Heat-Triggered Remote Control of CRISPR-dCas9 for Tunable Transcriptional Modulation.

CRISPR-associated proteins (Cas) are enabling powerful new approaches to control mammalian cell functions, yet the lack of spatially defined, noninvasive modalities limits their use as biological tools. Here, we integrate thermal gene switches with dCas9 complexes to confer remote control of gene activation and suppression with short pulses of heat. Using a thermal switch constructed from the heat shock protein A6 (HSPA6) locus, we show that a single heat pulse 3-5 °C above basal temperature is sufficient to trigger expression of dCas9 complexes. We demonstrate that dCas9 fused to the transcriptional activator VP64 is functional after heat activation, and, depending on the number of heat pulses, drives transcription of endogenous genes GzmB and CCL21 to levels equivalent to that achieved by a constitutive viral promoter. Across a range of input temperatures, we find that downstream protein expression of GzmB closely correlates with transcript levels (R2 = 0.99). Using dCas9 fused with the transcriptional suppressor KRAB, we show that longitudinal suppression of the reporter d2GFP depends on key thermal input parameters including pulse magnitude, number of pulses, and dose fractionation. In living mice, we extend our study using photothermal heating to spatially target implanted cells to suppress d2GFP in vivo. Our study establishes a noninvasive and targeted approach to harness Cas-based proteins for modulation of gene expression to complement current methods for remote control of cell function.

All-Cause Mortality for Life Insurance Applicants with a History of Breast Cancer.

Breast cancer is the most commonly diagnosed cancer worldwide. Breast cancer is also the second leading cause of cancer death among women in the United States after lung cancer with over 40,000 breast cancer deaths occurring each year. The purpose of this research was to determine the all-cause mortality of applicants diagnosed with breast cancer currently or at some time in the past. Life insurance applicants with reported breast cancer were extracted from data covering United States residents between November 2007 and November 2014. Information about these applicants was matched to the Social Security Death Master (SSDMF) file for deaths occurring from 2007 to 2011 and to another commercially available death source file (Other Death Source, ODS) for deaths occurring from 2007 to 2014 to determine vital status. If there was a death from the other death source, then the SSDMF was searched to verify the death. The study had approximately 561,000 person-years of exposure. Actual-to-expected (A/E) mortality ratios were calculated using the Society of Actuaries 2008 Valuation Basic Table (2008VBT), select and ultimate table (age last birthday) and the 2010 US population as expected mortality ratios. Since the A/Es presented in this paper were known to be an underestimate due to the exclusion of the recent SSDMF deaths, comparative analysis of the mortality ratios was done. Since there was no smoking status information in this study, all expected bases were not smoker distinct. Overall, the 35-44 age group had 6.3 times the relative mortality ratio than those in the 65-75 age group. The relative mortality ratio for the 35-44 age group applicants, when cancer severity was accounted for in combination with 3 or more nodes of cancer involvement, was 29.3 times that when compared to those in the 65-75 age group having localized cancer, where no nodes are involved. The 35-44 age group applicants who were diagnosed with cancer within the last year had over 10-fold increase in relative mortality ratios compared to the 65-75 age group, who were over 10 years from diagnosis. Taking the severity of cancer along with time from diagnosis showed over a 12 times relative mortality ratio between the low rate of over 10 years from diagnosis and localized involvement to those diagnosed within the last year having 3 or more nodes with cancer. Applicant age, time since diagnosis and cancer severity were the most significant variables to predict the relative mortality ratios.

What influences the implementation of the New Zealand stroke guidelines for physiotherapists and occupational therapists?

Purpose To explore perceived barriers and facilitators to the use of the New Zealand (NZ) stroke guidelines by occupational therapists and physiotherapists. Methods A qualitative descriptive methodology was used. Eligible physiotherapists and occupational therapists (NZ registered, working in one of two hospitals, treating at least 10 patients with stroke in the previous year) were invited to participate in semi-structured interviews to elicit their perceptions of the utility and feasibility of the NZ stroke guidelines and identify barriers and facilitators to their implementation. All interviews were audio-recorded and transcribed. Conventional content analysis with constant comparative methods was used for coding and analysis. Results The main themes influencing guideline implementation were resources and characteristics of the guidelines, the organization, the patient and family and the therapist. Insufficient resources were a major barrier that crossed many of the themes. Participants suggested a range of strategies relating to the organization to improve therapists' alignment to the guidelines. Conclusion Alignment to the guidelines in NZ is influenced both positively and negatively by a range of interacting factors, consistent with other studies. Alignment might be improved by the introduction of some relatively simple strategies, such as ring-fencing time for access to resources and training in the use of the guidelines. Many of the barriers and related interventions are likely to be more complex. Implications for rehabilitation Alignment with stroke guidelines has been shown to improve patient outcomes. Therapist alignment with the implementation of the New Zealand stroke guidelines is influenced by guideline characteristics, organizational characteristics, resources, patient and family characteristics and therapist characteristics. Frequently encountered barriers related to limited resources, particularly time. Ring-fencing regular time for access to resources and training in the use of guidelines are examples of simple strategies that may reduce barriers.

