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The sirolimus-eluting stent has shown promise in the prevention of restenosis after balloon dilation of simple coronary lesions. This clinical trial compared the sirolimus-eluting stent with a standard stent in patients with complex coronary lesions. The sirolimus-eluting stent proved to be superior in the prevention of restenosis and neointimal hyperplasia. Superior prevention of restenosis and hyperplasia with the sirolimus-eluting stent. The demonstrated clinical usefulness of the implantation of a coronary stent as the preferred method of percutaneous revascularization is due to improved procedural safety as compared with balloon angioplasty and reduced rates of restenosis. 1 – 7 But despite the use of coronary stents, the frequency of restenosis may be more than 30 percent in several subgroups of patients, including subgroups with diabetes mellitus, small coronary vessels, and long lesions. 8 – 15 During the past two decades, attempts to reduce restenosis after angioplasty with the use of locally delivered or systemic pharmaceutical agents have been largely unsuccessful. 16 – 19 Recently, sirolimus (rapamycin), a cytostatic . . .

Clinical trials in neurological and psychiatric indications are hampered by poor measurement fidelity in currently used \"standardized\" rating scales. Digital, repeatable tests that can be remotely administered offer a more fine-grained understanding of the patient's clinical trajectory. Several such tools are being developed, but only a few have been validated in terms of their ability to discern and describe change over time-a critical element of clinical trials. Four cognitive tasks from a digital battery (delivered via tablet) are administered at high frequency following an alcohol challenge to assess sensitivity to change. The tasks are novel, repeatable, and self-administered implementations of classic neurobehavioral paradigms. Thirty healthy younger adults were assessed on 2 separate days, once under the influence of alcohol and once under a placebo, with order counterbalanced. Each day included 8 assessments. The tasks comprised novel, engaging implementations of the Digit Symbol Substitution Task (DSST), reaction time, N-back working memory, and visual associative/episodic memory, and were compared with benchmark measures. In-laboratory assessments were preceded by massed practice (3 sessions), and blood alcohol concentration was monitored throughout using a breathalyzer and a Visual Analog Scale. Alcohol-related impairment was observed across multiple measures, followed by a return to baseline as blood alcohol concentration declined. A slight practice effect was noted between the first and second sessions for the digital DSST, along with a longer-term effect across the 2 days. Moderate to strong correlations between digital and benchmark measures were observed at peak intoxication. Under alcohol challenge, this battery, along with benchmark standardized tests, demonstrates sensitivity to subtle changes in cognitive performance over time. Practice effects are minimal within this condensed protocol. Patient-friendly, repeatable tests administered via a digital platform, such as those in the current battery, warrant further investigation in the context of remote clinical studies that require methodological approaches capable of discerning and describing small changes over time. The availability of validated single tests or test batteries as sensitive tools that can be easily and frequently administered (eg, daily) would address a critical gap: the lack of descriptors with sufficient sensitivity, specificity, and reliability to detect cognitive changes over time in clinical trials of new therapies for neurological and psychiatric conditions.

Background The Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales are widely accepted tools that measure overall disease severity and change, synthesizing the clinician’s impression of the global state of an individual. Frequently employed in clinical trials for neuropsychiatric disorders, the CGI scales are typically used in conjunction with disease-specific rating scales. When no disease-specific rating scale is available, the CGI scales can be adapted to reflect the specific symptom domains that are relevant to the disorder. Angelman syndrome (AS) is a rare, clinically heterogeneous condition for which there is no disease-specific rating scale. This paper describes efforts to develop standardized, adapted CGI scales specific to AS for use in clinical trials. Methods In order to develop adapted CGI scales specific to AS, we (1) reviewed literature and interviewed caregivers and clinicians to determine the most impactful symptoms, (2) engaged expert panels to define and operationalize the symptom domains identified, (3) developed detailed rating anchors for each domain and for global severity and improvement ratings, (4) reviewed the anchors with expert clinicians and established minimally clinically meaningful change for each symptom domain, and (5) generated mock patient vignettes to test the reliability of the resulting scales and to standardize rater training. This systematic approach to developing, validating, and training raters on a standardized, adapted CGI scale specifically for AS is described herein. Results The resulting CGI-S/I-AS scales capture six critical domains (behavior, gross and fine motor function, expressive and receptive communication, and sleep) defined by caregivers and expert clinicians as the most challenging for patients with AS and their families. Conclusions Rigorous training and careful calibration for clinicians will allow the CGI-S/-I-AS scales to be reliable in the context of randomized controlled trials. The CGI-S/-I-AS scales are being utilized in a Phase 3 trial of gaboxadol for the treatment of AS.

Introduction Down syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting pre‐dementia stages. Methods We used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composites that were sensitive to change over time. We then conducted additional analyses to provide support for the utility of the composites. The composites were presented to an expert panel to determine the most optimal cognitive battery based on predetermined criteria. Results There were common cognitive domains across site composites, which were sensitive to early decline. The final composite consisted of memory, language/executive functioning, selective attention, orientation, and praxis tests. Discussion We have identified a composite that is sensitive to early decline and thus may have utility as an outcome measure in trials to prevent or delay symptoms of AD in DS.

Practical algorithms predicting the probability of amyloid pathology among patients with subjective cognitive decline or mild cognitive impairment may help clinical decisions regarding confirmatory biomarker testing for Alzheimer's disease. Algorithm feature selection was conducted with Alzheimer's Disease Neuroimaging Initiative and Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing data. Probability algorithms were developed in Alzheimer's Disease Neuroimaging Initiative using nested cross-validation accompanied by stratified subsampling to obtain 1000 internally validated decision trees. Semi-independent validation was conducted using Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. Independent external validation was conducted in the population-based Mayo Clinic Study of Aging. Two algorithms were developed using age and normalized immediate recall z-scores, with or without apolipoprotein E ε4 carrier status. Both algorithms had robust performance across data sets and when substituting different recall memory tests. The statistical framework resulted in robust probability estimation. Application of these algorithms may assist in clinical decision-making for further testing to diagnose amyloid pathology.

Affective and emotional symptoms such as depression, anxiety, euphoria, and irritability are common neuropsychiatric symptoms (NPS) in pre-dementia and cognitively normal older adults. They comprise a domain of Mild Behavioral Impairment (MBI), which describes their emergence in later life as an at-risk state for cognitive decline and dementia, and as a potential manifestation of prodromal dementia. This selective scoping review explores the epidemiology and neurobiological links between affective and emotional symptoms, and incident cognitive decline, focusing on recent literature in this expanding field of research. Existing literature in prodromal and dementia states was reviewed, focusing on epidemiology, and neurobiology. Search terms included: “mild cognitive impairment,” “dementia,” “prodromal dementia,” “preclinical dementia,” “Alzheimer's,” “depression,” “dysphoria,” “mania,” “euphoria,” “bipolar disorder,” and “irritability.” Affective and emotional dysregulation are common in preclinical and prodromal dementia syndromes, often being harbingers of neurodegenerative change and progressive cognitive decline. Nosological constraints in distinguishing between pre-existing psychiatric symptomatology and later life acquired NPS limit historical data utility, but emerging research emphasizes the importance of addressing time frames between symptom onset and cognitive decline, and age of symptom onset. Affective symptoms are of prognostic utility, but interventions to prevent dementia syndromes are limited. Trials need to assess interventions targeting known dementia pathology, toward novel pathology, as well as using psychiatric medications. Research focusing explicitly on later life onset symptomatology will improve our understanding of the neurobiology of NPS and neurodegeneration, enrich the study sample, and inform observational and clinical trial design for prevention and treatment strategies.

