Globally, 20 million children are born with a birth weight below 2500 g every year, which is considered as a low birthweight (LBW) baby. This study investigates the contribution of modifiable risk factors in a nationally representative Welsh e-cohort of children and their mothers to inform opportunities to reduce LBW prevalence.A longitudinal cohort study based on anonymously linked, routinely collected multiple administrative data sets.The cohort, (N=693 377) comprising of children born between 1 January 1998 and 31 December 2018 in Wales, was selected from the National Community Child Health Database.The risk factors associated with a binary LBW (outcome) variable were investigated with multivariable logistic regression (MLR) and decision tree (DT) models.The MLR model showed that non-singleton children had the highest risk of LBW (adjusted OR 21.74 (95% CI 21.09 to 22.40)), followed by pregnancy interval less than 1 year (2.92 (95% CI 2.70 to 3.15)), maternal physical and mental health conditions including diabetes (2.03 (1.81 to 2.28)), anaemia (1.26 (95% CI 1.16 to 1.36)), depression (1.58 (95% CI 1.43 to 1.75)), serious mental illness (1.46 (95% CI 1.04 to 2.05)), anxiety (1.22 (95% CI 1.08 to 1.38)) and use of antidepressant medication during pregnancy (1.92 (95% CI 1.20 to 3.07)). Additional maternal risk factors include smoking (1.80 (95% CI 1.76 to 1.84)), alcohol-related hospital admission (1.60 (95% CI 1.30 to 1.97)), substance misuse (1.35 (95% CI 1.29 to 1.41)) and evidence of domestic abuse (1.98 (95% CI 1.39 to 2.81)). Living in less deprived area has lower risk of LBW (0.70 (95% CI 0.67 to 0.72)). The most important risk factors from the DT models include maternal factors such as smoking, maternal weight, substance misuse record, maternal age along with deprivation—Welsh Index of Multiple Deprivation score, pregnancy interval and birth order of the child.Resources to reduce the prevalence of LBW should focus on improving maternal health, reducing preterm births, increasing awareness of what is a sufficient pregnancy interval, and to provide adequate support for mothers’ mental health and well-being. This study has built an e-cohort using data-linkage across multiple routinely collected administrative data sets to investigate the risk factors of low birth weight (LBW) for the population of Wales.The study has investigated the modifiable risk factors of LBW in a holistic framework by linking primary and secondary care physical and mental health, socio-demographic and pregnancy-related routine data including police record for a nationally representative sample.This study undertook two different statistical approaches  which is a strength of the study.This work was unable to include any important risk factors which were not recorded in the healthcare system or any conditions which were undiagnosed hence that did not result in the system.The WHO defines low birth weight (LBW) as infants weighing less than 2500 g (5.5 pounds) irrespective of gestational age.10Existing research has found factors linked with mothers, such as age, high deprivation and low academic qualification, are associated with increased odds of LBW.25 26It is important to gain an understanding of these risk factors, particularly modifiable risk factors, so that resources and interventions can be scheduled effectively. Moreover, the wide range of risk factors cannot be addressed in isolation. Most of the risk factors that are strongly independently associated with LBW are correlated. This study aimed to understand the contributions of risk factors to the burden of LBW for the population of Wales, using traditional statistical methods and supervised machine learning models.The linked data cohort (N=693 377) comprised of children born in Wales between 1 January 1998 and 31 December 2018. The study population was identified in the National Community Child Health Database (NCCHD), which is a local Child Health System database held by the National Health Service. The participants were linked to the Wales-wide administrative register, the Wales Demographic Service (WDS) dataset. Linkage was undertaken using an anonymised encrypted linkage key, the anonymised linking field, in the Secure Anonymised Information Linkage (SAIL) Databank.et al was identifiedA literature review was conducted at the beginning of the study to identify the explanatory variables associated with LBW. A study by Johnson et al.Any published systematic reviews since 2013 which focused on risk factors identified in Johnson et al.Any published systematic reviews since 2010 for all additional risk factors not identified in Johnson This study therefore considered a wide range of explanatory and confounding variables that have a plausible causal link to LBW and are potentially modifiable at a population level. The literature review to select the explanatory variables has been described in a 10.1136/bmjopen-2022-063836.supp3Supplementary data10.1136/bmjopen-2022-063836.supp1Supplementary dataA subset of the study population  was linked with the Public Protection Notification (PPN) dataset to investigate the impact of the PPN during pregnancy along with other existing risk factors on the risk of LBW.A binary variable was created using the birth weight variable obtained from NCCHD.LBW=birth weight <2500.Not LBW=birth weight ≥2500.It is known that gestational age is highly correlated with LBW. However, as the gestational age is only obtained at the point of birth, making it a non-modifiable risk factor, this study has not considered it as a predictor variable. The models were stratified by the multiple birth as this is one of the main predictors of LBW. The missing records in the birthweight variable were removed from the analysis. Since there was around 15% missing data in the maternal weight variable, the variable was imputed by the simple random imputation method.The statistical analysis of the current study was carried out using two statistical approaches: (a) building a holistic regression model to investigate the association between the risk factors and LBW and (b) building a predictive model using a supervised classification method. Both methods were capable of handling binary outcome variables. The models that were developed by the above-mentioned methods were built independently, however they both were informed by the same dataset. This enabled us to evaluate and validate the findings of the models and helped to gain insight on the generalisability of the findings.A multivariable logistic regression (MLR) model was developed to identify the most important risk factors associated with LBW. The MLR model was built on the overall study population  to examine the associations between all the explanatory and outcome variables. The holistic model considering all the risk factors identified from literature review and selected or derived from routine data includes maternal physical and mental health during pregnancy, maternal smoking, alcohol and other substance misuse record, maternal age, maternal weight, pregnancy interval, living area, LA and deprivation—WIMD score. The MLR model also included the birth order of the child and the multiple birth flag. The birth order highlights the sequential birth position of the child for a mother, and it does not vary among the children who were non-singleton in the same family (please see A supervised machine learning classifier—decision tree (DT) model was developed to build a risk profile for LBW and test its predictive performance. Classification tree—DT models were constructed using RPART (Recursive Partitioning And Regression Trees) packages in R.A separate data linkage was undertaken with a subset of the study population which was linked to the mother’s domestic abuse record from PPN dataset . Another adjusted MLR model was developed on this linked data to investigate the risk association for LBW.No patient involved.The study population consisted of 693 377 children of which 54 214 were from Rhondda, Cynon, Taf, and 639 163 were from other LAs. The children from Rhondda, Cynon, Taf, which was later used as a test set for DT were well representative of the Welsh population see . In the Non-singleton children were at almost 22 times higher risk of LBW than singleton children (aOR—21.74 (95% CI 21.09 to 22.40)). Mothers with diabetes-related GP visits (2.03 (95% CI 1.81 to 2.28)) and hospital admission records of anaemia (1.26 (95% CI 1.16 to 1.36)) during pregnancy were at very high risk of having LBW children. Poor mental health during pregnancy such as severe depression (1.58 (95% CI 1.43 to 1.75)), serious mental illness (1.46 (95% CI 1.04 to 2.05)), severe anxiety (1.22 (95% CI 1.08 to 1.38)) and antidepressant medications (1.92 (95% CI 1.20 to 3.07)) were risk factors for LBW. The other highly significant modifiable risk factors linked with pregnant mothers include maternal smoking (1.80 (95% CI 1.76 to 1.84)), alcohol-related hospital admissions (1.60 (95% CI 1.30 to 1.97)) and any substance misuse  (1.35 (95% CI 1.29 to 1.41)) during pregnancy. Higher maternal age was also associated with the risk of LBW. Though maternal age less than 19 was significantly associated with the risk of LBW in the univariable model, after adjusting all the other explanatory variables, this did not remain as a risk factor of LBW. The first child born was at higher risk of LBW than subsequent births, The odds of LBW for the second child was 0.59 (95% CI 0.57 to 0.60) compared with the first child. Mothers living in the least deprived and rural areas during pregnancy were at lower risk of having LBW children than others living in more deprived and urban areas. The statistically significant risk factors with their aOR and CI have been visualised and described in A data set of 5854 mothers were obtained from the PPN data linkage. Those who had a PPN call during pregnancy, 18% of them had an LBW child and those who did not have a PPN call, 8.7% of them had an LBW child see . Mothers10.1136/bmjopen-2022-063836.supp2Supplementary dataSince LBW were disproportionately more prevalent in non-singleton children (5.61% singleton vs 53.91% of the non-singleton children were LBW) , two sepThere were 619 458 observations in the training model. The most important risk factors selected by the DT algorithm to develop the final tree were maternal smoking, maternal weight, pregnancy interval, birth order, maternal substance misuse record (any), maternal age, deprivation—WIMD score, maternal substance misuse record (other drug) and maternal substance misuse record . The test data was built on the 52 583 singleton children, which is 7.82% of the total singleton children in this study. The model performance is explained in a confusion matrix with 60.54% accuracy, 60.41% sensitivity, 60.55% specificity, 9.68% positive predictive values and 95.63% negative predictive value see .There were 19 705 children in the non-singleton training subset. The variables selected to generate the tree by the DT algorithm in the importance order were pregnancy interval, birth order, maternal weight, maternal age, gender, deprivation—WIMD score, maternal smoking, living area, deprivation—WIMD (environment) score and maternal substance misuse record (any). The test set was built on the 1631 non-singleton children, which is 7.64% of the total non-singleton children in this study. The model performance was measured as 58.74% accuracy, 68.71% sensitivity, 41.09% specificity, 67.36% positive predictive values and 42.61% negative predictive value see .Among the overall study population in Wales 7.1% was LBW between 1998 and 2018. Global trend of LBW is around 7.0% in both 2000 and 2015 for the developed regions , which is consistent with our finding.et al highlighted that several studies examining long interpregnancy intervals are prone to measurement error because miscarriages and abortions within this time period are difficult to capture. Hence the authors suggest that caution should be exercised when interpreting these findings.38The findings of short and long pregnancy intervals being associated with increased odds of LBW has been reported previously.The study undertook two statistical methods; (a) regression and (b) supervised classification model with the aim that the regression model would identify the risk factors with highest association/OR but not frequently observed factors at the population level for, for example, only 0.09% mothers had diabetes-related GP visit during pregnancy, and they had two times higher risk of having a LBW child (2.03 (95% CI 1.81 to 2.28)). However, the DT models consider the number of people affected by the risk factor rather than just strength of association, hence capable of identifying the factors at a population level  that can result in higher risk of LBW.et al has an incidence of 13.45% in work that builds over 60 different machine learning models,et al assess logistic regression and random forests in a cohort with LBW rate of 9.5%.There are similarities between the findings of our DT models and existing literature using machine learning to predict LBW, for example, urban living, higher deprivation and poorer families are at higher risk of LBW.The strength of this study lies in using a wide spectrum of routinely collected nationally representative administrative data sets of all births in Wales across a large time. This is a very first of its kind study in Wales and adds novelty in the research field of LBW. However, this work can only identify the more severe cases which are recorded in the healthcare system, and undiagnosed cases that did not result in the system will be missed which is a limitation of this work. Since the study was developed on the linked routine data, the limitation of the routine data was encountered in this study, for example, though the maternal weight variable came from two different sources, data was missing for many participants which was addressed by imputation methods. Also, this study was unable to capture lifestyle factors  which can be important in determining LBW.42 43The two different models (MLR and DT) used in this study have very similar findings suggesting that factors which are common and so are predictive (using DT methods) such as maternal smoking status and maternal weight could be targeted to address population-level risk of LBW. Factors which have a strong association with LBW , such as a mother with diabetes or mother on antidepressants as having plausible causal link to LBW, can be addressed to reduce individual risk for that mother/child.This study suggests that the most important factors to reduce the risk of LBW are to address multiple birth , addressing factors associated with preterm births (previous history of preterm birth), addressing maternal health such as reducing smoking, investment in maternal mental health, addressing substance use , treating underlying health conditions (diabetes/anaemia) and promoting planning of pregnancy to give an adequate pregnancy interval and healthy weight of mother especially for those in deprived urban areas.


Intragenic exonic deletions are known to contribute to genetic diseases and are often flanked by regions of homology.In order to get a more clear view of these interspersed repeats encompassing a coding sequence, we have developed EDIR (Exome Database of Interspersed Repeats) which contains the positions of these structures within the human exome. EDIR has been calculated by an inductive strategy, rather than by a brute force approach and can be queried through an R/Bioconductor package or a web interface allowing the per-gene rapid extraction of homology-flanked sequences throughout the exome.https://github.com/lauravongoc/EDIR. The full dataset of EDIR can be queried via an Rshiny application at http://193.70.34.71:3857/edir/. The R package for querying EDIR is called ‘EDIRquery’ and is available on Bioconductor. The full EDIR dataset can be downloaded from https://osf.io/m3gvx/ or http://193.70.34.71/EDIR.tar.gz.The code used to compile EDIR can be found at Bioinformatics online. Intragenic exonic deletions have been shown to contribute to genetic defects in a wide subset of genes and diseases , we were unable to identify the presence of known repetitive elements in the breakpoint region of the above-detected deletion  we could also not identify the CCCCGTG interspersed repeat which was detected (Our group has recently identified a Pompe’s disease patient who is compound heterozygous for the NM_000152.4(GAA): c.2331 + 2T>A, p.? alteration together with the 343 bp NM_000152.4(GAA): c.1327-61_1437 + 172del, p.? deletion spanning exon 9 and which is flanked by a 7 bp CCCCGTG repeat. This hints to the presence of microhomology as the major prerequisite for the deletion. Using the UCSC repeat browser tool (detected . This poCompilation of EDIR was accomplished in four distinct steps: (i) mapping of interspersed repeat sequence (IRS) structures starting with a 7 bp repeat seed sequence (written in Python) and (ii) annotation and selection of the mapped structures according to their position in the exome (written in R), followed by (iii) extension of the 7 bp repeat to 20 bp. An additional user-friendly script was written (iv) allowing querying of the data base through a web interface (using R Shiny). EDIR was furthermore calculated allowing a 1 bp mismatch between any two flanking repeat sequences.7 = 16 384) and once mapped, the genomic start and stop positions of IRS were stored. We aimed to include only IRS in which minimally one repeat was located in an exon or both repeats were situated in different introns flanking one or more exons. As such, a selection of regions has been done which, in case of recombination or replication errors, could potentially result in the expression of aberrant mRNA and protein and thus could lead to disease. For this purpose, the start and end positions of all detected 7 bp IRS were compared to the start and stop positions of all known exons. . The calculation (mapping and intron-exon selection) for all 7 bp permutations allowing a maximum of one mismatch was performed on a virtual machine with 40 cores and 40 Gb of RAM and took ±193 h to complete and resulted in a 60 Gb data file. As we aimed to extend our analysis towards 8–20 bp repeats, the number of possible permutations of for instance the 20 bp IRS even without a 1 bp mismatch would attain 420 > 1E12, a combination size too large for calculation. However, theoretically, the generated data of the 7 bp IRS also encompasses the sets of 8 bp and larger  and the location of the files provided to the query function is https://github.com/lauravongoc/EDIR.This has resulted in an R package which is available on Bioconductor and which contains the different IRS for the http://193.70.34.71:3857/edir/ in which the queried data is downloadable in a .csv format. In addition, the web interface links each IRS to its genomic region in the UCSC Genome Browser (https://genome.ucsc.edu), ClinVar (https://www.ncbi.nlm.nih.gov/clin-var) and dbVar (https://www.ncbi.nlm.nih.gov/dbvar/).An overview of the general EDIR data is depicted in GAA gene cannot be attributed to any known TE-like element in the msRepDB repository, while several IRS containing this repeat can indeed be traced to TEs outside the GAA gene . Nevertheless, our approach to IRS identification still allows for the inclusion of these known TEs, while most importantly not being limited to them. For instance, our initially detected CCCCGTG repeat flanking exon 9 in the With this broad scope, EDIR can amongst others be used to couple exonic deletions to certain IRS’s and vice versa, to identify which IRS’s and/or genomic regions are more prone to recombinatory effects. Furthermore, EDIR may guide genetic researchers to investigate specific exons for deletions in case of patients where only a single pathogenic alteration has been found in a gene with recessive inheritance. Because the collection of IRS’s is wider than known TE-related sequences this can also be done at a finer scale.n bp in length naturally contains within it the set of IRS with repeats of n + 1 bp in length. By applying this methodology, calculating IRS with large repeats (e.g. larger than 100) is possible.We have constructed EDIR by making use of an inductive algorithm whereby we reasoned that each set of IRS with repeats of btac771_Supplementary_DataClick here for additional data file.


