bluuebunny/crossref_metadata_2025 huggingface dataset:
Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17
Authors: Maney Sathish K. , McIlwain David R. , Polz Robin , Pandyra Aleksandra A. , Sundaram Balamurugan , Wolff Dorit , Ohishi Kazuhito , Maretzky Thorsten , Brooke Matthew A. , Evers Astrid , Vasudevan Ananda A. Jaguva , Aghaeepour Nima , Scheller Jürgen , Münk Carsten , Häussinger Dieter , Mak Tak W. , Nolan Garry P. , Kelsell David P. , Blobel Carl P. , Lang Karl S. , Lang Philipp A.
Published: November 2015

Without the N terminus, iRhom proteins cannot properly limit ADAM17 activity, resulting in impaired cancer cell death.
A circuit controlling mechanical itch
Authors: Stern Peter
Published: November 2015

Neuropeptide Y–expressing inhibitory neurons selectively gate mechanical itch sensations but not chemical itch.
In Vitro
Activity of β-Lactams in Combination with β-Lactamase Inhibitors against Multidrug-Resistant Mycobacterium tuberculosis Isolates
Authors: Zhang Dan , Wang Yufeng , Lu Jie , Pang Yu
Published: November 2015

The combination of β-lactams and β-lactamase inhibitors has been shown to have potent
in vitro
activity against multidrug-resistant tuberculosis (MDR-TB) isolates. In order to identify the most potent β-lactam–β-lactamase inhibitor combination against MDR-TB, we selected nine β-lactams and three β-lactamase inhibitors, which belong to different subgroups. A total of 121 MDR-TB strains were included in this study. Out of the β-lactams used herein, biapenem was the most effective against MDR-TB and had an MIC
50
value of 8 μg/ml. However, after the addition of clavulanate or sulbactam, meropenem exhibited the most potent anti-MDR-TB activity with an MIC
50
value of 4 μg/ml. For meropenem, 76 (62.8%), 41 (33.9%), and 22 (18.2%) of the 121 MDR-TB strains were subjected to a synergistic effect when the drug was combined with sulbactam, tazobactam, or clavulanate, respectively. Further statistical analysis revealed that significantly more strains experienced a synergistic effect when exposed to the combination of meropenem with sulbactam than when exposed to meropenem in combination with tazobactam or clavulanate, respectively (
P
< 0.01). In addition, a total of 10.7% (13/121) of isolates harbored mutations in the
blaC
gene, with two different nucleotide substitutions: AGT333AGG and ATC786ATT. For the strains with a Ser111Arg substitution in BlaC, a better synergistic effect was observed in the meropenem-clavulanate and in the amoxicillin-clavulanate combinations than that in a synonymous single nucleotide polymorphism (SNP) group. In conclusion, our findings demonstrate that the combination of meropenem and sulbactam shows the most potent activity against MDR-TB isolates. In addition, the Ser111Arg substitution of BlaC may be associated with an increased susceptibility of MDR-TB isolates to meropenem and amoxicillin in the presence of clavulanate.
No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects
Authors: Salem Ahmed Hamed , Jones Aksana Kaefer , Santini-Oliveira Marilia , Taylor Graham P. , Patterson Kristine B. , Nilius Angela M. , Klein Cheri Enders
Published: November 2015

Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0–12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0–12orCpredosevalues observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy.
Pharmacodynamics of Ceftazidime and Avibactam in Neutropenic Mice with Thigh or Lung Infection
Authors: Berkhout Johanna , Melchers Maria J. , van Mil Anita C. , Seyedmousavi Seyedmojtaba , Lagarde Claudia M. , Schuck Virna J. , Nichols Wright W. , Mouton Johan W.
Published: November 2015

Avibactam is a new non-β-lactam β-lactamase inhibitor that shows promising restoration of ceftazidime activity against microorganisms producing Ambler class A extended-spectrum β-lactamases (ESBLs) and carbapenemases such as KPCs, class C β-lactamases (AmpC), and some class D enzymes. To determine optimal dosing combinations of ceftazidime-avibactam for treating infections with ceftazidime-resistant
Pseudomonas aeruginosa
, pharmacodynamic responses were explored in murine neutropenic thigh and lung infection models. Exposure-response relationships for ceftazidime monotherapy were determined first. Subsequently, the efficacy of adding avibactam every 2 h (q2h) or q8h to a fixed q2h dose of ceftazidime was determined in lung infection for two strains. Dosing avibactam q2h was significantly more efficacious, reducing the avibactam daily dose for static effect by factors of 2.7 and 10.1, whereas the mean percentage of the dosing interval that free drug concentrations remain above the threshold concentration of 1 mg/liter (%
f
T>C
T
1 mg/liter) yielding bacteriostasis was similar for both regimens, with mean values of 21.6 (q2h) and 18.5 (q8h). Dose fractionation studies of avibactam in both the thigh and lung models indicated that the effect of avibactam correlated well with %
f
T>C
T
1 mg/liter. This parameter of avibactam was further explored for four
P. aeruginosa
strains in the lung model and six in the thigh model. Parameter estimates of %
f
T>C
T
1 mg/liter for avibactam ranged from 0 to 21.4% in the lung model and from 14.1 to 62.5% in the thigh model to achieve stasis. In conclusion, addition of avibactam enhanced the effect of ceftazidime, which was more pronounced at frequent dosing and well related with %
f
T>C
T
1 mg/liter. The thigh model appeared more stringent, with higher values, ranging up to 62.5%
f
T>C
T
1 mg/liter, required for a static effect.
Cefotaxime and Amoxicillin-Clavulanate Synergism against Extended-Spectrum-β-Lactamase-Producing
Escherichia coli
in a Murine Model of Urinary Tract Infection
Authors: Rossi B. , Soubirou J. F. , Chau F. , Massias L. , Dion S. , Lepeule R. , Fantin B. , Lefort A.
Published: November 2015

We investigated the efficacies of cefotaxime (CTX) and amoxicillin (AMX)-clavulanate (CLA) (AMC) against extended-spectrum-β-lactamase (ESBL)-producing
Escherichia coli
in vitro
and in a murine model of urinary tract infection (UTI). MICs, the checkerboard dilution method, and time-kill curves were used to explore the
in vitro
synergism between cefotaxime and amoxicillin-clavulanate against two isogenic
E. coli
strains—CFT073-RR and its transconjugant, CFT073-RR Tc
bla
CTX-M-15
—harboring a
bla
CTX-M-15
plasmid and a
bla
OXA-1
plasmid. For
in vivo
experiments, mice were separately infected with each strain and treated with cefotaxime, amoxicillin, and clavulanate, alone or in combination, or imipenem, using therapeutic regimens reproducing time of free-drug concentrations above the MIC (
fT
≥MIC) values close to that obtained in humans. MICs of amoxicillin, cefotaxime, and imipenem were 4/>1,024, 0.125/1,024, and 0.5/0.5 mg/liter, for CFT073-RR and CFT073-RR Tc
bla
CTX-M-15
, respectively. The addition of 2 mg/liter of clavulanate (CLA) restored the susceptibility of CFT073-RR Tc
bla
CTX-M-15
to CTX (MICs of the CTX-CLA combination, 0.125 mg/liter). The checkerboard dilution method and time-kill curves confirmed an
in vitro
synergy between amoxicillin-clavulanate and cefotaxime against CFT073-RR Tc
bla
CTX-M-15
.
In vivo
, this antibiotic combination was similarly active against both strains and as effective as imipenem. In conclusion, the cefotaxime and amoxicillin-clavulanate combination appear to be an effective, easy, and already available alternative to carbapenems for the treatment of UTI due to CTX-M-producing
E. coli
strains.
Type III Secretion-Dependent Sensitivity of Escherichia coli O157 to Specific Ketolides
Authors: Fernandez-Brando Romina J. , Yamaguchi Nao , Tahoun Amin , McAteer Sean P. , Gillespie Trudi , Wang Dai , Argyle Sally A. , Palermo Marina S. , Gally David L.
Published: November 2015

A subset of Gram-negative bacterial pathogens uses a type III secretion system (T3SS) to open up a conduit into eukaryotic cells in order to inject effector proteins. These modulate pathways to enhance bacterial colonization. In this study, we screened established bioactive compounds for any that could repress T3SS expression in enterohemorrhagic
Escherichia coli
(EHEC) O157. The ketolides telithromycin and, subsequently, solithromycin both demonstrated repressive effects on expression of the bacterial T3SS at sub-MICs, leading to significant reductions in bacterial binding and actin-rich pedestal formation on epithelial cells. Preincubation of epithelial cells with solithromycin resulted in significantly less attachment of
E. coli
O157. Moreover, bacteria expressing the T3SS were more susceptible to solithromycin, and there was significant preferential killing of
E. coli
O157 bacteria when they were added to epithelial cells that had been preexposed to the ketolide. This killing was dependent on expression of the T3SS. Taken together, this research indicates that the ketolide that has accumulated in epithelial cells may traffic back into the bacteria via the T3SS. Considering that neither ketolide induces the SOS response, nontoxic members of this class of antibiotics, such as solithromycin, should be considered for future testing and trials evaluating their use for treatment of EHEC infections. These antibiotics may also have broader significance for treating infections caused by other pathogenic bacteria, including intracellular bacteria, that express a T3SS.
Effect of High-Dose Antimicrobials on Biofilm Growth of Achromobacter Species Isolated from Cystic Fibrosis Patients
Authors: Tom Sean K. , Yau Yvonne C. W. , Beaudoin Trevor , LiPuma John J. , Waters Valerie
Published: November 2015

MICs and biofilm inhibitory concentrations (BICs) were measured for 68 cystic fibrosis (CF)
Achromobacter
isolates for amikacin, aztreonam, colistin, levofloxacin, and tobramycin. With the exception of colistin and levofloxacin, the remaining antibiotics had MIC
90
s, BICs at which 50% of the isolates were susceptible (BIC
50
s), and BICs at which 90% of the isolates were susceptible (BIC
90
s) equal to or above the highest concentrations tested. In a biofilm model, tobramycin was able to significantly increase killing of bacterial cells compared to controls, for intermediate-resistant strains only, at concentrations of 1,000 and 2,000 μg/ml.
Pneumococcal 6-Phospho-β-Glucosidase (BglA3) Is Involved in Virulence and Nutrient Metabolism
Authors: Terra Vanessa Sofia , Zhi Xiangyun , Kahya Hasan F. , Andrew Peter W. , Yesilkaya Hasan
Published: November 2015

