A localizing nanocarrier formulation enables multi-target immune responses to multivalent replicating RNA with limited systemic inflammation.

RNA vaccines possess significant clinical promise in counteracting human diseases caused by infectious or cancerous threats. Self-amplifying replicon RNA (repRNA) has been thought to offer the potential for enhanced potency and dose sparing. However, repRNA is a potent trigger of innate immune responses in vivo, which can cause reduced transgene expression and dose-limiting reactogenicity, as highlighted by recent clinical trials. Here, we report that multivalent repRNA vaccination, necessitating higher doses of total RNA, could be safely achieved in mice by delivering multiple repRNAs with a localizing cationic nanocarrier formulation (LION). Intramuscular delivery of multivalent repRNA by LION resulted in localized biodistribution accompanied by significantly upregulated local innate immune responses and the induction of antigen-specific adaptive immune responses in the absence of systemic inflammatory responses. In contrast, repRNA delivered by lipid nanoparticles (LNPs) showed generalized biodistribution, a systemic inflammatory state, an increased body weight loss, and failed to induce neutralizing antibody responses in a multivalent composition. These findings suggest that in vivo delivery of repRNA by LION is a platform technology for safe and effective multivalent vaccination through mechanisms distinct from LNP-formulated repRNA vaccines.

Effect of Peripheral Magnetic Stimulation on Acute and Chronic Pain After Surgery: A Systematic Review and Meta-Analysis.

Peripheral magnetic stimulation (PMS) is a potentially promising modality to help manage postoperative pain. We systematically reviewed the effect of PMS on acute and chronic postoperative pain. MEDLINE, Cochrane CENTRAL, EMBASE, ProQuest Dissertations, and clinical trials.gov were searched from inception until May 2021. We included studies of any study design that included patients ≥18 years of age undergoing any type of surgery that administered PMS within the perioperative period and evaluated postoperative pain. Seventeen randomized controlled trials and 1 nonrandomized clinical trial were included into the review. Thirteen out of the 18 studies found a positive effect with PMS on postoperative pain scores. In our meta-analysis, peripheral magnetic stimulation was more efficacious than sham or no intervention within the first 7 postoperative days (mean difference [MD] -1.64 on a 0 to 10 numerical rating score, 95% confidence interval [CI] -2.08 to -1.20, I2 = 77%, 6 studies, 231 patients). This was also true at 1 and 2 months after surgery (MD -1.82, 95% CI -2.48 to -1.17, I2 = 0%, 3 studies, 104 patients; and MD -1.96, 95% CI -3.67 to -.26, I2 = 84%, 3 studies, 104 patients, respectively). A difference was not seen with persistent pain at 6 and 12-months after surgery, acute postoperative opioid consumption, or adverse events between groups. Results are limited by heterogeneity and generally low-quality studies, as well as low or very low quality of evidence. High-quality and adequately blinded trials are needed to definitively confirm the benefits of peripheral magnetic stimulation administered in the perioperative period. PERSPECTIVE: This review evaluates the efficacy and safety of PMS on postoperative pain. The results help elucidate PMS' role in postoperative pain management and identify gaps where more research is required.

Biochemical and clinical studies of putative allergens to assess what distinguishes them from other non-allergenic proteins in the same family.

Many protein families have numerous members listed in databases as allergens; however, some allergen database entries, herein called "orphan allergens", are members of large families of which all other members are not allergens. These orphan allergens provide an opportunity to assess whether specific structural features render a protein allergenic. Three orphan allergens [Cladosporium herbarum aldehyde dehydrogenase (ChALDH), Alternaria alternata ALDH (AaALDH), and C. herbarum mannitol dehydrogenase (ChMDH)] were recombinantly produced and purified for structure characterization and for clinical skin prick testing (SPT) in mold allergic participants. Examination of the X-ray crystal structures of ChALDH and ChMDH and a homology structure model of AaALDH did not identify any discernable epitopes that distinguish these putative orphan allergens from their non-allergenic protein relatives. SPT results were aligned with ChMDH being an allergen, 53% of the participants were SPT (+). AaALDH did not elicit SPT reactivity above control proteins not in allergen databases (i.e., Psedomonas syringae indole-3-acetaldehyde dehydrogenase and Zea mays ALDH). Although published results showed consequential human IgE reactivity with ChALDH, no SPT reactivity was observed in this study. With only one of these three orphan allergens, ChMDH, eliciting SPT(+) reactions consistent with the protein being included in allergen databases, this underscores the complicated nature of how bioinformatics is used to assess the potential allergenicity of food proteins that could be newly added to human diets and, when needed, the subsequent clinical testing of that bioinformatic assessment.Trial registration number and date of registration AAC-2017-0467, approved as WIRB protocol #20172536 on 07DEC2017 by WIRB-Copernicus (OHRP/FDA Registration #: IRB00000533, organization #: IORG0000432).

Factors Contributing to the Need for Non-Elective Explant following Surgical Repair of Tibial Tuberosity Avulsion Fracture.

OBJECTIVE: The aim of this study was to evaluate factors contributing to the need for non-elective explant following surgical repair of tibial tuberosity avulsion fractures. STUDY DESIGN: Retrospective multicentre case-control study. Over a 5-year period, dogs (n = 63) that underwent surgical repair of tibial tuberosity avulsion fractures (n = 64) were considered. Dogs that underwent a non-elective explant were compared with those that did not. Continuous variables were compared with the Mann-Whitney U test. Categorical variables were compared with the Fisher's exact test. Variables which were significant on univariate analysis were entered into a multiple logistic regression model. Significance was set at p < 0.05. RESULTS: Non-elective explant was performed in 20/64 fractures and elective explant was performed in 2/64 fractures. Neutered dogs were found to be 19 times (95% confidence interval: 2.1-172) more likely to require explant compared with intact dogs (p = 0.009). Every 0.25 mm increase in average pin size was found to make it 2.5 times (95% confidence interval: 1.3-4.9) more likely to require explant (p = 0.006). CONCLUSION: The findings suggest that use of the smallest appropriate pin should be considered for standard surgical repair of tibial tuberosity avulsion fractures to minimize the risk of requiring non-elective explant.

Virtual breakout rooms: an effective approach to offer guidance to medical students on residency applications.

Peer mentorship on residency applications has been difficult due to recent public health measures, prompting a shift from in-person events to virtual platforms. To address gaps in career exploration, we created a virtual, non-recorded space that allowed medical students and residents to discuss the Canadian Resident Matching Service (CaRMS) process meaningfully and transparently. Attendees reported a greater understanding of the match process and reduced anxiety after the event. This model provides a virtual framework that can be adapted for various mentorship opportunities.

Le mentorat par les pairs offert aux étudiants concernant les demandes de résidence a été difficile à mettre en œuvre en raison des récentes mesures de santé publique, entraînant le transfert des activités en personne vers les plateformes virtuelles. Pour combler les lacunes dans l'exploration des carrières, nous avons créé un espace virtuel, sans enregistrement, qui a permis aux étudiants et aux résidents de discuter du processus du Service canadien de jumelage des résidents (CaRMS) de manière approfondie et transparente. Les participants ont indiqué qu'à la suite de la rencontre, ils comprenaient mieux le processus de jumelage et qu'ils étaient moins anxieux. Ce modèle virtuel peut être adapté et utilisé pour diverses activités de mentorat.

High prevalence of Helicobacter pylori clarithromycin resistance mutations among Seattle patients measured by droplet digital PCR.

BACKGROUND: Treatment of Helicobacter pylori infection is often empiric; however, current guidelines for management of Helicobacter pylori infection advise against the use of standard triple therapy (clarithromycin, amoxicillin, and proton-pump inhibitor) when clarithromycin resistance exceeds 20%. We developed and tested a new culture-free assay to detect clarithromycin resistance-conferring mutations to determine the prevalence of H. pylori clarithromycin resistance in patients from the United States Pacific Northwest. MATERIALS AND METHODS: Droplet digital PCR (ddPCR) was used to detect the H. pylori 23S rRNA gene, and resistance-conferring mutations, in archived, formalin-fixed, paraffin-embedded (FFPE) gastric tissue and to retrospectively determine the prevalence of clarithromycin-resistant H. pylori among 110 patients at an academic medical center in the Northwest United States between 2012 and 2014. RESULTS: Of 102 patients with the H. pylori 23S rRNA gene detected by the ddPCR assay, 45 (44%) had clarithromycin resistance mutations. Thirty-three of the 45 patients with clarithromycin resistance mutations had a mix of wild-type and resistance alleles. Prevalence of clarithromycin resistance mutations differed among racial groups and was highest among Asians, with mutations detected in 14 (67%) of the 21 patient samples. CONCLUSIONS: The prevalence of clarithromycin resistance detected in this region exceeds 20%, indicating that standard triple therapy should not be the first-line antibiotic treatment for H. pylori infection. Culture-free assays for detecting clarithromycin resistance mutations can be performed on archived tissue samples and will aid in informing tailored treatment for effective H. pylori eradication.

Racial Differences in Mental Health Recovery among Veterans with Serious Mental Illness.

Black consumers with serious mental illness (SMI) face significant challenges in obtaining quality mental health care and are at risk for experiencing significant disparities in mental health care outcomes, including recovery from mental illness. Patient-provider interactions may partly contribute to this disparity. The purpose of the current study was to understand the effects of race, psychosis, and therapeutic alliance on mental health recovery orientation among Veterans with SMI. Participants were Veterans who had an SMI being treated at two Veteran Affairs outpatient mental health clinics by a psychiatrist or nurse practitioner. Participants completed the Behavior and Symptom Identification Scale (BASIS-24), Mental Health Recovery Measure, and patient-report Scale to Assess the Therapeutic Relationship (STAR-P) which includes three subscales: positive collaboration, positive clinician input, and non-supportive clinician input. Regression analyses were used to determine interactive effects of race, psychosis severity, and therapeutic alliance variables. The sample was 226 Veterans (50% black, 50% white). Black participants were slightly older (p < .05), had higher baseline psychosis (p < .05), higher mental health recovery (p < .05), and perceived less non-supportive clinician input (p < .01) than white participants. Regression analyses indicated a significant three-way interaction among race, psychosis, and positive collaboration (p < .01). Greater positive collaboration attenuated the negative effect of higher levels of psychosis on mental health recovery orientation for black participants. Conversely, for white participants, positive collaboration had little effect on the negative relationship between psychosis severity and mental health recovery orientation. Increased levels of psychosis may inhibit patients' perceptions of their ability to recover from SMI. However, for black participants, positive collaboration with mental health providers may moderate the effects of psychotic symptomatology.

Predictors of Employment Burnout Among VHA Peer Support Specialists.

OBJECTIVE: This study evaluated three domains of job burnout (emotional exhaustion, depersonalization, and personal accomplishment) and factors associated with burnout in a national sample of peer specialists (PSs) employed at 138 Veterans Health Administration (VHA) health care systems in 49 states. METHODS: Data were drawn from an observational study in which participants (N=152) completed online, self-report surveys about their mental health recovery, quality of life, and employment experiences at baseline, six months, and 12 months. Levels of burnout were analyzed at each time point, and regression analyses that controlled for baseline levels identified potential predictors of burnout (demographic, clinical, and employment characteristics) at six and 12 months. RESULTS: Compared with previously published burnout levels of other mental health workers in the VHA, PSs reported similar levels of emotional exhaustion, depersonalization, and personal accomplishment. At baseline, increased burnout was correlated with white race, fewer hours providing direct services, greater psychiatric symptoms, and lower self-efficacy. However, analyses did not reveal strong predictors of burnout scores at six or 12 months. CONCLUSIONS: In the first study to prospectively examine job burnout among PSs employed by the VHA, results illustrate the nuanced experience of burnout over a 12-month period and suggest the need for replication and further research on employment experiences of this emerging workforce.

Predictors of patient communication in psychiatric medication encounters among veterans with serious mental illnesses.

OBJECTIVE: Person-centered psychiatric services rely on consumers actively sharing personal information, opinions, and preferences with their providers. This research examined predictors of consumer communication during appointments for psychiatric medication prescriptions. METHODS: The Roter Interaction Analysis System was used to code recorded Veterans Affairs psychiatric appointments with 175 consumers and 21 psychiatric medication prescribers and categorize communication by purpose: biomedical, psychosocial, facilitation, or rapport-building. RESULTS: Regression analyses found that greater provider communication, symptomology, orientation to psychiatric recovery, and functioning on the Repeatable Battery for the Assessment of Neuropsychological Status Attention and Language indices, as well as consumer diagnostic label, were positive predictors of consumer communication, though the types of communication impacted varied. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Provider communication is the easiest variable to intervene on to create changes in consumer communication. Future research should also consider how cognitive and symptom factors may impact specific types of consumer communication in order to identify subgroups for targeted interventions. (PsycINFO Database Record

The interactive effects of negative symptoms and social role functioning on suicide ideation in individuals with schizophrenia.

Findings regarding the protective effect of social role functioning on suicide ideation in individuals with schizophrenia have been mixed. One reason for such inconsistencies in the literature may be that individuals with prominent negative symptoms of schizophrenia may not experience a desire for social closeness, and therefore social role functioning may not influence suicide risk in these individuals. The aim of this study was to examine the moderating effects of self-reported desire for social closeness and interviewer-rated negative symptoms on the relationship between social role functioning and suicide ideation. Our sample consisted of 162 individuals who had been diagnosed with schizophrenia-spectrum disorders; all participants completed self-report questionnaires and clinician-administered interviews, and moderation hypotheses were tested with a non-parametric procedure. The results indicated that motivation and pleasure-related negative symptoms moderated the relationship between social role functioning and suicide ideation; self-reported desire for social closeness and negative symptoms related to expression did not have such a moderating effect. Specifically, better social role functioning was associated with less suicide ideation only in those individuals who had low motivation and pleasure-related negative symptoms; no significant relationship was observed between social role functioning and suicide ideation among those with elevated motivation and pleasure-related negative symptoms. These findings suggest that assessing for negative symptoms and social role functioning may inform suicide risk assessments in individuals with schizophrenia, and improving social role functioning may reduce suicide ideation among those with few motivation and pleasure-related negative symptoms.

Access to and Use of the Internet by Veterans with Serious Mental Illness.

This study evaluated internet use among 239 veterans with serious mental illness who completed questionnaires assessing demographics and internet use in 2010-2011. The majority of individuals (70 %) reported having accessed the internet and among those, 79 % had accessed it within the previous 30 days. Those who were younger and more educated were more likely to have accessed the internet, as were those with a schizophrenia spectrum disorder, bipolar disorder, or major depressive disorder, compared to individuals with PTSD. Veterans with serious mental illness commonly use the internet, including to obtain health information, though use varies across demographic characteristics and clinical diagnosis.

Social affiliation and negative symptoms in schizophrenia: Examining the role of behavioral skills and subjective responding.

Schizophrenia is characterized by profound impairment in the motivation for social affiliation. Negative symptoms are associated with such impairment but the contribution of behavioral skill deficits is unclear. In this study we utilized a novel video paradigm to assess performance-based affiliative behavioral skills in individuals with schizophrenia (N=48) and community controls (N=29). Individuals with schizophrenia displayed significant impairment in behavioral affiliative skills compared to controls; however, in response to the affiliative interaction the groups did not differ on self-reported affective responding, appraisal of the interaction partner, or desire to interact with the partner in the future. Importantly, within the patient group more severe negative symptoms (particularly those related to motivation and pleasure) were associated with poorer affiliative social skills and this relationship was independent of instrumental (non-social) skills, depression or positive symptoms. More severe negative symptoms were also associated with less positive affect in response to the interaction and less positive appraisals of the interaction partner. Self-reported social anhedonia was related to patients' diminished willingness to interact with the partner in the future. These results demonstrate that negative symptoms in schizophrenia are related to both affiliative skill deficits and less affiliative subjective responses to interaction partners.

