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1.  Radiologists’ perspectives about evidence-based medicine and their clinical practice: a semistructured interview study 
BMJ Open  2014;4(12):e006199.
To describe radiologist's attitudes and perspectives on evidence-based medicine (EBM) and their practice.
Face-to-face semistructured interviews, thematic analysis.
24 institutions across six Australian states and New Zealand. Transcripts were imported into HyperRESEARCH software and thematically analysed.
25 radiologists.
Six themes were identified: legitimising decisions (validated justification, prioritising patient preferences, reinforcing protocols), optimising outcomes (ensuring patient safety, maximising efficiency), availability of access (requiring immediacy, inadequacy of evidence, time constraints, proximity of peer networks, grasping information dispersion), over-riding pragmatism (perceptibly applicability, preserving the art of medicine, technical demands), limited confidence (conceptual obscurity, reputation-based trust, demands constant practice, suspicion and cynicism), and competing powers (hierarchical conflict, prevailing commercial interests).
Radiologists believe EBM can support clinical decision-making for optimal patient outcomes and service efficiency but feel limited in their capacities to assimilate and apply EBM in practice. Improving access to evidence, providing ongoing education and training supplemented with practical tools for appraising evidence; and developing evidence-based guidelines and protocols may enhance feasibility and promote the confidence and skills among radiologists in applying EBM in radiology practice for better patient care.
PMCID: PMC4265099  PMID: 25500161
2.  Protocol for REducing Anti-Psychotic use in residential care-Huntington Disease (REAP-HD): a pilot cluster randomised controlled trial of a multifaceted intervention for health professionals 
BMJ Open  2014;4(12):e006151.
Antipsychotics are commonly used for management of behavioural symptoms in dementia, among people in residential care. This continues to occur despite their modest effectiveness, potential harms including increased risk of death and stroke, and absence of detrimental effect when people with dementia were randomised to antipsychotic withdrawal. This study aims to test the hypothesis that the multifaceted REducing Anti-Psychotic use in residential care-Huntington Disease (REAP-HD) programme is more effective than standard staff education (SSE) in reducing antipsychotic use for people with HD in residential care facilities (RCF).
Methods and analysis
this is a cluster randomised controlled trial with blinded outcome assessment. The study population is healthcare professionals looking after people with HD in individual RCF, in the state of New South Wales. Each RCF will be centrally randomised to the REAP-HD programme or the comparator, SSE. Blinded outcome assessment will be performed by examining drug charts and using the Neuropsychiatric Inventory-Q (NPI-Q). Primary outcome is the proportion of people with HD who have had a reduction in antipsychotic use 4 months after the intervention. Secondary outcome measures are (1) change in severity of behavioural symptoms, as measured by the NPI-Q at 4 months (to ensure antipsychotic reduction has not lead to worsening behavioural symptoms), and (2) proportion of people with HD who have had a reduction in antipsychotic dosage at 4 months for each strategy, compared to 4 months prior to enrolment (to capture the possibility that both arms reduced antipsychotic use). Analysis will be by Intention-To-Treat and take into account the clustering. Recruitment is ongoing, as of July 2014.
Ethics and dissemination
This protocol has been approved by the Western Sydney Local Health District Human Research Ethics Committee, trial registration ACTRN12614000083695. Study results will be disseminated through peer-reviewed publication in an anonymous manner.
Trial registration number
ACTRN12614000083695, the Australian New Zealand Clinical Trials Registry.
PMCID: PMC4256606  PMID: 25468506
3.  Genes related to emphysema are enriched for ubiquitination pathways 
BMC Pulmonary Medicine  2014;14(1):187.
Increased small airway resistance and decreased lung elasticity contribute to the airflow limitation in chronic obstructive pulmonary disease (COPD). The lesion that corresponds to loss of lung elasticity is emphysema; the small airway obstruction is due to inflammatory narrowing and obliteration. Despite their convergence in altered physiology, different mechanisms contribute to these processes. The relationships between gene expression and these specific phenotypes may be more revealing than comparison with lung function.
We measured the ratio of alveolar surface area to lung volume (SA/V) in lung tissue from 43 smokers. Two samples from 21 subjects, in which SA/V differed by >49 cm2/mL were profiled to select genes whose expression correlated with SA/V. Significant genes were tested for replication in the 22 remaining subjects.
The level of expression of 181 transcripts was related to SA/V ( p < 0.05). When these genes were tested in the 22 remaining subjects as a replication, thirty of the 181 genes remained significantly associated with SA/V (P < 0.05) and the direction of association was the same in 164/181. Pathway and network analysis revealed enrichment of genes involved in protein ubiquitination, and western blotting showed altered expression of genes involved in protein ubiquitination in obstructed individuals.
This study implicates modified protein ubiquitination and degradation as a potentially important pathway in the pathogenesis of emphysema.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-187) contains supplementary material, which is available to authorized users.
PMCID: PMC4280711  PMID: 25432663
Pulmonary emphysema; Surface area to lung volume ratio; Gene expression; Transcriptional analysis; mRNA; Cigarette smoking; Protein ubquitination
5.  QTLs associated with dry matter intake, metabolic mid-test weight, growth and feed efficiency have little overlap across 4 beef cattle studies 
BMC Genomics  2014;15(1):1004.
The identification of genetic markers associated with complex traits that are expensive to record such as feed intake or feed efficiency would allow these traits to be included in selection programs. To identify large-effect QTL, we performed a series of genome-wide association studies and functional analyses using 50 K and 770 K SNP genotypes scored in 5,133 animals from 4 independent beef cattle populations (Cycle VII, Angus, Hereford and Simmental × Angus) with phenotypes for average daily gain, dry matter intake, metabolic mid-test body weight and residual feed intake.
A total of 5, 6, 11 and 10 significant QTL (defined as 1-Mb genome windows with Bonferroni-corrected P-value <0.05) were identified for average daily gain, dry matter intake, metabolic mid-test body weight and residual feed intake, respectively. The identified QTL were population-specific and had little overlap across the 4 populations. The pleiotropic or closely linked QTL on BTA 7 at 23 Mb identified in the Angus population harbours a promising candidate gene ACSL6 (acyl-CoA synthetase long-chain family member 6), and was the largest effect QTL associated with dry matter intake and mid-test body weight explaining 10.39% and 14.25% of the additive genetic variance, respectively. Pleiotropic or closely linked QTL associated with average daily gain and mid-test body weight were detected on BTA 6 at 38 Mb and BTA 7 at 93 Mb confirming previous reports. No QTL for residual feed intake explained more than 2.5% of the additive genetic variance in any population. Marker-based estimates of heritability ranged from 0.21 to 0.49 for residual feed intake across the 4 populations.
This GWAS study, which is the largest performed for feed efficiency and its component traits in beef cattle to date, identified several large-effect QTL that cumulatively explained a significant percentage of additive genetic variance within each population. Differences in the QTL identified among the different populations may be due to differences in power to detect QTL, environmental variation, or differences in the genetic architecture of trait variation among breeds. These results enhance our understanding of the biology of growth, feed intake and utilisation in beef cattle.
PMCID: PMC4253998  PMID: 25410110
GWAS; QTL; Genomic selection; Feed efficiency; Beef cattle
6.  The Many Facets of Unawareness in Huntington Disease 
Unawareness or diminished awareness is present when a patient's perception of obvious disease manifestations and impact differ from that of observers such as clinicians or family members.
We examined studies that specifically investigate unawareness in Huntington disease (HD).
Unawareness of motor, cognitive, behavioral, and functional aspects of HD has been documented throughout the disease course. This can occur at motor and cognitive onset but is more pronounced as the disease progresses.
We discuss the implications for diagnosis, symptom report at presentation, timing of diagnosis, acceptance of symptomatic care strategies, and reporting in clinical trials. Assessments of work place competency, discrimination, driving, and the particular challenges of isolated patients without caregivers are described. Engaging with a person who is unaware of their disease or its impact presents a number of conflicts, including maintaining the right to autonomy, privacy, confidentiality, and independence while recognizing concerns for the wellbeing of the vulnerable person with HD and their caregiver when the unaware person refuses assistance. Unawareness is seen increasingly as neurologically based due to the impairment of functional networks, predominantly in nondominant frontostriatal pathways.
PMCID: PMC4231168  PMID: 25411649
Huntington disease; awareness; agnosia; denial
7.  Improved characterization of medically relevant fungi in the human respiratory tract using next-generation sequencing 
Genome Biology  2014;15(10):487.
Fungi are important pathogens but challenging to enumerate using next-generation sequencing because of low absolute abundance in many samples and high levels of fungal DNA from contaminating sources.
Here, we analyze fungal lineages present in the human airway using an improved method for contamination filtering. We use DNA quantification data, which are routinely acquired during DNA library preparation, to annotate output sequence data, and improve the identification and filtering of contaminants. We compare fungal communities and bacterial communities from healthy subjects, HIV+ subjects, and lung transplant recipients, providing a gradient of increasing lung impairment for comparison. We use deep sequencing to characterize ribosomal rRNA gene segments from fungi and bacteria in DNA extracted from bronchiolar lavage samples and oropharyngeal wash. Comparison to clinical culture data documents improved detection after applying the filtering procedure.
We find increased representation of medically relevant organisms, including Candida, Cryptococcus, and Aspergillus, in subjects with increasingly severe pulmonary and immunologic deficits. We analyze covariation of fungal and bacterial taxa, and find that oropharyngeal communities rich in Candida are also rich in mitis group Streptococci, a community pattern associated with pathogenic polymicrobial biofilms. Thus, using this approach, it is possible to characterize fungal communities in the human respiratory tract more accurately and explore their interactions with bacterial communities in health and disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0487-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4232682  PMID: 25344286
8.  Antibodies reacting with JCPyV_VP2 _167-15mer as a novel serological marker for JC polyomavirus infection 
Virology Journal  2014;11(1):174.
