The Development of Cannabinoids as Therapeutic Agents in the United States.

Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents while underscoring the risks related to interfering with the endogenous system during nonmedical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility to ultimately extend our knowledge of the risks and benefits of cannabinoids for patients and providers. SIGNIFICANCE STATEMENT: This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.

Phencyclidine-Like Abuse Liability and Psychosis-Like Neurocognitive Effects of Novel Arylcyclohexylamine Drugs of Abuse in Rodents.

Abuse of novel arylcyclohexylamines (ACX) poses risks for toxicities, including adverse neurocognitive effects. In vivo effects of ring-substituted analogs of phencyclidine (PCP), eticyclidine (PCE), and ketamine are understudied. Adult male National Institutes of Health Swiss mice were used to assess locomotor effects of PCP and its 3-OH, 3-MeO, 3-Cl, and 4-MeO analogs, PCE and its 3-OH and 3-MeO analogs, and ketamine and its deschloro and 2F-deschloro analogs, in comparison with those of methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), and two benzofuran analogs of MDMA. PCP-like interoceptive effects for all of these ACXs were determined using a food-reinforced drug discrimination procedure in adult male Sprague Dawley rats. A novel operant assay of rule-governed behavior incorporating aspects of attentional set-shifting was used to profile psychosis-like neurocognitive effects of PCP and 3-Cl-PCP in rats, in comparison with cocaine and morphine. PCP-like ACXs were more effective locomotor stimulants than the amphetamines, PCE-like ACXs were as effective as the amphetamines, and ketamine-like ACXs were less effective than the amphetamines. Addition of -Cl, -OH, or -OMe at the 3-position on the aromatic ring did not impact locomotor effectiveness, but addition of -OMe at the 4-position reduced locomotor effectiveness. Lethal effects were induced by drugs with -OH at the 3-position or -OMe at the 3- or 4-position. All novel ACXs substituted at least partially for PCP, and PCP and 3-Cl-PCP elicited dose-dependent psychosis-like neurocognitive deficits in the rule-governed behavior task not observed with cocaine or morphine. Novel ACXs exhibit substantial abuse liability and toxicities not necessarily observed with their parent drugs. SIGNIFICANCE STATEMENT: Novel arylcyclohexylamine analogs of PCP, PCE, and ketamine are appearing on the illicit market, and abuse of these drugs poses risks for toxicities, including adverse neurocognitive effects. These studies demonstrate that the novel ACXs exhibit PCP-like abuse liability in the drug discrimination assay, elicit varied locomotor stimulant and lethal effects in mice, and induce psychosis-like neurocognitive effects in rats.

Hospital costs for unplanned re-admissions within 30 days of hospitalisations with heart failure, Australia, 2013-2017: a retrospective cohort study.

OBJECTIVES: To assess the direct hospital costs for unplanned re-admissions within 30 days of hospitalisations with heart failure in Australia; to estimate the proportion of these costs attributable to potentially preventable re-admissions. STUDY DESIGN: Retrospective cohort study; analysis of linked admitted patient data collections data. SETTING, PARTICIPANTS: People admitted to hospital (all public and most private hospitals in Australia) with primary diagnoses of heart failure, 1 January 2013 - 31 December 2017, who were discharged alive and re-admitted to hospital at least once (any cause) within 30 days of discharge. MAIN OUTCOME MEASURES: Estimated re-admission costs based on National Hospital Cost Data Collection, by unplanned re-admission category based on the primary re-admission diagnosis: potentially hospital-acquired condition; recurrence of heart failure; other diagnoses related to heart failure; all other diagnoses. The first two groups were deemed the most preventable. RESULTS: The 165 612 eligible hospitalisations of people with heart failure during 2013-2017 (mean age, 79 years [standard deviation, 12 years]; 85 964 men [51.9%]) incurred direct hospital costs of $1881.4 million (95% confidence interval [CI], $1872.5-1890.2 million), or $376.3 million per year (95% CI, $374.5-378.1 million per year) and $11 360 per patient (95% CI, $11 312-11 408 per patient). A total of 41 125 people (24.8%) experienced a total of 58 977 unplanned re-admissions within 30 days of discharge from index admissions; these re-admissions incurred direct hospital costs of $604.4 million (95% CI, $598.2-610.5 million), or 32% of total index admission costs; that is, $120.9 million per year (95% CI, $119.6-122.1 million per year), and $14 695 per patient (95% CI, $14 535-14 856 per patient). Re-admissions with potentially hospital-acquired conditions (21 641 re-admissions) accounted for 40.1% of unplanned re-admission costs, recurrence of heart failure (18 666 re-admissions) for 35.6% of re-admission costs. CONCLUSION: Unplanned re-admissions after hospitalisations with heart failure are expensive, incurring costs equivalent to 32% of those for the initial hospitalisations; a large proportion of these costs are associated with potentially preventable re-admissions. Reducing the number of unplanned re-admissions could improve outcomes for people with heart failure and reduce hospital costs.

Cost-effectiveness of nasal high-flow in children with acute hypoxaemic respiratory failure.

AIM: A pilot randomised controlled trial assessed the early application of nasal high-flow (NHF) therapy compared with standard oxygen therapy (SOT), in children aged 0 to 16 years presenting to paediatric emergency departments with acute hypoxaemic respiratory failure (AHRF). The study estimated the need to escalate therapy and hospital length of stay in the NHF group compared with SOT. This sub-study then assessed the subsequent cost-effectiveness. METHODS: A decision tree-based model was developed, alongside the clinical study, to estimate cost-effectiveness, from the healthcare sector perspective. The primary health economics outcome is measured as incremental cost per length of hospital stay avoided. Incremental cost effectiveness ratios (ICER) measuring change in cost per change in length of stay, were obtained for four samples, depending on responder status and obstructive airways disease. These were (1) obstructive and responder, (2) non-obstructive and responder, (3) obstructive and non-responder and (4) non obstructive and non-responder. Bootstrapping of parameters accounted for uncertainty in estimates of cost and outcome. RESULTS: The ICER for patients randomised to NHF, indicated an additional A$367.20 for a lower hospital length of stay (in days) in the non-obstructive/non-responder sample. In the bootstrap sample, this was found to be cost effective above a willingness to pay threshold of A$10 000. The ICER was A$440.86 in the obstructive/responder sample and A$469.56 in the non-obstructive/responder sample - but both resulted in a longer length of stay. The ICER in the obstructive/non-responder sample was A$52 167.76, also with a longer length of stay, mainly impacted by a small sample of severe cases. CONCLUSION: As first-line treatment, NHF is unlikely to be cost-effective compared with SOT, but for non-obstructive patients who required escalation in care (non-obstructive non-responder), NHF is likely to be cost-effective if willingness-to-pay per reduced hospital length of stay is more than A$10 000 per patient.

Excess healthcare costs of psychological distress in young women: Evidence from linked national Medicare claims data.

The prevalence of mental health disorders in young adults is increasing, yet there is limited empirical evidence on its economic consequences. We contribute to the literature by estimating the healthcare costs of psychological distress using panel data of young women (aged 18-23 years with a 5-year follow-up) from the Australian Longitudinal Study on Women's Health and linked administrative data from Medicare Australia. Our empirical strategy is based on the classical two-part model of healthcare costs with individual specific fixed-effects. We complement our analysis with a test for selection on unobservables to address potential concerns of endogeneity. We find that young women with psychological distress have 15% higher annual healthcare costs (excluding hospital costs) than women with no psychological distress. A large proportion of these costs is driven by the use of antidepressants and the services of psychiatrists and psychologists. We further find that women with psychological distress have higher out-of-pocket costs on these mental health related services compared to non-mental health specific services. Additionally, we show that the effect of psychological distress on healthcare costs is highest during the first 6 months of onset, which gradually decreases afterwards. The findings justify the importance of policy initiatives towards early prevention and treatment of psychological distress, especially among young women.

The social predictors of paternal antenatal mental health and their associations with maternal mental health in the Queensland Family Cohort prospective study.

Antenatal depression (AND) affects 1 in 10 fathers, potentially negatively impacting maternal mental health and well-being during and after the transition to parenthood. However, few studies have assessed the social predictors of paternal AND or their possible associations with maternal mental health. We analysed data from 180 couples participating in the Queensland Family Cohort longitudinal study. Both parents completed surveys measuring mental health, relationship quality, social support, and sleep quality at 24 weeks of pregnancy. Mothers also completed the same surveys 6 weeks' postpartum. Antenatal depression, stress, and anxiety were highest among fathers reporting lower social support and higher sleep impairment. Maternal AND, stress, and anxiety were higher among mothers reporting higher physical pain and poor sleep quality. Postnatally, mothers reporting lower social support also reported higher depression, anxiety, stress, and psycho-social well-being. While there were no significant associations between AND among fathers and maternal antenatal or postnatal depression, an exploratory analysis revealed that mothers whose partners reported lower antenatal social support also reported lower postnatal social support and higher postnatal depression. Our findings highlight the importance of including data among fathers to achieve a whole family approach to well-being during the transition to parenthood.

Effect of Early High-Flow Nasal Oxygen vs Standard Oxygen Therapy on Length of Hospital Stay in Hospitalized Children With Acute Hypoxemic Respiratory Failure: The PARIS-2 Randomized Clinical Trial.

Importance: Nasal high-flow oxygen therapy in infants with bronchiolitis and hypoxia has been shown to reduce the requirement to escalate care. The efficacy of high-flow oxygen therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure without bronchiolitis is unknown. Objective: To determine the effect of early high-flow oxygen therapy vs standard oxygen therapy in children with acute hypoxemic respiratory failure. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted at 14 metropolitan and tertiary hospitals in Australia and New Zealand, including 1567 children aged 1 to 4 years (randomized between December 18, 2017, and March 18, 2020) requiring hospital admission for acute hypoxemic respiratory failure. The last participant follow-up was completed on March 22, 2020. Interventions: Enrolled children were randomly allocated 1:1 to high-flow oxygen therapy (n = 753) or standard oxygen therapy (n = 764). The type of oxygen therapy could not be masked, but the investigators remained blinded until the outcome data were locked. Main Outcomes and Measures: The primary outcome was length of hospital stay with the hypothesis that high-flow oxygen therapy reduces length of stay. There were 9 secondary outcomes, including length of oxygen therapy and admission to the intensive care unit. Children were analyzed according to their randomization group. Results: Of the 1567 children who were randomized, 1517 (97%) were included in the primary analysis (median age, 1.9 years [IQR, 1.4-3.0 years]; 732 [46.7%] were female) and all children completed the trial. The length of hospital stay was significantly longer in the high-flow oxygen group with a median of 1.77 days (IQR, 1.03-2.80 days) vs 1.50 days (IQR, 0.85-2.44 days) in the standard oxygen group (adjusted hazard ratio, 0.83 [95% CI, 0.75-0.92]; P < .001). Of the 9 prespecified secondary outcomes, 4 showed no significant difference. The median length of oxygen therapy was 1.07 days (IQR, 0.50-2.06 days) in the high-flow oxygen group vs 0.75 days (IQR, 0.35-1.61 days) in the standard oxygen therapy group (adjusted hazard ratio, 0.78 [95% CI, 0.70-0.86]). In the high-flow oxygen group, there were 94 admissions (12.5%) to the intensive care unit compared with 53 admissions (6.9%) in the standard oxygen group (adjusted odds ratio, 1.93 [95% CI, 1.35-2.75]). There was only 1 death and it occurred in the high-flow oxygen group. Conclusions and Relevance: Nasal high-flow oxygen used as the initial primary therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure did not significantly reduce the length of hospital stay compared with standard oxygen therapy. Trial Registration: anzctr.org.au Identifier: ACTRN12618000210279.

Associations between COVID-19 lockdown and post-lockdown on the mental health of pregnant women, postpartum women and their partners from the Queensland family cohort prospective study.

BACKGROUND: There are very few developed countries where physical isolation and low community transmission has been reported for COVID-19 but this has been the experience of Australia. The impact of physical isolation combined with low disease transmission on the mental health of pregnant women is currently unknown and there have been no studies examining the psychological experience for partners of pregnant women during lockdown. The aim of the current study was to examine the impact of the first COVID-19 lockdown in March 2020 and post lockdown from August 2020 on the mental health of pregnant women or postpartum women and their partners. METHODS: Pregnant women and their partners were prospectively recruited to the study before 24 weeks gestation and completed various questionnaires related to mental health and general wellbeing at 24 weeks gestation and then again at 6 weeks postpartum. The Depression, Anxiety and Stress Scale (DASS-21) and the Edinburgh Postnatal Depression Scale (EPDS) were used as outcome measures for the assessment of mental health in women and DASS-21 was administered to their partners. This analysis encompasses 3 time points where families were recruited; before the pandemic (Aug 2018-Feb 2020), during lockdown (Mar-Aug 2020) and after the first lockdown was over (Sept-Dec 2020). RESULTS: There was no significant effect of COVID-19 lockdown and post lockdown on depression or postnatal depression in women when compared to a pre-COVID-19 subgroup. The odds of pregnant women or postpartum women experiencing severe anxiety was more than halved in women during lockdown relative to women in the pre-COVID-19 period (OR = 0.47; 95%CI: 0.27-0.81; P = 0.006). Following lockdown severe anxiety was comparable to the pre-COVID-19 women. Lockdown did not have any substantial effects on stress scores for pregnant and postpartum women. However, a substantial decrease of over 70% in the odds of severe stress was observed post-lockdown relative to pre-COVID-19 levels. Partner's depression, anxiety and stress did not change significantly with lockdown or post lockdown. CONCLUSION: A reproductive age population appear to be able to manage the impact of lockdown and the pandemic with some benefits related to reduced anxiety.

