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Resurgence is an increase in the rate of a previously suppressed behavior that occurs when an alternative source of reinforcement is made worse in some way. The Resurgence as Choice model offers a quantitative approach to understanding resurgence that may provide important insights into the variables that affect this form of relapse in the natural environment. Bringing this model to bear on relapse following reinforcement-based interventions for alcohol and other substance use disorders, however, may not be straightforward. Laboratory work on which the Resurgence as Choice model is based has almost exclusively focused on resurgence following extinction of target behavior, but abstinence from alcohol during intervention is often voluntary: Patients may drink alcohol and forfeit therapeutic reinforcers at any time. In this article, we first will review recent data from our group that demonstrate a method for studying resurgence following voluntary abstinence from alcohol seeking in rats. In a previous experiment, we reduced rats' alcohol-maintained lever pressing to low levels without placing it on extinction by arranging nondrug differential reinforcement of other behavior. Further, when we suspended nondrug reinforcement, resurgence of lever pressing occurred. Next, we will explore methods for modeling these outcomes using the Resurgence-as-Choice framework. We conclude that the data under consideration may not be sufficient to discriminate between candidate models of resurgence following voluntary abstinence and point to areas for future empirical and theoretical development. This work may provide a stronger bridge between preclinical and conceptual work on resurgence and clinical treatments for alcohol use disorder.
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In treatments based on differential reinforcement of alternative behavior, applied researchers and clinicians often provide multiple, qualitatively different reinforcers (i.e., synthesized reinforcement) rather than a single reinforcer (i.e., isolated reinforcement) contingent on alternative behavior. Some research shows that providing synthesized reinforcement for alternative responses within such treatments produces more rapid and complete suppression of target behavior; however, there is limited research evaluating the durability of these effects during treatment disruptions. Conceptual explanations of resurgence (e.g., resurgence as choice, context theory) suggest that treatments that include synthesized alternative reinforcement may lead to more resurgence of target behavior when alternative reinforcement is disrupted relative to treatments using isolated reinforcement. We evaluated this hypothesis within a three-phase resurgence evaluation. We exposed rats to isolated or synthesized reinforcement for alternative responding in the second phase, and we exposed rats to extinction in the third phase. Synthesized alternative reinforcement produced more rapid and complete suppression of target behavior than did isolated reinforcement in the second phase; however, exposure to extinction following synthesized reinforcement produced more resurgence. We discuss these results in terms of their implications for applied research and their support for current conceptual explanations for resurgence.
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Understanding local hydraulic conditions is imperative to coastal harmful algal bloom (HAB) monitoring. The research summarized herein describes how the locations and tidal phases selected for coastal hazard sampling can influence measurement results used to guide management decisions for HABs. Our study was conducted in Frenchman Bay, Maine, known for its complex deglaciated coastline, strong tidal influence, and shellfishing activities that are susceptible to problematic HABs such as those produced by some species (spp.) of the diatom genus Pseudo-nitzschia. In-situ measurements of current velocity, density, and turbulence collected over a semidiurnal tidal cycle and a companion numerical model simulation of the study area provide concurrent evidence of two adjacent counter-rotating sub-mesoscale eddies (2-4 km diameter) that persist in the depth-averaged residual circulation. The eddies are generated in the wake of several islands in an area with abrupt bathymetric gradients, both legacy conditions partly derived from deglaciation â¼15 kya. Increased concentrations of Pseudo-nitzschia spp. measured during the semidiurnal survey follow a trend of elevated turbulent dissipation rates near the water surface, indicating that surface sampling alone might not adequately indicate species abundance. Additional measurements of Pseudo-nitzschia spp. from two years of weekly sampling in the region show that algal cell abundance is highest where residual eddies form. These findings provide incentive to examine current practices of HAB monitoring and management by linking coastal geomorphology to hydraulic conditions influencing HAB sampling outcomes, coastal morphometric features to material accumulation hotspots, and millennial time scales to modern hydraulic conditions.
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Diatomeas , Monitoreo del Ambiente , Estuarios , Floraciones de Algas Nocivas , Hidrodinámica , Diatomeas/fisiología , Monitoreo del Ambiente/métodos , Maine , Movimientos del AguaRESUMEN
Introduction: Nucleic acid tests for blood donor screening have improved the safety of the blood supply; however, increasing numbers of emerging pathogen tests are burdensome. Multiplex testing platforms are a potential solution. Methods: The Blood Borne Pathogen Resequencing Microarray Expanded (BBP-RMAv.2) can perform multiplex detection and identification of 80 viruses, bacteria and parasites. This study evaluated pathogen detection in human blood or plasma. Samples spiked with selected pathogens, each with one of 6 viruses, 2 bacteria and 5 protozoans were tested on this platform. The nucleic acids were extracted, amplified using multiplexed sets of primers, and hybridized to a microarray. The reported sequences were aligned to a database to identify the pathogen. To directly compare the microarray to an emerging molecular approach, the amplified nucleic acids were also submitted to nanopore next generation sequencing (NGS). Results: The BBP-RMAv.2 detected viral pathogens at a concentration as low as 100 copies/ml and a range of concentrations from 1,000 to 100,000 copies/ml for all the spiked pathogens. Coded specimens were identified correctly demonstrating the effectiveness of the platform. The nanopore sequencing correctly identified most samples and the results of the two platforms were compared. Discussion: These results indicated that the BBP-RMAv.2 could be employed for multiplex detection with potential for use in blood safety or disease diagnosis. The NGS was nearly as effective at identifying pathogens in blood and performed better than BBP-RMAv.2 at identifying pathogen-negative samples.
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BACKGROUND: PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia. METHODS: Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks. RESULTS: The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = -4.7 [95 % CI: -9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = -7.3 [95 % CI: -14.0,-0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: -4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = -2.2 [95 % CI: -3.8,-0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight. CONCLUSIONS: These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03055338.
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Antipsicóticos , Hidrolasas Diéster Fosfóricas , Pirimidinas , Risperidona , Esquizofrenia , Compuestos de Azufre , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Enfermedad Aguda , Antipsicóticos/farmacología , Antipsicóticos/efectos adversos , Antipsicóticos/administración & dosificación , Método Doble Ciego , Evaluación de Resultado en la Atención de Salud , Inhibidores de Fosfodiesterasa/efectos adversos , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/metabolismo , Prueba de Estudio Conceptual , Pirimidinas/efectos adversos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Risperidona/farmacología , Risperidona/efectos adversos , Risperidona/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Compuestos de Azufre/efectos adversos , Compuestos de Azufre/farmacología , Compuestos de Azufre/uso terapéuticoRESUMEN
OBJECTIVE: To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in â¼650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. The recruitment period is between 3/31/2021 and 12/31/2025. Written consent will be sought from the subject or the subject's legally authorized representative during enrollment. RESULTS: The endpoints of this study include: 1) whether adding IMC to the Awaji ALS criteria improve its sensitivity in early ALS and can allow for diagnosis earlier; 2) constructing a database of IMC across different ages, genders, and ethnicities. SIGNIFICANCE: This study may validate a new inexpensive, painless, and widely available tool for the diagnosis of ALS.
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Esclerosis Amiotrófica Lateral , Biomarcadores , Electromiografía , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/fisiopatología , Biomarcadores/análisis , Electromiografía/métodos , Neuronas Motoras/patología , Músculo Esquelético/fisiopatología , Músculo Esquelético/patología , Estudios Prospectivos , Estudios Multicéntricos como AsuntoRESUMEN
Background: Adolescence and transition into adulthood are periods shaping life-long mental health, cardiometabolic risk, and inequalities. However, they are poorly studied and understood. By extending and expanding the Born in Bradford (BiB) cohort study through this period using innovative, co-produced approaches to collect and analyse data, we aim to understand better the interplay of factors that influence health and wellbeing, and inform/evaluate interventions to improve them and reduce inequalities. Protocol: BiB Age of Wonder (AoW) is a large, whole city cohort that will capture the contemporary lived experience amongst multi-ethnic adolescents progressing into young adulthood. We will collect repeated data from existing BiB participants and their peers (N~30,000 adolescents). The protocol for the first phase of the quantitative methods, involving survey measurements and health assessments in mainstream secondary schools is described here. We describe the co-production behind these methods, and lessons learned from the first year of data collection.