JC polyomavirus (JCPyV) is a widespread human polyomavirus that usually resides latently in its host, but can be reactivated under immune-compromised conditions potentially causing Progressive Multifocal Leukoencephalopathy (PML). Detection of antibodies against the major capsid protein VP1 currently is the main marker for assessment of infection with JCPyV.
Based on a peptide microarray, peptide JCPyV_VP2_167-15mer was selected and a peptide ELISA was developed for detection of antibodies directed against this peptide. Epitope mapping and computational modelling was performed to further characterize this peptide. In a cohort of 204 healthy subjects it was investigated whether antibodies against JCPyV_VP2_167-15mer were correlated with VP1 serology or urinary viral load.
Epitope mapping of peptide JCPyV_VP2_167-15mer showed that the minimal epitope consisted of L173PALTSQEI181 with amino acids P174, L176 and E180 being essential for antibody recognition. Computational analysis was used to predict that this epitope is located at an exposed domain of the VP2 capsid protein, readily accessible for immune recognition upon infection. No correlation could be observed with JCPyV VP1 antibody levels, or urinary viral load.
This work indicates that specific antibodies against JCPyV_VP2_167-15mer might be considered as a novel serological marker for infection with JCPyV.
Electronic supplementary material
The online version of this article (doi:10.1186/1743-422X-11-174) contains supplementary material, which is available to authorized users.
PMCID: PMC4194363  PMID: 25273879
JC Polyomavirus; Biomarker; Peptide serology; VP2; Progressive Multifocal Leukoencephalopathy
9.  Unawareness of motor phenoconversion in Huntington disease 
Neurology  2013;81(13):1141-1147.
To determine whether Huntington disease (HD) mutation carriers have motor symptoms (complaints) when definite motor onset (motor phenoconversion) is diagnosed and document differences between the groups with and without unawareness of motor signs.
We analyzed data from 550 HD mutation carriers participating in the multicenter PREDICT-HD Study followed through the HD prodrome. Data analysis included demographics, the Unified Huntington’s Disease Rating Scale (UHDRS) and the Participant HD History of symptoms, self-report of progression, and cognitive, behavioral, and imaging measures. Unawareness was identified when no motor symptoms were self-reported but when definite motor HD was diagnosed.
Of 38 (6.91%) with onset of motor HD, almost half (18/38 = 47.36%) had no motor symptoms despite signs of disease on the UHDRS motor rating and consistent with unawareness. A group with motor symptoms and signs was similar on a range of measures to the unaware group. Those with unawareness of HD signs reported less depression. Patients with symptoms had more striatal atrophy on imaging measures.
Only half of the patients with newly diagnosed motor HD had motor symptoms. Unaware patients were less likely to be depressed. Self-report of symptoms may be inaccurate in HD at the earliest stage.
PMCID: PMC3795599  PMID: 23966256
10.  Viral miRNAs in plasma and urine divulge JC polyomavirus infection 
Virology Journal  2014;11(1):158.
JC polyomavirus (JCPyV) is a widespread human polyomavirus that usually resides latently in its host, but can be reactivated under immune-compromised conditions potentially causing Progressive Multifocal Leukoencephalopathy (PML). JCPyV encodes its own microRNA, jcv-miR-J1.
We have investigated in 50 healthy subjects whether jcv-miR-J1-5p (and its variant jcv-miR-J1a-5p) can be detected in plasma or urine.
We found that the overall detection rate of JCPyV miRNA was 74% (37/50) in plasma and 62% (31/50) in urine. Subjects were further categorized based on JCPyV VP1 serology status and viral shedding. In seronegative subjects, JCPyV miRNA was found in 86% (12/14) and 57% (8/14) of plasma and urine samples, respectively. In seropositive subjects, the detection rate was 69% (25/36) and 64% (23/36) for plasma and urine, respectively. Furthermore, in seropositive subjects shedding virus in urine, higher levels of urinary viral miRNAs were observed, compared to non-shedding seropositive subjects (P < 0.001). No correlation was observed between urinary and plasma miRNAs.
These data indicate that analysis of circulating viral miRNAs divulge the presence of latent JCPyV infection allowing further stratification of seropositive individuals. Also, our data indicate higher infection rates than would be expected from serology alone.
Electronic supplementary material
The online version of this article (doi:10.1186/1743-422X-11-158) contains supplementary material, which is available to authorized users.
PMCID: PMC4168162  PMID: 25178457
JC Polyomavirus; Viral microRNA; Circulating microRNA; Progressive Multifocal Leukoencephalopathy; Biomarker; Viral activity
11.  Translating Community-Based Participatory Research (CBPR) Principles into Practice: Building a Research Agenda to Reduce Intimate Partner Violence 
While academics are trained in research methods, few receive formal training in community engaged research approaches. They and their community partners can benefit from direction and assistance as they establish and maintain community-based participatory research (CBPR) partnerships.
This article provides an overview of CBPR workshops jointly held for academic and community members and explores suggestions from the workshop participants about how to put the CBPR principles into practice to promote community engaged research to reduce intimate partner violence (IPV).
Twenty-four academic and community partners participated in two workshops designed to increase capacity to conduct IPV-related CBPR. Facilitators led discussions based on the CPBR principles. Participants were asked to interpret those principles; identify actions that could help put the principles into practice; and discuss challenges related to CBPR approaches for IPV research. Notes and video transcripts of the discussions and workshop evaluations are summarized.
The CBPR principles were interpreted and revised into common language that reflected the group discussion of the principles. Participants suggested a range of actions for putting the principles into practice and identified the need for sensitivity in IPV research. A majority of participants felt that the workshop generated novel ideas about how they could use CPBR in their own work.
Translating CBPR principles into common, action-oriented language specific to the health issue such as IPV is a useful first step when building a new academic-community research partnership. This approach fostered open communication, clear expectations and commitment to moving forward collaboratively.
PMCID: PMC4138529  PMID: 23793242
12.  The Ca2+ Sensor Protein Swiprosin-1/EFhd2 Is Present in Neurites and Involved in Kinesin-Mediated Transport in Neurons 
PLoS ONE  2014;9(8):e103976.
Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca2+ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2−/−/lacZ reporter mice and showed that lacZ was strongly expressed in the cortex, the dentate gyrus, the CA1 and CA2 regions of the hippocampus, the thalamus, and the olfactory bulb. Immunohistochemistry and western blotting confirmed this pattern and revealed expression of EFhd2 during neuronal maturation. In cortical neurons, EFhd2 was detected in neurites marked by MAP2 and co-localized with pre- and post-synaptic markers. Approximately one third of EFhd2 associated with a biochemically isolated synaptosome preparation. There, EFhd2 was mostly confined to the cytosolic and plasma membrane fractions. Both synaptic endocytosis and exocytosis in primary hippocampal EFhd2−/− neurons were unaltered but transport of synaptophysin-GFP containing vesicles was enhanced in EFhd2−/− primary hippocampal neurons, and notably, EFhd2 inhibited kinesin mediated microtubule gliding. Therefore, we found that EFhd2 is a neuronal protein that interferes with kinesin-mediated transport.
PMCID: PMC4136728  PMID: 25133820
13.  Is a Motor Criterion Essential for the Diagnosis of Clinical Huntington Disease? 
PLoS Currents  2013;5:ecurrents.hd.f4c66bd51e8db11f55e1701af937a419.
While there has been a guideline for laboratory/genetic diagnosis of Huntington Disease (HD) since 1998, no such statement exists for the diagnosis of clinical HD. Informally, the most frequently used criteria for diagnosis of clinical HD is ‘Motor 4’ within the Unified Huntington Disease Rating Scale ’99 (motor), made when the rater is highly confident that ‘motor abnormalities observed are unequivocal signs of HD’. Recent studies involving pre-manifest individuals illustrated the shortcomings of this motor-only diagnostic approach. For instance, PREDICT-HD found cognitive changes decades before the expected date of motor diagnosis. Using a number of case studies, we highlight some of the subtleties involved in diagnosing clinical HD, in the absence of unequivocal motor signs for HD. New, broader, criteria for the diagnosis of clinical HD would be helpful in many ways. However its formulation will need to flexible rather than prescriptive, and will require extensive consultation with clinicians and families with HD.
PMCID: PMC3644296  PMID: 23653281
14.  Intestinal bacteria modify lymphoma incidence and latency by affecting systemic inflammatory state, oxidative stress, and leucocyte genotoxicity 
Cancer research  2013;73(14):4222-4232.
Ataxia-telangiectasia (A-T) is a genetic disorder associated with high incidence of B cell lymphoma. Using an A-T mouse model, we compared lymphoma incidence in several isogenic mouse colonies harboring different bacterial communities, finding that intestinal microbiota are a major contributor to disease penetrance and latency, lifespan, molecular oxidative stress and systemic leucocyte genotoxicity. High throughput sequence analysis of rRNA genes identified mucosa-associated bacterial phylotypes that were colony-specific. Lactobacillus johnsonii, which was deficient in the more cancer-prone mouse colony, was causally tested for its capacity to confer reduced genotoxicity when restored by short-term oral transfer. This intervention decreased systemic genotoxicity, a response associated with reduced basal leucocytes and the cytokine-mediated inflammatory state, and mechanistically linked to the host cell biology of systemic genotoxicity. Our results suggest that intestinal microbiota are a potentially modifiable trait for translational intervention in individuals at risk for B cell lymphoma, or for other diseases that are driven by genotoxicity or the molecular response to oxidative stress.
