Attention Deficit Hyperactivity Disorder (ADHD) is raising concerns across health systems, affecting about 5% of the school-age population. Therapy usually involves psychostimulants, which are prone to adverse drug reactions (ADRs). Teachers have many contact hours with children and can easily detect behavioral changes upon the beginning of medication. However, few studies have focused on the role of teachers in the management of ADHD children and detection of ADRs. The present work aimed to characterize the perception of primary school teachers regarding the impact of ADHD therapeutics. A questionnaire was constructed focused on teachers’ training regarding ADHD and its therapy; experience with students with ADHD; changes upon beginning of medication; and observation of ADRs. A total of 107 completed questionnaires were obtained. The results indicate that more than 40% of the inquired teachers have received training in ADHD, but in most cases, the theme of therapeutics was absent from that training. The vast majority of teachers (91.6%) have had students with ADHD and observed mood alterations associated with medications. More than 60% of the teachers answered that they are aware of the ADRs and of these, 24% have already detected them in their students. The teachers reported the observed ADRs to parents in 93% of the cases and to doctors in 28% of the cases. In conclusion, the results show the need to reinforce teachers’ training in ADHD and its therapeutics. Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopment disorder characterized by symptoms of hyperactivity, impulsivity, and inattention in excess for a person’s certain age or development stage ,2. AlthoThe increasing diagnosis of ADHD in the last decades is concerning parents and teachers across countries ,6. This Recent guidelines in managing ADHD point to a comprehensive treatment plan encompassing both pharmacological and non-pharmacological approaches . The mosDue to the early onset of the disease, its symptoms are often first detected by school teachers . ChildrePharmacovigilance reporting systems are a precious asset in every health system. They provide the most data on ADRs. Nevertheless, their limitations are known, with under-reporting being one of the most common . LegislaTherefore, our aim was to explore primary school teachers’ perceptions about ADHD therapy efficacy and safety, as well as to understand their knowledge of the Portuguese pharmacovigilance system.In order to accomplish the aim of this study, a survey had to be developed. We started with a literature review on the subject, performed in Pubmed and Google Scholar databases. Several papers of interest were found, focusing on drug therapy, ADHD diagnostic tools, ADRs rating scales, and teachers or parents’ role in the detection of ADRs ,12,13,23Although many papers were found about the role of teachers in dealing with children with ADHD, none reported the use of an instrument to ADRs detection that could be applied to our population. As such, we decided to develop a set of questions inspired by the literature review that would allow the exploration of teachers’ perceptions on the subject. The survey consisted of 12 questions, including socio-demographic variables, open and closed questions about teachers’ perceptions of ADHD and its therapy, including perceived impact on children’s behavior; teachers’ education and training relative to ADHD therapy; number and type of ADRs identified and to whom they were reported.® Forms platform.The survey was then piloted in its paper version on a group of 12 teachers, representative of the study’s population. The possibility to convert this version to an online version was also assessed during this stage, to allow for maximum dissemination. After assessing the feasibility of this survey, an online version was designed, using GoogleThe defined study population were all 1st–4th grade public school teachers (1st cycle or primary school) in the greater Lisbon area. Schools in Portugal are grouped according to a set of rules established by the Education Ministry, supported by demographic and geographic criteria . 229 gro®  and SPSS® v.22 . Chi-square tests were used to assess association between categorical variables. The significance level was set to 5%.Descriptive statistics and all statistical analyses were performed using Microsoft ExcelThe online survey yielded 107 responses, of which, 89.7% were women. The mean age of the sample was 47 years, with 68.2% being born before 1975. A minimum of 2 and a maximum of 44 years of teaching experience were reported, with an average of 21.6 years of teaching experience. 22% of teachers had less than 10 years of teaching experience, and 29.2% had more than 25 years of experience.p = 0.184)  .n = 99) answered that they already had students with ADHD, with 76 teachers declaring that they had students who were medicated after being in their class. 91.9% of teachers reported that the medication produced changes in behavior, most notably less agitated (87.6%), less impulsive (83.7%), and more attentive (76.2%) students. Regarding medication adverse reactions, 63.6% of teachers reported to be aware of ADRs but only 26% said that they found at least one ADR in their students. Twenty-seven teachers observed 42 possible ADRs, an average of 1.6 ADRs per teacher. Amongst these ADRs, apathy was the mostly cited (48.1% of teachers), followed by loss of appetite (25.9%), and stomach and abdominal problems . Several ADRs were cited only once, such as “weight gain”, “indifference”, “low self-esteem”, “anxiety, sadness and depression”, “absences”, and “prostration”. More experienced professionals had a tendency to detect more ADRs   .p = 0.704)  .n = 18) stated that they are unaware of the NPS or of the process of reporting ADRs; while 20% said that they consider that ADRs reporting is not a teacher’s responsibility.All the teachers that found ADRs in their students reported it to the parents. Only 29.2% reported it also to the child’s physician and none reported it to the National Pharmacovigilance System (NPS). When asked why they did not report, 72% , 80% of primary school teachers are women, which is a similar proportion to that of our respondents. In addition, the average age of 47 years old indicates that our respondents may be representative of a typical first cycle teacher population in Lisbon region . The resOur results suggest that most teachers in greater Lisbon have had contact with at least one student with ADHD. In fact, it appears that almost all teachers have had contact with students with this condition and that approximately 50% consider that they show essentially beneficial changes with the medication. Most feel that students have become more attentive, less agitated, less distracted, less impulsive, and more emotionally stable. Since these are the symptoms associated with the disease that often lead to taking medications, it seems teachers’ perceptions are that the medications are efficient for the purposes for which they were developed. However, teachers tend to over-estimate the number of children with ADHD in their classes, and this estimate is amplified by classes’ size . Our surAlthough some teachers referred that they had training about ADHD, the large majority felt the need to have more training about this subject, preferably including medication-related themes. This may be the reason behind the non-apparent effect of training in ADRs detection: it seems that current training programs do not highlight the subject of ADRs and do not emphasize its importance to a well-managed ADHD patient. However, years of experience seem to be associated with a higher detection of ADRs, confirming the importance of experience and confidence in identifying and managing children with ADHD . This hiIn this study, “apathy” was the adverse reaction most often perceived by teachers. Since “apathy” is not one of the most frequent ADRs in these medications, this fact seems to highlight that this symptom is the trigger for teachers to refer a child as having ADHD. However, “apathy” may be what in other studies was identified as “staring”. This “staring” side-effect has frequently been reported in some studies ,25. ConfWhen devising a training strategy for ADHD and ADRs detection by teachers, it is important to account for the different therapeutic groups that may be prescribed by child psychiatrists when dealing with an ADHD child. The myriad of possible combinations will make it a challenge. However, the ADRs reported in this study are similar to teacher and parent reporting of ADRs found in the literature , suggestTeachers’ role in detection and notifying ADRs is intimately related to their relation with parents. In our study, every teacher that found ADRs reported it to the parents. It is understandable that teachers would avoid reporting and ADRs directly to some surveillance system without prior notification of a parent or health professional. As such, and as our results suggest, the focus of training in ADRs detection for teachers should also include communication skills to contact with health professionals after parental consent. An information system that provides the foundation for this communication should be developed. Nevertheless, and assuming that all the reports would be done with prior parent consent, more research is needed on the ethical implications and practicality of having teachers reporting ADRs directly to a health professional or a pharmacovigilance system. Our results show that the National Pharmacovigilance System (NPS) is not sufficiently disseminated amongst the society. The Portuguese NPS allows notifications both from health professionals and from the general population. However, the majority of our respondents reported to be unaware of the existence of the NPS or of the process of ADRs notification. In fact, the surveyed teachers had never reported ADRs detected in their students to the NPS. As for the reason why this report was not made to the NPS, 72% responded that they do not know of its existence or do not know the process by which the report is made. Thus, the need for disseminating information about the NPS and how it works is evident, since teachers are aware of possible adverse reactions that may arise from taking medication and have even detected them, but they only reported them to the parents or the student’s physician, being a passive actor in the spontaneous reporting system. The communication of the reactions observed by teachers to the NPS would also contribute to maintain medication safety and public health.It seems clear that teachers can notice when a change in behavior occurs, but without proper training and knowledge, they will not know which medicine is causing the ADRs in question. We suggest that community pharmacists could play an active role in this context. Community pharmacists have developed a wide range of services and are the most accessible and available health professional ,29. BesiAlso of importance is the role of new technologies to increase learning capabilities that may assist teachers in dealing with students with ADHD . In thisDue to the timing and way the online survey was disseminated and being aware of the low number of respondents in a universe of possible thousands of answers, one must be careful in interpreting and extrapolating these results. Nevertheless, as they match the socio-demographics of Lisbon teachers’ population, the results here presented may represent a large majority of teachers perceptions on ADHD and ADRs detection.Our results support the perception that more experienced teachers can better detect and manage children with ADHD. The identification and characterization of the ADRs related to medications for ADHD need to be improved. Thus, teachers need more training to deal with children bearing ADHD, starting at the early stages of their careers and supported by peers. This training should include more topics on drug therapy and associated side-effects. Teachers’ knowledge of a pharmacovigilance system is non-existent, reinforcing the need to present the system to teachers and parents alike. Here, we consider that community pharmacists, as the dispenser of the drug therapy and most accessible health professional, may be well positioned to assume the role of trainer and ADRs reporter in the team dealing with an ADHD child.


