Psoriatic Arthritis (PsA) is estimated to occur in 10-15% of people with psoriasis and accounts for 13% of people attending early arthritis clinics. With an increasing awareness of the poor outcomes associated with PsA and the availability of new effective, but costly, treatments, there is an urgent need to research the optimal treatment for patients with PsA. The aim of the TICOPA study is to establish whether, in treatment naive early PsA patients, “tight control” intensive management with protocol driven therapies and pre-defined objective targets for treatment can improve clinical outcome compared to standard care alone.
TICOPA is a UK multicentre, open-label, randomised controlled, parallel group trial of 206 patients with early PsA. Patients will be randomised on a 1:1 basis to receive either standard care (12 weekly review) or intensive management (4 weekly review) for a period of 48 weeks. Patients assigned to the intensive management group will follow a strict treatment protocol whereby dose continuation/escalation is determined through the objective assessment of the minimal disease activity (MDA) criteria. Patients assigned to the standard care group will have treatment prescribed as felt appropriate by the treating clinician, with no set protocol. The primary objective of the trial is to compare intensive management with standard care in terms of the proportion of patients achieving an ACR 20 response at 48 weeks post-randomisation, in order to determine whether intensive management has superior clinical efficacy. Key secondary outcomes include ACR 50 and 70, PASI 75 and X-ray Van der Heijde score at 48 weeks post-randomisation along with cost-effectiveness at 12, 24 and 28 weeks.
The TICOPA trial will provide direct evidence as to whether the use of early and intensive treatment in PsA in routine clinical care leads to an improvement in patients’ disease activity and a reduction in radiological joint damage.
Psoriatic arthritis; Early psoriatic arthritis; Tight management; Tight control; Intensive management; Standard care
To evaluate three measures related to electronic health record (EHR) implementation: clinical volume, time requirements, and nature of clinical documentation. Comparison is made to baseline paper documentation.
An academic ophthalmology department implemented an EHR in 2006. A study population was defined of faculty providers who worked the 5 months before and after implementation. Clinical volumes, as well as time length for each patient encounter, were collected from the EHR reporting system. To directly compare time requirements, two faculty providers who utilized both paper and EHR systems completed time-motion logs to record the number of patients, clinic time, and nonclinic time to complete documentation. Faculty providers and databases were queried to identify patient records containing both paper and EHR notes, from which three cases were identified to illustrate representative documentation differences.
Twenty-three faculty providers completed 120,490 clinical encounters during a 3-year study period. Compared to baseline clinical volume from 3 months pre-implementation, the post-implementation volume was 88% in quarter 1, 93% in year 1, 97% in year 2, and 97% in year 3. Among all encounters, 75% were completed within 1.7 days after beginning documentation. The mean total time per patient was 6.8 minutes longer with EHR than paper (P<.01). EHR documentation involved greater reliance on textual interpretation of clinical findings, whereas paper notes used more graphical representations, and EHR notes were longer and included automatically generated text.
This EHR implementation was associated with increased documentation time, little or no increase in clinical volume, and changes in the nature of ophthalmic documentation.
Whereas considerable evidence links childhood physical abuse with later perpetration of intimate partner violence (IPV), research to identify moderators of this relationship will increase our understanding of which victims of childhood abuse are at risk for later IPV. The present study examined dimensions of psychopathy as moderators of the relationship between physical abuse in childhood and perpetration of IPV in a sample of criminal offenders. Results indicated that, among individuals with higher levels of impulsive-irresponsible (i.e., Lifestyle) traits of psychopathy, childhood physical abuse was associated with later perpetration of IPV. Findings have implications for the propensity toward IPV perpetration among individuals who have experienced childhood physical abuse.
child abuse; psychopathy; intimate partner violence; aggression; antisocial behavior
Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer.
In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m2 intravenous irinotecan every 3 weeks (300 mg/m2 if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876.
Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12–13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83–1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64–0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 % vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group.
Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents.
Cancer Research UK, Amgen Inc.
Fire is a major disturbance process in many ecosystems world-wide, resulting in spatially and temporally dynamic landscapes. For populations occupying such environments, fire-induced landscape change is likely to influence population processes, and genetic patterns and structure among populations. The Mallee Emu-wren Stipiturus mallee is an endangered passerine whose global distribution is confined to fire-prone, semi-arid mallee shrublands in south-eastern Australia. This species, with poor capacity for dispersal, has undergone a precipitous reduction in distribution and numbers in recent decades. We used genetic analyses of 11 length-variable, nuclear loci to examine population structure and processes within this species, across its global range. Populations of the Mallee Emu-wren exhibited a low to moderate level of genetic diversity, and evidence of bottlenecks and genetic drift. Bayesian clustering methods revealed weak genetic population structure across the species' range. The direct effects of large fires, together with associated changes in the spatial and temporal patterns of suitable habitat, have the potential to cause population bottlenecks, serial local extinctions and subsequent recolonisation, all of which may interact to erode and homogenise genetic diversity in this species. Movement among temporally and spatially shifting habitat, appears to maintain long-term genetic connectivity. A plausible explanation for the observed genetic patterns is that, following extensive fires, recolonisation exceeds in-situ survival as the primary driver of population recovery in this species. These findings suggest that dynamic, fire-dominated landscapes can drive genetic homogenisation of populations of species with low-mobility and specialised habitat that otherwise would be expected to show strongly structured populations. Such effects must be considered when formulating management actions to conserve species in fire-prone systems.
Glycans are key determinants of host range and transmissibility in several pathogens. In the case of adeno-associated viruses (AAV), different carbohydrates serve as cellular receptors in vitro; however, their contributions in vivo are less clear. A particularly interesting example is adeno-associated virus serotype 9 (AAV9), which displays systemic tropism in mice despite low endogenous levels of its primary receptor (galactose) in murine tissues. To understand this further, we studied the effect of modulating glycan binding avidity on the systemic fate of AAV9 in mice. Intravenous administration of recombinant sialidase increased tissue levels of terminally galactosylated glycans in several murine tissues. These conditions altered the systemic tropism of AAV9 into a hepatotropic phenotype, characterized by markedly increased sequestration within the liver sinusoidal endothelium and Kupffer cells. In contrast, an AAV9 mutant with decreased glycan binding avidity displayed a liver-detargeted phenotype. Altering glycan binding avidity also profoundly affected AAV9 persistence in blood circulation. Our results support the notion that high glycan receptor binding avidity appears to impart increased liver tropism, while decreased avidity favors systemic spread of AAV vectors. These findings may not only help predict species-specific differences in tropism for AAV9 on the basis of tissue glycosylation profiles, but also provide a general approach to tailor AAV vectors for systemic or hepatic gene transfer by reengineering capsid-glycan interactions.
The quality of the parent–child relationship has an important effect on a wide range of child outcomes. The evaluation of interventions to promote healthy parenting and family relationships is dependent on outcome measures which can quantify the quality of parent–child relationships. Between the Mothers’ Object Relations – Short Form (MORS-SF) scale for babies and the Child–parent Relationship Scale (C-PRS) there is an age gap where no validated scales are available. We report the development and testing of an adaptation of the MORS-SF; the MORS (Child) scale and its use in children from the age of 2 years to 4 years. This scale aims to capture the nature of the parent–child relationship in a form which is short enough to be used in population surveys and intervention evaluations.
Construct and criterion validity, item salience and internal consistency were assessed in a sample of 166 parents of children aged 2–4 years old and compared with that of the C-PRS. The performance of the MORS (Child) as part of a composite measure with the HOME inventory was compared with that of the C-PRS using data collected in a randomised controlled trial and the national evaluation of Sure Start.
MORS (Child) performed well in children aged 2–4 with high construct and criterion validity, item salience and internal consistency. One item in the C-PRS failed to load on either subscale and parents found this scale slightly more difficult to complete than the MORS (Child). The two measures performed very similarly in a factor analysis with the HOME inventory producing almost identical loadings.
Adapting the MORS-SF for children aged 2–4 years old produces a scale to assess parent–child relationships that is easy to use and outperforms the more commonly used C-PRS in several respects.
Parent; Child; Relationship; Outcome measure; Psychometrics; Validity; Internal consistency
Effective programs to help children manage their weight are required. Families for Health focuses on a parenting approach, designed to help parents develop their parenting skills to support lifestyle change within the family. Families for Health V1 showed sustained reductions in overweight after 2 years in a pilot evaluation, but lacks a randomized controlled trial (RCT) evidence base.
This is a multi-center, investigator-blind RCT, with parallel economic evaluation, with a 12-month follow-up. The trial will recruit 120 families with at least one child aged 6 to 11 years who is overweight (≥91st centile BMI) or obese (≥98th centile BMI) from three localities and assigned randomly to Families for Health V2 (60 families) or the usual care control (60 families) groups. Randomization will be stratified by locality (Coventry, Warwickshire, Wolverhampton).
Families for Health V2 is a family-based intervention run in a community venue. Parents/carers and children attend parallel groups for 2.5 hours weekly for 10 weeks. The usual care arm will be the usual support provided within each NHS locality.
A mixed-methods evaluation will be carried out. Child and parent participants will be assessed at home visits at baseline, 3-month (post-treatment) and 12-month follow-up. The primary outcome measure is the change in the children’s BMI z-scores at 12 months from the baseline. Secondary outcome measures include changes in the children’s waist circumference, percentage body fat, physical activity, fruit/vegetable consumption and quality of life. The parents’ BMI and mental well-being, family eating/activity, parent–child relationships and parenting style will also be assessed.
Economic components will encompass the measurement and valuation of service utilization, including the costs of running Families for Health and usual care, and the EuroQol EQ-5D health outcomes. Cost-effectiveness will be expressed in terms of incremental cost per quality-adjusted life year gained. A de novo decision-analytic model will estimate the lifetime cost-effectiveness of the Families for Health program.
Process evaluation will document recruitment, attendance and drop-out rates, and the fidelity of Families for Health delivery. Interviews with up to 24 parents and children from each arm will investigate perceptions and changes made.
This paper describes our protocol to assess the effectiveness and cost-effectiveness of a parenting approach for managing childhood obesity and presents challenges to implementation.
Current Controlled Trials http://ISRCTN45032201
Childhood obesity; Weight management; Parenting; Randomized controlled trial; Economic evaluation
Many children spend too much time screen-viewing (watching TV, surfing the internet and playing video games) and do not meet physical activity (PA) guidelines. Parents are important influences on children’s PA and screen-viewing (SV). There is a shortage of parent-focused interventions to change children’s PA and SV.
Teamplay was a two arm individualized randomized controlled feasibility trial. Participants were parents of 6–8 year old children. Intervention participants were invited to attend an eight week parenting program with each session lasting 2 hours. Children and parents wore an accelerometer for seven days and minutes of moderate-to-vigorous intensity PA (MVPA) were derived. Parents were also asked to report the average number of hours per day that both they and the target child spent watching TV. Measures were assessed at baseline (time 0) at the end of the intervention (week 8) and 2 months after the intervention had ended (week 16).
There were 75 participants who provided consent and were randomized but 27 participants withdrew post-randomization. Children in the intervention group engaged in 2.6 fewer minutes of weekday MVPA at Time 1 but engaged in 11 more minutes of weekend MVPA. At Time 1 the intervention parents engaged in 9 more minutes of weekday MVPA and 13 more minutes of weekend MVPA. The proportion of children in the intervention group watching ≥ 2 hours per day of TV on weekend days decreased after the intervention (time 0 = 76%, time 1 = 39%, time 2 = 50%), while the control group proportion increased slightly (79%, 86% and 87%). Parental weekday TV watching decreased in both groups. In post-study interviews many mothers reported problems associated with wearing the accelerometers. In terms of a future full-scale trial, a sample of between 80 and 340 families would be needed to detect a mean difference of 10-minutes of weekend MVPA.
Teamplay is a promising parenting program in an under-researched area. The intervention was acceptable to parents, and all elements of the study protocol were successfully completed. Simple changes to the trial protocol could result in more complete data collection and study engagement.
Parenting; Intervention; Feasibility trial; Physical activity; TV
We aimed to validate the Warwick-Edinburgh Mental Well-being Scale (WEMWBS) among English speaking adults representing two of the minority ethnic groups living in the UK, self-identified as Chinese or Pakistani by background, in a mixed methods study.