Attention-deficit hyperactivity disorder is one of the public neurodevelopmental disorders characterized by impulsivity and restlessness or hyperactivity. This study aimed to assess the prevalence of Attention-deficit hyperactivity disorder and its associated factors among children aged 6 to 17 years in Shewa Robit town, Northeastern Ethiopia, 2020.A community-based cross-sectional study was conducted among 365 children aged 6–17 years from Feb 1-March 30, 2020, at Shewa Robit town. Systematic random sampling was employed to select study participants. Data were collected by interview using structured and pretested questionnaires. Finally, data was entered using Epi-data 4.2 and analyzed using SPSS version 25. Bivariable and multivariable binary logistic regression analysis was conducted to identify associated factors of attention deficit hyperactivity disorder. Odds ratios with 95% CI were calculated, and variables having a p-value < 0.05 were considered statistically significant.The prevalence of ADHD among children aged 6 to 17 years was 13%. Financial crises [AOR 4.76(95% CI 1.51–15.05)], children a previous history of the mental problem [AOR 8.45(95% CI 1.24–57.43)], C/S delivery [AOR 6.38(95% CI 1.26–32.26)] and substance use in life [AOR 2.43(95% CI 1.09–5.43)] were significantly associated with attention deficit hyperactivity disorder.The prevalence of ADHD in children 6 to 17 years old was high (13%). Financial crises, children's history of mental disorders, C/S delivery, and lifetime substance use were significantly associated with attention deficit hyperactivity disorder. Therefore, particular attention should be given to mothers and children with significant factors. Attention-deficit hyperactivity disorder (ADHD) is a commonest neurodevelopmental disorder characterized by impulsivity and restlessness, affecting all age groups with variation in prevalence rate and symptom presentation in children, adolescents, and adults. According to DSM 1V criteria, ADHD is defined as inattention, including increased distractibility and difficulty sustaining attention, poor impulse control and decreased self-inhibitory capacity, and motor overactivity and restlessness in a child than expected for someone of that age and developmental level. Global epidemiological prevalence of 5.3% is one of the most common mental illnesses in childhood and adolescence . HoweverResearch conducted in psychiatry advisory indicated that from 1997/1998 to 2015/2016, there was an increase in the prevalence of ADHD among children and adolescents. The research found that 7.9% of children and adolescents were reported to have been diagnosed with ADHD. In 2015/2016, the reported prevalence of diagnosed ADHD was 10.2% . Most ofStudy area and period: This study was conducted in Shewa Robit town, Northeastern Ethiopia, from February 1 to March 30, 2020. Shewa Robit town is one of the 24 Woredas in the North Shoa Zone of the Amhara region. The town is located 225 km north of the capital city of Ethiopia, Addis Ababa. According to the woreda health sector annual plan of 2019, Shewa Robit has a total population of 54,306, of whom 26,176 are a man and 28,130 women  using a pretested questionnaire written in English, administered in the Amharic language. In addition, parents were asked to recall symptoms from a list of criteria for diagnosing ADHD exhibited by their children at home.A multi-stage sampling technique was used for the selection of sampling units. First, it was assumed that the population of Shewa Robit town is homogenous. Therefore, the town has nine kebele with 8500 households. From this, three kebeles were selected by a simple random sampling technique. Those three kebeles in Shewa Robit town have 3000 households. Of those, 2200 households have children aged 6 to 17 years. Three hundred sixty-five households with at least one child aged 6 to 17 years were allocated for three selected kebeles using systematic random sampling techniques every six intervals (2200/365= 6) by proportional allocation. The household sampling frame was obtained from Health extension workers found in each kebele of Shewa Robit town. Only one child was selected using the lottery method during the availability of more than one child in a household. ADHD was screened using the disruptive behavior disorder rating scale .Attention deficit hyperactivity disorder was the dependent varibales.The following are taken as independent variables.socio-demographic factors Psychosocial factors: stressful life eventsSubstance-related factors Clinical factors  throughout the child's gestation.Lifetime substance use: this study defined the use of any substance  at least once throughout their lifetimeLow APGAR score: Our study defined it as when the child fails to cry soon after delivery or fails to suck breast milk 30 minutes after delivery.Data quality control measures: Experts in related fields evaluated the questionnaire. The questionnaire was first prepared in English and translated to Amharic and back to English to check for language consistency. Then, the data collection instrument was pretested on 5% of the sample size in Shewa Robit town other than selected kebeles to avoid information contamination. The pretest was used to check for language clarity, appropriateness of data collection tools, estimate time required, and the necessary amendments were considered. In addition, training was given concerning the data collection tool and process for data collectors. Finally, three psychiatry nurses collected the data. During the data collection time, close supervision was carried out by supervisors and investigators to ensure the quality of the data. Finally, the supervisor and investigator checked all the collected data for completeness and consistency. Consistency was examined through a random selection of questionnaires.Data processing and analysis: Before analysis, data were cleaned, edited, and coded. Data was entered using Epi-Data version 4.2 and analyzed using SPSS 25 statistical software. Based on the nature of variables frequency distribution, summary statistics are used to explain variables' characteristics. Independent variables having a P-value less than or equal to 0.25 in the bivariable analysis were exported to the multivariable logistic regression model. In multivariable regression P-value, less than 0.05 was considered statistically significant. Finally, data were presented in text, table, and graphs.Ethics approval: Helsinki's declaration for medical research involving human subjects was followed. Ethical clearance was obtained from the Institutional Health Research Review Committee (Ref. No/NURS/19/2021) of the college of health and medicine, Debre Berhan University. Ethical clearance was obtained from the Institutional Health Research Review Committee of Debre Berhan University, college of health science. A permission letter was written for each study health institution, and a permission letter was taken from the study institution administrator. Written informed consent was taken from each study participant.Socio-demographic characteristics: A total of 355 study participants were included in this study, which made the response rate 97.3%. More than half of the participants, 205(57.7%), were between ages 6–11 years. The mean ages of participants were (10.99 ± 3.036). Nearly half of the respondents (51.5%) were male. The majority (83.7%) of the participants belonged to the Amhara in ethnicity, and 43.4% were orthodox religious followers. Of the respondents, 60% live within a family size of 2–4 members. Children whose parents earn more than 2000 birr per month were 57.5%, and whose mother and father had a diploma and above by educational background were 14.6%, and 27.9%, respectively . The younger the birth order, the higher the prevalence of ADHD. The proportion of ADHD subtype in this study was inattentive type 10.8% with slightly higher in male 1.5: 1, the hyperactivity-impulsivity type represented 14.15% with a male-female ratio of 2.25:1, and the combined type represented 25% with a malefemale ratio of 1.55:1Psychosocial factors: More than half of the study participants (52.9%) didn't experience psychosocial stress. Related to stress full life events, 27.9% of study participants reported losing a loved one. Of this 12.5% due to serious illness, 5.6% reported a loss of friends, and 10.1% reported a loss of family members. Sixty-eight (19.2%) have gone through financial stress within the last six months , sexually transmitted disease 1.7%, and others (1.7%). The majority of mothers from the study participants gave birth through SVD, 284 (80%) mode of delivery, whereas 71(20%) of mothers gave birth by others  (and C/S) .Factors Associated with ADHD: Binary logistic regression analysis examined the association between ADHD and each determinant factor. After adjusting all factors having p-value ≤ 0.25 on bivariate analysis, multivariable logistic regression analysis was done, and the following variable were found significantly associated (P <0.05).Children who reported a history of previously diagnosed psychiatric illness had almost nine times higher odds of experiencing ADHD than those who did not report [AOR 8.45(95% CI 1.24–57.43)]. Among the neonatal and obstetric problems, children who delivered using cesarean section had higher odds of experiencing ADHD than those who delivered spontaneously [AOR 6.38 (95% CI 1.26–32.26)]. Maternal substance use during pregnancy was also associated with increasing the odds of having ADHD compared to those who had no substance use history [AOR 2.43(95% CI 1.09–5.43)] .ADHD remains a significant cause of cognitive and social impairment among children. Hence, this study was conducted on prevalence and associated factors of Attention-deficit hyperactivity disorder among children aged 6 to 17 years at Shewa Robit town. Factors significantly associated with ADHD were; financial crises, children's previous history of mental problems, C/S delivery, and substance use.According to this study, the total prevalence of ADHD was 13% among children aged 6 to 17 years old. This result is nearly similar to the findings done in Ethiopia Jimma, which