All-Cause Mortality for Diabetics or Individuals with Hyperglycemia Applying for Life Insurance.

Diabetics and individuals with lab results consistent with a diagnosis of diabetes or hyperglycemia were extracted from data covering US residents who applied for life insurance between January 2007 and January 2014. Information about these applicants was matched to the Social Security Death Master File (SSDMF) and another commercially available death source file to determine vital status. Due to the inconsistencies of reporting within the death files, there were two cohorts of death cases, one including the imputed year of birth (full cohort of deaths), and the second where the date of birth was known (reduced cohort of deaths). The study had approximately 8.5 million person-years of exposure. Actual to expected (A/E) mortality ratios were calculated using the Society of Actuaries 2008 Valuation Basic Table (2008VBT) select table, age last birthday and the 2010 US population as expected mortality rates. With the 2008VBT as an expected basis, the overall A/E mortality ratio was 3.15 for the full cohort of deaths and 2.56 for the reduced cohort of deaths. Using the US population as the expected basis, the overall A/E mortality ratio was 0.98 for the full cohort of deaths and 0.79 for the reduced cohort. Since there was no smoking status information in this study, all expected bases were not smoker distinct. A/E mortality ratios varied by disease treatment category and were considerably higher in individuals using insulin. A/E mortality ratios decreased with increasing age and took on a J-shaped distribution with increasing BMI (Body Mass Index). The lowest mortality ratios were observed for overweight and obese individuals. The A/E mortality ratio based on the 2008VBT decreased with the increase in applicant duration, which was defined as the time since initial life insurance application.

Transparency in drug regulation: public assessment reports in Europe and Australia.

Openness and transparency are important considerations for medicines regulators, where public health is of paramount concern. As part of their commitment to transparency, the European Medicines Agency (EMA) and Therapeutic Goods Administration (TGA) in Australia publish information relating to their evaluation of medicines via public assessment reports. European Public Assessment Reports (EPARs) and Australian Public Assessment Reports (AusPARs) provide information about the considerations that led the regulator to approve or refuse the application. The reports summarise assessments by each regulator of the information provided on the quality, safety, and efficacy of the medicine under evaluation. Here, we describe the experiences of two established medicines regulators in publishing public assessment reports, and reflect on their future role in communicating medicines information.

Managing Safety and Operations: The Effect of Joint Management System Practices on Safety and Operational Outcomes.

OBJECTIVE: The aim of this study was to determine whether management system practices directed at both occupational health and safety (OHS) and operations (joint management system [JMS] practices) result in better outcomes in both areas than in alternative practices. METHODS: Separate regressions were estimated for OHS and operational outcomes using data from a survey along with administrative records on injuries and illnesses. RESULTS: Organizations with JMS practices had better operational and safety outcomes than organizations without these practices. They had similar OHS outcomes as those with operations-weak practices, and in some cases, better outcomes than organizations with safety-weak practices. They had similar operational outcomes as those with safety-weak practices, and better outcomes than those with operations-weak practices. CONCLUSIONS: Safety and operations appear complementary in organizations with JMS practices in that there is no penalty for either safety or operational outcomes.

A cost-benefit analysis of peer coaching for overhead lift use in the long-term care sector in Canada.

OBJECTIVES: To evaluate whether a peer-coaching programme for patient lift use in British Columbia, Canada, was effective and cost-beneficial. METHODS: We used monthly panel data from 15 long-term care facilities from 2004 to 2011 to estimate the number of patient-handling injuries averted by the peer-coaching programme using a generalised estimating equation model. Facilities that had not yet introduced the programme served as concurrent controls. Accepted lost-time claim counts related to patient handling were the outcome of interest with a denominator of full-time equivalents of nursing staff. A cost-benefit approach was used to estimate the net monetary gains at the system level. RESULTS: The coaching programme was found to be associated with a reduction in the injury rate of 34% during the programme and 56% after the programme concluded with an estimated 62 lost-time injury claims averted. 2 other factors were associated with changes in injury rates: larger facilities had a lower injury rate, and the more care hours per bed the lower the injury rate. We calculated monetary benefits to the system of $748 431 and costs of $894 000 (both in 2006 Canadian dollars) with a benefit-to-cost ratio of 0.84. The benefit-to-cost ratio was -0.05 in the worst case scenario and 2.31 in the best case scenario. The largest cost item was peer coaches' time. A simulation of the programme continuing for 5 years with the same coaching intensity would result in a benefit-to-cost ratio of 0.63. CONCLUSIONS: A peer-coaching programme to increase effective use of overhead lifts prevented additional patient-handling injuries but added modest incremental cost to the system.

The cost of lost productivity due to fetal alcohol spectrum disorder-related premature mortality.

BACKGROUND: Individuals with Fetal Alcohol Spectrum Disorder (FASD) have increased mortality as compared to the general population. OBJECTIVES: To estimate the productivity losses due to premature mortality of individuals with FASD in Canada in 2011. METHODS: A demographic approach with a counterfactual scenario in which nobody in Canada is born with FASD was used. Population estimates were calculated using data on the labour force, unemployment rate, and average weekly wage obtained from Statistics Canada. The number of FASD-related deaths, coded in the International Classification of Diseases, version 10, was estimated based on data from Statistics Canada and pooled prevalence estimates of the major disease conditions associated with FASD were obtained from a meta-analysis. The estimates of FASD-related mortality rates served as a basis for the length of working life span estimation. Once the number of working years lost to premature deaths was derived, productivity losses were computed. RESULTS: It was estimated that in total 327 individuals with FASD aged 20 to 69 (almost twice as many men as women) died in Canada in 2011. As a result, there were 2,877 years of potential employment lost, which translated to a loss ranging from $88 million to $126 million. This amount represents the increase in national income, had there been no premature mortality from FASD and the workers with FASD had been typical members of the labour force (without compromised productivity due to FASD). CONCLUSIONS: The estimates of productivity losses further reinforce the value of FASD prevention as a primary strategy.

Productivity losses because of morbidity attributable to fetal alcohol spectrum disorder in Canada: a demographic approach.

OBJECTIVE: The purpose of this study was to estimate the productivity losses due to morbidity of individuals with fetal alcohol spectrum disorder (FASD). METHOD: A demographic approach was used. Population estimates were calculated using data for the most recent available year (i.e., 2011) on the population of Canada by provinces, the labor force, unemployment rate, and the average weekly wage, all of which were obtained from Statistics Canada. To estimate the number of FASD cases in Canada in 2011, the prevalence of FASD, obtained from the available epidemiological literature, was applied to the general population of Canada. Assumptions made on the level of impairment that would affect the ability of individuals with FASD to participate in the workforce or reduce their productivity were based on data obtained from the current epidemiological literature and experts' opinions. To estimate the cost of FASD, a counterfactual scenario was used with an assumption that there is no one born with FASD in Canada. RESULTS: About 0.03% of the Canadian workforce experiences a loss of productivity because of FASD-attributable morbidity, which translates to aggregate losses ranging from $418 million Canadian dollars (CND) to $1.08 billion CND annually. CONCLUSIONS: FASD imposes a considerable economic toll on Canadian society and therefore requires more preventive efforts.

A web-based self-management intervention for Bipolar Disorder 'living with bipolar': a feasibility randomised controlled trial.

BACKGROUND: Bipolar Disorder (BD) is a severe mental health problem. Psychological interventions are recommended by the National Institute for Health and Care Excellence (NICE) but patients experience severe inequalities in access. This study assessed the feasibility and potential effectiveness of a recovery informed web-based self-management intervention for people with BD. METHODS: An online randomised controlled trial (n=122) compared treatment as usual (TAU) plus the 'Living with Bipolar' (LWB) intervention with a waiting list control (WLC) group. RESULTS: The study recruited to target and the retention rates were high. Participants engaged with the approach. Compared with the WLC, those receiving LWB showed the most robust improvement in psychological and physical domains of quality of life, wellbeing and recovery at the end of the intervention. LIMITATIONS: The trial was not definitive and requires further investigation. CONCLUSIONS: There is preliminary evidence that a web-based treatment approach in BD is feasible and potentially effective. Such interventions could form part of the Improving Access to Psychological Therapy (IAPT) initiative in severe mental health.

Vitamins C and E for asthma and exercise-induced bronchoconstriction.

BACKGROUND: The association between dietary antioxidants and asthma or exercise-induced bronchoconstriction (EIB) is not fully understood. Vitamin C and vitamin E are natural antioxidants that are predominantly present in fruits and vegetables; inadequate vitamin E intake is associated with airway inflammation. It has been postulated that the combination may be more beneficial than either single antioxidant for people with asthma and exercise-induced bronchoconstriction. OBJECTIVES: To assess the effects of supplementation of vitamins C and E versus placebo (or no vitamin C and E supplementation) on exacerbations and health-related quality of life (HRQL) in adults and children with chronic asthma. To also examine the potential effects of vitamins C and E on exercise-induced bronchoconstriction in people with asthma and in people without a diagnosis of asthma who experience symptoms only on exercise. SEARCH METHODS: Trials were identified from the Cochrane Airways Review Group Specialised Register and from trial registry websites. