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(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.
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BACKGROUND: Children enrolled in private insurance had reduced preventive health care during the coronavirus disease 2019 (COVID-19) pandemic. However, the impact of the pandemic on children enrolled in Medicaid has been minimally described. METHODS: We used an administrative claims database from North Carolina Medicaid to evaluate the rates of well-child visits and immunization administration for children ≤14 months of age, and used a quasi-Poisson regression model to estimate the rate ratio (RR) of each outcome during the pandemic period (3/15/2020 through 3/15/2021) compared with the pre-pandemic period (3/15/2019 through 3/14/2020). RESULTS: We included 83 442 children during the pre-pandemic period and 96 634 children during the pandemic period. During the pre-pandemic period, 405 295 well-child visits and 715 100 immunization administrations were billed; during the pandemic period, 287 285 well-child visits and 457 144 immunization administrations were billed. The rates of well-child visits (RR 0.64; 95% CI, 0.64-0.64) and vaccine administration (RR 0.55; 95% CI, 0.55-0.55) were lower during the pandemic compared with the pre-pandemic period. CONCLUSIONS: The rates of well-child visits and immunization administrations among North Carolina children enrolled in public insurance substantially decreased during the first year of the COVID-19 pandemic.
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COVID-19 , Medicaid , Estados Unidos/epidemiología , Niño , Humanos , North Carolina/epidemiología , Pandemias/prevención & control , COVID-19/epidemiología , COVID-19/prevención & control , Servicios Preventivos de SaludRESUMEN
BACKGROUND: Neighbourhood factors are associated with cardiovascular health in adults, but these relationships are under-explored in youth. OBJECTIVES: To characterize the associations between neighbourhood factors and child and adolescent health among youth with obesity. METHODS: Data were drawn from patient health records at a pediatric weight management clinic (n = 2838) and the Child Opportunity Index (COI). Exposures were area-level neighbourhood factors (commute duration, walkability, greenspace and industrial pollutants). Outcomes included BMI relative to the 95th percentile (BMIp95) and blood pressure (continuous variables). Longitudinal models examined associations between COI indicators and outcomes. RESULTS: Shorter commute duration (ß = -4.31, 95% CI: -5.92, -2.71) and greater walkability (ß = -4.40, 95% CI: -5.98, -2.82) were negatively associated with BMIp95. Increased greenspace availability was positively associated with BMIp95 (ß = 1.93, 95% CI: 0.19, 3.67). None of the COI indicators were associated with cardiovascular outcomes in the full sample. Analyses stratified by sex and race/ethnicity showed similar patterns for BMIp95. For commute duration, there was a negative association with blood pressure for female, non-Hispanic White and other race/ethnicity youth. CONCLUSIONS: Neighbourhood factors should be considered as contextual factors when treating youth with obesity. Additional research is needed to understand the relationship between neighbourhood factors and cardiovascular outcomes.
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Enfermedades Cardiovasculares , Adulto , Niño , Humanos , Femenino , Adolescente , Enfermedades Cardiovasculares/epidemiología , Factores de Riesgo , Obesidad/epidemiología , Obesidad/terapia , Presión Sanguínea , Factores de Riesgo de Enfermedad Cardiaca , Características de la ResidenciaRESUMEN
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening testing is a recommended mitigation strategy for schools, although few descriptions of program implementation are available. METHODS: Kindergarten through 12th grade (K-12) students and staff practicing universal masking during the delta and omicron variant waves from five schools in Durham, North Carolina and eight schools in Kansas City, Missouri participated; Durham's program was structured as a public health initiative facilitated by school staff, and Kansas City's as a research study facilitated by a research team. Tests included school-based rapid antigen or polymerase chain reaction testing, at-home rapid antigen testing, and off-site nucleic acid amplification testing. RESULTS: We performed nearly 5700 screening tests on more than 1600 K-12 school students and staff members. The total cost for the Durham testing program in 5 public charter K-12 schools, each with 500-1000 students, was $246 587 and approximately 752 h per semester; cost per test was $70 and cost per positive result was $7076. The total cost for the Kansas City program in eight public K-12 schools was $292 591 and required approximately 537 h in personnel time for school-based testing; cost per test was $132 and cost per positive result was $4818. SARS-CoV-2 positivity rates were generally lower (0-16.16%) than rates in the community (2.7-36.47%) throughout all testing weeks. CONCLUSIONS AND RELEVANCE: Voluntary screening testing programs in K-12 schools are costly and rarely detect asymptomatic positive persons, particularly in universally masked settings. CLINICAL TRIAL REGISTRATION: NCT04831866.
