bluuebunny/crossref_metadata_2025 huggingface dataset:
Managing the initiation and early implementation of health promotion interventions: a study of a parental support programme in primary care
Authors: Westerlund Anna , Garvare Rickard , Nyström Monica E. , Eurenius Eva , Lindkvist Marie , Ivarsson Anneli
Published: June 2016

Background

Mental health problems are increasing among children and adolescents worldwide, and parental support programmes have been suggested as one preventive intervention. However, the actual impact and low rates of adoption and sustainability of prevention programmes have proven to be a concern, and thus, further studies on their implementation are needed.

Aim

This study focused on the initial implementation of the International Child Development Programme (ICDP) in primary care. The aim was to investigate the involved actors’ views on factors likely to affect implementation and the strategies used to manage them.

Design

A case study design with a mixed‐methods approach combining quantitative and qualitative data from questionnaires and interviews was used.

Methods

Eighty‐two professionals at different positions in the involved organisations participated. Directed content analysis was used for analyses, focusing on perceived levels of importance and the manifestation of implementation factors.

Findings

Interviews and questionnaires provided descriptions of factors influencing the initial ICDP implementation. Uncertainty on how to manage important factors and vague change strategies was reported. Discrepancies in the perceived levels of importance versus manifestation were found regarding several factors, including hands‐on support, time and resources, communication and information, a comprehensive plan of action, follow‐ups, and external and internal collaborations. Manifested factors were a need for change, motivation and the ICDP's compatibility with existing norms, values and practices.

Conclusions

Implementing a parental support programme in a complex setting will benefit from being preceded by a thorough examination of the intervention and the target context and the development of clear implementation strategies based on the results of that examination. This study provides insights into how and by whom knowledge on implementation is applied during the launch of a health promotion programme, and these insights might help increase the rate of adoption and the use of such programmes and thereby increase their effectiveness.
Impact of cord blood banking technologies on clinical outcome: a Eurocord/Cord Blood Committee (CTIWP), European Society for Blood and Marrow Transplantation and NetCord retrospective analysis
Authors: Saccardi Riccardo , Tucunduva Luciana , Ruggeri Annalisa , Ionescu Irina , Koegler Gesine , Querol Sergio , Grazzini Giuliano , Lecchi Lucilla , Nanni Costa Alessandro , Navarrete Cristina , Pouthiers Fabienne , Larghero Jerome , Regan Donna , Freeman Taryn , Bittencourt Henrique , Kenzey Chantal , Labopin Myriam , Baudoux Etienne , Rocha Vanderson , Gluckman Eliane
Published: June 2016

BACKGROUND

Techniques for banking cord blood units (CBUs) as source for hematopoietic stem cell transplantation have been developed over the past 20 years, aimed to improve laboratory efficiency without altering the biologic properties of the graft. A large‐scale, registry‐based assessment of the impact of the banking variables on the clinical outcome is currently missing.

STUDY DESIGN AND METHODS

A total of 677 single cord blood transplants (CBTs) carried out for acute leukemia in complete remission in centers affiliated with the European Society for Blood and Marrow Transplantation were selected. An extensive set of data concerning CBU banking were collected and correlations with clinical outcome were assessed. Clinical endpoints were transplant‐related mortality, engraftment, and graft‐versus‐host disease (GVHD).

RESULTS

The median time between collection and CBT was 4.1 years (range, 0.2‐16.3 years). Volume reduction (VR) of CBUs before freezing was performed in 59.2% of available reports; in half of these the frozen volume was less than 30 mL. Cumulative incidences of neutrophil engraftment on Day 60, 100‐day acute GVHD (II‐IV), and 4‐year chronic GVHD were 87, 29, and 21 ± 2%. The cumulative incidence of nonrelapse mortality (NRM) at 100 days and 4‐year NRM were, respectively, 16 ± 2 and 30 ± 2%. Neither the variables related to banking procedures nor the interval between collection and CBT influenced the clinical outcome.

CONCLUSION

These findings indicate a satisfactory validation of the techniques associated with CBU VR across the banks. Cell viability assessment varied among the banks, suggesting that efforts to improve the standardization of CBU quality controls are needed.
Associations of ABO, D, and Lewis blood groups and HLA Class I and Class II alleles with West Nile virus Lineage 2 disease outcome in Greece, 2010 to 2013
Authors: Politis Constantina , Parara Myrsini , Kremastinou Jenny , Hasapopoulou Eleni , Iniotaki Aliki , Siorenta Alexandra , Richardson Clive , Papa Anna , Kavallierou Lilian , Asariotou Marina , Katsarou Olga , Mougiou Athina , Dadiotis Lukas , Alexandropoulou Zafeiria , Megalou Angelica , Magoula Evangelia , Papadopoulou Margarita , Pervanidou Danai , Baka Agoritsa , Hadjichristodoulou Christos
Published: June 2016

BACKGROUND

West Nile virus (WNV) infection, commonly asymptomatic, may cause mild West Nile fever (WNF) or potentially fatal neuroinvasive disease (WNND). An outbreak of 262 cases of the new Lineage 2 strain in Greece in 2010 continued with high mortality (17%) in WNND. The objective was to investigate ABO, D, and Lewis blood groups, as well as HLA Class I and Class II alleles, in relation to WNV Lineage 2 disease morbidity.

STUDY DESIGN AND METHODS

A cohort of 132 Greek WNV cases in 2010 to 2013 (65% male; mean age 64 years; 41% WNF, 59% WNND) was compared to 51,339 healthy WNV‐negative blood donors and 246 healthy subjects.

RESULTS

Blood group A was more common in WNV cases (51%) than blood donors (39%) and group O less common (32% vs. 42%). D negativity within group A was higher in WNV than in blood donors (18% vs. 10%, p = 0.044). The frequency of secretors (Lewis(a–b+)) was 60% in WNV and 68% in donors (p = 0.16). HLA alleles C*08, DRB1*O4:O5, and DQB1*O2 occurred significantly less frequently in WNV than controls (p < 0.05 unadjusted for multiple testing) and DRB1*10:O1 more frequently (p = 0.039).

CONCLUSION

This first study of symptomatic WNV Lineage 2 suggests A/D negativity as a new risk factor associated with WNV infection and level of morbidity. Further studies are required of the possibility that HLA C*08, DRB1*O4:O5, and DQB1*O2 are protective alleles and DRB1*10:O1 a “susceptible” allele to WNV infection and the role of secretor status in relation to WNV infection.
Level raising mod 2 and arbitrary 2-Selmer ranks
Authors: Le Hung Bao V. , Li Chao
Published: June 2016

We prove a level raising mod $\ell =2$ theorem for elliptic curves over $\mathbb{Q}$. It generalizes theorems of Ribet and Diamond–Taylor and also explains different sign phenomena compared to odd $\ell$. We use it to study the 2-Selmer groups of modular abelian varieties with common mod 2 Galois representation. As an application, we show that the 2-Selmer rank can be arbitrary in level raising families.
An application of the -adic analytic class number formula
Authors: Fieker Claus , Zhang Yinan
Published: June 2016

We propose an algorithm to verify the$p$-part of the class number for a number field$K$, provided$K$is totally real and an abelian extension of the rational field$\mathbb{Q}$, and$p$is any prime. On fields of degree 4 or higher, this algorithm has been shown heuristically to be faster than classical algorithms that compute the entire class number, with improvement increasing with larger field degrees.
Towards In-Flight Applications? A Review on Dielectric Barrier Discharge-Based Boundary-Layer Control
Authors: Kriegseis Jochen , Simon Bernhard , Grundmann Sven
Published: June 2016

Active control of laminar boundary layers with dielectric barrier discharge (DBD) plasma actuators (PAs) has made considerable progress in the last 15 years. First pioneering experiments have motivated numerous researchers to gain a deeper insight into the underlying working principles and corresponding quantification of the actuator performance. These investigations clearly show the strengths but also the weaknesses of the PA as a flow control device. Presently, the boundary-layer control (BLC) with PAs experiences the transition from lab studies to real flight applications. However, the PA community still struggles with the poor fluid mechanic efficiency and the limited momentum flux of the actuator. This review therefore addresses the question how applicable the actuator is as an energy efficient flow control device for future in-flight applications. Since any successful flow control requires detailed knowledge of the actuator’s control authority, this discussion is built upon a careful and comprehensive summary of performance evaluation measures and the interplay with various changes of thermodynamic and kinematic environmental conditions. Consequently, this review for the first time provides a comprehensive discussion of all required steps for successful DBD-based in-flight flow control spanning from the power supply to the achieved flow-control success in one coherent document.
The Primary Bilayer Ruga-Phase Diagram II: Irreversibility in Ruga Evolution
Authors: Zhao R. , Diab M. , Kim K.-S.
Published: June 2016

When an elastic thin-film/substrate bilayer is cyclically compressed with a large plane-strain stroke, various surface morphologies develop either reversibly or irreversibly with cyclic hysteresis. Here, we examine the cyclic morphology evolution with extensive finite-element analyses and present a generic irreversibility map on the primary bilayer Ruga-phase diagram (PB-RPD). The term “PB” refers to a system of a film on a substrate, both of which are incompressible neo-Hookean, while the term “Ruga-phase” refers to the classification of corrugated surface morphologies. Our generic map reveals two configurational irreversibility types of Ruga-phases during a loading and unloading cycle. One, localization irreversibility, is caused by unstable crease localization and the other, modal irreversibility, by unstable mode transitions of wrinkle-Ruga configurations. While the instability of crease localization depends mainly on smoothness of the creasing surface or interface, the instability of Ruga-mode transition is sensitive to film/substrate stiffness ratio, film/substrate strain mismatch (εps), and material viscosity of the bilayer. For small strain mismatches (εps ≲ 0.5), PB Ruga structures are ordered; otherwise, for large strain mismatches, the Ruga structures can evolve to ridge configurations. For evolution of ordered Ruga phases, the configurational irreversibility leads to shake-down or divergence of cyclic hysteresis. Underlying mechanisms of the cyclic hysteresis are found to be the unstable Ruga-phase transitions of mode-period multiplications in the loading cycle, followed by either mode “locking” or primary-period “switching” in the unloading cycle. In addition, we found that the primary-period switching is promoted by the strain mismatch and material viscosity. These results indicate that various Ruga configurations can be excited, and thus, diverse Ruga-phases can coexist, under cyclic loading. Our irreversibility map will be useful in controlling reversibility as well as uniformity of Ruga configurations in many practical applications.
An Efficient Operational Matrix Technique for Multidimensional Variable-Order Time Fractional Diffusion Equations
Authors: Zaky M. A. , Ezz-Eldien S. S. , Doha E. H. , Tenreiro Machado J. A. , Bhrawy A. H.
Published: June 2016

This paper derives a new operational matrix of the variable-order (VO) time fractional partial derivative involved in anomalous diffusion for shifted Chebyshev polynomials. We then develop an accurate numerical algorithm to solve the 1 + 1 and 2 + 1 VO and constant-order fractional diffusion equation with Dirichlet conditions. The contraction of the present method is based on shifted Chebyshev collocation procedure in combination with the derived shifted Chebyshev operational matrix. The main advantage of the proposed method is to investigate a global approximation for spatial and temporal discretizations, and it reduces such problems to those of solving a system of algebraic equations, which greatly simplifies the solution process. In addition, we analyze the convergence of the present method graphically. Finally, comparisons between the algorithm derived in this paper and the existing algorithms are given, which show that our numerical schemes exhibit better performances than the existing ones.
On Architecting and Composing Engineering Information Services to Enable Smart Manufacturing
Authors: (Serm) Kulvatunyou Boonserm , Ivezic Nenad , Srinivasan Vijay
Published: June 2016

Engineering information systems play an important role in the current era of digitization of manufacturing, which is a key component to enable smart manufacturing. Traditionally, these engineering information systems spanned the lifecycle of a product by providing interoperability of software subsystems through a combination of open and proprietary exchange of data. But research and development efforts are underway to replace this paradigm with engineering information services that can be composed dynamically to meet changing needs in the operation of smart manufacturing systems. This paper describes the opportunities and challenges in architecting such engineering information services and composing them to enable smarter manufacturing.
Novel Design and Three-Dimensional Printing of Variable Stiffness Robotic Grippers
Authors: Yang Yang , Chen Yonghua , Wei Ying , Li Yingtian
Published: June 2016

In this paper, a novel robotic gripper design with variable stiffness is proposed and fabricated using a modified additive manufacturing (hereafter called 3D printing) process. The gripper is composed of two identical robotic fingers and each finger has three rotational degrees-of-freedom as inspired by human fingers. The finger design is composed of two materials: acrylonitrile butadiene styrene (ABS) for the bone segments and shape-memory polymer (SMP) for the finger joints. When the SMP joints are exposed to thermal energy and heated to above their glass transition temperature (Tg), the finger joints exhibit very small stiffness, thus allow easy bending by an external force. When there is no bending force, the finger will restore to its original shape thanks to SMP's shape recovering stress. The finger design is actuated by a pneumatics soft actuator. Fabrication of the proposed robotic finger is made possible by a modified 3D printing process. An analytical model is developed to represent the relationship between the soft actuator's air pressure and the finger's deflection angle. Furthermore, analytical modeling of the finger stiffness modulation is presented. Several experiments are conducted to validate the analytical models.
Notch Behavior of Components Under the Stress-Controlled Creep–Fatigue Condition: Weakening or Strengthening?
Authors: Gong Jian-Guo , Xuan Fu-Zhen
Published: June 2016

Notch-related weakening and strengthening behavior under creep–fatigue conditions was studied in terms of the elastic–viscoplasticity finite-element method (FEM). A coupled damage analysis, i.e., the skeletal point method for creep damage evaluation coupled with the equivalent strain range method for fatigue damage, was employed in the notch effect evaluation. The results revealed that, under the short holding time condition, a weakening behavior was observed for the notch, while a strengthening effect was detected with the increase of holding time. The difference could be ascribed to the creep damage contribution in the holding stage. The influence of stress concentration factor (SCF), stress ratio, and the maximum stress was strongly dependent on the competition of creep and fatigue mechanism.
Maximal Lactate Steady State’s Dependence on Cycling Cadence
Authors: Beneke Ralph , Leithäuser Renate M.
Published: June 2016

The maximal lactate steady state (MLSS) depicts the highest blood lactate concentration (BLC) that can be maintained over time without a continual accumulation at constant prolonged workload. In cycling, no difference in the MLSS was combined with lower power output related to peak workload (IMLSS) at 100 than at 50 rpm. MLSS coincides with a respiratory exchange ratio (RER) close to 1. Recently, at incremental exercise, an RER of 1 was found at similar workload and similar intensity but higher BLC at 100 than at 50 rpm. Therefore, the authors reassessed a potential effect of cycling cadences on the MLSS and tested the hypothesis that the MLSS would be higher at 105 than at 60 rpm with no difference in IMLSS in a between-subjects design (n = 16, age 25.1 ± 1.9 y, height 178.4 ± 6.5 cm, body mass 70.3 ± 6.5 kg vs n = 16, 23.6 ± 3.0 y, 181.4 ± 5.6 cm, 72.5 ± 6.2 kg; study I) and confirmed these findings in a within-subject design (n = 12, 25.3 ± 2.1 y, 175.9 ± 7.7 cm, 67.8 ± 8.9 kg; study II). In study I, the MLSS was lower at 60 than at 105 rpm (4.3 ± 0.7 vs 5.4 ± 1.0 mmol/L; P = .003) with no difference in IMLSS (68.7% ± 5.3% vs 71.8% ± 5.9%). Study II confirmed these findings on MLSS (3.4 ± 0.8 vs 4.5 ± 1.0 mmol/L; P = .001) and IMLSS (65.0% ± 6.8% vs 63.5% ± 6.3%; P = .421). The higher MLSS at 105 than at 60 rpm combined with an invariance of IMLSS and RER close to 1 at MLSS supports the hypothesis that higher cadences can induce a preservation of carbohydrates at given BLC levels during low-intensity, high-volume training sessions.
Training-Load-Guided vs Standardized Endurance Training in Recreational Runners
Authors: Schumann Moritz , Botella Javier , Karavirta Laura , Häkkinen Keijo
Published: June 2016

Purpose:

To compare the effects of a standardized endurance-training program with individualized endurance training modified based on the cumulative training load provided by the Polar training-load feature.

Methods:

After 12 wk of similar training, 24 recreationally endurance-trained men were matched to a training-load-guided (TL, n = 10) or standardized (ST, n = 14) group and continued training for 12 wk. In TL, training sessions were individually chosen daily based on an estimated cumulative training load, whereas in ST the training was standardized with 4–6 sessions/wk. Endurance performance (shortest 1000-m running time during an incremental field test of 6 × 1000 m) and heart-rate variability (HRV) were measured every 4 wk, and maximal oxygen consumption (VO2max) was measured during an incremental treadmill test every 12 wk.

Results:

During weeks 1–12, similar changes in VO2max and 1000-m time were observed in TL (+7% ± 4%, P = .004 and –6% ± 4%, P = .069) and ST (+5% ± 7%, P = .019 and –8% ± 5%, P < .001). During wk 13–24, VO2max statistically increased in ST only (3% ± 4%, P = .034). The 1000-m time decreased in TL during wk 13–24 (–9% ± 5%, P = .011), but in ST only during wk 13–20 (–3% ± 2%, P = .003). The overall changes in VO2max and 1000-m time during wk 0–24 were similar in TL (+7% ± 4%, P = .001 and –9% ± 5%, P = .011) and ST (+10% ± 7%, P < .001 and –13% ± 5%, P < .001). No between-groups differences in total training volume and frequency were observed. HRV remained statistically unaltered in both groups.

Conclusions:

The main finding was that training performed according to the cumulative training load led to improvements in endurance performance similar to those with standardized endurance training in recreational endurance runners.
Predicting High-Power Performance in Professional Cyclists
Authors: Sanders Dajo , Heijboer Mathieu , Akubat Ibrahim , Meijer Kenneth , Hesselink Matthijs K.
Published: June 2016

Purpose:

To assess if short-duration (5 to ~300 s) high-power performance can accurately be predicted using the anaerobic power reserve (APR) model in professional cyclists.

Methods:

Data from 4 professional cyclists from a World Tour cycling team were used. Using the maximal aerobic power, sprint peak power output, and an exponential constant describing the decrement in power over time, a power-duration relationship was established for each participant. To test the predictive accuracy of the model, several all-out field trials of different durations were performed by each cyclist. The power output achieved during the all-out trials was compared with the predicted power output by the APR model.

Results:

The power output predicted by the model showed very large to nearly perfect correlations to the actual power output obtained during the all-out trials for each cyclist (r = .88 ± .21, .92 ± .17, .95 ± .13, and .97 ± .09). Power output during the all-out trials remained within an average of 6.6% (53 W) of the predicted power output by the model.

Conclusions:

This preliminary pilot study presents 4 case studies on the applicability of the APR model in professional cyclists using a field-based approach. The decrement in all-out performance during high-intensity exercise seems to conform to a general relationship with a single exponential-decay model describing the decrement in power vs increasing duration. These results are in line with previous studies using the APR model to predict performance during brief all-out trials. Future research should evaluate the APR model with a larger sample size of elite cyclists.
Optimization of a Class of Tryptophan Dendrimers That Inhibit HIV Replication Leads to a Selective, Specific, and Low-Nanomolar Inhibitor of Clinical Isolates of Enterovirus A71
Authors: Rivero-Buceta Eva , Sun Liang , Martínez-Gualda Belén , Doyagüez Elisa G. , Donckers Kim , Quesada Ernesto , Camarasa María-José , Delang Leen , San-Félix Ana , Neyts Johan , Leyssen Pieter
Published: June 2016

Tryptophan dendrimers that inhibit HIV replication by binding to the HIV envelope glycoproteins gp120 and gp41 have unexpectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus A71. Dendrimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series, is 3-fold more potent against the BrCr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low-nanomolar/high-picomolar range.
Antimicrobial Susceptibility and Clonality of Clinical Ureaplasma Isolates in the United States
Authors: Fernández Javier , Karau Melissa J. , Cunningham Scott A. , Greenwood-Quaintance Kerryl E. , Patel Robin
Published: June 2016

Ureaplasma urealyticum
and
Ureaplasma parvum
are pathogens involved in urogenital tract and intrauterine infections and also in systemic diseases in newborns and immunosuppressed patients. There is limited information on the antimicrobial susceptibility and clonality of these species. In this study, we report the susceptibility of 250 contemporary isolates of
Ureaplasma
(202
U. parvum
and 48
U. urealyticum
isolates) recovered at Mayo Clinic, Rochester, MN. MICs of doxycycline, azithromycin, ciprofloxacin, tetracycline, erythromycin, and levofloxacin were determined by broth microdilution, with MICS of the last three interpreted according to CLSI guidelines. Levofloxacin resistance was found in 6.4% and 5.2% of
U. parvum
and
U. urealyticum
isolates, respectively, while 27.2% and 68.8% of isolates, respectively, showed ciprofloxacin MICs of ≥4 μg/ml. The resistance mechanism of levofloxacin-resistant isolates was due to mutations in
parC
, with the Ser83Leu substitution being most frequent, followed by Glu87Lys. No macrolide resistance was found among the 250 isolates studied; a single
U. parvum
isolate was tetracycline resistant.
tet
(M) was found in 10
U. parvum
isolates, including the single tetracycline-resistant isolate, as well as in 9 isolates which had low tetracycline and doxycycline MICs. Multilocus sequence typing (MLST) performed on a selection of 46 isolates showed high diversity within the clinical
Ureaplasma
isolates studied, regardless of antimicrobial susceptibility. The present work extends previous knowledge regarding susceptibility to antimicrobial agents, resistance mechanisms, and clonality of
Ureaplasma
species in the United States.
Discovery and Analysis of Natural-Product Compounds Inhibiting Protein Synthesis in Pseudomonas aeruginosa
Authors: Hu Yanmei , Keniry Megan , Palmer Stephanie O. , Bullard James M.
Published: June 2016

Bacterial protein synthesis is the target for numerous natural and synthetic antibacterial agents. We have developed a poly(U) mRNA-directed aminoacylation/translation (A/T) protein synthesis system composed of phenylalanyl-tRNA synthetases (PheRS), ribosomes, and ribosomal factors from
Pseudomonas aeruginosa
. This system has been used for high-throughput screening of a natural-compound library. Assays were developed for each component of the system to ascertain the specific target of inhibitory compounds. In high-throughput screens, 13 compounds were identified that inhibit protein synthesis with 50% inhibitory concentrations ranging from 0.3 to >80 μM. MICs were determined for the compounds against the growth of a panel of pathogenic organisms, including
Enterococcus faecalis
,
Escherichia coli
,
Haemophilus influenzae
,
Moraxella catarrhalis
,
P. aeruginosa
,
Staphylococcus aureus
, and
Streptococcus pneumoniae
. Three of the compounds were observed to have broad-spectrum activity and inhibited a hypersensitive strain of
P. aeruginosa
with MICs of 8 to 16 μg/ml. The molecular target of each of the three compounds was determined to be PheRS. One compound was found to be bacteriostatic, and one compound was bactericidal against both Gram-positive and Gram-negative pathogens. The third compound was observed to be bacteriostatic against Gram-positive and bactericidal against Gram-negative bacteria. All three compounds were competitive with the substrate ATP; however, one compound was competitive, one was uncompetitive, and one noncompetitive with the amino acid substrate. Macromolecular synthesis assays confirm the compounds inhibit protein synthesis. The compounds were shown to be more than 25,000-fold less active than the control staurosporine in cytotoxicity MTT testing in human cell lines.
Systematic Review and Meta-analysis of Clinical and Economic Outcomes from the Implementation of Hospital-Based Antimicrobial Stewardship Programs
Authors: Karanika Styliani , Paudel Suresh , Grigoras Christos , Kalbasi Alireza , Mylonakis Eleftherios
Published: June 2016

The implementation of antimicrobial stewardship programs (ASPs) is a promising strategy to help address the problem of antimicrobial resistance. We sought to determine the efficacy of ASPs and their effect on clinical and economic parameters. We searched PubMed, EMBASE, and Google Scholar looking for studies on the efficacy of ASPs in hospitals. Based on 26 studies (extracted from 24,917 citations) with pre- and postimplementation periods from 6 months to 3 years, the pooled percentage change of total antimicrobial consumption after the implementation of ASPs was −19.1% (95% confidence interval [CI] = −30.1 to −7.5), and the use of restricted antimicrobial agents decreased by −26.6% (95% CI = −52.3 to −0.8). Interestingly, in intensive care units, the decrease in antimicrobial consumption was −39.5% (95% CI = −72.5 to −6.4). The use of broad-spectrum antibiotics (−18.5% [95% CI = −32 to −5.0] for carbapenems and −14.7% [95% CI = −27.7 to −1.7] for glycopeptides), the overall antimicrobial cost (−33.9% [95% CI = −42.0 to −25.9]), and the hospital length of stay (−8.9% [95% CI = −12.8 to −5]) decreased. Among hospital pathogens, the implementation of ASPs was associated with a decrease in infections due to methicillin-resistant
Staphylococcus aureus
(risk difference [RD] = −0.017 [95% CI = −0.029 to −0.005]), imipenem-resistant
Pseudomonas aeruginosa
(RD = −0.079 [95% CI = −0.114 to −0.040]), and extended-spectrum beta-lactamase
Klebsiella
spp. (RD = −0.104 [95% CI = −0.153 to −0.055]). Notably, these improvements were not associated with adverse outcomes, since the all-cause, infection-related 30-day mortality and infection rates were not significantly different after implementation of an ASP (RD = −0.001 [95% CI = −0.009 to 0.006], RD = −0.005 [95% CI = −0.016 to 0.007], and RD = −0.045% [95% CI = −0.241 to 0.150], respectively). Hospital ASPs result in significant decreases in antimicrobial consumption and cost, and the benefit is higher in the critical care setting. Infections due to specific antimicrobial-resistant pathogens and the overall hospital length of stay are improved as well. Future studies should focus on the sustainability of these outcomes and evaluate potential beneficial long-term effects of ASPs in mortality and infection rates.
First Report of
bla
IMP-14
on a Plasmid Harboring Multiple Drug Resistance Genes in Escherichia coli Sequence Type 131
Authors: Stoesser Nicole , Sheppard Anna E. , Peirano Gisele , Sebra Robert P. , Lynch Tarah , Anson Luke W. , Kasarskis Andrew , Motyl Mary R. , Crook Derrick W. , Pitout Johann D.
Published: June 2016

The
bla
IMP-14
carbapenem resistance gene has largely previously been observed in
Pseudomonas aeruginosa
and
Acinetobacter
spp. As part of global surveillance and sequencing of carbapenem-resistant
Escherichia coli
, we identified a sequence type 131 strain harboring
bla
IMP-14
within a class 1 integron, itself nested within an ∼54-kb multidrug resistance region on an epidemic IncA/C
2
plasmid. The emergence of
bla
IMP-14
in this context in the ST131 lineage is of potential clinical concern.
Extensive Shared Chemosensitivity between Malaria and Babesiosis Blood-Stage Parasites
Authors: Paul Aditya S. , Moreira Cristina K. , Elsworth Brendan , Allred David R. , Duraisingh Manoj T.
Published: June 2016

The apicomplexan parasites that cause malaria and babesiosis invade and proliferate within erythrocytes. To assess the potential for common antiparasitic treatments, we measured the sensitivities of multiple species of
Plasmodium
and
Babesia
parasites to the chemically diverse collection of antimalarial compounds in the Malaria Box library. We observed that these parasites share sensitivities to a large fraction of the same inhibitors and we identified compounds with strong babesiacidal activity.
Determination of MIC Breakpoints for Second-Line Drugs Associated with Clinical Outcomes in Multidrug-Resistant Tuberculosis Treatment in China
Authors: Zheng Xubin , Zheng Rongrong , Hu Yi , Werngren Jim , Forsman Lina Davies , Mansjö Mikael , Xu Biao , Hoffner Sven
Published: June 2016

Our study aims to identify the clinical breakpoints (CBPs) of second-line drugs (SLDs) above which standard therapy fails in order to improve multidrug-resistant tuberculosis (MDR-TB) treatment. MICs of SLDs were determined for
M. tuberculosis
isolates cultured from 207 MDR-TB patients in a prospective cohort study in China between January 2010 and December 2012. Classification and regression tree (CART) analysis was used to identify the CBPs predictive of treatment outcome. Of the 207 MDR-TB isolates included in the present study, the proportion of isolates above the critical concentration recommended by WHO ranged from 5.3% in pyrazinamide to 62.8% in amikacin. By selecting pyrazinamide as the primary node (CBP, 18.75 mg/liter), 72.1% of sputum culture conversions at month four could be predicted. As for treatment outcome, pyrazinamide (CBP, 37.5 mg/liter) was selected as the primary node to predict 89% of the treatment success, followed by ofloxacin (CBP, 3 mg/liter), improving the predictive capacity of the primary node by 10.6%. Adjusted by identified confounders, the CART-derived pyrazinamide CBP remained the strongest predictor in the model of treatment outcome. Our findings indicate that the critical breakpoints of some second-line drugs and PZA need to be reconsidered in order to better indicate MDR-TB treatment outcome.
Chemically Attenuated Blood-Stage Plasmodium yoelii Parasites Induce Long-Lived and Strain-Transcending Protection
Authors: Raja Amber I. , Cai Yeping , Reiman Jennifer M. , Groves Penny , Chakravarty Sumana , McPhun Virginia , Doolan Denise L. , Cockburn Ian , Hoffman Stephen L. , Stanisic Danielle I. , Good Michael F.
Published: June 2016

The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccine has not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuated whole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuatedPlasmodium yoelii17X and demonstrate significant protection following homologous and heterologous blood-stage challenge. Protection against blood-stage infection persisted for at least 9 months. Activation of both CD4+and CD8+T cells was shown after vaccination; however,in vivostudies demonstrated a pivotal role for both CD4+T cells and B cells since the absence of either cell type led to loss of vaccine-induced protection. In spite of significant activation of circulating CD8+T cells, liver-stage immunity was not evident. Neither did vaccine-induced CD8+T cells contribute to blood-stage protection; rather, these cells contributed to pathogenesis, since all vaccinated mice depleted of both CD4+and CD8+T cells survived a challenge infection. This study provides critical insight into whole-parasite vaccine-induced immunity and strong support for testing whole-parasite vaccines in humans.
Helicobacter saguini, a Novel Helicobacter Isolated from Cotton-Top Tamarins with Ulcerative Colitis, Has Proinflammatory Properties and Induces Typhlocolitis and Dysplasia in Gnotobiotic IL-10
−/−
Mice
Authors: Shen Z. , Mannion A. , Whary M. T. , Muthupalani S. , Sheh A. , Feng Y. , Gong G. , Vandamme P. , Holcombe H. R. , Paster B. J. , Fox J. G.
Published: June 2016

A urease-negative, fusiform, novel bacterium named
Helicobacter saguini
was isolated from the intestines and feces of cotton-top tamarins (CTTs) with chronic colitis.
Helicobacter
sp. was detected in 69% of feces or intestinal samples from 116 CTTs. The draft genome sequence, obtained by Illumina MiSeq sequencing, for
H. saguini
isolate MIT 97-6194-5, consisting of ∼2.9 Mb with a G+C content of 35% and 2,704 genes, was annotated using the NCBI Prokaryotic Genomes Automatic Annotation Pipeline.
H. saguini
contains homologous genes of known virulence factors found in other enterohepatic helicobacter species (EHS) and
H. pylori
. These include flagellin, γ-glutamyl transpeptidase (
ggt
), collagenase, the secreted serine protease
htrA
, and components of a type VI secretion system, but the genome does not harbor genes for cytolethal distending toxin (
cdt
).
H. saguini
MIT 97-6194-5 induced significant levels of interleukin-8 (IL-8) in HT-29 cell culture supernatants by 4 h, which increased through 24 h. mRNAs for the proinflammatory cytokines IL-1β, tumor necrosis factor alpha (TNF-α), IL-10, and IL-6 and the chemokine CXCL1 were upregulated in cocultured HT-29 cells at 4 h compared to levels in control cells. At 3 months postinfection, all
H. saguini
-monoassociated gnotobiotic C57BL/129 IL-10
−/−
mice were colonized and had seroconverted to
H. saguini
antigen with a significant Th1-associated increase in IgG2c (
P
< 0.0001).
H. saguini
induced a significant typhlocolitis, associated epithelial defects, mucosa-associated lymphoid tissue (MALT) hyperplasia, and dysplasia. Inflammatory cytokines IL-22, IL-17a, IL-1β, gamma interferon (IFN-γ), and TNF-α, as well as inducible nitric oxide synthase (iNOS) were significantly upregulated in the cecal tissues of infected mice. The expression of the DNA damage response molecule γ-H2AX was significantly higher in the ceca of
H. saguini
-infected gnotobiotic mice than in the controls. This model using a nonhuman primate
Helicobacter
sp. can be used to study the pathogenic potential of EHS isolated from primates with naturally occurring inflammatory bowel disease (IBD) and colon cancer.
Fecal Indole as a Biomarker of Susceptibility to Cryptosporidium Infection
Authors: Chappell Cynthia L. , Darkoh Charles , Shimmin Lawrence , Farhana Naveed , Kim Do-Kyun , Okhuysen Pablo C. , Hixson James
Published: June 2016

Cryptosporidium
causes significant diarrhea worldwide, especially among children and immunocompromised individuals, and no effective drug treatment is currently available for those who need it most. In this report, previous volunteer infectivity studies have been extended to examine the association between fecal indole and indole-producing (IP) gut microbiota on the outcome of a
Cryptosporidium
infection. Fecal indole concentrations (FICs) of 50 subjects and 19 taxa of common gut microbiota, including six IP taxa (11 subjects) were determined in stool samples collected before and after a challenge with
Cryptosporidium
oocysts. At the baseline, the mean FIC (± the standard deviation) was 1.66 ± 0.80 mM in those who became infected after a challenge versus 3.20 ± 1.23 mM in those who remained uninfected (
P
= 0.0001). Only 11.1% of the subjects with a FIC of >2.5 mM became infected after a challenge versus 65.2% of the subjects with a FIC of <2.5 mM. In contrast, the FICs of infected subjects at the baseline or during diarrhea were not correlated with infection intensity or disease severity. The relative abundances (percent) of
Escherichia coli
,
Bacillus
spp., and
Clostridium
spp. were greater ≥2.5-fold in volunteers with a baseline FIC of >2.5 mM, while those of
Bacteroides
pyogenes
,
B. fragilis
, and
Akkermansia
muciniphila
were greater in those with a baseline FIC of <2.5 mM. These data indicate that some IP bacteria, or perhaps indole alone, can influence the ability of
Cryptosporidium
to establish an infection. Thus, preexisting indole levels in the gut join the oocyst dose and immune status as important factors that determine the outcome of
Cryptosporidium
exposure.
A Mutation in the 16S rRNA Decoding Region Attenuates the Virulence of Mycobacterium tuberculosis
Authors: Watanabe Shinya , Matsumura Kazunori , Iwai Hiroki , Funatogawa Keiji , Haishima Yuji , Fukui Chie , Okumura Kayo , Kato-Miyazawa Masako , Hashimoto Masahito , Teramoto Kanae , Kirikae Fumiko , Miyoshi-Akiyama Tohru , Kirikae Teruo
Published: June 2016

Mycobacterium tuberculosis
contains a single rRNA operon that encodes targets for antituberculosis agents, including kanamycin. To date, only four mutations in the kanamycin binding sites of 16S rRNA have been reported in kanamycin-resistant clinical isolates. We hypothesized that another mutation(s) in the region may dramatically decrease
M. tuberculosis
viability and virulence. Here, we describe an rRNA mutation, U1406A, which was generated
in vitro
and confers resistance to kanamycin while highly attenuating
M. tuberculosis
virulence. The mutant showed decreased expression of 20% (
n
= 361) of mycobacterial proteins, including central metabolic enzymes, mycolic acid biosynthesis enzymes, and virulence factors such as antigen 85 complexes and ESAT-6. The mutation also induced three proteins, including KsgA (Rv1010; 16S rRNA adenine dimethyltransferase), which closely bind to the U1406A mutation site on the ribosome; these proteins were associated with ribosome maturation and translation initiation processes. The mutant showed an increase in 17S rRNA (precursor 16S rRNA) and a decrease in the ratio of 30S subunits to the 70S ribosomes, suggesting that the U1406A mutation in 16S rRNA attenuated
M. tuberculosis
virulence by affecting these processes.
Rotation of Vibrio fischeri Flagella Produces Outer Membrane Vesicles That Induce Host Development
Authors: Aschtgen Marie-Stephanie , Lynch Jonathan B. , Koch Eric , Schwartzman Julia , McFall-Ngai Margaret , Ruby Edward
Published: June 2016

Using the squid-vibrio association, we aimed to characterize the mechanism through which
Vibrio fischeri
cells signal morphogenesis of the symbiotic light-emitting organ. The symbiont releases two cell envelope molecules, peptidoglycan (PG) and lipopolysaccharide (LPS) that, within 12 h of light organ colonization, act in synergy to trigger normal tissue development. Recent work has shown that outer membrane vesicles (OMVs) produced by
V. fischeri
are sufficient to induce PG-dependent morphogenesis; however, the mechanism(s) of OMV release by these bacteria has not been described. Like several genera of both beneficial and pathogenic bacteria,
V. fischeri
cells elaborate polar flagella that are enclosed by an extension of the outer membrane, whose function remains unclear. Here, we present evidence that along with the well-recognized phenomenon of blebbing from the cell's surface, rotation of this sheathed flagellum also results in the release of OMVs. In addition, we demonstrate that most of the development-inducing LPS is associated with these OMVs and that the presence of the outer membrane protein OmpU but not the LPS O antigen on these OMVs is important in triggering normal host development. These results also present insights into a possible new mechanism of LPS release by pathogens with sheathed flagella.

