bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Light Chain Defines the Duration of Action of Botulinum Toxin Serotype A Subtypes
Authors: Pellett Sabine , Bradshaw Marite , Tepp William H. , Pier Christina L. , Whitemarsh Regina C. M. , Chen Chen , Barbieri Joseph T. , Johnson Eric A. 
Published: March 2018

ABSTRACT
Botulinum neurotoxin (BoNT) is the causative agent of botulism and a widely used pharmaceutical to treat a variety of neurological diseases. BoNTs are 150-kDa protein toxins organized into heavy chain (HC) and light chain (LC) domains linked by a disulfide bond. The HC selectively binds to neurons and aids cell entry of the enzymatically active LC. There are seven immunological BoNT serotypes (A to G); each serotype includes genetic variants, termed subtypes. Only two subtypes, BoNT/A1 and BoNT/B1, are currently used as therapeutics. BoNT serotype A (BoNT/A) subtypes A2 to A8 show distinct potency, duration of action, and pathology relative to BoNT/A1. Specifically, BoNT/A3 possesses shorter duration of action and elicits distinct symptoms in mice at high toxin doses. In this report, we analyzed the roles of LC and HC of BoNT/A3 for duration of action, neuronal cell entry, and mouse pathology by using clostridium-derived recombinant hybrid BoNTs consisting of reciprocal LC and HC (BoNTA1/A3 and BoNTA3/A1). Hybrid toxins were processed in their expression host to a dichain BoNT consisting of LC and HC linked via a disulfide bond. The LC and HC defined BoNT potency in mice and BoNT toxicity for cultured neuronal cells, while the LC defined the duration of BoNT action in cell and mouse models. Protein alignment identified a previously unrecognized region within the LC subtype A3 (LC/A3) relative to the other LC serotype A (LC/A) subtypes (low primary acid homology [LPH]) that correlated to intracellular LC localization. This study shows the utility of recombinant hybrid BoNTs with new therapeutic potential, while remaining sensitive to antitoxins and therapies to native BoNT.

IMPORTANCE
Botulinum neurotoxins are the most potent protein toxins for humans and potential bioterrorism threats, but they are also widely used as pharmaceuticals. Within the large family of BoNTs, only two subtypes are currently used as pharmaceuticals, with a large number of BoNT subtypes remaining as untapped potential sources for unique pharmaceuticals. Here, two recombinant hybrid toxins were engineered, consisting of domains from two BoNT subtypes that possess distinct duration of action and activity in human neurons and mice. We define the functional domains responsible for BoNT action and demonstrate creation of functional hybrid BoNTs with new therapeutic potential, while remaining sensitive to antitoxins and therapies to native BoNT.
Concurrent Host-Pathogen Transcriptional Responses in a
Clostridium perfringens
Murine Myonecrosis Infection
Authors: Low Lee-Yean , Harrison Paul F. , Gould Jodee , Powell David R. , Choo Jocelyn M. , Forster Samuel C. , Chapman Ross , Gearing Linden J. , Cheung Jackie K. , Hertzog Paul , Rood Julian I. 
Published: March 2018

ABSTRACT

To obtain an insight into host-pathogen interactions in clostridial myonecrosis, we carried out comparative transcriptome analysis of both the bacterium and the host in a murine
Clostridium perfringens
infection model, which is the first time that such an investigation has been conducted. Analysis of the host transcriptome from infected muscle tissues indicated that many genes were upregulated compared to the results seen with mock-infected mice. These genes were enriched for host defense pathways, including Toll-like receptor (TLR) and Nod-like receptor (NLR) signaling components. Real-time PCR confirmed that host TLR2 and NLRP3 inflammasome genes were induced in response to
C. perfringens
infection. Comparison of the transcriptome of
C. perfringens
cells from the infected tissues with that from broth cultures showed that host selective pressure induced a global change in
C. perfringens
gene expression. A total of 33% (923) of
C. perfringens
genes were differentially regulated, including 10 potential virulence genes that were upregulated relative to their expression
in vitro
. These genes encoded putative proteins that may be involved in the synthesis of cell wall-associated macromolecules, in adhesion to host cells, or in protection from host cationic antimicrobial peptides. This report presents the first successful expression profiling of coregulated transcriptomes of bacterial and host genes during a clostridial myonecrosis infection and provides new insights into disease pathogenesis and host-pathogen interactions.

IMPORTANCE
Clostridium perfringens
is the causative agent of traumatic clostridial myonecrosis, or gas gangrene. In this study, we carried out transcriptional analysis of both the host and the bacterial pathogen in a mouse myonecrosis infection. The results showed that in comparison to mock-infected control tissues, muscle tissues from
C. perfringens
-infected mice had a significantly altered gene expression profile. In particular, the expression of many genes involved in the innate immune system was upregulated. Comparison of the expression profiles of
C. perfringens
cells isolated from the infected tissues with those from equivalent broth cultures identified many potential virulence genes that were significantly upregulated
in vivo
. These studies have provided a new understanding of the range of factors involved in host-pathogen interactions in a myonecrosis infection.
The Sole DEAD-Box RNA Helicase of the Gastric Pathogen
Helicobacter pylori
Is Essential for Colonization
Authors: El Mortaji Lamya , Aubert Sylvie , Galtier Eloïse , Schmitt Christine , Anger Karine , Redko Yulia , Quentin Yves , De Reuse Hilde 
Published: March 2018

ABSTRACT

Present in every kingdom of life, generally in multiple copies, DEAD-box RNA helicases are specialized enzymes that unwind RNA secondary structures. They play major roles in mRNA decay, ribosome biogenesis, and adaptation to cold temperatures. Most bacteria have multiple DEAD-box helicases that present both specialized and partially redundant functions. By using phylogenomics, we revealed that the
Helicobacter
genus, including the major gastric pathogen
H. pylori
, is among the exceptions, as it encodes a sole DEAD-box RNA helicase. In
H. pylori
, this helicase, designated RhpA, forms a minimal RNA degradosome together with the essential RNase, RNase J, a major player in the control of RNA decay. Here, we used
H. pylori
as a model organism with a sole DEAD-box helicase and investigated the role of this helicase in
H. pylori
physiology, ribosome assembly, and during
in vivo
colonization. Our data showed that RhpA is dispensable for growth at 37°C but crucial at 33°C, suggesting an essential role of the helicase in cold adaptation. Moreover, we found that a Δ
rhpA
mutant was impaired in motility and deficient in colonization of the mouse model. RhpA is involved in the maturation of 16S rRNA at 37°C and is associated with translating ribosomes. At 33°C, RhpA is, in addition, recruited to individual ribosomal subunits. Finally, via its role in the RNA degradosome, RhpA directs the regulation of the expression of its partner, RNase J. RhpA is thus a multifunctional enzyme that, in
H. pylori
, plays a central role in gene regulation and in the control of virulence.

IMPORTANCE
We present the results of our study on the role of RhpA, the sole DEAD-box RNA helicase encoded by the major gastric pathogen
Helicobacter pylori
. We observed that all the
Helicobacter
species possess such a sole helicase, in contrast to most free-living bacteria. RhpA is not essential for growth of
H. pylori
under normal conditions. However, deletion of
rhpA
leads to a motility defect and to total inhibition of the ability of
H. pylori
to colonize a mouse model. We also demonstrated that this helicase encompasses most of the functions of its specialized orthologs described so far. We found that RhpA is a key element of the bacterial adaptation to colder temperatures and plays a minor role in ribosome biogenesis. Finally, RhpA regulates transcription of the
rnj
gene encoding RNase J, its essential partner in the minimal
H. pylori
RNA degradosome, and thus plays a crucial role in the control of RNA decay.
Optical coherence tomography angiography in comparison with other multimodal imaging techniques in punctate inner choroidopathy
Authors: Pohlmann Dominika , Pleyer Uwe , Joussen Antonia M , Winterhalter Sibylle 
Published: March 2018

AimsTo characterise punctate lesions and choroidal neovascularisation (CNV) in eyes with punctate inner choroidopathy (PIC) using current standard multimodal imaging techniques and optical coherence tomography angiography (OCTA).MethodsIn our prospective, single-centre study, 20 individuals with PIC underwent imaging with spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), indocyanine green angiography, fundus autofluorescence, fundus colour photography and OCTA.ResultsThirty-two eyes of 20 patients were affected. Eight (20%) eyes revealed typical punctate lesions, while 24 (60%) eyes had confirmed CNV on SD-OCT and FA in addition to punctate lesions. Of these 24 eyes with CNV, a reoccurrence of active CNV was detected in 5 (21%) eyes, a residual fluid in 3 (13%) eyes, while 16 (67%) eyes were defined as being stable. On OCTA, CNV was classified as having ‘lacy wheel’, ‘pruned large-trunk’ and ‘dead tree aspect’ vessel shapes with or without areas of non-perfusion. The disease activity was dependent on several predictors in the regression analysis such as intraretinal fluid (p=0.0014), CNV type (p=0.0199), leakage (p<0.0001) and hypoperfusion/non-perfusion (p<0.0001) on OCTA.ConclusionOCTA offers additional valuable insight into the current standard multimodal imaging techniques used for characterisation of PIC. This imaging technique can be a useful tool for analysis of disease activity.
Care home services at the vanguard: a qualitative study exploring stakeholder views on the development and evaluation of novel, integrated approaches to enhancing healthcare in care homes
Authors: Stocker Rachel , Bamford Claire , Brittain Katie , Duncan Rachel , Moffatt Suzanne , Robinson Louise , Hanratty Barbara 
Published: March 2018

ObjectivesTo explore stakeholders’ understanding of novel integrated approaches to enhancing care in care homes (a care home ‘vanguard’) and identify priorities for evaluation.DesignA qualitative study, using semistructured interviews with commissioners and service providers to/within care homes, and third sector organisations with thematic analysis.SettingA Clinical Commissioning Group (CCG) area in England.ParticipantsThirty interviewees from care homes, the National Health Service (NHS; England) and local authority, third sector (10 care home managers, 5 general practitioners, 4 CCG employees, 4 local authority employees, 1 national (NHS England) vanguard lead, 2 specialist nurses, 2 geriatricians, 1 third sector and 1 health manager).ResultsFour higher level themes emerged from the data: understanding of proposed changes, communication, evaluation of outcome measures of success, and trust and complexity. The vision for the new programme was shared by stakeholders, with importance attached to equitable access to high-quality care. Support for the programme was described as being ‘the right thing to do’, inferring a moral imperative. However, the practical implications of key aspects, such as integrated working, were not clearly understood and the programme was perceived by some as being imposed, top down, from the health service. Barriers and facilitators to change were identified across themes of communication, outcomes, trust and complexity. Importance was attached to the measurement of intangible aspects of success, such as collaboration. Interviewees understood that outcome-based commissioning was one element of the new programme, but discussion of their aspirations and practices revealed values and beliefs more compatible with a system based on trust.ConclusionsInnovation in service delivery requires organisations to adopt common priorities and share responsibility for success. The vanguard programme is working to ensure health and local authorities have this commitment, but engaging care homes that may feel isolated from the welfare system needs sustained dialogue over the longer term. Evaluation of the programme needs to measure what is important to stakeholders, and not focus too closely on resource consumption.
A cross-sectional study of all clinicians’ conflict of interest disclosures to NHS hospital employers in England 2015-2016
Authors: Feldman Harriet Ruth , DeVito Nicholas J , Mendel Jonathan , Carroll David E , Goldacre Ben 
Published: March 2018

ObjectiveWe set out to document how NHS trusts in the UK record and share disclosures of conflict of interest by their employees.DesignCross-sectional study of responses to a Freedom of Information Act request for Gifts and Hospitality Registers.SettingNHS Trusts (secondary/tertiary care organisations) in England.Participants236 Trusts were contacted, of which 217 responded.Main outcome measuresWe assessed all disclosures for completeness and openness, scoring them for achieving each of five measures of transparency.Results185 Trusts (78%) provided a register. 71 Trusts did not respond within the 28 day time limit required by the FoIA. Most COI registers were incomplete by design, and did not contain the information necessary to assess conflicts of interest. 126/185 (68%) did not record the names of recipients. 47/185 (25%) did not record the cash value of the gift or hospitality. Only 31/185 registers (16%) contained the names of recipients, the names of donors, and the cash amounts received. 18/185 (10%) contained none of: recipient name, donor name, and cash amount. Only 15 Trusts had their disclosure register publicly available online (6%). We generated a transparency index assessing whether each Trust met the following criteria: responded on time; provided a register; had a register with fields identifying donor, recipient, and cash amount; provided a register in a format that allowed further analysis; and had their register publicly available online. Mean attainment was 1.9/5; no NHS trust met all five criteria.ConclusionOverall, recording of employees’ conflicts of interest by NHS trusts is poor. None of the NHS Trusts in England met all transparency criteria. 19 did not respond to our FoIA requests, 51 did not provide a Gifts and Hospitality Register and only 31 of the registers provided contained enough information to assess employees’ conflicts of interest. Despite obligations on healthcare professionals to disclose conflicts of interest, and on organisations to record these, the current system for logging and tracking such disclosures is not functioning adequately. We propose a simple national template for reporting conflicts of interest, modelled on the US ‘Sunshine Act’.
Validation of an algorithm to identify heart failure hospitalisations in patients with diabetes within the veterans health administration
Authors: Presley Caroline A , Min Jea Young , Chipman Jonathan , Greevy Robert A , Grijalva Carlos G , Griffin Marie R , Roumie Christianne L 
Published: March 2018

ObjectivesWe aimed to validate an algorithm using both primary discharge diagnosis (International Classification of Diseases Ninth Revision (ICD-9)) and diagnosis-related group (DRG) codes to identify hospitalisations due to decompensated heart failure (HF) in a population of patients with diabetes within the Veterans Health Administration (VHA) system.DesignValidation study.SettingVeterans Health Administration—Tennessee Valley Healthcare SystemParticipantsWe identified and reviewed a stratified, random sample of hospitalisations between 2001 and 2012 within a single VHA healthcare system of adults who received regular VHA care and were initiated on an antidiabetic medication between 2001 and 2008. We sampled 500 hospitalisations; 400 hospitalisations that fulfilled algorithm criteria, 100 that did not. Of these, 497 had adequate information for inclusion. The mean patient age was 66.1 years (SD 11.4). Majority of patients were male (98.8%); 75% were white and 20% were black.Primary and secondary outcome measuresTo determine if a hospitalisation was due to HF, we performed chart abstraction using Framingham criteria as the referent standard. We calculated the positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity for the overall algorithm and each component (primary diagnosis code (ICD-9), DRG code or both).ResultsThe algorithm had a PPV of 89.7% (95% CI 86.8 to 92.7), NPV of 93.9% (89.1 to 98.6), sensitivity of 45.1% (25.1 to 65.1) and specificity of 99.4% (99.2 to 99.6). The PPV was highest for hospitalisations that fulfilled both the ICD-9 and DRG algorithm criteria (92.1% (89.1 to 95.1)) and lowest for hospitalisations that fulfilled only DRG algorithm criteria (62.5% (28.4 to 96.6)).ConclusionsOur algorithm, which included primary discharge diagnosis and DRG codes, demonstrated excellent PPV for identification of hospitalisations due to decompensated HF among patients with diabetes in the VHA system.
Study protocol for a self-controlled cluster randomised trial of the Alert Program to improve self-regulation and executive function in Australian Aboriginal children with fetal alcohol spectrum disorder
Authors: Wagner Bree , Fitzpatrick James P , Mazzucchelli Trevor G , Symons Martyn , Carmichael Olson Heather , Jirikowic Tracy , Cross Donna , Wright Edie , Adams Emma , Carter Maureen , Bruce Kaashifah , Latimer Jane 
Published: March 2018

IntroductionWhile research highlights the benefits of early diagnosis and intervention for children with fetal alcohol spectrum disorders (FASD), there are limited data documenting effective interventions for Australian children living in remote communities.Methods and analysisThis self-controlled cluster randomised trial is evaluating the effectiveness of an 8-week Alert Program school curriculum for improving self-regulation and executive function in children living in remote Australian Aboriginal communities. Children in grades 1–6 attending any of the eight participating schools across the Fitzroy Valley in remote North-West Australia (N≈ 363) were invited to participate. Each school was assigned to one of four clusters with clusters randomly assigned to receive the intervention at one of four time points. Clusters two, three and four had extended control conditions where students received regular schooling before later receiving the intervention. Trained classroom teachers delivered the Alert Program to students in discrete, weekly, 1-hour lessons. Student outcomes were assessed at three time points. For the intervention condition, data collection occurred 2 weeks immediately before and after the intervention, with a follow-up 8 weeks later. For control conditions in clusters two to four, the control data collection matched that of the data collection for the intervention condition in the preceding cluster. The primary outcome is change in self-regulation. FASD diagnoses will be determined via medical record review after the completion of data collection. The results will be analysed using generalised linear mixed modelling and reported in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines.Ethics and disseminationEthical approval was obtained from the University of Western Australia (WA) (RA/4/1/7234), WA Aboriginal Health Ethics Committee (601) and WA Country Health Service (2015:04). The Kimberley Aboriginal Health Planning Forum Research Sub-Committee and WA Department of Education also provided approval. The results will be disseminated through peer-reviewed journals, conference presentations, the media and at forums.Trial registration numberACTRN12615000733572; Pre-results.
Socioeconomic inequalities in child vaccination in low/middle-income countries: what accounts for the differences?
Authors: Hajizadeh Mohammad 
Published: March 2018

BackgroundSocioeconomic inequalities in child vaccination continue to be a global public health concern. This study aimed to measure and identify factors associated with socioeconomic inequalities in full immunisation coverage against the four core vaccine-preventable diseases (ie, bacille Calmette-Guérin, diphtheria-tetanus-pertussis (three doses), polio (three doses) and measles vaccines) in 46 low/middle-income countries.MethodsThe most recent nationally representative samples of children (aged 10–59 months, n=372 499) collected through the Demographic Health Surveys were used to measure vaccination rates. The concentration index (C) was used to quantify socioeconomic inequalities in vaccination coverage. Furthermore, meta-regression analyses were used to determine factors affecting socioeconomic inequalities in vaccination coverage across countries.ResultsResults suggested that immunisation coverage was pro-rich in most countries (median C=0.161, IQR 0.131). Gambia (C=−0.146, 95% CI −0.223 to −0.069), Namibia (C=−0.093, 95% CI −0.145 to −0.041) and Kyrgyz Republic (C=−0.227, 95% CI −0.304 to −0.15) were the only countries where children who belong to higher socioeconomic status group were less likely to receive all the four core vaccines than their lower socioeconomic status counterparts. Meta-regression analyses suggested that, across countries, the concentration of antenatal care visits among wealthier mothers was positively associated with the concentration of vaccination coverage among wealthier children (coefficient=0.606, 95% CI 0.301 to 0.911).ConclusionsPro-rich distribution of child vaccination in most low/middle-income countries remains an important public health policy concern. Policies aimed to improve antenatal care visits among mothers in lower socioeconomic groups may mitigate socioeconomic inequalities in vaccination coverage in low/middle-income countries.
Environmental cadmium exposure is associated with elevated risk of chronic otitis media in adults
Authors: Lee Dong-Wook , Oh Seung-Ha , Park Moo-Kyun , Lim Youn-Hee , Hong Yun-Chul 
Published: March 2018

ObjectivesChronic otitis media (COM) is caused by an infection of the middle ear, although it may also be associated with environmental pollutants. Recent reports found that cadmium exposure could be toxic to middle ear cell lines, but the role of cadmium in the development of COM in humans has not been examined to date. We hypothesised that environmental cadmium exposure was associated with an increased risk of COM in the general population.MethodsWe analysed cross-sectional data for 5331 adults of 20 years of age or above, obtained from the Korea National Health and Nutrition Examination Survey 2010–2012. We examined the association between blood cadmium levels and COM diagnosed by an otolaryngologist.ResultsThe highest quartile group of cadmium blood concentration was associated with an OR of 3.33 (95% CI 1.78 to 7.53) for COM, after adjusting for potential confounding factors. Doubling blood cadmium concentration resulted in an OR of 1.58 (95% CI 1.19 to 2.08) for COM. These associations were robust on sensitivity analyses after excluding current smokers and former smokers and after excluding subjects with a potential history of occupational exposure to cadmium.ConclusionsThe results of our study suggest that environmental cadmium exposure is associated with increased risk of COM, and further studies are warranted to understand the pathogenetic mechanism by which COM is caused by cadmium exposure.