The evaluation of performance validity is an essential part of any neuropsychological evaluation. Validity indicators embedded in routine neuropsychological tests offer a time-efficient option for sampling performance validity throughout the assessment while reducing vulnerability to coaching. By administering a comprehensive neuropsychological test battery to 57 adults with ADHD, 60 neurotypical controls, and 151 instructed simulators, we examined each test’s utility in detecting noncredible performance. Cut-off scores were derived for all available outcome variables. Although all ensured at least 90% specificity in the ADHD Group, sensitivity differed significantly between tests, ranging from 0% to 64.9%. Tests of selective attention, vigilance, and inhibition were most useful in detecting the instructed simulation of adult ADHD, whereas figural fluency and task switching lacked sensitivity. Five or more test variables demonstrating results in the second to fourth percentile were rare among cases of genuine adult ADHD but identified approximately 58% of instructed simulators. A considerable minority of examinees underperforms in neuropsychological assessments due to a wide array of possible reasons, including maladaptive responses to genuine health conditions and the exaggeration or feigning of symptoms . The evaDue to their favorable time efficiency and low face validity ,11,12,13The high base rates of symptoms associated with the condition, various incentives, and the potentially far-reaching consequences of false positive diagnoses make the evaluation of symptoms and performance particularly pertinent to the assessment of ADHD. Motivated by the prescription of stimulant medication, access to accommodations, or social incentives, examinees have been shown to feign or exaggerate symptoms of ADHD convincingly with relative ease ,24,25,26The consequences of false-positive diagnoses are potentially severe, both at the individual and the societal level. Superfluous treatment with stimulant medication puts people at risk of adverse events. Scarce resources, including the previously mentioned assisting technology, may not be adequately allocated as a consequence of unwarranted diagnoses, and false-positive diagnoses violate the principle of equal opportunity in academic settings. Furthermore, they may undermine the public perception of ADHD. Including feigned cases of ADHD in research studies could ‘dilute’ samples and therefore contribute to heterogeneous findings.Although no single distinct cognitive profile can be associated with ADHD ,29,30 anContinuous performance tests (CPTs), for example, are among the most commonly used neuropsychological tests  and the Findings on other tests have been more heterogenous, particularly with regard to sensitivity. The Processing Speed Index (PSI), measured as part of the Wechsler Adult Intelligence Scale-IV (WAIS-IV) , has shoThe wide array of available instruments has complicated efforts to estimate the base rate of noncredible performance in the assessment of adult ADHD and to characterize examinees who fail PVTs. Early studies, which commonly used a single PVT to evaluate performance validity, reported base rates between 15% and 48% ,77,78. LWe administered an extensive neuropsychological test battery to adults with ADHD, neurotypical controls, and instructed simulators to examine their use as PVTs. Our primary aim was to develop cut-off scores for various outcome variables yielded by the tests in our battery and determine their accuracy in detecting the instructed simulation of adult ADHD. Since the battery included numerous tests in addition to a CPT, we were able to provide additional insights into the classification accuracy of multiple embedded performance validity indicators considered jointly . Moreover, it allowed us to examine possible changes in simulation effort throughout a comprehensive assessment. That is, whether instructed simulators show invalid performance throughout the assessment or on specific tests only and whether simulation efforts remain stable or fluctuate throughout the completion of said test battery.Two approaches were used to recruit participants: first, 247 students enrolled in undergraduate psychology courses at the University of Groningen participated in exchange for course credit. Second, archival data collected as part of the clinical assessment of 73 adults diagnosed with ADHD were made available to the Department of Clinical and Developmental Neuropsychology at the University of Groningen.Seventy-nine adults were initially considered for inclusion in the ADHD Group. Among them were archival data of 73 individuals with suspected ADHD, who had been referred to the Department of Psychiatry and Psychotherapy at the SHR Clinic Karlsbad-Langensteinbach for their clinical evaluation, as well as six additional participants from the student sample who presented with secured diagnoses of ADHD.As a specialized outpatient clinic, the SRH clinic provides comprehensive diagnostic workups to adults whose general practitioners, psychiatrists, or neurologists suspect the presence of ADHD but do not believe they are sufficiently experienced or qualified to diagnose the disorder in adulthood. Despite the fact that all participants in this group experienced ADHD symptoms and impairments throughout childhood and adolescence, reliable information on a formal diagnosis of ADHD having been made in childhood could not be retrieved for all cases. Consequently, the diagnostic procedure followed the criteria for first-time adult ADHD diagnoses e.g., .Diagnostic and Statistical Manual of Mental Disorders [With participants having been informed that their participation in this study would not affect their clinical evaluation or treatment, this diagnostic procedure was undertaken by two experienced professionals who conducted extensive clinical interviews based on the isorders . CorroboDiagnoses of ADHD could ultimately not be confirmed for 16 participants, who were consequently excluded from the present study. Five participants were further excluded due to incomplete (n = 1) or failed (n = 4) validity tests . Missing data on the neuropsychological test battery led to the exclusion of one additional participant. A summary of the demographic data for the remaining 57 adults with ADHD can be found in Seventy-three participants randomly drawn from the student sample were allocated to the Control Group and completed all tests to the best of their ability. Twelve participants were excluded due to neurological or psychiatric comorbidities, and one participant had to be excluded due to a possible but uncertain diagnosis of ADHD. As such, the Control Group included 60 participants whose demographic data are summarized in Also drawn from the student sample, 168 participants were randomly assigned to the Simulation Group and received one of three sets of instructions: naive simulators received general instructions to feign ADHD and no additional information (n = 57), symptom-coached simulators were given the DSM diagnostic criteria of ADHD (n = 53), and fully coached simulators (n = 58) received information on both the neuropsychological assessment of ADHD and its diagnostic criteria. These three coaching conditions were summarized into one Simulation Group, as examinees intending to feign ADHD are likely to have varying levels of knowledge about ADHD and its assessment in real-life settings. Seventeen participants were excluded from this group due to failed manipulation checks. Demographic data describing the remaining 151 instructed simulators can be found in A brief demographic questionnaire was used to collect information about the participants’ demographics , potential psychiatric comorbidities, medications, and ADHD diagnostic status.Wender Utah Rating Scale (WURS-K). The WURS-K is the abbreviated German form of the Wender Utah Rating Scale, a self-report questionnaire used to retrospectively assess ADHD symptoms that occurred in childhood . It contADHD Self-Report Scale (ADHS-SB). The ADHS-SB  is an 18As part of the diagnostic process, all adults with ADHD took the Test of Memory Malingering (TOMM) . The TOMAll participants completed the Vienna Test System’s (VTS)  computerThe test battery is a compilation of established, valid ability tests that assess the cognitive areas in which adults with ADHD frequently exhibit impairments, including aspects of attention and executive functions. Its norm sample included individuals aged 15 years to 85 years without neurological or psychiatric illnesses who did not take any medication known to affect the central nervous system at the time of their participation in the validation study. Sample sizes differed between individual tests, ranging from 270 to 359 individuals. Genders were similarly represented, and educational attainment spanned all educational levels.The CFADHD is used to assess the cognitive status of adults with ADHD and to support the diagnostic process. It provides valuable information about individual cognitive strengths and weaknesses, which may aid in treatment planning and the design of compensation strategies. Objectifying subjective impairments of cognition may further increase compliance and treatment adherence . HoweverProcessing Speed and Cognitive Flexibility. The Langensteinbach Version of the Trail Making Test (TMT-L)  was usedSelective Attention. Selective attention was measured using the Perceptual and Attention Functions—selective Attention (WAFS) . In thisWorking Memory. Working memory was assessed using the 2-back design of Kirchner’s  verbal NFigural Fluency. To assess figure fluency, the Langensteinbach Version of the 5-point test was used (5POINT-L) . This teTask Switching. Task switching was measured using the SWITCH . In thisVigilance. The Perceptual and Attention Functions were used to measure vigilance (WAFV) . It inclResponse Inhibition. The Go/No-Go test paradigm was used to assess response inhibition (INHIB) . ThroughInterference Control. The Stroop Interference Test, first introduced in 1935, was used to evaluate interference control . The forThe following assessment procedures were approved by the University of Heidelberg and the Ethical Committee Psychology (ECP) at the University of Groningen .Each participant provided written informed consent and was subsequently tested individually. Adults with ADHD and neurotypical controls continued to complete all further tasks to the best of their ability. This included an extensive neuropsychological evaluation encompassing a brief history taking, self-report measures, neuropsychological performance tests, and a validity test.Participants randomly allocated to the Simulation Group, on the other hand, received the instruction to complete the same assessment protocol as though they had ADHD. As people who aim to feign ADHD in real life likely differ in their knowledge of the disorder and the evaluation of symptom and performance validity, participants in this group were further divided into subgroups that received different levels of coaching see . Naive sCompletion took approximately 2 ½ h. Following the completion of the last test, all instructed simulators were asked to stop simulating ADHD and answered three questions regarding self-reported effort, subjective success in simulating the disorder, and strategies used to feign it.To provide context for all further analyses, we first computed summary statistics on the neuropsychological test performance and gauged the base rate of impairments across various domains. By determining which values ensured at least 90% specificity among adults with ADHD, we further derived new cut-off scores for 21 test parameters gathered by the CFADHD. Subsequently, we calculated the percentages of instructed simulators identified by these cut-off scores as well as the cut-off scores’ positive (PPV) and negative predictive values (NPV).gtsummary (Version 1.6.1) [papaja (Version 0.1.1) [tidyverse (Version 1.3.2) [yardstick (Version 1.1.0) [Data analysis was conducted in SPSS  and R (Vn 1.6.1) , papaja n 0.1.1) , tidyvern 1.3.2) , and yarn 1.1.0) .Aggregate statistics on participants’ neuropsychological test performance can be found in Impairments, as defined by at least one result  falling below the 9th percentile, were most commonly observed in the domain of selective attention (WAFS) in both adults with ADHD (50.9%) and controls (28.3%). Impairments noted on the WAFS were most often due to an unusually high dispersion of response times in either group , followed by high numbers of omission errors among adults with ADHD  and commission errors among controls . In both groups, impairments of vigilance  and inhibition  were second and third to those seen in selective attention. Omission errors  and commission errors  were the most common causes of below-average WAFV results for adults with ADHD. Both types of errors, as well as the dispersion of reaction times, showed similar rates of impairments in the Control Group . Irrespective of group membership, omission errors were the driving force behind impairments of response inhibition . In addition to these three tests, impairments in processing speed , interference control , or flexibility  were also common among adults with ADHD.Instructed simulators showed an overall poorer neuropsychological test performance than adults with ADHD. The percentage of participants demonstrating impairments tended to be higher in the Simulation Group than the ADHD Group and Control Group. Exceptions included the TMT-B, the number of correct responses on the NBV and the 5POINT, and the accuracy and speed measured throughout the SWITCH, where more adults with ADHD than instructed simulators presented with results below the ninth percentile.Cut-off scores, which ensured at least 90% specificity in our ADHD Group, are shown in The Simulation Group showed a higher median number of test results falling into the suspect range based on the newly derived cut-off scores than the ADHD Group and Control Group. Fewer than 10% of participants with ADHD presented with five or more measured outcomes marked as suspect by the respective cut-off scores . In contThere is broad consensus on the importance of considering symptom and performance validity when assessing adults for possible ADHD. A plethora of embedded and stand-alone, ADHD-specific, and general-purpose instruments are available to clinicians intending to follow this recommendation. Studies on these instruments have suggested an added value for a conservative approach, which requires multiple validity tests to yield suspect results for an examinee to be considered noncredible . ApproxiThe base rates of impairment demonstrated by neurotypical controls were in line with the tests’ standardizations. Results below the ninth percentile were more common in tests that included the highest number of outcome measures, namely those evaluating the domains of selective attention , vigilance , and inhibition . Across all tests and assessed cognitive domains, at least 20% of adults with ADHD showed one or more results below the ninth percentile. Impairments could most commonly be observed in the domains of selective attention , vigilance , and inhibition . Additionally, reductions in processing speed were common in our sample of adults with ADHD . The outcome variables that contributed to these impairment rates differed between tests. On the WAFS, impairments were most often due to an elevated dispersion of response times or errors of omission, whereas errors of omission and commission were most commonly below average on the WAFV.Easier tests have been suggested to provide tendentially higher classification accuracies than their more difficult counterparts, likely as a result of the latter tapping genuine impairment e.g., , see 7373 for a The cut-off scores we derived for these 21 outcome measures painted a picture in agreement with previous studies. Although all ensured at least 90% specificity in our group of adults with ADHD, sensitivity to feigned ADHD varied significantly between the outcome variables and their respective cut-off scores. Tests measuring aspects of attention showed the highest sensitivity to the instructed simulation of ADHD, and the sensitivity of tests tapping executive functions was as broad ranging as the wide array of executive functions themselves. Tests of selective attention (WAFS) and vigilance (WAFV) detected approximately 60% of the Simulation Group, making them the most promising instruments in the present study. A variation of the Go/NoGo paradigm included in our test battery  correctly identified up to 45% of instructed simulators and therefore emerged as a potentially useful adjunct marker of invalid performance. As was the case for the WAFV, omission errors were most sensitive to the instructed simulation of ADHD. The comparative high sensitivity of the vigilance test included in our test battery is in line with earlier findings on the usefulness of continuous performance tests (CPTs) in the detection of invalid performance. Indeed, the sensitivity of errors of omission and commission resembled estimates reported earlier ,43,48, wSeveral other tests showed lower sensitivities in the present study than previously estimated. Both versions of the TMT were less sensitive to the instructed simulation of ADHD than the detection of invalid performance described in earlier studies ,47,61,70Previous studies differed in whether raw scores, T-Scores adjusted for age, or both were considered when developing cut-off scores for EVIs. Raw scores have been reported to have favorable sensitivity, yet greater demographic diversity or formally lower educational attainment in the population under study may tip the scales in favor of T-Scores ,61. IndeAggregating multiple indicators, rather than interpreting individual metrices, has previously been implied as a promising approach to the evaluation of performance validity ,16. AlthThe following limitations inherent to our study may also inform future research. The limitations inherent to simulation designs, including reduced external validity, are relevant to the present study and its findings. By drawing our sample of instructed simulators from a pool of university students, we also included a population highly relevant to research on feigned ADHD. However, this recruitment procedure resulted in significant demographic differences between the groups, with the Simulation Group being significantly younger than the ADHD Group and the Control Group.The development of embedded validity indicators based on raw scores may further produce misleading results when applied to populations that differ from the initial study sample. Indicators which were, for example, developed based on data collected in a sample of young adults may prove less accurate when applied to older adults. This concern may be alleviated, in part, by the age brackets and demographic backgrounds covered in our ADHD Group. Our sample of adults with ADHD was, however, unusually often diagnosed with the combined symptom presentation. The applicability of our cut-off scores and findings would therefore be reduced should different symptom presentations be associated with distinct cognitive profiles. Additionally, the inclusion of cases with invalid performance cannot be ruled out conclusively; even though experienced clinicians consulted a variety of instruments and sources throughout the diagnostic process, diagnoses were only made where there was objective evidence of impairment, and all participants in the current study passed an independent performance validity test. The rate of performance validity test failure  was lower than the estimated base rate of noncredible test performance in the evaluation of adult ADHD , likely in part due to the referral context. For example, adults being referred to specialized clinics for the clinical evaluation of ADHD may present with lower base rates of noncredible performance than college students. Not every sub-population of examinees may show a base rate of validity test failure equal to or above 20%.Having derived our cut-off scores from raw scores bears the risk of overfitting. Cut-off scores for reaction time measures, for example, required three decimals to ensure adequate specificity, thereby potentially reducing their generalizability to other samples or settings. Lastly, a small percentage of participants missed data parts of the test battery, which may have influenced our analysis of the number of test failures. Taken together, these limitations underscore the importance of independent validation before our findings are applied in clinical practice. To counteract concerns about the external validity of analogue designs, such a validation study should preferably be conducted on a large clinical sample.Impairments demonstrated by instructed simulators go beyond the neuropsychological test profiles of genuine patients in both magnitude and frequency: adults instructed to feign ADHD present with more extreme scores and higher impairment rates in most cognitive domains and tests. Simulation effort could thus be observed throughout the assessment, yet certain cognitive domains appeared more promising in detecting invalid performance than others. Selective attention, vigilance, and inhibition were most accurate in detecting the instructed simulation of adult ADHD in our sample, whereas figural fluency and task switching lacked sensitivity. Results falling between the second to fourth percentile were very rare among adults with ADHD in our sample but could more often be noted among instructed simulators. If these findings stand the test of independent validation, five or more outcome variables in this extreme range can help clinicians detect invalid performance in the neuropsychological assessment of ADHD.


Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are closely connected and commonly seen in both children and adults. Each of the disorders has major psychosocial and quality of life (QOL) effects, and their co-occurrence makes coping even more challenging for both the patients and their families. Moreover, an adverse effect of some anti-seizure medications can potentially induce or exacerbate symptoms of ADHD on the one hand, while some ADHD medications may increase seizure risk on the other. The combination of proper diagnosis and appropriate treatment may improve or even prevent many of the complications associated with these conditions. The objectives of this review are to present the complex relationship between epilepsy and ADHD, looking into the pathophysiological, anatomical, and functional perspectives along with the psychosocial and QOL influences and the recommended treatment approaches in accordance with the latest literature. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders, with a prevalence of 5–7% among children and young adults . It is aPatients with coexisting epilepsy and ADHD present several different characteristics compared to patients with a sole diagnosis. The first is the disappearance of the usual sex differences in the prevalence of ADHD: in the absence of epilepsy, ADHD is seen in school-aged children with a male-to-female ratio of 2–3:1 while that ratio is 1:1 when coexisting with epilepsy . A variaMany hypotheses have been proposed regarding the association between epilepsy and ADHD; the independent  hypothesis - holds that both disorders are highly prevalent, hence it is very probable that some of the children will eventually be found to have both diagnoses. The second theory claims dependent association which can be direct contribution of the seizures, interictal epileptiform discharges and the anti-seizure medications to the attention deficit and hyperactive behavior or a multifactorial linkage . The funWe present a review of the possible pathophysiological and extrinsic factors which promote the disproportionately higher rate of ADHD among children with epilepsy.The records were obtained by searching the PubMed database for studies conducted in children and adolescents. Search terms were “Epilepsy” and “ADHD” or “Attention-Deficit/Hyperactivity Disorder” and “children” and “adolescents” and “pediatric age” with “anti-seizure treatment,” “epilepsy syndrome,” “interictal discharges,” “ADHD treatment,” “QOL,” “psychosocial,”, “etiology” and “pathophysiology.”The overlapping diagnosis of both conditions may be attributed to a common genetic etiology. The latest technological abilities, such as quantitative and functional magnetic resonance imaging (MRI) point at another possible pathophysiology underlying the co-occurrence of epilepsy and ADHD. One study on MRI-based volumetric measurements demonstrated that ADHD and epilepsy were associated with a significantly increased volume of gray matter distributed throughout regions of the frontal lobe as well as with a smaller brainstem volume . One posNevertheless another study found reduced cortical thickness in the bilateral areas of the frontal, parietal, and temporal lobes . The finThe reported volumetric differences are not reflected in functional studies. Despite the disparate methodologies of these studies, the conclusions are in keeping with those reported in studies of idiopathic ADHD, which have shown disruption within a broad fronto-striatal-cerebellar network  and simiThere is also a neurotransmitter-related hypothesis based upon animal models of ADHD, which suggests that functional impairments in excitatory glutamatergic synaptic transmissions may be one of the underlying mechanisms leading to increased susceptibility to both epilepsy and ADHD .There are certain generalized epileptic and non-lesional focal syndromes which are more likely to present with ADHD-like behaviors, supporting the structural/genetic theory. Self-limited epilepsy with centrotemporal spikes (SeLECTS) is probably the epileptic syndrome most identified with ADHD. The frequency of centrotemporal spikes in non-epileptic children with ADHD is significantly higher than would be expected in these children . When peRegardless of the epilepsy type and anatomical location of seizures, there is robust evidence that uncontrolled epilepsy with a high seizure load is strongly associated with ADHD. p = 0.004) and higher impulsivity (p = 0.016)  . Those f= 0.016) .The relation or impact of interictal epileptiform discharges (IED) with attention and cognition in children has long been presumed. The prevalence of IED in the healthy population varied between 1.4 to 6.5% depending upon sex, age, state, and type of data collection  . A similp = 0.039) in children with SeLECTS  is based upon studies in children with SeLECTS. This specific population has no seizures or a low seizure load, does not require anti-seizure medications (ASM), and awake IED may be rare compared to marked activation during sleep. In a review of the literature,  SeLECTS . There i SeLECTS . In thatTwo main hypotheses have been suggested in an attempt to explain the role of the interictal activity on behavior and cognition . The firAttention-deficit/hyperactivity disorder is a disorder with a higher risk of seizures with a possibility that treatment itself may lower seizure threshold. Overall, there is a paucity of data about seizure risk in non-epileptic children treated with stimulants therefore there is no clear, evidence-based answer to this question. A cohort analysis evaluated the risk of seizures among pediatric patients naïve to ADHD medication therapy. No statistically significant difference was found in the adjusted relative risk in 13,322 patients exposed to atomoxetine relative to 13,398 patients treated with stimulant over a follow-up period of 6 months . SimilarIntrafamilial relations  were directly associated with adjustment difficulties in the child with ADHD as well as with the frequency of seizures. In a survey of 48 families, The ASM and their side effects have significant potential of influencing many aspects of behavior, cognition, and quality of life . The assAccording to the International League Against Epilepsy (ILAE) task force 2016 report on the older group of medications, phenobarbital showed the most convincing evidence of negative effects on both cognition and behavior, with behavioral problems ranging from hyperactivity to withdrawal or sedation . SimilarAmong the newer ASM, the interpretation of the behavioral data for vigabatrin was distorted since the primary etiology of the majority of the studied children included those with behavioral impairments. Topiramate can cause adverse effects in behavior, particularly in children and adolescents with intellectual disabilities, and those effects tend to persist as long as the treatment is continued. This is also the case for levetiracetam, where the available data are still contradictory, although they suggest that caution should be used due to possible association with aggression . OxcarbaThe evidence for behavior and cognitive difficulties contributed by anti-seizure treatment is more established than in related to the specific symptoms of ADHD. Therefore, any medication which may cause significant behavioral or cognitive side effects should be avoided or be used with caution, in patients with ADHD or those who already struggle with these challenges.A consensus paper issued by the Task Force on Comorbidities of the ILAE Pediatric Commission in 2018 recommended screening for ADHD in every child with epilepsy starting at the age of 6 years, or at the time of diagnosis if older than 6 years. The child should be reevaluated annually and after any ASM change. The screening should not be performed within 48 h of a seizure associated with a postictal state . It shouThe primary role and efficacy of the medications indicated for ADHD are well established in the literature and their use is common practice in pediatric neurology, including children with epilepsy . HoweverThere is limited data on other ADHD medications. Amphetamines were found to be less effective than MPH  in an observational retrospective study of 36 children and adolescents. Seizure aggravation was not reported, however, the level of tolerability was low, with a dropout of 53% of amphetamine-treated patients due to side effects . AtomoxeAttention-deficit/hyperactivity disorder is a ubiquitous and major developmental and functional challenge in children with epilepsy. The direct cause for this comorbidity has not yet been elucidated, although we do know that it is probably not a direct result of a single factor, but rather of many extrinsic and intrinsic components in combination. Each patient presents a variety of characteristics which eventually determine whether ADHD will become a significant comorbidity. Pediatric neurologists must be aware of this comorbidity, assess it early in the course of the disease, and determine whether it preceded the onset of epilepsy. Upon diagnosis, depending on severity, and alongside the medical treatment, we should consider treating or changing existing factors such as ASM, parental education, and seizure control. Future and more systematic studies on the association between epilepsy and ADHD are warranted with the aim of refining current approaches and enhancing the pediatric patient’s function, achievements, and behavior.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.SU-S, VC, IT, and YL contributed to the conception and design of the study. SU-S wrote the first draft of the manuscript. VC, IT, and YL wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.


Kangxian flowers (PKFs) using ultrasonic-assisted extraction (UAE) and to explore the structural features and cosmetic potential of PKFs obtained under the optimized UAE. According to response surface methodology, the optimal UAE for PKFs were liquid-to-solid ratio of 59: 1 mL/g, ultrasonic power of 404 W, time of 48 min, and temperature of 66℃, under which the yield of PKFs reached 26.8 ± 1.76 %, 2.6-folds higher than hot-water extraction. By comparing the microstructures, it can be seen that ultrasonication exerted great damage on Kangxian flowers to promote the outflow of PKFs. Various analyses revealed that the PKFs extracted with UAE were acidic polysaccharides with relatively lower molecular weights of 0.92 – 76.9 kDa, negatively charged potential of −16.3 mV, and arabinose the dominant monosaccharide followed by galactose. These structural features conferred PKFs pronounced antioxidant, moisture absorption and retention properties, showing great potential for cosmetic application.The purpose of this work was to ameliorate the yield of polysaccharides from  It is the most popular member of genus Dianthus and the second most common cut flowers worldwide Kangxian flower, an edible species of carnation is mainly distributed in high-altitude areas, especially in the Tibetan Plateau being deemed as “Tibetan Holy Flower”. In China, the edible history of Kangxian flower can be traced back to hundreds of years ago. The Compendium of Materia Medica described that it has sweet taste and slight coolness as well as benefits liver and kidney Kangxian flower-based tonic teas have been available on the market and exported abroad due to the fast development of international logistics Kangxian flower-related products are still limited to tonic teas, lacking high-value and comprehensive development. Thus, the bioactive constituents present in Kangxian flower urgently need to be explored.About 600 species of the genus Kangxian flowers (PKFs). After purification and characterization, the cosmetic potential of PKFs, including antioxidant, moisture absorption and retention properties were then evaluated. The present contribution will evidence the value-added utilization of Kangxian flowers, more importantly further enrich the research cases on UAE of cosmetic polysaccharides.In this work, the UAE process was first optimized to extract polysaccharides from 22.1Kangxian flowers were bought from Bozhou Chinese Herbal Medicine Market  on 20 October 2022, and authenticated by Dr. Zhaowei Yan from Soochow University . The involved reagents and drugs were of analytical grade and provided by local suppliers.Dried 2.2Kangxian flowers were cut into pieces and passed through a 40-mesh sieve. After being soaked in water for 4 h at various liquid-to-solid ratios (20: 1 – 60: 1 mL/g), the mixture suspension was placed in a XH-2008D ultrasonic extractor  and extracted at different powers (200 – 600 W) and temperatures (30 – 70℃) for 10 – 50 min. After filtration under vacuum, the filtrate was metered to calculate extraction yield, and then condensed to 1/4 of the original volume, followed by adding 3-fold anhydrous ethanol to precipitate crude PKFs at 4℃, which were collected by centrifugation and dried by lyophilization Dried Y = 0.012X + 0.0224 (R2 = 0.9997) based on the principle of phenol–sulfuric acid method Total carbohydrates were determined using a standard glucose curve of Kangxian flower powders (g).Extraction yield of crude PKFs was calculated according to Eq. (1).2.3The four UAE parameters, including liquid-to-solid ratio , ultrasonic power , ultrasonic time , and temperature  were appraised via single factor test using PKFs yield as the evaluation index.2.4Design-Expert 13 software was used to design and analyze the four-factor (A – D) and three-level (-1 – 1) response surface methodology (RSM) according to Box-Behnken design (BBD). The proper values of A – D were selected based on the results of single factor test using PKFs yield as the response.2.5According to the optimized UAE condition and previous literature 2.6Free proteins in crude PKFs were removed by the Sevag method for three times 2.72.7.1Y = 7.25X − 0.0356 (R2 = 0.9998), the m-hydroxybiphenyl method Y = 8.4688X − 0.0187 (R2 = 0.9992), and the barium chloride-gelatin method Y = 8.4688X − 0.0187 (R2 = 0.9995), respectively.Total carbohydrates were measured according to the method described in 2.7.2TM ICS-5000 ion chromatograph  equipped with a pulsed ampere detector and a CarboPac PA20 ion chromatographic column. The injection volume was 20 µL, and velocity of flow was 0.5 mL/min with the following gradient elution: 0 – 21 min, 98 % ultrapure water + 2 % 250 mM NaOH solution; 21.1 – 30 min, 93 % ultrapure water + 2 % 250 mM NaOH solution + 5 % 1 M NaAc solution Trifluoroacetic acid was used to hydrolyze purified PKFs into monosaccharides, which were analyzed by a DionexTM G4000PWXL column. A 1220 Infinity II high performance liquid chromatograph  served as the analyzer. The injection volume was 20 µL, mobile phase was ultrapure water with a flow rate of 0.9 mL/min, and the column temperature was 45℃ The molecular weight (Mw) of purified PKFs was determined by high performance size exclusion chromatography (HPSEC) using a TSKgel2.7.3TM ZS90 Zetasizer Nano  at a concentration of 1 mg/mL in distilled water.The particle size and zeta potential of purified PKFs were measured with a Malvern2.7.4−1 was scanned using a Spotlight 200i Fourier transform infrared microscope .The UV spectrum of purified PKFs within 200 – 800 nm was scanned using a Lambda 750 ultraviolet spectrophotometer , and IR spectrum within 4000 – 400 cm2.7.5Kangxian flower powders, dried residuals after extraction, and purified PKFs were placed onto silicon pellets, respectively. After being spattered with gold powders, a Regulus 8100 ultrahigh-resolution scanning electron microscope  served to exhibit the SEM images.The untreated 2.7.6Ten microliters of purified PKFs at a concentration of 1 mg/mL in ultrapure water were loaded onto a cleaved mica sheet. After being dried under vacuum, a XE-120 atomic force microscope  was applied to exhibit the AFM image.2.82.8.14 solution, 1 mL of 6 mM salicylic acid in ethanol, and 1 mL of 6 mM H2O2 solution. After incubation at 37℃ for 30 min, the absorbance at 510 nm (As) was read 0), and the reaction system lacking H2O2 was applied as the normal control (Ac). L-Ascorbic acid (LAA) served as the positive control. The scavenging rate against hydroxyl radical was calculated based on Eq. (2).One milliliter of purified PKFs solution (0.2 – 1 mg/mL) was sequentially mixed with 1 mL of 6 mM FeSO2.8.20), and the reaction system without DPPH was used as the normal control (Ac). LAA acted as the positive control One milliliter of purified PKFs solution (0.1 – 0.8 mg/mL) was blended with 1 mL of 0.1 mM DPPH in ethanol and reacted under the dark for 30 min, then the absorbance at 517 nm (As) was determined. Distilled water replacing PKFs served as the blank control (A2.92.9.10) was placed in a humidity chamber with saturated (NH4)2SO4 (81 % RH) at room temperature. At indicated time (4 – 48 h), the samples were respectively weighed (Wt) All the samples  were dried at 100℃ for 4 h, then 0.5 g of each sample (W2.9.20) were placed in a humidity chamber with distilled water. After being humidified for 24 h, the samples were weighed (Wm) and transferred to desiccators with dried silica gel to dehydrate at room temperature. At indicated time (4 – 48 h), the samples were respectively weighed again (Wt) Fifty milligrams of each sample , but continuous increase in ultrasonic power led to marked decrease in PKFs yield (P < 0.01). Mechanical force generated by ultrasound facilitates the release and diffusion of PKFs, but too strong ultrasonication can degrade polysaccharides, leading to a reduction in yield P < 0.05 or P < 0.01), and notably deceased when ultrasonic time reached 50 min (P < 0.01). P < 0.05). When temperature was raised to 70℃, PKFs yield significantly decreased (P < 0.05). Proper heating enhances the thermal diffusion of PKFs, but too high temperature as hot-water extraction can cause a reduction in yield via degrading structures As shown in Through single-factor experiment, the liquid-to-solid ratio (A) of 50: 1 mL/g, ultrasonic power (B) of 400 W, time (C) of 40 min and temperature (D) of 60℃ were selected for the experimental design of RSM-BBD optimization.3.2Y) and coded factors (A – D).P < 0.01) and insignificance for Lack of Fit (P > 0.05) indicated that present model was reliable to forecast and analyze the UAE of PKFs 2 – D2 were remarkable (P < 0.05 or P < 0.01), suggesting that these items can significantly influence PKFs yield, and the influence ranked as A > D > B > C 2 was 0.9856, demonstrating that the model can interpret 98.65 % of the variations, and a relatively lower C.V. (2.15 %) verified that the