Non-pharmaceutical interventions to reduce COVID-19 transmission in the UK: a rapid mapping review and interactive evidence gap map.

BACKGROUND: Non-pharmaceutical interventions (NPIs) were crucial in the response to the COVID-19 pandemic, although uncertainties about their effectiveness remain. This work aimed to better understand the evidence generated during the pandemic on the effectiveness of NPIs implemented in the UK. METHODS: We conducted a rapid mapping review (search date: 1 March 2023) to identify primary studies reporting on the effectiveness of NPIs to reduce COVID-19 transmission. Included studies were displayed in an interactive evidence gap map. RESULTS: After removal of duplicates, 11 752 records were screened. Of these, 151 were included, including 100 modelling studies but only 2 randomized controlled trials and 10 longitudinal observational studies.Most studies reported on NPIs to identify and isolate those who are or may become infectious, and on NPIs to reduce the number of contacts. There was an evidence gap for hand and respiratory hygiene, ventilation and cleaning. CONCLUSIONS: Our findings show that despite the large number of studies published, there is still a lack of robust evaluations of the NPIs implemented in the UK. There is a need to build evaluation into the design and implementation of public health interventions and policies from the start of any future pandemic or other public health emergency.

The School of Hard Talks: A telehealth parent training group for caregivers of adolescents and young adults.

AIM: A large body of evidence demonstrates the importance of the family environment in the developmental trajectory of mental illness in young people. Caregiver communication skills training represents a potential model for influencing the outcomes of adolescents and young adults struggling with emerging mental health and behavioural difficulties. The aim of the current study is to describe the development of a telehealth group training intervention for caregivers of adolescents and young adults, and to report the results of a pilot feasibility-effectiveness study that took place in 2020-2021. METHODS: The "School of Hard Talks" intervention consisted of 8 h of training in communication skills consistent with motivational interviewing techniques. All pilot study participants were assigned to receive the intervention. Outcomes of interest were family conflict, caregiver stress, caregiver self-efficacy and expressed emotion (EE). Participants were assessed three times: prior to the intervention, after the intervention and 12 weeks later. RESULTS: A total of 62 participants enrolled in the study, of whom 49 completed the intervention. Large, significant improvements were observed over time in all four domains of interest. Qualitative feedback from parents was very positive and added context to quantitative observations. CONCLUSIONS: The School of Hard Talks was a feasible and effective intervention targeting both caregiver wellbeing as well as important mechanisms of risk for youth psychopathology, namely family conflict and EE. Further research involving a larger sample and a control condition are needed to confirm these findings.

Effects of the serotonin 5-HT1B receptor agonist CP 94253 on the locomotor activity and body temperature of preweanling and adult male and female rats.

Serotonin 5-HT1A receptor agonists increase locomotor activity of both preweanling and adult rodents. The part played by the 5-HT1B receptor in locomotion is less certain, with preliminary evidence suggesting that the actions of 5-HT1B receptor agonists are not uniform across ontogeny. To more fully examine the role of 5-HT1B receptors, locomotor activity and axillary temperatures of preweanling and adult male and female rats was assessed. In the first experiment, adult (PD 70) and preweanling (PD 10 and PD 15) male and female rats were injected with the 5-HT1B agonist CP 94253 (2.5-10 mg/kg) immediately before locomotor activity testing and 60 min before axillary temperatures were recorded. In the second experiment, specificity of drug action was determined in PD 10 rats by administering saline, WAY 100635 (a 5-HT1A antagonist), or GR 127935 (a 5-HT1B antagonist) 30 min before CP 94253 (10 mg/kg) treatment. CP 94253 significantly increased the locomotor activity of preweanling rats on PD 10, an effect that was fully attenuated by GR 127935. Conversely, CP 94253 significantly decreased the locomotor activity of male and female adult rats, while CP 94253 did not affect the locomotor activity of PD 15 rats. Regardless of age, CP 94253 (2.5-10 mg/kg) significantly reduced the axillary temperatures of preweanling and adult rats. When considered together, these results show that 5-HT1B receptor stimulation activates motor circuits in PD 10 rats; whereas, 5-HT1B receptor agonism reduces the overall locomotor activity of adult rats, perhaps by blunting exploratory tendencies.

Effects of repeated treatment with the 5-HT1A and 5-HT1B agonists (R)-( +)-8-hydroxy-DPAT and CP-94253 on the locomotor activity and axillary temperatures of preweanling rats: evidence of tolerance and behavioral sensitization.

RATIONALE: Drugs that stimulate 5-HT1A/1B receptors produce both tolerance and behavioral sensitization in adult rats and mice, yet it is unknown whether the same types of plasticity are evident during earlier ontogenetic periods. OBJECTIVE: The purpose of this study was to determine whether repeated treatment with selective 5-HT1A and/or 5-HT1B agonists cause tolerance and/or sensitization in preweanling rats. METHODS: In Experiments 1 and 2, male and female preweanling rats were given a single pretreatment injection of saline, the 5-HT1A agonist (R)-( +)-8-hydroxy-DPAT (8-OH-DPAT), or the 5-HT1B agonist CP-94253 on PD 20. After 48 h, rats received a challenge injection of 8-OH-DPAT or CP-94253, respectively. In Experiment 3, rats were pretreated with saline or DPAT + CP on PD 20 and challenged with the same drug cocktail on PD 22. In Experiment 4, the tolerance- or sensitization-inducing properties of 8-OH-DPAT, CP-94253, or DPAT + CP were tested after a 4-day pretreatment regimen on PD 17-20. RESULTS: On the first pretreatment day, 8-OH-DPAT, CP-94253, and DPAT + CP increased locomotion and caused hypothermia. Repeated treatment with 8-OH-DPAT (2 or 8 mg/kg) or DPAT + CP caused locomotor sensitization in preweanling rats. In contrast, tolerance to the hypothermic effects of 8-OH-DPAT (8 mg/kg), CP-94253 (5-20 mg/kg), or DPAT + CP was evident after repeated drug treatment. CONCLUSIONS: During the preweanling period, a single injection of a selective 5-HT1A or 5-HT1B agonist is capable of producing drug-induced plasticity. A pretreatment administration of 8-OH-DPAT causes both tolerance (hypothermia) and behavioral sensitization (locomotor activity) in preweanling rats, whereas repeated CP-94253 treatment results in tolerance.

Changes in community providers' screening behaviours, referral practices, and clinical confidence following participation in an early psychosis educational campaign.

AIM: Successful delivery of care to individuals with early psychosis depends on the ability of community providers to identify and refer appropriate candidates for services. Although specialty centres commonly rely upon education and outreach campaigns to building bridges with community providers, few studies have examined the effectiveness of these campaigns or the mechanisms by which they may achieve their intended effects. METHODS: We surveyed community clinicians (N = 39) about their screening behaviours, referral practices, and confidence in managing early psychosis just before and 3-6 months after attending an educational event designed to promote recognition and quality treatment of early psychosis. RESULTS: Three to six months following attendance, providers reported screening a greater proportion of clients for early psychosis, referring a greater number of clients to specialty services, and feeling more confident in their ability to respond to clients with early psychosis. Increases in confidence following attendance were associated with corresponding increases in screening behaviour. CONCLUSIONS: The results suggest that outreach campaigns designed to enhance community providers' knowledge about early psychosis assessment and resources may be effective in promoting screening, referrals, and confidence in managing psychosis. Gains in provider confidence may contribute to increases in screening. Given the lack of control group and relatively short follow-up period, more research is needed to determine the effects of early psychosis educational events and the mechanisms by which they may promote successful treatment delivery for young people in need.

Reciprocal cross-sensitization between cocaine and RU 24969 in male and female preweanling rats.

Neuronal adaptations involving dopaminergic, glutamatergic, and serotonergic neurotransmitter systems are responsible for behavioral sensitization. Because of common underlying mechanisms, cross-sensitization between compounds of different drug classes can be observed. The purpose of the present study was to determine whether a one- or four-day pretreatment regimen of RU 24969 (a 5-HT1A/1B receptor agonist) would reciprocally cross-sensitize with cocaine or methamphetamine in male and female preweanling rats. Rats were pretreated with RU 24969 (0 or 5 mg/kg) for 4 days (PD 17-20) and then challenged with cocaine (10 or 20 mg/kg) or methamphetamine (1 or 2 mg/kg) on PD 22. Reciprocal cross-sensitization was also assessed (i.e., rats were pretreated with psychostimulants and tested with RU 24969). In a follow-up experiment, the ability of RU 24969 and cocaine to reciprocally cross-sensitize was assessed using a one-day pretreatment regimen. Reciprocal cross-sensitization between cocaine and RU 24969 was evident in preweanling rats, whereas methamphetamine and RU 24969 did not cross-sensitize. When a one-trial pretreatment regimen was used, cross-sensitization was only detected when rats were pretreated with RU 24969 and tested with cocaine, but not the reverse. In sum, the present results show that the nonselective 5-HT1A/1B receptor agonist RU 24969 cross-sensitizes with cocaine, but not methamphetamine, in preweanling rats. This dichotomy may be a function of cocaine having a greater affinity for the serotonin transporter than methamphetamine.

