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Objective: The aim of this scoping review was to report on the planning and implementation of a disaster exercise for undergraduate nursing students, which included the participation of other health students, allied health students, or professionals, for the purpose of preparing them to respond to a disaster., Introduction: Recently, the world has witnessed an increasing frequency of natural disasters, emergencies, and public health events. These events often adversely influence many individuals' health, and as such, require health professionals to be prepared and ready to effectively respond. Health students, including nursing, medical, and allied health professionals, need to be provided with opportunities to learn about disasters and to practice responding to them within a team context. This scoping review examined the planning and implementation of disaster exercises that have conceptualized an interprofessional team approach inclusive of nursing students., Inclusion Criteria: Quantitative studies, qualitative studies, mixed method studies, discussions, and text or opinion papers reporting a disaster simulation or drill, involving undergraduate nursing and other health students, allied health discipline students, practitioners, and non-health personnel were included. There was no limit on the publication period or languages., Methods: MEDLINE (EBSCOhost), CINAHL (EBSCOhost), ERIC (EBSCOhost), Embase (Ovid), Web of Science Core Collection, ProQuest Nursing and Allied Health (Ovid), and PsycINFO (Ovid) were searched for relevant reports. Titles and abstracts and then full texts were screened independently by 2 reviewers. A data extraction tool developed specifically for this review was used to chart evidence pertaining to planning and implementing a disaster exercise, nursing students' roles, and measured outcomes., Results: A total of 1429 titles were screened; 42 full texts were assessed against the eligibility criteria and 13 papers were selected for review. Nursing students had opportunities to practice performing a single role or a combined role as observers, triage nurses, direct care providers, or assisting health professionals, depending on their year level. Nursing students' roles were sometimes not well identified and not clearly communicated to them prior to the exercise, resulting in ambiguous expectations for some participants. By involving multiple health students and professionals, the nursing students had the opportunity to participate and perform tasks within their scope of practice while observing the roles of other disciplines. In a few studies, participants teamed up to triage, assess, and provide care for simulated patients. A variety of outcomes were categorized, such as students' knowledge, skills, attitudes, satisfaction with the learning experience, self-confidence, communication, collaboration, readiness for a disaster event, critical decision-making, and empathy. Important lessons regarding decision-making preparations (such as planning, coordinating, and implementing a disaster exercise), scheduling and sequencing for optimal times to ensure participating disciplines can attend, identification and effective communication of students' roles, plus ensuring manageable group sizes will optimize a more authentic learning opportunity for all involved in disaster exercises., Conclusions: Overall, the exercises were perceived as a positive learning opportunity for students to understand what is required in disaster responses and to practice their skills. Adequate preparation for a disaster exercise is crucial for a successful experience and should prepare nursing students and other participants for the roles they need to fulfill., Supplemental Digital Content: A Vietnamese-language version of the abstract of this review is available as Supplemental Digital Content http://links.lww.com/SRX/A24 ., Competing Interests: SH is a senior associate editor of JBI Evidence Synthesis, but was not involved in the editorial processing of this manuscript. The other authors declare no conflicts of interest., (Copyright © 2023 JBI.)

Competing Interests: The authors declare no conflict of interest.

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for half of all HF diagnoses, and its prevalence is increasing at an alarming rate. Lately, it has been recognized as a clinical syndrome due to diverse underlying etiology and pathophysiological mechanisms. The classic echocardiographic features of HFpEF have been well described as preserved ejection fraction (≥50%), left ventricular hypertrophy, and left atrial enlargement. However, echocardiography can play a key role in identifying the principal underlying mechanism responsible for HFpEF in the individual patient. The recognition of different phenotypic presentations of HFpEF (infiltrative, metabolic, genetic, and inflammatory) can assist the clinician in tailoring the appropriate management, and offer prognostic information. The goal of this review is to highlight several key phenotypes of HFpEF and illustrate the classic clinical scenario and echocardiographic features of each phenotype with real patient cases., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Development of the Nurse practitioner role and the specialisation of practice is an increasing focus in healthcare. To date, a bibliometric evaluation of scholarly work referring to Nurse Practitioners, has not been located in the published literature., Objective: With the aim of identifying the top 100 cited articles in the Nurse Practitioner domain, the Scopus™ database was searched for Nurse Practitioner studies during 2007-2021. Using bibliometric analysis we identified prolific authors; annual trend; citation rates; countries of origin; and study design., Results: There were 1768 papers identified across 360 peer reviewed journals in 33 countries., Conclusions: Finding from this analysis provides evidence of an evolving research area of inquiry which contributes to knowledge of the Nurse Practitioner role and scope of practice.

Objectives: To clarify capability for work readiness in newly graduated registered nurses as viewed from the perspective of clinicians in practice, educators in tertiary institutions, and graduates., Design: Integrative review., Data Sources: Databases searched for peer-reviewed studies included PubMed, MEDLINE, ERIC, Campbell collaboration, Google Scholar, and Cochrane databases., Review Methods: Pragmatism informed this integrative review. The five-stage method described by Whittemore and Knafl was used to enable rigorous examination of the expected capability of graduate nurses. A comprehensive database search was conducted using PRISMA guidelines. Eighteen articles were appraised and analysed for this review. The capability concept was used as a framework for analysis., Results: Eighteen articles met the inclusion criteria. Findings revealed that although there is no definition for graduate nurses' work readiness, there is a common theme. Graduate nurses are expected to have broad theoretical knowledge (knowing) along with practical knowledge (doing). They are also expected to demonstrate integrity, honesty, respect, compassion, and a moral compass. A list of personal attributes and organisational acumen was also reflective of graduate readiness upon entering the workforce and identified as necessary capabilities for graduates., Conclusions: A picture of the perfect employee is illustrated in the definition of work readiness by the participants of the original studies. Yet there is a lack of stakeholder consensus on the capabilities expected from a graduate nurse., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Patients who want to know how to access their medical records from a health organization's website have certain expectations about what must be included to assist in this process. The purpose of this article is to detail patient expectations of a health care organization website when searching for information on how to apply for access to their medical records. Using expectation confirmation theory, a survey was developed to ask patients, as consumers of health care, about their expectations when accessing websites. The results revealed that patients want websites to be safe and secure and have help available if there are questions about the website or search functionality. In order to improve the patient experience, health care providers need to understand these expectations from the patient perspective about this information-seeking exercise.

People who are homeless experience significantly poorer health than the general population and often face multifaceted challenges engaging with public healthcare services. Mission Health Nurse-led Clinic (MHNC) was established in 2019 to meet the healthcare needs of this marginalised population in Launceston, Tasmania. This study examines barriers to healthcare access amongst individuals who experience homelessness, client and staff perceptions of the MHNC services and explored opportunities for service expansion. Descriptive statistics were drawn from administrative data, and all interviews were thematically analysed. A total of 426 presentations were reported for 174 individuals experiencing homelessness over 26 months. The median client age was 42 years and 60.9% were male; A total of 38.5% were homeless or lived in a supported accommodation. The predominant reasons for clinic visits included prescription requests (25.3%) and immunisations (20.1%). A total of 10 clients and 5 City Mission staff were interviewed with three themes emerging from the findings: personal vulnerability, disconnectedness and acceptability of the MHNC. The MHNC services were reported to be highly appreciated by all clients. Mental health and allied health, extra operating hours and maintaining the flexibility of walk-in appointments were suggested as expansion areas for the service and were highlighted as ways to increase engagement for improved health outcomes. Continued partnerships with interprofessional primary healthcare providers would contribute to addressing unmet healthcare needs in this vulnerable population.

Cholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis.

Objective: This scoping review will map the literature related to interprofessional learning among undergraduate nursing, and other health and allied health students and professionals to prevent, prepare, or respond to a simulated disaster event., Introduction: The frequency of disasters has been increasing globally. Nurses constitute the largest proportion of the health workforce and play an important role in disaster response, together with other health and allied health professionals. The development and implementation of disaster exercises that are inclusive of nursing, as well as other health, and allied health students or professionals will benefit students' learning around disaster response. Therefore, it is timely to conduct a review of disaster exercises that have conceptualized and implemented an interprofessional team approach inclusive of nursing students., Inclusion Criteria: Publications of quantitative, qualitative, mixed method studies, discussions, text, or opinion reporting a disaster simulation or drill involving nursing and other health, allied health discipline students, or practitioners will be included. There is no limit on the publication period or languages. All types of natural and human-induced disasters will be considered., Methods: The search will be conducted in MEDLINE, CINAHL, ERIC, Embase, Web of Science, ProQuest Nursing and Allied Health, and PsycINFO. Two reviewers will screen titles and abstracts for potential papers, and the full texts will be examined against eligibility criteria. Data will be extracted using the tool developed for this review. Nursing roles and how nursing students have collaborated with other team members will be discussed., Competing Interests: SH is a senior associate editor for JBI Evidence Synthesis, but had no input in the editorial decision for this protocol. The other authors declare no conflict of interest., (Copyright © 2021 JBI.)

Contemporary sociopolitical circumstance impedes the delivery of primary health care in keeping with its underlying philosophy and tenets. Skills to negotiate the maintenance of best practice and quality care in an evolving practice environment are fundamental to nursing. Nurse education needs to incorporate the ideals of best practice ideology to ensure that all are prepared to negotiate the realities of nursing practice. In this discussion paper the experience of moral distress by community health nurses is used to illustrate why skills in political advocacy and action are equally essential as clinical skills in nurse education and professional practice.

Aim: The aim was to determine how nurse practitioner (NP) roles are translated into clinical practice across Victoria, Australia. This paper reports details about NP work patterns and scopes of practice across multiple clinical settings and geographic locations., Design: A quantitative survey design was used. A data abstraction tool, based on previous work, was adapted for this study., Methods: All NPs in one state of Australia were eligible to participate in the study and invited to complete an online survey about their NP practice. A previously developed data collection tool, capturing practice patterns of NPs, was adapted for online use in REDCAP. The data were exported, and descriptive statistics were analysed using SPSS., Results: Participants were mostly female, with males accounting for 25%. Findings indicate several NPs working in outpatient settings, community settings and forensic care. Patterns of practice-prescribing and ordering diagnostics-are associated with clinical context and model of care of the NP work., (© 2020 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

With 2020 being designated the Year of the Nurse and Midwife, it is opportune to acknowledge and recognise the role that nurses undertake in primary care environments. Nurses and midwives play a pivotal role in the delivery of high-quality health care, particularly in geographically challenged areas of Australia, where they may be the only provider of care within their communities. Rural and remote health services require strategic planning to develop and implement solutions responsive to the challenges of rural and remote communities. Maintenance of health services in rural and remote areas is a challenge, crucial to the equity of health outcomes for these communities. Many small communities rely on visiting medical officers to provide the on-call care to facility services, including emergency departments, urgent care centres, acute wards and aged care facilities. It is increasingly difficult to maintain the current rural workforce models, particularly the provision of after-hours 'on-call' care necessary in these communities. An alternative model of health care service delivery staffed by nurse practitioners (NP) is one proposed solution. NPs are educated, skilled and proven in their ability to provide an after-hours or on-call service to meet the expectations of rural and remote communities. Achievement of high-quality health care that is cost-efficient, safe and demonstrates improved patient outcomes has been reported in NP-led health care delivery impact evaluations. The value of an NP locum service model is the provision of a transparent, reliable service delivering consistent, equitable and efficient health care to rural and remote communities.

We examine the relationship between dementia and psychiatric disorder diagnoses among long-term care residents in nursing homes across the state of Rhode Island (RI), USA.Observational clinical study.Two hundred fifty-five residents with and without the diagnosis of dementia were included in this study.Prevalence analysis was used to elucidate information on psychiatric disorders in the overall cohort, and among residents with dementia. Questions from the quality of life questionnaire (EQ-5D-3L) that provides information on self-care, anxiety/depression, and resident's view of how healthy they are, were used to evaluate their association with dementia and psychiatric disorders. A logistic regression analysis was conducted to understand the relationship between dementia and mental illness diagnoses in long-term care facilities. Finally, a subgroup logistic regression analysis was performed for residents with Alzheimer disease.65.1% of all residents suffered from at least 1 psychiatric disorder. Anxiety was the most common diagnosis (36.5%), followed by depression (28.6%), and insomnia (14.9%). There was a positive and statistically significant association between any mental illness diagnosis and dementia (adjusted OR: 3.73; 95% CI: 1.34-10.41). Bipolar disorder and insomnia were negatively and statistically significantly associated with dementia (adjusted OR: 0.17; 95% CI: 0.03-0.89 AND adjusted OR: 0.39; 95% CI: 0.16-0.96 respectively). Age and COPD were also statistically associated with dementia (adjusted OR: 1.07; 95% CI: 1.03-1.11 AND adjusted OR: 0.28, 95% CI: 0.12-0.66). Alzheimer disease was positively and significantly associated with the diagnosis of any mental illness (adjusted OR: 3.77; 95% CI: 1.17-12.20).We studied the relationship between dementia and diagnoses of psychiatric disorders present in long-term care residents. We found that residents with a diagnosis of dementia were more likely to suffer from at least 1 psychiatric disorder. Further work is needed to establish the neuropathophysiological relationship between psychiatric disorders and dementia.

We examined the process of obtaining informed consent (IC) for clinical research purposes in long-term care facilities (LTCFs) in Rhode Island (RI), USA. We assessed factors that were associated with resident ability to consent, such as Brief Interview for Mental Status scores. We used a self-administered questionnaire to further understand the effect of LTCF staff evaluation of ability to consent on residents' autonomy and control over their medical decision making.Observational clinical studyLong-term care setting.LTCF personnel provided us with residents' names, as well as their professional assessment of resident ability to consent. We used Brief Interview for Mental Status (BIMS) scores to assess the cognitive capacity of all residents to assess, and compare it to the assessment provided by LTCF personnel. A logistic regression analysis was performed to determine the relationship between LTCF assessment of resident ability to consent and BIMS score or confirmed diagnosis of dementia as seen from residents' medical charts. A self-administered questionnaire was filled out by the personnel of 10 LTCFs across RI, USA.LTCF personnel in 9 out of 10 recruited facilities reported that their assessment of resident ability to consent was based on subjective assessment of the resident as alert and oriented. There was a statistically significant relationship between the LTCF assessment of resident ability to consent and previously diagnosed dementia (OR: 0.211, 95% CI 0.107-0.415). Therefore, as BIMS scores increased, the likelihood that the resident would be deemed able to consent by LTCF personnel also increased. Furthermore, there was a statistically significant relationship between LTCF assessment of resident ability to consent and BIMS scores (OR: 1.430, 95% CI 1.274-1.605).There is no standard on obtaining IC for research studies conducted in LTCFs. We recommend that standardizing the process of obtaining IC in LTCFs can enhance the ability to perform research with LTCF residents.

Background: T2Bacteria assay uses T2 magnetic resonance (T2MR) technology for the rapid diagnosis of bacterial bloodstream infections (BSIs). This FDA cleared technology can detect 5 of the most prevalent pathogens causing bacteremia (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecium). Because the significance of discordant results between the T2Bacteria assay and blood culture (BC) remains a challenge, in this case series we reviewed the medical records of patients who had a positive T2Bacteria test and a concurrent negative BC., Methods: Among 233 participants, we identified 20 patients with 21 (9%) discordant T2Bacteria-positive/BC-negative (T2+/BC-) results. We classified these results based on clinical cultures and clinical evidence., Results: When we analyzed these 21 discordant results in-depth, 11 (52.5%) fulfilled criteria for probable BSI, 4 (19%) for possible BSI, and 6 (28.5%) were presumptive false positives. Among the probable/possible BSIs, discordant results were often associated with patients diagnosed with closed space and localized infections [pyelonephritis (n = 7), abscess (n = 4), pneumonia (n = 1), infected hematoma (n = 1), and osteomyelitis (n = 1)]. Also, within the preceding 2 days of the T2+/BC- blood sample, 80% (16/20) of the patients had received at least one dose of an antimicrobial agent which was active against the T2Bacteria-detected pathogen., Conclusions: In the majority of discrepant results, the T2Bacteria assay detected a plausible pathogen that was supported by clinical and/or microbiologic data. Discrepancies appear to be associated with closed space and localized infections and the recent use of effective antibacterial agents. The clinical significance and potential implications of such discordant results should be further investigated.

Purpose: Febrile neutropenia has a significant clinical and economic impact on cancer patients. This study evaluates the cost-effectiveness of different current empiric antibiotic treatments., Methods: A decision analytic model was constructed to compare the use of cefepime, meropenem, imipenem/cilastatin, and piperacillin/tazobactam for treatment of high-risk patients. The analysis was performed from the perspective of U.S.-based hospitals. The time horizon was defined to be a single febrile neutropenia episode. Cost-effectiveness was determined by calculating costs and deaths averted. Cost-effectiveness acceptability curves for various willingness-to-pay thresholds (WTP), were used to address the uncertainty in cost-effectiveness., Results: The base-case analysis results showed that treatments were equally effective but differed mainly in their cost. In increasing order: treatment with imipenem/cilastatin cost $52,647, cefepime $57,270, piperacillin/tazobactam $57,277, and meropenem $63,778. In the probabilistic analysis, mean costs were $52,554 (CI: $52,242-$52,866) for imipenem/cilastatin, $57,272 (CI: $56,951-$57,593) for cefepime, $57,294 (CI: $56,978-$57,611) for piperacillin/tazobactam, and $63,690 (CI: $63,370-$64,009) for meropenem. Furthermore, with a WTP set at $0 to $50,000, imipenem/cilastatin was cost-effective in 66.2% to 66.3% of simulations compared to all other high-risk options., Discussion: Imipenem/cilastatin is a cost-effective strategy and results in considerable health care cost-savings at various WTP thresholds. Cost-effectiveness analyses can be used to differentiate the treatments of febrile neutropenia in high-risk patients.

Tumor metastasis to the draining lymph nodes is critical in patient prognosis and is tightly regulated by molecular interactions mediated by lymphatic endothelial cells (LECs). The underlying mechanisms remain undefined in the head and neck squamous cell carcinomas (HNSCCs). Using HNSCC cells and LECs we determined the mechanisms mediating tumor-lymphatic cross talk. The effects of a pentacyclic triterpenoid, methyl 2-trifluoromethyl-3,11-dioxoolean-1,12-dien-30-oate (CF 3 DODA-Me), a potent anticancer agent, were studied on cancer-lymphatic interactions. In response to inflammation, LECs induced the chemokine (C-X-C motif) ligand 9/10/11 chemokines with a concomitant increase in the chemokine (C-X-C motif) receptor 3 (CXCR3) in tumor cells. CF 3 DODA-Me showed antiproliferative effects on tumor cells, altered cellular bioenergetics, suppressed matrix metalloproteinases and chemokine receptors, and the induction of CXCL11-CXCR3 axis and phosphatidylinositol 3-kinase/AKT pathways. Tumor cell migration to LECs was inhibited by blocking CXCL11 whereas recombinant CXCL11 significantly induced tumor migration, epithelial-to-mesenchymal transition, and matrix remodeling. Immunohistochemical analysis of HNSCC tumor arrays showed enhanced expression of CXCR3 and increased lymphatic vessel infiltration. Furthermore, The Cancer Genome Atlas RNA-sequencing data from HNSCC patients also showed a positive correlation between CXCR3 expression and lymphovascular invasion. Collectively, our data suggest a novel mechanism for cross talk between the LECs and HNSCC tumors through the CXCR3-CXCL11 axis and elucidate the role of the triterpenoid CF 3 DODA-Me in abrogating several of these tumor-promoting pathways., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether sex differences exist in the triage, management and outcomes associated with non-traumatic chest pain presentations in the emergency department (ED)., Methods: All adults (≥18 years) with non-traumatic chest pain presentations to three EDs in Melbourne, Australia between 2009 and 2013 were retrospectively analysed. Data sources included routinely collected hospital databases. Triage scoring of the urgency of presentation, time to medical examination, cardiac troponin testing, admission to specialised care units, and in-ED and in-hospital mortality were each modelled using the generalised estimating equations approach., Results: Overall 54 138 patients (48.7% women) presented with chest pain, contributing to 76 216 presentations, of which 26 282 (34.5%) were cardiac. In multivariable analyses, compared with men, women were 18% less likely to be allocated an urgency of 'immediate review' or 'within 10 min review' (OR=0.82, 95% CI 0.79 to 0.85), 16% less likely to be examined within the first hour of arrival to the ED by an emergency physician (0.84, 0.81 to 0.87), 20% less likely to have a troponin test performed (0.80, 0.77 to 0.83), 36% less likely to be admitted to a specialised care unit (0.64, 0.61 to 0.68), and 35% (p=0.039) and 36% (p=0.002) more likely to die in the ED and in the hospital, respectively., Conclusions: In the ED, systemic sex bias, to the detriment of women, exists in the early management and treatment of non-traumatic chest pain. Future studies that identify the drivers explaining why women presenting with chest pain are disadvantaged in terms of care, relative to men, are warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillin-resistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membrane-active antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent., Competing Interests: Conflict of interest statement: F.M.A. and E.M. have financial interests in Genma Biosciences and Octagon Therapeutics, companies that are engaged in developing antimicrobial compounds. E.M.’s and F.M.A.’s interests were reviewed and are managed by Rhode Island Hospital (E.M.) and Massachusetts General Hospital and Partners HealthCare (F.M.A.) in accordance with their conflict of interest policies. The remaining authors declare no competing financial interests.

Chronic Staphylococcus aureus infections are complicated by frequent relapses not only from the development of drug resistance to conventional antibiotics, but also through the formation of persister bacterial cells. Bacterial persisters are in a transient, metabolically inactive state, making conventional antibiotics that target essential cellular growth processes ineffective, resulting in high clinical failure rates of antibiotic chemotherapy. The development of new antibiotics against persistent S. aureus is an urgent issue. Over the last decade, new strategies to identify S. aureus persister-active compounds have been proposed. This review summarizes the proposed targets, antipersister compounds and innovative methods that may augment conventional antibiotics against S. aureus persisters. The reviewed antipersister strategies can be summarized as two broad categories; directly targeting growth-independent targets and potentiating existing, ineffective antibiotics by aiding uptake or accessibility.

Background: Glycaemic control is recognized as one of the important aspects in managing critically ill patients. Both hyperglycaemia and hypoglycaemia independently increase the risk of patient mortality. Hence, the identification of optimal glycaemic control is of paramount importance in the management of critically ill patients., Aims and Objectives: The aim of this literature review is to examine the current status of glycaemic control in critically ill adult patients. This literature review will focus on randomized controlled trials comparing intensive insulin therapy to conventional insulin therapy, with an objective to identify optimal blood glucose level targets for critically ill adult patients., Design and Methods: A literature review was conducted to identify large randomized controlled trials for the optimal targeted blood glucose level for critically ill adult patients published since 2000. A total of eight studies fulfilled the selection criteria of this review., Results: With current human and technology resources, the results of the studies support commencing glycaemic control once the blood glucose level of critically ill patients reaches 10 mmol/L and maintaining this level between 8 mmol/L and 10 mmol/L., Conclusion: This literature review provides a recommendation for targeting the optimal blood glucose level for critically ill patients within moderate blood glucose level target range (8-10 mmol/L). The need for uniformed glucometrics for unbiased reporting and further research for optimal blood glucose target is required, especially in light of new technological advancements in closed-loop insulin delivery and monitoring devices., Relevance to Clinical Practice: This literature review has revealed a need to call for consensus in the measurement and reporting of glycaemic control using standardized glucometrics., (© 2017 British Association of Critical Care Nurses.)

Inteins are the protein equivalent of introns. They are seamlessly removed during post-translational maturation of their host protein (extein). Inteins from extremophiles played a key role in understanding intein-mediated protein splicing. There are currently three classes of inteins defined by catalytic mechanism and sequence signatures. This study demonstrates splicing of three class 3 mini-inteins: Burkholderia vietnamiensis G4 Bvi IcmO intein, Mycobacterium smegmatis MC2 155 Msm DnaB-1 intein and Mycobacterium leprae strain TN Mle DnaB intein. B. vietnamiensis has a broad ecological range and remediates trichloroethene. M. smegmatis is a biofilm forming soil bacteria. Although other intein classes have only a single branched intermediate at the C-terminal splice junction, the class 3 intein reaction pathway includes two branched intermediates. The class 3 specific branched intermediate is formed by an internal cysteine, while the C-terminal branch intermediate is at a serine or threonine in all class 3 inteins except the Bvi IcmO intein, where it is a cysteine. This latter cysteine was unable to compensate for mutation of the class 3-specific internal catalytic cysteine despite the Bvi IcmO intein having an N-terminal splice junction naturally tuned for a cysteine nucleophile, demonstrating the mandatory order of branch intermediates in class 3 inteins.

