bluuebunny/crossref_metadata_2025 huggingface dataset:
Inter‐country exploration of factors associated with admission to long‐term institutional dementia care: evidence from the RightTimePlaceCare study
Authors: Verbeek Hilde , Meyer Gabriele , Challis David , Zabalegui Adelaida , Soto Maria E. , Saks Kai , Leino‐Kilpi Helena , Karlsson Staffan , Hamers Jan P.H. ,   the RightTimePlaceCare Consortium
Published: April 2015

Aim

To explore inter‐country variation of factors associated with institutionalization of people with dementia.

Background

There is an urgent need for evidence on whether factors associated with admission to institutional dementia care are applicable across healthcare systems, as increasing evidence suggests that these factors could be country‐specific.

Design

A prospective cohort study.

Method

Primary data were collected in eight European countries, at baseline and after 3 months follow‐up (November 2010–April 2012). The sample included 2014 dyads of people with dementia and their informal caregivers; 791 patients were recently institutionalized, 1223 patients lived at home and were at risk of institutionalization. Associations between care setting (institution vs. home) and factors shown to influence institutionalization (e.g. cognition, independence in activities of daily life, behaviour) were studied.

Results

Considerable differences were found between the eight countries in characteristics of people with dementia who had been recently admitted to ILTC. However, caregiver burden appeared the most consistent factor associated with institutionalization in all analyses. Indications for the importance of independence in activities of daily life were found as well, although country differences may be more prominent for this factor.

Conclusion

Evidence was found for two common factors, crucial in the process of institutionalization across countries: caregiver burden and independency in activities of daily life. However, this study also suggests that admission to institutional dementia care is context‐specific, as wide variation exists in factors associated with institutionalization across countries. Tailored best‐practice strategies are needed to reflect variations in response to these needs.
Enhancing nurses' empowerment: the role of supervisors' empowering management practices
Authors: Montani Francesco , Courcy François , Giorgi Gabriele , Boilard Amélie
Published: April 2015

Aim

This study tests a theoretical model where: (a) nurses' dispositional resistance to change is indirectly negatively related to behavioural empowerment through the mediating role of psychological empowerment; and (b) supervisors' empowering management practices buffer both the negative relationship between dispositional resistance to change and psychological empowerment and the indirect negative relationship between resistance to change and behavioural empowerment via psychological empowerment.

Background

Promoting a high level of empowerment among nursing personnel is important to ensure their effectiveness in the context of organizational change. It is thus essential to advance our current understanding of the factors that hamper nurses' psychological and behavioural expressions of empowerment and to clarify supervisor practices that can overcome such barriers.

Design

A cross‐sectional research design.

Method

We collected survey data during 2012 from a sample of 197 nurses from a Canadian hospital undergoing a major organizational change.

Results

Results from moderated mediation analyses provided evidence for an indirect negative relationship between dispositional resistance to change and behavioural empowerment through psychological empowerment, and for a moderating (buffering) effect of supervisors' empowering management practices on this mediated relationship. These findings provided support for our hypotheses.

Conclusions

Supervisors' empowering management practices represent an important contextual buffer against the negative effects of dispositional resistance to change on nurses' empowerment. Organizations should develop empowering management skills among nurses' supervisors to counteract the detrimental effects of dispositional resistance to change and to sustain an empowered nursing workforce.
Identification of Low‐Risk Adult Congenital LQTS Patients
Authors: ZHANG CLAIRE , KUTYIFA VALENTINA , MCNITT SCOTT , ZAREBA WOJCIECH , GOLDENBERG ILAN , MOSS ARTHUR J.
Published: April 2015

Long‐Term Mortality in Low‐Risk Adult LQTS

Introduction

To date, most risk stratification studies in long‐QT syndrome (LQTS) have focused on identification of high‐risk subjects. Current data on the long‐term clinical course of low‐risk adult LQTS patients are limited.

Methods and Results

Patients in this study were from the Rochester‐based LQTS Registry. We hypothesized that long‐term survival of LQT1‐2 patients with QTc <500 milliseconds and no cardiac symptoms before age 20 (n = 523) would be similar to that of their unaffected genotype‐negative family members (n = 1,134). Kaplan–Meier survival analysis and multivariate Cox proportional hazards regression models were used to evaluate the incidence and risk of all‐cause mortality in the study population. The low‐risk LQTS study group comprised 27% (523/1,919) of genetically confirmed LQTS Registry patients alive at age 20. The cumulative probability of all‐cause mortality between age 20 and 65 was similar in the low‐risk LQTS group and the genotype‐negative control group (4.3% and 4.4%, respectively at age 65; P = 0.49 for overall difference). Multivariate analysis showed no significant difference in the risk of all‐cause mortality between the 2 groups (HR = 0.89; 95% CI 0.33–2.43, P = 0.82). Consistent results were revealed in subgroup analyses in female and male LQTS patients and in patients with genetically identified LQT1 and LQT2 mutations.

Conclusions

We identified a sizeable proportion of low‐risk, adult LQTS patients with no cardiac symptoms before age 20 and QTc<500 milliseconds who had 45‐year survival similar to unaffected family members.
Aspirating during the intramuscular injection procedure: a systematic literature review
Authors: Sisson Helen
Published: April 2015

Aims and objectives

To review the available evidence on aspirating when administering intramuscular injections and suggest recommendations for practice.

Background

The process of aspiration has been ingrained in the intramuscular injection procedure, and whilst many policies no longer recommend this practice, it often continues to be taught and practiced. The result is a variation in this procedure not always consistent with an evidence‐based approach.

Design

A systematic literature review.

Methods

A systematic approach to searching the literature was undertaken using identified academic databases from inception to May 2014. Citation searching identified additional data sources. Six studies met the search criteria.

Results

The majority of health professionals do not aspirate for the recommended 5–10 seconds. Administering an injection faster without aspiration is less painful than injecting slowly and aspirating. The main influences on the decision of whether or not to aspirate are based on what health professionals are taught and fear of injecting into a blood vessel.

Conclusions

In the paediatric vaccination setting, the practice of aspirating during the administration of an intramuscular injection is unnecessary and there is no clinical reason to suggest that these principles may not be applied when using the deltoid, ventrogluteal and vastus lateralis sites in other settings. Owing to its proximity to the gluteal artery, aspiration when using the dorsogluteal site is recommended. Nurses must be supported in all settings, by clear guidance which rejects traditional practice and facilitates evidence‐based practice.

Relevance to clinical practice

Educators need to ensure that their knowledge is up to date so that what they teach is based on evidence. This may be facilitated via regular educational updates. Further research and subsequent guidance are needed to support evidence‐based practice in intramuscular injection techniques in all nursing settings.
Strategic Leadership and Leaders in Entrepreneurial Contexts: A Nexus for Innovation and Impact Missed?
Authors: Simsek Zeki , Jansen Justin J. P. , Minichilli Alessandro , Escriba‐Esteve Alejandro
Published: April 2015

Research at the nexus of strategic leadership and entrepreneurial contexts has been encouraging, but some of the more innovative and impactful questions remain underexplored. The purpose of the Special Issue was to provide a forum for works that build on the constraints, challenges, characteristics, and other salient elements of entrepreneurial settings to advance theory and testing on strategic leadership effects, as well as enrich our understanding of firm behaviour and outcomes in entrepreneurial contexts. We first provide an overview and background of the Special Issue. We then provide a summary of the process and outcomes, including a synopsis of the accepted manuscripts. The discussion finally traces the implications of the Special Issue for future research directions on strategic leadership and leaders in entrepreneurial contexts.
Stenosing ureteritis in Henoch–Schönlein purpura: Report of two cases
Authors: Kasahara Katsuaki , Uemura Osamu , Nagai Takuhito , Yamakawa Satoshi , Nakano Masaru , Iwata Naoyuki
Published: April 2015

Stenosing ureteritis (SU), a rare complication of Henoch–Schönlein purpura (HSP), typically presents with severe symptoms. We report the cases of two HSP patients presenting with gross hematuria, blood clotting, and colicky flank pain, followed by purpura on the lower extremities. Early‐stage ultrasonography indicated hydronephrosis, thickened renal pelvic mucous membrane, and ureteral dilatation (UD), suggesting HSP complicated with SU. After early SU treatment with prednisolone, kidney function, thickened renal pelvic mucous membrane, and UD progressively normalized and the pain gradually disappeared. Regular ultrasonography of HSP patients from the onset of gross hematuria can be useful to detect early SU and facilitate conservative therapy with prednisolone. Diagnosis of SU can be easily missed by assuming HSP nephritis, particularly owing to the non‐specific symptoms. Common characteristics as well as treatment methods and prognosis of SU are given in the literature review.
Diffuse neonatal hemangiomatosis in a very low‐birthweight infant treated with erythropoietin
Authors: Okuno Takashi , Tokuriki Shuko , Yoshino Tomomi , Tanaka Nanae , Ohshima Yusei
Published: April 2015

Diffuse neonatal hemangiomatosis (DNH) is a rare condition characterized by the concomitant development of multiple cutaneous infantile hemangiomas (IH) and visceral hemangiomas. Recently, an association between erythropoietin treatment and an increased incidence of infantile hemangioma was noted. A Japanese male infant was born via cesarean section at 27 weeks of gestation. Following the commencement of erythropoietin treatment for anemia of prematurity, he developed multiple cutaneous hemangiomas, high cardiac output heart failure and hepatomegaly. Abdominal imaging indicated comorbidity of diffuse infantile hepatic hemanigomas, resulting in the final diagnosis of DNH. The discontinuation of erythropoietin treatment and long‐term therapy with propranolol improved the hepatic lesions and cutaneous hemangiomas. The possibility of multiple organ involvement and the exacerbating effects of erythropoietin treatment should be considered in cases in which multiple cutaneous hemangiomas develop in preterm infants receiving erythropoietin treatment.
Diffuse alveolar hemorrhage secondary to ANCA‐associated vasculitis in a patient with Down syndrome
Authors: Hori Ikumi , Nakaseko Haruna , Kamei Michi , Nomura Takayasu , Iwata Naomi , Ito Yasuhiko , Saitoh Shinji
Published: April 2015

Diffuse alveolar hemorrhage (DAH) is a rare disease characterized by dyspnea, cough, hemoptysis, and new alveolar infiltrates. Among the various underlying disorders, vasculitis is believed to play a significant role in the pathogenesis of DAH. Here we report the first case of a patient with Down syndrome who developed DAH secondary to anti‐neutrophil cytoplasmic antibody‐associated vasculitis. This case highlights the significance of vasculitis as well as pulmonary hypoplasia and vulnerability associated with Down syndrome in the development of DAH.
Relationship of vitamin D status with lung function and exercise capacity in COPD
Authors: Jung Ji Ye , Kim Young Sam , Kim Se Kyu , Kim Ha Yan , Oh Yeon Mok , Lee Sang Min , Seo Joon Beom , Lee Sang‐Do ,   KOLD Study
Published: April 2015

Background and objective

The relationship between blood vitamin D level and clinical parameters in patients with chronic obstructive pulmonary disease (COPD) has been reported with conflicting results. We explored the effects of vitamin D on clinical characteristics of patients with COPD in Korea.