For the generation of energy, the important human pathogen
Streptococcus pneumoniae
relies on host-derived sugars, including β-glucoside analogs. The catabolism of these nutrients involves the action of 6-phospho-β-glucosidase to convert them into usable monosaccharaides. In this study, we characterized a 6-phospho-β-glucosidase (BglA3) encoded by SPD_0247. We found that this enzyme has a cell membrane localization and is active only against a phosphorylated substrate. A mutated pneumococcal ΔSPD0247 strain had reduced 6-phospho-glucosidase activity and was attenuated in growth on cellobiose and hyaluronic acid compared to the growth of wild-type D39. ΔSPD0247-infected mice survived significantly longer than the wild-type-infected cohort, and the colony counts of the mutant were lower than those of the wild type in the lungs. The expression of SPD_0247 in
S. pneumoniae
harvested from infected tissues was significantly increased relative to its expression
in vitro
on glucose. Additionally, ΔSPD0247 is severely impaired in its attachment to an abiotic surface. These results indicate the importance of β-glucoside metabolism in pneumococcal survival and virulence.
Global Regulator of Virulence A (GrvA) Coordinates Expression of Discrete Pathogenic Mechanisms in Enterohemorrhagic Escherichia coli through Interactions with GadW-GadE
Authors: Morgan Jason K. , Carroll Ronan K. , Harro Carly M. , Vendura Khoury W. , Shaw Lindsey N. , Riordan James T.
Published: November 2015

Global regulator of virulence A (GrvA) is a ToxR-family transcriptional regulator that activates locus of enterocyte effacement (LEE)-dependent adherence in enterohemorrhagic
Escherichia coli
(EHEC). LEE activation by GrvA requires the Rcs phosphorelay response regulator RcsB and is sensitive to physiologically relevant concentrations of bicarbonate, a known stimulant of virulence systems in intestinal pathogens. This study determines the genomic scale of GrvA-dependent regulation and uncovers details of the molecular mechanism underlying GrvA-dependent regulation of pathogenic mechanisms in EHEC. In a
grvA
-null background of EHEC strain TW14359, RNA sequencing analysis revealed the altered expression of over 700 genes, including the downregulation of LEE- and non-LEE-encoded effectors and the upregulation of genes for glutamate-dependent acid resistance (GDAR). Upregulation of GDAR genes corresponded with a marked increase in acid resistance. GrvA-dependent regulation of GDAR and the LEE required
gadE
, the central activator of GDAR genes and a direct repressor of the LEE. Control of
gadE
by GrvA was further determined to occur through downregulation of the
gadE
activator GadW. This interaction of GrvA with GadW-GadE represses the acid resistance phenotype, while it concomitantly activates the LEE-dependent adherence and secretion of immune subversion effectors. The results of this study significantly broaden the scope of GrvA-dependent regulation and its role in EHEC pathogenesis.

IMPORTANCE
Enterohemorrhagic
Escherichia coli
(EHEC) is an intestinal human pathogen causing acute hemorrhagic colitis and life-threatening hemolytic-uremic syndrome. For successful transmission and gut colonization, EHEC relies on the glutamate-dependent acid resistance (GDAR) system and a type III secretion apparatus, encoded on the LEE pathogenicity island. This study investigates the mechanism whereby the DNA-binding regulator GrvA coordinates activation of the LEE with repression of GDAR. Investigating how these systems are regulated leads to an understanding of pathogenic behavior and novel strategies aimed at disease prevention and control.
AcrB-AcrA Fusion Proteins That Act as Multidrug Efflux Transporters
Authors: Hayashi Katsuhiko , Nakashima Ryosuke , Sakurai Keisuke , Kitagawa Kimie , Yamasaki Seiji , Nishino Kunihiko , Yamaguchi Akihito
Published: November 2015

The AcrAB-TolC system in
Escherichia coli
is an intrinsic RND-type multidrug efflux transporter that functions as a tripartite complex of the inner membrane transporter AcrB, the outer membrane channel TolC, and the adaptor protein AcrA. Although the crystal structures of each component of this system have been elucidated, the crystal structure of the whole complex has not been solved. The available crystal structures have shown that AcrB and TolC function as trimers, but the number of AcrA molecules in the complex is now under debate. Disulfide chemical cross-linking experiments have indicated that the stoichiometry of AcrB-AcrA-TolC is 1:1:1; on the other hand, recent cryo-electron microscopy images of AcrAB-TolC suggested a 1:2:1 stoichiometry. In this study, we constructed 1:1-fixed AcrB-AcrA fusion proteins using various linkers. Surprisingly, all the 1:1-fixed linker proteins showed drug export activity under both
acrAB
-deficient conditions and
acrAB acrEF
double-pump-knockout conditions regardless of the lengths of the linkers. Finally, we optimized a shorter linker lacking the conformational freedom imparted by the AcrB C terminus. These results suggest that a complex with equal amounts of AcrA and AcrB is sufficient for drug export function.

IMPORTANCE
The structure and stoichiometry of the RND-type multidrug exporter AcrB-AcrA-TolC complex are still under debate. Recently, electron microscopic images of the AcrB-AcrA-TolC complex have been reported, suggesting a 1:2:1 stoichiometry. However, we report here that the AcrB-AcrA 1:1 fusion protein is active for drug export under
acrAB
-deficient conditions and also under
acrAB
acrEF
double-deficient conditions, which eliminate the aid of free AcrA and its close homolog AcrE, indicating that the AcrB-AcrA 1:1 stoichiometry is enough for drug export function. In addition, the AcrB-AcrA fusion protein can function without the aid of free AcrA. We believe that these results are very important for considering the structure and mechanism of AcrAB-TolC-mediated multidrug export.
Glutamate Limitation, BvgAS Activation, and (p)ppGpp Regulate the Expression of the Bordetella pertussis Type 3 Secretion System
Authors: Hanawa Tomoko , Kamachi Kazunari , Yonezawa Hideo , Fukutomi Toshiyuki , Kawakami Hayato , Kamiya Shigeru
Published: November 2015

Bordetella pertussis
is a bacterium that is considered to be highly adapted to humans, and it has not been isolated from the environment. As this bacterium does not utilize sugars, the abundant supply of glutamate in Stainer Scholte (SS) medium enables
B. pertussis
to grow efficiently in liquid culture
in vitro
, and as such, SS medium is a popular choice for laboratory experiments. However, the concentration of glutamate in the
in vivo
niche of
B. pertussis
is quite low. We investigated the bacterial response to low concentrations of glutamate to elucidate bacterial physiology via the expression of the type 3 secretion system (T3SS), and we discuss its relationship to the Bvg mode in which the two-component regulator of pathogenesis (BvgAS) is activated. Glutamate limitation induced the expression of both the T3SS apparatus and effector genes at the transcriptional level. (p)ppGpp, a modulator of the stringent response, was necessary for maximum expression of the T3SS genes. These observations indicate that the expression of the T3SS is managed by nutrient starvation. In addition, the autoaggregation ability was high in the absence of glutamate and no autoaggregation was observed in glutamate-replete medium. Taken together, glutamate-limited conditions in Bvg
+
mode elicit the high expression of T3SS genes in
B. pertussis
and promotes its sessile form.

IMPORTANCE
Bordetella pertussis
is a highly contagious pathogen that causes respiratory infectious disease. In spite of the increasing use of vaccination, the number of patients with pertussis is increasing. The proteins produced
in vivo
often are different from the protein profile under laboratory conditions; therefore, the development of conditions reflecting the host environment is important to understand native bacterial behavior. In the present study, we examined the effect of glutamate limitation, as its concentration
in vivo
is much lower than that in the culture medium currently used for
B. pertussis
experiments. As predicted, the T3SS was induced by glutamate limitation. These results are suggestive of the importance of regulation by nutrient conditions and in the pathogenicity of
B. pertussis
.
Identification of the Key Sequence in the FliK C-Terminal Domain for Substrate Specificity Switching in the Flagellar Protein Secretion
Authors: Uchida Kaoru , Dono Kohei , Aizawa Shin-Ichi
Published: November 2015

The flagellar hook is a short tubular structure located between the external filament and the membrane-bound basal body. The average hook length is 55 nm and is determined by the soluble protein FliK and the integral membrane protein FlhB. Hook elongation is terminated by FliK-mediated cessation of hook protein secretion, followed by the secretion of filamentous proteins. This process is referred to as the substrate specificity switch. Switching of the secretion modes results from a direct interaction between the FliK C-terminal domain (FliK
C
) and the secretion gate in FlhB. FliK
C
consists of two α-helices and four β-strands. Loop 2 connects the first two β-sheets and contains a conserved sequence of 9 residues. Genetic and physiological analyses of various
fliK
partial deletion mutants pointed to loop 2 as essential for induction of a conformational change in the FlhB gate. We constructed single-amino-acid substitutions in the conserved region of loop 2 of FliK and discovered that the loop sequence LRL is essential for the timely switching of secretion modes.

IMPORTANCE
Flagellar protein secretion is controlled by the soluble protein FliK. We discovered that the loop 2 sequence LRL in the FliK C terminus was essential for timely switching of secretion modes. This mechanism is applicable to type three secretions systems that secrete virulence factors in bacterial pathogens.
Mutation of the Thiol-Disulfide Oxidoreductase SdbA Activates the CiaRH Two-Component System, Leading to Bacteriocin Expression Shutdown in Streptococcus gordonii
Authors: Davey Lauren , Halperin Scott A. , Lee Song F.
Published: November 2015

Streptococcus gordonii
is a commensal inhabitant of the human oral cavity. To maintain its presence as a major component of oral biofilms,
S. gordonii
secretes inhibitory molecules such as hydrogen peroxide and bacteriocins to inhibit competitors.
S. gordonii
produces two nonmodified bacteriocins (i.e., Sth
1
and Sth
2
) that are regulated by the Com two-component regulatory system, which also regulates genetic competence. Previously we found that the thiol-disulfide oxidoreductase SdbA was required for bacteriocin activity; however, the role of SdbA in Com signaling was not clear. Here we demonstrate that Δ
sdbA
mutants lacked bacteriocin activity because the bacteriocin gene
sthA
was strongly repressed and the peptides were not secreted. Addition of synthetic competence-stimulating peptide to the medium reversed the phenotype, indicating that the Com pathway was functional but was not activated in the Δ
sdbA
mutant. Repression of bacteriocin production was mediated by the CiaRH two-component system, which was strongly upregulated in the Δ
sdbA
mutant, and inactivation of CiaRH restored bacteriocin production. The CiaRH-induced protease DegP was also upregulated in the Δ
sdbA
mutant, although it was not required for inhibition of bacteriocin production. This establishes CiaRH as a regulator of Sth bacteriocin activity and links the CiaRH and Com systems in
S. gordonii
. It also suggests that either SdbA or one of its substrates is an important factor in regulating activation of the CiaRH system.

IMPORTANCE
Streptococcus gordonii
is a noncariogenic colonizer of the human oral cavity. To be competitive in the oral biofilm,
S. gordonii
secretes antimicrobial peptides called bacteriocins, which inhibit closely related species. Our previous data showed that mutation of the disulfide oxidoreductase SdbA abolished bacteriocin production. In this study, we show that mutation of SdbA generates a signal that upregulates the CiaRH two-component system, which in turn downregulates a second two-component system, Com, which regulates bacteriocin expression. Our data show that these systems are also linked in
S. gordonii
, and the data reveal that the cell's ability to form disulfide bonds is sensed by the CiaRH system.
Cost-effectiveness of integrated COPD care: the RECODE cluster randomised trial
Authors: Boland Melinde R S , Kruis Annemarije L , Tsiachristas Apostolos , Assendelft Willem J J , Gussekloo Jacobijn , Blom Coert M G , Chavannes Niels H , Rutten-van Mölken Maureen P M H
Published: November 2015

Objectives

To investigate the cost-effectiveness of a chronic obstructive pulmonary disease (COPD) disease management (COPD-DM) programme in primary care, called RECODE, compared to usual care.

Design

A 2-year cluster-randomised controlled trial.

Setting

40 general practices in the western part of the Netherlands.

Participants

1086 patients with COPD according to GOLD (Global Initiative for COPD) criteria. Exclusion criteria were terminal illness, cognitive impairment, alcohol or drug misuse and inability to fill in Dutch questionnaires. Practices were included if they were willing to create a multidisciplinary COPD team.

Interventions

A multidisciplinary team of caregivers was trained in motivational interviewing, setting up individual care plans, exacerbation management, implementing clinical guidelines and redesigning the care process. In addition, clinical decision-making was supported by feedback reports provided by an ICT programme.

Main outcome measures

We investigated the impact on health outcomes (quality-adjusted life years (QALYs), Clinical COPD Questionnaire, St. George's Respiratory Questionnaire and exacerbations) and costs (healthcare and societal perspective).

Results

The intervention costs were €324 per patient. Excluding these costs, the intervention group had €584 (95% CI €86 to €1046) higher healthcare costs than did the usual care group and €645 (95% CI €28 to €1190) higher costs from the societal perspective. Health outcomes were similar in both groups, except for 0.04 (95% CI −0.07 to −0.01) less QALYs in the intervention group.

Conclusions

This integrated care programme for patients with COPD that mainly included professionally directed interventions was not cost-effective in primary care.

Trial registration number

Netherlands Trial Register NTR2268.
‘The phone reminder is important, but will others get to know about my illness?’ Patient perceptions of an mHealth antiretroviral treatment support intervention in the HIVIND trial in South India
Authors: Rodrigues Rashmi , Poongulali S , Balaji Kavitha , Atkins Salla , Ashorn Per , De Costa Ayesha
Published: November 2015

Objectives

The recent explosion of mHealth applications in the area of HIV care has led to the development of mHealth interventions to support antiretroviral treatment adherence. Several of these interventions have been tested for effectiveness, but few studies have explored patient perspectives of such interventions. Exploring patient perspectives enhances the understanding of how an intervention works or why it does not. We therefore studied perceptions regarding an mHealth adherence intervention within the HIVIND trial in South India.

Methods

The study was conducted at three clinics in South India. The intervention comprised an automated interactive voice response (IVR) call and a pictorial short messaging service (SMS), each delivered weekly. Sixteen purposively selected participants from the intervention arm in the HIVIND trial were interviewed. All participants had completed at least 84 weeks since enrollment in the trial. Perceptions on the usefulness and perceived benefits and risks of receiving the intervention were sought. The interviews were transcribed and analysed using the framework approach to qualitative data analysis.

Results

Despite varying perceptions of the intervention, most participants found it useful. The intervention was perceived as a sign of ‘care’ from the clinic. The IVR call was preferred to the SMS reminder. Two-way communication was preferred to automated calls. Participants also perceived a risk of unintentional disclosure of their HIV status and stigma thereof via the intervention and took initiatives to mitigate this risk. Targeting reminders at those with poor adherence and those in need of social support was suggested.

Conclusions

mHealth adherence interventions go beyond their intended role to provide a sense of care and support to the recipient. Although automated interventions are impersonal, they could be a solution for scale up. Interventions that engage both the recipient and the healthcare provider have greater potential for success. Personalising mHealth interventions could mitigate the risk of stigma and promote their uptake.

Trial registration number

ISRCTN79261738.
Is it possible to predict improved diabetes outcomes following diabetes self-management education: a mixed-methods longitudinal design
Authors: Huxley Caroline , Sturt Jackie , Dale Jeremy , Walker Rosie , Caramlau Isabela , O'Hare Joseph P , Griffiths Frances
Published: November 2015

Objective

To predict the diabetes-related outcomes of people undertaking a type 2 Diabetes Self-Management Education (DSME) programme from their baseline data.

Design

A mixed-methods longitudinal experimental study. 6 practice nurses and 2 clinical academics undertook blind assessments of all baseline and process data to predict clinical, behavioural and psychological outcomes at 6 months post-DSME programme.

Setting

Primary care.

Participants

–31 people with type 2 diabetes who had not previously undertaken DSME.

Intervention

All participants undertook the Diabetes Manual 1:1 self-directed learning 12-week DSME programme supported by practice nurses trained as Diabetes Manual facilitators.

Outcome variables

Glycated haemoglobin (HbA1c), diabetes knowledge, physical activity, waist circumference, self-efficacy, diabetes distress, anxiety, depression, demographics, change talk and treatment satisfaction. These variables were chosen because they are known to influence self-management behaviour or to have been influenced by a DSME programme in empirical evidence.

Results

Baseline and 6-month follow-up data were available for 27 participants of which 13 (48%) were male, 22 (82%) white British, mean age 59 years and mean duration of type 2 diabetes 9.1 years. Significant reductions were found in HbA1c t(26)=2.35, p=0.03, and diabetes distress t(26)=2.30, p=0.03, and a significant increase in knowledge t(26)=−2.06, p=0.05 between baseline and 6 months. No significant changes were found in waist circumference, physical activity, anxiety, depression or self-efficacy. Accuracy of predictions varied little between clinical academics and practice nurses but greatly between outcome (0–100%). The median and mode accuracy of predicted outcome was 66.67%. Accuracy of prediction for the key outcome of HbA1c was 44.44%. Diabetes distress had the highest prediction accuracy (81.48%).

Conclusions

Clinicians in this small study were unable to identify individuals likely to achieve improvement in outcomes from DSME. DSME should be promoted to all patients with diabetes according to guidelines.
Can clinical features be used to differentiate type 1 from type 2 diabetes? A systematic review of the literature
Authors: Shields Beverley M , Peters Jaime L , Cooper Chris , Lowe Jenny , Knight Bridget A , Powell Roy J , Jones Angus , Hyde Christopher J , Hattersley Andrew T
Published: November 2015

Objective

Clinicians predominantly use clinical features to differentiate type 1 from type 2 diabetes yet there are no evidence-based clinical criteria to aid classification of patients. Misclassification of diabetes is widespread (7–15% of cases), resulting in patients receiving inappropriate treatment. We sought to identify which clinical criteria could be used to discriminate type 1 and type 2 diabetes.

Design

Systematic review of all diagnostic accuracy studies published since 1979 using clinical criteria to predict insulin deficiency (measured by C-peptide).

Data sources

14 databases including: MEDLINE, MEDLINE in Process and EMBASE. The search strategy took the form of: (terms for diabetes) AND (terms for C-Peptide).

Eligibility criteria

Diagnostic accuracy studies of any routinely available clinical predictors against a reference standard of insulin deficiency defined by cut-offs of C-peptide concentrations. No restrictions on race, age, language or country of origin.

Results

10 917 abstracts were screened, and 231 full texts reviewed. 11 studies met inclusion criteria, but varied by age, race, year and proportion of participants who were C-peptide negative. Age at diagnosis was the most discriminatory feature in 7/9 studies where it was assessed, with optimal cut-offs (>70% mean sensitivity and specificity) across studies being <30 years or <40 years. Use of/time to insulin treatment and body mass index (BMI) were also discriminatory. When combining features, BMI added little over age at diagnosis and/or time to insulin (<1% improvement in classification).

Conclusions

Despite finding only 11 studies, and considerable heterogeneity between studies, age at diagnosis and time to insulin were consistently the most discriminatory criteria. BMI, despite being widely used in clinical practice, adds little to these two criteria. The criteria identified are similar to the Royal College of General Practitioners National Health Service (RCGP/NHS) Diabetes classification guidelines, which use age at diagnosis <35 years and time to insulin <6 m. Until further studies are carried out, these guidelines represent a suitable classification scheme.

Systematic review registration

PROSPERO reference CRD42012001736.
Predicting physical activity energy expenditure in wheelchair users with a multisensor device
Authors: Nightingale T E , Walhin J P , Thompson D , Bilzon J L J
Published: November 2015

Aim

To assess the error in predicting physical activity energy expenditure (PAEE), using a multisensor device in wheelchair users, and to examine the efficacy of using an individual heart rate calibration (IC) method.

Methods

15 manual wheelchair users (36±10 years, 72±11 kg) completed 10 activities: resting, folding clothes, wheelchair propulsion on a 1% gradient (3456 and 7 km/h) and propulsion at 4 km/h (with an additional 8% of body mass, 2% and 3% gradient) on a motorised wheelchair treadmill. Criterion PAEE was measured using a computerised indirect calorimetry system. Participants wore a combined accelerometer and heart rate monitor (Actiheart). They also performed an incremental arm crank ergometry test to exhaustion which permitted retrospective individual calibration of the Actiheart for the activity protocol. Linear regression analysis was conducted between criterion (indirect calorimetry) and estimated PAEE from the Actiheart using the manufacturer's proprietary algorithms (group calibration, GC) or IC. Bland-Altman plots were used and mean absolute error was calculated to assess the agreement between criterion values and estimated PAEE.

Results

Predicted PAEE was significantly (p<0.01) correlated with criterion PAEE (GC, r=0.76 and IC, r=0.95). The absolute bias ±95% limits of agreement were 0.51±3.75 and −0.22±0.96 kcal/min for GC and IC, respectively. Mean absolute errors across the activity protocol were 51.4±38.9% using GC and 16.8±15.8% using IC.

PAEE can be accurately and precisely estimated using a combined accelerometer and heart rate monitor device, with integration of an IC. Interindividual variance in cardiovascular function and response to exercise is high in this population. Therefore, in manual wheelchair users, we advocate the use of an IC when using the Actiheart to predict PAEE.
Validity of theFitbitactivity tracker for measuring steps in community-dwelling older adults
Authors: Paul Serene S , Tiedemann Anne , Hassett Leanne M , Ramsay Elisabeth , Kirkham Catherine , Chagpar Sakina , Sherrington Catherine
Published: November 2015

Background

Commercially available activity monitors, such as theFitbit, may encourage physical activity. However, the accuracy of theFitbitin older adults remains unknown. This study aimed to determine (1) the criterion validity ofFitbitstep counts compared to visual count andActiGraphaccelerometer step counts and (2) the accuracy ofActiGraphstep counts compared to visual count in community-dwelling older people.

