Additive effects of the dopamine D2 receptor and dopamine transporter genes on the error-related negativity in young children

The error-related negativity (ERN) is a negative deflection in the event-related potential that occurs approximately 50ms following the commission of an error at fronto-central electrode sites. Previous models suggest dopamine plays a role in the generation of the ERN. We recorded event-related potentials (ERPs) while 279 children aged 5-7 years completed a simple Go/No-Go task; the ERN was examined in relation to the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes. Results suggest an additive effect of the DRD2 and DAT1 genotype on ERN magnitude such that children with at least one DRD2 A1 allele and children with at least one DAT1 9 allele have an increased (i.e. more negative) ERN. These results provide further support for the involvement of dopamine in the generation of the ERN. © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society

Segmentation of vestibular schwannoma from MRI, an open annotated dataset and baseline algorithm

Automatic segmentation of vestibular schwannomas (VS) from magnetic resonance imaging (MRI) could significantly improve clinical workflow and assist patient management. We have previously developed a novel artificial intelligence framework based on a 2.5D convolutional neural network achieving excellent results equivalent to those achieved by an independent human annotator. Here, we provide the first publicly-available annotated imaging dataset of VS by releasing the data and annotations used in our prior work. This collection contains a labelled dataset of 484 MR images collected on 242 consecutive patients with a VS undergoing Gamma Knife Stereotactic Radiosurgery at a single institution. Data includes all segmentations and contours used in treatment planning and details of the administered dose. Implementation of our automated segmentation algorithm uses MONAI, a freely-available open-source framework for deep learning in healthcare imaging. These data will facilitate the development and validation of automated segmentation frameworks for VS and may also be used to develop other multi-modal algorithmic models

Structure and rheological properties of model microemulsion networks filled with nanoparticles

Model microemulsion networks of oil droplets stabilized by non ionic surfactant and telechelic polymer C18-PEO(10k)-C18 have been studied for two droplet-to-polymer size ratios. The rheological properties of the networks have been measured as a function of network connectivity and can be described in terms of simple percolation laws. The network structure has been characterised by Small Angle Neutron Scattering. A Reverse Monte Carlo approach is used to demonstrate the interplay of attraction and repulsion induced by the copolymer. These model networks are then used as matrix for the incorporation of silica nanoparticles (R=10nm), individual dispersion being checked by scattering. A strong impact on the rheological properties is found for silica volume fractions up to 9%

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial.

IMPORTANCE Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear. OBJECTIVE To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment. DESIGN, SETTING, AND PARTICIPANTS This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis. INTERVENTIONS Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care. MAIN OUTCOME AND MEASURES The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis. RESULTS Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing. CONCLUSIONS AND RELEVANCE This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04863924

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs

Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap‐prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude‐intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2‐weeks following noise‐exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20–60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus‐specific changes were particularly prominent in hippocampal synapse‐rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus‐specific changes occurred in synapse‐rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150542/1/hipo23058.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150542/2/hipo23058_am.pd

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial

IMPORTANCE: Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear. OBJECTIVE: To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment. DESIGN, SETTING, AND PARTICIPANTS: This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis. INTERVENTIONS: Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care. MAIN OUTCOME AND MEASURES: The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis. RESULTS: Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P \u3c .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P \u3c .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing. CONCLUSIONS AND RELEVANCE: This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing

Влияние давления при формировании селективного слоя на структуру и свойства динамических композиционных мембран для первапорации

Composite membranes for pervaporation were prepared by forming a selective layer based on cross-linked polyvinyl alcohol (PVA) on the porous membrane-substrate surface in the dynamic mode (via PVA solution ultrafiltration). It was found that the pressure growth results in increasing the thickness of the composite membrane selective layer. Composite membrane contact angle, flux, water content in permeate in ethanol/water (mass ratio 90/10) pervaporation were revealed to have maximum values at 3–4 atm depending on the PVA concentration in the feed solution. It was shown that the revealed dependence of the contact angle, selectivity, and permeability on the pressure of the selective layer formation is due to the compaction of the polymer matrix-substrate under the action of the transmembrane pressure and its relaxation after pressure release. When using elevated pressures (more than 3–4 atm), the relaxation of the polymer matrix causes the microdefect to form as a result of deformation of the selective layer.Композиционные мембраны для первапорации были получены методом формирования селективного слоя на основе сшитого поливинилового спирта (ПВС) на поверхности пористой мембраны-подложки в динамическом режиме (ультрафильтрации растворов ПВС). Установлено, что повышение давления приводит к увеличению толщины селективного слоя композиционных мембран; при этом их контактный угол смачивания, удельная производительность, содержание воды в пермеате в процессе первапорации смеси этанол/вода 90/10 изменяются экстремально с максимумом при 3–4 атм в зависимости от концентрации раствора ПВС. Экстремальная зависимость краевого угла смачивания, коэффициента разделения и проницаемости композиционных мембран объясняется процессами уплотнения полимерной матрицы-подложки под действием трансмембранного давления и ее релаксации после снятия давления. При использовании повышенных давлений (более 3–4 атм) релаксация полимерной матрицы приводит к появлению микродефектов в результате деформации сформированного селективного слоя

Effects of noise exposure on young adults with normal audiograms II: Behavioral measures

An estimate of lifetime noise exposure was used as the primary predictor of performance on a range of behavioral tasks: frequency and intensity difference limens, amplitude modulation detection, interaural phase discrimination, the digit triplet speech test, the co-ordinate response speech measure, an auditory localization task, a musical consonance task and a subjective report of hearing ability. One hundred and thirty-eight participants (81 females) aged 18–36 years were tested, with a wide range of self-reported noise exposure. All had normal pure-tone audiograms up to 8 kHz. It was predicted that increased lifetime noise exposure, which we assume to be concordant with noise-induced cochlear synaptopathy, would elevate behavioral thresholds, in particular for stimuli with high levels in a high spectral region. However, the results showed little effect of noise exposure on performance. There were a number of weak relations with noise exposure across the test battery, although many of these were in the opposite direction to the predictions, and none were statistically significant after correction for multiple comparisons. There were also no strong correlations between electrophysiological measures of synaptopathy published previously and the behavioral measures reported here. Consistent with our previous electrophysiological results, the present results provide no evidence that noise exposure is related to significant perceptual deficits in young listeners with normal audiometric hearing. It is possible that the effects of noise-induced cochlear synaptopathy are only measurable in humans with extreme noise exposures, and that these effects always co-occur with a loss of audiometric sensitivity

Dihydrotestosterone Ameliorates Degeneration in Muscle, Axons and Motoneurons and Improves Motor Function in Amyotrophic Lateral Sclerosis Model Mice

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients