Adjuvant-dependent impact of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus.

Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.

Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population.

The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. However, there is significant individual-to-individual variation in vaccine efficacy due to factors including viral variants, host age, immune status, environmental and host genetic factors. Understanding those determinants driving this variation may inform the development of more broadly protective vaccine strategies. While host genetic factors are known to impact vaccine efficacy for respiratory pathogens such as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. To model the impact of host genetic variation on SARS-CoV-2 vaccine efficacy, while controlling for the impact of non-genetic factors, we used the Diversity Outbred (DO) mouse model. We found that DO mice immunized against SARS-CoV-2 exhibited high levels of variation in vaccine-induced neutralizing antibody responses. While the majority of the vaccinated mice were protected from virus-induced disease, similar to human populations, we observed vaccine breakthrough in a subset of mice. Importantly, we found that this variation in neutralizing antibody, virus-induced disease, and viral titer is heritable, indicating that the DO serves as a useful model system for studying the contribution of genetic variation of both vaccines and disease outcomes.

Pharmacokinetic Considerations for Optimizing Inhaled Spray-Dried Pyrazinoic Acid Formulations.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of death with 1.6 million deaths worldwide reported in 2021. Oral pyrazinamide (PZA) is an integral part of anti-TB regimens, but its prolonged use has the potential to drive the development of PZA-resistant Mtb. PZA is converted to the active moiety pyrazinoic acid (POA) by the Mtb pyrazinamidase encoded by pncA, and mutations in pncA are associated with the majority of PZA resistance. Conventional oral and parenteral therapies may result in subtherapeutic exposure in the lung; hence, direct pulmonary administration of POA may provide an approach to rescue PZA efficacy for treating pncA-mutant PZA-resistant Mtb. The objectives of the current study were to (i) develop novel dry powder POA formulations, (ii) assess their feasibility for pulmonary delivery using physicochemical characterization, (iii) evaluate their pharmacokinetics (PK) in the guinea pig model, and (iv) develop a mechanism-based pharmacokinetic model (MBM) using in vivo PK data to select a formulation providing adequate exposure in epithelial lining fluid (ELF) and lung tissue. We developed three POA formulations for pulmonary delivery and characterized their PK in plasma, ELF, and lung tissue following passive inhalation in guinea pigs. Additionally, the PK of POA following oral, intravenous, and intratracheal administration was characterized in guinea pigs. The MBM was used to simultaneously model PK data following administration of POA and its formulations via the different routes. The MBM described POA PK well in plasma, ELF, and lung tissue. Physicochemical analyses and MBM predictions suggested that POA maltodextrin was the best among the three formulations and an excellent candidate for further development as it has: (i) the highest ELF-to-plasma exposure ratio (203) and lung tissue-to-plasma exposure ratio (30.4) compared with POA maltodextrin and leucine (75.7/16.2) and POA leucine salt (64.2/19.3) and (ii) the highest concentration in ELF (CmaxELF: 171 nM) within 15.5 min, correlating with a fast transfer into ELF after pulmonary administration (KPM: 22.6 1/h). The data from the guinea pig allowed scaling, using the MBM to a human dose of POA maltodextrin powder demonstrating the potential feasibility of an inhaled product.

Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)-encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated. During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs. These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.

Effect of Viral Strain and Host Age on Clinical Disease and Viral Replication in Immunocompetent Mouse Models of Chikungunya Encephalomyelitis.

The alphavirus chikungunya virus (CHIKV) represents a reemerging public health threat as mosquito vectors spread and viruses acquire advantageous mutations. Although primarily arthritogenic in nature, CHIKV can produce neurological disease with long-lasting sequelae that are difficult to study in humans. We therefore evaluated immunocompetent mouse strains/stocks for their susceptibility to intracranial infection with three different CHIKV strains, the East/Central/South African (ECSA) lineage strain SL15649 and Asian lineage strains AF15561 and SM2013. In CD-1 mice, neurovirulence was age- and CHIKV strain-specific, with SM2013 inducing less severe disease than SL15649 and AF15561. In 4-6-week-old C57BL/6J mice, SL15649 induced more severe disease and increased viral brain and spinal cord titers compared to Asian lineage strains, further indicating that neurological disease severity is CHIKV-strain-dependent. Proinflammatory cytokine gene expression and CD4+ T cell infiltration in the brain were also increased with SL15649 infection, suggesting that like other encephalitic alphaviruses and with CHIKV-induced arthritis, the immune response contributes to CHIKV-induced neurological disease. Finally, this study helps overcome a current barrier in the alphavirus field by identifying both 4-6-week-old CD-1 and C57BL/6J mice as immunocompetent, neurodevelopmentally appropriate mouse models that can be used to examine CHIKV neuropathogenesis and immunopathogenesis following direct brain infection.

Pharmacokinetic considerations for optimizing inhaled spray-dried pyrazinoic acid formulations.

Tuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), remains a leading cause of death with 1.6 million deaths worldwide reported in 2021. Oral pyrazinamide (PZA) is an integral part of anti-TB regimens, but its prolonged use has the potential to drive development of PZA resistant Mtb . PZA is converted to the active moiety pyrazinoic acid (POA) by the Mtb pyrazinamidase encoded by pncA , and mutations in pncA are associated with the majority of PZA resistance. Conventional oral and parenteral therapies may result in subtherapeutic exposure in the lung, hence direct pulmonary administration of POA may provide an approach to rescue PZA efficacy for treating pncA- mutant PZA-resistant Mtb . The objectives of the current study were to i) develop novel dry powder POA formulations ii) assess their feasibility for pulmonary delivery using physicochemical characterization, iii) evaluate their pharmacokinetics (PK) in the guinea pig model and iv) develop a mechanism based pharmacokinetic model (MBM) using in vivo PK data to select a formulation providing adequate exposure in epithelial lining fluid (ELF) and lung tissue. We developed three POA formulations for pulmonary delivery and characterized their PK in plasma, ELF, and lung tissue following passive inhalation in guinea pigs. Additionally, the PK of POA following oral, intravenous and intratracheal administration was characterized in guinea pigs. The MBM was used to simultaneously model PK data following administration of POA and its formulations via the different routes. The MBM described POA PK well in plasma, ELF and lung tissue. Physicochemical analyses and MBM predictions suggested that POA maltodextrin was the best among the three formulations and an excellent candidate for further development as it has: (i) the highest ELF-to-plasma exposure ratio (203) and lung tissue-to-plasma exposure ratio (30.4) compared with POA maltodextrin and leucine (75.7/16.2) and POA leucine salt (64.2/19.3); (ii) the highest concentration in ELF ( Cmac ELF : 171 nM) within 15.5 minutes, correlating with a fast transfer into ELF after pulmonary administration ( k PM : 22.6 1/h). The data from the guinea pig allowed scaling, using the MBM to a human dose of POA maltodextrin powder demonstrating the potential feasibility of an inhaled product.

Fc-mediated pan-sarbecovirus protection after alphavirus vector vaccination.

Group 2B ß-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. Here, we evaluate the mechanisms of cross-sarbecovirus protective immunity, currently less clear yet important for pan-sarbecovirus vaccine development, using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination does not prevent virus replication, it protects against lethal heterologous disease outcomes in both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clade 2 bat sarbecovirus challenge models. The spike vaccines tested primarily elicit a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. Rather, non-neutralizing antibody functions, mechanistically linked to FcgR4 and spike S2, mediate cross-protection in wild-type mice. Protection is lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs.

Epidemiological Profile of Intimate Partner Homicides of Sexual and Gender Minority Women in the United States, 2003 to 2017.

