More than 80% of adolescent and young adult cancer patients (AYACPs) experienced psychological distress. Physical activity and behavioral activation are effective to relieve the psychological distress in AYACPs.N = 48) received routine care, the physical activity group (N = 47) received 8 weeks of physical activity program based on intelligent wearable devices, and the behavioral activation group (N = 48) received an internet‐based modified behavioral activation program for 8 weeks. Objective outcome measures included salivary cortisol and testosterone.Participants aged 15–39 years diagnosed with malignant tumors were included. A total of 143 eligible AYACPs were randomly assigned to three groups. The treatment‐as‐usual group (d = 0.53) (1 week after intervention), moderate activity (d = 0.61), and walking activity (d = 0.57) (3‐month follow‐up).Linear mixed‐model analyses showed significant differences between treatment‐as‐usual, physical activity and behavioral activation in salivary cortisol, as well as total scores on depression and anxiety, physical activity, self‐efficacy, and social support. Significantly stronger effect sizes for physical activity group compared with behavioral activation group were found on physical activity  to explore the effect of an intelligent wearable device‐based physical activity program and internet‐based modified behavioral activation program on alleviating psychological distress in adolescent and young adult cancer patients (AYACPs) by a three‐arm RCT. The results demonstrated that an intelligent wearable device‐based physical activity program and internet‐based modified behavioral activation program can effectively alleviate anxiety and depression in AYACPs. Including objective evaluation metrics in psychological distress research is feasible. The treatment‐as‐usual group received routine nursing psychological care. The two experimental groups were (1) the physical activity group, which participated in physical activity based on intelligent wearable devices plus treatment‐as‐usual and (2) the behavioral activation group, which received an online behavioral activation program plus treatment‐as‐usual.This was a randomized controlled, three‐arm trial with repeated measures conducted between March 2018 and August 2019. In this randomized controlled trial, the physical activity group was compared with the behavioral activation group and with the treatment‐as‐usual group to expect a significant reduction in salivary cortisol levels, anxiety, and depression at both follow‐up time points. Three occasions of assessment were conducted: at baseline . The Distress Thermometer (DT)2.2The inclusion criteria were as follows: (1) 15–39 years of age; (2) diagnosed with cancer in the past 5 years; (3) adults voluntarily participate in the study and sign an informed consent form; minors must be willing and have their guardians' consent and co‐sign an informed consent form; and (4) Chinese speaker. Participants were excluded if they (1) had an existing mental illness or other systemic diseases; (2) had a communication disorder; (3) exhibited drug or alcohol dependency; (4) suffering from other oral type diseases such as oral mucosal disease, periodontal disease, and dental caries; and (4) had a DT score <4 points  or if the participant answered “yes” to any of the PAR‐Q questions.2.3Before beginning the study, each potential participant was seen individually either in person or by video call, particularly for those who were invited through social media.2.3.1Participants in the treatment‐as‐usual group received usual treatment and follow‐up, which included providing disease‐related knowledge, training in self‐care skills, and routine nursing psychological care by clinical nurses.2.3.2In addition to usual treatment and follow‐up, each participant in the physical activity group was given an actigraph and an exercise instruction manual. The manual explained how to use the exercise bracelet, the method, intensity and frequency of exercise, how to prevent exercise injuries, precautions during exercise, and the start and end time nodes of the whole intervention. The actigraph was used to ensure that participants engaged for the expected. According to the American Cancer Society's recommendation of “moderate‐intensity exercise for at least 150 minutes a week”,2.3.3Other than usual treatment and follow‐up, participants in the behavioral activation group were further divided into smaller groups of 6–10 participants each, and a 120‐ to 180‐min online video seminar was offered to them once a week. Based on the modified behavioral activation treatment suggested by Xie et al.In addition, for the intervention groups, participants' relatives or friends were supported to join the WeChat group to understand the intervention dynamics and provide social support and assistance to the AYACPs.2.42.4.1Demographic information, including gender, age, educational background, marital status, monthly income, time for diagnosis, living situation, occupation, residence, complications, treatment program, cancer classifications, and cancer staging, was collected.2.4.2Since the levels of cortisol and testosterone will influence the state of the HPA axis, they can be used as effective indicators to observe the HPA axis response.Because the biosynthesis and secretion of cortisol are regulated by the HPA axis and have a fixed diurnal pattern of change, reaching a maximum in the early morning and a minimum at midnight, all biochemical samples were collected in the morning from 7:00 to 8:00 a.m. and completed within the time window of the psychological test to avoid the influence of time on the assessment index.The Hospital Anxiety and Depression Scale (HADS) was developed to assess anxiety and depression experienced in the previous week.2.4.3The International Physical Activity Questionnaire (IPAQ) was used to measure the level of physical activity, which was formulated by the World Health Organization in 1998. There are 27 items in total, which are composed of seven parts: occupation, family, transportation, physical activities related to leisure and entertainment, and sedentary. Divided into three kinds of physical activities: high‐intensity, moderate, and walking.The Social Support Rating Scale (SSRS) was used to measure social support through three subscales: objective support (three items), subjective support (four items), and support utilization (three items).The General Self‐Efficacy Scale (GSES) reflects optimistic self‐belief.The Pittsburgh Sleep Quality Index (PSQI) was used to assess subjective sleep quality in the recent month.0), 1 week after the intervention (T1), and 3 months after intervention (T2).All these measures were selected based on their satisfactory construct validity and reliability and their availability in Chinese. Three occasions of assessment were conducted: at baseline . Registration number: ChiCTR2100049229. All participants signed written consent prior to randomization into different groups.2.72 tests were used to determine whether participants' characteristics  were different across experimental conditions. A predefined alpha of 0.05 was used. The corrected statistical significance was α (0.05)/k. Missing data were filled in by intention‐to‐treat analysis. Linear mixed models (LMMs), with fixed effects and interaction effects for group and time, assessment and their two‐way interaction, as well as a random intercept for randomization group and participants (nested within the randomization group), were used to investigate differences in the course of the outcome measures between the three groups. Between‐group and within‐group differences were assessed by LMM and independent sample t‐tests with post hoc analysis, respectively. For the latter, Bonferroni's correction was employed for multiple testing. Effect sizes (Cohen's d) were calculated by dividing the difference in change between groups by the pooled standard deviation at separate assessment time points (1 week post‐intervention and 3 months post‐intervention). Effect sizes of 0.2 were categorized as small, 0.5 as medium, and 0.8 as large.All statistical analyses were performed by SPSS 24.0 software for Windows (IBM Corp). Descriptive statistics, ANOVAs, Kruskal–Wallis tests, Tamhane tests, and χ33.1p > 0.05) . Psychological distress (HADS)  and self‐efficacy were statistically significantly different between the three groups and at different assessment time points (p < 0.001). The depression  and sleep quality (PSQI) indicated statistically significant differences across different assessment time points (p < 0.001). However, there was no statistically significant difference in testosterone between and within the three groups across different assessment time points.Table p < 0.05). Compared with treatment‐as‐usual groups, there were significantly better intervention effects for decreasing saliva cortical penetration concentration, relieving psychological distress, and anxiety, improving physical activity, moderate and walking activity, social support, and general self‐efficacy in the physical activity group (p < 0.05). We also found that physical activity, moderate and walking activities performed finer in the physical activity group than in the behavioral activation group (p < 0.05)  Table .3.30) and 1 week (T1) and 3 months (T2) after the intervention. When comparing the physical activity group with the treatment‐as‐usual group between baseline and 1 week after the intervention, large effect sizes were found for the primary outcome measure of salivary cortisol , secondary outcome measure of total physical activity , moderate activity , walking activity , and social support . However, high‐intensity activity was observed at a moderate effect size . Three months after the intervention, a moderate effect size was still found for salivary cortisol , but total physical activity , moderate activity , walking activity , and social support  were able to sustain a large effect size between baseline and 3 months after the intervention.Table d = 1.71, p < 0.001), total physical activity , and social support . Three months after the intervention, a moderate effect size was still found for salivary cortisol . Similar to the physical activity group, total physical activity , moderate activity , and social support  were able to sustain a large effect size between baseline and 3 months after the intervention.Likewise, when comparing the behavioral activation group with the treatment‐as‐usual group between baseline and 1 week after the intervention, large effect sizes were found for salivary cortisol  and T2 . Finally, moderate effect sizes were observed for moderate activity  and walking activity  at T2.For the comparison of the physical activity group and behavioral activation group, moderate effect sizes were observed for total physical activity at T4In this study, the physical activity group was designed to alleviate participants' psychological distress by increasing their exercise levels, while the behavioral activation group was based on a cognitive program with light activity. This study used a rigorous design to compare the effects of physical activity and behavioral activation programs on psychological distress in AYACPs and clearly described