A phase 2, randomized, blinded, dose-finding, controlled clinical trial to evaluate the safety, tolerability, and immunogenicity of a 24-valent pneumococcal conjugate vaccine (VAX-24) in healthy adults 65 years and older.

Despite current polysaccharide and conjugate vaccine use, pneumococcal diseases remain prevalent in older adults. VAX-24 is a 24-valent pneumococcal conjugate vaccine (PCV) containing eCRM, a proprietary carrier protein with non-native amino acids (para-azidomethyl-L-phenylalanine) that undergo site-specific conjugation to pneumococcal polysaccharides that have been activated with a small-molecule linker (dibenzocyclooctyne). Site-specific conjugation utilizing click chemistry enables consistent exposure of T-cell epitopes, reduction in carrier protein to pneumococcal polysaccharide ratio, and enhances manufacturing process consistency to improve PCVs by increasing serotype coverage while minimizing carrier suppression. Healthy adults aged 65 or older were randomized in a 1:1:1:1 ratio to receive a single injection of VAX-24 at 1 of 3 dose levels (1.1, 2.2, or a mixed dose of 2.2 or 4.4 mcg) or Prevnar 20® (PCV20) in a phase 2, blinded study. Primary outcome measures were solicited local and systemic events within 7 days post-vaccination, unsolicited adverse events (AEs) within 1 month, and serious AEs, medically attended AEs, or new onset of chronic disease within 6 months of vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) were measured pre-vaccination and at 1 month post-vaccination. Of 207 participants enrolled, 200 completed the trial. Safety profiles were comparable across the three VAX-24 doses and PCV20. Robust OPA and IgG immune responses were seen for all 24 serotypes. On average, immune responses to VAX-24 2.2 mcg dose were similar or higher compared to PCV20. In adults ≥ 65 years, VAX-24 had a safety profile similar to PCV20 through six months post-vaccination and induced robust OPA and IgG responses to all 24 serotypes, supporting prior data showing that site-specific conjugation allows for increased serotype coverage with similar or higher immune response vs other PCVs. The outcome of this phase 2 study further supports use of VAX-24 2.2 mcg dose in phase 3 trials. Clinicaltrials.gov: NCT05297578.

Structural characterization of aspartate-semialdehyde dehydrogenase from Pseudomonas aeruginosa and Neisseria gonorrhoeae.

Gonorrhoea infection rates and the risk of infection from opportunistic pathogens including P. aeruginosa have both risen globally, in part due to increasing broad-spectrum antibiotic resistance. Development of new antimicrobial drugs is necessary and urgent to counter infections from drug resistant bacteria. Aspartate-semialdehyde dehydrogenase (ASADH) is a key enzyme in the aspartate biosynthetic pathway, which is critical for amino acid and metabolite biosynthesis in most microorganisms including important human pathogens. Here we present the first structures of two ASADH proteins from N. gonorrhoeae and P. aeruginosa solved by X-ray crystallography. These high-resolution structures present an ideal platform for in silico drug design, offering potential targets for antimicrobial drug development as emerging multidrug resistant strains of bacteria become more prevalent.

Shaping nursing profession regulation through history - a systematic review.

AIM: The aim of this systematic review was to provide a critical synthesis of the factors that historically shaped the advancements of nursing regulators worldwide. BACKGROUND: An in-depth examination of the different factors that moulded regulatory changes over time is pivotal to comprehend current issues in nursing. INTRODUCTION: In the light of global health scenarios, the researchers explored the factors that historically influenced the socio-contextual circumstances upon which governments made regulatory changes. METHODS: A systematic search was performed on the following databases: PubMed, CINAHL, Scopus, OpenGrey and ScienceDirect. The review included papers from January 2000 to October 2016 published in English. The authors used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and an inductive thematic approach for synthesis. RESULTS: Two main themes were identified: factors underpinning current challenges and historical and contextual triggers of regulation. The first theme was composed of three aspects: education, migration and internationalization, and policy and regulation; the second theme consisted of four attributes: demographics, economics, history of registration and wars, and historical changes in nursing practice. DISCUSSION: Factors that shaped nursing regulation were linked to changing demographics and economics, education, history of nursing registration, shifting patterns of migration and internationalization, nursing practice, policy and regulation and significant societal turns often prompted by wars. CONCLUSION: A deeper understanding of the developments of the nursing regulatory institutions provides the foundation for portable standards that can be applied across an array of jurisdictions to guarantee a better public safety. IMPLICATION FOR NURSING AND HEALTH POLICY: Understanding factors that socially, legislatively and politically have influenced the development of regulatory bodies over time helps to mould local, national and international policies that have a stronger impact on health worldwide. To achieve this, there must be effective cooperation among systems of nursing regulations globally.

Liposome-DNA complexes infused intravenously inhibit tumor angiogenesis and elicit antitumor activity in dogs with soft tissue sarcoma.

Intravenous gene delivery using liposome-DNA complexes (LDC) has previously been shown to elicit antitumor activity, but only in rodent tumor models. Therefore, we conducted a study to determine in a large animal spontaneous tumor model whether intravenous infusions of LDC could target gene expression to cutaneous tumor tissues and whether repeated treatments had an effect on tumor growth or angiogenesis. A total of 13 dogs with cutaneous soft tissue sarcomas were enrolled in the study and were randomized to receive a series of 6 weekly infusions of LDC containing either canine endostatin DNA or DNA encoding an irrelevant gene (luciferase). Serial tumor biopsies were obtained to assess transgene expression, tumor microvessel density (MVD), and intratumoral leukocyte inflammatory responses. We found that intravenous infusion of LDC did not result in detectable gene expression in cutaneous tumor tissues. However, two of 13 treated dogs had objective tumor responses and eight dogs had stable disease during the treatment period. In addition, a significant decrease in tumor MVD was noted in six of 12 treated dogs at the completion of six treatments. These results suggest that intravenous infusions of LDC may elicit nonspecific antitumor activity and inhibit tumor angiogenesis.

Oral history of Florence Downs; the early years.

BACKGROUND: Florence Downs is a well-recognized nursing leader, educator, editor, and scholar who helped shape nursing as an intellectual discipline, and wrote extensively about the importance of links between research and practice. OBJECTIVES: Through the use of oral history data garnered over 15 hours of interviews, we constructed a narrative that describes some of Downs' formative experiences. METHODS: Oral history is used to place the "stories" of an individual into a social and cultural context, in this case, the development of the profession of nursing. RESULTS: From the interviews, several strands emerged that defined Downs' extended career, including the importance of developing a community of scholars both in and outside of nursing, the dangers of parochialism, and the necessity of a perspective on life that melded a keen sense of humor. Factors that affected Downs' style and choice, especially her mother, and her educational experiences, were revealed. DISCUSSION: From the interviews we gained a sense of how Downs constructed her conceptual universe of nursing, as well as the language and political effectiveness to overcome barriers confronting the intellectual growth of nursing mounted by other nursing leaders as well as traditional academic disciplines.

Social and professional influences of the technology of electronic fetal monitoring on obstetrical nursing.

Electronic fetal monitoring (EFM) is one example of a biomedical technology that rapidly diffused from an experimental innovation into a standard medical practice. First developed in the 1950s, EFM became commercially available in the early 1970s and quickly transformed intrapartum obstetrical practice. Assessments and interventions, which practitioners had previously based primarily on laboring women's subjective reports of bodily sensations, were now being based on quantifiable objective data from uterine activity and fetal heart rate transducers. Despite concerns of over-medicalization of the natural event of birth, iatrogenesis related to the increased incidence of operative deliveries, and escalating costs, EFM became widely accepted as routine and necessary by both practitioners and patients. By presenting the confident expectations and cautious reservations of various practitioners and patients to EFM, this article explores the rapid diffusion of EFM within the social context of the 1970s. A special focus is given to the perspective of intrapartum obstetrical nurses, because they have been the primary users of this perinatal technology since its introduction.

Inhibition of tumor growth correlates with the expression level of a human angiostatin transgene in transfected B16F10 melanoma cells.

Although the therapeutic value of angiostatin, a proteolytic fragment of plasminogen, has been recognized for the treatment of cancer, the production of bioactive angiostatin remains a difficult task. Here we report that expression of a cDNA encoding a secreted, four-kringle human angiostatin inhibited tumor growth of B16F10 melanoma cells in mice but did not suppress tumor cell growth in culture. After transfection and selection, stable expression of the angiostatin cDNA was demonstrated in several B16F10 clones by quantitative mRNA analysis using the Taqman method. Cells that expressed angiostatin at either a low, medium, or high level were injected into C57BL/6 mice. s.c. Growth of B16F10 tumors was diminished by the angiostatin transgene, and the inhibition was directly proportional to the expression level of angiostatin in the transfected cells. However, suppression of s.c. tumor growth was transient, and eventually, tumors emerged with a strongly decreased expression of the transgene. Angiostatin expression also reduced lung metastasis from i.v.-injected B16F10 cells. Our data indicate that a cDNA encoding bioactive human angiostatin is potentially useful for gene therapy of human cancers, but the delivery of the transgene may require repeated dosing to achieve sustained dormancy of primary tumors and cancer metastases.

Quantitative RT-PCR to evaluate in vivo expression of multiple transgenes using a common intron.

An assay measuring RNA expression levels of a gene-encoded therapeutic must distinguish between endogenous mRNA and mRNA transcribed from the transgene. Specificity for the delivered transgene is especially critical when the treatment involves genes that are expressed in the target tissue. To facilitate uniform detection of transgene RNA without interference from endogenous mRNA, we have engineered expression vectors that include a 5' untranslated region (5' UTR) containing a synthetic intron (PGL3). The synthetic intron splice junction was the target sequence for a quantitative reverse transcription (RT)-PCR assay utilizing Taq-Man technology. In this study, we demonstrate that a quantitative RT-PCR assay designed to recognize an engineered intron splice site in the 5'UTR of expression constructs effectively measures the expression level of in vivo-delivered gene therapeutics.

Creating critical care: the case of the Hospital of the University of Pennsylvania, 1950-1965.

This article examines the development of critical care nursing from 1950 to 1965 through the lens of a local story--the development of the critical care unit at the Hospital of the University of Pennsylvania (HUP) in Philadelphia, Pennsylvania. The methodology used is social history. The data for the analysis were derived from oral history interviews, archival material, and secondary sources. The study concludes that powerful social contextual factors, such as work force and economic issues, architectural changes, and an increasingly complex hospital population--rather than new technology--supported the development of critical care. The study also provides parallels to contemporary nurse work force issues.

Virtual power: gendering the nurse-technology relationship.

To date, studies of the relationship between technology and its consumers have used the constructs of traditional paradigms of production and consumption as the foundation for analysis. These studies have served to reinforce traditional concepts of gender and hierarchy in the nursing-technology dichotomy. To propose a new and more relevant framework for analysing the technology-nursing relationship, the analysis of gender within the methodology of the social history of technology will be used. Healthcare will be viewed as a technologic network, and within that network multiple knowledge domains reside and interact. These domains, in turn, are socially constructed and historically contingent. This paper operationalizes this argument by examining the domain of the early nurse practitioner movement of the 1960s as part of a gendered technologic system. The findings of this study illuminate the agency of nurses in the shaping of traditionally male knowledge domains and as a crucial factor for understanding the evolution of not only the particularities of the nurse-technology relationship, but also the generalities of the gendered ways of knowing within the healthcare-technology relationship. Perhaps most importantly, different sets of questions can be formulated to analyse the history of the nurse practitioner movement from a technologic perspective that will provide new standpoints for the nursing-technology dichotomy in the millennium.

5q- in a child with refractory anemia with excess blasts: similarities to 5q- syndrome in adults.

A 19-month-old boy was referred to our institution because of chronic macrocytic anemia and severe thrombocytopenia. At age 17 months, he had developed petechiae. He had a leukocyte count of 4.4 x 10(9)/L, hemoglobin concentration of 7.9 g/dL, packed cell volume of 21%, mean corpuscular volume of 101 fL, and platelet count of 19 x 10(9)/L. At the time of referral, a bone marrow aspirate and biopsy revealed myelodysplastic changes that included megakaryocytic hyperplasia with hypolobated megakaryocytes, megaloblastoid erythropoiesis, 12% blast cells, and bone marrow fibrosis; the diagnosis was refractory anemia with excess blasts (RAEB). Cytogenetic analysis showed the following abnormalities: 47, XY, inv(3)(p21q25), del(5)(q22q31), +21/46, XY. By dinucleotide polymorphism analysis, the 5q22-q31 loci were normal in peripheral blood granulocytes. Because of severe thrombocytopenia that became refractory to platelet transfusions and because of possible progression to leukemia, the patient received an unrelated-donor bone marrow transplant. Recovery was complicated by a visceral fungal infection, but the patient now has normal, fully reconstituted bone marrow function. This patient is the youngest to be reported with RAEB and a 5q- anomaly accompanied by thrombocytopenia, megakaryocytic hyperplasia with hypolobated megakaryocytes, and macrocytic anemia with megaloblastoid erythropoiesis, similar to "5q- syndrome" in adults.

The unexplored 5q13 locus: a role in hematopoietic malignancies.

Deletions and translocations at 5q13 point out a locus involved in the development of acute myeloblastic leukemia (AML) and myelodysplastic syndromes (MDS) as well as other neoplasms. The chromosomal rearrangements of 5q13 are well documented, but have not been a primary focus of research. In this report, we provide evidence for a novel critical locus at 5q13.3, encoding gene(s) which may be disrupted by chromosomal translocations or deletions. Rare cases of myeloid neoplasms with t(5q13) as the sole chromosomal anomaly argue for a gene which gives rise to fusion proteins. Our preliminary studies have localized one of the critical genes to a <3 Mb. interval between the polymorphic markers AFMB347yf9 and GATAP18104 at the band 5q13.3. Other results also suggest that the 5q 13.3 locus may span a fragile site which undergoes unbalanced translocations and interstitial deletions accompanied by loss of significant segments of chromosome 5. Molecular reagents generated by the human genome mapping and sequencing initiative will allow us to characterize the critical genes at 5q13.3 and facilitate genotypic analysis of AML and MDS.

Molecular anatomy of chromosome 7q deletions in myeloid neoplasms: evidence for multiple critical loci.

Complete or partial deletions of the long arm of chromosome 7 (7q- and -7) are nonrandom abnormalities seen in primary and therapy-induced myelodysplasia (MDS) and acute myelogenous leukemia (AML). Monosomy 7, occurring as the sole cytogenetic anomaly in a small but significant number of cases, may denote a dominant mechanism involving critical tumor suppressor gene(s). We have determined the extent of allele loss in cytogenetically prescreened MDS and AML patients for microsatellite markers from chromosome 7q22 and 7q31. Whereas >80% of these cases revealed allele loss for the entire region, a rare case of the 7q- chromosome showed allele loss for only the proximal 7q31.1 loci flanked by the markers D7S486 and D7S2456, and a case of monosomy 7 revealed allele loss for loci at both 7q31 and 7q22 with retention of sequences between these sets of loci. Furthermore, a case of AML with no cytogenetic anomaly of chromosome 7 revealed a submicroscopic allelic imbalance for a third distal locus, D7S677. These findings suggest the presence of three distinct critical loci that may contribute alone or in combination to the evolution of MDS and AML. The data also provide molecular evidence for unbalanced translocation with noncontiguous deletions, as an alternate mechanism underlying monosomy 7.

Localization of SMAD5 and its evaluation as a candidate myeloid tumor suppressor.

Acquired interstitial or complete losses of chromosome 5 are recurring anomalies associated with preleukemic myelodysplasia and acute myelogenous leukemia with a poor prognosis. Previous studies have delineated a potential myeloid tumor suppressor locus to a <2.4-Mb interval between the genes for IL9 and EGR1 on 5q31. In this report, we have localized the SMAD5 gene, a homologue of the tumor suppressor genes SMAD4/DPC-4 and SMAD2/JV18.1, to the minimal myeloid tumor suppressor locus and characterized its open reading frame and genomic organization. SMAD5 transcripts are readily detectable in hematolymphoid tissues and leukemic blasts. Absence of intragenic mutations in the remaining SMAD5 allele of leukemic patients and multiple solid tumor cell lines prescreened for loss of heterozygosity suggests that SMAD5 may not be a common target of somatic inactivation in malignancy.