Community-Identified Implementation Strategies for Promoting the Adoption of HIV Self-Testing in a Southern California American Indian community: A Rapid Qualitative Analysis.

HIV incidence increased by 18% between 2015 and 2019 among American Indians (AIs) despite declining rates in other racial/ethnic groups. Culturally-appropriate implementation of prevention programs is needed to address the intersectional conditions contributing to HIV vulnerabilities experienced by AIs. The objectives of this study were to understand factors influencing HIV testing decisions and identify implementation strategies to promote the acceptability of HIV self-testing (HIVST) in a southern California AI community. A total of 15 semi-structured interviews were completed with adult community members of a southern California AI reservation. Analysis used a rapid analytic approach that was guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework and expert recommendations for implementing change (ERIC) compilation. Two team members applied a standardized summary template to elucidate implementation determinants and implementation strategies for adopting HIVST. Barriers to HIV testing identified by community members included HIV-related stigma and privacy concerns within their community. Community members expressed positive perceptions of the acceptability of HIVST, with many identifying ease of use and privacy as appealing attributes. Several implementation strategies were suggested for facilitating the adoption of HIVST, including increasing access to tests by mailing kits to community members and increasing demand for kits through media campaigns (e.g., local flyers, social media posts, and booths at tribal events). Community members also recommended discreet packaging of kits and cultural adaptation of accompanying materials (e.g., educational videos featuring community members). The qualitative input from AI community members facilitated identification of implementation strategies that may promote the acceptability and culturally-appropriateness of HIVST.

RESUMEN: Entre 2015 y 2019, la incidencia del VIH entre los indígenas norteamericanos (INs) aumentó un 18%, a pesar de que en otros grupos étnicos y raciales se observaron reducciones. La implementación culturalmente apropiada de programas preventivos es fundamental para abordar las circunstancias interseccionales que contribuyen a la vulnerabilidad al VIH entre INs. Los objetivos de este estudio fueron comprender los factores que influyen en la decisión de hacerse la prueba del VIH e identificar estrategias para fomentar la aceptabilidad de las auto pruebas, en una comunidad de INs en el Sur de California. Se realizaron 15 entrevistas semiestructuradas con los miembros adultos de una reserva situada en el Sur de California. El análisis se realizó utilizando un método cualitativo rápido, basado en el marco Exploration, Preparation, Implementation and Sustainment (EPIS) (español: Exploración, Preparación, Implementación y Sostenimiento) así como una recopilación de sugerencias de expertas en implementación de intervenciones, conocida como ERIC. Dos miembros del equipo de investigación utilizaron una plantilla estandarizada resumida para investigar factores determinantes y estrategias para la adopción de las auto pruebas del VIH. Los miembros de la reserva de INs identificaron el estigma asociado al VIH, así como preocupación por la privacidad entre la comunidad, como barreras para realizarse las pruebas del VIH. Los miembros reaccionaron positivamente a la aceptabilidad de las auto pruebas del VIH, destacándola facilidad del uso y la privacidad asociadas con estas pruebas. También, se sugirieron varias estrategias para facilitar la adopción de las auto pruebas, incluyendo el envío de pruebas a miembros de la comunidad y el aumento de la demanda de pruebas a través de difusión (e.g., folletos, publicaciones en las redes sociales, y puestos en eventos tribales). Los miembros también recomendaron que los empaques de las auto pruebas sean discretos, y que contengan materiales educativos culturalmente apropiados. Las contribuciones cualitativas de la comunidad INs ayudaron identificar estrategias de implementación que pueden fomentar la aceptabilidad de las auto pruebas del VIH en una manera culturalmente apropiada.

Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression.

OBJECTIVES: The aim of this study was to repurpose a drug for the treatment of bipolar depression. METHODS: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). RESULTS: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test. CONCLUSION: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.

Community-Based Public Health Vaccination Campaign (VaccinateLA) in Los Angeles' Black and Latino Communities: Protocol for a Participatory Study.

