Orientia tsutsugamushi Stimulates an Original Gene Expression Program in Monocytes: Relationship with Gene Expression in Patients with Scrub Typhus

Orientia tsutsugamushi is the causal agent of scrub typhus, a public health problem in the Asia-Pacific region and a life-threatening disease. O. tsutsugamushi is an obligate intracellular bacterium that mainly infects endothelial cells. We demonstrated here that O. tsutsugamushi also replicated in monocytes isolated from healthy donors. In addition, O. tsutsugamushi altered the expression of more than 4,500 genes, as demonstrated by microarray analysis. The expression of type I interferon, interferon-stimulated genes and genes associated with the M1 polarization of macrophages was significantly upregulated. O. tsutsugamushi also induced the expression of apoptosis-related genes and promoted cell death in a small percentage of monocytes. Live organisms were indispensable to the type I interferon response and apoptosis and enhanced the expression of M1-associated cytokines. These data were related to the transcriptional changes detected in mononuclear cells isolated from patients with scrub typhus. Here, the microarray analyses revealed the upregulation of 613 genes, which included interferon-related genes, and some features of M1 polarization were observed in these patients, similar to what was observed in O. tsutsugamushi-stimulated monocytes in vitro. This is the first report demonstrating that monocytes are clearly polarized in vitro and ex vivo following exposure to O. tsutsugamushi. These results would improve our understanding of the pathogenesis of scrub typhus, during which interferon-mediated activation of monocytes and their subsequent polarization into an M1 phenotype appear critical. This study may give us a clue of new tools for the diagnosis of patients with scrub typhus

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy

Background: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. Objective: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. Methods: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non-oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. Results: For non-OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. Conclusions: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction

An interactive computer program can effectively educate patients about genetic testing for breast cancer susceptibility

As genetic testing for susceptibility to breast cancer becomes more widespread, alternative methods for educating individuals prior to testing will be needed. Our objective was to compare face-to-face education and counseling by a genetic counselor with education by an interactive computer program, assessing the effects of each on knowledge of breast cancer genetics and intent to undergo genetic testing. We used a randomized, controlled trial. Seventy-two self-referred women with a first-degree relative with breast cancer received outpatient education and counseling at the Clinical Center of the National Institutes of Health (NIH). Twenty-nine received individualized counseling from a genetic counselor (counseling group), 29 received education from an interactive computer program followed by individualized counseling (computer group), and 14 were controls. Both pre- and postintervention assessment of knowledge about breast cancer genetics and intent to undergo genetic testing were measured. The control group participants correctly answered 74% of the knowledge questions; the counselor group, 92%; and the computer group, 96% (P P = .048), but they were equivalent when adjusted for demographic differences (P = 0.34). Intent to undergo genetic testing was influenced by the interventions: preintervention, a majority in all groups (69%) indicated that they were likely (definitely and most likely) to undergo testing; after either intervention coupled with counseling, only 44% indicated that they were likely to do so (P = .0002; odds ratio = 2.8, 95% CI = 1.7–4.9). We concluded that a computer program can successfully educate patients about breast cancer susceptibility, and, along with genetic counseling, can influence patients' intentions to undergo genetic testing

Faculty development to enhance humanistic teaching and role modeling: a collaborative study at eight institutions.

BackgroundThere is increased emphasis on practicing humanism in medicine but explicit methods for faculty development in humanism are rare.ObjectiveWe sought to demonstrate improved faculty teaching and role modeling of humanistic and professional values by participants in a multi-institutional faculty development program as rated by their learners in clinical settings compared to contemporaneous controls.DesignBlinded learners in clinical settings rated their clinical teachers, either participants or controls, on the previously validated 10-item Humanistic Teaching Practices Effectiveness (HTPE) questionnaire.ParticipantsGroups of 7-9 participants at 8 academic medical centers completed an 18-month faculty development program. Participating faculty were chosen by program facilitators at each institution on the basis of being promising teachers, willing to participate in the longitudinal faculty development program.InterventionOur 18-month curriculum combined experiential learning of teaching skills with critical reflection using appreciative inquiry narratives about their experiences as teachers and other reflective discussions.Main measuresThe main outcome was the aggregate score of the ten items on the questionnaire at all institutions.Key resultsThe aggregate score favored participants over controls (P = 0.019) independently of gender, experience on faculty, specialty area, and/or overall teaching skills.ConclusionsLongitudinal, intensive faculty development that employs experiential learning and critical reflection likely enhances humanistic teaching and role modeling. Almost all participants completed the program. Results are generalizable to other schools

Faculty Development to Enhance Humanistic Teaching and Role Modeling: A Collaborative Study at Eight Institutions

BACKGROUND: There is increased emphasis on practicing humanism in medicine but explicit methods for faculty development in humanism are rare. OBJECTIVE: We sought to demonstrate improved faculty teaching and role modeling of humanistic and professional values by participants in a multi-institutional faculty development program as rated by their learners in clinical settings compared to contemporaneous controls. DESIGN: Blinded learners in clinical settings rated their clinical teachers, either participants or controls, on the previously validated 10-item Humanistic Teaching Practices Effectiveness (HTPE) questionnaire. PARTICIPANTS: Groups of 7-9 participants at 8 academic medical centers completed an 18-month faculty development program. Participating faculty were chosen by program facilitators at each institution on the basis of being promising teachers, willing to participate in the longitudinal faculty development program. INTERVENTION: Our 18-month curriculum combined experiential learning of teaching skills with critical reflection using appreciative inquiry narratives about their experiences as teachers and other reflective discussions. MAIN MEASURES: The main outcome was the aggregate score of the ten items on the questionnaire at all institutions. KEY RESULTS: The aggregate score favored participants over controls (P = 0.019) independently of gender, experience on faculty, specialty area, and/or overall teaching skills. CONCLUSIONS: Longitudinal, intensive faculty development that employs experiential learning and critical reflection likely enhances humanistic teaching and role modeling. Almost all participants completed the program. Results are generalizable to other schools