Mentoring the next generation of neuroscience nurses: a pilot study of mentor engagement within an academic-service partnership.

Resulting from a system-wide launch of an academic-service partnership that united a research-intensive School of Nursing and a tertiary healthcare system, neuroscience nurses used a team-based approach in mentoring undergraduate nursing students in neuroscience nursing. They linked their team approach to the Institute of Medicine's Future of Nursing report and American Association of Neuroscience Nurses' (2012) strategic plan to prepare neuroscience nurses for the future. Using case reports containing both the mentors' and students' perspective, we showcase sophomore nursing students' development in neuroscience nursing with focus on their developing skills in competency, leadership, and collaboration. Results from this implementation phase include improved reliability in performing undergraduate neurological assessments; developing competency in collaborating with the health team using a culturally sensitive approach; beginning leadership in managing a patient with seizures; and collaborating with families in patient-family-focused care. Evaluation of the effectiveness of this mentored approach to clinical undergraduate nursing education will focus on confidence building for students and mentors.

Consumer satisfaction with psychiatric services: The role of shared decision making and the therapeutic relationship.

OBJECTIVE: Although dissatisfaction is a primary reason for disengagement from outpatient psychiatric care among consumers with serious mental illnesses, little is known about predictors of their satisfaction with medication management visits. The primary purpose of this study was to explore how dimensions of consumer preferences for shared decision making (i.e., preferences for obtaining knowledge about one's mental illness, being offered and asked one's opinion about treatment options, and involvement in treatment decisions) and the therapeutic relationship (i.e., positive collaboration and type of clinician input) were related to visit satisfaction. METHODS: Participants were 228 Veterans with serious mental illnesses who completed a 19-item self-report questionnaire assessing satisfaction with visits to prescribers (524 assessments) immediately after visits. In this correlational design, a 3-level mixed model with the restricted maximum likelihood estimation procedure was used to examine shared decision-making preferences and therapeutic alliance as predictors of visit satisfaction. RESULTS: Preferences for involvement in treatment decisions was the unique component of shared decision making associated with satisfaction, such that the more consumers desired involvement, the less satisfied they were. Positive collaboration and prescriber input were associated with greater visit satisfaction. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: When consumers with serious mental illnesses express preferences to be involved in shared decision making, it may not be sufficient to only provide information and treatment options; prescribers should attend to consumers' interest in involvement in actual treatment decisions. Assessment and tailoring of treatment approaches to consumer preferences for shared decision making should occur within the context of a strong therapeutic relationship.

Factors associated with shared decision-making preferences among veterans with serious mental illness.

OBJECTIVE: This study evaluated preferences for shared decision making with respect to mental health treatment in a sample of veterans who were diagnosed as having serious mental illness. METHODS: Participants were 239 outpatients receiving care from the Department of Veterans Affairs who completed self-report questionnaires assessing demographic factors, shared decision-making preferences, psychiatric symptom severity, and the therapeutic relationship with their second-generation antipsychotic prescribers (N=21). Preferences were assessed in regard to three components of decision making: knowledge about mental illness, options about mental health treatment, and decisions about mental health care. RESULTS: Most participants (85%) indicated that they preferred to be offered options and to be asked their opinions about mental health treatment. More variability was noted in preferences for obtaining knowledge and making final treatment decisions; 61% preferred to rely on their providers' knowledge and 64% preferred their provider to make treatment final decisions. Greater preferences for participation in shared decision making were found among African American clients, those currently working for pay, those with college or higher education, those with other than a schizophrenia spectrum diagnosis, and those who reported a poorer therapeutic relationship with their prescribers. CONCLUSIONS: The degree to which veterans with serious mental illness desired to participate in their mental health care differed in terms of the aspect of care and across demographic and clinical factors. A thorough assessment of shared decision-making preferences is an important component of recovery-oriented, client-centered care.