Born in Bradford have been following the health and wellbeing of over 13,000 Bradford children since they were born. This group of children are now in their teenage years a time that is crucial for their future mental and physical health. Age of Wonder aims to capture this journey through adolescence and early adulthood with up to 30,000 young people in Bradford over 7 years. In the first phase of this project, data collection is taking part in secondary schools in Bradford. This protocol describes how this data collection is currently being carried out in the schools. Young people aged 12-15 are being asked to complete questionnaires, covering topics such as mental and physical health. These topics have been designed with groups of young people, schools and other partners, to make sure we are capturing data on the things most important to young people. Those in Year 9 (13-14 years old), are also asked to take part in physical health measurements such as height, weight, blood pressure and a blood sample, as well as computer-based assessments of cognition (memory), movement and language. There have been a number of lessons learned from the first full year of data collection, such as how to make the research as easy as possible for schools to take part in when they have so many competing demands on their time.
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Photoreduction of carbon dioxide (CO2) on plasmonic structures is of great interest in photocatalysis to aid selectivity. While species commonly found in reaction environments and associated intermediates can steer the reaction down different pathways by altering the potential energy landscape of the system, they are often not addressed when designing efficient plasmonic catalysts. Here, we perform an atomistic study of the effect of the hydroxyl group (OH) on CO2 activation and hot electron generation and transfer using first-principles calculations. We show that the presence of OH is essential in breaking the linear symmetry of CO2, which leads to a charge redistribution and a decrease in the OîCîO angle to 134°, thereby activating CO2. Analysis of the partial density of states (pDOS) demonstrates that the OH group mediates the orbital hybridization between Au and CO2 resulting in more accessible states, thus facilitating charge transfer. By employing time-dependent density functional theory (TDDFT), we quantify the fraction of hot electrons directly generated into hybridized molecular states at resonance, demonstrating a broader energy distribution and an 11% increase in charge-transfer in the presence of OH groups. We further show that the spectral overlap between excitation energy and plasmon resonance plays a critical role in efficiently modulating electron transfer processes. These findings contribute to the mechanistic understanding of plasmon-mediated reactions and demonstrate the importance of co-adsorbed species in tailoring the electron transfer processes, opening new avenues for enhancing selectivity.
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Resurgence refers to the relapse of a target behavior following the worsening of a source of alternative reinforcement that was made available during response elimination. Most laboratory analyses of resurgence have used a combination of extinction and alternative reinforcement to reduce target behavior. In contingency-management treatments for alcohol use disorder, however, alcohol use is not placed on extinction. Instead, participants voluntarily abstain from alcohol use to access nondrug alternative reinforcers. Inasmuch, additional laboratory research on resurgence following voluntary abstinence is warranted. The present experiment evaluated resurgence of rats' ethanol seeking following voluntary abstinence produced by differential reinforcement of other behavior (DRO). Lever pressing produced ethanol reinforcers during baseline phases. During DRO phases, lever pressing continued to produce ethanol and food reinforcers were delivered according to resetting DRO schedules. Ethanol and food reinforcers were suspended during resurgence test phases to evaluate resurgence following voluntary abstinence. Lever pressing was elevated during baseline phases and occurred at near-zero rates during DRO phases. During the resurgence test phases, lever pressing increased, despite that it no longer produced ethanol. The procedure introduced here may help researchers better understand the variables that affect voluntary abstinence from ethanol seeking and resurgence following voluntary abstinence.
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Condicionamiento Operante , Comportamiento de Búsqueda de Drogas , Etanol , Extinción Psicológica , Refuerzo en Psicología , Animales , Ratas , Masculino , Esquema de Refuerzo , Autoadministración/psicología , Recurrencia , Ratas Long-EvansRESUMEN
Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization of an orally bioavailable and CNS penetrant isoindolinone class of GCS inhibitors. Starting from advanced lead 1, we describe efforts to identify an improved compound with a lower human dose projection, minimal P-glycoprotein (P-gp) efflux, and acceptable pregnane X receptor (PXR) profile through fluorine substitution. Our strategy involved the use of predicted volume ligand efficiency to advance compounds with greater potential for low human doses down our screening funnel. We also applied minimized electrostatic potentials (Vmin) calculations for hydrogen bond acceptor sites to rationalize P-gp SAR. Together, our strategies enabled the alignment of a lower human dose with reduced P-gp efflux, and favorable PXR selectivity for the discovery of compound 12.
