Divergence Between Clinical Trial Evidence and Actual Practice in Use of Dual Antiplatelet Therapy After Transient Ischemic Attack and Minor Stroke.

BACKGROUND: Randomized controlled trials (RCTs) proved that short-term (21-90 days) dual antiplatelet therapy (DAPT) reduces the risk of early ischemic recurrences after a noncardioembolic minor stroke or high-risk transient ischemic attack (TIA) without substantially increasing the hemorrhagic risk. We aimed at understanding whether and how real-world use of DAPT differs from RCTs. METHODS: READAPT (Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or TIA) is a prospective cohort study including >18-year-old patients treated with DAPT after a noncardioembolic minor ischemic stroke or high-risk TIA from 51 Italian centers. The study comprises a 90-day follow-up from symptom onset. In the present work, we reported descriptive statistics of baseline data of patients recruited up to July 31, 2022, and proportions of patients who would have been excluded from RCTs. We compared categorical data through the χ² test. RESULTS: We evaluated 1070 patients, who had 72 (interquartile range, 62-79) years median age, were mostly Caucasian (1045; 97.7%), and were men (711; 66.4%). Among the 726 (67.9%) patients with ischemic stroke, 226 (31.1%) did not meet the RCT inclusion criteria because of National Institutes of Health Stroke Scale score >3 and 50 (6.9%) because of National Institutes of Health Stroke Scale score >5. Among the 344 (32.1%) patients with TIA, 69 (19.7%) did not meet the RCT criteria because of age, blood pressure, clinical features, duration of TIA, presence of diabetes score <4 and 252 (74.7%) because of age, blood pressure, clinical features, duration of TIA, presence of diabetes score <6 and no symptomatic arterial stenosis. Additionally, 144 (13.5%) patients would have been excluded because of revascularization procedures. Three hundred forty-five patients (32.2%) did not follow the RCT procedures because of late (>24 hours) DAPT initiation; 776 (72.5%) and 676 (63.2%) patients did not take loading doses of aspirin and clopidogrel, respectively. Overall, 84 (7.8%) patients met the RCT inclusion/exclusion criteria. CONCLUSIONS: The real-world use of DAPT is broader than RCTs. Most patients did not meet the RCT criteria because of the severity of ischemic stroke, lower risk of TIA, late DAPT start, or lack of antiplatelet loading dose. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05476081.

How much do children with disabilities participate in Clinical Trials? A Scoping review.

BACKGROUND: Children with disabilities (CWDs) are often excluded from scientific research, but no precise data are available on their participation in Clinical Trials. The aim of this study was to evaluate the rates of exclusion of CWDs from recent medical research. SUBJECTS AND METHODS: The protocol of the study was designed according to Prisma-ScR guidelines. All completed interventional Clinical Trials registered on Clinicaltrials.gov between 2010 and 2020 related to the Leading 10 Level 3 causes of global Disability-adjusted life years (DALYs) for both sexes combined for all ages of the updated Global Burden of Disease Study 2019 were analysed. The exclusion criteria were considered explicit if related to the following categories: disability, physical impairment, cognitive impairment, behavioural or psychiatric disorders, language and communication impairment, sensory impairment. Any generic or poorly specified exclusion criteria or statements that left wide discretion to researchers were considered "implicit exclusion criteria". We assessed the appropriateness of explicit exclusion criteria in relation to the primary objectives of the trials and labelled them as "absolute", "relative", or "questionable". RESULTS: The trials selected according to the inclusion criteria of the scoping review were 328; 166 (50.6%) were pediatric-only studies, and 162 (49.4%) trials comprising subjects of all ages. Explicit exclusion criteria were found in 82 trials (25%) and the disability category most frequently excluded was "Behavioural or psychiatric disorders" present in 46 trials (56.1%). Explicit exclusion criteria were considered "relative" in over 90% of the selected studies. Implicit exclusion criteria were present in 153 trials (46.6%) and the number and percentage of studies with at least one explicit or implicit exclusion criterion were 193 and 58.8% respectively. CONCLUSIONS: This study highlights a high rate of exclusion of CWDs from medical research and the need for an inclusive approach that comprises the study design and any necessary adaptations for specific needs.