was 13.7%, Uganda 11.7%, and Jidda 11.6 % , 19, 20.On the contrary, the current study finding was higher than the studies done in Girja district rural Ethiopia, which was 7.3%  in NairoOn the other hand, this finding was lower than the study conducted in Mekelle Tigray Ethiopia 18.5%  and EgypThe subtype of ADHD is also different among studies concerning the methodological differences. For example, the percentage of ADHD subtypes found in this study was in-attentive (10.8 %), hyperactivity-impulsivity (14.15%), and combined (25%). This displayed a difference in distribution compared to the studies that used the same tool, i.e., the studies from Ethiopia, Nairobi, and Trebizond reported the most common subtype was inattentive, hyperactivity-impulsivity, hyperactivity-impulsivity, and hyperactivity-impulsivity, respectively , 21, 23.th edition books. Synopsis of psychiatry recognizes that comorbidity is a rule (This study also revealed that ADHD was also predicted by children's history of previous mental problems. Children with a history of last mental problems are almost nine times more likely to develop ADHD than children with no history of mental problems. This study is in line with the fact described in the synopsis of psychiatry 11s a rule .Moreover, children delivered by cesarean section had six times higher than to develop ADHD than their counterparts. Similarly, a study done in AL-Qalyubia primary school showed as caesarian section delivery was associated with ADHD. This might be due to caesarian section delivery will be predisposed the child to immune disorders. This may lead to altered immune maturation, increased exposure to the maternal microbial, and trauma in the brain , 28.In this study, the odds of ADHD in children with a maternal history of substance use during pregnancy had nearly three times higher than sober mothers. This may be because substance use during pregnancy is not safe for the mother and the fetus , 30. As


Occupational therapy (OT) offers evidence-based methods to address daily functioning improvement and better health promotion. However, many adults who are dealing with deficient daily functioning due to unrecognized Attention Deficit Hyperactivity disorder (ADHD) do not benefit from these developed methods. Thus, they are at risk of experiencing adjustment barriers and poor mental health.The aim of this project is to develop a dissemination strategy in order to reach-out for this unrecognized ADHD population and grasp their attention in an early stage of life. The study following this project is measuring the possibility of this action to reach out to the individuals and make a small change in their daily functional capabilities.The Laboratory for the Study of Complex Human Activity and Participation (CHAP) is a lab sited in the occupational therapy department at the University of Haifa. Its research address ADHD as part of further neuro-developmental challenges in the life span. The lab started a dissemination program including 4 OT researchers, and a group of former researchers for materials feedback.In the presentation we will share the dissemination strategy and it implementation during 6 months. Moreover, we will present a theoretically map relevant virtual pathways that adults with unrecognized ADHD may cross since childhood.This preventative program towards health promotion aims to help people achieve meaningful milestones in life and live more fully. Moreover, this strategy may serve as a prototype for similar approaches in other outreach processes.No significant relationships.


Sometimes treatment is not necessarily according to guidelines, which is partly due to attitudes rather than lack of knowledge. In Germany, regional differences concerning prevalence rates of ADHD exist without valid explanation. We contribute with our data to the question of attitudes toward ADHD among pediatricians in Germany.A specially designed questionnaire based on the Knowledge of Attention Deficit Disorders Scale and previous surveys was sent to pediatricians. In addition to descriptive statistics, we performed factor analysis and multiple linear regression analysis.The vast majority (85.5%) of 581 respondents have a positive attitude toward ADHD, i.e., ADHD exists and should be treated appropriately. Physicians with positive attitudes were older and more often had a neuropediatric specialization.Most of the pediatricians surveyed in Germany assess ADHD and treatment in line with medical guidelines and treat as part of multimodal therapy.The online version contains supplementary material available at 10.1007/s10389-022-01758-4. Attention-deficit hyperactivity disorder (ADHD) is one of the most common behavioral disorders  specialization with focus on developmental problems. Also, a pediatric working group on children with ADHD exists. Additionally, there are approximately 1100 residential child and youth psychiatrists.www.soscisurvey.de). After completion of the questionnaire, the link to the survey was sent by e-mail to those members of the BVKJ who have provided an e-mail address and have given the BVKJ their consent to receive information or inquiries by e-mail (n = 5531).Participants of this cross-sectional descriptive study were recruited by the mailing list of members of the Association of Child and Adolescent Physicians in Germany . This association represents the interests of its approximately 12,000 members in rights, organizational, social, and political matters. Most of the members are working as residential pediatricians. The survey was conducted between November 1, 2020 until December 11, 2020, and programmed with the online questionnaire tool “SoSci Survey”  dealt with demographic details of the participants: age, gender, specialist for pediatrics and adolescent medicine, professional years as a pediatrician, focus on neuropediatrics, work area and place  serves as the basis for the survey. The KADDS is a validated instrument for the assessment of knowledge about symptoms, diagnostics, causes and interventions in ADHD, which is also used in international studies  were computed to describe demographic data, qualification and place/area of work, opinions on the appropriateness prevalence of ADHD, degree of specialization, attitudes toward ADHD and medication treatment for ADHD of the total sample.The structure of the instruments surveying attitudes toward ADHD (12 statements) and attitudes toward ADHD medication (7 statements) was examined using two separate exploratory factor analyses. We used to force two-way factor solution analysis for each of these question blocks using principal component analysis extraction with varimax rotation and Kaiser normalization to obtain interpretable factors .Finally, a multiple linear regression was conducted to determine which demographic characteristics and qualification were associated with positive and negative attitudes of pediatricians toward ADHD in Germany. Significance level was set to The study authors respected and abided by the legal version of the Declaration of Helsinki, published by the World Medical Association (WMA). Electronic informed consent was obtained before the survey began. Consent was given by actively ticking the consent checkbox. Study fully respected German data protection regulations.n = 6), after informed consent (n = 7), or after demographic data entry (n = 21) were not considered for analysis. In addition, there were 12 records with more than one missing response concerning the attitudes that we also excluded. Here, however, there was no clustering as to the respective missing responses. A total of 46 data records could therefore not be considered for the evaluation. Thus, after data cleaning, 581 questionnaires were available for further analysis.Of a total of 5531 invited pediatricians, 627 (11%) responded to the questionnaire. In a first step, we checked the data sets for completeness. Those responses where the survey was terminated immediately  rated ADHD as sometimes underdiagnosed and sometimes overdiagnosed, while 9.1% thought that ADHD was underdiagnosed, 19.6% overdiagnosed, and 20.8% thought the rate of diagnosis was appropriate. Of the 578 participants, 19 answered the question with “no answer.”Of respondents 64% (372/580) reported referring patients to a collaborative partner when ADHD was suspected, 28.2% performed the diagnosis in the practice itself according to the guidelines, and 3.4% according to their own information.In terms of treatment, 85.0% (494/581) of respondents reported that they care for children and adolescents with ADHD in their practice and also write the prescriptions. A small proportion of respondents indicated that they either provide treatment without writing prescriptions (9.6%) or have no patients with ADHD in their practice at all (2.4%).2 (66) = 1515.48, p < .001) and Kaiser–Meyer–Olkin measure of sampling adequacy (KMO = .844) for the ADHD attitudes survey instrument indicated that the variables were suitable for factor analysis. Thus, a principal component analysis with varimax rotation was performed. Although this indicated the presence of four factors with eigenvalues greater than 1.0, based on the scree plot and theoretical considerations, a two-factor solution was chosen, which explained 43.2% of the variance. Table Bartlett’s test of sphericity , those with more negative attitudes (higher scores in factor 2), and those with not clearly defined attitudes  toward ADHD. The vast majority of our respondents have a positive attitude toward ADHD, i.e., ADHD is a valid disease that should be treated. A small group, as many as 6.7%, disagrees with this opinion Table . This coPhysicians with positive attitudes according to factor analysis were older and more often had a neuropediatric specialization. Attitudes were slightly more negative among younger physicians Table .Table 4MThe seven statements assessing attitudes to medication treatment for ADHD were too heterogeneous and correlated very poorly with each other; therefore, the extraction and interpretation of factors “positive” and “negative” was not possible, which is also due to the construct of the questions Fig. . The queThe starting