bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms, Chromosomal Rearrangements, and Mutator Phenotype Development during Experimental Evolution of Lactobacillus rhamnosus GG
Authors: Douillard François P. , Ribbera Angela , Xiao Kun , Ritari Jarmo , Rasinkangas Pia , Paulin Lars , Palva Airi , Hao Yanling , de Vos Willem M.
Published: April 2016

Lactobacillus rhamnosus
GG is a lactic acid bacterium widely marketed by the food industry. Its genomic analysis led to the identification of a gene cluster encoding mucus-binding SpaCBA pili, which is located in a genomic island enriched in insertion sequence (IS) elements. In the present study, we analyzed by genome-wide resequencing the genomic integrity of
L. rhamnosus
GG in four distinct evolutionary experiments conducted for approximately 1,000 generations under conditions of no stress or salt, bile, and repetitive-shearing stress. Under both stress-free and salt-induced stress conditions, the GG population (excluding the mutator lineage in the stress-free series [see below]) accumulated only a few single nucleotide polymorphisms (SNPs) and no frequent chromosomal rearrangements. In contrast, in the presence of bile salts or repetitive shearing stress, some IS elements were found to be activated, resulting in the deletion of large chromosomal segments that include the
spaCBA-srtC1
pilus gene cluster. Remarkably, a high number of SNPs were found in three strains obtained after 900 generations of stress-free growth. Detailed analysis showed that these three strains derived from a founder mutant with an altered DNA polymerase subunit that resulted in a mutator phenotype. The present work confirms the stability of the pilus production phenotype in
L. rhamnosus
GG under stress-free conditions, highlights the possible evolutionary scenarios that may occur when this probiotic strain is extensively cultured, and identifies external factors that affect the chromosomal integrity of GG. The results provide mechanistic insights into the stability of GG in regard to its extensive use in probiotic and other functional food products.

IMPORTANCE
Lactobacillus rhamnosus
GG is a widely marketed probiotic strain that has been used in numerous clinical studies to assess its health-promoting properties. Hence, the stability of the probiotic functions of
L. rhamnosus
GG is of importance, and here we studied the impact of external stresses on the genomic integrity of
L. rhamnosus
GG. We studied three different stresses that are relevant for understanding its robustness and integrity under both
ex vivo
conditions, i.e., industrial manufacturing conditions, and
in vivo
conditions, i.e., intestinal tract-associated stress. Overall, our findings contribute to predicting the genomic stability of
L. rhamnosus
GG and its ecological performance.
Nitrous Oxide Reduction Kinetics Distinguish Bacteria Harboring Clade I NosZ from Those Harboring Clade II NosZ
Authors: Yoon Sukhwan , Nissen Silke , Park Doyoung , Sanford Robert A. , Löffler Frank E.
Published: April 2016

Bacteria capable of reduction of nitrous oxide (N
2
O) to N
2
separate into clade I and clade II organisms on the basis of
nos
operon structures and
nosZ
sequence features. To explore the possible ecological consequences of distinct
nos
clusters, the growth of bacterial isolates with either clade I (
Pseudomonas stutzeri
strain DCP-Ps1,
Shewanella loihica
strain PV-4) or clade II (
Dechloromonas aromatica
strain RCB,
Anaeromyxobacter
dehalogenans
strain 2CP-C)
nosZ
with N
2
O was examined. Growth curves did not reveal trends distinguishing the clade I and clade II organisms tested; however, the growth yields of clade II organisms exceeded those of clade I organisms by 1.5- to 1.8-fold. Further, whole-cell half-saturation constants (

K
s

s) for N
2
O distinguished clade I from clade II organisms. The apparent

K
s

values of 0.324 ± 0.078 μM for
D. aromatica
and 1.34 ± 0.35 μM for
A. dehalogenans
were significantly lower than the values measured for
P. stutzeri
(35.5 ± 9.3 μM) and
S. loihica
(7.07 ± 1.13 μM). Genome sequencing demonstrated that
Dechloromonas denitrificans
possessed a clade II
nosZ
gene, and a measured

K
s

of 1.01 ± 0.18 μM for N
2
O was consistent with the values determined for the other clade II organisms tested. These observations provide a plausible mechanistic basis for why the relative activity of bacteria with clade I
nos
operons compared to that of bacteria with clade II
nos
operons may control N
2
O emissions and determine a soil's N
2
O sink capacity.

IMPORTANCE
Anthropogenic activities, in particular fertilizer application for agricultural production, increase N
2
O emissions to the atmosphere. N
2
O is a strong greenhouse gas with ozone destruction potential, and there is concern that nitrogen may become the major driver of climate change. Microbial N
2
O reductase (NosZ) catalyzes N
2
O reduction to environmentally benign dinitrogen gas and represents the major N
2
O sink process. The observation that bacterial groups with clade I
nosZ
versus those with clade II
nosZ
exhibit distinct affinities to N
2
O has implications for N
2
O flux models, and these distinct characteristics may provide opportunities to curb N
2
O emissions from relevant soil ecosystems.
Geochemical and Temporal Influences on the Enrichment of Acidophilic Iron-Oxidizing Bacterial Communities
Authors: Sheng Yizhi , Bibby Kyle , Grettenberger Christen , Kaley Bradley , Macalady Jennifer L. , Wang Guangcai , Burgos William D.
Published: April 2016

