Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder reported in both children and adults; it is often associated with a variety of executive functioning deficits.This study investigated the extent to which working memory and set-shifting are impaired in school children with and without ADHD.This included primary schools in Lepelle-Nkumpi Municipality in Limpopo province, South Africa.A total of 216 children (108 screened positive for ADHD and 108 matched controls without ADHD symptoms), aged between 6 and 15 years, participated in the study. The performance of the two groups was compared on tests of working memory  and set-shifting (Trail Making Test Part B). The scores were analysed as a function of gender and age.The group with possible ADHD performed worse than the neurotypical control group on tasks of working memory and set-shifting. The results did not indicate that gender affected performance. However, the younger age group performed worse than the older children.Children classified as ADHD showed significantly more impairments in working memory and set-shifting than neurotypical controls. Neither test showed any significant difference between male and female performance, whilst age was shown to affect performance on both tests. Early identification and treatment of children with attention-deficit hyperactivity disorder are crucial to their well-being. Barkley’s model stresses the importance of self-directed behaviour to explain the difficulties of children with ADHD. According to this model, successful EF-related behaviour is regulated in the prefrontal cortex and requires the individual to use six self-directed actions: attention, restraint , sensing , speech , emotions and motivations, and finally, planning, to adapt their behaviour and achieve a desired goal. Dysfunction of the prefrontal cortex results in HI, inattention and deficits in EFs.16 Given that EF difficulties are associated with ADHD, this study focused on testing individuals by means of the standardised performance-based measures of WM and set-shifting.Barkley’s EF modelWorking memory refers to systems that are necessary to enable the individual to remember information over the short-term and mentally use this information to learn, understand and reason.17 Baddeley18 proposed two basic subsystems for maintaining information – the visuospatial sketchpad that holds visual information and the phonological loop that stores auditory material. The WM model20 posits that children with ADHD tend to direct their attention to preferred activities, which place minimal demands on the central executive (CE) and the phonological short-term memory (PHSTM). It appears that children with ADHD pay attention to what they prefer, which means that they often display increased inattentiveness on tasks that require more WM function, when compared with neurotypical controls.21 Inattention in children with ADHD is largely related to their WM deficits,22 as an improvement in visual WM is associated with a decrease in symptoms of inattention.2324 A diversity of ADHD symptoms is caused by WM deficits,25 which may contribute to problems with inhibition and variable attention span, such as impulsiveness, and losing track of others’ conversations,2 as children with ADHD tend to display more WM deficits,26 which are not related to the limitations in the hippocampus.23Working memory functions are located in the mid-lateral prefrontal cortex and the interconnected networks, which involve updating, dual processing and serial or temporal recording.27 found increased WM deficits in boys with ADHD, a finding which was contradictory to that of Fried et al.,26 who showed that gender differences were not significant in WM. Similarly, the meta-analytic study by Savci et al.,28 aimed at reviewing the impact of EF in ADHD and its treatment, found no gender differences in WM functioning.In terms of gender differences in WM, a meta-analysis of 11 studies by Maric et al.27 found age differences in children’s ability to sustain memory functions whilst engaging in cognitive activities, whereas Skogli et al.29 reported contrary findings. This suggests that although WM functions are partly determined by environmental factors, the underlying neuropsychological mechanisms remain the same across the different age categories.8There have been mixed opinions as to whether age affects WM functions amongst children with ADHD. Maric et al.Set-shifting is ‘the ability to shift between tasks, to strategize diverse ways to resolve a problem, and to look at events from a different angle.’32 Children with ADHD exhibit difficulties in sustaining attention,2 and more set-shifting deficits, when compared to neurotypical controls.34 However, Irwin et al.30 showed that children with ADHD could sustain attention whilst switching between different domains as effectively as the control groups. This suggests that although EF deficits are more pronounced in ADHD, these deficits are not limited to children with ADHD,35 as the controls also showed deficits.2836 demonstrated no gender differences in set-shifting as measured by performance in neuropsychological tests. It appears that set-shifting improves with age as the older children out-performed the younger ones, who required a longer time to complete set-shifting tasks.36 However, some studies37 suggest that age does not affect set-shifting performance from childhood to early adulthood, as adults with putative ADHD were also found to have impaired set-shifting abilities.31Some studies13 and set-shifting34 amongst children with ADHD appear to be neurologically based. Changes in the frontal lobe are implicated in EF deficits,38 which often lead to behavioural and emotional impairments, functional disturbances and academic failures.39 The frequently observed brain and behavioural abnormalities in ADHD may have genetic origins,40 which suggests that the structural deficits in brain networks require enabling genes and environment to produce functional impairments.40The reported deficits in WMThe main aims of this study were to establish whether children with possible ADHD symptoms have deficits in WM and set-shifting as measured by the Digit Span and Trail-making Test Part B, respectively, and to examine their within-group gender and age differences in performance.A case-controlled, quantitative, experimental design was employed to establish whether children who screened positive for ADHD are impaired in WM and set-shifting. The sample was divided into participants classified as ADHD and matched controls without symptoms of ADHD.Eleven primary schools from rural areas of the Limpopo province of South Africa were selected for the study.44 to identify children with ADHD symptoms. A total of 5451 learners were screened using the DBD rating scale. Children with scores above the 95th percentile were selected as the ADHD group.42 Learners who scored below the 85th percentile formed the control group, in order to decrease the risk of false positives in the group. Children with scores of ≥ 26 on either or both the Inattentive and HI scales, matched for gender and age, were assigned to the ADHD group. These cut-off points were based on the results of the previous study by Meyer et al.,41 which was conducted on more than 6000 children in the Limpopo province and also employed the DBD. The control group, matched for gender and age, was established from the remaining cohort of children, who did not meet the inclusion criteria.Participants were Sepedi-speaking, Grade 1–7 learners, aged 6–15 years, whose teachers and parents completed the Disruptive Behaviour Disorders (DBD) rating scaleN = 216) comprised 100 male and 116 female participants, and contained children who screened positive for ADHD symptoms  and a matched control group . Based on collateral information obtained from parents, teachers and school records, children with cerebral palsy, severe psychopathology, auditory and visual impairments, and intellectual disabilities were excluded from participation in the study.The resulting sample  were recorded.44: inattention (9 items); HI (9 items). The parents also completed the DBD rating scale to confirm the existence of symptoms, as the symptoms must be present in two settings.45 The DBD was used to assess the presence and severity of ADHD symptoms; its 18 items diagnostic criteria are based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)2 as updated from the fourth edition of the DSM-IV-TR.46 The study employed the DBD as it is translated, normed and standardised for the Sepedi-speaking participants.41 Subsequent studies48 found the DBD to be a valid and reliable screening tool for ADHD amongst the Sepedi-speaking school children.Disruptive Behaviour Disorders: The teachers screened the children for the presence of ADHD symptoms using the 18-item DBD rating scale41 For this study sample, Cronbach’s α was 0.74 for the HI scale and 0.79 for the inattention scale.Each respondent was asked to rate the behaviour of the child on a four-point Likert scale: not at all (0), just a little (1), pretty much (2) and very much (3). Cronbach’s α for the targeted population was calculated at 0.92 for the inattention scale and 0.90 for the HI scale.49 were administered to assess the phonological loop (forward digit span) and CE (backward digit span) components of WM.18 Digits Forward (FDS) involves the passive maintenance of verbal information, whereas the backward version (BDS) requires the active manipulation of that information. In the FDS, the participant was presented with an oral series of digits that they had to recall and repeat immediately in the same order, whereas for the BDS, the participants had to recall immediately but repeat the digits in the reverse order. The length of the trials increased; they began with a series of two digits, and one digit was added for each level. Each level contained nine trials of the same length, each divided into a series of three. A series was successfully achieved when the participant did not make any errors in at least two of the three trials. If the participant did not achieve a series, the task was discontinued. One point was awarded for each span level that was successfully achieved. Higher score indicates more effective WM functions. Adequate psychometric properties have been established for the subtest.49 Internal reliability ranges from 0.83 to 0.90, with construct validity of 0.1-0.5.50 The Cronbach’s α for this study was calculated at 0.78.Both Digits Forward and Digits Backward from the Wechsler Intelligence Scale for Children – Fourth Edition (WISC-IV)51 measures the participant’s ability to keep other matters in mind whilst attending to a task.15 The TMT-B consists of 25 circles which are distributed on a sheet of paper. The TMT requires the participant to connect a series of letters and numbers in ascending order by alternating between numbers and letters .The TMT-B34 Test-retest reliability ranges from 0.60 to 0.90.32 The Cronbach’s α for the present sample was 0.67 and 0.72 for Part A and B, respectively.Participants were instructed to work as quickly as possible, without lifting their pen or pencil from the paper. Whenever the child made an error, this was pointed out immediately, and they were allowed to self-correct. Errors affected the score as their correction increased the completion time of the task. Higher scores indicate difficulties in set-shifting.52 was used for statistical analysis. MANOVA models were employed to examine probability between-group differences. Between-group differences were established using a 2 × 2 × 2 (ADHD group × gender × age) multifactorial ANOVA. Post hoc analysis (Bonferroni) was used to determine within-group differences (differences in gender and age).Statistica 12.7 Ethical clearance was obtained from the Biomedical Research Ethics Committee of University of KwaZulu-Natal, Durban, South Africa (reference number HSS/1446/015D) and the Department of Education, Limpopo province, South Africa. Principals of the selected schools provided their verbal consent for the study to be undertaken in their schools. Written, informed consent was obtained from parents or legal guardians of the learners to participate in the study. The researchers read out the assent form to children, and, after it was established that they had understood and agreed with the content, they were asked to assent to take part in the study. All children irrespective of age were treated in the same way. Voluntary participation was ensured, as participants were informed that they could withdraw at any stage should they want to do so. Parents of children who obtained positive scores were referred to the nearest hospital for further assessments and management.F = 56.15, p < 0.001, ƞp2 = 0.35. A main effect for age was indicated: Wilks L = 0.90, F = 11.48, p < 0.001, ƞp2 = 0.10, whilst no interactions effect was revealed for age. Post hoc analysis (Bonferroni) revealed that for both the Digits Forward and Digits Backwards, the older age group performed significantly better than the younger age group (both p < 0.001). An effect size  of 0.35 (ADHD vs. control) can be considered as large and of 0.10 (difference in age) as medium.53Descriptive statistics, the MANOVA and the post hoc results for Digit Span are shown in F = 69.74, p < 0.001, ƞp2 = 0.25. A main effect was indicated for age: F = 49.67, p < 0.001, ƞp2 = 0.19, whilst no interactions effect for age was revealed. Post hoc analysis revealed that the older group performed significantly better than the younger age group (p < 0.001). Effect sizes  of 0.25 (ADHD vs. control) and of 0.19 (difference in age) can be considered as large.53Descriptive statistics, the ANOVA and the post hoc results for Trails-B are shown in 49 and the TMT-B that assesses set-shifting.51 Thus, this study investigated set-shifting by studying the ability of participants to alternate between numbers and letters.This study investigated whether gender and age differences in performance in children with and without possible ADHD may be because of the specific components of the WM system, namely, the active versus passive processing, or the coding, namely, the visuo-spatial or verbal coding, and whether the ability to keep other details in mind whilst attending to other tasks (set-shifting) may be affected by gender and age. In order to achieve these aims, two standard instruments were employed, namely, the two processing conditions of the DS (i.e. forward and backward repetition) that measure passive and active components of WM, respectively,It was found that children who screened positive for ADHD symptomatology performed more poorly than the controls in respect of both WM and set-shifting. Gender did not affect their performance on either the DS or TMT-B; however, specific age differences were detected by both tests.55 which suggested a significant difference between the two groups. The finding of this study supports Barkley’s EF model,15 which posits that children with putative ADHD experience difficulty retrieving information and keeping other details in mind whilst they attend to other activities. A study by Elosúa et al.32 also showed more WM deficits in children with possible ADHD, as indicated by lower scores on both the Digits Forward and Backward tests, when compared with the controls.The results reveal that children with symptoms of ADHD, when compared with controls, showed significantly more WM deficits. This finding is in accordance with those of previous studies,56 which showed higher rates of WM deficits in females with putative ADHD. The absence of gender interaction suggests that group differences in WM deficits may not be due to gender, as has previously been reported, where boys showed significant WM deficits when compared to girls.27 This finding echoes some previous studies28 that found no statistically significant gender differences in WM deficits amongst children with possible ADHD. A study by Piccardi et al.57 also found no gender differences in WM amongst young adults (21–35 year olds) on DS, which suggests that in the case of persons who screened positive for ADHD, at least from childhood through to young adulthood, gender does not affect their ability to remember information over a short period of time, or to mentally utilise such information to learn, comprehend, and reason.This study showed no gender differences in WM deficits in either the group with possible ADHD or the neurotypical controls. This finding contradicts previous findings by Skogli et al.34 The finding that younger children with or without putative ADHD displayed more deficits in WM suggests that the WM functions have possible neurodevelopmental basis associated with the maturation of the frontal lobe. Although it was not the primary focus of the current study, the fact that we could not find the group-related age differences in performance on functions of WM offers an explanation to previous research,24 which reported that frontal lobe matures with age; however, the maturation does not depend on whether the person screened positive for ADHD symptoms. This finding is consistent with some previous studies,58 which found that age significantly improved WM functioning in children with possible ADHD with regard to computerised tasks. In terms of age differences in WM functions amongst children with ADHD, the meta-analytical study by Kasper et al.25 showed that WM functions tend to improve with age amongst children with possible ADHD and typically developing children aged 8–16 years, which suggests that although these functions are partly determined by environmental22 influences, the underlying developmental factors59 and brain alterations that influence WM functioning24 are similar across groups (viz. possible ADHD and Controls). This finding echoed that of Karalunas et al.,23 which suggested that individual differences in visuospatial WM during the late childhood (7 through 13 years of age) predict ADHD symptom improvement as those who performed better in WM tasks also showed adequate improvement in ADHD symptoms. Consequently, older children with possible ADHD would be expected to show improved functioning, as they would have more time to developmentally ‘catch up’ to their typically developing peers.The findings of this study indicate the group independent age differences in WM functions, by showing that older children outperformed their younger peers on the Digits Span measurements, irrespective of whether they have possible symptoms of ADHD. This finding is contrary to some studies, which found that age did not affect the ability of children (viz. possible ADHD and controls) to sustain memory functions whilst engaging in cognitive activities.34 this study found that children with possible ADHD performed poorly and made more errors on the TMT-B, and therefore, often required more time to complete the test when compared with the controls. This suggests that children with putative ADHD exhibit more deficits in set-shifting skills.34 However, some studies found that children who screened positive for ADHD effectively sustain attention whilst switching between different domains.30 Poor performance on the TMT indicates brain dysfunction in the prefrontal cortex, which is responsible for the set-shifting functions.30Consistent with some previous studies,24 This finding converges with that of other studies,35 which reported that children who screened positive for ADHD, irrespective of gender, performed poorly on the TMT-B, and therefore, took more time to complete the task. Consistent with some previous studies,26 older children performed better than the younger age group, who needed more time to complete the TMT-B. This finding departs from that of Rose et al.37 who found no age differences in children’s ability to keep other matters in mind whilst attending to tasks.This study found no gender differences in set-shifting performance, which suggests that although behaviour is influenced by environment or culture, the neuropsychological mechanisms underlying behaviour are the same across genders.21 that children with possible ADHD have difficulty retrieving information from memory and keeping other details in mind whilst attending to different tasks.15 However, Minervino and Pereira60 found non-significant group differences in WM and set-shifting, which suggests that individual deficits may not explain the multifaceted nature of ADHD. The contradictory results may imply that other psychological processes, which were not controlled in this study, may be involved. Whilst neuroimaging was not conducted, the results would be theoretically consistent with deficiencies in the dopamine reward valuation system.38 In line with Seidman et al.,8 this study did not find gender differences in executive functioning, which suggests that whilst diverse environmental and/or cultural factors have impact on behaviour, possibly similar neuropsychological mechanisms underlie the executive functioning in children with putative ADHD across both genders. The fact that older children performed better than the younger age group could imply that ADHD and executive functioning are developmental processes.28 In addition, the age of the sample may account for the lack of gender differences, as the gender-related differences may only be detected from the age of 12 years, with the onset of puberty,59 when pubertal gonadal changes and related increased neural activation in the ventral striatum play a pivotal role in heightening ADHD symptoms.7 The ventral striatum is a part of the brain’s reward system that increases in typically developing pubertal samples, following positive reward, and is associated with heightened gonadal hormones.7Overall, these findings suggest that children with putative ADHD displayed more EF deficits, which supports Barkley’s model26 and set-shifting acuity,35 often perform poorly at school when compared with the typically developing control group.4 Earlier identification and intervention for children screening positive for ADHD and EF deficits can improve the functioning of these children.The implications of this study are that children with putative ADHD symptoms are significantly impaired in WM and set-shifting skills. The literature suggests that children with possible ADHD, and with deficits in WMFirstly, the homogeneity of the sample, as our mean age was 10 years, limited a significant representation for adolescents. Secondly, the sample only represented Sepedi-speaking children from one specific area in Limpopo, and therefore, cannot be generalised. For further investigation, heterogeneous samples, where different measurements are used, should be considered.2.The current study showed that children with possible ADHD symptomatology display more deficits in WM and set-shifting when compared with controls without putative ADHD. Amongst children classified as ADHD, no gender differences were found in their performance on the selected tasks of EFs, whilst the younger children appeared to be significantly impaired on both WM and set-shifting, compared with the older ones. Children with possible ADHD and executive dysfunction are more likely to be significantly impaired in both academic and social functioning, given their poorer attention, concentration, memory and impulsiveness4 which has clinical implications for the management and treatment of these children.This debilitating effect of executive dysfunction in children with putative ADHD has been demonstrated in the literature,


Estimates of the expected co-occurrence rates of idiopathic language disorder and attention-deficit/hyperactivity disorder (ADHD) provide a confusing and inconsistent picture. Potential sources for discrepancies considered so far include measurement and ascertainment biases , 2016b. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition language disorder  communication disorder designation provided the clearest segregation of idiopathic language deficits from elevated ADHD symptoms, showing only a 2% co-occurrence rate. In contrast, applying the broader developmental language disorder designation raised the observed co-occurrence rate to 22.3%. The specific language impairment designation yielded an intermediate value of 16.9%.The Co-occurrence rates varied as a function of designation adopted. The presence of pragmatic symptoms exerted a stronger influence on observed co-occurrence rates than low nonverbal abilities. Impacts on clinical management and research priorities are discussed.https://doi.org/10.23641/asha.13063751 Children affected by language disorders represent a heterogeneous group. For some children, their acquisition of linguistic proficiency is complicated by either injury or concomitant neurodevelopmental disruption or both. Language outcomes within groups of children affected by clinical conditions such as strokes, traumatic brain injury, cerebral palsy, hearing impairments, autism spectrum disorder, intellectual disability (ID), and attention-deficit/hyperactivity disorder (ADHD) have been highly variable, complicating efforts to attribute children's linguistic deficits to their deficits in other areas see . The exiAdvances in Specific Language Impairment Research and Intervention. Specific language impairment (SLI) has been one of the more commonly used terms in research studies to refer to the idiopathic subgroup of children with language disorders . DSM-5 also introduced a new communication disorder, social (pragmatic) communication disorder (S(P)CD), a designation intended to be separate from language disorder and autism spectrum disorder. The primary clinical features of S(P)CD consists of persistent difficulties in communicating for social purposes, in adjusting to listener needs, in following conversational and narrative conventions, and in understanding nonliteral and ambiguous meanings.This research symposium forum article provides the companion report to my presentation at the 2019 American Speech-Language-Hearing Association's (ASHA) Convention Research Symposium isorders . The timisorders , 2018b. isorders . 2017, hn DSM-5;  establisDSM-5 language disorder designations for idiopathic disorder overlap considerably, there are potentially nontrivial differences as well that could affect our capacity to differentiate idiopathic language disorder from other neurodevelopmental conditions and, in turn, could complicate efforts at identifying and treating cases of comorbidity. The main areas of divergence across the SLI, DLD, and DSM-5 language disorder designations are the degrees to which children with concomitant low nonverbal abilities and children with pragmatic symptoms are accommodated.Differential diagnosis is the linchpin of any successful clinical taxonomy, a prerequisite for the just allocation of personalized services to support those who need them when they need them. Molecular genetic studies and other empirical efforts to account for the underlying disruptions involved in disorders are highly dependent on our ability to differentiate one clinical condition from another. Reproducibility and external validity associated with these and other empirical efforts are compromised when researchers apply criteria inconsistently. Furthermore, there are serious ethical and forensic implications for practitioners when their diagnostic decisions are guided by overly permissive criteria or when they deviate too far from evidence-based practices . AlthougDSM-5 language disorder criteria for idiopathic language disorder could introduce another major source of instability.One clinical boundary worth revisiting in this context of increasing diagnostic options is the separation of idiopathic language disorder from ADHD. Commonly cited estimates of the expected co-occurrence rates of idiopathic language disorder and ADHD date as far back as the 1980s , and newDSM-5 language disorder designations could prejudice our understanding of the boundaries between idiopathic language disorder, and ADHD is examined through an appraisal of the relevant literature and an empirical demonstration. To illustrate potential trade-offs involved in adopting one designation over the others in observed rates of co-occurrence, cases selected from the DSM-5 language disorder extrapolations than those used here. Nonetheless, the absence of universal consensus on how to implement each designation's criteria does not preclude using their differences to explore the clinical intersections among idiopathic language disorder, S(P)CD, and ADHD.In this research symposium forum article, the extent to which differences across the SLI, DLD, and DSM-5 where it is noted that, in academic settings, “children with specific learning disability may appear inattentive because of frustration, lack of interest, or limited ability”  below a standard score of 85. The rationale for selecting language composites rather than tests/subtests targeting only one linguistic domain has been to accommodate for variability across children in their presenting symptoms across expressive and receptive language skills . The excStandardized behavioral rating scales, like the widely used Child Behavioral Checklist CBCL; , represeDifferential diagnosis is a coin with two sides. It is equally important to consider the potential impact ADHD status might have on the valid assessment of children's language skills. For example, when children display signs of inattention and distractibility over the course of a formal language assessment it can be unclear how much faith should be put into the integrity of the information collected. Fortunately, signs of language disorder identified through language sample analysis (LSA) do not require assumptions that children were consistently paying attention to the relevant aspects of the testing prompts or that they understood the task. This makes LSA a particularly apt starting point to consider the potential impact of ADHD on children's language skills. DSM-5 language disorder would enjoy the same level of taxonomic clarity observed with SLI and ADHD is unknown.In summary, when clinical measures are selected carefully and, where appropriate, are adjusted to account for potential overlapping symptoms, differential diagnosis of SLI and ADHD and the identification of their comorbidity can be successfully executed. However, by design, the studies addressing these issues did not include children with concomitant low nonverbal abilities or children who presented with pragmatic deficits only. The presence of concomitant low nonverbal abilities in children with more broadly defined language disorders relative to children with SLI-type profiles has been associated with lower levels of language performance, slower language growth, and higher levels of risk for emotional and behavioral disorders . Thus, tSDs below age expectations). Although a relatively understudied subgroup of children, prevalence estimates suggest that children with this profile represent 3.4%–6.9% of the student population CD. As an integrated scheme, adjustments that occur within one clinical designation across editions of the DSM taxonomy have both intended and unintended consequences on other clinical designations. For example, major adjustments in the criteria for autism spectrum disorders occurred over the transition from Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision , whereas in the current DSM-5 taxonomy, language impairment is no longer a required element for diagnosis but instead represents a potential specifier for autism spectrum disorder. These adjustments resulted in fewer individuals meeting DSM-5 criteria relative to DSM-IV TR criteria CD designation, which shares some of the social communication features with autism spectrum disorder but is differentiated from it by the severity/scope of these difficulties and by the absence of restricted, repetitive patterns of behavior, interests, and activities. The criteria for S(P)CD stipulates further that it represents a condition separate from language disorder.The  DSM-IV;  TR to DScriteria . Some ofDSM-5 taxonomy relevant to considerations of idiopathic language disorder include historical changes replacing the mental retardation designation with the ID designation CD designation, but they would include cases with co-occurring low nonverbal abilities/borderline intellectual functioning. More specifically, the DSM-5 criteria combine cases that meet SLI criteria with cases of concomitant nonverbal abilities that are below normal but do not meet suggested thresholds for ID (IQ standard score < 70). The CATALISE DLD designation would include all cases meeting S(P)CD criteria, with or without accompanying deficits in other areas of language. Like the DSM-5, DLD criteria also incorporates cases of low nonverbal abilities/borderline intellectual functioning down to the current thresholds of ID, provided either S(P)CD-type deficits or deficits in other language areas were present. Although hotly contested  were invited to participate in laboratory-based confirmatory assessments. Examiners conducting the confirmatory