PMCID: PMC3718495  PMID: 23860718
Ataxia telangiectasia; genotoxicity; Lactobacillus johnsonii; lymphoma; oxidative stress
15.  Maternal Serum and Breast Milk Vitamin D Levels: Findings from the Universiti Sains Malaysia Pregnancy Cohort Study 
PLoS ONE  2014;9(7):e100705.
Vitamin D deficiency has become a global health issue in pregnant women. This study aimed to assess the adequacy of maternal vitamin D status by measuring maternal serum and breast milk 25-hydroxyvitamin D [25(OH)D] levels and to determine the association between maternal serum and milk 25(OH)D levels.
Data was obtained from the Universiti Sains Malaysia Pregnancy Cohort Study. This study was conducted from April 2010 to December 2012 in the state of Kelantan, Malaysia. Blood samples from pregnant women aged 19 to 40 years were drawn in the second and third trimesters of pregnancy, while breast milk samples at delivery, 2, 6 and 12 months postpartum were collected to analyze for 25(OH)D levels. A total of 102 pregnant women were included in the analysis.
Vitamin D deficiency [25(OH)D <50 nmol/L] was detected in 60% and 37% of women in the second and third trimesters of pregnancy, respectively. There were 6% and 23% of women who reached normal level of vitamin D status in the second trimester and the third trimester, respectively. Multivitamin intakes during pregnancy were significantly associated with higher serum 25(OH)D levels in the second trimester (β = 9.16, p = 0.005) and the third trimester (β = 13.65, p = 0.003). 25(OH)D levels in breast milk during the first year of lactation ranged from 1.01 to 1.26 nmol/L. Higher maternal serum 25(OH)D level in the second trimester of pregnancy was associated with an elevated level of 25(OH)D in breast milk at delivery (β = 0.002, p = 0.026).
This study shows that high proportions of Malay pregnant women are at risk of vitamin D deficiency. Maternal vitamin D status in the second trimester of pregnancy was found to influence vitamin D level in breast milk at delivery.
PMCID: PMC4081124  PMID: 24992199
16.  Endospores of thermophilic bacteria as tracers of microbial dispersal by ocean currents 
The ISME Journal  2013;8(6):1153-1165.
Microbial biogeography is influenced by the combined effects of passive dispersal and environmental selection, but the contribution of either factor can be difficult to discern. As thermophilic bacteria cannot grow in the cold seabed, their inactive spores are not subject to environmental selection. We therefore conducted a global experimental survey using thermophilic endospores that are passively deposited by sedimentation to the cold seafloor as tracers to study the effect of dispersal by ocean currents on the biogeography of marine microorganisms. Our analysis of 81 different marine sediments from around the world identified 146 species-level 16S rRNA phylotypes of endospore-forming, thermophilic Firmicutes. Phylotypes showed various patterns of spatial distribution in the world oceans and were dispersal-limited to different degrees. Co-occurrence of several phylotypes in locations separated by great distances (west of Svalbard, the Baltic Sea and the Gulf of California) demonstrated a widespread but not ubiquitous distribution. In contrast, Arctic regions with water masses that are relatively isolated from global ocean circulation (Baffin Bay and east of Svalbard) were characterized by low phylotype richness and different compositions of phylotypes. The observed distribution pattern of thermophilic endospores in marine sediments suggests that the impact of passive dispersal on marine microbial biogeography is controlled by the connectivity of local water masses to ocean circulation.
PMCID: PMC4030223  PMID: 24351936
biogeography; endospores; marine microorganisms; ocean currents; thermophiles
17.  Increased Workload for Systematic Review Literature Searches of Diagnostic Tests Compared With Treatments: Challenges and Opportunities 
JMIR Medical Informatics  2014;2(1):e11.
Comprehensive literature searches are conducted over multiple medical databases in order to meet stringent quality standards for systematic reviews. These searches are often very laborious, with authors often manually screening thousands of articles. Information retrieval (IR) techniques have proven increasingly effective in improving the efficiency of this process. IR challenges for systematic reviews involve building classifiers using training data with very high class-imbalance, and meeting the requirement for near perfect recall on relevant studies. Traditionally, most systematic reviews have focused on questions relating to treatment. The last decade has seen a large increase in the number of systematic reviews of diagnostic test accuracy (DTA).
We aim to demonstrate that DTA reviews comprise an especially challenging subclass of systematic reviews with respect to the workload required for literature screening. We identify specific challenges for the application of IR to literature screening for DTA reviews, and identify potential directions for future research.
We hypothesize that IR for DTA reviews face three additional challenges, compared to systematic reviews of treatments. These include an increased class-imbalance, a broader definition of the target class, and relative inadequacy of available metadata (ie, medical subject headings (MeSH) terms for medical literature analysis and retrieval system online). Assuming these hypotheses to be true, we identify five manifestations when we compare literature searches of DTA versus treatment. These manifestations include: an increase in the average number of articles screened, and increase in the average number of full-text articles obtained, a decrease in the number of included studies as a percentage of full-text articles screened, a decrease in the number of included studies as a percentage of all articles screened, and a decrease in the number of full-text articles obtained as a percentage of all articles screened. As of July 12 2013, 13 published Cochrane DTA reviews were available and all were included. For each DTA review, we randomly selected 15 treatment reviews published by the corresponding Cochrane Review Group (N=195). We then statistically tested differences in these five hypotheses, for the DTA versus treatment reviews.