Methods

Thirty-two community-dwelling adults aged over 60 woreFitbitandActiGraphdevices simultaneously during a 2 min walk test (2MWT) and then during waking hours over a 7-day period. A physiotherapist counted the steps taken during the 2MWT.

Results

There was excellent agreement betweenFitbitand visually counted steps (intraclass correlation coefficient (ICC2,1)=0.88, 95% CI 0.76 to 0.94) from the 2MWT, and good agreement betweenFitbitandActiGraph(ICC2,1=0.66, 95% CI 0.41 to 0.82), and betweenActiGraphand visually counted steps (ICC2,1=0.60, 95% CI 0.33 to 0.79). There was excellent agreement between theFitbitandActiGraphin average steps/day over 7 days (ICC2,1=0.94, 95% CI 0.88 to 0.97). Percentage agreement was closest forFitbitsteps compared to visual count (mean 0%, SD 4%) and least forFitbitaverage steps/day compared to theActiGraph(mean 13%, SD 25%).

Conclusions

TheFitbitaccurately tracked steps during the 2MWT, but theActiGraphappeared to underestimate steps. There was strong agreement betweenFitbitandActiGraphcounted steps. TheFitbittracker is sufficiently accurate to be used among community-dwelling older adults to monitor and give feedback on step counts.
Force and acceleration characteristics of military foot drill: implications for injury risk in recruits
Authors: Carden Patrick P J , Izard Rachel M , Greeves Julie P , Lake Jason P , Myers Stephen D
Published: November 2015

Background

Foot drill involving marching and drill manoeuvres is conducted regularly during basic military recruit training. Characterising the biomechanical loading of foot drill will improve our understanding of the contributory factors to lower limb overuse injuries in recruits.

Aim

Quantify and compare forces, loading rates and accelerations of British Army foot drill, within and between trained and untrained personnel.

Methods

24 trained soldiers (12 men and 12 women; TRAINED) and 12 civilian men (UNTRAINED) performed marching and five drill manoeuvres on force platforms; motion capture recorded tibial position. Peak vertical impact force (PF), peak vertical loading rate (PLR), expressed as multiples of body weight (BW) and peak tibial impact acceleration (PTA) were recorded.

Results

Drill manoeuvre PF, PLR and PTA were similar, but higher in TRAINED men (PF, PLR: p<0.01; PTA: p<0.05). Peak values in TRAINED men were shown for the halt (mean (SD); PF: 6.5 (1.5) BW; PLR: 983 (333) BW/s PTA; PTA: 207 (57) m/s2) and left turn (PF: 6.6 (1.7) BW; PLR: 928 (300) BW/s; 184 (62) m/s2). Marching PF, PLR, PTA were similar between groups and lower than all drill manoeuvres (PF: 1.1–1.3 BW; PLR: 42–70 BW/s; p<0.01; PTA: 23–38 m/s2; p<0.05).

Conclusions

Army foot drill generates higher forces, loading rates and accelerations than activities such as running and load carriage, while marching is comparable to moderate running (10.8 km/h). The large biomechanical loading of foot drill may contribute to the high rate of overuse injuries during initial military training, and strategies to regulate/reduce this loading should be explored.
Arm-cycling sprints induce neuromuscular fatigue of the elbow flexors and alter corticospinal excitability of the biceps brachii
Authors: Pearcey Gregory E.P. , Bradbury-Squires David J. , Monks Michael , Philpott Devin , Power Kevin E. , Button Duane C.
Published: November 2015

We examined the effects of arm-cycling sprints on maximal voluntary elbow flexion and corticospinal excitability of the biceps brachii. Recreationally trained athletes performed ten 10-s arm-cycling sprints interspersed with 150 s of rest in 2 separate experiments. In experiment A (n = 12), maximal voluntary contraction (MVC) force of the elbow flexors was measured at pre-sprint 1, post-sprint 5, and post-sprint 10. Participants received electrical motor point stimulation during and following the elbow flexor MVCs to estimate voluntary activation (VA). In experiment B (n = 7 participants from experiment A), supraspinal and spinal excitability of the biceps brachii were measured via transcranial magnetic and transmastoid electrical stimulation that produced motor evoked potentials (MEPs) and cervicomedullary motor evoked potentials (CMEPs), respectively, during a 5% isometric MVC at pre-sprint 1, post-sprint 1, post-sprint 5, and post-sprint 10. In experiment A, mean power output, MVC force, potentiated twitch force, and VA decreased 13.1% (p < 0.001), 8.7% (p = 0.036), 27.6% (p = 0.003), and 5.6% (p = 0.037), respectively, from pre-sprint 1 to post-sprint 10. In experiment B, (i) MEPs decreased 42.1% (p = 0.002) from pre-sprint 1 to post-sprint 5 and increased 40.1% (p = 0.038) from post-sprint 5 to post-sprint 10 and (ii) CMEPs increased 28.5% (p = 0.045) from post-sprint 1 to post-sprint 10. Overall, arm-cycling sprints caused neuromuscular fatigue of the elbow flexors, which corresponded with decreased supraspinal and increased spinal excitability of the biceps brachii. The different post-sprint effects on supraspinal and spinal excitability may illustrate an inhibitory effect on supraspinal drive that reduces motor output and, therefore, decreases arm-cycling sprint performance.
Crown allometry and application of the pipe model theory to white spruce (Picea glauca (Moench) Voss) and aspen (Populus tremuloides Michx.) in the western boreal forest of Canada
Authors: Sattler Derek F. , Comeau Philip G.
Published: November 2015