assessments were naïve to children's screening performance and to any clinical services these children were receiving at the time of testing . Twelve of these cases (cell C) met CBCL criteria for ADHD (23%). Most of the cases that met criteria for language impairment  did so within the context of measured estimates of their nonverbal abilities within the normal range (cells H + L). Eleven of the 45 children with a profile consistent with an SLI designation (24.4%) received behavioral ratings from their parents that were consistent with ADHD status (cell H). Eight of the children with SLI-type profiles (17.8%) met our criteria for S(P)CD (cells R + Y).Seven of the 52 children with language impairment (13.5%) met our criteria for NLI—namely, below-average performance (< 80) on the NNAT (cells G + K). One of these seven children with an NLI profile (14.2%) met our criteria for ADHD (cell G). Three children with NLI profiles met our criteria for S(P)CD . Thus, relative to rates associated with SLI, NLI was co-occurring more frequently with pragmatic limitations and co-occurring with elevated ADHD symptoms at a comparable level. These group comparisons, however, are limited by the small number of observed NLI cases.There were 40 children who met our criteria for S(P)CD (cells O + Q + S + U + W + Y + AA + CC). Eighteen of these children (45%) also met out criteria for ADHD (cells O + Q + S + U). Twelve of these children (30%) presented with a profile consistent with an SLI designation (cells Q + W)—but most of those (10/12) were accounted for by co-occurring ADHD + SLI . Three of the 40 children (7.5%) with elevated S(P)CD symptoms presented with low nonverbal abilities (cells O + S + W + AA). Thirteen of the 40 children (32.5%) with elevated S(P)CD symptoms represented cases of “S(P)CD only.” In other words, roughly a third of children assigned S(P)CD status did not meet our thresholds for assigning ADHD status and displayed normal levels of general verbal and nonverbal functioning as indexed by their CELF-4 and NNAT scores.DSM-5 language disorder, and SLI). Then, for each designation, the number of cases that met both was divided by the total number of cases that met either. For example, the co-occurrence rate of DLD and ADHD was calculated by taking the number of comorbid cases and dividing that value by the sum of all cases of DLD and all cases of ADHD: DLD-with-ADHD / (DLD-with-ADHD + ADHD only + DLD only).Co-occurrence rates were recalculated by pooling all cases that met our criteria for ADHD status with those that met criteria extrapolated from each of three different designations of idiopathic language disorder CD. This separation of linguistic domains parallels clinical traditions of distinguishing speech sound disorders from language disorders for the purposes of clinical management, even though linguistic theories and psycholinguistic models consider phonology to be a primary construct that interacts in important ways with other language constructs. To incorporate this separation in our calculation of DSM-5 language disorder cases, we combine cells P + R + X + Z = 32. When we exclude children with significant pragmatic deficits from consideration, the single case of co-occurring DSM-5 language disorder and ADHD without S(P)CD appears in cell R. This leaves the number of “DSM-5 language disorder only” cases at 31. The 13 cases of “ADHD only” that do not include elevated pragmatic symptoms are represented in cell V. Using these values, the co-occurrence rate of DSM-5 language disorder and ADHD is quite modest: 1 / (1 + 31 + 13) = 2.22%.In contrast, the Criteria for SLI have been used for decades in research studies to address questions regarding the scope, progression, and underlying nature of language disorder in children when confounding nonlinguistic conditions are controlled. Children with co-occurring speech sound disorders are usually  excluded from study samples of SLI as well see . In contShifting enthusiasm for new terms and new criteria for idiopathic language disorder places the field of child language disorders in an interesting and potentially vulnerable place. As laid out by the CATALISE group, there are several reasons to prefer a term over its alternatives . In thislanguage disorder as defined by the DSM-5 taxonomy (DSM-5 language disorder), which introduced S(P)CD as a separate designation for pragmatic symptoms but allows for the inclusion of cases with accompanying low nonverbal abilities into its language disorder designation; (b) SLI, which allows for social/pragmatic symptoms when they are concomitant with semantic, syntactic, and/or verbal memory symptoms but excludes cases with low nonverbal abilities; and (c) DLD, which accommodates both social/pragmatic symptoms and low nonverbal abilities in its designation. Eighty-five cases from the Three different designations for idiopathic language disorder enjoying currency within the research literature and clinical practice were examined to address this question: (a) DSM-5 language disorder designation appears to be preferred over the others considered in this analysis. The DSM-5 taxonomy, which separates profiles involving syntactic, semantic, and/or verbal memory deficits from profiles involving pragmatic deficits, displayed minimal (2%) overlap with cases of ADHD. In contrast, a 10-fold increase in relative co-occurrence rate was observed with the more inclusive DLD criteria, where pragmatic deficits represent one of the many possible manifestations of the DLD phenotype . The SLI criteria, which exclude cases of concomitant low nonverbal ability , arrived at an intermediate value of 16.9% co-occurrence with ADHD.Observed co-occurrence rates within the convenience sample varied dramatically based on criteria used. For the purposes of establishing co-occurrence rates for idiopathic language disorder and ADHD, the The amplification of ADHD co-occurrence rates brought in by the inclusions of pragmatic deficits and, to a lesser extent, low nonverbal abilities potentially impacts other aspects of research practices in child language disorders. For example, future studies using the SLI designation to explore the socioemotional development of affected children should consider the potential explanatory value that pragmatic deficits and their links to ADHD might have on observed differences between groups and the variability observed within groups. Depending on the nature of the research questions being asked, this can be accomplished through the selection of participants that do not bias toward supporting the hypothesis  or through statistical modeling . These considerations should apply as well to studies employing the DLD term but applying the SLI criteria  to their study samples. For studies embracing the broader DLD phenotype , the potential influence of nonverbal deficits on socioemotional development should be considered as well.As currently conceived, the DLD criteria could be adjusted to accommodate for what appear to be rather robust qualitative differences between the S(P)CD profile and other profiles of linguistic deficit when it comes to risk for ADHD and possibly other clinical conditions. For example, a “primarily pragmatic” subtype of DLD, alongside other DLD subtypes, could capture this clinically relevant distinction. The CATALISE group failed to reach consensus on the issue of subtyping, but this is the direction the upcoming International Classification of Diseases (ICD-11) system seems to be embracing.DSM-5's S(P)CD designation might be better conceptualized as a collection of symptoms that cut across various clinical designations rather than as a separate, cohesive, diagnostic entity. This would make the scope of pragmatic deficits comparable to executive function deficits and soft neurological signs that have both been characterized as being highly “transdiagnostic” CD and ADHD. Pragmatic deficits of the kind presently captured by the gnostic” . Transdignostic” .DSM-5's categorical perspective with prominent theoretical accounts. For example, DSM-5 by its S(P)CD designation within the larger contexts of idiopathic language disorder, ADHD, and other clinical conditions will have to await the collection of additional data.The transdiagnostic perspective of S(P)CD-like symptoms probably aligns better than the Co-occurrence rates among disorders represent important considerations in the development of risk models, societal cost estimates, theoretical accounts, and key aspects of clinical management. It is in the best interest of all stakeholders to have a clearer understanding of how often and under what circumstances language disorders and ADHD co-occur and what this entails for individual outcomes. Imprecisions, either at the level of our measurement systems or when brought in by overly flexible clinical constructs and taxonomies, undermine these efforts. In this report, data from a convenience sample initially designed to examine the accuracy of different language screening measures were repurposed to illustrate potential trade-offs in adopting different criteria for idiopathic language disorder. To this end, the data served their (re)purpose. The extent to which the estimates of co-occurrence rates calculated based on this convenience sample, however, would generalize to younger, older, more ethnically/racially diverse, or otherwise different groups of children is unknown. Estimates based on this convenience sample would need to be replicated in independent samples before placing too much stock in them. Arriving at replicable co-occurrence rates would represent a substantial improvement over the current situation, but it would be insufficient to guide clinical management. Unfortunately, co-occurrence rates tell us nothing about how comorbidity among disorders comes about within individual cases. Longitudinal studies following symptoms progression among children affected by idiopathic language disorder, ADHD, and both are needed to delineate the range of risk and protective mechanisms involved as well as their timing in the establishment of comorbidity.Results of this study were limited by the measures selected. Parent ratings were used to estimate the severity of children's ADHD and S(P)CD symptoms. A key advantage to using standardized parent ratings is parents are uniquely situated to observe their children's behaviors across different contexts and over extended periods of time. A potential drawback of relying exclusively on parent ratings, however, is that observed overlaps in this convenience sample could have been a function of shared measurement variance. It is possible that reassessing the clinical intersections among idiopathic language disorder, S(P)CD, and ADHD using teacher ratings, self-reports, or basing them on children's performances on behavioral measures  would yield different results. However, each of these alternatives involves their own psychometric limitations and trade-offs . The arr10.1044/2020_JSLHR-20-00050SMS1TranscriptClick here for additional data file.