Sexual and gender minority (SGM) women are among the many victims killed by intimate partner homicide (IPH) each year, though the differences between different SGM groups (and how these groups compare to non-SGM IPH) have not been well established. The objective of this article was to identify practicable, correlated risk factors of IPH of SGM women that may have utility in prevention of future IPH among these populations in the U.S. Homicide data from the National Violent Death Reporting System spanning 2003 to 2017 were used to identify a profile of IPH specific to SGM women compared to women who were neither sexual nor gender minorities. Situational and individual characteristics significantly differentiated sexual minority (SM) women from non-SGM women victims of IPH, including substance abuse history (adjusted odds ratio [AOR] = 4.80 [2.42, 9.51]), having themselves used a weapon during the incident (AOR = 3.63 [1.44, 9.16]), and the type of weapon(s) used, such as firearms (AOR = 0.61 [0.40, 0.91]), with notably different differentiating characteristics for gender minority (GM) women (vs. non-SGM women) such as the likelihood that the victim was known to have experienced interpersonal violence victimization in the previous month (AOR = 0.50 [0.07, 3.67]). Lesbian and bisexual women homicide victims were far more likely to have been killed via IPH than non-SGM women (AOR for Black SM women = 7.84 [3.65, 16.88], AOR for White SM women = 2.30 [1.03, 5.17]). There was no corresponding difference for GM women victims, whose likelihood of being killed by an intimate partner was similar to that of non-SGM women. Based on these findings, actionable public health recommendations-centered around evidence that neither "all women" nor "all LGBTQ people" are appropriate intimate partner violence prevention umbrellas-are proposed.

Fc mediated pan-sarbecovirus protection after alphavirus vector vaccination.

Two group 2B ß-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. The mechanisms of cross protection driven by the sarbecovirus spike, a dominant immunogen, are less clear yet critically important for pan-sarbecovirus vaccine development. We evaluated the mechanisms of cross-sarbecovirus protective immunity using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination did not prevent virus replication, it protected against lethal heterologous disease outcomes in both SARS-CoV-2 and clade 2 bat sarbecovirus HKU3-SRBD challenge models. The spike vaccines tested primarily elicited a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. We found non-neutralizing antibody functions that mediated cross protection in wild-type mice were mechanistically linked to FcgR4 and spike S2-binding antibodies. Protection was lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs.

A retrospective cohort study of the effect of rapid versus delayed-result procalcitonin testing on antibiotic use at a community hospital.

BACKGROUND: Procalcitonin is a serum biomarker used to distinguish bacterial infection from viral or noninfectious syndromes. Primary literature shows mixed data on use of procalcitonin for de-escalation of antimicrobials. Delays in test results of send-out procalcitonin assays may result in prolonged antimicrobial durations. It is unknown whether availability of rapid-result assays may shorten time to antibiotic de-escalation. AIM: This retrospective, cohort study compared antibiotic durations of treatment between groups with rapid-result versus delayed send-out, procalcitonin test modality. This study was exempt from Ethics Committee Approval, as determined by the Institutional Review Board at the study site. METHOD: Adult hospitalized patients were included if they had at least one procalcitonin test performed during the study period. The primary outcome compared mean duration of antimicrobial therapy between groups receiving a rapid-result procalcitonin test and a send-out test. Secondary outcomes included incidence of Clostridiodes difficile infection, mention of procalcitonin testing in the electronic medical record in reference to antimicrobial therapy decision making, and presence of comorbidities which affect procalcitonin levels independent of infection. RESULTS: A total of 350 lab results were analyzed. The duration of antimicrobial treatment between groups was not statistically different with the median duration of treatment in the send-out group being 2.95 days compared to 3.35 in the rapid result group, p = 0.856. Patient comorbidities with potential to lead to a noninfectious elevation or falsely high level of procalcitonin were common. CONCLUSION: Use of a rapid-result procalcitonin assay does not reduce hospital antimicrobial therapy duration as compared with send-out testing.

Taxonomic and thematic semantic relationships in picture naming as revealed by Laplacian-transformed event-related potentials.

Semantically related concepts co-activate when we speak. Prior research reported both behavioral interference and facilitation due to co-activation during picture naming. Different word relationships may account for some of this discrepancy. Taxonomically related words (e.g., WOLF-DOG) have been associated with semantic interference; thematically related words (e.g., BONE-DOG) have been associated with facilitation. Although these different semantic relationships have been associated with opposite behavioral outcomes, electrophysiological studies have found inconsistent effects on event-related potentials. We conducted a picture-word interference electroencephalography experiment to examine word retrieval dynamics in these different semantic relationships. Importantly, we used traditional monopolar analysis as well as Laplacian transformation allowing us to examine spatially deblurred event-related components. Both analyses revealed greater negativity (150-250 ms) for unrelated than related taxonomic pairs, though more restricted in space for thematic pairs. Critically, Laplacian analyses revealed a larger negative-going component in the 300 to 500 ms time window in taxonomically related versus unrelated pairs which were restricted to a left frontal recording site. In parallel, an opposite effect was found in the same time window but localized to a left parietal site. Finding these opposite effects in the same time window was feasible thanks to the use of the Laplacian transformation and suggests that frontal control processes are concurrently engaged with cascading effects of the spread of activation through semantically related representations.

Validation and Assessment of a Tool to Measure Psychosocial Readiness to Use Modern Contraceptives among Women in Tigray, Ethiopia.

Social norms, beliefs, and attitudes around modern contraception (MC) use can influence the decision to take up a method, but susceptibility to these factors varies between individuals. The effect of psychosocial readiness to use MC at the individual level is not established for women in Ethiopia. Data from 349 women were used for validity and reliability testing of a 12-item MC psychosocial readiness scale. A rating-scale Rasch model tested for unidimensionality, rating scale functioning, and construct and content validity. Multiple linear regression assessed the effect of respondent characteristics on MC psychosocial readiness scores. The psychometric properties of the univariate MC psychosocial readiness scale were satisfactory after the stepwise removal of two items. Prior MC use, socioeconomic status, geographic zone, and education were significantly associated with increased endorsement of MC psychosocial readiness. The 10-item scale measures the extent of endorsement of MC psychosocial readiness for childbearing women in Tigray, Ethiopia. Further research should qualitatively explore the identified influence of education on MC psychosocial readiness.

TARGETED DOWN REGULATION OF CORE MITOCHONDRIAL GENES DURING SARS-COV-2 INFECTION.

Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been reported in COVID-19 patients, but the timing and organs affected vary among reports. Here, we reveal the dynamics of COVID-19 through transcription profiles in nasopharyngeal and autopsy samples from patients and infected rodent models. While mitochondrial bioenergetics is repressed in the viral nasopharyngeal portal of entry, it is up regulated in autopsy lung tissues from deceased patients. In most disease stages and organs, discrete OXPHOS functions are blocked by the virus, and this is countered by the host broadly up regulating unblocked OXPHOS functions. No such rebound is seen in autopsy heart, results in severe repression of genes across all OXPHOS modules. Hence, targeted enhancement of mitochondrial gene expression may mitigate the pathogenesis of COVID-19.

Factors related to long-lasting insecticidal net (LLIN) use during travel in western Kenya: A descriptive analysis.

BACKGROUND: Overnight travel predicts increased likelihood of Plasmodium infection and may introduce parasite strains to new areas, but deviations from routine at-home use of long-lasting insecticidal nets (LLINs) during travel are not well studied. METHODS: Cross-sectional data were taken in 2015 from the western Kenyan highlands and lowlands. Household surveys assessed individual travel activity during the previous month, LLIN use (at home and away), and current Plasmodium infection status. Crude and adjusted logistic regression was used to estimate the odds ratios (OR) of current malaria infection relative to travel within the last month. RESULTS: Highland residents who had traveled were more likely to have Plasmodium infection at the time of interview than highland residents who had not traveled (adjusted OR = 4.09 [1.60, 10.52]). Alternately, in the lowlands those who traveled overnight were significantly less likely to be infected vs non-travelers (adjusted OR = 0.56 [0.39,0.96]). Rates of LLIN use during travel were lower than reported rates while at home. Despite this, among travelers, LLIN use during travel was not associated with likelihood of Plasmodium infection for either region. CONCLUSIONS: Travel had heterogeneous associations with infection status for the lowlands and highlands of western Kenya. Given the higher prevalence of malaria in the lowlands, travel is unlikely to increase likelihood of exposure. Conversely, travel from the lower-prevalence highlands may have taken respondents to higher prevalence areas. LLIN use while traveling differed from at-home habits and may depend on availability of LLINs where the traveler sleeps.

Trends in telephonic comprehensive medication review in the United States from 2000 to present: a scoping literature review.

BACKGROUND: Although comprehensive medication review (CMR) services have been shown to provide value to patients and payers, the extent of uniformity in service delivery is unknown. A variety of standards and recommendations are available from academic and professional sources, but variation in service provision is an important consideration when attempting to measure or compare service quality nationally. OBJECTIVE: This study aimed to identify and summarize trends in the peer-reviewed and gray literature describing telephonic CMR delivery and content. METHODS: A scoping review of peer-reviewed and gray literature was conducted to quantify and qualify trends in CMR service. Two independent reviewers screened abstracts from 9 bibliographic databases and selected gray literature sources in accordance with the Joanna Briggs Institute guidelines and an internally developed protocol. Inclusion criteria for the review were English language; discussion of telephonic CMR service in the United States; research, legislation, or guidelines that describe CMR content coverage requirements for payment; and publication from the year 2000 to the present. Data relating to publication type, study design, setting, region, and themes of CMR content were collated into a Microsoft Excel data extraction form. Qualitative thematic analysis was conducted, and key findings and concepts were reported contextually. RESULTS: Of 374 identified documents screened, 15 were included in this scoping review and thematic analysis. The following characteristics of CMRs were identified: content, coverage, eligibility, frequency, process, and responsiveness. All published documents (n = 15, 100%) included a discussion of CMR content, and 14 sources (93%) addressed process elements of providing a CMR. Discussion of other themes varied in frequency across documents, ranging from 3 articles (20%) addressing organizational goals for CMR to 12 articles (80%) including elements of responsiveness. Within-theme variation was also observed for several CMR content areas. CMR process was the most heterogeneous theme with topics ranging from access to patient health records to pharmacist training. CONCLUSIONS: Assessment of telephonic CMR comprised a small but steadily increasing portion of the medication therapy management literature. Publications since 2015 have shown an increasing consensus of CMR content and purpose. Per the identified literature, there is an ongoing demand for higher-quality, more holistic CMRs, but there is no consensus on how to measure CMR quality. Future work should include engaging with CMR experts to understand variability in measures of CMR success.

Key informant perspectives about telephonic comprehensive medication review services in the United States.

