This study compares the effectiveness of different trolling strategies in two online contexts: politically oriented forums that address issues like global warming, and interest-based forums that deal with people’s personal interests. Based on previous research, we consider trolling as context-bound and suggest that relevance theory and common grounding theory can explain why people may attend and react to certain types of troll posts in one forum, but pay scant attention to them in another. We postulate two hypotheses on how successful  trolling varies according to context: that trolls’ messaging strategies appear in different frequencies in political and interest forums (H1), and that context-matching strategies also produce longer futile conversations (H2). Using Hardaker’s categorization of trolling strategies on a covert–overt continuum, our statistical analysis on a dataset of 49 online conversations verified H1: in political forums covert strategies were more common than overt ones; in interest forums the opposite was the case. Regarding H2 our results were inconclusive. However, the results motivate further research on this phenomenon with larger datasets. Online discussion platforms, such as online forums and news articles’ comment sections, connect millions of people daily. There are platforms and topics for everyone, hosting discussions ranging from seeking advice for personal trouble to heated debates on political matters. Many discussion platforms are vulnerable to malicious and disruptive behavior, which wreaks havoc in conversations and causes emotional distress to the people involved. Although online trolling is a diverse phenomenon, and perceptions towards it vary, 5.Considering the widespread agreement that Internet trolling can cause significant societal harm, it is surprising how little is known about the conversational strategies that trolls use. Evidence suggests, though, that trolling may manifest differently across contexts, 25. TheThis paper’s findings come from a research project that has been launched to address the problem of trolling. Under the course of our research, we have made an initial observation that trolls seem to use different trolling strategies in political and interest discussions. Using a small dataset of 68 online discussions around political or societal themes  and interest themes , all of which included successful  trolling, we tested two hypotheses: that successful trolling strategies would indeed be applied with different frequencies depending on the topic of discussion (H1), and that the reply chains to trolls would also differ in their length, depending on the strategy used by the troll (H2). For distinguishing different trolling activities, we utilized the already well-established categorization by Hardaker that desThe amount of data is so far limited, but our analysis suggest that H1 holds. We found a statistically significant difference between successful trolling strategies in political vs. interest discussions: in political discussions trolls apply covert strategies  more often than in interest discussions, where the strategies contrariwise are predominantly overt . On the other hand, we could not confirm H2 about reply chain lengths. The limited amount of data, however, pointed towards the direction predicted by the hypothesis: that covert trolling would lead to longer derailed discussions in political discussions, while overt strategies would do the same for interest discussion. The lack of confirmation to H2 notwithstanding, our findings have both academic and real-life implications, which we will cover in the Discussion.Our hypotheses did not result from serendipitous discoveries but had a theoretical backing that sensitized us to pay attention to their possible existence.Trolls take advantage of the ambiguities of computer-mediated communication and the vulnerabilities of internet discussion communities to lure others into fruitless, frustrating or circular discussions and to waste their time. TrollinPrevious studies have illustrated various types of trolling. They have often oriented to analyzing and understanding one type of trolling at a time, such as memorial page trolling, signallThe relevance of a comment in an online forum depends on the content that has started the conversation. For example, a discussion in an online newspaper’s comment section happens in the context of the related news article. Similarly, in Reddit (a popular online news aggregator and discussion forum) a message is visible in relation to a “subreddit” (a discussion section) and an original post within it. Therefore the boundaries for the discussions that unfold are set to a specific topic that also sets the conversational context, 20. ThiRelevance theory[e theory, which be theory, 13, maye theory. We arguConsequently, we believe that political forum discussions are more vulnerable to covert trolling attempts by being more neutral, information-centered and less personal.Compared to other less serious arenas, political forums discussing larger societal issues orientate more strongly toward more serious deliberative discourse or debate, and exhibit higher levels of interactivity and topical coherence . They awe maintain that interest forums match with overt strategies, i.e. they are more vulnerable to more personal and visible overt trolling attempts like direct insults. Therefore, in summary, we hypothesize that:H1: The frequencies of covert and overt trolling strategies are different in political and interest forums.Contrarily to political arenas, interest forums serve as spaces for bonding with people with similar interests, beliefs or hobbies, 21. CenIn particular, we hypothesize that covert trolling is common in political discussion while overt trolling is common in interest forums.Our second hypothesis is derived from the first one. If trolls match their trolling strategy to the type of the online forum, this may be because they know (consciously or sub-consciously) it will be more effective. One method for measuring the effectiveness of trolling is to measure the amount of engagement that a message manages to garner from others in the discussion.theory of common grounding[Along with relevance theory, the rounding, 7 provirounding, p. 223.rounding, 7. All H2: The quantity of replies to trolls will vary in different types of forums depending on the employed trolling strategy.As mentioned, contextual differences require learning the conversational conventions of a given online forum in order to gain access to the type of interaction others on the forum usually deem relevant, 9, 26. In particular, covert strategies would incite longer conversations on political forums, whereas overt strategies would have the same effect on interest forums.Reddit and comment sections on English language online newspapers, including the Telegraph, the Guardian and the Washington Post. Having a large readership, these are influential media platforms that are likely to be targeted by trolls.Through selective sampling of online forums, we have manually acquired a corpus of conversations containing trolling. Keeping in mind our two hypotheses, we have selected several differing platforms to increase the heterogeneity of conversational and trolling styles. The corpus covers several discussion areas on climate change and Brexit) and the other around interest discussions (cats and fitness). Important political topics, especially climate issues and Brexit , are likely to attract serious or ideological trolls wishing to disrupt or polarize the dialogue  , 23 clime .In this data collection process, we have continued browsing the above-listed forums and their topic-specific discussion spaces until we have identified 2–5 conversation threads for each topic on each platform. We have particularly looked for activity-rich discussions in order to find successful trolling that has managed to elicit a lot of responses. Here successful trolling has referred to managing to formulate posts and/or responses to others’ posts that provoke others into responding directly or indirectly. Comments like ‘Don’t answer him, he’s a troll.’ and troll-triggered off-topic arguments among other participants have also qualified as responses. For the online newspaper comment sections, successful trolling has typically meant 8–15 response posts in a thread triggered by the troll, while on Reddit the range has been 15–20 replies. The differing numbers are due to the average number of replies having been smaller in newspaper comment sections as compared to Reddit, and the need for context-sensitivity as some topics inspired more replies in general than others, even within the same platform.Finally, we have tagged all the trolling content in this dataset following Hardaker’s six-cateMost trolling styles in Hardaker could beOur first hypothesis (H1), more specifically, was that trolls would be more likely to use covert trolling strategies criticism or antipathy) in political discussions and overt strategies  in interest forums. To evaluate this hypothesis, we counted the frequency of each trolling strategy used in each discussion in our sample. We created two larger groups of trolling (covert and overt) by pooling together the frequencies of the three first and the three last strategies. This resulted in a In the preparation of this table, we removed the following cases that would have confounded our analysis. First, 13 discussions could be classified both as covert and overt trolling. After their removal, each discussion represented exclusively either covert or overt trolling. Second, there were 4 trolls (identified by their nickname) that appeared several times in our data . To remove the possibility that their behaviors would be over-represented and would thus skew our data, we used a random number generator to sample only one discussion from each troll in our analysis. In one case, both confoundments were present within the same discussion. As a result, altogether we removed 19 discussions from the analysis. Table  Chi-square contingency table analysis: in political discussions, covert trolling was more frequent while the opposite was true for interest discussions (H1 was confirmed: trolls appear to use more covert trolling styles to (successfully) disrupt political conversations, whereas for invading interest conversations they use more overt styles.Already with a plain visual inspection of the frequencies, our hypothesis seemed to be true: there were more discussions in the political-covert quadrant than in the political-overt quadrant (19 vs. 5), and the inverse held in the interest-covert and interest-overt (5 vs. 20) quadrants. We confirmed the hypothesis by comparing frequencies between categories using a We also studied how the removal of the fore-mentioned 13 discussions (where trolls had applied both overt and covert trolling strategies) had possibly skewed our findings. We included the removed discussions in our analysis by assigning them either to an overt or covert category. We implemented the assignment so that the frequencies between the categories would come as close to each other as possible, thus making it maximally difficult to find differences in a statistical test. Out of the 13 discussions 8 were political, 1 of which included a troll who had also appeared in another discussion in our data. We assigned the resulting 7 discussions to the overt trolling category, resulting in a 19 vs. 12 comparison between covert and overt strategies in political discussions  would not only be more frequent but also, from the troll’s point of view, more “successful” in luring others into longer arguments. The success could be measured by the number of replies that others would post to the troll’s messages. Long chains of replies would best serve the trolls’ interest of creating havoc and destroying civic discussion in online spaces. The length of individual posts was not considered due to the fact that it may vary in online discussions for several reasons which cannot be controlled here.To evaluate hypothesis H2, we counted the number of replies that others had posted to the discussion thread after the trolls’ original message. If the trolls themselves engaged in these subsequent discussions, we excluded their messages from these counts. We then compared the lengths of the reply chains in the U tests did not yield significant results either. Thus, H2 was not confirmed.Table The reason for this failure becomes apparent when one inspects the numbers of cases in each quadrant. The earlier-presented Table  Chi-square analysis, which encourages further studies on the phenomenon with larger datasets. The second hypothesis was that covert strategies produce longer futile conversations in political arenas, whereas overt strategies drag on longer arguments in interest conversations. This claim was not supported by our statistical analyses at this point, but the data suggest it plausible for larger datasets to yield better results.To recap, our first hypothesis was that commonly used successful trolling strategies differ according to the conversational context of the forum: political–covert or interest–overt. It was validated by a A better dataset would include a larger number or conversations, ranging through a greater variety of topics on the political and interest axes, including also unsuccessful troll posts. It would also allow for a more specific analysis of different trolling strategies, like the ones that Hardaker identifiWe also have other considerations that future research needs to address. First, how exactly the nature of the conversational space and its norms  affectsThis also gives rise to further considerations beyond those that we put forward in our hypotheses. In particular, we find it worthwhile to consider relevance theory more broadly in the context of analyzing trolling. A relevance theoretical approach helps to further explicate the relationship between trolling and expectations of context-specific posts. Firstly, why some troll posts are noticed in the discussion while others receive very little attention, and secondly, why people engage in selected communicational breakdowns, despite their redundancy, provocativeness and frustrating effects. In interest discussions, for instance, participants seem to pay attention to overt troll posts because they seek to resolve norm-violations in order to reach common grounding and to maintain the friendly atmosphere. Arguably, participants on political forums put emphasis on factual correctness and enjoy sharing knowledge, which is why they are more inclined to be baited by epistemic incoherence or challenges against information they have provided. Thus, another possible course for future studies could involve deepening our understanding on how exactly discussion spaces give higher cognitive relevance to certain trolling strategies than others, e.g. why exactly certain posts are relevant to the people partaking in given discussions.An issue to be aware of is that the results of the research presented in this paper, and in more extensive studies in the future, might be used for malicious purposes by aspiring trolls and bodies who are interested in large-scale misinformation campaigns. However, we believe that the results we presented here are mostly known to trolls already, whereas other discussants on online forums are probably less informed about trolling strategies. This makes them more vulnerable, which is why the results should yield positive results in raising awareness.Assuming that the finding from H1 survives the test with a larger dataset, and H2 can eventually be proved, the implications are that we can expect certain types of online forums to be vulnerable to specific types of trolling strategies. The findings of this study already take us a step closer to identifying a given forum’s weak spots that enable trolling behaviors, thus helping in predicting and detecting trolling attempts. Developing awareness of the type of lures trolls use to attack different conversational groups would arguably also improve conversants’ resistance to trolls’ harassment. Future studies with larger sets of data will likely enhance the opportunities for identifying trolling patterns out of larger collections of online conversations, and therefore take us closer to more accurate automatizations of trolling detection and prevention, and moderation practices. Considering the recent developments in organized trolling of political discussions, detecting trolling patterns in these arenas on a larger scale would help in battling trolling used in information operations and to ensure democratic public spaces for online civic discussion. On the other hand, this would also help in ensuring that minority groups, for instance, will have safe spaces for meeting others with similar experiences, not having to be terrorized by trolls who seek only to amuse themselves or to oppress others.


It is controversial whether ADHD solely or its comorbid disorders account for eating behaviors associated with obesity.A high rate of attention deficit and hyperactivity disorder After presurgery psychiatric assessment, 100 severely obese patients (50 with ADHD and 50 without ADHD) were administered Adult Attention Deficit Hyperactivity Disorder Self‐Report Scale(ASRS), Wender Utah Rating Scale(WURS), Three‐Factor Eating Questionnaire(TFEQ), and Beck Depression Inventory(BDI) and Beck Anxiety Inventory(BAI).Patients with obesity and ADHD had significantly greater emotional eating, susceptibility to hunger, depression, and anxiety but less restraint of eating scores than those without ADHD. Disinhibition of eating scores and presence of Binge Eating Disorder(BED) did not differ significantly between ADHD and non‐ADHD groups. Obese patients with major depression had significantly higher ASRS, WURS, TFEQ, BAI scores, disinhibition of eating control, emotional eating, susceptibility to hunger, and diagnosis of BED than nondepressed ones.Major depression and anxiety disorder have associations with disinhibition of eating control, emotional eating, susceptibility to hunger and BED, ADHD. Disinhibition of eating and BED did not differ according to the presence of ADHD; thus, depression was associated with eating control on more constructs than ADHD in our study. Major Depression has associations with almost all disordered eating behaviors including disinhibition of eating control, emotional eating, susceptibility to hunger and BED, ADHD and anxiety disorder. Disinhibition of eating and BED did not differ according to the presence of ADHD in our sample; thus, depression seems to be associated with eating control on more constructs than ADHD. Information about the study was given to patients. Two participants with alcohol use disorder, 1 with mental retardation, and 1 with a psychotic disorder were excluded from the study. 3 surgery applicants for the second time (gastric bypass surgery) were excluded, and 3 patients did not participate voluntarily  was used to determine the diagnoses of ADHD, BED, major depressive disorder (MDD), and anxiety disorders (AD) according to DSM‐5. Adult Attention Deficit Hyperactivity Disorder Self‐Report Scale (ASRS), Wender Utah Rating Scale (WURS), Three‐Factor Eating Questionnaire (TFEQ) and Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI) were administered.2.32.3.1Structured Clinical Interview for DSM‐5‐ClinicianVersion is a semi‐structured interview developed for DSM‐V diagnoses First,  and is u2.3.2Validity and reliability study of the Turkish version of the Adult Attention Deficit Hyperactivity Disorder Self‐Report Scale (ASRS) was conducted in 2009 by Dogan et al.  is a scale that can help to diagnose Attention Deficit and Hyperactivity Disorder (ADHD) in adults. WURS is a five‐point Likert‐type self‐report scale in which each item is rated 0–4 . The cutoff score was 36. When this cutoff point was taken, the sensitivity was 82.5% and the specificity was 90.8%. The validity and reliability study of the Turkish 25‐item version was done in 2005. For the internal consistency analysis of WURS, Cronbach alpha coefficient was 0.93 for the whole scale. Item‐total score correlations were between 0.60 and 0.75. One month test–retest reliability was found to be 0.81. It was shown to be a valid and reliable scale that can help clinicians to diagnose ADHD in adults  version 22.0  program was used to evaluate findings in this study. Categorical variables are reported as numbers and percentages. Continuous variables were checked for the normal distribution assumption using the Shapiro–Wilk test. Kruskal–Wallis test was used for comparison of nonparametric quantitative data. Mann–Whitney U test was used to compare nonparametric variables between two groups. Fisher's exact test and Continuity (Yates) Correction were used to compare qualitative data. Spearman's rho test was used to investigate the relationships between numerical variables. Significance was evaluated at 3The mean BMI of non‐ADHD obese patients was 44.81 ± 4.88, and the mean BMI of ADHD obese was 45.35 ± 5.21. The mean age of non‐ADHD obese patients was 34.46 ± 10.54, and the mean age of ADHD patients with obesity was 35.59 ± 12.12. Sociodemographic characteristics and scale scores of the participants are shown in Table The rate of patients with obesity for at least one psychiatric disorder was found as 22.0%, two psychiatric disorders 14.0%, and three psychiatric disorders 7%. Psychiatric evaluations were made by a psychiatrist based on SCID‐5. Distribution of psychiatric disorders was major depression 20.0%, generalized anxiety disorder 12%, social phobia 5.0%, panic disorder 5.0%, obsessive–compulsive disorder 2.5%, and post‐traumatic stress disorder 1%. Bulimia nervosa and anorexia nervosa were not found.p = .017), susceptibility to hunger (p = .040), and BAI scores (p = .011) than men. Participants who had psychiatric treatment in the past or receiving psychiatric treatment at the time of assessment had higher disinhibition of eating control (p = .044) and lower cognitive restraint of eating (p = .003) scores than those without a psychiatric disorder in the whole sample.Women participants of our study had higher scores on emotional eating (p = .189). Table The percentage of Binge Eating Disorder in obese ADHD participants was 16.3%, and the percentage of BED in non‐ADHD obese participants was 6% (Continuity Yates correction p = .005). Table The percentage of Binge Eating Disorder in obese participants with major depression was %21.7, and the percentage of BED in obese participants without depression was %1.9 (Continuity Yates correction p = 0.091).The percentage of Binge Eating Disorder in obese participants with an anxiety disorder was 18.2%, and the percentage of BED in obese participants without depression was 6.5%.  did not differ significantly between ADHD and non‐ADHD groups. Obese patients with major depression or anxiety disorder had significantly higher ASRS, WURS, TFEQ, BAI scores, disinhibition of eating control, emotional eating, susceptibility to hunger, and diagnosis of BED than nondepressed or nonanxious ones in our study.Our study revealed that obese ADHD patients—both men and women—were less successful in cognitive restraint of eating. In ADHD adults, the readiness to act rashly without worrying about future outcomes can bring on unrestrained eating which can be one of the pathways in the development of obesity. In a study of 223 obese women, those scoring higher on restraint at baseline had lower body weights. During weight‐loss treatment, as restraint score increased, disinhibition and hunger susceptibility decreased. Besides, patients who increased restraint scores during treatment lost more weight . This was surprising and not consistent with some of the studies in the literature. The number of patients with BED was low  in our sample which might have concealed a significant difference. It is not clear how much relevant is BED for the obesity–ADHD relationship and which mediators are involved. de Zwaan, et al. , they argued that ADHD can be an eminent risk factor for binge eating and related EDs  and variability of medications, dosages, and durations in the treatments.Before surgical treatment, a substantial proportion of obese patients report disordered eating behaviors, most implying mental health problems . When working with obese ADHD patients, clients eating in response to emotions, and vulnerable to their perceptions of hunger should be supported in the acquisition of how to realize, preclude, and plan for these situations and psychiatrists also need to tailor the approach MD and AD . Even so, this study contributes to the increasing body of knowledge about the relationship between obesity and eating behaviors, ADHD, MD, and anxiety, yet there is much that remains unknown.5Major Depression and anxiety disorder have associations with disinhibition of eating control, emotional eating, susceptibility to hunger, BED, and ADHD. Disinhibition of eating and BED did not differ according to the presence of ADHD; thus, depression and anxiety were associated with eating control on more constructs than ADHD in our study. The identification and effective management of psychiatric symptoms in obese individuals with treatment may alleviate more competent management of eating behaviors that yield obesity and may reduce the need for invasive and costly procedures for the treatment of obesity.We have no conflicts of interest to disclose. This study is not supported by any drug or other companies. No grants or fees were taken from any institution or firm.E.Ş. and M.Z.E. conceived of the presented idea and developed the theory. M.Z.E. and S.S. performed the computations and verified the analytical methods. E.Ş. and M.Z.E. wrote the manuscript in consultation with S.S who reviewed the literature. All authors discussed the results and contributed to the final manuscript.https://publons.com/publon/10.1002/brb3.1915.The peer review history for this article is available at


Objective: Insights to underlying neural mechanisms in attention deficit hyperactivity disorder (ADHD) have emerged from neuroimaging research; however, the neural mechanisms that distinguish ADHD subtypes remain inconclusive.Method: We reviewed 19 studies integrating magnetic resonance imaging  findings into a framework exploring pathophysiological mechanisms underlying the combined (ADHD-C) and predominantly inattentive (ADHD-I) ADHD subtypes.Results: Despite equivocal structural MRI results, findings from fMRI and DTI imaging modalities consistently implicate disrupted connectivity in regions and tracts involving frontal striatal thalamic in ADHD-C and frontoparietal neural networks in ADHD-I. Alterations of the default mode, cerebellum, and motor networks in ADHD-C and cingulo-frontoparietal attention and visual networks in ADHD-I highlight network organization differences between subtypes.Conclusion: Growing evidence from neuroimaging studies highlight neurobiological differences between ADHD clinical subtypes, particularly from a network perspective. Understanding brain network organization and connectivity may help us to better conceptualize the ADHD types and their symptom variability. Neurobiological research in attention deficit hyperactivity disorder (ADHD) has witnessed exponential growth over the past two decades, uncovering key brain features underlying functional deficits in response inhibition, hyperactivity, and inattention typically observed in individuals with this disorder. These advances are important as ADHD has an estimated global prevalence of 3.4% in children and adolescents -based research has made attempts to establish clear neurobiological pathways of the ADHD subtypes utilizing measures of cortical functional activation, structural volumes, and