Despite low statistical power caused by the small sample size for DTA reviews, strong (P<.01) or very strong (P<.001) evidence was obtained to support three of the five expected manifestations, with evidence for at least one manifestation of each hypothesis. The observed difference in effect sizes are substantial, demonstrating the practical difference in reviewer workload.
Reviewer workload (volume of citations screened) when screening literature for systematic reviews of DTA is especially high. This corresponds to greater rates of class-imbalance when training classifiers for automating literature screening for DTA reviews. Addressing concerns such as lower quality metadata and effectively modelling the broader target class could help to alleviate such challenges, providing possible directions for future research.
PMCID: PMC4288066  PMID: 25600450
meta-analysis; data mining; review literature; information storage and retrieval; classification and clustering
18.  Expression of Matrix Metalloproteinase-1 in Alveolar Macrophages, Type II Pneumocytes, and Airways in Smokers: Relationship to Lung Function and Emphysema 
Lung  2014;192(4):467-472.
An imbalance between proteolytic enzymes and their inhibitors is thought to be involved in the pathogenesis of chronic obstructive pulmonary disease. Matrix metalloproteinase-1, also known as interstitial collagenase, has been implicated as a potentially important proteinase in the genesis of chronic obstructive pulmonary disease and, more specifically, emphysema.
We performed quantitative immunohistochemical assessment of matrix metalloproteinase-1 expression in the resected lung of 20 smokers/ex-smokers who had varying severity of airflow obstruction and emphysema and compared this with the lungs of 5 nonsmokers. Emphysema was measured using a morphometric measure of the lungs’ surface area/volume ratio and with qualitative and quantitative computed tomography (CT) measures of emphysema.
There were significantly more matrix metalloproteinase-1-expressing alveolar macrophages and type II pneumocytes as well as a greater percentage of small airways that stained positively for matrix metalloproteinase-1 in the lungs of smokers than in those of nonsmokers (p < 0.0001, p < 0.0001, and p = 0.0003, respectively). The extent of staining of type II pneumocytes and airways for matrix metalloproteinase-1 was significantly related to the extent of smoking (p = 0.012 and p = 0.013, respectively). In addition, the extent of matrix metalloproteinase-1 staining of alveolar macrophages was related to the lung surface area/volume ratio and to qualitative estimates of emphysema on CT.
These findings suggest that cigarette smoking increases expression of matrix metalloproteinase-1 in alveolar macrophages as well as in alveolar and small airway epithelial cells. Smokers who develop emphysema have increased alveolar macrophage expression of matrix metalloproteinase-1.
Electronic supplementary material
The online version of this article (doi:10.1007/s00408-014-9585-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4104162  PMID: 24792232
Computed tomography; Emphysema; Expression; Immunohistochemistry; Metalloproteinase; Lung
19.  Longitudinal study of murine microbiota activity and interactions with the host during acute inflammation and recovery 
The ISME Journal  2014;8(5):1101-1114.
Although alterations in gut microbiota composition during acute colitis have been repeatedly observed, associated functional changes and the recovery from dysbiosis received little attention. In this study, we investigated structure and function of the gut microbiota during acute inflammation and recovery in a dextran sodium sulfate (DSS)-colitis mouse model using metatranscriptomics, bacterial 16S rRNA gene amplicon sequencing and monitoring of selected host markers. Parallel to an increase of host markers of inflammation during acute colitis, we observed relative abundance shifts and alterations in phylotype composition of the dominant bacterial orders Clostridiales and Bacteroidales, and an increase of the low abundant Enterobacteriales, Deferribacterales, Verrucomicrobiales and Erysipelotrichales. During recovery, the microbiota began to resume, but did not reach its original composition until the end of the experiment. Microbial gene expression was more resilient to disturbance, with pre-perturbation-type transcript profiles appearing quickly after acute colitis. The decrease of Clostridiales during inflammation correlated with a reduction of transcripts related to butyrate formation, suggesting a disturbance in host-microbe signalling and mucosal nutrient provision. The impact of acute inflammation on the Clostridiales was also characterized by a significant downregulation of their flagellin-encoding genes. In contrast, the abundance of members of the Bacteroidales increased along with an increase in transcripts related to mucin degradation. We propose that acute inflammation triggered a selective reaction of the immune system against flagella of commensals and temporarily altered murine microbiota composition and functions relevant for the host. Despite changes in specific interactions, the host–microbiota homeostasis revealed a remarkable ability for recovery.
PMCID: PMC3996699  PMID: 24401855
butyrate; flagellin; metatranscriptomics; mucin; recovery
20.  Common strength and localization of spontaneous and evoked synaptic vesicle release sites 
Molecular Brain  2014;7:23.