Two acid mine drainage (AMD) sites in the Appalachian bituminous coal basin were selected to enrich for Fe(II)-oxidizing microbes and measure rates of low-pH Fe(II) oxidation in chemostatic bioreactors. Microbial communities were enriched for 74 to 128 days in fed-batch mode, then switched to flowthrough mode (additional 52 to 138 d) to measure rates of Fe(II) oxidation as a function of pH (2.1 to 4.2) and influent Fe(II) concentration (80 to 2,400 mg/liter). Biofilm samples were collected throughout these operations, and the microbial community structure was analyzed to evaluate impacts of geochemistry and incubation time. Alpha diversity decreased as the pH decreased and as the Fe(II) concentration increased, coincident with conditions that attained the highest rates of Fe(II) oxidation. The distribution of the seven most abundant bacterial genera could be explained by a combination of pH and Fe(II) concentration.
Acidithiobacillus
,
Ferrovum
,
Gallionella
,
Leptospirillum
,
Ferrimicrobium
,
Acidiphilium
, and
Acidocella
were all found to be restricted within specific bounds of pH and Fe(II) concentration. Temporal distance, defined as the cumulative number of pore volumes from the start of flowthrough mode, appeared to be as important as geochemical conditions in controlling microbial community structure. Both alpha and beta diversities of microbial communities were significantly correlated to temporal distance in the flowthrough experiments. Even after long-term operation under nearly identical geochemical conditions, microbial communities enriched from the different sites remained distinct. While these microbial communities were enriched from sites that displayed markedly different field rates of Fe(II) oxidation, rates of Fe(II) oxidation measured in laboratory bioreactors were essentially the same. These results suggest that the performance of suspended-growth bioreactors for AMD treatment may not be strongly dependent on the inoculum used for reactor startup.

IMPORTANCE
This study showed that different microbial communities enriched from two sites maintained distinct microbial community traits inherited from their respective seed materials. Long-term operation (up to 128 days of fed-batch enrichment followed by up to 138 days of flowthrough experiments) of these two systems did not lead to the same, or even more similar, microbial communities. However, these bioreactors did oxidize Fe(II) and remove total iron [Fe(T)] at very similar rates. These results suggest that the performance of suspended-growth bioreactors for AMD treatment may not be strongly dependent on the inoculum used for reactor startup. This would be advantageous, because system performance should be well constrained and predictable for many different sites.
Symbiotic Nitrogen Fixation and the Challenges to Its Extension to Nonlegumes
Authors: Mus Florence , Crook Matthew B. , Garcia Kevin , Garcia Costas Amaya , Geddes Barney A. , Kouri Evangelia D. , Paramasivan Ponraj , Ryu Min-Hyung , Oldroyd Giles E. D. , Poole Philip S. , Udvardi Michael K. , Voigt Christopher A. , Ané Jean-Michel , Peters John W.
Published: April 2016

Access to fixed or available forms of nitrogen limits the productivity of crop plants and thus food production. Nitrogenous fertilizer production currently represents a significant expense for the efficient growth of various crops in the developed world. There are significant potential gains to be had from reducing dependence on nitrogenous fertilizers in agriculture in the developed world and in developing countries, and there is significant interest in research on biological nitrogen fixation and prospects for increasing its importance in an agricultural setting. Biological nitrogen fixation is the conversion of atmospheric N
2
to NH
3
, a form that can be used by plants. However, the process is restricted to bacteria and archaea and does not occur in eukaryotes. Symbiotic nitrogen fixation is part of a mutualistic relationship in which plants provide a niche and fixed carbon to bacteria in exchange for fixed nitrogen. This process is restricted mainly to legumes in agricultural systems, and there is considerable interest in exploring whether similar symbioses can be developed in nonlegumes, which produce the bulk of human food. We are at a juncture at which the fundamental understanding of biological nitrogen fixation has matured to a level that we can think about engineering symbiotic relationships using synthetic biology approaches. This minireview highlights the fundamental advances in our understanding of biological nitrogen fixation in the context of a blueprint for expanding symbiotic nitrogen fixation to a greater diversity of crop plants through synthetic biology.
Occurrence and Spread of Quinolone-Resistant Escherichia coli on Dairy Farms
Authors: Duse Anna , Persson Waller Karin , Emanuelson Ulf , Ericsson Unnerstad Helle , Persson Ylva , Bengtsson Björn
Published: April 2016

Quinolone-resistant
Escherichia coli
(QREC) is common in feces from young calves, but the prevalence and genetic diversity of QREC in groups of cattle of other ages and the farm environment are unknown. The aims of the study were to obtain knowledge about the occurrence of QREC on dairy farms, the genetic diversity of QREC within and between farms, and how these relate to the number of purchased animals and geographic distances between farms. We analyzed the within-sample prevalence of QREC in individual fecal samples from preweaned dairy calves and postpartum cows and in environmental samples from 23 Swedish dairy farms. The genetic diversity of the QREC isolates on 10 of these farms was assessed. In general, QREC was more prevalent in the dairy farm environment and in postpartum cows if QREC was commonly found in calves than if QREC was rare in calves. In particular, we found more QREC organisms in feed and water troughs and in environments that may come into contact with young calves. Thus, the results suggest that QREC circulates between cattle and the farm environment and that calves are important for the maintenance of QREC. Some genotypes of QREC were widespread both within and between farms, indicating that QREC has spread within the farms and likely also between farms, possibly through purchased animals. Farms that had purchased many animals over the years had greater within-farm diversity than farms with more closed animal populations. Finally, animals on more closely located farms were more likely to share the same genotype than animals on farms located far apart.

