Generation of induced pluripotent stem cells from ADHD patients who do or do not respond to Methylphenidate treatment.

As a neurodevelopmental multifactorial disorder whose prevalence has been increasing worldwide, attention-deficit hyperactivity disorder (ADHD) is considered a public health concern. Methylphenidate (MPH) is the drug of choice for ADHD; however, not all patients respond fully to this treatment. Therefore, exploring the underlying molecular mechanisms involved in ADHD and potential novel therapeutic targets is crucial. Here, we generated induced pluripotent stem cells (iPSCs) from Peripheral Blood Mononuclear Cells (PBMCs) retrieved from four ADHD patients (two MPH responders and two non-responders) using Sendai virus. These lines might be helpful for the in vitro investigation of ADHD pathophysiology in a patient-specific manner.

Stress as a mediator of brain alterations in attention-deficit hyperactivity disorder: A systematic review.

OBJECTIVE: Stress is a known risk factor for numerous psychopathologies, whereas evidence is lacking regarding the specific consequences of stress on the neural basis of attention-deficit hyperactivity disorder (ADHD). A systematic literature review was thus conducted to clarify the role of stress in the association between the resulting alterations of brain structure, connectivity, and function in ADHD. METHODS: The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under identifier CRD42023379809. A systematic search of the PubMed and CINAHL databases was conducted for articles published prior to December 22nd, 2022. Retrieved literature was screened in Rayyan and data extraction was performed with respect to neuroimaging, stress exposure, and ADHD outcomes. The Quality in Prognosis Studies (QUIPS) tool was adapted based on the Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology (COSMOS-E) guidance article to assess risk of bias and quality of studies. Strength of the evidence was assessed under the guidance of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: Screening 25,026 non-duplicate articles yielded 20 eligible studies for inclusion. Exposure to early life trauma, institutionalization, prenatal smoking or alcohol consumption, air pollution, low socioeconomic status, or low birth weight were associated with alterations in brain structure, function, and connectivity in ADHD. However, most studies did not provide strong evidence due to small sample sizes and lack of statistical approaches to determine a direct mediation of the association between stress and ADHD by neural outcomes. CONCLUSION: This systematic review was the first to summarize evidence of structural and functional stress-associated alterations in the brain, which were found to be directly and indirectly associated with ADHD outcomes. Overall, stress requires consideration as a significant determinant of neurodevelopmental outcomes in ADHD. However, extensive further research is warranted due to little available evidence and the difficulty of obtaining clear results. In light of such a complex research question, in order to confirm findings, provide further evidence, and establish causality systematic longitudinal studies would be required. Investigating the topic may provide invaluable information when it comes to tailoring prevention and treatment strategies in ADHD, and should be pursued in order to integrate the factor of stress into a more comprehensive understanding of ADHD.

Protocol for a Wnt reporter assay to measure its activity in human neural stem cells derived from induced pluripotent stem cells.

The canonical Wnt signaling is an essential pathway that regulates cellular proliferation, maturation, and differentiation during neurodevelopment and maintenance of adult tissue homeostasis. This pathway has been implicated with the pathophysiology of neuropsychiatric disorders and was associated with cognitive processes, such as learning and memory. However, the molecular investigation of the Wnt signaling in functional human neural cell lines might be challenging since brain biopsies are not possible and animal models may not represent the polygenic profile of some neurological and neurodevelopmental disorders. In this context, using induced pluripotent stem cells (iPSCs) has become a powerful tool to model disorders that affect the Central Nervous System (CNS) in vitro, by maintaining patients' genetic backgrounds. In this method paper, we report the development of a virus-free Wnt reporter assay in neural stem cells (NSCs) derived from human iPSCs from two healthy individuals, by using a vector containing a reporter gene (luc2P) under the control of a TCF/LEF (T-cell factor/lymphoid enhancer factor) responsive element. Dose-response curve analysis from this luciferase-based method might be useful when testing the activity of the Wnt signaling pathway after agonists (e.g. Wnt3a) or antagonists (e.g. DKK1) administration, comparing activity between cases and controls in distinct disorders. Using such a reporter assay method may help to elucidate whether neurological or neurodevelopmental mental disorders show alterations in this pathway, and testing whether targeted treatment may reverse these. Therefore, our established assay aims to help researchers on the functional and molecular investigation of the Wnt pathway in patient-specific cell types comprising several neuropsychiatric disorders.

Generation of induced pluripotent stem cells from two ADHD patients and two healthy controls.

Attention-deficit hyperactivity disorder is a neurodevelopmental disorder which prevalence has been increasing in the past decades, affecting more than 5% of children, adolescents worldwide. Regarding etiology, polygenic, environmental factors contribute to the occurrence of ADHD even though molecular mechanisms are not known. Understanding the pathophysiology in patient-specific cells is crucial for the discovery of potential predictive markers, the establishment of new therapeutic targets. In this study, we generated further lines from ADHD patients, healthy controls using Sendai virus transduction, which may help on the study of ADHD at the molecular, cellular levels.

Growth rates of human induced pluripotent stem cells and neural stem cells from attention-deficit hyperactivity disorder patients: a preliminary study.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental polygenic disorder that affects more than 5% of children and adolescents around the world. Genetic and environmental factors play important roles in ADHD etiology, which leads to a wide range of clinical outcomes and biological phenotypes across the population. Brain maturation delays of a 4-year lag are commonly found in patients, when compared to controls of the same age. Possible differences in cellular growth rates might reflect the clinical observations in ADHD patients. However, the cellular mechanisms are still not elucidated. To test this hypothesis, we analysed the proliferation of induced pluripotent stem cells (iPSCs) and neural stem cells (NSCs) derived from male children and adolescents diagnosed with ADHD and with genetic predisposition to it (assessed using polygenic risk scores), as well as their respective matched controls. In the current pilot study, it was noticeable that NSCs from the ADHD group proliferate less than controls, while no differences were seen at the iPSC developmental stage. Our results from two distinct proliferation methods indicate that the functional and structural delays found in patients might be associated with these in vitro phenotypic differences, but start at a distinct neurodevelopmental stage. These findings are the first ones in the field of disease modelling of ADHD and might be crucial to better understand the pathophysiology of this disorder.

A Study on the Sound Absorption Properties of Mycelium-Based Composites Cultivated on Waste Paper-Based Substrates.

Mycelium-based composites have the potential to replace petrochemical-based materials within architectural systems and can propose biodegradable alternatives to synthetic sound absorbing materials. Sound absorbing materials help improve acoustic comfort, which in turn benefit our health and productivity. Mycelium-based composites are novel materials that result when mycelium, the vegetative root of fungi, is grown on agricultural plant-based residues. This research presents a material study that explores how substrate variants and fabrication methods affect the sound absorption properties of mycelium-based composites grown on paper-based waste substrate materials. Samples were grown using Pleurotus ostreatus fungi species on waste cardboard, paper, and newsprint substrates of varying processing techniques. Measurements of the normal-incidence sound absorption coefficient were presented and analyzed. This paper outlines two consecutive acoustic tests: the first round of experimentation gathered broad comparative data, useful for selecting materials for sound absorption purposes. The second acoustic test built on the results of the first, collecting more specific performance data and assessing material variability. The results of this study display that cardboard-based mycelium materials perform well acoustically and structurally and could successfully be used in acoustic panels.

Brief Provider Opioid Education Is Associated with Decreased Super-Utilization in a Rural Emergency Department.

BACKGROUND: Patients who suffer chronic pain may seek the emergency department for opioids. There is no consensus on what constitutes an ED super-utilizer, so our definition is anyone who presented to the ED more than once for the same painful complaint. We sought to assess the effect of opioid guideline education for providers on super-utilizer visits for pain. METHODS: We performed a retrospective review of visits for chief complaints of pain one year before (phase one) and one year after (phase two) educating ED providers. The educational intervention consisted of a 20-minute explanation of the American Academy of Emergency Medicine's Model ED Pain Treatment Guidelines. McNemar's test was applied to the resultant data. RESULTS: Phase one identified 218 super-utilizers accounting for 660 ED visits. Phase two identified 190 super- utilizers accounting for 604 ED visits. Both groups were stratified into those using the ED more than once, more than twice, and more than three times. There was a statistically significant difference in patients visiting the ED more than once (p=0.01) and more than three times (p=0.027), but not for those visiting more than twice (p=0.18). There was no statistically significant difference in total patient ED visits in any subgroup. CONCLUSION: The total number of super-utilizers significantly decreased after the educational intervention. This educational intervention required minimal monetary and time investment. Further research is needed to determine if the educational intervention resulted in decreased opioid prescriptions and decreased number of people utilizing these drugs for non-medical purposes.

Remifentanil inhibits rapid eye movement sleep but not the nocturnal melatonin surge in humans.

BACKGROUND: Postoperative patients are sleep deprived. Opioids, commonly administered for postoperative pain control, are often mistakenly considered inducers of naturally occurring sleep. This study describes the effect of the opioid remifentanil on nocturnal sleep in healthy volunteers. In addition, this study tests the hypothesis that opioid-induced sleep disturbance is caused by a circadian pacemaker disturbance, reflected by suppressed nocturnal plasma concentration of melatonin. METHODS: Polysomnography was performed in 10 volunteers from 11:00 pm to 7:00 am for four nights at 6-day intervals. On two nights, remifentanil (0.01-0.04 microg x kg x min) was infused from 10:30 pm to 7:00 am, and either a placebo capsule or 3.0 mg melatonin was administered at 10:30 pm. On two additional nights, saline was infused, and the placebo or melatonin capsules were administered at 10:30 pm. Blood was drawn at 12:00 am, 3:00 am, and 6:00 am to measure the plasma concentration of melatonin and cortisol. A repeated-measures analysis of variance model was used to determine the effect of remifentanil on sleep stages, the effect of remifentanil on the plasma concentration of melatonin, and the effect of exogenous melatonin on remifentanil-induced sleep disturbance. RESULTS: Remifentanil inhibited rapid eye movement sleep (14.1 +/- 7.2% to 3.9 +/- 6.9%). The amount of slow wave sleep decreased from 6.8 +/- 7.6% to 3.2 +/- 6.1%, but this decrease was not statistically significant. Remifentanil did not decrease melatonin concentration. Melatonin administration did not prevent remifentanil-induced sleep disturbance. CONCLUSIONS: An overnight constant infusion of remifentanil inhibits rapid eye movement sleep without suppressing the nocturnal melatonin surge.