results of actual experiments were credible As summarized in The model-predicted conditions for PKFs extraction were: liquid-to-solid ratio (59.3706: 1 mL/g), ultrasonic power (403.798 W), time (48.2009 min), and temperature (66.1443℃), under which the predicted yield of PKFs was 27.0816 %. To facilitate operation, the predicted conditions were adjusted to be liquid-to-solid ratio (59: 1 mL/g), ultrasonic power (404 W), time (48 min), and temperature (66℃), under which the practical yield of PKFs was 26.8 ± 1.76 %, with an error of −1.04 % in comparison with model prediction, further confirming the feasibility and accuracy of this model in predicting the UAE of PKFs.3.3P < 0.01) than that of UAE (26.8 ± 1.76 %). By comparing the SEM images of untreated and treated Kangxian flowers . It is widely distributed in the body and can react with almost all the biomolecules. Thus, hydroxyl radical is one of the main causes of senescence and various diseases P < 0.01). Despite continuous increase in concentration led to a higher scavenging rate at 1 mg/L (92.9 ± 2.14 %), when compared with that of 0.8 mg/L (86.8 ± 1.69 %), there was no statistical difference (P > 0.05). As exhibited in P < 0.01). The scavenging rate maximized at 0.8 mg/mL was 85.8 ± 1.65 %, slightly lower that of LAA (88.2 ± 1.81 %), but remarkable difference was not observed (P > 0.05).As shown in P < 0.05 or P < 0.01). However, within 0.4 – 0.8 mg/mL, the scavenging rates of PKFs against DPPH radical were similar to those of LAA (P > 0.05), suggesting that PKFs possessed DPPH radical-scavenging capacity close to LAA.LAA is recognized as one of the most potent antioxidants, and few substances can surpass it. Not surprisingly, the scavenging rates of PKFs against hydroxyl radical were notably lower than those of LAA at any of the tested concentrations . At 48 h, the moisture-absorbing rate reached 52.2 ± 1.41 %, which was significantly higher (P < 0.01) than that of chitosan (20.9 ± 1.41 %), but markedly lower (P < 0.01) than that of glycerol (74.3 ± 1.27 %). The results indicated that PKFs outperformed chitosan but underperformed glycerol on moisture absorption.The moisture-absorbing properties of PKFs and two controls (glycerol and chitosan) were showed in P > 0.05). The moisture-preserving rate of PKFs at 48 h was 95.6 ± 0.69 %, which was significantly higher (P < 0.05 or P < 0.01) than those of chitosan (92.1 ± 1.16 %) and glycerol (87.4 ± 1.04 %). The results suggested that PKFs outperformed both chitosan and glycerol on moisture preservation.The moisture-preserving profiles were displayed in PKFs exhibited moderate moisture-absorbing property and excellent moisture-preserving performance. They could be preferentially contributed by the polar groups in PKFs, such as hydroxyl, carbonyl and carboxyl groups, which can bind water by hydrogen bond association The first concern in cosmetic development is the moisturizing properties of the products, since adequate moisture can make the skin soft and elastic 4P < 0.01) than HWE (10.4 ± 1.41 %). SEM observation further revealed that ultrasonication greatly damaged the microstructure of materials to facilitate the release of PKFs. The PKFs extracted with UAE were acidic polysaccharides with a negatively charged potential of −16.3 mV, a molecular weight range of 0.92 – 76.9 kDa, and a particle size of 547.7 nm. Meanwhile, PKFs were composed of eight monosaccharides with arabinose the dominant one followed by galactose. PKFs exhibited pronounced antioxidant, moisture absorption and retention properties, especially for DPPH radical-scavenging capacity and moisture-preserving performance. In summary, ultrasonic processing efficiently led to the PKFs with great cosmetic potential.In the present investigation, the UAE process for PKFs was optimized by RSM-BBD. Under an optimized UAE condition , the yield of PKFs reached 26.8 ± 1.76 %, significantly higher (Suzhou Science and Technology Bureau (Grant No. SNG2022060), and 2023 Innovation Training Programs for College Students in Jiangsu Province.The present investigation was supported by Yang Zhang: Conceptualization, Methodology, Writing – review & editing, Funding acquisition, Project administration, Supervision. Yihui Liu: Conceptualization, Methodology, Investigation, Data curation, Writing – original draft, Funding acquisition. Yingying Cai: Methodology, Investigation, Data curation, Formal analysis. Yuping Tian: Resources, Formal analysis, Validation. Lianfa Xu: Investigation, Data curation. Aibei Zhang: Software, Visualization. Chen Zhang: Validation, Formal analysis. Shushu Zhang: Investigation.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Progress in reducing the global low birthweight (LBW) has been insufficient. Although the focus has been on preventing preterm birth, evidence regarding LBW in term births is limited. Despite its low preterm birth prevalence, Japan has a higher LBW proportion than other developed countries. This study aimed to examine the prevalence of LBW in term singleton births and its associated factors using a national database.We retrospectively analyzed the data of neonates registered in the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System who were born 2013–2017. Exclusion criteria included stillbirths, delivery after 42 gestational weeks, and missing data. Logistic regression analyses were performed to investigate the maternal and perinatal factors associated with LBW in term singletons using the data of 715,414 singleton neonates.The overall prevalence of LBW was 18.3%, and 35.7% of LBWs originated from singleton term pregnancies. Multiple logistic regression analyses indicated that both modifiable and non-modifiable factors were independently associated with LBW in term neonates. The modifiable maternal factors included pre-pregnancy underweight, inadequate gestational weight gain, and smoking during pregnancy, while the non-modifiable factors included younger maternal age, nulliparity, hypertensive disorders of pregnancy, cesarean section delivery, female offspring, and congenital anomalies.Using the Japanese pregnancy birth registry data, more than one-third of LBWs were found to originate from singleton term pregnancies. Both modifiable and non-modifiable factors were independently associated with LBW in term neonates. Prevention strategies on modifiable risk factor control will be effective in reducing LBW worldwide. LBW neonates not only have a higher risk of infant mortality but are also susceptible to long-term health consequences, such as a lower intelligence quotient2), inadequate gestational weight gain (GWG), and educational background have been shown to be associated with increased LBW risk.5–7 However, most studies to date have focused on preterm infants, and few studies have clarified these associations in neonates born at term. In our previous single-institutional study of 1,028 LBW neonates, 27.1% were singletons delivered at or after 37 gestational weeks, and 12.6% of multiple births were born at term.8 Other reports also suggest that Japan has one of the lowest proportions of preterm births but has a higher prevalence of LBW compared with other developed countries , pre-pregnancy underweight , gestational age at delivery ≥42 weeks , and missing data , 852,351 neonates were selected. Missing data included the lack of data on maternal age, maternal weight (pre-pregnancy or at delivery), maternal height, neonate’s sex, birthweight, and gestational age at delivery. There were 54,127 multiple births and 798,224 singleton births, of which 715,414 singleton neonates delivered at term were included in the final analysis  was computed using a previously reported method.16 Using the Institute of Medicine criteria, GWG was classified as inadequate, appropriate, or excessive, based on the pre-pregnancy BMI category. The pre-pregnancy BMI was categorized as underweight (less than 18.5 kg/m2), normal weight (18.5 to less than 25.0 kg/m2), overweight (25.0 to less than 30.0 kg/m2), and obese (30.0 kg/m2 or more). The appropriate ranges of GWG based on pre-pregnancy BMI were 12.7–18.1 kg for underweight, 11.3–15.9 kg for normal weight, 6.8–11.3 kg for overweight, and 5.0–9.1 kg for obese patients.17 The diagnosis and management of premature labor, premature rupture of membranes, gestational diabetes, HDP, and anemia during pregnancy were performed at the discretion of each obstetrician based on the clinical recommendations of the Japan Society of Obstetrics and Gynecology guideline.18 HDP was classified into two categories: hypertension without proteinuria  and hypertension with proteinuria .18 Hypertension was defined as a systolic blood pressure of ≥140 mm Hg and/or a diastolic blood pressure of ≥90 mm Hg, observed on at least two occasions, and proteinuria as the presence of ≥300 mg of protein per day in the urine. Congenital anomalies were defined as those with all types of anomalies registered in the database. These were diagnosed prenatally and/or at the time of delivery by obstetricians and/or after birth by neonatologists. The severity of an anomaly was not recorded.Using Japanese standard sex- and parity-specific birthweight percentile curves, a birthweight above the 90th percentile was defined as large for gestational age (LGA), and a birthweight below the 10th percentile was defined as small for gestational age (SGA).19 clinical relevance, and univariable screening: maternal age at delivery, parity (nulliparous or multiparous), method of conception , pre-pregnancy BMI , GWG (inadequate/adequate/excessive), smoking during pregnancy, gestational age at delivery (37 weeks/≥38 weeks), delivery via cesarean section (CS), HDP (none/hypertension without proteinuria/hypertension with proteinuria), anemia during pregnancy, offspring sex, and neonatal congenital anomaly. Multicollinearity was assessed for each independent variable using variance inflation factors, and all values were less than two. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were evaluated for the association between LBW and the aforementioned clinical features. Statistical analyses were performed using JMP software , and SAS .Data are presented as mean (standard deviation) or number of cases (percentage). Multiple logistic regression analysis was performed to evaluate the relative contributions of various maternal and perinatal factors to LBW among singleton neonates delivered at term. The following independent variables were included in the multivariate model based on prior knowledge,n = 156,450) of the total 852,351 neonates, of which 35.7%  were singleton term pregnancies. The maternal outcomes and the perinatal outcomes of the singleton term neonates are shown in Table n = 22,907), 8,426 mothers underwent planned elective CS (36.8%). In the LBW group, 53.5% were classified as SGA, and none were found to be LGA.LBW was observed in 18.3%  compared to normal pre-pregnancy weight, while it was 1.92  for those with inadequate GWG compared with those with appropriate GWG. Nulliparity , smoking during pregnancy , delivery at 37 gestational weeks , CS , female offspring , and congenital anomalies  also independently contributed to the risk of LBW in term singletons. Compared to those with no HDP, those with hypertension without proteinuria  had an increased risk of delivering LBW neonates , whereas hypertension with proteinuria  was associated with an even higher risk of LBW in term singletons .Using the pregnancy birth registry data, this study revealed that more than one-third (35.7%) of the nation’s LBWs were singleton term births. Multiple factors were identified to be independently associated with LBW singleton infants born at term. The associated maternal factors included age, parity, mode of conception, pre-pregnancy BMI, GWG, and smoking during pregnancy. Associated perinatal factors included HDP, anemia during pregnancy, mode and timing of delivery, and the neonatal factors included offspring sex and presence of a congenital anomaly. Our data are among the first to provide evidence that LBW is not only an issue with multiples and preterm birth but also with term birth. As such, LBW term infants and their associated factors should also be addressed when discussing preventive strategies.20,21 Underweight and low GWG has been a problem among Japanese women in recent years. According to the Japanese National Health and Nutrition Survey, 19.8% of Japanese women in their 20s were underweight, higher than that in other developed countries, and the GWG tended to be lower in Japanese mothers than in non-Hispanic white mothers.22 As maternal body image and eating habits during pregnancy are modifiable, raising awareness and educating women on these issues may reduce the risk of LBW. It should be noted that Asian women are known to have reduced beta-cell function and are more likely to develop glucose intolerance than Caucasians or Hispanics, even if insulin resistance increases similarly during pregnancy.23,24 Therefore, setting appropriate goals for pre-pregnancy BMI and GWG in Asian mothers may require further study.Maternal underweight and inadequate GWG remained independent risk factors for LBW in term singletons after adjusting for other traditionally reported factors, which was consistent with previous findings explored in the context of preterm birth.25 Increased maternal age is often associated with other risk factors for LBW, such as the mode of conception and obstetric complications. We adjusted for possible confounding factors through logistic regression analysis and found a negative association between advanced maternal age and LBW in term singletons, irrespective of the mode of conception and obstetric complications.The association between advanced maternal age and LBW has been inconsistent, depending on the study population and point in time.26 Although the detailed method of IVF-ET was missing, conception by IVF-ET may have reduced the risk of LBW, given that the mainstream method in Japan is frozen-thawed embryo transfer. The mechanism underlying anemia as a protective factor against LBW in our study is unclear. Since many pregnant women diagnosed with anemia often receive supplemented iron in Japan, it is possible that iron administration had a positive effect on the reduction of LBW, rather than anemia itself.27 Finally, delivery by CS was independently associated with LBW in term neonates. In the present study, 36.8% of LBW term infants delivered at 37 weeks of gestation were done so via elective CS. Due to the lack of detailed indications for elective CS, it is difficult to make concrete assumptions. However, if nonmedically indicated deliveries are included at a fixed number, scheduling them at later weeks might lead to a reduced risk of LBW in CS births.LBW and its associations with IVF-ET, the presence of anemia during pregnancy, and delivery with CS have not been well investigated. In the present study, a negative association was observed between IVF-ET and LBW. This observation is supported by one finding that neonates conceived by frozen-thawed embryo transfer are heavier than those conceived through natural conception or fresh embryo transfer.28 The present study indicated that infant sex is associated with birthweight, with female neonates having a higher risk of LBW than male neonates among term singletons. Sex differences have also been reported in the risk of future metabolic syndrome in a prospective cohort of infants with very LBW , where the risks were higher in men than in females.29 There is indeed evidence that sex-specific differences exist in the association between birthweight and adult resting metabolic rate, a factor associated with weight gain and metabolic syndrome.30 Given the differences in the risk of future health disorders, modifying the cut-off points for LBW based on sex may be relevant.It has been reported that maternal body composition affects fetal growth differently, depending on the offspring sex.In the present study, neonatal congenital anomalies were associated with a higher risk of LBW in term singletons. Although not preventable, neonates with congenital anomalies may have neuropsychiatric and endocrine disorders, which may intervene in the association between LBW and the risk of developing NCD in the future. Previous studies have rarely explored this issue and have either excluded neonates with congenital anomalies or analyzed them together with neonates without anomalies. Examining LBW and the risk of developing NCDs in children with congenital anomalies may provide new insights into their health care.The present study has several limitations. First, Japan may have different frequencies of preterm birth or LBW and their subgroups than other developed countries . As suchIn conclusion, using the Japanese pregnancy birth registry data, which included 715,414 singleton neonates delivered at term from an Asian population, this study showed that LBW comprised not only preterm and multiple births but also term singleton births in comparable proportions. This study expounded on previous findings by showing that factors known to elevate the risk of LBW in preterm births, such as smoking, maternal malnutrition, and presence of HDP, were also independently associated with LBW in term births. Our study provided data on the prevalence of LBW, which has not been well addressed in the past, enabling us to evaluate the status and monitor progress within and across countries on this issue. Although the situation may be different in each country, our results suggest that strategies to reduce preterm births and LBW could be equally effective in preventing LBW of term births. Therefore, continued and accelerated efforts are expected to contribute to the overall reduction of LBW worldwide.


