Complement C3 variant and the risk of age-related macular degeneration

Background: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.Methods: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.Results: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9 x 10(sup -5)) and the Scottish group (244 cases and 351 controls, P=5.0 x 10(sup -5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.Conclusions: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease

Computed cardiopulmonography and the idealized lung clearance index, iLCI2.5, in early-stage cystic fibrosis.

This study explored the use of computed cardiopulmonography (CCP) to assess lung function in early-stage cystic fibrosis (CF). CCP has two components. The first is a particularly accurate technique for measuring gas exchange. The second is a computational cardiopulmonary model where patient-specific parameters can be estimated from the measurements of gas exchange. Twenty-five participants (14 healthy controls, 11 early-stage CF) were studied with CCP. They were also studied with a standard clinical protocol to measure the lung clearance index (LCI2.5). Ventilation inhomogeneity, as quantified through CCP parameter σlnCl, was significantly greater (P < 0.005) in CF than in controls, and anatomical deadspace relative to predicted functional residual capacity (DS/FRCpred) was significantly more variable (P < 0.002). Participant-specific parameters were used with the CCP model to calculate idealized values for LCI2.5 (iLCI2.5) where extrapulmonary influences on the LCI2.5, such as breathing pattern, had all been standardized. Both LCI2.5 and iLCI2.5 distinguished clearly between CF and control participants. LCI2.5 values were mostly higher than iLCI2.5 values in a manner dependent on the participant's respiratory rate (r = 0.46, P < 0.05). The within-participant reproducibility for iLCI2.5 appeared better than for LCI2.5, but this did not reach statistical significance (F ratio = 2.2, P = 0.056). Both a sensitivity analysis on iLCI2.5 and a regression analysis on LCI2.5 revealed that these depended primarily on an interactive term between CCP parameters of the form σlnCL*(DS/FRC). In conclusion, the LCI2.5 (or iLCI2.5) probably reflects an amalgam of different underlying lung changes in early-stage CF that would require a multiparameter approach, such as potentially CCP, to resolve.NEW & NOTEWORTHY Computed cardiopulmonography is a new technique comprising a highly accurate sensor for measuring respiratory gas exchange coupled with a cardiopulmonary model that is used to identify a set of patient-specific characteristics of the lung. Here, we show that this technique can improve on a standard clinical approach for lung function testing in cystic fibrosis. Most particularly, an approach incorporating multiple model parameters can potentially separate different aspects of pathological change in this disease

A systematic review and narrative synthesis of footwear and orthotic devices used in the management of ankle haemarthrosis and haemarthropathy in haemophilia

Introduction Haemarthrosis is a clinical feature of haemophilia leading to haemarthropathy. The ankle joint is most commonly affected, resulting in significant pain, disability and a reduction in health-related quality of life. Footwear and orthotic devices are effective in other diseases that affect the foot and ankle, such as rheumatoid arthritis, but little is known about their effect in haemophilia. Aims To review the efficacy and effectiveness of footwear and orthotic devices in the management of ankle joint haemarthrosis and haemarthropathy in haemophilia. Methods A systematic literature review was conducted. Two review authors independently screened studies for inclusion and appraised methodological quality using Joanna Briggs Institute Critical Appraisal checklists. A narrative analysis was undertaken. Results Ten studies involving 271 male participants were eligible for inclusion. All studies were quasi-experimental; three employed a within-subject design. Two studies included an independent comparison or control group. A range of footwear and orthotic devices were investigated. Limited evidence from non-randomised studies suggested that footwear and orthotic devices improve the number of ankle joint bleeding episodes, gait parameters, and patient-reported pain. Conclusion This review demonstrates a lack of robust evidence regarding the efficacy and effectiveness of footwear and orthotic devices in the management of ankle joint haemarthrosis and haemarthropathy in haemophilia. Methodological heterogeneities and limitations with the study designs, small sample sizes and limited follow-up of participants exist. Future studies utilising randomised designs, larger sample sizes, long-term follow-up, and validated patient-reported outcome measures are needed to inform the clinical management of ankle joint haemarthrosis and haemarthropathy

The 'Switch' study protocol: a randomised-controlled trial of switching to an alternative tumour-necrosis factor (TNF)-inhibitor drug or abatacept or rituximab in patients with rheumatoid arthritis who have failed an initial TNF-inhibitor drug