Quantitative data were collected in two cities in the West Midlands, UK. Item response, dimensionality, internal consistency, and construct validity of the WEMWBS were assessed in Chinese and Pakistani groups separately, using data from both cities combined.
Qualitative data were collected in the first city in eight focus groups of different ages recruited by the community workers. Three mixed sex Chinese and five single sex Pakistani groups discussed ease of completion and comprehension of items, together with overall reactions to the scale and underlying concept.
Results of quantitative and qualitative analysis were examined for commonalities and differences.
Item completion and item total correlations were satisfactory in both groups. In the Chinese data, Exploratory Factor Analysis showed a single factor with loadings ranging from 0.60 to 0.82 for all 14 items. In the Pakistani data, three factors reached statistical significance; however, a substantial drop in eigenvalues between the first and second factors and the limited variance explained by the second and third factors supported a one-factor model. All items loaded on this factor from 0.51 to 0.83.
In the Chinese and Pakistani data respectively, Cronbach’s alpha was 0.92 (0.89 – 0.94) and 0.91 (0.88 – 0.94); Spearman’s correlation with GHQ-12 was - 0.63 (−0.73 to −0.49) and −0.55 (−0.70 to −0.36), and with the WHO-5 0.62 (0.46-0.75) and 0.64 (0.50 to 0.76).
Qualitative analysis revealed good comprehension and ease of completion of almost all items. Some culturally determined differences in understanding of mental well-being, which varied both between and within communities, emerged.
The WEMWBS was well received by members of both Pakistani and Chinese communities. It showed high levels of consistency and reliability compared with accepted criteria. Data were sufficiently strong to recommend the WEMWBS for use in general population surveys.
Mental well-being; WEMWBS; Cross cultural; Validation; PROMS (patient reported outcome measures); Ethnicity (MeSH: ethnic groups)
Acute low back pain (ALBP) may limit mobility and impose functional limitations in active duty military personnel. Although some manual therapies have been reported effective for ALBP in military personnel, there have been no published randomized controlled trials (RCTs) of osteopathic manipulative treatment (OMT) in the military. Furthermore, current military ALBP guidelines do not specifically include OMT.
This RCT examined the efficacy of OMT in relieving ALBP and improving functioning in military personnel at Fort Lewis, Washington. Sixty-three male and female soldiers ages 18 to 35 were randomly assigned to a group receiving OMT plus usual care or a group receiving usual care only (UCO).
The primary outcome measures were pain on the quadruple visual analog scale, and functioning on the Roland Morris Disability Questionnaire. Outcomes were measured immediately preceding each of four treatment sessions and at four weeks post-trial. Intention to treat analysis found significantly greater post-trial improvement in ‘Pain Now’ for OMT compared to UCO (P = 0·026). Furthermore, the OMT group reported less ‘Pain Now’ and ‘Pain Typical’ at all visits (P = 0·025 and P = 0·020 respectively). Osteopathic manipulative treatment subjects also tended to achieve a clinically meaningful improvement from baseline on ‘Pain at Best’ sooner than the UCO subjects. With similar baseline expectations, OMT subjects reported significantly greater satisfaction with treatment and overall self-reported improvement (P<0·01).
This study supports the effectiveness of OMT in reducing ALBP pain in active duty military personnel.
Low back pain; Manual medicine; Manipulation
The long-lasting high affinity opioid buprenorphine has complex pharmacology including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacological activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine.
Competitive inhibition of radioligand binding to human mu, kappa, delta opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in Swiss Webster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing.
Buprenorphine-3-glucuronide had high affinity for human mu (Ki = 4.9±2.7 pM), delta (Ki = 270±0.4 nM), and nociceptin (Ki = 36±0.3 μM) but not kappa receptors. Norbuprenorphine-3-glucuronide had affinity for human kappa (Ki = 300±0.5 nM) and nociceptin (Ki= 18±0.2 μM) but not mu or delta receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation.
Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.
Accurate identification of pathogens, rather than colonising bacteria, is a prerequisite for targeted antibiotic therapy to ensure optimal patient outcome in wounds, such as diabetic foot ulcers. Wound swabs are the easiest and most commonly used sampling technique but most published guidelines recommend instead removal of a tissue sample from the wound bed, which is a more complex process. The aim of this study was to assess the concordance between culture results from wound swabs and tissue samples in patients with suspected diabetic foot infection.
Methods and analysis
Patients with a diabetic foot ulcer that is thought to be infected are being recruited from 25 sites across England in a cross-sectional study. The coprimary endpoints for the study are agreement between the two sampling techniques for three microbiological parameters: reported presence of likely isolates identified by the UK Health Protection Agency; resistance of isolates to usual antibiotic agents; and, the number of isolates reported per specimen. Secondary endpoints include appropriateness of the empiric antibiotic therapy prescribed and adverse events. Enrolling 400 patients will provide 80% power to detect a difference of 3% in the reported presence of an organism, assuming organism prevalence of 10%, discordance of 5% and a two-sided test at the 5% level of significance. Assumed overall prevalence is based on relatively uncommon organisms such as Pseudomonas. We will define acceptable agreement as κ>0.6.
Ethics and dissemination
Concordance in diabetic foot ulcer infection (CODIFI) will produce robust data to evaluate the two most commonly used sampling techniques employed for patients with a diabetic foot infection. This will help determine whether or not it is important that clinicians take tissue samples rather than swabs in infected ulcers. This study has been approved by the Sheffield NRES Committee (Ref: 11/YH/0078) and all sites have obtained local approvals prior starting recruitment.
NRES Ref: 11/YH/0078, UKCRN ID: 10440, ISRCTN: 52608451
Mental well-being now features prominently in UK and international health policy. However, progress has been hampered by lack of valid measures that are responsive to change. The objective of this study was to evaluate the responsiveness of the Warwick Edinburgh Mental Well-being Scale (WEMWBS) at both the individual and group level.
Secondary analysis of twelve different interventional studies undertaken in different populations using WEMWBS as an outcome measure. Standardised response mean (SRM), probability of change statistic (P̂) and standard error of measurement (SEM) were used to evaluate whether WEMWBS detected statistically important changes at the group and individual level, respectively.
Mean change in WEMWBS score ranged from −0.6 to 10.6. SRM ranged from −0.10 (95% CI: -0.35, 0.15) to 1.35 (95% CI: 1.06, 1.64). In 9/12 studies the lower limit of the 95% CI for P̂ was greater than 0.5, denoting responsiveness. SEM ranged from 2.4 to 3.1 units, and at the threshold 2.77 SEM, WEMWBS detected important improvement in at least 12.8% to 45.7% of participants (lower limit of 95% CI>5.0%).
WEMWBS is responsive to changes occurring in a wide range of mental health interventions undertaken in different populations. It offers a secure base for research and development in this rapidly evolving field. Further research using external criteria of change is warranted.
Well-being; WEMBWBS; Responsiveness; Sensitivity to change
Establishing healthy physical activity (PA) behaviours in early childhood is important for future PA behaviours. Parents play a central role in young children’s PA. However, there is currently little research on parenting interventions to increase child PA. This study was formative work to inform the content of a pilot randomised-controlled trial.
In-depth telephone interviews were carried out with 32 parents of 6 to 8 year old children residing in two areas that varied in their socio-economic characteristics, in Bristol, UK. Data were analysed thematically using a framework approach.
Most parents described their child as being active or very active and indicated that they did not perceive a need for an increase in their child’s PA. Parents used a variety of visual cues to make this judgement, the most common being that they perceived their child as having lots of energy or that they did not view them as overweight. Parents reported environmental factors such as monetary cost, time constraints, lack of activity provision and poor weather as the main barriers to their child’s PA. Parental support and child’s enjoyment of PA appeared to be important facilitators to children participating in PA.
Improving parents’ knowledge of the PA recommendations for children, and increasing their awareness of the benefits of PA beyond weight status may be an important first step for a parenting PA intervention. Although parents commonly perceive environmental factors as the main barriers to their child’s PA, parental concern about low levels of child PA, their capacity to support behaviour change, child motivation, self confidence and independence may be key areas to address within an intervention to increase child PA. Effective methods of helping parents address the latter have been developed in the context of generic parenting programmes.
Physical activity; Parenting; Intervention
Background: Lipoxygenases (LOXs) generate eicosanoids in inflammation.
Results: Monocyte/macrophage LOXs generate novel phospholipid-esterified eicosanoids containing ketoeicosatetraenoic acid or hydroperoxyeicosatetraenoic acid. They activate peroxisome proliferator-activated receptor-γ transcriptional activity and are found in cystic fibrosis bronchoalveolar fluid.
Significance: LOXs generate esterified eicosanoids in vitro and in vivo.
Conclusion: These new lipids represent new families of bioactive mediators.
12/15-Lipoxygenases (LOXs) in monocytes and macrophages generate novel phospholipid-esterified eicosanoids. Here, we report the generation of two additional families of related lipids comprising 15-ketoeicosatetraenoic acid (KETE) attached to four phosphatidylethanolamines (PEs). The lipids are generated basally by 15-LOX in IL-4-stimulated monocytes, are elevated on calcium mobilization, and are detected at increased levels in bronchoalveolar lavage fluid from cystic fibrosis patients (3.6 ng/ml of lavage). Murine peritoneal macrophages generate 12-KETE-PEs, which are absent in 12/15-LOX-deficient mice. Inhibition of 15-prostaglandin dehydrogenase prevents their formation from exogenous 15-hydroxyeicosatetraenoic acid-PE in human monocytes. Both human and murine cells also generated analogous hydroperoxyeicosatetraenoic acid-PEs. The electrophilic reactivity of KETE-PEs is shown by their Michael addition to glutathione and cysteine. Lastly, both 15-hydroxyeicosatetraenoic acid-PE and 15-KETE-PE activated peroxisome proliferator-activated receptor-γ reporter activity in macrophages in a dose-dependent manner. In summary, we demonstrate novel peroxisome proliferator-activated receptor-γ-activating oxidized phospholipids generated enzymatically by LOX and 15-prostaglandin dehydrogenase in primary monocytic cells and in a human Th2-related lung disease. The lipids are a new family of bioactive mediators from the 12/15-LOX pathway that may contribute to its known anti-inflammatory actions in vivo.
Eicosanoid; Innate Immunity; Lipoxygenase Pathway; Macrophages; Mass Spectrometry (MS); Monocytes; Phospholipid
According to the UK Adult Dental Health Survey (2009) 15% of adults aged 65–74, 30% aged 75–84 and 47% aged >85 years are edentulous and require complete dentures. Patients’ quality of life and nutrition status are affected by poor dentures. The quality of the dental impression is the most important issue for improving the fit and comfort of new dentures. There is paucity of RCT evidence for which impression material is best for complete dentures construction. This study aims to compare two impression materials for effectiveness and cost effectiveness.
IMPROVDENT is a double-blind crossover trial comparing the use of alginate and silicone, two commonly used denture impression materials, in terms of patient preference and cost-effectiveness. Eighty five edentulous patients will be recruited and provided with two sets of dentures, similar in all aspects except for the impression material used (alginate or silicone). Patients will try both sets of dentures for a two-week period, unadjusted, to become accustomed to the feel of the new dentures (habituation period). Patients will then wear each set of dentures for a period of 8 weeks (in random order) during which time the dentures will be adjusted for optimum comfort. Finally, patients will be given both sets of dentures for a further two weeks to wear whichever denture they prefer (confirmation period).
Patients will be asked about quality of life and to rate dentures on function and comfort at the end of each trial period and asked which set they prefer at the end of the habituation period (unadjusted denture preference) and confirmation period (adjusted denture preference). A health economic evaluation will estimate incremental cost-effectiveness ratios of producing dentures from the two materials. A qualitative study will investigate the impact of dentures on behaviour and quality of life.
Funding: IMPROVDENT is funded by NIHR RfPB (PB-PG-0408-16300).
This trial aims to provide evidence on the costs and quality of dentures cast from two different commonly used impression materials; the intention is to significantly impact on the quality of denture production within NHS dentistry.
