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1.  Cervical Dystonia: A Disorder of the Midbrain Network for Covert Attentional Orienting 
While the pathogenesis of cervical dystonia remains unknown, recent animal and clinical experimental studies have indicated its probable mechanisms. Abnormal temporal discrimination is a mediational endophenotype of cervical dystonia and informs new concepts of disease pathogenesis. Our hypothesis is that both abnormal temporal discrimination and cervical dystonia are due to a disorder of the midbrain network for covert attentional orienting caused by reduced gamma-aminobutyric acid (GABA) inhibition, resulting, in turn, from as yet undetermined, genetic mutations. Such disinhibition is (a) subclinically manifested by abnormal temporal discrimination due to prolonged duration firing of the visual sensory neurons in the superficial laminae of the superior colliculus and (b) clinically manifested by cervical dystonia due to disinhibited burst activity of the cephalomotor neurons of the intermediate and deep laminae of the superior colliculus. Abnormal temporal discrimination in unaffected first-degree relatives of patients with cervical dystonia represents a subclinical manifestation of defective GABA activity both within the superior colliculus and from the substantia nigra pars reticulata. A number of experiments are required to prove or disprove this hypothesis.
doi:10.3389/fneur.2014.00054
PMCID: PMC4009446  PMID: 24803911
cervical dystonia; temporal discrimination; covert attention; GABA; superior colliculus
2.  Revision Arthroplasty in the Haemophiliac Patient 
Case Reports in Orthopedics  2013;2013:348080.
Arthroplasty in the haemophiliac patient is associated with higher rates of infection and is traditionally performed in a younger age group. Despite this there is little evidence in the literature regarding revision arthroplasty in this cohort of patients. We describe the case of a periprosthetic fracture in a haemophiliac patient requiring revision arthroplasty, who did not consent to receiving blood products due to religious beliefs, with a successful outcome.
doi:10.1155/2013/348080
PMCID: PMC3659652  PMID: 23738171
3.  Attitudes of undergraduate health science students towards patients with intellectual disability, substance abuse, and acute mental illness: a cross-sectional study 
BMC Medical Education  2010;10:71.
Background
There is a long history of certain medical conditions being associated with stigma, stereotypes, and negative attitudes. Research has shown that such attitudes can have a detrimental effect on patients presenting with stigmatised medical conditions and can even flow on to impact their family. The objective of this study was to measure the attitudes of undergraduate students enrolled in six different health-related courses at Monash University toward patients with intellectual disability, substance abuse, and acute mental illness.
Methods
A convenience sample of undergraduate students enrolled in six health-related courses in first, second and third years at Monash University were surveyed. The Medical Condition Regard Scale - a valid and reliable, self-report measure of attitudes - was administered to students along with a brief demographic form. Mean scores, t-tests, and ANOVA were used to analyse student attitudes. Ethics approval was granted.
Results
548 students participated. Statistically significant differences were found between the courses (p = 0.05), year of the course (p = 0.09), and gender (p = 0.04) for the medical condition of intellectual disability. There was no statistically significant difference between the courses, year of the course, gender, and age group for substance abuse or acute mental illness conditions.
Conclusion
The findings suggest that students in undergraduate health-related courses, as a group, have a strong regard for patients with intellectual disability and some regard for patients with acute mental illness, but not for patients presenting with substance abuse problems.
doi:10.1186/1472-6920-10-71
PMCID: PMC2972293  PMID: 20964840
4.  Myocarditis as a prognostic indicator in systemic lupus erythematosus 
Postgraduate Medical Journal  2004;80(944):366-367.
Lupus myocarditis is a life threatening complication of systemic lupus erythematosus (SLE). A case of left ventricular failure secondary to myocarditis occurring in a patient with SLE is reported. Despite resolution of the cardiac failure with pulsed cyclophosphamide and steroids, she eventually died of non-cardiac complications 18 months later. The literature is also reviewed.
doi:10.1136/pgmj.2003.012450
PMCID: PMC1743021  PMID: 15192176
5.  CAHM, a long non-coding RNA gene hypermethylated in colorectal neoplasia 
Epigenetics  2014;9(8):1071-1082.