Biotin immunoassay interference: A UK-based prevalence study.

BACKGROUND: Biotin interference in biotin-streptavidin-based immunoassays is increasingly reported due to individuals taking biotin-containing supplements and patients prescribed biotin. The reported prevalence of serum biotin above the lowest threshold (≥10 µg/L) for interference in Roche Diagnostics immunoassay tests is 0.8% in Australia and 7.4% in the USA. There are, however, no such data in UK populations. In a service evaluation, we therefore studied the prevalence of biotin interference in routine serum samples received in our laboratory. METHODS: Biotin was measured in 524 anonymized surplus serum samples in which at least one immunoassay test had been requested. RESULTS: The median (95% confidence intervals) for serum biotin was 0.27 µg/L (0.07-0.93 µg/L). Serum biotin was <10 µg/L in all samples, <5 µg/L in 522 (99.6%) and <1 µg/L in 513 (98.1%) samples. In four samples, serum biotin was ≥2.5 µg/L (0.8%). CONCLUSIONS: These data indicate that the probability of biotin immunoassay interference in our patient population is extremely low, with the exception of assays reporting the lowest interference thresholds (e.g. Ortho Troponin I assay [threshold ≥2.5 µg/L]).

Effects of repeated RU 24969 treatment on the locomotor activity, motoric capacity, and axillary temperatures of male and female preweanling rats.

Serotonin (5-HT) 1A and 1B receptors have been implicated in behavioral sensitization, but adult rats appear to develop tolerance to RU 24969 (a 5-HT1A/1B receptor agonist) rather than a sensitized response. The purpose of the present study was to determine whether a one- or four-day pretreatment regimen of RU 24969 would cause sensitization or tolerance in male and female preweanling rats. Depending on experiment, rats were pretreated with RU 24969 (0, 2.5, or 5 mg/kg) for 1 or 4 days (PD 17-20), while testing with lower or higher doses of RU 24969 occurred on PD 22. Locomotor activity, motoric capacity, and axillary temperatures were recorded. The role of Pavlovian contextual conditioning was assessed by administering RU 24969 to rats in either the home cage or a novel environment. On the first pretreatment day, RU 24969 caused both an increase in forward locomotion and motoric impairment, along with a substantial decrease in axillary temperatures. Repeated treatment with the same dose of RU 24969 caused all three dependent measures to show a tolerance response. When given a higher dose of RU 24969 on the test day, the responses lost due to repeated drug treatment were fully (locomotor activity) or partially (motoric capacity and axillary temperatures) reinstated. There was no evidence of behavioral tolerance. Results are consistent with the hypothesis that a subsensitivity of 5-HT1A/1B receptors is at least partially responsible for the tolerance caused by RU 24969, but dispositional tolerance cannot be excluded as a contributing factor.

Implementation case study: Multifamily group intervention in first-episode psychosis programs.

AIM: Family interventions are a core component of first-episode psychosis (FEP) treatment; however, low implementation rates are consistently reported. As such, work is needed to understand the factors impacting real-world treatment delivery. The present paper describes the implementation of the McFarlane-model multifamily psychoeducational groups (MFG) in established FEP early intervention programs within a single state. The aims were to examine (a) training participation and implementation of MFG, (b) barriers and facilitators to implementation, and (c) modifications made to MFG. METHODS: Practitioners from six established FEP early intervention programs received in-person training and ongoing consultation in MFG. Training participation data were obtained via attendance and implementation outcomes were obtained from practitioner reports. Fifteen months following the initial training, practitioners reported on clinic-specific barriers, facilitators, and modifications across four categories (context, intervention, practitioner, and recipient). RESULTS: Twenty-three practitioners across six clinics received in-person training and were offered ongoing consultation to support implementation. Difficulties in starting MFG were salient as the earliest group was run 7 months after the initial training, thereby resulting in low overall frequency of groups. A number of barriers spanning context, intervention, practitioner, and recipient domains were noted, the majority of which were clinic-specific. Despite challenges, practitioners identified several facilitators and made modifications to the intervention and its delivery in service of implementation. CONCLUSIONS: Results from this implementation case study highlighted the challenges of delivering MFG in real-world FEP early intervention programs. Further, this paper emphasizes the value in identifying and addressing clinic-specific factors when implementing MFG.

Importance of dopaminergic neurotransmission for the RU 24969-induced locomotor activity of male and female rats during the preweanling period.

There is disagreement about whether the locomotor activity produced by serotonin (5-HT) 1A/1B receptor agonists is ultimately mediated through a dopaminergic mechanism or is independent of dopamine (DA) system functioning. Using a developing rat model, we examined whether DA neurotransmission is necessary for the locomotor activity produced by 5-HT1A/1B receptor stimulation. Depending on experiment, male and female preweanling rats were pretreated with vehicle, the monoamine-depleting agent reserpine, the 5-HT synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), the DA synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), or the D1 and D2 receptor antagonists SCH 23390 and raclopride, respectively. After completing the pretreatment regimen, the behavioral effects of saline and the 5-HT1A/1B receptor agonist RU 24969 were assessed during a 2-h test session. Locomotor activity in the center and margin of the testing chamber was recorded. RU 24969's locomotor activating effects were sensitive to blockade of the D2 receptor, but not the D1 receptor. The DA synthesis inhibitor (AMPT) significantly attenuated the RU 24969-induced locomotor activity of preweanling rats, as did the 5-HT synthesis inhibitor PCPA. The latter result suggests that presynaptic 5-HT1A/1B receptors may have a role in mediating RU 24969-induced locomotion during the preweanling period. DA neurotransmission, especially involving D2 receptors, is necessary for the 5-HT1A/1B-mediated locomotor activity of preweanling rats. The actions of PCPA, reserpine, and SCH 23390 differ substantially between preweanling and adult rats, suggesting that the neural mechanisms underlying these DA/5-HT interactions vary across ontogeny.

MK801-induced locomotor activity in preweanling and adolescent male and female rats: role of the dopamine and serotonin systems.

RATIONALE: MK801, like other NMDA receptor open-channel blockers (e.g., ketamine and phencyclidine), increases the locomotor activity of rats and mice. Whether this behavioral effect ultimately relies on monoamine neurotransmission is of dispute. OBJECTIVE: The purpose of this study was to determine whether these psychopharmacological effects and underlying neural mechanisms vary according to sex and age. METHODS: Across four experiments, male and female preweanling and adolescent rats were pretreated with vehicle, the monoamine-depleting agent reserpine (1 or 5 mg/kg), the dopamine (DA) synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), or both AMPT and PCPA. The locomotor activity of preweanling and adolescent rats was then measured after saline or MK801 (0.3 mg/kg) treatment. RESULTS: As expected, MK801 increased the locomotor activity of all age groups and both sexes, but the stimulatory effects were significantly less pronounced in male adolescent rats. Preweanling rats and adolescent female rats were more sensitive to the effects of DA and 5-HT synthesis inhibitors, as AMPT and PCPA caused only small reductions in the MK801-induced locomotor activity of male adolescent rats. Co-administration of AMPT+PCPA or high-dose reserpine (5 mg/kg) treatment substantially reduced MK801-induced locomotor activity in both age groups and across both sexes. CONCLUSIONS: These results, when combined with other recent studies, show that NMDA receptor open-channel blockers cause pronounced age-dependent behavioral effects that can vary according to sex. The neural changes underlying these sex and age differences appear to involve monoamine neurotransmission.

Serotonin 5-HT1A and 5-HT1B receptors co-mediate the RU 24969-induced locomotor activity of male and female preweanling rats.