Search strategies in systematic reviews in periodontology and implant dentistry.

OBJECTIVE: To perform an overview of literature search strategies in systematic reviews (SRs) published in periodontology and implant dentistry. MATERIALS AND METHODS: Two electronic databases (PubMed and Cochrane Database of SRs) were searched, independently and in duplicate, for SRs with meta-analyses on interventions, with the last search performed on 11 November 2012. Manual searches of the reference lists of included SRs and 10 specialty dental journals were conducted. Methodological issues of the search strategies of included SRs were assessed with Cochrane collaboration guidelines and AMSTAR recommendations. The search strategies employed in Cochrane and paper-based SRs were compared. RESULTS: A total of 146 SRs with meta-analyses were included, including 19 Cochrane and 127 paper-based SRs. Some issues, such as "the use of keywords," were reported in most of the SRs (86%). Other issues, such as "search of grey literature" and "language restriction," were not fully reported (34% and 50% respectively). The quality of search strategy reporting in Cochrane SRs was better than that of paper-based SRs for seven of the eight criteria assessed. CONCLUSION: There is room for improving the quality of reporting of search strategies in SRs in periodontology and implant dentistry, particularly in SRs published in paper-based journals.

Caspase 9 is constitutively activated in mouse oocytes and plays a key role in oocyte elimination during meiotic prophase progression.

In many mammalian species, more than half of the initial oocyte population is eliminated by neonatal life, thus limiting the oocyte reserve for reproduction. The cause or mechanism of this major oocyte loss remains poorly understood. We examined the apoptotic pathway involved in oocyte elimination in wild-type mouse ovaries as well as in Msh5 -/- ovaries, in which all oocytes were eliminated due to a lack of double strand break repair. Immunoblot and immunofluorescence staining showed that an initiator caspase 9 and an effector caspase 7 were constitutively activated in almost all oocytes in fetal ovaries regardless of their genotypes. In caspase 9 -/- ovaries, the total number of oocytes remained high while that in wild-type ovaries steadily declined during ovarian development. Therefore, the activation of caspase 9 was required for but did not immediately lead to oocyte demise. We found that XIAP, an endogenous inhibitor of apoptosis, was also abundant in oocytes during meiotic prophase progression. On the other hand, a cleaved form of PARP1, a target of effector caspases, was localized to the nuclei of a limited number of oocytes, and the frequency of cleaved PARP1-positive oocyte nuclei increased significantly higher before all oocytes disappeared in Msh5 -/- ovaries. We conclude that the mitochondrial apoptotic pathway mediated by caspase 9 is constitutively activated in oocytes and renders the elimination of oocytes with meiotic errors, which can be captured by the cleavage of PARP1.

The Motivation and Pleasure Scale-Self-Report (MAP-SR): reliability and validity of a self-report measure of negative symptoms.

The Clinical Assessment Interview for Negative Symptoms (CAINS) is an empirically developed interview measure of negative symptoms. Building on prior work, this study examined the reliability and validity of a self-report measure based on the CAINS-the Motivation and Pleasure Scale-Self-Report (MAP-SR)-that assesses the motivation and pleasure domain of negative symptoms. Thirty-seven participants with schizophrenia or schizoaffective disorder completed the 18-item MAP-SR, the CAINS, and other measures of functional outcome. Item analyses revealed three items that performed poorly. The revised 15-item MAP-SR demonstrated good internal consistency and convergent validity with the clinician-rated Motivation and Pleasure scale of the CAINS, as well as good discriminant validity, with little association with psychotic symptoms or depression/anxiety. MAP-SR scores were related to social anhedonia, social closeness, and clinician-rated social functioning. The MAP-SR is a promising self-report measure of severity of negative symptoms.