more recently, by studying brain connectivity and networks. The proposal of a neurocircuitry-based model in ADHD incorporates knowledge on the role of inter-regional network organization involving frontal, temporal, and parietal regions, indicating the default mode network (DMN) and cingulo-frontal parietal (CFP) attention network to underlie the ADHD types Bush, .Emerging evidence suggests that connectivity differences may better conceptualize ADHD subtypes and explain its variations in functional symptoms, which have led to an increase in the adoption of network-based analyses in the ADHD literature  2015 checklist to include in a systematic review protocol  AND (subtype or combined presentation or inattentive presentation) AND . The study selection process was conducted in accordance with PRISMA  criteria , focused on the evaluation of pharmacological treatment, written in a language other than English, or review papers were excluded . Full-text articles were then screened based on the exclusion criteria. Articles that met the eligibility criteria and were included in this review article are summarized in Data extraction tools involved standardized database templates and forms using excel and Endnote X8. Quality check and accuracy of the first reviewer's (JFS) data extraction was performed by the second reviewer (MSK). Data extracted from the studies were study design, population source, the sample size, age range, location, gender, DSM edition, neuroimaging measures used, and study findings/outcome. Data were then organized into categories based on the type of neurobiological measure used.Magnetic resonance imaging (MRI) allows non-invasive measurements of neuroanatomical properties of the brain  is an MRI technique, which can provide information on the microstructural properties of brain white matter (WM) by observing the directionality and coherence of water diffusion  changes in response to stimuli (task-based paradigms) or at resting state (rs-fMRI)  measures], 3 articles could not be located, and 2 conference papers (both investigating neurofeedback efficacy in ADHD subtypes). A total of 19 studies from the selection process were included in this study as illustrated in The characteristics and outcomes of the studies included in this review examining neural mechanisms in the clinical subtypes of ADHD are summarized in All the eight studies using sMRI to examine neuroanatomical differences in the ADHD-C and ADHD-I subtypes evaluated gray matter volumes  analyses of FA, RD, AD , relative to ADHD-I (n = 28), involving the motor circuit, with increased FA and RD in the right thalamus, increased AD in the left postcentral gyrus and right caudate, and increased RD in the left postcentral gyrus and supplementary motor area  analyses to examine differences of FA, RD, AD, and MD between the ADHD-C and ADHD-I subtype showed interesting findings. Svatkova et al.  comparedOverall, seven studies were available to review which have used fMRI to examine functional activation and connectivity differences between the ADHD-C and ADHD-I subtypes. Of these seven studies, two utilized task-based fMRI , 53 ADHD-I (n = 53), and 44 ADHD-HI (n = 44) compared to 170 controls. They found increased resting state connectivity in the right ventral attention network in ADHD-I relative to the ADHD-C and ADHD-HI types and also controls  data to explore the neural mechanisms that underlie the combined and inattentive subtypes of ADHD. The goal was to synthesize these results and examine if these findings were consistent across different modalities and produced similar patterns. Furthermore, our second aim was to present these findings from a perspective of brain circuitry dysfunction and its role in understanding the subtypes of ADHD wherever possible. Overall, of these studies reviewed, findings support that a shift in understanding ADHD symptom deficits from solely region-based structural or functional abnormalities to a more holistic connectivity perspective focusing on brain network framework is necessary. While it may be expected that an overlap in abnormalities would occur given the shared core inattentive symptoms across the two most common subtypes, the combined and inattentive type, imaging results support distinct differences.In summary, the structural MRI studies reviewed produced equivocal results, with only one of these studies reporting volumetric differences between the combined and inattentive subtypes. Findings from these studies generally found no significant volumetric differences between the ADHD-C and ADHD-I subtypes for global and specific subregions of the basal ganglia. Furthermore, another research, which has examined volumetric differences in just one subtype comparably to controls also reveals mixed results. For example, relative to controls, de Mello et al.  found reWhile volumetric data preclude any interpretations related to brain networks, only one study, that of Saad et al. , has so Overall, of the four studies reviewed, aberrant white matter brain microstructure between the subtypes was reported, though with varied differing results mostly driven by differences in methodological or participant characteristics. For example, despite both studies employing a TBSS approach, opposing findings of increased RD may be due to the treatment-naïve status and exclusion of comorbidity, except ODD, from the Ercan et al.  participNotably, there were more resting-state functional connectivity studies than task-based studies available for review. Overall, the key findings from the fMRI studies reviewed indicate frontoparietal, cerebellar deficits, and aberrant CFP attention network patterns in ADHD-I, and frontostriatal thalamic and visual deficits in addition to aberrant DMN connectivity in ADHD-C. Interestingly to note, these rs-fMRI results produce an opposing pattern to the atypical cerebellar findings observed in the ADHD-C type in DTI and structural volume studies reviewed earlier. However, this is not a surprising finding in the inattentive type, as the role of the cerebellar system in modulating motor movement is suggested to extend its involvement of executive control and coordination of executive functioning  attention in ADHD-I. Additionally, while cerebellar abnormalities were found in the ADHD-C type across measures of brain structure, rs-fMRI deficits involving the cerebellar network were also reported for the ADHD-I type. There were also findings, which were consistent across some, but not all, imaging modalities involving the cerebellum and motor networks in ADHD-C, and differences involving the visual network in ADHD-I. Collectively, these findings might suggest that there are core differences in large-scale brain networks between the two ADHD subtypes. Variations in the presentation of the clinical symptoms of ADHD between the subtypes have been highlighted in a recent review by Bush , acknowlGrowing evidence from both functional and structural connectivity studies highlight brain connectivity differences between ADHD subtypes, which extends support for key brain networks that may underlie the combined and inattentive types  from this systematic review, as conference abstracts typically are not rigorously peer reviewed, and the results reported tend to be preliminary and not finalized in preparation for conference presentation, with difficulty to effectively assess the details of the study in depth  measures of the clinical subtypes of ADHD. Our primary objective was to examine these findings and present a summary of the literature to explore the neurobiological mechanisms that may underlie these subtypes and shed insight on possible neurobiological distinction underlying differing symptoms. To summarize, the results from the reviewed studies examining the subtypes of ADHD across neuroimaging measures lend further support toward the view of brain circuitry dysfunction to inform the ADHD neurobiological framework. Furthermore, the value of understanding brain network organization and connectivity may help us to better conceptualize the ADHD presentation types and their symptom variability.JS was responsible for substantial contributions to the conception or design of the work or the acquisition, analysis or interpretation of data for the work, as first author. MK and KG both were involved in revising the review paper critically for important intellectual content and to ultimately provide approval for publication of the content. All authors contributed to the article and approved the submitted version.KG has received honoraria from Shire. JS has received honoraria for educational seminars from Shire. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


N = 53,293, N = 681,275, and N = 98,697, respectively). We then conducted genome-wide ADHD–BMI and ADHD–obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD–BMI overlapping genes with brain volumes . The dopaminergic gene set was associated with both ADHD (P = 5.81 × 10−3) and BMI (P = 1.63 × 10−5); the circadian rhythm was associated with BMI (P = 1.28 × 10−3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD–BMI and ADHD–obesity results. The ADHD–BMI overlapping genes were associated with putamen volume —a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD–obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of  Attention-Deficit/Hyperactivity Disorder (ADHD) is a psychiatric disorder characterized by developmentally inappropriate and impairing levels of inattention and/or hyperactivity and impulsivity. The prevalence of ADHD is estimated as 5.3% during childhood/adolescence  and arou2). A BMI > 25 kg/m2 signals overweight and a BMI > 30 kg/m2 is regarded as obesity, which can be further subdivided into classes defined based on increasing BMI [High comorbidity rates are a hallmark of ADHD, further increasing disease burden. These comorbidities include both psychiatric and non-psychiatric (somatic) diseases and traits . Among tsing BMI . The gensing BMI . Severalsing BMI . A prevising BMI . The autsing BMI .The reported prevalence of ADHD among adults seeking weight loss treatment for obesity is around 27%, reaching up to 43% when considering only those with extreme obesity  , 14. Thirg = 0.21–0.26, [rg = 0.285 to rg = 0.338 for different obesity classes) and other obesity-related phenotypes have been reported [Specific factors underlying the comorbidity between ADHD and obesity remain largely unknown. Recently, significant genetic correlations between ADHD and BMI  andreported . These fIn addition to clinical and genetic overlap between ADHD and obesity measures, volumetric differences in specific brain regions have been associated with ADHD  and/or ohttps://coca-project.eu/), of which this study is a part.Some candidate biological systems have been suggested to underly ADHD comorbidity patterns, including dopaminergic neurotransmission and circadian rhythm systems. These