BACKGROUND: Comprehensive medication reviews (CMRs) are provided by providers such as pharmacists to eligible beneficiaries. Although CMRs have been shown to provide value to patients, little is known about the service uniformity, quality, and content of CMRs. OBJECTIVE: This study aimed to characterize the current state of CMR services from diverse stakeholder perspectives and describe variation in responses to content and delivery of telephonic CMR services. METHODS: Semistructured interviews were conducted with 10 key informants. The interview guide contained 6 key questions with additional probing questions. Transcripts were analyzed using the inductive saturation model and phenomenological approach to code emergent themes, which were iteratively refined until saturation was achieved. RESULTS: Key informants included CMR payers (n = 3), providers (n = 5), and standards-setting organizations (n = 2). Ten themes about CMRs emerged from qualitative analysis: (1) definition, (2) organizational goals, (3) content, (4) eligibility, (5) frequency, (6) acceptance and completion, (7) process and personnel, (8) quality assurance, (9) preparation, and (10) future directions. CMR content descriptions were consistent across perspectives. Key informants described scenarios appropriate for expanded CMR eligibility criteria, although none were consistently reported. Providers emphasized patient CMR acceptance rates whereas payers and standard-setting organizations emphasized completion rates. Completion rates and adherence to Centers for Medicare and Medicaid Services standards were characterized as core organizational goals (n = 8), whereas patient satisfaction was less frequently identified (n = 4). A lack of incentive for CMR providers to follow-up with patients was a barrier to expanded services. Overall, key informants were dissatisfied with the CMR completion rate measure and would prefer measures focused on service quality and outcomes. CONCLUSIONS: CMR services largely met perceived guidelines, with variation in value-added services. Key informants desired adoption of an actionable measure that is focused on quality rather than completion rate. To inform a quality measure, future research should analyze completed CMRs to determine the extent of variation in content and delivery.

Modulation of dopamine release by ethanol is mediated by atypical GABAA receptors on cholinergic interneurons in the nucleus accumbens.

Previous studies indicate that moderate-to-high ethanol (EtOH) concentrations enhance dopamine (DA) neurotransmission in the mesolimbic DA system from the ventral tegmental area (VTA) and projecting to the nucleus accumbens core (NAc). However, voltammetry studies demonstrate that moderate-to-high EtOH concentrations decrease evoked DA release at NAc terminals. The involvement of γ-aminobutyric acid (GABA) receptors (GABAA Rs), glycine (GLY) receptors (GLYRs) and cholinergic interneurons (CINs) in mediating EtOH inhibition of evoked NAc DA release were examined. Fast scan cyclic voltammetry, electrophysiology, optogenetics and immunohistochemistry techniques were used to evaluate the effects of acute and chronic EtOH exposure on DA release and CIN activity in C57/BL6, CD-1, transgenic mice and δ-subunit knockout (KO) mice (δ-/-). Ethanol decreased DA release in mice with an IC50 of 80 mM ex vivo and 2.0 g/kg in vivo. GABA and GLY decreased evoked DA release at 1-10 mM. Typical GABAA R agonists inhibited DA release at high concentrations. Typical GABAA R antagonists had minimal effects on EtOH inhibition of evoked DA release. However, EtOH inhibition of DA release was blocked by the α4 ß3 δ GABAA R antagonist Ro15-4513, the GLYR antagonist strychnine and by the GABA ρ1 (Rho-1) antagonist TPMPA (10 µM) and reduced significantly in GABAA R δ-/- mice. Rho-1 expression was observed in CINs. Ethanol inhibited GABAergic synaptic input to CINs from the VTA and enhanced firing rate, both of which were blocked by TPMPA. Results herein suggest that EtOH inhibition of DA release in the NAc is modulated by GLYRs and atypical GABAA Rs on CINs containing δ- and Rho-subunits.

Psychometric evaluation of a comprehensive medication management service experience instrument.

BACKGROUND: The Health-Systems Alliance for Integrated Medication Management (HAIMM) instrument was developed to estimate patient experience following pharmacist-delivered comprehensive medication management (CMM). OBJECTIVES: The objective of this paper was to assess the psychometric properties and factor structure of the HAIMM instrument. METHODS: Data were collected from 5 members of the HAIMM collaborative. A one-factor confirmatory factor analysis (CFA) model was used to assess instrument dimensionality. A partial-credit item response theory model was used to assess the psychometric properties of the ten-item HAIMM patient experience instrument, consisting of tests for rating scale functioning, person and item fit, and content validity. RESULTS: Among 516 respondents, there was a strong skew toward high satisfaction, including a strong ceiling effect. CFA results suggest a unidimensional construct. Item difficulty was spread across a low range and content redundancies were identified. The mean-square values for both infit and outfit all fell within the recommended range, whereas the z-standard fit was within the recommended range for most items. The 5-point Likert scale used in the HAIMM instrument did not distinguish between participants' level of experience following the pharmacist-delivered CMM service. CONCLUSION: The psychometric analysis showed the HAIMM survey tool does not cover all of the content that should be assessed to fully evaluate CMM experiences. In its current form, the HAIMM instrument should not be used to make comparisons about the quality of CMM services provided, although it may be useful to monitor patient satisfaction for quality improvement purposes. Further research is required to develop an improved instrument that contains expanded content coverage, response options, and aspects of CMM to be useful by health care providers, health systems, and other decision makers.

