Miracle-dz/UniFAR-FTUs huggingface dataset:
Factors influencing job satisfaction of front line nurse managers: a systematic review.

AIM The purpose of this study was to systematically review the research literature that examined the determinants of front line nurse managers' job satisfaction. BACKGROUND Front line managers are the vital link between senior management and clinical nurses. They influence organizational culture and outcomes for patients and staff so their job satisfaction and ultimately retention is of importance. EVALUATIONS A review of research articles that examined the determinants of front line nurse managers' job satisfaction was conducted. These managers supervise staff nurses and have direct responsibility for the management of a nursing unit or team in any type of healthcare facility. Fourteen studies were included in the final analysis. KEY ISSUES Evidence of significant positive relationships were found between span of control, organizational support, empowerment and the job satisfaction of front line nurse managers. CONCLUSION The review suggests that job satisfaction of front line managers may be improved by addressing span of control and workload, increasing organizational support from supervisors and empowering managers to participate in decision-making. IMPLICATIONS FOR NURSING MANAGEMENT Healthcare organizations may enhance the recruitment, retention and sustainability of future nursing leadership by addressing the factors that influence job satisfaction of front line managers.
Functional Analysis of the Anti-adalimumab Response Using Patient-derived Monoclonal Antibodies♦

Background: Therapeutic antibodies such as adalimumab can elicit anti-drug antibodies. Results: Monoclonal patient-derived antibodies were generated and found to compete for binding to adalimumab and are neutralizing, but they show markedly different fine-specificity. Conclusion: Anti-adalimumab antibodies bind to overlapping but distinct epitopes on adalimumab. Significance: Even for a fully human therapeutic antibody, there may be multiple determinants that contribute to immunogenicity. The production of antibodies to adalimumab in autoimmune patients treated with adalimumab is shown to diminish treatment efficacy. We previously showed that these antibodies are almost exclusively neutralizing, indicating a restricted response. Here, we investigated the characteristics of a panel of patient-derived monoclonal antibodies for binding to adalimumab. Single B-cells were isolated from two patients, cultured, and screened for adalimumab specificity. Analysis of variable region sequences of 16 clones suggests that the immune response against adalimumab is broad, involving multiple B-cell clones each using different combinations of V(D)J segments. A strong bias for replacement mutations in the complementarity determining regions was found, indicating an antigen-driven response. We recombinantly expressed 11 different monoclonal antibodies and investigated their affinity and specificity. All clones except one are of high affinity (Kd between 0.6 and 233 pm) and compete with TNF as well as each other for binding to adalimumab. However, binding to a panel of single-point mutants of adalimumab indicates markedly different fine specificities that also result in a differential tendency of each clone to form dimeric and multimeric immune complexes. We conclude that although all anti-adalimumab antibodies compete for binding to TNF, the response is clonally diverse and involves multiple epitopes on adalimumab. These results are important for understanding the relationship between self and non-self or idiotypic determinants on therapeutic antibodies and their potential immunogenicity.
Pioneering a new role: the beginning, current practice and future of the Clinical Nurse Leader.

AIM To discuss the development of a new nursing role in response to the health care crisis in the United States. BACKGROUND The nursing shortage and fragmentation of care has contributed to the need for nurses who are prepared to laterally integrate care, bring evidence-based practice to the bedside and provide continuity of care to patients and families. EVALUATION The CNLs review the literature, share their experiences, and discuss outcomes related to improved quality of care. KEY ISSUES Having clinical nurses with a global perspective acting as facilitators and integrators of care is essential to maintaining a high standard of care. Organizational and management support is critical. The more CNLs that can be embedded in an institution, the more successful the role can be. CONCLUSIONS The varied utilization of the CNLs in this practice setting has proven its value in a short period of time and facilitated better communication and collaboration among patients and their health care team. IMPLICATIONS FOR NURSING MANAGEMENT The flexibility and broad scope of this role allows for its use in any practice setting to realize gains in quality outcomes, cost savings, improved patient flow, increased safety, nurse satisfaction and increasing organizational capacity.
Evaluation of Anti-HIV-1 Mutagenic Nucleoside Analogues*

Background: Lethal mutagenesis is an antiviral strategy. Results: Nucleoside analogue mutagenicity is correlated to base pair stability and the ability to function as a template during reverse transcription. Conclusion: Two simple biophysical/biochemical assays predict mutagenicity of nucleoside analogues. Significance: Mutagenicity of anti-HIV-1 compounds can be reliably predicted in vitro without labor-intensive and costly in cellula tests. Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the concept of “lethal mutagenesis” that prompted us to synthesize pyrimidine nucleoside analogues with antiviral activity in cell culture consistent with an accumulation of deleterious mutations in the HIV-1 genome. However, testing all potentially mutagenic compounds in cell-based assays is tedious and costly. Here, we describe two simple in vitro biophysical/biochemical assays that allow prediction of the mutagenic potential of deoxyribonucleoside analogues. The first assay compares the thermal stabilities of matched and mismatched base pairs in DNA duplexes containing or not the nucleoside analogues as follows. A promising candidate should display a small destabilization of the matched base pair compared with the natural nucleoside and the smallest gap possible between the stabilities of the matched and mismatched base pairs. From this assay, we predicted that two of our compounds, 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine, should be mutagenic. The second in vitro reverse transcription assay assesses DNA synthesis opposite nucleoside analogues inserted into a template strand and subsequent extension of the newly synthesized base pairs. Once again, only 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine are predicted to be efficient mutagens. The predictive potential of our fast and easy first line screens was confirmed by detailed analysis of the mutation spectrum induced by the compounds in cell culture because only compounds 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine were found to increase the mutation frequency by 3.1- and 3.4-fold, respectively.
Trends in Thermostability Provide Information on the Nature of Substrate, Inhibitor, and Lipid Interactions with Mitochondrial Carriers

Background: Methods for rapid assessment of interactions of small molecules with membrane proteins in detergent are lacking. Results: Thermostability measurements of mitochondrial transporters display informative trends about detergent, lipid, substrate, and inhibitor interactions. Conclusion: Mechanistic insights are obtained by studying the thermostability of mitochondrial transporters. Significance: Information about the nature of compound interactions with membrane proteins can be obtained rapidly. Mitochondrial carriers, including uncoupling proteins, are unstable in detergents, which hampers structural and mechanistic studies. To investigate carrier stability, we have purified ligand-free carriers and assessed their stability with a fluorescence-based thermostability assay that monitors protein unfolding with a thiol-reactive dye. We find that mitochondrial carriers from both mesophilic and thermophilic organisms exhibit poor stability in mild detergents, indicating that instability is inherent to the protein family. Trends in the thermostability of yeast ADP/ATP carrier AAC2 and ovine uncoupling protein UCP1 allow optimal conditions for stability in detergents to be established but also provide mechanistic insights into the interactions of lipids, substrates, and inhibitors with these proteins. Both proteins exhibit similar stability profiles across various detergents, where stability increases with the size of the associated detergent micelle. Detailed analysis shows that lipids stabilize carriers indirectly by increasing the associated detergent micelle size, but cardiolipin stabilizes by direct interactions as well. Cardiolipin reverses destabilizing effects of ADP and bongkrekic acid on AAC2 and enhances large stabilizing effects of carboxyatractyloside, revealing that this lipid interacts in the m-state and possibly other states of the transport cycle, despite being in a dynamic interface. Fatty acid activators destabilize UCP1 in a similar way, which can also be prevented by cardiolipin, indicating that they interact like transport substrates. Our controls show that carriers can be soluble but unfolded in some commonly used detergents, such as the zwitterionic Fos-choline-12, which emphasizes the need for simple validation assays like the one used here.
A Study of the Generalized Shwartzman Phenomenon