BACKGROUND: The COVID-19 pandemic has significantly affected Los Angeles County and disproportionately impacted Black and Latino populations who experienced disparities in rates of infection, hospitalizations, morbidity, and mortality. The University of Southern California (USC), USC Keck School of Medicine, Southern California Clinical and Translational Science Institute, USC Mann School of Pharmacy and Pharmaceutical Sciences, Annenberg School for Journalism and Communication, and Children's Hospital Los Angeles will launch a collaborative public health campaign called VaccinateLA. OBJECTIVE: VaccinateLA will implement a community-based, community-partnered public health campaign that (1) delivers culturally tailored information about COVID-19 and available vaccines; and (2) addresses misinformation and disinformation, which serves as a barrier to vaccine uptake. The campaign will be targeted to communities in Los Angeles with the highest rates of COVID-19 infection and the lowest vaccination rates. Using these criteria, the campaign will be targeted to neighborhoods located in 34 zip codes in the Eastside and South Los Angeles. The primary aim of VaccinateLA will be to design and deliver an evidence-based multimedia public health campaign tailored for Black and Latino populations. A secondary aim will be to train and deploy community vaccine navigators to deliver COVID-19 education, help individuals overcome barriers to getting vaccinated (eg, transportation and challenges registering), and assist with delivering vaccinations in our targeted communities. METHODS: We will use a community-based, participatory research approach to shape VaccinateLA's public health campaign to address community members' attitudes and concerns in developing campaign content. We will conduct focus groups, establish a community advisory board, and engage local leaders and stakeholders to develop and implement a broad array of educational, multimedia, and field-based activities. RESULTS: As of February 2023, target communities have been identified. The activities will be initiated and evaluated over the course of this year-long initiative, and dissemination will occur following the completion of the project. CONCLUSIONS: Engaging the community is vital to developing culturally tailored public health messages that will resonate with intended audiences. VaccinateLA will serve as a model for how an academic institution can quickly mobilize to address a pressing public health crisis, particularly in underrepresented and underresourced communities. Our work has important implications for future public health campaigns. By leveraging community partnerships and deploying community health workers or promotores into the community, we hope to demonstrate that urban universities can successfully partner with local communities to develop and deliver a range of culturally tailored educational, multimedia, and field-based activities, which in turn may change the course of an urgent public health crisis, such as the COVID-19 pandemic. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/40161.

The Effect of Chronic Alcohol on Cognitive Decline: Do Variations in Methodology Impact Study Outcome? An Overview of Research From the Past 5 Years.

Excessive alcohol use is often associated with accelerated cognitive decline, and extensive research using animal models of human alcohol consumption has been conducted into potential mechanisms for this relationship. Within this literature there is considerable variability in the types of models used. For example, alcohol administration style (voluntary/forced), length and schedule of exposure and abstinence period are often substantially different between studies. In this review, we evaluate recent research into alcohol-induced cognitive decline according to methodology of alcohol access, as well as cognitive behavioral task employed. Our aim was to query whether the nature and severity of deficits observed may be impacted by the schedule and type of alcohol administration. We furthermore examined whether there is any apparent relationship between the amount of alcohol consumed and the severity of the deficit, as well as the potential impact of abstinence length, and other factors such as age of administration, and sex of subject. Over the past five years, researchers have overwhelmingly used non-voluntary methods of intake, however deficits are still found where intake is voluntary. Magnitude of intake and type of task seem most closely related to the likelihood of producing a deficit, however even this did not follow a consistent pattern. We highlight the importance of using systematic and clear reporting styles to facilitate consistency across the literature in this regard. We hope that this analysis will provide important insights into how experimental protocols might influence findings, and how different patterns of consumption are more or less likely to produce an addiction-vulnerable cognitive phenotype in animal models.

Availability of drinking water in rural and remote communities in New South Wales, Australia.

Many rural communities in New South Wales (NSW), Australia, have poor-quality water supplies. The lack of a palatable alternative increases the risk of the high consumption of sugar-sweetened beverages, a significant contributor to adverse health outcomes. This disproportionately effects Aboriginal people living in these towns, who are also profoundly affected by the social determinants of health. Therefore, examining health inequalities linked to water access is important. This study investigated the availability of drinking water fountains in rural and remote communities in NSW. Telephone interviewer-assisted surveys were conducted with 32 representatives from local government councils or Local Aboriginal Land Councils in NSW from communities with a population of <5000 and an Aboriginal population of at least 3%. The results were analysed descriptively. Towns and communities with a higher population of Aboriginal people and lower median weekly income were less likely to have access to free refrigerated and filtered water within the community or at local schools compared with towns and communities with a lower Aboriginal population and higher median weekly income. The availability of free, clean and refrigerated water in rural and remote communities is critical to reducing the consumption of sugar-sweetened beverages and the promotion of water as the preferred drink.