An innovative immunosuppressant with a minimally invasive delivery system has emerged in the biomedical field. The application of biodegradable and biocompatible polymer forms, such as hydrogels, scaffolds, microspheres, and nanoparticles, in transplant recipients to control the release of immunosuppressants can minimize the risk of developing unfavorable conditions. In this review, we summarized several studies that have used implantable immunosuppressant delivery to release therapeutic agents to prolong allograft survival. We also compared their applications, efficacy, efficiency, and safety/side effects with conventional therapeutic-agent administration. Finally, challenges and the future prospective were discussed. Collectively, this review will help relevant readers understand the different approaches to prevent transplant rejection in a new era of therapeutic agent delivery. Innovations in immunosuppressant delivery to prevent allotransplant rejection have grown rapidly in recent decades. The immunosuppressant carriers should ideally meet two prerequisites. First, they should deliver the immunosuppressant in a controlled dose directed to the organ target during the treatment period. Second, they should facilitate the active entity of the immunosuppressant to the site of rejection. Conventional systemic drug administrations, such as oral intake, intravenous, intraperitoneal, intramuscular, and subcutaneous injections, are unable to meet any of these prerequisites. To circumvent this, biodegradable polymers  for biomaterial formulation have been developed to provide advantages for immunosuppressant delivery, including the ability to support the local delivery of the drugs at a constant rate, to minimize the dosage requirement and then further enhance drug efficacy, and prevent adverse effects. Moreover, these polymers have good stability and high biocompatibility. Many reports have applied the biodegradable polymers as implantable immunosuppressant delivery carriers and show potential in suppressing transplantation rejection. Herein, we will review the current application of implantable immunosuppressant delivery that employ biodegradable polymers to prevent rejection in allotransplantation.Transplantation is used to transfer an organ, a tissue, or a group of cells from the donor to the recipient (or host) or to different sites in the same individual , with th+ T cells), cytotoxic T cells (CD8+ T cells), B cells, as well as cytokines and antibodies are involved in the direct or indirect immune mechanism of allograft rejection [In a transplantation setting, both innate  and adap cells CD+ T cellsejection , the comejection , anti-inejection ,12, immuejection , and antejection ,15.The early development of immunosuppressants, such as cyclosporine (CsA), tacrolimus (TAC), and rapamycin (RAPA), targeted the T cells pathways . This isBroadly speaking, the transplant recipients may receive pharmacological treatments during the induction, maintenance, or rejection phases ,29 basedImplantable immunosuppressant delivery systems have been devised to localize drug delivery and minimize the side effects of post-transplantation therapies. Implantable immunosuppressant delivery can be made through various systems, such as hydrogels, nano/microparticles , micelled,l-lactic-co-glycolic (PLGA), polyethylene glycol (PEG), and triglycerol monostearate (TGMS) [A hydrogel has hydrophilic properties that are constructed from a 3D network polymer, is able to swell under water, and retains a large amount of water. It is feasible for immunosuppressant delivery because their unique physical characteristic to transform from liquid into a gel due to environmental changes, such as physical stimuli  and chemical stimuli  . Hydrogee (TGMS) ,38. Theye (TGMS) ,38,39. Te (TGMS) ,41.Double-walled polymer microspheres, with a 1–1000 μm diameter size, could be synthesized by emulsification . ScientiNanoparticles have been extensively studied as delivery vehicles for therapeutics. They are called nano since they have a 1–100 nm diameter size . BecauseMicelles and liposomes are vesicular structures composed of lipids that are formed in aqueous solutions. Unlike liposomes composed of lipid bilayers, polymer-based micelles comprise only closed lipid monolayers that are hydrophilic on the polar side and have fatty acids on the core side . PreviouThe scaffold delivery system can be implantable or injectable . ScaffolVarious types of immunosuppressants are used to prevent rejection after transplantation. Recent studies have reported innovative delivery systems to carry immunosuppressants successfully .Immunosuppressants commonly utilized to treat patients who receive allotransplants, such as TAC , RAPA 7, and tofl-alanine) with l-lysine segments at both ends) copolymers [l-alanine) acts as the hydrophobic chain of P-Lys-Ala-PLX copolymers, which have been designed to capture the hydrophobic agents. A drug release kinetic study has shown that P-Lys-Ala-PLX hydrogel releases TAC drugs at a constant rate, indicating that this hydrogel type is appropriate for negatively charged proteins and drugs. A mixed hydrogel is formulated by adding poloxamers (Pluronic® F127) to increase drug encapsulation efficiency and drug release rates. Furthermore, a supplement of methoxy-poly(ethylene glycol)-co-poly(lactic acid)-poly(ε-caprolactone) (mPEG-PLCL) and 0.5% polyvinylpyrrolidone (PVP) improve the stability of the hydrogel such that the drug was released in a stable and sustained fashion for 30 days. The allograft outcome was improved without significantly affecting systemic immune responses [For this reason, potential candidates, including thermosensitive polymer hydrogels, have been developed for TAC delivery. Thermosensitive polymer hydrogels exhibit excellent biocompatibility and biodegradability, have a low concentration requirement for gelation, and rapidly react to temperature change . Chu et polymers  to encappolymers . Poly and is likely to cause rapid burst release. Thus, materials that contain the microcrystalline deposits of drugs encapsulated within an injectable hydrogel matrix can slow down the release rate. Therefore, hydrogel matrices allow drugs to stay localized, but early allograft rejection occurs when the location of administration is too far from the allograft .The recent successful nanoparticle, micelle, and microsphere application for local immunosuppressant delivery systems in transplantation are listed . For ins+ cytotoxic T cell population [Antibodies and peptides that block inflammatory cytokines and interleukins are good candidates to prevent rejection. Naturally derived hydrogels, such as photocross-linkable gelatin-methacryloyl (GelMA)-based hydrogels, have been used for the controlled release of anti-IL-6 for skin allografts. Anti-IL-6 is locally released, as indicated by its local effects, such as less severe inflammation, nonoccurrence of matrix accumulation in draining lymph nodes, and unchanged systemic immune responses . Anotherpulation . On the pulation . Microsppulation . This prpulation . The conpulation ,78. In tpulation ,67,79,80Efficacy and efficiency are very crucial for drug administration. Although the conventional immunosuppressant administration has resulted in the inhibition of the alloimmune response, the dosage may not be optimal. Without the help of biomaterials that can sustain long-term drug release, their effects in recipients will not be long lasting . TherefoTo overcome these problems, localized and sustained immunosuppressant delivery is urgent. Implantable immunosuppressant delivery may be a safer route for drug administration. The several advantages of local immunosuppressant delivery compared to systemic delivery are shown in High biocompatibility of the novel immunosuppressant-delivery systems is indicated by their high flexibility to interact with the cell surface or any protein in the body. Biocompatibility can be tested in vitro or in vivo. In vitro tests cannot replace in vivo tests but can minimize the animal sacrifice . To stanTesting the safety of biomaterials usually includes a sensitization test, an irritation test in animals/humans, and a cytotoxicity assay both in the in vitro and in vivo systems . In vitrThe unique properties of implantable immunosuppressant delivery, such as hydrogels, micelles, and microspheres, are suitable to avoid rapid immunosuppressant release. The ability to transform from solution into a solid form makes hydrogels excellent platforms for localized drug delivery applications. The nanosize of the nanoparticle will enhance the absorption by the targeted organ and the antigen-specific modification will improve their site-specific targeting. In addition, the toxicity studies on these delivery systems have validated their safety. The current literature review of the applications of various implantable delivery systems, including hydrogel-based , modified hydrogel-based systems with scaffolds and peptides, and others  for the delivery of immunosuppressants to allografts, demonstrates that implantable immunosuppressant delivery systems provide many advantages, such as limited toxicity in normal tissues, the localized and sustained delivery of the immunosuppressants in the allograft vicinity, improved stability of the immunosuppressants, increased efficiency of the immunosuppressant effect, and enhanced allograft acceptance compared with systemic immunosuppressant administrations.The effectiveness of these delivery systems for localized immunotherapy has been well characterized with standard in vitro environment protocols. The proof-of-principle demonstrations of their activities in various rodent–porcine allograft models are also encouraging. Although many of the in vivo studies exploring hydrogels have been extensively conducted, studies on nonhuman primates are still required. Moreover, necessary validation of the biocompatible and biodegradable polymers as immunosuppressant-delivery treatment options should be addressed in clinical studies to assess the effectiveness of these drug delivery platforms for allograft treatment.Although the burst release pattern of immunosuppressants after injection is still below the maximum safety dose, modifications may be required to avoid incidence. Furthermore, the site-specific immunosuppression offered by this innovative delivery system is an effective strategy to achieve favorable results without the side effects of systemic immunosuppression. This provides an attractive option, not only in organ transplantation, but also in vascularized composite allotransplantation, where the transplanted allograft is easily visible.


In veterinary medicine, the availability of an easy tool for the immediate evaluation of biological fluids’ composition on site is desirable and beneficial as a first-line diagnostic instrument in many instances and in several animal species. The aim of the present study was to assess the usefulness of reagent urinary test strips marketed for urines for the on-field evaluation of fetal fluids’ composition in newborn dogs at elective caesarean section. From surviving newborns, a collection of 113 amniotic and 107 allantoic samples was performed, and 8 amniotic and allantoic fluids were collected from non-surviving newborns. All the fetal fluids were assessed by urinary test strips within 5 min from collection. Significant differences were found for both types of fluid between surviving and non-surviving puppies, and between medium/large and small-sized puppies. Differences were also depicted between amniotic and allantoic fluids within the surviving group. These results seem to suggest that the on-site analysis of fetal fluids’ composition by reagent test strips could represent a first-line tool for the evaluation of puppies and for the quick identification of puppies requiring special monitoring and assistance.The reagent urinary test strips (TS) marketed for urines represent the first-line diagnostic tool in many instances. Therefore, the aim of the study was to assess the usefulness of TS for the on-field evaluation of fetal fluids’ composition in newborn dogs at elective caesarean section. Of a total of 137 puppies born at term, 127 survived and 10 did not survive. One hundred and thirteen amniotic and 107 allantoic samples from surviving newborns were collected, and 8 amniotic and allantoic fluids were collected from the non-surviving newborns and assessed by strips. Significantly lower amounts of amniotic glucose and higher amounts of amniotic and allantoic nitrites, amniotic protein, allantoic urobilinogen, and amniotic bilirubin concentrations were found in non-surviving when compared to surviving newborns. In the surviving ones, higher specific gravity and bilirubin concentrations, and lower pH, were found in allantoic than in amniotic fluids. Higher amniotic and allantoic glucose concentrations, higher amniotic and allantoic pH, and lower amniotic and allantoic protein concentrations were found in medium/large- than in small-sized puppies. The TS allowed the quick evaluation of fetal fluids in puppies at birth. The differences between surviving and non-surviving puppies seem to suggest that the on-site analysis of fetal fluids’ composition by TS could represent a first-line diagnostic tool in the field of canine neonatology, allowing the quick recognition of puppies needing assistance as a complementary tool for clinical evaluation. In mammals, fetal fluids hold a significant role in the process of fetal development and growth and reflect fetal well-being. As reported by Underwood et al. , amniotiThe composition and amount of fetal fluid changes widely during gestation, with the final form reflecting not only the simple filtration from maternal blood, but also resulting from the activity of the fetus itself . The chaDespite the undoubted utility of those studies, the traditional timing of laboratories for the analysis of fetal fluids does not fit with the need of a quick and easy tool for the first-line analysis of fetal fluids. In this case, as explained above, the immediate assessment of amniotic glucose concentrations at birth could be helpful for the prompt management of newborns. Different to humans, who give birth at hospitals, where laboratories can immediately process and analyze the biological samples, a dog’s whelping occurs more frequently at the owner’s house or at the breeder’s facility. Even when caesarean section is performed, the prompt analysis of biological samples by a laboratory could be difficult to assure.In human medicine, the development of the “dry chemistry diagnostic test” allowed the rapid analysis of urines and other biological specimens under every condition, directly by the patient themself, for a quick measurement of some parameters . The “drIn veterinary medicine, the availability of an easy tool for the immediate evaluation of biological fluid composition on site is even more desirable and beneficial as a first-line diagnostic instrument in many instances and in several animal species. Although marketed for human urine analysis, some studies proved the usefulness of urine analysis reagent strips for the on-field evaluation of uterine lavage fluids in cows , for theBased on the above reported reasons, the aim of this study was to assess, by use of commercial semi-quantitative test strips marketed for human urine analysis: (1) possible differences in fluid composition between amniotic and allantoic sacs in surviving and non-surviving newborns born at term of pregnancy from healthy dogs; (2) possible differences in composition between the two types of fluid in surviving puppies; (3) to assess possible effects of maternal age, parity, by newborn gender, Apgar score, and by breed body-size on the composition of fluids in amniotic and allantoic sacs in surviving puppies.The study was performed in agreement with the animal welfare committee ethical guidelines and it was approved by the Ethical Committee of the University of Milan (OPBA_121_2021). All owners, before every procedure of caesarean section, signed a written informed consent, allowing for both surgery and the specific collection of fetal fluids and clinical records for scientific research.n = 26; 9 Chihuahua, 4 Maltese, 4 Dachshund, 3 toy Poodle, 3 Jack Russell terrier, 3 Pug) and in a combined class of medium and large-sized breeds .The study enrolled 37 purebred dogs, 2–9 years old, 1–6 parity, belonging to several breeds. According to bodyweight, the dogs were grouped in small-sized breeds , providing information about the following 10 parameters: specific gravity (SG), pH (pH), leucocytes (L), nitrite (N), glucose (G), protein (P), ketones (K), urobilinogen (U), bilirubin (BR), and erythrocytes (ERY)/hemoglobin (HB). According to the manufacturer instructions, each strip was dipped into the vials containing the amniotic or the allantoic fluid. After the collection and during this procedure, the vials were constantly put on a shaker in order to maintain the homogeneity of the fluid collected and, after dripping on blotting paper, a wait of 60 s was sufficient to have all parameters apart from leucocytes (readable at 120 s). Results for each parameter were recorded in several categories, according to the manufacturer label: specific gravity (Kg/L), ranging from 1000 to 1030; pH, ranging from 5 to 9; leucocytes, ranging from negative to 1 + (~10–25 cells/μL), 2 + (~75 cells/μL), 3 + (~500 cells/μL); nitrites, ranging between negative and positive (0.05 mg/dL); glucose, ranging from negative to 1 + (50 mg/dL), 2 + (100 mg/dL), 3 + (300 mg/dL), 4 + (1000 mg/dL); proteins, ranging from negative to 1 + (30 mg/dL), 2 + (100 mg/dL), 3 + (500 mg/dL); ketons, ranging from negative to 1 + (10 mg/dL), 2 + (50 mg/dL), 3 + (150 mg/dL); urobilinogen, ranging from normal to 1 + (1 mg/dL), 2 + (4 mg/dL), 3 + (8 mg/dL), 4 + (12 mg/dL); bilirubin, ranging from negative to 1 + (0.5 mg/dL), 2 + (not specified), 3 + (6 mg/dL); erythrocyte, ranging from negative to 1 + (~5–10 ery/μL), 2 + (~25 ery/μL), 3 + (~50 ery/μL), 4 + (~250 ery/μL); hemoglobin, ranging from negative to 1 + (~10 ery/μL), 2 + (~25 ery/μL), 3 + (~50 ery/μL), 4 + (~250 ery/μL). Data about erythrocytes/hemoglobin are expressed as “blood”. The sample positivity was considered as the number and percentage of positivity on the total of strips analyzed for each parameter within each group.Contemporary to the immediate newborn clinical evaluation, and always within 5 min after birth, the fetal fluids belonging to each newborn were immediately evaluated by commercial urine test strips (Combur-Testp ≤ 0.05). The ANCOVA test was used to assess the possible effect of maternal age and parity, newborn gender, and Apgar score on each parameter in both amniotic and allantoic fluids. Statistical analyses were performed by SPSS 15.0  and significance was set at p < 0.05.The Levene’s t-test was used to evaluate any difference between surviving and non-surviving puppies in both amniotic and allantoic sacs fluids, between amniotic and allantoic fluids inside the group of surviving newborns, and between amniotic and allantoic fluids in small and medium/large-sized surviving puppies. Levene’s test was used for homoscedasticity and the Shapiro–Wilk test for data normality ; 6.4 ± 1.85 in medium-large and 3.4 ± 1.39 in small-sized breeds. At birth, 127/137 (92.7%) neonates were alive, healthy, and viable (Apgar score ≥ 7) [From the surviving newborns, a total of 113 and 107 collections were performed from amniotic and allantoic fluids respectively, while the collection of eight amniotic and eight allantoic fluids was performed on non-surviving newborns.In some cases, during the collection of specimens, surgical manipulations prevented the collection, or the presence of gross contaminations induced the operator to exclude that sample from the study.Data about the mean ± SD (range) and number and percentage of the samples’ positivity  for each strip parameter in the amniotic and allantoic fluids of surviving and non-surviving newborns are reported in According to breed body-size, 62 amniotic and 57 allantoic samples were collected from surviving small-sized breeds dogs, while 51 amniotic and 50 allantoic samples were collected in surviving medium/large-sized breeds dogs.Data about the mean ± SD (range) and the number and percentage of samples’ positivity  for the significant parameters in the 113 amniotic and 107 allantoic canine fluid samples, grouped according to breed body-size, are reported in Statistical analysis did not detect any significant effects played by newborn gender, maternal age, parity, and by Apgar score on all the parameters investigated in both amniotic and allantoic fluids within the group of surviving newborns.The present study was proposed to assess the usefulness of the on-site evaluation of fetal fluids collected from surviving and non-surviving puppies born at term of pregnancy from healthy dogs by reagent test strip marketed for urine analysis in humans as a possible complementary tool in the clinical evaluation of newborns immediately after birth to allow a more focused neonatal assistance. The first-line and irreplaceable method to assess the viability of puppies is their clinical evaluation through the APGAR score, but the evaluation of fetal fluids may add important information. All the puppies were born by elective caesarean section, and this represents an advantage because of the homogeneity among the puppies’ conditions, but also a weakness because fluids collected by puppies born by emergency caesarean section or vaginal delivery could be different. Moreover, when vaginal delivery occurs, the collection of fetal fluids for analyses could be difficult, limiting the usefulness of this diagnostic tool. Lastly, it should be underlined that an additional person is needed for fluid collection and prompt analysis.Although a real validation of their use for fetal fluid evaluation is lacking, the commercial reagent test strips have been previously used and validated for uterine lavage fluid evaluation in cows , used foIn agreement with the first aim of this study, differences about the ten parameters tested in both fluids  between surviving and non-surviving newborns were provided. Despite the small number of non-surviving puppies, results showed significantly lower glucose concentrations in the amniotic fluids of non-surviving puppies than surviving, normal subjects. This finding agrees with previous studies, in which lower fetal fluid glucose concentrations were associated with a negative outcome of the puppies ,14, highWhen surviving puppies are concerned, the results from the present study evidenced some differences between the amniotic and the allantoic fluids, in accordance to literature ,13,15 boIn a dog, large differences exist among the many recognized breeds, mainly related to the different body sizes. A study  evidenceNo significant differences were found between both fetal fluids’ composition in relation to newborn gender. These findings contrast, for example, with the finding of higher glucose concentrations in the amniotic fluids of males when compared to females for normal puppies , but agrA last mention to the percentages of positive reactions and ranges for those parameters that did not show significant differences at the statistical analysis. In the present study, leukocytes showed higher percentages of positive reactions in both fluids, slightly higher in surviving than non-surviving newborns, with ranges from negative to 75 cells/μL. The percentage of positivity to leukocytes (0–17%) was, however, slightly lower than the about 50% reported by . KetonesThe findings of this study demonstrated the usefulness of commercial reagent test strips for urine analysis for the quick evaluation of fetal fluids in puppies at elective caesarean section. Although the small number of non-surviving newborns, the differences between surviving and non-surviving puppies seem to suggest that the on-site analysis of fetal fluids’ composition by reagent test strips could represent a first-line tool for the evaluation of puppies and for the quick identification of newborns needing special monitoring or assistance. The comparison between the obtained results and data provided in the bibliography by traditional laboratory analyses cautiously suggest the reliability of the reagent test strips for the on-field assessment of fetal fluids’ composition as a complementary tool in the clinical evaluation of the newborn dog. Further studies should clarify the effect of emergency caesarean section or vaginal delivery on fetal fluids’ composition assessment by reagent test strips. For some parameters, however, further investigations are needed to better define their significance in the clinical assessment of newborn dogs.