S-transferase (GST) pulldown, and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) and was then confirmed by traditional co-IPs and a novel far-red mNeptune-based bimolecular fluorescence complementation system. VP56 binds to the helicase domain of RIG-I. VP56 enhances K48-linked ubiquitination of RIG-I to degrade it by the proteasomal pathway. Thus, VP56 impedes the initial immune function of RIG-I by dual mechanisms (blockade and degradation) and attenuates signaling from RIG-I recognizing viral RNA, subsequently weakening downstream signaling transduction and interferon (IFN) responses. Accordingly, host antiviral effectors are reduced, and cytopathic effects are increased. These findings were corroborated by RNA sequencing (RNA-seq) and VP56 knockdown. Finally, we found that VP56 and the major outer capsid protein VP4 bind together in the cytosol to enhance the degradation of RIG-I and more efficiently facilitate viral replication. Collectively, the results indicated that VP56 allies VP4, recruits, blocks, and degrades RIG-I, thereby attenuating IFNs and antiviral effectors to facilitate viral evasion more effectively. This study reveals a virus attacking target and an escaping strategy from host antiviral immunity for GCRV and will help understand mechanisms of infection of reoviruses.Grass carp reovirus (GCRV), the most virulent aquareovirus, causes epidemic hemorrhagic disease and tremendous economic loss in freshwater aquaculture industry. VP56, a putative fibrin inlaying the outer surface of GCRV-II and GCRV-III, is involved in cell attachment. In the present study, we found that VP56 localizes at the early endosome, lysosome, and endoplasmic reticulum, recruits the cytoplasmic viral RNA sensor retinoic acid-inducible gene I (RIG-I) and binds to it. The interaction between VP56 and RIG-I was detected by endogenous coimmunoprecipitation (co-IP), glutathione IMPORTANCE Grass carp reovirus (GCRV) fibrin VP56 and major outer capsid protein VP4 inlay and locate on the outer surface of GCRV-II and GCRV-III, which causes tremendous loss in grass carp and black carp industries. Fibrin is involved in cell attachment and plays an important role in reovirus infection. The present study identified the interaction proteins of VP56 and found that VP56 and VP4 bind to the different domains of the viral RNA sensor retinoic acid-inducible gene I (RIG-I) in grass carp to block RIG-I sensing of viral RNA and induce RIG-I degradation by the proteasomal pathway to attenuate signaling transduction, thereby suppressing interferons (IFNs) and antiviral effectors, facilitating viral replication. VP56 and VP4 bind together in the cytosol to more efficiently facilitate viral evasion. This study reveals a virus attacking a target and an escaping strategy from host antiviral immunity for GCRV and will be helpful in understanding the mechanisms of infection of reoviruses. Ctenopharyngodon idella) and black carp (Mylopharyngodon piceus). It is a pathogenic agent with high virulence, leading to severe epidemic hemorrhagic disease outbreaks annually and tremendous mortality (up to 90%)  seriously threatens production of grass carp  to 90%) . GCRV beus genus . The GCRus genus , 4, encaus genus . Accordius genus . Type IIus genus . Segmentus genus . Fiber p0% . GCRVus genus . The fibus genus .Following pathogen invasion, innate immunity senses microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) to initiate immune responses. Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are a crucial family of cytoplasmic PRRs sensing viral RNA . The RLR20–23–After millions of years of coevolution, along with genome mutations, gene recombination, and rearrangements, viruses have evolved mechanisms to escape host immune responses . For RNAS-transferase (GST) pulldown, and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) were performed (Escherichia coli BL21(DE3) pLysS cells and purified by affinity chromatography (C. idella kidney (CIK) cells were infected with GCRV, and a co-IP was performed with VP56 polyclonal Ab, GST Ab, and negative serum, respectively, followed by LC-MS/MS , glutathione erformed . Recombitography . The polLC-MS/MS , left. FLC-MS/MS , right. To understand the molecular action of fibrin VP56 during GCRV infection, subcellular localization of VP56 was detected by confocal microscopy . Fathead minnow (FHM) cells were cotransfected with VP56-green fluorescent protein (GFP) fusion vector and relevant organelle protein markers followed by 4′,6-diamidino-2-phenylindole (DAPI) staining for the cell nucleus. As shown in Fig. S1, appearances of yellow signals indicating overlapping of green and red were observed in cells cotransfected with VP56 and RAB5, LAMP2, and GRP78, which are the marker proteins of early the endosome, lysosome, and endoplasmic reticulum (ER), respectively. These results demonstrated that VP56 localizes at the early endosome , lysosome , and ER  but not the late endosome . Colocalizations of VP56 with cytoplasmic organelles imply the possible distribution of VP56 after virus uncoating in the cytoplasm.The direct interaction between VP56 and RIG-I was further confirmed by traditional co-IPs  and far-Ubiquitination modifications of RIG-I play a pivotal role in the activation and attenuation of innate antiviral immunity. The effects of VP56 on expression and ubiquitination of RIG-I protein were investigated . ProteinRIG-I is a crucial PRR in the antiviral signaling pathway, sensing viral dsRNA in the cytoplasm. VP56 binding and degrading of RIG-I is supposed to be beneficial for GCRV evasion and replication. At the promoter level, VP56 suppresses the promoter activities of the key molecules in the RLR signaling pathway, including RIG-I, IPS-1, STING, TBK1, and IRF3 by dual-luciferase assays . At the Mx2] and GCRV-induced gene 1 [gig1]), viral genes , viral titers (50% tissue culture infective dose [TCID50]), and cell death caused by VP56   was performed with VP56/empty vector stable expression in CIK cells . KEGG fuVP56 knockdown potentiates IFN responses and reduces GCRV replication and titer . The CIKIFN1 and Mx2 were inhibited strongly  but not the late endosome, which is the same location as VP56 . VP4 alsThe present work reveals that GCRV fibrin VP56 acts as a forceful weapon for GCRV infection to inhibit IFN responses and boost viral evasion . GCRV inC. idella kidney) and FHM (fathead minnow) cells were respectively cultured in Dulbecco’s modified Eagle’s medium (DMEM) and M199 supplemented with 10% fetal bovine serum (FBS) (Gibco), 100 U/ml penicillin (Sigma), and 100 μg/ml of streptomycin (Sigma). Cells were incubated at 28°C with 5% CO2 humidified atmosphere. Stably expressed CIK cell lines were screened with G418.CIK  of 1 as previously described .50). Cells were incubated at 28°C for 7 days. On day 7, the plates were examined for the presence of viral cytopathic effect under the microscope.Samples were infected with the GCRV-097 strain (MOI = 1) for 24 h. The supernatants were serially diluted 10-fold and incubated with CIK cells in a flat 96-well plate to determine the 50% tissue culture infective dose  was prepared and conserved by our lab. Anti-IRF3 rabbit polyclonal antiserum was previously prepared and presented by Yibing Zhang, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China . These AThe plasmids pGEX-4T-1 and pCMV-GFP were used for construction of expression vectors with specific primers . VP56/VP56-Flag was ligated into pGEX-4T-1 and pCMV-GFP, respectively, to construct expression vectors. Expression plasmids RIG-I-HA, RIG-I-Flag, RIG-I-CARD-HA, RIG-I-helicase-HA, and RIG-I-RD-HA were saved in our lab . For duaE. coli BL21(DE3) pLysS cells for prokaryotic expression. The fusion protein was induced by isopropyl-β-d-1-thiogalactopyranoside (IPTG) and purified by GST-bind resin (Genscript) chromatography.Full-length GCRV-097 VP56 was amplified with corresponding primers (Table S2) and cloned into pGEX-4T-1 vector. The plasmid pGEX-4T1-VP56 was transformed into Co-IP assays and GST pulldown were performed to explore CIK cell proteins interacting with VP56. For co-IP, CIK cells were infected with GCRV for 24 h, and co-IP was performed with GST Ab, GST-VP56 Ab, or negative serum (NS) using a coimmunoprecipitation kit (Pierce). The eluant was analyzed by SDS-PAGE and subsequent silver staining.For GST pulldown, CIK cell proteins were extracted with a membrane and cytosol protein extraction kit (Beyotime). Two hundred microliters of GST-VP56 and 200 μl of CIK protein solutions  were incubated at 4°C for 30 min, and then GST-bind resin (20 μl) was added. After 6 h of incubation at 4°C, the resin was washed with TBS thoroughly and eluted with elution buffer  and then analyzed using SDS-PAGE and subsequent silver staining.http://www.uniprot.org/), Grass Carp Genome Database (GCGD) (http://bioinfo.ihb.ac.cn/gcgd/php/index.php), and a grass carp transcriptome database in the NCBI SRA browser (BioProject accession number SRP049081)  by Shanghai Applied Protein Technology Co. Ltd. LC-MS/MS spectra were searched using the MASCOT engine (Matrix Science) against the actinopterygii UniProt sequence database (P049081) .For Western blotting, protein extracts were separated by 8–12% SDS-PAGE gels and transferred onto nitrocellulose membranes (Millipore). The membranes were blocked in fresh 2% bovine serum albumin (BSA) dissolved in Tris-buffered saline with Tween 20 (TBST) buffer at 4°C overnight and incubated with appropriate indicated primary Abs for 2 h at room temperature. They were then washed three times with TBST buffer and incubated with secondary Ab for 1 h at room temperature. After washing four times with TBST buffer, the nitrocellulose membranes were scanned and imaged by an Odyssey CLx imaging system (LI-COR) or an ImageQuant (GE). The results were performed in triplicate.2 dishes were cotransfected with the indicated plasmids for 48 h. The cells were lysed in IP lysis buffer  (Beyotime) added with 1 mM phenylmethylsulfonyl fluoride (PMSF) for 30 min on ice, and the cellular debris was removed by centrifugation at 12,000 × g for 30 min at 4°C. The supernatant was transferred to a fresh tube and incubated with 1 μg of Ab with gentle shaking overnight at 4°C. Protein A+G Sepharose beads (Beyotime) (30 ml) were added to the mixture and incubated for 2 h at 4°C. After centrifugation at 3,000 × g for 5 min, the beads were collected and washed four times with lysis buffer. Subsequently, the beads were suspended in 20 ml of 2× SDS loading buffer and denatured at 95°C for 10 min followed by Western blotting.For co-IP, CIK cells in 10-cmFor ubiquitination detection, FHM cells were seeded in dishes and transfected with corresponding plasmids. At 48 h posttransfection, the cells were treated with MG132 (Selleck) for another 6 h. The cells were then harvested for IP with Flag Ab and immunoblotted with HA and Flag Ab, respectively. The experiments were repeated at least three times. The histogram exhibits the relative protein expression levels, which were quantified using ImageJ software.A far-red mNeptune-based bimolecular fluorescence complementation (BiFC) system is used to determine whether two proteins are interactive based on reconstitution of two nonfluorescent fragments of a fluorescent protein . In the CIK cells were seeded in 24-well plates for 24 h. Cotransfection was performed with corresponding expression plasmid, target promoter luciferase plasmid, and internal control reporter vector (pRL-TK). At 24 h posttransfection, cells were infected with GCRV or uninfected for 24 h. The cells were washed with phosphate-buffered saline (PBS) and lysed with passive lysis buffer (Promega) for 30 min. Luciferase activities were detected by a dual-luciferase reporter assay system (Promega). The luciferase reading was normalized against those in the pRL-TK levels, and the relative light unit intensity was presented as the ratio of luciferase of firefly to renilla.SRP212372, sample SAMN12168356/SAMN12168358) (Transcriptome data of empty vector stably transfected or VP56 stably transfected CIK cells were derived from previous studies performed by our lab and deposited in transcriptome databases (NCBI SRA number 2168358) . TranscrFor crystal violet staining, CIK cells were seeded into 24-well plates overnight and transiently transfected with empty vector or VP56. At 24 h posttransfection, cells were infected with GCRV or uninfected. At 24 h postinfection, cells were washed and fixed with 4% paraformaldehyde for 15 min at room temperature and stained with 0.05% (wt/vol) crystal violet  for 30 min then washed with water and drained. Finally, the plates were photographed under a light box (Bio-Rad).CUCCACAACUUUAGAUGAATT, si-VP56-2 [sense 5′ to 3′], CCUAUAGCCGUCGCUAAAUTT, and si-VP56-3 [sense 5′ to 3′], GGAGGAAGCAUUUGUAGGUTT) targeting different regions of VP56 were synthesized by GenePharma . CIK cells were transfected with siRNA using GP-siRNA-Mate Plus  for 24 h. Silencing efficiencies of the candidate siRNAs were evaluated by qRT-PCR, and results were compared with those in the negative-control siRNA (si-NC) provided by the supplier. A preliminary experiment indicated that si-VP56-1 possessed the best silencing efficiency at a final concentration of 100 nM at the mRNA level. For Western blotting, CIK cells stably expressing VP56 were plated in 6-well plates and transfected with si-VP56-1 using GP-siRNA-Mate Plus  for 24 h and infected with GCRV for another 24 h. The cells were lysed, and proteins were extracted for Western blotting.CIK cells stably expressing VP56 were used for VP56 knockdown assays. Transient knockdown of VP56 was achieved by transfection of siRNA targeting VP56 mRNA. Three siRNA sequences .The data were analyzed as previously described . Briefly