Examining Sex Differences in Conditioned Place Preference or Aversion to Methamphetamine in Adolescent and Adult Mice.

Adolescence marks a particularly vulnerable period to developing substance use disorders. Human and rodent studies suggest that hypersensitivity to reward may contribute towards such vulnerability when adolescents are exposed to casual drug use. Methamphetamine is a popular illicit substance used by male and female youths. However, age- and sex-specific research in methamphetamine is scarce. The present study therefore aimed to examine potential sex differences in methamphetamine-conditioned place preference in adolescent and adult mice. Mice (n = 16-24/group) were conditioned to methamphetamine (0.1 mg/kg). We observed that regardless of age, females were more hyperactive compared to males. Individually normalized score against baseline preference indicated that on average, adolescents formed stronger preference compared to adults in both sexes. This suggests that adolescents are more sensitive to the rewarding effects of methamphetamine compared to adults. Surprisingly, individual data showed that some mice formed a conditioned place aversion instead of preference, with females less likely to form an aversion compared to males. These results suggest that adolescents may be hypersensitive to methamphetamine's rewarding effects. In addition, female resistance to the aversive effects of methamphetamine may relate to the sex-specific findings in humans, including quicker transition to regular methamphetamine use observed in females compared to males.

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19.

BACKGROUND: In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. METHODS: In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated. RESULTS: Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log10 copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log10 copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups. CONCLUSIONS: REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).

Hippocampal neurogenesis mediates sex-specific effects of social isolation and exercise on fear extinction in adolescence.

Impaired extinction of conditioned fear is associated with anxiety disorders. Common lifestyle factors, like isolation stress and exercise, may alter the ability to extinguish fear. However, the effect of and interplay between these factors on adolescent fear extinction, and the relevant underlying neural mechanisms are unknown. Here we examined the effects of periadolescent social isolation and physical activity on adolescent fear extinction in rats and explored neurogenesis as a potential mechanism. Isolation stress impaired extinction recall in male adolescents, an effect prevented by exercise. Extinction recall in female adolescents was unaffected by isolation stress. However, exercise disrupted extinction recall in isolated females. Extinction recall in isolated females was positively correlated to the number of immature neurons in the ventral hippocampus, suggesting that exercise affected extinction recall via neurogenesis in females. Pharmacologically suppressing cellular proliferation in isolated adolescents using temozolomide blocked the effect of exercise on extinction recall in both sexes. Together, these findings highlight sex-specific outcomes of isolation stress and exercise on adolescent brain and behavior, and highlights neurogenesis as a potential mechanism underlying lifestyle effects on adolescent fear extinction.

N-acetylcysteine reduces addiction-like behaviour towards high-fat high-sugar food in diet-induced obese rats.

Compulsive forms of eating displayed by some obese individuals share similarities with compulsive drug-taking behaviour, a hallmark feature of substance use disorder. This raises the possibility that drug addiction treatments may show utility in the treatment of compulsive overeating. N-Acetylcysteine (NAC) is a cysteine pro-drug which has experienced some success in clinical trials, reducing cocaine, marijuana and cigarette use, as well as compulsive behaviours such as gambling and trichotillomania. We assessed the impact of NAC on addiction-like behaviour towards highly palatable food in a rat model of diet-induced obesity. Adult male Sprague-Dawley rats were placed on a high-fat high-sugar diet for 8 weeks and then assigned to diet-induced obesity-prone (DIO) or diet-induced obesity-resistant (DR) groups based on weight gain. DIO and DR rats were subjected to an operant conditioning paradigm whereby rats could lever press for high-fat high-sugar food pellets. This alternated with periods of signalled reward unavailability. Before treatment DIO rats ate more in their home cage, earned more food pellets in operant sessions, and responded more during periods that signalled reward unavailability (suggestive of compulsive-like food seeking) compared with DR rats. This persistent responding in the absence of reward displayed by DIO rats was ameliorated by daily injections of NAC (100 mg/kg, i.p.) for 14 days. By the end of the treatment period, lever-pressing by NAC-treated DIO rats resembled that of DR rats. These findings suggest that NAC reduces addiction-like behaviour towards food in rats and supports the potential use of this compound in compulsive overeating.