Background: Vancomycin-resistant enterococci (VRE) cause severe infections among patients with malignancy, and these infections are usually preceded by gastrointestinal colonization., Methods: We searched the PubMed and EMBASE databases (up to May 26, 2016) to identify studies that reported data on VRE gastrointestinal colonization among patients with solid or hematologic malignancy., Results: Thirty-four studies, reporting data on 8391 patients with malignancy, were included in our analysis. The pooled prevalence of VRE colonization in this population was 20% (95% confidence interval [CI], 14%-26%). Among patients with hematologic malignancy, 24% (95% CI, 16%-34%) were colonized with VRE, whereas no studies reported data solely on patients with solid malignancy. Patients with acute leukemia were at higher risk for VRE colonization (risk ratio [RR] = 1.95; 95% CI, 1.17-3.26). Vancomycin use or hospitalization within 3 months were associated with increased colonization risk (RR = 1.92, 95% CI = 1.06-3.45 and RR = 4.68, 95% CI = 1.66-13.21, respectively). Among the different geographic regions, VRE colonization rate was 21% in North America (95% CI, 13%-31%), 20% in Europe (95% CI, 9%-34%), 23% in Asia (95% CI, 13%-38%), and 4% in Oceania (95% CI, 2%-6%). More importantly, colonized patients were 24.15 (95% CI, 10.27-56.79) times more likely to develop a bloodstream infection due to VRE than noncolonized patients., Conclusions: A substantial VRE colonization burden exists among patients with malignancy, and colonization greatly increases the risk for subsequent VRE bloodstream infection. Adherence to antimicrobial stewardship is needed, and a re-evaluation of the use of vancomycin as empiric therapy in this patient population may be warranted., (© The Author 2016. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Inteins are naturally occurring intervening sequences that catalyze a protein splicing reaction resulting in intein excision and concatenation of the flanking polypeptides (exteins) with a native peptide bond. Inteins display a diversity of catalytic mechanisms within a highly conserved fold that is shared with hedgehog autoprocessing proteins. The unusual chemistry of inteins has afforded powerful biotechnology tools for controlling enzyme function upon splicing and allowing peptides of different origins to be coupled in a specific, time-defined manner. The extein sequences immediately flanking the intein affect splicing and can be defined as the intein substrate. Because of the enormous potential complexity of all possible flanking sequences, studying intein substrate specificity has been difficult. Therefore, we developed a genetic selection for splicing-dependent kanamycin resistance with no significant bias when six amino acids that immediately flanked the intein insertion site were randomized. We applied this selection to examine the sequence space of residues flanking the Nostoc punctiforme Npu DnaE intein and found that this intein efficiently splices a much wider range of sequences than previously thought, with little N-extein specificity and only two important C-extein positions. The novel selected extein sequences were sufficient to promote splicing in three unrelated proteins, confirming the generalizable nature of the specificity data and defining new potential insertion sites for any target. Kinetic analysis showed splicing rates with the selected exteins that were as fast or faster than the native extein, refuting past assumptions that the naturally selected flanking extein sequences are optimal for splicing.

Nucleases play important roles in all DNA transactions, including replication, repair, and recombination. Many different nucleases from bacterial and eukaryotic organisms have been identified and functionally characterized. However, our knowledge about the nucleases from Archaea, the third domain of life, is still limited. We searched for 3'-5' exonuclease activity in the hyperthermophilic archaeon, Pyrococcus furiosus, and identified a protein with the target activity. The purified protein, encoded by PF2046, is composed of 229 amino acids with a molecular weight of 25,596, and displayed single-strand specific 3'-5' exonuclease activity. The protein, designated as PfuExo I, forms a stable trimeric complex in solution and excises the DNA at every two nucleotides from the 3' to 5' direction. The amino acid sequence of this protein is conserved only in Thermococci, one of the hyperthermophilic classes in the Euryarchaeota subdomain in Archaea. The newly discovered exonuclease lacks similarity to any other proteins with known function, including hitherto reported 3'-5' exonucleases. This novel nuclease may be involved in a DNA repair pathway conserved in the living organisms as a specific member for some hyperthermophilic archaea.

We report the complete and annotated genome sequence of Bacillus cereus NC7401, a representative of the strain group that causes emetic-type food poisoning. The emetic toxin, cereulide, is produced by a nonribosomal protein synthesis (NRPS) system that is encoded by a gene cluster on a large resident plasmid, pNCcld.

Inteins and other self-catalytic enzymes, such as glycosylasparaginases and hedgehog precursors, initiate autocleavage by converting a peptide bond to a (thio)ester bond when Ser, Thr, or Cys undergoes an N-[S/O] acyl migration assisted by residues within the precursor. Previous studies have shown that a His at position 10 in intein Block B is essential for this initial acyl migration and N-terminal splice junction cleavage. This His is present in all inteins identified to date except the Thermococcus kodakaraensis Tko CDC21-1 intein orthologs and the inactive Arthrobacter species FB24 Arth_1007 intein. This study demonstrates that the Tko CDC21-1 intein is fully active and has replaced the lost catalytic function normally provided by the Block B His using a compensatory mechanism involving a conserved ortholog-specific basic residue (Lys(58)) present outside the standard intein conserved motifs. We propose that Lys(58) catalyzes the initial N-S acyl migration by stabilizing the thiazolidine-tetrahedral intermediate, allowing it to be resolved by water-mediated hydrolysis rather than by protonating the leaving group as His is theorized to do in many other inteins. Autoprocessing enzymes may have more flexibility in evolving catalytic variations because high reaction rates are not required when performing single-turnover reactions on "substrates" that are covalently attached to the enzyme. Consequently, inteins have more flexibility to sample catalytic mechanisms, providing insight into various strategies that enzymes use to accomplish catalysis.

Inteins are the protein equivalent of introns. Their protein splicing activity is essential for the host protein's maturation and function. Inteins are grouped into three classes based on sequence signature and splicing mechanism. The sequence signature of the recently characterized class 3 inteins is a noncontiguous Trp-Cys-Thr (WCT) motif and the absence of the standard class 1 Cys¹ or Ser¹ N-terminal nucleophile. The intein N-terminal Cys¹ or Ser¹ residue is essential for splicing in class 1 inteins. The mycobacteriophage Catera Gp206, Nocardioides sp. strain JS614 TOPRIM, and Thermobifida fusca YX Tfu2914 inteins have a mixture of class 1 and class 3 motifs. They carry the class 3 Trp-Cys-Thr motif and have the standard class 1 N-terminal Ser¹ or Cys¹. This study determined which class the mycobacteriophage Catera Gp206 and Nocardioides sp. JS614 TOPRIM inteins belong to based on catalytic mechanism. The mycobacteriophage Catera Gp206 intein (starting with Ser¹) is a class 3 intein, and its Ser¹ residue is not required for splicing. Based on phylogenetic analysis, we propose that class 3 inteins arose from a single mutated intein that was spread by phage into predominantly helicase genes in various phages and their hosts.

An Arthrobacter species FB24 gene (locus tag Arth_1007) was previously annotated as a putative intein-containing DnaB helicase of phage origin (Arsp-FB24 DnaB intein). However, it is not a helicase gene because the sequence similarity is limited to inteins. In fact, the flanking exteins total only 66 amino acids. Therefore, the intein should be referred to as the Arsp-FB24 Arth_1007 intein. The Arsp-FB24 Arth_1007 intein failed to splice in its native precursor and in a model precursor. We previously noted that the Arsp-FB24 Arth_1007 intein is the only putative Class 3 intein that is missing the catalytically essential Cys at position 4 of intein Motif F, which is one of the three defining signature residues of this class. Additionally, a catalytically essential His in position 10 of intein Motif B is also absent; this His is the most conserved residue amongst all inteins. Splicing activity was not rescued when these two catalytically important positions were 'reverted' back to their consensus residues. This study restores the unity of the Class 3 intein signature sequence in active inteins by demonstrating that the Arsp-FB24 Arth_1007 intein is an inactive pseudogene.

Inteins are the protein equivalent of introns. They are remarkable and robust single turnover enzymes that splice out of precursor proteins during post-translational maturation of the host protein (extein). The Deinococcus radiodurans Snf2 intein is the second member of the recently discovered Class 3 subfamily of inteins to be characterized. Class 3 inteins have a unique sequence signature: (a) they start with residues other than the standard Class 1 Cys, Ser or Thr, (b) have a noncontiguous, centrally located Trp/Cys/Thr triplet, and (c) all but one have Ser or Thr at the start of the C-extein instead of the more common Cys. We previously proposed that Class 3 inteins splice by a variation in the standard intein-mediated protein splicing mechanism that includes a novel initiating step leading to the formation of a previously unrecognized branched intermediate. In this mechanism defined with the Class 3 prototypic Mycobacteriophage Bethlehem DnaB intein, the triplet Cys attacks the peptide bond at the N-terminal splice junction to form the class specific branched intermediate after which the N-extein is transferred to the side chain of the Ser, Thr, or Cys at the C-terminal splice junction to form the standard intein branched intermediate. Analysis of the Deinococcus radiodurans Snf2 intein confirms this splicing mechanism. Moreover, the Class 3 specific Block F branched intermediate was isolated, providing the first direct proof of its existence.

Inteins are single turnover enzymes that splice out of protein precursors during maturation of the host protein (extein). The Cys or Ser at the N terminus of most inteins initiates a four-step protein splicing reaction by forming a (thio)ester bond at the N-terminal splice junction. Several recently identified inteins cannot perform this acyl rearrangement because they do not begin with Cys, Thr, or Ser. This study analyzes one of these, the mycobacteriophage Bethlehem DnaB intein, which we describe here as the prototype for a new class of inteins based on sequence comparisons, reactivity, and mechanism. These Class 3 inteins are characterized by a non-nucleophilic N-terminal residue that co-varies with a non-contiguous Trp, Cys, Thr triplet (WCT) and a Thr or Ser as the first C-extein residue. Several mechanistic differences were observed when compared with standard inteins or previously studied atypical KlbA Ala(1) inteins: (a) cleavage at the N-terminal splice junction in the absence of all standard N- and C-terminal splice junction nucleophiles, (b) activation of the N-terminal splice junction by a variant Block B motif that includes the WCT triplet Trp, (c) decay of the branched intermediate by thiols or Cys despite an ester linkage at the C-extein branch point, and (d) an absolute requirement for the WCT triplet Block F Cys. Based on biochemical data and confirmed by molecular modeling, we propose roles for these newly identified conserved residues, a novel protein splicing mechanism that includes a second branched intermediate, and an intein classification with three mechanistic categories.

The proliferating cell nuclear antigen (PCNA) is well recognized as one of the essential cellular components of the DNA replication machinery in all eukaryotic organisms. Despite their prominent importance, very little biochemical and structural information about plant PCNAs is available, in comparison with that obtained from other eukaryotic organisms. We have determined the atomic resolution crystal structures of the two distinct Arabidopsis thaliana PCNAs (AtPCNA), both complexed with the C-terminal segment of human p21. Both AtPCNAs form homotrimeric ring structures, which are essentially identical to each other, including the major contacts with the p21 peptide. The structure of the amino-terminal half of the p21 peptide, containing the typical PIP box sequence, is remarkably similar to those observed in the previously reported crystal structures of the human and archaeal PCNA-PIP box complexes. Meanwhile, the carboxy-terminal halves of the p21 peptide in the plant PCNA complexes are bound to the protein in a unique manner, most probably because of crystal packing effects. A surface plasmon resonance analysis revealed high affinity between each AtPCNA and the C-terminal fragment of human p21. This result strongly suggests that the interaction is functionally significant, although no plant homologs of p21 have been identified yet. We also discovered that AtPCNA1 and AtPCNA2 form heterotrimers, implying that hetero-PCNA rings may play critical roles in cellular signal transduction, particularly in DNA repair.