IMPORTANCE
Determining the function(s) of sheathed flagella in bacteria has been challenging, because no known mutation results only in the loss of this outer membrane-derived casing. Nevertheless, the presence of a sheathed flagellum in such host-associated genera as
Vibrio
,
Helicobacter
, and
Brucella
has led to several proposed functions, including physical protection of the flagella and masking of their immunogenic flagellins. Using the squid-vibrio light organ symbiosis, we demonstrate another role, that of
V. fischeri
cells require rotating flagella to induce apoptotic cell death within surface epithelium, which is a normal step in the organ's development. Further, we present evidence that this rotation releases apoptosis-triggering lipopolysaccharide in the form of outer membrane vesicles. Such release may also occur by pathogens but with different outcomes for the host.
The Bacterial
iprA
Gene Is Conserved across Enterobacteriaceae, Is Involved in Oxidative Stress Resistance, and Influences Gene Expression in Salmonella enterica Serovar Typhimurium
Authors: Herman Allison , Serfecz Jacquelyn , Kinnally Alexandra , Crosby Kathleen , Youngman Matthew , Wykoff Dennis , Wilson James W.
Published: June 2016

The
iprA
gene (formerly known as
yaiV
or STM0374) is located in a two-gene operon in the
Salmonella enterica
serovar Typhimurium genome and is associated with altered expression during spaceflight and rotating-wall-vessel culture conditions that increase virulence. However,
iprA
is uncharacterized in the literature. In this report, we present the first targeted characterization of this gene, which revealed that
iprA
is highly conserved across
Enterobacteriaceae
. We found that
S
. Typhimurium,
Escherichia coli
, and
Enterobacter cloacae
Δ
iprA
mutant strains display a multi-log-fold increase in oxidative stress resistance that is complemented using a plasmid-borne wild-type (WT) copy of the
S
. Typhimurium
iprA
gene. This observation was also associated with increased catalase activity, increased
S
. Typhimurium survival in macrophages, and partial dependence on the
katE
gene and full dependence on the
rpoS
gene. Our results indicate that IprA protein activity is sensitive to deletion of the N- and C-terminal 10 amino acids, while a region that includes amino acids 56 to 80 is dispensable for activity. RNA sequencing (RNA-Seq) analysis revealed several genes altered in expression in the
S
. Typhimurium Δ
iprA
mutant strain compared to the WT, including those involved in fimbria formation,
spvABCD
-mediated virulence, ethanolamine utilization, the phosphotransferase system (PTS) transport, and flagellin phase switching from FlgB to FliC (likely a stochastic event) and several genes of hypothetical or putative function.

IMPORTANCE
Overall, this work reveals that the conserved
iprA
gene measurably influences bacterial biology and highlights the pool of currently uncharacterized genes that are conserved across bacterial genomes. These genes represent potentially useful targets for bacterial engineering, vaccine design, and other possible applications.
Interrogating Genes That Mediate Chlamydia trachomatis Survival in Cell Culture Using Conditional Mutants and Recombination
Authors: Brothwell Julie A. , Muramatsu Matthew K. , Toh Evelyn , Rockey Daniel D. , Putman Timothy E. , Barta Michael L. , Hefty P. Scott , Suchland Robert J. , Nelson David E.
Published: June 2016

Intracellular bacterial pathogens in the family
Chlamydiaceae
are causes of human blindness, sexually transmitted disease, and pneumonia. Genetic dissection of the mechanisms of chlamydial pathogenicity has been hindered by multiple limitations, including the inability to inactivate genes that would prevent the production of elementary bodies. Many genes are also
Chlamydia
-specific genes, and chlamydial genomes have undergone extensive reductive evolution, so functions often cannot be inferred from homologs in other organisms. Conditional mutants have been used to study essential genes of many microorganisms, so we screened a library of 4,184 ethyl methanesulfonate-mutagenized
Chlamydia trachomatis
isolates for temperature-sensitive (TS) mutants that developed normally at physiological temperature (37°C) but not at nonphysiological temperatures. Heat-sensitive TS mutants were identified at a high frequency, while cold-sensitive mutants were less common. Twelve TS mutants were mapped using a novel markerless recombination approach, PCR, and genome sequencing. TS alleles of genes that play essential roles in other bacteria and chlamydia-specific open reading frames (ORFs) of unknown function were identified. Temperature-shift assays determined that phenotypes of the mutants manifested at distinct points in the developmental cycle. Genome sequencing of a larger population of TS mutants also revealed that the screen had not reached saturation. In summary, we describe the first approach for studying essential chlamydial genes and broadly applicable strategies for genetic mapping in
Chlamydia
spp. and mutants that both define checkpoints and provide insights into the biology of the chlamydial developmental cycle.

IMPORTANCE
Study of the pathogenesis of
Chlamydia
spp. has historically been hampered by a lack of genetic tools. Although there has been recent progress in chlamydial genetics, the existing approaches have limitations for the study of the genes that mediate growth of these organisms in cell culture. We used a genetic screen to identify conditional
Chlamydia
mutants and then mapped these alleles using a broadly applicable recombination strategy. Phenotypes of the mutants provide fundamental insights into unexplored areas of chlamydial pathogenesis and intracellular biology. Finally, the reagents and approaches we describe are powerful resources for the investigation of these organisms.
Multifaceted Interfaces of Bacterial Competition
Authors: Stubbendieck Reed M. , Straight Paul D.
Published: June 2016

Microbial communities span many orders of magnitude, ranging in scale from hundreds of cells on a single particle of soil to billions of cells within the lumen of the gastrointestinal tract. Bacterial cells in all habitats are members of densely populated local environments that facilitate competition between neighboring cells. Accordingly, bacteria require dynamic systems to respond to the competitive challenges and the fluctuations in environmental circumstances that tax their fitness. The assemblage of bacteria into communities provides an environment where competitive mechanisms are developed into new strategies for survival. In this minireview, we highlight a number of mechanisms used by bacteria to compete between species. We focus on recent discoveries that illustrate the dynamic and multifaceted functions used in bacterial competition and discuss how specific mechanisms provide a foundation for understanding bacterial community development and function.