Novel virus-like nanoparticle vaccine effectively protects animal model from SARS-CoV-2 infection.

The key to battling the COVID-19 pandemic and its potential aftermath is to develop a variety of vaccines that are efficacious and safe, elicit lasting immunity, and cover a range of SARS-CoV-2 variants. Recombinant viral receptor-binding domains (RBDs) are safe vaccine candidates but often have limited efficacy due to the lack of virus-like immunogen display pattern. Here we have developed a novel virus-like nanoparticle (VLP) vaccine that displays 120 copies of SARS-CoV-2 RBD on its surface. This VLP-RBD vaccine mimics virus-based vaccines in immunogen display, which boosts its efficacy, while maintaining the safety of protein-based subunit vaccines. Compared to the RBD vaccine, the VLP-RBD vaccine induced five times more neutralizing antibodies in mice that efficiently blocked SARS-CoV-2 from attaching to its host receptor and potently neutralized the cell entry of variant SARS-CoV-2 strains, SARS-CoV-1, and SARS-CoV-1-related bat coronavirus. These neutralizing immune responses induced by the VLP-RBD vaccine did not wane during the two-month study period. Furthermore, the VLP-RBD vaccine effectively protected mice from SARS-CoV-2 challenge, dramatically reducing the development of clinical signs and pathological changes in immunized mice. The VLP-RBD vaccine provides one potentially effective solution to controlling the spread of SARS-CoV-2.

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.

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.

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.

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.

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.

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.

Impact of Telehealth Interventions on Medication Adherence for Patients With Type 2 Diabetes, Hypertension, and/or Dyslipidemia: A Systematic Review.

OBJECTIVE: To describe telehealth interventions and determine their effect on medication adherence for patients with type 2 diabetes, hypertension, and/or dyslipidemia. DATA SOURCES: PubMed/MEDLINE, EMBASE, Cochrane, CINAHL Plus, PsycINFO, Academic Search Ultimate, International Pharmaceutical Abstracts, Scopus, Web of Science, WHO Global Index Medicus, association websites, and gray literature were searched from January 1, 1998, to December 31, 2019. STUDY SELECTION AND DATA EXTRACTION: Eligible studies reported eHealth, mobile health, and telehealth interventions for adult patients prescribed medications for chronic condition management (eg, type 2 diabetes, hypertension, and/or dyslipidemia). Studies were required to evaluate medication adherence outcomes (eg, medication possession ratio [MPR], proportion of days covered (PDC)]. Randomized controlled trials, cohort studies, and controlled before-and-after studies were included. Multiple reviewers independently extracted data and evaluated risk of bias. DATA SYNTHESIS: Of 8693 studies identified, 13 reported either an MPR or PDC and were included in the systematic review. The systematic review demonstrated that electronic health (eHealth) and telehealth interventions were successful at improving medication adherence, whereas mobile health interventions did not improve medication adherence. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This systematic review highlighted the available research and findings of studies assessing interventions to improve medication nonadherence among patients with type 2 diabetes, hypertension, and/or dyslipidemia. The evaluated findings lend support to the need for targeted medication adherence interventions based on patient population and practice settings. CONCLUSIONS: Telehealth modalities include telephonic outreach and specialized tools designed to increase health literacy. eHealth and telehealth medication adherence interventions were associated with improved MPR and/or PDC rates.

Expanding pharmacists' roles: Pharmacists' perspectives on barriers and facilitators to collaborative practice.

