Adverse birth outcomes have serious health consequences, not only during infancy but throughout the entire life course. Most evidence linking neighbourhood socioeconomic status (SES) to birth outcomes is based on cross-sectional SES measures, which do not reflect neighbourhoods’ dynamic nature. We investigated the association between neighbourhood SES trajectories and adverse birth outcomes, i.e. preterm birth and being small-for-gestational-age (SGA), for births occurring in the Netherlands between 2003 and 2017.We linked individual-level data from the Dutch perinatal registry to the Netherlands Institute for Social Research neighbourhood SES scores. Based on changes in their SES across four-year periods, neighbourhoods were categorised into seven trajectories. To investigate the association between neighbourhood SES trajectories and birth outcomes we used adjusted multilevel logistic regression models.Data on 2 334 036 singleton births were available for analysis. Women living in stable low-SES neighbourhoods had higher odds of preterm birth (OR[95%CI]= 1·12[1·07-1·17]) and SGA (OR[95%CI]= 1·19[1·15-1·23]), compared to those in high SES areas. Higher odds of preterm birth (OR[95%CI]= 1·12[1·05-1·20]) and SGA (OR[95%CI]=1·12[1·06-1·18]) were also observed for those living in areas declining to low SES. Women living in a neighbourhood where SES improved from low to medium showed higher odds of preterm birth (OR[95%CI]= 1·09[1·02-1·18]), but not of SGA (OR[95%CI]= 1·04[0.98-1·10]). The odds of preterm or SGA birth in other areas were comparable to those seen in high SES areas.In the Netherlands, disadvantaged neighbourhood SES trajectories were associated with higher odds of adverse birth outcomes. Longitudinal neighbourhood SES measures should also be taken into account when selecting a target population for public health interventions.Erasmus Initiative Smarter Choices for Better Health. We searched PubMed and MEDLINE databases for literature published in any language before December 1, 2020, using the following search terms: “neighbourhood” AND “trajector* OR change* OR histor*” AND “socioeconomic OR social OR economic OR poverty OR deprivation” AND “birth outcome* OR preterm birth OR prematur* OR small-for-gestational-age OR birth weight”. We identified three relevant studies. The first study was conducted in California (US) and used the Maternal Infant and Health Assessment survey . Their study investigated the association between longitudinal neighbourhood poverty trajectories and preterm birth. Compared to births from long-term low poverty neighbourhoods, those from areas with long-term high or increasing poverty had 41% and 37% increased odds of preterm birth, respectively. The second study used Texas (US) birth certificate data  to examine the association between longitudinal measures of neighbourhood poverty and adverse birth outcomes, i.e., preterm birth, low birth weight and small-for-gestational-age (SGA). They found that long-term high and moderate poverty histories, along with increasing and decreasing poverty were associated with higher odds of adverse birth outcomes. Both studies used an extensive period (20 and 40 years) to construct the neighbourhood trajectories. Last, a study conducted in New York City explored the association between living in a gentrifying neighbourhood and birth outcomes . They found that, for disadvantaged groups, living in rapidly gentrifying neighbourhoods was associated with increased incidence of preterm birth.Based on data from the nationwide perinatal registry in the Netherlands , we investigated the association between trajectories of neighbourhood socioeconomic status (SES) and adverse birth outcomes, i.e. preterm birth and SGA. Our study shows that, in the Netherlands, adverse neighbourhood SES trajectories were associated with higher odds of adverse birth outcomes. Women living in persistently low SES areas or areas that declined to low SES had higher odds of preterm and SGA birth than women living in the most advantaged areas. Also, living in a neighbourhood whose SES shifted from low to medium was associated with higher odds of preterm birth, but not SGA. Importantly, the odds of preterm or SGA birth in other areas were comparable to those seen in high SES areas. To our knowledge, this is the largest study to have investigated the relationship between neighbourhood SES trajectories and birth outcomes, and the first to use short-term changes in neighbourhood SES.Our results indicate that, in the Netherlands, disadvantaged neighbourhood SES trajectories were associated with higher odds of adverse birth outcomes. Results from this study suggest that longitudinal neighbourhood SES measures should also be taken into account when selecting a target population for public health interventions.Alt-text: Unlabelled box1Adverse birth outcomes, defined here as preterm birth and small-for-gestational-age (SGA), have serious health consequences, not only during infancy but throughout the entire life course Longitudinal approaches to investigating the link between neighbourhood conditions on health outcomes are scarce. The best available evidence comes from social experiments, e.g., Moving to Opportunity (MTO), a program that randomised disadvantaged families in the US to receive vouchers for residential mobility. People who moved to low poverty neighbourhoods within MTO experienced improvements in various health outcomes Few studies have investigated the association between the change in neighbourhood socioeconomic characteristics and birth outcomes ,7,11. ThThe Netherlands offers an ideal setting for the study of short-term changes in neighbourhood conditions and their association with birth outcomes. Previous research has shown that a fifth of the Dutch neighbourhoods experienced decline or improvement in four years 22.1In this retrospective population-based cohort study, we linked individual-level birth records to routinely collected neighbourhood-level data, population register data, and income and tax records. The cohort comprised singleton births with gestational ages between 24+0 and 41+6 weeks registered in the Netherlands between 1 January 2003 and 31 December 2017. Birth records before 2003 were not included in the analysis as information on household income is only available from 2003 onwards.We obtained the birth records from the Netherlands Perinatal Registry (Perined). Perined comprises routinely collected data on maternal characteristics, pregnancy, delivery, and birth outcomes, covering 97% of all births in the Netherlands Statistics Netherlands (CBS) performed the individual-level linkage of Perined records to the national population registry held at CBS. As a result of this linkage, CBS assigns each mother and child a unique identification number (RIN number). This identifier is a meaningless and dimensionless number that identifies a natural person CBS population and income and tax records include sociodemographic information of the country's residents. This information is routinely collected from different sources, e.g., municipality records and the Dutch Tax and Customs Authority. CBS data registries are subject to strict quality checks and follow several procedures to ensure the validity of the data 2.2th centile adjusted for gestational age and sex, according to national reference curves The following definitions were used for the birth outcomes: 1) preterm birth, any livebirth occurring from 24+0 weeks of gestational age and before 37+0 weeks, and 2) SGA birth, birth weight below the 10We used the household income corresponding to the child's year of birth to measure individual-level SES. Researchers have recommended using household income to better measure women's SES over other individual-level measures for health inequalities research We obtained information on maternal ethnicity and residential history from CBS records. Ethnicity was assigned based on the mother's country of birth. CBS categorises this variable based on the largest ethnic groups present in the Netherlands: Dutch background, Turkish, Moroccan, Surinamese, Antillean, others western, others non-western 2. The SCP Status Scores are based on postcode-level data collected yearly by CBS, which is calculated by aggregating the information of all residents from each four-digit postcode We used the Netherlands Institute for Social Research (SCP) Status Scores to measure neighbourhood socioeconomic status The exposure of interest was neighbourhood SES trajectory. To construct the SES trajectories, we first created cross-sectional measures of neighbourhood SES by categorising the SCP Status Scores into Low (lowest quintile), Medium (second to fourth quintiles), and High (highest quintile). Then, by comparing two consecutive cross-sectional SES measures (e.g. 2006 vs 2002), the neighbourhoods were categorised into seven SES trajectories: 1) Stable High, 2) Stable Medium, 3) Stable Low, 4) Improving to High, 5) Improving to Medium, 6) Declining to Medium, and 7) Declining to Low. Categories portraying a drastic change in neighbourhood SES, i.e., Improving Low to High and Declining High to Low were also considered. However, such steep changes are rare in the Netherlands Birth records were grouped into four mutually exclusive periods . The expDue to privacy considerations, SCP does not calculate status scores for areas with less than 100 households 2.3To assess the relationships between neighbourhood SES trajectories and adverse birth outcomes, we used two-levels  logistic random-intercepts regression models with pooled cross-sections. The pooled cross-sections technique combines elements from time series and cross-sectional data to analyse datasets that consist of several cross-sections from the same population collected at different time points (e.g. years or periods) but where the observations do not refer to the same units ,40. The We considered a set of potential confounders, i.e., variables that are  associated with the outcome and related to the exposure but are not intermediate variables in the causal pathway between exposure and outcome (mediators) ,43. We a[18]Dummy variables for all but one time period were included in the models to account (and test) for changes in the outcomes across different periods We conducted a set of sensitivity analyses to assess the robustness of our findings: 1) Models were additionally adjusted for the duration of residence in the neighbourhood at the time of delivery (in years). 2) We excluded births in 2006, 2010 and 2014 to assess whether our results were driven by cases born in the first years of the periods. 3) We conducted two analyses to assess the impact of women moving to a different neighbourhood during, or before, their pregnancy on the results: a) including only women who had been living in the neighbourhood for at least one year at the time of delivery, and b) restricting the analysis to women who have resided in the same residential address throughout the entire four years period corresponding to the assigned exposure see . 4) We aFor all analyses, a p value of less than 0·05 was used to indicate statistical significance. All analyses were performed using R version 3.6.3 2.3.1According to Dutch law (WMO) no formal ethical review was required. According to standard procedures and under strict conditions that were fulfilled, CBS anonymised the data before making it available to the researchers 2.3.2The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.3Between 2003 and 2017, 2 629 207 births were registered in the Netherlands, of which 2 538 897 (∼97%) could be linked by CBS. After removing multiple births, births with gestational age below 24+0 weeks or above 41+6 weeks, and births with missing data on covariates, 2 334 036 births were available for the analysis .Fig. 1StDuring each of the periods, roughly one-fifth (19.5%) of the neighbourhoods saw a change in their SES, while most of the areas (80·5%) remained stable . The meaAdjusted regression models show that higher odds of having a preterm birth  or SGA birth  were observed for women living in Stable Low SES areas, compared to women living in (the most advantaged) Stable High SES neighbourhoods A. MoreovChanges in the exposure-outcome relationship across time-points were assessed using interaction terms time-period × neighbourhood SES trajectory. For SGA, a downwards trend over time for the Declining to Low and Stable Low trajectories was found. For example, for the Stable Low trajectory, the odds ratios changed from 1·19 (95% 1·15-1·23) in the first period to 1·13 (95% CI 1·10 to 1·17) in the last period . HoweverThe patterns found in the main analysis remained unchanged in the sensitivity analyses where 1) models were adjusted for the time that the mother has been living in the registered neighbourhood , 2) we e4In this study, using a large nationwide perinatal registry linked to a comprehensive measure of neighbourhood socioeconomic status, we found a detrimental  association between disadvantaged neighbourhood SES trajectories and adverse birth outcomes. Women living in persistently low SES areas or areas that declined to low SES had higher odds of preterm or SGA birth, compared to women living in the most advantaged areas. Also, living in a neighbourhood whose SES shifted from low to medium was associated with higher odds of preterm birth, but not SGA. Importantly, odds of preterm or SGA birth in other areas were comparable to those seen in high SES areas.To the best of our knowledge, this is the first study to have examined the association between changes in neighbourhood SES occurring in short (four years) periods and birth outcomes in a nationwide cohort. The findings from this study are consistent with previous evidence while adding to the literature in meaningful ways. Our finding that women in stable low SES and declining SES areas have higher odds of preterm birth and SGA births is in line with studies conducted in the US by Cubbin et al. (Texas) Previous studies have suggested lifestyle factors as mediators for the relationship between neighbourhood SES and birth outcomes ,48. HoweA unique strength of this study is its longitudinal approach towards neighbourhood social and economic conditions, which allows taking into account neighbourhoods’ dynamic nature. Using national-level routinely collected data corresponding to an extended period (2003-2017) led to over two million individual records available for analysis. By assessing several types of declining, ascending and stable neighbourhood trajectories, our results provide more precise information about the type of change that might be the most detrimental (i.e. decline to low SES). A limitation of this study is that CBS could not link some of the births, and therefore these could not be included in the analysis. However, the impact of this is likely small as the percentage of unlinked births was only around 3%. Furthermore, it cannot be ruled out that the observed association can be due to compositional effects related to the selective sorting of people into neighbourhoods ,71. HoweFrom a public health standpoint, this study has several implications. Our findings indicate a higher risk of adverse birth outcomes for mothers living in persistently low SES neighbourhoods and areas in decline. At the same time, the odds of SGA for mothers living in improving neighbourhoods (improving to medium SES) is not significantly different from the odds for mothers in the most advantaged areas. This study suggests that longitudinal neighbourhood SES measures should also be taken into account when selecting a target population for public health interventions. Last, in agreement with previous research Future studies should focus on how changes in neighbourhood SES affect different strata of the population, e.g. ethnic minorities. Furthermore, future research needs to further investigate the underlying mechanisms driving the observed association, e.g., healthcare uptake and access, neighbourhood crime rates, social cohesion, air pollution, greenness, and walkability. To appropriately inform decision-makers when developing public health interventions, further research is necessary to pinpoint the causal pathways by which neighbourhood SES trajectories affect birth outcomes.In conclusion, our results indicate that, in the Netherlands, women living in neighbourhoods with disadvantaged SES trajectories were more likely to experience adverse birth outcomes. Results from this study suggest that, longitudinal neighbourhood SES measures should also be taken into account when selecting a target population for public health interventions.JVB and LCMB obtained funding for the study. LBO JVB and LCMB conceived the study. LBO and LCMB analysed the data. All authors were involved in interpreting the data. LBO wrote the draft paper and JVB supervised the writing. LCMB EAPS TVO and PGG provided additional input at the writing stage. All authors read and approved the final version of the manuscript.The authors are open to sharing statistical codes. Linked electronic health records require separate permission from Perined and Statistics Netherlands.We declare no competing interests.


Conclusion: Advanced stages of ROP following treatment with laser- and cryocoagulation lead to a smaller ACA width until adulthood, and hence may increase the risk of angle closure in later life.Purpose: To determine whether prematurity and associated factors affect the anterior chamber angle (ACA) width in adulthood. Methods: The Gutenberg Prematurity Eye Study (GPES) is a retrospective cohort study with a prospective ophthalmologic examination of adults (age 18–52 years) in Germany. All participants were examined with Scheimpflug imaging  using linear regression analysis to assess the associations of ACA in the different sectors with gestational age (GA), birth weight, birth weight percentile, retinopathy of prematurity (ROP), ROP treatment, placental insufficiency, preeclampsia, and breastfeeding. Results: In total, 516 eyes of 319 preterm and full-term individuals  were examined. ROP treatment was associated with smaller ACA width in the nasal (B = −9.6  degree;  Prematurity, low birth weight, and the postnatal occurrence of retinopathy of prematurity (ROP) are associated with altered ocular anatomic development in childhood. Children born preterm have altered corneal shape ,2,3,4, sSeveral factors are associated with anterior chamber angle (ACA) width in adults, namely gender, age, corneal curvature, and refractive state . HoweverThe Gutenberg Prematurity Eye Study (GPES) is a single-center cohort study at the University Medical Center of the Johannes Gutenberg University Mainz in Germany (UMCM) that recruits individuals that (i) were born preterm or at term between 1969 and 2002 and (ii) were between 18 and 52 years of age at study enrolment. According to these design elements, the study is a retrospective cohort study with a prospective acquisition of follow-up data. Every preterm newborn with gestational age at birth (GA) ≤ 32 weeks and every second randomly chosen preterm newborn with GA 33–36 weeks was contacted and invited to participate in the study. Three male and three female randomly selected full-term subjects with a birth weight between the 10th and 90th percentile were also invited to serve as controls for each calendar month (from 1969 to 2002).The study examinations were performed between 2019 and 2021 and the flow chart for eligibility and effective recruitment efficacy proportion is displayed in Written informed consent was obtained from all participants before enrolment. The GPES was carried out in conformity with Good Clinical Practice, Good Epidemiological Practice, and the ethical principles of the Declaration of Helsinki. The research project was supported by the local ethics commission of the Medical Chamber of Rhineland-Palatinate, Germany .The participants’ medical history was assessed from their medical files stored at the UMCM to collect data regarding GA (weeks), birth weight (kg), diagnosis of ROP, stage of ROP and ROP treatment, placental insufficiency, preeclampsia, and breastfeeding. Birth weight percentiles were calculated according to Voigt et al. .For descriptive analysis, participants were grouped into full-term participants (GA ≥ 37 completed weeks) (group 1), preterm participants with GA between 33 and 36 weeks without ROP (group 2), preterm participants with GA between 29 and 32 weeks without ROP (group 3), preterm participants with GA ≤ 28 weeks without ROP (group 4); and preterm participants with GA ≤ 32 with the postnatal presence of ROP, without ROP treatment (group 5) and with ROP treatment (group 6). In the case that only one eye of a participant had ROP, the other non-ROP eye was excluded from the analysis.A comprehensive ophthalmologic examination was conducted consisting of testing visual acuity and refraction  and intraocular pressure measurement with a non-contact tonometer . Scheimpflug imaging was performed using a Pentacam™ instrument  and biometry measurement with a Lenstar LS900 .A Pentacam HR rotating Scheimpflug camera was used for detailed tomography of the anterior eye enabling three-dimensional tomography. Each examination was conducted in congruence with strict standardized SOPs to reduce examiner-dependent variance. When optimal alignment was provided, Scheimpflug imaging was performed while participants had to fixate on a fixation light. Within every Scheimpflug measurement, 25 Scheimpflug images were captured for the anterior segment and all scans and quality descriptions of the device were checked. The nasal and temporal ACA were calculated by the device and participants were only included in the present analysis when nasal or temporal ACA width measurements were available. Each of the 25 scans was reviewed and checked. If ACA angle measurements were invalid, these scans were excluded. ACA width measurements were also controlled for outliers, and in the case of a suspected artefact or invalid measurement, removed. Superior and inferior ACA width were not included because these measurements are frequently invalid due to an overlapping upper or lower lid.The factors considered to affect the main outcome measures include GA (weeks), birth weight (kg), birth weight percentile, ROP (yes), ROP treatment (yes), placental insufficiency (yes), preeclampsia (yes), and breastfeeding (yes). Participants with a history of corneal or cataract surgery were excluded as this may have contributed to altered ocular anatomy.The