The Management of Pediatric Asthma Using Telehealth: An Integrative Review.

Introduction: Asthma is one of the most chronic noncommunicable diseases of childhood, affecting 1 in 12 children in the United States. The use of telemedicine for the management of pediatric asthma has shown improved health outcomes; however, it is important to understand what can impact its acceptance. The purpose of this review was to identify the facilitators and barriers to pediatric asthma management, as viewed by stakeholders. Methods: An electronic literature search was performed using PubMed, Scopus, and Cumulative Index to Nursing and Allied Health Literature Complete. Articles included in the review contained perceptions of the use of telemedicine for the management of pediatric asthma, as viewed by stakeholders. The socioecological model was used as the theoretical framework to extract data based on its five levels. Results: After reviewing full texts of 143 articles, 118 were excluded, leaving 25 articles included in this review. A majority of included articles focused on mobile health (m-Health) studies for the management of pediatric asthma, with the remaining articles studying synchronous telemedicine or a combination of modalities. Common themes were identified; however, most were focused on the use of m-Health and few studies contained the viewpoints of the caregiver, children, or providers regarding synchronous telemedicine. Discussion: This integrative review identified a number of facilitators and barriers for the management of asthma using telemedicine. However, more qualitative studies are needed to evaluate the perceptions of caregivers, patients, and primary providers regarding synchronous telehealth. It was also recognized that telemedicine may increase instead of reduce health care disparities.

A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer.

The use of T-cell engagers (TCEs) to treat solid tumors is challenging, and several have been limited by narrow therapeutic windows due to substantial on-target, off-tumor toxicities due to the expression of low levels of target antigens on healthy tissues. Here, we describe TNB-928B, a fully human TCE that has a bivalent binding arm for folate receptor alpha (FRα) to selectively target FRα overexpressing tumor cells while avoiding the lysis of cells with low levels of FRα expression. The bivalent design of the FRα binding arm confers tumor selectivity due to low-affinity but high-avidity binding to high FRα antigen density cells. TNB-928B induces preferential effector T-cell activation, proliferation, and selective cytotoxic activity on high FRα expressing cells while sparing low FRα expressing cells. In addition, TNB-928B induces minimal cytokine release compared to a positive control TCE containing OKT3. Moreover, TNB-928B exhibits substantial ex vivo tumor cell lysis using endogenous T-cells and robust tumor clearance in vivo, promoting T-cell infiltration and antitumor activity in mouse models of ovarian cancer. TNB-928B exhibits pharmacokinetics similar to conventional antibodies, which are projected to enable favorable administration in humans. TNB-928B is a novel TCE with enhanced safety and specificity for the treatment of ovarian cancer.

Telehealth Professionalism Education for Advanced Practice Nursing Students.

ABSTRACT: Telehealth professionalism is an often-overlooked element when performing telehealth visits, but it is one that can impact patient and provider satisfaction with this health care delivery modality. This article describes a telehealth professionalism activity that was integrated into the education of advanced practice registered nursing students as one part of their telehealth education. Attainment in knowledge with this activity, in conjunction with positive student feedback, shows promise regarding the impact of the educational intervention and its sustainability.

Telehealth Educational Resources for Graduate Nurse Faculty.

BACKGROUND: The rapid acceleration of virtual health care delivery, telehealth, has underlined the pressing need for graduate nursing students to gain skills and competencies that will ensure effective and efficient delivery of telehealth care in future generations. PROBLEM: There is a need for graduate nursing students to be prepared to use telehealth, but few nursing programs offer this training. Barriers to this implementation may be due to lack of faculty knowledge, telehealth resources, or telehealth opportunities. SOLUTION: Graduate nursing faculty should use resources and the wisdom of early adopters of telehealth to ensure adequate telehealth preparation is integrated into all graduate nursing programs. CONCLUSION: This article describes emerging core competencies for telehealth education and offers guidance, resources, and activities for nurse educators who seek to prepare emerging advanced practice RNs to plan, deliver, and implement effective telehealth practices.

Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release.

BACKGROUND: Therapeutic options currently available for metastatic castration-resistant prostate cancer (mCRPC) do not extend median overall survival >6 months. Therefore, the development of novel and effective therapies for mCRPC represents an urgent medical need. T cell engagers (TCEs) have emerged as a promising approach for the treatment of mCRPC due to their targeted mechanism of action. However, challenges remain in the clinic due to the limited efficacy of TCEs observed thus far in solid tumors as well as the toxicities associated with cytokine release syndrome (CRS) due to the usage of high-affinity anti-CD3 moieties such as OKT3. METHODS: Using genetically engineered transgenic rats (UniRat and OmniFlic) that express fully human IgG antibodies together with an NGS-based antibody discovery pipeline, we developed TNB-585, an anti-CD3xPSMA TCE for the treatment of mCRPC. TNB-585 pairs a tumor-targeting anti-PSMA arm together with a unique, low-affinity anti-CD3 arm in bispecific format. We tested TNB-585 in T cell-redirected cytotoxicity assays against PSMA+ tumor cells in both two-dimensional (2D) cultures and three-dimensional (3D) spheroids as well as against patient-derived prostate tumor cells. Cytokines were measured in culture supernatants to assess the ability of TNB-585 to induce tumor killing with low cytokine release. TNB-585-mediated T cell activation, proliferation, and cytotoxic granule formation were measured to investigate the mechanism of action. Additionally, TNB-585 efficacy was evaluated in vivo against C4-2 tumor-bearing NCG mice. RESULTS: In vitro, TNB-585 induced activation and proliferation of human T cells resulting in the killing of PSMA+ prostate tumor cells in both 2D cultures and 3D spheroids with minimal cytokine release and reduced regulatory T cell activation compared with a positive control antibody that contains the same anti-PSMA arm but a higher affinity anti-CD3 arm (comparable with OKT3). In addition, TNB-585 demonstrated potent efficacy against patient-derived prostate tumors ex vivo and induced immune cell infiltration and dose-dependent tumor regression in vivo. CONCLUSIONS: Our data suggest that TNB-585, with its low-affinity anti-CD3, may be efficacious while inducing a lower incidence and severity of CRS in patients with prostate cancer compared with TCEs that incorporate high-affinity anti-CD3 domains.

A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells.

The use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential binding of IL-2 to cells that express the high-affinity, trimeric receptor, IL-2Rαßγ such as endothelial cells and T-regulatory cells, respectively. Here, we describe a novel bispecific heavy-chain only antibody which binds to and activates signaling through the heterodimeric IL-2Rßγ receptor complex that is expressed on resting T-cells and NK cells. By avoiding binding to IL-2Rα, this molecule circumvents the preferential T-reg activation of native IL-2, while maintaining the robust stimulatory effects on T-cells and NK-cells in vitro. In vivo studies in both mice and cynomolgus monkeys confirm the molecule's in vivo biological activity, extended pharmacodynamics due to the Fc portion of the molecule, and enhanced safety profile. Together, these results demonstrate that the bispecific antibody is a safe and effective IL-2R agonist that harnesses the benefits of the IL-2 signaling pathway as a potential anti-cancer therapy.

TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL.

The therapeutic potential of targeting CD19 in B cell malignancies has garnered attention in the past decade, resulting in the introduction of novel immunotherapy agents. Encouraging clinical data have been reported for T cell-based targeting agents, such as anti-CD19/CD3 bispecific T-cell engager blinatumomab and chimeric antigen receptor (CAR)-T therapies, for acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma (B-NHL). However, clinical use of both blinatumomab and CAR-T therapies has been limited due to unfavorable pharmacokinetics (PK), significant toxicity associated with cytokine release syndrome and neurotoxicity, and manufacturing challenges. We present here a fully human CD19xCD3 bispecific antibody (TNB-486) for the treatment of B-NHL that could address the limitations of the current approved treatments. In the presence of CD19+ target cells and T cells, TNB-486 induces tumor cell lysis with minimal cytokine release, when compared to a positive control. In vivo, TNB-486 clears CD19+ tumor cells in immunocompromised mice in the presence of human peripheral blood mononuclear cells in multiple models. Additionally, the PK of TNB-486 in mice or cynomolgus monkeys is similar to conventional antibodies. This new T cell engaging bispecific antibody targeting CD19 represents a novel therapeutic that induces potent T cell-mediated tumor-cell cytotoxicity uncoupled from high levels of cytokine release, making it an attractive candidate for B-NHL therapy.

