ABSTRACT
BACKGROUND: The profession of nursing has recognized the lack of diversity in nursing leadership. Nurses of color represent fewer than 20% of leadership roles in nursing administration, education, and professional organizations. Efforts are needed to identify and implement strategies to increase the representation of nurses of color in positions of high influence. PURPOSE: To review the literature to uncover the factors that may impact Black nurses in their pursuit of leadership roles in nursing administration, education, and professional organizations. METHODS: The authors conducted a scoping review, searching CINAHL and PubMed databases in November 2022 for peer-reviewed English-language studies of leadership among U.S. nurses. They excluded studies that did not include a research method, did not have participants, a minimum of baccalaureate preparation as an inclusion criterion for participants, or were published before January 1, 2012. DISCUSSION: Of 331 articles identified, a total of 12 met the inclusion criteria. Evaluation of the studies revealed three concepts related to mentorship, racism, and hiring practices. Of the 12 studies, 9 addressed issues related to mentorship, 5 addressed issues related to racism, and 2 addressed issues related to hiring practices. Some studies address more than one of the concepts. Ten were qualitative studies, and two were quantitative studies. CONCLUSION: Findings suggest that Black nurse leaders are faced with obstacles and challenges when considering entering and/or staying in leadership roles. The limited amount of research on Black nurses in leadership roles remains inadequate.
ABSTRACT
With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.
Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/enzymology , Macrocyclic Compounds/pharmacology , Quinazolinones/pharmacology , Sulfones/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Crystallography, X-Ray , Drug Discovery , Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacokinetics , Models, Molecular , Mutation , Quinazolinones/chemistry , Quinazolinones/pharmacokinetics , Rats , Sulfones/pharmacokinetics , Viral Nonstructural Proteins/geneticsABSTRACT
BACKGROUND: There is limited evidence on physical activity patterns among Hispanic adolescents in Puerto Rico. This restricts opportunities to implement effective interventions and policies to increase physical activity in schools. The purpose of this study was to examine the physical activity behaviors of adolescents attending middle and high schools in Puerto Rico based on a compendium of moderate to vigorous physical activities including walking, jogging or running, bicycling, sports and more. A secondary purpose was to examine group differences as a function of gender and school level. METHOD: A cross-sectional survey research design was used. Students (N = 637) attending public middle and high schools completed a Visual 7-Day Physical Activity Recall survey. Both descriptive and inferential analyses were conducted to describe the sample and to determine group differences. RESULTS: Puerto Rican adolescents' levels of physical activity decreased throughout the week. Only a small proportion of them reached at least 60 minutes everyday of the week. Differences were found between middle and high school students' daily and weekly participation in physical activities. CONCLUSIONS: Most adolescents do not engage in sufficient physical activity. IMPLICATIONS: IMPLICATIONS of the results are discussed and recommendations are articulated for policy makers, educators, and other professionals.
Subject(s)
Cross-Cultural Comparison , Hispanic or Latino , Motor Activity , Adolescent , Cross-Sectional Studies , Female , Health Surveys , Humans , Male , Puerto Rico , Schools , Sex FactorsABSTRACT
We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
ABSTRACT
A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Binding Sites , Carrier Proteins/metabolism , Catalytic Domain , Cyclization , Genotype , Half-Life , Hepacivirus/genetics , Intracellular Signaling Peptides and Proteins , Kinetics , Liver/metabolism , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Molecular Docking Simulation , Mutation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Carrier Proteins/metabolism , Cyclization , Genotype , Half-Life , Hepacivirus/genetics , Intracellular Signaling Peptides and Proteins , Kinetics , Liver/metabolism , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Quinolines/chemistry , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
ABSTRACT
The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.
ABSTRACT
A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