the intervention steps and follow‐up. Modified Internet‐based behavioral activation reduces the geographic isolation of participants.p < 0.001). It was significantly lower in the physical activity and behavioral activation groups 1 week after the interventions. This result was similar to that of Rao et al.,The results of this study showed that there was a statistically significant difference between the three groups in AYACP salivary cortisol levels (p < 0.001), and there was also a moderate effect size of the difference between the two intervention groups (d > 0.5) at T2. This result suggested that compared with behavioral activation program, physical activity programs were more likely to promote high levels of physical activity in AYACPs. Although there was no significant difference between the two intervention groups in terms of relieving anxiety and depression, reducing morning salivary cortisol secretion, or improving quality of life, social support, and sleep quality, the findings suggest a tendency for the intervention effect of physical activity program to be better to that of behavioral activation program. This is consistent with the study by Soucy et al.,In this study, 8 weeks of an intelligent wearable device‐based physical activity program presented a higher total IPAQ score for AYACPs than a web‐based modified behavioral activation program (p < 0.05), verifying that the 8‐week intelligent wearable device‐based physical activity program was not only effective in relieving patients' anxiety and depression and improving their physical activity, social support, and self‐efficacy but also in maintaining the intervention effect for at least 3 months. Participation in regular physical activities can foster psychological growth experiences after cancer diagnosis and treatment.The HADS, IPAQ, SSRS, GSES, and PSQI scores of the physical activity group at 3 months after the intervention were significantly higher than the preintervention scores, with statistically significant differences  compared with the other two groups. Unlike the physical activity group, which used intelligent wearable devices, the behavioral activation group in this study adopted a web‐based modified behavioral activation program that required intensive participation in sessions and had more therapeutic components and was thus time‐consuming. Compared with children and the elderly, the AYACP group is more geographically mobile,4.1The strengths of this study were the specific focus on AYACPs, an important life development stage of cancer patients. Furthermore, we explored the advantage of implementing physical activity program with intelligent wearable devices in AYACPs and used objective outcomes  to assess the treatment effect. Nevertheless, there were some limitations in this study. First, we only set up the treatment‐as‐usual, physical activity, and behavioral activation groups, separately. But there is no physical activity combined behavioral activation group, confounding bias may exist in this study. Second, this study was conducted in Hunan Province, central China, and thus, its epidemiological representativeness may be challenged. Finally, the present study reassessed outcomes until 3 months after the intervention. Therefore, future studies are recommended to extend the follow‐up period to determine the maintenance effects of the interventions.5To conclude, the results of this study suggested that both intelligent wearable‐based physical activity programs and web‐based modified behavioral activation programs were effective in relieving anxiety and depression, reducing morning salivary cortisol, and improving physical activity, self‐efficacy, social support, and sleep quality in AYACPs. Intelligent wearable device‐based physical activity program has advantages over web‐based modified behavioral activation programs in improving physical activity in youth.All authors certify that they have participated in this work. The manuscript was conceptualized and supervised by Lijun Li and Lu Wang, with data curation, original draft writing, and review and editing by Lijun Li. Jianfei Xie contributed to methodology, formal analysis, project administration, funding acquisition. Lu Wang assisted with data curation. Lijun Li, Lu Wang, Yinglong Duan, Panpan Xiao, Yi Zhou, Xiaofei Luo and Xiangyu Liu all contributed to investigation. Jianfei Xie and Andy SK Cheng participated in review and editing. All authors read and approved the final manuscript.This study funded by The Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University (no. YX202006) and The National Natural Science Foundation of China (no. 82073409).The authors declare no conflicts of interest.This study was conducted according to the guidelines of the Declaration of Helsinki, and ethical approval was granted by the Ethics Committee of The Third Xiangya Hospital of Central South University (no. 2015‐S032). Registration number: ChiCTR2100049229.Figure S1Click here for additional data file.


To compare two cohorts of 75‐year‐old persons, born 10 years apart, in regard to reported symptoms related to temporomandibular disorders (TMD) and orofacial complaints with special reference to gender differences.N = 5195), and in 2017 to all born in 1942 (N = 7204). The response rate for the cohort examined in 2007 was 71.9% (n = 3735) and 70.7% (n = 5091) for the cohort examined in 2017. Bivariate statistical analyses were applied.In 2007, a questionnaire comprising questions on social factors, general and oral health, and a series of attitude‐related questions was mailed to all individuals born in 1932 living in two Swedish counties (Reported bruxism and pain from the temporomandibular joint were significantly higher in the 1942 cohort compared to the 1932 cohort, while reports of oral lesions and daytime dry mouth were lower. Women reported problems significantly more frequently in most of the domains investigated in both 2007 and 2017, that is, TMD, burning mouth, sensitive teeth, oral lesions, taste changes, daytime/night‐time dry mouth, except bad breath.TMD‐related symptoms increased while complaints from oral lesions and daytime mouth dryness decreased between 2007 and 2017. Temporal changes were otherwise few, but the findings underline the gender inequalities that exist, to the disadvantage of women. This must be considered when planning for clinical care/dental education to appropriately address the needs of older people. Women live longer than men but score lower in most domains related to health, functioning, and self‐reported well‐being, while older women suffer more from disability, loneliness, and depression compared to men Carmel, . Higher As regards gender differences related to oral health impairments in the elderly, women are more affected by poorer oral health‐related quality of life  has been reported  and 70.7% , respectively.In 2007 and 2017, a questionnaire was sent to all 75‐year‐olds  residing in Örebro and Östergötland counties in Sweden. The response rates in 2007 and in 2017 were 71.9%  on an IBM Personal Computer. 2.3The Ethics Committee in Uppsala, Sweden, approved the study (Dnr 2016/424). Informed consent was obtained from all the participants.33.1p < .05). Women reported pain significantly more frequently than men in both the 2007 (10.0% vs. 7.2%) and 2017 (13.6% vs. 7.0%) cohorts (Table p < .001). Here too women reported bruxism significantly more frequently than men in both 2007 (14.5% vs. 11.0%) and 2017 (18.1% vs. 15.1%). The increases in reported bruxism between the two examination points were similar for women (3.6%) and men (4.1%).Reported TMJ pain was significantly higher in 2017 than in 2007  and similarly so for the latter (37.5% vs. 34.8%) (p < .05). Also, women reported problems significantly more frequently in both 2007 and 2017 for “burning mouth,” “oral lesions,” “sensitive teeth,” and dry mouth during daytime and night‐time  to 2017 (12.2%) (4n = 4080) were mailed to randomly selected households living close to an airport, only 11.4% responded , which is in line with a systematic report on gender differences for TMD‐related problems . In another study and with stricter criteria applied, 0.17% of women were affected compared to only 0.04% of men among all age groups, although the highest prevalence was found in women aged 70−79 years, and to a lesser extent also in men of the same age group  to 2017 (12.2%). Taste changes were reported to be just under 10% in both cohorts, with women having significantly more of this condition in 2017. These findings show that these conditions are common in the elderly and, again, that women are more affected.Bad breath was a commonly reported finding in both 2007 (19.3%) and 2017 (17.8%). A gender difference was also reported in the present study where men reported significantly more problems with bad breath than women, although to a lesser degree than in a Brazilian report . In a US study of 787 dental patients, aged 18−44, 45−64, and 65+ years, the overall prevalence of hypersensitivity was 12.3%, but in the 65+ years group, it was 6.1%  and night‐time (>50%), and with a striking gender difference. Mouth dryness was about 10% more common in women than in men both at night‐time and daytime and in both the 2007 and 2017 cohorts. The prevalence of reported dry mouth steadily increases from age 50 years (A. K. Johansson, Johansson et al., Two limitations with regard to the self‐administered questionnaire should be mentioned. First, even though concise explanatory notes accompanied the questionnaire to guide respondents in their interpretation and responses to questions/statements, the chances of less than precise responses being given cannot be excluded; nevertheless, the high response rate of more than 70% from all the 75‐year‐olds in the targeted counties may go some way to reducing this risk. Second, a known drawback with questionnaire surveys in general, is that they are at risk of conveying what respondents think they believe the interviewer wishes to hear, or indeed, in the absence of clear instructions and guidelines for answering questions, respondents may simply guess answers (Helminen et al., 5TMD‐related reported symptoms increased while complaints from oral lesions and daytime mouth dryness decreased between the two examination points in 2007 and 2017. Temporal changes were otherwise few and largely in line with the first hypothesis, but the findings of this study clearly underline the gender inequalities that exist in oral health‐related symptoms in the elderly population and confirmed the second hypothesis that women report poorer oral health than men. This has to be taken into account when planning for clinical care, as well as in the design of undergraduate and postgraduate dental education for appropriately addressing the needs of older people.Investigation, project administration & data curation: Josefin Sannevik and Berit Mastrovito. Formal analysis: Anders Johansson, Ridwaan Omar, Gunnar E. Carlsson, Josefin Sannevik, Berit Mastrovito, and Ann‐Katrin Johansson. Writing – original draft preparation & writing – review and editing: Anders Johansson, Ridwaan Omar, Gunnar E. Carlsson, Josefin Sannevik, Berit Mastrovito, and Ann‐Katrin Johansson.The authors declares no conflict of interest.


The consequences for children born with birth defects and developmental disabilities encompassed by foetal alcohol spectrum disorder (FASD) are profound, affecting all areas of social, behavioural and cognitive functioning. Given the strong evidence for a core deficit in executive functioning, underpinned by impaired self‐regulation skills, there has been a growing focus on the development of interventions that enhance or support the development of executive functions (EFs).The primary objective of this review is to synthesise the evidence for structured psychological interventions that explicitly aim to improve EF in children. The review also sought to ascertain if the effectiveness of interventions were influenced by characteristics of the intervention, participants or type of EF targeted by the intervention.Sixteen databases, 18 grey literature search locations and 9 trial registries were systematically searched to locate eligible studies (up to December 2020). These searches were supplemented with reference harvesting, forward citation searching, hand searches of topic‐relevant journals and contact with experts.Studies were included in the review if they reported on an impact evaluation of a psychological intervention aiming to improve EF in children 3–16 years who either had confirmed prenatal alcohol exposure or a formal diagnosis falling under the umbrella term of FASDs. Eligible study designs included randomised controlled trials (RCTs) and quasi‐experimental designs with either no treatment, wait list control or an alternative treatment as a comparison condition. Single‐group pre‐post designs were also included.Standard methodological procedures expected by the Campbell Collaboration were used at all stages of this review. Standardised mean differences (SMDs) were used to estimate intervention effects, which were combined with random effects meta‐analysis (data permitting). Risk of bias was assessed using the Cochrane Risk of Bias Tool (RoB2) and Cochrane Risk of Bias in Non‐Randomised Studies‐Interventions tool (ROBINS‐I).k = 3; SMD = 0.06, 95% confidence interval [CI] = −1.06, 1.18), visual attention , cognitive flexibility , attentional inhibition , response inhibition , or verbal working memory . Significant heterogeneity was found across studies on measures of auditory attention and visual attention, but not for measures of cognitive flexibility, attentional inhibition or response inhibition. Available data prohibited further exploration of heterogeneity. There was no statistical difference between intervention and comparison groups on indirect measures of global executive functioning , behavioural regulation , or emotional control . Effect sizes were positive and not significant for meta‐cognition , shifting , initiation , monitoring  and organisation of materials . Effect sizes were negative and not statistically different for effortful control , inhibition , working memory , and planning and organisation . No statistically significant heterogeneity was found for any of the syntheses of indirect measures of EF. Based on pre‐post single‐group designs, there was evidence for small to medium sized improvements in EF based on direct measures  and indirect measures . However, these results must be interpreted with caution due to high risk of bias.The systematic search identified 3820 unique records. After title/abstract and full‐text screening, 11 eligible studies (reported in 21 eligible documents) were deemed eligible, with a combined 253 participants. Of the 11 studies, 6 were RCTs, 1 was a quasi‐experiment and 4 were single‐group pre‐post intervention designs. All studies were rated as having an overall high or serious risk of bias, with some variation across domains for RCTs. For RCT and quasi‐experimental studies, the overall effect of EF interventions on direct and indirect measures of EF generally favoured the experimental condition, but was not statistically significant. There was no difference between intervention and comparison groups on direct measures of auditory attention (This review found limited and uncertain evidence for the effectiveness of interventions for improving executive functioning in children with FASD across 8 direct and 13 indirect measures of EF. The findings are limited by the small number of high‐quality studies that could be synthesised by meta‐analysis and the very small sample sizes for the included studies. However, the ability to detect overall effects is severely limited by a lack of large comparison studies in the area.1.2Foetal alcohol spectrum disorder (FASD) is a preventable, life‐long disability which poses significant cost to individuals, families, and societies. Despite growing evidence exploring the profile of FASD, evidence on effective treatments of the condition is sparse.Given prevalence estimates of around 5% in the general population, and higher in vulnerable samples, rigorous and comprehensive evaluation of feasible interventions for FASD are a necessity.The focus of this review is studies which assess the impact of psychological interventions designed to improve EF in children impacted by PAE. Eligible outcomes include any measure of EF as per contemporary popular models of the construct (discussed in detail in methodology section of the systematic review). Examples include: attention, working memory, cognitive flexibility, inhibition, planning and organisation.1.3This Campbell systematic review examines the impact of interventions designed to improve executive functioning in children with a history of prenatal alcohol exposure. The review summarises evidence from eleven studies, including seven treatment‐comparison studies and four single‐group studies, with pre‐post outcome assessments.1.4Eleven studies are included, with only seven randomised or high‐quality quasi‐ experimental studies, and four single group pre‐post intervention studies. The randomised and quasi‐experimental studies are synthesised using meta‐analysis. Of these seven studies, all were carried out in either Canada or the USA.1.5Overall, the studies have important methodological weaknesses that temper the review findings, most notably very small sample sizes or incomplete reporting.While the pattern of results arising from the synthesis generally suggest positive intervention effects, the analyses did not reach statistical significance. There appear to be no statistically significant differences between children with PAE who participated in EF interventions versus those who did not on the following direct measures of EF: auditory attention, visual attention, cognitive flexibility, attentional inhibition, response inhibition, verbal working memory, or planning.Similarly, there appear to be no statistically significant differences between children with PAE who participated in EF interventions versus those who did not on the following indirect measures of EF: global executive function, behavioural regulation, emotional control, shifting or inhibition.1.6n = 7), and it is likely that relatively small sample sizes hinder detection of effects across outcomes.Only a small number of eligible comparison group studies are included in the present analyses  is associated with profound and lifelong disability. The umbrella term foetal alcohol spectrum disorder (FASD) describes a spectrum of impairments resulting from the deleterious effects of PAE   a face‐to‐face format, (ii) computerised format, or (iii) both formats. in individual or group format, and/or where the intervention is administered either (i) directly to children  or (ii) to children and caregivers/families .2.32.3.1A common intervention of this type is specific or targeted EF training. Training interventions are the intentional teaching of skills through repetitive experience aimed at restoring or improving functions and are generally completed in the presence of a qualified practitioner. These interventions can be delivered face‐to‐face 3.Variation in the type of EF targeted by the intervention.A limitation of Reid et al.'s  review iA systematic review protocol has also recently been published by Singal  aiming t2.4.2Globally, there have been a range of initiatives aimed at preventing FASD through increased public awareness of the effects of PAE. Concurrently, there has been development of clearer diagnostic processes  characteristics of the intervention ; (ii) characteristics of the participants ; or (iii) type of EF targeted by the intervention? To answer these research questions, the review systematically gathers and synthesises published and unpublished impact evaluations of psychological interventions aimed at improving the executive functioning of children with FASD. Data permitting, the review  provides quantitative effect estimates for the overall treatment effect for EFs in children with FASD and whether it varies by the aforementioned factors.44.14.1.1This review included randomised controlled trials (RCTs) where participants were randomly allocated to an experimental or comparison treatment condition, and also randomised cluster control trials where pre‐defined clusters of groups were randomised to the experimental or comparison condition. This review also included quasi‐experimental designs where participants were allocated to conditions in a manner other than randomisation . In all of these designs, the experimental or treatment group refers to eligible participants who took part in the intervention designed to improve executive functioning, and the comparison group refers to those who were allocated to a wait‐list control or to receive, treatment‐as‐usual, no treatment or an alternative treatment.Due to the burgeoning nature of this area of research, single‐group pre‐post designs were also included in the review. These designs are, however, subject to concerns regarding bias and are therefore analysed separately to RCTs and quasi‐experimental studies  a formal diagnosis of FAS, FASD, pFAS, ARND or ‘at risk of FASD’ using any of the following diagnostic systems: The Institute of Medicine Diagnostic system Hoyme, , The WasThe minimum age range of 3 years was selected as it is possible to measure EFs at this age  a face‐to‐face format, (ii) computerised format, or (iii) both. The review included interventions delivered in individual or group format, and/or where the intervention was administered either (i) directly to children  or (ii) to children and caregivers/families . Studies where participants received both psychological interventions and pharmacological interventions concurrently as part of a focal treatment group were excluded.The protocol for the review , a direct neuropsychological assessment that measures attention while screening for ADHD , which is a direct standardised assessment consisting of 32 sub‐tests for use in neuropsychological assessment with pre‐schoolers, children and adolescents , which is a standardised indirect psychological assessment tool that measures EFs in pre‐schoolers , which is a parent‐ or teacher‐completed indirect measure that includes broad competencies, adaptive functions and problems in children :After identifying the final corpus of eligible studies, outcomes were initially separated in to either direct or indirect measures of EF to separate synthesis. This dichotomy reflects a distinction in the measurement of EF between performance, task‐related data  and that of itemised, self‐ or other‐reported data . These forms of measurement were separated as there is evidence demonstrating poor convergence between direct and indirect measures of EF across a range of populations , medium (>3−6 months) and long‐term follow‐up (>6 months).4.1.4.2No secondary outcomes were included in the review.4.2A number of sources were searched to ensure comprehensive coverage of the literature. The final search strategy included key psychological and allied health electronic databases, trial registers and grey literature sources. The reference lists of reviews relevant to the review topic were harvested, along with the references lists of studies included in the review. Studies included in the review were also used to conduct forward citation searching in Google Scholar. An additional hand‐search was conducted using key journal titles, covering a period of 12 months before execution of the search date to capture published articles not yet indexed in academic databases during the search period. As FASD was not adequately described before 1973, the search was limited to studies published after 1972. There were no restrictions placed on publication status or language. Each search is reported in Supporting Information: Appendix 4.2.11.