The CAHM gene (Colorectal Adenocarcinoma HyperMethylated), previously LOC100526820, is located on chromosome 6, hg19 chr6:163 834 097–163 834 982. It lacks introns, encodes a long non-coding RNA (lncRNA) and is located adjacent to the gene QKI, which encodes an RNA binding protein. Deep bisulphite sequencing of ten colorectal cancer (CRC) and matched normal tissues demonstrated frequent hypermethylation within the CAHM gene in cancer. A quantitative methylation-specific PCR (qMSP) was used to characterize additional tissue samples. With a threshold of 5% methylation, the CAHM assay was positive in 2/26 normal colorectal tissues (8%), 17/21 adenomas (81%), and 56/79 CRC samples (71%). A reverse transcriptase-qPCR assay showed that CAHM RNA levels correlated negatively with CAHM % methylation, and therefore CAHM gene expression is typically decreased in CRC. The CAHM qMSP assay was applied to DNA isolated from plasma specimens from 220 colonoscopy-examined patients. Using a threshold of 3 pg methylated genomic DNA per mL plasma, methylated CAHM sequences were detected in the plasma DNA of 40/73 (55%) of CRC patients compared with 3/73 (4%) from subjects with adenomas and 5/74 (7%) from subjects without neoplasia. Both the frequency of detection and the amount of methylated CAHM DNA released into plasma increased with increasing cancer stage. Methylated CAHM DNA shows promise as a plasma biomarker for use in screening for CRC.
doi:10.4161/epi.29046
PMCID: PMC4164492  PMID: 24799664
CAHM gene (LOC100526820); colorectal neoplasia; DNA methylation; Long non-coding RNA; Biomarker; circulating DNA; QKI
6.  The Risk Instrument for Screening in the Community (RISC): a new instrument for predicting risk of adverse outcomes in community dwelling older adults 
BMC Geriatrics  2015;15:92.
Background
Predicting risk of adverse healthcare outcomes, among community dwelling older adults, is difficult. The Risk Instrument for Screening in the Community (RISC) is a short (2–5 min), global subjective assessment of risk created to identify patients’ 1-year risk of three outcomes:institutionalisation, hospitalisation and death.
Methods
We compared the accuracy and predictive ability of the RISC, scored by Public Health Nurses (PHN), to the Clinical Frailty Scale (CFS) in a prospective cohort study of community dwelling older adults (n = 803), in two Irish PHN sectors. The area under the curve (AUC), from receiver operating characteristic curves and binary logistic regression models, with odds ratios (OR), compared the discriminatory characteristics of the RISC and CFS.
Results
Follow-up data were available for 801 patients. The 1-year incidence of institutionalisation, hospitalisation and death were 10.2, 17.7 and 15.6 % respectively. Patients scored maximum-risk (RISC score 3,4 or 5/5) at baseline had a significantly greater rate of institutionalisation (31.3 and 7.1 %, p < 0.001), hospitalisation (25.4 and 13.2 %, p < 0.001) and death (33.5 and 10.8 %, p < 0.001), than those scored minimum-risk (score 1 or 2/5). The RISC had comparable accuracy for 1-year risk of institutionalisation (AUC of 0.70 versus 0.63), hospitalisation (AUC 0.61 versus 0.55), and death (AUC 0.70 versus 0.67), to the CFS. The RISC significantly added to the predictive accuracy of the regression model for institutionalisation (OR 1.43, p = 0.01), hospitalisation (OR 1.28, p = 0.01), and death (OR 1.58, p = 0.001).
Conclusion
Follow-up outcomes matched well with baseline risk. The RISC, a short global subjective assessment, demonstrated satisfactory validity compared with the CFS.
doi:10.1186/s12877-015-0095-z
PMCID: PMC4520060
Screening; Frailty; Risk; Adverse outcomes; Risk Instrument for Screening in the Community (RISC); Clinical Frailty Scale (CFS); and public health nurses (PHNs)
7.  A randomised controlled trial comparing opt-in and opt-out home visits for tracing lost participants in a prospective birth cohort study 
Background
Attrition is an important problem in cohort studies. Tracing cohort members who have moved or otherwise lost contact with the study is vital. There is some debate about the acceptability and relative effectiveness of opt-in versus opt-out methods of contacting cohort members to re-engage them in this context. We conducted a randomised controlled trial to compare the two approaches in terms of effectiveness (tracing to confirm address and consenting to continue in the study), cost-effectiveness and acceptability.
Methods
Participants in this trial were individuals (young people and mothers) recruited to the Avon Longitudinal Study of Parents and Children (ALSPAC), who had not engaged with the study in the previous 5 years and for whom mail had been returned from their last known address. The sampling frame was restricted to those for whom database searching led to a potential new address being found in the Bristol area. 300 participants were randomly selected and assigned using stratified randomisation to the opt-in or opt-out arm. A tailored letter was sent to the potential new address, either asking participants to opt in to a home visit, or giving them the option to opt out of a home visit. Fieldworkers from Ipsos MORI conducted home visits to confirm address details.
Results
The proportion who were traced was higher in the opt-out arm (77/150 = 51 %) than the opt-in arm (6/150 = 4 %), as was the proportion who consented to continue in ALSPAC (46/150 = 31 % v 4/150 = 3 %). The mean cost per participant was £8.14 in the opt-in arm and £71.93 in the opt-out arm. There was no evidence of a difference in acceptability between the opt-in and opt-out approaches.
Conclusion
Since the opt-in approach yielded very low response rates, and there were no differences in terms of acceptability, we conclude that the opt-out approach is the most effective method of tracing disengaged study members. The gains made in contacting participants must be weighed against the increase in cost using this methodology.
Electronic supplementary material
The online version of this article (doi:10.1186/s12874-015-0041-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12874-015-0041-y
PMCID: PMC4512038  PMID: 26202794
Opt-in; Opt-out; Consent; Tracing; Tracking; Participation; Cohort study; Acceptability; Cost-effectiveness
8.  Identification of the minimal cytolytic unit for streptolysin S and an expansion of the toxin family 
BMC Microbiology  2015;15:141.
Background
Streptolysin S (SLS) is a cytolytic virulence factor produced by the human pathogen Streptococcus pyogenes and other Streptococcus species. Related “SLS-like” toxins have been characterized in select strains of Clostridium and Listeria, with homologous clusters bioinformatically identified in a variety of other species. SLS is a member of the thiazole/oxazole-modified microcin (TOMM) family of natural products. The structure of SLS has yet to be deciphered and many questions remain regarding its structure-activity relationships.
Results
In this work, we assessed the hemolytic activity of a series of C-terminally truncated SLS peptides expressed in SLS-deficient S. pyogenes. Our data indicate that while the N-terminal poly-heterocyclizable (NPH) region of SLS substantially contributes to its bioactivity, the variable C-terminal region of the toxin is largely dispensable. Through genome mining we identified additional SLS-like clusters in diverse Firmicutes, Spirochaetes and Actinobacteria. Among the Spirochaete clusters, naturally truncated SLS-like precursors were found in the genomes of three Lyme disease-causing Borrelia burgdorferi sensu lato (Bbsl) strains. Although unable to restore hemolysis in SLS-deficient S. pyogenes, a Bbsl SLS-like precursor peptide was converted to a cytolysin using purified SLS biosynthetic enzymes. A PCR-based screen demonstrated that SLS-like clusters are substantially more prevalent in Bbsl than inferred from publicly available genome sequences.
Conclusions
The mutagenesis data described herein indicate that the minimal cytolytic unit of SLS encompasses the NPH region of the core peptide. Interestingly, this region is found in all characterized TOMM cytolysins, as well as the novel putative TOMM cytolysins we discovered. We propose that this conserved region represents the defining feature of the SLS-like TOMM family. We demonstrate the cytolytic potential of a Bbsl SLS-like precursor peptide, which has a core region of similar length to the SLS minimal cytolytic unit, when modified with purified SLS biosynthetic enzymes. As such, we speculate that some Borrelia have the potential to produce a TOMM cytolysin, although the biological significance of this finding remains to be determined. In addition to providing new insight into the structure-activity relationships of SLS, this study greatly expands the cytolysin group of TOMMs.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-015-0464-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12866-015-0464-y
PMCID: PMC4513790  PMID: 26204951
Streptolysin S; Streptococcus pyogenes; Group A Streptococcus; Thiazole/oxazole-modified microcin; Cytolysin; Borrelia burgdorferi sensu lato; Lyme disease; Linear azole-containing peptide
9.  Solution-Processed Mesoscopic Bi2S3:Polymer Photoactive Layers 
Chemphyschem  2014;15(6):1019-1023.
The fabrication of solution-processed nontoxic mesoporous Bi2S3 structures is demonstrated and the suitability of these structures for use in hybrid solar cells investigated. Mesoporous Bi2S3 electrodes are prepared via thermal decomposition of a thin film composed of a bismuth xanthate single source precursor. The resultant Bi2S3 films are made up of regular needles with approximate dimensions of 50×500 nm, as confirmed by scanning electron microscopy (SEM). The crystallinity of the Bi2S3 is found to be dependent on the annealing temperature, as determined by X-ray diffraction. The porous Bi2S3 films are infiltrated with the hole conductor P3HT to generate novel hybrid films, and laser-based transient absorption spectroscopy is used to interrogate the charge-separation reaction at the resulting Bi2S3/P3HT heterojunction. Specifically, optical excitation of the hybrid films results in efficient and long-lived charge separation (microsecond to millisecond timescale), thereby rendering such films suitable for the development of novel low-cost solar-energy conversion devices.