Integration of Telehealth Education into the Health Care Provider Curriculum: A Review.

Introduction: Telehealth is a rapidly expanding health care delivery modality with increasing utility in the health care community. It is imperative that telehealth education is provided during the training of health care providers to ensure the proper usage and application of this health care delivery system. A comprehensive literature review of telehealth education integrated into the curricula of physician, physician assistant, and advanced practiced registered nurse training programs has not been reported to date. Materials and Methods: An electronic literature search was performed using Scopus®, PubMed, and 17 of the 35 databases on the EBSCOHost platform. We included studies where telehealth concepts and components were integrated in the curriculum for primary care students. We extracted information pertinent to understanding the scope and sustainability of the curriculum and tabulated the results. Results: After a full-text screening of 164 articles and critically analyzing 34, eight articles were included in this review. Comparison of these articles showed no consistency in how telehealth was integrated into the various health care curricula. Content delivered usually included basic telehealth information, however, the depth and breadth of content varied significantly based on the interventions. Discussion: For the articles included in this review, there were no formal study designs regarding basic telehealth educational integration or competencies. While authors recommended conducting evaluation and determining the effectiveness of the interventions, they did not provide a clear picture as to how these efforts should be conducted. Conclusions: In addition to developing a standardized telehealth curriculum, national competencies need to be created, which will guide the development of standardized curriculum across health care training programs.

Graduate Nursing Telehealth Education: Assessment of a One-Day Immersion Approach.

The ability to effectively understand and utilize telehealth technologies is an important skill for health care providers. Currently there is limited literature on integrating telehealth education into health care curricula. This article describes a one-day telehealth immersion event for graduate nursing students that combined lectures with hands-on training. Feedback from students was positive, and all participants expressed a need for telehealth education before graduating with an advanced practice nursing degree.

Asthma 101: Teaching children to use metered dose inhalers.

Providers across the spectrum of healthcare must be aware of their patients' inhaler use. This article addresses common errors and the proper use of pressurized metered-dose inhalers in pediatric patients.

Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies.

T-cell-recruiting bispecific antibodies (T-BsAbs) have shown potent tumor killing activity in humans, but cytokine release-related toxicities have affected their clinical utility. The use of novel anti-CD3 binding domains with more favorable properties could aid in the creation of T-BsAbs with improved therapeutic windows. Using a sequence-based discovery platform, we identified new anti-CD3 antibodies from humanized rats that bind to multiple epitopes and elicit varying levels of T-cell activation. In T-BsAb format, 12 different anti-CD3 arms induce equivalent levels of tumor cell lysis by primary T-cells, but potency varies by a thousand-fold. Our lead CD3-targeting arm stimulates very low levels of cytokine release, but drives robust tumor antigen-specific killing in vitro and in a mouse xenograft model. This new CD3-targeting antibody underpins a next-generation T-BsAb platform in which potent cytotoxicity is uncoupled from high levels of cytokine release, which may lead to a wider therapeutic window in the clinic.

Effect of Facilitated Discharge in Pediatric Orthopedic Patients at an Academic Medical Facility.

INTRODUCTION: Because health care reimbursement is being linked to discharge quality and patient satisfaction, this quality improvement initiative reviewed the outcomes of embedding a pediatric nurse practitioner within the resident team at an academic medical facility. METHODS: The project was completed at a pediatric orthopedic unit at a large Southeastern U.S. academic medical facility. During the intervention, the pediatric nurse practitioner student completed daily rounds, communicated with the resident team, assessed readiness for discharge, provided patient education, and ensured that comprehensive discharge materials were completed. RESULTS: Analyses were completed for 219 patients (pre-intervention, n = 116; post-intervention, n = 103). Patient satisfaction was measured for provider communication and discharge. All areas experienced improvement, with provider communication benchmarks obtained. Ambulatory call volume decreased from 97 to 45 calls/100 patients. DISCUSSION: This study shows that embedding a pediatric nurse practitioner into the resident team helped improve patient satisfaction and reduce ambulatory workload by decreasing call volume.

Sequence-Based Discovery Demonstrates That Fixed Light Chain Human Transgenic Rats Produce a Diverse Repertoire of Antigen-Specific Antibodies.

We created a novel transgenic rat that expresses human antibodies comprising a diverse repertoire of heavy chains with a single common rearranged kappa light chain (IgKV3-15-JK1). This fixed light chain animal, called OmniFlic, presents a unique system for human therapeutic antibody discovery and a model to study heavy chain repertoire diversity in the context of a constant light chain. The purpose of this study was to analyze heavy chain variable gene usage, clonotype diversity, and to describe the sequence characteristics of antigen-specific monoclonal antibodies (mAbs) isolated from immunized OmniFlic animals. Using next-generation sequencing antibody repertoire analysis, we measured heavy chain variable gene usage and the diversity of clonotypes present in the lymph node germinal centers of 75 OmniFlic rats immunized with 9 different protein antigens. Furthermore, we expressed 2,560 unique heavy chain sequences sampled from a diverse set of clonotypes as fixed light chain antibody proteins and measured their binding to antigen by ELISA. Finally, we measured patterns and overall levels of somatic hypermutation in the full B-cell repertoire and in the 2,560 mAbs tested for binding. The results demonstrate that OmniFlic animals produce an abundance of antigen-specific antibodies with heavy chain clonotype diversity that is similar to what has been described with unrestricted light chain use in mammals. In addition, we show that sequence-based discovery is a highly effective and efficient way to identify a large number of diverse monoclonal antibodies to a protein target of interest.

Multispecific Antibody Development Platform Based on Human Heavy Chain Antibodies.

Heavy chain-only antibodies (HCAbs) do not associate with light chains and their VH regions are functional as single domains, forming the smallest active antibody fragment. These VH regions are ideal building blocks for a variety of antibody-based biologics because they tolerate fusion to other molecules and may also be attached in series to construct multispecific antibodies without the need for protein engineering to ensure proper heavy and light chain pairing. Production of human HCAbs has been impeded by the fact that natural human VH regions require light chain association and display poor biophysical characteristics when expressed in the absence of light chains. Here, we present an innovative platform for the rapid development of diverse sets of human HCAbs that have been selected in vivo. Our unique approach combines antibody repertoire analysis with immunization of transgenic rats, called UniRats, that produce chimeric HCAbs with fully human VH domains in response to an antigen challenge. UniRats express HCAbs from large transgenic loci representing the entire productive human heavy chain V(D)J repertoire, mount robust immune responses to a wide array of antigens, exhibit diverse V gene usage and generate large panels of stable, high affinity, antigen-specific molecules.

A synthetic model of Hg(II) sequestration.

Tridentate ligand N-(2-pyridylmethyl)-N-(2-(ethylthiolato)amine (L) forms the novel complex [Hg(5)(L)(6)](ClO(4))(4).toluene () with a bicyclo[3.3.3] Hg(5)S(6) core and 4-, 5- and 6-coordinate metal centers; characterization of a solution of by ESI-MS revealed elaborate speciation involving [Hg(n)L(n+1)(ClO(4))(n-2)](+), [Hg(n)L(n)(ClO(4))(n-1)](+) and [Hg(n)L(n-1)(ClO(4))(n)](+) ion families.

Regression of electrocardiographic left ventricular hypertrophy is associated with less hospitalization for heart failure in hypertensive patients.

