A biparatopic agonistic antibody that mimics fibroblast growth factor 21 ligand activity.

Bispecific antibodies have become important formats for therapeutic discovery. They allow for potential synergy by simultaneously engaging two separate targets and enable new functions that are not possible to achieve by using a combination of two monospecific antibodies. Antagonistic antibodies dominate drug discovery today, but only a limited number of agonistic antibodies (i.e. those that activate receptor signaling) have been described. For receptors formed by two components, engaging both of these components simultaneously may be required for agonistic signaling. As such, bispecific antibodies may be particularly useful in activating multicomponent receptor complexes. Here, we describe a biparatopic (i.e. targeting two different epitopes on the same target) format that can activate the endocrine fibroblast growth factor (FGF) 21 receptor (FGFR) complex containing ß-Klotho and FGFR1c. This format was constructed by grafting two different antigen-specific VH domains onto the VH and VL positions of an IgG, yielding a tetravalent binder with two potential geometries, a close and a distant, between the two paratopes. Our results revealed that the biparatopic molecule provides activities that are not observed with each paratope alone. Our approach could help address the challenges with heterogeneity inherent in other bispecific formats and could provide the means to adjust intramolecular distances of the antibody domains to drive optimal activity in a bispecific format. In conclusion, this format is versatile, is easy to construct and produce, and opens a new avenue for agonistic antibody discovery and development.

CellCelector™ as a platform in isolating primary B cells for antibody discovery.

The most robust strategy in antibody discovery is the use of immunized animals and the ability to isolate and immortalize immune B-cells to hybridoma for further interrogation. However, capturing the full repertoire of an immunized animal is labor intensive, time consuming and limited in throughput. Therefore, techniques to directly mine the antibody repertoire of primary B-cells are of great importance in antibody discovery. In the current study, we present a method to isolate individual antigen-specific primary B-cells using the CellCellector™ single-cell isolation platform from XenoMouse® (XM) immunized with a recombinant therapeutic protein, EGFR. We screened a subset of CD138+ B-cells and identified 238 potential EGFR-specific B-cells from 1189 antibody-secreting cells (ASCs) and isolated 94 by CellCellector. We identified a diverse set of heavy chain complementarity-determining region sequences and cloned and expressed 20 into a standard human immunoglobulin G1 antibody format. We further characterized and identified 13 recombinant antibodies that engage soluble and native forms of EGFR. By extrapolating the method to all 400 000 CD138+ B-cells extracted from one EGFR immunized XM, a potential 1196 unique EGFR-specific antibodies could be discovered. CellCelector allows for interrogating the B-cell pool directly and isolating B-cells specific to the therapeutic target of interest. Furthermore, antibody sequences recovered from isolated B-cells engage the native and recombinant target, demonstrating the CellCellector can serve as a platform in antibody discovery.

Readiness for practice: the senior practicum experience.

Nursing students must be prepared to enter the practice environment ready to competently care for patients. The purpose of this study was to examine factors hypothesized to influence senior nursing students' perceptions of readiness for practice and to determine their level of comfort performing skills independently. This study also validates an investigator-developed instrument, the Casey-Fink Readiness for Practice Survey. Factor loading indicated four components tested by subscales in the survey: clinical problem solving, learning techniques, professional identity, and trials and tribulations. The greatest challenges reported by students were managing multiple patient care assignments, communicating with physicians, and caring for dying patients. Clinical competency, role development, and career planning support were areas in which students desired more assistance during their senior practicum course. Most survey respondents voiced confidence in their ability to problem solve and felt ready to assume the professional nursing role.

Twenty-first century doctoral education: online with a focus on nursing education.

The acute shortage of doctorally prepared nursing faculty has prompted the nursing profession to look to new and creative ways of delivering doctoral-level preparation to currently employed nurse educators. The development of an online PhD program, based on recommended benchmark guidelines for a "best practice" approach to Internet-based education, led to a program evaluation matrix for formative and summative student advising and program review. In addition, efforts to seek the student voice in formative as well as summative evaluation provided a well-rounded plan to monitor program outcomes based on recommended benchmark guidelines. The results of first-year student feedback and perceptions reflect that online PhD program delivery promotes high quality professional socialization, mentoring, and student-faculty interaction. The online education experience has served as a stimulus for the incorporation of new learning into the student workplace setting, provides opportunity for educational access not previously available, and builds strong personal and professional relationships among nurse educators.

Nursing Academic Administrators' Lived Experiences With Incivility and Bullying From Faculty: Consequences and Outcomes Demanding Action.

There are an increasing number of nursing academic administrators who identify themselves as victims of faculty incivility. This study examined experiences that academic administrators encountered with faculty incivility using a phenomenological research design. Three major themes emerged: faculty inappropriate behaviors, consequences of faculty behaviors on administrator targets, and administrators call for action. Findings revealed that incivility had devastating effects on administrators personally and professionally.

Pregnancy and pulmonary hypertension: a practical approach to management.

Pulmonary hypertension remains a major cause of cardiac maternal death in the developed world. Over the last two decades, effective therapies for pulmonary hypertension have been developed, improving symptoms and survival. Consequently, increasing numbers of women with pulmonary hypertension and childbearing potential exist, with a number considering pregnancy. Patients with pulmonary hypertension may also present for the first time during pregnancy or shortly following delivery. The last decade has seen increasing reports of women with pulmonary hypertension surviving pregnancy using a variety of approaches but there is still a significant maternal mortality at between 12% and 33%. Current recommendations counsel that patients with known pulmonary hypertension should be strongly advised to avoid pregnancy with the provision of clear contraceptive advice and termination of pregnancy should be considered in its eventuality. In patients who are fully informed and who have been counselled regarding the risks of continuing with pregnancy, there is growing evidence that a multi-professional approach with expert care in pulmonary hypertension centres may improve outlook, although the mortality remains high.

Effects of a cost-sharing policy on disenrollment from a state health insurance program.

Subsidized public health insurance programs face financial difficulties and are increasingly implementing policies to pass on greater costs to low-income enrollees. Results of a stratified, random sample of 1,153 enrollees and disenrollees of a state program after introduction of increased cost sharing revealed three main reasons for disenrollment, which varied by enrollee income: finding other coverage, becoming financially ineligible, or dropping coverage as too expensive. Seventeen percent of disenrollees cited cost sharing as a reason for disenrollment. Persons who disenrolled were more likely to be younger adults, male, and have fewer children. Persons who disenrolled reported greater subsequent out-of-pocket costs, more difficulty providing coverage for children, and less access to care than persons who stayed enrolled. Most enrollees stayed enrolled despite the cost sharing increases, and persons who did disenroll left for a variety of reasons, only one of which was cost. Implications for state health insurance policies are discussed.

Mentorship: increasing retention probabilities.

Retaining nurses is a significant workforce issue. Experienced nurses in particular are getting harder to retain within hospitals and the discipline at large. One solution to boost retention is to give serious attention to professional socialization activities through contemporary nurse mentorship experiences. The authors contend that contemporary mentoring programmes, targeting developmental quality of life issues of the expert nurse, would appreciably benefit retention programmes within the hospital environment.