N = 1182) and a subsample (n = 327) of students including individuals fulfilling cutoff for at least one BA. Results: LPA on the subsample mostly replicated the previous four profiles found in the full sample. However, LCA on a full sample did not replicate previous findings using LPA and showed only two classes: those with relatively high probabilities on all BAs and low probabilities. LCA on the subsample conflated profiles identified with LPA and classes found with LCA in the full sample. Conclusions: LCA on dichotomized scores (screened positively vs. negatively) were less effective in identifying clear patterns of interrelationships between BAs based on relatively strong theoretical assumptions and found in previous research. BAs can be investigated on the whole spectrum of behavior, and person-centered analyses might be more useful when they are based on continuous scores. This paper provides more detailed analyses of the four basic clusters of BAs, prevalence, and co-occurrence of particular BAs within and between them, their gender and personality risk factors, relationships to well-being, and their interrelationships as emerging from the results of this and previous studies.Background: Relatively strong theoretical assumptions and previous studies concerning co-occurring addictive behaviors suggest a subpopulation representing general proclivity to behavioral addictions (BAs), and there are gender-specific subpopulations. This study aimed to compare latent profile analysis (LPA) and latent class analysis (LCA) as the methods of investigating different clusters of BAs in the general student population and among students positively screened for at least one BA. Participants and procedure: Analyses of six BAs  and their potential antecedents  and consequences (well-being) were conducted on a full sample of Polish undergraduate students ( A recent study using latent profile analysis (LPA) showed four profiles of behavioral addictions (BAs) severity, including a profile with a general proclivity to addiction, two gender-specific profiles, one almost exclusively female and a second predominantly male, and a profile with low levels of BAs . These pSubstantial co-occurrence among different addictive behaviors and pronounced gender differences in the risk for particular addictions and clusters of addictions ,3,4 suggLatent trait modeling and person-centered approaches can, to a large extent, give similar results, particularly in situations where profiles or classes of symptoms of a single addictive behavior are distinguished but differ only in the severity of symptom clusters . In facDifferent factors such as samples  or measurement scales (continuous scores vs. dichotomized) may affect the results of person-centered analyses, particularly by determining the type of possible analysis (latent class or latent profiles). At present, a limited number of studies have compared different person-centered approaches in the addiction field, and therefore, systematic analyses of their properties and performance are lacking. Moreover, LCA is predominantly used, with very few studies applying LPA, and studies analyzing models with numerous addictive behaviors are still very rare. The categorical classifications, especially dichotomous , may be attractive due to easy and intuitive interpretation, as well as simple and convenient measurement. However, it should be emphasized that proper justification for the choice of categorical measurement of addictive behaviors or for recoding continuous scores into a categorical variable is typically missing in the papers using such an approach  is highly problematic since the vast majority of addicted individuals never seek help, and there is considerable heterogeneity among treated individuals. In such cases, being in treatment should be considered a separate variable from an individual’s addiction status. Additionally, it may be appropriate to analyze, for example, a set of symptoms (present vs. absent) of alcohol addiction with LCA and find various classes . HoweverAddictions share common etiological factors and expressions, i.e., manifestations and sequels, which can be organized in biological, psychological, and social clusters; natural history; treatment non-specificity; and object substitution ,6. TheseFrom this perspective, addiction syndrome may also manifest in specific clusters of co-occurring addictive behaviors with their particular specific risk factors, apart from generally shared etiology. One such crucial factor is gender, which differentiates risks not only for SUDs  but alsoThe gender differences concerning the risk of addiction and various types of addictive behaviors are well-established ,3,4,38 bThere is a similar general rationale referring to emotional sensitivity to stress-system changes, related to different motives for performing particular behaviors (stimulation seeking vs. negative emotion avoidance), most often grounded in evolutionary psychology and sex roles related to hunter–gatherer societies. This reasoning is explicitly or implicitly involved in providing theoretical explanations for gender differences in BAs. Most data come from studies on particular BAs and provide some idiosyncratic theoretical reasons, discussed below, for the observed differences. Previous studies showed that study ,42, sociShopping addiction has been explained in terms of evolutionary psychology, referring to collecting tendencies that had been typically assigned to females within their social groups . InternePreviously, the profile representing general proclivity to BAs was related to the highest narcissism, and lowest emotional stability among all profiles ; see Tab. SimilarA person-centered approach to investigating addiction may be indispensable because otherwise, results such as different types of particular addictions and within-addiction variability of risk factors might be ambiguous and confusing. Reviews of findings of studies based on a person-centered approach showed that this methodology might produce significant benefits and more accurate models of vulnerability to psychiatric disorders ,75. SomeThe analyses of prevalence and co-occurrence of BAs within and between properly identified clusters may allow for a better understanding of the addictive process and of the specificity and importance of particular addictive behaviors. Since LCA and LPA may produce different results, it has a significant meaning for the way we understand the co-occurrence of BAs, its causes, and consequences. Gaming disorder and gambling disorder are classified as disorders due to addictive behaviors in the eleventh revision of the International Classification of Diseases . NeverthThe pooled prevalence of Internet gaming disorder (IGD) among adolescents in 16 studies was 4.6% , similarIt needs to be emphasized that there are currently no reliable estimates of BAs comorbidity  due to  and that there are gender-specific clusters. These are also supported by previous studies. However, the differences between LPA and LCA, particularly regarding the reduced information used by LCA, suggest that these methods may produce different profiles/classes and that LCA may be less effective in identifying clear patterns of interrelationships between BAs than LPA. Following the assumptions behind the confirmatory approach in science , the preThe general sample of students consisted of 1182 participants (25 responses were eliminated due to more than 70% of missing data) and was described in detail elsewhere [The subsample was extracted from the full sample. To be included in the current sample, a person had to meet the criteria for at least one BA. To be classified as a person meeting the criteria for a BA, participants had to score four or five points for at least four diagnostic criteria (see the detailed description of cutoff scores in ). The fiData collection used convenience sampling. The study was a part of a larger project, “Study addiction in the context of other behavioral addictions: Co-occurrence, potential determinants and consequences from the perspective of the addiction model as an ineffective way of coping with stress”. Data collection took place during the winter semester (October–December) in 2016. It finished several weeks before the examination session to reduce the effects of exam stress. This was particularly important in relation to such variables as study addiction. BAs questionnaires asked about experiences from the previous year (12 months). Lecturers were first contacted via e-mail to invite their students to the study. Then, students were invited to participate anonymously in the study during lectures or classes. The estimated response rate was above 95%. No monetary or other material rewards were offered. Filling in the paper-and-pencil questionnaires took on average 15–20 min.In the preliminary analysis, we calculated descriptive statistics and zero-order correlations. Next, we conducted comparisons between the persons without BAs and persons with at least one BA in terms of sociodemographics, personality, and well-being indicators. Then we examined what percentage of participants met the cutoff of a particular BA and the co-occurring BAs.n = 327); (ii) latent class analysis for BAs treated as nominal variables , conducted in the full sample (n = 1157); (iii) latent class analysis for BAs treated as nominal variables , carried out among persons with at least one BA (n = 327). For each analysis, we first examined models containing from one to seven clusters and compared them using the model fit criteria recommended by the simulation studies [R2 [In the next step of the analysis, we performed three analyses using a person-centered approach: (i) latent profile analysis for BAs treated as continuous variables, carried out among persons with at least one BA   studies : the Bay studies ,119,120)dies [R2 ), which dies [R2 . An averdies [R2 .After establishing the optimal number of clusters, we calculated bivariate residuals (BVRs) to test the assumption of local independence. BVRs greater than 3.84 identify correlations between the pairs of indicators that the model has not adequately explained at α = 0.05 . In the When the optimal number of clusters was established, participants were classified into clusters using their probability scores. Using the submodule Step3 included in Latent GOLD 5.1 , we testn = 161; 49.2%) met the criteria for study addiction  are presented in Regarding well-being indicators, the general proclivity profile (Profile 4) demonstrated lower health quality and higher anxiety and hopelessness than students in the female-majority (Profile 1) and male-majority profiles  had a higher proportion of women to men (62.2%) compared with students who belonged to the class with a low probability of all potential BAs . The procedures for identifying the model best fitting to the data are described in The three-profile solution established by LCA is presented in For well-being indicators, the only significant differences between the classes were noted for hopelessness. Specifically, students who had a very high probability of study addiction (Class 2) scored lower on hopelessness than members of other classes.Since only LPA consistently replicated profiles, Relatively strong theoretical assumptions and previous studies concerning co-occurring addictive behaviors suggested a cluster reflecting general proclivity to (BAs) and gender-specific clusters. LPA on the subsample mostly replicated the previous four profiles found in full sample: the first profile with elevated levels of study, Facebook, shopping, and food addictions; the second profile with elevated levels of gaming and pornography addictions; the third profile with the average levels of all addictions and low level of pornography addiction; and the fourth profile with the high levels of all addictions (H1 substantiated). The third profile in the subsample represents a cluster with relatively low levels compared with other profiles of particular BAs see , and froHowever, LCA on a general student sample did not replicate previous findings using LPA and showed only two classes: those having relatively high probabilities on all BAs and those with low probabilities on all BAs (H2 not substantiated). LCA on a subsample conflated profiles identified with LPA and classes found with LCA in the general student sample . Overall, LCA on dichotomized scores (screened positively vs. negatively) was less effective in identifying theoretically expected and clear groupings of BAs. It suggests that BAs can be investigated on the whole spectrum of behavior and that a person-centered approach might be more useful when it is based on continuous scores.In the more clinical subsample, some of the patterns of potential antecedents and consequences were less pronounced, probably due to range restriction effects and decreased variability in the scores . Additionally, LCA generally produced fewer of the expected patterns of the potential risk factors and outcomes.The comparison between LPA and LCA shows that dichotomizing continuous scores on addiction tests may limit the effectiveness of the analysis to identify clear and distinct clusters by limiting the available information. Dichotomizing continuous variables is a well-recognized practice to avoid in any statistical analyses ,129,130.The analysis of previous studies showed that most person-centered research on co-occurring addictive behaviors is based on LCA and produces mostly clusters differentiating general addiction severity or ad hoc identified clusters see . These aProper identification of theoretically expected clusters of BAs with the person-centered approach may be crucial for improving our understanding of the addictive process. In this context, a detailed analysis of prevalence and co-occurrence of the investigated BAs is particularly useful. Four major conclusions of high importance to the addictive disorders field can be drawn from the current study. First, the general proclivity to the addiction profile showing the worst well-being indicators in the subsample included 29.5% of individuals, meaning that it constituted about 8% of the total sample. Second, study addiction had the highest rates among all BAs, exceeding even food addiction, being up to about 4 to 7 times higher than some of the other BAs (shopping or pornography), constituting almost half of the cases in the subsample, and permeating all profiles. Third, individuals at risk for different BAs  also had a significant risk of food and study addictions. Fourth, individuals at risk of shopping and pornography addiction had a high risk for other BAs, including a high risk for such seemingly dissimilar behaviors as compulsive studying.The most severe cases of BAs representing a general proclivity for addiction with clearly decreased well-being and the most pronounced personality risk factors constituted about 8% of the general student sample. It is almost 4 times less than the number of individuals who fulfilled the cutoff score for at least one addictive behavior . On the other hand, the LCA-based class representing a high risk for BAs in the general student sample also included about 9% of the total sample. However, only about half of the cases in this class were part of the subsample’s general proclivity to an addiction profile. The other half mostly included female-majority profile cases. First, this suggests that estimating prevalence rates of addictive disorders in a general population-based on screening for single BAs may significantly overestimate the rates of clinical cases of addiction. Moreover, these most severe cases constituted about 30% of the corresponding profile in the general student sample, meaning that most cases in this profile in the full sample are probably not clinically relevant. It shows that LPA on co-occurring BAs in the general population is probably not efficient enough to be used as a diagnostic method and might include a majority of false positives. This is also true for the gender-specific profiles. However, in conjunction with other criteria, such as fulfilling a cutoff score for at least one addictive behavior, it might prove useful in identifying the most severe cases of addiction. Second, the female-majority profile included some of the most severe cases identified in the general student sample by LCA, and generally, LCA conflated cases representing general proclivity and female-majority profiles. This suggests that the female-majority profile includes severe and probably clinically relevant cases of BAs. It was mostly not the case in relation to the male-majority profile, which almost exclusively included low severity cases in the general sample.Study addiction, as well as work addiction, are consistently found to have the highest rates among all BAs ,97,98,99The highest co-occurrences were noted among food, shopping, and Facebook addictions, as well as between gaming and pornography addictions. Moreover, study addiction and food addiction were highly prevalent among individuals with all other addictions  was less effective in identifying clear patterns of interrelationships between BAs than LPA. This study suggests that profiles identified within the full spectrum of behavior with LPA are similar to profiles found in the potentially more clinical subsample of BAs. It is consistent with the assumption that addictions can be studied along the continuum of severity of the behavior. Based on these results, it can be recommended to investigate profiles of BAs and their co-occurrences with continuous variables in samples representing the general population. It has an important advantage, as it could overcome limitations related to small sample sizes typical for clinical samples. Furthermore, continuous scores on valid and reliable addiction scales provide more information than dichotomized scores or clinical classifications, and they limit the problems of (i) borderline cases (slightly above and slightly below the cutoff score), (ii) misdiagnoses , (iii) false homogeneity among those classified as addicted in terms of severity of symptoms, and (iv) false homogeneity among those classified as non-addicted in terms of risk levels. It has to be emphasized, however, that the validity of such analyses is dependent to a large degree on the validity of the assessment tools. In recent years, there have been substantial developments in the measurement of psychopathological phenomena, including addiction and BAs. Still, there is room for considerable improvement ,139,140.This and previous studies have shown that there are different clusters of individuals manifesting specific risks for addictions. Most notably, a cluster representing general proclivity for addiction with high co-occurring risks of numerous addictive behaviors requires the most attention from addiction professionals and researchers. Moreover, clusters representing gender-specific addictions need more research to establish whether these are individuals on a trajectory to full-blown addiction syndrome or cases of people highly engaged in a non-pathological way in particular sets of behaviors. It is especially important in relation to gaming and pornography consumption, as these are typically recognized as major threats despite quite a lot of evidence that, in most cases, there is limited empirical support suggesting their negative consequences on a population level ,141. On A general proclivity profile includes behaviors present in female- and male-majority profiles. This suggests that within a particular behavior, different clusters of risk or addiction levels can be distinguished. It was repeatedly shown for shopping addiction, food addiction , social The female-majority profile is probably least recognized as a genuine addiction profile, and none of the prevalent behaviors constituting it are currently officially recognized in the formal classification systems as addiction . It may To the Authors’ knowledge, the current study is the first to investigate the latent profiles and latent classes based on highly gender-differentiated BAs. A range of their potential antecedents and consequences were analyzed. A relatively large sample size provided high statistical power. Commonly used, valid, and reliable psychometric tools were included. LPA has identified and replicated three types of potential BAs severity profiles, which have considerable potential for generality. Moreover, this study has provided important information on the differences between results obtained with LPA and LCA, suggesting the higher effectiveness of LPA in identifying clear patterns of clusters in the same samples. Therefore, the study significantly adds to the addiction literature, particularly in the area of research related to BAs. The results increase our understanding of the nature of the addictive process.The study also has some limitations. All data were self-reported, resulting in a susceptibility to the usual weaknesses of such data . Although the used cutoff scores are well-grounded in the modern nomological systems, are commonly used, and were validated psychometrically, they are all arbitrary. The subsample was based on psychometric cutoff scores and not clinically derived. Therefore, it is likely that a considerable number of cases do not fulfill the criteria for a disorder because screening tools, in general, overestimate the number of addiction cases , and parLPA on a sample of students positively screened for at least one BA mostly replicated previous findings in a general student sample. They suggest a profile reflecting general proclivity to BAs and gender-specific profiles of BAs. According to the results, men show a higher proclivity towards gaming and pornography and women towards study, Facebook, shopping, and food addictions. It suggests that profiles identified within the full spectrum of behavior are similar to profiles found in a potentially more clinical subsample of BAs. Our findings are consistent with the assumption that addictions can be studied along the continuum of severity of the behavior. The profiles identified in the subsample showed significantly fewer differences, especially in terms of the relationship with well-being, which is expected because they all reflect a more clinical subset of individuals with high risk for at least one BA and a limited variability of scores in comparison with the general student sample. Still, the profile representing general proclivity for BAs scored significantly higher on hopelessness and anxiety and lower on health quality than most of the other profiles.Moreover, LCA on a full sample did not replicate previous findings using LPA. LCA on dichotomized scores (screened positively vs. negatively) was less effective in identifying clear and replicable groupings based on relationships among various BAs. Person-centered analyses might be more useful when they are based on continuous scores. Measuring scores on the whole spectrum of addictive behavior is recommended, and reducing continuous scores into few categories, especially only two (addicted vs. non-addicted), is not advisable.Finally, a detailed analysis of the prevalence and co-occurrence of the investigated BAs suggests three major conclusions of high importance to the addictive disorders field. First, studies investigating multiple addictive behaviors may overestimate their total prevalence in the population. Second, study addiction has the highest rates among all BAs, exceeding even food addiction, permeating all profiles, and is most or second-most prevalent in each of them. Third, individuals at risk for different BAs  have a significant risk of food and study addictions. Fourth, individuals at risk of shopping and pornography addictions have a high risk for other addictive behaviors, including a high risk for such seemingly dissimilar behaviors as studying. Based on these findings, identifying individuals with high risk for multiple addictive behaviors is recommended to improve prevention programs and to understand the addictive process. Specifically, diagnosis of one addictive behavior should be complemented by detailed inquiry into other potential addictions. Consequently, the treatment process should address general proclivity to addiction to assure that one addictive behavior will not be substituted with another, including those such seemingly less damaging as study addiction. As the most prevalent and almost completely unrecognized potential BA, study addiction urgently needs widespread acknowledgment, more research, and potentially population-based prevention programs and proper policy responses.Future studies should investigate a wider range of addictive behaviors with LPA and further compare results based on LPA and LCA. Additionally, a more theoretically derived investigation of profiles of addictive behaviors based on a confirmatory approach and enabling more generalizations and replications based on person-centered analyses is warranted. Currently, the overwhelming majority of studies on co-occurring addictive behaviors are based on LCA and produce either clusters differentiating general addiction risk or ad hoc established clusters that are never or very rarely replicated. This, to a considerable extent, may be due to limited information associated with dichotomous variables  used in LCA.


Introduction: Recently, bile acids (BAs) are increasingly being considered as unique metabolic integrators and not just for the cholesterol metabolism and absorption of dietary lipids. Human BAs profiles are evolved to be individual under different environmental, dietary, and inherited factors. Variation of BAs for crewmembers from freshly prepared kitchen diets to wholly prepackaged industrial foods in a ground-based spacecraft simulator has not been clearly interpreted.Methods: Three crewmembers were confined in a docked spacecraft and supplied with 7 days periodic wholly prepackaged industrial foods for 50 days. Fecal samples were collected before entry in the spacecraft simulator and after evacuation. Determination of 16 kinds of BAs was carried out by high-performance liquid chromatography tandem mass spectrometry method.Results: Bile acids metabolism is sensitive to diet and environment transition from freshly prepared kitchen diets in the canteen to wholly prepackaged industrial foods in a ground-based spacecraft simulator, which is also specific to individuals. A significant positive relationship with a coefficient of 0.85 was found for primary BAs as chenodeoxycholic acid (CDCA) and cholic acid (CA), and a significantly negative relationship with a coefficient of −0.69 for secondary BAs as lithocholic acid (LCA) and deoxycholic acid (DCA).Discussion: The profile of BA metabolism of individuals who share the same food in the same environment appears to be unique, suggesting that the inherent ability of different individuals to adapt to diet and environment varies. Since the transition from the free diet in open space to whole prepackaged space food diet in a space station simulator causes the variations of BAs pool in an individual manner, assessment of BA metabolic profiles provides a new perspective for personalized diet design, astronaut selection and training, and space flight diet acclimatization. Bile acids (BAs) are synthesized in the liver with the gastrointestinal tract being the principal location where metabolism occurs. BAs are important endogenous substances in mammals with many important physiological functions, such as cholesterol balance, lipid absorption, carbohydrate metabolism, absorption of drugs and excretion of a toxic substance, immune regulation, and regulation of the composition of gut microbiota  in the research and proportion of energy supply of the scheduled periodic diet served as shown in Determination of the fecal BAs was carried out according to the liquid chromatography tandem–mass spectrometry method described by Hagio et al. with minor modifications  between crewmembers, indicating that the synthesis and metabolism intensity of BAs in the crewmembers were different. Structure profiling of BAs pool for each crewmember was shown in p < 0.01), while the levels of total BAs, LCA, and DCA of crewmember 01 were significantly lower than those of crewmembers 02 and 03 (p < 0.01).Longitude variation profiling of the fecal BAs of the three crewmembers during the experiment was shown in Temporal variation dynamics of the fecal BAs during the experiments was shown in p < 0.05) with a coefficient of 0.85 was found for primary BAs, CDCA, and CA. The quantity of the two most dominant lipophilic secondary BAs (LCA and DCA) was significantly negatively correlated with a correlation coefficient of −0.69 (p < 0.05). There was a significant positive correlation between glycine-conjugated BA and taurine-conjugated BA (p < 0.01), with a correlation coefficient of 0.79.As shown in Bacteroides, Clostridium, Lactobacillus, Bifidobacterium, and Listeria, and then dehydroxylated by Clostridium and Eubacterium to form secondary BAs such as LCA and DCA  and the secondary BAs (DCA and LCA), indicates that the synthesis and metabolism of BAs were affected by the specific diet and environment. Both the host and gut microbiota regulate the size of BAs pools. Through hydrolysis of BAs brine and 7α-dehydroxylation, gut microbiota transform primary BAs synthesized by the host liver into secondary BAs such as DCA and LCA  and 7α-dehydroxylase are responsible for the formation of secondary BAs through the metabolism of primary BAs. The disruption of homeostasis of BA plays a key role in intestinal inflammation , the Space Gut Research Project (BZZ20J001), and the Shenzhen Science and Technology Plan Project .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.


PLCG2 gene. Here we report a rare case of APLAID patient carrying a novel heterozygous missense PLCG2 I169V mutation with gangrenous pyoderma and concomitant high serum immunoglobulin (Ig) E level.Autoinflammatory phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) is a rare autoinflammatory disease caused by gain-of-function mutations in the The patient was diagnosed as APLAID and has been treated in our department. His phenotype and genotype were carefully documented and studied. We also conducted a comprehensive literature review on APLAID.PLCG2 gene p. I169V was identified. His vesiculopustular and IgE level responded to medium dose corticosteroids. After withdrawal of steroids, he developed severe arthritis and a large deteriorating ulceration resembling pyoderma gangrenosum on the left knee. Large dose corticosteroids were suboptimal. Then he received adalimumab with satisfactory response for arthritis and skin lesion. But he got an immunodeficiency-associated lymphoproliferative disorder 2 months later. Through literature review, there were a total of 10 APLAID patients reported by six English-language publications. Vesiculopustular rashes, sinopulmonary infection and immunodeficiency were the most frequent symptoms of APLAID patients. Glucocorticoids, intravenous immunoglobulin and biologics were clinically used to treat APLAID but none of these patients had a complete recovery.A 23-year-old Chinese Han man presented with recurrent fever for 18 years and vesiculopustular rashes for 9 years, along with chronic bronchitis, leukocytosis, increased C-reactive protein, immunodeficiency and high serum IgE. Skin biopsy showed chronic inflammatory cells infiltration. A paternal heterozygous missense variant in exon 6 of the PLCG2 mutation, which may expand the clinical phenotype and genotype of APLAID.The rarity and diversity of APLAID make it difficult to be diagnosed. Our study reported the first case of APLAID with gangrenous pyoderma and concomitant high IgE carrying a novel  PLCG2 gene (OMIM 600220). PLCG2 is located in chromosome 16, and encodes PLCγ2, an enzyme with a regulatory function in immune and inflammatory pathways, which is highly expressed in hematopoietic cells, including B cells, natural killer (NK) cells, mast cells and macrophages. PLCγ2 can hydrolyze the substrate phosphatidylinositol 4,5-bis-phosphate (PIP2) to generate diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). IP3 functions as a second messenger to increase intracellular calcium concentration, inducing downstream cell activities (PLCG2 gene (NM_002661.3) c.2120C>A, p.Ser707Tyr was confirmed, and this mutation located at the SH2 domain was found to create a novel signaling receptor site, resulting in hyper-reactive protein and constitutively activated down-stream signaling pathways  E level, which has not been reported before. We also reviewed the published English literature of APLAID.Until now, only a few cases of APLAID have been reported in English literature. Here, we report the first case of a Chinese patient with APLAID caused by a novel The patient was referred to and followed up in our tertiary medical center. Complete medical records and detailed data were collected and documented. Whole exome sequencing by Next Generation Sequencing was performed in the Center for Genetic Testing, MyGenotics Medical Laboratory, Beijing, China. We performed a systematic literature search in PubMed using the terms as “APLAID” OR “autoinflammatory phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation”. After screening, six articles containing a total of 10 cases of APLAID patients were reviewed.This research was approved by the Institutional Review Board of Peking Union Medical College Hospital and performed according to the Declaration of Helsinki. Informed consent was obtained from the participant.A 23-year-old Chinese Han man was presented with recurrent fever for 18 years and vesiculopustular rashes for 9 years. He started to have recurrent low-grade fever since 5 years old. Each episode lasted 2 to 3 days and repeated every several months. No accompanying symptoms were noticed then and it stopped at the age of 7 years. At the age of 14 years, painless and non-itching vesiculopustular rashes were noticed all-over his body . He was treated with prednisone 30 mg per day, methotrexate 12.5 mg per week and intravenous immunoglobulin (IVIG) 20 g per day once for 3 days every 3 months, with a satisfactory response for the fever, rashes :0.7–4.0], IgG , and IgM , while significantly increased level of IgE . B cell counts decreased to 51/µL (RR: 90–660), and NK cell counts decreased to 15/μL (RR: 46–590). Testing for antinuclear antibodies (ANAs) and anti-neutrophil cytoplasmic antibodies (ANCA) were negative. EBV-DNA and CMV-DNA were within normal levels. Ultrasound imaging revealed superficial lymph nodes enlargement and splenomegaly. Computerized tomography demonstrated chronic inflammatory bronchial wall thickening of the bilateral lower lobes and lympho-splenomegaly. A skin biopsy showed superficial dermis infiltration by chronic inflammatory cells. Whole exome sequencing identified a novel paternal heterozygous missense mutation in exon 6 of the He remained stable with only regular IVIG infusion for 6 months, when he noticed pitting edema in his left lower limb, followed by two lumps in his left leg and knee arthritis  have been treated with glucocorticoids, and inflammatory manifestations were partially ameliorated in five (45.5%) patients. However, the side effects limited the dosage and duration of glucocorticoids in two 18.2%) patients 2.7% have. TNFα in.2% patiePLCG2 gene. According to gnomAD database, the Minor Allele Frequency (MAF) of this variant was 0.0013, and it is predicted to be damaging when using a variety of in silico pathogenicity prediction tools including MutationTaster, M-CAP, VEST3, Genocanyon, and FATHMM_MKL. Besides, sequence alignment of PLCγ2 among various vertebrates demonstrates that Ile169 is a highly conserved residue, indicating it may play a fundamental role in cell and any mutation may lead to dysfunction. Although we were not able to carry out functional studies, we suggest this PLCG2 variant is associated with the phenotype of the patient, and diagnosis of APLAID could be confirmed due to the combination of characteristic phenotype and genotype results. To the best of our knowledge, this is the very first case of Chinese Han patient with APLAID, indicating that APLAID may occur in various ethnic groups worldwide. Intriguingly, we noticed a high serum IgE level in this patient, which had not been observed in APLAID patients before. No infections, autoimmune diseases, allergic diseases, and gene mutations associated with hyperimmunoglobulinemia E syndrome were found. His IgE level fluctuated with his systemic inflammation and his asymptomatic father also had increased IgE level, which suggests that increased IgE level might be related to his genomic abnormality. Interestingly, the patient’s father carried the same PLCG2 mutation while presented no other symptoms except for the high IgE level. Similar to our case, it has been previously reported that parents of an APLAID patient were heterozygous without any manifestation of the disease despite the dominant inheritance of this syndrome  from APLAID patients, suggesting that NLRP3 inflammasome activation may play a role in the pathogenesis of APLAID , owing to deletions of the CG2 gene . In cont protein –12, PLAI protein , 17.To date, there is no standard management strategy for APLAID. High-dose corticosteroids were partially effective in some patients but the dosage and duration of treatment have been limited by side effects. IVIG was given for hypogammaglobulinemia. Similar to other autoinflammatory diseases, biologics served as a potential therapy, yet the effectiveness was not obvious. Early hematopoietic stem-cell transplantation was considered to improve the condition , 12, butThis case report is limited by the fact that we did not perform functional studies for the defined variant. However, using a variety of silico analysis algorithm, this variant was predicted to be damaging. Thus, we suggest that this variant is associated with the phenotype of the patient, and we hope further studies will enlighten the underlying mechanisms, particularly its relationship with increased IgE level. Second, treatment with adalimumab was only empirical. Long-term follow-up was needed to evaluate the effect of adalimumab.PLCG2 mutation, which may expand the clinical phenotype and genotype of APLAID. TNFα inhibitors could be considered in APLAID patient with gangrenous pyoderma.In conclusion, APLAID is a newly-defined autoinflammatory disease. Due to its rarity and heterogeneous clinical manifestations, it is difficult to be diagnosed and treated. Our study reported the first case of APLAID with gangrenous pyoderma and concomitant high IgE carrying a novel The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was supported by the Natural Science Foundation of Beijing (Grant No. 7192170), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS) (Grant No. 2017-I2M-3-001), Fundamental Research Funds for the Central Universities (Grant No. APL20100310010301019), and the National Key Research and Development Program of China .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.


Leishmania infantum and Dirofilaria immitis are among the most important canine vector-borne pathogens (CVBPs) of zoonotic concern in Europe. In endemic areas for both of these CVBPs, the use of systemic ectoparasiticides, such as afoxolaner , may have the potential for controlling these infections. The aim of this study was to assess, for the first time, the insecticidal efficacy of NexGard® in decreasing the transmission of D. immitis and L. infantum to sheltered dogs living in a hyperendemic area, compared to the year before treatment, as well as its impact on the abundance of mosquito and sand fly populations.n = 179) enrolled in the study were divided into two groups based on their infection status at enrollment: a non-infected group (G1) and an infected group . The study was conducted from March 2020 to March 2021. In order to exclude all animals infected with L. infantum and D. immitis before March 2020 (sampling time: T0), dogs in G1 were sampled in June  and in October 2020 . From March to September 2020, all animals (G1 and G2) were weighed and treated monthly with NexGard®. Animals in G1 were tested for the last time in March 2021  for assessing post-treatment incidence rate of infection and prevention efficacy.All dogs  and that of L. infantum was 3.6% . Considering the annual incidence in 2019 and 2020, the protective efficacy against D. immitis and L. infantum infections was 94.2 and 64%, respectively. Of the female mosquitoes collected (n = 146), only one pool out of 50 tested positive for D. immitis DNA, whereas out of 1252 female Sergentomya minuta specimens collected, only four tested positive for L. infantum (0.3%).The post-treatment incidence of D. immitis and L. infantum; however, comparison of the pre- and post-treatment period demonstrated that there was a significant difference only in the seasonal incidences of D. immitis infection. Preventive measures are recommended throughout the year in endemic areas to reduce the risk of pathogen transmission to animals and humans.Afoxolaner is efficacious in decreasing the rate of transmission of both  Leishmania infantum and Dirofilaria spp. are among the most important canine vector-borne pathogens (CVBPs) in Europe ).cticides –39. Sincia canis , as an eve bites , 41.n = 146) represents a 30% decrease compared to the number collected the previous year (n = 208; Table A. caspius testing positive for D. immitis DNA. Moreover, the relative decrease in the number of A. caspius and relative increase in the number of C. pipiens collected compared to the year before could be due to the average temperature of the 2020 season being lower than that of the previous year [S. minuta, the sand fly species with herpetophilic attitude, than P. perniciosus, with mostly zoophilic behavior, could be related to the effect of afoxolaner treatment on the studied dog population. However, despite their different blood-feeding behaviors, four S. minuta tested positive for L. infantum, suggesting a putative role of this sand fly species in the transmission of this pathogen [P. perniciosus [The low number of female mosquitoes collected (ous year , as wellpathogen , 43 and niciosus , 44. BotD. immitis and L. infantum, although we found a significant difference between the 2 years of study only in the seasonal incidences of D. immitis infection. Our study is the first demonstration that systemic insecticides without repellent activity may play a role in decreasing the risk of pathogen transmission by mosquitoes and sand flies.The protection of dogs from infective bites of mosquito and sand fly vectors reduces their capacity to act as reservoirs of pathogens. Based on the One Health approach, dogs in endemic areas with a high risk of VBP exposure should be treated to decrease/prevent the risk of infection as well as the spread of these parasites to other animals and humans living in the same geographical area. Afoxolaner is efficacious in decreasing the rate of transmission of both


Most children globally are not breastfed to recommendations. Medical practitioners are frequently visited in the first 6 months post‐partum, and the interaction at such visits significantly influences subsequent infant feeding decisions. Medical practitioners report that clinical practice in lactation is often disproportionately reliant on personal experience. This systematic review synthesises the literature on lactation health interventions used to support clinical decision making by medical practitioners. MEDLINE, Embase, PsycINFO, Scopus and Cochrane Library databases were searched for peer‐reviewed empirical studies published after 2000. Two reviewers independently screened and then assessed full‐text articles against inclusion criteria. Quality of reporting and risk of bias were independently assessed using three validated tools. No conclusions can be made regarding the success or failure of implementation strategies used or the outcomes of putting them into effect due to problems with study methodology, intervention reporting and risk of bias. Good‐quality research, which follows proven implementation frameworks, is needed to guide and sustain the incorporation of evidence‐based decision support into medical practitioners' care of breastfeeding mothers and infants. Breastfeeding is not meeting recommendations globally with inconsistent advice contributing to early weaning.Medical practitioners influence infant feeding decisions but report reliance on personal experience for clinical decision making.Health interventions deliver evidence‐based decision support and improve consistency of care, but few lactation interventions are used by medical practitioners.No conclusions can be made regarding implementation strategies and outcomes of those reported due to poor study quality and bias.Good‐quality research is needed to guide and sustain the incorporation of evidence‐based decision support into medical practitioners' care of breastfeeding mothers and infants.1Human lactation is well established as a foundation for human health  methodology with checklist available as an additional file Appendix . The pro2.2A search strategy was devised in consultation with a health and medical sciences librarian from J Robin Warren Library at The University of Western Australia. Search terms and Medical Subject Headings (MeSH) chosen were those relevant to ‘doctor’ AND ‘lactation’ AND ‘intervention’. Databases searched were MEDLINE, Embase, PsycINFO, Scopus and Cochrane Library Appendix . The sea2.3Publications were selected on the basis of the PICOS  outlined below  classification of health workers WHO, . General2.3.2Based on the WHO International Classification of Health Interventions WHO, , the int2.3.3The comparator was ‘usual practice’. Usual practice was indicated by no health intervention targeted to the medical practitioner to change current practice with respect to lactation.2.3.4Understanding implementation processes is assisted by conceptualising implementation outcomes  web‐based systematic review software.Data were independently abstracted by two reviewers (M. B. and N. S.) using a series of forms applied through DistillerSR. These forms were used to extract data regarding study design, implementation strategy, implementation outcome variables, quality of study methodology, quality of health intervention reporting and risk of bias. Forms were each piloted independently using three articles from the included references with disagreements discussed and resolved by consensus. If consensus could not be achieved, a third researcher (R. C.) was available for mediation. The two reviewers then independently extracted data from the remaining included articles for each form. Disagreements were resolved by discussion and moderation.The form used for categorising study design was based on the Cochrane EPOC classification of study designs for evaluating the effect of healthcare interventions EPOC, .Implementation science taxonomies are helpful to articulate both the strategies used to deliver a health intervention as well as the results of putting a health intervention into effect   tool  or critical (too problematic to provide useful evidence of intervention effect) within all included studies Figure . ConfounThus, the outcomes of these studies are unlikely to be reliable.4The findings of this systematic review highlight a need for high‐quality implementation research on lactation interventions for medical practitioners caring for breastfeeding families. The limited studies reporting on lactation interventions all identified a need for medical practitioner lactation education, but poor quality of study methodology and reporting and serious to critical risk of bias precluded further conclusions from being made. As evidence‐based knowledge has been shown to improve consistency of medical care and optimise outcomes . Use of three validated tools to comprehensively assess the quality of included studies allowed detailed insight into the strength of evidence reported.Conclusions were limited by the presence of serious to critical risk of bias in all studies, which was compounded by poor quality in study methodology and intervention reporting. Although this meant that there was little to inform specific implementation strategies for LactaMap, the value of using theory‐based models or frameworks to help inform study design and mitigate the challenges of complex intervention development and evaluation was highlighted Nilsen, .5This systematic review highlighted the deficit in medical practitioner lactation interventions and indicates an urgent need for high‐quality research on their uptake in practice. No conclusions can be made regarding the success or failure of implementation strategies used or the outcomes of putting them into effect due to problems with study methodology, intervention reporting and risk of bias.This has several implications for further research. Breastfeeding mothers and infants are not meeting recommendations globally. Medical practitioners supporting them are reporting that clinical practice is overly reliant on personal experience and social networks, which is likely contributing to inconsistent care. Few lactation interventions have been implemented to support clinical decision making. Good‐quality research, which follows proven implementation frameworks, is needed to guide and sustain the incorporation of evidence‐based decision support into medical practitioners' care of breastfeeding mothers and infants (Pérez‐Escamilla & Odle, The authors declare that they have no conflicts of interest.MB developed the search question and strategy with considerable input and supervision from RC, DP and RP‐E. MB conducted the search. MB and NS selected full‐text articles for eligibility, abstracted data and assessed quality of evidence of the selected articles. MB wrote the manuscript and developed figures and tables with review and input from RC, DP and RP‐E. All authors gave final approval of drafts and final version of this manuscript.


As orthopedic surgeons we have a strong inclination towards bringing broken bones together. Traditionally, in displaced fractures the anatomy should be restored and the success of surgery should subsequently be documented by postoperative imaging. In some common upper limb fractures, for example in displaced fractures of the proximal humerus, best evidence challenges our intuitions. On the one hand, current evidence has failed to demonstrate any benefits to patients in bringing the displaced fragments together by means of plating or nailing or even by replacing the joint , even when randomized trials  definition of evidence-based practice: Evidence-based practice includes the integration of best available evidence, clinical expertise, and patient values Sackett .1st, best available evidence does not support surgery in this case. 2nd, clinical expertise is limited when it comes to severely displaced fractures managed nonoperatively. Experience is mainly surgical, and the vast majority of studies read in orthopedic departments are clinical series concerning surgical techniques and implants. 67% of the literature on proximal humerus fractures concerns operative treatments compared with 4% including nonoperative treatments , clearly stated the point:“The impacted fracture of the neck of the humerus always unites with a certain amount of deformity … it would be imprudent to restore to the joint its natural form, even were it in our power to accomplish it, for we would thus materially diminish the chance of the occurrence of osseous consolidation … but the prudent surgeon will never omit to announce to the patient that a certain degree of impairment of the motions of the joint will be a permanent result of the injury (Smith ).”ry Smith .”


Impact ejecta formation and emplacement is of great importance when it comes to understanding the process of impact cratering and consequences of impact events in general. Here we present a multidisciplinary investigation of a distal impact ejecta layer, the Blockhorizont, that occurs near Bernhardzell in eastern Switzerland. We provide unambiguous evidence that this layer is impact-related by confirming the presence of shocked quartz grains exhibiting multiple sets of planar deformation features. Average shock pressures recorded by the quartz grains are ~ 19 GPa for the investigated sample. U–Pb dating of zircon grains from bentonites in close stratigraphic context allows us to constrain the depositional age of the Blockhorizont to ~ 14.8 Ma. This age, in combination with geochemical and paleontological analysis of ejecta particles, is consistent with deposition of this material as distal impact ejecta from the Ries impact structure, located ~ 180 km away, in Germany. Our observations are important for constraining models of impact ejecta emplacement as ballistically and non-ballistically transported fragments, derived from vastly different depths in the pre-impact target, occur together within the ejecta layer. These observations make the Ries ejecta one of the most completely preserved ejecta deposit on Earth for an impact structure of that size. During the formation of an impact crater, fractured, crushed, melted, and vaporized rocks and minerals are excavated from the opening transient cavity, forming an ejecta layer that thins away with increasing distance from the crater, e.g., Refs.3 and references therein. The distribution of ejecta around an impact crater varies, and is dependent on various factors, including impact angle, impact velocity, volatile content, cohesiveness, and composition of target rocks, as well as the size of the impactor, e.g., Ref.4. Ejecta layers known on Earth are described as either proximal or distal3. The division between the two is either made on the basis that proximal ejecta occurs at less than 5 crater radii from the center of the crater, and ejecta outside of that limit is then considered to be distal, e.g., Ref.3, or distal ejecta are defined as ejecta occurring outside of the continuous ejecta blanket, which extends 2–3 crater radii from the center of the crater5.Impact cratering is a ubiquitous process throughout the solar system, although its effects are obscured and/or removed on Earth due to its active geological nature , as for the Australasian tektite strewn field, e.g., Refs.8, or act as the only source of information on the Earth’s early bombardment history2.Few distal impact ejecta layers have been identified on Earth9. Shocked quartz is characterized by the presence of planar deformation features (PDFs)1. They consist of thin, straight, planar lamellae of amorphous or high-dislocation-density material, forming sets of features spaced 2–10 µm apart, oriented along rational crystallographic orientations, e.g., Refs.10. There is only one diagnostic macroscopic indicator for shock metamorphism, namely shatter cones. They are macro- to mesoscopic pervasive, curved to curvilinear fractures decorated with more or less divergent striations that radiate from an apex or an apical area, e.g., Ref.1 and references therein.Impact ejecta can be identified and characterized based on, e.g., the presence of shock metamorphic features. In fact, the occurrence of shocked quartz in Cretaceous–Paleogene (K–Pg) boundary layers around the world was key evidence for understanding that ejected material from the Chicxulub impact had spread across Earth11, which has been previously proposed to be distal impact ejecta from the Ries impact structure (Germany)13. An important aspect motivating this work is that failing to simulate important components of the ejecta layer at the Ries impact structure is explained by a lack of knowledge of some physical processes that act when impact ejecta is formed14. Studies of impact ejecta deposits, such as the one presented here, are thus crucial for the possibility to further constrain these models.The aim of this study is to confirm and refine the origin, mechanism of emplacement, and age of the enigmatic “Blockhorizont”, known from three different localities in eastern Switzerland, e.g., Ref.We apply a multi-disciplinary approach that involves detailed petrographic analyzes, Universal stage (U-stage) characterization of shocked quartz grains (for confirmation of the mode of formation of the planar microstructures and for the estimation of the experienced shock pressures), U–Pb dating of bentonite horizons adjacent to the Blockhorizont to determine the age of deposition, as well as whole-rock element analysis, C- and O-isotopes, and paleontology to constrain the provenance of the ejecta components.15  as its possible source. These authors also reported the detection of suspected shocked quartz within the layer but did not provide any detailed descriptions or crystallographic constraints to confirm this.The Blockhorizont is a ~ 10 cm thick layer of marl containing randomly distributed angular blocks and smaller fragments of rocks, mainly limestone and red mudstone, and mineral grains. The layer is not defined by sharp boundaries in the field, but is clearly visible due to the presence of fragments of various sizes. Individual mineral grains and rock fragments in the layer vary between < 1 mm to 40 cm in size. The horizon is known from three different localities in north-eastern Switzerland, embedded in Middle Miocene Upper Freshwater Molasse, in the North Alpine Foreland Basin15 Figs. , 3. The 13 Ries impact structure  isolated Upper Jurassic limestone blocks which are sometimes shatter cone-bearing , as well as the Moldavite tektite strewn field, e.g., Refs.26 and references therein, that extends for ~ 200–500 km from the center of the Ries to the east-northeast , located just 875 m northwest of one of the exposures of the Blockhorizont in Switzerland , based on lithostratigraphy. The sediments of the Miocene Molasse in this area are close to horizontal and some thick conglomerate beds can be correlated from one outcrop to another . There is another outcrop of bentonite at Mollen-Waldkirch, just 4.2 km NE of Tiefenbachtobel. The Mollen bentonite is equivalent in age to the Bischofszell bentonite28 and can be correlated with the one at Tiefenbachtobel based on lithostratigraphy. While the correlation between bentonites occurring in eastern Switzerland  was uncertain30, recent zircon ages obtained by the British Geological Survey have now shown that all these horizons correspond to the same horizon28, which is also supported by lithostratigraphy29. The weighted mean age, as calculated by us, of the four localities is 14.34 ± 0.03 Ma.The bentonite at Tiefenbachtobel can be correlated with a bentonite from Bischofszell, for which consistent age determinations of 14.28 ± 0.24Analysis of rock fragments  and sand grains from three individual samples of the Blockhorizont from the Bernhardzell locality Fig.  in easteRock fragments were further characterized in the investigated thin sections Fig. . In the We have conducted the first detailed investigation of quartz grains from the Blockhorizont. The grains range from 140 to 630 μm in size, are mainly monocrystalline, and constitute individual mineral grains. Shock metamorphic features in the form of PDFs were detected in ~ 5% of the investigated quartz grains Fig. . The PDF32 and references therein). The average shock pressure for the investigated quartz grains in the sample was estimated after assigning each grain with a specific pressure tied to the PDF population of that specific grain. This gave an average shock pressure of ~ 19 GPa (see details of the method in Ref.32). No shock metamorphic features were detected in the investigated mudstone samples.Based on our investigations of the PDF orientations we can estimate that the quartz grains experienced shock pressures of up to ~ 25 GPa, based on the occurrence of grains with sets parallel to the {The shocked quartz grains display typical signs of being affected by abrasion Fig. a,c. The 33.Compared with Keuper clay from the Ries structure (clasts from the Bunte Breccia), the red mudstone occurring as fragments in the Blockhorizont shows some differences in major and trace element concentrations, especially for Si/Al, Cs, and REEs, as well as in mineralogy, implying that the mudstone from the Blockhorizont is not of Keuper origin Fig.  and S3. 13C and δ18O values between 2.0 and 2.5‰, and between − 2.1 and − 2.4‰, respectively  is slightly more negative than the values of the limestone clasts from the Blockhorizont. Δ18O values of carbonate rocks are commonly more variable than δ13C values, because the oxygen isotopic composition is more prone to diagenetic alteration . The small difference in δ18O between clasts of the Blockhorizont and the shatter cone sample from Steinheim therefore is still consistent with the hypothesis that the limestone clasts are derived from Upper Jurassic carbonate units in the Ries/Steinheim area, for which36 reported δ18O values ranging from − 2.6 to − 3.8‰.Three aliquots of each of the three limestone clasts (two of them with shatter cones) from the Blockhorizont yielded δTaxodiumpollenites hiatus probably represents the flora growing at the time of impact and could have been incorporated into the sample at or immediately after deposition at Bernhardzell. This may also be the case for two dinoflagellate specimens . According to Ref.38, red claystones are typical Miocene deposits of the Upper Freshwater Molasse in the Ries area, and these deposits pre-date the formation of the impact structure.The red mudstone from the Blockhorizont contains palynomorphs that are either of late Jurassic or Miocene age, or long-ranging taxa . The new age is consistent with the 14.28 ± 0.24 Ma age obtained from this bentonite by Ref.28, and the 14.417 ± 0.023 Ma age obtained from the same bentonite by Ref.27. We thus confirm the age of the Bischofszell bentonite.For this study, the bentonite horizon at Tiefenbachtobel (which has not previously been dated) as well as one occurring at Bischofszell Fig. , were sa207Pb-corrected age of 14.79 ± 0.34 Ma , indistinguishable from the age of sample NMBE 36981. The new U–Pb data are fully consistent with the Tiefenbachtobel bentonite having the same depositional age as the Bischofszell bentonite, despite not conclusively proving it.Sample from the Tiefenbachtobel bentonite (NMBE 43558) displays more spread in U–Pb dates. Eleven Miocene-aged grains give a weighted mean 15 and this 70 m sequence of strata is typical of the whole Miocene molasse sequence in the area . Therefore, we can assume a mean sedimentation rate of 150 to 200 m/Myr for the Miocene Upper Freshwater Molasse (based on Ref.30), making the Blockhorizont 0.35–0.47 Ma older than the bentonite in the Tiefenbachtobel profile.The absolute age of the Blockhorizont can be estimated from the stratigraphic position of the related dated bentonite horizons. The bentonite layer at Tiefenbachtobel is located 70 m above the impact horizon28. Considering the results of our analysis, we conclude that Tiefenbachtobel has the same age as Bischofszell, and therefore we use the most precise available determination of 14.417 ± 0.023 Ma for the Bischofszell bentonite27 as the age of the Tiefenbachtobel bentonite. Therefore, together with the age difference between the bentonite and the impact layer of 0.35–0.47 Ma, an age of 14.74–14.91 Ma can be estimated for the Blockhorizont impact ejecta layer. This age overlaps the age estimated for the deposition of the Brockhorizont, ~ 14.9–15.1 Ma, which was achieved using a bracketing method27, see also discussion in Refs.42, and indistinguishable within error from the age of the Ries impact of 14.808 ± 0.038 Ma17. Additionally, the palynological results also support a Miocene age (pre-late Tortonian) for the Blockhorizont . Hence, long distance transport of the material by fluvial processes from the Ries to the outcrop locality is highly unlikely . However, our main argument against fluvial transport from Ries is the fact that all the known Blockhorizont localities are situated on an alluvial fan system consisting of material transported from the Alps, thus from the south (see Ref.30). In addition, it is very unlikely that the concentration of shocked quartz grains would be as high as observed in this study if the grains would have been fluvially transported for ~ 200 km. Fluvial transportation is expected to dilute the population of shocked quartz grains, especially over ~ 200 km distance. This was demonstrated e.g., in the case of investigation of detrital shocked quartz grains derived from the Vredefort impact structure and fluvially transported46. It is also difficult to imagine how large limestone clasts, up to 40 cm in size, would be fluvially transported for such a large distance, especially since both fragments from the Blockhorizont, as well as those from the Brockhorizont16, are angular in shape. Several models47 show that large rock fragments from the Ries ejecta, as large as the ones described from the Blockhorizont, could have been ballistically transported as far as the location investigated here.The present study with the characterization of shocked quartz grains unequivocally confirms that the Blockhorizont was formed by impact, supporting previous works based on the finding of shatter cone clasts17. All results taken together, i.e., our palynological and paleontological investigations that reveal that mudstone and limestone clasts recovered from the Blockhorizont have ages that are consistent with equivalent lithologies in the Ries target stratigraphy, as well as the reported geochemical analysis, are consistent with clasts being derived from the Ries area, and, along with the age estimate of the horizon, support the hypothesis that the Blockhorizont is in fact indeed derived from the Ries impact. This means that the Blockhorizont constitutes the most distal horizon of distal Ries ejecta (not including the moldavite tektites). On this basis, the inventory of outcrops where distal Ries ejecta has been described from southern Germany can be confidently extended to eastern Switzerland .Our age estimate of 14.74–14.91 Ma for the Blockhorizont impact ejecta layer is fully consistent with the 14.808 ± 0.038 Ma age of the Ries impact structure38; however, the clasts and the individual grains are very angular, and there is no evidence of rounding of grains comprising the fragments. Only one possible exception would be the fragment in Supplementary Fig. 13 and references therein). Our observations are thus consistent with the investigated quartz grains, as well as the majority of the investigated quartz-bearing fragments, being derived from the crystalline rocks located underneath the sedimentary cover, that were shocked and ejected during the Ries impact event.In principle, both quartz-bearing clasts and individual quartz grains could be derived from the sedimentary target rocks at the Ries. Sandstones of Triassic and Jurassic age are part of the target rocks, as well as surficial unconsolidated sands48. Impact-generated dust and gas injection into the atmosphere was one of the driving forces of the mass extinction at the K–Pg boundary, leading to changes in solar irradiation reaching Earth’s surface which in combination with other (modelled) factors such as e.g., darkness, fireball effects, and increased thermal radiation created stressful conditions for biota, e.g., Ref.49. Smaller impact events may cause regional perturbation of the ecosystem, very much influenced by the ejecta distribution48.Understanding the formation and mode of emplacement of impact ejecta is fundamental in the evaluation of effects of an impact event on the biosphere50. Many Martian impact craters have, however, been discussed as being Earth-like in terms of ejecta deposition, e.g., Refs.50 .Due to the very limited and poor preservation of terrestrial impact ejecta, but also because of the challenging identification of ejecta deposits in the geological record and also difficulties in tying layers to specific impact structures, the process of impact ejecta emplacement on Earth is relatively poorly understood. Analogies to other cratered bodies in the Solar System are not straight-forward, e.g., due to the differences in gravity, volatile content, and cohesiveness of target bedrock, e.g., Ref.52, at a distance of 250–300 km from the structure. The Acraman ejecta horizon consists of two distinct grain size populations: poorly sorted breccia and larger clasts, and graded sand. It was suggested by Ref.51 that the material was deposited via different mechanisms during the impact event based on these two grain size populations, the breccia by ejecta-flow and/or fireball transport, and the graded sand by impact-induced air-blast transport. The Blockhorizont differs from the Acraman ejecta in that it is not composed of separate units, i.e., the quartz grains are found in the same interval as the limestone and mudstone fragments. The Acraman units are even separated by a sandy mud unit that was interpreted by Ref.51 as a short time gap between the arrivals of the different materials. However, the Acraman ejecta horizon occurs within deep-water shales, and the material was thus deposited in a vastly different setting than the ejecta that now forms the Blockhorizont, and the effects of gravitational settling through the water column will induce differences that make the two ejecta layers difficult to compare. In fact, Chicxulub distal ejecta particles, even if they were deposited via both ballistic and non-ballistic mechanisms, were deposited at roughly the same time . During that impact event, numerical models demonstrate that distinct transport mechanisms for the different ejecta components are needed in order to match observational data and, specifically, distal transportation of single shocked quartz grains is proposed to be non-ballistic53. Distal impact ejecta emplacement for smaller impacts is a similarly complex process, despite the differences in magnitude, as discussed in Ref.14. Other works using numerical models and laboratory experiments to improve understanding of impact ejecta formation include e.g., Refs.55, and references therein.The Blockhorizont contains material of different size ranges, stratigraphic position in the pre-impact setting, and with distinctly different mechanical properties . We observe Upper Jurassic limestone blocks, up to 40-cm in size, with well-developed shatter cones, together with angular fragments of soft mudstone (of probable Miocene age), angular fragments of crystalline bedrock (up to 1 mm in size), and individual shocked quartz grains (tens to hundreds of micrometers in size) likely derived from the basement. In that sense, the Blockhorizont displays similar characteristics to ejecta from the Acraman impact structure , which also includes small fragments of individual mineral grains and larger fragments, up to 30 cm in size, that display shatter cones54. In the model by Ref.14, the early ejecta particles originate from the uppermost 50 m of the target sequence, and they experienced relatively low shock pressures (2–6 GPa). This could explain why the analyzed mudstone fragments are inconsistent with a Keuper origin, since Keuper mudstone belongs to a deeper portion of the target rocks  have bearing on aspects that are important to this work, e.g., how far ejecta is transported and the depth of excavation, we note that our observations can be used to improve models of ejecta emplacement, e.g., in testing whether the shocked quartz grains described in the present study were transported ballistically or non-ballistically. It is stated in Ref.14 that ballistic sedimentation of crystalline material preferentially occurs near the crater . Material comprising the distal ejecta of the Chicxulub impact was recently proposed to be transported in a fast-moving dust cloud of material from the ejecta curtain 56. In this model, shocked mineral grains traveling at velocities of a few km s−1 could reach distal sites. Combined with previous models of distal ejecta distribution from Chicxulub53 that predict delivery of shocked quartz non-ballistically, this leads us to conclude that the presence of shocked quartz grains in the Blockhorizont can be explained by non-ballistic ejecta transportation, either through a mechanism related to re-distribution from a hot, expanding atmosphere (“impact plume”), or as material incorporated in a dust cloud. This separates the mineral grains from the large fragments that follow ballistic ejecta trajectories (see Ref.53). In Chicxulub distal ejecta, spherules are more or less abundant57, and these are distributed from the vapor plume58. In the Blockhorizont, no definitive impact spherules were recovered by us in the investigated samples. However, this is not surprising as recent modelling58 suggests that the average size of spherules for an impact equivalent in size to the Ries-forming event would be on the order of ~ 10 μm. We have to stress that such tiny spherules may be present in our samples but were overlooked as this size fraction was not investigated.In several models, the large limestone fragments in Ries ejecta are transported ballistically as early ejecta48) or representing the fast-moving dense dust cloud56 formed by the Ries impact occurs in localities up to ~ 200 km away from the impact point. Although the most famous example of impact-induced environmental havoc is the far greater (in terms of energy release) Chicxulub/K–Pg event, the regional effects of smaller impacts was demonstrated, see e.g., Ref.48. In the case of the Ries ejecta, we have seen a vast difference in abundance pattern of clastic