Safety outcomes of apixaban in patients with nonvalvular atrial fibrillation and severe renal impairment.

Apixaban is prescribed for stroke prevention in nonvalvular atrial fibrillation (NVAF) in patients with varying degrees of renal dysfunction. While pharmacokinetic data support apixaban in severe renal impairment, clinical safety outcomes data are limited. This retrospective cohort analysis was conducted to evaluate the safety of apixaban in patients with NVAF and renal impairment. A total of 340 patients with NVAF receiving apixaban 5 mg or 2.5 mg twice daily were included for analysis; 287 preserved renal function (pRF: CrCl ≥ 25 ml/min and SCr ≤ 2.5 mg/dl) and 53 impaired renal function (iRF: CrCl < 25 ml/min and/or SCr > 2.5 mg/dl). The primary endpoint was major bleeding in patients taking apixaban 5 mg. Secondary endpoints included major bleeding with apixaban 2.5 mg and minor bleeding in both groups. There was no difference in major bleeding events in the 5 mg pRF group (4.41%) versus iRF group (3.57%) (P = 0.66). Similar rates occurred between the 2.5 mg pRF and iRF groups. Minor bleeding events were similar regardless of renal function. The incidence of bleeding in the 5 mg group was 11.45% with pRF versus 10.71% with iRF (P = 0.6). In the 2.5 mg group, bleeding incidence was 10% with pRF versus 16% with iRF (P = 0.47). There were no observed differences in bleeding between groups with pRF or iRF, regardless of apixaban dose. Because patients with severe renal impairment were excluded from original trials, this study contributes clinical safety outcomes to the limited data for use of apixaban in this patient population.

Macrophage-Lineage Cells Negatively Regulate the Hematopoietic Stem Cell Pool in Response to Interferon Gamma at Steady State and During Infection.

Bone marrow (BM) resident macrophages (Mϕs) regulate hematopoietic stem cell (HSC) mobilization; however, their impact on HSC function has not been investigated. We demonstrate that depletion of BM resident Mϕs increases HSC proliferation as well as the pool of quiescent HSCs. At the same time, during bacterial infection where BM resident Mϕs are selectively increased we observe a decrease in HSC numbers. Moreover, strategies that deplete or reduce Mϕs during infection prevent HSC loss and rescue HSC function. We previously found that the transient loss of HSCs during infection is interferon-gamma (IFNγ)-dependent. We now demonstrate that IFNγ signaling specifically in Mϕs is critical for both the diminished HSC pool and maintenance of BM resident Mϕs during infection. In addition to the IFNγ-dependent loss of BM HSC and progenitor cells (HSPCs) during infection, IFNγ reduced circulating HSPC numbers. Importantly, under infection conditions AMD3100 or G-CSF-induced stem cell mobilization was impaired. Taken together, our data show that IFNγ acts on Mϕs, which are a negative regulator of the HSC pool, to drive the loss in BM and peripheral HSCs during infection. Our findings demonstrate that modulating BM resident Mϕ numbers can impact HSC function in vivo, which may be therapeutically useful for hematologic conditions and refinement of HSC transplantation protocols.

MyD88 signaling in CD4 T cells promotes IFN-γ production and hematopoietic progenitor cell expansion in response to intracellular bacterial infection.

Hematopoietic stem and progenitor cell (HSPC) phenotype and function can change in response to infectious challenge. These changes can be mediated by cytokines, IFNs, and pathogen-associated molecules, via TLR, and are thought to promote tailored immune responses for particular pathogens. In this study, we investigated the signals that activate HSPCs during ehrlichiosis, a disease characterized by profound hematopoietic dysfunction in both humans and mice. In a mouse model of ehrlichiosis, we observed that infection-induced proliferation of bone marrow HSPCs was dependent on IFN-γ signaling and was partially dependent on MyD88. However, MyD88 was not required in HSPCs for their expansion during infection, because similar frequencies of MyD88-deficient and wild-type HSPCs proliferated in mixed bone marrow chimeric mice. MyD88-deficient mice exhibited low serum and bone marrow concentration of IFN-γ compared with wild-type mice. We next identified CD4 T cells as the primary cells producing IFN-γ in the bone marrow and demonstrated a nonredundant role for CD4-derived IFN-γ in increased HSPCs. Using mixed bone marrow chimeric mice, we identified a requirement for MyD88 in CD4 T cells for increased T-bet expression, optimal IFN-γ production, and CD4 T cell proliferation. Our data demonstrate an essential role for CD4 T cells in mediating HSPC activation in response to bacterial infection and illustrate a novel role for MyD88 signaling in CD4 T cells in this process. These findings further support the idea that IFN-γ production is essential for HSPC activation and hematopoietic responses to infection.

Type I interferons promote severe disease in a mouse model of lethal ehrlichiosis.

Human monocytic ehrlichiosis (HME) is caused by a tick-borne obligate intracellular pathogen of the order Rickettsiales. HME disease can range from mild to a fatal, toxic shock-like syndrome, yet the mechanisms regulating pathogenesis are not well understood. We define a central role for type I interferons (alpha interferon [IFN-α] and IFN-ß) in severe disease in a mouse model of fatal ehrlichiosis caused by Ixodes ovatus Ehrlichia (IOE). IFN-α and IFN-ß were induced by IOE infection but not in response to a less virulent strain, Ehrlichia muris. The major sources of type I IFNs during IOE infection were plasmacytoid dendritic cells and monocytes. Mice lacking the receptor for type I IFNs (Ifnar deficient) or neutralization of IFN-α and IFN-ß resulted in a reduced bacterial burden. Ifnar-deficient mice exhibited significantly increased survival after IOE infection, relative to that of wild-type (WT) mice, that correlated with increased type II IFN (IFN-γ) production. Pathogen-specific antibody responses were also elevated in Ifnar-deficient mice, and this required IFN-γ. Remarkably, increased IFN-γ and IgM were not essential for protection in the absence of type I IFN signaling. The direct effect of type I IFNs on hematopoietic and nonhematopoietic cells was evaluated in bone marrow chimeric mice. We observed that chimeric mice containing Ifnar-deficient hematopoietic cells succumbed to infection early, whereas Ifnar-deficient mice containing WT hematopoietic cells exhibited increased survival, despite having a higher bacterial burden. These data demonstrate that IFN-α receptor signaling in nonhematopoietic cells is important for pathogenesis. Thus, type I IFNs are induced during a rickettsial infection in vivo and promote severe disease.

B cell activating factor inhibition impairs bacterial immunity by reducing T cell-independent IgM secretion.

B cell activating factor of the tumor necrosis factor family (BAFF) is an essential survival factor for B cells and has been shown to regulate T cell-independent (TI) IgM production. During Ehrlichia muris infection, TI IgM secretion in the spleen was BAFF dependent, and antibody-mediated BAFF neutralization led to an impairment of IgM-mediated host defense. The failure of TI plasmablasts to secrete IgM was not a consequence of alterations in their generation, survival, or early differentiation, since all occurred normally in infected mice following BAFF neutralization. Gene expression characteristic of plasma cell differentiation was also unaffected by BAFF neutralization in vivo, and except for CD138, plasmablast cell surface marker expression was unaffected. IgM was produced, since it was detected intracellularly, and impaired secretion was not due to a failure to express the IgM secretory exon. Addition of BAFF to plasmablasts in vitro rescued IgM secretion, suggesting that BAFF signaling can directly regulate secretory processes. Our findings indicate that BAFF signaling can modulate TI host defense by acting at a late stage in B cell differentiation, via its regulation of terminal plasmablast differentiation and/or IgM secretion.

Human Immunodeficiency Virus in Pregnancy.

Approximately 5000 people living with human immunodeficiency virus (HIV) give birth each year. Perinatal transmission of HIV will occur in about 15% to 45% of pregnancies without treatment. With appropriate antiretroviral therapy for pregnant people as well as appropriate intrapartum and postpartum interventions, the rate of perinatal transmission can be reduced to less than 1%. Antiretroviral therapy will also reduce health risks for pregnant patients living with HIV. All pregnant people should be offered the opportunity to learn their HIV status and access treatment as needed.

Evaluation of student-perceived growth in entrustable professional activities after involvement in a transitions-of-care process within an adult medicine advanced pharmacy practice experience.

BACKGROUND AND PURPOSE: Involvement of pharmacists and trainees in care transitions reduces medication-related problems. Participation in the transitions-of-care (TOC) process may impact self-perceived growth of autonomy within selected entrustable professional activities (EPAs). EDUCATIONAL ACTIVITY AND SETTING: A student-driven TOC documentation process was implemented within an inpatient family medicine advanced pharmacy practice experience. During the month-long rotation, students rounded with an interdisciplinary care team. Responsibilities included ensuring accurate medication reconciliation at care transitions throughout hospitalization and prior to discharge as well as medication optimization during hospitalization. Another responsibility was completing a medication-specific TOC note in the clinic-based electronic health record at discharge for patients receiving primary care from the associated clinic. The note was available to the outpatient interdisciplinary care team during the hospital follow-up appointment. Student-perceived growth in autonomy within selected EPAs was determined through an online anonymous survey. FINDINGS: Ninety percent (n = 18) of eligible students completed the survey. For specific EPA statements (collecting information, establishing patient-centered goals and establishing a care plan, implementing a care plan, collaborating as an interdisciplinary team member, and ensuring immunization), student-perceived autonomy increased after involvement in this student-driven TOC process. During the study period, 215 notes were generated by student pharmacists and included interventions/recommendations within the following themes: evidence-based changes in therapy, patient counseling, and medication access. SUMMARY: The importance of pharmacist and pharmacy trainee involvement in the TOC process has been well-documented. Involving students in student-driven TOC documentation processes serves to facilitate student-perceived growth in autonomy within selected EPAs.