BACKGROUND: Reduction of electrocardiographic left ventricular hypertrophy (LVH) has been associated with decreased cardiovascular death, stroke, myocardial infarction, and atrial fibrillation. However, whether reduction of electrocardiographic LVH is associated with decreased heart failure is unclear. OBJECTIVE: To examine the relation of reduction of electrocardiographic LVH to incident heart failure. DESIGN: Multicenter cohort study derived from a randomized, controlled trial. SETTING: Losartan Intervention For Endpoint reduction in hypertension study. PATIENTS: 8479 hypertensive patients without history of heart failure who were randomly assigned to losartan or atenolol treatment. MEASUREMENTS: Change in Cornell product electrocardiographic LVH between baseline and in-study electrocardiograms, examined as both a continuous variable and a dichotomous variable (above or below the median decrease of 236 mm x msec) to predict heart failure hospitalization occurring after the 6-month follow-up visit. RESULTS: During mean follow-up of 4.7 years (SD, 1.1 years), 214 patients were hospitalized for heart failure (2.5%): 77 patients with an in-treatment decrease of 236 mm x msec or more (4.4 per 1000 patient-years) and 137 patients with a reduction less than 236 mm x msec during treatment (6.8 per 1000 patient-years). In a univariate Cox analysis in which change in Cornell product was treated as a time-varying continuous variable, decrease in Cornell product during treatment was associated with a decreased risk for new-onset heart failure, with a 24% lower risk for heart failure for every 817-mm x msec (1 SD of the mean) lower Cornell product (hazard ratio, 0.76 [95% CI, 0.72 to 0.80]). In a parallel analysis in which change in Cornell product was entered as a time-varying dichotomous variable, a greater-than-median in-treatment decrease in Cornell product (236 mm x msec) was associated with a 43% lower risk for heart failure (hazard ratio, 0.57 [CI, 0.44 to 0.76]). After adjustment for treatment, baseline risk factors for heart failure, baseline and in-treatment blood pressure, and baseline severity of electrocardiographic LVH, in-treatment decrease of Cornell product LVH in time-varying multivariate Cox models remained strongly associated with new heart failure hospitalization, with a 19% lower risk for every 817-mm . msec lower Cornell product treated as a continuous variable (hazard ratio, 0.81 [CI, 0.77 to 0.85]) or a 36% decreased rate of new heart failure in patients with an in-treatment reduction in Cornell product of 236 mm x msec or more (hazard ratio, 0.64 [CI, 0.47 to 0.89]; P < 0.001 for all comparisons). LIMITATIONS: Use of electrocardiographic LVH to select patients may have increased risk compared with unselected hypertensive patients, and use of hospitalization for heart failure as the end point will underestimate the incidence of new heart failure. CONCLUSION: Reduction in Cornell product electrocardiographic LVH during antihypertensive therapy is associated with fewer hospitalizations for heart failure, independent of blood pressure lowering, treatment method, and other risk factors for heart failure. ClinicalTrials.gov registration number: NCT00338260.

In-treatment resolution or absence of electrocardiographic left ventricular hypertrophy is associated with decreased incidence of new-onset diabetes mellitus in hypertensive patients: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study.

Treatment of hypertensive patients with electrocardiographic left ventricular hypertrophy with losartan-based therapy is associated with lower incidence of diabetes mellitus and greater regression of hypertrophy than atenolol-based therapy. However, whether in-treatment resolution or continued absence of electrocardiographic hypertrophy is independently associated with decreased incidence of diabetes is unclear. Electrocardiographic hypertrophy was evaluated over time in 7998 hypertensive patients without diabetes at baseline in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study who were treated with losartan- or atenolol-based regimens and followed with serial electrocardiograms and blood pressure determinations. Electrocardiographic hypertrophy was defined using gender-adjusted Cornell voltage-duration product criteria >2440 mm.ms. During mean follow-up of 4.6+/-1.2 years, diabetes developed in 562 patients (7.0%). In a Cox model adjusting for treatment assignment, in-treatment resolution or continued absence of Cornell product hypertrophy was associated with a 38% lower risk of new diabetes (HR 0.62, 95% CI 0.50 to 0.78). After adjusting for the association of new diabetes with prior antihypertensive treatment, baseline glucose, and Framingham risk score, baseline and in-treatment systolic and diastolic pressure, HDL, uric acid, and body mass index, and the decreased incidence associated with losartan-based therapy, in-treatment continued absence, or resolution of Cornell product hypertrophy remained associated with a 26% lower risk of new diabetes (HR 0.74, 95% CI 0.58 to 0.93). Thus, compared with presence of hypertrophy by Cornell product criteria during antihypertensive treatment, resolution or continued absence of Cornell product hypertrophy is associated with a lower incidence of diabetes, even after adjusting for the impact of treatment with losartan and other risk factors for diabetes.