two candidate mechanisms have been selected as the main focus of a large European Union consortium aimed at studying comorbid conditions of ADHD  and disturbances  have been repeatedly associated with ADHD and/or ADHD symptoms . These pIn this paper, we aimed to identify shared etiological factors underlying the observed associations of ADHD with obesity measures and to explore the relationship of overlapping genes with brain volumes. Specifically, we conducted (1) candidate gene-set association analyses and (2) genome-wide gene-based cross-disorder(/trait) meta-analyses, from which the identified overlapping genes were taken forward for (3.1) pathway enrichment analyses and (3.2) testing gene-set association with brain volumes.This study used publicly available summary statistics of GWAS of ADHD, BMI, obesity, and selected brain volumes. These are briefly described below, and further information is provided in The ADHD data was derived from 19,099 cases and 34,194 controls, composed by samples from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) and the Psychiatric Genomics Consortium (PGC) samples of European ancestry [N = 681,275) from the Genetic Investigation of ANthropometric Traits (GIANT) consortium [For BMI, we used summary statistics from the most recent BMI GWAS of European ancestry  [2; controls had a BMI < 25 kg/m2.For obesity, summary statistics from a GWAS from European ancestry cohorts within the GIANT consortium on obesity class I were used (ontrols) . SubjectN range = 10,720–10,928) [N = 8,428) [Summary statistics for selected brain volumes were derived from GWAS by the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium  score regression analysis  to (re-)In order to assess the links of dopaminergic neurotransmission and circadian rhythm pathways with ADHD, BMI, and obesity, we assembled gene sets and tested their associations to the individual phenotypes of interest using the GWAS summary statistics described above. Dopaminergic neurotransmission and circadian rhythm gene sets were assembled based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Gene Ontology (GO) databases. The final dopaminergic (DOPA) and circadian rhythm (CIRCA) gene sets comprised 264 and 284 unique autosomal genes, respectively. Details on the selection of the gene sets are provided in P value) with each phenotype. Next, we tested the association of each gene set, through competitive analyses, by aggregating the gene-based P values according to their presence (or not) in the gene sets . We firP values for ADHD, BMI, and obesity (obtained as described above) and the gene meta-analysis option in the MAGMA software —and thus per gene—within- and between-GWAS summary statistics). Since we were interested in the combined effect of each gene on both phenotypes in each pair-wise meta-analysis, only genes present in both gene-based GWAS results were included. The gene-based P value threshold for genome-wide significance was set to 0.05 divided by the number of genes in each gene-based meta-analysis.In addition to the hypothesis-driven approach described above, we performed genome-wide gene-based cross-disorder(/trait) meta-analyses by using gene-based on 1.05b ). The wePmeta-analysis < PADHD/10 and Pmeta-analysis < P(obesity or BMI)/10) were considered as overlapping genes and taken forward for follow-up analyses. This measure was taken in order to avoid including genes for which the association signal is driven solely by one of the phenotypes being meta-analyzed, especially considering the difference in the GWAS sample sizes.From each pair-wise gene-based cross-disorder(/trait) meta-analysis, the genome-wide significant genes that increased significance by at least one order of magnitude compared to each of the original gene-based results , using its default parameters and Benjamini–Hochberg correction for multiple testing . This is similar to estimates based on smaller BMI data sets as well as to estimates for the obesity classes previously reported [The ADHD–BMI genetic correlation was estimated as reported  and mentP = 5.81 × 10−3) and BMI (P = 1.63 × 10−5); the CIRCA gene set was associated with BMI (P = 1.28 × 10−3). These results were not driven by one or few individual genes that were highly associated with either ADHD or BMI (Supplementary Table We tested the association of two gene sets—DOPA (264 genes) and CIRCA (284 genes)—with ADHD, BMI, and obesity. Results of these gene-set analyses are shown in Table P value) of at least one order of magnitude compared to both individual GWASs. These genes, which were all at least nominally significant in the original GWASs being meta-analyzed, are listed in Supplementary Tables The gene-based cross-disorder(/trait) meta-analysis between ADHD and BMI resulted in 1684 genome-wide significant genes, while the one for ADHD and obesity resulted in 22 significant genes. Of those, 211 genes for the ADHD–BMI meta-analysis and 9 genes for the ADHD–obesity meta-analysis showed an increase in their association significance .The stratified LD score regression showed that the set of 211 ADHD–BMI overlapping genes explain 9.7% and 3.7% of the SNP heritability of ADHD and BMI, respectively, yielding significant heritability enrichment (h2_E) in this set of genes  meta-analysis to address the small sample overlap between the data sets . This association was replicated in the UK Biobank GWAS results (P = 3.9 × 10−2). Associations with other subcortical volumes and intracranial volume were also tested, as exploratory analyses, and were all non-significant , which showed that the dopaminergic neurotransmission system partially explains the genetic overlap between ADHD and BMI. Our data-driven, genome-wide approach subsequently showed that dopaminergic signaling, specifically Both ADHD and obesity measures have been linked to disturbances in dopaminergic signaling. Alterations of the brain’s executive and reward circuits—modulated by mesocortical and mesolimbic dopamine, respectively—have been postulated as the basis of the deficient inhibitory control and impaired reward processing characteristics of ADHD . The abiper1b, a key gene in circadian rhythm regulation, and Per1-knockout mice display hyperactive, impulsivity-like, and attention deficit-like behaviors [Also confirming our hypothesis, the CIRCA gene set was associated with BMI, but the absence of a significant association with ADHD was unexpected. ADHD has previously been associated with altered circadian rhythmicity at molecular, endocrine, and behavior levels . Furtherehaviors . The lacDopamine-DARPP32 Feedback in cAMP Signaling pathway. This postsynaptic pathway centers around the Dopamine- and cAMP-regulated neuronal phosphoprotein ), the phosphorylation state of which modulates dopaminergic neurotransmission  overlapping genes were carried forward into two follow-up approaches: one testing the association of (ADHD–BMI) overlapping genes with specific subcortical brain volumes previously linked to these phenotypes and the other aimed at identifying enriched biological pathways underlying the shared heritability. Both follow-up approaches again pointed to a role of the dopaminergic system. Through the first, we observed a significant association of ADHD–BMI overlapping genes with putamen volume in two independent samples Table . This fihttps://gtexportal.org/home/gene/PPP1R1B). As described above, poor inhibitory control and altered reward processing, in the form of steeper delay discounting, are key neurobiological circuitries implicated in both ADHD and obesity [Dopamine-DARPP32 Feedback in cAMP Signaling pathway was found to be enriched among differentially expressed genes, both the ventral striatum and in frontal cortex [DARPP-32 is primarily expressed in postsynaptic dopaminergic neurons in the dorsal striatum , which is involved in certain executive functions, such as inhibitory control, and in the ventral striatum, which is the main brain region responsible for reward processing  complex Fig. , and CREMC4R) gene [MC4R mutation carriers [Additional evidence for an involvement of DARPP-32 signaling to the ADHD–BMI/obesity overlap comes from the study of rare variants. The most common form of monogenic obesity is caused by mutations in the melanocortin 4 receptor (4R) gene , and MRC4R) gene . In addicarriers . It has carriers , and anicarriers .N = 32,858 cases, N = 65,839 controls; class II N = 9889 cases, N = 62,657 controls; class III N = 2896 cases, N = 47,468 controls; [Our study has strengths and limitations. A clear strength is that we make use of the largest GWAS results available for each of the phenotypes being investigated. The sample sizes used to generate the (European ancestry) summary statistics used here were, in total, >53,000 for the iPSYCH-PGC ADHD GWAS, up to 700,000 for the GIANT-UK Biobank BMI GWAS, and almost 99,000 for the GIANT obesity GWAS. Obesity measures were, therefore, assessed both as a trait and a state. Although we performed the  obesity analysis using GWAS data from the obesity class with the largest sample size , it is Overall, the findings of the present study identify dopaminergic neurotransmission as a key player underlying the shared heritability of ADHD and BMI/obesity, implicating mechanisms involving DARPP-32 signaling in particular and possibly involving neurobiological features related to putamen, such as inhibitory control. This is especially interesting since DARPP-32 has been directly implicated in the mechanism of action of ADHD medication , which hhttp://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. BF discloses having received educational speaking fees from Shire and Medice. AR is part of advisory boards and has received speaker fees from Shire, Medice, Janssen, Servier, and Neuraxpharm, as well as research grants from Medice. GP is director of Drug Target ID (DTID) Ltd. All other authors report no biomedical financial interests or potential conflicts of interest. This publication reflects only the author’s view and the European Commission is not responsible for any use that may be made of the information it contains.This work was supported by the European Community’s Horizon 2020 Programme (H2020/2014 – 2020) under grant agreement nos. 667302 (CoCA), 728018 (Eat2beNICE), and 643051 (MiND). The work was also supported by the ECNP Network “ADHD across the Lifespan.” BF was supported by a personal grant from the Netherlands Organization for Scientific Research (NWO) Innovation Program (Vici grant 016-130-669). BC received funding from the Spanish “Ministerio de Economía y Competitividad” (SAF2015-68341-R) and AGAUR, “Generalitat de Catalunya” (2017-SGR-738) and NF-C was funded by “Centro de Investigación Biomédica en Red de Enfermedades Raras” . AR received support from the DFG (SFB CRC 1193 Z03) and the BMBF (BipoLife). Statistical analyses were carried out on the Genetic Cluster Computer (Supplementary Material