The objective of this article was to provide an overview of the development and recommendations from the Australian evidence-based clinical practice guideline for attention deficit hyperactivity disorder (ADHD). The guideline aims to promote accurate and timely identification and diagnosis, and optimal and consistent treatment of ADHD.Development integrated the best available evidence with multidisciplinary clinical expertise and the preferences of those with lived experience, underpinned by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. The 23 guideline development group members included psychiatrists, paediatricians, general practitioners, psychologists, speech pathologists, occupational therapists, educators, Indigenous psychologists, and people with a lived experience; with two independent chairs and a methodologist. Where appropriate, evidence reviews from the National Institute for Health and Care Excellence (NICE) 2018 ‘Attention Deficit Hyperactivity Disorder: Diagnosis and Management’ guideline were updated. Fifty prioritised clinical questions were addressed in 14 systematic reviews (new and updated from NICE 2018) and 28 narrative reviews.https://adhdguideline.aadpa.com.au/The 113 clinical recommendations apply to young children (5 years and under), children, adolescents and adults. They provide guidance for clinicians on identification, screening, diagnosis, multimodal treatment and support, including pharmacological and non-pharmacological interventions. The guideline and supporting information are available online: The guideline was approved by the National Health and Medical Research Council (NHMRC) of Australia and relevant medical and allied health professional associations. It is anticipated that successful implementation and uptake of the guideline by organisations, health care providers and other professionals will increase delivery of evidence-based treatment and improve health outcomes for the more than 800,000 Australians with ADHD. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition with an onset before 12 years of age . It is oTo date, there has not been a cross-discipline, evidence-based Australian ADHD clinical guideline approved by Australia’s peak medical research body, the National Health and Medical Research Council (NHMRC). This has resulted in an absence of clear and consistent guidance for organisations and clinicians in the identification, diagnosis and treatment of ADHD across the lifespan. It has also had the unintended consequence of devaluing the lived experience of those with ADHD.The recently NHMRC-approved Australian evidence-based clinical practice guideline for ADHD  aims to promote accurate and timely diagnosis, and provide guidance on optimal and consistent assessment and treatment of ADHD across the lifespan . The guiThe Australian ADHD Professionals Association (AADPA) was invited by the Australian Government’s Department of Health (Grant Agreement ID: 4-A168GGT) in 2018 to deliver the Support for People Impacted by ADHD Program. Monies from this grant were used to fund the development of the guideline. No other funding was received or used in the development of the guideline. The guideline development process defined by the The Australian ADHD guideline is based, in part, on the evidenced-based UK National Institute for Health and Care Excellence (NICE) guidance on the diagnosis and management of ADHD . It was https://adhdguideline.aadpa.com.au/. Factsheets and other supporting information can also be found at this website.The methods used to develop the Australian ADHD guideline were aligned with international gold standard Appraisal of Guidelines for Research & Evaluation (AGREE II) criteria, ADAPTE II, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to meet the comprehensive NHMRC criteria for approval of evidence-based guidelines. All methods, administrative documentation and the guideline, all recommendations and the technical report can be found at Searches for existing ADHD evidence-based guidelines were conducted by the project’s methodologist, with 25 guidelines published between 2001 and 2018 identified. Only three completed evidence review searches within the previous 5 years. The most current of those, the UK National Institute for Health and Care Excellence 2018 guideline ‘Attention Deficit Hyperactivity Disorder: Diagnosis and Management’ [NICE guideline NG87] , coveredClinical questions were identified by the Australian ADHD Professionals Association (AADPA) in consultation with stakeholders. The preliminary list of clinical questions was refined through a structured prioritisation process conducted by a multidisciplinary group representing a broad range of perspectives including clinicians, academics and people with lived experience of ADHD, conducted over 2 days of face-to-face workshops. Contributors reached consensus on the resulting 50 clinical questions to be addressed by this guideline and the method for answering each (either a new or updated NICE systematic review or narrative review).The multidisciplinary GDG was convened by inviting people with experience living with ADHD, people caring for people with ADHD, and academics with experience in ADHD, to participate in the development of the guideline. Disciplines represented included psychology, child and adolescent psychiatry, adult psychiatry, paediatrics, general practice, applied neuroscience, speech pathology, occupational therapy, nursing, education, clinical pharmacology, and government and private health services. There were eight content subgroups led by members of the GDG.A formal process was followed to identify and manage competing interests among GDG members. A Conflict of Interest (COI) was defined as an interest of a member of the GDG that conflicted with, or could be perceived to conflict with, the duties and responsibilities of membership and the process of guideline development. This included any outside interest which could introduce any bias into the decision making of committee members. Potential members were asked to declare any COIs over the 3 years preceding the formation of the group and any arising during guideline development.Conflicts or potential conflicts were managed by a COI Management Group, which comprised the two GDG Chairs, and an ethicist , who did not otherwise participate in the guideline development process. This group operated within the AADPA policy for the Identification and Management of Potential Conflict of Interests, which was developed to align with standard A6 of the NHMRC ‘Procedures and Requirements for Meeting the 2011 NHMRC Standard for Clinical Practice Guidelines’ . The inthttps://www.nice.org.uk/guidance/ng87) were adopted and rerun from the Where appropriate, evidence reviews in the NICE guideline were updated, with permission. The selection criteria and search methods used in the NICE guideline  (https:/https://www.nice.org.uk/guidance/ng87). It was combined with specific searches tailored for the clinical question according to the selection criteria and PICO framework. The search terms used to identify studies addressing the population of interest were not limited, so that studies addressing people with ADHD in all cultural, geographical and socio-economic backgrounds and settings would be identified by the search. The search strategy was limited to English language articles, and there were no limits on year of publication. Searched databases included Medline, PsycINFO, EBM Review, and EMBASE.Where no evidence review existed in the NICE guideline to address the clinical questions, the patient/population, intervention, comparison and outcomes (PICO) framework was used to explore the components of each question and finalise the selection criteria. These components were used to design the search strategies and to include and exclude studies in the evidence review screening stage. A broad-ranging systematic search strategy for terms related to ADHD was adopted from the NICE guideline  .All search strategies, PRISMA flow charts, and results for new and updated searches can be found in the guideline Technical Report  or clinical practice points (CPP) and were informed by published research and clinical experience.Evidence-based recommendations were underpinned by the GRADE framework. This considers the volume and quality of evidence informing a recommendation, and the feasibility, acceptability, applicability, cost and implementation considerations of the recommendation.Specific, unambiguous, actionable recommendations were drafted by the GDG taking into consideration evidence certainty, relevance to the Australian population, the balance of benefits and harms, the values and preferences of the community and clinicians, resource implications, and feasibility and fairness, using the GRADE framework. Three types of recommendations were made, as described in The 50 prioritised clinical questions were addressed in 14 systematic reviews :People with borderline personality disorderPeople with Internet addictionPeople with psychotic disordersPeople with substance use disorderPeople with intermittent explosive disorderPeople with a family history of ADHDPeople with suicidal ideation/behaviourA further narrative review identified additional groups, for example, people with foetal alcohol spectrum disorder , extremeshould be aware that some groups of people are more likely to meet criteria for a diagnosis of ADHD, such as people with a family history of ADHD, people with other neurodevelopmental and mental health conditions and people in some settings, such as in out-of-home care. They should be aware that ADHD could be under-recognised in girls and women.Clinicians A narrative review was conducted given the existence of a recent systematic review with meta-analysis on this topic . ScreeniDSM-5 version of the ASRS, the ASRS-5, have found both specificity and sensitivity levels above 80% in non-clinical controls , health and correctional settings. However, the recommendations were based on the levels of screening test accuracy noted above and costs/benefits.should not occur at the population level .Routine screening for ADHD should be aware of the sensitivity and specificity of screening tools used. Positive screening should be followed by comprehensive clinical assessment for ADHD.Services and clinicians Narrative reviews were completed for making an ADHD diagnosis, co-occurring conditions and differential diagnosis.DSM or ICD classifications . All recommended using interview and questionnaires, as well as multiple informants, as key components of the diagnostic process. Also identified was a CAADRA review of systematic reviews and meta-analyses published between 2006 and 2016 on the diagnosis of ADHD. It found no strategies that achieved additional benefit beyond that of clinician interview in combination with rating scales. Direct observations such as observing children in their educational setting, neuropsychological and psychoeducational assessments, computerised cognitive assessments, neuroimaging and electroencephalography (EEG) did not increase the accuracy of diagnosis. The recommendations for diagnosis were consistent with NICE and CAADRA recommendations.A recent review of the quality of five major international diagnostic guidelines  reported that all guidelines recommended a categorical diagnosis approach based on the A high proportion of people with ADHD have co-occurring neurodevelopmental, mental health and medical conditions. In