Bartonella are facultative intracellular alphaproteobacteria with zoonotic potential. Bartonella infections in humans range from mild with unspecific symptoms to life threatening, and can be transmitted via arthropod vectors or through direct contact with infected hosts, although the latter mode of transmission is rare. Among the small mammals that harbour Bartonella spp., rodents are the most speciose group and harbour the highest diversity of these parasites. Human–rodent interactions are not unlikely as many rodent species live in proximity to humans. However, a surprisingly low number of clinical cases of bartonellosis related to rodent-associated Bartonella spp. have thus far been recorded in humans.Species of the genus Bartonella species, some of which have been newly described in recent years. Thus, another focus of this review are these recently proposed species.The main purpose of this review is to determine explanatory factors for this unexpected finding, by taking a closer look at published clinical cases of bartonellosis connected with rodent-associated Bartonella in small mammal species are (i) a lack of awareness amongst physicians of Bartonella infections in humans in general, and especially those caused by rodent-associated bartonellae; and (ii) a frequent lack of the sophisticated equipment required for the confirmation of Bartonella infections in laboratories that undertake routine diagnostic testing. As regards recently described Bartonella spp., there are presently 14 rodent-associated Candidatus taxa. In contrast to species which have been taxonomically classified, there is no official process for the review of proposed Candidatus species and their names before they are published. This had led to the use of malformed names that are not based on the International Code of Nomenclature of Prokaryotes. Researchers are thus encouraged to propose Candidatus names to the International Committee on Systematics of Prokaryotes for approval before publishing them, and only to propose new species of Bartonella when the relevant datasets allow them to be clearly differentiated from known species and subspecies.Worldwide, only 24 cases of bartonellosis caused by rodent-associated bartonellae have been reported in humans. Possible reasons for this low number of cases in comparison to the high prevalences of The online version contains supplementary material available at 10.1186/s13071-022-05162-5. Bartonella  comprises facultative intracellular alphaproteobacteria. An increasing number of Bartonella species are recognized as zoonotic pathogens ; or [name of any continent in the world]. Furthermore, a separate search was conducted with the search term [name of any small mammal genus] in combination with one of the following terms: [Bartonella]; [Bartonellae]; [Bartonellosis]. Only studies published in the English language and in peer-reviewed journals were taken into consideration. In total, 132 studies were included in the analysis, representing research on Bartonella in a total of 231 small mammal species and subspecies (excluding bats). Research on Bartonella in small mammals has been conducted in 67 of the 195 countries (34.4%) of the world. Most of these studies were conducted in North America [in both Canada and the USA (100%)], followed by Europe [25 out of 44 countries (54.6%)] and Asia [19 out of 48 countries (39.6%)]. The continents/regions for which the lowest numbers of studies were reported are as follows: Africa [15 out of 54 countries (27.8%)], Oceania [two out of 14 countries (14.3%)], and Latin America and the Carribean [four out of 33 countries (12.1%)] . The studies undertaken in the USA were conducted thoroughly and, in total, reported 25 small mammal species positive for Bartonella , followed by R. rattus (41 studies), Mus musculus (25 studies) and Clethrionomys glareolus (24 studies). The five Bartonella species most frequently detected in small mammal hosts were Bartonella grahamii , Bartonella elizabethae , Bartonella tribocorum , Bartonella taylorii , and Bartonella queenslandensis . Small mammals positive for Bartonella were found in 65 (97.0%) of 67 investigated countries (they were not found in Hungary and Pakistan). The five most frequently listed Bartonella species in Additional file B. elizabethae is one of the first rodent-associated species to have been described (in 1993) whereas other rodent-associated species such as B. kosoyi were not described until much later (in 2018). Furthermore, it should be noted that various methods were used in the studies, and that not all the published sequences had a homology of 100%.The most frequently studied genus was  rattus 4 studies,Bartonella species pathogenic for humans include the human-specific species Bartonella bacilliformis (transmitted via sand flies), which causes Carrion’s disease in South America; the zoonotic, cat-transmitted species B. henselae, which is responsible for cat scratch disease; and the human-specific species Bartonella quintana (transmitted via body lice), the causative agent of trench fever ’ where the species was one of the 33 Bartonella species given in Table B. alsatica’) and (‘infection’)] revealed only 14 publications citing evidence for human infections  were reported , only eight The analysis of the frequencies of clinical entities showed that 12 patients suffered from acute febrile illness (most likely associated with bacteremia/blood stream infections) (50%), three patients from endocarditis or prosthetic valvular graft infections (12.5%), three patients from lymphadenopathy (12.5%), two from nonspecific symptoms (8.3%), and one each from bacillary angiomatosis, hepatic lesions or neuroretinitis (4.2%). Two of these patients were immunocompromised ; no clear association with an underlying comorbidity was reported for the remaining patients. The reported antibiotic therapy regime varied but often included the administration of a macrolide combined with doxycycline for some weeks, which often resulted in clinical improvement.Bartonella spp. are rare. To our knowledge, there are several possible reasons for this low number of case reports: (i) physicians are very likely unaware of Bartonella infections , and thus do not include them in their differential diagnosis; (ii) laboratories may not able to detect these pathogens due to their fastidious nature, and because their diagnostic portfolio does not include PCR tests for the detection of Bartonella spp. or they do not carry out long, sterile microaerophilic incubations for the cultivation of samples from patients. Moreover, (iii) bartonellosis might only cause mild and unspecific symptoms; and (iv) rodent-associated Bartonella infections of humans may simply be rare medical entities. A possible molecular explanation for the latter is the host restriction of Bartonella species mediated by their respective Trw type IV secretion systems (T4SSs) [Bartonella with mutations in the trwE gene (signature-tagged mutagenesis) are unable to establish long-lasting bacteremia in certain rodent infection models. It has been demonstrated that the Trw systems of certain Bartonella spp. are responsible for species-specific host-restricted adhesion to erythrocytes. For instance, the Trw T4SS of B. tribocorum mediates a significant bacterial infection in Wistar rats, but infection human erythrocytes is 23 times less efficient. It seems likely that infections of humans by rodent-adapted Bartonella spp. rarely occur because the rodent-pathogen Trw system and human erythrocyte host receptors simply do not match.From a clinical point of view, ‘acute febrile illness’ and ‘endocarditis’ can be classified as ‘bacteremia/blood stream infections’, which 15 of 24 reported patients (62.5%) suffered from. Although these cases were anecdotal, it can be suggested that human infections by rodent-associated  (T4SSs) . The TrwBartonella species are pathogenic for humans. However, B. henselae, B. bacilliformis and B. quintana cause most cases of Bartonella disease in humans [Bartonella spp. [B. henselae, B. quintana, and/or B. vinsonii berkhoffii. Bartonella spp. were even isolated from 7.9% of the positive individuals, although all of them were asymptomatic [Bartonella henselae is also reported to have possibly contributed to the death of two veterinarians [B. henselae is associated with scratches received from both cats and dogs [B. henselae compared to those with a cat > 12 months old [Bartonella spp. [Many n humans , 11. Vetlla spp. –14. Oteolla spp.  found thptomatic . Bartoneinarians . Cat andand dogs . Owners nths old . Forest nths old , 20. Furnths old , 22. Tholla spp. .Bartonella infections in humans are similar to those mentioned above for Bartonella transmitted via other animals (Table Bartonella infection.The risk factors for rodent-associated ls Table . Most ofB. henselae (and Bartonella clarridgeiae and Bartonella kohlerae) and dogs of Bartonella rochalimae. Thus far, there have only been occasional reports of clinical symptoms in cats and dogs related to Bartonella spp. infection, and even fewer related to rodent-associated bartonellae. Whether bartonellae are primary or opportunistic pathogens for cats and dogs is not entirely clear. Clinical manifestations of bartonellosis are rarely seen in domestic cats, and to the best of our knowledge, there have been no case reports of rodent-associated bartonellosis in them. However, there is one report of a cat which was thought to have transmitted rodent-associated B. grahamii to a human via a scratch [B. elizabethae, B. grahamii, B. taylori and a Bartonella volans-like strain have been detected in dogs [B. elizabethae infections could be linked directly to a canine clinical case. An 8-year-old dog suffering from unspecific symptoms including lethargy, appetite and weight loss was diagnosed with B. elizabethae infection in the blood stream. The dog died immediately before the diagnosis was confirmed, and no other pathogen was detected in the blood [B. volans after its death [Bartonella grahamii, B. elizabethae, B. taylorii were found to have a moderate prevalence (9.4%) in stray dogs without a clinical record in Thailand, highlighting the potential reservoir competence of dogs for rodent-associated bartonellae [Cats are known hosts of  scratch . Unlike  scratch . Thus fa in dogs –29. Howehe blood . Furthertonellae .Bartonella. There are presently 84 known species and subspecies of Bartonella, of which 38 were initially found in specimens belonging to the order Rodentia, followed by 10 species each in specimens of the orders Carnivora and Artiodactyla, and seven in humans. The number of newly described species has