ISRCTN Register: ISRCTN01528038
UKCRN Portfolio ID: 8305
Complete dentures; Edentulous; Impression material; Cost-effectiveness; Crossover trial
Recent developments aiming to standardise and streamline processes of gaining the necessary approvals to carry out research in the National Health Service (NHS) in the United Kingdom (UK), have resulted in lengthy and costly delays. The national UK governmental Department of Health’s Research Governance Framework (RGF) for Health and Social Care requires that appropriate checks be conducted before research involving human participants, their organs, tissues or data can commence in the NHS. As a result, medical research has been subjected to increased regulation and governance, with the requirement for approvals from numerous regulatory and monitoring bodies. In addition, the processes and outcomes of the attribution of costs in NHS research have caused additional difficulties for researchers. The purpose of this paper is to illustrate, through three trial case studies, the difficulties encountered during the set-up and recruitment phases of these trials, related to gaining the necessary ethical and governance approvals and applying for NHS costs to undertake and deliver the research.
Empirical evidence about delays and difficulties related to regulation and governance of medical research was gathered during the period 2009–2010 from three UK randomised controlled trials with sites in England, Wales and Scotland (1. SAFER 2- an emergency care based trial of a protocol for paramedics to refer patients directly to community based falls services; 2. COnStRUCT- a trial of two drugs for acute ulcerative colitis; and 3. Family Links - a trial of a public health intervention, a 10 week community based parenting programme). Findings and recommendations were reported in response to a call for evidence from The Academy of Medical Sciences regarding difficulties encountered in conducting medical research arising from R&D governance and regulation, to inform national policy.
Difficulties and delays in navigating and gaining the appropriate approvals and NHS costs required to undertake the research were encountered in all three trials, at various points in the bureaucratic processes of ethical and research and information governance approvals. Conduct of each of the three trials was delayed by at least 12 months, with costs increasing by 30 – 40%.
Whilst the three trials encountered a variety of challenges, there were common issues. The processes for gaining approvals were overly complex and differed between sites and UK countries; guidance about processes was unclear; and information regarding how to define and claim NHS costs for undertaking the research was inconsistent. The competitive advantage of a publicly funded, open access health system for undertaking health services research and clinical trials within the UK has been outweighed in recent years by stifling bureaucratic structures and processes for governance of research. The recommendations of the Academy of Medical Sciences are welcomed, and the effects of their implementation are awaited with interest.
Trial Registration numbers
SAFER 2: ISRCTN 60481756; COnStRUCT: ISRCTN22663589; Family Links: ISRCTN 13929732
Many children do not engage in sufficient levels of physical activity (PA) and spend too much time screen-viewing (SV). High levels of SV (e.g. watching TV, playing video games and surfing the internet) and low levels of PA have been associated with adverse health outcomes. Parenting courses may hold promise as an intervention medium to change children’s PA and SV. The current study was formative work conducted to design a new parenting programme to increase children’s PA and reduce their SV. Specifically, we focussed on interest in a course, desired content and delivery style, barriers and facilitators to participation and opinions on control group provision.
In-depth telephone interviews were conducted with thirty two parents (29 female) of 6–8 year olds. Data were analysed thematically. An anonymous online survey was also completed by 750 parents of 6–8 year old children and descriptive statistics calculated.
Interview participants were interested in a parenting course because they wanted general parenting advice and ideas to help their children be physically active. Parents indicated that they would benefit from knowing how to quantify their child’s PA and SV levels. Parents wanted practical ideas of alternatives to SV. Most parents would be unable to attend unless childcare was provided. Schools were perceived to be a trusted source of information about parenting courses and the optimal recruitment location. In terms of delivery style, the majority of parents stated they would prefer a group-based approach that provided opportunities for peer learning and support with professional input. Survey participants reported the timing of classes and the provision of childcare were essential factors that would affect participation. In terms of designing an intervention, the most preferred control group option was the opportunity to attend the same course at a later date.
Parents are interested in PA/SV parenting courses but the provision of child care is essential for attendance. Recruitment is likely to be facilitated via trusted sources. Parents want practical advice on how to overcome barriers and suggest advice is provided in a mutually supportive group experience with expert input.
Parenting; Physical activity; TV; Intervention
Cystic fibrosis (CF) is characterized by bronchoalveolar neutrophilia and submucosal lymphocytosis. We hypothesized that Th17 lymphocytes are part of this submucosal infiltrate.
Quantification and phenotyping of the lymphocytic infiltrate in the bronchial submucosa of patients with CF (n=53, of which 20 were newly diagnosed), non-CF bronchiectasis (n = 17), and healthy control subjects (n = 13).