How do patients pass through stroke services? Identifying stroke care pathways using national audit data.

OBJECTIVE: To map and describe how patients pass through stroke services. METHODS: Data from 94,905 stroke patients (July 2013-July 2015) who were still inpatients 72 hours after hospital admission were extracted from a national stroke register and were used to identify the routes patients took through hospital and community stroke services. We sought to categorize these routes through iterative consultations with clinical experts and to describe patient characteristics, therapy provision, outcomes and costs within each category. RESULTS: We identified 874 routes defined by the type of admitting stroke team and subsequent transfer history. We consolidated these into nine distinct routes and further summarized these into three overlapping 'pathways' that accounted for 99% of the patients. These were direct discharge (44%), community rehabilitation (47%) and inpatient transfer (19%) with 12% of the patients receiving both inpatient transfer and community rehabilitation. Patients with the mildest and most severe strokes were more likely to follow the direct discharge pathway. Those perceived to need most therapy were more likely to follow the inpatient transfer pathway. Costs were lowest and mortality was highest for patients on the direct discharge pathway. Outcomes were best for patients on the community rehabilitation pathway and costs were highest where patients underwent inpatient transfers. CONCLUSION: Three overarching stroke care pathways were identified which differ according to patient characteristics, therapy needs and outcomes. This pathway mapping provides a benchmark to develop and plan clinical services, and for future research.

Factors influencing the amount of therapy received during inpatient stroke care: an analysis of data from the UK Sentinel Stroke National Audit Programme.

OBJECTIVES: To understand why most stroke patients receive little therapy. We investigated the factors associated with the amount of stroke therapy delivered. METHODS: Data regarding adults admitted to hospital with stroke for at least 72 hours (July 2013-July 2015) were extracted from the UK's Sentinel Stroke National Audit Programme. Descriptive statistics and multilevel mixed effects regression models explored the factors that influenced the amount of therapy received while adjusting for confounding. RESULTS: Of the 94,905 patients in the study cohort (mean age: 76 (SD: 13.2) years, 78% had a mild or moderate severity stroke. In all, 92% required physiotherapy, 87% required occupational therapy, 57% required speech therapy but only 5% were considered to need psychology. The average amount of therapy ranged from 2 minutes (psychology) to 14 minutes (physiotherapy) per day of inpatient stay. Unmodifiable characteristics (such as stroke severity) dominated the variation in the amount of therapy. However important, modifiable organizational factors were the day and time of admission, type of stroke team, timely therapy assessments, therapy and nursing staffing levels (qualified and support staff), and presence of weekend or early supported discharge services. CONCLUSION: The amount of stroke therapy is associated with unmodifiable patient-related characteristics and modifiable organizational factors in that more therapy was associated with higher therapy and nurse staffing levels, specialist stroke rehabilitation services, timely therapy assessments, and the presence of weekend and early discharge services.

Inhibition of Cocaine and 3,4-Methylenedioxypyrovalerone (MDPV) Self-Administration by Lorcaserin Is Mediated by 5-HT2C Receptors in Rats.