point of our considerations was the fact that medical decisions do not always depend on the available knowledge but also on attitudes. This is clearly demonstrated by the different vaccination rates against COVID-19 among medical personnel. However, other diseases also reflect such different attitudes. For years, there have been wide regional variations in the prevalence of ADHD in Germany. No plausible explanation has yet been found for the variations in ADHD prevalence and also methylphenidate prescription rates within Germany. For example, the effect of variables such as gender and age structure, social status of parents, availability of specialists, etc., on the regionally varying ADHD diagnosis rates has been analyzed. In some studies, a small influence of urbanity and specialist density is suspected, but this cannot be conclusively proven. Based on our results, we have no evidence that attitudes toward ADHD or medication among practicing pediatricians may play a role in the differences. On the other hand, our research does not allow us to exclude such a relationship with certainty, since the number of responses is too small. After all, 19.5% of respondents rather or strongly disagree that “ADHD is a clearly defined psychiatric disorder.” Even 27.2% disagree with the statement that “The etiology of ADHD lies in a predominantly genetically caused cerebral developmental disorder.”The demographic data, distribution of responses by region, and other basic data reflect well the distribution of the professional association’s membership, although we do not wish to claim statistical representativeness. Response trends reflect current knowledge and guidelines. Of course, there are limitations regarding the validity due to the overall low response rate, although this is comparable to other studies. Fitzgerald sent more than 22,000 emails and postal invitations and 134 health professionals completed the survey . However, this system does not exist in the countries where the main focus of the previous investigations was . The different classification systems in the respective countries must also be taken into account, which can sometimes lead to different classifications , French Classification of Child and Adolescent Mental Disorders (CFTMEA) or Diagnostic and Statistical Manual of Mental Disorders (DSM-5)). Vallée also reported some cultural differences in training and conceptualization, particularly with regard to ADHD, which he then related to the very different prescription frequencies of stimulants in, for example, a comparison of France and the United States Vallée .There are several studies in which surveys were conducted, especially among general practitioners, and their results differ significantly from ours. In one survey, 665 Iranian general practitioners cited sugar and food additives as the cause in 37% of cases, 52% chaotic and dysfunctional family, and 83% stated children with ADHD misbehave because they do not want to obey rules. Almost half of respondents believed that they had adequate knowledge about ADHD . Also, the wording used in this regard is not accurate in every case. Nevertheless, we have chosen this method because it allows a subsequent multivariate analysis and a comparability with other studies is given Supplemental file 2ADHD-Questionnaire-English (PDF 123 kb)


Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) are two debilitating neurodevelopmental disorders. The former is associated with social impairments whereas the latter is associated with inattentiveness, hyperactivity, and impulsivity. There is recent evidence that both disorders are somehow related and that genes may play a large role in these disorders. Despite mounting human and animal research, the neurological pathways underlying ASD and ADHD are still not well understood. Scientists investigate neurodevelopmental disorders by using animal models that have high similarities in genetics and behaviours with humans. Mice have been utilized in neuroscience research as an excellent animal model for a long time; however, the zebrafish has attracted much attention recently, with an increasingly large number of studies using this model. In this review, we first discuss ASD and ADHD aetiology from a general point of view to their characteristics and treatments. We also compare mice and zebrafish for their similarities and discuss their advantages and limitations in neuroscience. Finally, we summarize the most recent and existing research on zebrafish and mouse models of ASD and ADHD. We believe that this review will serve as a unique document providing interesting information to date about these models, thus facilitating research on ASD and ADHD. Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) are two distinct neurodevelopmental disorders that share symptoms and genes, making it difficult to understand and separate them. Common signs and symptoms include difficulty paying attention and problems related to concentration, activity, and relationships. However, although the same individual can have both conditions, there are key differences in their prevalence, causes, diagnostics, and treatment therapies. ASD or autism refers to a broad range of conditions characterized by repetitive behaviours and difficulties in social skills, speech, and nonverbal communication. There are several subtypes of autism caused by a combination of genetic and environmental influences, whereas ADHD  is not a spectrum disorder. Moreover, these disorders can cause a range of difficulties from one individual to another. To research therapies for these disorders, animal models are often used, especially mouse and zebrafish models. This review focuses on first describing the two disorders and then presenting existing models of ASD and ADHD in mice and zebrafish.Difficulty communicating and interacting with others.Limited interests and repetitive behaviours.Troubles in functioning at school, work, and in society.Autism or ASD is a neurological and developmental disorder affecting individuals in diverse aspects of their life, such as interaction, communication, learning and social behaviour. Symptoms are usually detected in early life (~2 years), and according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) , individAlthough there is no cure for ASD to date, treatments and services can improve an individual’s symptoms and daily life.https://data.cdc.gov/Public-Health-Surveillance/autism-prevalence-studies/9mw4-6adp, accessed on 20 April 2022). The worldwide prevalence of ASD is estimated to be close to 1.5% ,3,4,5. AIndividuals with ASD often display difficulty with social life, restricted interests, and repetitive behaviours . NeverthGenetics are primarily involved in the vast majority of ASD cases . HoweverASD is diagnosed by evaluating behaviour and development. Although diagnosis can be performed at any age, it is better to diagnose ASD by the age of two, and treatments can be started earlier for better efficacy ,23,24. FOnce the diagnosis is confirmed, ASD treatment should begin immediately because treatment timing could impact the outcome . The difInattention: difficulty doing a task and staying focused and organized.Hyperactivity: moving constantly, including in inappropriate situations, or demonstrating excessive fidgets, taps, or talks. In adults, hyperactivity is manifested by extreme restlessness or talking too much.Impulsivity: acting without thinking or difficulty with self-control. Importantly, it can be manifested by a desire for immediate rewards or the incapacity to wait for gratification.Attention-deficit/hyperactivity disorder (ADHD) is a particular disorder marked by an alternation of inattention and/or hyperactivity-impulsivity that interferes with functioning or development. People with ADHD face an ongoing pattern of:ADHD prevalence can be classified into two types: among children and adolescents and among adults. The average worldwide prevalence of ADHD is ~2.2% overall  in children and adolescents (aged < 18 years). From a range of countries in Asia, Europe, the Americas and the Middle East, the prevalence is ~2.8% overall . Worldwide prevalence data on ADHD in children are scarce; however, country-specific prevalence studies have been conducted all over the world. As demonstrated in ADHD symptoms are expressed either by inattention or by hyperactivity-impulsivity. However, both types of symptoms can be observed in the same individual. These symptoms can be severe and impede social activity at school, work or in general life. In general, central nervous system (CNS)-related disorders such as stress, sleep disorders, anxiety and depression can cause symptoms like those of ADHD. Therefore, the diagnosis must be pronounced by having chronic or long-lasting symptoms of inattention and/or hyperactivity-impulsivity. In addition, these symptoms must be troublesome to the person’s activities and lead them to fall behind typical development for their age. ADHD symptoms are first observed at the ages of 3–6 years old and can persist through adolescence and adulthood or change as the individual grows up. Hyperactivity-impulsivity is the most predominant symptom in childhood, and with age, the symptom of inattention may become more prominent. In contrast, during adolescence, hyperactivity starts to lessen, but inattention and impulsivity may remain. Inattention, restlessness, and impulsivity are reported to persist into adulthood .Like ASD, the causes of ADHD are not well understood. However, the genetic component seems to play a major role. In addition, environmental factors such as strong stimuli, brain injuries, nutrition, and social factors might play a role in ADHD. It is important to note that ADHD is more frequent in boys than in girls, and girls are more likely to demonstrate inattention symptoms. Learning disabilities, anxiety disorder, conduct disorder, depression, substance abuse, and early life exposure to chemicals such as lead or nicotine from tobacco are often associated with ADHD ,33.To date, there is no cure for ADHD, but the symptoms can be managed with adequate treatment. Current therapies include medication, psychotherapy, education, or