Subgaleal hematoma is a well-known life-threatening complication of instrumentation at birth. Even though most cases of subgaleal hematomas occur in the neonatal period, older children and adults are also at risk for subgaleal hematomas and their complications, following head trauma.We hereby report the case of a 14-year-old boy who presented with a traumatic subgaleal hematoma requiring drainage and review the relevant literature regarding potential complications and indications for surgical intervention.Infection, airway compression, orbital compartment syndrome and anemia requiring transfusion are potential complications of subgaleal hematomas. Although rare, surgical drainage and embolization are occasionally required interventions.Subgaleal hematomas following head trauma can occur in children beyond the neonatal period. Large hematomas may require drainage to relieve pain or when compressive or infectious complications are suspected. Although usually not life-threatening, physicians taking care of children must be cognizant of this entity when caring for a patient with a large hematoma following head trauma and in severe cases, consider a multidisciplinary approach. Subgaleal hematomas occurs when blood accumulates between the periosteum and the aponeurosis due to the tearing of emissary veins. It is a known complication of instrumentation at birth, and neonates can have up to 50% of the body blood volume accumulate in the space, leading to hemorrhagic shock and death , 2. EvenA 14-year-old otherwise healthy boy was brought to the pediatric emergency department (PED) of a tertiary care urban medical center by his parents 3 days after sustaining a skateboarding injury. The patient reports falling directly on his head from his height, striking the top of his head on the halfpipe cement structure of the skatepark, while not wearing a helmet. He denies loss of consciousness, nausea, vomiting, abnormal behavior, or any other injury at the time and did not seek medical consultation. He has however since complained of a progressively worsening headache when moving his head from side to side and felt a lump on the frontoparietal part of his head. With the headache becoming severe, the patient and his family decided to seek care in the PED.Vital signs revealed a normal heart rate of 80 beats per min, a slightly elevated blood pressure of 133/90 mmHg, a normal respiratory rate of 16 per min, normal oxygen saturation at 98% in ambient air, and no fever. The patient appeared well, was alert, interactive and conversive, he complained of mild discomfort at rest but pain that is difficult to tolerate when ambulating, particularly when moving his head from side to side. On inspection, a large area of fluctuant swelling on the right frontoparietal region of the scalp was noted, which was painful to palpation. The remainder of the examination including the neurological examination showed no abnormalities.Given the suspicion for an underlying skull fracture and given the severity of the headache, the decision was made to obtain a non-contrast computed tomography (CT) of the head. CT revealed no evidence of intracranial hemorrhage, intracranial hypertension, or skull fracture, and confirmed the diagnosis of a right voluminous frontoparietal subgaleal hematoma extending to the left frontal region .Laboratory examination showed normal coagulation studies and no thrombocytopenia. Neurosurgical consultation was obtained to help guide management, and given the severity of the headache, the decision was made to drain the collection. Bedside needle drainage was performed by the neurosurgeon in the PED, with insertion of a butterfly needle in sterile conditions and aspiration of 100 cc of blood, followed by application of a compression bandage. The patient was subsequently discharged from the PED with a follow up appointment with his pediatrician.The compression bandage was kept for 48 h, and headaches resolved in that timeframe. There were no other symptoms in the days and weeks following his admission to the PED. No further analgesia was needed, and the swelling progressively decreased then completely resolved over the course of 3 weeks, as documented by a telephone conversation with the patient and his family.Subgaleal hematoma is a complication known to pediatricians attending the delivery room. The condition is much rarer in older children. The patient described above presented with severe pain from a traumatic subgaleal hematoma, improved with needle drainage, and had no further complications.We searched PubMed for articles published in the last forty years in English with the title containing “subgaleal hematoma,” with available abstracts and accessible full-texts, and retained only the ones involving otherwise healthy children outside of the neonatal period. Our literature review reveals that the main reasons for subgaleal hematomas in children are minor head injury, hair pulling or braiding and trauma leading to a skull fracture. Reports of child abuse with hair pulling, hair braiding or corporal punishment leading to subgaleal hematoma are also described .Intervening on a subgaleal hematoma is rarely needed in children. The symptoms of pain and swelling usually resolve within a few days to weeks after the injury and drainage is rarely necessary. The usual work up performed includes complete blood count looking for thrombocytopenia and coagulation profiles looking for a bleeding diathesis , 17, 25.We hereby discuss the potential complications of traumatic subgaleal hematomas and related interventions.Airway compression is a rare complication of a traumatic subgaleal hematoma. Nichter et al. describe a 12-year-old healthy child who suffered a mild blow to the head leading to a massive hematoma of the head and neck resulting in airway compression. Emergency tracheostomy and surgical drainage was required, with concern for impending skin necrosis . In theiOrbital compartment syndrome has also been described as a complication of subgaleal hematoma, with extension of the hematoma to the orbital subperiosteum , 25, 26.Infection of subgaleal hematomas secondary to a scalp laceration during instrumented delivery has been well described in the neonatal period . In oldeIt is worth noting that even though the relative volume of blood in traumatic hematomas is usually less important than in newborns, transfusion might be needed in some cases . In addiWhen the above complications are suspected, surgical drainage may be necessary. Drainage however carries a risk of complications, particularly iatrogenic infection, as emissary veins communicate with the dural sinuses.In the patient described in this case report, drainage was deemed appropriate to relieve the discomfort of the patient, after weighing the risks and benefits of the procedure.Subgaleal hematomas might also lead to calcification, motivating drainage to avoid such complications. In rare cases, calcifications can indeed lead to cranial deformation requiring reconstructive surgery, especially in patients with hematologic disease such as Kasabach-Merrit phenomenon, whereby a vascular lesion causes platelet and coagulation factor consumption . ConcernWhen calcifications or complications are present, however, surgical drainage and evacuation may be warranted. Edmondson et al. report a case of a 16-year-old boy who presented with a large subgaleal hematoma following hair braiding 10 days prior, with magnetic resonance imaging revealing areas of calcification . There wEmbolization has also been described after subgaleal hematoma , 23. WajAlthough rare, physicians must be cognizant of the complications above and the indications for intervention, when presented with a subgaleal hematoma in a pediatric patient.Although rare, subgaleal hematomas can occur in children beyond the neonatal period and are mostly associated with trauma, at times as benign as a minor fall, hair-braiding or hair pulling. While it is rare, voluminous subgaleal hematomas may require drainage to relieve pain or when compressive or infectious complications are suspected, especially in a patient with a known coagulopathy. Although usually not life-threatening unlike in the neonatal period, physicians taking care of children must be cognizant of this entity when caring for a patient with a large hematoma following head trauma, anticipate potential complications and consider a multidisciplinary approach with neurosurgery and hematology consultation if the presentation or evolution is atypical.