A patient with novel MBOAT7 variant: The cerebellar atrophy is progressive and displays a peculiar neurometabolic profile.

Mutations in the MBOAT7 gene have been described in 43 patients, belonging to 18 families, showing nonspecific clinical features (intellectual disability [ID], seizures, microcephaly or macrocephaly, and mild to moderate cerebellar atrophy) that make the clinical diagnosis difficult. Here we report the first Italian patient, a 22.5-year-old female, one of the oldest reported, born to apparently consanguineous parents. She shows severe ID, macrocephaly, seizures, aggressive outbursts, hyperphagia. We also documented progressive atrophy of the cerebellar vermis, that appeared not before the age of 7. The whole-exome sequencing of the trio identified a novel homozygous variant c.1057_1058delGCinsCA (p.Ala353His) in the MBOAT7 gene. The variant is considered to be likely pathogenic, since it is absent from population database and it lies in a highly conserved amino acid residue. This disorder has a neurometabolic pathogenesis, implicating a phospholipid remodeling abnormalities. A brain hydrogen-magnetic resonance spectroscopy (H-MRS) examination in our patient disclosed a peculiar neurometabolic profile in the cerebellar hemispheric region. This new finding could address the clinical suspicion of MBOAT7-related disorder, among the wide range of genetic conditions associated with ID and cerebellar atrophy. Moreover, the documented progression of cerebellar atrophy and the worsening of the disease only after some years open to the possibility of a therapeutic window after birth.

Bladder and bowel dysfunction, adaptive behaviour and psychiatric profiles in adults affected by autism spectrum disorders.

AIMS: Bladder and bowel dysfunction (BBD) have been recognized in children affected by autism spectrum disorder (ASD), but no consistent information exist in adults with the condition. We evaluated the prevalence of BBD and the impact of psychiatric and behavioural profiles in adults affected by ASD. METHODS: Twenty-two adults and 13 children/teens with ASD and a matched group of typically developing subjects (TD) were prospectively studied. Patients and TD subjects underwent the evaluation of urinary incontinence (UI: diurnal, continuous or intermittent), nocturnal enuresis (NE), and bowel disturbances with the 3-day voiding and bowel diary. In addition, assessment of intellectual disability (ID) and psychiatric and adaptive behaviours with the Neuropsychiatric Inventory Scale (NPI) and the Vineland Adaptive Behaviour Scale 2nd Edition (Vineland-II), was performed. RESULTS: In adults, any type of incontinence was observed in 81.8% of cases, and NE and intermittent UI in 59.0% and 36.3% of patients, respectively. Faecal incontinence and constipation were detected 36.3% and in 68.1% of cases, respectively. ID was severe in 2 cases and profound in 18; NPI and Vineland-II items most affected were "Irritability/Lability," "Motor Activity," and "Agitation," and IQ-Socialization and IQ-Communication. Significant relationships were identified between intermittent UI and greater ID (P < .02) and high "anxiety" (P < .05), and between NE and high "euphoria/elevated mood" (P < .05). These results were similar to those observed in children/teens. CONCLUSIONS: Adults with ASD, and greater ID and mood disorders, present with a high prevalence of BBD. A shared pathogenetic mechanism could underlie the co-occurrence of ASD, mood disorders, and BBD.

Beyond the Disease: "...Am I My Brother's Keeper?"

Today, the concepts of health and illness require a global vision of man; the suffering of the person places the entire environment in great difficulty: health professionals, family, society. It is important not to simplify the response to a purely health-focused view of the disorder, because fragile people possess a deep need to feel welcomed, listened to, understood and accepted. Service provision that is respectful of the dignity of the person is an important challenge both for those who are responsible for providing services to individuals and their families as well as for the entire community. Therefore in providing care the human qualities of the health professional and not only his technical skills come into play: blending together science and humanitarian ethos. The provision of care therefore "forces" us to broaden our horizons and requires us to face the challenge of responsibility towards the Other, the human condition of being-for. However, ethical capacity cannot be born solely out of sharing standards or adhering to regulations and respecting prohibitions: it stems from high and unconditional moral values and meanings. The ME-YOU relationship represents the primary ethical factor of the human being: my responsibility towards the Other is unconditional. In the book of Genesis when the Lord asks Cain: "... where is Abel, your brother?" He responds with another question: "Am I my brother's keeper?" In this biblical passage Cain kills Abel: the rejection of brotherhood and the care of the other only leads to the death of the Other. "Where is your brother?" This question is crucial in today's day and age and must be taken seriously: it is the decisive question that forces us to decide how to place ourselves in relationship with the other and with the world: do we choose proximity or distance, connection or indifference?

Urinary and bowel disfunction in autism spectrum disorder: a prospective, observational study.

BACKGROUND: Vesico- sphincter and bowel dysfunction have been frequently detected in Autism spectrum disorder (ASD) patients, but to date no consistent information exist on adults affected by the disease. We evaluated the prevalence and types of bladder and bowel disfunction (BBD) in young and adult patients affected by ASD. SUBJECTS AND METHODS: Twenty- seven adults and 20 children/teens with ASD and a matched group of typically developing subjects were enrolled. Daily pads use and episodes of urinary incontinence (UI) were recorded in a 3- day voiding diary. Patients underwent also the measurement of post-void urinary residual volume and 3- day bowel diary. In addition, type and duration of the pharmacological agents assumed by the patients were accurately recorded. RESULTS: Any type of UI was observed in 85.1% of adults and in 90% of children/teens. In adults, nocturnal enuresis (NE, 62.9%) and diurnal intermittent UI (37%) were the most frequently observed bladder dysfunction while in children/ teens were NE (75%) and diurnal continuous UI (40%). In all patients was demonstrated a significant relationship between urinary symptoms and pharmacological agents, particularly NE and clotiapine (p<0.004) and periciazine (p<0.008). CONCLUSIONS: Young and adult patients with ASD present with a high prevalence of BBD and concomitant antipsychotic medications could to play a contribution in induction and/or maintaining of BBD.

New technologies for art therapy interventions tailored to severe disabilities.

Individuals with multiple disabilities can have a wide range of characteristics depending on the combination and severity of the disabilities, such as intellectual disability, mobility issues, sensorial impairment, language issues and brain injury. New technologies can help therapists find an alternative way to engage and interact with clients by opening a communication window and starting to build the therapeutic relationship. The need to use more customized technological tools led us to develop the Painteraction system, an intuitive tool based on Augmented Reality that allows clients to be immersed in their own images. Just by moving their bodies individuals are able to make drawings and receive visual feedback, both from themselves and their therapists, as it appears on the screen. The pilot testing of Painteraction was performed on 21 inpatients at Istituto Serafico (Assisi, Italy) with severe/multiple disabilities in order to explore and assess reaction and responsiveness in a semi-structured art therapy setting. The sample was formed by 14 males and 7 females (N=21) between the ages of 7 and 35. All participants attended three twenty-minute individual art therapy sessions which were approximately one week apart. Through direct and indirect (video recordings) observation of the sessions, it appeared that the specific Augmented Reality tool introduced in the art therapy setting was easily accepted by most of the clients involved and generally allowed the development of an interpersonal therapist-client relationship. The present study therefore gave us the opportunity to test new digital tools in the challenging setting of severe/multiple disabilities and observe the huge potential of new media to empower clients to express themselves and their creativity, and ultimately overcome mental and physical barriers. We propose that Augmented Reality tools are particularly well-suited to art therapy and create an equally suitable therapeutic environment to address specific client needs.

Mathematics Anxiety and Cognitive Performance in Adolescent Students.