IMPORTANCE
This study investigates the occurrence of a specific type of antimicrobial-resistant bacterium on dairy farms. It contributes to increased knowledge about the occurrence and spread of these bacteria, and the results pave the way for actions or further studies that could help mitigate the spread of these bacteria on dairy farms and in the community as a whole.
Functional Analysis of the Role of Toxoplasma gondii Nucleoside Triphosphate Hydrolases I and II in Acute Mouse Virulence and Immune Suppression
Authors: Olias Philipp , Sibley L. David
Published: April 2016

Bioluminescent reporter assays have been widely used to study the effect of
Toxoplasma gondii
on host gene expression. In the present study, we extend these studies by engineering novel reporter cell lines containing a gamma-activated sequence (GAS) element driving firefly luciferase (FLUC). In RAW264.7 macrophages,
T. gondii
type I strain (GT1) infection blocked interferon gamma (IFN-γ)-induced FLUC activity to a significantly greater extent than infection by type II (ME49) and type III (CTG) strains. Quantitative trait locus (QTL) analysis of progeny from a prior genetic cross identified a genomic region on chromosome XII that correlated with the observed strain-dependent phenotype. This QTL region contains two isoforms of the
T. gondii
enzyme nucleoside triphosphate hydrolase (NTPase) that were the prime candidates for mediating the observed strain-specific effect. Using reverse genetic analysis we show that deletion of NTPase I from a type I strain (RH) background restored the higher luciferase levels seen in the type II (ME49) strain. Rather than an effect on IFN-γ-dependent transcription, our data suggest that NTPase I was responsible for the strain-dependent difference in FLUC activity due to hydrolysis of ATP. We further show that NTPases I and II were not essential for tachyzoite growth
in vitro
or virulence in mice. Our study reveals that although
T. gondii
NTPases are not essential for immune evasion, they can affect ATP-dependent reporters. Importantly, this limitation was overcome using an ATP-independent
Gaussia
luciferase, which provides a more appropriate reporter for use with
T. gondii
infection studies.
The diagnosis and treatment of adrenal insufficiency during childhood and adolescence
Authors: Park Julie , Didi Mohammed , Blair Joanne
Published: April 2016

The diagnosis and treatment of adrenal insufficiency in childhood and adolescence poses a number of challenges. Clinical features of chronic adrenal insufficiency are vague and non-specific, and mimic many other causes of chronic ill health. A range of diagnostic tests are available for the assessment of adrenal function, all of which have advantages and disadvantages. Cortisol responses to these tests may vary with age and between genders. Knowledge of normal cortisol levels during health and ill health in childhood is also limited, and the cortisol replacement therapies available in clinical practice enable only crude mimicry of physiological patterns of cortisol secretion. An awareness of the limitations of diagnostic tests and treatments is important, and critical clinical assessment, integrating clinical and biochemical data, is essential for the diagnosis and treatment of children with suspected adrenal insufficiency. The aim of this review is to draw on data from clinical studies to inform a pragmatic approach to the child presenting with symptoms of chronic adrenal insufficiency. Clinical features of primary and secondary adrenal insufficiency, and syndromes associated with these diagnoses are described. Factors to consider when selecting a diagnostic test of adrenal function and interpretation of test results are considered. Finally, the limitations of cortisol replacement therapy are also discussed.
The prevalence of congenital heart defects in infants with cholestatic disorders of infancy: a single-centre study
Authors: Fattouh Aya M , Mogahed Engy A , Abdel Hamid Nehal , Sobhy Rodina , Saber Noha , El-Karaksy Hanaa
Published: April 2016

Background

There is deficiency of data about congenital heart defects (CHDs) in cholestatic disorders of infancy other than Alagille syndrome (AGS). We aimed to define the prevalence and types of CHDs in infants with various causes of cholestatic disorders of infancy.

Methods

This cross-sectional study was conducted on 139 infants presenting with cholestasis whether surgical or non-surgical. The study was carried out at the Pediatric Hepatology Unit, Cairo University Children's Hospital, Egypt. Full examination and investigations were done in an attempt to reach an aetiologic diagnosis for cholestasis, in addition to a comprehensive echocardiographic study.

Results

The age at the onset of cholestasis ranged from 1 day to 7 months. Males constituted 61.2%. Biliary atresia (BA) was diagnosed in 39 patients (28%), AGS in 16 patients (11.5%), 27 patients had miscellaneous diagnoses and 57 cases had indeterminate aetiology. CHDs were detected in 55 patients (39.5%). Shunt lesions were detected in 24 patients (43.6%), pulmonary stenosis in 18 patients (32.7%) and combined lesions in 9 patients (16.4%). Three patients (5.5%) had abnormal cardiac situs. Only seven patients had clinical presentation suggestive of CHD. CHDs were detected in 14 patients with BA (35.9%), 15 patients with AGS (93.7%) and 26 patients in the remaining group (30.9%).