Growing evidence supports a possible link between gut microbiota and attention-deficit/hyperactivity disorder (ADHD) via the gut-brain axis. Short-chain fatty acids (SCFAs), the major metabolites produced by gut microbiota through anaerobic fermentation, may influence gut-brain communication.To determine the alterations of gut microbiota and fecal SCFAs in children diagnosed with ADHD compared to healthy subjects.Fecal samples were collected from children with ADHD (n=10), and age- and sex-matched healthy controls (n=10) for gut microbiota and SCFAs analysis.Figure1). Interestingly, acetic acid and propionic acid levels were negatively correlated with ADHD symptoms (Table 1). Macronutrient and fiber intake, determined from food frequency questionnaires, did not differ between groups.There were no significant differences in the abundance of any bacterial phyla in feces between groups. However, fecal concentrations of acetic acid, propionic acid, and butyric acid were significantly lower in children with ADHD compared to those of controls (Image:Our findings suggested that gut dysbiosis was possibly developed in children with ADHD, as indicated by a significant decrease in fecal SCFAs. In fact, fecal acetic acid, propionic acid, and butyric acid may potentially be the early detector for ADHD. In addition, fecal acetic acid and propionic acid could be potential biomarkers for the severity of ADHD.None Declared


Studies report an elevated risk of maltreatment in children with attention deficit/hyperactivity disorder (ADHD), and elevated levels of ADHD in people who suffered childhood maltreatment (CM). However, the direction(s) of causality between CM and ADHD remain unclear—does ADHD create a context for CM, does CM cause ADHD, or both?strength, temporality, dose‐response and plausibility.This study systematically reviews and qualitatively synthesizes the research evidence relating to this question using Bradford‐Hill criteria for establishing causality—We conducted a systematic review, following PRISMA guidelines, of prospective longitudinal studies examining both CM and ADHD. We then used Bradford‐Hill criteria to assess the quality of evidence for a causal link between CM and ADHD.All 11 included studies demonstrated an association between CM and ADHD. Seven included evidence for temporality: five suggesting that CM precedes ADHD in the lifespan; two suggesting ADHD precedes CM. Four studies demonstrated a dose response relationship in which greater CM exposure was associated with elevated risk of ADHD. Studies presented a range of plausible mechanisms, including CM causing ADHD through biological programming, versus ADHD causing CM through parental stress.The high quality prospective longitudinal studies reviewed confirm the association between ADHD and CM, but present conflicting evidence about the direction of causality and mechanisms underpinning this association. To better understand the complex interplay between CM and ADHD, more studies using new research designs will be required that can partition effects by type of CM and account for bidirectional effects and other complexities. There is an association between attention deficit/hyperactivity disorder (ADHD) and childhood maltreatment (CM), irrespective of which condition precedes the other.There is no consistency in the included studies about the direction of causality—probably because they involve CM exposure that differ in type and degree.There is dose‐response relationship: multiple or more frequent exposure to CM is associated with higher risk of ADHD symptoms.Although authors suggest various plausible explanations for the association between CM and ADHD, further research is needed to disentangle the complexity of this association.Childhood maltreatment (CM), defined as physical abuse and neglect  emotional abuse and neglect; sexual abuse; and early deprivation APA, , is assoHypothesis ACM is a causal factor in the etiology of ADHD through biological programming in which adverse experiences are embedded  and a disease outcome Hill, .strength, dose‐response, plausibility and temporality. The stronger the association is, the more likely that the association is to be causal. A dose‐response relationship between an exposure and an outcome means that the more frequent (or more severe) the exposure, the greater the risk of the outcome. Temporality refers to the necessity of a temporal relationship between exposure and outcome. Epidemiologists agree that temporality offers crucial information about the direction of causality. Prospective longitudinal studies are therefore regarded as essential in teasing apart direction(s) of causality as they avoid the potential biases inherent in retrospective assessments of CM and ADHD , consistency (across the studies), specificity , experimental evidence , and analogy .A further five Bradford Hill criteria can be used to examine a body of literature as a whole and we critically examine these in the Discussion section of the paper, across all of the studies in the review. These are strength of the association between CM and ADHD?What is the Did CM precede ADHD or vice versa?Was there evidence for a dose response relationship between either the intensity or duration of the CM exposure and ADHD?How plausible is the effect?We systematically reviewed prospective longitudinal studies (published between 1985 and 2023) that included measurement of CM and/or ADHD at a minimum of two time points. Exclusion of studies prior to 1985 was to allow use of modern definitions of ADHD in accordance with the publication of DSM‐III. We assessed the extent to which findings of each study satisfied Bradford Hill criteria, asking:The systematic literature review was conducted following the PRISMA guideline  AND , (ADHD) AND , (ADHD) AND  AND (children), ((ADHD) AND ) AND ,  AND (ADHD)),  AND (ADHD)),  AND (ADHD)),  AND (ADHD),  AND (ADHD), (attention deficit) AND , (attention deficit) AND , (hyperactivity) AND , (deprivation) AND (ADHD), (deprivation) AND (attention deficit), (deprivation) AND (hyperactivity).The initial search was carried out in June 2020 and updated in March 2022 and January 2023. We excluded abstracts, conference proceedings, reviews, meta‐analyses, retrospective studies and RCTs ; and studies without adequate assessment of symptoms or diagnosis conducted by professionals using standardized clinical methods. After removing duplicates, all remaining articles were checked in a first  and second (whole article) screening. The initial PRISMA search was performed independently by two reviewers. Full papers were reviewed by three co‐authors to decide which articles were selected for the final review.The study was prospective and longitudinal.The population of interest was children (including adolescence) followed for a minimum of 1 year.Eligible studies needed to have measured CM and/or ADHD at a minimum of two timepoints including at least one assessment of CM and at least one assessment ADHD before age 18 years.Studies included ADHD diagnosis and/or symptoms as exposure or outcome, and one or more forms of CM: physical neglect and abuse, sexual abuse, emotional  neglect and abuse, or early deprivation.Where a cohort had more than one publication associated with it, we selected the most recent publication that focused specifically on ADHD and CM.Studies were judged by two independent raters to be “high quality” see below under risk of bias assessment.Articles that were available in English and were published between years 1985–2023 were selected based on the following inclusion criteria:preliminaries, introduction, design, sampling, data collection, ethical matters, results, and discussion, resulting in a total score out of 40. A score of <20 is considered low quality; 20−30 moderate quality, and >30 high quality. Quality assessment for each included article was completed independently by two reviewers we included only high‐quality studies.To assess the quality of the included studies and the risk of bias on estimates, we used the Crowe Critical Appraisal Tool  Crowe, . CCAT crd formula to examine the effect size of the results in each study  from 11 prospective longitudinal studies were included. The participants were all children at the time of study initiation in 10 studies  ADHD with comorbidities is associated with a higher risk of maltreatment: Stern et al. , Calhoun(b)Early maltreatment, deprivation or malnutrition has a negative impact on neurodevelopment: Wong et al. , Kennedy(c)Confounders could provoke both CM and ADHD: Hunt et al.  and Boyd(d)Nature‐nurture interplay: González et al.  discuss,Ten of the 11 studies suggested plausible—but not proven—mechanisms for the association between CM and ADHD. There were four predominant plausible explanations:strength, dose‐response, plausibility, and temporality . What is clear from the review is that there are likely to be underlying biological and environmental factors that might exacerbate or minimize the strength of this relationship and the included studies, despite their highly quality, cannot resolve the conflicts regarding whether any, or all, of these plausible mechanisms are correct.coherence, consistency, specificity, analogy and experimental evidence  demonstrated no effect of removing young children to foster care on ADHD symptoms (Humphreys et al., Limitations to the evidence for causality in the 11 included papers.There are issues regarding the timing of CM and ADHD assessment which cannot be overcome in the prospective longitudinal design as discussed above.It is already well known the there is an important role for genes in susceptibility for ADHD (Demontis et al., The range of cultural settings where the nature of the relationship between CM and ADHD has been examined is limited. Studies have been mainly in Western samples, so do not fully account for socio‐cultural factors that may shape the association between ADHD and CM. Studies conducted in a wider range of social environments are required to explore generalizability of findings.d in future studies should be done carefully in consideration the research and clinical context in order not to be misleading or inaccurate (Carey et al., Traditional linear epidemiological methods with a reliance on specific exposures leading to specific outcomes cannot disentangle the complex relations between CM and ADHD. A more sophisticated analytic research approach, where multiple outputs and inputs can be assessed simultaneously, including controlling for genetic factors alongside environmental factors, are required (Silverman et al., Although all the included studies are longitudinal and prospective, and the overall quality of the reviewed papers is high, there are some limitations that prevent clear conclusions about causality (see Appendix There are few limitations to consider about the present systematic review too. Our review wasn't register in PROSPERO. We had limited information from the included studies to assess the association between each type of CM separately with ADHD. Our findings should also be interpreted in the context of limitations. First, the interpretation of BH criteria should not be regarded as rigid criteria, but instead as tool to provide serious considerations regarding causality and as a framework for further analyses and studies. For example, it is difficult to understand how the plausibility criteria is applied in this context. Also, confounding is major factor to consider in the context of causal inference, but this was not part of the Bradford criteria. Second, it would have been helpful if it had been possible to examine some of the key theoretical models for the impact of maltreatment, such as the dimensional deprivation versus threat model (McLaughlin et al., and for ADHD provoking maltreatment. Therefore, further research should be done to detangle this association in order to prevent the risk of maltreatment in children with ADHD and provide better assessment and therapeutic options in children with history of maltreatment to prevent the risk of psychopathology.The present systematic review reveals an association between CM and ADHD, as well as compelling but not yet conclusive evidence for child maltreatment causing ADHD Paraskevi Bali: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Software; Writing – original draft; Writing – review & editing. Edmund Sonuga‐Barke: Conceptualization; Methodology; Supervision; Writing – review & editing. Christina Mohr‐Jensen: Conceptualization; Methodology; Project administration; Supervision; Writing – review & editing. Ditte Demontis: Supervision. Helen Minnis: Conceptualization; Methodology; Project administration; Supervision; Writing – review & editing.Ditte Demontis serves on the JCPP Advances Editorial Advisory Board. The remaining authors have declared they have no competing or potential conflicts of interest.No ethical approval was required for this research review.Supporting Information S1Click here for additional data file.


Attention Deficit Hyperactivity Disorder (ADHD) is a widespread condition that affects human behaviour and can interfere with daily activities and relationships. Medication or medical information about ADHD can be found in several data sources on the Web. Such distribution of knowledge raises notable obstacles since researchers and clinicians must manually combine various sources to deeply explore aspects of ADHD. Knowledge graphs have been widely used in medical applications due to their data integration capabilities, offering rich data stores of information built from heterogeneous sources; however, general purpose knowledge graphs cannot represent knowledge in sufficient detail, thus there is an increasing interest in domain-specific knowledge graphs.In this work we propose a Knowledge Graph of ADHD. In particular, we introduce an automated procedure enabling the construction of a knowledge graph that covers knowledge from a wide range of data sources primarily focusing on adult ADHD. These include relevant literature and clinical trials, prescribed medication and their known side-effects. Data integration between these data sources is accomplished by employing a suite of information linking procedures, which aim to connect resources by relating them to common concepts found in medical thesauri.The usability and appropriateness of the developed knowledge graph is evaluated through a series of use cases that illustrate its ability to enhance and accelerate information retrieval.The Knowledge Graph of ADHD can provide valuable assistance to researchers and clinicians in the research, training, diagnostic and treatment processes for ADHD. Attention Deficit Hyperactivity Disorder (ADHD) is a widespread condition characterized by inattention, hyperactivity, and/or impulsivity that causes significant impairment across various domains. It is considered as a childhood-onset disorder that can continue into adulthood. Recent studies , howeverKnowledge graphs have been used extensively for knowledge representation in the medical domain due to their ability to effectively integrate information from various data sources and provide explanations in processes such as diagnosis and treatment . Some exhttps://w3id.org/ADHD-KG.Considering these limitations, we propose the construction of a knowledge graph for adult ADHD integrating a variety of resources including relevant literature, clinical trials, drug knowledge bases and general purpose medical vocabularies. ADHD-KG is an ADHD-specific graph that can transform and connect disparate sources of structured or unstructured information into a well-organised network of knowledge. ADHD-KG has been developed and tested on several use cases illustrating its suitability for supporting (a) medical queries for clinicians or researchers to explore the latest advances in ADHD literature, (b) training inquiries that aid clinicians to acquire information about ADHD and (c) clinical queries for assisting clinicians in the diagnostic and treatment procedures for patients with particular characteristics or qualities. To the best of our knowledge, ADHD-KG is the first knowledge graph in relation to ADHD. ADHD-KG version 1.0 is available at ADHD researchers and clinicians can conduct effective automated medical question answering through ADHD-KG, reducing the time spent in manual reviews of medical literature.ADHD-KG supports both complex queries, integrating constraints that combine multiple information sources, as well as time-sensitive ones, associated with a particular time reference. This allows researchers to pinpoint the most relevant and up-to-date knowledge related to their area of focus.Artificial Intelligence researchers focusing on healthcare applications can integrate ADHD-KG with generative models to develop solutions that benefit from the inherent explainability of the former and the natural language processing capabilities of the latter.The rest of this paper is organised as follows: background and related work is presented in Section “The contribution and potential impact of ADHD-KG to relevant research communities is summarised below:Semantic networks representing entities of a specific domain and their properties and relations have been used in various application areas that involve complex information. Such representations are particularly useful in the medical domain where the formal machine readable semantics of knowledge graphs increase the efficiency of information retrieval processes. Furthermore when open standards such as RDF and RDFS  are usedMassively integrated knowledge graphs, such as Google Health Knowledge Graph, LinkedLifeDataThe developers of HKGB, a framework for semi-automated disease-specific knowledge graph construction , highligADHD is a widespread condition, thus tools and resources such as the knowledge graph proposed in this work are of great importance to the wider society. ADHD is characterised by a persistent and inappropriate pattern of inattention, hyperactivity, and/or impulsivity that causes significant impairment across domains. People with ADHD also present with deficits in executive functions, behaviour and emotion regulation and motivation , 20. It 4Delayed diagnosis and treatment for ADHD can be harmful to people, leading to broader mental health conditions, relationship and employment problems, criminal activities, and substance misuse. The adverse effects of untreated ADHD are well documented blue in literature, indicatively including effects on academic outcomes , social Our methodology followed involves combining several medical data sources to construct a knowledge graph of ADHD (henceforth ADHD-KG). This section describes each step of the construction process, including data acquisition Section “”, data cWe start by defining the scope of the knowledge base. Considering the extensively large volume of literature about ADHD on the Web, this work focuses on scientific resources that specialise on adult ADHD. The proposed knowledge graph incorporates information from the data sources described next.Medical Subject Headings (MeSH)PubMedClinical TrialsSide Effect Resource [Resource  (SIDER):DrugBank [DrugBank  is a datMost of the knowledge sources described in Section “ADHD-KG integrates five heterogeneous data sources; although each dataset specialises in unique biomedical information, semantic links between resources enable connections between different data sources. We identify two types of links: direct information linking occurs when a data source contains explicit references to resources defined in an external dataset; indirect information linking, on the other hand, is realised when disparate data sources contain resources that refer to a common medical concept. Regardless of the type of linkage, connections between data sources are expressed as custom RDF statements that associate the related resources. Figure For indexing purposes, entities within knowledge bases are assigned to unique identifiers, which can also be used by external sources to refer to the entity in question. For instance, a report of a clinical trial refers to the PubMed ID of a publication to facilitate direct retrieval from the PubMed repository. These direct references introduce direct connections between data sources, which can be mined via regular expressions against the format of the unique identifiers.k most relevant MeSH concepts given a keyword and a similarity threshold .Keywords are often assigned to scientific resources and serve as topic descriptors. Aligning keywords with universal vocabularies, such as MeSH, allows the association of resources with the most important concepts found in them. Detecting resources that refer to the same concept reveals a direct semantic relation, which further supports data integration. Matching keywords with concepts is accomplished through the approximate nearest neighbours search over MeSH Terms . SpecifiA significant part of the information found in the data sources described in Section “The linking procedures mentioned so far capture conceptual associations between entities by systematically linking MeSH concepts to resources. There are cases, however, where relations might exist at a finer level, such as string patterns which are not necessary linked to medical concepts. In these cases, we employed semantic queries combined with regular expressions to enable the discovery of equivocal links during query processing time. These links are generated dynamically at a cost of latency which is justified, as the process facilitates the detection of indirect associations among sources that rely explicitly on free text.ADHD-KG is constructed through a four-step procedure: (a) data collection, (b) RDF conversion, (c) information linking and (d) graph assembly. Methodologies for steps (a) to (c) are covered in the previous subsections, while this subsection focuses on the final step which assembles all collected knowledge into a graph, shaping it according to thematic groups that reflect the design shown in Fig. ADHD-KG comprises six named graphs; four graphs (denoted as data graphs) store information about PubMed, Clinical Trials, DrugBank and SIDER, extended with linking statements generated during step (c). The other two graphs result from the linking procedure. The connection graph is a copy of MeSH vocabulary, which anchors the direct links from data graphs to medical concepts. Finally, the annotation graph contains semantic annotations that associate textual information from the data graphs PubMed and Clinical Trials with the connection graph. Figure ADHD-KG is available for convenient access through a web portal,This section exemplifies applications of the ADHD-KG by answering complex queries through semantic search. The demonstration includes several use cases of common and prevailing ADHD-related questions, which are analysed and encoded into SPARQL queries answerable through the ADHD-KG. Due to space limitations, we provide a visualisation of the query answer instead of the query itself, where the query is too long. The graph was imported and queried in the GraphDBSearching publications using keywords is limited to text similarity; semantic annotations, on the other hand, support linking between publications with medical concepts through terms that are mentioned with variable spelling, abbreviations or even synonyms. Consider the case where a researcher wants to retrieve publications about ADHD combined with obesity. This question is expressed as a SPARQL query  in 124K triples  is more efficient compared to the full 43 M triple graph. We quantify query performance by testing an unrealistic query template that links information from every data source within ADHD-KG. Note that we exclude queries that implement online information linking, since they introduce latency that heavily depends on the complexity of the regular expression used.The test query aims to find all drug actions (DrugBank) and side effects (SIDER) of a concept named after a known drug such as “Methylphenidate” (MeSH), which must appear as a semantic annotation (annotation graph) within publications (PubMed) or clinical trials. The average execution time recorded for the test query does not exceed 0.8 s when run on a Intel Core i7-4790 processor at 3.60GHZ with 16GB RAM. We consider such execution times as suitable for integrating ADHD-KG queries in clinical, training or research processes , which interconnects various biomedical vocabularies including MeSH. In particular, every pair of textual mention and medical concept is validated by online term-based queries against the UMLS Metathesaurus database.In what concerns quality of query output, results were thoroughly examined by a team of 5 clinical experts in adult ADHD (one of which is co-author), who were involved in the planning, design and validation of ADHD-KG. These experts were contacted and asked to provide 10 questions needing answer through ADHD-KG, ranging from simple questions  to open questions . The objective of the validation process was to compare answers generated by ADHD-KG to the answers expected by the experts. The criteria for evaluation were how relevant and correct the produced answers are. A detailed summary of the evaluation results is depicted in Table Each question is transformed into a SPARQL query, which is issued against ADHD-KG and results into a number of resources. These include text summaries , semantic annotations within text or database entries such as medicine or medical concepts. Resources are used to inform the answer for the question under consideration and they result from the triple matching procedures as part of querying the ADHD-KG. Depending on the complexity of the question, aggregation is applied to provide a more direct answer. In particular, for questions that afford quantification, such as ordering entities based on some constraints, post-hoc aggregation procedures were applied to generate representative frequencies or plots.Upon resource retrieval and generation of direct answers (when applicable), each expert was contacted separately and was asked to rate generated answers according to the criteria of relevance and correctness.In terms of relevance, experts were presented with a random sample of 10 retrieved resources for each question, which were rated as “irrelevant” or “relevant”. Correctness was estimated by asking experts to classify the generated plots or frequencies as“valid” or “invalid”. In cases where the retrieved resources could not be aggregated, these were excluded from the estimation of the overall correctness; we denote these cases with “N/A” under correctness. The final scores of relevance per question are estimated by averaging the individual expert ratings and converting them into percentages depicting the overall agreement. For correctness, we used majority voting .In most questions, ADHD-KG results were considered relevant and correct by experts, confirming correspondence to relevant research in ADHD. The experts did note that ADHD-KG query output sometimes included information that may be considered outdated. This is due to the fact that the queries that were executed were time insensitive, therefore an exhaustive set of results was returned. The overall relevance of the retrieved resources across all 10 questions is 77%, whereas the validity of the generated result is 85%. It is worth noting that 7 out of 10 questions were addressed with a direct answer in the form of a chart, but the remaining three  are quite elaborate to be quantified with simple aggregation. The score of 85% considers only the 7 questions were a direct answer was possible, with 6 out of 7 returning a valid result.Elaborating on relevance results, ADHD-KG excels in addressing straightforward questions, which are based on medical concepts, for example associating medical documents with medication, side effects, proteins and so on. Relevance drops when answering questions related to textual information; this is prevalent in open questions such as patterns of ADHD onset or differences in ADHD symptoms in the presence of co-occurring conditions. Performance is expected to be affected in such scenarios, since these rely on text understanding, which is not implemented in ADHD-KG, apart from preliminary annotation of text in terms of medical concepts. Extending the annotation and connection graph Section “” with a It should be noted that this is a preliminary validation, thus we excluded completeness of the generated answers. We intend to follow this expert-based validation which confirmed the appropriateness of ADHD-KG in answering relevant questions, with a wider clinician-oriented validation phase as discussed in Section “Clinical queries include scenarios where a doctor treating a particular patient needs to investigate relevant knowledge in ADHD literature, in order to decide the best course of action. For instance, they may need to find an alternative medication that limits unwanted side effects or gain insights about a case by examining correlated clinical trials.Training queries focus on supporting junior clinicians in learning the basics of the ADHD domain, such as ADHD medication that impedes sleep quality or mental disorders known to hinder the ADHD diagnosis.Medical queries refer to queries about the latest developments in the field of ADHD, which medical experts and researchers wish to explore. These may indicatively involve applied scenarios, such as progress in using stimulants to improve emotional dysregulation, or prevailing questions, such as reviewing literature that explores whether ADHD diagnosis increases stigma.By querying ADHD-KG instead of conducting a laborious manual search, we expect efficiency improvements in all three contexts: reduced time taken to identify appropriate treatment, faster training processes reducing the reliance of junior clinicians to senior colleagues and easier access to state of the art in adult ADHD for medical experts and researchers. In the long term, these efficiency improvements depend on the ability of ADHD-KG to account for the latest developments and debates in relevant literature, given the fact that contributions in ADHD research are quite frequent. The modular architecture of ADHD-KG allows for effective maintenance and evolution practices by enabling on-demand updates on the individual constituent graphs through the integration pipeline described in Section “We identify three major use cases, in which ADHD-KG has the potential to improve current practice. These relate to answering clinical, training and medical queries, as follows:In this section, we expand on the contributions of ADHD-KG to relevant academic communities, in particular researchers within the ADHD and Artificial Intelligence in healthcare fields. In addition, we provide some insights on how the proposed technology can be integrated with complementary emerging technologies using Large Language Models (LLMs).As medical practice becomes more complicated and the available literature on ADHD is increasing, experts face difficulties in retrieving the best evidence to inform their practice, research or clinical trials. This task becomes a notable challenge, when considering that medical literature is often distributed in several knowledge sources with disparate schemas , raising the need for manual inspection and association of different resources. ADHD-KG simplifies information retrieval and has the potential to set the foundation for effective medical question answering. Knowledge about ADHD is integrated into a single resource, which facilitates the transition from time-consuming manual reviews of medical literature towards automated semantic search over encoded knowledge using powerful SPARQL queries.Using the developed graph, ADHD researchers are capable of issuing queries referring to medical entities and also considering multiple sources in their search space. As a result, ADHD-KG speeds up the acquisition of medical knowledge by lifting the burden of information alignment and enabling flexible information retrieval. In particular, search with ADHD-KG goes beyond word matching, benefitting, for instance, from class hierarchies of symptoms or categories of medicine. It can also be customised using complex constraints that combine multiple information sources, e.g., retrieve every stimulant that is included in clinical trials, where participants are classified as obese. In addition to these, ADHD-KG can be useful within training processes of junior clinicians and researchers who have limited ADHD-related experience. Instead of the traditional clinical case study approach to demonstrate a learning point, senior colleagues who act as trainers can ask ADHD-KG a specific question and demonstrate the learning point from the provided answer.Another area where ADHD-KG can have a positive impact is related to currency of knowledge. On many occasions, clinical guidelines become obsolete as soon as they are published, therefore valuable time is spent by clinicians and researchers to seek the most up-to-date knowledge. ADHD-KG supports time-sensitive information retrieval. All entries are associated with time references , allowing users to discern whether an entry is deprecated or contemporaneous, thus keeping track of their currency and validity. Through the frequent update cycle that is planned for ADHD-KG, we ensure that the latest information is always included.The importance of ADHD-KG as a collection and integration of high-quality knowledge about the specific disease is topical in that it may complement perfectly recent developments in artificial intelligence and its application to healthcare. Since the publication of ChatGPT,In this work, we propose a procedure for building a Knowledge Graph about adult ADHD by incorporating knowledge from various relevant resources. Data integration technologies provide a well-structured network of knowledge enabling the exploration of various aspects of adult ADHD. This is the first graph for ADHD offering a rich source of information using open Semantic Web standards that can be extended for other disorders. A series of use cases, evaluated by experts, demonstrate the benefits of ADHD-KG showcasing its usability and fast response times compared to manual knowledge discovery or retrieval. ADHD-KG is designed to cover queries related to training, retrieving information about the state of the art on ADHD and assisting diagnosis and treatment.In future work, we intend to extend the ADHD-KG with additional knowledge sources, such as proteins and genes catalogs and electronic medical records, as well as explore data fusion with additional medical thesauri, such as SNOMED. We plan to improve information linking procedures by introducing graph embeddings and through the inclusion of experts in the linking process . Additio


With increased consensus regarding the validity and reliability of diagnosing Borderline PersonalityDisorder (BPD) in adolescents, clinicians express concern over the distinction between BPD and Attention-Deficit/Hyperactivity Disorder (ADHD), and its co-morbidity in clinical settings.The goal of this study was to evaluate differences between BPD, ADHD and BPD + ADHD in terms of co-morbid psychiatric disorders and a range of selfreported behavioral problems in adolescents.Our sample consisted of N = 550 inpatient adolescents with behavioral and emotional disorders that have not responded to prior intervention. We took a person-centered approach  and compared adolescents with ADHD, BPD and ADHD+BPD in terms of co-occurring psychiatric disorders and behavioral problems. We performed a regression analysis to test whether BPD symptoms make an incremental contribution to the prediction of psychiatric symptoms over ADHD symptoms.The severity of almost all co-occurring disorders, aggression, self-harm, suicidal thoughts, and substance use, were higher in the ADHD+BPD group. Borderline symptoms made an incremental contribution to the prediction of psychiatric symptoms beyond the contribution of ADHD.The findings of this study demonstrated that ADHD and BPD have different psychiatric symptomatology. In addition, subjects who meet criteria for both the BPD and ADHD diagnoses may have more severe psychiatric and behavioral problems compared to individuals with only ADHD or BPD.None Declared


Bartonella spp., Coxiella burnetti, Tropheryma whipplei, and some fungi.Blood culture-negative infective endocarditis is a potentially severe disease that can be associated with infectious agents such as Bartonella henselae deoxyribonucleic acid was detectable in the blood samples and cardiac valve with vegetation paraffin-fixed tissue samples. Additionally, an investigation was carried out on patients’ pets, within the context of One Health, and serum samples collected from cats and dogs were reactive by indirect immunofluorescence assay.Reported here are two cases of blood culture-negative infective endocarditis in patients with severe aortic and mitral regurgitation in Brazil; the first case is a 47-year-old white man and the second is a 62-year-old white woman. Bartonella, particularly in patients with weight loss, kidney changes, and epidemiological history for domestic animals.Even though the frequency of bartonellosis in Brazil is unknown, physicians should be aware of the possibility of blood culture-negative infective endocarditis caused by The online version contains supplementary material available at 10.1186/s13256-023-03839-8. Viridans streptococci, Streptococcus bovis, Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, and Kingella spp. (HACEK) group, Staphylococcus aureus, or community-acquired enterococci are classic typical microorganisms causing IE, an infection associated with the proliferation of microorganisms on the endocardium [Coxiella burnetii and Bartonella spp.Infective endocarditis (IE) is a life-threatening systemic infectious disease in which a multidisciplinary group of specialists is required for patient treatment and follow-up. ocardium . Vegetatocardium . The risocardium . The diaocardium , 4, whicocardium , 2, 4, 5Bartonella spp., C. burnetti, and Tropheryma whipplei, some fungi such as Aspergillus spp. and Histoplasma must be searched when facing blood culture-negative infective endocarditis (BCNIE), since these etiological agents are harder to be cultivated in vitro [C. burnetti, Bartonella quintana, and Bartonella henselae are not easy to isolate in blood cultures, and classic Duke criteria do not identify patients with IE.At least two separated positive blood cultures samples, with typical microorganisms, are required to meet major microbiological criteria. Gram-negative bacillus such as in vitro –9. SpeciC. burnetti and Bartonella spp. in the last decades in Brazil. The genus Bartonella is recognized as the second most frequent etiological agent in HACEK group, non-HACEK groups, and BCNIE. B. henselae is the most prevalent of the 14 species of associated with Bartonella endocarditis. This species is also known to be the main cause of cat scratch disease (CSD), a typical zoonotic disease in Brazil [B. henselae [In this context, serological and molecular methods have become an important tool in the detection of n Brazil . Althoughenselae –13, dogshenselae .Bartonella [The risk is not limited to clinical cases in humans; dogs and cats can also develop cardiac complications related to infection by rtonella , 16–20. rtonella . The mosrtonella . Thus, trtonella .Bartonella endocarditis, although we have been working on retrospective studies since 2006 [B. henselae endocarditis associated with Bartonella-infected domestic animals during the COVID-19 pandemic in Rio de Janeiro, in the southeast region of Brazil. We considered the modified Duke criteria to establish the diagnosis of IE caused by Bartonella, including the presence of titer Immunoglobulin type G (IgG) antibodies against Bartonella spp. ≥ 800 of dilution and a positive result of molecular testing obtained from cardiac valve and blood samples.In Brazil, where most cases of endocarditis are found in the Southeast region, we still have few epidemiological data on nce 2006 , 22–24. A 47-year-old white man was admitted to Pedro Ernesto University Hospital of the State of Rio de Janeiro (HUPE-UERJ) with a history of tachycardia palpitations, atrial fibrillation associated with recurrent episodes of fever, and weight loss of 3 kg in the last 40 days. At admission, he had a mild acute kidney injury, with hematuria and no proteinuria. The echocardiogram showed severe mitral and aortic stenosis associated with rheumatic valvular disease and aortic valve vegetation, with normal left and right ventricular systolic function. He was febrile and had high levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF). As comorbidities, he had tooth infections and recent untreated nephrolithiasis. Three sets of blood culture samples were collected at admission, and they were all negative. Antibiotic therapy was withheld since there was no clear evidence of vegetation seen on transesophageal echocardiography (TEE). However, there was a severe aortic insufficiency with clear evidence of rheumatic valve degeneration, and due to the risk of imminent death, the patient was referred for a surgical procedure. The entire surgical procedure was performed using transesophageal echocardiography and an aortic valve was evidenced with fusion of its cusps and friable additive image, compatible with vegetation caused by infective endocarditis. The valve was resected and it was possible to see an abscess affecting the mitral aortic curtain. The mitral valve was also rheumatic and dysfunctional. The two valves were replaced uneventfully and the extracted material was sent for analysis. The collected samples were analyzed by the pathologist in the operating room, confirming the diagnostic suspicion Fig. . SamplesBartonella considering a cut-off titer of 64  for antibodies anti-gltA, groEL, and htrA genes were evaluated by routine of the National Reference Laboratory for Rickettsioses (NRLR), Oswaldo Cruz Institute (IOC), and Oswaldo Cruz Foundation (FIOCRUZ) and segments of Bartonella genes were amplified , the DNA sequence of groEL was similar 100% to HQ704721 B. henselae isolate of feral cat blood, and the DNA sequence of htrA was similar 100% to CP020742, B. henselae strain Houston-I  assay, despite blood, serum, and plasma samples being negative, the PCR assay on the paraffin-fixed tissue samples targeting the The patient had two adult dogs, and one of them slept with him and his wife. Serum samples collected from the patient’s wife were nonreactive. Dogs were assessed by veterinarians for the presence of ectoparasites, general aspects of health, and living conditions in the home environment Fig. . Blood sPatient 2 is a 62-year-old white woman with a history of chronic renal disease, anemia, and reported loss of 10 kg in the last 9 months. She was admitted to the Pedro Ernesto University Hospital of the State of Rio de Janeiro (HUPE-UERJ) to explore the cause of consumptive syndrome. She had undergone a mitral valve prothesis replacement with a biological prosthesis 2 years before due to complications from rheumatic heart disease. Echocardiography revealed a dysfunctional biological mitral valve associated with rheumatic valve disease. The patient also had acute on chronic renal failure with hematuria, severe anemia, splenomegaly, paratracheal lymphadenomegaly, and arterial hypertension, associated with high levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF). During hospitalization, kidney biopsy showed glomerulonephritis with crescents, tubular atrophy, and interstitial fibrosis. Blood culture samples were all negative and the patient was treated with ceftriaxone and doxycycline. She improved and was discharged for outpatient follow-up.Bartonella IgG-antibodies: (i) with titers of 8192, without antibiotic treatment, and (ii) with titers of 512, subsequently after antibiotic treatment  to research etiologic agents associated with BCNIE . Since the first publication of infective endocarditis due to Bartonella spp. confirmed by serologic test in Brazil, few cases of this endocarditis infection have been reported, although cases of cat scratch disease (CSD) are often reported, especially in the southeast Brazilian region [n region .B. henselae. Often the Bartonella diagnosis is determined using serological tests, mainly by IFA. In this study, the patients presented high IgG-antibodies titers to Bartonella spp., a fact that allows the confirmation of BCNIE caused by this zoonotic agent exclusively by serological testing, since the IFA results with IgG titers ≥ 1:800 have a sensitivity of 90% and specificity of 99%.On the basis of clinical and diagnostic protocols in this case report, both patients met the evaluation criteria for infective endocarditis associated with blood culture-negative, a heart disease infection often severe and difficult to diagnose. In view of the inconclusive microbiological research with blood cultures, serum samples collected from the two patients and cardiac valve tissue sample (patient 1) were analyzed by both serological and molecular tests and the results confirmed infection by B. henselae species as the causative agent of BCNIE. Since 2009, the National Reference Laboratory for Rickettsioses/Ministry of Health (NRLR), Laboratory of Hantaviruses and Rickettsiosis, Oswaldo Cruz Institute, and FIOCRUZ, have been collaborating with our IE team at our teaching hospital. It is the first time we have B. henselae endocarditis in our series of 110 cases of IE defined by modified Duke criteria in Rio de Janeiro, Brazil. The incidence of BCNIE in this Brazilian cohort was 10.9%, although the frequency of BCNIE in review of IE in low- and middle-income countries during the years 2002–2017 ranged from 10.8–69.1% [Subsequent molecular analysis performed on blood and cardiac tissue  sample collected from patients allowed for the identification of the .8–69.1% .Bartonella IE cases are a classic example of a zoonosis where a One Health approach must be applied [B. henselae, a multidisciplinary team carried out visits at the homes of both patients. The participation of a veterinarian allowed for the handling of domestic animals, the collection of blood samples, and the search for ectoparasites in these animals. From the epidemiological inquiry, both patients maintained very close contact with the animals, living with the pets until bedtime.These  applied . After tBartonella spp. in the patients’ pets. Information regarding intimate contact with these pets, as well as our serological results, reinforce the likelihood of contagion through this human–pet relationship. It is interesting to consider that during the isolation caused by the SARS-CoV-2 pandemic, this contact between humans and their pets increased, which may have facilitated exposure to B. henselae. In this context, the presence of ectoparasites and the possibility of injury caused by scratches can facilitate the inoculation of this agent in humans [Serological investigation of domestic animals showed IgG reactivity to n humans , 26, 27.Bartonella spp. having already been reported in other studies from Rio de Janeiro [Bartonella that cause infections in humans and animals, also considering the non-specificity of this bacteria genus, which can be found in humans as well as in domestic and wild animals in several different environments [Despite evidence of circulation of  Janeiro , 28, in  Janeiro . The forronments , 29, 30.Bartonella henselae infection exemplify two difficulties in defining Bartonella IE. Firstly, finding the vegetation in the valvular endocardium in the echocardiography proved to be very difficult. Secondly, although both patients had a subacute temporal course with weight loss and changes in kidney function, they did not have vascular phenomena. Bartonella endocarditis is a diagnostic challenge even for cardiac surgery referral centers. Health professionals should be alert to an atypical case of infective endocarditis, especially when patients have weight loss, kidney injury, and epidemiological history for domestic animals with ectoparasites.Our two cases of Additional file 1:Methods S1. Serological and molecular investigation. Table S1. Serological results of serum samples of the patients and their pets. Table S2.Bartonella species detected in paraffin-fixed human tissue and blood samples from Patients P1 and P2.


Bartonella colonizes endothelial cells (ECs), enters the bloodstream, and infects erythrocytes. Current research primarily focuses on investigating the interaction between Bartonella and ECs and erythrocytes, with recent attention also paid to immune-related aspects. Various molecules related to Bartonella’s pathogenicity have been identified. The present review aims to provide a comprehensive overview of the newly described molecular and immune responses associated with Bartonella’s pathogenicity.Bartonellae are considered to be emerging opportunistic pathogens. The bacteria are transmitted by blood-sucking arthropods, and their hosts are a wide range of mammals including humans. After a protective barrier breach in mammals,  Bartonella into three phylogenetic clades, which include the honeybee symbiont Bartonella apis, the pathogenic Bartonella tamiae, and the eubartonellae, which are further separated into Bartonella australis and four distinct lineages  facilitated by dendritic cells (DCs) and Bartonella effector proteins (Beps)  . Subsequs (Beps) .Bartonella bacilliformis, Bartonella quintana, and Bartonella henselae are three major species that trigger pathological angiogenesis during infection in humans. These three species are the etiological agents of Carrion’s disease, trench fever, and cat scratch disease (CSD), respectively  typically survive in arthropod feces for several days  cats  cats . Althougted cats . Bartonemophilia , and theB. henselae underscores the likelihood that this applies to most Bartonella species , along with other bacteria like lla spp. , utilizella spp. . The patlla spp. . The Virnvasomes . Inducednvasomes . BepF isnvasomes . BepC convasomes .Bartonella from the dermal niche to the blood-seeding niche. It is achieved by translocating BepE into host cells, which inhibits cell fragmentation caused by BepC or other Beps and ensures the migration of Bartonella-infected DCs to deliver the pathogen from the derma site to the blood-seeding niche , followed by elevated cAMP levels   , but theian host , 2019. Tian host . Bartoneradation . Plasminradation . The seqeriments . As a reentering .Bartonella expresses surface adhesins, such as Bartonella adhesin A (BadA) in B. henselae (B. quintana (Bartonella repeat protein A (BrpA) in Bartonella vinsonii  and C-X-C motif chemokine ligand (CXCL) 8 , is identified as a key Bartonella-derived mitogenic factor , nucleotide-binding oligomerization domain-containing protein 1 (NOD1), and epidermal growth factor receptor (EGFR) are identified as the receptors involved in the recognition of B. henselae by MSCs  8 , contribcted ECs . Anotherc factor , 2022. Bc factor . BafA fa of BafA . In addi by MSCs . Meanwhiogenesis . The maiBartonella is divided into three main stages: adhesion, erythrocyte deformation, and invasion, with various virulence factors involved  are crucial for the invasive behavior of the bacteria. IalB protein locates on the outer membrane of B. henselae  of nfection . CFA washenselae . Autotrahenselae . Comparac region . Meanwhic region .Bartonella after erythrocyte invasion plays a significant role in its spread, aided by the mobility and the lack of organelles in mature red blood cells, posing challenges for treatment selection. Research on Bartonella will provide insight into intracellular parasitology.The undetectable situation of Bartonella can cause a broad spectrum of diseases in humans, and the severity of symptoms is closely related to the immune status of the patients. It can be self-limited in immunocompetent individuals -1β, and IL-6 by J774   .Bartonella has also developed several strategies to evade the host’s immune response. Evasion of innate immune response is a prerequisite for Bartonella to establish intracellular infection in the host. When Bartonella is inoculated at subcutaneous or intradermal sites, it is first and foremost exposed to resident DCs and macrophages. B. tribocorum has been reported to be resistant to phagocytosis in rats (badA knock-out Bartonella strain is more susceptible to phagocytosis by macrophages (Bartonella can inhibit pyroptosis and suppress the expansion of the inflammatory response (Bartonella-containing vacuole (BCV) that can delay lysosomal targeting and destruction  component on the outer membrane that is a well-known ligand for Toll-like receptor 4 (TLR4). However, ccharide . Furtherpathways . During ognition . In the ammation . HoweverBartonella. BadA is proven to be critical for bacterial resistance to the host complement system. A badA-knockout Bartonella birtlesii mutant was susceptible to mouse serum, whereas the wild-type B. birtlesii expressing active BadA was resistant, which could be neutralized by anti-BadA antibodies , and the increase of bacterial load within the cellular niche does not affect the proliferation of DPSCs (The intracellular persistence of nfection , 2003. Rof DPSCs .Bartonella immune escape competes and restricts each other as shown in Bartonella infection, which can even be life-threatening. Therefore, studying the host immune response after Bartonella infection can help understand the causes of bacillary angiomatosis, peliosis hepatis, CSD, and other diseases, and provide new ideas for alleviating the clinical symptoms of patients after Bartonella infection.The host immune response and Bartonella is primarily transmitted through the feces of blood-sucking arthropods or traumatic contact with infected animals. The invasion of Bartonellae in lineage 3 and lineage 4 is facilitated by the VirB/VirD4 T4SS system and Beps protein. The pathogen’s invasion triggers the humoral and cellular immune responses of the host. Particularly, the immune system produces various antibodies to neutralize pathogens, playing a vital role in the removal of Bartonella from the bloodstream.Bartonella species have developed several mechanisms to evade or resist the host’s immune response, which allow them to cause long-termed and repeated bacteremia. Some Bartonella species rely on special LPS structure or are hidden in host cells, while others stimulate the host to produce cytokines that weaken the immune response. Here we briefly summarized the recent findings on how Bartonella interacts with host ECs. Among the well-studied molecules are the trimeric family of autotransporters, α-enolase, and BafA. Additionally, Bartonella infection of MSCs can increase the susceptibility of ECs to Bartonella. The molecular involvement during erythrocyte invasion has also deepened our understanding of Bartonella infection. Investigating the mechanism of Bartonella infection on ECs and erythrocytes is crucial for comprehending Bartonella disease. Despite significant efforts, there remain numerous uncertain aspects that require further investigation, such as fully elucidating the functions of various types of molecules mentioned above. Future studies on Bartonella may require more appropriate in vitro and in vivo infection models, as well as functional genomics studies. Our efforts would be directed toward developing more effective and economical methods for detecting Bartonella in the population, as well as preventing and treating the diseases caused by Bartonella.However, TL and JF contributed to the conception of the review and reviewed and revised the manuscript. XJ, YG, TL, JF, YX, JL, and JS collected and organized the data. XJ and YG wrote the manuscript. All authors contributed to the article and approved the submitted version.