(executive* adj3 (function* or control* or atten*)).ab,hw,id,ot,ti.2.(self adj3 regulat*).ab,hw,id,ot,ti.3.(emotion* adj3 (regulat* or inhibit*)).ab,hw,id,ot,ti.4.(cognitive adj3 flexib*).ab,hw,id,ot,ti.5.(‘effortful control’ or ‘working memory’ or ‘set shift*’ or reasoning or planning or attention or inhibit*).ab,hw,id,ot,ti.6.1 or 2 or 3 or 4 or 57.).ab,hw,id,ot,ti.8.‘sentinel facial feature*’.ab,hw,id,ot,ti.9.foetal alcohol spectrum disorders.mh.10.7 or 8 or 911..ab,hw,id,ot,ti.12.6 and 10 and 11Search terms were pilot‐tested and refined based on the rate of eligibility for each iteration, with the final search reflecting the search providing optimum sensitivity and specificity. The search implemented for PsycINFO (OvidSp) is provided below, as an example, and the exact search structure for each search provided in Supporting Information: Appendix 4.2.2ScopusPubMedEmbase (Elsevier)PsycINFO (OvidSp)PsycEXTRA (OvidSp)CINAHL (EBSCOhost)ProQuest Platform: Dissertations and Theses Global, Family Health, Psychology Journals, Health and Medical Complete, Nursing and Allied Health, Social Services AbstractsWeb of Science Platform: Social Science Citation Index, Conference proceedings Index, Current Contents ConnectCochrane and Campbell Collaboration librariesThe search encompassed January 1972 to December 31, 2020, with specific search dates provided in Supporting Information: Appendix 4.2.3The following additional sources were systematically searched for the review.Websites and research repositorieshttps://adf.org.au/Alcohol and Drug Foundation; URL: https://alcoholchange.org.uk/Alcohol Concern (UK) [now Alcohol Change]; URL: https://www.unisa.edu.au/Research/Australian-Centre-for-Child-Protection/Australian Centre for Child Protection; URL: https://www.aracy.org.au/Australian Research Alliance for Children and Youth; URL: CanFASD (Canada FASD Research Network)https://canfasd.ca/FASD outreach; URL: https://www.fasdhub.org.au/FASDHub Australia; URL: https://www.fasd-can.org.nzFetal Alcohol Network NZ; URL: https://fare.org.au/Foundation for Alcohol Research and Education; URL: https://www.niaaa.nih.gov/National Institute on Alcohol Abuse and Alcoholism; URL: NoFAS.org; URL: www.nofas.orghttps://www.nofasd.org.au/NoFASD Australia; URL: https://www.surgeons.org/enRoyal Australasian College of Surgeons; URL: https://rffada.org/Russell Family Fetal Alcohol Disorders Association; URL: https://www.ssrn.com/index.cfm/en/Social Science Research Network; URL: https://www.srcd.org/Society for Research on Child Development; URL: https://sites.duke.edu/apep/The Alcohol Pharmacology Education Partnership; URL: One website included in the review protocol controlled-trials.com)ISRCTN Registry UK Clinical Research Network (UKCRN Study Portfolio)WHO International Clinical Trials RegistryThe following trial registries were searched:As a final search step, authors of eligible and ongoing studies were contacted to identify any unpublished studies.4.34.3.14.3.1.1SysReview 3.Document does not relate to PAE in humansAll records retrieved by the systematic search were imported to Endnote for removal of duplicates and ineligible document types  and the remaining records were exported to Records not excluded at the title and abstract screening stage progressed to full‐text literature retrieval. In the case that full‐text documents could not be retrieved through existing university pipelines, they were ordered through university libraries or authors were contacted for provision of documents.4.3.1.21.Duplicate document2.Ineligible document type3.Document is published before 19734.Document does not relate to PAE in humans5.Ineligible participants6.Ineligible intervention/no intervention7.Ineligible outcome measure(s)8.Ineligible methodological designAll records retained through title and abstract screening were screened based on the following exclusion criteria , with 99% agreement on inclusion/exclusion for this sample. As such, independent screening was conducted for the remainder of documents by two authors . Where an inclusion/exclusion decision could not be made, the relevant screener discussed the study with the other screener. A third author (S.D.) was consulted in the case of disagreement until consensus was achieved.4.3.2SysReview as per the standardised coding form and relevant risk of bias tool (see section below). Two authors independently coded all eligible studies  and discrepancies were resolved through discussion with a third author  until consensus was reached. Studies were coded along the following broad dimensions 2.Methodological issues 3.Participant information 4.Intervention 5.Outcomes 6.Effect size Studies retained following both stages of screening were coded in 4.3.3The Cochrane Risk of Bias Tool . Discrepancies were discussed with a third author (S.D.) until consensus was achieved. Coders were not blinded to study details during coding , as research suggests little benefit of blinding coders because they are often familiar with research that is relevant to the review . Where studies reported baseline and post‐intervention outcome data, SMDs were calculated using baseline adjusted mean differences , using the formula provided by Lipsey and Wilson  by entering the required data into RevMan , medium (>3–6 months) and long‐term follow‐up (>6 months).In cases where studies included multiple types of experimental groups, those which most closely matched inclusion criteria were included, and others excluded  was used to conduct random effects inverse variance meta‐analyses with 95% confidence intervals (CIs). If at least two studies with conceptually similar interventions, participants and outcomes were identified, a meta‐analysis was conducted. This resulted in 10 meta‐analyses across five EFs for direct measures and five EFs for indirect measures. If a study was considered too conceptually different to be included in meta‐analyses, single effect sizes were calculated and reported. Single effect sizes and those derived from meta‐analyses were interpreted using Cohen's rule of thumb, whereby 0.2 represents a small effect, 0.5 a medium effect and 0.8 a large effect Cohen, .4.3.10The review protocol outlined the intended approach for investigating heterogeneity through specific sub‐group analyses . Only one sensitivity analysis was possible based on the studies located for the review. Sensitivity analyses were used to assess the impact of estimating intra‐class correlation coefficients (ICC) for studies with clustering on the results of meta‐analyses. Of the randomised and two‐group quasi‐experimental studies using direct measures of EFs, only one study—Nash —had clus55.15.1.1SysReview ; (b) did not relate to PAE in humans (n = 64); (c) utilised ineligible participants (n = 337); (d) reported ineligible outcomes (n = 39); or (e) did not report on or evaluate an eligible intervention using an eligible research design (n = 1077). A full list of the excluded studies is available from the authors by request. The remaining 21 documents deemed eligible for the review reported on 11 unique studies. Of these 11 studies, there was variation in the sufficiency of the data to calculate effect sizes for all eligible outcomes, which is reported by outcome in the relevant ‘Effects of interventions’ subsection. Attempts were made to contact authors of studies with insufficient data for effect size calculation, with only one group of study authors able to provide the data required. All 11 eligible studies are included in the study summary tables and included studies section below.Of the remaining 1550 documents, 1529 were excluded after confirmation that the document/study (a) was a duplicate . The subsections below provide an overview of the included studies with further detail provided in the summary tables for each included study and abbreviated study summaries provided in Table 5.1.2.1k = 14), with a smaller number reported in theses (k = 4), technical reports (k = 1), trial registries (k = 1) or conference abstracts (k = 1). Eight studies reported funding support for either the intervention or evaluation , aside from one study which conducted post‐intervention measures approximately 6 months after the completion of the intervention . A total of 31 studies explored improving outcomes in children with FASD but did not evaluate an intervention exclusively or clearly focused on improving EF  Program: A program designed to improve mathematics ability in children through direct teaching of skill development in arithmetic . The overall effect for auditory attention across studies was small in size and positive , but not statistically significant. This indicates that participants receiving an EF‐focused psychological intervention did not differ from comparison participants on direct measures of auditory attention. A forest plot of the distribution of effect sizes is presented in Figure τ² = 0.76; χ² = 8.92, df = 2; p = 0.01; I² = 78%). However, the small number of studies precludes an accurate estimate of the variance component, τ2. Potential sources of this heterogeneity  did not report post‐intervention data (NEPSY: Auditory Attention). Hutchison . Hutchison (d of 0.83 (N = 9) and Kerns et al. (d of 1.26 (N = 10). All authors were contacted to obtain missing data and permit meta‐analysis, however, author contact details could not be located for Hutchison  and the overall effect for visual attention across studies was medium in size and positive, but not statistically significant . This indicates that participants receiving an EF‐focused psychological intervention did not differ from comparison participants on direct measures of visual attention. A forest plot of the distribution of effect sizes is presented in Figure τ2 = 2.43; χ2 = 7.84, df = 1, p = 0.005; I2 = 87%). However, the small number of studies precludes an accurate estimate of the variance component, τ2. Potential sources of this heterogeneity  and posttreatment , with a standardised mean gain score of 0.25 (SE = 0.125). Leung et al. . The overall effect for cognitive flexibility across studies was positive , but small and not statistically significant. This indicates that participants receiving an EF‐focused psychological intervention did not differ from comparison participants on direct measures of cognitive flexibility. A forest plot of the distribution of effect sizes is presented in Figure τ² = 0.00; χ² = 0.65, df = 1, p = 0.42; I² = 0%. However, the small number of studies precludes an accurate estimate of the variance component, τ2. Sensitivity analyses indicated that when the standard errors of the single study with clustering  did not report post‐intervention data to allow calculation of an effect size (NEPSY: inhibition/switching (switching subtest); NEPSY: response set). Hutchison . Hutchison (N = 9) reported a Cohen's d of 0.98, 0.17 and 0.32 across the three direct measures of cognitive flexibility (NEPSY: inhibition/switching (switching subtest); NEPSY response set combined; NIH: dimensional card sort respectively). Kerns et al. (N = 10) reported a Cohen's d of 0.58 for KiTAP (owls). All authors were contacted to obtain missing data and permit meta‐analysis, however, author contact details could not be located for Hutchison (Four single‐group pre‐post studies reported direct measures of cognitive flexibility before and after an eligible intervention (utchison  and Kernutchison  both reputchison  (N = 9) s et al.  (N = 10)utchison , Leung eutchison  could noutchison . Reid etutchison  reported5.3.1.4n = 22; comparison n = 23). The overall effect for attentional inhibition across studies was positive , but small and not statistically significant. This indicates that participants receiving an EF‐focused psychological intervention did not differ from comparison participants on direct measures of attentional inhibition. A forest plot of the distribution of effect sizes is presented in Figure τ² = 0.02; χ² = 1.09, df = 1, p = 0.30; I² = 8%. However, the small number of studies precludes an accurate estimate of the variance component, τ2. Sensitivity analyses indicated that when the standard errors of the single study with clustering . The overall effect for response inhibition across studies was positive, medium‐sized, but not statistically significant . This indicates that participants receiving an EF‐focused psychological intervention did not differ from comparison participants on direct measures of response inhibition. A forest plot of the distribution of effect sizes is presented in Figure τ2 = 0.00; χ2 = 1.75, df = 2, p = 0.42; I2 = 0%).For outcomes with sufficient data, the effects sizes were combined within each study before meta‐analysis using the approach specified in Section d, but no other data which could be used to combine the effect sizes with meta‐analysis . The authors were contacted to obtain missing data and permit meta‐analysis, however, author contact details could not be located for Hutchison  reported Cohen's ds of 0.6 and 0.32 for two different direct measures of response inhibition. Kerns et al. (N = 10) reported Cohen's ds of 1.07, 1.00, 0.58 and 0.3 across four measures of response inhibition. Leung et al. (N = 20) used two direct measures of response inhibition: TOVA (commissions) and NEPSY (Inhibition) but only reported post‐intervention data for the TOVA. Leung et al.  and posttreatment , with a standardised mean gain score of 0.24 (SE = 0.124). Leung et al. (Hutchison  (N = 9) s et al.  (N = 10)g et al.  (N = 20)g et al.  reportedg et al.  did not g et al.  reported5.3.1.6n = 12; comparison n = 13) and the effect of the intervention was positive  and not statistically significant. This indicates that participants receiving the psychological EF‐focused intervention did not significantly differ from comparison participants on the direct measure of planning.One of the RCT/quasi‐experimental studies with a comparison group reported a direct measure of planning as an outcome. Nash  includedNo single‐group studies included any direct measures of planning.5.3.1.7d using the t‐value reported for the between group effect after the intervention. This effect size was calculated using David B. Wilson's suite of effect size calculators . The effect size calculated was moderate and favoured the experimental group participants  but was not statistically significant.Two RCT/quasi‐experimental studies with a comparison group reported a direct measure of verbal working memory as an outcome, yet both reported insufficient data to calculate an effect size using RevMan analysis tools . Hutchison . Kerns et al. . Leung et al.  and posttreatment , with a standardised mean gain score of 0.32 (SE = 0.183). Leung et al. . Hutchison (N = 9) reported a Cohen's d of 0.15 and 0.14 across two direct measures of visual working memory . Kerns et al. (N = 10) reported a Cohen's d of 0.63 for a direct measure of verbal working memory . While these studies collectively suggest small to medium‐sized effects, they must be interpreted with caution due to the tendency for single‐group studies to over‐estimate true effects and their high risk of bias.Three single‐group pre‐post studies reported direct measures of visual working memory before and after an eligible intervention. However, Leung et al.  did not utchison  (N = 9) s et al.  (N = 10)5.3.2Most eligible indirect outcome measures were derived from the BRIEF, which is a questionnaire designed to measure caregiver or teacher perceptions of behaviours in children which reflect various EFs. The measure is comprised of nine subscales  and three composite scales that combine the subscales . Other similar indirect measures of executive functioning follow a similar approach . Based on the structure of these measures, the sections below begin with a synthesis of composite measures of EF, followed by a synthesis of specific EF subscales from the indirect measures.5.3.2.15.3.2.1.1n = 20; comparison n = 22). The overall effect for global EF across studies was positive  but not statistically significant. This indicates that participants receiving an EF‐focused psychological intervention did not differ from comparison participants on indirect measures of global EF. A forest plot of the distribution of effect sizes is presented in Figure τ2 = 0.00; χ2 = 0.01, df = 1, p = 0.91; I2 = 0%). Sensitivity analyses indicated that when the standard errors of the single study with clustering  reported a Cohen's d, but no other data which could be used to combine the effect sizes with meta‐analysis . Leung et al. (N = 20) did not report post‐intervention data to allow calculation of effect sizes for either measure of global EF .Three single‐group pre‐post studies reported indirect measures of global EF before and after an eligible intervention N = 9) reported a large Cohen's d of 0.925 for the teacher‐report BRIEF. Reid et al. (Hutchison  (N = 9) d et al.  reported5.3.2.1.2n = 8; comparison n = 9) and the effect of the intervention was negative . This indicates that participants receiving the psychological EF‐focused intervention did not significantly differ from comparison participants on the indirect measure of effortful control.One RCT/quasi‐experimental study with a comparison group reported an indirect measure of effortful control as an outcome. This is a composite measure of four subscales from the CBQ: attentional focusing, inhibitory control, low‐intensity pleasure and perceptual sensitivity. Coles et al.  includedNo single‐group studies included any indirect measures of effortful control.5.3.2.1.3n = 20; comparison n = 22) and the overall effect was positive  but not statistically significant. This indicates that participants receiving an EF‐focused psychological intervention did not differ from comparison participants on indirect measures of global behavioural regulation. A forest plot of the distribution of effect sizes is presented in Figure τ2 = 0.00; χ2 = 0.18, df = 1, p = 0.68; I2 = 0%). Sensitivity analyses indicated that when the standard errors of the single study with clustering  reported a Cohen's d, but no other data which could be used to allow effect sizes combine the effect sizes with meta‐analysis . Leung et al. (N = 20) did not report post‐intervention data to allow calculation of an effect size.Three single‐group pre‐post studies reported an indirect measure of behavioural regulation using the BRIEF BRI composite before and after an eligible intervention N = 9) reported a small Cohen's d of 0.267 for the teacher‐report BRIEF. Reid et al. (Hutchison  (N = 9) d et al.  reported5.3.2.1.4n = 8; comparison n = 9) and the effect of the intervention was positive , but not statistically significant. This indicates participants receiving the psychological EF‐focused intervention did not significantly differ from comparison participants on the indirect measure of inhibition.One RCT/quasi‐experimental study with a comparison group reported an indirect measure of meta‐cognition as an outcome. Coles et al.  includedN = 9) reported a Cohen's d, but no other data which could be used to combine the effect sizes with meta‐analysis . Leung et al. (N = 20) did not report post‐intervention data to allow calculation of an effect size.Three single‐group pre‐post studies reported an indirect measure of meta‐cognition using the BRIEF MI composite before and after an eligible intervention N = 9) reported a large Cohen's d of 1.6 for the teacher‐report BRIEF. Reid et al. (Hutchison  (N = 9) d et al.  reported5.3.2.2One RCT/quasi‐experimental study with a comparison group reported an indirect measure of attention as an outcome . The overall effect for emotional control across studies was small and positive  but not statistically significant. This indicates that participants receiving psychological EF‐focused interventions did not significantly differ from comparison participants on indirect measures of emotional control. A forest plot of the distribution of effect sizes is presented in Figure χ2 = 0.78, df = 2, p = 0.68; I2 = 0%; τ2 = 0.00). Sensitivity analyses indicated that when the standard errors of the two studies with clustering , which indicated that the emotional control in both groups remained mostly stable. The effect size for their indirect measure of emotional control between the post‐intervention and follow‐up measurement continued to favour the experimental group, but was small in size and not statistically significant .Petrenko et al.  conducteNo single‐group studies included any indirect measures of emotional control.5.3.2.4n = 52; comparison n = 51). The overall effect for inhibition across studies was negative  but not statistically significant. This indicates that participants receiving an EF‐focused intervention did not significantly differ from comparison participants on indirect measures of inhibition. A forest plot of the distribution of effect sizes is presented in Figure χ2 = 0.52, df = 1, p = 0.47; I2 = 0%; τ2 = 0.00). Sensitivity analyses indicated that when the standard errors of one study with clustering  reported a small and positive Cohen's d of 0.168 for the teacher‐report BRIEF. While the reported results from this single‐group study differs from the synthesis of the two group experimental studies, the effect must be interpreted with caution due to the tendency for single‐group studies to over‐estimate true effects and their high risk of bias.One single‐group pre‐post study reported an indirect measure of inhibition before and after an eligible intervention. Hutchison  (N = 9) 5.3.2.5n = 52; comparison n = 51) and the overall effect for shifting was positive  but not statistically significant. This indicates that participants receiving an EF‐focused intervention did not significantly differ from comparison participants on indirect measures of shifting. A forest plot of the distribution of effect sizes is presented in Figure χ2 = 0.01, df = 1, p = 0.93; I2 = 0%; τ2 = 0.00). Sensitivity analyses indicated that when the standard errors of one study with clustering  reported a medium and positive Cohen's d of 0.55 for the teacher‐report BRIEF. While the reported results from this single‐group study suggests larger effects than the synthesis of the two group experimental studies, the effect must be interpreted with caution due to the tendency for single‐group studies to over‐estimate true effects and their high risk of bias.One single‐group pre‐post study reported an indirect measure of shifting before and after an eligible intervention. Hutchison  (N = 9) 5.3.2.6n = 40; comparison n = 38) and the effect of the intervention was negligible . This indicates participants receiving the psychological EF‐focused intervention did not differ from comparison participants on the indirect measure of working memory.One of the RCT/quasi‐experimental studies with a comparison group reported an indirect measure of working memory as an outcome. Wells et al.  includedN = 9) reported a large and positive Cohen's d of 1.01 for the teacher‐report BRIEF. While the reported results from this single‐group study suggests larger effects than the two group experimental study, the effect must be interpreted with caution due to the tendency for single‐group studies to over‐estimate true effects and their high risk of bias.One single‐group pre‐post study reported an indirect measure of working memory before and after an eligible intervention. Hutchison  (N = 9) 5.3.2.7n = 40; comparison n = 38; Wells et al., Initiate Monitoring Planning and organisation Organisation of materials One of the RCT/quasi‐experimental studies with a comparison group reported indirect measures of EF using the individual subscales of the BRIEF with a total of 78 participants , but did not reach statistical significance, for visual attention, cognitive flexibility, or attentional inhibition. Across studies using single‐group pre‐post intervention measures, the effect sizes ranged from small to large and suggest improvement in EFs, as measured by direct assessments. However, these single group studies are at high risk of bias and should be interpreted with caution.The effect estimates for RCT/quasi‐experimental studies reporting indirect measures indicate that EF‐focused psychological interventions do not improve EFs compared to children who received no EF‐focused intervention . The direction of the effects was mixed, with some effect estimates favouring the comparison condition and others favouring EF‐focused interventions. Across studies using single‐group pre‐post intervention measures, the effect sizes ranged from small to large and suggest improvement in EFs, as measured by indirect assessments. However, these single group studies are at high risk of bias and should be interpreted with caution.6.2k = 11), all with small sample sizes and almost half of which are single‐group pre‐post intervention studies (k = 4). Second, some effect estimates are incomplete due to missing data in study reports and inability to obtain missing data from study authors. Third, the review was also unable to assess whether the impact of EF‐focused interventions change overtime, with almost all studies only reporting post‐intervention data or follow‐up data only for significant effects or the treatment group. Similarly, the review was unable to assess whether the impact of EF‐focused interventions varies by a range of important moderating variables . Fourth, most of the included studies were also conducted in North America (k = 10), with only one study conducted elsewhere . Therefore, the findings may not generalise to other cultures or geographical settings. This may be particularly pertinent in the area of FASD due to the strong cultural influences around patterns of alcohol consumption and differential expectations regarding normative child development across different cultural settings  or single studies. Second, all studies had very small sample sizes which impacts the precision and power of the estimates. Third, there is high to serious risk of bias across the corpus of studies. Collectively, these issues reduce the certainty and confidence in the review findings.The results of this review should be interpreted with utmost caution due to issues with the quality of the located and included evidence. First, effect estimates are based on either meta‐analyses using very few studies .All data extraction and effect size calculation was completed by two independent reviewers, thereby minimising the potential for any bias in the results of the review. Decision‐making regarding syntheses are clearly reported in this review, with sensitivity analyses conducted where possible to examine the impact of that decision‐making on the results. Overall, the review adhered to current Campbell Collaboration guidelines for reporting and conduct standards. Therefore, there is limited potential for bias arising from review process.6.5The current review found a lack of high quality evidence assessing the impact of interventions on EF in children diagnosed with FASD. According to the small number of extant studies, results of meta‐analysis suggest that there is limited evidence to support EF‐focused psychological interventions for children with FASD. This conclusion tends to differ from the included studies, many of which report favourable conclusions, albeit not consistently based on the full range of outcome data in study reports. Results of the current review echo conclusions of a number of previous reviews in the area, which also emphasise that the ability to draw strong conclusions regarding efficacy is limited by the relative dearth of research on interventions in FASD  and examine impact of interventions over the course of children's development .Joseph Betts is a registered psychologist with experience leading analytic projects as a statistician for central government (United Kingdom) and previous experience and training in systematic reviews. Joseph's PhD research is focused on exploring new mechanisms of early detection and treatment in FASD populations.Elizabeth Eggins is a registered psychologist and a Research Fellow with a PhD in Clinical Psychology. She has co‐authored and managed numerous research projects grounded in systematic review methodology, including Campbell Collaboration and industry funded systematic, rapid and scoping reviews. She is an editor for the Campbell Collaboration Crime and Justice Coordinating Group.Doctor Doug Shelton is a registered Paediatrician who specialises in community health and child development. Doctor Shelton's special interest area is FASD, for which he has received accolades for investigating the production of a comprehensive assessment and intervention service of children with FASD.Doctor Haydn Till is a registered psychologist and endorsed Clinical Neuropsychologist with clinical and research experience across the age spectrum. His PhD was a systematic review and meta‐effect size analysis of cognition research in cardiac surgery. He currently holds the position of Clinical Associate Professor of Neuropsychology and sub‐investigator on genetic and clinical drug trials for dementia with the Queensland University of Technology. He currently leads the neuropsychological services of the Child Development Service at Gold Coast Health and supervises the clinical assessments conducted by the FASD clinics.Paul Harnett is a Clinical Psychologist and Associate Professor in Criminology. He has worked clinically and conducted research in the field of child protection for three decades. He has an interest in program development for high risk families. His research includes evaluation of program efficacy and implementation, as well as decision making in the context of child protection.Ned Chandler‐Mather is a provisionally registered psychologist with experience in leading experimental research and clinical trials in paediatric populations. Ned's PhD is focused on understanding and treating sleep problems in children with FASD.Sharon Dawe is a Professor of Clinical Psychology and has a strong background in research pertaining to parental substance use and child/family functioning. Professor Dawe has made significant contributions in research, policy and practice areas.Content: Dawe, Betts, Eggins, Shelton, Till, HarnettSystematic review methods: Eggins, Betts, Chandler‐MatherStatistical analysis: Betts, EgginsInformation retrieval: Betts, Eggins, Chandler‐MatherReview tasks were distributed as follows:Professor Sharon Dawe and Associate Professor Paul Harnett are co‐founders and have been involved in the evaluation of the Parents under Pressure (PuP) program. PuP is a parenting program designed to improve outcomes (including executive function) in high‐risk, substance misusing families and would therefore qualify for inclusion as an eligible intervention. Both Dawe and Harnett have co‐authored a recent systematic review on interventions for improving outcomes in the context of FASD  and have published in the area of assessment and treatment of children with FASD. In addition, all study authors have been involved—to varying degrees—in the diagnostic assessment of children for FASD and their treatment. To minimise potential bias three procedures were implemented while producing this review: (1) authors Dawe, Shelton and Till were not involved in the coding or analysis stages of the review; (2) all studies were double‐coded independently by two authors  and then checked for consistency and translated into summary tables by a third author (EE); and (3) all effect size calculations and analyses were conducted by Betts and then reviewed by Eggins.Elizabeth Eggins is an Editor for the Campbell Crime and Justice Coordinating Group, however, she will not be privy to any internal editorial or Campbell Social Welfare Coordinating Group communications during the peer‐review process.The review makes two deviations from the protocol. The protocol stated that studies would be included in the intervention was conducted in schools, hospitals or other clinics. Upon screening potentially eligible studies, it became clear that the intervention setting was not consistently or clearly reported. To provide a comprehensive review, studies that did not clearly specify the setting, but met all other eligibility criteria were included in the review.The second deviation was adjusting the full‐text screening strategy due to the large number of documents. As independent double screening is not a mandatory MECCIR standard, an approach similar to other reviews published by the Campbell Collaboration was taken Auditory attention (direct)Cognitive flexibility (direct)Attentional inhibition (direct)Response inhibition (direct)Global executive function (indirect)Behavioural regulation (indirect)Emotional control (indirect)Inhibition (indirect)Shifting (indirect)Internal sourcesPhD Scholarship, AustraliaPaid to the lead author as part of grant: Drug and Alcohol Program: Foetal Alcohol Spectrum Disorder (FASD) Diagnostic Services and Models of Care Grant Opportunity—H1617G038.External sourcesDrug and Alcohol Program: Foetal Alcohol Spectrum Disorder (FASD) Diagnostic Services and Models of Care Grant Opportunity—H1617G038, Commonwealth Government, AustraliaSupporting information.Click here for additional data file.


