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Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT 2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT 2A -Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT 2A -selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT 2A -Gq but not 5-HT 2A -β-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT 2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT 2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT 2A agonists. We also demonstrate that β-arrestin-biased 5-HT 2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT 2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics. Serotonin 5-HT 2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT 2A -selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT 2A -Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as 'legal highs' in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many 'legal highs', little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine.

Rationale This study investigated the coadministration of an energy drink with alcohol to study the effects on subjective intoxication and objective performance. Objectives This study aims to evaluate the objective and subjective effects of alcohol versus placebo at two alcohol doses, alone and in combination with an energy drink, in a balanced order, placebo-controlled, double-blind design. Methods Two groups of ten healthy volunteers, mean (SD) age of 24 (6.5), participated in the study. One group consumed energy drink containing 80 mg of caffeine and the other consumed a placebo drink, with both receiving two alcohol doses (0.046 and 0.087% breathalyser alcohol concentration). Tests included breath alcohol assessment, objective measures of performance (reaction time, word memory and Stroop task) and subjective visual analogue mood scales. Results Participants showed significantly impaired reaction time and memory after alcohol compared to the no alcohol condition and had poorer memory after the higher alcohol dose. Stroop performance was improved with the energy drink plus alcohol combination compared to the placebo drink plus alcohol combination. Participants felt significant subjective dose-related impairment after alcohol compared to no alcohol. Neither breath alcohol concentration nor the subjective measures showed a significant difference between the energy drink and the placebo energy drink when combined with alcohol. Conclusions Subjective effects reflected awareness of alcohol intoxication and sensitivity to increasing alcohol dose. There were no overall significant group differences for subjective measures between energy drink and placebo groups in the presence of alcohol and no evidence that the energy drink masked the subjective effects of alcohol at either dose.

Objective. To determine rates and risk factors for self-discharge by Aboriginal medical inpatients at Alice Springs Hospital. Methods. Prospective cohort study. Interviews were conducted in primary language by Aboriginal Liaison Officers, from July 2006 to August 2007. Topics included understanding of diagnosis, satisfaction with services and perceptions of staff and environment. Risk factors for self-discharge were then determined prospectively. Results. During the study period 202 (14.7%) of 1380 patients admitted to general medical units at Alice Springs Hospital, were interviewed. Self-discharge rates for all admissions were significantly lower during the study period than they had been previously (pre-study, mean 22.9-standard error 0.3%; study, 17.0-0.2%) (P < 0.001). Most interviewees (73.4%) did not know their reason for admission (73.4%) or estimated length of stay (82.3%). Forty interviewees (19.8%) self-discharged. Mean monthly self-discharge rates differed between the three medical units (Unit A, 13.9_0.3%; Unit B, 17.3-1.37%; Unit C, 20.0-0.4%) (P = 0.005). Multivariable predictors of self-discharge included male sex (hazard ratio (HR) 2.4; 95% confidence interval (CI) 1.1, 5.2), a past history of self-discharge (HR 3.2; 95%CI 1.5, 6), planned transfer to a tertiary referral centre (HR 3.8; 95%CI 1.3-7.4) and a desire to drink alcohol (HR 4.5; 95%CI 1.8-10.2). Conclusions. Physician, institutional and patient factors all contribute to self-discharge. Improving cultural safety may be the key to lowering self-discharge rates.

Supplemental Digital Content is available in the text. Objective:Applied to value-based health care, the economic term \"individual productivity\" refers to the quality of an outcome attributable through a care process to an individual clinician. This study aimed to (1) estimate and describe the discharge preparation productivities of individual acute care nurses and (2) examine the association between the discharge preparation productivity of the discharging nurse and the patient's likelihood of a 30-day return to hospital [readmission and emergency department (ED) visits].Research Design:Secondary analysis of patient-nurse data from a cluster-randomized multisite study of patient discharge readiness and readmission. Patients reported discharge readiness scores; postdischarge outcomes and other variables were extracted from electronic health records. Using the structure-process-outcomes model, we viewed patient readiness for hospital discharge as a proximal outcome of the discharge preparation process and used it to measure nurse productivity in discharge preparation. We viewed hospital return as a distal outcome sensitive to discharge preparation care. Multilevel regression analyses used a split-sample approach and adjusted for patient characteristics.Subjects:A total 522 nurses and 29,986 adult (18+ y) patients discharged to home from 31 geographically diverse medical-surgical units between June 15, 2015 and November 30, 2016.Measures:Patient discharge readiness was measured using the 8-item short form of Readiness for Hospital Discharge Scale (RHDS). A 30-day hospital return was a categorical variable for an inpatient readmission or an ED visit, versus no hospital return.Results:Variability in individual nurse productivity explained 9.07% of variance in patient discharge readiness scores. Nurse productivity was negatively associated with the likelihood of a readmission (−0.48 absolute percentage points, P<0.001) and an ED visit (−0.29 absolute percentage points, P=0.042).Conclusions:Variability in individual clinician productivity can have implications for acute care quality patient outcomes.

The downward trend in readmissions has recently slowed. New enhancements to hospital readmission reduction efforts are needed. Structured assessment of patient readiness for discharge has been recommended as an addition to discharge preparation standards of care to assist with tailoring of risk-mitigating actions. To determine the effect of unit-based implementation of readiness evaluation and discharge intervention protocols on readmissions and emergency department or observation visits. The Readiness Evaluation and Discharge Interventions (READI) cluster randomized clinical trial conducted in medical-surgical units of 33 Magnet hospitals between September 15, 2014, and March 31, 2017, included all adult (aged ≥18 years) patients discharged to home. Baseline and risk-adjusted intent-to-treat analyses used difference-in-differences multilevel logistic regression models with controls for patient characteristics. Of 2 adult medical-surgical nursing units from each hospital, 1 was randomized to the intervention and 1 to usual care conditions. Using the 8-item Readiness for Hospital Discharge Scale, the 33 intervention units implemented a sequence of protocols with increasing numbers of components: READI1, in which nurses assessed patients to inform discharge preparation; READI2, which added patient self-assessment; and READI3, which added an instruction to act on a specified Readiness for Hospital Discharge Scale cutoff score indicative of low readiness. Thirty-day return to hospital (readmission or emergency department and observation visits). Intervention units above median baseline readmission rate (>11.3%) were categorized as high-readmission units. Among the 33 intervention units, 17 were low-readmission units and 16 were high-readmission units. The sample included 144 868 patient discharges (mean [SD] age, 59.6 [17.5] years; 51% female; 74 605 in the intervention group and 70 263 in the control group); 17 667 (12.2%) were readmitted and 12 732 (8.8%) had an emergency department visit or observation stay. None of the READI protocols reduced the primary outcome of return to hospital in intent-to-treat analysis of the full sample. In exploratory subgroup analysis, when patient self-assessments were combined with readiness assessment by nurses (READI2), readmissions were reduced by 1.79 percentage points (95% CI, -3.20 to -0.40 percentage points; P = .009) on high-readmission units. With nurse assessment alone and on low-readmission units, results were mixed. Implemented in a broad range of hospitals and patients, the READI interventions were not effective in reducing return to hospital. However, adding a structured discharge readiness assessment that incorporates the patient's own perspective to usual discharge care practices holds promise for mitigating high rates of return to the hospital following discharge. ClinicalTrials.gov Identifier: NCT01873118.

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT -Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT -selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT -Gq but not 5-HT -β-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT agonists. We also demonstrate that β-arrestin-biased 5-HT receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.

State governments play a major role in the United States health care market. Moreover, states administer much of the regulation, budgeting, and policy for their own markets, which creates idiosyncratic differences across states. This dissertation contributes to the literature by evaluating those differences to analyze the effectiveness of certain regulations and policies and to explore the relationship between state health care markets and other state obligations. The first chapter uses state differences in the nurse practitioner (NP) market to evaluate the effects of state laws allowing NPs to prescribe controlled substances on prescription opioid use. I study these effects by merging nationwide data from the Medical Expenditure Panel Survey (MEPS) over 18 years (1996–2013) with data on state laws. I then exploit variation in these laws over time to create a quasi-natural experiment and to estimate the causal impact of NP deregulation on prescription opioid use. I find, relative to patients living in more restrictive states, that patients who live in states with more flexible NP laws emph{reduce} their prescription opioid use by 7 percent to 9 percent. I also find that health outcomes either slightly improve or remain unaffected by the enactment of these laws. Taken together, these results indicate that NP deregulation slows the trend in prescription opioid growth while potentially improving patient outcomes. Furthermore, suggestive evidence implies that these effects may be even larger for the least restrictive states, opening the door for future reforms. The second chapter (co-authored with Andrew Litten) seeks to identify the causal relationship between increased state Medicaid obligations and higher education spending. After several decades of federal mandates and high rates of health cost inflation, Medicaid spending has taken an increasingly larger share of state budgets, forcing states to make offsetting cuts elsewhere. We argue that state governments are likely to cut higher education in response to these changes, as institutions of higher education have the capacity to find additional revenues elsewhere. We use federally administered Supplemental Security Income (SSI) enrollments to instrument for state Medicaid spending. We find that a one dollar increase in Medicaid costs leads to a decrease in higher education subsidies of 20 cents to 37 cents. Our approach provides estimates which are both more credible and more precise than those which have previously been used in the literature. The third chapter studies the effectiveness of Prescription Drug Monitoring Programs (PDMPs). These programs are widely considered to be a promising tool for preventing prescription opioid misuse. Using a nationally representative sample that spans the majority of PDMP implementation, I find little evidence that PDMP implementation is effective in preventing prescription opioid misuse. Nonetheless, I find that when states pair PDMPs with policies mandating health care provider use (\"must access\" laws), they can successfully reduce high-volume opioid prescriptions. States that add \"must access\" laws reduce high-volume prescriptions by about 20 percent. In addition, these states do not appear to affect overall prescribing behavior, suggesting that PDMPs with \"must access\" laws can target potential misuse without hindering medically appropriate access.

System-wide research on the use of out-of-home care among children and youth is needed to inform the development of policies and services. We used Medicaid claims from North Carolina to examine patterns of out-of-home care, identify demographic and diagnostic differences between those who received care in residential treatment, psychiatric hospitals, or general hospitals, and determine whether demographic or diagnostic characteristics were associated with having more than one out-of-home stay during the year. Among those who received out-of-home care during a 1 year period, 36% received care in residential treatment only, 32.4% in general hospitals only, and 17.6% in psychiatric hospitals only, while 14.0% used more than one sector of out-of-home care. Boys, teenagers, and youth in foster care or diagnosed with emotional disturbance or hyperkinetic syndrome had higher odds of receiving care in residential treatment only whereas girls, youth age 19–21, and those with depressive and stress and adjustment disorders had higher odds of receiving care from hospitals only. Teenagers and youth in foster care had higher odds of having more than one stay. Among those with more than one stay, there were 300 patterns of care and nearly half received care from more than one service sector. The implications for services and policy are discussed. Further research is needed to understand patterns of out-of-home care and the factors that influence placement decisions.