N-dodecyl-N,N-dimethylammonium bromide) is one such representative compound that is a better alternative to a single analogue. It shows excellent surface, antimicrobial, and anticorrosion properties. With a highly efficient synthetic method and a good ecological profile, it is a potential candidate for numerous applications, including biomedical applications.Surfactants are amphiphilic molecules and one of the most versatile products of the chemical industry. They can be absorbed at the air–water interface and can align themselves so that the hydrophobic part is in the air while the hydrophilic part is in water. This alignment lowers the surface or interfacial tension. Gemini surfactants are a modern variety of surfactants with unique properties and a very wide range of potential applications. Hexamethylene-1,6-bis( Interactions at the interface are of fundamental importance in chemistry, physics, and biology. The thermodynamic parameters of these interactions can be modulated using surfactants. Owing to their amphiphilic structure, which comprises a hydrophilic and hydrophobic part, surfactants decrease the surface tension or interfacial tension between two liquids, a liquid and gas, or a liquid and solid. Hence, they can act as wetting, dispersing, and emulsifying agents. These properties enable the production of a large number of products required in household chemistry and cosmetic, pharmaceutical, agrochemical, petrochemical, textile, and paper industries.The dynamic development of surfactant chemistry is a continuation of what was initiated by nature, which created the biosurfactants necessary for the functioning of living organisms. Biosurfactants usually refer to surfactants of microbial origin and comprise lecithin, rhamnolipids, sophorolipids, and emulsan ,2. BiosuCurrently, the widest groups of surfactants that meet the application requirements are nonionic, anionic, cationic, and amphoteric synthetic surfactants. The global demand for these surfactants, including soaps, exceeds 20 million tons per year . The gloCationic gemini surfactants have emerged as a result of the research conducted in this field over the last several years. Gemini surfactants are compounds that are composed of two hydrophilic head groups and two hydrophobic tails linked by a spacer at the head groups or close to them . The spaThe critical micelle concentration (CMC), surface tension (γ), and minimal inhibitory concentration (MIC) of gemini surfactants are a dozen times lower than those of monomeric surfactants. The unique properties of gemini surfactants with a wide range of hydrophilic–lipophilic balance (HLB) render them a very useful and innovative material in chemistry  ,12,13,14N-dodecyl-N,N-dimethylammonium bromide) (12-6-12) deserves a special mention from the viewpoint of application. This review systematically presents the current studies devoted to the structure elucidation, synthesis, properties, and applications of 12-6-12, which can be a safer alternative to the surfactants used so far.There is an increasing interest in gemini surfactants . Among tN-dodecyl-N,N-dimethylammonium units connected with a chain of six methylene groups as a spacer. Bromine ions are present as counterions , which is commonly used as a microbiocide.12-6-12 consists of two nterions . This coN,N-dimethylamine) with 1-dodecylbromide  were reacted in ethanol for the synthesis (yield 70%) . A . A mic),N2 reaction, without the need for ion-exchange columns . The. The7]. Plasmodium falciparum and exhibited good antimalarial activity. They reported the IC50 values of 12-6-12 and DTAB to be 0.22 and 0.5 µM, respectively [The antimicrobial activity of gemini surfactants against algae  and protectively .Recent studies suggest that gemini surfactants exhibit antiviral activity. Khodsiani et al. reported that 12-6-12 and other gemini surfactants with long hydrocarbon chains showed the highest antiviral activity against influenza virus H1N1. This kind of compound may physically interact with hemagglutinin, a glycoprotein on the virus surface, at any dilution, indicating the ability of the compounds to inhibit viral attachment to the cell and the subsequent viral propagation. Apoptotic evaluation of the gemini surfactants highlighted their anti-apoptotic potential, especially for hydrophobic compounds .Recently, considerable attention has been paid to the use of gemini surfactants as corrosion inhibitors for metals and alloys. The mechanism of corrosion inhibition is based on the adsorption of the surfactant molecules onto the metal surface by displacing water molecules and the subsequent formation of a protective film. The mechanism can involve physical adsorption (electrostatic interaction), chemical adsorption (donor–acceptor interaction), or mixed adsorption . The ads12-6-12 shows excellent anticorrosion activity in acidic and salty media . The antThe strong ability of 12-6-12 to adsorb onto a steel surface is responsible for its high anticorrosion activity. Analogous relationships have been demonstrated for metallic surfaces such as zinc surfaces .D. salexigens and can act as a biocorrosion inhibitor even at low concentrations. After 12 days, the corrosion resistance was remarkably greater than that without an inhibitor, and no significant increase in sulfate-reducing bacteria was observed. The MIC against D. salexigens was 0.018 mM. An open-circuit potential experiment showed that this compound is an efficient biocide and corrosion inhibitor [12-6-12 exhibits antibacterial activity against nhibitor .Gemini surfactants, as compounds containing ammonium cations, can interact with oppositely charged compounds and surfaces. Studies have been conducted on the adsorption of 12-6-12 on many non-organic surfaces, such as the silica–aqueous solution interface ,76; hydrMixtures of surfactants and polymers can be used to endow improved properties or novel functions that cannot be achieved using surfactants or polymers alone. Consequently, such mixtures have many practical applications, such as in paint and coating products, food processing, personal care formulations, enhanced oil recovery, and pharmaceutical formulations ,81,82,83Gemini surfactants can interact effectively with biological macromolecules such as DNA . This inGenerally, amphiphiles are known to influence the organisation of lipid membranes, and surfactants have been extensively studied in systems involving interactions with lipid membranes . Above aAlmeida et al. studied the cytotoxicity of gemini surfactants and suggested that the toxicity increases with increasing spacer length and that surfactants with longer tails are less toxic than those with shorter tails . They chKoziróg and Brycki tested the haemolytic activity of 12-6-12 and DTAB in terms of the MIC against the morphotic elements of sheep blood . 12-6-1250 values, which were 5.1 and 3.3 µM for C6 and HEK293, respectively [Zhang et al. studied the cytotoxicity of gemini surfactants against a rat glioma cell line (C6) and human kidney cell line (HEK293) . They prectively . Thus, 12 headspace test was 0% [D. magna, and the IC50 values were 0.65 and 0.38 mg/L, respectively [Research on the ecotoxicity of 12-6-12 and other gemini surfactants is sparse. Generally, these compounds are not readily biodegradable . Howevert was 0% . Garcia ectively . This coin foaming, agrichemical spreading aids, and cleaning;from industrial to personal care applications;phase transfer catalyst;bleach activator;as hair conditioners and fabric softeners.Surfactants are ubiquitous, being key components in a diverse range of complex industrial processes and utilitarian products such as dispersants, solubilisers, emulsifiers, demulsifiers, foaming agents, wetting agents, disinfectants, corrosion inhibitors, antistatic agents, and viscosity modifiers. In the last few decades, significant efforts have been made for the synthesis of new gemini surfactants, fuelled by their remarkably improved physicochemical properties that can be achieved by the modification of structural factors . Cationi12-6-12 was first described 55 years ago, but the increased application interest of this compound can be defined in the 21st century. 12-6-12 can be used in several practical applications .12-6-12 is characterised by excellent surface, antimicrobial, and anticorrosion properties. As a compound that can be obtained economically and ecologically, it is an ideal product that has many industrial applications, including bioapplications .Moreover, 12-6-12 can be used in chemical synthesis for the preparation of supramolecular gels  and as aIn conclusion, quaternary ammonium gemini surfactants are known for their multifunctional utility properties such as antimicrobial, surfactant, and anticorrosion properties. 12-6-12 has all the above mentioned properties of gemini surfactants and can be obtained in a one-step reaction, which is an indisputable and economically justified advantage over other gemini surfactants. Compared to its monochain counterpart, it shows better surface, antimicrobial, and anticorrosion activity and is characterised by a lower toxicity. The use of this compound in concentrations much lower than DTAB while providing the same utility effect makes 12-6-12 a candidate in many applications. Initially, this compound was used in applications as typical quaternary ammonium salts as an interfacial transfer catalyst. Currently, this compound finds potential applications in many different areas of life. Particularly noteworthy is the testing of this compound in biomedical applications. Due to its anticorrosive, biocidal, dispersing, and detergent properties, 12-6-12 can be used as an additive to car fuels and as an anticorrosion and antimicrobial agent in oil pipelines, smart anticorrosion coatings, etc. Hence, the possibility of producing it in large quantities in a one-step, waste-free synthesis is a huge advantage over other gemini surfactants.


Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder among school-age children, characterized by persistent behavioral patterns of inattention and/or hyperactivity/impulsivity. These behaviors can create stress for teachers and negatively affect teacher–student interactions. This study hypothesized that a high frequency of ADHD students in the classroom can increase internal and external entropy, ultimately resulting in a negative stress impact on teachers. The physical concept of entropy, which measures the degree of disorder in a system, was used to better understand this relationship. The study evaluated 177 primary school teachers in their response to interacting with students with ADHD, using the Measurement of Psychological Stress (MPS) to evaluate subjective stress levels and the QUEIs and QUEIp questionnaires to measure structural and personal entropy. Path analysis was applied to identify the factors associated with the total score of MPS. The hypothesis was confirmed, as the frequency of ADHD students had a negative impact on teachers’ entropy levels and personal entropy was found to significantly increase stress levels. The study highlights the negative impact of ADHD symptoms on stress levels and personal entropy of teachers when interacting with students with ADHD. These findings suggest the need for interventions aimed at balancing the frequency of students with ADHD and promoting positive training on stress reduction for teacher–student interactions. The significance of the teacher–student relationship in the social and academic development of students has been extensively documented in various studies ,2,3,4. IADHD is one of the most prevalent neuropsychiatric disorders, especially among school-age children . AccordiThis study incorporates the concept of “entropy”, derived from thermodynamics and information theory, to gain insights into disruptive situations that may occur in the classroom. Entropy, in this context, refers to the measure of uncertainty and disorder within a system . Self-orPsychological entropy can manifest in various ways, such as memory loss, emotional confusion, lack of motivation, or difficulty in making decisions. Psychological entropy can be triggered by various factors, including stress, depression, or anxiety .In the school context, the concept of “structural entropy” and “personal teacher’s entropy” have been measured. Structural entropy refers to a set of physical variables that make up the school environment and somehow influence the behavior of students and teachers, such as classroom disorder, irregular schedules, unclear rules, and classroom noise. On the other hand, personal teacher’s entropy is linked to subjective aspects of the teacher, such as attitudes, behaviors, educational styles, and classroom management approaches .In this study, the hypothesis proposed is that a high frequency of ADHD symptoms may be associated with perceived teacher entropy, both structural and personal, and that this, in turn, is correlated with teacher stress . It is eOut of 372 questionnaires distributed to teachers, only 47% responded to the questions