OBJECTIVE: The pharmacy profession is shifting from transactional dispensing of medication to a more comprehensive, patient-centered model of care. Collaborative practice agreements (CPAs) extend the role of a pharmacist to initiate, monitor, modify, and discontinue drug therapies and provide other clinical services. Although collaborative practice has been shown to improve health system efficiency and patient outcomes, little is known about how pharmacists perceive CPAs. To explore pharmacists' perspectives of CPAs, including barriers and facilitators to CPA implementation. METHODS: Semistructured key informant interviews were used to elicit information from licensed pharmacists practicing in a variety of settings in Arizona. Thematic analysis was used to identify key qualitative themes. RESULTS: Seventeen interviews of pharmacists with (n = 11, 64.7%) and without (n = 6, 35.3%) CPAs were conducted in April-May 2019. The pharmacists saw their role in CPAs as supportive, filling a care gap for overburdened providers. A heightened sense of job satisfaction was reported owing to increased pharmacist autonomy, application of advanced knowledge and clinical skills, and ability to have a positive impact on patients' health. Challenges to the implementation of CPAs included liability and billing issues, logistic concerns, some experiences with provider hesitancy, and lack of information and resources to establish and maintain a CPA. The barriers could be overcome with conscious team-building efforts to establish trust and prove the worth of pharmacists in health care teams; strategic engagement of stakeholders in the development of CPAs, including billing and legal departments; and mentorship in the CPA creation process. CONCLUSIONS: The pharmacists in this study enjoyed practicing collaboratively and had overall positive perceptions of CPAs. As health worker shortages become more dire and pharmacy practice evolves to expand the role of pharmacists in providing direct patient care, CPAs will be an important tool for restructuring care tasks within health systems.

Pharmacists' perceptions of the pharmacists' patient care process and performance in a simulated patient interaction.

OBJECTIVES: To (1) evaluate the use of the pharmacists' patient care process (PPCP) by licensed pharmacists through a simulated patient activity and (2) describe pharmacists' awareness and perceptions of the PPCP in the state of Arizona. DESIGN: Interviews were conducted to elicit pharmacists' perceptions and awareness of the PPCP. A simulated patient activity involved a role-play pharmacist-patient interaction in a community pharmacy setting. The PPCP was employed as the evaluative framework to assess pharmacist behavior. SETTING AND PARTICIPANTS: Pharmacists licensed in the state of Arizona practicing in various pharmacy settings were recruited through e-mail list serves and snowball recruitment. Data were collected in person, by telephone, and via video chat. OUTCOME MEASURES: Emergent qualitative themes from interviews were used to describe pharmacists' awareness and perceptions of the PPCP. The presence or absence of PPCP elements were assessed during the simulations. RESULTS: A total of 17 pharmacists were interviewed; 16 participated in the simulated activity. Of these, 7 (41.2%) participants recalled specific details regarding the PPCP process. Participants felt that the PPCP accurately reflected their daily workflow. Accordingly, a mean of 15.8 of the 19 PPCP elements was observed in simulated pharmacist-patient interactions, still allowing room for improvement in pharmacist-led care planning. Participants indicated perceived value in a shared patient care process that facilitates collaboration with myriad health professionals and as an aid to leverage pharmacists' role on health care teams. CONCLUSION: In this study, pharmacists practicing in Arizona in various settings expressed an awareness of the PPCP, felt it accurately reflected the work they do, and expressed that the tool potentially added value to their work.

Community health worker perspectives of an academic community medication therapy management collaboration.

OBJECTIVE: To qualitatively assess community health workers' (CHWs') perceptions of the challenges and benefits associated with participating in a collaborative, interprofessional medication therapy management (MTM) program for rural, underserved, predominantly Latinx, patients with diabetes and hypertension. METHODS: Nine CHWs participated in a 1-hour, semistructured focus group that explored their experiences while assisting in the delivery of MTM services through an academic community partnership between an MTM provider and participating rural clinics. Audio recordings of the focus group were transcribed and thematically analyzed by 2 independent reviewers. RESULTS: All program-involved CHWs participated in the focus group. Qualitative analysis identified 2 overarching themes: (1) opportunities and (2) challenges. Opportunities were further subcategorized as benefits to (1) CHWs, (2) patients, or (3) academic community MTM research. The CHWs perceived that they served as a liaison among the medical provider (prescriber), patient, and MTM pharmacist. Benefits to the patients focused on the integration of CHWs as essential to patient recruitment, especially for those who were reluctant to participate or receive a phone call from a stranger. The major challenges identified were (1) interruptions in workflow and (2) communication between CHWs and the health care practitioners (physicians, nurse practitioners, pharmacists). Specifically, the CHWs universally agreed that they needed more time after receiving patient report, scheduling a visit with the patient, and communicating with the patient's health care provider to better understand the individual's circumstances and needs. CONCLUSION: This study identified perceived opportunities and challenges faced by CHWs and chronically ill, rural Latinx patients in the acceptance of MTM program. These findings may be useful for all interprofessional health care team members to better understand and appreciate the role of CHWs, while simultaneously enhancing and improving respective medication adherence efforts, and to improve collaborative, academic community programs in the future.

Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents.

Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease ß-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 µM and 0.099 µM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.

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.

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.

Cryopreserved bovine spermatozoal transcript profile as revealed by high-throughput ribonucleic acid sequencing.

Ejaculated bovine spermatozoa retain a pool of RNAs that may have a function in early embryogenesis and be used as predictors of male fertility. The bovine spermatozoal transcript profile remains incomplete because previous studies have relied on hybridization-based techniques, which evaluate a limited pool of transcripts and cannot identify full-length transcripts. The goal of this study was to sequence the complete cryopreserved bovine spermatozoal transcript profile using Illumina RNA-Sequencing (RNA-Seq). Spermatozoal RNA was pooled from nine bulls with conception rate scores ranging from -2.9 to 3.5 and confirmed to exclude genomic DNA and somatic cell mRNA. After selective amplification of poly(A)(+) RNA and high-throughput sequencing, 6166 transcripts were identified via alignment to the bovine genome (UMD 3.1/bosTau6). RNA-Seq transcript levels (n = 9) were highly correlated with quantitative PCR copy number (r(2) = 0.9747). The bovine spermatozoal transcript profile is a heterogeneous population of degraded and full-length predominantly nuclear-encoded mRNAs. Highly abundant spermatozoal transcripts included PRM1, HMGB4, and mitochondrial-encoded transcripts. Full-length transcripts comprised 66% of the top 368 transcripts (fragments per kilobase of exon per million fragments mapped [FPKM] > 100) and amplification of the full-length transcript or 5' and 3' ends was confirmed for selected transcripts. In addition to the identification of transcripts not previously reported in spermatozoa, several known spermatozoal transcripts from various species were also found. Gene ontology analysis of the FPKM > 100 spermatozoal transcripts revealed that translation was the most predominant biological process represented. This is the first report of the spermatozoal transcript profile in any species using high-throughput sequencing, supporting the presence of mRNA in spermatozoa for further functional and fertility studies.

Difficulty giving feedback on underperformance undermines the educational value of multi-source feedback.

BACKGROUND: Multi-source feedback (MSF) was intended to provide both a summative and formative assessment of doctors' attitudes and behaviours. AIMS: To explore the influences of feedback quality and trainees' acceptance of the assessment on formative educational gains from MSF. METHODS: Semi-structured interviews were conducted with a convenience sample of eight dermatology trainees, from an insider researcher position, following two pilot interviews. Interviews were manually transcribed and coded to permit template analysis, a subtype of thematic analysis. RESULTS: The interview data indicated that MSF provides relatively little formative educational gains largely because of a paucity of constructive feedback on sub-optimal performance. This was due to difficulties encountered by raters giving developmental feedback, in particular, potential loss of anonymity, and by trainees selecting raters expected to give favourable comments. Dual use of MSF as a summative assessment in annual appraisals also inhibited educational gains by promotion of a 'tick box' mentality in which trainees' need to pass their assessment superseded their desire for self-improvement. CONCLUSIONS: A relative lack of developmental feedback limits the formative educational gains from MSF and could provide false reassurance that might reinforce negative behaviours.

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.

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.