New approved and emerging pharmacological approaches to alcohol use disorder: a review of clinical studies.

introduction: The number of medications approved for AUD is small and they generally have limited efficacy. We need new pharmacotherapies for the management of AUD.Areas covered: In this review, the authors aim to synthesise literature for new approved and emerging pharmacotherapies for AUD. Recently approved medications include nalmefene, which was approved in Europe and Australia for the purposes of controlled drinking. Baclofen has also been approved in France but not in other countries. Off label medications including topiramate and gabapentin have received significant attention with multiple RCTs and meta-analyses and have widespread use in several countries including the USA. Several novel medications have emerged over the last decade but further work is required to determine their efficacy and safety for the widespread management of AUD.Expert opinion: Despite significant advances in our understanding of the neurobiological basis of factors that contribute to the development and maintenance of AUD, there have been few new AUD medications approved for almost 20 years. There are many challenges to the development and introduction of new pharmacotherapies for AUD. Strategies for improving the translational pipeline include drug repurposing and utilisation of human acute laboratory models.

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.

BACKGROUND: Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. METHODS: In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients. RESULTS: Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log10 copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log10 copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group. CONCLUSIONS: In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.).

Sex differences in the neurochemistry of frontal cortex: Impact of early life stress.

Traumatic events during early life have been linked with later life psychopathology. To understand this risk factor, researchers have studied the effects of prenatal and postnatal early life stress on neurochemical changes. Here we review the rodent literature on sex differences and sex-specific impact of early life stress on frontal cortex neurochemistry. This region is implicated in regulating motivation and emotion, which are often disrupted in psychological disorders. The prefrontal cortex (PFC) in particular is one of the last brain regions to develop, and there are sex differences in the rate of this development. To draw direct comparisons between sexes, our review of the literature was restricted to studies where the effects of prenatal or postnatal stress had been described in male and female littermates. This literature included research describing glutamate, γ-amino butyric acid (GABA), corticosteroids, monoamines, and cannabinoids. We found that sex-dependent effects of stress are mediated by the age at which stress is experienced, age at test, and type of stress endured. More research is required, particularly into the effects of adolescent stress on male and female littermates. We hope that a greater understanding of sex-specific susceptibilities in response to stress across development will help to uncover risk factors for psychological disorders in vulnerable populations.

Assessment of conditioned fear extinction in male and female adolescent rats.

Pavlovian fear conditioning and extinction have been widely studied across many species to understand emotional learning and memory. Importantly, it is becoming clear that these processes are affected by sex and age. In adult rodents and humans, sex differences are evident in extinction, with estradiol playing a significant role. In adolescence, an extinction deficit has been reported in rodents and humans. However, the influence of sex on extinction during adolescence is unknown. This is surprising, since adolescence coincides with the onset of hormone cycling, and therefore it might be expected that hormones fluctuations exert a more profound effect at this time. Therefore, we examined Pavlovian fear conditioning and extinction in adolescent male and female rats. In experiment 1, 35-day-old male and female rats were exposed to 6 pairings of a conditioned stimulus (CS, a tone) with an aversive unconditioned stimulus (US, a footshock). The next day they were extinguished in a contextually distinct chamber, via 60 presentations of the CS without the US. Extinction recall was tested 24 hours later in the extinction context. Estrous phase was monitored by cytology on vaginal smears taken 1 hour after each behavioral session. In experiment 2, male and female rats were given sham surgery or gonadectomy at 21 days of age. They were then trained and tested as for experiment 1. We observed that females in proestrus or met/diestrus during extinction showed delayed extinction and impaired extinction recall the next day compared to males. Ovariectomy enhanced extinction for female rats, but orchidectomy delayed extinction for males. Plasma analyses showed that met/di/proestrus phases were associated with high estradiol levels. These findings suggest that high plasma estradiol levels impair extinction for adolescent females. These results contradict what is reported in adult animals, suggesting that hormonal influences on extinction are dependent on age. Given that impaired extinction is widely used as a model to understand resistance to exposure-based therapies, our findings have important implications for understanding mental health treatments in adolescents.