BackgroundAttention-deficit/hyperactivity disorder (ADHD) patients have many comorbidities. Narcoleptic patients have a big prevalence of ADHD (15%-30%). Both groups suffer from similar symptoms and benefit from the same class of medications. As such, narcolepsy could be masked in ADHD patients. Low serum ferritin has been found both in ADHD patients as well as in patients with narcolepsy.Materials & methodsWe enrolled 26 participants (14 ADHD patients and 12 controls). They answered several questionnaires, and blood samples were obtained from 20 participants. We had clear exclusion criteria.ResultsUsing the Ullanlinna Narcolepsy Scale (UNS), we identified three possible narcolepsy patients within the ADHD group and no suspects in the control group. There was a statistically significant negative correlation between serum iron levels and ADHD symptom severity. No correlation was found measuring serum ferritin levels.ConclusionsNarcolepsy may be more common within ADHD patients than in the general population. Some of these patients could benefit from a change in medication. Low serum iron and ferritin levels could be relevant in ADHD pathophysiology. This requires further exploratory research. Epidemiology of attention-deficit/hyperactivity disorder (ADHD)ADHD is a psychiatric disorder characterized by inattention, hyperactivity, and impulsiveness, with an estimated worldwide prevalence of 7.2%, according to a meta-analysis . The diaPathophysiology of ADHDThe pathophysiology of ADHD is not yet fully understood, but it has been proposed that problems could occur because of hypoactive monoaminergic neurons, which project to the prefrontal cortex. This hypothesis has been founded on the phenomenon where the prefrontal cortical functions of ADHD patients are briefly hypoactive . AstrocyComorbidities in ADHDADHD patients are at greater risk for several psychiatric disorders such as depression, bipolar disorder, and anxiety disorders . OverlapPharmacological treatment in ADHDStimulants (methylphenidate and amphetamines) are first-line pharmacological agents and the most commonly used in ADHD. Methylphenidate appears to be the most efficient treatment . AtomoxeNarcolepsyNarcolepsy is a chronic neurological condition. It is characterized by two main symptoms, excessive daytime sleepiness (EDS) and cataplexy. The reported global mean prevalence is approximately 30 per 10,000 . Other sRelationship between ADHD and narcolepsyThree out of 15 ADHD children showed narcolepsy-like symptoms during their sleep . AlthougAimsADHD patients often suffer from daytime sleepiness; in addition, some of them are also using medications as in narcolepsy , and it is possible that at least mild forms of narcolepsy remain masked. Our aim was to clarify the prevalence of narcolepsy symptoms among adult ADHD patients as compared to controls of the same age and gender. This included defining the appearance of daytime sleepiness and cataplectic symptoms. We also wanted to evaluate the association of low serum ferritin and iron levels to ADHD and symptoms of narcolepsy.Subjects and clinical assessmentsFourteen adult ADHD patients  and 12 age-matched (± 10 years) healthy controls (8 women and 4 men) were included. The information was gathered during the timeframe of March 2015 to October 2019. Exclusion criteria for controls included a prior diagnosis of ADHD or narcolepsy. The ADHD patients had either been previously diagnosed by an experienced psychiatrist or were recruited from the Finnish union for ADHD patients. The DSM-5 diagnostic criteria of the American Psychiatric Association for ADHD were used [QuestionnairesWe used a structured questionnaire based on the Basic Nordic Sleep Questionnaire (BNSQ) to chart the participants for narcoleptic symptoms, other sleep disorders, ADHD severity, and general well-being. For the mapping of the narcoleptic symptoms, the Ullanlinna Narcolepsy Scale (UNS) was also used . The queOther assessments2) was computed from weight and height. Serum samples were analyzed in an accredited laboratory of the University of Helsinki.The clinical assessments included taking of the medical history and computing the Body Mass Index . The normality of the distributions was tested by the Shapiro-Wilk test. Parametric or non-parametric tests were used according to the distribution. Means and 95% confidence intervals (CI) were computed. For normally distributed variables Student’s t-test and linear regression were used. Fisher’s exact test was used in cross-tabulations. We used two-sided P-values with a limit of significance of P <0.05. The ethical approval was given by the Helsinki and Uusimaa District Ethical Committee.The age among the participants was normally distributed . The gender (8 women and 6 men among patients vs. 9 women and 3 men among controls) of the participants did not statistically differ (Fisher’s exact = 0.429) and the age did not differ among groups  . A two-sample T-test revealed no difference between the groups . When only counting the points for cataplexy in UNS, we used a cut-off point of ≥ 3 for addressing cataplexy. This point was chosen due to it being the best point for separating between if the symptoms are felt on a weekly-monthly basis or not. Using this, five out of 14 ADHD patients screened positive for cataplectic symptoms, whereas no controls did. This difference was statistically significant (Fisher’s exact P = 0.042). For EDS, five out of 14 screened positive and one out of 12 controls also did. This was not statistically significant (Fisher’s exact = 0.170). Using ESS, a two-sample t-test revealed no difference between the groups .Comparing the groups' ADHD symptoms and well-beingThe prevalence of WURS scores greater than 44 (likely ADHD) was nine out of nine in the ADHD group and three out of 10 in the control group. The lowest WURS score in the ADHD group was higher than the highest score from the controls, indicating a strong difference between groups. Using the ASRS questionnaire as a diagnostic tool, where on getting a score of ≥ 4 in part A, none of the controls had adulthood ADHD, whereas seven out of 10 of the ADHD group qualified. A two-sample t-test, comparing WHO-5 scores among groups, revealed a statistically significant difference in favor of controls . Comparing patients with UNS ≥ 13 with the others for WHO-5 scores revealed no difference between groups .Iron levels and ADHDWe used the whole ASRS questionnaire to get a score for the severity. This was done by adding up all 18 questions. The serum iron and ASRS score negatively correlated , and a linear regression revealed the statistical significance of this negative correlation . This correlation is illustrated in Figure As far as we know, no studies comparing adult ADHD patients with healthy controls, regarding narcoleptic symptoms, has been made before. UNS revealed three possible narcolepsy patients in the ADHD group. And this is, although not statistically relevant, at least clinically relevant. The pharmacological treatment of EDS experienced in narcolepsy resembles the pharmacological treatment in ADHD, but there are differences. One could hypothesize whether these three patients are receiving the wrong treatment. Could the patients possibly be doing better if receiving modafinil instead of methylphenidate, as is the case now? In our study, only two of the possible narcoleptics answered the WHO-5, making a statistical analysis comparing these persons to others unreliable.We strongly believe that a bigger cohort could reveal a statistical difference between the groups. If the prevalence of narcolepsy would be as big as in this study (≈21%), it would mean that the global prevalence of narcoleptic symptoms would be higher than what is assumed at the present. A study revealed a mean UNS score of 22.0 within NT1 patients and 13.7 in NT2 . The UNSADHD patients have more cataplectic symptoms than controls. What we do not know is if the patients affected experience these symptoms as handicapping. One could also speculate whether these patients could benefit from a cataplexy-reducing agent. Considering atomoxetine, which is a second-line agent for ADHD but first-line treatment for cataplexy, the question is: whether these patients would benefit from an atomoxetine medication, possibly allowing them to stop their stimulant medication.We did not find any differences between the groups regarding excessive daytime sleepiness either from the questions regarding EDS in UNS nor from ESS. It has to be kept in mind that all ADHD patients use stimulants on a daily basis, which reduces EDS symptoms. It would be very interesting to see a study comparing adult ADHD patients not receiving stimulants with healthy controls regarding this subject.We found a statistically significant negative correlation between serum iron levels and ADHD symptom severity, as well as a statistically significant difference between the groups regarding serum iron levels. Serum ferritin levels have been believed to estimate the bodies' iron reservoir in a better manner than serum iron, but we found no statistical correlation between serum ferritin levels and ADHD symptom severity. With a bigger sample, we would get more clear estimates on the possible correlations and, therefore, the relevance of these markers.Unfortunately, our study has several weaknesses. The sample size is small. Finding participants was even more difficult than we expected. We are aiming to find more subjects, which is, however, even more difficult during the present time (COVID-19). Due to the present situation, obtaining blood samples and actigraphic measures from all participants was not timely. The samples taken were obtained in 2015-2016. This led to the fact that a part of the participants didn’t have results on some variables. We didn’t measure hypocretin levels in the cerebrospinal fluid (CSF), which is a more specific diagnostic tool for narcolepsy Type 1 than UNS. With hypocretin levels, we could estimate the prevalence more precisely. However, NT2 patients have normal CSF-hypocretin levels. Therefore we cannot exclude the possibility that some of our patients may have had low CSF-hypocretin levels.Our study shows that narcolepsy may be more common in subjects with ADHD than in subjects without ADHD. If this is the case, one could hypothesize that these patients could benefit from a change in medication. Serum ferritin levels are widely used clinically for various purposes. Serum-free iron levels, however, are not as commonly measured or used. Serum iron levels correlated negatively with the ASRS score. More studies are needed in this regard. At the present time, we do not know whether ADHD patients or a sub-group of ADHD patients could benefit from iron supplementation. We also need randomized controlled studies on the use of iron supplementation in patients with narcolepsy.