Background: Rheumatoid Arthritis (RA) is one of the most common autoimmune diseases, affecting approximately 1% of the UK adult population. Patients suffer considerable pain, stiffness and swelling and can sustain various degrees of joint destruction, deformity, and significant functional decline. In addition, the economic burden due to hospitalisation and loss of employment is considerable, with over 50% of patients being work-disabled within 10 years of diagnosis. Despite several biologic disease modifying anti-rheumatic drugs (bDMARD) now available, there is a lack of data to guide biologic sequencing. In the UK, second-line biologic treatment is restricted to a single option, rituximab. The aim of the SWITCH trial is to establish whether an alternative-mechanism-TNF-inhibitor (TNFi) or abatacept are as effective as rituximab in patients with RA who have failed an initial TNFi drug. Methods/Design: SWITCH is a pragmatic, phase IV, multi-centre, parallel-group design, open-label, randomised, controlled trial (RCT) comparing alternative-mechanism-TNFi and abatacept with rituximab in patients with RA who have failed an initial TNFi drug. Participants are randomised in a 1:1:1 ratio to receive alternative mechanism TNFi, (monoclonal antibodies: infliximab, adalimumab, certolizumab or golimumab or the receptor fusion protein, etanercept), abatacept or rituximab during the interventional phase (from randomisation up to week 48). Participants are subsequently followed up to a maximum of 96 weeks, which constitutes the observational phase. The primary objective is to establish whether an alternative-mechanism-TNFi or abatacept are non-inferior to rituximab in terms of disease response at 24 weeks post randomisation. The secondary objectives include the comparison of alternative-mechanism-TNFi and abatacept to rituximab in terms of disease response, quality of life, toxicity, safety and structural and bone density outcomes over a 12-month period (48 weeks) and to evaluate the cost-effectiveness of switching patients to alternative active therapies compared to current practice. Discussion: SWITCH is a well-designed trial in this therapeutic area that aims to develop a rational treatment algorithm to potentially inform personalised treatment regimens (as opposed to switching all patients to only one available (and possibly unsuccessful) therapy), which may lead to long-term improved patient outcomes and gains in population health

The foot posture index, ankle lunge test, Beighton scale and the lower limb assessment score in healthy children: a reliability study

<p>Abstract</p> <p>Background</p> <p>Outcome measures are important when evaluating treatments and physiological progress in paediatric populations. Reliable, relevant measures of foot posture are important for such assessments to be accurate over time. The aim of the study was to assess the intra- and inter-rater reliability of common outcome measures for paediatric foot conditions.</p> <p>Methods</p> <p>A repeated measures, same-subject design assessed the intra- and inter-rater reliability of measures of foot posture, joint hypermobility and ankle range: the Foot Posture Index (FPI-6), the ankle lunge test, the Beighton scale and the lower limb assessment scale (LLAS), used by two examiners in 30 healthy children (aged 7 to 15 years). The Oxford Ankle Foot Questionnaire (OxAFQ-C) was completed by participants and a parent, to assess the extent of foot and ankle problems.</p> <p>Results</p> <p>The OxAFQ-C demonstrated a mean (SD) score of 6 (6) in adults and 7(5) for children, showing good agreement between parents and children, and which indicates mid-range (transient) disability. Intra-rater reliability was good for the FPI-6 (ICC = 0.93 - 0.94), ankle lunge test (ICC = 0.85-0.95), Beighton scale (ICC = 0.96-0.98) and LLAS (ICC = 0.90-0.98). Inter-rater reliability was largely good for each of the: FPI-6 (ICC = 0.79), ankle lunge test (ICC = 0.83), Beighton scale (ICC = 0.73) and LLAS (ICC = 0.78).</p> <p>Conclusion</p> <p>The four measures investigated demonstrated adequate intra-rater and inter-rater reliability in this paediatric sample, which further justifies their use in clinical practice.</p

Designing an automated clinical decision support system to match clinical practice guidelines for opioid therapy for chronic pain

Abstract Background Opioid prescribing for chronic pain is common and controversial, but recommended clinical practices are followed inconsistently in many clinical settings. Strategies for increasing adherence to clinical practice guideline recommendations are needed to increase effectiveness and reduce negative consequences of opioid prescribing in chronic pain patients. Methods Here we describe the process and outcomes of a project to operationalize the 2003 VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Non-Cancer Pain into a computerized decision support system (DSS) to encourage good opioid prescribing practices during primary care visits. We based the DSS on the existing ATHENA-DSS. We used an iterative process of design, testing, and revision of the DSS by a diverse team including guideline authors, medical informatics experts, clinical content experts, and end-users to convert the written clinical practice guideline into a computable algorithm to generate patient-specific recommendations for care based upon existing information in the electronic medical record (EMR), and a set of clinical tools. Results The iterative revision process identified numerous and varied problems with the initially designed system despite diverse expert participation in the design process. The process of operationalizing the guideline identified areas in which the guideline was vague, left decisions to clinical judgment, or required clarification of detail to insure safe clinical implementation. The revisions led to workable solutions to problems, defined the limits of the DSS and its utility in clinical practice, improved integration into clinical workflow, and improved the clarity and accuracy of system recommendations and tools. Conclusions Use of this iterative process led to development of a multifunctional DSS that met the approval of the clinical practice guideline authors, content experts, and clinicians involved in testing. The process and experiences described provide a model for development of other DSSs that translate written guidelines into actionable, real-time clinical recommendations.http://deepblue.lib.umich.edu/bitstream/2027.42/78267/1/1748-5908-5-26.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/2/1748-5908-5-26.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/3/1748-5908-5-26-S3.TIFFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/4/1748-5908-5-26-S2.TIFFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/5/1748-5908-5-26-S1.TIFFPeer Reviewe

Annotation of two large contiguous regions from the Haemonchus contortus genome using RNA-seq and comparative analysis with Caenorhabditis elegans

The genomes of numerous parasitic nematodes are currently being sequenced, but their complexity and size, together with high levels of intra-specific sequence variation and a lack of reference genomes, makes their assembly and annotation a challenging task. Haemonchus contortus is an economically significant parasite of livestock that is widely used for basic research as well as for vaccine development and drug discovery. It is one of many medically and economically important parasites within the strongylid nematode group. This group of parasites has the closest phylogenetic relationship with the model organism Caenorhabditis elegans, making comparative analysis a potentially powerful tool for genome annotation and functional studies. To investigate this hypothesis, we sequenced two contiguous fragments from the H. contortus genome and undertook detailed annotation and comparative analysis with C. elegans. The adult H. contortus transcriptome was sequenced using an Illumina platform and RNA-seq was used to annotate a 409 kb overlapping BAC tiling path relating to the X chromosome and a 181 kb BAC insert relating to chromosome I. In total, 40 genes and 12 putative transposable elements were identified. 97.5% of the annotated genes had detectable homologues in C. elegans of which 60% had putative orthologues, significantly higher than previous analyses based on EST analysis. Gene density appears to be less in H. contortus than in C. elegans, with annotated H. contortus genes being an average of two-to-three times larger than their putative C. elegans orthologues due to a greater intron number and size. Synteny appears high but gene order is generally poorly conserved, although areas of conserved microsynteny are apparent. C. elegans operons appear to be partially conserved in H. contortus. Our findings suggest that a combination of RNA-seq and comparative analysis with C. elegans is a powerful approach for the annotation and analysis of strongylid nematode genomes

A survey on knowledge and self-reported formula handling practices of parents and child care workers in Palermo, Italy

Powdered infant formula (PIF) is not a sterile product, but this information appears to be poorly diffused among child caregivers. Parents and child care workers may behave in an unsafe manner when handling PIF. Methods: This study involved parents and child care workers in the 24 municipal child care centres of Palermo. Knowledge and self-reported practices about PIF handling were investigated by a structured questionnaire. A Likert scale was used to measure the strength of the respondent's feelings. Association of knowledge and self-reported practices with demographic variables was also evaluated. Results: 42.4% of parents and 71.0% of child care workers filled in the questionnaire. Significant differences were found between parents and child care workers for age and education. 73.2% of parents and 84.4% of child care workers were confident in sterility of PIF. Generally, adherence to safe procedures when reconstituting and handling PIF was more frequently reported by child care workers who, according to the existing legislation, are regularly subjected to a periodic training on food safety principles and practices. Age and education significantly influenced the answers to the questionnaire of both parents and child care workers. Conclusion: The results of the study reveal that parents and child care workers are generally unaware that powdered formulas may contain viable microorganisms. However, child care workers consistently chose safer options than parents when answering the questions about adherence to hygienic practices. At present it seems unfeasible to produce sterile PIF, but the risk of growth of hazardous organisms in formula at the time of administration should be minimized by promoting safer behaviours among caregivers to infants in both institutional settings and home. \ua9 2009 Calamusa et al; licensee BioMed Central Ltd

The paediatric flat foot and general anthropometry in 140 Australian school children aged 7 - 10 years

<p>Abstract</p> <p>Background</p> <p>Many studies have found a positive relationship between increased body weight and flat foot posture in children.</p> <p>Methods</p> <p>From a study population of 140 children aged seven to 10 years, a sample of 31 children with flat feet was identified by screening with the FPI-6. Basic anthropometric measures were compared between subjects with and without flat feet as designated.</p> <p>Results</p> <p>The results of this study, in contrast to many others, question the association of flat feet and heavy children. A significant relationship between foot posture and weight (FPI (L) r = -0.186 (p < 0.05), FPI(R) r = -0.194 (p < 0.05), waist girth (FPI (L) r = -0.213 (p < 0.05), FPI(R) r = -0.228 (p < 0.01) and BMI (FPI (L) r = -0.243 (p < 0.01), FPI(R) r = -0.263 (p < 0.01) was identified, but was both weak and inverse.</p> <p>Conclusions</p> <p>This study presents results which conflict with those of many previous investigations addressing the relationship between children's weight and foot posture. In contrast to previous studies, the implication of these results is that heavy children have less flat feet. Further investigation is warranted using a standardized approach to assessment and a larger sample of children to test this apparent contradiction.</p