been increasing in the past decade [Bartonella species have been proposed and/or published since 2011 (Table Bartonella species (n = 30) were reported in wild small mammal or specifically rodent species such as Acomys russatus (golden spiny mouse), Mastomys erythroleucus (Guinea multimammate mouse), and Pachyuromys duprasi (fat-tailed gerbil) . Authors are welcome to submit the proposed names to the Judicial Commission on Prokaryote Nomenclature of the International Committee on Systematics of Prokaryotes (ICSP), but they are not obliged to do so. The committee reviews Candidatus species through an extensive literature review, as many Candidatus names have not been qualitatively validated or do not follow the rules of the International Code of Nomenclature of Prokaryotes [Candidatus names in use for newly described Bartonella species are malformed. However, suggested corrections for these malformed names are regularly published [Candidatus taxa being proposed, particularly those with rodents and other small mammals as their origin and likely reservoir hosts, the lists of corrected names are not exhaustive and constantly evolving [There is an increasing number of newly discovered, not yet fully characterized, he 1990s  and allokaryotes , which eublished . Neverthevolving , 32.Candidatus species and their published names. A mandatory submission process for the validation of species names prior to the publication of newly proposed Candidatus species would help to avoid the time-consuming renaming process carried out by the ICSP, and would further help to avoid the circulation in the literature of malformed Candidatus names. For example, the ICSP proposes that ‘Bartonella bandicootii’ should be re-named ‘Bartonella paramelis’  is both malformed and in violation of recommendation 6 (3) of the ICNP. The genus name of the host animal, which is Parameles, should be used as the basis for the specific epithet of the Bartonella species rather than the English common name, bandicoot, which is why the current name of this species should be Bartonella paramelis [Thus, the above should be borne in mind with respect to newly described s’ Table . ‘Bandicaramelis .Bartonella species without Candidatus status have not been validly published according to the ICNP. In total, there are 44 Bartonella species names currently in use that have not been validly published. Of these species, 40 have been described since 2007, and 17 are from rodents or other small mammals  cannot be completely ruled out [Clethrionomys glareolus could not experimentally prove transplacental or transovarial transmission of B. taylorii and B. grahamii to the offspring. There is one report of possible vertical transmission of B. birtlesii in BALB/c mice [Bartonella spp. However, a few flea species are known to be more host opportunistic [Yersinia pestis, the causative agent of the plague, is known to be transmitted from rats to humans mainly through Xenopsylla cheopis, the oriental rat flea [Xenopsylla cheopis is also known to harbour DNA of zoonotic Bartonella spp. such as B. elizabethae, and it was experimentally shown that X. cheopis can excrete this species over time [Rodent-associated uled out , 37. Sevuled out . HoweverB/c mice . Most rotunistic . Yersinirat flea , which cver time , 44. NonB. henselae to humans through their scratches [B. grahamii, which is a rodent-associated pathogen, to its owner [Another possible means of infection is direct contact with a reservoir host. Cats may transmit cratches . There its owner . The expts owner . Howeverts owner .Bartonella is not fully understood. Studying the transmission of Bartonella spp. from rodents to humans would help in assessing the potential risk of the former for the latter.Notwithstanding the cases described above, rodent-associated bartonellae are the principal cause of bartonellosis in humans. However, how and to what extent rodents and their ectoparasites are involved in the zoonotic transmission cycle of Bartonella infections in humans arise from direct contact with small mammals or rather indirectly via infestation with a rodent-associated ectoparasite vector. The total number of confirmed human cases of bartonellosis worldwide caused by rodent-associated bartonellae is much lower than expected when taking into account the abundance of Bartonella spp. in rodents, and possible reasons for this have been discussed in this review. Many small mammal species are considered reservoir hosts for the increasing number of newly described Bartonella spp., although some of the latter have yet to be experimentally confirmed. Even though most Bartonella spp. show high adaptation to their hosts, this is not the case for all rodent-associated species. That is why further experimental research is needed to increase our understanding of host–pathogen interactions between rodents and Bartonella species.The zoonotic transmission cycle of rodent-associated bartonellae is not fully understood. It is especially unknown whether Additional file 1: Table S1. Worldwide prevalence levels of Bartonella spp. in small mammal species including the detection method.


Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a childhood prevalence of 5%. In about two-thirds of the cases, ADHD symptoms persist into adulthood and often cause significant functional impairment. Based on the results of family and twin studies, the estimated heritability of ADHD approximates 80%, suggests a significant genetic component in the etiological background of the disorder; however, the potential genetic effects on disease risk, symptom severity, and persistence are unclear. This article provides a brief review of the genome-wide and candidate gene association studies with a focus on the clinical aspects, summarizing findings of ADHD disease risk, ADHD core symptoms as dimensional traits, and other traits frequently associated with ADHD, which may contribute to the susceptibility to other comorbid psychiatric disorders. Furthermore, neuropsychological impairment and measures from neuroimaging and electrophysiological paradigms, emerging as potential biomarkers, also provide a prominent target for molecular genetic studies, since they lie in the pathway from genes to behavior; therefore, they can contribute to the understanding of the underlying neurobiological mechanisms and the interindividual heterogeneity of clinical symptoms. Beyond the aforementioned aspects, throughout the review, we also give a brief summary of the genetic results, including polygenic risk scores that can potentially predict individual response to different treatment options and may offer a possibility for personalized treatment for the therapy of ADHD in the future. Due to its high heritability and neurodevelopmental nature, Attention-Deficit Hyperactivity Disorder (ADHD) is a condition receiving significant interest in psychiatric genetics. The childhood prevalence is 5–7% , and in The heritability of ADHD is high compared to most psychiatric disorders and compares to the heritability rates found in autism spectrum disorder (ASD), bipolar disorder, and schizophrenia . HoweverOne explanation is that the overall effect of the SNPs that impact ADHD is relatively small. Moreover, the allele frequency of rare variants is below the detection threshold, because linkage disequilibrium (LD) is low; therefore, the GWAS do not have enough statistical power to detect them . Even inDRD4) and maternal smoking (DAT1) and maternal alcohol consumption during pregnancy (5HTT) and adverse psychosocial events  , whereasSeveral genetic findings, such as the genetic correlation for both common and rare variants, significantly overlap with ASD , or the DRD4 gene related to ADHD may be the result of positive selection since it is associated with both ADHD and the personality trait of novelty seeking ; however, after correcting for the general psychopathology factor, only the association with neurodevelopmental disorders remained moderately strong , which is largely influenced by genetic factors. The association with externalizing disorders was lower , which is largely influenced by environmental effects, and there was no significant association with internalizing disorders. Overall, current studies suggest that although the genetic overlap between ADHD and other psychiatric disorders is significant, it could likely be explained by general psychopathology factors, and the role of unique genetic effects may be plausible mostly between ADHD and other neurodevelopmental disorders.The correlation between ADHD and internalizing, externalizing, and neurodevelopmental diseases has been targeted in several studies . In a laThe diagnosis of ADHD is hindered by the heterogeneity of the disease, variability of symptom presentation over time, and subjectivity of symptom severity, as potential confounding factors; therefore, interest in predictive biomarkers that could aid the diagnosis, prognosis, and assessment of the response to pharmacological interventions has increased substantially . EndopheDAT1 and DRD4 in terms of various endophenotypes  codes for the solute carrier protein responsible for the reuptake of dopamine from the synaptic cleft. Gene expression is most pronounced in the striatum. The most intensively studied variant of DAT1 is variable tandem repeats (VNTRs) of 40 base pairs located at the 3’untranslated region (3′UTR) of which 10-repeat (10R) and 9-repeat (9R) alleles occur most frequently. An additional VNTR polymorphism located in intron 8 containing 5R and 6R alleles, which has also been associated with increased susceptibility to ADHD, is also being studied as a haplotype. Interestingly, based on the previous studies, whereas the 10R/10R genotype and 10/6 haplotypes are likely to be risk factors in children , a brain region of major importance for attentional and inhibitory processes. The most commonly studied polymorphism of the DRD4 gene is the 48-bp VNTR in exon3, the 7R allele of which is linked to an increased risk of ADHD in the Caucasian population , and noradrenaline transporter (SLC6A2) genes, and MPH responsiveness (ADGRL3 = LPHN3) carrying the G allele has also been correlated with MPH treatment response , tryptophan hydroxylase (TPH2), dopamine β-hydroxylase (DBH), 5HTT, and synaptosomal-associated protein 25 (SNAP25) genes, only with DAT1 (DAT1, no association was detected between the 40-bp VNTR and the MPH response (SNARE complex polymorphism and MPH responsiveness in an adult sample (Although only a small proportion of the vulnerability to ADHD is linked to a single gene, given the monoaminergic attack points of drugs, pharmacogenetic studies initially focused on the potential associations of candidate ADHD genes and drug efficacy. Most data are available for methylphenidate and atomoxetine. Results from a meta-analysis of childhood and adolescent ADHD indicated significant associations between several common variants, namely siveness . In addiresponse . In adulresponse , 2013 foith DAT1 . In contresponse . An addit sample .DBH and SLC6A2 in a Chinese sample, and later in a broader sample (In the case of atomoxetine, significant correlation was found between the response status in childhood ADHD and r sample . Furtherr sample .A summary of pharmacogenetic studies  assessinIn terms of pharmacogenetic studies, genome-wide association studies, which are not hypothesis-driven, do not overlap with the results of candidate gene studies. In a GWAS study with the highest sample size and statistical power available to date , no assoCompared with the extensive description of the psychiatric comorbidities, the somatic comorbidities of ADHD have received much less attention in the research literature despite the fact that ADHD has been associated with a broad range of medical health problems, such as obesity , asthma Finally, it is important to emphasize that the drugs currently used in ADHD are not curative and thus only allow symptomatic treatment of the disorder. A clearer understanding of the molecular biological background underlying ADHD would be essential for finding causal therapy, to this end, animal models and pluripotent stem cell studies could provide a promising perspective .In our brief review, without