The serotonin (5-HT) 1A/1B agonist RU 24969 robustly increases the locomotor activity of adult male rats and mice; however, studies using selective antagonists alternately report that 5-HT1A, 5-HT1B, or both receptor types mediate RU 24969's locomotor activating effects. The purpose of the present study was to extend these past findings by administering a selective 5-HT1 agonist and/or antagonists to male and female preweanling rats. This age group was tested because younger rats often exhibit psychopharmacological responses that are quantitatively or qualitatively different from adult rats. In a series of experiments, male and female preweanling rats were pretreated with vehicle, the 5-HT1A antagonist WAY 100635 (0.5, 1, 5, or 10 mg/kg), or the 5-HT1B antagonists NAS-181 (5 or 10 mg/kg) or SB 216641 (5 or 10 mg/kg) 30 min before assessment of locomotor activity. Rats were injected with saline or RU 24969 immediately prior to testing. Results showed that RU 24969 (0.625, 1.25, 2.5, or 5 mg/kg) significantly increased the locomotor activity of both male and female preweanling rats (no sex differences were apparent). Antagonism of either the 5-HT1A or the 5-HT1B receptor was sufficient to significantly reduce the locomotor activity of RU 24969-treated preweanling rats. Unexpectedly, NAS-181 did not act as a silent receptor antagonist, as both doses of NAS-181 significantly increased the locomotor activity of saline-treated preweanling rats. In sum, the present results show that both the 5-HT1A and 5-HT1B receptor systems mediate locomotion during the late preweanling period, and this mediation does not vary according to sex.

Effects of monoamine depletion on the ketamine-induced locomotor activity of preweanling, adolescent, and adult rats: Sex and age differences.

Ketamine significantly increases the locomotor activity of rodents, however this effect varies according to the sex and age of the animal being tested. To determine the role monoamine systems play in ketamine's locomotor activating effects: (a) male and female preweanling, adolescent, and adult rats were pretreated with vehicle or the monoamine depleting agent reserpine (1 or 5 mg/kg), and (b) the behavioral actions of ketamine (20 or 40 mg/kg) were then compared to d-amphetamine (2 mg/kg) and cocaine (10 or 15 mg/kg). The ability of reserpine to deplete dorsal striatal dopamine (DA) and serotonin (5-HT) in male and female rats was determined using HPLC. Ketamine caused substantial increases in the locomotion of preweanling rats and older female rats (adolescents and adults), but had only small stimulatory effects on adolescent and adult male rats. When compared to cocaine and d-amphetamine, ketamine was especially sensitive to the locomotor-inhibiting effects of monoamine depletion. Ketamine-induced locomotion is at least partially mediated by monoamine systems, since depleting DA and 5-HT levels by 87-96% significantly attenuated the locomotor activating effects of ketamine in male and female rats from all three age groups. When administered to reserpine-pretreated rats, ketamine produced a different pattern of behavioral effects than either psychostimulant, suggesting that ketamine does not stimulate locomotor activity via actions at the presynaptic terminal. Instead, our results are consistent with the hypothesis that ketamine increases locomotor activity through a down-stream mechanism, possibly involving ascending DA and/or 5-HT projection neurons.

Effects of dopamine and serotonin synthesis inhibitors on the ketamine-, d-amphetamine-, and cocaine-induced locomotor activity of preweanling and adolescent rats: sex differences.

The pattern of ketamine-induced locomotor activity varies substantially across ontogeny and according to sex. Although ketamine is classified as an NMDA channel blocker, it appears to stimulate the locomotor activity of both male and female rats via a monoaminergic mechanism. To more precisely determine the neural mechanisms underlying ketamine's actions, male and female preweanling and adolescent rats were pretreated with vehicle, the dopamine (DA) synthesis inhibitor ∝-methyl-DL-p-tyrosine (AMPT), or the serotonin (5-HT) synthesis inhibitor 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA). After completion of the pretreatment regimen, the locomotor activating effects of saline, ketamine, d-amphetamine, and cocaine were assessed during a 2 h test session. In addition, the ability of AMPT and PCPA to reduce dorsal striatal DA and 5-HT content was measured in male and female preweanling, adolescent, and adult rats. Results showed that AMPT and PCPA reduced, but did not fully attenuate, the ketamine-induced locomotor activity of preweanling rats and female adolescent rats. Ketamine (20 and 40 mg/kg) caused a minimal amount of locomotor activity in male adolescent rats, and this effect was not significantly modified by AMPT or PCPA pretreatment. When compared to ketamine, d-amphetamine and cocaine produced different patterns of locomotor activity across ontogeny; moreover, AMPT and PCPA pretreatment affected psychostimulant- and ketamine-induced locomotion differently. When these results are considered together, it appears that both dopaminergic and serotonergic mechanisms mediate the ketamine-induced locomotor activity of preweanling and female adolescent rats. The dichotomous actions of ketamine relative to the psychostimulants in vehicle-, AMPT-, and PCPA-treated rats, suggests that ketamine modulates DA and 5-HT neurotransmission through an indirect mechanism.

A Content Analysis of Personal Safety Apps: Are They Keeping Us Safe or Making Us More Vulnerable?

Despite personal safety apps claiming to increase safety, few studies have examined the usefulness of such apps in reducing public stranger violence. A content analysis of personal safety apps available in the iTunes store and Google Play identified location-based services, personal alarms, crowd-sourced hot spot data, and geofencing as the most common features. The majority of apps offered interventions either at the time of the event or post-event, suggesting that they may reduce a user's fear of crime but have limited usefulness in reducing vulnerability to victimization. Implications for users, app designers, and key stakeholders are discussed.

Emulation of Community Water Fluoridation Coverage Across US Counties.

INTRODUCTION: Expansion of community water fluoridation has stalled in the United States, leaving 115 million Americans without fluoridated drinking water. OBJECTIVE: This study used spatial regression methods to assess contributions of supply-side factors (neighboring counties' fluoridation coverage) and demand-side factors (health literacy, education, and population density of the local county) in predicting the extent of fluoridation in US counties. METHODS: For this cross-sectional ecological analysis, data from the 2014 Water Fluoridation Reporting System for all 3,135 US counties were merged with sociodemographic data from the 2014 American Community Survey and county-level estimates of health literacy based on the National Association of Adult Literacy Survey. We employed multilevel geographically weighted autoregressive models to predict fluoridation coverage of each county as a function of fluoridation coverage of neighboring counties and local-county covariates: either health literacy or sociodemographic characteristics. Akaike's Information Criterion was used to distinguish the better model in terms of explanatory power and parsimony. RESULTS: In the best-fit model, an increase from the first to third quartile of neighboring counties' fluoridation coverage was associated with an increase of 27.76 percentage points (95% confidence limits [CI] = 27.71, 27.81) in a local county's fluoridation coverage, while an increase from the first to third quartile of local county's health literacy was associated with an increase of 2.8 percentage points (95% CL = 2.68, 2.89). The results are consistent with a process of emulation, in which counties implement fluoridation based upon their population's health literacy and the extent of fluoridation practiced in neighboring counties. CONCLUSION: These results suggest that demand for community water fluoridation will increase as health literacy increases within a county. Furthermore, when considering expansion of fluoridation, non-fluoridated communities can benefit from precedents from nearby communities that are fluoridated. KNOWLEDGE TRANSFER STATEMENT: Expanded coverage of community water fluoridation has stalled in the United States. The economic theory of diffusion describes how, over time and space, policy enacted in one community can influence public opinion in a neighboring community. This study applies geospatial analysis of county-level data and the theory of policy diffusion to demonstrate that fluoridated counties can promote the implementation of community water fluoridation in their neighboring, non-fluoridated communities.

Age-dependent effects of dopamine receptor inactivation on cocaine-induced behaviors in male rats: Evidence of dorsal striatal D2 receptor supersensitivity.

N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which irreversibly inactivates dopamine (DA) receptors, causes pronounced age-dependent behavioral effects in rats. For example, EEDQ either augments or does not affect the DA agonist-induced locomotor activity of preweanling rats while attenuating the locomotion of adolescent and adult rats. The twofold purpose of this study was to determine whether EEDQ would: (a) potentiate or attenuate the cocaine-induced locomotor activity of preweanling, adolescent, and adult rats; and (b) alter the sensitivity of surviving D2 receptors. Rats were treated with vehicle or EEDQ (2.5 or 7.5 mg/kg) on postnatal day (PD) 17, PD 39, and PD 84. In the behavioral experiments, saline- or cocaine-induced locomotion was assessed 24 hr later. In the biochemical experiments, dorsal striatal samples were taken 24 hr after vehicle or EEDQ treatment and later assayed for NPA-stimulated GTPγS receptor binding, G protein-coupled receptor kinase 6 (GRK6), and ß-arrestin-2 (ARRB2). GTPγS binding is a direct measure of ligand-induced G protein activation, while GRK6 and ARRB2 modulate the internalization and desensitization of D2 receptors. Results showed that EEDQ potentiated the locomotor activity of preweanling rats, while attenuating the locomotion of older rats. NPA-stimulated GTPγS binding was elevated in EEDQ-treated preweanling rats, relative to adults, indicating enhanced functional coupling between the G protein and receptor. EEDQ also reduced ARRB2 levels in all age groups, which is indicative of increased D2 receptor sensitivity. In sum, the present results support the hypothesis that D2 receptor supersensitivity is a critical factor mediating the locomotor potentiating effects of EEDQ in cocaine-treated preweanling rats.