Methods

The study population comprised 193 patients with COPD from Korean Obstructive Lung Disease Cohort. The plasma level of 25‐OH vitamin D3 (25‐OH‐VitD3) was measured every year along with various clinical parameters such as lung function, 6‐min walking (6MW) distance, quality of life, exacerbations and emphysema index. Generalized estimating equations and linear mixed model were used for statistical analysis.

Results

Of the 193 patients, 12 (6.2%), 28 (14.5%) and 153 (79.3%) were categorized into normal, insufficiency and deficiency groups. Clustered analysis showed that the plasma 25‐OH‐VitD3 level was associated with the post‐bronchodilator ratio of force expiratory volume in 1 s/forced vital capacity (FEV1/FVC) (estimated = 0.001; P = 0.022). The vitamin D deficiency group showed lower FEV1 (estimated = −0.129, P = 0.043), FEV1 % predicted (estimated = −4.994, P = 0.029) and FEV1/FVC ratio (estimated = −0.048, P = 0.001) than did the non‐deficiency group. The 6MW distance tended to be shorter in deficiency group (estimated = −17.26, P = 0.069) than in non‐deficiency group. Quality of life, exacerbation and emphysema index were not associated with plasma 25‐OH‐VitD3 level.

Conclusions

We demonstrated a high prevalence of vitamin D deficiency in Korean patients with COPD and a significant relationship between vitamin D deficiency and airflow limitation. The exercise capacity tended to be decreased in the vitamin D deficiency group.
Are Economic Development and Education Improvement Associated with Participation in Transnational Terrorism?
Authors: Elbakidze L. , Jin Y. H.
Published: April 2015

Using transnational terrorism data from 1980 to 2000, this study empirically examines the relationships between frequency of participation in transnational terrorism acts and economic development and education improvement. We find an inverse U‐shaped association between the frequency of various nationals acting as perpetrators in transnational terrorism acts and per capita income in their respective home countries. As per capita incomes increase from relatively low levels, frequencies of participation in transnational terrorism increase. However, at sufficiently higher levels of per capita income, further increase in per capita income is negatively associated with the rate of participation in transnational terrorism. Education improvement from elementary to secondary is positively correlated with frequency of participation in transnational terrorism events, whereas further improvement from secondary to tertiary level is negatively correlated with participation in transnational terrorism. We also find that citizens of countries with greater openness to international trade, lower degree of income inequality, greater economic freedom, larger proportion of population with tertiary education, and less religious prevalence participate in transnational terrorism events less frequently.
High levels of soluble MICA are significantly related to increased disease‐free and disease‐specific survival in patients with cervical adenocarcinoma
Authors: Samuels S. , Ferns D. M. , Meijer D. , van Straalen J. P. , Buist M. R. , Zijlmans H. J. , Kenter G. G. , Jordanova E. S.
Published: April 2015

Downregulation of major histocompatibility complex class I chain‐related molecule A (MICA) and upregulation of human leukocyte antigen G (HLA‐G) on the tumor cells are important immune escape mechanisms for different epithelial tumors. In addition, upregulation of the soluble forms of the latter molecules in serum leads to peripheral T‐cell and natural killer (NK)‐cell tolerance. As for cervical cancer, it remains unknown whether soluble MICA (sMICA) and soluble HLA‐G (sHLA‐G) concentrations are related to tumor characteristics or patient survival rates. We measured sMICA and sHLA‐G in pre‐treatment sera of a large cohort of cervical cancer patients (n = 366) by enzyme‐linked immunosorbent assay (ELISA). We detected a median sMICA of 174.73 pg/ml and a median sHLA‐G of 5.35 U/ml. We did not find an association between sHLA‐G levels and clinicopathological characteristics. In adenocarcinoma, low sMICA concentration was positively related to recurrent disease, a higher International Federation of Gynecology and Obstetrics (FIGO) stage and vaginal involvement (Mann–Whitney U‐test; P = 0.018, P = 0.042 and P = 0.013, respectively). In the latter patient group, high sMICA levels were associated with better disease‐free survival (DFS) and disease‐specific survival (DSS) (P = 0.011 and P = 0.047). After adjusting for confounding factors, high sMICA proved to be an independent predictor for a better DFS and DSS [HR 0.16; 95% confidence interval (CI) 0.04–0.64; P = 0.009 and HR 0.12; 95% CI 0.03–0.50; P = 0.004]. sHLA‐G did not influence survival in cervical cancer patients, regardless of histology. We conclude that cervical adenocarcinoma patients with high sMICA levels have an increased DFS and DSS. This data warrants a prospective trial to study the functional role of sMICA in cervical adenocarcinoma.
Red cell alloimmunisation in regularly transfused beta thalassemia patients in Pakistan
Authors: Zaidi U. , Borhany M. , Ansari S. , Parveen S. , Boota S. , Shamim I. , Zahid D. , Shamsi T.
Published: April 2015

Background

In Pakistan routine blood group typing of thalassemia patients identifies ABO and Rh(D) antigens only. Therefore, other antigen incompatibilities between blood donor and blood recipient may cause alloimmunisation.

Objective

The aim of this study was to estimate the frequency of alloimmunisation and to evaluate the risk factors associated with its development in beta (β)‐thalassemia patients receiving regular blood transfusions.

Materials and Methods

In total 162 β thalassemia patients were included in this study. An extended red cell antigen panel was performed to detect antibodies. Patients received red cell concentrates, which were matched for ABO and Rh(D) antigens. Clinical and laboratory data were collected and analysed to estimate the frequency of alloantibodies and the factors influencing immunisation in patients on regular blood transfusion.

Results

The median age of patients was 6·7 (range: 0·5–25) years. A total of 14 (8·6%) patients developed alloantibodies against red cell antigens. The most frequently occurring alloantibodies was anti‐E (2·5%), anti‐K (1·8%), anti‐e (1·2%) and anti‐D (0·6%). Five (3·1%) patients developed more than one red blood cell (RBC) alloantibody. Age at first transfusion in alloimmunised patients was 1·22 ± 0·87 years. The frequency of blood transfusion in alloimmunised patients was 23 ± 8·81 days and in those without alloimmunisation was 31·8 ± 16 days (p = 0·02). Logistic regression analysis showed no independent risk factor associated with alloimmunisation.

Conclusion

The frequency of transfusion was increased in patients who developed alloantibodies. Typing patients and donors to match for Rh and Kell antigens would prevent more than 90% of RBC alloantibodies and reduce the frequency of transfusion in thalassemia patients.
Effect of aliovalent impurities on the resistance switching characteristics of sputtered hafnium oxide films
Authors: Lee Kyumin , Kim Youngjae , Na Heedo , Sohn Hyunchul
Published: April 2015

In this work, the effects of various aliovalent impurities on the resistance switching characteristics of hafnium oxide (HfO2) films were investigated in conjunction with analyses of chemical bonding states and film microstructure. HfO2 films were cosputtered with magnesium, aluminum, and niobium by reactive DC magnetron sputtering. Doping with aliovalent elements caused the nonlattice oxygen concentration of HfO2 to increase and grain size to decrease. Also, post-thermal annealing induced a further increase of the concentration of nonlattice oxygen in the doped HfO2. Impurity doping improved the uniformities of the resistances of the low and high resistance states for cycled SET/RESET operations of titanium nitride/doped HfO2/platinum stacks, particularly for the magnesium-doped HfO2 films.
Game Performance and Understanding Within a Hybrid Sport Education Season
Authors: Farias Cláudio Filipe , Mesquita Isabel Ribeiro , Hastie Peter A.
Published: April 2015

The impact of a hybrid Sport Education-Invasion Games Competence Model (IGCM) unit of instruction on students’ game performance and game understanding in soccer was examined in this study. Pre- and posttest measures were collected from one fifth grade class of students (n = 24, mean age 10.3) residing in Portugal during a 17-lesson unit of instruction (season). Students’ game performance during multiple 10-min long matches was assessed using the coding instrument of Blomqvist, Vänttinen, and Luhtanen (2005). An author developed game understanding test was used to assess knowledge on decision making and skill execution. Performance differences between males and females were examined using the Mann-Whitney test and student improvement pre- to poststudy was examined using the Wilcoxon test. The combined application of Sport Education (authentic learning environment) and the IGCM (with learning tasks focused on the specific tactical-content and skills of soccer) promoted improvements in students’ game performance and understanding, and increments on the correlations between both constructs.
Slit halts muscles
Authors: VanHook Annalisa M.
Published: April 2015

Cleavage of Slit generates a membrane-associated N-terminal fragment that halts muscle migration in fly embryos.
Imatinib self-sabotages
Authors: Ferrarelli Leslie K.
Published: April 2015

The anticancer drug imatinib dampens its own toxicity by inducing a feedback loop that promotes proliferative signaling by fibroblast growth factor.
Dual action: Demethylase and ubiquitin ligase
Authors: Gough Nancy R.
Published: April 2015

The unexpected E3 ubiquitin ligase activity of a histone demethylase suppresses cancer cell growth.
Development and Validation of a High-Throughput Cell-Based Screen To Identify Activators of a Bacterial Two-Component Signal Transduction System
Authors: van Rensburg Julia J. , Fortney Kate R. , Chen Lan , Krieger Andrew J. , Lima Bruno P. , Wolfe Alan J. , Katz Barry P. , Zhang Zhong-yin , Spinola Stanley M.
Published: April 2015

CpxRA is a two-component signal transduction system (2CSTS) found in many drug-resistant Gram-negative bacteria. In response to periplasmic stress, CpxA autophosphorylates and donates a phosphoryl group to its cognate response regulator, CpxR. Phosphorylated CpxR (CpxR-P) upregulates genes involved in membrane repair and downregulates multiple genes that encode virulence factors, which are trafficked across the cell membrane. Mutants that constitutively activate CpxRA in
Salmonella enterica
serovar Typhimurium and
Haemophilus ducreyi
are avirulent in mice and humans, respectively. Thus, the activation of CpxRA has high potential as a novel antimicrobial/antivirulence strategy. Using a series of
Escherichia coli
strains containing a CpxR-P-responsive
lacZ
reporter and deletions in genes encoding CpxRA system components, we developed and validated a novel cell-based high-throughput screen (HTS) for CpxRA activators. A screen of 36,000 compounds yielded one hit compound that increased reporter activity in wild-type cells. This is the first report of a compound that activates, rather than inhibits, a 2CSTS. The activity profile of the compound against CpxRA pathway mutants in the presence of glucose suggested that the compound inhibits CpxA phosphatase activity. We confirmed that the compound induced the accumulation of CpxR-P in treated cells. Although the hit compound contained a nitro group, a derivative lacking this group retained activity in serum and had lower cytotoxicity than that of the initial hit. This HTS is amenable for the screening of larger libraries to find compounds that activate CpxRA by other mechanisms, and it could be adapted to find activators of other two-component systems.
Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation
Authors: Roy Sujayita , He Ran , Kapoor Arun , Forman Michael , Mazzone Jennifer R. , Posner Gary H. , Arav-Boger Ravit
Published: April 2015

Artemisinin-derived monomers and dimers inhibit human cytomegalovirus (CMV) replication in human foreskin fibroblasts (HFFs). The monomer artesunate (AS) inhibits CMV at micromolar concentrations, while dimers inhibit CMV replication at nanomolar concentrations, without increased toxicity in HFFs. We report on the variable anti-CMV activity of AS compared to the consistent and reproducible CMV inhibition by dimer 606 and ganciclovir (GCV). Investigation of this phenomenon revealed that the anti-CMV activity of AS correlated with HFFs synchronized to the G
0
/G
1
stage of the cell cycle. In contact-inhibited serum-starved HFFs or cells arrested at early/late G
1
with specific checkpoint regulators, AS and dimer 606 efficiently inhibited CMV replication. However, in cycling HFFs, in which CMV replication was productive, virus inhibition by AS was significantly reduced, but inhibition by dimer 606 and GCV was maintained. Cell cycle analysis in noninfected HFFs revealed that AS induced early G
1
arrest, while dimer 606 partially blocked cell cycle progression. In infected HFFs, AS and dimer 606 prevented the progression of cell cycle toward the G
1
/S checkpoint. AS reduced the expression of cyclin-dependent kinases (CDK) 2, 4, and 6 in noninfected cycling HFFs, while the effect of dimer 606 on these CDKs was moderate. Neither compound affected CDK expression in noninfected contact-inhibited HFFs. In CMV-infected cells, AS activity correlated with reduced CDK2 levels. CMV inhibition by AS and dimer 606 also correlated with hypophosphorylation (activity) of the retinoblastoma protein (pRb). AS activity was strongly associated with pRb hypophosphorylation, while its reduced anti-CMV activity was marked by pRb phosphorylation. Roscovitine, a CDK2 inhibitor, antagonized the anti-CMV activities of AS and dimer 606. These data suggest that cell cycle modulation through CDKs and pRb might play a role in the anti-CMV activities of artemisinins. Proteins involved in this modulation may be identified and targeted for CMV inhibition.
Bactericidal Activities of Cathelicidin LL-37 and Select Cationic Lipids against the Hypervirulent Pseudomonas aeruginosa Strain LESB58
Authors: Wnorowska Urszula , Niemirowicz Katarzyna , Myint Melissa , Diamond Scott L. , Wróblewska Marta , Savage Paul B. , Janmey Paul A. , Bucki Robert
Published: April 2015

Pseudomonas aeruginosa
Liverpool epidemic strain (LES) infections in cystic fibrosis (CF) patients are associated with transmissibility and increased patient morbidity. This study was designed to assess the
in vitro
activities of cathelicidin LL-37 peptide (LL-37) and select cationic lipids against
Pseudomonas aeruginosa
LESB58 in CF sputum and in a setting mimicking the CF airway. We found that LL-37 naturally present in airway surface fluid and some nonpeptide cationic lipid molecules such as CSA-13, CSA-90, CSA-131, and D2S have significant, but broadly differing, bactericidal activities against
P. aeruginosa
LESB58. We observed strong inhibition of LL-37 bactericidal activity in the presence of purified bacteriophage Pf1, which is highly expressed by
P. aeruginosa
LES, but the activities of the cationic lipids CSA-13 and CSA-131 were not affected by this polyanionic virus. Additionally, CSA-13 and CSA-131 effectively prevent LESB58 biofilm formation, which is stimulated by Pf1 bacteriophage, DNA, or F-actin. CSA-13 and CSA-131 display strong antibacterial activities against different clinical strains of
P. aeruginosa
, and their activities against
P. aeruginosa
LESB58 and Xen5 strains were maintained in CF sputum. These data indicate that synthetic cationic lipids (mimics of natural antimicrobial peptides) are suitable for developing an effective treatment against CF lung
P. aeruginosa
infections, including those caused by LES strains.
Evaluation of a Modified EUCAST Fragmented-Mycelium Inoculum Method for
In Vitro
Susceptibility Testing of Dermatophytes and the Activity of Novel Antifungal Agents
Authors: Risslegger B. , Lass-Flörl C. , Blum G. , Lackner M.
Published: April 2015

For antifungal susceptibility testing of nonsporulating or poorly sporulating dermatophytes, a fragmented-mycelium inoculum preparation method was established and compared to broth microdilution testing according to CLSI and EUCAST guidelines. Moreover, the
in vitro
activity of new antifungal agents against dermatophytes was evaluated. Agreement between the mycelial inoculum method and the CLSI broth microdilution method was high (93% to 100%). Echinocandins (minimal effective concentration [MEC], ≤0.5 mg/liter) and posaconazole (MIC, ≤3.00 mg/liter) showed good activity against all tested dermatophytes.
War Wound Treatment Complications Due to Transfer of an IncN Plasmid Harboring
bla
OXA-181
from Morganella morganii to CTX-M-27-Producing Sequence Type 131 Escherichia coli
Authors: McGann Patrick , Snesrud Erik , Ong Ana C. , Appalla Lakshmi , Koren Michael , Kwak Yoon I. , Waterman Paige E. , Lesho Emil P.
Published: April 2015

A 22-year-old male developed a recurrent sacral abscess associated with embedded shrapnel following a blast injury. Cultures grew extended-spectrum β-lactamase (ESBL)-producing, carbapenem-susceptible
Escherichia coli
. Ertapenem was administered, but the infection recurred after each course of antibiotics. Initial surgical interventions were unsuccessful, and subsequent cultures yielded
E. coli
and
Morganella morganii
, both nonsusceptible to carbapenems. The isolates were Carba NP test negative, gave ambiguous results with the modified Hodge test, and amplified the
bla
OXA48
-like gene by real-time PCR. All
E. coli
isolates were sequence type 131 (ST131), carried nine resistance genes (including
bla
CTX-M-27
) on an IncF plasmid, and were identical by genome sequencing, except for 150 kb of plasmid DNA in carbapenem-nonsusceptible isolates only. Sixty kilobases of this was shared by
M. morganii
and represented an IncN plasmid harboring
bla
OXA-181
. In
M. morganii
, the gene was flanked by IS
3000
and IS
Kpn19
, but in all but one of the
E. coli
isolates containing
bla
OXA-181
, a second copy of IS
Kpn19
had inserted adjacent to IS
3000
. To the best of our knowledge, this is the first report of
bla
OXA-181
in the virulent ST131 clonal group and carried by the promiscuous IncN family of plasmids. The tendency of
M. morganii
to have high MICs of imipenem, a
bla
OXA-181
substrate profile that includes penicillins but not extended-spectrum cephalosporins, and weak carbapenemase activity almost resulted in the presence of
bla
OXA-181
being overlooked. We highlight the importance of surveillance for carbapenem resistance in all species, even those with intrinsic resistances, and the value of advanced molecular techniques in detecting subtle genetic changes.
Dissemination of the Same
cfr
-Carrying Plasmid among Methicillin-Resistant Staphylococcus aureus and Coagulase-Negative Staphylococcal Isolates in China
Authors: Cai Jia Chang , Hu Yan Yan , Zhou Hong Wei , Chen Gong-Xiang , Zhang Rong
Published: April 2015

Six
cfr
-harboring methicillin-resistant
Staphylococcus aureus
(MRSA) isolates, which belonged to the same clone of sequence type 5 (ST5)-staphylococcal cassette chromosome
mec
element II (SCC
mec
II)-
spa
t311, were investigated in this study. Complete sequencing of a
cfr
-carrying plasmid, pLRSA417, revealed an 8,487-bp fragment containing a Tn
4001
-like transposon,
cfr
,
orf1
, and IS
Enfa4
. This segment, first identified in an animal plasmid, pSS-01, was observed in several plasmids from clinical coagulase-negative staphylococci in China, suggesting that the
cfr
gene, which might originate from livestock, was located in the same mobile element and disseminated among different clinical staphylococcal species.
Safety and Pharmacokinetics of Solithromycin in Subjects with Hepatic Impairment
Authors: Jamieson Brian D. , Ciric Sabrina , Fernandes Prabhavathi
Published: April 2015

Solithromycin, a new macrolide and the first fluoroketolide, is in late-stage clinical development and, like older macrolides, is primarily metabolized and excreted through liver-dependent mechanisms. This study evaluated the safety and pharmacokinetics of solithromycin in patients with chronic liver disease. This open-label, multiple-dose study in subjects with hepatic impairment and in healthy control subjects (matched for age, weight, and sex) enrolled 8 Child-Pugh class A (mild), 8 class B (moderate), and 8 class C (severe) patients and 9 healthy controls. Subjects (
n
= 33) received one 800-mg dose on day 1 followed by once-daily doses of 400 mg on days 2 through 5. The most commonly reported adverse events were mild diarrhea and mild headache, and no significant differences were noted between hepatically impaired subjects and healthy controls. The pharmacokinetics of plasma solithromycin in subjects with mild and moderate impairment was similar to that in control subjects. In subjects with severe impairment, total exposure to solithromycin at steady state (area under the plasma concentration-time curve [AUC
0–tau
]) was decreased compared to that in control subjects, which may have been related to the higher body mass index of individuals in this group. No greater accumulation was noted in any hepatically impaired cohort on day 5 compared to that in control subjects. No decrease in dosage is therefore needed when administering solithromycin to patients with mild, moderate, or severe hepatic impairment. Solithromycin was well tolerated in this patient population, and no significant differences in safety, compared to healthy controls, were noted.
Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects
Authors: Zhu Li , Hruska Matthew , Hwang Carey , Shah Vaishali , Furlong Michael , Hanna George J. , Bertz Richard , Savant Landry Ishani
Published: April 2015

BMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+T cells. This open-label, multiple-dose, four-sequence, crossover study addressed potential two-way drug-drug interactions following coadministration of BMS-663068 (BMS-626529 is a CYP3A4 substrate), atazanavir (ATV), and ritonavir (RTV) (ATV and RTV are CYP3A4 inhibitors). Thirty-six healthy subjects were randomized 1:1:1:1 to receive one of four treatment sequences with three consecutive treatments: BMS-663068 at 600 mg twice daily (BID), BMS-663068 at 600 mg BID plus RTV at 100 mg once daily (QD), ATV at 300 mg QD plus RTV at 100 mg QD (RTV-boosted ATV [ATV/r]), or BMS-663068 at 600 mg BID plus ATV at 300 mg QD plus RTV at 100 mg QD. Compared with the results obtained by administration of BMS-663068 alone, coadministration of BMS-663068 with ATV/r increased the BMS-626529 maximum concentration in plasma (Cmax) and the area under the concentration-time curve in one dosing interval (AUCtau) by 68% and 54%, respectively. Similarly, coadministration of BMS-663068 with RTV increased the BMS-626529Cmaxand AUCtauby 53% and 45%, respectively. Compared with the results obtained by administration of ATV/r alone, ATV and RTV systemic exposures remained similar following coadministration of BMS-663068 with ATV/r. BMS-663068 was generally well tolerated, and there were no adverse events (AEs) leading to discontinuation, serious AEs, or deaths. Moderate increases in BMS-626529 systemic exposure were observed following coadministration of BMS-663068 with ATV/r or RTV. However, the addition of ATV to BMS-663068 plus RTV did not further increase BMS-626529 systemic exposure. ATV and RTV exposures remained similar following coadministration of BMS-663068 with either ATV/r or RTV. BMS-663068 was generally well tolerated alone or in combination with either RTV or ATV/r.
Narrow-Spectrum Inhibitors of Campylobacter jejuni Flagellar Expression and Growth
Authors: Johnson Jeremiah G. , Yuhas Caroline , McQuade Thomas J. , Larsen Martha J. , DiRita Victor J.
Published: April 2015

Campylobacter jejuni
is a major cause of food-borne illness due to its ability to reside within the gastrointestinal tracts of chickens. Multiple studies have identified the flagella of
C. jejuni
as a major determinant of chicken colonization. An inhibitor screen of approximately 147,000 small molecules was performed to identify compounds that are able to inhibit flagellar expression in a reporter strain of
C. jejuni
. Several compounds that modestly inhibited motility of wild-type
C. jejuni
in standard assays were identified, as were a number of small molecules that robustly inhibited
C. jejuni
growth,
in vitro
. Examination of similar bacterial screens found that many of these small molecules inhibited only the growth of
C. jejuni
. Follow-up assays demonstrated inhibition of other strains of
C. jejuni
and
Campylobacter coli
but no inhibition of the closely related
Helicobacter pylori
. The compounds were determined to be bacteriostatic and nontoxic to eukaryotic cells. Preliminary results from a day-of-hatch chick model of colonization suggest that at least one of the compounds demonstrates promise for reducing
Campylobacter
colonization loads
in vivo
, although further medicinal chemistry may be required to enhance bioavailability.
Novel Aggregation Properties of Candida albicans Secreted Aspartyl Proteinase Sap6 Mediate Virulence in Oral Candidiasis
Authors: Kumar Rohitashw , Saraswat Darpan , Tati Swetha , Edgerton Mira
Published: April 2015

Candida albicans
, a commensal fungus of the oral microbiome, causes oral candidiasis in humans with localized or systemic immune deficiencies. Secreted aspartic proteinases (Saps) are a family of 10 related proteases and are virulence factors due to their proteolytic activity, as well as their roles in adherence and colonization of host tissues. We found that mice infected sublingually with
C. albicans
cells overexpressing Sap6 (
SAP6
OE and a Δ
sap8
strain) had thicker fungal plaques and more severe oral infection, while infection with the Δ
sap6
strain was attenuated. These hypervirulent strains had highly aggregative colony structure
in vitro
and higher secreted proteinase activity; however, the levels of proteinase activity of
C. albicans
Saps did not uniformly match their abilities to damage cultured oral epithelial cells (SCC-15 cells). Hyphal induction in cells overexpressing Sap6 (
SAP6
OE and Δ
sap8
cells) resulted in formation of large cell-cell aggregates. These aggregates could be produced in germinated wild-type cells by addition of native or heat-inactivated Sap6. Sap6 bound only to germinated cells and increased
C. albicans
adhesion to oral epithelial cells. The adhesion properties of Sap6 were lost upon deletion of its integrin-binding motif (RGD) and could be inhibited by addition of RGD peptide or anti-integrin antibodies. Thus, Sap6 (but not Sap5) has an alternative novel function in cell-cell aggregation, independent of its proteinase activity, to promote infection and virulence in oral candidiasis.
Macrophage Polarization during Murine Lyme Borreliosis
Authors: Lasky Carrie E. , Olson Rachel M. , Brown Charles R.
Published: April 2015

Infection of C3H mice withBorrelia burgdorferi, the causative agent of Lyme disease, reliably produces an infectious arthritis and carditis that peak around 3 weeks postinfection and then spontaneously resolve. Macrophage polarization has been suggested to drive inflammation, the clearance of bacteria, and tissue repair and resolution in a variety of infectious disease models. During Lyme disease it is clear that macrophages are capable of clearingBorreliaspirochetes and exhausted neutrophils; however, the role of macrophage phenotype in disease development or resolution has not been studied. Using classical (NOS2) and alternative (CD206) macrophage subset-specific markers, we determined the phenotype of F4/80+macrophages within the joints and heart throughout the infection time course. Within the joint, CD206+macrophages dominated throughout the course of infection, and NOS2+macrophage numbers became elevated only during the peak of inflammation. We also found dual NOS2+CD206+macrophages which increased during resolution. In contrast to findings for the ankle joints, numbers of NOS2+and CD206+macrophages in the heart were similar at the peak of inflammation. 5-Lipoxygenase-deficient (5-LOX−/−) mice, which display a failure of Lyme arthritis resolution, recruited fewer F4/80+cells to the infected joints and heart, but macrophage subset populations were unchanged. These results highlight differences in the inflammatory infiltrates during Lyme arthritis and carditis and demonstrate the coexistence of multiple macrophage subsets within a single inflammatory site.
A CLAG3 Mutation in an Amphipathic Transmembrane Domain Alters Malaria Parasite Nutrient Channels and Confers Leupeptin Resistance
Authors: Sharma Paresh , Rayavara Kempaiah , Ito Daisuke , Basore Katherine , Desai Sanjay A.
Published: April 2015

