A Proposal for Certification in Nursing Theory

The author proposes the development of different levels of certification in the knowledge of nursing theory that would be based on the level of formal education attained. At present, nurses are being required to obtain higher levels of formal education in order to serve patients safely in a technologically complex health care system. Although evidence-based practice is strongly desired in contemporary health care, less consideration has been given to the value of theory-based nursing practice or the relationship between theory and research. The author explains multiple background issues and then highlights several questions that are important for disciplinary discussion at this point in time

Guest Editorial: Working at the Edge of Unknown Knowledge

Whenever I teach the graduate level course in Nursing Theory, my students and I discuss why experienced, licensed, professional nurses will benefit from learning nursing theory very well. Our conversation revolves around the idea that leaders are those professional people who often work at the edge of unknown knowledge. What is unknown knowledge

Critical Path to Tuberculosis Drug Regimens: Global collaboration to accelerate development of novel drug regimens and rapid drug susceptibility tests for tuberculosis

The Critical Path to Tuberculosis Drug Regimens (CPTR) initiative aims to support the rational deployment of new tuberculosis (TB) therapies by speeding the development and impact of new and markedly improved drug regimens as well as rapid drug susceptibility tests. Co-founded by the Bill & Melinda Gates Foundation, the Critical Path Institute, and the TB Alliance in 2010, CPTR is a coalition comprising the world’s leading pharmaceutical companies, product development sponsors, diagnostic companies, regulatory agencies, and civil society organizations which support and catalyze advances in regulatory science, the development of infrastructure, and other progress needed to accelerate the pace of development and introduction of novel regimens and rapid drug susceptibility tests. This manuscript summarizes the work of two subgroups within CPTR, the Regulatory Sciences and Rapid Drug Susceptibility Test consortia, and their efforts to drive innovation. These consortia are supported by a robust TB clinical data platform, which continues to evolve through contributions of contemporary TB clinical trial data sets as well as whole genome sequence level data from isolates across the globe. Examples of innovation are described and include a recently-qualified drug development tool and emerging programs to support the development of clinical trial simulation tools

Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development

Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk. The algorithm correctly classified 89% of reference compounds with moderate sensitivity and high specificity (71 and 96%, respectively) as well as 10 out of 12 external validation compounds and the anti-TB drugs moxifloxacin and bedaquiline. The cardiac risk algorithm is suitable to help inform early drug development decisions in TB and will evolve with the addition of emerging data

Model-Based Meta-Analysis of Relapsing Mouse Model Studies from the Critical Path to Tuberculosis Drug Regimens Initiative Database

Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious disease-related cause of death worldwide, necessitating the development of new and improved treatment regimens. Nonclinical evaluation of candidate drug combinations via the relapsing mouse model (RMM) is an important step in regimen development, through which candidate regimens that provide the greatest decrease in the probability of relapse following treatment in mice may be identified for further development. Although RMM studies are a critical tool to evaluate regimen efficacy, making comprehensive “apples to apples” comparisons of regimen performance in the RMM has been a challenge in large part due to the need to evaluate and adjust for variability across studies arising from differences in design and execution. To address this knowledge gap, we performed a model-based meta-analysis on data for 17 unique regimens obtained from a total of 1592 mice across 28 RMM studies. Specifically, a mixed-effects logistic regression model was developed that described the treatment duration-dependent probability of relapse for each regimen and identified relevant covariates contributing to interstudy variability. Using the model, covariate-normalized metrics of interest, namely, treatment duration required to reach 50% and 10% relapse probability, were derived and used to compare relative regimen performance. Overall, the model-based meta-analysis approach presented herein enabled cross-study comparison of efficacy in the RMM and provided a framework whereby data from emerging studies may be analyzed in the context of historical data to aid in selecting candidate drug combinations for clinical evaluation as TB drug regimens

NF05-628 Helping Children Resolve Conflict \u3cem\u3eConflict Mediation Model\u3c/em\u3e

During conflict mediation children learn the skills necessary to reach peaceful resolutions. These skills involve communication, compromise, the ability to see how different aspects of a dispute are related and the ability to consider their own perspective as well as that of another person. Adults play an important role in the socialization of children. They help children develop social skills. This NebFact discusses how to teach children to resolve conflicts

NF05-628 Helping Children Resolve Conflict \u3cem\u3eConflict Mediation Model\u3c/em\u3e

During conflict mediation children learn the skills necessary to reach peaceful resolutions. These skills involve communication, compromise, the ability to see how different aspects of a dispute are related and the ability to consider their own perspective as well as that of another person. Adults play an important role in the socialization of children. They help children develop social skills. This NebFact discusses how to teach children to resolve conflicts

Mechanisms Mediating the Biologic Activity of Synthetic Proline, Glycine, and Hydroxyproline Polypeptides in Human Neutrophils

The accumulation of neutrophils at sites of tissue injury or infection is mediated by chemotactic factors released as part of the inflammatory process. Some of these factors are generated as a direct consequence of tissue injury or infection, including degradation fragments of connective tissue collagen and bacterial- or viral-derived peptides containing collagen-related structural motifs. In these studies, we examined biochemical mechanisms mediating the biologic activity of synthetic polypeptides consisting of repeated units of proline (Pro), glycine (Gly), and hydroxyproline (Hyp), major amino acids found within mammalian and bacterial collagens. We found that the peptides were chemoattractants for neutrophils. Moreover, their chemotactic potency was directly related to their size and composition. Thus, the pentameric peptides (Pro-Pro-Gly)(5) and (Pro-Hyp-Gly)(5) were more active in inducing chemotaxis than the corresponding decameric peptides (Pro-Pro-Gly)(10) and (Pro-Hyp-Gly)(10). In addition, the presence of Hyp in peptides reduced chemotactic activity. The synthetic peptides were also found to reduce neutrophil apoptosis. In contrast to chemotaxis, this activity was independent of peptide size or composition. The effects of the peptides on both chemotaxis and apoptosis were blocked by inhibitors of phosphatidylinositol 3-kinase (PI3-K) and p38 mitogen-activated protein (MAP) kinase. However, only (Pro-Pro-Gly)(5) and (Pro-Pro-Gly)(10) induced expression of PI3-K and phosphorylation of p38 MAP kinase, suggesting a potential mechanism underlying reduced chemotactic activity of Hyp-containing peptides. Although none of the synthetic peptides tested had any effect on intracellular calcium mobilization, each induced nuclear binding activity of the transcription factor NF-κB. These findings indicate that polymeric polypeptides containing Gly-X-Y collagen-related structural motifs promote inflammation by inducing chemotaxis and blocking apoptosis. However, distinct calcium-independent signaling pathways appear to be involved in these activities

Integrating standardized whole genome sequence analysis with a global mycobacterium tuberculosis antibiotic resistance knowledgebase

Drug-resistant tuberculosis poses a persistent public health threat. The ReSeqTB platform is a collaborative, curated knowledgebase, designed to standardize and aggregate global Mycobacterium tuberculosis complex (MTBC) variant data from whole genome sequencing (WGS) with phenotypic drug susceptibility testing (DST) and clinical data. We developed a unified analysis variant pipeline (UVP) ( https://github.com/CPTR-ReSeqTB/UVP ) to identify variants and assign lineage from MTBC sequence data. Stringent thresholds and quality control measures were incorporated in this open source tool. The pipeline was validated using a well-characterized dataset of 90 diverse MTBC isolates with conventional DST and DNA Sanger sequencing data. The UVP exhibited 98.9% agreement with the variants identified using Sanger sequencing and was 100% concordant with conventional methods of assigning lineage. We analyzed 4636 publicly available MTBC isolates in the ReSeqTB platform representing all seven major MTBC lineages. The variants detected have an above 94% accuracy of predicting drug based on the accompanying DST results in the platform. The aggregation of variants over time in the platform will establish confidence-graded mutations statistically associated with phenotypic drug resistance. These tools serve as critical reference standards for future molecular diagnostic assay developers, researchers, public health agencies and clinicians working towards the control of drug-resistant tuberculosis

SMN1 dosage analysis in spinal muscular atrophy from India

BACKGROUND: Spinal muscular atrophy (SMA) represents the second most common fatal autosomal recessive disorder after cystic fibrosis. Due to the high carrier frequency, the burden of this genetic disorder is very heavy in developing countries like India. As there is no cure or effective treatment, genetic counseling becomes very important in disease management. SMN1 dosage analysis results can be utilized for identifying carriers before offering prenatal diagnosis in the context of genetic counseling. METHODS: In the present study we analyzed the carrier status of parents and sibs of proven SMA patients. In addition, SMN1 copy number was determined in suspected SMA patients and parents of children with a clinical diagnosis of SMA. RESULTS: wenty nine DNA samples were analyzed by quantitative PCR to determine the number of SMN1 gene copies present, and 17 of these were found to have one SMN1 gene copy. The parents of confirmed SMA patients were found to be obligate carriers of the disease. Dosage analysis was useful in ruling out clinical suspicion of SMA in four patients. In a family with history of a deceased floppy infant and two abortions, both parents were found to be carriers of SMA and prenatal diagnosis could be offered in future pregnancies. CONCLUSION: SMN1 copy number analysis is an important parameter for identification of couples at risk for having a child affected with SMA and reduces unwarranted prenatal diagnosis for SMA. The dosage analysis is also useful for the counseling of clinically suspected SMA with a negative diagnostic SMA test