particles between the Blockhorizont and samples adjacent to the horizon. If we make the conservative assumption that the Blockhorizont is 5 cm thick, has a density of 2 g/cm3, and consists of ~ 2% impact ejecta , using a stereographic projection template, displaying the possible pole orientations of common PDF planes within a 5° envelope of measurement error31. In order to attain precise angular relations, all the polar angles between PDFs and c-axis were further checked using the computer program Stereo32 .The material (loose sediment constituting the Blockhorizont) studied for possible microscopic shock metamorphic features in minerals was first dispersed in water and then sieved  in order to remove the clay fraction and also the larger fraction, i.e., fragments larger than 5 mm in size. The remaining fraction of the sample was then leached in HCl and mounted in epoxy blocks from which thin sections were prepared. The four thin sections where then searched for shocked quartz grains under an optical microscope. All quartz grains displaying PDFs were further studied using a Leitz 5-axis U-stage mounted on an optical microscope. Orientations of optic axes (c-axes) and poles perpendicular to PDF planes in quartz grains were measured and indexed following the technique described in Ref.The presence of planar fractures (PFs) was also noted, but their orientation was only measured in ten quartz grains, in order to obtain a general impression of their orientation pattern. All percentage calculations presented here represent absolute frequencies. An estimate of the frequency of shocked quartz in the sample was obtained by point counting and comparing the number of quartz grains displaying and devoid of PDFs in the investigated thin sections.The thin sections were also studied using a Hitachi S-3400N scanning electron microscope at the Department of Geology, Lund University.43) and divided into the following categories: very angular (1), angular (2), sub angular (3), sub rounded (4), rounded (5), and well rounded (6).In addition, all shocked quartz grains were subjected to a roundness analysis to assess how the grains were affected by abrasion, based on the Pettijohn scale  of the red mudstone from the Blockhorizont was processed using standard palynological methods at the Palynological laboratory, GEUS, Copenhagen, Denmark. The cleaned and crushed sample was digested in HCl and HF acids to remove carbonate and silicate minerals. After heavy liquid separation, to remove heavy minerals, and subsequent mild oxidation with Schulze’s solution, the organic residue was sieved on an 11 µm mesh. Three strew slides were curated with glycerin gel and carefully scanned for palynomorphs. The sample contained only low amounts of organic material.Limestone fragments from the horizon were analyzed for their nannofossil and macrofossil content for age determination.59. The mineralogy  of these samples was determined by X-ray diffraction at the Institute of Geological Sciences, University of Bern. Bulk samples were measured on un-oriented samples, and clay minerals were analyzed on oriented samples of the fraction < 2 micron, both air-dry and after saturation with ethylene glycol. Lithium fluoride was used as an internal standard for the bulk mineralogy.Whole rock element analysis was carried out on one sample of the red mudstone (clast within the Blockhorizont), one sample of loose sediment constituting the Blockhorizont, and on eight samples of Keuper clay clasts from the proximal Ries ejecta . The concentrations of major and trace elements were determined by AcmeLabs, Canada, using an ICP-ES/ICP-MS. For REE normalization we used the CI chondrite values from Ref.13), were analyzed for their oxygen and carbon isotopic composition using a ThermoFisher GasBench II linked to a DeltaplusXL mass spectrometer at the University of Innsbruck, Austria. The δ13C and δ18O values are reported relative to the Vienna Pee Dee Belemnite (VPDB) standard. See Ref.60 for details on the method.In addition, three limestone clasts, two of which show shatter cones, and one shatter cone-bearing limestone sample from the Steinheim impact structure  and cathodoluminescence (CL) modes on an FEI Quanta FEG 650 scanning electron microscope (SEM) at the Swedish Museum of Natural History, Stockholm, Sweden. The carbon coat was removed with a brief (less than 30 s) polish with 1 µm diamond polishing paste and after cleaning the mount was gold coated for in situ U–Pb analysis.62, specifically by utilizing the Hyperion H201 RF plasma high-brightness oxygen source. This produced an analysis pit approximately 10 µm across. Fifteen analyses were performed on fifteen separate grains in each of the two samples, all in a single analytical session. The zircon standard 91500 isotope dilute-thermal ionization mass spectrometry [ID-TIMS] 206Pb/238U age = 1062.4 ± 0.8 Ma; all uncertainties reported at 2σ unless otherwise stated; Ref.63 was used as the calibration reference material and Penglai (with an age of 4.4 ± 0.1 Ma62) was analysed as a quality control material. Six analyses on Penglai gave a weighted average 207Pb-corrected age of 4.41 ± 0.16 Ma , in agreement with the preferred age of Ref.64. Full U–Pb data for the two samples and Penglai are available in Supplementary Table The grains were analyzed for U–Pb isotopic composition and age by secondary ion mass spectrometry (SIMS) on the Cameca IMS1280 ion microprobe at the NordSIMS Laboratory, Swedish Museum of Natural History. The methodology was modified from that described by Refs.Supplementary Information.Supplementary Table S3.Supplementary Table S6.


The effectiveness of evidence-based practices, such as use of behavioral interventions, can be improved when delivered under conditions of an implementation framework. This pragmatic trial used the Evidence Integration Triangle (EIT) which is a parsimonious, community-engaged participatory framework that brings evidence and facility stakeholders together. Active engagement empowers key stakeholders to integrate evidence into practice using a simple three-pronged framework: (1) A participatory implementation process which was done via monthly meetings and weekly emails between stakeholders and a clinical expert as they worked on facility based goals; (2) Implementation of the four steps delineated in the EIT-4-BPSD; and (3) evaluation using practical progress measures. There was some evidence of implementation of the EIT-4-BPSD based on participation in Stakeholder team meetings, settings working towards goal achievement, and increased use of behavioral interventions among staff. The EIT approach is a useful implementation framework to help change staff behavior in long term care.


The presence of others helps us when we are good or an expert at something and hinders us when we are bad or novice. Such social facilitation or inhibition is well-documented in adults, but much less in children despite the omnipresence of peers throughout education. To explore potential peer presence effects on children’s academic performance, fourth-graders performed basic numerical and language skills  either alone or with a schoolmate. For comparison, the same was performed in adults. We found that a schoolmate’s presence enabled children to perform more like adults, with a better response strategy and faster and less variable response times than children tested alone. This provides research-based evidence supporting pedagogical methods promoting collective practice of individually acquired knowledge. Future studies pursuing this hitherto neglected developmental exploration of peer presence effects on academic achievements might have the potential to help educators tailor their pedagogical choices to maximize peer presence when beneficial and minimize it when harmful. The present study also paves the way towards a neuroimaging investigation of how peer presence changes the way the child brain processes cognitive tasks relevant to education.Little is known about how peers’ mere presence may, in itself, affect academic learning and achievement. The present study addresses this issue by exploring whether and how the presence of a familiar peer affects performance in a task assessing basic numeracy and literacy skills: numerosity and phonological comparisons. We tested 99 fourth-graders either alone or with a classmate. Ninety-seven college-aged young adults were also tested on the same task, either alone or with a familiar peer. Peer presence yielded a reaction time (RT) speedup in children, and this social facilitation was at least as important as that seen in adults. RT distribution analyses indicated that the presence of a familiar peer promotes the emergence of adult-like features in children. This included shorter and less variable reaction times , increased use of an optimal response strategy, and, based on Ratcliff’s diffusion model, speeded up nondecision (memory and/or motor) processes. Peer presence thus allowed children to at least narrow , and at best, virtually fill in  the developmental gap separating them from adult levels of performance. These findings confirm the influence of peer presence on skills relevant to education and lay the groundwork for exploring how the brain mechanisms mediating this fundamental social influence evolve during development.  An unvarying feature of schools worldwide is that children are educated in the constant presence of peers, yet scientific research does not always take this social aspect of learning into account. The cognitive literature traditionally ignores it. The educational literature did explore classrooms’ peer compositions to determine the impact of peers’ attributes: same- or other-sex, same- or other-ethnicity, same or different cognitive and academic abilities, etc., on academic achievements ,2,3,4,5.A long history of social psychology studies showed that others’ presence changes adults’ performance, generally facilitating the expression of mastered responses while impairing the acquisition of novel ones . This ubThe present study’s first aim was to measure the extent to which peer presence might affect skills that are relevant to fundamental education in elementary school children. To address this question, we measured the change in performance on literacy and numeracy tasks produced by the presence of a coacting classmate in 8 to 10-year-old fourth-graders. We designed a task taping two skills, one (numerosity comparison) relevant to numeracy, and the other  relevant to literacy. The reason for this choice was two-fold. Firstly, numerosity and phonological comparisons are simple skills typically mastered before 4th grade ,26, and The present study’s second aim was to assess the development of the peer presence effect by comparing children to adults. To this aim, we tested college-aged young adults while they performed the same task, either alone or in the presence of a coacting familiar peer. We analyzed errors, reaction times (RTs) and effect sizes. RTs were also analyzed using (1) the ex-Gaussian model  to deterwww.gpower.hhu.de accessed on 10 September 2021) with α = 0.05, an overall sample size of 82 cases was required to detect with adequate power (1-β = 0.80) the effect size of Wolf et al., (2015) Age × Condition × Difficulty interaction , which revealed adolescents’ greater social inhibition of difficult relational reasoning relative to adults. The present sample of 196 subjects thus represents more than twice as many subjects as required to detect such an effect size and provides a power of 1−β = 0.99 to detect it.We recruited 111 4th-graders , and 100 college-aged young adults . Adults were compensated for their participation (10€). Eight children were excluded from the analyses because they suffered from reading disability, attention deficit, or