claiming to be exhaustive, we intended to give an overview of the genetic results relevant to the clinical practice of ADHD and the emerging issues. The clinical need to be addressed by genetic studies can be summarized as the prediction of disease heritability, the identification of diagnostic aids, and the assessment of responsiveness to medication, thus taking into account individual characteristics in the hope of establishing an individualized treatment approach . Table 3The applicability of the current genetic results to the clinical practice is still limited; nevertheless, the focus and the methodology of the studies increasingly accommodate clinical needs. It is also important to highlight that genetic testing seems to be a promising approach for predicting response to treatment and drug tolerability; however, the study results available are still limited. In addition, a more comprehensive determination of the clinical phenotype entailing not only the core symptoms of ADHD but also the related traits and the associated somatic symptoms would prove beneficial for the routine clinical practice. In conclusion, the findings are encouraging for the long-term development of the clinical practice, which is exactly what we need to strive for.LB drafted the first version of the manuscript. JR and AP participated in writing and critical revision of the manuscript. All authors approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The main objective of this study was to analyze the time trend in the incidence of ADHD diagnoses in Navarre (Spain) from 2003 to 2019 in children and adolescents from 5 to 19 years old. Additionally, the seasonal trends of ADHD incidence and ADHD prevalence were determined. (2) Methods: A population-based observational retrospective study, which included people born between 1991 and 2011 and who attended compulsory education between 2007 and 2017 in Navarre (Spain), was carried out with data from both the Education and Health Department databases. (3) Results: The incidence rate increased from 4.18 cases per 1000 person-years in 2003 to 7.43 cases per 1000 person-years in 2009, before decreasing progressively to 2.1 cases per 1000 person-years in 2019. A peak incidence rate at 7–8 years of age was observed, which is consistent across the study period and for both genders. Males were more than twice as likely to be diagnosed with ADHD than females, with similar time trends in both. A seasonal pattern in ADHD diagnosis was found, with peaks in February–March and the lowest rates in the summer months. Inattentive cases were much more frequent than hyperactive cases, whereas combined cases remained low across the study period. (4) Conclusions: In this age-period-cohort analysis, a clear period and age effect was observed. We found a decreasing trend in the ADHD incidence rate since 2015. Further research is needed to confirm whether a change of trend is occurring globally. Attention deficit hyperactivity disorder (ADHD) constitutes one of the leading mental health and behavioral disorders in childhood and adolescence. The American Psychiatric Association’s Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines ADHD in children younger than age 17 years as the presence of six or more symptoms in either the inattentive or hyperactive and impulsive domains, or both .ADHD shows a marked heterogeneity at clinical, aetiological, and pathophysiological levels . The likGender differences in ADHD diagnosis have also been documented, with girls being less likely to be diagnosed . In chilAn association between the month of birth and the likelihood of being diagnosed with ADHD has also been identified ,6,13. HoSeveral studies and systematic reviews have been conducted to estimate the prevalence of ADHD, reporting highly variable rates, which may be attributable to differences in the population studied, the diagnostic criteria used, sources of information, and the methodology, among other factors . SystemaDifferences in the ADHD prevalence have also been identified in the different geographic regions . The ADHMost of the studies analyzing the ADHD incidence in the long term reported an increasing trend in the incidence rate over the course of the years studied ,23,24,25ADHD medication use also experienced an increasing tendency over the years, with rates varying in the different countries. A population-based study including 13 countries worldwide found that the prevalence of ADHD medication use in children aged 3–18 years ranged between 0.3% and 6.7% in 2010, with an increasing tendency over time both in children and adults. North America had the highest prevalence of ADHD medication . A seasoKnowledge about the trends in ADHD diagnoses is essential to organize health resources with a forward-looking approach. To our knowledge, few studies have been carried out with the aim to analyze the time trend incidence of ADHD in Spain, and none of those studies included an extended period of time. Additionally, the potential impact of seasonality in ADHD diagnosis has not been evaluated to date. Therefore, the main objective of this study was to analyze the time trend in the incidence of ADHD diagnoses from 2003 to 2019 according to calendar year, patients’ age at the time of ADHD diagnosis, and gender. The secondary objectives were to analyze: (1) the incidence of ADHD diagnoses according to the ADHD presentation; (2) the monthly variation of the ADHD incidence , also according to the clinical setting where the ADHD diagnosis was registered; and (3) the time trend of the prevalence of the ADHD diagnosis, also differentiating by the patients’ age and gender.An observational retrospective study was carried out with data from the database of the Education Department in Navarre (EDUCA) and the Navarre Health Service population database (BARDENA). Both databases were linked, matching and anonymizing the subjects. Inconsistencies were solved by creating decision algorithms and using automatic probabilistic methods.The study included people who were born between 1991 and 2011, were entitled to public health services, and who also attended at least one annual course of compulsory education between 2007 and 2017 in public schools or centers subsidized by the Government of Navarre (in this period there was only one non-subsidized private center in Navarre). Students who held health insurance different from that provided by the National Health System  were excluded from the study.The follow-up of children started at the age of 5 years. Follow-up ended in the event of death or the end of compulsory education or health data availability (whichever occurred later), and ended, in any case, at the age of 20 years or on 20 November 2019 (end of the study period).ADHD diagnoses from both Primary Care [through the International Classification of Primary Care-2 (ICPC-2)] and Specialized Care [through the 10th Revision of the International Classification of Diseases (ICD-10)] were considered . Two revRegistered variables included the patients’ age, gender, nationality, ADHD diagnosis, date of diagnosis, the clinical setting in which the ADHD was diagnosed , and the ADHD presentation profile .Median and interquartile range (IQR) were calculated for continuous variables, and proportion and confidence interval for dichotomous variables.The ADHD incidence rate was calculated as the ratio of incident cases per 1000 person-years of exposure. The ADHD incidence was described according to the patients’ age at the time of the ADHD diagnosis, their gender, and the calendar year in biennial groups. Results were also provided according to the ADHD profile. Age-period-cohort (APC) regression models were performed to investigate how ADHD incidence was affected by age at the time of ADHD diagnosis, period of ADHD diagnosis and cohort of birth .Additive time series decomposition and Poisson regression models were developed to describe the evolution of ADHD incidence according to gender, age, calendar month and year-period of ADHD diagnosis.Decomposition of the monthly time series of the standardized ADHD incidence rate was represented according to the calendar year, showing separately the observed cases, trend, seasonality and the random error. Results were also shown according to the clinical setting of the ADHD diagnosis. The seasonality of the incidence of ADHD in women and men was analyzed using box diagrams showing the incidence of new diagnoses throughout the different months of the year.The prevalence of ADHD diagnosis was provided for four different time points across the study period: 2007, 2011, 2015 and 2019. Results were also shown according to the patients’ age and gender. As for the analyses of the prevalence, the patients’ follow-up and, where possible, the closing/ending of the ADHD diagnoses were considered.All the analyses were made using R software  ,31,32.The study protocol was approved by the Ethics Committee of the Government of Navarre, Spain, in 2016 (project 2016/73).During the study period, 124,582 individuals were part of the cohort , of which 51.2% were males. The majority were Spanish (82.8%), followed by Latin Americans (7.6%). The median follow-up was 11 years (IQR: 7–15). A total of 7391 ADHD cases were detected .The ADHD cases, person-years and incident rate in biennial groups are shown in The age-period-cohort model is shown in The incidence rate of ADHD diagnosis by calendar year and ADHD profile is shown in The incidence of new diagnoses throughout the different months in males and females are shown in Data according to the clinical setting of the ADHD diagnosis are shown in Data for the prevalence of ADHD diagnoses are shown in This observational study with a 16-year follow-up showed remarkable findings on the incidence of ADHD in children and adolescents in a Spanish region, regarding temporal changes and the effect of age, gender, or the setting of diagnosis. We observed a clear period, gender and age effect. ADHD incidence increased by 77% from 2003 to 2009. After a plateau period, it started decreasing in 2015, reaching rates in 2019 even lower than those at the beginning of the study. So far, most epidemiological studies on ADHD incidence have shown a continuously increasing temporal trend, which is not in line with the decreasing trend observed in Navarre over the last few years ,23,24,25The shifts in temporal trends of ADHD incidence observed in our study may be in part related to several contextual factors. The approval of ADHD medication could indirectly have had an impact on the increase in the new ADHD diagnoses observed in the first period. Moreover, the increasing awareness among the parents, teachers and healthcare professionals about ADHD occurrence at early years may explain this tendency. However, the efforts made in recent years for the early detection of signs of inattention and hyperactivity in children could have facilitated the adoption of early measures both in the childrens’ home and school environments, avoiding the need for intervention by health professionals and thus contributing to a deceleration of identification of new confirmed ADHD cases.The ADHD prevalence increased over the years from 0.15% to 8.74% according to age and calendar year. The age with the highest prevalence also increased as the study period progressed; this was due to the decrease in incidence rate in recent years.A systematic review including studies published between 1980 and 2011 showed an ADHD pooled-prevalence of 6.8% in children and adolescents under 18 years from Spain . DiffereThe age effect, with a peak incidence rate at 7–8 years and progressively decreasing afterwards, is consistent across the study period. Previous studies in different locations found a similar distribution, with ADHD diagnosis most commonly observed during primary school years  ,24,34. IA clear gender effect was also found, with a generally higher ADHD incidence and prevalence in males. These findings are consistent with results from previous studies that have typically found ADHD to be 2–4 times more common in males than in females ,23,26,34A well-defined seasonal pattern was observed in the diagnosis of ADHD, with peaks of incidence in February and