Dissociated roles of dorsal and ventral hippocampus in recall and extinction of conditioned fear in male and female juvenile rats.

Reduction of conditioned fear expression by extinction underlies cue exposure therapies that treat anxiety disorders. Extinction is context-specific. Renewal, for example, is the relapse of extinguished fear when subjects are tested in a different context to extinction. This context-specificity is developmentally regulated and sex-dependent, with renewal being observed in postnatal day (P) 18 female, but not in male, rats. Given the hippocampus (HPC) is critical for context-specific extinction in adult rodents, we investigated dorsal or ventral hippocampus (dHPC or vHPC) involvement in context-specific extinction in P18 male and female rats. We microinfused muscimol (GABAA agonist) to inactivate either structure before extinction, then tested rats for renewal the next day. Regardless of sex, dHPC inactivation accelerated extinction acquisition, while vHPC inactivation reduced fear expression during extinction and impaired extinction recall. Consistent with previous findings, renewal was observed in females but not in males. Surprisingly, inactivation of dHPC or vHPC had no effects on renewal in either sex, indicating that the hippocampus does not play a critical role in context-dependent extinction learning in juvenile rats. These findings are the first to demonstrate dissociated roles of dHPC and vHPC in conditioned fear expression and extinction in juvenile rats. In addition, context-specific extinction shown by juvenile females, but not males, likely is not due to potential sex differences in hippocampus involvement in extinction of conditioned fear in developing rats.

Chronic voluntary alcohol consumption causes persistent cognitive deficits and cortical cell loss in a rodent model.

Chronic alcohol use is associated with cognitive decline that impedes behavioral change during rehabilitation. Despite this, addiction therapy does not address cognitive deficits, and there is poor understanding regarding the mechanisms that underlie this decline. We established a rodent model of chronic voluntary alcohol use to measure ensuing cognitive effects and underlying pathology. Rats had intermittent access to alcohol or an isocaloric solution in their home cage under voluntary 2-bottle choice conditions. In Experiments 1 and 2 cognition was assessed using operant touchscreen chambers. We examined performance in a visual discrimination and reversal task (Experiment 1), and a 5-choice serial reaction time task (Experiment 2). For Experiment 3, rats were perfused immediately after cessation of alcohol access period, and volume, cell density and microglial populations were assessed in the prefrontal cortex and striatum. Volume was assessed using the Cavalieri probe, while cell and microglial counts were estimated using unbiased stereology with an optical fractionator. Alcohol-exposed and control rats showed comparable acquisition of pairwise discrimination; however, performance was impaired when contingencies were reversed indicating reduced behavioral flexibility. When tested in a 5-choice serial reaction time task alcohol-exposed rats showed increased compulsivity and increased attentional bias towards a reward associated cue. Consistent with these changes, we observed decreased cell density in the prefrontal cortex. These findings confirm a detrimental effect of chronic alcohol and establish a model of alcohol-induced cognitive decline following long-term voluntary intake that may be used for future intervention studies.

Effects of Methamphetamine Exposure on Fear Learning and Memory in Adult and Adolescent Rats.

Methamphetamine (meth) use is often comorbid with anxiety disorders, with both conditions predominant during adolescence. Conditioned fear extinction is the most widely used model to study the fear learning and regulation that are relevant for anxiety disorders. The present study investigates how meth binge injections or meth self-administration affect subsequent fear conditioning, extinction and retrieval in adult and adolescent rats. In experiment 1, postnatal day 35 (P35-adolescent) and P70 (adult) rats were intraperitoneally injected with increasing doses of meth across 9 days. At P50 or P85, they underwent fear conditioning followed by extinction and test. In experiments 2a-c, P35 or P70 rats self-administered meth for 11 days then received fear conditioning at P50 or P85, followed by extinction and test. We observed that meth binge exposure caused a significant disruption of extinction retrieval in adult but not adolescent rats. Interestingly, meth self-administration in adolescence or adulthood disrupted acquisition of conditioned freezing in adulthood. Meth self-administration in adolescence did not affect conditioned freezing in adolescence. These results suggest that intraperitoneal injections of high doses of meth and meth self-administration have dissociated effects on fear conditioning and extinction during adulthood, while adolescent fear conditioning and extinction are unaffected.

Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions.

Healthy brain function requires a balance between the activity of dopamine receptor 1 (D1) and dopamine receptor 2 (D2). Alterations in this balance increase the risk for numerous developmental brain disorders. Indeed, D1 and D2 expression fluctuates throughout maturation, although there is conflicting evidence regarding the precise changes that occur. Here, we used stereology to investigate the developmental changes in the number of D1- or D2-expressing neurons in the prelimbic cortex, infralimbic cortex (IL), insula cortex, dorsal striatum, and ventral striatum of female and male mice with green fluorescent protein-tagged D1 or D2. Postnatal day 17, 25, 35, 49, and 70 were examined to cover juvenility to adulthood. In all regions, analysis of D1 density compared to D2 density within each sex seldom detected effects or interactions involving age. However, D1:D2 density ratio changed across age depending on sex. In the IL, D1:D2 density ratio increased in females from adolescence, whereas it was stable in males. In the insula cortex, D1:D2 ratio initially increased in males but decreased in females from juvenility to preadolescence. The ratio then increased in males and females from adolescence to adulthood, with males showing a more dramatic increase. In both the dorsal and ventral striatum, the ratio increased from adolescence. In all regions, females had a higher ratio compared to males throughout maturation except in the insula cortex at P25. These comprehensive observations are novel, and highlight how the maturational changes in the expression of these receptors may contribute to developmental disorders.

New steps for treating alcohol use disorder.

Alcohol use disorder is a complex syndrome with multiple treatment points including drug-induced pathology, withdrawal management, behavioral/cognitive strategies, and relapse prevention. These different components may be complicated by genotype and phenotype. A huge milestone for the treatment of alcohol use disorder across several countries in the last 10 years was the introduction of practice guidelines integrating clinical expertise and research evidence. These provide a summary of interventions that have been shown to be effective following rigorous and replicated clinical trials. Inspection of these guidelines reveals good consistency, but little evidence of progress in treatment approaches for alcohol use disorder over the past decade. In this mini-review, we discuss emerging treatments for alcohol use disorder that may supplement or improve the evidence-based treatments that are currently recommended. New medications, the emergence of digital technology, and other novel approaches such as transcranial magnetic stimulation are all discussed with reference to treatments already in practice. We also consider how individual differences in genotype and phenotype may affect outcomes. Together with improvements in technology, this knowledge offers a powerful tool for designing personalized approaches to treatment, and hence improving prognosis for rehabilitation programs.

The behaviours of nurses that increase student accountability for learning in clinical practice: An integrative review.

OBJECTIVE: To identify nurses' behaviours that promote student accountability for learning in clinical practice. BACKGROUND: Health care services are experiencing significant strain in meeting clinical education requirements of increasing numbers of nursing students enrolled in undergraduate nursing programs. Internationally, the transition to university based education for nurses has seen the emergence of issues for busy clinicians trying to manage increasing workloads with responsibility for student learning. An understanding of what types of supervisor behaviours promote student accountability for learning, may support clinicians to more effectively manage their dual roles of clinical care and student support. DESIGN: An integrative approach was adopted for this review. DATA SOURCES: A search of the Cumulative Index of Nursing and Allied Health Literature, Pubmed, Scopus and Embase was undertaken, limited to articles published between 2000 and March 2017. REVIEW METHODS: Whittemore and Knafls' (2005) framework for conducting integrative reviews was used to ensure a methodological and rigorous approach. RESULTS: Nine studies were considered. Behaviours emerged in relation to four themes including: belongingness associated with a genuine partnership; empowerment and increasing student self-efficacy; trust linked to increasing and staged independence; and balancing clinical and educational requirements. CONCLUSION: Behaviours of nurses significantly influence students' accountability for learning and accordingly, their ability to be adequately prepared for professional nursing practice. Understanding behaviours that impact on students' approach to clinical placement can guide nurses in their approach to facilitating student learning, in particular, behaviours that increase student responsibility and independence over the continuum of clinical education.