ObjectiveThe study aims to determine the demographic predictors of attention-deficit/hyperactivity disorder (ADHD) in hospitalized children with autism spectrum disorder (ASD) and the impact of comorbidities on the length of stay (LOS).MethodsA retrospective study was performed using a nationwide inpatient sample from US hospitals. All patients were ≤18 years in age with a primary diagnosis of ASD  and grouped by co-diagnosis of ADHD based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Logistic regression was used to calculate the odds ratio (OR) and linear regression for estimated LOS.ResultsMale patients had a higher odds of comorbid ADHD (OR: 2.2). Age and race were not significant predictors of ADHD though the condition was found to be prevalent in adolescents and Caucasians. These children were mainly from the South (30.8%) and the Midwest (29.9%) regions of the US. Psychosis was seen in 37.3% of patients with ADHD and was more likely to be comorbid psychosis (OR: 1.8). Depression and ADHD increased the LOS in hospitals for ASD by 2.1 days and 0.9 days, respectively.ConclusionOur study led us to determine the demographic predictors of comorbid ADHD in patients with autism, and we believe that our findings can help to better serve these patients and their families. Comorbid ADHD and depression can prolong the length of hospitalization and they necessitate the need for acute inpatient care in such patients. Autism spectrum disorder (ASD) is a lifelong, pediatric neurodevelopmental disorder characterized by marked impairments in socialization, communication, and the presence of restricted, repetitive behaviors or interests . It is eIn children diagnosed with ASD, 59% also suffer from attention-deficit/hyperactivity disorder (ADHD). Even though ASD and ADHD are separate conditions, there is an overlap in their disease presentations . SimilarThis study aims to determine the demographic predictors and the risk of comorbidities of ADHD in patients with ASD in the inpatient population. The demographic matrix plays an important role in behavioral conditions and our results may help the physicians to identify ADHD in autistic children. Further research is required to measure the impact of demographic characteristics and comorbidities on the duration of hospitalization for ASD.Data sourceA retrospective analysis was performed using the Healthcare Cost and Utilization Project's (HCUP) Nationwide Inpatient Sample (NIS) data from January 2012 to January 2014 . The AgeSample selectionBased on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes, we identified the patients (≤18 years) hospitalized with a primary diagnosis of ASD (ICD-9-CM code: 299.00). The primary diagnoses in the NIS refer to the condition for which the patient is mainly managed during the hospitalization stay. The sample population was further divided into two groups (ADHD and non-ADHD) based on ADHD as a secondary diagnosis (ICD-9-CM codes: 314.00 or 314.01).Variables of interestIn order to measure the differences in demographic characteristics, we included age (<11 and 12-18 years), gender , race , median household income (based on quartile classification) and geographic region (based on the American Heart Association (AHA) annual survey of hospitals) . We evalComorbidities are defined as coexisting conditions in hospitalized patients with ASD and are not directly related to the primary diagnosis, and maybe present prior to the inpatient admission. AHRQ comorbidity software was utilized to generate binary variables . Using IStatistical analysisAn exploratory data analysis was performed using cross-tabulation and descriptive statistics over the NIS to summarize the results. Pearson’s chi-square test and independent-sample T-test were utilized for categorical data and continuous data, respectively. Logistic regression was used to calculate the odds ratio (OR) of the demographic variables and comorbidities in the ADHD group, by keeping the non-ADHD group as the reference category. A linear regression model was used to study the impact of various demographic variables and comorbidities on the LOS. We used the discharge weight variable which is given in the NIS database to obtain the nationally-representative inpatient data . All sigEthical approvalTo protect the privacy of the patients, physicians and hospitals were de-identified . Our datDemographic predictors of comorbid ADHDWe analyzed 3,095 hospital admissions for primary diagnoses of ASD and 32.5% of them had a co-diagnosis of ADHD n = 1,005). About three-fifths of the patients with ASD were adolescents (12-18 years), yet age was not a significant predictor for a co-diagnosis of ADHD. About 90% of the children in the ADHD group were males and they had two-fold higher odds of ADHD co-diagnosis . The majority of the ASD patients were Caucasians, and gender was not a significant predictor for ADHD in these inpatients. Children from middle-income families (51st-75th percentile) had higher odds for comorbid ADHD and those from high-income families (>75th percentile) were less likely to have a co-diagnosis of ADHD. About 60% of the patients in the ADHD group were from the Midwest and the South, and they were more likely to have a co-diagnosis of ADHD compared to the children with ASD from the Northeast. The differences in demographic characteristics in ADHD versus non-ADHD groups are shown below , with the majority of the inpatients having moderate loss of function. Children in the ADHD group had a higher mean number of chronic conditions (3.9 ±1.508) compared to the non-ADHD group 2.9 ±1.451). Psychosis was the most common comorbidity seen (29.9%) in the sample inpatient population (37.3% ADHD and 24.9% non-ADHD). Children with comorbid ADHD had a two-fold higher odds of comorbid psychosis compared to patients without ADHD (95% CI: 1.485-2.090). The difference in comorbid drug abuse and depression was not significant between both groups  compared to the non-ADHD group (7.9 days ±11.971). As per the linear regression model adjusted for demographic variables and comorbidities, ADHD increased the LOS by one day and depression increased it by two days. On the contrary, comorbid drug abuse decreased the LOS by six days. Adolescents had longer LOS, while Caucasians and females had shorter LOS comparatively  . And theOur study has a few limitations. The NIS is an administrative database and lacks the patient-level data to make accurate clinical associations. The selection of the patients from the dataset was based on the ICD-9-CM diagnosis codes only and this prevents rater and reporting bias . DespiteIdentification of ASD and ADHD is becoming increasingly important given their growing prevalence among the population. Our study led us to determine the demographic predictors of comorbid ADHD in patients with autism, which we believe can help physicians in the early diagnosis and management. Due to the nature of the disease and comorbidities, there is a critical need to invest further in the versatile and tailored care of the patients.