Different Wnt signals act through the Frizzled and RYK receptors during Drosophila salivary gland migration.

Guided cell migration is necessary for the proper function and development of many tissues, one of which is the Drosophila embryonic salivary gland. Here we show that two distinct Wnt signaling pathways regulate salivary gland migration. Early in migration, the salivary gland responds to a WNT4-Frizzled signal for proper positioning within the embryo. Disruption of this signal, through mutations in Wnt4, frizzled or frizzled 2, results in misguided salivary glands that curve ventrally. Furthermore, disruption of downstream components of the canonical Wnt pathway, such as dishevelled or Tcf, also results in ventrally curved salivary glands. Analysis of a second Wnt signal, which acts through the atypical Wnt receptor Derailed, indicates a requirement for Wnt5 signaling late in salivary gland migration. WNT5 is expressed in the central nervous system and acts as a repulsive signal, needed to keep the migrating salivary gland on course. The receptor for WNT5, Derailed, is expressed in the actively migrating tip of the salivary glands. In embryos mutant for derailed or Wnt5, salivary gland migration is disrupted; the tip of the gland migrates abnormally toward the central nervous system. Our results suggest that both the Wnt4-frizzled pathway and a separate Wnt5-derailed pathway are needed for proper salivary gland migration.

Two ligands signal through the Drosophila PDGF/VEGF receptor to ensure proper salivary gland positioning.

The Drosophila embryonic salivary gland is a migrating tissue that undergoes a stereotypic pattern of migration into the embryo. We demonstrate that the migratory path of the salivary gland requires the PDGF/VEGF pathway. The PDGF/VEGF receptor, Pvr, is strongly expressed in the salivary glands, and Pvr mutations cause abnormal ventral curving of the glands, suggesting that Pvr is involved in gland migration. Although the Pvr ligands, Pvf1 and Pvf2, have distinct expression patterns in the Drosophila embryo, mutations for either one of the ligands result in salivary gland migration defects similar to those seen in embryos that lack Pvr. Rescue experiments indicate that the PDGF/VEGF pathway functions autonomously in the salivary gland. The results of this study demonstrate that the Drosophila PDGF/VEGF pathway is essential for proper positioning of the salivary glands.

Blood pressure reduction and antihypertensive medication use in the losartan intervention for endpoint reduction in hypertension (LIFE) study in patients with hypertension and left ventricular hypertrophy.

OBJECTIVE: To compare blood pressure response and antihypertensive medication use visit-by-visit from baseline in patients receiving losartan-based or atenolol-based therapy in the LIFE study. RESEARCH DESIGN: LIFE was a randomized, double-blind trial comparing losartan-based and atenolol-based treatment regimens on the primary composite endpoint of death, myocardial infarction (MI), or stroke in 9193 patients aged 55-80 years with hypertension and left ventricular hypertrophy. Systolic and diastolic, pulse, and mean arterial pressures, blood pressure responder rates, distribution of open-label antihypertensive agents utilized, and the proportion of patients on randomized treatment were determined for each group at each clinic visit over a follow-up period of at least 4 years. RESULTS: Overall blood pressure reductions were comparable in the losartan-based and atenolol-based treatment groups. The mean reductions in sitting trough systolic and diastolic blood pressures from baseline to the end of follow-up (or last visit before a primary endpoint event) were 30.2/16.6 mmHg in the losartan group and 29.1/16.8 mmHg in the atenolol group. The time-averaged difference in overall mean arterial pressure was similar between groups. The proportion of patients on individual dose combinations varied visit by visit but was generally comparable between groups. During the entire study, 56% (2579/4605) of losartan-treated patients received at least one dose of the combination of losartan 100 mg plus hydrochlorothiazide 12.5 mg and 51% of atenolol-treated patients received 100 mg of atenolol plus hydrochlorothiazide 12.5 mg at some time during the study. CONCLUSIONS: Differences in blood pressure or distribution of add-on medications between treatment groups were not evident in the LIFE trial and, thus, cannot account for the observed outcome difference in the primary endpoint of risk reduction of the composite of cardiovascular death, stroke and MI favoring losartan.