Syzygium comprises 1200–1800 species that belong to the family of Myrtaceae. Moreover, plants that are belonged to this genus are being used in the traditional system of medicine in Asian countries, especially in China, India, and Bangladesh. The aim of this review is to describe the scientific works and to provide organized information on the available traditional uses, phytochemical constituents, and pharmacological activities of mostly available species of the genus Syzygium in Bangladesh. The information related to genus Syzygium was analytically composed from the scientific databases, including PubMed, Google Scholar, Science Direct, Web of Science, Wiley Online Library, Springer, Research Gate link, published books, and conference proceedings. Bioactive compounds such as flavanone derivatives, ellagic acid derivatives and other polyphenolics, and terpenoids are reported from several species of the genus Syzygium. However, many members of the species of the genus Syzygium need further comprehensive studies regarding phytochemical constituents and mechanism‐based pharmacological activities.The genus  Syzygium was analytically composed from the scientific databases, including PubMed, Google Scholar, Science Direct, Web of Science, Wiley Online Library, Springer, Research Gate link, published books, and conference proceedings. Bioactive compounds such as flavanone derivatives, ellagic acid derivatives and other polyphenolics, and terpenoids are reported from several species of the genus Syzygium. However, many members of the species of the genus Syzygium need further comprehensive studies regarding phytochemical constituents and mechanism‐based pharmacological activities.The information related to genus  In both of them, majority of the compounds are sesquiterpene and monoterpene hydrocarbons ‐caryophyllene; n‐heneicosane; α‐humulene; thujopsan‐2‐α‐ol  analysis. Sesquiterpenes were the major class of compounds. Among them, major compounds identified are β‐caryophyllene; α‐pinene; α‐selinene; and α‐humulene , assessed through GC‐MS analysis ‐β‐pinene; α‐terpineol; (+)‐α‐pinene) were the major class of compounds, followed by sesquiterpene (e.g. (−)‐β‐caryophyllene; Karioti et al., S. myrtifolium ethanol leaf extracts yielded few compounds; among them, major compounds identified were 1‐octadecene; bis (2‐ethylhexyl) hexanedioic and bis (2‐ethylhexyl) phthalate, determined by GC‐MS analysis  and GC‐MS analysis; the major compounds identified were α‐pinene; (Z)‐β‐ocimene; limonene; and α‐ terpineol, rich in terpenes  analysis of 55.1S. anisatum  against UVA damage  assays  and TBARS levels at a dose of 200 mg/kg  against the cytotoxic action and OS‐induced diabetic rats  and SOD levels and by decreasing the lipid peroxidation, determined by DPPH assay and reducing power assay  in LPS‐activated RAW 264.7 cells and exhibited in vitro potential anti‐inflammatory activity , suggesting the efficiency of bark extract to inhibit the migration inflammatory cells and to prevent abnormal permeability of the blood capillaries and showed anti‐inflammatory activity  anti‐inflammatory and analgesic effects on the writhing test at a concentration of 1000 mg/kg in rat models  by suppressing them by 74%–99%  inhibition of carrageenan‐induced paw edema  against P. gingivalis concentration of 31.25 μM  and minimum bactericidal concentration (MBC) values of 0.06 and 0.10 mg/ml, respectively. Time kill susceptibility at MBC value showed significant decrease in the optical density and colony‐forming unit (CFU) of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus , determined by disk diffusion method  and gram‐negative bacteria (e.g. E. coli) with zone of inhibition ranging from 7 to 14 mm as compared to standard ciprofloxacin (zone of inhibition of 50 mm), determined by disk diffusion method ) except S. forte , with MIC value 624 and 1250 ppm, respectively, and gram‐negative bacteria (e.g. P. aeruginosa), with MIC value 156 and 624 ppm, respectively, determined using the microbroth dilution technique  and gram‐negative bacteria (e.g. E. coli), determined by Kirby–Bauer method  and gram‐negative bacteria  with zone of significant inhibition  with significant zone of inhibition  with significant zone of inhibition , determined by disk diffusion method  and gram‐negative bacteria (e.g. E. coli) with significant zone of inhibition, determined by agar well diffusion method  showed strong antifungal activity against Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum gypseum, and Microsporum canis, and Eugenol was the most effective antifungal constituent of clove oil , S. jambos (leaf), S. luehmannii (leaf and fruit) methanol extracts showed potent activity against fungal growth through inhibiting the growth of human dermatophytes , assessed in disk diffusion method , determined by disk diffusion method , determined by disk diffusion method  when compared with others human cancer cell lines (MCF‐7) and human prostate cancer cell lines (DU‐145). S. aromaticum bud essential oil extract was evaluated to determine the cytotoxicity using MTT assay, colony formation assay, and Annexin V‐FITC assay against the thyroid cancer cell line (HTh‐7) and found that the extract showed significant anticancer activity  cell line  cell line ‐induced Swiss albino mice , determined by MTT assay  and cytotoxic effect on Hela , determined by MTT assay ‐induced diabetic rats ‐induced diabetic rats through lowering the blood glucose levels  reduction in blood glucose level ‐induced diabetic Wistar rats by lowering the plasma insulin and C‐peptide levels  by inhibiting the intrinsic small intestinal propulsion and itopride‐induced propulsive activity , total cholesterol (TC), and triglycerides (TG) in rats with acute CCl4‐induced intoxication. In addition to reducing the high MDA level, the extract noticeably restored GSH and SOD to the normal control levels in liver tissue homogenate and counteracted the deleterious histopathologic changes in liver after CCl4 injection  model  food supplementation reduced the high‐fat diet‐induced fatty liver or hepatic steatosis in rats. It is also noted that its seed powder prevented the rise of plasma TC and TG levels  as natural resource of plants counteract that effects by reducing the injury level by different facts  and showed antimutagenic effects  of glutamate‐induced orofacial nociception  when compared with the control group ‐induced food allergy  at doses of 600 and 400 mg/kg  cell line of monkey, respectively (Sit et al., S. samarangense methanol leaf extract exhibited analgesic and CNS depressant activities, determined by writhing test and reduction of locomotor and exploratory activities in the open field and hole cross tests, respectively (Mollika et al., S. zeylanicum leaf essential oil exhibited potent larvicidal effect against larvae of mosquitos (e.g. Aedes albopictus, Anopheles subpictus; Govindarajan & Benelli, The addition of polyphenolic‐rich extracts from the leaves of 6Syzygium. The collected data from various literatures turned evident that the plants of the genus Syzygium had prominent traditional uses along with potential pharmacological properties. The reviewed investigation revealed many different pharmacological activities obtained from several organic extracts, essential oils, and compounds isolated from Syzygium species. Some of the activities such as antioxidant, anti‐inflammatory, antibacterial, anticancer, hepatoprotective, antidiarrheal activities, etc. were exhibited as pharmacological activities. Many of them also applied on the animal model for better result along with in vitro screening. The in vivo data complied with the data obtained from the in vitro studies. However, only few species of the genus were studied for their phytochemical constituents that could arbitrate pharmacological activities and still many are unidentified and multiple gaps in the knowledge exist for the lack of isolated compounds. Many of the implemented pharmacological studies were limited to the in vitro screening, many of the pharmacological studies were not correlated with traditional uses, and also many of the animal model‐based investigations were done without mentioning their detailed mechanisms of action. This review article linked the phytochemical constituents to pharmacological activities and provided perception of the biological potential of the genus Syzygium. Study of pharmacological activities delivered supportive evidence for therapeutic effect of this genus. However, many members of the genus Syzygium need more inclusive studies regarding phytochemical constituents and mechanism‐based pharmacological activities. Also, in vitro and in vivo animal studies are necessary to ascertain the safety, clarification of the effective doses, and the mechanisms of action before future clinical studies.In this review article, we have tried to present the organized information on traditional uses, phytochemical constituents, and mechanism‐based pharmacological activities of plants belonging to the genus All the authors have read and approved the manuscript for this journal. They do not have any conflict of interest.A. B. M Neshar Uddin: investigated the study and provided resources. Farhad Hossain: performed data curation, investigated the study, contributed to software, and wrote the original draft. A. S. M. Ali Reza: conceived and designed the review. Mst Samima Nasrin: interpreted the data and drafted the manuscript. A. H. M. Khurshid Alam: corrected the manuscript and interpreted the data.