Several studies highlight that many students feel negative feelings about mathematical learning and that the mathematics anxiety seems to play a central role in mathematical performance. More specifically students with higher level of maths anxiety are less efficient in mathematical tasks. The aim of this study was to investigate the relationship between specific mathematics anxiety as assessed by AMAS, trait and state anxiety as assessed by STAI-Y, and mathematical skills assessed through the ABCA tests in a sample of 83 adolescent students (78.3% males) without diagnosis of dyscalculia and cognitive disorder attending their first year of secondary school. Results showed that 38% of the students referred high level of maths anxiety. Independent T-test revealed that female students referred a higher level of maths anxiety as well as of trait and state anxiety than male ones, while there were no differences in the mathematics performance. The simultaneous multivariate linear regression analysis showed that maths anxiety was influenced by trait anxiety and in its turn has an impact on the high level mathematics performances (i.e. arithmetic facts). Understanding the relationships between maths anxiety and maths learning and performance may have relevant implications in clinical, educational and didactic practice.

Evaluation of the Quality of Rehabilitation Treatment in Neurodevelopmental Disorder.

Complex disability is very difficult to manage. It usually subtends very serious clinical pictures, because it affect several body systems, or because it is associated with intellectual disability and behavioral disorders. Often affected patients are unable to communicate their basic needs. All these factors combine to make the management of these patients very complex, and those who care for them realize how important it is to find a way to detect their state and to identify their potential capabilities. Developing appropriate rehabilitation programs for these patients requires additional effort and an assessment capacity that is as objective as possible. Few scales cited in the literature are capable of evaluating these aspects in patients with complex disabilities, among them the Barthel Index (Mahoney & Barthel 1965) and the Vineland Adaptive Behavior scale II (Sparrow et al. 2005). The majority of these scales often tend to depict the data regarding the disease to a degree of severity that precludes adequate individual rehabilitation program development. There is a dire need for a more appropriate instrument, an observational grid that is capable of identifying the potential of this patient population and evaluate the effectiveness of rehabilitation interventions provided. The aim of the study is to evaluate the efficacy of rehabilitation interventions in a group of patients with IQ <32 (determined by the Vineland II scale) using an evaluation tool created ad hoc called D-Rubrics, designed with the intent to identify "micro-differences" between baseline (T0) and post-rehabilitation (T1). The goal is part of a more long term-term objective which involves developing an effective assessment tool for patients with complex disabilities. Such an assessment tool should be practical, easy to administer and useful in both clinical and research settings.

The Effect of Mozart's Music in Severe Epilepsy: Functional and Morphological Features.

Music is a very important factor in everyday life, involving mood, emotions and memories. The effect of music on the brain is very debated. Certainly, music activates a complex network of neurones in auditory areas, mesolimbic areas, cerebellum and multisensory areas. In particular, music exerts its effects on the brain of patients with epilepsy, having a dichotomous influence: it can either be seizure-promoting in musicogenic epilepsy or antiepileptic. Several studies have shown that seizure-prone neural networks may be stimulated by certain periodicities while other frequencies may prevent seizure activity. There are a lot of data in the literature about the so-called "Mozart effect" (Rauscher et al. 1993). In previous studies we observed that in institutionalized subjects with severe/profound intellectual disability and drug-resistant epilepsy, a systematic music listening protocol reduced the frequency of seizures in about 50% of the cases. In this study we are conducting a survey on the observation of what happens to the brain of patients suffering from drug-resistant epilepsy through electroencephalographic investigations, brain MRI and behavioural analysis before and after six months of listening to Mozart music (Sonata K.448). The first step is to present the data of the first patient under investigation.

Antiepileptic drugs in migraine and epilepsy: Who is at increased risk of adverse events?

Background The impact of adverse events (AEs) of antiepileptic drugs (AEDs) have an impact on compliance and dropouts. We compared tolerability of AEs of AEDs among patients with migraine, epilepsy, or both. Methods Overall, 335 patients (epilepsy (n = 142), migraine (n = 131), and both (n = 62)), were evaluated with the Liverpool Adverse Events Profile (LAEP) to assess the magnitude, profile and occurrence rate of the AEs of valproate, topiramate, and lamotrigine. Results AEs were significantly more common with topiramate treatment (71.0%) and among migraineurs (69.5%), the latter being more prone to discontinue AEDs (46.6%). The profile of AEs with topiramate and valproate differed among groups. Moreover, treatment with both topiramate and valproate was associated, for all groups, with a worse tolerability profile compared to lamotrigine. Conclusion Our data suggest a specific drug and disease AE profile of AEDs. Specifically, migraineurs are the most affected by AEs, even though they receive very low dosages of AEDs. This finding might be considered a clinical implication of central sensitization mechanisms. Both the profile and tolerability of AEs, highly influencing quality of life, depended on the underlying conditions, and deeply impacted on treatment dropout. Therefore, before starting, switching or stopping AED treatment, all options need to be considered.

Liverpool Adverse Events Profile: Italian validation and predictive value for dropout from antiepileptic treatment in people with epilepsy.

INTRODUCTION: Adverse events (AEs) of antiepileptic drugs (AEDs) affect patient compliance and dropout. No questionnaire measuring AEs of AEDs is available for Italian-speaking people with epilepsy. Moreover, no questionnaire has been shown to predict patient dropout. OBJECTIVE: The aim of this study was to provide a validated Italian version of the Liverpool Adverse Events Profile (iLAEP) and to define iLAEP reliability in AE monitoring and dropout risk prediction. METHODS: The original LAEP was translated and tested for internal consistency and reliability. Patients with epilepsy who are on stable AED regimen completed the questionnaire as well as a 3-month follow-up to assess dropouts. RESULTS: Overall, 204 patients with epilepsy were enrolled (mean age: 47.1±21.5). High internal consistency (Cronbach's α=0.88) was demonstrated, and very quick completion time was registered (mean=9min). A 3-month follow-up was performed to assess treatment discontinuation and potential predictive value of the iLAEP score. Treatment was discontinued in 33.3% of the cohort. Moreover, iLAEP scores (mean=30.71) significantly differed between patients interrupting (39.15±5.66) and those prosecuting treatment (29.4±6.54, p<.001). A cutoff of 36.5 had an 85% accuracy in predicting treatment discontinuation (85% sensitivity, 79% specificity). Scores >36.5 were associated with a 20.27-fold increase in dropout relative risk (RR), with a 66% positive predictive value. CONCLUSIONS: The iLAEP represents a reliable, quick, and inexpensive assessment tool for patient-reported AEs of AEDs. An iLAEP cutoff of 36.5 differentiates patients unlikely to interrupt treatment from those more prone to stop AEDs in the following 3months. The iLAEP might help clinicians in weighting the risk of dropout and better tailor treatment to patients.

Effectiveness of serotonergic drugs in the management of problem behaviors in patients with neurodevelopmental disorders.

Neurodevelopmental disorders often result in disabilities associated with auto- and / or hetero-aggressive behaviors, that can be defined as "problem behaviors" (Lacy 2007). Therapeutic interventions are mainly directed towards the use of neuroleptic drugs or benzodiazepines, to ensure a rapid and significant sedation in most of cases. These pharmacological devices exposes the patient to clinical risks and/or long-term management difficulties. The main problem of the chronic use of benzodiazepines is the development of tolerance and dependence; furthermore benzodiazepine withdrawal or their abrupt reduction may lead to rebound effect. Regarding the long-term effects of neuroleptics, it is necessary to focus on extrapyramidal effects, motor restlessness and akathisia, anticholinergic effects, as well as endocrine and metabolic alterations. Several studies have shown that the reduction of serotonergic receptor activity is associated with the appearance of aggressive behavior (Farnam et al. 2017), especially impulsive behaviors (Manchia et al. 2017, Takahashi et al. 2012). The dynamics that subtend these data are still not fully clarified, however there are evidences that the use of selective serotonin reuptake inhibitors (SSRI) is helpful in the treatment of aggressive behavior in mental disabilities (Sterke et al. 2012, Janowsky et al. 2015). In this study we observe the behavioral response to sertraline, for minors, and to vortioxetine, for adults, considering that the literature shows significant evidence of modulation of synaptic neuroplasticity (Waller et al. 2017). To support the observation we used behavioural scales to collect the data, before the administration of the drug, during the course of treatment, at 3 months from the start of the administration. We detected the improve of behavioral disorders with the less use neuroleptic drugs and benzodiazepines.

Mozart's music and multidrug-resistant epilepsy: a potential EEG index of therapeutic effectiveness.

Multidrug-resistant epilepsy is a pathological condition that affects approximately one-third of patients with epilepsy, especially those with associated intellectual disabilities. Several non-pharmacological interventions have been proposed to improve quality of life of these patients. In particular, Mozart's sonata for two pianos in D major, K448, has been shown to decrease interictal electroencephalography (EEG) discharges and recurrence of clinical seizures in these patients. In a previous study we observed that in institutionalized subjects with severe/profound intellectual disability and drug-resistant epilepsy, a systematic music listening protocol reduced the frequency of seizures in about 50% of cases. This study aims to assess electroencephalography as a quantitative (qEEG) predictive biomarker of effectiveness of listening to music on the frequency of epileptic discharges and on background rhythm frequency (BRF).

National Survey on bladder and bowel dysfunctions in Autism Spectrum Disorder population.

Introduction: To evaluate lower urinary tract symptoms (LUTS) and bowel disorders in a population of young subjects with autism spectrum disorder (ADS) by a national survey and to assess the relationship between the occurrence, frequency, and type of LUTS and the severity of behavioral and neuropsychiatric characteristics. Materials and methods: A survey on LUTS and bowel disorders in the ASD population was sent by mail and social media through the main Italian Associations of ASD between February and September 2022. The correlation between LUTS and ASD severity was also assessed. Results: The survey was completed by 502 subjects with a mean age of 16.6 years ± 10 years: male participants were 413 (mean age: 16.5 years ± 9.8 years), while female participants 89 (mean age: 17.2 years ± 10.9 years). ADS severity was found low in 29.9%, moderate in 27.1%, and severe in 43%. LUTS were reported by 77.1%, storage symptoms in 51.4%, and voiding symptoms in 60.6%. Urinary incontinence was reported by 12.5%. Enuresis was reported by 14.3% (72/502) of the respondents: primary enuresis in 70.8% (51/72), secondary in the remaining. Pads were used by 40 subjects with a median of 2.9 pads/day (range, 0-8). A toilet training program was performed by 61 of the respondents, with satisfactory results in 40/61 (65.6%). A significant correlation was found between greater ASD severity and higher LUTS rates. The mean VAS score on the impact of LUTS on family relationships was 2 ± 2.9. Regular bowel function was reported by 57.4% (288/502) of the respondents, while increased daily defecations were present in 11.2% (56/502), constipation in 31.5% (158/502), and fecal incontinence in 7.9% (40/502). Conclusion: This survey demonstrated that LUTS are very common in the young ASD population and that the prevalence of urinary symptoms is related to higher severity of the ASD condition. Bowel disorders are often associated with urinary symptoms and dysfunctions. Urologists should be aware of the frequent occurrence of urological disorders and symptoms in individuals with ASD and should be involved in their clinical management in a multidisciplinary team that cares for these people.

Beyond RCTs: Short-term dual antiplatelet therapy in secondary prevention of ischemic stroke and transient ischemic attack.

BACKGROUND AND PURPOSE: Randomized controlled trials (RCTs) proved the efficacy of short-term dual antiplatelet therapy (DAPT) in secondary prevention of minor ischemic stroke or high-risk transient ischemic attack (TIA). We aimed at evaluating effectiveness and safety of short-term DAPT in real-world, where treatment use is broader than in RCTs. METHODS: READAPT (REAl-life study on short-term Dual Antiplatelet treatment in Patients with ischemic stroke or Transient ischemic attack) (NCT05476081) was an observational multicenter real-world study with a 90-day follow-up. We included patients aged 18+ receiving short-term DAPT soon after ischemic stroke or TIA. No stringent NIHSS and ABCD2 score cut-offs were applied but adherence to guidelines was recommended. Primary effectiveness outcome was stroke (ischemic or hemorrhagic) or death due to vascular causes, primary safety outcome was moderate-to-severe bleeding. Secondary outcomes were the type of ischemic and hemorrhagic events, disability, cause of death, and compliance to treatment. RESULTS: We included 1920 patients; 69.9% started DAPT after an ischemic stroke; only 8.9% strictly followed entry criteria or procedures of RCTs. Primary effectiveness outcome occurred in 3.9% and primary safety outcome in 0.6% of cases. In total, 3.3% cerebrovascular ischemic recurrences occurred, 0.2% intracerebral hemorrhages, and 2.7% bleedings; 0.2% of patients died due to vascular causes. Patients with NIHSS score ⩽5 and those without acute lesions at neuroimaging had significantly higher primary effectiveness outcomes than their counterparts. Additionally, DAPT start >24 h after symptom onset was associated with a lower likelihood of bleeding. CONCLUSIONS: In real-world, most of the patients who receive DAPT after an ischemic stroke or a TIA do not follow RCTs entry criteria and procedures. Nevertheless, short-term DAPT remains effective and safe in this population. No safety concerns are raised in patients with low-risk TIA, more severe stroke, and delayed treatment start.

