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.).

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.).

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.

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.

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.

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.

The effects of shoe-worn insoles on gait biomechanics in people with knee osteoarthritis: a systematic review and meta-analysis.

OBJECTIVES: The effect of shoe-worn insoles on biomechanical variables in people with medial knee osteoarthritis has been studied extensively. The majority of research has focused specifically on the effect of lateral wedge insoles at the knee. The aim of this systematic review and meta-analysis was to summarise the known effects of different shoe-worn insoles on all biomechanical variables during level walking in this patient population to date. METHODS: Four electronic databases were searched to identify studies containing biomechanical data using shoe-worn insole devices in the knee osteoarthritis population. Methodological quality was assessed and a random effects meta-analysis was performed on biomechanical variables reported in three or more studies for each insole. RESULTS: Twenty-seven studies of moderate-to-high methodological quality were included in this review. The primary findings were consistent reductions in the knee adduction moment with lateral wedge insoles, although increases in ankle eversion with these insoles were also found. CONCLUSION: Lateral wedge insoles produce small reductions in knee adduction angles and external moments, and moderate increases in ankle eversion. The addition of an arch support to a lateral wedge minimises ankle eversion change, and also minimises adduction moment reductions. The paucity of available data on other insole types and other biomechanical outcomes presents an opportunity for future research.

Postnatal development of neurotransmitter systems and their relevance to extinction of conditioned fear.

Remembering and forgetting are fundamental features of an organism. Extinction is a type of forgetting where there is a decrease in the significance and/or the meaning of an associative memory when elements of that memory no longer predict one another. The neural mechanisms underlying extinction of fear memories have been extensively studied in the laboratory because extinction processes are clinically relevant to exposure therapies that treat anxiety disorders. However, only in the last decade have we begun to unveil the similarities and differences in plasticity underlying extinction across development. So far it is clear that extinction is a developmentally dissociated process in behavior and in pharmacology, however there are many large gaps in the literature in understanding how the developmental trajectory of different neurotransmitters contribute to changes in the nature of extinction across development. We attempt to address these gaps in the present review. Major neurotransmitter systems including the glutamatergic and GABAergic systems, the monoamines, the endogenous opioid and cannabinoid systems, acetylcholines, and neuropeptides such as oxytocin have all been identified to play some role in extinction of fear memories and have been covered in this review. We hope to facilitate more research into mechanisms of extinction at different stages of life, especially noting that mental disorders are increasingly classified as neurodevelopmental disorders.

Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats.

Adolescent drug users display resistance to treatment such as cue exposure therapy (CET), as well as increased liability to relapse. The basis of CET is extinction learning, which involves dopamine signaling in the medial prefrontal cortex (mPFC). This system undergoes dramatic alterations during adolescence. Therefore, we investigated extinction of a cocaine-associated cue in adolescent and adult rats. While cocaine self-administration and lever-alone extinction were not different between the two ages, we observed that cue extinction reduced cue-induced reinstatement in adult but not adolescent rats. Infusion of the selective dopamine 2 receptor (D2R)-like agonist quinpirole into the infralimbic cortex (IL) of the mPFC prior to cue extinction significantly reduced cue-induced reinstatement in adolescents. This effect was replicated by acute systemic treatment with the atypical antipsychotic aripiprazole (Abilify), a partial D2R-like agonist. These data suggest that adolescents may be more susceptible to relapse due to a deficit in cue extinction learning, and highlight the significance of D2R signaling in the IL for cue extinction during adolescence. These findings inspire new tactics for improving adolescent CET, with aripiprazole representing an exciting potential pharmacological adjunct for behavioral therapy.

Nucleus incertus corticotrophin-releasing factor 1 receptor signalling regulates alcohol seeking in rats.

Alcoholism is a chronic relapsing disorder, and stress is a key precipitant of relapse. The nucleus incertus (NI) is highly responsive to corticotrophin-releasing factor (CRF) and psychological stressors, receives a CRF innervation and expresses CRF1 and CRF2 receptor mRNA. Furthermore, the ascending NI relaxin-3 system is implicated in alcohol seeking in rats. Therefore, in alcohol-preferring rats, we examined the effect of bilateral injections into the NI of the CRF1 receptor antagonist, CP376395 or the CRF2 receptor antagonist, astressin-2B on yohimbine-induced reinstatement of alcohol seeking. Using quantitative PCR analysis of NI micropunches, we assessed the effects of chronic alcohol consumption on gene expression profiles for components of the relaxin-3 and CRF systems. Bilateral intra-NI injections of CP376395 (500 ng/0.25 µl) attenuated yohimbine-induced reinstatement of alcohol seeking. In contrast, intra-NI injections of astressin-2B (200 ng/0.25 µl) had no significant effect. In line with these data, CRF1 , but not CRF2 , receptor mRNA was upregulated in the NI following chronic ethanol intake. Relaxin family peptide 3 receptor mRNA was also increased in the NI following chronic ethanol. Our quantitative PCR analysis also identified CRF mRNA within the rat NI, and the existence of a newly identified population of CRF-containing neurons was subsequently confirmed by detection of CRF immunoreactivity in rat and mouse NI. These data suggest that NI neurons contribute to reinstatement of alcohol seeking, via an involvement of CRF1 signalling. Furthermore, chronic ethanol intake leads to neuroadaptive changes in CRF and relaxin-3 systems within rat NI.

Degree of Rectal Distension Seen on Prostate Radiotherapy Planning CT Scan Is Not a Negative Prognostic Factor in the Modern Era of Image-Guided Radiotherapy.

BACKGROUND: Studies have shown that rectal distension has a significant impact on treatment failure in patients receiving radical radiotherapy for prostate cancer. A distended rectum contributes to excessive organ movement during treatment, resulting in significant underdosing of the target volume and higher treatment failure rates. The increasing use of highly conformal, precise radiotherapy techniques places greater importance on reducing this risk. We tested whether imaging during radiotherapy helps minimise the negative impact that rectal distension has on long-term tumour control. FINDINGS: The rectal diameter (anterior/posterior and lateral) was prospectively measured at radiotherapy planning in 172 consecutive patients undergoing radical radiotherapy with three-dimensional conformal radiotherapy. Daily, and then weekly, imaging during radiotherapy ensured that prostate movement remained within predefined tolerances. Patients were followed up for a median of 72 months with regular prostate-specific antigen (PSA) measurements to ascertain biochemical PSA relapse and survival information. CONCLUSIONS: In this cohort of predominately high-risk localised prostate cancer, rectal distension had no significant impact on PSA relapse. We suggest that regular imaging during radiotherapy negates the risk caused by rectal distension on local treatment failure.

Extinction of a cocaine-taking context that protects against drug-primed reinstatement is dependent on the metabotropic glutamate 5 receptor.

We investigated the effects of extinguishing action-reward versus context-reward associations on drug-primed reinstatement, and the potential role of the metabotropic glutamate 5 receptor (mGlu5) in these different types of extinction in rats that self-administer cocaine. We observed that daily context extinction (non-reinforced exposures to the cocaine-taking context with retracted levers) was just as effective as daily lever extinction in reducing cocaine-primed reinstatement compared with passive abstinence. Additionally, systemic injections of the mGlu5 negative allosteric modulator MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine) following each extinction session significantly impaired the ability of context extinction to reduce cocaine-primed reinstatement, without affecting reinstatement after lever extinction or passive abstinence.

Clinicopathological significance of human apurinic/apyrimidinic endonuclease 1 (APE1) expression in oestrogen-receptor-positive breast cancer.

Oestrogen metabolites can induce oxidative DNA base damage and generate potentially mutagenic apurinic sites (AP sites) in the genomic DNA. If unrepaired, mutagenic AP sites could drive breast cancer pathogenesis and aggressive phenotypes. Human apurinic/apyrimidinic endonuclease 1 (APE1) is a key DNA base excision repair (BER) protein and essential for processing AP sites generated either directly by oestrogen metabolites or during BER of oxidative base damage. Our hypothesis is that altered APE1 expression may be associated with aggressive tumour biology and impact upon clinical outcomes in breast cancer. In the current study, we have investigated APE1 protein expression in a large cohort of breast cancers (n = 1285) and correlated to clinicopathological features and survival outcomes. Low APE1 protein expression was associated with high histological grade (p < 0.000001), high mitotic index (p < 0.000001), glandular de-differentiation (p < 0.000001), pleomorphism (p = 0.003), absence of hormonal receptors (ER-/PgR-/AR-) (p < 0.0001) and presence of triple negative phenotype (p = 0.001). Low APE1 protein expression was associated with loss of BRCA1, low XRCC1, low FEN1, low SMUG1 and low pol ß (ps < 0.0001). High MIB1 (p = 0.048), bcl-2 negativity (p < 0.0001) and low TOP2A (p < 0.0001) were likely in low APE1 tumours. In the ER-positive sub-group, specifically, low APE1 remains significantly associated with high histological grade, high mitotic index, glandular de-differentiation (ps < 0.00001) and poor breast cancer specific survival (p = 0.007). In the ER-positive cohort that received adjuvant endocrine therapy, low APE1 protein expression is associated with poor survival (p = 0.006). In multivariate analysis, low APE1 remains independently associated with poor survival in ER-positive tumours (p = 0.048). We conclude that low APE1 expression may have prognostic and predictive significance in ER-positive breast cancers.

Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end-joining pathway required for the repair of DNA double-strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. We evaluated clinicopathological significance of DNA-PKcs protein expression in 1,161 tumours and DNA-PKcs mRNA expression in 1,950 tumours. We correlated DNA-PKcs to markers of aggressive phenotypes, DNA repair, apoptosis, cell cycle regulation and survival. Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps < 0.05). The absence of BRCA1, low XRCC1, low SMUG1, low APE1 and low Polß was also more likely in low DNA-PKcs expressing tumours (ps < 0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer-specific survival (BCSS) in univariate and multivariate analysis (ps < 0.01). At the mRNA level, similarly, low DNA-PKcs was associated with poor BCSS. In patients with ER-positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER-negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers.

A mixed methods study of food safety knowledge, practices and beliefs in Hispanic families with young children.

Children are at a higher risk for foodborne illness. The objective of this study was to explore food safety knowledge, beliefs and practices among Hispanic families with young children (≤10 years of age) living within a Midwestern state. A convergent mixed methods design collected qualitative and quantitative data in parallel. Food safety knowledge surveys were administered (n = 90) prior to exploration of beliefs and practices among six focus groups (n = 52) conducted by bilingual interpreters in community sites in five cities/towns. Descriptive statistics determined knowledge scores and thematic coding unveiled beliefs and practices. Data sets were merged to assess concordance. Participants were female (96%), 35.7 (±7.6) years of age, from Mexico (69%), with the majority having a low education level. Food safety knowledge was low (56% ± 11). Focus group themes were: Ethnic dishes popular, Relating food to illness, Fresh food in home country, Food safety practices, and Face to face learning. Mixed method analysis revealed high self confidence in preparing food safely with low safe food handling knowledge and the presence of some cultural beliefs. On-site Spanish classes and materials were preferred venues for food safety education. Bilingual food safety messaging targeting common ethnic foods and cultural beliefs and practices is indicated to lower the risk of foodborne illness in Hispanic families with young children.

A role for the ventral pallidum in context-induced and primed reinstatement of alcohol seeking.

The ventral pallidum (VP) is a major target of projections from the nucleus accumbens, and has been implicated in the reinstatement of psychostimulant seeking as part of a cortical-striatal-pallidal 'final common pathway' for relapse. Here, we studied the role of the VP in context-induced and primed reinstatement of alcoholic beer seeking, using a combination of microinjections and tract tracing studies. In experiment 1, rats were trained to respond to alcoholic beer in one context (A), and then extinguished in a second context (B), prior to testing for reinstatement (ABA renewal) and extinction (ABB). VP microinjection of the µ-opioid receptor (MOR) antagonist CTAP prevented reinstatement. In experiment 2, VP microinjection of CTAP also prevented the primed reinstatement of alcoholic beer seeking after rats were trained, extinguished, and tested in the same context. In experiment 3, we employed retrograde neural tract tracing together with c-Fos immunohistochemistry to identify the VP afferents recruited during context-induced reinstatement of alcoholic beer seeking. There was evidence for the recruitment of accumbens core→VP, basolateral amygdala→VP and paraventricular thalamus→VP pathways during context-induced reinstatement. These results indicate that the VP MORs are critical for context-induced reinstatement, and that the VP receives inputs from a number of regions known to be important in reinstatement of drug seeking.

Pharmacogenomics of anti-platelet therapy: how much evidence is enough for clinical implementation?

Pharmacogenomics, the study of the genomics of drug response and adverse effects, holds great promise for more effective individualized (personalized) medicine. Recent evidence supports a role of loss-of-function (LOF) variants in the cytochrome P450 enzyme CYP2C19 as a determinant of clopidogrel response. Patients given clopidogrel after percutaneous coronary intervention who carry LOF variants do not metabolize clopidogrel, a prodrug, into its active form resulting in decreased inhibition of platelet function and a higher likelihood of recurrent cardiovascular events. Despite a large body of evidence supporting clinical utility, adoption of anti-platelet pharmacogenetics into clinical practice has been slow. In this review, we summarize the pharmacokinetic, pharmacodynamic and clinical evidence, identify gaps in knowledge and other barriers that appear to be slowing adoption, and describe CYP2C19 pharmacogenetics implementation projects currently underway. Only when we surmount these barriers will clinicians be able to use pharmacogenetic information in conjunction with the history, physical examination and other medical tests and information to choose the most efficacious anti-platelet therapy for each individual patient.

Pharmacogenomics of anti-platelet and anti-coagulation therapy.

Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and clopidogrel are effective in inhibiting cardiovascular events; however, there is great inter-individual variability in response to these medications. In recent years, it has been recognized that genetic factors play a significant role in drug response, and, subsequently, common variants in genes responsible for metabolism and drug action have been identified. These discoveries along with new diagnostic targets and therapeutic strategies hold promise for more effective individualized anti-coagulation and anti-platelet therapy.

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.