shows that, when WTP equals US$100, rapid tests are the strategy with the highest monetary benefit: in incremental terms, rapid tests sum up to US$10,000 when WTP is equivalent to $200, and up to $150,000 when WTP is equivalent to $1,000, respectively  was equal to US$2.5 million; with a WTP of US$12,000, it was US$1.7 million; with an WTP of US$6,000, EVPI was equal to US$822,929; with a WTP of US$500, EVPI was equal to US$28,813 and, with a WTP of US$200, EVPI was equal to US$11,281. This implies that the cost of uncertainty (maximum amount payable that the system is willing to pay in order to implement rapid tests) is relatively low.This is the first comprehensive economic assessment in Colombia with a cost-effectiveness analysis of gestational malaria diagnosis and treatment at endemic areas. This study collected high-quality scientific evidence that may be used by the government in prioritizing financing strategies for this type of intervention, in order to avoid the negative outcomes of malaria for mother and child. This intervention would also provide benefits for the rest of the population, by interrupting the transmission of the parasite. This would help in advancing towards disease elimination and in the development of other strategies included in the Regional Malaria Elimination Initiative   by extraEven when there have been advances in malaria control over the Americas, the disease remains as a major public health issue in many countries of the region . ParticuMicroscopy examinations are the most common tool for diagnosis and, although they help to quantify parasitic burden, limitations in equipment and experienced personnel make their implementation impossible in remote areas. Therefore, rapid diagnostic tests become a viable alternative in these areas for the active detection and timely treatment of gestational malaria  since thWhile effectiveness measurement is highly heterogeneous in economic assessments, the results from this study are consistent with others that have showed evidence in favour of the use of rapid tests for the diagnosis of gestational malaria. In 2014, a cost-effectiveness assessment of rapid tests compared to thick blood smears in Africa found that the use of rapid tests would render economic savings for the health system that sum up to US$63.47 per case of gestational malaria. This study also states that rapid tests perform better when diagnosing asymptomatic and sub-microscopic infections . SimilarP. falciparum resistance to sulfadoxine-pyrimethamine in Africa have motivated researchers to seek for alternatives in order to prevent PAM complications. One of the most evaluated is intermittent screening and treatment with artemether-lumefantrine (ISTp-AL), a strategy comparable to the one evaluated in this cost-effectiveness analysis, focused on timely diagnosis and treatment of all pregnant women in risk of contracting malaria by using rapid tests. Studies have shown that, although this type of intervention cannot replace IPTp-SP in highly endemic African countries, its effectiveness is comparable if used in areas with extremely high parasitic resistance or low-endemic regions [High rates of  regions , 43. A s regions  in termsP. falciparum, a predominant species in African countries [P. vivax on the health of mother and child. Nevertheless, no differences have been reported on inflammation profiles of placental infection, suggesting that the pathogenicity and health outcomes generated by both species are similar [Although scientific literature worldwide provides extensive evidence of the complications for mother and foetus associated with ountries , 45, lit similar , with ca similar –49.Cost-effective analyses conducted in countries where both species are found, have reported that rapid diagnostic tests show a higher cost-effectiveness rate compared to microscopic examinations or clinical diagnosis. In Afghanistan, rapid tests had higher ICER values than thick blood smears, accounting for US$4.5 per adequately treated patient, compared to clinical diagnosis . In EthiP. vivax and > 83% for P. falciparum, microscopic examinations would be more cost-effective [In Peru, a cost-effectiveness assessment of the general population  reportedffective .In Colombia, rural malaria areas show similar conditions to those in Peru, Brazil and other endemic countries. In these areas, additionally to living far from health centres, pregnant women have unmet basic needs and unfavourable social conditions. The application of rapid diagnostic tests would contribute to improving their health conditions by reducing the time to diagnosis, and increasing the number of patients with an adequate diagnosis and timely treatment in places where no equipment, trained personnel or infrastructure are available for diagnosis through microscopic examination; thus preventing the negative effects on maternal–fetal health and stopping the transmission of the parasite , 52, 54.P. falciparum-specific antigens and a genus antigen that detects Plasmodium spp (P.f/pan), since this type of tests has shown better diagnostic performance compared to immunochromatography incorporating P. falciparum and P. vivax (P.f/P.v)-specific antigens [P. falciparum with HRP2 protein polymorphism