We measured IL-17 levels in bronchoalveolar lavage and CD4+, CD8+, and IL-17+ cell counts in endobronchial biopsies. Correlations were made with infection status and other inflammatory markers. Potential cellular sources of IL-17 were determined by double staining.
Measurements and Main Results
IL-17+ cell counts (median [interquartile range] cells/mm2) were significantly higher in patients with established CF (205 [115–551]) and non-CF bronchiectasis (245 [183–436]) than in control subjects (53 [12–82]) (P<0.01 for both). Patients with newly diagnosed CF had intermediate counts (171 [91–252]). IL-17–positive CD4+ T cells, γδT cells, natural killer T cells, and neutrophils were identified. Bronchoalveolar lavage IL-17 levels (pg/ml) were highest in established CF (14.6 [2.2–38.4]), low in newly diagnosed CF and control subjects (1.7 [1.7–1.74]; 1.7 [1.7–3]), and intermediate in non-CF bronchiectasis (9.1 [1.7–34] pg/ml) (Kruskal-Wallis P = 0.001). There was a significant correlation between IL-17 and neutrophil counts (P < 0.001, R = 0.6) as well as IL-4 (P < 0.001, R = 0.84).
Th17 lymphocytes are present in the airway submucosa in CF, even in a young, newly diagnosed group. Other IL-17+ cells include neutrophils, γδ T cells, and natural killer T cells.
Th17 cells; cystic fibrosis; inflammation
Norbuprenorphine-3-β-D-glucuronide (nBPN-3-β-D-G, 1) is a major phase II metabolite of buprenorphine, a pharmaceutical used for the treatment of opioid addiction. The pharmacological activity of compound 1 is not clear because investigations have been limited by the lack of chemically pure, well characterized 1 in sufficient quantities for in vitro and in vivo experiments. This work describes two concise, new methods of synthesis of 1, a chemical and an enzyme-assisted synthesis. The chemical synthesis used a strategy based on a combination of Koenig-Knorr coupling and amino-silyl protection. The enzyme-assisted synthesis used dog liver to convert substrate norbuprenorphine (nBPN, 2) to 1. Both methods provided 1, characterized by 1H NMR and tandem mass spectrometry, with purity >96%. The fractional yield of the enzyme-assisted synthesis was greater than that of the chemical synthesis (67% vs 5.3%), but due to larger reaction volumes, the chemical synthesis afforded greater amounts of total 1.
Childhood physical abuse (CPA) has numerous short and long-term negative effects. One of the most serious consequences of CPA is an increased risk for suicide attempts. Clarifying the mechanisms by which CPA increases risk for suicidal behavior may enhance preventative interventions. One potential mechanism is a tendency toward aggression. In a sample of 266 criminal offenders, ages 18–62, we examined the relationships among CPA, lifetime aggression, and suicide attempts and tested lifetime history of aggression as a mediator of the relationship between CPA and suicide attempts. Results indicated that CPA and aggression were associated with suicide attempts. Consistent with our hypothesis, lifetime aggression mediated the CPA-suicide attempt relationship. Findings suggest that aggression may be an important mediator of the relationship between CPA and suicide attempts among criminal offenders, and are consistent with the possibility that treating aggression may reduce risk for suicide attempts.
child abuse; aggression; suicide; violence; offenders
Liposome-based chemotherapeutics used in the treatment of breast cancer can in principle enhance the therapeutic index of otherwise unencapsulated anticancer drugs. This is partially attributed to the fact that encapsulation of cytotoxic agents within liposomes allows for increased concentrations of the drug to be delivered to the tumor site. In addition, the presence of the phospholipid bilayer prevents the encapsulated active form of the drug from being broken down in the body prior to reaching tumor tissue and also serves to minimize exposure of the drug to healthy sensitive tissue. While clinically approved liposome-based chemotherapeutics such as Doxil have proven to be quite effective in the treatment of breast cancer, significant challenges remain involving poor drug transfer between the liposome and cancerous cells. In this review, we discuss the recent advancements made in the development of liposome-based chemotherapeutics with respect to improved drug transfer for use in breast cancer therapy.