Lorcaserin is a serotonin (5-HT)2C receptor-preferring agonist approved by the US Food and Drug Administration to treat obesity. Lorcaserin decreases cocaine self-administration in rats and monkeys. Although this effect is partially inhibited by a 5-HT2C receptor antagonist (SB242084), lorcaserin also has effects at 5-HT2A and 5-HT1A receptors, and the relative contribution of these receptors to its anti-cocaine effects has not been investigated. The goals of this study were to determine 1) the potency and effectiveness of lorcaserin to decrease self-administration of cocaine and 3,4-methylenedioxypyrovalerone (MDPV), a common "bath salts" constituent; and 2) the receptor(s) mediating the effects of lorcaserin on cocaine and MDPV self-administration. Male Sprague-Dawley rats (n = 6) were trained to self-administer MDPV under a progressive ratio schedule of reinforcement and maintained under this schedule with daily access to 0.32 mg/kg per infusion of cocaine or 0.032 mg/kg per infusion of MDPV. Dose-response curves for the effects of lorcaserin on cocaine and MDPV self-administration were generated by administering lorcaserin (0.1-5.6 mg/kg) 25 minutes before the start of the session. To assess the effects of 5-HT2C (SB242084, 0.1 mg/kg), 5-HT2A (MDL100907, 0.1 mg/kg), and 5-HT1A (WAY100635, 0.178 mg/kg) receptor antagonists, they were administered 15 minutes before lorcaserin. Lorcaserin decreased cocaine and MDPV self-administration with equal potency. Antagonism of 5-HT2C (but not 5-HT1A or 5-HT2A) receptors blocked the effects of lorcaserin on cocaine and MDPV self-administration. Taken together, these data provide additional support for further development of 5-HT2C receptor agonists, such as lorcaserin, for the treatment of stimulant abuse.

Measurement tools of resource use and quality of life in clinical trials for dementia or cognitive impairment interventions: A systematically conducted narrative review.

OBJECTIVE: Knowledge is limited about the standardised instruments used to collect resource use and quality of life data alongside trials of dementia interventions. This review aimed to identify the trials using such instruments in order to guide the design of future trial-based cost-effectiveness studies. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement, this review examined all original, peer-reviewed research in major databases and general searches published until June 2017, including randomised clinical trials, pilot studies, or feasibility studies about interventions for older adults with dementia or cognitive impairment. RESULTS: Forty-one studies were identified. Only 8 collected the resource use data using adapted Client Service Receipt Inventory (CSRI), Resource Use Inventory (RUI), cost diary, or study-specific questionnaire. Quality of life was assessed using a wide range of instruments. The most frequently used dementia-specific instrument was Quality of Life in Alzheimer's Disease (QOL-AD) and Dementia Quality of Life questionnaire (DEMQOL). Among the generic measures, EuroQol 5-dimentison (EQ-5D) was mostly used to collect health utility data, and Short Form surveys (SF-36 or SF-12) were widely to measure general health. CONCLUSIONS: Several useful resource use and quality of life measurement instruments have been identified by this review. For resource use, CSRI was mostly used, but no studies have used Resource Utilisation in Dementia (RUD); for quality of life, we recommend the inclusion of dementia-specific DEMQOL, generic SF-12, and health utility EQ-5D-5L, based on both self-report and proxy-report.

A prospective cohort study measuring cost-benefit analysis of the Otago Exercise Programme in community dwelling adults with rheumatoid arthritis.

BACKGROUND: Falls are one of the major health problems in adults with Rheumatoid Arthritis (RA). Interventions, such as the Otago Exercise Programme (OEP), can reduce falls in community dwelling adults by up to 35%. The cost-benefits of such a programme in adults with RA have not been studied. The aims of this study were to determine the healthcare cost of falls in adults with RA, and estimate whether it may be cost efficient to roll out the OEP to improve function and prevent falls in adults living with RA. METHODS: Patients with Rheumatoid Arthritis aged ≥18 years were recruited from four rheumatology clinics across the Northwest of England. Participants were followed up for 1 year with monthly fall calendars, telephone calls and self-report questionnaires. Estimated medical cost of a fall-related injury incurred per-person were calculated and compared with OEP implementation costs to establish potential economic benefits. RESULTS: Five hundred thirty-five patients were recruited and 598 falls were reported by 195 patients. Cumulative medical costs resulting from all injury leading to hospital services is £374,354 (US$540,485). Average estimated cost per fall is £1120 (US$1617). Estimated cost of implementing the OEP for 535 people is £116,479 (US$168,504) or £217.72 (US$314.34) per-person. Based on effectiveness of the OEP it can be estimated that out of the 598 falls, 209 falls would be prevented. This suggests that £234,583 (US$338,116) savings could be made, a net benefit of £118,104 (US$170,623). CONCLUSIONS: Implementation of the OEP programme for patients with RA has potentially significant economic benefits and should be considered for patients with the condition.