March and lower values in July–September, coinciding with the summer school holidays. Although many published studies have shown a seasonal pattern on the ADHD medication use (use being lower during the summer months) ,29, we hAs for the gender factor, trends are very similar throughout the periods, months of the year and age at diagnosis, but always with higher rates in males. Some studies have found the same pattern ,24, althSince 2005, inattentive cases have been much more frequent than hyperactive cases, and their incidence rate continued increasing until 2012. Combined cases remained low across the study period. This relevant finding seems to confirm that current ADHD diagnoses differ to a high extent from the original hyperactive disorder as defined in the late 1960s by the DSM-II, showing a closer connection to academic performance at present.Information bias in our sources may exist due to a possible absence of ADHD diagnosis records when those records have been made in private health centers. This motivated the exclusion of the people whose diagnosis, treatment and/or monitoring were carried out in private health centers. However, even in these cases, the patient’s general practitioner or Primary Care pediatrician of the National Health System usually includes this diagnosis in the clinical record. The diagnoses of Primary Care may have a closing or completion date, while those of Specialized Care always remain active in the system. This can lead to some inaccuracies in the prevalence data, although the impact is limited, given that not many diagnoses are expected to be reversed during adolescence. Another potential limitation is related to the fact that, according to our protocol design, some population ages are not represented in the extreme dates of the considered time interval. However, any potential bias was minimized by the use of incidence rates within each age.Despite these limitations, to our knowledge, this is the first age-period-cohort analysis to assess temporal changes in the incidence of ADHD, and one of the first to study ADHD incidence over an extended time period in Spain, including the most recent years. Spain’s National Health System provides universal access to health services for all children and adolescents, so the cohort includes most of the population, regardless of their socioeconomic status, place of birth or racial/ethnic identification. The electronic health record of the National Health System is probably the most ideal of all data sources in Spain to study temporal changes of a medical condition such as ADHD. Moreover, the diagnoses are very reliable, as the codes were individually validated, and unconfirmed or doubtful cases of ADHD were excluded. We also stratified the analyses by ADHD subtypes , which has not been reported in most ADHD incidence studies. Finally, a substantial number of participants, together with a long follow-up period, provided the obtained results with adequate accuracy.In this age-period-cohort analysis of a population-based study, a clear period and age effect was observed. The period effect showed an incidence increase in the first years, followed by a plateau period, and then a progressive decrease in the last years. Further research should confirm whether there has been a global change in trend in recent years. The age effect, with a peak incidence rate at 7–8 years of age is consistent across the study period and for both genders. The well-known predominance of ADHD diagnoses in males was also observed, along with similar time trends in males and females. Clear evidence for a seasonal pattern in ADHD diagnosis was found for the first time, with peaks in February–March and the lowest rates in the summer months. Inattentive cases were much more frequent than hyperactive cases, and combined cases remained low across the study period.


Are there associations between prenatal, early postnatal, or current exposure to secondhand smoke (SHS) and symptoms or subtypes of attention-deficit/hyperactivity disorder (ADHD) among children?In this cross-sectional study of 45 562 school-aged children in China, SHS exposure from pregnancy to childhood was associated with higher odds of having ADHD symptoms and subtypes. When considering the timing of SHS exposure, the associations were somewhat stronger in the prenatal and early postnatal periods.These findings support the association of SHS exposure with ADHD-related symptoms among children and highlight the importance of strengthening public health efforts to reduce SHS exposure. Few studies have investigated the association between the exposure window  of secondhand smoke (SHS) and attention-deficit/hyperactivity disorder (ADHD) symptoms and subtypes in children.To evaluate the associations of prenatal, early postnatal, or current SHS exposure with ADHD symptoms and subtypes among school-aged children.In this cross-sectional study, 48 612 children aged 6 to 18 years from elementary and middle schools in Liaoning province, China, between April 2012 and January 2013 were eligible for participation. Data on SHS exposure and ADHD symptoms and subtypes for each child were collected via questionnaires administered to parents or guardians by school teachers. Data were analyzed from September 14 to December 2, 2020.Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). Generalized linear mixed models were evaluated to estimate the association of SHS exposure with ADHD symptoms and subtypes.The ADHD symptoms and subtypes  were measured based on a validated tool developed from the A total of 45 562 participants completed the questionnaires and were included in this study . Compared with their unexposed counterparts, children who were ever exposed  or always exposed to SHS  from pregnancy to childhood had higher odds of having ADHD symptoms and subtypes . Compared with their unexposed counterparts, children with SHS exposure had higher odds of having ADHD symptoms when exposed in the prenatal period , early postnatal period , or current period . Compared with their unexposed counterparts, children whose fathers smoked 10 or more cigarettes/d on both weekdays and weekends had higher odds of having ADHD symptoms and subtypes .Being exposed to SHS from pregnancy to childhood was associated with higher odds of having ADHD symptoms and subtypes among school-aged children, and the associations were somewhat stronger for SHS exposure during prenatal and early postnatal periods. Our findings highlight the important public health implications of reducing SHS exposure, which may decrease the health and economic burdens of individuals with ADHD. This cross-sectional study analyzes data collected via questionnaires to assess whether associations exist between prenatal, early postnatal, or current exposure to secondhand smoke and symptoms or subtypes of attention-deficit/hyperactivity disorder among school-aged children in China. Therefore, the association of the specific timing of SHS exposure with ADHD symptoms has not yet been clarified. Although paternal smoking is the main source of SHS,4 few fathers report prenatal smoking abstinence and continue to smoke during pregnancy, after childbirth, or both.14 Detailed investigations of paternal smoking are still warranted.Although most studies addressing SHS and ADHD symptoms have evaluated prenatal exposure  reporting guideline for cross-sectional studies. This study was approved by the Ethical Review Committee for Biomedical Research, Sun Yat-sen University. All children and their parents provided written informed consent that was obtained in a manner consistent with the Common Rule requirements. No one received compensation or was offered any incentive for participating in this study.We used the cross-sectional data embedded in the second wave of the Seven Northeastern Cities study, which was conducted between April 2012 and January 2013. For our sampling strategy, we generated a representative sample by randomly selecting half of the 14 cities in Liaoning province, located in northeastern China. We included 24 urban districts from the 7 selected cities, randomly choosing 1 elementary school and 1 middle school. From each grade level of the included schools, we invited students from 1 or 2 classrooms who lived within the study district for at least 2 years before the start of this study to participate in our survey. We followed the Strengthening the Reporting of Observational Studies in Epidemiology  and the teachers and principals to enable them to understand the study aims, proposed methods, and study procedures in detail. We provided structural procedures for the teachers who were required to distribute and collect the questionnaires and envelopes and forms to record the questionnaire responses. Teachers were responsible for explaining the study aim to parents, obtaining informed consent, and collecting the questionnaires during regular parent-teacher conferences. Parents were allowed to fill out the questionnaires during the conference or to take them home and return them in a sealed envelope. Parents were also given the opportunity to decline to consent and to refuse to join the study.18 was developed based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV).19 The scale consists of 18 queries categorized as 9 symptoms of inattention and 9 symptoms of hyperactivity-impulsivity. Each item or symptom was rated on a 4-point Likert scale . Children with ADHD symptoms were defined as presenting often or very often with 6 or more symptoms of inattention or with 6 or more symptoms of hyperactivity-impulsivity. The ADHD symptoms were further classified into 3 subtypes: (1) inattentive (ADHD-I), defined as presenting often or very often with 6 or more symptoms of inattention; (2) hyperactivity-impulsivity (ADHD-HI), defined as presenting often or very often with 6 or more symptoms of hyperactivity-impulsivity; and (3) combined (ADHD-C), defined as presenting often or very often with 6 or more symptoms of inattention and with 6 or more symptoms of hyperactivity-impulsivity. The sensitivity and specificity of this psychometric property were 91% and 97%, respectively.We asked parents to fill out both the symptom inventory scale of ADHD (SIS-ADHD) and the Conners Abbreviated Symptom Questionnaire (C-ASQ) to measure ADHD symptoms in all children. The Chinese version of the SIS-ADHD20 The C-ASQ is a set of 10 checklist items rated on a 4-point Likert scale . The Conners Hyperkinesis Index is a sum of the total score and ranges from 0 to 30, with a score higher than 15 defined as having ADHD symptoms. The sensitivity and specificity were 76.0% and 92.2%, respectively.We reevaluated ADHD symptoms by using the Conners Hyperkinesis Index based on the validated Chinese version of the C-ASQ.We collected information on SHS exposure for different exposure windows, including the prenatal, postnatal , and current periods. We defined having prenatal SHS exposure based on an affirmative answer to the question, “Did anyone who lived with the mother during her pregnancy smoke anywhere inside the house?” We defined having postnatal SHS exposure based on an affirmative answer to the question, “Did anyone who lived with the child during his or her first 2 years smoke anywhere inside the house?” We collected information on the current number of cigarettes smoked inside the house per day during weekdays and weekends by all family members who lived with the child. We defined having current SHS exposure if any family member who lived with the child smoked cigarettes. Therefore, the SHS exposure for the different exposure windows was a binary variable encoded as 0 for no and 1 for yes. We further grouped SHS exposure from pregnancy to childhood into 3 categories: unexposed, ever exposed, and always exposed. We analyzed current paternal smoking on weekdays or weekends because this was the main source of children’s SHS exposure, and we grouped the number of cigarettes per day into 4 categories .t tests for continuous variables and χ2 tests for categorical variables.We conducted data analyses from September 14 to December 2, 2020. We calculated mean (SD) values for continuous variables and percentages for categorical variables. The