anxiety disorder. Data were entirely missing from four children and three adults due to recording problems. These were excluded from the analyses. Data were partially missing  from two adults and one child. These data were retained (without imputation). This resulted in a final sample size of 196 cases, including 99 children  and 97 adults . Based on an a priori power analysis conducted through G*Power 3.1.9.7 , and the other half was tested in pairs of coactors . For children, pairs were formed by their teacher according to known affinities among classmates. For adults, half of the recruited subjects were same-age (±2 years) pairs of friends, siblings, or significant others . In both conditions, the subject was facing the screen of a laptop computer with the two index fingers positioned over two keyboard response keys. When present, the familiar peer was seated next to the subject and performed the same task at the same time on a second computer. The experimenter always left the testing room after having instructed the subject(s) and started the appropriate computerized task. Each subject completed the experimental task plus a series of questionnaires as described in the next paragraphs. Testing took place in a quiet room, either at school for children, or in the laboratory for adults. Half of the subjects underwent solitary testing , we programmed a task comprising 288 trials for adults. The task was downsized to 144 trials for children to minimize the duration of the interruption of their school day. For both adults and children, half of the trials involved numerosity comparison trials, the other half involved phonological comparison. To assess social facilitation, we probed two skills present before the age of 8 ,26, i.e.In numerosity comparison trials, subjects were asked to decide which of two arrays of dots (presented one after the other) had the largest number of dots. Each dot array was presented for 800 ms, with a 200 ms white screen in between. The second dot array was then replaced by a red square for a duration varying randomly from 2800–3600 ms. Subjects were asked to respond as fast and as accurately as possible by pressing a keyboard key as soon as the second dot array appeared and before the red square turned off. One key was associated with “the first dot array has the largest number of dots” answer and another key with “the second dot array has the largest number of dots” answer A. In phoAs in Prado et al.  ,31, eachTo avoid carryover effects , trial types , and difficulty levels (1–4) were not presented successively. Rather, each block of eight trials comprised four trials of each type, one per difficulty level, appearing in pseudorandom order with no more than three consecutive trials of the same type. This design mixing numerosity and phonological comparisons entails switch costs , but these specific costs were found to be stable across age when general development-related slowing is taken into account . They thn = 51), we used easier to discriminate arrays of 12, 18, 24, or 36 dots made with the less controlled “simple-sensory condition” of Dehaene et al., 2005 generator (www.unicog.org accessed on 10 September 2021). For the other children (n = 48), we used tightly controlled arrays generated with Gebuis and Reynvoet’s generator with half the number of dots used for adults, i.e., 6, 9, 12, or 18 dots. Children’s data were pooled across the two types of stimuli as preliminary analyses revealed no effect of this variable. Words contained 1 or 2 syllables and 3–8 letters, as in earlier studies ; phonological comparison: F = , p’s < 0.001 and ηp2 =  for v and t0, p = 0.43 for a). Trial-by-trial variability was also generally smaller in adults  = , p = 0.05 and p < 0.001 for sv and st0 respectively, ηp2 = ; phonological comparison: F = , p = 0.04 and p < 0.001 for szr and st0 respectively, ηp2 = ). p < 0.001, ηp2 = 0.71; st0: F = 38.37, p < 0.001, ηp2 = 0.17; phonological comparison: t0: F = 490.2, p < 0.001, ηp2 = 0.72; st0: F = 34.02, p < 0.001, ηp2 = 0.15). Posthoc analyses revealed no other differences between fast and slow responders, whatever the age, trial type, or condition. Finally, p < 0.001; phonological comparison: F = 24.59, p < 0.001). t0 was reduced in the Social relative to the Alone condition. There was no Condition × Age effect on any parameter, indicating that the peer presence effect on t0 was comparable in children and adults. This was confirmed by posthoc analyses of t0 in the Alone vs. Social conditions (p’s ≤ 0.005 for both children and adults in both tasks). In addition, a correlation test between t0 and the mean RT revealed a significant positive correlation for both children and adults across both trial types and both conditions . The main results are illustrated in The diffusion model analysis therefore suggests that peer presence did not affect the decision parameters v and a, respectively modeling how fast and confidently subjects make their decision. Peer presence selectively shortened the nondecision parameter t0, which models all other information processes including, in our paradigm, the memory process necessary to compare the two successively presented stimuli and the motor process necessary to prepare the response. This t0 shortening enabled subjects to adopt the faster of the two response strategies adapted to solve the present task.p = 0.02). As familiarity was reported to exacerbate peer presence effects [Both adult and children coactors reached IOS scores greater than the 4/7 score considered as reflecting close relationships , thereby confirming that, as intended, the coactor was a familiar peer (rather than a stranger) for both age groups. IOS scores in the adult pairs of friends, siblings, or significant others did exceed, however, the IOS scores of the children pairs of classmates . As extraverted individuals tend to show greater peer presence effects [ effects , this slp < 0.001), associated with a positive correlation between RPI scores and age . It ascertained, in addition, that there was no main effect of Condition on RPI scores  = 0.74, p = 0.39). Finally the Condition × Age ANOVA on RPI scores did confirm earlier reports  of a lowNumerosity and phonological comparisons, two cognitive skills mastered early during education, were performed faster by 8 to 10-year-old 4th graders in the presence of a classmate than alone. This social facilitation was at least as important as that seen in adults. Ex-Gaussian decomposition of RTs revealed no peer presence effect on the extremely slow RTs thought to reflect lapses of attention . Rather,As evoked in the Introduction, the abilities to compare numerical quantities or language sounds are two early developing skills that are foundational to the growth of math and reading skills in children. Both are arguably mastered by 4th grade, so social psychology consensual rule that others’ presence helps us execute mastered tasks predicted that both should be socially facilitated. We could not be certain, however, that this would be the case here, as our paradigm mixed trials of unequal difficulty. Indeed, whether a behavior is socially facilitated or inhibited eventually depends on the overall level of difficulty of the task it is embedded into. Bond showed as early as 1982 that an observer’s presence impairs the learning of three simple items if they are mixed with 10 difficult ones, and does not impair the learning of three complex items if they are mixed with 10 easy ones . LikewisAs also evoked earlier, the long history of social psychology SFI studies predominantly concerned adults. In children, available studies often highlighted the positive influences of peers on basic acts and physical activities. In adolescents, available studies rather emphasized the negative influences of peers on cognitive skills. The present findings provide evidence that peer presence effects extend to the cognitive domain not only in adolescents, but also in children. They also underscore that sensitivity to peer presence in the cognitive domain is not always a liability, and can, at times, be adaptive. To improve our understanding of peers influences on academic achievements, future studies will therefore need to encompass both their harmful and their beneficial consequences throughout the entire course of education, from childhood to early adulthood ,68. s, for example, reached medium effect sizes of 0.61 and 0.51 in children , compared to small effect sizes of 0.38 and 0.21 in adults. Testing the present paradigm in a greater variety of school ages is therefore needed to determine whether the present difference in effect size represents the very early stage of a developmental difference peaking during adolescence. The developmental trajectory of SFI remains unknown, as few studies compared peer presence effects across different ages. One study compared completion of jigsaw puzzles in children aged 5 and 8 years, and early adolescents aged 11 years . Only thThe past fifteen years or so saw a tremendous interest in using findings from neuroscience and cognitive psychology to inform the practice of education . It was We found that a schoolmate’s presence enabled children to perform mastered numerosity and phonological comparisons more like adults, with a better response strategy and faster and less variable response times than children tested alone. These findings confirm the influence of peer presence on skills relevant to education and stress the need for additional studies including older individuals and nonmastered tasks. They also lay the groundwork for exploring how the brain mechanisms mediating this fundamental social influence evolve during development.


The National Institute for Health and Care Excellence (NICE) has been applying the principles of evidence-based medicine to public health problems for over twelve years. This application is in effect the practice of evidence-based public health (EBPH) . NICE asInfrequently is it practical to assess the effectiveness of interventions for complex public health problems by traditional gold standard randomised control trials. The importance of context, wider determinants, subpopulation variability and the role of the non-human biology element often mean that specific high quality evidence is unavailable. There is often a lack of good outcome studies answering the specific ‘what works’ question. There are often fewer studies still that answer the questions what works for whom and under what circumstances? The evidence is also often too imprecise to determine the relationship between the intervention and the outcome.The public health evidence base is rarely perfect, if it were it would likely negate the need for, or change the approach and role of organisations such as NICE. Perhaps more importantly the question asked in the evidence interrogation at NICE is ‘What is the best available evidence to answer the specific question being addressed?’ We know public health questions may benefit from exploration of a broader range of evidence including that which is further down the hierarchy of evidence. By taking a transparent and systematic approach and pulling from evidence from a range of disciplines, NICE has been able to review and synthesise evidence for complex public health problems .The evidence used to generate NICE guidelines is diverse and consists not only of the traditional scientific published evidence but also stakeholder comments, grey literature, real world evidence and expert testimony . The defThis presentation will aim to describe the approach taken by NICE in interrogating the evidence base to develop national public health guidelines. The key challenges and some solutions will be illustrated through examples from evidence synthesis to support guidelines for non-communicable diseases.