Development and validation of a gene expression test to identify hard-to-heal chronic venous leg ulcers.

BACKGROUND: Chronic venous leg ulcers pose a significant burden to healthcare systems, and predicting wound healing is challenging. The aim of this study was to develop a genetic test to evaluate the propensity of a chronic ulcer to heal. METHODS: Sequential refinement and testing of a gene expression signature was conducted using three distinct cohorts of human wound tissue. The expression of candidate genes was screened using a cohort of acute and chronic wound tissue and normal skin with quantitative transcript analysis. Genes showing significant expression differences were combined and examined, using receiver operating characteristic (ROC) curve analysis, in a controlled prospective study of patients with venous leg ulcers. A refined gene signature was evaluated using a prospective, blinded study of consecutive patients with venous ulcers. RESULTS: The initial gene signature, comprising 25 genes, could identify the outcome (healing versus non-healing) of chronic venous leg ulcers (area under the curve (AUC) 0·84, 95 per cent c.i. 0·73 to 0·94). Subsequent refinement resulted in a final 14-gene signature (WD14), which performed equally well (AUC 0·88, 0·80 to 0·97). When examined in a prospective blinded study, the WD14 signature could also identify wounds likely to demonstrate signs of healing (AUC 0·73, 0·62 to 0·84). CONCLUSION: A gene signature can identify people with chronic venous leg ulcers that are unlikely to heal.

Sex-dependent changes in ketamine-induced locomotor activity and ketamine pharmacokinetics in preweanling, adolescent, and adult rats.

Although ketamine has long been known to increase locomotor activity, only recently was it realized that this behavioral effect varies according to both sex and age. The purpose of the present study was threefold: first, to measure the locomotor activating effects of ketamine in male and female rats across early ontogeny and into adulthood; second, to assess ketamine and norketamine pharmacokinetics in the dorsal striatum and hippocampus of the same age groups; and, third, to use curvilinear regression to determine the relationship between locomotor activity and dorsal striatal concentrations of ketamine and norketamine. A high dose of ketamine (80 mg/kg, i.p.) was administered in order to examine the complete cycle of locomotor responsiveness across a 280-min testing session. In separate groups of rats, the dorsal striata and hippocampi were removed at 10 time points (0-360 min) after ketamine administration and samples were assayed for ketamine, norketamine, and dopamine using HPLC. In female rats, ketamine produced high levels of locomotor activity that varied only slightly among age groups. Male preweanling rats responded like females, but adolescent and adult male rats exhibited lesser amounts of ketamine-induced locomotor activity. Ketamine and norketamine pharmacokinetics, especially peak values and area under the curve, generally mirrored age- and sex-dependent differences in locomotor activity. Among male rats and younger female rats, dorsal striatal ketamine and norketamine levels accounted for a large proportion of the variance in locomotor activity. In adult female rats, however, an additional factor, perhaps involving other ketamine and norketamine metabolites, was influencing locomotor activity.

Stomaching the pain of spinal fusion: gastrointestinal discomfort is as severe as back pain in 50% of adolescent idiopathic scoliosis patients following posterior spinal fusion.

PURPOSE: There have been no prospective studies investigating gastrointestinal (GI) symptoms of patients with adolescent idiopathic scoliosis (AIS) following posterior spinal fusion (PSF). The purpose of this study was to evaluate the incidence and severity of self-reported GI symptoms following PSF. METHODS: In all, 40 AIS patients undergoing PSF were prospectively enrolled between March 2015 and October 2016. Patients completed a survey on each postoperative, inpatient day regarding nausea, emesis, constipation, abdominal pain and back pain, rating their pain on a scale of 1 to 10. RESULTS: Abdominal pain (50%), emesis (63%), nausea (65%) and constipation (68%) were experienced by the majority of patients. Of those reporting back pain, the mean pain level during the postoperative period was 5.1 (0.2 to 9.6). Of those reporting abdominal pain, the mean pain level during the postoperative period was 5.5 (1.4 to 8.6), which was not different than the severity of their back-pain levels (mean = 6.0, p = 0.31). CONCLUSIONS: Gastrointestinal issues in AIS patients following PSF are common. Abdominal pain was as severe as the back pain for half of the patients. LEVEL OF EVIDENCE: II.