doi:10.1002/cphc.201301103
PMCID: PMC4501321  PMID: 24596301
bismuth sulfide; hybrid photovoltaics; nontoxic materials; solution processing; transient absorption spectroscopy
10.  Young Women do it Better: Sexual Dimorphism in Temporal Discrimination 
The temporal discrimination threshold (TDT) is the shortest time interval at which two sensory stimuli presented sequentially are detected as asynchronous by the observer. TDTs are known to increase with age. Having previously observed shorter thresholds in young women than in men, in this work we sought to systematically examine the effect of sex and age on temporal discrimination. The aims of this study were to examine, in a large group of men and women aged 20–65 years, the distribution of TDTs with an analysis of the individual participant’s responses, assessing the “point of subjective equality” and the “just noticeable difference” (JND). These respectively assess sensitivity and accuracy of an individual’s response. In 175 participants (88 women) aged 20–65 years, temporal discrimination was faster in women than in men under the age of 40 years by a mean of approximately 13 ms. However, age-related decline in temporal discrimination was three times faster in women so that, in the age group of 40–65 years, the female superiority was reversed. The point of subjective equality showed a similar advantage in younger women and more marked age-related decline in women than men, as the TDT. JND values declined equally in both sexes, showing no sexual dimorphism. This observed sexual dimorphism in temporal discrimination is important for both (a) future clinical research assessing disordered mid-brain covert attention in basal-ganglia disorders, and (b) understanding the biology of this sexual dimorphism which may be genetic or hormonal.
doi:10.3389/fneur.2015.00160
PMCID: PMC4497309  PMID: 26217303
sexual dimorphism; temporal discrimination; movement disorders; covert attention; adult onset dystonia; superior colliculus
11.  A Case of Bordetella brochiseptica at a Military Medical Facility in Hawai‘i: Phenotypic and Molecular Testing of an Uncommon Human Pathogen 
Bordetella bronchiseptica (B. bronchiseptica) is rarely implicated in human disease. Human infections typically occur in the context of immunosuppression and while human infection has been sporadically reported in the literature, the majority of these reports are largely descriptive and do not explore the molecular and phenotypic properties of the isolates in question. Here we report the isolation and characterization of a B. bronchiseptica isolate derived from an HIV positive patient at Tripler Army Medical Center on O‘ahu. This case represents the first published report of human infection of B. bronchiseptica in the state of Hawai‘i and the most detailed description of the biochemical and molecular features of a Hawaiian isolate to date.
PMCID: PMC4507362  PMID: 26225268
12.  AMBITION-cm: intermittent high dose AmBisome on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a randomized controlled trial 
Trials  2015;16:276.
Background
Cryptococcal meningitis (CM) is a leading cause of mortality among HIV-infected individuals in Africa. Poor outcomes from conventional antifungal therapies, unavailability of flucytosine, and difficulties administering 14 days of amphotericin B are key drivers of this mortality. Novel treatment regimes are needed. This study examines whether short-course high-dose liposomal amphotericin B (AmBisome), given with high dose fluconazole, is non-inferior (in terms of microbiological and clinical endpoints) to standard-dose 14-day courses of AmBisome plus high dose fluconazole for treatment of HIV-associated CM.
Methodology/design
This is an adaptive open-label phase II/III randomised non-inferiority trial comparing alternative short course AmBisome regimens. Step 1 (phase II) will compare four treatment arms in 160 adult patients (≥18 years old) with a first episode of HIV-associated CM, using early fungicidal activity (EFA) as the primary outcome: 1) AmBisome 10 mg/kg day one (single dose); 2) AmBisome 10 mg/kg day one and AmBisome 5 mg/kg day three (two doses); 3) AmBisome 10 mg/kg day one, and AmBisome 5 mg/kg days three and seven (three doses); and 4) AmBisome 3 mg/kg/d for 14 days (control); all given with fluconazole 1200 mg daily for 14 days. STEP 2 (phase III) will enrol 300 participants and compare two treatment arms using all-cause mortality within 70 days as the primary outcome: 1) the shortest course AmBisome regimen found to be non-inferior in terms of EFA to the 14-day control arm in STEP 1, and 2) AmBisome 3 mg/kg/d for 14 days (control), both given with fluconazole 1200 mg daily for 14 days. STEP 2 analysis will include all patients from STEP 1 and STEP 2 taking the STEP 2 regimens. All patients will be followed for ten weeks, and mortality and safety data recorded. All patients will receive consolidation therapy with fluconazole 400–800 mg daily and ART in accordance with local guidelines. The primary analysis (for both STEP 1 and STEP 2) will be intention-to-treat.
Trial registration
ISRCTN10248064. Date of Registration: 22 January 2014
doi:10.1186/s13063-015-0799-6
PMCID: PMC4479349  PMID: 26081985
Cryptococcal meningitis; HIV; AmBisome; Amphotericin B; Fluconazole; Clinical trial
13.  Modelling Tradescantia fluminensis to assess long term survival 
PeerJ  2015;3:e1013.
We present a simple Poisson process model for the growth of Tradescantia fluminensis, an invasive plant species that inhibits the regeneration of native forest remnants in New Zealand. The model was parameterised with data derived from field experiments in New Zealand and then verified with independent data. The model gave good predictions which showed that its underlying assumptions are sound. However, this simple model had less predictive power for outputs based on variance suggesting that some assumptions were lacking. Therefore, we extended the model to include higher variability between plants thereby improving its predictions. This high variance model suggests that control measures that promote node death at the base of the plant or restrict the main stem growth rate will be more effective than those that reduce the number of branching events. The extended model forms a good basis for assessing the efficacy of various forms of control of this weed, including the recently-released leaf-feeding tradescantia leaf beetle (Neolema ogloblini).
doi:10.7717/peerj.1013
PMCID: PMC4465954  PMID: 26082865
Invasive species; Branching process; Biocontrol; Stochastic model
14.  Feedback Valence Affects Auditory Perceptual Learning Independently of Feedback Probability 
PLoS ONE  2015;10(5):e0126412.
Previous studies have suggested that negative feedback is more effective in driving learning than positive feedback. We investigated the effect on learning of providing varying amounts of negative and positive feedback while listeners attempted to discriminate between three identical tones; an impossible task that nevertheless produces robust learning. Four feedback conditions were compared during training: 90% positive feedback or 10% negative feedback informed the participants that they were doing equally well, while 10% positive or 90% negative feedback informed them they were doing equally badly. In all conditions the feedback was random in relation to the listeners’ responses (because the task was to discriminate three identical tones), yet both the valence (negative vs. positive) and the probability of feedback (10% vs. 90%) affected learning. Feedback that informed listeners they were doing badly resulted in better post-training performance than feedback that informed them they were doing well, independent of valence. In addition, positive feedback during training resulted in better post-training performance than negative feedback, but only positive feedback indicating listeners were doing badly on the task resulted in learning. As we have previously speculated, feedback that better reflected the difficulty of the task was more effective in driving learning than feedback that suggested performance was better than it should have been given perceived task difficulty. But contrary to expectations, positive feedback was more effective than negative feedback in driving learning. Feedback thus had two separable effects on learning: feedback valence affected motivation on a subjectively difficult task, and learning occurred only when feedback probability reflected the subjective difficulty. To optimize learning, training programs need to take into consideration both feedback valence and probability.
doi:10.1371/journal.pone.0126412
PMCID: PMC4422442  PMID: 25946173
15.  A Two-Gene Blood Test for Methylated DNA Sensitive for Colorectal Cancer 
PLoS ONE  2015;10(4):e0125041.
Background
Specific genes are methylated with high frequency in colorectal neoplasia, and may leak into blood. Detection of multiple methylated DNA biomarkers in blood may improve assay sensitivity for colorectal cancer (CRC) relative to a single marker. We undertook a case-control study evaluating the presence of two methylation DNA markers, BCAT1 and IKZF1, in circulation to determine if they were complementary for detection of CRC.
Methods
Methylation-specific PCR assays were developed to measure the level of methylated BCAT1 and IKZF1 in DNA extracted from plasma obtained from colonoscopy-confirmed 144 healthy controls and 74 CRC cases.
Results
DNA yields ranged from 2 to 730 ng/mL plasma (mean 18.6ng/mL; 95% CI 11-26 ng/mL) and did not correlate with gender, age or CRC status. Methylated BCAT1 and IKZF1 DNA were detected in respectively 48 (65%) and 50 (68%) of the 74 cancers. In contrast, only 5 (4%) and 7 (5%) controls were positive for BCAT1 and IKZF1 DNA methylation, respectively. A two-gene classifier model (“either or” rule) improved segregation of CRC from controls, with 57 of 74 cancers (77%) compared to only 11 of 144 (7.6%) controls being positive for BCAT1 and/or IKZF1 DNA methylation. Increasing levels of methylated DNA were observed as CRC stage progressed.
Conclusions
Detection of methylated BCAT1 and/or IKZF1 DNA in plasma may have clinical application as a novel blood test for CRC. Combining the results from the two methylation-specific PCR assays improved CRC detection with minimal change in specificity. Further validation of this two-gene blood test with a view to application in screening is now indicated.
doi:10.1371/journal.pone.0125041
PMCID: PMC4416022  PMID: 25928810
16.  Alcohol brief interventions practice following training for multidisciplinary health and social care teams: A qualitative interview study 
Drug and Alcohol Review  2014;34(2):185-193.
Introduction and Aims
Few studies of the implementation of alcohol brief interventions (ABI) have been conducted in community settings such as mental health, social work and criminal justice teams. This qualitative interview study sought to explore the impact of training on ABI delivery by staff from a variety of such teams.
Design and Methods
Fifteen semi-structured telephone interviews were carried out with trained practitioners and with managers to explore the use of, perceived need for and approaches to ABI delivery and recording with clients, and compatibility of ABIs with current practice. Interviews were analysed thematically using an inductive approach.
Results
Very few practitioners reported delivery of any ABIs following training primarily because they felt ABIs to be inappropriate for their clients. According to practitioners, this was either because they drank too much or too little to benefit. Practitioners reported a range of current activities relating to alcohol, and some felt that their knowledge and confidence were improved following training. One practitioner reported ABI delivery and was considered a training success, while expectations of ABIs did not fit with current practice including assessment procedures for the remainder.
Discussion and Conclusions
Identified barriers to ABI delivery included issues relating to individual practitioners, their teams, current practice and the ABI model. They are likely to be best addressed by strategic team- and setting-specific approaches to implementation, of which training is only one part. [Fitzgerald N, Molloy H, MacDonald F, McCambridge J. Alcohol brief interventions practice following training for multidisciplinary health and social care teams: A qualitative interview study. Drug Alcohol Rev 2015;34:185–93]
doi:10.1111/dar.12193
PMCID: PMC4405088  PMID: 25196713
alcohol consumption; brief intervention; training; qualitative; social work
17.  Barriers to primary care clinician adherence to clinical guidelines for the management of low back pain: protocol of a systematic review and meta-synthesis of qualitative studies 
BMJ Open  2015;5(4):e007265.
Introduction
Low back pain is the highest ranked condition contributing to years lived with disability, and is a significant economic and societal burden. Evidence-based clinical practice guidelines are designed to improve quality of care and reduce practice variation by providing graded recommendations based on the best available evidence. Studies of low back pain guideline implementation have shown no or modest effects at changing clinical practice.
Objectives
To identify enablers and barriers to adherence to clinical practice guidelines for the management of low back pain.
Methods and analysis
A systematic review and meta-synthesis of qualitative studies that will be conducted and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement guidelines. Eight databases will be searched using a priori inclusion/exclusion criteria. Two independent reviewers will conduct a structured review and meta-synthesis, and a third reviewer will arbitrate where there is disagreement. This protocol has been registered on PROSPERO 2014.
Ethics and dissemination
Ethical approval is not required. The systematic review will be published in a peer-reviewed journal. The review will also be disseminated electronically, in print and at conferences. Updates of the review will be conducted to inform and guide healthcare translation into practice.
Trial registration number
PROSPERO 2014:CRD42014012961. Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014012961
doi:10.1136/bmjopen-2014-007265
PMCID: PMC4410131  PMID: 25900462
PRIMARY CARE; QUALITATIVE RESEARCH
18.  Optimism and Recovery After Acute Coronary Syndrome: A Clinical Cohort Study 
Psychosomatic Medicine  2015;77(3):311-318.
ABSTRACT
Objective
Optimism is associated with reduced cardiovascular mortality, but its impact on recovery after acute coronary syndrome (ACS) is poorly understood. We hypothesized that greater optimism would lead to more effective physical and emotional adaptation after ACS and would buffer the impact of persistent depressive symptoms on clinical outcomes.
Methods
This prospective observational clinical study took place in an urban general hospital and involved 369 patients admitted with a documented ACS. Optimism was assessed with a standardized questionnaire. The main outcomes were physical health status, depressive symptoms, smoking, physical activity, and fruit and vegetable consumption measured 12 months after ACS, and composite major adverse cardiac events (cardiovascular death, readmission with reinfarction or unstable angina, and coronary artery bypass graft surgery) assessed over an average of 45.7 months.
Results
We found that optimism predicted better physical health status 12 months after ACS independently of baseline physical health, age, sex, ethnicity, social deprivation, and clinical risk factors (B = 0.65, 95% confidence interval [CI] = 0.10–1.20). Greater optimism also predicted reduced risk of depressive symptoms (odds ratio = 0.82, 95% CI = 0.74–0.90), more smoking cessation, and more fruit and vegetable consumption at 12 months. Persistent depressive symptoms 12 months after ACS predicted major adverse cardiac events over subsequent years (odds ratio = 2.56, 95% CI = 1.16–5.67), but only among individuals low in optimism (optimism × depression interaction; p = .014).
Conclusions
Optimism predicts better physical and emotional health after ACS. Measuring optimism may help identify individuals at risk. Pessimistic outlooks can be modified, potentially leading to improved recovery after major cardiac events.
doi:10.1097/PSY.0000000000000155
PMCID: PMC4396437  PMID: 25738438
myocardial infarction; optimism; depression; recovery; ACS = acute coronary syndrome; CI = confidence interval; GRACE = Global Registry of Acute Coronary Events; BDI = Beck Depression Inventory; CHD = coronary heart disease; SES = socioeconomic status; SF-12 = 12-Item Short Form Health Survey
21.  A multiplexed, targeted mass spectrometry assay of the S100 protein family uncovers the isoform-specific expression in thyroid tumours 
BMC Cancer  2015;15:199.
Background
Mounting evidence demonstrates a causal role for S100 proteins in tumourigenesis and several S100 isoforms have shown utility as biomarkers of several types of cancer. The S100 family is comprised of 21 small isoforms, many of them implicated in important cellular functions such as proliferation, motility and survival. Furthermore, in vivo experiments have proven the role of S100 proteins in tumour growth and disease progression, while other studies have shown their prognostic value and involvement in resistance to chemotherapy drugs. Taken together, all these aspects highlight S100 proteins as potential therapeutic targets and as a promising panel of cancer biomarkers. In this work, we have developed a mass spectrometry (MS)-based method for the multiplexed and specific analysis of the entire S100 protein family in tumour tissues and have applied it to investigate the expression of S100 isoforms in the context of thyroid cancer, the main endocrine malignancy.
Methods
Selected Reaction Monitoring (SRM)-MS and stable isotope labelling/label-free analysis were employed to investigate the expression of the 21 S100 protein isoforms in thyroid tissue samples. Specimens included 9 normal thyroid tissues and 27 tumour tissues consisting of 9 follicular adenomas (FA), 8 follicular carcinomas (FTC) and 10 papillary carcinomas (PTC).
Results
The multiplexed and targeted mass spectrometry method led to the detection of eleven S100 protein isoforms across all tissues. Label- and label-free analyses showed the same significant differences and results were confirmed by western blot. S100A6, S100A11 and its putative interaction partner annexin A1 showed the highest overexpression in PTC compared to normal thyroid. S100A13 was also elevated in PTC. Reduced S100A4 expression was observed in FA compared to all other tissues. FA and FTC showed reduction of S100A10 and annexin A2 expression.
Conclusions
Targeted mass spectrometry allows the multiplexed and specific analysis of S100 protein isoforms in tumour tissue specimens. It revealed S100A13 as a novel candidate PTC biomarker. Results show that S100A6, S100A11 and Annexin A1 could help discriminate follicular and papillary tumours. The diagnostic and functional significance of S100A4 and S100A10 reduction in follicular tumours requires further investigation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1217-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1217-x
PMCID: PMC4391164  PMID: 25880590
S100 proteins; Selected reaction monitoring; Mass spectrometry; Thyroid cancer; Tumour tissue samples
22.  The Cascading Development of Autonomy and Relatedness From Adolescence to Adulthood 
Child development  2014;86(2):472-485.
We tested a developmental cascade model of autonomy and relatedness in the progression from parent to friend to romantic relationships across ages 13, 18, and 21. Participants included 184 adolescents (53% female, 58% Caucasian, 29% African American) recruited from a public middle school in Virginia. Parental psychological control at age 13 undermined the development of autonomy and relatedness, predicting relative decreases in autonomy and relatedness with friends between ages 13 and 18 and lower levels of autonomy and relatedness with partners at age 18. These cascade effects extended into adult friendships and romantic relationships, with autonomy and relatedness with romantic partners at age 18 being a strong predictor of autonomy and relatedness with both friends and partners at age 21.
doi:10.1111/cdev.12313
PMCID: PMC4376599  PMID: 25345623
psychological control; friendships; romantic relationships; transition to adulthood
23.  Small is challenging; distal femur fracture management in an elderly lady with achondroplastic dwarfism 
BMJ Case Reports  2013;2013:bcr2013008793.