When rabbits are given intravenous injections of certain bacterial culture filtrates at the beginning and at the end of a period of twenty-four hours, death follows within forty-eight hours after the second injection. At autopsy, characteristic changes in the kidney and hemorrhagic diathesis are frequently noted. An investigation of certain of the factors involved in this phenomenon revealed an almost complete parallelism with those concerned in the hemorrhagic skin reaction (Shwartzman phenomenon). These findings therefore appear to justify its designation as the “generalized Shwartzman phenomenon. ” Local and generalized Shwartzman reactions represent different localizations of the same type of injury. Additional evidence has been obtained which indicates that a single injection of a potent bacterial filtrate is sufficient to produce regularly a generalized Shwartzman phenomenon in pregnant rabbits.
Glycogen Synthase Kinase-3 (GSK3) Inhibition Induces Prosurvival Autophagic Signals in Human Pancreatic Cancer Cells*

Background: Glycogen synthase kinase-3 (GSK3) inhibition promotes apoptosis of pancreatic cancer cells. Results: GSK3 inhibition concomitantly triggers a prosurvival autophagic response. Conclusion: Autophagy inhibition promotes GSK3 inhibition-induced apoptosis. Significance: GSK3 has a dual role in pancreatic cancer cell survival. Glycogen synthase kinase-3 (GSK3) are ubiquitously expressed serine-threonine kinases involved in a plethora of functions ranging from the control of glycogen metabolism to transcriptional regulation. We recently demonstrated that GSK3 inhibition triggers JNK-cJUN-dependent apoptosis in human pancreatic cancer cells. However, the comprehensive picture of downstream GSK3-regulated pathways/functions remains elusive. Herein, counterbalancing the death signals, we show that GSK3 inhibition induces prosurvival signals through increased activity of the autophagy/lysosomal network. Our data also reveal a contribution of GSK3 in the regulation of the master transcriptional regulator of autophagy and lysosomal biogenesis, transcription factor EB (TFEB) in pancreatic cancer cells. Similarly to mammalian target of rapamycin (mTOR) inhibition, GSK3 inhibitors promote TFEB nuclear localization and leads to TFEB dephosphorylation through endogenous serine/threonine phosphatase action. However, GSK3 and mTOR inhibition impinge differently and independently on TFEB phosphorylation suggesting that TFEB is regulated by a panel of kinases and/or phosphatases. Despite their differential impact on TFEB phosphorylation, both GSK3 and mTOR inhibitors promote 14-3-3 dissociation and TFEB nuclear localization. Quantitative mass spectrometry analyses further reveal an increased association of TFEB with nuclear proteins upon GSK3 and mTOR inhibition suggesting a positive impact on TFEB transcriptional function. Finally, a predominant nuclear localization of TFEB is unveiled in fully fed pancreatic cancer cells, whereas a reduction in TFEB expression significantly impairs their capacity for growth in an anchorage-independent manner. In addition, TFEB-restricted cells are more sensitive to apoptosis upon GSK3 inhibition. Altogether, our data uncover new functions under the control of GSK3 in pancreatic cancer cells in addition to providing key insight into TFEB regulation.
SMAD3 Negatively Regulates Serum Irisin and Skeletal Muscle FNDC5 and Peroxisome Proliferator-activated Receptor γ Coactivator 1-α (PGC-1α) during Exercise*

Background: Mothers against decapentaplegic homolog 3 (SMAD3) and FNDC5/irisin are molecules that modulate energy metabolism and body weight regulation. Results: SMAD3 negatively regulates irisin during exercise and suppresses FNDC5 and PGC-1α in cultured skeletal muscle cells. Conclusion: SMAD3 suppresses irisin/FNDC5 in skeletal muscle. Significance: This study sheds light on the poorly understood regulation of irisin/FNDC5 in skeletal muscle. Beige adipose cells are a distinct and inducible type of thermogenic fat cell that express the mitochondrial uncoupling protein-1 and thus represent a powerful target for treating obesity. Mice lacking the TGF-β effector protein SMAD3 are protected against diet-induced obesity because of browning of their white adipose tissue (WAT), leading to increased whole body energy expenditure. However, the role SMAD3 plays in WAT browning is not clearly understood. Irisin is an exercise-induced skeletal muscle hormone that induces WAT browning similar to that observed in SMAD3-deficient mice. Together, these observations suggested that SMAD3 may negatively regulate irisin production and/or secretion from skeletal muscle. To address this question, we used wild-type and SMAD3 knock-out (Smad3−/−) mice subjected to an exercise regime and C2C12 myotubes treated with TGF-β, a TGF-β receptor 1 pharmacological inhibitor, adenovirus expressing constitutively active SMAD3, or siRNA against SMAD3. We find that in Smad3−/− mice, exercise increases serum irisin and skeletal muscle FNDC5 (irisin precursor) and its upstream activator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) to a greater extent than in wild-type mice. In C2C12 myotubes, TGF-β suppresses FNDC5 and PGC-1α mRNA and protein levels via SMAD3 and promotes SMAD3 binding to the FNDC5 and PGC-1α promoters. These data establish that SMAD3 suppresses FNDC5 and PGC-1α in skeletal muscle cells. These findings shed light on the poorly understood regulation of irisin/FNDC5 by demonstrating a novel association between irisin and SMAD3 signaling in skeletal muscle.
Computation and Functional Studies Provide a Model for the Structure of the Zinc Transporter hZIP4*

Background: ZIP transporters increase the cytosolic concentration of first row transition metals. Results: We have developed a structural model of hZIP4 by combining protein prediction methods with in situ experiments. Conclusion: Analysis of our experiments provides insight into the permeation pathway of hZIP4. Significance: Comparison of this model to membrane transporter crystal structures provides a structural linkage to MFS proteins. Members of the Zrt and Irt protein (ZIP) family are a central participant in transition metal homeostasis as they function to increase the cytosolic concentration of zinc and/or iron. However, the lack of a crystal structure hinders elucidation of the molecular mechanism of ZIP proteins. Here, we employed GREMLIN, a co-evolution-based contact prediction approach in conjunction with the Rosetta structure prediction program to construct a structural model of the human (h) ZIP4 transporter. The predicted contact data are best fit by modeling hZIP4 as a dimer. Mutagenesis of residues that comprise a central putative hZIP4 transmembrane transition metal coordination site in the structural model alter the kinetics and specificity of hZIP4. Comparison of the hZIP4 dimer model to all known membrane protein structures identifies the 12-transmembrane monomeric Piriformospora indica phosphate transporter (PiPT), a member of the major facilitator superfamily (MFS), as a likely structural homolog.
Relationship between mean arterial pressure and end-tidal partial pressure of carbon dioxide during.

Objectives. We examined the relationship between partial end-tidal CO2 (pet) and mean arterial pressure in patients with traumatic hemorrhagic shock, who were receiving constant minute ventilation. Methods. In 61 patients we continuously measured pet CO2 with a capnograph, direct arterial pressure via a cannula, oxygen levels via pulse oximetry and body temperature. Results. We observed significant changes in pet CO2 (increase) after volume resuscitation and a quantitative linear relationship between pet CO2 and mean arterial pressure. Conclusions. Partial end-tidal CO2 can be used as a reliable non-invasive monitoring device in patients with hemorrhagic shock when minute ventilation is relatively constant. The monitoring of pet CO2 might also be a useful guide for volume resuscitation in hemorrhagic shock, especially in the pre-hospital setting. STEFEK GRMEC • MIRJAM GOLUB • ALINA JELATANCEV
T Cell Lymphoma: A Rough Road to Diagnosis

Introduction: Lymphoproliferative disorders are well known for their variable presentation. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) is one subtype which is especially notorious. It has a variable age of onset, predominantly a nodal presentation and immunohistochemistry (IHC) depicting mature T cells. Presentation of case: We share our experience of a 33 year old patient who presented with mediastinal mass with pericardial effusion. However the histopathology revealed PTCL-NOS Conclusion: This case in one of the manifestations of heterogeneity encompassing T cell neoplasms where discordance in clinical and pathological behaviour caused not only diagnostic confusion but also complicated treatment decisions.
Effects of work environments on nurse and patient outcomes.

AIM To determine the relationship between nurses' perceptions of their work environment and quality/risk outcomes for patients and nurses in acute care settings. BACKGROUND Nurses are leaving the profession as a result of high levels of job dissatisfaction arising from current working conditions. To gain organizational support for workplace improvements, evidence is needed to demonstrate the impact of the work environment on patient care. METHOD A multi-level design was used to collect data from nurses (n=679) and patients (n=1005) within 61 medical and surgical units in 21 hospitals in Canada. RESULTS Using multilevel structural equation modelling, the hypothesized model fitted well with the data [χ(2)=21.074, d.f. =10, Comparative Fit Index (CFI)=0.985, Tucker-Lewis Index (TLI)=0.921, Root Mean Square Error of Approximation (RMSEA)=0.041, Standardized Root Mean Square Residual (SRMR) 0.002 (within) and 0.054 (between)]. Empowering workplaces had positive effects on nurse-assessed quality of care and predicted fewer falls and nurse-assessed risks as mediated through group processes. These conditions positively impacted individual psychological empowerment which, in turn, had significant direct effects on empowered behaviour, job satisfaction and care quality. CONCLUSIONS Empowered workplaces support positive outcomes for both nurses and patients. IMPLICATIONS FOR NURSING MANAGEMENT Managers employing strategies to create more empowered workplaces have the potential to improve nursing teamwork that supports higher quality care, less patient risk and more satisfied nurses.
Biophysical Measurement of the Balance of Influenza A Hemagglutinin and Neuraminidase Activities*

Background: Influenza A viruses contain the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA), responsible for receptor binding and virus release, respectively. Results: The contribution of HA and NA to virus interactions with receptor-coated surfaces was measured using bio-layer interferometry. Conclusion: The balance between the activities of the two glycoproteins controls virus-cell interactions, therefore transmissibility. Significance: This technique can be used to examine factors underlying emergent virus transmissibility. The interaction of influenza A viruses with the cell surface is controlled by the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). These two glycoproteins have opposing activities: HA is responsible for binding the host receptor (sialic acid) to allow infection, and NA is responsible for cleaving the receptor to facilitate virus release. Several studies have demonstrated that compatible levels of HA and NA activity are required for a virus to replicate efficiently. This is consequently of great interest for determining virus transmissibility. The concurrent role of these two proteins in receptor binding has never been directly measured. We demonstrate a novel biophysical approach based on bio-layer interferometry to measure the balance of the activities of these two proteins in real time. This technique measures virus binding to and release from a surface coated with either the human-like receptor analog α2,6-linked sialic acid or the avian-like receptor analog α2,3-linked sialic acid in both the presence and absence of NA inhibitors. Bio-layer interferometry measurements were also carried out to determine the effect of altering HA receptor affinity and NA stalk length on receptor binding.
Plasma lipid changes after supplementation with β-glucan fiber from yeast

BACKGROUND Dietary fiber has been shown to improve blood lipids. OBJECTIVE The purpose of this study was to evaluate the effect on serum lipids of a yeast-derived beta-glucan fiber in 15 free-living, obese, hypercholesterolemic men. DESIGN After a 3-wk period in which subjects ate their usual diet, 15 g fiber/d was added to the diet for 8 wk and then stopped for 4 wk. Plasma lipids were measured weekly during baseline and at week 7 and 8 of fiber consumption, and again at week 12. RESULTS Compared with baseline, fiber consumption significantly reduced plasma total cholesterol (by 8% at week 7 and 6% at week 8; P < 0.05 using Bonferroni correction); week 12 values did not differ from baseline. No significant differences were noted between baseline LDL cholesterol and values at weeks 7, 8, or 12 when comparing individual groups by using Bonferroni correction, even though the overall one-way analysis of variance with repeated measures was highly significant (P < 0.001). LDL-cholesterol concentrations did decline by 8% at week 8 compared with baseline. There was a significant effect of diet on plasma HDL-cholesterol concentrations (P < 0.005 by one-way ANOVA with repeated measures). However, a group difference was observed only between baseline and week 12 (16% increase; P < 0.05 by Bonferroni correction). Triacylglycerol concentrations did not change. CONCLUSIONS The yeast-derived beta-glucan fiber significantly lowered total cholesterol concentrations and was well tolerated; HDL-cholesterol concentrations rose, but only 4 wk after the fiber was stopped.