Conclusion

CHDs are not uncommon among cholestatic infants and are mostly asymptomatic. Echocardiographic examination of cholestatic infants is recommended particularly for patients with BA before undergoing hepatic portoenterostomy as presence of CHD may impact the anaesthetic planning and affect the outcome of hepatobiliary surgery.
MRI findings and return to play in football: a prospective analysis of 255 hamstring injuries in the UEFA Elite Club Injury Study
Authors: Ekstrand Jan , Lee Justin C , Healy Jeremiah C
Published: April 2016

Aim

The present study evaluated whether the MRI parameters of hamstring injuries in male professional football players correlate with time to return to play (RTP).

Methods

46 elite European football teams were followed prospectively for hamstring injuries between 2007 and 2014. Club medical staff recorded individual player exposure and time-loss after hamstring injury. MRI parameters were evaluated by two independent radiologists and correlated with the RTP data.

Results

A total of 255 grade 1 and 2 injuries were evaluated in this study. RTP was longer for grade 2 than grade 1 injuries (24±13, 95% CI 21 to 26 days vs 18±15, 95% CI 16 to 20 days; mean difference: 6, 95% CI 2 to 9 days, p=0.004, d=0.39). 84% of injuries affected the biceps femoris (BF) muscle, whereas 12% and 4% affected the semimembranosus (SM) and semitendinosus (ST), respectively. No difference in lay-off time was found for injuries to the three different muscles (BF 20±15 days, SM 18±11 days, ST 23±14 days; p=0.83). The recurrence rate was higher for BF injuries than for SM and ST injuries combined (18% vs 2%, p=0.009). The size of the oedema weakly correlated with time to RTP (r2=6–12%). No correlation was found between location of injury and time to RTP. The majority of the intramuscular injuries affected the MT junction (56% in grade 1 and 2 injuries), but no difference in lay-off time was found between the different types of injuries.

Conclusions

The radiological grade and size of the oedema correlate with time to RTP for both, grade 1 and 2 injuries. No correlations were found between time to RTP and the location and type of injury.
How does venture capital operate in medical innovation?
Authors: Lehoux P , Miller F A , Daudelin G
Published: April 2016

While health policy scholars wish to encourage the creation of technologies that bring more value to healthcare, they may not fully understand the mandate of venture capitalists and how they operate. This paper aims to clarify how venture capital operates and to illustrate its influence over the kinds of technologies that make their way into healthcare systems. The paper draws on the international innovation policy scholarship and the lessons our research team learned throughout a 5-year fieldwork conducted in Quebec (Canada). Current policies support the development of technologies that capital investors identify as valuable, and which may not align with important health needs. The level of congruence between a given health technology-based venture and the mandate of venture capital is highly variable, explaining why some types of innovation may never come into existence. While venture capitalists’ mandate and worldview are extraneous to healthcare, they shape health technologies in several, tangible ways. Clinical leaders and health policy scholars could play a more active role in innovation policy. Because certain types of technology are more likely than others to help tackle the intractable problems of healthcare systems, public policies should be equipped to promote those that address the needs of a growing elderly population, support patients who are afflicted by chronic diseases and reduce health disparities.
Does current provision of undergraduate education prepare UK medical students in ENT? A systematic literature review
Authors: Ferguson Gary R , Bacila Irina A , Swamy Meenakshi
Published: April 2016

Objective

To systematically identify and analyse all published literature relating to the provision of undergraduate education for preparedness in ear, nose and throat (ENT) surgery, as perceived by medical students and clinicians in the UK.

Design

Systematic literature review.

Data sources

5 major databases were searched: MEDLINE, EMBASE, ERIC, Cochrane and Web of Science. The literature search was conducted from February to April 2015.

Eligibility criteria for selecting studies

Primary research or studies that report on the provision of undergraduate education for preparedness in ENT, from the perspective of medical students and clinicians in the UK. The timescale of searches was limited from 1999 onwards (ie, the past 15 years).

Data extraction

The literature search was conducted by 2 independent reviewers. Search terms used involved the combination and variation of 5 key concepts, namely: medical student, clinician, ENT, undergraduate medical education and UK. A data extraction form was designed for and used in this study, based on guidelines provided by the UK National Health Service (NHS) Centre for Reviews and Dissemination. Textual narrative synthesis was used for data analysis.

Results

A total of 7 studies were included in the final review. 4 main themes were identified: confidence in managing patients, teaching delivery, student assessment and duration of rotations. A consistent finding in this review was that the majority of final year medical students and junior doctors did not feel adequately prepared to practise ENT. Important factors influencing preparedness in ENT included the duration of clinical rotations, the opportunity for hands-on learning and formal assessment.

Conclusions

The findings of this review suggest the need for further development of the ENT undergraduate curricula across the UK. However, there is insufficient evidence from which to draw strong conclusions; this in itself is beneficial as it highlights a gap in the existing literature and supports the need for primary research.
Proposals for enhanced health risk assessment and stratification in an integrated care scenario
Authors: Dueñas-Espín Ivan , Vela Emili , Pauws Steffen , Bescos Cristina , Cano Isaac , Cleries Montserrat , Contel Joan Carles , de Manuel Keenoy Esteban , Garcia-Aymerich Judith , Gomez-Cabrero David , Kaye Rachelle , Lahr Maarten M H , Lluch-Ariet Magí , Moharra Montserrat , Monterde David , Mora Joana , Nalin Marco , Pavlickova Andrea , Piera Jordi , Ponce Sara , Santaeugenia Sebastià , Schonenberg Helen , Störk Stefan , Tegner Jesper , Velickovski Filip , Westerteicher Christoph , Roca Josep
Published: April 2016

Objectives

Population-based health risk assessment and stratification are considered highly relevant for large-scale implementation of integrated care by facilitating services design and case identification. The principal objective of the study was to analyse five health-risk assessment strategies and health indicators used in the five regions participating in the Advancing Care Coordination and Telehealth Deployment (ACT) programme (http://www.act-programme.eu). The second purpose was to elaborate on strategies toward enhanced health risk predictive modelling in the clinical scenario.

Settings

The five ACT regions: Scotland (UK), Basque Country (ES), Catalonia (ES), Lombardy (I) and Groningen (NL).

Participants

Responsible teams for regional data management in the five ACT regions.

Primary and secondary outcome measures

We characterised and compared risk assessment strategies among ACT regions by analysing operational health risk predictive modelling tools for population-based stratification, as well as available health indicators at regional level. The analysis of the risk assessment tool deployed in Catalonia in 2015 (GMAs, Adjusted Morbidity Groups) was used as a basis to propose how population-based analytics could contribute to clinical risk prediction.

Results

There was consensus on the need for a population health approach to generate health risk predictive modelling. However, this strategy was fully in place only in two ACT regions: Basque Country and Catalonia. We found marked differences among regions in health risk predictive modelling tools and health indicators, and identified key factors constraining their comparability. The research proposes means to overcome current limitations and the use of population-based health risk prediction for enhanced clinical risk assessment.

Conclusions

The results indicate the need for further efforts to improve both comparability and flexibility of current population-based health risk predictive modelling approaches. Applicability and impact of the proposals for enhanced clinical risk assessment require prospective evaluation.
Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study
Authors: Haslett Kate , Franks Kevin , Hanna Gerard G , Harden Susan , Hatton Matthew , Harrow Stephen , McDonald Fiona , Ashcroft Linda , Falk Sally , Groom Nicki , Harris Catherine , McCloskey Paula , Whitehurst Philip , Bayman Neil , Faivre-Finn Corinne
Published: April 2016

Introduction

The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of ‘isotoxic’ radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable.

Methods and analysis

Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years.

Ethics and dissemination

The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West—Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally.

Trial registration number

NCT01836692; Pre-results.
Effectiveness of multidisciplinary team case management: difference-in-differences analysis
Authors: Stokes Jonathan , Kristensen Søren Rud , Checkland Kath , Bower Peter
Published: April 2016

Objectives

To evaluate a multidisciplinary team (MDT) case management intervention, at the individual (direct effects of intervention) and practice levels (potential spillover effects).

Design

Difference-in-differences design with multiple intervention start dates, analysing hospital admissions data. In secondary analyses, we stratified individual-level results by risk score.

Setting

Single clinical commissioning group (CCG) in the UK's National Health Service (NHS).

Participants

At the individual level, we matched 2049 intervention patients using propensity scoring one-to-one with control patients. At the practice level, 30 practices were compared using a natural experiment through staged implementation.

Intervention

Practice Integrated Care Teams (PICTs), using MDT case management of high-risk patients together with a summary record of care versus usual care.

Direct and indirect outcome measures

Primary measures of intervention effects were accident and emergency (A&E) visits; inpatient non-elective stays, 30-day re-admissions; inpatient elective stays; outpatient visits; and admissions for ambulatory care sensitive conditions. Secondary measures included inpatient length of stay; total cost of secondary care services; and patient satisfaction (at the practice level only).

Results

At the individual level, we found slight, clinically trivial increases in inpatient non-elective admissions (+0.01 admissions per patient per month; 95% CI 0.00 to 0.01. Effect size (ES): 0.02) and 30-day re-admissions (+0.00; 0.00 to 0.01. ES: 0.03). We found no indication that highest risk patients benefitted more from the intervention. At the practice level, we found a small decrease in inpatient non-elective admissions (−0.63 admissions per 1000 patients per month; −1.17 to −0.09. ES: −0.24). However, this result did not withstand a robustness check; the estimate may have absorbed some differences in underlying practice trends.

Conclusions

The intervention does not meet its primary aim, and the clinical significance and cost-effectiveness of these small practice-level effects is debatable. There is an ongoing need to develop effective ways to reduce unnecessary attendances in secondary care for the high-risk population.
Assessment of the quantity of microorganisms associated with bronchiectasis in saliva, sputum and nasal lavage after periodontal treatment: a study protocol of a randomised controlled trial
Authors: Pinto Erika Horácio , Longo Priscila Larcher , Camargo Caroline Cristina Batista de , Dal Corso Simone , Lanza Fernanda De Cordoba , Stelmach Rafael , Athanazio Rodrigo , Fernandes Kristianne Porta Santos , Mayer Marcia Pinto Alves , Bussadori Sandra Kalil , Mesquita Ferrari Raquel Agnelli , Horliana Anna Carolina Ratto Tempestini
Published: April 2016

Introduction

The association between periodontal disease (PD) and chronic obstructive pulmonary disease (COPD) has been widely studied, with aspiration of periodontal pathogens being one of the most accepted causal mechanisms for pulmonary exacerbation. Periodontal treatment (PT) was associated with a decrease in these exacerbations. Bronchiectasis is a pulmonary disease that has many similarities to COPD; however, there are no studies correlating this condition to PD thus far. This study will evaluate if PT reduces proinflammatory cytokines in serum and saliva, as well as halitosis and the amount of microorganisms associated with exacerbation of bronchiectasis in saliva, sputum and nasal lavage 3 months after PT.

Methods and analysis

A total of 182 patients with PD and bronchiectasis will be randomly allocated to group 1 (positive control; scaling and root planing (SRP)+oral hygiene (OH)) or group 2 (experimental; SRP+photodynamic therapy+OH). After 3 months, samples of saliva, nasal lavage and sputum will be collected to determine the level ofPseudomonas aeruginosa,Staphylococcus aureusandPorphyromonas gingivalisby quantitative PCR. This protocol will determine the efficacy of PT in reducing the most likely niches of bronchiectasis exacerbation by comparing pre- and post-treatment microbiology samples. Furthermore, there will be assessment of oral halitosis and verification of inflammatory cytokines in serum and saliva.

Ethics and dissemination

This protocol has been approved by the Research Ethics Committee of Universidade Nove de Julho. Data will be published in a peer-reviewed journal.

Trial registration number

NCT02514226.
Pharmaceutical treatments to prevent recurrence of endometriosis following surgery: a model-based economic evaluation
Authors: Sanghera Sabina , Barton Pelham , Bhattacharya Siladitya , Horne Andrew W , Roberts Tracy Elizabeth
Published: April 2016

Objective

Conduct an economic evaluation based on best currently available evidence comparing alternative treatments levonorgestrel-releasing intrauterine system, depot-medroxyprogesterone acetate, combined oral contraceptive pill (COCP) and ‘no treatment’ to prevent recurrence of endometriosis after conservative surgery in primary care, and to inform the design of a planned trial-based economic evaluation.

Methods

We developed a state transition (Markov) model with a 36-month follow-up. The model structure was informed by a pragmatic review and clinical experts. The economic evaluation adopted a UK National Health Service perspective and was based on an outcome of incremental cost per quality-adjusted life year (QALY). As available data were limited, intentionally wide distributions were assigned around model inputs, and the average costs and outcome of the probabilistic sensitivity analyses were reported.

Results

On average, all strategies were more expensive and generated fewer QALYs compared to no treatment. However, uncertainty attributing to the transition probabilities affected the results. Inputs relating to effectiveness, changes in treatment and the time at which the change is made were the main causes of uncertainty, illustrating areas where robust and specific data collection is required.

Conclusions

There is currently no evidence to support any treatment being recommended to prevent the recurrence of endometriosis following conservative surgery. The study highlights the importance of developing decision models at the outset of a trial to identify data requirements to conduct a robust post-trial analysis.
Pain mechanisms and ultrasonic inflammatory activity as prognostic factors in patients with psoriatic arthritis: protocol for a prospective, exploratory cohort study
Authors: Højgaard Pil , Christensen Robin , Dreyer Lene , Mease Philip , Wit Maarten de , Skov Lone , Glintborg Bente , Christensen Anton Wulf , Ballegaard Christine , Bliddal Henning , Bukhave Kristine , Bartels Else Marie , Amris Kirstine , Ellegaard Karen , Kristensen Lars Erik
Published: April 2016

Introduction

Persistent pain is a major concern for patients with psoriatic arthritis (PsA). Pain may be due to inflammatory activity or augmented central pain processing. Unawareness of the origin and mechanisms of pain can lead to misinterpretation of disease activity (by composite scores) and erroneous treatments. Ultrasonography (US) is a highly sensitive method to detect tissue inflammation. Evaluating pain mechanisms in relation to US measures may prove valuable in predicting response to treatment in PsA.

Aims

To study the association and prognostic value of pain mechanisms, ultrasonic activity and clinical outcomes in patients with PsA who intensify antirheumatic treatment.

Methods and analyses

100 participants >18 years of age with PsA who initiate or switch antirheumatic treatment (biologicals and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs)) will be prospectively recruited from outpatient clinics in Copenhagen. All data (demographics, clinical, imaging, blood samples and patient-reported outcomes) will be collected at baseline and after 4 months. Pain is assessed by the PainDETECT Questionnaire, Visual Analogue Scale for pain, Swollen to Tender Joint Count Ratio, Widespread Pain Index and tender point examination. The association between pain variables and clinical/US characteristics will be described by correlation analyses. The predictive value of pain measures and baseline US scores on treatment response will be analysed with regression models. Outcomes are composite and clinical, as well as patient reported.