differences between children with and children without ADHD symptoms were analyzed using We analyzed the associations of ADHD symptoms and subtypes with SHS exposure from pregnancy to childhood, the timing of the SHS exposure, and current paternal smoking by fitting generalized linear mixed models with a logit link function. We fit crude models with school as the random intercept. We fit adjusted models for each outcome, adjusting for covariates collected from the questionnaires . We adjusted for previous SHS exposure in the analyses of the timing of the SHS exposure.DSM-5 criteria; (3) we analyzed the ADHD symptoms as continuous variables ; and (4) we grouped SHS exposure from pregnancy to childhood into more detailed categories of exposure . No stratified analyses were conducted because the interaction terms between each exposure variable and the covariates were not significant in any analysis.We conducted several sensitivity analyses: (1) we redefined ADHD symptoms using the Conners Hyperkinesis Index; (2) we redefined ADHD symptoms using the P < .05 was considered statistically significant.Statistical analyses were conducted with the statistical software R, version 3.6.1 (R Core Team 2019). We present the results as odds ratios (ORs) with 95% CIs. All applicable tests were 2-sided tests, and A total of 48 612 eligible children and adolescents participated in this survey, of which 45 562 completed the assessments of ADHD symptoms and were included in the final analyses . As shown in In the fully adjusted model , compareIn the fully adjusted model , compareFurther investigation of current paternal cigarette smoking  indicateDSM-5 criteria or using continuous scores from the SIS-ADHD scale or the Conners Hyperkinesis Index, the associations remained robust in all analyses .22 When combining SHS exposures from the prenatal and postnatal periods, previous studies and our results indicated that the associations may be stronger. Three cohorts  indicated that SHS exposure from pregnancy to childhood was associated with ADHD symptoms in children 10 years of age based on rating scales without considering ADHD subtypes. A case-control study suggested that SHS exposure in both prenatal and early postnatal periods was associated with ADHD and the ADHD-HI subtype based on clinical interviews with Korean children 6 to 10 years of age.6 The most rapid period of brain growth with the highest plasticity occurs in the last trimester of pregnancy and the first 2 years of life , providing the time of greatest brain vulnerability to any SHS exposure.9 However, late postnatal SHS exposure may also be important because genetic and neurobiological associations with ADHD-related symptoms are enhanced during that period.28 Cotinine, the metabolite of nicotine contained in SHS smoke, has been commonly used to determine current SHS exposure when studying the role of late postnatal SHS exposure. For example, the performance on an attention test has been correlated with urine cotinine levels in Egyptian children (aged 10-12 years).29 In addition, 2 case-control studies in Korea26 and 2 cross-sectional studies in the US28 suggested that urine or serum cotinine levels were associated with higher parental self-reported or diagnosed ADHD symptoms in school-aged children across different age groups. Moreover, a 3-year follow-up study in Hong Kong, China, indicated that saliva cotinine levels were associated with ADHD symptoms based on rating scales.30 In our study, although the association between current SHS exposure and ADHD symptoms was less pronounced, we believe that the focus should not only be on SHS exposure in the first 1000 days of life; effective and continuous interventions for parental smoking cessation in late postnatal periods are still needed.Inconsistent results were previously obtained in a meta-analysis assessing prenatal SHS exposure in association with ADHD symptoms.31 Rodent studies indicate that developmental nicotine exposure induces abnormal expression of nAChRs, hypersensitivity to nAChR-mediated dopamine release, and dopamine transporter dysfunction in the frontal cortex.32 The regulation of attentional behaviors by the prefrontal cortex is dependent on optimal levels of dopamine,33 and a functional reduction of dopamine in the prefrontal cortex may lead to ADHD-related symptoms.34 Neuroimaging studies indicate that young adults prenatally exposed to nicotine exhibit weaker activation of the inferior frontal gyrus during attention test paradigms than their unexposed counterparts, suggesting a functional involvement of prenatal exposure to tobacco smoke in ADHD-related neural alterations.35 Because the expression of neural nAChRs continues through gestation into adulthood, the developmental defects caused by nicotine may be dependent on the timing of exposure. Therefore, more studies are needed to understand the association of SHS exposure from pregnancy to childhood with ADHD symptoms.Mechanistically, neuronal nicotinic acetylcholine receptors (nAChRs), which are primary targets for unhealthy activation by nicotine exposure, regulate brain maturation.36 Pregnancy is considered a reasonable time to help parents who smoke cigarettes to quit. However, few studies have targeted expectant fathers,14 and current evidence suggests that the behavioral interventions for smoking relapse after birth are not effective.37 Both fathers and mothers need to be informed of the neurotoxic effects associated with SHS exposure throughout the development of children, and more interventions for smoking cessation are needed.It is important to encourage all adults to avoid smoking, and our results indicated that fathers may be one of the most important target populations to reduce SHS exposure. There is still limited evidence of effective interventions for reducing SHS exposure in children.26 whereas early postnatal SHS exposure was associated with the ADHD-HI subtype.6 No previous study has investigated the association between the ADHD-C subtype and exposure to SHS. In our study, the association between SHS exposure and ADHD-I symptoms was more pronounced than the other 2 subtypes, but these results should be interpreted cautiously. The prevalence of ADHD symptoms observed in our study was slightly lower than that observed in a meta-analyses of Chinese studies, and the relative proportion of subtypes was also different compared with other areas of China.38 The methodological approaches, including the sampling process, sources of information, and ADHD-related measurements, may have contributed to these differences. In addition, the small number of children with the ADHD-HI and ADHD-C subtypes may have decreased the statistical power of our study. Future research is needed to understand the heterogeneity regarding the association between SHS exposure and different ADHD subtypes.Among the ADHD subtypes, 2 case-control studies in Korea found that current SHS exposure  was associated with the ADHD-I subtype,39 Third, although we used validated DSM-IV–based questionnaires to identify ADHD symptoms and subtypes in our study, we were unable to diagnose the cases. However, our results were robust across different sensitivity analyses. Fourth, we did not collect data on parental ADHD history, and therefore we cannot exclude the possibility that the associations may be confounded by parental ADHD history. Despite these limitations, our study had notable strengths, including a large sample size covering a wide developmental range of children, comprehensive information on SHS exposure with numerous exposure windows, and several ADHD assessments, all which helped to strengthen our findings.Several study limitations should be taken into consideration. First, because this was a cross-sectional study, we were unable to assess the temporality of our results. Second, we used self-reported questionnaires to measure SHS exposure, which may have resulted in recall bias and exposure misclassification. However, a previous review indicated that it is the most cost-effective method to assess long-term SHS exposure for different critical developmental periods in pediatric research.Our study results indicated that SHS exposure from pregnancy to childhood was associated with higher odds of ADHD symptoms and subtypes in school-aged children, with somewhat stronger associations observed for prenatal and early postnatal periods. Our findings highlight the importance of strengthening public health efforts to reduce SHS exposure, which may reduce the health and economic burdens of individuals with ADHD.


Introduction: Attention deficit hyperactivity disorder (ADHD) is a common disease in childhood and adolescence. In about 60% of pediatric patients, the symptoms persist into adulthood. Treatment guidelines for adult ADHD patients suggest multimodal therapy consisting of psychostimulants and psychotherapy. Many adult ADHD patients also suffer from psychiatric comorbidities, among others obsessive–compulsive disorder (OCD). The treatment of the comorbidity of ADHD and OCD remains challenging as the literature is sparse. Moreover, the impact of psychostimulants on obsessive–compulsive symptoms is still unclear.Case Presentation: Here, we report on a 33-year-old patient with an OCD who was unable to achieve sufficient remission under long-term guideline-based treatment for OCD. The re-examination of the psychological symptoms revealed the presence of adult ADHD as a comorbid disorder. The patient has already been treated with paroxetine and quetiapine for the OCD. Due to the newly established diagnosis of ADHD, extended-release methylphenidate (ER MPH) was administered in addition to a serotonin reuptake inhibitor. After a dose of 30 mg ER MPH, the patient reported an improvement in both the ADHD and the obsessive–compulsive symptoms. After discharge, the patient reduced ER MPH without consultation with a physician due to subjectively described side effects. The discontinuation of medication led to a renewed increase in ADHD and obsessive–compulsive symptoms. The readjustment to ER MPH in combination with sertraline and quetiapine thereafter led to a significant improvement in the compulsive symptoms again.Conclusion: The present case shows that in ADHD and comorbid obsessive–compulsive disorder, treatment with psychostimulants can improve the obsessive–compulsive symptoms in addition to the ADHD-specific symptoms. To our knowledge, this is only the second case report describing a treatment with ER MPH for an adult patient with OCD and ADHD comorbidity in the literature. Further research, especially randomized controlled trials, is needed to standardize treatment options. Attention deficit hyperactivity disorder (ADHD) is a frequent mental disorder with childhood onset and a worldwide prevalence of at least 2.8% . It is cIt has been discussed that the ADHD-like symptoms in OCD, for example inattention, may have contributed to the inconsistency of the reported co-occurrence rates. Furthermore, familial link between OCD and ADHD, disturbances in attention, and executive function and the high comorbidity of tic disorders are common features of these two disorders –9.On the other hand, these disorders have reverse fronto-striatal abnormalities . OCD patPsychostimulants such as methylphenidate are regarded as the first-line treatment for ADHD. They increase prefrontal activation and improve both clinical symptomology and neurocognitive functioning in ADHD by modulating dopamine reuptake. Guidelines for the treatment of OCD recommend serotonin reuptake inhibitors as first-line pharmacotherapy, which are thought to modulate fronto-striatal hyperactivity. In the case of partial response to serotonin reuptake inhibitors, an augmentation therapy with antipsychotics has also been shown to have a useful effect .Although the pharmacotherapy of each of these disorders has been well-established, the effective treatment and management of patients with comorbid ADHD and OCD remains challenging. While stimulant medication is recommended as the first-line treatment for ADHD, findings suggest that its use in OCD may exacerbate the OCD symptoms. To our knowledge, there have been only a few studies, mostly case reports and case studies, reporting on the pharmacotherapy of this comorbidity. Some of these reports have shown that the use of stimulants may cause obsessive–compulsive symptoms as side effects –14, whilIn this report, we present a case of an adult patient with comorbid ADHD and OCD treated successfully with stimulants and serotonin reuptake inhibitors.In November 2017, a 33-year-old patient presented at our ADHD outpatient clinic in the Department of Psychiatry and Psychotherapy at the University Hospital of Leipzig for diagnostic clarification. During a previous psychiatric examination organized by the federal employment agency, a tentative ADHD diagnosis was made for the first time. The patient reported impulsiveness and physical restlessness that had persisted since childhood. He stated that he could hardly sit still or stay in one place for a longer period of time. He also described a lack of concentration and problems sustaining attention in given tasks . These obsessions began after he watched a film about aliens as a teenager, which frightened him enormously although he does not believe in aliens. Overall, obsessive and compulsive symptoms have been affecting his life in many ways, but especially his work life, disrupting his functionality. He had been treated as an inpatient and outpatient several times, yet the OCD symptoms would still occupy 3–4 h per day see . In addiThe patient also reported that, in the past, he had been drinking a lot of alcohol to compensate for his compulsions and impulsiveness. However, alcohol had disinhibited him in parts even more, and it had come to physical confrontations several times. He had lost control in situations in which he felt provoked. In the past, criminal proceedings had also been brought against him in this context. In the course of time, he developed an alcohol addiction. At the time of the first visit to our outpatient clinic, he had been completely abstinent from alcohol for 6 years. Drug consumption was also negated, which could also be confirmed by a toxicological screen at the inpatient admission.The following information was gathered on the past psychiatric history: a first inpatient treatment because of the OCD (ICD-10: F42.2) took place in 2006. During that time, a suspected diagnosis of paranoid schizophrenia (ICD-10: F20.0) was made and treatment with risperidone 1.5 mg/day, olanzapine 10 mg/day, and lorazepam 1 mg/day was started. Risperidone was discontinued due to akathisia, and the patient was then treated with olanzapine 10 mg/day and paroxetine 20 mg/day. In 2008, the patient was treated in a day clinic for 1.5 months, where an OCD (ICD-10: F42.2) and an immature personality accentuation were diagnosed. During this treatment, the dose of sulpride was increased from 200 to 400 mg/day, which was prescribed during the outpatient treatment. Subsequently, sulpride was switched to paroxetine 60 mg/day. In 2009, the patient was hospitalized again due to worsening of the OCD symptoms. In 2012, an alcohol withdrawal treatment was completed. The discharge medication consisted of paroxetine 60 mg/day and olanzapine 10 mg/day. The diagnoses then consisted of alcohol dependence (ICD-10: F10.2), alcohol withdrawal syndrome (ICD-10: F10.3), OCD (ICD-10: F42.2), personality accentuation (ICD-10: F60.9), and an unspecified form of schizophrenia (ICD-10: F20.8). In 2013, another alcohol withdrawal treatment due to a relapse followed. Since then, he has been abstinent of alcohol according to his own statement. Discharge medication consisted of paroxetine 60 mg/day and promethazine 25 mg as needed. Since 2015, the patient has been undergoing an outpatient behavioral therapy treatment, without achieving complete remission of the OCD so far.While there were no relevant diseases in the medical anamnesis, the family history revealed that his mother had been diagnosed with schizophrenia and his father had a history of alcohol addiction.After the initial presentation in our outpatient clinic (December 2017), detailed diagnostic tests were performed, including the Diagnostic Interview for ADHD in adults (DIVA) and ADHD-specific questionnaires [Conners Adult ADHD Rating Scales (CAARS)—Self-Report: Long Version , Wender Due to the complex comorbidity of psychiatric illnesses, the patient was admitted to our inpatient unit in January 2018 for medication adjustment. At that time, the Yale–Brown Obsessive Compulsive Scale (Y-BOCS)  was perfIn accordance with existing literature, we switched the medication from paroxetine 30 mg to sertraline 50 mg/day because of the lack of therapy response to paroxetine treatment for many years , 21. A pOne day before discharge (after 42 days on board), Y-BOCS and CAARS were applied again. The patient reported observing one out of 37 typical obsessive thoughts and one of 21 typical compulsive behaviors in the last 7 days. In the severity rating, the patient reached a total score of seven points (five points for obsessive thoughts and two points for compulsive behavior). The CAARS resulted in an ADHD index in percentile rank of 5, a DSM-IV Inattentive symptom scale in percentile rank of 10, a DSM-IV Hyperactive–Impulsive symptom scale in percentile rank of 14, and a DSM-IV ADHD Symptoms Total in percentile rank of 10 see . The medAfter discharge, the patient attended our ADHD outpatient clinic for regular follow-ups. On his first visit (1 day after the discharge), he reported a good response to the medical therapy with ER MPH and assured that he did not notice any side effects. He expressed the wish to increase the sertraline dose from 25 to 37.5 mg/day. In the following visit after 26 days, the patient reported unspecific anxiety and panic attacks and claimed to have reduced ER MPH to 10 mg on his own responsibility after having read the package leaflet and worrying about potential side effects. Thus, the remaining medication consisted of sertraline 50 mg/day and quetiapine 25 mg/day, which he started again without a consultation with our outpatient clinic.In March 2018, a month later after the discharge, a second inpatient admission was initiated after an emergency contact of the patient with the ward. He described an increase in obsessive–compulsive symptoms and restlessness and reported that he suffered from panic attacks and sleep disorders and that he lost his appetite. The patient observed severe mood swings and distrust toward other people. The medication at administration consisted of ER MPH 10 mg/day, sertraline 37.5 mg/day, and quetiapine 25 mg as needed. However, he reported that he did not want to continue to take ER MPH. Therefore, therapy with atomoxetine was started as ER MPH was discontinued. Due to the worsened symptomatology, the sertraline dose was increased to 150 mg/day and quetiapine was dosed up to 125 mg/day. However, the OCD symptoms worsened further after the discontinuation of ER MPH despite increasing the doses of sertraline and quetiapine. After weighing up the symptoms before and after treatment with ER MPH, we decided together with the patient to restart the treatment with ER MPH. Physical well-being and a reduction of the OCD and ADHD symptoms were described after switching the medication from atomoxetine to ER MPH. On the first day of the switch, we performed Y-BOCS and CAARS again. For the last 7 days, the patient reported observing four of 37 typical obsessive thoughts and four of 21 typical compulsive behaviors. In the severity rating, the patient reached a total score of 20 points, of which 11 points were on the scale of obsessive thoughts and nine points were on the scale of compulsive behavior. The CAARS showed an ADHD Index in percentile rank of 76, a DSM-IV Inattentive symptom scale in percentile rank of 54, a DSM-IV Hyperactive–Impulsive scale in percentile rank of 82, and a DSM-IV ADHD Symptoms Total in percentile rank of 69 see .An improvement of compulsive thoughts and joyfulness was observed when sertraline was added. The patient was discharged in April 2018 (after 27 days on board) into outpatient care at the ADHS outpatient clinic. Five days after discharge, CAARS and Y-BOCS were performed again: the patient reported observing two of 37 typical obsessive thoughts and four of 21 typical compulsive behaviors within the last 7 days. In the severity rating, the patient reached a total score of 18 points, of which 10 points were on the scale of obsessive thoughts and 8 points were on the scale of compulsive behavior. The CAARS revealed an ADHD Index in percentile rank of 42, a DSM-IV Inattentive symptom scale in percentile rank of 38, a DSM-IV Hyperactive–Impulsive scale in percentile rank of 35, and a DSM-IV ADHD Symptoms Total in percentile rank of 35 see . DischarIn this case report, we present a case of successful treatment with psychostimulants in an adult patient with ADHD and comorbid OCD. Due to the late diagnosis of ADHD , no effective treatment was initiated in his early life, resulting in an impacted quality of life up to now. After diagnosing ADHD, we treated the patient with ER MPH in addition to antidepressants for OCD treatment and observed that the adjunctive use of ER MPH resulted in enhanced treatment response. Contrary to reports in the literature, treatment with a stimulant did not cause a worsening of the OCD symptoms. Rather, the patient reported a severe decrease in OCD symptoms, which was also observable by the treatment team. A second administration was necessary due to a worsening of the OCD and ADHD symptoms occurring after the patient had reduced the dose of ER MPH on his own, because he was worried about side effects, which he had never actually experienced during the inpatient treatment. This case highlights the importance of frequent reassessment of comorbid conditions in the case of low treatment response to serotonin reuptake inhibitors and psychotherapy in patients with OCD. Untreated ADHD as a comorbid condition to OCD may reduce the treatment response on the OCD, as shown in previous studies .Recognizing ADHD and OCD comorbidity is important for the clinical course of these disorders considering that the onset of OCD is significantly higher in adults with childhood ADHD symptoms and that the comorbidity is associated with more severe OCD symptoms and their persistence , 24. DesOn the basis of neuroimaging findings, structural and functional abnormalities in ADHD and OCD have been reported . A shareDespite the high prevalence of OCD and ADHD comorbidity, only a few reports on the treatment of this comorbidity exist. Most of these studies were performed in child and adolescent populations, and as far as we know, only one was conducted in an adult population . Some ofThe present case report highlights that treatment with psychostimulants in addition to a serotonin reuptake inhibitor can improve the obsessive–compulsive symptoms as well as the ADHD-specific symptoms in patients with ADHD and OCD comorbidity. Still, the treatment of this comorbidity remains challenging. Underdetection, misdiagnosis, as well as delay in the diagnosis of this comorbidity may cause a reduction in quality of life and low treatment response. Treating both disorders concurrently may help to decrease the symptom severity of both conditions. Monitoring the progress may also support the treatment process, allowing improvement of the treatment compliance as well as observing side effects. Yet, longitudinal and clinical controlled trials are needed to gain more information about the treatment of this comorbidity and to observe the treatment response longitudinally.The data analyzed in this study is subject to the following licenses/restrictions: identifying/confidential patient data cannot be shared. Requests to access the data should be directed to the corresponding author.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ED-S and MS were the main authors of the manuscript. ED-S performed the literature research on the comorbidity of ADHD and OCD. Both authors participated substantially in the writing and editing of the final manuscript.MS has received speaker fees from Lilly, Medice Arzneimitte Pütter GmbH & Co. KG and Servier and was an advisory board member for Shire/Takeda. 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.