Individual Differences in the Relative Reinforcing Effects of 3,4-Methylenedioxypyrovalerone under Fixed and Progressive Ratio Schedules of Reinforcement in Rats.

The recreational use of designer drugs, including synthetic cathinones (bath salts), is associated with high levels of abuse and toxicity, and represents a growing threat to public health. 3,4-Methylenedioxypyrovalerone (MDPV) is a cocaine-like monoamine uptake inhibitor, and one of the most widely available and abused synthetic cathinones. The present study used male Sprague-Dawley rats to directly compare: (1) the acquisition of responding for MDPV and cocaine under a fixed ratio (FR) 1 schedule of reinforcement; (2) full dose-response curves for MDPV and cocaine under a FR5 schedule; and (3) progressive ratio (PR) schedules of reinforcement. Self-administration of MDPV and cocaine was acquired at comparable rates, and by a similar percentage of rats. Compared with cocaine, MDPV was ∼10-fold more potent and ∼3-fold more effective at maintaining responding (PR; final ratio completed). Unlike cocaine, for which little variability was observed among rats, the FR5 dose-response curve for MDPV was shifted ∼3-fold upward for a subset of rats (high-responders) relative to other rats with identical histories (low-responders). Compared with low-responding rats, high responders also self-administered more cocaine under the FR5 schedule, and earned significantly more MDPV, cocaine, and methamphetamine under a PR schedule of reinforcement. In addition to functioning as a significantly more effective reinforcer than either cocaine or methamphetamine, MDPV also appears to be unique in its capacity to establish an enduring phenotype in rats, characterized by unusually high levels of drug intake. Although the factors underlying this high-responder phenotype are unclear, they might be related to individual differences in human drug-taking behavior.

Reinforcing effects of abused 'bath salts' constituents 3,4-methylenedioxypyrovalerone and α-pyrrolidinopentiophenone and their enantiomers.

Synthetic cathinones found in abused 'bath salts' preparations are chiral molecules. Racemic 3,4-methylenedioxypyrovalerone (MDPV) and α-pyrrolidinopentiophenone (α-PVP) are two common constituents of these preparations that have been reported to be highly effective reinforcers; however, the relative contribution of each enantiomer toward these effects has not been determined. Thus, male Sprague-Dawley rats were trained to respond for racemic MDPV or α-PVP (n=9/drug), with full dose-response curves for the racemate and the S and R enantiomers of MDPV and α-PVP generated under a progressive ratio schedule of reinforcement. Racemic mixtures of both MDPV and α-PVP as well as each enantiomer maintained responding in a dose-dependent manner, with racemic MDPV and α-PVP being equipotent. The rank order of potency within each drug was S enantiomer>racemate ≫ R enantiomer. Although both enantiomers of α-PVP were as effective as racemic α-PVP, R-MDPV was a slightly less effective reinforcer than both S and racemic MDPV. The results of these studies provide clear evidence that both enantiomers of MDPV and α-PVP function as highly effective reinforcers and likely contribute toward the abuse-related effects of 'bath salts' preparations containing racemic MDPV and/or α-PVP.

Stereoselective Effects of Abused "Bath Salt" Constituent 3,4-Methylenedioxypyrovalerone in Mice: Drug Discrimination, Locomotor Activity, and Thermoregulation.

3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of illicit "bath salts" products. MDPV is a chiral molecule, but the contribution of each enantiomer to in vivo effects in mice has not been determined. To address this, mice were trained to discriminate 10 mg/kg cocaine from saline, and substitutions with racemic MDPV, S(+)-MDPV, and R(-)-MDPV were performed. Other mice were implanted with telemetry probes to monitor core temperature and locomotor responses elicited by racemic MDPV, S(+)-MDPV, and R(-)-MDPV under a warm (28°C) or cool (20°C) ambient temperature. Mice reliably discriminated the cocaine training dose from saline, and each form of MDPV fully substituted for cocaine, although marked potency differences were observed such that S(+)-MDPV was most potent, racemic MDPV was less potent than the S(+) enantiomer, and R(-)-MDPV was least potent. At both ambient temperatures, locomotor stimulant effects were observed after doses of S(+)-MDPV and racemic MDPV, but R(-)-MDPV did not elicit locomotor stimulant effects at any tested dose. Interestingly, significant increases in maximum core body temperature were only observed after administration of racemic MDPV in the warm ambient environment; neither MDPV enantiomer altered core temperature at any dose tested, at either ambient temperature. These studies suggest that all three forms of MDPV induce biologic effects, but R(-)-MDPV is less potent than S(+)-MDPV and racemic MDPV. Taken together, these data suggest that the S(+)-MDPV enantiomer is likely responsible for the majority of the biologic effects of the racemate and should be targeted in therapeutic efforts against MDPV overdose and abuse.