Different pools and functions have recently been attributed to spontaneous and evoked vesicle release. Despite the well-established function of evoked release, the neuronal information transmission, the origin as well as the function of spontaneously fusing synaptic vesicles have remained elusive. Recently spontaneous release was found to e.g. regulate postsynaptic protein synthesis or has been linked to depressive disorder. Nevertheless the strength and cellular localization of this release form was neglected so far, which are both essential parameters in neuronal information processing.
Here we show that the complete recycling pool can be turned over by spontaneous trafficking and that spontaneous fusion rates critically depend on the neuronal localization of the releasing synapse. Thereby, the distribution equals that of evoked release so that both findings demonstrate a uniform regulation of these fusion modes.
In contrast to recent works, our results strengthen the assumption that identical vesicles are used for evoked and spontaneous release and extended the knowledge about spontaneous fusion with respect to its amount and cellular localization. Therefore our data supported the hypothesis of a regulatory role of spontaneous release in neuronal outgrowth and plasticity as neurites secrete neurotransmitters to initiate process outgrowth of a possible postsynaptic neuron to form a new synaptic connection.
PMCID: PMC4022376  PMID: 24694031
21.  Circulating human microRNAs are not linked to JC polyomavirus serology or urinary viral load in healthy subjects 
Virology Journal  2014;11:41.
JC polyomavirus (JCPyV) is a widespread human polyomavirus that usually resides latently in its host. It can be reactivated under immunomodulating conditions and cause Progressive Multifocal Leukoencephalopathy (PML). Circulating microRNAs (miRNAs) are emerging as promising biomarkers for several pathologies. In this study, we have investigated whether circulating miRNAs exist that are differentially expressed between JCPyV seropositive and JCPyV seronegative on the one hand or between JCPyV shedders and JCPyV non-shedders on the other hand.
Human miRNA expression profiling was performed in a small set of plasma samples obtained from seronegative subjects, seropositive shedders and seropositive non-shedders. A set of 10 miRNAs was selected for further analysis in a larger group of samples.
Based on the plasma profiling experiment of 30 samples, 6 miRNAs were selected that were possibly differentially expressed between seropositive and seronegative subjects and 4 miRNAs were selected that were possibly differentially expressed between shedders and non-shedders. Subsequently, expression of these 10 selected miRNAs was assessed in an independent set of 100 plasma samples. Results indicated that none of them were differentially expressed.
This study could not identify circulating human miRNAs that were differentially expressed between plasma from JCPyV seropositive and JCPyV seronegative subjects or between JCPyV shedders and JCPyV non-shedders.
PMCID: PMC3945012  PMID: 24588811
JC polyomavirus; microRNA; Circulating microRNA; Plasma; Serology; Viral load
22.  Dispersal of thermophilic Desulfotomaculum endospores into Baltic Sea sediments over thousands of years 
The ISME Journal  2012;7(1):72-84.
Patterns of microbial biogeography result from a combination of dispersal, speciation and extinction, yet individual contributions exerted by each of these mechanisms are difficult to isolate and distinguish. The influx of endospores of thermophilic microorganisms to cold marine sediments offers a natural model for investigating passive dispersal in the ocean. We investigated the activity, diversity and abundance of thermophilic endospore-forming sulfate-reducing bacteria (SRB) in Aarhus Bay by incubating pasteurized sediment between 28 and 85 °C, and by subsequent molecular diversity analyses of 16S rRNA and of the dissimilatory (bi)sulfite reductase (dsrAB) genes within the endospore-forming SRB genus Desulfotomaculum. The thermophilic Desulfotomaculum community in Aarhus Bay sediments consisted of at least 23 species-level 16S rRNA sequence phylotypes. In two cases, pairs of identical 16S rRNA and dsrAB sequences in Arctic surface sediment 3000 km away showed that the same phylotypes are present in both locations. Radiotracer-enhanced most probable number analysis revealed that the abundance of endospores of thermophilic SRB in Aarhus Bay sediment was ca. 104 per cm3 at the surface and decreased exponentially to 100 per cm3 at 6.5 m depth, corresponding to 4500 years of sediment age. Thus, a half-life of ca. 300 years was estimated for the thermophilic SRB endospores deposited in Aarhus Bay sediments. These endospores were similarly detected in the overlying water column, indicative of passive dispersal in water masses preceding sedimentation. The sources of these thermophiles remain enigmatic, but at least one source may be common to both Aarhus Bay and Arctic sediments.
PMCID: PMC3524260  PMID: 22832348
biogeography; dispersal; endospores; population half-life; sulfate-reducing bacteria
23.  High-speed upper-airway imaging using full-range optical coherence tomography 
Journal of Biomedical Optics  2012;17(11):110507.