Heart failure is a devastating clinical syndrome, but current therapies are unable to abolish the disease burden. New strategies to treat or prevent heart failure are urgently needed. Over the past decades, a clear relationship has been established between poor cardiac performance and metabolic perturbations, including deficits in substrate uptake and utilization, reduction in mitochondrial oxidative phosphorylation and excessive reactive oxygen species production. Together, these perturbations result in progressive depletion of cardiac adenosine triphosphate (ATP) and cardiac energy deprivation. Increasing the delivery of energy substrates  to the mitochondria will be worthless if the mitochondria are unable to turn these energy substrates into fuel. Micronutrients  are required to efficiently convert macronutrients to ATP. However, up to 50% of patients with heart failure are deficient in one or more micronutrients in cross‐sectional studies. Micronutrient deficiency has a high impact on mitochondrial energy production and should be considered an additional factor in the heart failure equation, moving our view of the failing myocardium away from an “an engine out of fuel” to “a defective engine on a path to self‐destruction.” This summary of evidence suggests that supplementation with micronutrients—preferably as a package rather than singly—might be a potential therapeutic strategy in the treatment of heart failure patients.       Low plasma concentrations of several micronutrients have been associated with reduced quality of life and adverse outcomes in heart failure (HF) , 2, 3, 4Reduction in bioenergetic capacity plays a major role in the development and worsening of HF , 14. MacDespite the identification of a high prevalence of micronutrient deficiencies in HF and their association with an adverse prognosis, with the exception of iron, very few randomized trials of micronutrient interventions have been conducted . Therefo2) to oxygen (O2) by a series of electron carriers [Micronutrients serve as cofactors or part of essential amino acids in enzymatic reactions because they facilitate the transition between oxidized and reduced states. The systemic and cellular levels of some micronutrients—iron and copper in particular—must be balanced, as deficiency leads to loss of activity of crucial enzymes, but their accumulation may be toxic. Micronutrients are particularly important for normal mitochondrial function, especially in mitochondria‐rich tissues such as the myocardium. Oxidative phosphorylation is the process by which ATP is formed by the transfer of electrons from 1,4‐dihydronicotinamide adenine dinucleotide (NADH) or dihydroflavine‐adenine dinucleotide (FADHcarriers . Mitocho2+) and trivalent (Fe3+) form [Iron is essential for oxygen transport and ATP production, but an excess of nonferritin‐bound iron in cells is potentially extremely toxic. Iron accepts and donates electrons, switching between its bivalent (Fe3+) form , leading3+) form , 66. Mos3+) form . The abi3+) form . Special3+) form . Mitocho3+) form . Iron is3+) form , but iro3+) form . Activit3+) form ). These 3+) form , who con3+) form , who als2−) by complexes I and III [Several in vitro studies have shown detrimental effects of iron deficiency on mitochondrial function and morphology in human cardiomyocytes and myoblasts , 72, 73. and III , causing and III . It need and III .31P MRS). This technique allows for noninvasive, real‐time detection of phosphocreatine (PCr), inorganic phosphate and ATP. PCr comprises a pool of chemical energy, rapidly available during exercise, which gets replenished during periods of rest. Impaired skeletal muscle energetics—often accompanied by lower pre‐exercise PCr levels, a lower pH and a slower recovery rate of PCr after exercise—are observed both in patients with Heart Failure with reduced Ejection Fraction (HFrEF) and Heart Failure with preserved Ejection Fraction (HFpEF) [Human mitochondrial function in patients with HF and iron deficiency has been assessed in skeletal muscle using phosphorus‐31 magnetic resonance spectroscopy ( (HFpEF) , 76, 77. (HFpEF) . Future  (HFpEF) .Iron deficiency is the most common nutritional deficiency, estimated to affect more than 2 billion people worldwide . Gastroin = 1038), which investigated the effects, compared with placebo, of IV ferric carboxymaltose administered prior to discharge to patients who had been admitted with acute HF, an LVEF less than 50% and iron deficiency using the FAIR‐HF trial criteria. Patients assigned to IV iron had fewer rehospitalizations for HF, but no effect on mortality was observed [p = 0.0007) but could not confirm an effect on cardiovascular mortality  [Several substantial, randomized, double‐blind, placebo‐controlled multicenter trials investigating intravenous (IV) iron—mainly with ferric carboxymaltose—in patients with HF and a reduced LVEF (HFrEF) have shown beneficial effects on symptoms, quality of life and exercise capacity , 30, 31.observed . Iron deobserved . An upda = 0.47) . This meSelenium is a component of selenocysteine , an aminSelenium deprivation in human pluripotent stem cell (PSC)‐derived cardiomyocytes impairs mitochondrial respiration, biogenesis and oxidative stress , which mSevere selenium deficiency in humans may be associated with a rare but fatal form of dilated cardiomyopathy (DCM)—Keshan disease—that was reported from a specific geographic region where there was a very low amount of selenium in the soil and therefore in food . Keshan n = 443) investigated the effects on cardiovascular mortality of supplements of selenium together with CoQ10 given for 4 years to older Swedish citizens, some of whom had HF  [p = 0.0003). Although most patients had cardiovascular problems, only a minority had HF. Additionally, one very small randomized controlled trial (RCT) has been performed in patients with HF from Iran. Garakyaraghi et al. [p = 0.02) [p = 0.02), but a possible increase in mortality when selenium soil content was high  [No substantial randomized trial of selenium supplements has yet been done in patients with HF. One placebo‐controlled, randomized trial (8 years) . Despitei et al.  supplemei et al. . Besides = 0.02) , even th = 0.02) , 113. On = 0.02) , 110. Mo = 0.02) , 114–117 = 0.03) . The hypZinc is vital for many physiological functions, including growth, reproduction, antioxidant defenses and the immune system. It is a critical component of the catalytic site of more than 300 enzymes and required for the synthesis and degradation of carbohydrates, lipids, proteins and nucleic acids . Zinc alThe World Health Organization (WHO) suggests that zinc deficiency is common in many regions of the world . Zinc deMitochondrial peroxiredoxin and metalloenzymes, such as superoxide dismutase (SOD), rely on zinc for antioxidant reactions . When miAnimal studies suggest that zinc supplementation may protect against loss of systolic function and enhance diastolic function during and after ischemia‐reperfusion injury . Zinc miIn HF, zinc deficiency may be due to low dietary intake, reduced gastrointestinal absorption, and/or increased excretion as the result of neurohormonal activation , 135–137p < 0.001), which were associated with clinical improvement. In myocardial biopsies, the content of selenium and zinc and GPX activity increased, with striking improvements in cardiomyocyte degenerative changes including a reduction of cell autophagy and myofibrillolysis [n = 25) were given zinc acetate—50 mg three times a day for 10 months—and were compared with 10 healthy subjects on similar treatment. However, the results of these studies have not yet been published [There is a paucity of evidence to support zinc supplements. In a small, non‐randomized, prospective study, 10 patients with malabsorption‐associated cardiomyopathy received zinc and selenium supplements  . Eight pllolysis . A recenublished . Recentlublished . SupplemThere are many copper‐dependent proteins (known as “cuproenzymes”), including transcriptional regulators, chaperones, oxidoreductases, free radical scavengers and immune function modulators –52, 141.Intracellular copper deficiency increases lipoprotein peroxidation, impairs nitric oxide (NO)‐mediated endothelial dilatation and increases the risk of cardiomyocyte oxidative damage . In the p < 0.001). A meta‐analysis comprising 13 studies including 1504 subjects identified an association between high serum copper and HF [Higher blood concentrations of copper have been found in patients with HF compared to healthy controls . Málek er and HF . High ser and HF . Cerulopr and HF , and it r and HF . Cerulopr and HF  and may r and HF . It has r and HF . Of noter and HF . Therefor and HF .n = 200) are being recruited for a randomized trial to evaluate the effects of a copper‐binding agent called INL1 in patients with HF (TRACER‐HF) [To our knowledge, there is no evidence to support copper supplements for patients with HF. Currently, patients with HFrEF (ACER‐HF) . It is hCoQ10, also known as ubiquinone, is found predominantly in meat, fish and nuts. Although CoQ10 is a common component of most cell membranes, it plays a key role in the mtETC to facilitate ATP production . MitochoCoQ10 facilitates electron transfer from complex I (NADH coenzyme Q reductase) to complex III (cytochrome bc1 complex), and from complex II (succinate dehydrogenase) to complex III , 59. It In patients with HF, lower plasma concentrations of CoQ10 are associated with poorer NYHA functional class, lower LVEF and higher plasma concentrations of NT‐proBNP , 62. Furn = 641) [p = 0.003). All‐cause mortality was also reduced . The KiSel‐10 trial also suggested that a combination of CoQ10 and selenium reduced cardiovascular mortality [Over the past few decades, several randomized trials of CoQ10 supplements in HF have failed to produce conclusive evidence. One of the earliest placebo‐controlled randomized trials studied the effects of 12‐month treatment with CoQ10 in patients with chronic CHF n = 641)  and repon = 641) . CoQ10 aortality . Many ot41  and rortality –180. Howortality  and was ortality . Therefonutrition of micronutrients has great impact on the human heart and especially on its ability to recover from damage, and consequently associates with prognosis. Improper micronutrient intake is frequently observed in HF patients, affecting 30%–50% of this population . Deficiep < 0.05) in the group assigned to receive micronutrients but not in those assigned to placebo. However, there was no improvement in NYHA classification in the patients receiving micronutrient therapy [Several small, double‐blind, randomized trials have evaluated the role for micro‐ and macronutritional supplementation in patients with HFrEF and ischemic heart disease , 48, 184 therapy . A seconOne important factor that is hampering consistency of study results is the supplementation of subjects who are nondeficient (for one or multiple micronutrients). As an example, selenoprotein activity, and therewith supplementation effectiveness, reaches plateau levels at serum selenium concentrations of approximately 125 μg/L, under a sufficiently high selenium supply , 186. ThThe failing myocardium might be “an engine out of fuel.” However, increasing the delivery of energy substrates  to the mitochondria  cannot sThe authors declare that there is no conflict of interest.Nils Bomer: conceptualization (lead); methodology (lead); supervision (lead). Mario G. Pavez‐Giani: conceptualization ; methodology (supporting). Niels Grote Beverborg: conceptualization (supporting). Peter van der Meer: conceptualization (supporting); supervision (supporting).