a combination of treatments. Medication includes the use of stimulants that increase dopamine and norepinephrine levels in the brain or non-stimulants that can also improve focus, attention, and impulsivity. Antidepressants are sometimes used alone or in combination with a stimulant to treat ADHD.Psychotherapy including only individual treatment sessions with the child (without parent involvement) is reported to not be effective for managing ADHD symptoms and behaviour. This demonstrates that in addition to psychotherapy, parents and family participation are important. Parents must reward positive behaviours, encourage behaviour changes, and improve interactions with the person with ADHD. Similarly, ignoring or redirecting the child’s inadequate behaviours can help improve symptoms.ASD and ADHD share several similarities and differences, as presented in GRM7) has spatiotemporal expression in the cerebral cortex, cerebellum, and hippocampus .,91.77,91This test investigates impulsiveness and attention by measuring the ability of zebrafish to respond to one of five perceptually identical stimuli that are applied randomly after a variable intertrial interval. It was adapted from the 5-CSRTT in rodents  and requires the animal to correctly identify which of the five apertures has been briefly illuminated to receive a reward. The results of this test in zebrafish are demonstrated to parallel those in mammals  82,83].,83.82,83This is the most commonly used test to assess locomotion and anxiety-like phenotypes, as the recorded parameters can be used to assess hyperactivity ,87,88. AZebrafish are placed in an experimental tank (L30 cm × H15 cm × W10 cm), and a mirror is placed at the side of the tank . Before The open field test is a well-recognized test to approach locomotor activity ,93,94,95In zebrafish, locomotor activity can be assessed in larval zebrafish by placing animals in well plates and recording for 5–10 min ,75,76,77In this test, a natural predator of zebrafish or mice is introduced into a tank/cage well known for a given subject, and the following parameters related to avoidance and fear are recorded: distance between predator and test subject, predator approaching time, geotaxis, locomotor/swimming activity, turn angle, number of freezing episodes, and time spent frozen  78,79].,79.78,79Spontaneous exploration of zebrafish or mice can also be assessed in the T-maze apparatus. In zebrafish, the device is a clear acrylic T-shaped box filled with water. Zebrafish or mice are introduced individually to the bottom arm of the T-maze  for a 6-min period. The number of centres and total arm entries and the number of freezing episodes and freezing duration are documented  77]. St. St77]. Face validity: mimic the fundamental behavioural deficits found in ASD or ADHD individuals;Construct validity: conform to the proposed pathophysiology or known therapeutics of ASD or ADHD;Predictive validity: predict unknown aspects of ASD or ADHD such as its genetics, neurobiology, or therapeutics.The development of an animal model is a common approach to studying the mechanisms of a specific disease or disorder. Given the complexity of ASD and ADHD and their aetiology, genetic or pharmacological models are mainly used. Genetic models have recently been explored with the advent of new genetic tools, such as CRISPR/Cas9 gene-editing technologies. These tools can mimic either ASD or ADHD symptoms and reflect the neurobiology in animals. In general, animal models should mimic a clinical disorder as much as possible, with similar symptoms, treatment responses, and pathophysiology. More specifically, an adequate ASD or ADHD model should have three types of validity :Face valhttps://gene.sfari.org/autdb/GS_Home.do, accessed on 10 May 2022), to date, more than 281 genes have been used to explore ASD phenotypes in mouse models [There are multiple genetic mouse models that can imitate ASD-like phenotypes in humans, and the majority of existing genetic models have been obtained by performing reverse genetics  . Accordie models . We firsThis mouse strain has demonstrated social behaviour impairments such as reduced interaction, aversion for frontal interaction; communication impairments such as altered patterns; high levels of repetitive behaviours such as increases in self-grooming and persistent burying behaviours; and difficulties in learning-related tasks. BTBR T+ tf/J mice also show alterations in the development of the brain, and several ASD-linked genes have been identified to be disrupted in this strain ,99.Shank3) is a postsynaptic density protein which plays a role in the structural and functional organization of the dendritic spine and synaptic junction [Shank3 includes an ankyrin repeat domain, a PDZ domain, and a Homer binding domain. Mutations can be inserted at each different domain, resulting in different impairments related to ASD phenotypes. For example, mice with a mutation in the ankyrin domain display impairments in excitatory neurotransmission and long-term potentiation; however, they show no trouble with sociability and only slight differences in ultrasonic vocalizations and repetitive behaviour [Shank3 KO mice demonstrate more aggressiveness, reduced long-term potentiation, and enhanced long-term depression [SH3 and multiple ankyrin repeat domains 3  gene [Fmr1 is a multifunctional polyribosome-associated RNA-binding protein playing a central role in neuronal development and synaptic plasticity through the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs [Fmr1 display impairments in long-term potentiation and abnormal social, cognitive, and anxiety-related behaviours [Fmr1 mutation is also implicated in the upregulation of mGluRS receptors [Fmr1 gene KO mice leads to rescue of the long-term depression and attenuation of seizures [Fragile X syndrome is one of the most frequent genetic causes of intellectual disabilities, and more than 30% of individuals with Fragile X syndrome meet the diagnostic criteria for autism . Constrir1) gene ,105. Fmrof mRNAs . Mice wihaviours ,107,108.eceptors . Interesseizures .Ube3a is the sole gene expressed from the maternal allele in mature neurons, and its deletion or mutations are responsible for Angelman syndrome [The 15q11-13 mutations are linked to duplication or gene deletion. For example, the loss of maternal genomic information at the 15q11.2-13 locus is responsible for Angelman syndrome, whereas paternal genetic material leads to Prader–Willi syndrome . In indisyndrome . It servsyndrome .Cntnap2 plays a role in the formation of functionally distinct domains critical for saltatory conduction of nerve impulses in myelinated nerve fibres [Cntnap2 has also been found in a different mouse inbred strain located in divergent regions within the C58/J gene [e fibres  and its e fibres . It is i8/J gene .Mecp2) is a chromosomal protein that binds to methylated DNA [Mecp2 gene, and only affects girls, as it is linked to chromosome X [Mecp2 gene in males provokes a total loss of function, whereas, in females, there are evident ASD-linked behaviours [Mecp2 from GABAergic neurons recapitulates different phenotypes such as repetitive behaviours, characteristic of Rett syndrome and ASD. More, Mecp2 deficiency provokes a reduction in glutamic acid decarboxylase (Gad) 1 and 2 levels, suggesting that the implication of Mecp2 in GABAergic neurons function is critical and that its mutation could alter GABA neurons and contribute to ASD [Mecp2-overexpressing mouse model or the use of an antisense oligonucleotide strategy successfully restored normal Mecp2 levels and phenotype in Mecp2 duplication adult mice [Methyl-CpG binding protein 2  is an antiepileptic drug also used for the treatment of bipolar disorders, migraine, headaches, and neuropathic pain. VPA has teratogenic effects, including neural tube defects, cardiovascular anomalies, limb anomalies, and neurodevelopmental delay . It is tThe dopamine transporter (DAT) is a presynaptic plasma protein found on dopaminergic nerve terminals that terminate dopamine signalling by rapidly sequestering dopamine released into the synaptic cleft ,216. The+/− mouse, which is the only viable strain, shows a variety of defects that resemble core features of ADHD. It shows, for example, delayed neurodevelopment and behavioural deficits such as hyperactivity and impulsivity [The coloboma mutant (Cm) mouse was developed by application of neutron irradiation, and the heterozygote Cmulsivity ,226,227.ulsivity . In addiulsivity ,228. FurThe I/LnJ mouse shows total callosal agenesis with complete penetrance, with behaviours such as learning deficits and hyperactivity, a reduced number of brief stops and a decrease in habituation in an open field ,229. BehThrb1 gene linked to human resistance to thyroid hormone (RTH) syndrome [Thrb1 is a nuclear hormone receptor having a high affinity for thyroid hormones and can act as a repressor or activator of transcription [Thrb1 transgenic mouse shows hyperactivity; however, it does not demonstrate impulsivity or signs of inattention [Thrb1 gene was used to demonstrate impulsivity, inattention, and hyperactivity in these mice [This model of ADHD carries a mutant human syndrome . Thrb1 icription . The Thrttention . Neverthese mice . The autese mice . It has ese mice . Howeverα, β, γ), which are mainly present in presynaptic terminals [α-synuclein protein was demonstrated to be involved in the pathogenesis of Parkinson’s disease [α- and γ-synuclein demonstrate signs of hyperactivity [The synucleins consist of a family of three proteins  or to pharmacological agents such as nicotine might lead to ADHD ,247,248.Adult offspring of mice treated with restraint stress during pregnancy have been shown to be hyperactive . FurtherOne useful aspect of zebrafish is the ease of genetic manipulations on embryos and larvae. The most used zebrafish models consist of morpholino-based (MO) expression silencing. MOs are small modified oligonucleotides that can bind a selected target by complementarily knocking down gene function without altering its sequence ,257. Sevhttps://www.sfari.org/resource/zebrafish-models/, accessed on 10 May 2022). To