children, the most common co-occurring disorders are oppositional defiant disorder, language disorders, autism spectrum disorders and anxiety disorders, with depressive disorders and substance use disorders emerging in adolescence. Specific learning disorders also commonly occur in people with ADHD and involve difficulties in reading, written expression or mathematics . Among ashould conduct a comprehensive assessment (including history and examination) to identify any possible differential medical causes for ADHD.Some medical disorders can be present and have symptoms and signs similar to those of ADHD, such as obstructive sleep apnoea/sleep deprivation. Several medications can also produce symptoms similar to those of ADHD, for example, anti-epileptics such as Keppra . CliniciDSM-5 provides further specific advice on differential and co-occurring diagnoses , with more benefits evident by parent report. There is limited evidence to suggest improvements in child ADHD symptoms and/or functioning by teacher report, which is not surprising given the focus of parent/family training is on the home context. Parents are typically unblinded when rating outcomes, whereas clinician and teacher ratings can be blinded, which could introduce bias in parent ratings. As such, the quality of the evidence for parent/family training was low to moderate for children under 5 and low for children and adolescents. It is also noted the narrative review which explored additional outcomes of parent family functioning suggested benefits of parent/family training in one or more of these domains, but again through parent ratings.Non-pharmacological interventions can improve broader aspects of functioning for individuals with ADHD and/or their families. Clinicians should offer guidance on lifestyle changes, such as promoting a healthy and active lifestyle, including considering sleep patterns, as these have the potential to improve day-to-day functioning. Parent/family training should be offered to parents/carers of children and adolescents with ADHD to support the functioning of the family and child with ADHD. Cognitive-behavioural interventions should be offered to adolescents and adults with ADHD. Making changes in a person’s school, university or workplace can help the person with ADHD succeed. This can include physical changes or educating other people on how to most helpfully interact with the person with ADHD.An updated evidence review was conducted regarding starting, adjusting, and discontinuing pharmacological treatment; however, new studies were not integrated into the NICE findings as their qualitative assessment had reached saturation (i.e. no further themes identified). A narrative review was also conducted.Evidence indicated that before prescribing medication to treat ADHD symptoms, clinicians should carefully assess the person’s general health, including the person’s physical health such as medical history, current medications, height and weight, and conduct a cardiovascular assessment. Clinicians should explain all medication options including potential benefits and side effects. Clinicians and people with ADHD (and/or their parents/carers) should make treatment decisions together. Choice and dosage of medication must be optimised for each person. Clinicians should provide adequate information about the benefits and side effects of medication treatment and address any concerns around long-term effects. The treating clinician should review progress regularly during the dose-titration period. The dose should be titrated against symptoms, level of functioning and adverse effects until the optimal dose has been identified .An updated evidence review of the efficacy of pharmacological treatments found 16 new studies. The same outcomes for non-pharmacological treatments were used with primary outcomes being ADHD symptom reduction and secondary outcomes including improved functioning and quality of life. Evidence was combined for studies of the same design, age range and medication types. There was a paucity of evidence for the effectiveness of medications in children under 5 years of age. As such, no evidence-based recommendation about medication use in this age range was made.should be involved in assessment and treatment decisions. For children, adolescents and adults, evidence showed monotherapy with methylphenidate, lisdexamfetamine or dexamfetamine was associated with a clinically important benefit, compared with placebo or other agents. It was recommended that methylphenidate or dexamfetamine/ lisdexamfetamine should be the first-line treatment for children aged 5 years and over, adolescents and adults, given the minimal difference in efficacy and tolerability in these agents. If one medication type or duration of action of stimulant medication is not effective or poorly tolerated, then other stimulant types or duration of action should be trialled before trialling other medications such as non-stimulants. Practice points regarding starting either short- or long-acting medications were made that differed from NICE recommendations, using an informed and shared decision-making approach rather than specifying first-, second- and third-line stimulants.An expert in child development and treating ADHD in young children should be offered as a second-line treatment. Atomoxetine and guanfacine were the non-stimulant drugs with the most convincing evidence. For adults, third-line treatments with very low certainty of evidence based on the evidence review, that could be offered included bupropion, clonidine, modafinil, reboxetine and venlafaxine. A practice point based on GDG clinical expertise was made regarding fourth-line treatments for adults that could be offered and included lamotrigine, aripiprazole, agomelatine, armodafinil, desvenlafaxine. The third- and fourth-line medications included for adults in the Australian ADHD guideline were not included in the NICE guidance.No new evidence was identified for sequence of pharmacological/non-pharmacological treatment to be offered when the initial treatment is ineffective, inadequate or treatment is not tolerated. If stimulants are not tolerated or are ineffective, atomoxetine, or guanfacine, and additionally clonidine in children and adolescents, should be careful baseline assessments and consideration of drug interactions, slower titration and more careful monitoring of adverse effects, and regular contact.There was very little evidence on medication choice for people with ADHD and most co-occurring conditions. However, the available evidence did not suggest a different approach was warranted for a different choice of ADHD medication for people with ADHD and coexisting conditions, but there No new evidence was found for an updated evidence review exploring whether planned breaks from stimulant medication should be taken. An updated evidence review was conducted for medication monitoring and discontinuation and one new study was identified. Evidence identified concerned inadequate follow‑up and medication review. Limited evidence showed possible worsening of ADHD symptoms on stopping medication but supported a reduction in adverse effects after withdrawal. The importance of assessing the overall benefits and harms of medication should be examined as part of the annual review.Evidence showed the clinically important differences in sleep disturbance, decreased appetite and weight changes in people with ADHD taking medication and that ongoing monitoring for these unwanted effects should be undertaken. People taking medication for ADHD should be encouraged to monitor and record their adverse effects. Standard symptom and adverse effect rating scales should be used for clinical assessment and throughout the course of treatment. A yearly review with an ADHD specialist is recommended including a comprehensive assessment that revisits the areas discussed when starting treatment and evaluates the effect of current treatment. This helps ensure that decisions around continuing or stopping treatment are fully informed.Regarding adherence to pharmacological and non-pharmacological treatment, an updated evidence review was conducted with four new studies identified. The evidence highlighted time management and forgetfulness as common barriers to adherence.should be aware that the symptoms of ADHD can reduce adherence, for example, forgetting to collect medication and/or organise review appointments to ensure uninterrupted supply of prescriptions.Clinicians Narrative reviews were conducted for three important subgroups identified in the guideline.ADHD prevalence is higher in custodial settings than in the general population, estimated to be 5 times higher among youth prisoners and 10 times higher among adult prisoners . UnidentCurrently, there is a lack of research on understanding, identifying, assessing and treating ADHD in Aboriginal and Torres Strait Islander peoples . This laADHD is a risk factor for the development of substance use disorders, and people presenting with substance use disorders are at increased risk of ADHD . RecommeThis is the first multidisciplinary, evidence-based clinical practice guideline for ADHD in Australia to be approved by the NHMRC. It has attempted to balance traditional medical, biopsychosocial and social disability models, to ensure a considered approach to the identification, diagnosis and support of people with ADHD. Through adoption of these recommendations, the guideline aims to improve the experience and health outcomes for the estimated more than 800,000 Australians with ADHD. It is hoped that the guideline will make clinical practice more consistent across Australia by providing clear advice about evidence-based ADHD identification, diagnosis and treatment.In addition to the clinical recommendations presented here, the guideline makes recommendations for research, service development, professional development and education. This includes recommending that primary care and public mental health services should make diagnosis and treatment available to people of all ages with ADHD. This is underpinned by a need for ADHD training to be added to the curriculum of relevant clinical programmes and be provided to clinicians working in organisations that provide services to people with ADHD, including all public health services .It is noteworthy that of the 113 recommendations made in this guideline, a relatively small number (i.e. 12) were evidence-based recommendations. This highlights limitations in the extant research literature of ADHD, wherein there is a lack of appropriately designed, controlled and powered studies that can be drawn upon to make recommendations for best care in response to key questions raised by the ADHD community. It is also noteworthy that the certainty of the evidence underpinning the evidence-based recommendations was more often rated as either low or moderate rather than high. We therefore call upon the ADHD research community to work with clinicians and individuals who have lived experience of ADHD to prioritise research questions and increase and focus their efforts to design high-quality studies. This can advance the scientific evidence-based of ADHD with a view to enhancing clinical practice and improving health outcomes for individuals with ADHD.In summary, this guideline provides a roadmap not only for ADHD clinical practice, but for research and policy, and highlights opportunities for further improvements in health care, research and policy to come.