Large-scale family studies on the co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of clinically ascertained ADHD and BPD diagnoses using the entire Swedish population. In a register-based cohort design we included individuals born in Sweden 1979–2001, and identified their diagnoses during 1997–2013; in total, 2,113,902 individuals were included in the analyses. We obtained clinical diagnoses of ADHD and BPD from inpatient and outpatient care. Individuals with an ADHD diagnosis had an adjusted  odds ratio (aOR) of 19.4  of also having a BPD diagnosis, compared to individuals not diagnosed with ADHD. Having a sibling with ADHD also increased the risk for BPD . Cousins also had an increased risk. The strength of the association between ADHD and BPD was similar in females and males, and full siblings showed similar increased risks regardless of sex. Among both males and females, ADHD and BPD co-occur within individuals and co-aggregate in relatives; the pattern suggests shared genetic factors and no robust evidence for etiologic sex differences was found. Clinicians should be aware of increased risks for BPD in individuals with ADHD and their relatives, and vice versa. Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder , with a The association between ADHD and BPD has been addressed in epidemiological studies, suggesting that the disorders often co-occur in the same individuals , an asso. but little is known about the extent to which the genetic risk factors of ADHD are also shared with BPD. Only one twin study has investigated the genetic and environmental contributions to the association between ADHD- and BPD-traits. It showed that half of the association between ADHD and BPD was explained by genetic factors, while the remaining part of the association was explained by environmental factors unique to the individual [Family and twin studies suggest that susceptibility to ADHD is largely genetic in origin –19. A nudividual . WhetherThe main objective of the current study was to estimate the co-occurrence and familial co-aggregation between clinically diagnosed ADHD and BPD in a total population cohort.We linked Swedish registers through the unique personal identification number given to each Swedish citizen. The Medical Birth Register  providedThe study was approved by the Regional Ethical Review Board in Stockholm (Dnr 2013/862–31/5); since it was a registry study no individual was contacted, and informed consent was waived. The validation sub-study was approved by the Swedish Central Ethics Board (Dnr Ö 27-2012).We linked the data to the Swedish National Patient Register  (NPR) anWe identified individuals with ADHD from the NPR  and/or from the PDR via prescriptions of ADHD medications . Details supporting the validity of this definition are available in previous publications, including the validity of using ADHD medications as proxy for ADHD diagnosis , 33.We identified individuals with BPD from the NPR  . As the Sex, birth year, and birth order are collectively referred to as the covariates below—included since they are potential confounders, associated with both ADHD and BPD. Birth year was included as a covariate to adjust for the secular changes affecting diagnostic practices through the follow-up period; for instance, incidence of ADHD diagnoses has seen a sharp increase. Birth order was included because the position among siblings may affect the likelihood of getting diagnoses.We estimated associations using logistic regression, thus viewing ADHD and BPD as binary variables. The choice of logistic regression, even though age at diagnosis is accessible to us, reflects that we do not believe the date of diagnosis accurately captures the date of disease onset. Additionally this means that analyses of temporal order of diagnoses could be misleading. To estimate appropriate associations we instead rely on a carefully selected cohort with reasonable follow-up, adjustment for birth year, and sensitivity analyses.We analyzed the within-individual association between ADHD (exposure) and BPD (outcome) to obtain crude and covariate-adjusted odds ratios (OR and aOR). Note though that the choice of which of diagnoses to view as exposure and outcome is arbitrary in the current design. We calculated proportions of BPD among those with and without ADHD in the total cohort and separately by sex (crudely and standardized over covariates) , and theWe estimated the risk of BPD (outcome) in individuals according to their relatives’ ADHD (exposure): crude and adjusted for covariates, including covariates for the relative. Similarly as in the within-individual analyses the choice of exposure and outcome is arbitrary. Comparing estimates across relatives informs about the role of genetic and/or environmental risk factors shared by the disorders. If the association between monozygotic twins is weaker than the within-individual association, then factors not shared by family members are likely to influence the co-occurrence. If the association between full siblings is weaker than between monozygotic twins, and the association between maternal half-siblings is weaker than between full siblings, genetic factors are likely to influence the association. Maternal half-siblings have similar intra-uterine environment, and usually grow up in similar environments since children predominantly stay with the mother following parental separation , 39. HenFurther, we calculated ORs in the full sibling subsample stratified by sex combinations, and calculated proportions with BPD diagnosis. We calculated similar proportions using ADHD as outcome and BPD as exposure.All analyses were performed in R, adjusting the precision of estimates for dependencies within family clusters using cluster-robust sandwich estimators, employing the packages drgee  and stdRThe main cohort covered many birth years to provide reasonable power for both the within individual and the relative analyses, which introduced a potential risk of bias due to both left truncation  and right censoring . To investigate if results were influenced by this we identified a sub-cohort where BPD was defined as present if an individual was eligible to get a diagnosis through high-risk age period from age 18 until at least age 23, taking migration and deaths into account, and was diagnosed with BPD at any time (including before age 18 and after age 23). If the individual did not have an uninterrupted period with possibility to get a diagnosis between ages 18 and 23—due to end of follow-up, not being alive, or not living in Sweden—we defined BPD as missing; else we defined it as “no BPD”. We defined ADHD correspondingly, with safeguarded observation from age 7 until age 12. Using these definitions, we investigated the robustness of associations.Between full siblings, we adjusted analyses for ADHD occurrence in the outcome individual, yielding estimates not interpretable as familial risks since the adjustment introduces bias. However, this analysis helps determine whether a shared familial cause  for an association likely exists, regardless of if one disease causes the other directly. If the association remains despite such adjustment, this supports the notion of a liability for both disorders shared by relatives  individuals were diagnosed with ADHD, while 9544 (0.5%) were diagnosed with BPD Table . Males wp = 0.041), suggesting that at least part of the association between BPD and ADHD is explained by genetic factors. The aORs were lower in both maternal  and paternal half-siblings  compared to full siblings (both p < 0.001), again supporting genetic contributions to the association. Further, maternal and paternal half-sibling estimates did not differ significantly from each other (p = 0.671), indicating that shared environmental effects have little or no impact on the association. Cousins whose parents were full siblings had an increased risk of having a diagnosis of BPD, aOR, 1.5 (95% CI = 1.4–1.6), while cousins whose parents were half-siblings had even lower aOR.Having a relative with an ADHD diagnosis increased the odds of a BPD diagnosis Table . The aORp = 0.087 in females and p = 0.683 in males; Table If etiological sex differences were present  the increased risk for BPD would be expected to differ depending on sex. That is, a same-sex sibling with ADHD should increase the risk for BPD more compared to having an opposite-sex sibling with ADHD. Further, it has been suggested that females’ ADHD diagnoses possibly represent a stronger genetic load compared to males . If thisAnalyses safeguarding follow-up during high-risk periods in ADHD and BPD revealed similar patterns of proportions of diagnoses, although with slightly higher percentages, 5.1% for ADHD and 0.7% for BPD . Altogether, findings support that familial factors are partly responsible for the observed co-aggregation within relatives, and not an artifact of one disorder causing the other within individuals.This is the largest study of ADHD and BPD co-occurrence, in a total population of over 2.1 million individuals, and the only one exploring familial co-aggregation of clinically diagnosed ADHD and BPD. We found that individuals with a diagnosis of ADHD had a 19.4 times higher odds of BPD diagnosis than individuals not diagnosed with ADHD. Furthering a previous twin study on the relation between ADHD- and BPD-like traits , the patEmotional dysregulation has since long been hypothesized to underlie BPD, but also suggested to be an important aspect of ADHD –45. ThisAlthough genetic factors were implied, the estimated associations between siblings compared to within individuals indicated that not all of the association was explained by these factors. Similarly to a previous study , our resWe found that BPD was more common among females, while ADHD was more so among males. In contrast, the data supported no, or only minor, differences in etiological factors responsible for the observed associations between ADHD and BPD in males and females. This may suggest that differences in the co-occurrence rates between males and females are probably explained by other factors, such as detection bias or diagnostic traditions—supported by lack evidence of sex differences in prevalence when assessed by face-to-face interviews of adults in the US .Limitations of this study include under-detection; the observed diagnoses are likely underestimations of the true proportion of individuals with symptom levels and impairments corresponding to diagnoses if assessed by healthcare professionals. Some individuals may have a diagnosis registered in sources not accessible by us, e.g. outpatient care prior to 2001, or just do not seek help. Under-detection would be likely to bias estimates towards null. Since ADHD and BPD are likely to suffer from different detection biases—including different likelihood of detection depending on during which ages the individuals were followed up in available registries—we performed sensitivity analyses in a subsample with better coverage in high-risk periods for both diagnoses; no major differences in results appeared  and acceptable precision (PPV = 81%). A further strength is the use of population registers, where data are gathered prospectively and primarily for administrative purposes, and, importantly, totally independently from the current study.ADHD and BPD co-occur in individuals, and co-aggregate in relatives—reflecting both shared genetic risk factors and individually unique risk factors. Although ADHD is more common in males and BPD in females, the strength of the individual and familial associations between the disorders is similar across sexes, indicating that etiologic sex differences are unlikely. Clinicians need to be aware of increased risk for BPD in individuals with a diagnosis of ADHD, as well as in their relatives, and vice versa.The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Supplemental online material