Obstruction in the upper airway can often cause reductions in breathing or gas exchange efficiency and lead to rest disorders such as sleep apnea. Imaging diagnosis of the obstruction region has been accomplished using computed tomography (CT) and magnetic resonance imaging (MRI). However CT requires the use of ionizing radiation, and MRI typically requires sedation of the patient to prevent motion artifacts. Long-range optical coherence tomography (OCT) has the potential to provide high-speed three-dimensional tomographic images with high resolution and without the use of ionizing radiation. In this paper, we present work on the development of a long-range OCT endoscopic probe with 1.2 mm OD and 20 mm working distance used in conjunction with a modified Fourier domain swept source OCT system to acquire structural and anatomical datasets of the human airway. Imaging from the bottom of the larynx to the end of the nasal cavity is completed within 40 s.
PMCID: PMC3494494  PMID: 23214170
optical coherence tomography; long-range optical coherence tomography; obstructive sleep apnea; Fourier domain optical coherence tomography
24.  Phylotype-level 16S rRNA analysis reveals new bacterial indicators of health state in acute murine colitis 
The ISME Journal  2012;6(11):2091-2106.
Human inflammatory bowel disease and experimental colitis models in mice are associated with shifts in intestinal microbiota composition, but it is unclear at what taxonomic/phylogenetic level such microbiota dynamics can be indicative for health or disease. Here, we report that dextran sodium sulfate (DSS)-induced colitis is accompanied by major shifts in the composition and function of the intestinal microbiota of STAT1−/− and wild-type mice, as determined by 454 pyrosequencing of bacterial 16S rRNA (gene) amplicons, metatranscriptomics and quantitative fluorescence in situ hybridization of selected phylotypes. The bacterial families Ruminococcaceae, Bacteroidaceae, Enterobacteriaceae, Deferribacteraceae and Verrucomicrobiaceae increased in relative abundance in DSS-treated mice. Comparative 16S rRNA sequence analysis at maximum possible phylogenetic resolution identified several indicator phylotypes for DSS treatment, including the putative mucin degraders Akkermansia and Mucispirillum. The analysis additionally revealed strongly contrasting abundance changes among phylotypes of the same family, particularly within the Lachnospiraceae. These extensive phylotype-level dynamics were hidden when reads were grouped at higher taxonomic levels. Metatranscriptomic analysis provided insights into functional shifts in the murine intestinal microbiota, with increased transcription of genes associated with regulation and cell signaling, carbohydrate metabolism and respiration and decreased transcription of flagellin genes during inflammation. These findings (i) establish the first in-depth inventory of the mouse gut microbiota and its metatranscriptome in the DSS colitis model, (ii) reveal that family-level microbial community analyses are insufficient to reveal important colitis-associated microbiota shifts and (iii) support a scenario of shifting intra-family structure and function in the phylotype-rich and phylogenetically diverse Lachnospiraceae in DSS-treated mice.
PMCID: PMC3475367  PMID: 22572638
gut microbiota; Lachnospiraceae; Akkermansia; Mucispirillum; dextran sodium sulfate; colitis
25.  Three manganese oxide-rich marine sediments harbor similar communities of acetate-oxidizing manganese-reducing bacteria 
The ISME Journal  2012;6(11):2078-2090.
Dissimilatory manganese reduction dominates anaerobic carbon oxidation in marine sediments with high manganese oxide concentrations, but the microorganisms responsible for this process are largely unknown. In this study, the acetate-utilizing manganese-reducing microbiota in geographically well-separated, manganese oxide-rich sediments from Gullmar Fjord (Sweden), Skagerrak (Norway) and Ulleung Basin (Korea) were analyzed by 16S rRNA-stable isotope probing (SIP). Manganese reduction was the prevailing terminal electron-accepting process in anoxic incubations of surface sediments, and even the addition of acetate stimulated neither iron nor sulfate reduction. The three geographically distinct sediments harbored surprisingly similar communities of acetate-utilizing manganese-reducing bacteria: 16S rRNA of members of the genera Colwellia and Arcobacter and of novel genera within the Oceanospirillaceae and Alteromonadales were detected in heavy RNA-SIP fractions from these three sediments. Most probable number (MPN) analysis yielded up to 106 acetate-utilizing manganese-reducing cells cm−3 in Gullmar Fjord sediment. A 16S rRNA gene clone library that was established from the highest MPN dilutions was dominated by sequences of Colwellia and Arcobacter species and members of the Oceanospirillaceae, supporting the obtained RNA-SIP results. In conclusion, these findings strongly suggest that (i) acetate-dependent manganese reduction in manganese oxide-rich sediments is catalyzed by members of taxa (Arcobacter, Colwellia and Oceanospirillaceae) previously not known to possess this physiological function, (ii) similar acetate-utilizing manganese reducers thrive in geographically distinct regions and (iii) the identified manganese reducers differ greatly from the extensively explored iron reducers in marine sediments.
PMCID: PMC3475373  PMID: 22572639
16S rRNA-SIP; manganese reduction; marine sediment; MPN counts

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