Impact of the COVID-19 Pandemic on the Emotional Intelligence of Student Pharmacist Leaders.

Objective. To assess changes in Emotional Intelligence Appraisal (EIA) scores following the COVID-19 pandemic for pharmacy students within a voluntary cocurricular leadership development program.Methods. Participants from the class of 2021 (pandemic group) completed an EIA self-assessment near the beginning of the leadership program in August 2019 (pre-pandemic) and at the end of the program in July 2020 (during peak first-wave COVID-19 activity) and wrote an accompanying self-reflection. To determine changes in students' emotional intelligence potentially attributable to COVID-19, differences in EIA scores from the pandemic group were compared to the pooled results of previous program cohorts (classes of 2017-2019). Prevalent themes in student self-reflections were also highlighted.Results. Thirty-five student leaders comprised the pandemic group, with 166 students included within the control group. The proportion of students with final EIA scores indicating high emotional intelligence was greater within the pandemic group (74.3% vs 50.6%). While both groups had increased final EIA scores compared to baseline values, score increases were significantly higher among students in the pandemic group with respect to overall emotional intelligence and relationship management. Students commented that the pandemic highlighted the importance of emotional intelligence during stressful situations, although the lack of in-person interaction was noted as a limitation for social development.Conclusion. Pharmacy students participating in a leadership development program during the COVID-19 pandemic experienced greater increases in emotional intelligence than did the program's pre-pandemic cohorts. This may support the ability of health professional students to maintain resiliency through the pandemic and develop both personal and interpersonal relationship-building skills.

A functional magnetic resonance imaging investigation of verbal working memory in adolescents with specific language impairment.

This study used neuroimaging and behavioral techniques to examine the claim that processing capacity limitations underlie specific language impairment (SLI). Functional magnetic resonance imaging (fMRI) was used to investigate verbal working memory in adolescents with SLI and normal language (NL) controls. The experimental task involved a modified listening span measure that included sentence encoding and recognition of final words in prior sets of sentences. The SLI group performed significantly poorer than the NL group for both encoding and recognition and displayed slower reaction times for correct responses on high complexity encoding items. fMRI results revealed that the SLI group exhibited significant hypoactivation during encoding in regions that have been implicated in attentional and memory processes, as well as hypoactivation during recognition in regions associated with language processing. Correlational analyses indicated that adolescents with SLI exhibited different patterns of coordinating activation among brain regions relative to controls for both encoding and recognition, suggesting reliance on a less functional network. These findings are interpreted as supporting the notion that constraints in nonlinguistic systems play a role in SLI.

Transient activation of hematopoietic stem and progenitor cells by IFNγ during acute bacterial infection.

How hematopoietic stem cells (HSCs) respond to inflammatory signals during infections is not well understood. Our studies have used a murine model of ehrlichiosis, an emerging tick-born disease, to address how infection impacts hematopoietic function. Infection of C57BL/6 mice with the intracellular bacterium, Ehrlichia muris, results in anemia and thrombocytopenia, similar to what is observed in human ehrlichiosis patients. In the mouse, infection promotes myelopoiesis, a process that is critically dependent on interferon gamma (IFNγ) signaling. In the present study, we demonstrate that E. muris infection also drives the transient proliferation and expansion of bone marrow Lin-negative Sca-1(+) cKit(+) (LSK) cells, a population of progenitor cells that contains HSCs. Expansion of the LSK population in the bone marrow was associated with a loss of dormant, long-term repopulating HSCs, reduced engraftment, and a bias towards myeloid lineage differentiation within that population. The reduced engraftment and myeloid bias of the infection-induced LSK cells was transient, and was most pronounced on day 8 post-infection. The infection-induced changes were accompanied by an expansion of more differentiated multipotent progenitor cells, and required IFNγ signaling. Thus, in response to inflammatory signals elicited during acute infection, HSCs can undergo a rapid, IFNγ-dependent, transient shift from dormancy to activity, ostensibly, to provide the host with additional or better-armed innate cells for host defense. Similar changes in hematopoietic function likely underlie many different infections of public health importance.