main outcome measures were the ACA width of the nasal and temporal sectors. Descriptive statistics were computed for ACA width stratified by clinical group. For dichotomous parameters, absolute and relative frequencies were calculated. The mean and standard deviation were computed for approximately normally distributed variables, otherwise median and interquartile range. Linear regression models with general estimating equations (GEE) were used to calculate associations and to account for correlations between two eyes of one study participant. Because of the low number of participants in group #6, a Mann–Whitney U test was conducted to compare ACA width with the control group. Univariate analyses between the main outcome measures and GA (weeks), birth weight (kg), birth weight percentile, ROP (yes), ROP treatment (yes), placental insufficiency (yes), preeclampsia (yes), and breastfeeding (yes) were computed. The present investigation was an explorative study and no adjustment for multiple testing was performed. Analyses were conducted with commercial software .In the present analysis, 516 eyes of 319 preterm and full-term individuals  were included. Overall, 182 eyes of 113 participants with GA ≥ 37 weeks (group 1), 160 eyes of 100 participants with a GA between 33 and 36 weeks without ROP (group 2), 101 eyes of 61 participants with a GA between 29 and 32 weeks without ROP (group 3), 18 eyes of 11 participants with a GA ≤ 28 weeks without ROP (group 4), 45 eyes of 28 participants with a GA between 24 and 32 weeks with ROP without treatment (group 5), and 10 eyes of 6 participants with a GA between 24 and 32 and with postnatal treatment for ROP were assessed (group 6). In the group with ROP treatment, three participants (five eyes) underwent laser coagulation and three participants (five eyes) underwent cryocoagulation . The recSmaller nasal (n = 10 eyes) and temporal (n = 10 eyes) ACA widths were descriptively observed in individuals born preterm with postnatal treatment for ROP compared with the control group assessed with Mann–Whitney U test. The nasal and temporal ACA width was comparable between the full-term control group and the preterm groups with and without ROP . The boxp < 0.001) and temporal position  was associated with ROP treatment, but neither with postnatal ROP occurrence nor gestational age, birth weight, birth weight percentile, preeclampsia, breastfeeding and placental insufficiency (In univariate analysis, a narrower ACA in the nasal (B = −9.6 ; degree ficiency .This study provides the first data about the association of prematurity and associated factors with ACA width in adulthood. Individuals born preterm with postnatal advanced ROP stages and following treatment revealed a smaller ACA width in the nasal and temporal sector compared with individuals born full-term. Furthermore, this study shows that low birth weight, preterm delivery, and lower ROP stages without need for ROP treatment do not alter the configuration of the ACA width, while advanced ROP stages following treatment with cryo- or laser-therapy are associated with a shallower ACA. This may be of clinical importance because a narrow ACA is a known risk factor for angle closure.Until recently, gonioscopy was used as the standard for measuring ACA width ,14, but There are only a few reports examining the ACA structures of individuals born preterm in the literature. Chang et al.  used gonPrevious authors reported that prenatal ACA formation takes until the eighth month of gestation. At the time of birth, there is a translucent membrane that then widens during the first years of life. Accordingly, it is of interest whether ACA developmental alterations are caused by low birth weight, prematurity, and ROP, and whether alterations persist until adulthood, contributing to an increased risk for ocular disease. Fiedler et al. hypothesized that a decisive factor influencing anterior segment development in preterm children may be the lower extrauterine temperature, probably leading to a developmental delay of the anterior segment . In contChang et al.  suggesteThe study was limited due to the single-center and hospital-based study design. Furthermore, as individuals born extremely preterm are at an increased risk for poorer fixation, this could have affected the ACA width measurements, even though these measurements were quality controlled. Missing contact details and declination to take part in this study are other restrictions, although the recruitment efficacy proportion was acceptable see . It is nThis study has numerous strengths. First, the sample size was large and the high proportion of subjects with ROP strengthens the analysis. Second, the large sample size of preterm individuals enables the scarce comparison between adults born at term with a high number of adults born preterm without ROP. Third, reviewing perinatal medical charts enabled a comprehensive analysis with the inclusion of several perinatal parameters potentially affecting ACA configuration. All measurements were performed according to strict standardized operating procedures to reduce examiner-dependent variation and every investigator was blinded to the participants’ birth history.In conclusion, the present data analyses revealed a smaller ACA width in adults with previous ROP treatment, while those with ROP without treatment or those with low gestational age without ROP had similar ACA widths to the control group of individuals born at term. This finding indicates that advanced stages of ROP with ROP treatment may lead to a smaller ACA width in adults aged 18 to 52 years, which may impact the development of ocular diseases, such as angle closure.


Stenothemusharmandi species-group has 10 species at present. They are S.harmandi  ; S.holosericus Švihla, 2005, S.orbiculatus Švihla, 2005 and S.subnitidus Švihla, 2005 (N. India); S.distortirudis Y. Yang & X. Yang, 2014, S.laticollis Y. Yang & X. Yang, 2014, S.parallelus Y. Yang & X. Yang, 2014 and S.septimus Y. Yang & X. Yang, 2014 (China: Xizang); S.fugongensis Y. Yang & X. Yang, 2014 (China: Yunnan) and S.leishanensis Y. Yang & X. Yang, 2014 (China: Guizhou). In the present study, two previously-known species are classified into this species-group, S.dentatus Wittmer, 1974 and S.alexandrae Švihla, 2004, of which the latter as a subspecies of the former is upgraded to the specific level and another two new species are discovered and described.The Stenothemusharmandi species-group are described, S.acuticollissp. n. (China: Yunnan) and S.nigricolorsp. n. (China: Xizang), which are illustrated with habitus photos and aedeagi of males, abdominal sternites VIII and internal genitalia of females. S.alexandrae Švihla, 2004 stat. n. is upgraded from a subspecies of S.dentatus Wittmer, 1974 and the two species are classified into this species-group. Characters of the female reproductive system are described for the first time for the following species: S.distortirudis Y. Yang & X. Yang, 2014; S.laticollis Y. Yang & X. Yang, 2014; S.leishanensis Y. Yang & X. Yang, 2014; S.orbiculatus Švihla, 2005; S.septimus Y. Yang & X. Yang, 2014 and S.subnitidus Švihla, 2005. Meanwhile, some additional distribution information is added for previously-described species. A key for the identification of all species is updated.Two new species of the  Stenothemus Bourgeois, 1907 is a moderately diverse group in Cantharidae, which contains 75 species hitherto known in total , the Museum of Hebei University, Baoding, China (MHBU), the Naturhistorisches Museum Basel, Switzerland (NHMB) and the National Museum, Prague, Czech Republic (NMPC).Genitalia of both sexes and abdominal sternites VIII of females were dissected and cleared in a solution of 10% sodium hydroxide (NaOH) and female genitalia were dyed with haematoxylin. In studying the morphology of the aedeagus or female genitalia, at least one specimen was dissected per species, more if any damage occurred during dissection. If the species had a rather wide distribution range, one specimen was dissected from each locality. The measurements were carried out with the aid of a Leica M205A stereomicroscope. Habitus photos were taken using a Leica M205A stereomicroscope and multiple layers were stacked using Combine ZM (Helicon Focus 5.3). Line drawings were made using a camera lucida attached to a Nikon SMZ1500 stereomicroscope, then edited in CorelDRAW 12 and Adobe Photoshop CS3.10.0.1.Complete label data in Chinese were transliterated for type specimens. Body length was measured from the anterior margin of the clypeus to the elytral apex and body width across the humeral part of elytra. Morphological terminology of aedeagus follows that of The information of the specimens in this paper is from the preserved specimens of IZAS and MHBU, as well as the type specimens of NMPC and NHMB, examined in this study.species-groupF46D0560-4B51-5536-9949-F0E6960D123EBody is usually brown and mixed with irregular dark brown markings, except for only a few which are uniformly dark brown or black. The posterior angles of pronotum are sharply protruding laterad or obtusely rounded. The aedeagus with both ventral process and dorsal plate of each paramere are bent ventrad, the ventral process is thickened apically in varying degrees in lateral view and the dorsal plate is greatly narrowed apically in dorsal view. In the female, the abdominal tergite VIII is curled ventrad to enfold lateral sides of sternite VIII, which is strongly narrowed posteriorly.China, India, Nepal.Švihla, 2004 stat. n.4DF6392D-FB89-558C-A104-3450ED95A836Stenothemusdentatusalexandrae Švihla, 2004: 196, figs. 142‒144.Type status:Holotype. Occurrence: recordedBy: Jan Schneider; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Stenothemusalexandrae; Location: country: India; stateProvince: Sikkim; locality: Gantok env.; verbatimElevation: 2000‒2500 m; locationRemarks: Fambong-Lho forest; Event: eventDate: 8.‒15.07.1997; Record Level: language: en; collectionCode: Insects; ownerInstitutionCode: NMPC; basisOfRecord: Preserved SpecimenIndia.S.alexandrae was treated as a subspecies of S.dentatus Wittmer, 1974. However, differences between the two taxa have been found not only in the external appearance, but also in the structure of the aedeagus. In S.alexandrae, the body is uniformly dark brown, pronotum bears projecting and sharp posterior angles : 6.4‒8.1 mm (6.5 mm in holotype); width: 1.5‒2.3 mm (1.5 mm in holotype).Male  in the shapes of pronotum and ventral process of each paramere of the aedeagus, but differs in the aedeagus which is strongly swollen dorsally at base in lateral view, with the dorsal plate of each paramere being abruptly narrowed apically in dorsal view. Unlike in the latter, the aedeagus is moderately swollen at the basal part and the dorsal plate of each paramere is evenly narrowed apically  and collum (neck), referring to its pronutum with sharp posterior angles.The specific name is derived from the Latin China (Yunnan).Y. Yang & S. Gesp. n.EBBF7B01-088F-5A95-8E0E-5BE5FEE7BE020DA06148-F090-4366-B3D5-06DB5FDBEF18Type status:Holotype. Occurrence: recordedBy: Qiu Tengfei; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Stenotemusnigricolor; Location: country: China; stateProvince: Xizang; locality: Nyingchi, Mêdog, Dagmo, 81 K; Event: eventDate: 10.08.2016; Record Level: collectionCode: Insects; ownerInstitutionCode: MHBU; basisOfRecord: Preserved SpecimenType status:Paratype. Occurrence: recordedBy: Qiu Tengfei; individualCount: 3; sex: males; lifeStage: adult; Taxon: scientificName: Stenotemusnigricolor; Location: country: China; stateProvince: Xizang; locality: Nyingchi, Mêdog, Dagmo, 81 K; Event: eventDate: 10.08.2016; Record Level: collectionCode: Insects; ownerInstitutionCode: MHBU; basisOfRecord: Preserved SpecimenType status:Paratype. Occurrence: recordedBy: Qiu Tengfei; individualCount: 6; sex: females; lifeStage: adult; Taxon: scientificName: Stenotemusnigricolor; Location: country: China; stateProvince: Xizang; locality: Nyingchi, Mêdog, Dagmo, 81 K; Event: eventDate: 10.08.2016; Record Level: collectionCode: Insects; ownerInstitutionCode: MHBU; basisOfRecord: Preserved SpecimenBody length (both sexes): 5.1‒6.5 mm (5.6 mm in holotype); width: 1.3‒1.8 mm (1.3 mm in holotype).Male  in the structure of aedeagus, but differs in the following characters: the body is black, pronotum is 1.1 times as wide as long, of which anterior margin is arcuate, the aedeagus has the ventral process of each paramere even in width in ventral view. In comparison, S.alexandrae has a dark brown body, pronotum is 1.4 times as wide as long, of which anterior margin is nearly straight and the ventral process of each paramere is widened apically (It resembles niger (black) and color (colour), referring to its black body colouration.The specific name is derived from the Latin China (Xizang).Y. Yang & X. Yang, 2014B97726FA-6B21-5EDA-96F8-AD00059E4426Stenothemusdistortirudis Y. Yang & X. Yang, 2014: 212, figs. 4, 16, 27‒29 and 44.Type status:Other material. Occurrence: recordedBy: Qiu Tengfei; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Stenothemusdistortirudis; Location: country: China; stateProvince: Xizang; locality: Nyingchi, Mêdog, Baibung, Gelin; Event: eventDate: 04.08.2016; Record Level: collectionCode: Insects; ownerInstitutionCode: MHBU; basisOfRecord: Preserved SpecimenType status:Other material. Occurrence: recordedBy: Qiu Tengfei; individualCount: 1; sex: female; lifeStage: adult; Taxon: scientificName: Stenothemusdistortirudis; Location: country: China; stateProvince: Xizang; locality: Nyingchi, Mêdog, Baibung, Gelin; Event: eventDate: 04.08.2016; Record Level: collectionCode: Insects; ownerInstitutionCode: MHBU; basisOfRecord: Preserved SpecimenFemale. Internal organ of reproductive system .Y. Yang & X. Yang, 20145EF4A01D-DF62-5EBC-B681-12394494FDDDStenothemuslaticollis Y. Yang & X. Yang, 2014: 217, figs. 8, 20, 39‒41 and 43.Type status:Other material. Occurrence: recordedBy: Shi Fuming; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Stenothemuslaticollis; Location: country: China; stateProvince: Xizang; locality: Nyingchi, Dongjug; Event: eventDate: 28.09.2007; Record Level: collectionCode: Insects; ownerInstitutionCode: MHBU; basisOfRecord: Preserved SpecimenType status:Other material. Occurrence: recordedBy: Shi Fuming; individualCount: 1; sex: female; lifeStage: adult; Taxon: scientificName: Stenothemuslaticollis; Location: country: China; stateProvince: Xizang; locality: Nyingchi, Dongjug; Event: eventDate: 28.09.2007; Record Level: collectionCode: Insects; ownerInstitutionCode: MHBU; basisOfRecord: Preserved SpecimenType status:Other material. Occurrence: recordedBy: Song Zhishun; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Stenothemuslaticollis; Location: country: China; stateProvince: Xizang; locality: Nyingchi, Pêlong; verbatimElevation: 2100 m; Event: eventDate: 01.09.2005; Record Level: collectionCode: Insects; ownerInstitutionCode: IZAS; basisOfRecord: Preserved SpecimenType status:Other material. Occurrence: recordedBy: Chen Xiaolin; individualCount: 1; sex: female; lifeStage: adult; Taxon: scientificName: Stenothemuslaticollis; Location: country: China; stateProvince: Xizang; locality: Nyingchi, Pêlong; verbatimElevation: 2100 m; Event: eventDate: 02.09.2005; Record Level: collectionCode: Insects; ownerInstitutionCode: IZAS; basisOfRecord: Preserved SpecimenType status:Other material. Occurrence: recordedBy: Han Yinheng; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Stenothemuslaticollis; Location: country: China; stateProvince: Xizang; locality: Bomi, Yi’ong; verbatimElevation: 2300 m; Event: eventDate: 14.08.1983; Record Level: collectionCode: Insects; ownerInstitutionCode: IZAS; basisOfRecord: Preserved SpecimenType status:Other material. Occurrence: recordedBy: Wang Xuejian; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Stenothemuslaticollis; Location: country: China; stateProvince: Xizang; locality: Nyingchi, Mainling, Nanyigou; verbatimElevation: 3173 m; Event: eventDate: 04.09.2005; Record Level: collectionCode: Insects; ownerInstitutionCode: IZAS; basisOfRecord: Preserved SpecimenFemale. Internal organ of reproductive system .Y. Yang & X. Yang, 20144E30D21E-DD74-565B-8BA2-5DFC730C6192Stenothemusleishanensis Y. Yang & X. Yang, 2014: 216, figs. 7, 19, 36‒38 and 44.Type status:Paratype. Occurrence: recordedBy: Wang Jiliang & Gao Chao; individualCount: 1; sex: female; lifeStage: adult; Taxon: scientificName: Stenothemusleishanensis; Location: country: China; stateProvince: Guizhou; locality: Leigongshan Forestry Centre; Event: eventDate: 13‒14.09.2005; Record Level: collectionCode: Insects; ownerInstitutionCode: MHBU; basisOfRecord: Preserved SpecimenType status:Other material. Occurrence: recordedBy: Wang Jiliang & Gao Chao; individualCount: 3; sex: males; lifeStage: adult; Taxon: scientificName: Stenothemusleishanensis; Location: country: China; stateProvince: Guizhou; locality: Leigongshan Forestry Centre; Event: eventDate: 13‒14.09.2005; Record Level: collectionCode: Insects; ownerInstitutionCode: MHBU; basisOfRecord: Preserved SpecimenFemale. Internal organ of reproductive system .Švihla, 2005C042A5BB-1CEB-5CF6-A81F-5C4BE998393EStenothemusorbiculatus Švihla, 2005: 99, figs. 58, 62 and 65.Type status:Other material. Occurrence: recordedBy: Liang Hongbin; individualCount: 2; sex: females; lifeStage: adult; Taxon: scientificName: Stenothemusorbiculatus; Location: country: China; county: Xizang; locality: Mêdog, Zhamo Highway, 62 K; verbatimElevation: 2787 m; Event: eventDate: 29.08.2015; Record Level: collectionCode: Insects; ownerInstitutionCode: IZAS; basisOfRecord: Preserved SpecimenType status:Other material. Occurrence: recordedBy: Yao Jian; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Stenothemusorbiculatus; Location: country: China; county: Xizang; locality: Mêdog, Zhamo Highway, 62 K; verbatimElevation: 2787 m; Event: eventDate: 29.08.2015; Record Level: collectionCode: Insects; ownerInstitutionCode: IZAS; basisOfRecord: Preserved SpecimenType status:Other material. Occurrence: recordedBy: Liang Hongbin & Wang Mingqiang; individualCount: 1; sex: male; lifeStage: adult; Taxon: scientificName: Stenothemusorbiculatus; Location: country: China; stateProvince: Xizang; locality: Mainling, Paimo Highway; verbatimElevation: 3321 m; Event: eventDate: 06.08.2015; Record Level: collectionCode: Insects; ownerInstitutionCode: IZAS; basisOfRecord: Preserved SpecimenFemale. Internal organ of reproductive system , India.Y. Yang & X. Yang, 201482917064-57D1-52EF-AEF0-063E4BC6DF8BStenothemusseptimus Y. Yang & X. Yang, 2014: 214, figs. 6, 18, 33‒35 and 43.Type status:Other material. Occurrence: recordedBy: Liang Hongbin; individualCount: 2; sex: males; lifeStage: adult; Taxon: scientificName: Stenothemusseptimus; Location: country: China; stateProvince: Xizang; locality: Mêdog, 80 K; verbatimElevation: 2129 m; Event: eventDate: 15.06.2016; Record Level: collectionCode: Insects; ownerInstitutionCode: IZAS; basisOfRecord: Preserved SpecimenFemale. Internal organ of reproductive system .Švihla, 20058C269164-6C16-5DCC-B6D9-419E0ADEB825Stenothemussubnitidus Švihla, 2005: 97, figs 60, 63.Type status:Other material. Occurrence: recordedBy: Shi Aimin; individualCount: 1; sex: female; lifeStage: adult; Taxon: scientificName: Stenothemussubnitidus; Location: country: China; stateProvince: Xizang; locality: Zham; Event: eventDate: 27.07.2005; Record Level: collectionCode: Insects; ownerInstitutionCode: MHBU; basisOfRecord: Preserved SpecimenFemale. Internal organ of reproductive system , India?S.harmandi speices-group. As in other Stenothemus species (Stenothemus from other genera of Cantharinae, such as Cantharis L. (Themus Motschulsky (Lycocerus Gorham (Cephalomalthinus Pic and Micropodabrus Pic (The present study first illustrates the female internal organ of the reproductive system for the  species , the oviharis L. , Themus schulsky , Lycocers Gorham , Cephalobrus Pic . Howeverbrus Pic . Maybe,


Well-established literature indicates that older adults have poorer cerebral white matter integrity, as measured through diffusion tensor imaging (DTI). Age differences in DTI have been observed widely across white matter, although some tracts appear more sensitive to the effects of aging than others. Factors like APOE ε4 status and sex may contribute to individual differences in white matter integrity that also selectively impact certain tracts, and could influence DTI changes in aging. The present study explored the degree to which age, APOE ε4, and sex exerted global vs. tract specific effects on DTI metrics in cognitively healthy late middle-aged to older adults. Data from 49 older adults (ages 54–92) at two time-points separated by approximately 2.7 years were collected. DTI metrics, including fractional anisotropy (FA) and mean diffusivity (MD), were extracted from nine white matter tracts and global white matter. Results showed that across timepoints, FA and MD increased globally, with no tract-specific changes observed. Baseline age had a global influence on both measures, with increasing age associated with lower FA and higher MD. After controlling for global white matter FA, age additionally predicted FA for the genu, callosum body, inferior fronto-occipital fasciculus (IFOF), and both anterior and posterior cingulum. Females exhibited lower global FA on average compared to males. In contrast, MD was selectively elevated in the anterior cingulum and superior longitudinal fasciculus (SLF), for females compared to males. APOE ε4 status was not predictive of either measure. In summary, these results indicate that age and sex are associated with both global and tract-specific alterations to DTI metrics among a healthy older adult cohort. Older women have poorer white matter integrity compared to older men, perhaps related to menopause-induced metabolic changes. While age-related alterations to white matter integrity are global, there is substantial variation in the degree to which tracts are impacted, possibly as a consequence of tract anatomical variability. The present study highlights the importance of accounting for global sources of variation in DTI metrics when attempting to investigate individual differences  in specific white matter tracts. Cerebral white matter undergoes multiple changes throughout healthy aging. Dysmyelination, axonal degeneration, ischemia, and inflammatory processes associated with aging may compromise the structural integrity of axonal fibers within cerebral white matter bundles Peters, . The oveAxial diffusivity (AD) and radial diffusivity (RD) are additional DTI metrics that may correlate more specifically to certain types of white matter pathology. AD represents diffusion occurring along the length of white matter fibers, while RD is calculated as the amount of diffusion perpendicular to the main directional axis of fibers. Early studies of optic nerve fiber damage  who participated in Ryan et al.  were recvia the Oragene-DNA device  from participants and sent to the Translational Genomics Research Institute  for genotyping. DNA was extracted from the saliva samples using the manufacturer’s protocol and genotyped for two single nucleotide polymorphisms within APOE, rs429358, and rs7412, via TaqMan chemistry . Participants with the ε2/ε4, ε3/ε4, or ε4/ε4 genotype were categorized as ε4 carriers (n = 20) for this study, while ε2/ε3 and ε3/ε3 individuals were considered non-carriers (n = 29). No ε2 homozygotes were present in this sample.Saliva samples were obtained 2, 58 contiguous axial sections, 2.6 mm thickness, TE = 71 ms, TR = 13,000 ms, matrix = 96 × 96, FOV = 250 × 250 mm2, voxel size = 2.6 mm3). High resolution T1-weighted SPGR images were obtained with the following parameters: 0.7 mm thickness, TE = 2 ms, TR = 5.1 ms, flip angle = 15°, matrix = 256 × 256, FOV = 260 × 260 mm2. Participants with incidental MR findings, such as evidence of past stroke damage, were excluded from the study.At both visits, images were obtained with a General Electric 3.0 T Signa  MR scanner. An echo-planar DTI sequence was used to collect two non-diffusion weighted images and diffusion-weighted images in 25 directions  modeled as a within-subject predictor. Mean-centered age at time point 1, sex , and APOE ε4 status  were included as between-subject predictors. All main effects and the interactions between time and the between-subject predictors were included in the model. Pillai’s Trace served as the test statistic in the MANOVA models, as it is more robust to inhomogeneity of covariance and variance. The second set of MANOVA models were identical to the first set but controlled for global sources of variation in DTI metrics, through the inclusion of the global DTI measures (at time 1) to their respective models as a covariate. The two sets of models were compared to identify associations with tract-specific DTI values that were independent of global white matter influences.As a follow-up analysis for each effect identified as tract-specific, stepwise regressions were conducted for each tract. Global FA or MD was entered as a predictor into each regression model first, followed by the predictor of interest. To further explore associations between our predictors and global DTI measures, we conducted mixed factor ANOVAs. These models included the same set of predictors as the tract-specific MANOVAs—the age at time 1 (mean-centered), sex, APOE ε4 status, time, and the interactions between time and each between-subject variable. In the two separate ANOVAs, global FA and global MD at time 1 and time 2 were entered as dependent variables.r coefficients greater than 0.9, while correlations between these measures and global FA were smaller with coefficients ranging between 0.4 and 0.7  modeled as a within-subject predictor. Mean-centered age at time point 1, sex , and APOE ε4 status  were included as between-subject predictors. All main effects and the interactions between time and the between-subject predictors were included in the model. Pillai’s Trace served as the test statistic in the MANOVA models, as it is more robust to inhomogeneity of covariance and variance. The second set of MANOVA models were identical to the first set but controlled for global sources of variation in DTI metrics. Global FA and MD values at time 1 were added to the models as covariates for FA and MD values, respectively. The two sets of models were compared to identify associations with tract-specific DTI values that were independent of global white matter influences. Results from the four mixed factor MANOVAs as well as appropriate follow-up analyses for specific tracts are described below.Results of the MANOVAs predicting FA are found in Results of the MANOVAs predicting MD are found in The MANOVAs indicated that age did not predict MD in specific tracts once global MD was accounted for. However, age predicted FA in specific tracts, even after controlling for global FA. To further explore the effect of age on tract-specific FA values, we first performed Pearson correlations between tract FA values and age at time 1, which showed that increasing age was associated with lower FA in all tracts except for the SLF see . StepwisIn contrast to age, sex did not predict tract-specific FA values once global FA was accounted for, but remained a significant predictor of tract-specific MD values, even after controlling for global MD at time 1. To further explore the association between sex and MD in specific tracts, stepwise regressions were conducted for each tract. Global MD at time 1 was entered as a predictor into each regression model first, followed by sex. Results listed in The results of the MANOVAs suggested that the effects of most, but not all, of the independent predictors on tract-specific DTI measures were accounted for, once a global DTI metric was included as a covariate. We therefore conducted two additional mixed factor ANOVAs to better understand the relationship between global DTI metrics and the independent variables. These models included the same set of predictors as the tract-specific MANOVAs—age at time 1 (mean-centered), sex, APOE ε4 status, time, and the interactions between time and each between-subject variable. In the two separate ANOVAs, global FA and global MD at time 1 and time 2 were entered as the dependent variables.t-tests revealed that global MD values were higher at the second time point (t(48) = −4.79, p < 0.001). Unexpectedly, FA values were also higher at the second time point compared to time 1 (t(48) = −3.33, p = 0.002). Age at time 1 also predicted global FA and global MD values  and higher global MD values  as age increased. Sex predicted global FA and showed a marginal effect on global MD (p = 0.051). Males showed higher global FA values at time 1 compared to females (t(47) = 3.14, p = 0.003; see The results are listed in lues see . CorrelaIn this study, we investigated the influence of age, APOE ε4 status, and sex on white matter microstructure by examining changes in DTI metrics across two time-points separated by an average of 2.7 years. We sought to clarify the extent to which associations between our variables of interest and DTI metrics are best characterized as global or tract-specific. The results of this study provide evidence of a complex pattern of global and tract-specific white matter differences influenced by time, baseline age, and sex, but not APOE ε4 status, on FA and MD metrics. These relationships are discussed in detail in the following sections.We did not observe differences between APOE ε4 carriers and non-carriers in either tract-specific or global measures of FA and MD. This result is in contrast to evidence from cross-sectional  compared to MD. Importantly, however, even after controlling for global FA, increasing age was associated with lower FA in multiple tracts including the genu and body of the corpus callosum, the anterior and posterior cingulum, and the IFOF. Age explained at minimum an additional 6% of the variance in FA values (IFOF), and up to 20% of the variance (posterior cingulum) beyond the variance explained by global FA. The results suggest that age influenced the integrity of white matter throughout the brain, but that certain tracts may be particularly vulnerable to the effects of age-related pathologies.The global influence of age on MD and FA values may stem from the variety of cardiovascular, metabolic, and inflammatory processes that are commonly seen in late adulthood. In particular, cardiovascular risk factors  have been linked to DTI alterations in late adulthood (McEvoy et al., a priori ROIs. These issues can affect the calculation of DTI metrics and artificially inflate variance among tracts. Utilizing a higher-resolution sequence, with a smaller voxel size and a greater number of diffusion gradients, would help to minimize partial volume effects in future studies. As well, replicating the present findings using alternative DTI methods including native-space fiber tracking or multivariate voxel-wise analyses that carry different advantages/disadvantages over ROI-based methods would help confirm a biological basis to these tract-specific age effects.Alternatively, it is important to consider that methodological issues may account for some of the tract-specific findings. ROI-based analyses are particularly sensitive to partial volume error, particularly in populations where atrophy is common, such as older adults. Differences in ROI size, tract size, or presence of crossing fibers can result in more or less sensitivity to partial volume error across tracts identified using Across the two timepoints sampled 2.7 years apart on average, we observed global changes in FA and MD. Once global DTI metrics were controlled for, there was no evidence of tract-specific changes over time. Consistent with prior research (de Groot et al., The changes observed in MD and FA overtime did not vary across individuals concerning other factors included in the present study such as APOE ε4 status and sex, despite prior evidence that APOE ε4 status moderates age-related declines in DTI metrics (Ryan et al., In summary, we found that age exerts a strongly negative influence on white matter microstructural health that is widespread among association, limbic, and commissural tracts. However, there is considerable variation in the extent to which these tracts are affected by age, with some like the posterior cingulum more severely affected than others like the IFOF. We also observed poorer white matter health in females relative to males. The results of this study highlight the importance of considering global white matter when attempting to understand how predictive factors such as age, sex, or APOE ε4 status influence DTI metrics. Findings that initially appeared to be tract-specific, such as the effect of sex on FA, arose because of a strong association between the predictor and global white matter FA. Considering the impact of aging on FA, controlling for global FA was important in allowing us to more precisely characterize the sensitivity of individual tracts to age-related damage. Though not a standard practice, other DTI studies have similarly controlled for global DTI metrics to ensure the specificity of relationships between tract integrity and outcome measures by deriving the mean of DTI values across white matter (Bennett et al., 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 University of Arizona’s Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.SM and LR designed the study, wrote, revised and approved the submitted manuscript. SM processed imaging data and performed the statistical analyses. All authors contributed to the article and approved the submitted version.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.


Conclusions: A single dose of betamethasone up to 3 h antepartum may reduce the rate of serious outcomes and the severity of neonatal RDS, especially in non-tertiary hospitals.Background: A complete course of prenatal corticosteroids reduces the possibility of morbimortality and neonatal respiratory distress syndrome (RDS). Occasionally, it is not possible to initiate or complete the maturation regimen, and the preterm neonate is born in a non-tertiary hospital. This study aimed to assess the effects of a single dose of betamethasone within 3 h before delivery on serious outcomes  and RDS in preterm neonates born in tertiary vs. non-tertiary hospitals. Materials and methods: Preterm neonates who were <35 weeks and ≤1500 g, treated during a period of five years in a level IIIC NICU, were included in this retrospective cohort study. Participants were divided into groups as follows: NM, non-matured; PM, partial maturation (one dose of betamethasone up to 3 h antepartum). They were further divided based on their place of birth . The morbimortality rates and the severity of neonatal RDS were evaluated. Results: A total of 76 preterm neonates were included. A decrease in serious outcomes was found in the PM group in comparison to the NM group ), as well as reduced need for mechanical ventilation (54% vs. 68%). The mean time between maternal admission and birth was similar in both cohorts. The mean time from the administration of betamethasone to delivery was 1 h in the PM cohort. With regard to births in NICU-IIIC, the PM group performed better in terms of serious outcomes (32% vs. 45%) and the duration of mechanical ventilation (117.75 vs. 132.18 h) compared to the NM group. In neonates born in non-tertiary hospitals with PM in comparison to the NM group, a trend towards a reduced serious outcome (28.5% vs. 62.2%) and a decreased need for mechanical ventilation ) and maximum FiO The benefits of antenatal corticosteroid (ACS) administration in terms of reduced mortality and neonatal respiratory distress syndrome (RDS) rates in the preterm population are well documented in the scientific literature. Exposure to antenatal corticosteroid has also been associated with a decrease in the occurrence of intraventricular haemorrhage (IVH) .These results have been verified for the full corticosteroid course, i.e., two doses of betamethasone, 12 mg each, 24 h apart, or four doses of dexamethasone, 6 mg each, 12 h apart, when preterm birth occurs within one to seven days of complete maturation .With regard to precipitous preterm deliveries or situations that have imminent risk to the mother or foetus, at least one dose of antenatal corticosteroid is recommended, even if the completion of the course is not possible. However, on some occasions when a rapid birth is anticipated, the delivery may be completed without any prenatal corticosteroid dose ,4.The minimum time interval between the administration of antenatal corticosteroids and the appearance of significant beneficial effects for the preterm infant has not been determined. A mathematical estimate has recently been published in the EPICE study, which concludes that a single dose of corticosteroid administered 3 h before birth could lead to a decrease in mortality rate of up to 26% in the preterm population . Situations regarding imminent delivery, either due to maternal, foetal, or membrane pathology, require rapid action by the obstetric team and may occur in both tertiary and secondary centres. Given the urgency of these events, on some occasions, it is not possible to transfer the pregnant woman from the regional hospital to the referral hospital, and the preterm is born in level I/II neonatal units, with subsequent transfer of the neonate, following stabilisation, to the referral level III unit for treatment .The aim of this study was to assess the effects of a single dose of betamethasone administered within 3 h prior to birth with regard to serious outcomes and neonatal respiratory distress syndrome (RDS) in preterm infants born in tertiary vs. secondary hospitals. A retrospective cohort study was conducted from 1 January 2015 to 31 December 2020, including preterm infants under 35 weeks of gestational age (GA), weighing ≤ 1500 g, admitted in a Neonatal Intensive Care Unit (NICU) IIIC level . Neonates with major malformations, genetic syndromes, and a prenatal diagnosis of intrauterine growth retardation were excluded from the study. Informed consent was obtained from parents upon admission to the NICU. The study population was divided based on the course of lung maturation administered: non-matured (NM), which included preterm infants who received no antenatal corticosteroid dose, and partial maturation (PM), which included preterm infants who received a single dose of betamethasone (12 mg) within 3 h before birth. The following variables were recorded as demographic and clinical characteristics: maternal age, primiparity, single/multiple gestations, the presence of gestational diabetes, hypertensive stages including pre-eclampsia, eclampsia and HELLP syndrome , chorioa2 for ≥28 days and FiO2 < 30% at 36 weeks postmenstrual age or discharge) or severe  bronchopulmonary dysplasia (BPD) [The main objective was to determine “serious outcomes”, defined as death or survival with serious sequelae, which included the following: intraventricular haemorrhage grade III–IV (IVH), according to Papile classification ; perivenia (BPD) .2 during admission, and the need for surfactant administration. Other variables analysed included hypotension during the first week of life requiring treatment (volume expansion or inotropic administration), persistent ductus arteriosus with haemodynamic repercussion requiring medical or surgical treatment, and the presence of sepsis , either early (in the first 72 h of life) or late (after the first 72 h of life) [As secondary outcomes, the severity of RDS was determined by establishing the need for mechanical ventilation (MV), time on VM, maximum FiOof life) .After the baseline characteristics of the study population were assessed, the population was further divided based on the place of birth .Finally, in order to determine whether there would have at least been sufficient time to administer a dose in the non-matured (NM) group, the time elapsed from the admission of the pregnant woman to the emergency department to the birth of the preterm infant, in minutes, was analysed with regard to the PM and NM cohorts. This analysis was completed for the PM population using the time interval from maternal admission to prenatal corticosteroid administration and from prenatal corticosteroid administration to birth.n < 5), Fisher’s exact test and the odds ratios were calculated. To carry out pairwise comparisons of quantitative variables the Student’s t-test was used. In all cases, a statistically significant difference was declared when the level for statistical significance was found to be below 5% (p < 0.05). For statistically significant results, a multivariate model was adjusted for the following confounding factors: GA, the presence of chorioamnionitis, hypertensive stages, and Apgar test score < 5 at 5 min of life. The statistical program SPSS 25.0  was used.Contingency tables and the chi-squared test were used for the comparison of qualitative variables. In the 2 × 2 tables with a low number of observations  and PM cohort (n = 35). The characteristics of the two cohorts are summarised in A total of 76 patients were studied, who were divided into the NM cohort  from the admission of the pregnant woman to preterm birth are shown in For the PM cohort, the time intervals from the admission of the pregnant woman to antenatal betamethasone administration and from corticosteroid administration to preterm birth were found to be 35.4 ± 58.2 and 61.8 ± 44.4 min, respectively.An analysis of the NM and PM cohorts of preterm infants born at the tertiary hospital was performed . In the 2 during admission was significantly lower in the PM group, p = 0.01; 95%CI . Time on VM was also significantly lower in the PM group, but when it was adjusted for confounding factors, significance was lost (p = 0.19).The analysis of the effects of partial maturation in the secondary hospital population is shown in p = 0.46; OR 0.38 95%CI (−126.6–9)).A further analysis was performed to assess the effect of birth in secondary hospitals and the subsequent transfer of the preterm infant with regard to the non-matured and partially matured populations  have been detected in the umbilical cord at the time of prenatal administration.  Based onIn some situations where delivery is imminent, prenatal corticosteroids were not administered because it was considered that there would not be enough time for them to have an effect on the neonate. In our study, the timeline from the moment a pregnant woman was admitted to the emergency department to the birth of a preterm infant was recorded. This time interval was similar for non-matured and partially matured neonates (with a mean of 150 min for the NM group vs. 126 min for the PM group). Our results indicate that some of the preterm infants in the non-matured cohort could have benefited from the effects of a single dose of antenatal betamethasone.2 in the group that received prenatal corticosteroids, although the sample of preterm infants for the PM cohort was smaller. In our study, a pre-delivery dose of betamethasone was shown to improve the outcome of preterm infants who had to undergo inter-hospital transfer to continue their treatment [Regarding the results found in preterm infants born in non-tertiary hospitals, the beneficial effect of antenatal betamethasone was evident. The PM cohort was found to exhibit a trend towards lower serious outcome rates. In addition, there was less need for MV and lower maximum FiOreatment .Mixed analysis between NM and PM cohorts born in secondary hospitals and the tertiary hospital reinforces the recommendations that favour preterm birth to take place in specialised units ,19.The strengths of this study include the homogeneity of the cohorts in terms of gestational age, birth weight, and perinatal history. Subsequent analysis controlling for confounding factors consolidated the results. The biological plausibility and the results according to the literature, support this research.Several limitations of our study have to be pointed out. First, the retrospective approach of this research prevents from obtaining definitive conclusions about single-dose maturation, although it poses an important hipothesys to be tested in a larger prospective clinical trial. Second, the small sample size of the study population probably had an influence on not reaching significant differences in some of the variables analysed. Despite this, trends towards better results were observed in the group that received at least one dose. Finally, long-term outcomes have not been addressed in our study.Given the international recommendation to initiate maturation with prenatal corticosteroids in situations of preterm birth, there are few cases in which maturation is not administered or in which it is administered just before delivery . FurtherIn conclusion, the administration of a single dose of betamethasone within 3 h prior to preterm birth may decrease the rates of serious outcomes and other morbidities in neonates. In particular, beneficial effects were observed when delivery takes place in non-tertiary hospitals. Given the available scientific evidence and the results of this study, we consider that urgent administration of antenatal betamethasone may be a safe and effective strategy in cases of imminent preterm birth.