'Being disabled' as an exclusion criterion for clinical trials: a scoping review.

BACKGROUND: People with disabilities (PWDs) are often excluded from biomedical research, but comprehensive data regarding their participation in clinical trials are not available. The objective of this study was to assess the rates of exclusion of PWDs from recent medical scientific research. METHODS: The protocol of the study was designed according to PRISMA-ScR (PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) extension for Scoping Reviews) guidelines. All completed interventional clinical trials registered on ClinicalTrials.gov between 2010 and 2020 regarding the 10 leading causes of global disability-adjusted life-years according to the Global Burden of Disease Study were analysed. An exclusion criterion from the study was considered explicit if it could be associated with one of the following seven categories: disability, physical impairment, cognitive impairment, behavioural or psychiatric disorders, language and communication impairment, sensory impairment. Comorbidities not more clearly defined and researcher discretion regarding exclusion of study participants were considered to be 'implicit exclusion criteria'. We assessed the appropriateness of explicit exclusion criteria in relation to the primary objectives of the trials and labelled them as 'absolute', 'relative' or 'questionable'. RESULTS: The total number of trials analysed was 2710; 170 were paediatric trials (6.3%), 2374 were adult trials (87.6%) and 166 were trials including subjects of all ages (6.1%). Explicit exclusion criteria were found in 958 trials (35.3%). The disability category most frequently excluded was behavioural or psychiatric disorders, present in 588 trials (61.4%). In only 3% and 1% of the trials, the exclusion criteria were considered either 'absolute' or 'questionable', while in 96% the exclusion criteria were judged as 'relative'. Implicit exclusion criteria were present in 1205 trials (44.5%). CONCLUSIONS: This study highlights the high rate of exclusion of PWDs from biomedical research and the widespread use of ill-defined exclusion criteria in clinical trials. It underscores the importance of more inclusive study designs so that PWDs can become active participants in research.

Alzheimer's disease and late-onset epilepsy of unknown origin: two faces of beta amyloid pathology.

Although amyloid pathology plays a role in epilepsy, little is known about the relationship between beta amyloid and progression to Alzheimer's disease (AD) among patients with late-onset epilepsy of unknown origin (LOEU). This multicenter, observational, prospective study enrolled 40 consecutive nondemented adults diagnosed with LOEU, together with 43 age- and sex-matched healthy controls. All patients completed neuropsychological tests, core CSF AD biomarkers assessment (Aß1-42, total tau, and phosphorylated tau), and follow-up for a mean of 3 years to verify cognitive decline. Despite age and baseline cognitive performance were similar to healthy controls, patients with LOEU had significant prevalence of CSF pathological Aß1-42 (<500 pg/mL; 37.5%), 7.5% displaying an AD-like CSF pattern. Moreover, 17.5% of patients with LOEU converted to AD dementia, versus none among healthy controls (p < 0.005). Patients with LOEU with pathological Aß1-42 had a hazard ratio 3.4 (CI 0.665-17.73) for progression to AD dementia at follow-up. Patients with LOEU have a high prevalence of abnormal CSF Aß1-42 and progression to AD dementia compared with healthy controls, and therefore should be monitored for cognitive decline.