asked. Therefore, the final sample included 178 teachers  aged between 30 and 60 years . On average, the participants had been working as primary school teachers for 19.78 years (SD = 11.03). Specifically, 9.04% had been working for less than 11 years, 14.69% from 11 to 20 years, 50.28% from 21 to 30 years, 11.86% for more than 30 years, and 14.13% did not indicate how many years they had been working in the school. This study included a total of 2339 children, who were enrolled from 177 classes in primary public schools located in Milan and Messina and their respective provinces. The age range of the children varied from 6 to 10 years old. The sample encompassed all the children within each classroom, comprising both clinically normal children and children with clinical conditions.All clinically significant children had received an official diagnosis from healthcare facilities in their respective regions. Among the sample, 4.98% exhibited symptoms of attention deficit hyperactivity disorder (ADHD), 1.2% displayed aggressive behaviors, 3.2% had language disorders, 3.6% experienced difficulties in mathematics, and 2% presented intellectual disabilities. In Italy, students with disabilities typically enroll in mainstream schools and attend regular sections and classes across all educational levels. The teachers were asked to complete a questionnaire, providing information on the number of students with ADHD and other disabilities present in their classrooms. In the present study, teachers filled the Classroom Behavior Survey to describe the prevalence of specific students’ issues. Moreover, the Italian version of Psychological Stress Measure (PSM) ,41 was uThe teachers were asked to complete a comprehensive information questionnaire known as the ‘Classroom Behavior Survey’ (CBS). In this survey, they were required to assess the prevalence of specific problem categories among students, namely aggressive behavior, language-related difficulties, mathematical difficulties, and intellectual disabilities . TeacherPsychological stress was assessed using the Italian version of the Psychological Stress Measure (PSM) ,41. The The Structural Education-School Entropy Questionnaire (QUEIs) is a measurement tool designed to assess the structural elements contributing to the entropy of the school environment ,44,45,46The internal consistency of the QUEIs questionnaire was assessed using Cronbach’s alpha coefficient, which is a measure of scale reliability. The questionnaire exhibited strong internal consistency, yielding a Cronbach’s alpha coefficient of 0.89. This indicates that the items in the questionnaire are highly correlated and collectively measure the intended construct effectively. Pinelli and De Nitto  confirmeThe Personal Teacher Entropy Questionnaire (QUEIp)  is a comThe experiment was conducted following the principles outlined in the Declaration of Helsinki. After obtaining written informed consent from the teachers, they were requested to complete the Classroom Behavior Survey to describe specific aspects related to the students’ issues, the Italian version of Psychological Stress Measure (PSM), the Structural Education-School Entropy Questionnaire (QUEIs) and the Personal Teacher Entropy Questionnaire (QUEIp). The order of presentation of the questionnaires was randomized.Descriptive statistics, such as means (SD) for continuous variables and frequencies for categorical variables, were used to summarize the demographic characteristics of the study population. The Pearson correlation coefficient was then calculated to assess the relationships among the variables. Subsequently, path analysis was utilized to analyze the collected data. Path analysis is a statistical technique used to examine the relationships between a set of independent variables and a dependent variable. It extends the regression model and allows researchers to assess the fit of a causal model based on the tested correlation matrix. In this study, path analysis was employed to evaluate the relationships among the Classroom Behavior Survey, the Psychological Stress Measure (PSM), the Structural Education-School Entropy Questionnaire (QUEIs), and the Personal Teacher Entropy Questionnaire (QUEIp).p < 0.01). The rate of children with aggressive behavior also influenced teachers’ stress levels . On the other hand, the presence of children with math difficulties, language-related difficulties, or intellectual disabilities did not show a significant correlation with teacher stress  = 0.36, p < 0.01. These findings indicate that all students with ADHD contributed to increasing teachers’ personal entropy  = 0.58,  entropy .p < 0.01), while structural entropy did not show a significant correlation with stress perception (r (177) = 0.221, p < 0.09). The subscales of the PSM that correlated with stress perception were loss of control (r (177) = 0.408, p < 0.01) and sense of effort and confusion (r (177) = 0.538, p < 0.01). p < 0.001), the rate of children exhibiting aggression in the classroom , and personal entropy. Likewise, personal entropy has a significant positive effect on stress . However, the path involving structural entropy was not found to be significant.Path analysis was conducted to estimate the relationships between variables and provide insights into the underlying causal processes. Not all hypothesized links emerged as significant from the analyses, resulting in the elimination of some, such as the presence of children with math difficulties, linguistic problems, or intellectual deficits. The findings of this study validate existing literature emphasizing the significance of the teacher–student relationship within the school environment. The interaction between teachers and students is recognized as a vital factor influencing both academic and social development ,2,3,4. PThe study provides valuable insights into the relationship between ADHD students in the classroom, teacher entropy levels, and stress. The initial hypothesis that a high frequency of ADHD students would increase entropy levels and result in negative stress impacts on teachers was supported by the findings. The presence of ADHD symptoms was found to have a negative impact on both the structural and personal entropy levels of teachers, ultimately leading to increased stress levels.The correlation analysis revealed that the presence of ADHD students and aggressive behavior in the classroom were significantly correlated with higher levels of perceived stress among teachers. This suggests that dealing with challenging behaviors associated with ADHD and aggression can be particularly stressful for teachers. On the other hand, the presence of students with math, language, or intellectual difficulties did not show a significant correlation with teacher stress levels. This highlights the unique challenges posed by ADHD symptoms and aggressive behaviors in the classroom.In this study, the concept of entropy, which originates from thermodynamics and information theory, was employed to examine the connection between students with ADHD and the levels of teacher entropy. Entropy refers to the measure of disorder or uncertainty within a given system. The results suggest that an increased frequency of ADHD symptoms can lead to higher levels of disorder and entropy within the classroom system. This finding aligns with the idea that ADHD symptoms disrupt the learning environment, leading to increased chaos and disorganization ,36,37,38The findings of this study align with previous research that has highlighted the stressful nature of working with students with ADHD. Teachers have consistently rated students with ADHD as more stressful to handle, particularly when they display oppositional and aggressive behaviors. This study contributes to the existing literature by providing a deeper understanding of the relationship between ADHD students, teacher entropy levels, and stress. It underscores the need for interventions aimed at balancing the frequency of students with ADHD and promoting stress reduction strategies for teacher–student interactions.The theoretical implications of this work are significant. By applying the concept of entropy to the classroom environment, this study offers a unique perspective on the impact of ADHD symptoms on teacher stress levels. It highlights the role of disorder and chaos in the classroom system and emphasizes the importance of maintaining a manageable level of internal entropy for effective teaching and learning. These findings contribute to our understanding of the psychological processes underlying teacher–student interactions and their implications for both teachers and students with ADHD.The practical implications of this study are also noteworthy. The results suggest the need for interventions and support systems that address the challenges faced by teachers in classrooms with a high frequency of ADHD students. Providing training on stress reduction techniques and strategies for managing disruptive behaviors can help teachers navigate the demands of teaching students with ADHD more effectively. Creating a supportive and structured classroom environment can also contribute to reducing teacher stress and promoting positive teacher–student relationships.One limitation of the present study is related to the assessment of classroom behavior. In this study, participant behaviors were evaluated using questionnaires, which introduced a level of subjectivity and reliance on self-reporting. Direct observation of real-time classroom behaviors was not employed, thereby limiting the ability to capture the nuanced interactions and intricacies of actual classroom dynamics. Future research could address this limitation by incorporating direct observational methods in conjunction with self-report measures. Additionally, in the Classroom Behavior Survey, teachers were asked to assess the prevalence of specific problem categories, potentially overlooking other possible issues. Therefore, it is suggested that future studies include a wider range of problem categories for a more comprehensive assessment.Another limitation pertains to the unknown baseline stress levels of teachers prior to their interactions with children diagnosed with ADHD. To address this issue, future researchers should employ an ABA design, which involves analyzing the basal stress levels and other personality profiles of teachers before the commencement of the school term (A1) and after two months of interaction with the children (A2). This would provide valuable insights into the potential impact of teacher–student interactions on teacher stress levels and overall wellbeing.All these suggestions would provide a more comprehensive and objective understanding of the phenomenon of classroom behavior. Further investigation can delve deeper into the factors that contribute to the structural and personal entropy of teachers. This may involve assessing the physical conditions of the classroom, teachers’ classroom management practices, and their emotional wellbeing. Also useful may be the exploration of the classroom environment: exploring the impact of classroom environmental factors such as classroom layout, organization, and visual stimuli on teacher entropy levels and stress. This could provide insights into how modifying the physical environment can contribute to reducing entropy and improving teacher wellbeing. Moreover, future research can analyze the investigation of teacher coping strategies: investigating the coping strategies employed by teachers when dealing with the challenges posed by students with ADHD. This could include analyzing the effectiveness of different coping mechanisms, such as mindfulness practices, relaxation techniques, or professional development programs focused on stress management.Future longitudinal studies can examine the long-term impact of teacher stress and entropy levels on their job satisfaction, retention rates, and overall professional development. This would provide a comprehensive understanding of the sustained effects of working with students with ADHD on teachers’ lives. Moreover, the comparison of teacher entropy across educational settings, such as mainstream classrooms, specialized ADHD support programs, or inclusive education settings, could shed light on how varying contexts influence teacher entropy and inform the development of targeted interventions.In conclusion, this study demonstrates that the presence of ADHD symptoms in the classroom has a negative impact on teacher entropy levels and significantly increases stress levels. The findings highlight the disruptive nature of ADHD symptoms and their implications for teacher wellbeing. The study emphasizes the need for interventions that promote a balanced classroom environment and provide teachers with the necessary tools to manage the challenges associated with ADHD. By addressing the stressors and entropy levels in the classroom, interventions can contribute to improving teacher–student interactions and ultimately enhance the educational experience for both teachers and students.