The present study aimed to determine the association between attention-deficit hyperactivity disorder (ADHD) symptoms severity, fibromyalgia (FM) severity, and QoL.While the FM group consisted of 113 (74%) patients, the control group consisted of 40 (26%) individuals. FM symptom severity, ADHD symptom severity, and QoL were evaluated using the fibromyalgia impact questionnaire (FIQ), adult ADHD self-report scale (ASRS), and World Health Organization quality of life scale-brief version (WHOQOL-BREF), respectively. It was found that the FM group had significantly higher scores on the ASRS than the control group (p < 0.05). There was a significant difference in FIQ scores and three WHOQOL-BREF domain scores between the FM alone and comorbid FM/high probability of ADHD groups (p < 0.05). We found a negative correlation between ASRS total scores and all other scale scores  and a positive correlation between ASRS total scores and FIQ scores in FM patients. ADHD scores would mediate the relationship between depression severity and QoL.Our findings indicated that the presence of ADHD symptoms was related to greater FM symptom severity and poorer QoL. Also, ADHD scores would mediate the relationship between depression severity and QoL. Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. ADHD affects approximately 5.29% to 7.10% of children [1] and can persist into adulthood in up to 65% of cases [2]. The hypodopaminergic state seems to play a central role in ADHD. A great body of evidence demonstrates that people with ADHD tend to be at greater risk for other mental disorders [3] and metabolic conditions (such as migraine and obesity) [4]. The other clinical condition in individuals with ADHD is pain disorders. Individuals with ADHD are more sensitive to pain than healthy controls. Fibromyalgia (FM) is one of the most important pain disorders [5].FM is a widespread musculoskeletal pain disorder accompanied by fatigue, stiffness, sleep disturbance, and cognitive impairment [6]. In addition to these medical conditions, FM patients often have other comorbidities  [7]. Thus, FM may impair quality of life (QoL) and has a large economic burden worldwide [8].It has been reported that FM affects 2.7% of the general population [9] and is seen in individuals aged 20 to 55 years, with a female to male ratio of 6:1 [10]. The etiology of FM has not been completely elucidated; however, several studies have proposed the role of genetic factors. Candidate genes relevant to the pathogenesis of FM include serotonergic, dopaminergic, and noradrenergic transporter polymorphisms of genes involved in pain transmission  has a crucial role in the etiology of both disorders. Restless legs syndrome, which is considered to be a dopamine dysregulation disorder [21], has been reported in up to 33% of ADHD patients [22] and up to 31% of FM patients [23]. Second, cognitive disturbances are a major clinical part of both disorders. Finally, case-control studies are reporting that ADHD medications are effective in both ADHD symptoms and FM-related pain [24]. Thus, we were aimed to determine the association between ADHD symptoms severity, FM severity, and QoL.Hypothesis:(1) ADHD symptoms are more common in patients with FM than in the control group.(2) There was a negative correlation between the ADHD symptoms severity and QoL, and a positive correlation with the FM severity.(3) ADHD scores would mediate the relationship between depression severity and quality of life.We used observational cross-sectional survey design. In the study in which 153 participants were included; 113 were FM patients and 40 were the control group. The age range of the participants was 18–65. Education and Research Hospital Physical Medicine and Rehabilitation Clinic was held in Konya/ Turkey between March 2019 and March 2020. Data of participants were randomly 113 female patients with FM were collected consecutively from the physical medicine and rehabilitation unit. Both data collection and assessment procedures were done blindly. Participants who were newly diagnosed with FM were included in the study. The physician diagnosed the FM according to the 2016 criteria established by the American College of Rheumatology (ACR). Three conditions must be met in order to be diagnosed according to ACR: 1) having symptoms of similar severity for at least 3 months; 2) widespread pain index (WPI) ≥7 and symptom severity scale (SSS) score ≥5 or WPI of 4–6 and SSS score ≥9; 3) Generalized pain in at least 4 of the 5 regions. In addition, the presence of FM does not exclude the presence of other diseases. Those with medical conditions considered to contribute to FM symptomology  were excluded from the study. Those who scored higher than the cut-off values for mental health screening tools applied to the participants by the physician and who had psychiatric complaints were referred to the psychiatrist in terms of the presence of ADHD and other psychiatric diagnoses. Those who had a psychiatric diagnosis other than ADHD were not included in the study. DSM-5 diagnostic criteria were used to diagnose ADHD. Each participant’s psychiatric/physical evaluation and psychometric tests were completed within an average of 90 min. The control group was composed of 40 age-matched patient relatives and hospital staff who were subjected to the same exclusion criteria as for the FM patients. There was no significant difference between the two groups in terms of marital status, income level, and educational level. Income level was classified into three groups as low, medium and high, according to the latest data from the relevant institutions in Turkey. A total of 217 patients with FM were evaluated for participation in the study. However, 104 of them were excluded from the study, 15 because of refusing participation and 89 because of not meeting the inclusion criteria. The sociodemographic data collection form, adult ADHD self-report scale (ASRS), fibromyalgia impact questionnaire (FIQ), World Health Organization quality of life scale-brief version (WHOQOL-BREF), and hospital anxiety and depression scale (HADS) were used to evaluate the study participants. Required permissions for this study were obtained from the Local Ethics Committee of Selcuk University.It was developed for screening ADHD in adults by the World Health Organization [25]. It was designed to investigate the prevalence of ADHD in the general population and was recommended for use in primary screening clinical trials on ADHD. It is a short self-administered questionnaire that is based on existing symptoms, unlike tools that retrospectively define childhood ADHD. It is rated using a five-point Likert scale (never (0), rarely (1), sometimes (2), often (3), and very often (4) and has two subscales with each subscale consisting of nine questions (‘attention deficit’ and ‘hyperactivity/impulsivity’). These questions are created to determine how often each symptom happens within the last 6 months. It was reported that those with scores of 24 or higher from any of the two subscales had “a high probability of ADHD” (ADHD), those with scores of 17–23 had “likely ADHD”, and those with scores of 0–16 had no ADHD. The validity and reliability of the Turkish version of the scale were made by Doğan et al. [26]. The Cronbach’s alpha coefficient of the translated and original versions were 0.88 and 0.70.It is a widely used scale to assess clinical severity in FM patients. It is a Likert-type scale that evaluates 10 different areas in FM patients. These areas are; anxiety, depression, well-being, stiffness, fatigue, work difficulty, morning tiredness, physical functioning, missed days of work, and pain. The total score of the scale is between 0 and 100 and a higher score indicates a more negative impact. Scores of 70 and above indicate severe engagement. FIQ was developed by Burchardt et al. [27] and a validity and reliability study was conducted for Turkish FM patients in 2000 [28]. The Cronbach’s alpha coefficient of the translated and original versions were 0.72 and 0.95, respectively.Anxiety and depression symptom levels of FM patients were evaluated with HADS. HADS-A subscale is used for anxiety symptoms and the HADS-D subscale is used for depression symptoms. The maximum score is 21 on both subscales, which are rated as a four-point Likert (0–3) and consist of 7 items. Higher scores show increased anxiety and depression symptom severity. The cutoff point was 7 for the depression subscale and 10 for the anxiety subscale. The Turkish validation and reliability of this scale, developed by Zigmond and Snaith [29], was made in 2003 [30]. The Cronbach’s alpha coefficient of the depression and anxiety subscales were 0.77 and 0.85, respectively.It was developed as a 27-item short version of WHOQOL-100 to reduce the burden on participants in clinical trials. Turkish validity and reliability study of the scale was published by Eser et al. [31]. It evaluates the participants’ QoL in 5 different domains. These domains are; physical health, general health, psychological well-being, social relationships, and the environment. Each item is rated on a 5-point Likert scale. The scale, which is converted with a total score between 0 and 100 points, has no cutoff value. The Cronbach’s alpha coefficient were calculated as 0.73 for the environmental domain, as 0.66 for the psychological domain, as 0.73 for the national environmental domain, as 0.83 for the physical domain, and as 0.53 for the social domain, respectively.IBM SPSS-23 program was used for data analysis . Groups were compared using the independent samples t-test for parametric continuous variables (such as age and psychometric test scores) and the chi-square test for categorical variables . The relationships between clinical variables and test scores were analyzed using the Pearson correlation coefficients. The bootstrap method of Preacher and Hayes (2008) was used to determine the significance of the mediation effect in the study [32]. SPSS Macro Process