Economic Theory and Self-Reported Measures of Presenteeism in Musculoskeletal Disease.

This study had two objectives: to describe the historical development of self-reported presenteeism instruments that can be used to identify and measure presenteeism as a result of musculoskeletal disease (MSD) and to identify if, and how many of these, presenteeism instruments are underpinned by economic theory. Systematic search methods were applied to identify self-report instruments used to quantify presenteeism caused by MSD. A total of 24 self-reported presenteeism instruments were identified; 24 were designed for use in general health, and 1 was specifically designed for use in rheumatoid arthritis. One generic self-reported presenteeism instrument was explicitly reported to be underpinned by economic theory. Overtime, self-reported presenteeism instruments have become more differentiated and complex by incorporating many different contextual factors that may impact levels of presenteeism. Researchers are encouraged to further develop presenteeism instruments that are underpinned by relevant economic theory and informed by robust empirical research.

Increased 4-hydroxynonenal protein adducts in male GSTA4-4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease.

To test the significance of lipid peroxidation in the development of alcoholic liver injury, an ethanol (EtOH) liquid diet was fed to male 129/SvJ mice (wild-type, WT) and glutathione S-transferase A4-4-null (GSTA4-/-) mice for 40 days. GSTA4-/- mice were crossed with peroxisome proliferator-activated receptor-α-null mice (PPAR-α-/-), and the effects of EtOH in the resulting double knockout (dKO) mice were compared with the other strains. EtOH increased lipid peroxidation in all except WT mice (P < 0.05). Increased steatosis and mRNA expression of the inflammatory markers CXCL2, tumor necrosis factor-α (TNF-α), and α-smooth muscle actin (α-SMA) were observed in EtOH GSTA4-/- compared with EtOH WT mice (P < 0.05). EtOH PPAR-α-/- mice had increased steatosis, serum alanine aminotransferase (ALT), and hepatic CD3+ T cell populations and elevated mRNA encoding CD14, CXCL2, TNF-α, IL-6, CD138, transforming growth factor-ß, platelet-derived growth factor receptor-ß (PDGFR-ß), matrix metalloproteinase (MMP)-9, MMP-13, α-SMA, and collagen type 1 compared with EtOH WT mice. EtOH-fed dKO mice displayed elevation of periportal hepatic 4-hydroxynonenal adducts and serum antibodies against malondialdehyde adducts compared with EtOH feeding of GSTA4-/-, PPAR-α-/-, and WT mice (P < 0.05). ALT was higher in EtOH dKO mice compared with all other groups (P < 0.001). EtOH-fed dKO mice displayed elevated mRNAs for TNF-α and CD14, histological evidence of fibrosis, and increased PDGFR, MMP-9, and MMP-13 mRNAs compared with the EtOH GSTA4-/- or EtOH PPAR-α-/- genotype (P < 0.05). These findings demonstrate the central role lipid peroxidation plays in mediating progression of alcohol-induced necroinflammatory liver injury, stellate cell activation, matrix remodeling, and fibrosis.

Threshold effects in nonlinear models with an application to the social capital-retirement-health relationship.

This paper considers the relationship between social capital and health in the years before, at and after retirement. This adds to the current literature that only investigates this relationship in either the population as a whole or two subpopulations, pre-retirement and post-retirement. We now investigate if there are further additional subpopulations in the years to and from retirement. We take an information criteria approach to select the optimal model of subpopulations from a full range of potential models. This approach is similar to that proposed for linear models. Our contribution is to show how this may also be applied to nonlinear models and without the need for estimating subsequent subpopulations conditional on previous fixed subpopulations. Our main finding is that the association of social capital with health diminishes at retirement, and this decreases further 10 years after retirement. We find a strong positive significant association of social capital with health, although this turns negative after 20 years, indicating potential unobserved heterogeneity. The types of social capital may differ in later years (e.g., less volunteering) and hence overall social capital may have less of an influence on health in later years.