Proliferating cell nuclear antigen (PCNA) is the sliding clamp that is essential for the high processivity of DNA synthesis during DNA replication. Pyrococcus furiosus, a hyperthermophilic archaeon, has at least two DNA polymerases, polymerase BI (PolBI) and PolD. Both of the two DNA polymerases interact with the archaeal P. furiosus PCNA (PfuPCNA) and perform processive DNA synthesis in vitro. This phenomenon, in addition to the fact that both enzymes display 3'-5' exonuclease activity, suggests that both DNA polymerases work in replication fork progression. We demonstrated here that both PolBI and PolD functionally interact with PfuPCNA at their C-terminal PIP boxes. The mutant PolBI and PolD enzymes lacking the PIP-box sequence do not respond to the PfuPCNA at all in an in vitro primer extension reaction. This is the first experimental evidence that the PIP-box motif, located at the C termini of the archaeal DNA polymerases, is actually critical for PCNA binding to form a processive DNA-synthesizing complex.

Background: International randomised controlled trials conducted over the last two decades have consistently demonstrated improved mortality and morbidity resulting from thrombolytic therapy for patients with acute myocardial infarction (AMI). Subsequently, evidence-based guidelines have been designed and implemented to optimize thrombolytic delivery. The effect of evidence-based clinical guidelines on clinical practice is heavily influenced by strategies used to develop, disseminate and implement those guidelines., Aims: This study evaluated the impact of a collaborative, multifaceted implementation strategy for AMI management guidelines on thrombolytic usage in the Loddon Mallee Region, Victoria, Australia., Intervention: The multi-faceted implementation strategy included an inter-disciplinary team representing all treating venues contributing to the content of the "Guidelines for the Early Management of Acute Myocardial Infarction" followed by education sessions that coincided with the dissemination of the guidelines., Methods: A retrospective medical records audit 12 weeks before and 12 weeks after the intervention was used to evaluate the impact on proportion of those patients eligible and receiving a thrombolytic and door-to-needle time. Variables of treating venue, age, gender, type of AMI, and type of transport to hospital were also measured to determine their impact on results., Results and Conclusions: A retrospective audit of 170 medical records found that the intervention appeared to have had no impact on the proportion of patients eligible and receiving a thrombolytic (74.2% vs. 62.5%: p=0.275), and door-to-needle time (67.7 min vs. 60.5 min: p=0.759). Venue specific influences produced a variety of patterns in thrombolytic delivery that require further exploration. This suggests that a single solution approach across multiple venues will have limited impact.

Relationships between the chemical reactivity of 3-substituted cephalosporins or 3-methylene-substituted cephalosporins and several parameters observed by 13C NMR and IR spectroscopies are described. Among 3-substituted cephalosporins, the values of delta (C-3) and delta (COO) of 13C NMR spectra are correlated with the logarithms of the rate constants for alkaline hydrolysis (log kobsd) when substituents at the 3-position are classified into two groups, i.e., OR substituents and others. Among the 3-methylene-substituted cephalosporins, the difference values of the 13C chemical shifts for C-3 and C-4, delta delta (4-3), are correlated with log kobsd. The beta-lactam vC = O value of the solution IR spectra is a good index for the prediction of a significant change of the beta-lactam reactivity resulting from modification of a 3-substituent or a 3-methylene substituent. From analysis of these observed parameters, both resonance and inductive effects of the substituent at the 3-position were found to affect the chemical reactivity of the beta-lactam ring in cephalosporin, while only the inductive effect of the substituent at the 3'-position was found to affect the beta-lactam reactivity.

Detailed studies on the 13C and 1H NMR spectra of chromomycins A2 and A3, olivomycins A and B, and their derivatives clarified the assignment of many signals which had been unassigned or erroneously reported in the literatures. The revised assignments for chromomycin A3 and olivomycin A include the assignment of a key 13C signal used to discuss the saccharide linkage in question. Structure analyses based on the revised assignments support the alpha,1----3-bond between components of the disaccharide moiety in the molecules. Some general information useful for structure analysis of saccharides is also reported.

Thiocillins I, II and III were compared with micrococcin P1 by analysis of acid hydrolyzates of the native and the reduced antibiotics as well as by means of 1H and 13CNMR spectroscopies. As a result of these studies, the differences of these antibiotics were clarified in their structural units, and the structures of thiocillins I, II and III were assigned on the basis of the proposed structure of micrococcin P1.

A trial application of a recent two-dimensional nuclear magnetic resonance experiment to the polypeptide antibiotic siomycin A is described. Proton--carbon-13 chemical shift correlation measures the proton and carbon-13 chemical shift for each directly bonded CH group in a molecule, in a single experiment. The resultant map of correlated chemical shifts enables the carbon-13 spectrum to be assigned directly from the known proton shifts, and allows individual proton signals to be identified without problems of overlap. The signal-to-noise ratio available from such techniques should enable their application to aqueous protein solutions using currently available high-field spectrometers.

The peptide antibiotic siomycin-A was transformed into half-esters with dicarboxylic acids with the intention of making siomycin-A soluble in water. Sodium salts of the half-esters were also prepared. Some of the salts showed antibacterial activities comparable to siomycin-A against Gram-positive bacteria in vitro and exhibited better therapeutic effects in infected mice than siomycin-A. The chemical structures of siomycin-A hemiadipate-II and -III were elucidated by comparing their 13C and 1H NMR spectra with those of siomycin-A. Their physicochemical properties are described.