program was used to calculate the Bootstrap method. Five thousand preloads were made in the calculation of the intermediary effect. Hayes’ (2013) Model 4 was used to identify the mediating role of ADHD scores in the effect of depression severity on quality of life [33]. Confidence intervals without zero indicate that the mediating effect is significant [32]. We also used the Sobel test to test significance of the mediation effect [34]. Probabilities less than 0.05 were used as the level of statistical significance in the analyzes.While the FM group consisted of 113 (74%) patients, the control group consisted of 40 (26%) individuals. The mean age was 41.38 ± 9.86 years in the FM group and 40.52 ± 10.72 years in the control group. No significant differences were found in age, education level, and marital status between the two groups (Table 1). ADHD was detected in 38.9% (n = 44) of the FM group and in 5% (n = 2) of the control group (p < 0.001). It was found that the FM group had significantly higher scores on the ASRS, all WHOQOL-BREF domains, HADS-A, and HADS-D than the control group (p < 0.05) (Table 2).The FM group was further divided into two subgroups as FM alone and comorbid FM/ADHD. There was a significant difference in FIQ scores and three WHOQOL-BREF domain scores  between the FM alone and comorbid FM/ADHD groups (p < 0.05) (Table 3).In the analysis using the Pearson correlation coefficient, there was a high negative correlation between the ASRS total score and all other subscales of the WHOQOL-BREF  and a high positive correlation with the FIQ, HADS-A, and HADS-D. The results of the Pearson correlation analysis are shown in Table 4.Hypothesis 3 predicted that ADHD scores would mediate the relationship between depression severity and QoL. To test this hypothesis, the SPSS process mediation test was performed to evaluate the mediation effect of ASRS-TOTAL between HADS-D and the WHOQOL-PH. Figure A shows that the total effect of HADS-D on WHOQOL -PH was significant . The 95% bias-corrected confidence intervals did not contain zero (32), which revealed that ASRS-TOTAL was a mediator in the relationship between HADS-D and the WHOQOL-PH, . This indicates partial mediation. Partial mediation indicates that some of the relationships between HADS-D on WHOQOL-PH occurs directly, while others are indirectly based on ASRS-TOTAL (32). The results of the mediation analyses are presented in Figure B. Results of the Sobel test indicate ADHD scores significantly mediated the relationship between depression severity and QoL .FM continues a complex pain disorder due to multiple comorbidities. In our study, the effect mechanism of ADHD symptoms presence on QoL in patients with FM was evaluated. The possible mediating effect of ADHD scores in the relationship between depression symptoms severity and QoL has never been investigated before.The possible overlap of FM with ADHD is underestimated, and thus the presence of ADHD in FM patients may be underreported. Indeed, studies have shown that the frequency of FM appears to be higher among adults with ADHD compared to controls or even patients with cognitive complaints without ADHD. Conversely, adult ADHD is more commonly seen in FM [35]. Persistent pain poses a definite effect on attention. Moore et al. (2012) demonstrated that it influenced complex attention performances  rather than simpler attention tasks [36]. Van Rensburg et al. found that 44.7% of patients with FM were diagnosed with comorbid adult ADHD according to the ASRS v1.1 [37]. Another study showed that 25% of FM patients had co-occurring ADHD [38]. Our study found that the rate of ADHD in patients with FM was 38.9%. This higher level of coexistence requires a common pathogenic perspective for both conditions. The common comorbidity of FM and adult ADHD can produce various therapeutic effects, as defects in dopaminergic circuits have been implicated in both cases. For instance, FM is associated with reduced repetition of the dopamine D4 receptor gene (DRD4), which is normally characterized by seven polymorphic repeats [39]. These seven repetitive variations are related to thinner right orbitofrontal, inferior prefrontal, and posterior parietal cortex in ADHD [40]. FM is characterized by decreased activity of the descending pain inhibitory pathways and low levels of dopamine, serotonin, norepinephrine, and endogenous opioids [41]. ADHD is characterized by abnormal neurodevelopmental processes that affect attention, emotion, and somatosensory functions, especially in frontostriatal, frontoparietotemporal, frontocerebellar, and frontolimbic regions. Both dopaminergic and noradrenergic systems are responsible for the greatest impairment in ADHD [42]. The other problematic area for both cases is emotional regulation. Deficits in recognition, regulation, and expression of emotions are one of the main problems in both ADHD and FM [43]. For the reasons mentioned above, the common etiologic factors that may be effective in the etiology and symptom severity of FM should be evaluated in each patient. Another perspective in the relationship between ADHD and FM is that pain affects cognitive structures by disrupting working memory [44] and can be the best indicator for objective results of cognitive function test [45]. Pain is considered a high-priority signal. It is thought that pain slows, stops, or impairs behavior when high cognitive demand is present [46]. Cognitive impairment in FM cannot be fully explained by pain. Other underlying factors contain anxiety, depression, sleep, and fatigue [47]. Therefore, early intervention for problems other than cognitive deficits is very important for preventing cognitive disturbances in FM. The fact that ADHD symptoms increase the severity of FM symptoms and worsen QoL in patients with FM is one of the important data from our study. In a recent study examining this relationship, ADHD symptoms were indicated to be associated with poor functionality in patients with FM. This relationship was even more pronounced in the presence of depression and anxiety symptoms [48]. In another study, the presence of comorbid ADHD was found to be associated with increased severity of FM symptoms and increased impairment in functionality [49]. Although some observations have previously been conducted for the link between adult ADHD and FM based on shared cognitive deficits, a small number of studies have been performed on the level of QoL and ADHD severity in FM patients. In addition to the fact that ADHD symptoms are more frequent in FM patients, our study demonstrated that the increased severity of ADHD symptoms would pose a negative impact on multiple domains of the QoL. Our study also showed that the general health, psychological health, physical health, environment domains of the WHOQOL-BREF strongly correlated with ADHD symptom severity. Until recently, cognitive dysfunction experienced by FM patients has been largely ignored due to the lack of diagnostic criteria. Cognitive dysfunction, such as memory and attention, can sometimes dramatically change the lives of FM patients. Patients with FM often report declines in cognitive function, memory, and mental alertness as well as forgetfulness that have been called “fibro fog”, which can be more disruptive than pain. Therefore, it should be one of the most important parts of clinical assessment in FM patients [19].In the present study, it is revealed that ADHD scores of the patients with FM have a partial mediating effect in the relationship depression severity and physical quality of life. It has been shown in many studies that FM patients show an increased rate of anxiety and depressive symptoms besides their cognitive symptoms [50]. In fact, depressive disorder is the most common comorbidity with a prevalence of 20%–80% [51]. It has been shown that somatic symptom/pain is more common when it accompanies depression in FM patients, related to the “pain relief hypothesis” . The presence of these comorbidities is important in that they seriously affect the QoL [53], apart from making treatment difficult. Emotion regulation problems, which are key components in ADHD, may cause sensitivity to depressive symptoms [54]. In addition, due to the cognitive and emotional symptoms of ADHD in FM patients, dysfunctional coping mechanisms may contribute to the development of depressive symptoms. While evaluating the psychical QoL, which is an important target in the FM management process, consideration of ADHD can make a significant contribution to treatment and prognosis. Our findings revealed that depression has an effect on QoL through ADHD symptoms. It can be interpreted that intervention in emotion regulation deficits/emotional responsiveness and other features mediating ADHD-related depression may have an effect on QoL in patients with FM.The present study has several limitations. First, it was not possible to exclude the influence of confounding factors such as physical exercise, sleep habits, and eating behavior. Second, our study included a relatively small number of subjects. Another limitation of our study is that all patients were not evaluated with a structured psychiatric interview. Furthermore, the absence of male FM patients in our study may limit the generalizability of the results. Finally, the relationship between FM and hyperactivity/impulsivity were not adequately addressed, but the attention and related factors were mainly evaluated. In conclusion, our findings indicated that in FM patients with ADHD, FM symptom severity is higher and the QoL is worse. Also, the partial mediating effect of ADHD symptom severity in the relationship between depression severity and physical QoL is an important finding. Thus, in FM patients may not respond adequately to standard treatment if their ADHD symptoms are not taken into consideration.The study protocol received institutional review board approval. All participants provided informed consent in the format required by the relevant authorities.