The phenomenon of population ageing observed over recent years involves growing healthcare needs and the limited staffing and financing of healthcare systems, and as such demands some functional changes in the healthcare model in many countries. This situation is particularly significant in the face of a pandemic, e.g., flu, and currently COVID-19.As well as social education, preventive vaccinations are the most effective method of fighting the infectious diseases posing a special threat to seniors. Despite this, the vaccination coverage level in most European countries is relatively low. This is largely due to patients having limited access to vaccinations. In some countries, implementing vaccinations in pharmacies and by authorized pharmacists has significantly improved vaccination coverage rates and herd immunity, while lowering the cost of treating infections and the resulting complications, as well as minimizing the phenomenon of inappropriate antibiotic therapies. This article presents the role of pharmacists in the prevention of infectious diseases, pointing out the measurable effects of engaging pharmacists in conducting preventive vaccinations, as well as analyzing the models of implementing and conducting vaccinations in pharmacies in selected countries, and depicting recommendations regarding vaccinations developed by international organizations. The presented data is used to suggest requirements for the implementation of preventive vaccinations in community pharmacies. The outbreak of the COVID-19 pandemic in 2020 has been a challenge for healthcare systems all over the world ,4, and aMeeting the challenges posed on healthcare systems, largely associated nowadays with the necessity of effective fighting infectious diseases, requires the engagement of many groups of medical staff. Here, the role of pharmacists should be emphasized. Despite being an essential element of the public healthcare system, their participation in efforts to prevent diseases, lengthen life, and promote health is relatively low. Apart from providing basic and advanced pharmaceutical services consisting in ensuring and optimizing pharmacotherapy, in the current situation, extended services focused on prevention, e.g., preventive vaccinations, such as flu vaccinations, are also essential . In some European countries, preventive vaccinations are administered by pharmacists or another medical staff in community pharmacies , with thThe objective of this article is to aggregate existing knowledge in the effectiveness of engaging pharmacists to conduct preventive vaccinations, and to prove the role of pharmacists and pharmaceutical care in infectious disease prevention. Scientific literature review was carried out to summarize key aspects related to the vaccination provided by pharmacies and the role of the pharmacists in that process. Following searching strategy was applied: articles were extracted from PubMed using the terms “vaccine”, “vaccination” “vaccination coverage” “infectious diseases, “ and “vaccination implementation” in combination with “community pharmacy” and “community pharmacist”.This article depicts the guidelines of international organizations and experiences connected with implementing models of flu vaccinations in pharmacies all over the world. Presentation of the current practices and outcomes of extending pharmaceutical services in these countries can foster discussion on the model of pharmacist involvement in conducting preventive vaccinations, especially against flu. Pharmaceutical service can be defined as the activities of pharmacists in the healthcare system to obtain a measurable benefit. Apart from providing access to high-quality medicinal products and the subsequent rational management, pharmaceutical services also include preventive medicine . The proInfectious diseases among seniors are often severe and more likely to involve complications . PreventDespite the fact that a vaccination against COVID-19 has not been available so far, intense research is being conducted to develop one. The launch of a vaccine against COVID-19 will require the considerable involvement of medical staff to achieve a high vaccination coverage level . A greatFlu places a substantial burden not only on healthcare systems, but also on the entire economy ,22. Due In December 2009, the Council of the European Union recommended attaining a flu vaccination coverage of 75% among seniors, and, if possible, to extend that to other risk groups . The fluUsing all contact with patients by medical professions to actively promote vaccinations can greatly increase vaccination coverage. For this to work in principal, it is crucial to provide a broad access to vaccinations for all patients, and the vaccinations should be widely offered and administered in healthcare facilities, including community pharmacies. Although pharmacists constitute a small percentage of healthcare workers, patient access to pharmacies and their services, with no necessity to make appointments, longer opening hours and the convenient locations of pharmacies, enable reaching a wider group of patients, largely eliminating the coverage barriers to vaccinations . The engA systematic review of studies on the effectiveness of vaccinations administered by pharmacists indicates that the vaccination coverage rates in these models are higher than in traditional systems of vaccinations . NeverthA similar situation was observed in Norway. Before implementing vaccinations in pharmacies, the flu vaccination coverage rate in Norway among people aged ≥65 years was relatively low (26.9% in the 2016/2017 flu season) . A gradun = 30) [There are a lot of models of implementing vaccinations in European pharmacies. In 2019, flu vaccinations were offered in pharmacies in 40% of European countries, and in 17%, other vaccinations were also available (n = 30) . Currentn = 30) ,29. Due Selected models of implementing vaccinations in pharmacies, with the most advanced vaccination pattern in community pharmacies, where the health care model is similar to Poland’s health care system. Portugal implemented the possibility of vaccination in the 2008/2009 flu season, being one of the first European countries in this respect. This was preceded by an information campaign. In the first flu season, 36.4% of all vaccinations were administered in Portuguese pharmacies. In the 2011/2012 flu season, nearly half of the vaccinations were conducted in pharmacies, although in the following years, due to changes in flu vaccination reimbursements that guaranteed people over 65 years of age free vaccinations in public healthcare facilities, the total number of vaccinations administered in pharmacies dropped by 25% in the 2014/2015 flu season .The Portuguese Pharmaceutical Association developed guidelines on the implementation of services connected with administering vaccinations and medications in the form of injections in pharmacies, including minimum requirements for the provision of services and describing the process of basic and additional training sessions for pharmacists . Having In Great Britain, flu vaccinations could be administered by pharmacists in pharmacies from 2002, but only on a private basis. The problem of vaccination coverage led to engaging local pharmacies in 2005, where people over 65 years of age and younger people with risk factors are vaccinated. Implementing vaccinations in pharmacies was considered the main factor of the significant increase in the vaccination coverage level in 2008 . From 20In 2017, a pilot project to increase the vaccination coverage rate was launched in France. It included nearly 3 thousand pharmacies located in four regions of France. A requirement for participation in the programme was the completion of special training sessions by pharmacists organized by the French Pharmaceutical Society (the project included over 5000 pharmacists). During the six months of the pilot project (September 2017–March 2018), 159,139 people were vaccinated against flu , which rCurrently, French pharmacists are authorized to administer flu vaccinations, and the law determines the staff qualifications and technical requirements for pharmacies. Pharmacists can administer flu vaccinations to adults, excluding patients with a history of allergic reactions. Patients can buy vaccinations in the pharmacy or receive it if they are entitled to free of charge vaccinations, and decide where the vaccination should be conducted. Vaccinations in Norwegian pharmacies became an element of the national vaccination programme in 2018, preceded by a pilot project with 23 facilities . Since tConducting flu vaccinations in community pharmacies is recommended by numerous international organizations. The report “Global Influenza Strategy 2019–2030” prepared by the World Health Organization, encourages developing and implementing individual policies and programs optimized with respect to the national needs and to integrate them with the existing systems . In this context, the European Observatory on Health Systems and Policies points out that limiting the possibility of administering flu vaccinations to just doctors is a great barrier in the execution of national vaccination programs. The availability of flu vaccinations in pharmacies is indicated as one of the effective initiatives in increasing flu vaccination rates . In responding to the threat connected with infectious diseases and fears regarding vaccinations in April 2018, the Pharmaceutical Group of the European Union (PGEU) published a document presenting best practices within services provided by pharmacists throughout Europe. Vaccinations administered by pharmacists and another medical staff working in pharmacies included vaccinations against pneumococcus, herpes zoster, HPV, influenza, and vaccinations recommended for travelers .The National Institute for Health and Care Excellence (NICE)  recommenThe guidelines for Good Pharmaceutical Practice by the International Pharmaceutical Federation (FIP and WHO) emphasize that good pharmaceutical practice (GPP) should entail education on vaccinations, encouraging patients to vaccinate, and administering vaccinations . Centers for Disease Control and Prevention (CDC) highlight the key role of pharmacists in protecting patients against seasonal influenza and the resulting complications. The American Pharmacists Association (APhA) recommends that protective vaccinations be an all-year-round action. They developed detailed recommendations on implementing vaccinations in pharmacies , pointinThe American Society of Health-System Pharmacists (ASHP) recommends that pharmacists should fulfil a leading role in immunization screening . In the The implementation of vaccinations in community pharmacies requires some legal and organizational changes, as well as determining the way of financing vaccinations. To complete these tasks, the cooperation between government representatives, pharmacists, other medical professionals and patients is necessary, and the effectiveness of this cooperation will influence the success of the implementation of the developed model and outcomes.→ training and granting authorization to pharmacists and changes in the pharmacy curriculum,→ qualifying patients to vaccinations administered by pharmacists,→ enabling pharmacists to conduct vaccinations,→ dispensing vaccinations without submitting prescriptions (which can have a significant effect on the availability of vaccinations),→ functioning of pharmacies as medical facilities,→ logistic and organizational requirements for pharmacies ,→ keeping records of vaccinations,→ ensuring patient rights,→ responsibility of pharmacies and pharmacists for the consequences of vaccinations,→ informing about the possibility to conduct vaccinations in pharmacies,→ financing vaccinations .Conducting preventive vaccinations by pharmacists needs to be preceded by appropriate legislative changes, the scope of which will depend on the existing legal solutions in a given country. Legislative works should concern the following issues:Conducting vaccinations by pharmacists should be preceded by a system of appropriate training sessions and confirmation of acquired qualifications. Additionally, extending the framework pharmacy curriculum by classes in conducting preventive vaccinations should be considered. Similarly to other countries , they woBefore conducting vaccinations, pharmacies should meet specific sanitary, organizational, logistic, and staff requirements. Rooms should ensure patient privacy when providing the service. They should include a chair for a patient , a fridge for the vaccines, working space for preparing vaccinations, containers for ordinary and medical waste, hand sanitizer products, compresses, and dressings . PharmacAdditionally, the work in pharmacies should be organized in such a way that the staff authorized to administer vaccinations are present for most of the time of the pharmacy hours. Studies show that convenient access to vaccinations is the main reason behind increased vaccination coverage rates ,25,45,46One condition for effective realization of vaccinations in pharmacies is appropriate remuneration to pharmacists for each vaccination, which should encourage them to provide this kind of service and to further develop pharmaceutical care. In Europe there are various mechanisms of payments for conducting vaccinations. For example, in Great Britain there is a complete reimbursement of the costs of vaccinations within the framework of the National Flu Immunization Programme, while in Portugal, the costs of vaccinations are borne by patients. For this reason, the implementation of vaccinations in community pharmacies requires an assessment of the possibility of financing vaccinations by public payers, which would be entail the necessity to conclude contracts between pharmacies and payers. In this context, all immunization cost elements, including cost of the vaccine, cold chain assurance, or service costs, should be considered.Preventive actions are the most effective way of fighting infectious diseases. Efficient preventive actions, including preventive vaccinations, require involvement and cooperation between numerous groups of medical workers, namely pharmacists, doctors and nurses. The issue regarding patient access to vaccinations is not without significance. → To increase the state of readiness for action in the face of the pandemic, → To lower the costs of treatment of infectious diseases and the subsequent complications,→ To limit unjustified use of antibiotics .In several European countries it is possible to conduct preventive vaccinations such as flu vaccinations in community pharmacies. In many of these countries, pharmacists are authorized to administer vaccinations. Numerous reports indicate that the use of the models engaging pharmacists in preventive actions has resulted in increased vaccination coverage rates and herd immunity, and thus has a significant benefit on public health. Additional objectives achieved by healthcare systems thanks to the possibility to conduct vaccinations in pharmacies are:Development of a model of conducting vaccinations in pharmacies by pharmacists requires appropriate legal and organizational frameworks, as well as determining the method of financing these services. The development of pharmacist competencies and effective cooperation between the various stakeholders of healthcare are also of key significance here. At this point, the barriers that may arise from patients should also be emphasized. Anti-vaccination movements can be of particular importance. Patients’ concerns about vaccination, such as pain or fear of side effects, may also be significant. The role of the pharmacist in addressing patients’ concerns can be crucial. Pharmacists, being more accessible healthcare professionals who can devote much more time to the patient at a more convenient time, can significantly reduce patients’ fears and provide broad health education. However, this area requires further research.