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COVID-19 , SARS-CoV-2 , Humanos , Instituciones Académicas , EscolaridadRESUMEN
BACKGROUND: Limited data are available to establish evidence-based management protocols for vestibulodynia (VBD), a chronic vulvar pain condition that affects approximately 14 million women in the U.S. For the purposes of the study, our group subdivided VBD subtypes that may benefit from different types of treatment: 1) VBD peripheral (VBD-p), characterized by pain localized to the vulvar vestibule and 2) VBD central (VBD-c), characterized by VBD alongside one or more other chronic overlapping pain conditions (e.g. irritable bowel syndrome, temporomandibular disorder, and fibromyalgia syndrome) that affect remote body regions. Here, we describe the rationale and design of an NIH-funded multicenter clinical trial comparing the effectiveness of topical and/or systemic medication for alleviating pain and normalizing pain- relevant biomarkers among women with VBD-p and VBD-c. METHODS: Participants will be randomly assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml 0.02% oestradiol compound cream + oral placebo pill, 2) central treatment with the tricyclic antidepressant nortriptyline + placebo cream, 3) combined peripheral cream and central pill treatments, or 4) placebo cream and placebo pill. The treatment phase will last 16 weeks, with outcome measures and biomarkers assessed at 4 time points (0, 8, 16, and 24 weeks). First, we will compare the efficacy of treatments in alleviating pain using standardized tampon insertion with a numeric rating scale and self-reported pain on the short form McGill Pain Questionnaire. Next, we will compare the efficacy of treatments in improving perceived physical, mental, and sexual health using standardized questionnaires. Finally, we will measure cytokines and microRNAs in local vaginal and circulating blood samples using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to predict treatment response. CONCLUSION: This is the first multicenter randomized controlled trial to evaluate the efficacy of peripherally and centrally acting medications currently used in clinical practice for treating unique VBD subtypes based on distinct clinical and biological signatures. ADMINISTRATIVE INFORMATION: Vestibulodynia UPDATe is a multi-centre, two-by-two factorial designed randomized, double-blind, placebo-controlled trial registered at clinical trials.gov (NCT03844412). This work is supported by the R01 HD096331 awarded to Drs. Nackley, Rapkin, Geller and Carey by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).Key messagesPeripheral lidocaine and oestradiol and centrally-targeted nortriptyline medications are used for the treatment of pain in women with VBD, but there is a lack of data from well-powered RCTs.This two-by-two factorial RCT will test the efficacy of these medications in VBD subtypes characterized by distinct clinical characteristics and biomarker profiles.We hope that results will provide clinicians with scientific evidence of therapeutic efficacy in distinct VBD subtypes in an effort to direct and optimize treatment approaches.
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MicroARNs , Vulvodinia , Femenino , Humanos , Antidepresivos Tricíclicos/uso terapéutico , Citocinas/uso terapéutico , Estradiol/uso terapéutico , Lidocaína/uso terapéutico , MicroARNs/uso terapéutico , Nortriptilina/uso terapéutico , Dolor , Vulvodinia/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
Activity that places demands on cognitive resources has positive effects on cognitive health in old age. To further understand determinants of age-group differences in participation, we examined how negative aging stereotypes and responses associated with a cognitively challenging activity influenced future willingness to engage in that activity. Sixty-nine young (20-40 years) and 80 older (63-84 years) adults performed a letter-number sequencing (LNS) task at different levels of demand for 15 min, during which systolic blood pressure responses-a measure of effort mobilization-and subjective perceptions of task demands were assessed. Approximately half the participants were primed with a negative aging stereotype prior to this task. Following the LNS task, participants completed an effort-discounting task, with resulting subjective values indicating their willingness to perform the task at each level of demand. As expected, both subjective and objective indicators of cognitive demands as well as performance were associated with future willingness to engage in a difficult task, with these effects being significantly greater for older adults. In addition, although stereotype activation influenced older adults' engagement levels in the LNS task, it did not moderate willingness. Together, the results indicate that, relative to younger adults, older adults' decisions to engage in cognitively challenging activities are disproportionately affected by their subjective perceptions of demands. Interestingly, actual engagement with the task and associated success result in reduced perceptions of difficulty and greater willingness to engage. Thus, overcoming faulty and discouraging task perceptions may promote older adults' engagement in demanding but potentially beneficial activities. (PsycInfo Database Record (c) 2021 APA, all rights reserved).