increases the risk of false negatives when using rapid diagnostic tests based on this antigen. Nevertheless, tests incorporating genus-specific antibodies have been reported to diagnose P. falciparum infections that would not be detected by species-specific antibodies [Currently, many types of malaria rapid diagnostic test are available, which differ in their diagnostic performance . In thisantigens , 55. Alsantigens . In additibodies .P. falciparum infections during periods of parasite sequestration and P. vivax latent infection. They may go undetected when using microscopic examinations and PCR, as malaria parasites do not circulate in peripheral blood. This would help in providing timely treatment and reduce false negatives, which may increase the risk of complications [Rapid diagnostic tests, as well as microscopic examinations, have detection limits that restrict the diagnosis of sub-microscopic infections. Therefore, in this economic assessment, these infections were considered within the ‘false-negative’ group, to avoid an overestimation of this intervention’s effectiveness and to calculate the burden of disease for pregnant women who have not been correctly diagnosed. Sub-microscopic infections are associated with an increased risk of maternal anaemia and LBW, and are responsible for a high percentage of the transmission in low-endemic areas. They constitute a challenge for malaria elimination schemes because they reduce the performance of diagnostic tests, and consequently the effectiveness of interventions , 57. Desications .P. falciparum and P. vivax for pregnant women. In Colombia, an efficacy study reported that the treatment scheme against both species was 100% effective, with mild adverse effects, comparable to those reported among non-pregnant population [An additional parameter is the efficacy of current treatment against pulation . Consistpulation , 43, 58.This study has shown evidence to demonstrate the high cost-effectiveness of rapid tests for the specific diagnosis and treatment of malaria during pregnancy. The consistency of the results evaluated during the sensitivity analysis, show that even with a cost-effectiveness < 5 times the per capita GDP, this is a high value for most scenarios, compared to thick blood smears. Although few studies evaluate malaria intervention in pregnant women, the results of this study are comparable to those from other countries , 50–53, Limitations of this study include the lack of standardization for some costs of rapid tests and the exclusion of effects such as reduced diagnosis and treatment time, DALYs for maternal anaemia, severe malaria, abortion, congenital malaria, LBW, and stillbirth in the evaluation . In addiThe use of rapid tests for the timely diagnosis and treatment of gestational malaria is a highly cost-effective strategy in Colombia. The Colombian health system would have to invest US$101 for each additional DALY compared to thick blood smears, after incorporating rapid tests during prenatal control. These results are consistent with the results of publications about countries where rapid diagnostic tests have shown high cost-effectiveness, even rendering savings for health systems. They also have demonstrated that they are effective not only for pregnant women, but also for the general population. This evidence shows that active diagnosis and timely treatment through cost-effective tests available in remote locations constitute a key intervention to prevent uncomplicated cases from progressing to serious illness or causing negative effects on maternal health and the fetus, and contributing to the attainment of the elimination target set by IREM and other WHO initiatives.


Cow's milk allergy (CMA) is one of the most prevalent food allergies and the most expensive allergic diseases in the pediatric age. There is no cure for CMA, and actual disease management is based on strict avoidance of cow milk protein-containing foods, access to rescue medication, and use of substitutive formulas. Early-life CMA could be one of the first steps of the “allergic march” (AM), leading to the occurrence of other atopic manifestations later in the life, including asthma and oculorhinitis, with subsequent further increase of costs for health care systems and families of affected children. In the last years, diet is emerged as a relevant strategy to prevent allergic diseases through, at least in part, epigenetic modulation of immune system. We provide an overview of studies that investigate the potential role of different dietary strategies in preventing the AM in pediatric patients with CMA. Affecting up to 3% of children worldwide, cow's milk allergy (CMA) is one of the earliest and most prevalent food allergies (FA) in the pediatric age. It is also responsible for the vast majority of food-induced anaphylaxis cases in the Italian pediatric population, with significant costs for the healthcare system and families, and it emerged as one of the most expensive allergic diseases –8.Although most subjects with CMA naturally outgrow it over time, studies evidence a wide range of ages and rates of resolution with an increased risk of persistence in recent decades, mainly due to negative gene–environment interaction leading to the