To describe the biomarkers of lipid metabolism in children and adolescents with polyarticular and systemic JIA and to relate them to diseases subtypes, diseases activity markers, and nutritional status.A cross-sectional study including 62 JIA patients was performed. The following variables were evaluated: disease activity and medications used, body mass index, height for age (z-score), skin folds , food intake based on three 24-h food recalls, lipid profile , low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG) and non-HDL (N-HDLc), glycemia and insulin, erythrocyte sedimentation rate (ESR), ultrasensitive C-reactive protein (us-CRP) and apolipoproteins A-I and B (Apo A-I and Apo B).p = 0.017, 0.001 and 0.042 respectively). Patients on biological therapy had a better adequacy of Apo A-I concentrations. The ESR showed a negative correlation with Apo A-I level .Dyslipidemia was observed in 83.3% of the patients. Based on classical lipid profile, low HDL-c levels was the most frequently alteration observed. Inadequate levels of LDL-c, Apo B and NHDL-c were significantly more frequent in the systemic JIA subtype when compared to the polyarticular subtype (We concluded that dyslipidemia is common in patients with JIA, especially in systemic subtype. The systemic subtype and an elevated ESR were associated with lower concentrations of Apo A-I, suggesting the participation of the inflammatory process. Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in the pediatric population , 2. JIA Advances in the diagnosis and treatment of JIA over the last few decades have modified outcomes in children and adolescents, resulting in a decrease in mortality due to the better controlof disease activity and reduction of secondary infectious complications. However, this group of patients coexists chronically with the disease, and they present early negative outcomes, such as osteoporosis and cardiovascular diseases later on .Studies have shown that adult patients with rheumatoid arthritis have an increased risk of atherosclerotic disease , 6. In tThe identification of cardiovascular risk in the pediatric age group is a major challenge, especially in patients with chronic conditions such as JIA . MeasureTo our knowledge, there are no studies in the literature on children and adolescents with JIA involving lipid biomarkers such as Apo A-I and Apo B that consider the disease onset subtypes.Thus, we aimed to describe the biomarkers of lipid metabolism in children and adolescents with polyarticular and systemic JIA and relate them to disease subtypes, disease activity markers, and nutritional status.In this cross-sectional study, at our pediatric rheumatology outpatient clinic, we included 68 consecutive children and adolescents of both genders who were age 5 to 19 years and who had polyarticular or systemic onset JIA according to the International League of Associations for Rheumatology (ILAR) .Patients who did not want to participate or who had insufficient data on disease onset were excluded. Therefore, the sample included 62 patients.This study was approved by the local ethics and research committee, and informed consent and assent were obtained from the caregivers or caregivers and patients.Data on the demographic, clinical, and laboratory findings were obtained, and a nutritional, food intake, and family cardiovascular risk assessment was performed. A blood sample was collected on the same day.Active disease was diagnosed according to the Wallace criteria, and the patients were classified as inactive, in remission on medication, in remission off medication, and active .The nutritional assessment was performed based on the body mass index (BMI) and height for age (H/A), and patients were classified according to World Health Organization data. Waist circumference was classified as increased when it was higher than the 90th percentile, according to Freedman et al. . Arm cirThe food intake assessment was performed through three 24-h food recalls . To calcAfter a 12-h fast, blood was collected for analysis of the following lipid metabolism biomarkers: total cholesterol (TC), lipid fractions , triglycerides (TG), Apo A-I and Apo B, insulin, glucose, and ultra-sensitive C-reactive protein (us-CRP). Insulin and us-CRP were determined using chemiluminescence and immunoturbidimetric methods, respectively.Apo A-I and Apo B were measured using enzyme-linked immunosorbent assay (ELISA) PRO kits for human Apo A-I and Apo B  and also evaluated glycemia by enzymatic colorimetric assay and erythrocyte sedimentation rate (ESR).The HOMA-IR (homeostasis model assessment of insulin resistance) value, classified as increased when > 3.16 . To clasp < 0.05.For the qualitative variables, Pearson’s Chi-square association test or Fisher’s exact test was used, and for the quantitative variables, the Mann-Whitney test was used. We used the median as a measure of central tendency and the interquartile range (IQ) (25–75%) as a measure of dispersion. To evaluate the correlations between cardiovascular risk factors and HDL-c and Apo A-I, the Spearman correlation test was performed. The level of significance was set at Table Table p = 0.017). In addition, we observed a higher frequency of Apo B and NHDL-c alterations and higher values of Apo B/Apo A-1 ratio, CT/HDL-c ratio, and LDL-c/HDL-c ratio in systemic JIA. Regarding the HDL-c variable, we observed that patients with borderline /low lipoprotein had lower levels and a higher frequency of inadequate Apo A-I. We also observed that familial cardiovascular risk was present in 42 patients (67%).Dyslipidemia was observed in 83.3% of the patients when altered lipid biomarkers  were considered. Borderline and low levels of HDL was the most frequent dyslipidemia based on classical lipid profile (20 patients - 32.3%). A decrease in Apo A-I level was present in 42 patients (67.7%) and more frequent in patients who did not use biological agents (83% versus 16%). The frequency of borderline /high values of LDL-c was statistically higher in systemic JIA than in polyarticular JIA  (p = 0.017). The Apo-A1 levels were not associated with laboratory findings, classic lipid profile, Apo B, or glucose levels.We did not find an association of inadequate Apo A-I or HDL-c with the time of disease duration and disease subtype, use of glucocorticoid, and with score-z BMI. The association of Apo A-I with disease activity showed a value of p = 0.017). In addition, we also observed statistically higher values of Apo B, Apo B / Apo A-1 ratio, non-HDL-c, CT / HDL-c ratio, and LDL-c / HDL-c in systemic JIA .The frequency of borderline/high LDL-c values was statistically higher in systemic JIA than in polyarticular JIA  . However, the ESR showed a negative correlation with Apo A-I levels (47) Fig. .Fig. 1Cr = 0.58, p = 0.018), LDL-c  and NHDL-c .We also observed a positive correlation between the cumulative glucocorticoid dose and TC .Studies evaluating non-classical biochemical markers related to lipid metabolism in children and adolescents with autoimmune rheumatic diseases are scarce , 24–26.The mechanisms involved in the pathogenesis of dyslipidemia and cardiovascular risk in patients with JIA have not yet been fully elucidated. Inflammation with endothelial dysfunction and increased levels of proinflammatory cytokines have been described . In addiIn patients with rheumatoid arthritis, the prevalence of dyslipidemia varies between 55 and 65% . In our Anthropometric markers of adiposity, such as BMI, waist circumference, and intake of fats and carbohydrates, were normal for most patients. This fact could be explained by the role of the multi-professional team in our service and suggests important participation of the disease and its treatment in the pathogenesis of dyslipidemia.Although glucocorticoids were used in only about 10% of our patients (two patients with systemic JIA and 4 patients with polyarticular JIA), we observed an association between the cumulative dose and dyslipidemia. Marangoni et al. reported a trend of association between glucocorticoid use and increased levels of LDL-c . They alWe know that systemic-onset JIA is associated with greater laboratory and inflammatory alterations, such as anemia, increased platelet count, and acute-phase proteins, and frequent use of corticosteroids. This explains the major changes in LDL-c, Apo B, and NHDL-c found in our patients with this JIA subtype. In a longitudinal study, Yeh et al. evaluated the lipid profile and atherogenic index of JIA patients after treatment with etanercept and found higher concentrations of HDL-c and lower TG and TC/HDL in the group they called responders (with the inactive disease) compared to non-responders . The nonAlthough an adequate HDL-c level was not associated with demographic and clinical characteristics, nutritional status, or food intake, patients with an adequate HDL-c had a higher value and higher frequency of normal levels of Apo A-I. In the literature, it is well-established that adequate levels of HDL-c, due to its antioxidant (mainly by the presence of Apo A-I), anti-inflammatory, antiatherogenic, antithrombotic functions, and cholesterol transportation, are related to a reduction in cardiovascular risk , 35. HowStudies have shown an association between disease activity and dyslipidemia , 36. AltThe decrease in the Apo A-I level was more frequent in patients who did not use biological agents (83% versus 16%). This can be explained by the action of these agents inhibiting the production of cytokines and, consequently, inflammation, thus improving the lipid profile.Rodriguez-Jimenez showed that tumor necrosis factor-α (TNF-α) is associated with increased cardiovascular risk, increased hepatic CRP synthesis, and decreased HDL-c levels . Under nInterestingly, a negative correlation between the ESR and Apo A-I concentration was observed. Similar results were showed by Bakkaloglu et al. , that evThis study has some limitations, such as the absence of a control group and the lack of an appropriate tool for the evaluation of the practice of physical activity by the patients. In addition, the sample size may have been insufficient to show significant differences between the various variables. However, this study is relevant and original because it is the first study on dyslipidemia, showing differences between the JIA subtypes.We concluded that dyslipidemia is frequently presented in patients with JIA, although the majority of patients presented a satisfactory nutritional status and absence of some components of metabolic syndrome. However, inadequate consumption of atherogenic lipids occurred frequently. Another important point was the association between the presence of systemic JIA and an elevated ESR with a higher frequency of an altered lipid profile. We also observed that the use of biological agents might be a protective factor for dyslipidemia. There was no association of BMI and HDL-c levels.Therefore, future studies should involve, in addition to lipid biomarkers such as Apo A-I and Apo B, the evaluation of biomarkers of inflammation (cytokines), direct markers of vascular injury, and the performance of imaging methods to measure atherosclerotic risk to understand the cardiovascular risk in these patients and thus be able to outline strategies and interventions to reduce this risk.


More recently, researchers have explored the processing of idiom modification and while a few studies indicate that familiarity benefits the processing of modified forms, the extent of this facilitation is unknown. In an eye-tracking study, we explored whether familiar idioms and modified versions with 1 or 2 adjectives {spicyspill the  beans} are processed faster than matched literal phrases {spicy, (red)] beansburn the [} when both were preceded by a biasing context. The results showed that adjectives inserted in idioms induced longer fixations and were more likely to elicit a regression. However, idiom verbs and final words were processed with the same ease in all adjective conditions, implying that modifying idioms did not impede their processing. In contrast to the widely reported “idiom advantage,” the results demonstrated that canonical and modified idioms were slower to read relative to matched literal controls. This was taken to reflect the competition between an idiom’s literal and figurative meaning, and subsequently the need to select and integrate the contextually appropriate one. In contrast, meaning integration in literal, unambiguous phrases was easier. We argue that processing costs associated with meaning selection may only manifest when idioms are preceded by a biasing context that allows disambiguation to occur in the idiom region, and/or when literal control phrases are contextually appropriate and carefully matched to idioms. Thus, idiom recognition/activation may elicit the well attested idiom advantage, while meaning selection and integration may come at a cost, and idiom modifications may simply add to the cognitive load.The literature on idioms often talks about an “idiom advantage,” such that familiar idioms ( Despitee storm) . For exaed storm . Here, tguistics , but we spill the beans) over literal phrases (spill the chips), regardless of whether they are intended figuratively or literally (horns in take the bull by the)  , and exp by the) .Although the idiom processing advantage was originally taken to indicate that idioms were stored holistically in the mental lexicon and were retrieved without undergoing compositional analysis , later fhit the nail, one might recognize the predictable idiom hit the nail on the head, leading to fast retrieval of the figurative meaning, without the need to process any of the constituents after the recognition point (the idiom key)  . Converse offset . In thised Model  maintained Model , and traed Model , but an ed Model , others ed Model , and yeted Model .spill + the + beans≠ “reveal the secret(s)”]. It is thought that familiarity may in fact be so powerful, as to mask potential effects from other factors  familiar and canonical idioms, little is currently known about the processing of modified forms. Recent psycholinguistic studies have demonstrated that modified idioms preserve their figurative meaning , despitecapable hands ofin the  versus in the hands of). The researchers concluded that the inserted adjectives restricted the range of possible phrase continuations, which increased the cloze probability of the nouns, yielding easier integration in the modified condition. In an eye-tracking study, some of the) informationprovide  informationcompare  were read at the same rate as their literal paraphrases (single wordhe didn’t say a ) in a self-paced reading task (bag in fat cat out of the baghe let the ) elicited longer reaction times than the same words in both canonical idioms (he let the cat out of the bag) and literal control phrases (fat cat out of the closethe let the ) . However, in their study, matched literal control phrases were not included.Some early behavioral studies looking at word insertion in idioms suggested that lexical insertion may neutralize the idiom advantage or even induce a processing cost relative to literal phrases. For example, idioms with added words (ing task . Further closet) . Howeveriron) bulletLarry bit the ( (and bought diamond earrings for his wife’s birthday)/]. Literal control phrases were constructed by replacing the idiom verb and were equally plausible in their context  beansburn the , relative to the same words in the unmodified condition (beans in spill the beans), but also relative to the same words in literal phrases , as idiom final words are likely to have a higher cloze probability than final words in literal phrases. If the addition of the adjectives further increases their cloze probability, this should further facilitate their processing relative to those in literal phrases. However, this potential facilitation might be offset by the cost of the metaphorical interpretation of the adjectives. That is, shorter fixations for idiom final words might not result in faster reading times for idioms as a whole. For this reason, it is important to look for an idiom advantage not only for the phrase as a region, but also in the verb, adjective, and final word region separately.Notably, adjectives in idioms have an unavoidable metaphoric interpretation and require inferencing. For instance, in a context about an illegitimate love affair, the addition of We hypothesized that when idioms are familiar and preceded by a context biasing their figurative meaning: (a) canonical forms should be faster to process than matched literal phrases, in accordance with the idiom processing advantage , and (b)Ninety native speakers of British English  took part in the eye-tracking experiment. Participants received course credit or compensation for their participation. This study was reviewed and approved by the Faculty of Arts Ethics of the University of Nottingham, and participants signed a consent form prior to participating.spill the beans/find your feet) were selected from the Collins COBUILT Idioms Dictionary (burn the beans/rub your feet). Verbs were matched for frequency 2, but idiom verbs were significantly shorter . However, both variables were considered in relevant models to account for any differences. The characteristics of the items are presented in Ninety idioms, comprised of a verb, determiner/pronoun, and noun (ctionary . Idioms t(89) = 4.41, p < 0.001]. Predictability was measured as the cloze probability of the final words of the phrases in context, via a completion task with 30 participants. The items were divided in two lists to counterbalance across Phrase Type  and included the stimuli sentences leading up to (but excluding) the final words of the phrases of interest. Thirty participants from a similar population to that of the main study were asked to complete the phrases with the first word that came to mind. Paired t-tests revealed that final words in idioms had a significantly higher cloze probability than (the same words) in the literal phrases , although cloze probability was fairly low in both Phrase Types .For both Phrase Types , we calculated frequency and predictability (used interchangeably with cloze probability). Both idioms and literal phrases were of relatively low frequency, but idioms were significantly more frequent than literal phrases  elicited significantly longer reading times than literal phrases with 1 and 2 adjectives, respectively . Further, modified idioms required greater reanalysis relative to their matched controls, being significantly more likely to elicit a regression. Similarly, idiom verbs, adjectives, and final words produced significantly longer total reading times than the equivalents in literal phrases, while idiom adjectives and final words also induced consistently longer fixations in go-past time, indicating greater processing effort already in the early stages of processing. No differences were noted between idiom and literal verbs, adjectives, or final words during first pass gaze duration. In sum, no advantages were noted for modified idioms relative to the literal phrases in any of the regions we examined, in any measure.Our findings suggest that there is no idiom processing advantage when adjectives are inserted into an idiomatic phrase. In the phrase region, idioms modified by 1 and 2 adjectives  did not exhibit an advantage over those in canonical forms (beans in spill the beans), as they were not faster to read in any measure. It seems, therefore, that the insertion of modifiers did not sufficiently reduce the number of possible phrase continuations as suggested by Idiom final words in the modified conditions , thus pImportantly, although the idioms in the current study were familiar and mostly transparent, as well as significantly more frequent and predictable than their matched literal phrases, this did not yield the typical idiom processing advantage for either their canonical or the modified forms. At best, we saw that transparent idioms were processed approximately at the same speed as their matched literal phrases with or without adjectives . Clearlykick the bucket meaning “die” or “boot the pail”), should require more processing effort than a compositional unambiguous, literal phrase (lift the bucket). The current results support this view, showing that idioms were more difficult to process than matched literal, unambiguous phrases. Importantly, this was not merely a side-effect of idiom modification since canonical idioms  exhibited the same pattern, nor was it due to our idioms being unfamiliar or infrequent (at least in comparison to the matched controls).Neurolinguistic findings indicate that idioms elicit stronger and more widespread activation in the brain . Activatpost hoc analysis in the phrase region including only idioms that were likely recognized before the phrase offset  and matched literal controls6. The analysis showed that these idioms were still significantly slower to read than their matched literal phrases , implying that the findings are not simply due to late idiom recognition/activation. Further, the differences noted in go-past time between idiom and literal phrase components, suggest that idioms were recognized right before or soon after their final word was encountered and that a certain level of semantic retrieval and meaning integration started as soon as the adjective region was reached .One might argue that the lack of an idiom processing advantage was due to the short length of our idioms and their relatively low predictability, even though idioms were more predictable than their matched control phrases . It is assumed that the figurative meaning of short and/or unpredictable idioms becomes activated around 300 ms after the phrase offset . Converspreceded by a biasing context, as opposed to a neutral one, the context favored the figurative  meaning of the idioms but made the literal controls semantically anomalous , where meaning selection can be stalled until further information clarifies the intended sense , and second, that adjective insertion in the modified conditions introduced an additional layer of processing difficulty, leading to yet longer processing times.The current results point to the need for idiom activation and recognition to be distinct from meaning selection (and integration); the former may elicit a processing advantage due to the availability of a lexical route , while meaning selection and integration might be associated with a processing disadvantage relative to unambiguous literal phrases. Encountering an ambiguous idiom without a prior biasing context may lead to quick recognition/activation of the phrase but meaning selection might be delayed until further information becomes available (in the post-idiom regions). Interestingly, this would mirror findings from the processing of lexically ambiguous words, and specifically of polysemes /(on the lake)” where on the lake is anomalous with a figurative interpretation]. This may have led to strategic processing, encouraging participants to keep both meanings activated until the entire sentence had been read. In line with the present findings, an ERP study by In support of such an argument, In the current study, we have demonstrated that adding adjectives increases processing times for idioms , reflecting the need to process the additional information. Although modified idioms in the 1- and 2-adjective conditions also received more regressions relative to their matched literal phrases – thus suggesting more problematic adjective integration – fixations to idiom verbs and final words did not differ in different Adjective Conditions. This implies that modified idioms were recognized as idioms and that their figurative meaning was activated despite the addition of adjectives. Thus, our findings are most in line with hybrid models of idiom representation , since tThe present results are best explained by differentiating idiom activation from meaning selection and integration. Our idioms were familiar, used in their figurative sense, and were preceded by context that foregrounded this meaning. The literal control phrases were equally felicitous in their respective contexts. Contrary to our hypotheses, and the wider literature, the observed reading times were slower for idioms with and without adjectives compared to matched literal phrases. The current results demonstrate the role of the “matched control phrase” and the biasing context in underpinning the idiom advantage. When a preceding context biases an idiomatic meaning or that of a literal phrase, there is no idiom advantage. In fact, processing of idioms is slower, likely because of the competition between an idiom’s literal and figurative senses. Conversely, a literal, unambiguous phrase only has one plausible interpretation and hence integrating this meaning is less effortful. In other studies, where the biasing context appears later in the sentence (after the idiom) or is not present, meaning integration may occur outside the idiom region. Thus, any processing difficulties may “fall off the radar” as the phrase region is often the sole focus of analyses. Furthermore, while factors such as high familiarity and predictability may contribute to idiom recognition, and hence fast activation, they do not make meaning integration easier for idioms relative to literal, unambiguous phrases. Finally, while adjectives in idioms are more difficult to interpret, as they involve complex inferencing, adjective insertion in idioms does not seem to inhibit recognition and activation of the phrase, nor does it result in loss of the figurative interpretation of the idiom.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 Faculty of Arts Ethics, University of Nottingham. The patients/participants provided their written informed consent to participate in this study.MK and KC contributed to the conception and design of the study. MK, KC, and DT contributed to the stimuli design. MK designed the study, collected and analyzed the data, and wrote the first full draft of the manuscript. KC contributed to substantial revisions of the original draft. All authors read, reviewed, and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.