date, eight lines with validated loss-of-function are available for distribution . These loss-of-function lines were validated by direct measurement of target mRNA or protein levels [cntnap2, dyrk1a, grin2b, nrxn1, shank3, and syngap1) have been validated but are not yet available at the Zebrafish International Research Center (ZIRC). Furthermore, based on the association of each gene with autism incidence, SFARI has established a gene scoring system classifying ASD genes into one “syndromic” category or one of three “idiopathic” categories: category 1 (high confidence), 2 (strong candidate), or 3 (suggestive evidence) . The use of mutant zebrafish to study gene function is a challenging task because gene loss-of-function manipulations may leave significant amounts of mRNA produced by the targeted gene . To facin levels . Of noteThe most-reported pharmacological model is valproic acid (VPA), a drug that is known to induce autism-like effects in animal models. Originally, VPA was used as an anticonvulsant drug to treat seizures, and studies have demonstrated that embryonic exposure to VPA can lead to ASD in children ,297,298.The noncompetitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) induces impaired shoaling and aggression in zebrafish ,303. TheLatrophilin 3 (lphn3), a G-protein-coupled receptor belonging to the adhesion subfamily, is a regulator of synaptic function and maintenance in brain regions that mediate locomotor activity, attention, and memory for location and path [lphn3 gene ortholog lphn3.1 induces hyperactivity and impulsivity in zebrafish, as observed in ADHD patients [neuromedin U (nmu) gene plays a role in pain, stress, immune-mediated inflammatory diseases and feeding regulation, and its mutants present a hypoactive phenotype [CLOCK gene period1b (per1b) implicated in the circadian rhythm, is responsible for hyperactivity, impulsivity, and circadian disturbance phenotypes similar to ADHD [cntnap2 mutants display ADHD-like phenotypes such as hyperactivity and GABAergic deficits in the forebrain [DEP domain containing 5, GATOR1 subcomplex subunit (depdc5), a protein-coding gene, generates mutants that demonstrate hyperactivity and cognitive deficits [micall2b ortholog in zebrafish leads to animals with hyperactive/impulsive behaviours. These behaviours were corrected by the administration of atomexine [exosome component 3 (exosc3) in zebrafish embryos causes abnormalities such as microcephaly and poor motility [cyclin K(ccnk) knockdown impairs brain and spinal cord development [taf1 gene causes developmental delay [bromodomain PHD finger transcription factor(bptf), suggested to be implicated in the regulation of transcription, causes smaller head size and craniofacial abnormalities [mecp2 gene are observed in more than 90% of Rett syndrome patients who also show signs of mental retardation. Interestingly, mecp2 KO zebrafish show reduced swimming activity [neurotrophic factor (bdnf) gene expression [per1b ortholog KO in zebrafish results in hyperactive juveniles, with increased aggressiveness. This mutant zebrafish also shows a decrease in levels of dopamine in the brain [solute carrier family 6 member 4 (slc6a4) which encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons, have also been demonstrated to impact ADHD phenotypes [solute carrier family 6 member 3 (slc6a3) [Several genetic models have been developed to study ADHD in larval and adult zebrafish. and path . Down-repatients . The neuhenotype . In addi to ADHD . In the orebrain . Knockdodeficits . Similartomexine . Furthermotility . Moreoveelopment . The X-lal delay . KO of tmalities . Mutatioactivity  and defipression . The genhe brain . In the he brain ,320,321 enotypes . Several(slc6a3) ,324.Pharmacological models of ADHD using zebrafish are scarce. Zebrafish exposed to 1% alcohol demonstrated motor hyperactivity. The mechanism involved is relevant to dopaminergic neuron stimulation . SimilarSimilarly, it has been reported that environmental lead (Pb) exposure can result in neurological alterations leading to ADHD phenotypes. For example, Pb exposure decreases the density of axon tracts in the zebrafish midbrain and forebrain, corresponding to the downregulation of two genes at 14 and 16 hpf (hours post-fertilization), respectively . The effIn conclusion, zebrafish and mice are useful models to investigate neurodevelopmental disorders such as ASD or ADHD. There is an increase in research on these disorders using either mouse or zebrafish experiments. However, the choice of a model to investigate a particular aspect of each disorder demands specific considerations, as we described that both mouse and zebrafish models include advantages and limitations. Studies to understand the genetic and neurochemical mechanisms should be considered, together with research on animal models to investigate the behavioural aspects of the disorders. The most important thing to consider is the impact of the proposed research on the scientific community. As demonstrated in this review, the results obtained from zebrafish, taking into consideration the advantages of this model, can be further extrapolated to mouse models and eventually humans, thus providing extensive information on different aspects of the disorders.


Background: This cross-sectional survey aimed to determine the knowledge, attitudes, and behaviors regarding vaccinations among schoolteachers in Italy. Methods: Data were collected through an online questionnaire from September 2020 to May 2021 from a sample of schoolteachers in the Campania region of southern Italy. Results: Only 27% of the participants had good knowledge about the vaccinations recommended for schoolteachers. Females who had children, who were unsatisfied by their health status, and not needing additional information about vaccinations were more likely to have good knowledge. Moreover, 61.5% perceived that vaccinations are useful in preventing infectious diseases, and 44.5% agreed or strongly agreed that vaccinations should be mandatory for schoolteachers. The results of multivariate logistic regression showed that schoolteachers who perceived that vaccinations are useful in preventing infectious diseases, who considered the recommended vaccinations to be useful to protecting their own and their students’ health, who believed that information received about vaccination was useful, and who needed additional information about vaccinations recommended for schoolteachers, were significantly more likely to agree or strongly agree that vaccinations should be mandatory for schoolteachers. Conclusions: These findings suggest the need for education strategies to ensure that schoolteachers are better informed about vaccinations recommended for their profession. Vaccinations represent one of the most effective tools for preventing infectious disease and protecting health ,2. In ItThe practice of vaccination, widely shared and implemented in the pediatric sector, is not yet sufficiently widespread in other age groups, such as adolescents, adults, and the elderly, or in some professional categories. In Italy, the National Vaccination Prevention Plan (PNPV) provides recommendations for specific vaccinations for adults and workers at high risk of exposure to infectious diseases . SchooltMoreover, schoolteachers are an important point of reference for students and families, as they approach them with confidence to ask their opinion on issues of common interest, and teachers support students beyond their school skills . Their rAlthough several studies have been conducted to evaluate knowledge, attitudes, and behavior towards vaccinations in different settings ,18,19,20Therefore, the objectives of this study were to investigate knowledge, attitudes, and behaviors about vaccinations among schoolteachers in order to be able to generate insight that may lead to interventions that improve vaccination rates in this professional category.This study was conducted from September 2020 to May 2021 among a sample of teachers randomly selected from kindergarten, primary, middle, and high schools in the Campania region, in the south of Italy. The sample was selected through a two-stage cluster sampling. In particular, from the list of all eligible schools in the Campania region, eight of them were randomly selected, 6 kindergarten, primary, and middle schools and 2 high schools, for a total of 782 eligible teachers and of a total of about 4000 students. In the second stage, teachers were recruited from each school. Before the initiation of the study, the sample size was calculated, considering a prevalence of 50% of teachers who knew the recommended vaccinations for their professional category, a margin of error of 5%, and a 95% confidence level. Therefore, the minimum total sample size was estimated at 384 schoolteachers.After school selection, a letter with a request for collaboration was sent to the heads of the selected schools, stating the purpose and the procedure of the survey. After approval, the schoolteachers received an email from the head of the school containing a link to the Google Drive platform providing access to the anonymous online questionnaire. The questionnaire contained a letter explaining that participation in the survey was voluntary and assuring them that privacy and confidentiality were strictly protected. Moreover, it was specified that sending back the questionnaire would be considered an implicit consent to participation. In order to improve the response rate, reminders were sent after two weeks. The participants did not receive any monetary compensation for survey completion.The questionnaire, prepared ad hoc after a review of the literature ,23,29,30Before starting the study, to evaluate the correct interpretation, clarity, and reliability of the questions, a pilot study was conducted on 50 teachers.The study protocol was approved by the Ethics Committee of the University of Campania “Luigi Vanvitelli” (0008667/i 15 April 2020).t-test and chi-square test) were conducted to assess the associations between each of the independent characteristics and the outcomes of interest. Then, only variables found to be associated at a p-value ≤ 0.25 were introduced into multivariate logistic regression models [p-value for entry and exclusion of 0.2 and 0.4, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were presented in all logistic and ordered regression models.All statistical analyses were performed using Stata statistical software version 15 . First, n models . The steMultivariate regression analysis was conducted to examine which of the characteristics were significantly associated with the following main outcomes: (1) good knowledge of recommended vaccinations for schoolteachers  (Model 1); (2) perception of the usefulness of vaccinations in preventing infectious diseases  (Model 2); (3) belief that vaccinations should be mandatory for schoolteachers  (Model 3); and (4) having been informed by their physicians about recommended vaccinations for their professional category  (Model 4). In all the models, the following independent variables were included: gender ; age in years ; marital status ; education level ; type of school ; number of years in practice ; number of cohabitants (continuous); having children ; family members under the age of 12 years ; family members over the age of 64 years ; relatives with underlying chronic medical conditions ; having a satisfactory self-reported health status ; physicians as sources of information about vaccinations ; usefulness of information received about vaccinations ; and need for additional information . Moreover, the following variables were also included: good knowledge of vaccinations recommended for schoolteachers  in Models 2 and 3; perception of usefulness of vaccinations in preventing infectious diseases ; perception of the usefulness of vaccinations for schoolteachers for their own health ; and beliefs about the usefulness of vaccinations for schoolteachers for their students’ health  in Model 3.Of the 782 schoolteachers invited, 519 agreed to participate in the survey, with a response rate of 66.4%. When knowledge of recommended vaccinations for schoolteachers was investigated, the correct responses ranged from 21% for influenza to 48.8% for tetanus vaccinations. Overall, only 27% of the respondents had good knowledge of recommended vaccinations for schoolteachers, and the results of the multiple logistic regression analyses showed that this knowledge was significantly higher in females , who had children , who were unsatisfied by their self-reported health status , and who did not need additional information about vaccinations  Model 1 .In regard to attitudes, 41.4% of respondents had no concerns about the safety of vaccinations, with a median value of 4, and 61.5% perceived that vaccinations are useful in preventing infectious diseases. The results of the multivariate logistic regression model showed that having fewer cohabitants , having a family member under the age of 12 years , having good knowledge of recommended vaccinations for schoolteachers , and believing that information received about vaccinations was useful  were significant predictors of the perception that vaccinations are useful in preventing infectious diseases. Model 2 .More than half of the teachers (58.6%) were in favor of vaccinations and considered the recommended vaccinations useful in protecting their (61.8%) and their students’ health (62.4%). Moreover, 76.5% considered themselves at high risk of transmitting an infectious disease to the students during teaching activities, 60.9% believed that there is a need to improve confidence in vaccinations, and 42.8% agreed or strongly agreed that the information received about vaccinations was reliable.Moreover, 44.5% agreed or strongly agreed that vaccinations should be mandatory for schoolteachers. The results of the multivariate logistic regression showed that those who believed that vaccinations are useful in preventing infectious diseases , who considered the recommended vaccinations useful in protecting their  and their students’ health , and who believed that information received about vaccinations was useful  were significantly more likely to agree or strongly agree that vaccinations should be mandatory for schoolteachers. Furthermore, respondents aged 23-44 years  and 45–55 years  were less likely to have this positive attitude compared to those aged more than 55 years Model 3 .Only 23.7% were informed by their physicians about recommended vaccinations for their professional category. The results of the multivariate logistic regression showed that those who had relatives with underlying chronic medical conditions , and who had received information from physicians about vaccinations  were significantly more likely to have been informed by their physicians about vaccinations recommended for them. Moreover, those who worked at high schools  were less informed by their physicians about recommended vaccinations for their professional category compared to those who worked at kindergarten/primary schools Model 4 . When asOverall, 98.6% of schoolteachers had received information about vaccination: 59.9% from physicians, 51.6% from the Internet, 49.3% from TV, and 15.2% from social networks. Only 31.2% of respondents had been informed by their physicians about influenza vaccination. Moreover, 24.8% of respondents judged the information received as useful, and 81.6% expressed the need for additional information about recommended vaccinations for schoolteachers.To the best of our knowledge, this study is one of the first conducted to specifically investigate the knowledge, attitudes, and behavior toward recommended vaccinations for schoolteachers in Italy. Comparison with other studies is difficult because of available samples and different methodologies used.Although the Italian PNPV recommends vaccinations for different professional categories, such as schoolteachers, our research findings revealed inaccurate knowledge about these vaccinations. Indeed, the study showed that only 27% of schoolteachers knew the vaccinations recommended for them. In comparison with similar previous studies conducted in different countries, this rate was lower than that reported in the USA in a survey among schoolteachers, in which a total of 40% gave incorrect answers about such knowledge . By contOverall, attitudes toward vaccinations were generally positive. Indeed, more than half were favorable toward vaccinations and considered the recommended immunizations for schoolteachers useful in protecting their own and their students’ health. These positive attitudes, joined with the perception of the risk of transmitting an infectious disease during their activities with their students, could be a facilitator in approaching vaccinations in a conscious way. Moreover, multivariate analysis has made it possible to identify positive predictors related to attitudes, highlighting that the information received, in particular that deemed to be of quality, has positively influenced attitudes about the usefulness of vaccinations and making them mandatory. When we investigated this attitude, 44.5% expressed their agreement with this statement. This finding was slightly lower than what is reported in two studies conducted in the USA, in which 45.7% and 46.3% believed that vaccinations should be mandatory ,23. The Moreover, only 31% of respondents reported having received at least one vaccination for influenza, and 11.4% for diphtheria, tetanus, and pertussis in the last 10 years. In particular, influenza vaccination coverage is alarmingly low, considering everyday contact with students and the subsequent possibility of spreading influenza within the context of schools. Influenza vaccination uptake was lower compared to that observed in other populations ,35 but hThis study has some limitations that need to be considered in interpreting the results. First, the design of the study was based on cross-sectional data, and therefore it is not possible to establish the direction of the associations and temporal relationships between the investigated outcomes and the independent variables. Second, only teachers with an e-mail account were included, but this bias is not relevant because in Italy communications with teachers are no longer by paper, and therefore all teachers are required to have a personal e-mail account. Third, data were collected during the COVID-19 pandemic, particularly in some periods in which in-person learning activity had been suspended, and when teachers’ interest was focused on the mandatory nature of the COVID-19 vaccine, and therefore their attitudes toward vaccination might change with the resumption of normal working activities. Fourth, a recall bias may have occurred, since we investigated vaccination uptake in the last 10 years. These limitations have been contained because the questionnaire was self-administered and therefore had the guarantee of the confidentiality and anonymity of responses. Fifth, the teachers were selected only in one region of Italy, and this can affect the generalizability of the findings. However, we selected only public schools, which represent the vast majority of Italian schools and whose organization is similar throughout the nation. Finally, the sample was selected from different types of schools. Thus, the specific context of work could influence the generalizability of the findings and, therefore, these results might not reflect the knowledge, attitudes, and behaviors of all teachers. Despite these limitations, this survey provides important insights on teachers’ knowledge, attitudes, and behavior toward vaccinations recommended for them.In conclusion, this study revealed an inaccurate level of knowledge but general positive attitudes toward vaccinations. Therefore, these findings suggest that communication and education strategies should be undertaken as part of a targeted vaccination program for schoolteachers, particularly during the current COVID-19 pandemic, to improve their knowledge and their compliance with vaccinations, and indirectly that of their students, given the social role of this professional category. Furthermore, a teacher trained in vaccination topics could be encouraged to take an active role in disseminating adequate information about vaccination.