Knowledge of Sexual Transmission of Zika Virus Among Women Who Are Pregnant or Intend to Become Pregnant, Arizona, 2017.

OBJECTIVES: Levels of knowledge about the sexual transmission of Zika virus are consistently low in populations at risk of a mosquito-borne outbreak, including among women of childbearing age and women who are pregnant or intend to become pregnant. We investigated the effectiveness of sources of public health messaging about sexual transmission to women who are pregnant or intend to become pregnant in Arizona. METHODS: In 2017, we conducted an Arizona-statewide survey 15 months after the initial release of US guidelines on sexual transmission of Zika virus. We used Poisson regression, adjusting for demographic factors, to estimate the likelihood among women who were pregnant or intended to become pregnant of knowing that Zika virus is sexually transmitted relative to other women of childbearing age. We used multinomial logistic regression models to explore associations with most used health information sources, either in person (eg, medical providers) or online (eg, Facebook), categorized by extent of dependability. RESULTS: Women who were pregnant or intended to become pregnant had similarly poor knowledge of the sexual transmission of Zika virus as compared with other women of childbearing age (adjusted prevalence ratio = 1.14 [95% CI, 0.83-1.55]). Only about one-third of all respondents reported knowledge of sexual transmission. Reliance on high- vs low-dependability information sources, whether in person or online, did not predict the extent of Zika virus knowledge among women who were pregnant or intended to become pregnant. CONCLUSION: As late as the second year of local Zika virus transmission in the United States, in 2017, women in Arizona were not receiving sufficient information about sexual transmission, even though it was available. To prepare for possible future outbreaks, research should explore which aspects of Zika information campaigns were ineffective or inefficient.

An Academic-Community Collaboration to Deliver Medication Therapy Management (MTM) Services to Patients Living in Rural Counties of a Southwestern State in the United States.

BACKGROUND: Patients living in rural communities often experience pronounced health disparities, have a higher prevalence of diabetes and hypertension, and poorer access to care compared to urban areas. To address these unmet healthcare service needs, an established, academic-based MTM provider created a novel, collaborative program to provide comprehensive, telephonic services to patients living in rural Arizona counties. OBJECTIVE: This study assessed the program effectiveness and described differences in health process and outcome measures (e.g., clinical outcomes, gaps in care for prescribed medications, medication-related problems) between individuals residing in different rural-urban commuting area (RUCA) groups (urban, micropolitan, and small town) in rural Arizona counties. METHODS: Subjects eligible for inclusion were 18 years or older with diabetes and/or hypertension, living in rural Arizona counties. Data were collected on: demographic characteristics, medical conditions, clinical values, gaps in care, medication-related problems (MRPs), and health promotion guidance. Subjects were analyzed using 3 intra-county RUCA levels (i.e., urban, micropolitan, and small town). RESULTS: A total of 384 patients were included from: urban (36.7%), micropolitan (19.3%) and small town (44.0%) areas. Positive trends were observed for clinical values, gaps in care, and MRPs between initial and follow-up consultations. Urban dwellers had significantly lower average SBP values at follow-up than those from small towns (p < 0.05). A total of 192 MRPs were identified; 75.0% were resolved immediately or referred to providers and 16.7% were accepted by prescribers. CONCLUSION: This academic-community partnership highlights the benefits of innovative collaborative programs, such as this, for individuals living in underserved, rural areas.