breakdown of immune tolerance mechanisms –12. In aThere is no cure for CMA, and actual disease management is based on strict avoidance of cow's milk protein-containing foods, access to rescue medication, and use of substitutive formulas –25.Due to the increasing prevalence, persistence, and risk for developing other atopic manifestations in children with CMA, preventive strategies are highly advocated. In the last years, diet is emerging as a relevant strategy to prevent allergic diseases through the active modulation of the immune system . This reBreastfeeding is the best dietary strategy for newborn infants due to its optimal nutritional properties and several bioactive compounds that influence health status. Studies suggest a protective role on the onset of FA, asthma, and AD, both in low- and high-risk infants breastfed for at least 3–4 months –33. A WH5 bacteria daily , in particular, butyrate  are a group of non-digestible carbohydrates that are able to regulate the immune system function in a direct or indirect way. The HMO composition in breast milk is influenced by environmental  and genetic factors, and a possible role in FA has been suggested . Recent e system ; but thebutyrate , 50–54. butyrate .Butyrate may prevent allergy diseases though different ways, involving a regulation of the epithelial barrier , a direct effect on Th1/Th2 cytokine expression, and the activation of regulatory T cells (Tregs) –60. ManyThe origin of butyrate in breast milk is still largely undefined. The mammalian gland is able to regulate the concentration of several macro- and micronutrients in human milk. Thus, it is possible to hypothesize that some mechanisms of regulation could modulate the butyrate content in human milk. However, recent evidence supports the hypothesis that, at least in part, human milk butyrate could be produced by the HMBs. The hypothesis of a pivotal contribution by mammalian gland/breast milk microbiota in butyrate production is supported by recent observations demonstrating the presence of potential butyrate-producer bugs , 61–65.An example of a potential pathway in butyrate production in breast milk could be derived by HMO metabolization by selected bacteria, as recently demonstrated by others , 66.Of note, increasing observations demonstrate the presence of significant butyrate concentrations in breast milk, ranging from 0.01 to >5.0 mM –70 Tabl.In line with these data, our preliminary observation from 109 healthy mothers show a median butyrate concentration in mature human milk of 0.75 mM range 0.16–1.97 mM) . Interes–1.97 mM Altogether, these data strongly suggest the potential pivotal role of a modulation of breast milk composition for innovate preventive strategies against CMA and against the occurrence of AM in CMA children.p = 0.038)  represented a protective factor for other allergic diseases, compared to other hypoallergenic formulas or soy-based formulas  .Lactobacillus rhamnosus GG (LGG)-based diet. Patients were followed up for 36 months. In the complete case analysis (CCA), the absolute risk difference (ARD) for the occurrence of at least one atopic manifestation over 36 months was −0.23 . Even under the worst-case scenario, a difference in favor of EHCF+LGG was still detected. Using the CCA estimate of the ARD, the number needed to treat was 4 (95% CI 3–10) (p = 0.02), and these results were stronger in patients treated with high-grade EHF+LGG . The authors concluded that the first-line approach with EHF may be beneficial to prevent the occurrence of AM, and LGG implementation strengthened this trend. They supposed that the hypoallergenic composition of this high-grade EHF and the GM may have helped to positively influence the immune tolerance network, decreasing the risk of developing AM (p < 0.001) and asthma  compared with those fed with EHCF+LGG. The authors concluded that the first-line therapeutic approach for newly diagnosed CMA children with EHCF+LGG, reducing the development of other allergic diseases later in life, may slow down the AM  . The autoping AM . Similarn the AM . Currentn the AM . All avaRoseburia, Coprococcus, and Blautia) with increased production of butyrate (It has been suggested that selected milk protein hydrolysates used for CMA management may be able to not only avoid allergic symptoms in CMA infants due to the breakdown of IgE antigens but also play a role in immune system modulation, inducing tolerance and preventing allergic sensitization –79. Thesbutyrate . A signibutyrate , 83. A Dbutyrate , 83. A lbutyrate . Moreovebutyrate . Howeverbutyrate . So, thebutyrate . AltogetDuring the last years, much has changed about AM knowledge. The actual strategies to halt the AM are depicted in RB designed and structured the review, wrote, and read the manuscript. LC and RN analyzed literature, wrote, and read the manuscript. LP and CD analyzed literature and read the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The Department of Translational Medical Science received research grants from Danone, Kraft Heinz, Humana, Mead Johnson Nutrition, Nestlè, and United Pharmaceutical. The authors have no other conflict of interests that are directly relevant to the content of this paper, which remains their sole responsibility.