Erythrocytes infected with malaria parasites have increased permeability to ions and nutrients, as mediated by the plasmodial surface anion channel (PSAC) and recently linked to parasite
clag3
genes. Although the encoded protein is integral to the host membrane, its precise contribution to solute transport remains unclear because it lacks conventional transmembrane domains and does not have homology to ion channel proteins in other organisms. Here, we identified a probable CLAG3 transmembrane domain adjacent to a variant extracellular motif. Helical-wheel analysis revealed strict segregation of polar and hydrophobic residues to opposite faces of a predicted α-helical transmembrane domain, suggesting that the domain lines a water-filled pore. A single CLAG3 mutation (A1210T) in a leupeptin-resistant PSAC mutant falls within this transmembrane domain and may affect pore structure. Allelic-exchange transfection and site-directed mutagenesis revealed that this mutation alters solute selectivity in the channel. The A1210T mutation also reduces the blocking affinity of PSAC inhibitors that bind on opposite channel faces, consistent with global changes in channel structure. Transfected parasites carrying this mutation survived a leupeptin challenge significantly better than a transfection control did. Thus, the A1210T mutation contributes directly to both altered PSAC activity and leupeptin resistance. These findings reveal the molecular basis of a novel antimalarial drug resistance mechanism, provide a framework for determining the channel's composition and structure, and should guide the development of therapies targeting the PSAC.
Australian Institute of Sport and the Australian Paralympic Committee position statement: urinary tract infection in spinal cord injured athletes
Authors: Compton Stacey , Trease Larissa , Cunningham Corey , Hughes David
Published: April 2015

Patients with spinal cord injuries are at increased risk of developing symptomatic urinary tract infections. Current evidence-based knowledge regarding prevention and treatment of urinary tract infection in the spinal cord injured population is limited. There are currently no urinary tract infection prevention and management guidelines specifically targeted towards elite spinal cord injured athletes. This position statement represents a set of recommendations intended to provide clinical guidelines for sport and exercise medicine physicians and other healthcare providers for the prevention and treatment of urinary tract infection in spinal cord injured athletes. It has been endorsed by the Australian Institute of Sport (AIS) and the Australian Paralympic Committee (APC).
To reduce the average length of stay of patients who are admitted for DA-EPOCH-R chemotherapy regimen
Authors: Lee Yee Mei
Published: April 2015

Healthcare institutions are often faced with bed crunch situation. As a result, patients requiring inpatient hospital stay for cancer treatment are delayed and this could lead to compromised overall disease response. Apart from the early discharge of patients to step-down care and explore alternatives of treatment setting, one of the ways to reduce length of stay is to improve on the efficiency of work processes.

A baseline study demonstrated that delays in prescribing chemotherapy orders has led to an increased inpatient stay of seven days for a five day treatment regimen. This has profound consequences in terms of costs, patient safety, and utilisation of healthcare resources. A quality improvement project was initiated to review and revise the workflow and processes involved for the entire episode of treatment. A post-implementation review of the interventions showed cost savings, a reduction of average length of stay from seven days to six days (with a total of 28 days saved over six months), and improved patient and staff experience.
European palliative care guidelines: how well do they meet the needs of people with impaired cognition?
Authors: Sampson E L , van der Steen J T , Pautex S , Svartzman P , Sacchi V , Van den Block L , Van Den Noortgate N
Published: April 2015

Objective

Numbers of people dying with cognitive impairment (intellectual disability (ID), dementia or delirium) are increasing. We aimed to examine a range of European national palliative care guidelines to determine if, and how well, pain detection and management for people dying with impaired cognition are covered.

Methods

Questionnaires were sent to 14 country representatives of the European Pain and Impaired Cognition (PAIC) network who identified key national palliative care guidelines. Data was collected on guideline content: inclusion of advice on pain management, whether cognitively impaired populations were mentioned, assessment tools and management strategies recommended. Quality of guideline development was assessed with the Appraisal of Guidelines Research and Evaluation (AGREE) instrument.

Results

11 countries identified palliative care guidelines, 10 of which mentioned pain management in general. Of these, seven mentioned cognitive impairment (3 dementia, 2 ID and 4 delirium). Half of guidelines recommended the use of pain tools for people with cognitive impairment; recommended tools were not all validated for the target populations. Guidelines from the UK, the Netherlands and Finland included most information on pain management and detection in impaired cognition. Guidelines from Iceland, Norway and Spain scored most highly on AGREE rating in terms of developmental quality.

Conclusions

European national palliative care guidelines may not meet the needs of the growing population of people dying with cognitive impairment. New guidelines should consider suggesting the use of observational pain tools for people with cognitive impairment. Better recognition of their needs in palliative care guidelines may drive improvements in care.