Ethics and dissemination

The study is approved by the ethics committee of the Capital Region of Denmark (H-15009080) and has been designed in cooperation with patient research partners. The study is registered at clinicaltrials.gov (numberNCT02572700). Results will be disseminated through publication in international peer-reviewed journals.

Trial registration number

NCT02572700, Pre-results.
Effectiveness of a nurse educational oral feeding programme on feeding outcomes in neonates: protocol for an interrupted time series design
Authors: Touzet Sandrine , Beissel Anne , Denis Angélique , Pillet Fabienne , Gauthier-Moulinier Hélène , Hommey Sophie , Claris Olivier
Published: April 2016

Introduction

Oral feeding is a complex physiological process. Several scales have been developed to assess the ability of the neonate to begin suck feedings and assist caregivers in determining feeding advancement. However, feeding premature neonates remains an ongoing challenge and depends above all on caregivers' feeding expertise. We will evaluate the effect of a nurse training programme on the achievement of full oral feeding with premature neonates.

Methods and analysis

The study design will be an interrupted time series design with 3 phases: (1) A 6-month baseline period; (2) a 22-month intervention period and (3) a 6-month postintervention period. The intervention will consist of an educational programme, for nurses and assistant nurses, on feeding patterns in neonates. The training modules will be composed of a 2-day conference, 2 interactive multidisciplinary workshops, and routine practice nurse coaching. A total of 120 nurses and 12 assistant nurses, who work at the neonatal unit during the study period, will participate in the study. All premature neonates of <34 weeks postmenstrual age (PMA) will be included. The primary outcome will be the age of tube withdrawal PMA and chronological age are taken into account. The secondary outcomes will be the transition time, length of hospital stay, competent suckle feeding without cardiorespiratory compromise, rate of neonates presenting with feeding issues or feeding rejection signs, and current neonatal pathologies or deaths during hospital stay. A segmented regression analysis will be performed to assess the impact of the programme.

Ethics and dissemination

Approval for the study was obtained from the Hospital Ethics Committee, and the Institutional Review Board, as well as the French Data Protection Agency. The findings from the study will be disseminated through peer-reviewed journals, national and international conference presentations and public events.

Trial registration number

NCT02404272 (https://clinicaltrials.gov).
Safety of Tdap vaccine in pregnant women: an observational study
Authors: Petousis-Harris Helen , Walls Tony , Watson Donna , Paynter Janine , Graham Patricia , Turner Nikki
Published: April 2016

Objectives

Actively recruit and intensively follow pregnant women receiving a dose of acellular pertussis vaccine for 4 weeks after vaccination.

Design and settings

A prospective observational study conducted in 2 New Zealand regions.

Participants

Women in their 28th–38th week of pregnancy, recruited from primary care and antenatal clinics at the time of Tdap administration. Telephone interviews were conducted at 48 h and 4 weeks postvaccination.

Main outcomes measures

Outcomes were injection site reactions, systemic symptoms and serious adverse events (SAEs). Where available, data have been classified and reported according to Brighton Collaboration definitions.

Results

793 women participated with 27.9% receiving trivalent inactivated influenza vaccine concomitantly. 79% of participants reported mild or moderate pain and 2.6% severe pain. Any swelling was reported by 7.6%, induration by 12.0% (collected from 1 site only, n=326), and erythema by 5.8% of participants. Fever was reported by 17 (2.1%) participants, 14 of these occurred within 24 h. Headache, dizziness, nausea, myalgia or arthralgia was reported by <4% of participants, respectively, and fatigue by 8.4%. During the study period, there were 115 adverse events in 113 participants, most of which were minor. At the end of the reporting period, 31 events were classified as serious (eg, obstetric bleeding, hypertension, infection, tachycardia, preterm labour, exacerbation of pre-existing condition and pre-eclampsia). All had variable onset time from vaccination. There were two perinatal deaths. Clinician assessment of all SAEs found none likely to be vaccine related.

Conclusions

Vaccination with Tdap in pregnant women was well tolerated with no SAE likely to be caused by the vaccine.

Trial registration number

ACTRN12613001045707.
A cross-sectional study on risk factors and their interactions with suicidal ideation among the elderly in rural communities of Hunan, China
Authors: Xu Huilan , Qin Lulu , Wang Jinhong , Zhou Liang , Luo Dan , Hu Mi , Li Zhenhua , Xiao Shuiyuan
Published: April 2016

Objectives

To identify risk factors, and their interactions, for suicidal ideation among the elderly in rural communities of Hunan and to provide some scientific basis for suicide prevention.

Design, setting and participants

A cross-sectional survey was conducted among the elderly in rural communities in China's Hunan Province. Thirteen areas were selected by multi-staged cluster random sampling, and 1887 rural elders were investigated via face-to-face interviews.

Main outcome measures

Measures included sociodemographic information, suicidal ideation, activities of daily living (ADL), major depression disorder (MDD), drinking, stressful life events and social support. Non-conditional logistic regression was preformed to explore the influencing factors for suicidal ideation, and additive interaction was used to analyse the interaction between risk factors.

Results

Incidence of suicidal ideation among the elderly was 14.5% (95% CI 12.9% to 16.1%) in rural communities of Hunan. The independent influencing factors for suicidal ideation were annual personal income (OR 3.14; 95% CI 2.15 to 4.59), MDD (OR 17.04; 95% CI 11.91 to 24.39), chronic diseases (OR 2.99; 95% CI 1.84 to 4.85) and ADL (OR 2.00; 95% CI 1.37 to 2.94). Additive interactions were detected between MDD and ADL with a relative excess risk of interaction (RERI) of 21.18 (95% CI 5.47 to 36.89), and between MDD and annual personal income with an RERI of 35.00 (95% CI 9.00 to 61.00).

Conclusions

The independent risk factors for suicidal ideation are annual personal income (≤2200 CNY), MDD, chronic diseases and disabled ADL status. MDD has additive interactions with ADL and annual personal income. These findings have significant implications for the prediction and prevention of suicidal behaviours.
Patient participation in free cataract surgery: a cross-sectional study of the low-income elderly in urban China
Authors: Lin Haotian , Lin Duoru , Long Erping , Jiang Haofeng , Qu Bo , Tang Jinzhu , Lin Yingfen , Chen Jingjing , Wu Xiaohang , Lin Zhuoling , Li Xiaoyan , Liu Zhenzhen , Zhang Bo , Chen Hui , Tan Xuhua , Luo Lixia , Liu Yizhi , Chen Weirong
Published: April 2016

Objectives

To explore the characteristics of the low-income elderly who underwent free cataract surgery and to determine the degree of patient satisfaction with the free cataract surgery programme in urban China.

Methods

A free cataract surgery management workflow was designed as a poverty relief project in Guangzhou. In this study, participants who underwent free cataract surgery between January and August 2014 received a telephone interview based on a structured questionnaire. Data were collected on patient demographics, resources, health conditions, reasons for undergoing the free surgery and overall evaluation of the free cataract surgery programme.

Results

Among the 833 participants, the mean surgical age was 76.85±7.46 years (95% CI 76.34 to 77.36), and the male to female ratio was 385:448. The majority (94.31%, 746/791) of patients resided in the main urban districts. Patients underwent surgery 61.08±60.15 months (95% CI 56.17 to 66.00) after becoming aware of the cataract, although 66.83% of them reported that their daily lives were influenced by cataracts. Only 21.5% of the respondents underwent physical examinations that included regular eye screening, and only 6.30% were highly educated patients. Financial problems were the primary reason cited by patients for participating in the free surgery programme. Those patients with a monthly family income of 1000–2999¥ (US$161–482) per capita constituted the largest patient population. The free clinics in the parks and the free cataract surgery were highly rated (9.46 and 9.11 of 10 points) by the beneficiaries.

Conclusions

The telephone survey revealed a high level of patient satisfaction regarding the free cataract surgery programme. Most of the patients who participated in the programme resided in major urban districts and had poor health awareness and a low level of education. The information provided by this study is crucial for improving and expanding the management of free cataract surgery programmes.

Trial registration number

NCT02633865; Post-results.
Safety and efficacy of the predictive low glucose management system in the prevention of hypoglycaemia: protocol for randomised controlled home trial to evaluate the Suspend before low function
Authors: Abraham M B , Nicholas J A , Ly T T , Roby H C , Paramalingam N , Fairchild J , King B R , Ambler G R , Cameron F , Davis E A , Jones T W
Published: April 2016

Introduction

Innovations with sensor-augmented pump therapy (SAPT) to reduce hypoglycaemia in patients with type 1 diabetes are an ongoing area of research. The predictive low glucose management (PLGM) system incorporates continuous glucose sensor data into an algorithm and suspends basal insulin before the occurrence of hypoglycaemia. The system was evaluated in in-clinic studies, and has informed the parameters of a larger home trial to study its efficacy and safety in real life.

Methods and analysis

The aim of this report is to describe the study design and outcome measures for the trial. This is a 6-month, multicentre, randomised controlled home trial to test the PLGM system in children and adolescents with type 1 diabetes. The system is available in the Medtronic MiniMed 640G pump as the ‘Suspend before low’ feature. Following a run-in period, participants are randomised to either the control arm with SAPT alone or the intervention arm with SAPT and Suspend before low. The primary aim of this study is to evaluate the time spent hypoglycaemic (sensor glucose <3.5 mmol/L) with and without the system. The secondary aims are to determine the number of hypoglycaemic events, the time spent hyperglycaemic, and to evaluate safety with ketosis and changes in glycated haemoglobin. The study also aims to assess the changes in counter-regulatory hormone responses to hypoglycaemia evaluated by a hyperinsulinaemic hypoglycaemic clamp in a subgroup of patients with impaired awareness. Validated questionnaires are used to measure the fear of hypoglycaemia and the impact on the quality of life to assess burden of the disease.

Ethics and dissemination

Ethics committee permissions were gained from respective Institutional Review boards. The findings of the study will provide high quality evidence of the ability of the system in the prevention of hypoglycaemia in real life.

Trial registration number

ACTRN12614000510640, Pre-results.