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Quality and safety in healthcare have emerged as key factors impacting on both clinical effectiveness and clinical outcomes. While improving the healthcare supply chain has been extensively researched, the impact of the healthcare supply chain on clinical safety has received little attention in the literature, largely due to the complexity of such studies and the involvement of multiple stakeholders. This research proposes an evaluation model using key performance measurements for an electronic procurement system that enables digital transformation of the healthcare supply chain. The model will be tested before and after the introduction of an electronic procurement system in the healthcare supply chain for small and medium sized healthcare providers to provide evidence of both the usefulness of the model itself within industry and to further contribute to the knowledge base. Future use of the model may provide benchmarking and important data and insights to enable enhanced clinical safety in the healthcare supply chain.
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Benchmarking , Electrónica , Humanos , Instituciones de Salud , Personal de Salud , Atención a la SaludRESUMEN
PURPOSE: Up to 50% of women treated for localized breast cancer will experience some degree of arm or shoulder morbidity. Although radiation is thought to contribute to this morbidity, the mechanism remains unclear. Prior studies have shown biologic and radiographic changes in the pectoralis muscles after radiation. This study thus aimed to investigate the relationship between radiation to the pectoralis muscles and referrals for rehabilitation services posttreatment for arm and shoulder morbidity. METHODS AND MATERIALS: A retrospective 1:1 matched case-control study was conducted for patients with breast cancer who were and were not referred for breast or shoulder rehabilitation services between 2014 and 2019 at a single academic institution. Patients were included if they had a lumpectomy and adjuvant radiation. Patients who underwent an axillary lymph node dissection were excluded. Cohorts were matched based on age, axillary surgery, and use of radiation boost. Muscle doses were converted to equivalent dose in 2 Gy fractions assuming an α:ß ratio of 2.5 and were compared between the 2 groups. RESULTS: In our cohort of 50 patients of a median age 60 years (interquartile range, 53-68 years), 36 patients (72%) underwent a sentinel lymph node biopsy in addition to a lumpectomy. Although pectoralis muscle doses were generally higher in those receiving rehabilitation services, this was not statistically significant. Pectoralis major V20-40 Gy reached borderline significance, as did pectoralis major mean dose (17.69 vs 20.89 Gy; P = .06). CONCLUSIONS: In this limited cohort of patients, we could not definitively conclude a relationship between pectoralis muscle doses and use of rehabilitation services. Given the borderline significant findings, this should be further investigated in a larger cohort.
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Neoplasias de la Mama , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/patología , Músculos Pectorales/patología , Estudios Retrospectivos , Estudios de Casos y Controles , Biopsia del Ganglio Linfático Centinela , Axila/patologíaRESUMEN
As ferroelectric hafnium zirconium oxide (HZO) becomes more widely utilized in ferroelectric microelectronics, integration impacts of intentional and nonintentional dielectric interfaces and their effects upon the ferroelectric film wake-up (WU) and circuit parameters become important to understand. In this work, the effect of the addition of a linear dielectric aluminum oxide, Al2O3, below a ferroelectric Hf0.58Zr0.42O2 film in a capacitor structure for FeRAM applications with niobium nitride (NbN) electrodes was measured. Depolarization fields resulting from the linear dielectric is observed to induce a reduction of the remanent polarization of the ferroelectric. Addition of the aluminum oxide also impacts the WU of the HZO with respect to the cycling voltage applied. Intricately linked to the design of a FeRAM 1C/1T cell, the metal-ferroelectric-insulator-metal (MFIM) devices are observed to significantly shift charge related to the read states based on aluminum oxide thickness and WU cycling voltage. A 33% reduction in the separation of read states are measured, which complicates how a memory cell is designed and illustrates the importance of clean interfaces in devices.
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In 2020, Novartis Pharmaceuticals Corporation and the U.S. Food and Drug Administration (FDA) started a 4-year scientific collaboration to approach complex new data modalities and advanced analytics. The scientific question was to find novel radio-genomics-based prognostic and predictive factors for HR+/HER- metastatic breast cancer under a Research Collaboration Agreement. This collaboration has been providing valuable insights to help successfully implement future scientific projects, particularly using artificial intelligence and machine learning. This tutorial aims to provide tangible guidelines for a multi-omics project that includes multidisciplinary expert teams, spanning across different institutions. We cover key ideas, such as "maintaining effective communication" and "following good data science practices," followed by the four steps of exploratory projects, namely (1) plan, (2) design, (3) develop, and (4) disseminate. We break each step into smaller concepts with strategies for implementation and provide illustrations from our collaboration to further give the readers actionable guidance.
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Inteligencia Artificial , Multiómica , Humanos , Aprendizaje Automático , GenómicaRESUMEN
High-energy-density lithium-ion batteries (LIBs) are essential to meet the requirements of emerging technologies for advanced power storage and enhanced device performance. The next generation of LIBs will require high-capacity anode materials that move beyond the lithium intercalation chemistry of conventional graphite electrodes. The use of two-dimensional (2D) bilayer structures offers immediate advantages in the development of LIBs. Herein, motivated by the recently synthesized 2D Cairo pentagon nickel diazenide (NiN2) material, we conduct a scrutiny of the intercalation process of lithium atoms in the interlayer gap of NiN2/NiN2 homostructure. Based on density functional theory (DFT), we demonstrate that the diffusion energy barrier of lithium move across the NiN2/NiN2 anode is relatively low, ranging from 0.058 to 0.52 eV, and the corresponding reversible capacity reaches a remarkable value of 499.0927 mA h g-1 per formula unit, surpassing that of graphite (372 mA h g-1). Furthermore, we investigate a 2D van der Waals (vdW) heterostructure composed of pre-strained structures of graphene and NiN2 for use as an anode material in LIBs. It is found that the introduction of graphene leads to improvements in both electrochemical activity and deformation characteristics. The presented results provide theoretical support for the potential of bilayer structures combining NiN2, suggesting them as promising candidates for the development of high-performance anode materials.
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Realizing Von Hove singularity (VHS) and extended flat bands of graphene near the Fermi level (EF) is of great significance to explore many-body interactions, with a high tendency towards superconductivity. In this study, we report that the VHS of π* bands near EF can be realized by high-density lithium intercalation in p-type doped twisted bilayer graphene (tBLG). First, a method to predict the highest lithium intercalation in tBLG systems with arbitrary twist angle was established which proves that the interlayer twisting leads to the clustering of lithium ions in the AA-region but reduces the overall concentration. Second, we show that the p-type doping (1.35% boron) in tBLGs enhances their electron acceptance capability by increasing lithium intercalation up to 47%. In this situation, the electron doping by lithium intercalation is sufficient to shift EF near the VHS which offers a strategic path to realize extended flat bands, and to investigate the strong correlations in the tBLG systems.
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Electrocatalytic urea synthesis through N2 + CO2 coreduction and C-N coupling is a promising and sustainable alternative to harsh industrial processes. Despite considerable efforts, limited progress has been made due to the challenges of breaking inert N≡N bonds for C-N coupling, competing side reactions, and the absence of theoretical principles guiding catalyst design. In this study, we propose a mechanism for highly electrocatalytic urea synthesis using two adsorbed N2 molecules and CO as nitrogen and carbon sources, respectively. This mechanism circumvents the challenging step of N≡N bond breaking and selective CO2 to CO reduction, as the free CO molecule inserts into dimerized *N2 and binds concurrently with two N atoms, forming a specific urea precursor *NNCONN* with both thermodynamic and kinetic feasibility. Through the proposed mechanism, Ti2@C4N3 and V2@C4N3 are identified as highly active catalysts for electrocatalytic urea formation, exhibiting low onset potentials of -0.741 and -0.738 V, respectively. Importantly, taking transition metal atoms anchored on porous graphite-like carbonitride (TM2@C4N3) as prototypes, we introduce a simple descriptor, namely, effective d electron number (Φ), to quantitatively describe the structure-activity relationships for urea formation. This descriptor incorporates inherent atomic properties of the catalyst, such as the number of d electrons, the electronegativity of the metal atoms, and the generalized electronegativity of the substrate atoms, making it potentially applicable to other urea catalysts. Our work advances the comprehension of mechanisms and provides a universal guiding principle for catalyst design in urea electrochemical synthesis.
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ABSTRACT: There is a gap in the literature on the best treatment of clinical sequelae within adolescent and young adult pediatric cancer populations. Children, adolescents, and young adults are at risk for a multitude of immediate and late effects of their disease and treatment that warrant a comprehensive, multidisciplinary team approach to optimize care. Sports medicine providers are well-equipped with their background to join the oncology rehabilitation team in diagnosing and managing cancer-related impairments to help these populations live a healthier and more active lifestyle. In this manuscript, four essential clinical components to consider when returning children, adolescents, and young adults with cancer history to physical activity are discussed: chemotherapy-induced peripheral neuropathy, cardiotoxicity, nutritional deficiencies, and deconditioning.