Achondroplasia is an autosomal dominant dwarfing condition that represents the most common form of skeletal dysplasia. The disease is caused by a mutation in the gene encoding fibroblast growth factor receptor 3 (FGFR3) found at the p16.3 locus on chromosome 4 which results in severe inhibition of subchondral bone growth. Anatomic variations, including articular and periarticular deformities classically seen with this condition, amplify the complexity of fracture fixation. Blood volume loss, age-related bone fragility, component selection and positioning pose serious orthopaedic challenges. Concomitant cardiovascular, respiratory and neurological comorbidities pose additional high-risk perioperative considerations. Despite an estimated prevalence of 1:25 000 in the general population, there is little literature concerning the operative and postoperative treatment challenges faced by orthopaedic surgeons dealing with fracture management on a patient with this condition. We present a case of an intercondylar femoral fracture in an elderly achondroplastic lady successfully treated with percutaneous screw fixation.
doi:10.1136/bcr-2013-008793
PMCID: PMC3618805  PMID: 23519511
24.  Do Web-Based and Clinic Samples of Gay Men Living With HIV Differ on Self-Reported Physical and Psychological Symptoms? A Comparative Analysis 
Background
Although the Internet is commonly used to recruit samples in studies of human immunodeficiency virus (HIV)-related risk behaviors, it has not been used to measure patient-reported well-being. As the burden of long-term chronic HIV infection rises, the Internet may offer enormous potential for recruitment to research and interventions.
Objective
This study aimed to compare two samples of gay men living with HIV, one recruited via the Web and the other recruited in outpatient settings, in terms of self-reported physical and psychological symptom burden.
Methods
The Internet sample was recruited from a UK-wide Web-based survey of gay men with diagnosed HIV. Of these, 154 respondents identified themselves as resident in London and were included in this analysis. The HIV clinic sample was recruited from five HIV outpatient clinics. Of these participants, 400 gay men recruited in London clinics were included in this analysis.
Results
The Web-based sample was younger than the clinic sample (37.3 years, SD 7.0 vs 40.9 years, SD 8.3), more likely to be in paid employment (72.8%, 99/136 vs 60.1%, 227/378), less likely to be on antiretroviral therapy (ART) (58.4%, 90/154 vs 68.0%, 266/391), and had worse mean psychological symptom burden compared to the clinic sample (mean scores: 1.61, SD 1.09 vs 1.36, SD 0.96) but similar physical symptom burden (mean scores: 0.78, SD 0.65 vs 0.70, SD 0.74). In multivariable logistic regression, for the physical symptom burden model, adjusted for age, ethnicity, employment status, and ART use, the recruitment setting (ie, Web-based vs clinic) was not significantly associated with high physical symptom score. The only variable that remained significantly associated with high physical symptom score was employment status, with those in employment being less likely to report being in the upper (worst) physical symptom tertile versus the other two tertiles (adjusted OR 0.41, 95% CI 0.28-0.62, P<.001). For the psychological symptom burden model, those recruited via the Web were significantly more likely to report being in the upper (worst) tertile (adjusted OR 2.20, 95% CI 1.41-3.44, P=.001). In addition, those in employment were less likely to report being in the upper (worst) psychological symptom tertile compared to those not in employment (adjusted OR 0.32, 95% CI 0.21-0.49, P<.001).
Conclusions
Our data have revealed a number of differences. Compared to the clinic sample, the Web-based sample had worse psychological symptom burden, younger average age, higher prevalence of employment, and a lower proportion on ART. For future research, we recommend that Web-based data collection should include the demographic variables that we note differed between samples. In addition, we recognize that each recruitment method may bring inherent sampling bias, with clinic populations differing by geographical location and reflecting those accessing regular medical care, and Web-based sampling recruiting those with greater Internet access and identifying survey materials through specific searches and contact with specific websites.
doi:10.2196/jmir.3800
PMCID: PMC4383834  PMID: 25793749
HIV; pain; symptoms; mental health; methods; recruitment; sampling; Internet
25.  Comparative Genomics of Cluster O Mycobacteriophages 
PLoS ONE  2015;10(3):e0118725.
Mycobacteriophages – viruses of mycobacterial hosts – are genetically diverse but morphologically are all classified in the Caudovirales with double-stranded DNA and tails. We describe here a group of five closely related mycobacteriophages – Corndog, Catdawg, Dylan, Firecracker, and YungJamal – designated as Cluster O with long flexible tails but with unusual prolate capsids. Proteomic analysis of phage Corndog particles, Catdawg particles, and Corndog-infected cells confirms expression of half of the predicted gene products and indicates a non-canonical mechanism for translation of the Corndog tape measure protein. Bioinformatic analysis identifies 8–9 strongly predicted SigA promoters and all five Cluster O genomes contain more than 30 copies of a 17 bp repeat sequence with dyad symmetry located throughout the genomes. Comparison of the Cluster O phages provides insights into phage genome evolution including the processes of gene flux by horizontal genetic exchange.
doi:10.1371/journal.pone.0118725
PMCID: PMC4351075  PMID: 25742016

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