Abstract Mismatch negativity (MMN) and P300 event-related potential (ERP) reductions in schizophrenia (SZ) reflect preattentive and attention-mediated auditory processing deficits, respectively. Although both have been linked to cognitive deficits in SZ, their relative contributions to real-world functioning are unclear. We sought to determine the functional significance of disrupted auditory processing in SZ by examining MMN and P300 in typically disabled low-functioning patients and in patients with high levels of independent role functioning. MMN to auditory deviants and P300 to infrequent auditory target and nontarget novel stimuli were assessed in 20 high-functioning SZ patients (HF-SZ), 17 low-functioning patients (LF-SZ), and 35 healthy comparison (HC) subjects. There was a group effect on MMN and P300 amplitudes across stimulus types. MMN was significantly diminished in LF-SZ compared to HF-SZ and HC, and HF-SZ demonstrated comparable MMN to HC. In contrast, P300 was significantly reduced in both LF-SZ and HF-SZ compared to HC. Logistic regression suggested independent sensitivity of MMN to functioning in SZ over and above P300 measures. Neither MMN nor P300 were associated with positive or negative symptom severity. Results replicate MMN and P300 abnormalities in SZ, and also suggest that the neural mechanisms associated with the preattentive detection of auditory deviance are most compromised in patients with functional disability. MMN may index pathophysiological processes that are critical for optimal functioning in SZ.

Introduction Obstructive sleep apnea (OSA) is a common disorder characterized by repeated intermittent airway collapse—often a hypoxic event—resulting in disrupted sleep and excessive daytime sleepiness (EDS). Positive Airway Pressure (PAP) therapy reduces hypoxic events and mitigates sleep disruption, but EDS often persists. Cognitive impairment is a burdensome symptom in many patients with EDS associated with OSA, which leads to occupational and social dysfunction and degrades quality of life. Solriamfetol (Sunosi®) is approved to improve wakefulness in adults with EDS associated with OSA, but its effect on cognitive impairment was unknown. The SHARP study evaluated whether solriamfetol improves cognitive function in patients with OSA-associated EDS and impaired cognition, and the durability of cognitive effects across the day. Methods SHARP was a randomized, double-blind, placebo-controlled, crossover trial in 59 patients with OSA-associated EDS and concurrent cognitive impairment. All patients received solriamfetol (75mg for 3 days followed by 150mg/day) for 2 weeks, and placebo for 2 weeks, with treatment periods separated by a 1-week washout. The primary endpoint was change from baseline on the Coding subtest of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which is equivalent to the Digit Symbol Substitution Test (DSST). Secondary endpoints measured durability of effect spanning an 8-hour period and Patient Global Impression of Severity (PGI-S). Results The study completion rate was 96.7%. Solriamfetol treatment improved performance on the DSST-RBANS compared to placebo (6.49 vs. 4.75, p=0.009), with an effect size (Cohen’s d) of 0.36. Solriamfetol also yielded improvements at post-dose timepoints throughout the day (solriamfetol-placebo difference): 2 hours (1.91, p=0.033), 4 hours (1.38, p=0.089; NS), 6 hours (2.33, p=0.004), 8 hours (1.58, p=0.022). Scores on the PGI-S improved with solriamfetol compared to placebo (-0.90 vs -0.61, p=0.034). The most common adverse events with solriamfetol treatment (incidence ≥3%) were nausea (6.9%) and anxiety (3.4%). Conclusion The adverse events profile and high completion rate suggest solriamfetol (150mg/day) was well tolerated. Moreover, solriamfetol improved cognition as measured by the DSST-RBANS, demonstrated durable effects over an 8-hour period, and reduced perceptions of symptom severity. Thus, in patients with OSA-associated EDS and impaired cognition, solriamfetol durably improved cognitive performance. Support (if any) Axsome Therapeutics Jazz Pharmaceuticals

Patients with moderate-to-severe atopic dermatitis (AD) experience intense chronic itch and impaired sleep. Reports from parents and teachers suggest that AD patients may also have attention problems. However, attention has not yet been directly assessed in AD patients. We utilized an objective, computer-based continuous performance test (CPT) validated for use in attention-deficit/hyperactivity disorder (ADHD) diagnosis to formally evaluate attention in adolescent AD subjects. This was a single-visit, cross-sectional, non-interventional study of moderate-to-severe (Investigator’s Global Assessment [IGA] ≥ 3) AD subjects aged 12–17 years without clinician-diagnosed ADHD. Attention was evaluated using two performance-based measures: Conners, CPT-3 and the Stroop Color and Word Test. The primary parameter was CPT-3 detectability (d’) measure. Lesional severity measures included Eczema Area and Severity Index (EASI) and body surface area (BSA) involvement. Subjects completed self-report rating scales assessing sensory responsiveness patterns (Adult/Adolescent Sensory Profile [AASP]), itch (Peak Pruritus Numerical Rating Scale [PP-NRS]), skin pain, quality of life, sleep, anxiety, and depressive symptoms. A total of 44 subjects were included in the study (61.4% female; mean age 15.0 [SD 1.78] years; mean EASI 20.4 [SD 7.8]; mean PP-NRS 7.0 [SD 1.8]). Results indicated substantial disease impact on sleep, quality of life, and comorbid anxiety and depressive symptoms. The mean (SD) Conners, CPT-3 dʹ T-score was 48.7 (SD 10.7), similar to the expected mean from a randomly selected age/gender-matched sample of the general population (50 [SD 10], by definition). Overall, 13.6% of subjects exhibited a dʹ T-score ≥ 60 (clinically significant poor performance), which was not greater than the expected general population value (15.9%). Subject-level data review by two psychologists determined that only 2 subjects demonstrated an overall response pattern that clearly indicated attention deficit. Many subjects had atypical sensory responsiveness profiles: sensory hypersensitivity (38.6%), sensory avoidance (50%), and low registration (hypo-sensitivity, 36.4%). Adolescents with moderate-to-severe AD without existing ADHD diagnosis did not demonstrate greater attention problems on performance-based measures than would be expected in age/gender-matched peers. Trial registration NCT05203380. Plain Language Summary Atopic dermatitis (often shortened to AD) is a long-term skin disease that causes intense itching. It affects patients’ lives in many ways, including interrupting their sleep. Parents and teachers of young people with AD have sometimes suggested that AD may also cause attention problems. But this has never been tested properly. We measured the attention of 44 adolescents aged between 12 and 17 years who all had moderate-to-severe AD. We used computerized tests of attention that were developed for young people with ADHD (attention deficit hyperactivity disorder). Also, we made sure that none of the 44 patients had also been diagnosed with ADHD. The severity and extent of the patients’ AD was measured by doctors. We also used some measures that allowed the patients to report how AD affected their lives, including things like itch, skin pain, quality of life, sleep, anxiety, and depression. The adolescent patients reported that AD had a negative effect on various areas of their lives, including sleep and quality of life, and that it resulted in anxiety and symptoms of depression. However, the results of the attention tests in adolescents with AD were similar to what would usually be expected in adolescents without AD. Only 2 of the 44 patients with AD were found to have clear evidence of attention problems. The study concluded that adolescents with moderate-to-severe AD did not have any greater attention problems than would usually be expected in adolescents without AD.

INTRODUCTION In EMERGE (NCT02484547), participants receiving aducanumab had significantly less progression versus placebo on all prespecified clinical endpoints at week 78. Here, we explicate the clinical meaningfulness of these treatment effects by analyzing item‐level data and the persistence of treatment benefit. METHODS Participants with early Alzheimer's disease (AD) were stratified by apolipoprotein E (APOE) ε4 status and randomized (1:1:1) to receive low‐ or high‐dose aducanumab, or placebo. Prespecified principal component analyses (PCAs) per the Statistical Analysis Plan were followed by post hoc examination of individual domains/items across all five clinical endpoints. Progression analysis assessed reduction in clinical decline. RESULTS High‐dose aducanumab demonstrated clinically meaningful slowing of progression across clinical endpoints measuring cognition, daily function, and behavioral symptoms. Delay of progression over 18 months was consistent across measures; treatment effects increased over time. DISCUSSION Across multiple analyses aducanumab slowed cognitive decline, prolonged functional independence, and attenuated behavioral symptoms in participants with early AD. These outcomes comprise the elements of a clinically meaningful response to treatment. Highlights Endpoints in EMERGE assessed different aspects of cognition, daily function, and behavioral symptoms. Treatment benefits were observed across subdomains on all five clinical endpoints. Aducanumab meaningfully slowed disease progression in participants with early AD.