White spruce (Picea glauca (Moench) Voss) and aspen (Populus tremuloides Michx.) from unmanaged stands in the boreal forest of Alberta, Canada, were examined for two of the main structural assumptions in the process-based model CROBAS: (i) a constant allometric relationship between foliage mass and crown length and (ii) a constant relationship between foliage mass and sapwood area. We evaluated these relationships at both at the whole-crown and within-crown levels. Results indicated that for both species, a constant allometric relationship between foliage mass and crown length was maintained at the whole-crown level over a period exceeding the peak mean annual increment of each species. Within the crowns of spruce, foliage mass accumulated faster near the tree apex as total crown length increased. For aspen, the increase in foliage mass per unit crown length for any section within the crown showed greater similarity to the relationship observed at the whole-crown level. The assumption of a constant relationship between foliage mass and sapwood area at the crown base generally held for spruce but showed considerable variation for any given diameter class. For aspen, this assumption did not appear to be appropriate. For both species, there was more foliage mass per unit sapwood area with increasing height from the ground for nearly all tree size classes. This latter finding was in conflict with the pipe model theory but could not be explained by the hydraulic theory of crown architecture, which predicts a decrease in the ratio of foliage mass to sapwood area with increasing path length.
Exploitation of a “hockey-puck” phenotype to identify pilus and biofilm regulators in Serratia marcescens through genetic analysis
Authors: Shanks Robert M.Q. , Stella Nicholas A. , Brothers Kimberly M. , Polaski Denise M.
Published: November 2015

Pili are essential adhesive determinants for many bacterial pathogens. A suppressor mutation screen that takes advantage of a pilus-mediated self-aggregative “hockey-puck” colony phenotype was designed to identify novel regulators of type I pili in Serratia marcescens. Mutations that decreased pilus biosynthesis mapped to the fimABCD operon; to the genes alaT, fkpA, and oxyR; upstream of the flagellar master regulator operon flhDC; and to an uncharacterized gene encoding a predicted DUF1401 domain. Biofilm formation and pilus-dependent agglutination assays were used to characterize the relative importance of the identified genes in pilus biosynthesis. Additional mutagenic or complementation analysis was used to verify the role of candidate genes in pilus biosynthesis. Presented data support a model that CRP negatively regulates pilus biosynthesis through increased expression of flhDC and decreased expression of oxyR. Further studies are warranted to determine the mechanism by which these genes mediate pilus biosynthesis or function.
Mangiferin suppressed advanced glycation end products (AGEs) through NF-κB deactivation and displayed anti-inflammatory effects in streptozotocin and high fat diet-diabetic cardiomyopathy rats
Authors: Hou Jun , Zheng Dezhi , Fung Gabriel , Deng Haoyu , Chen Lin , Liang Jiali , Jiang Yan , Hu Yonghe
Published: November 2015

Given the importance of the aggregation of advanced glycation end products (AGEs) and cardiac inflammation in the onset and progression of diabetic cardiomyopathy (DCM), our objective in this study was to demonstrate the cardioprotective effect of mangiferin, an antidiabetic and anti-inflammatory agent, on diabetic rat model. The DCM model was established by a high-fat diet and a low dose of streptozotocin. DCM rats were treated orally with mangiferin (20 mg/kg) for 16 weeks. Serum and left ventricular myocardium were collected for determination of inflammatory cytokines. AGEs mRNA and protein expression of nuclear factor kappa B (NF-κB) and receptor for AGEs (RAGE) in myocardium were assayed by real-time PCR and Western blot. ROS levels were measured by dihydroethidium fluorescence staining. NF-κB binding activity was assayed by TransAM NF-κB p65 ELISA kit. Chronic treatment with mangiferin decreased the levels of myocardial enzymes (CK-MB, LDH) and inflammatory mediators (TNF-α, IL-1β). Meanwhile, NF-κB is inhibited by the reduction of nuclear translocation of p65 subunit, and mangiferin reduced AGE production and decreased the mRNA and protein expression of RAGE in DCM rats. Our data indicated that mangiferin could significantly ameliorate DCM by preventing the release of inflammatory cytokines, and inhibiting ROS accumulation, AGE/RAGE production, and NF-κB nuclear translocation, suggesting that mangiferin treatment might be beneficial in DCM.
Sperm Storage in the Female Reproductive Tract
Authors: Holt William V. , Fazeli Alireza
Published: November 2015

The capacity for sperm storage within the female reproductive tract occurs widely across all groups of vertebrate species and is exceptionally well developed in some reptiles (maximum duration seven years) and fishes (maximum duration >1 year). Although there are many reports on both the occurrence of female sperm storage in diverse species and its adaptive benefits, few studies have been directed toward explaining the mechanisms involved. In this article we review recent findings in birds and mammals in an effort to develop hypotheses that could be translated into research applications in animal breeding technologies. There are pockets of evidence to suggest that the local epithelial cells, sometimes arranged as sperm storage tubules, can respond to spermatozoa by producing heat shock proteins as well as providing an environment rich in antioxidants. Moreover, the local immune system seems to tolerate the arrival of spermatozoa, while retaining the ability to combat the arrival of infectious microorganisms.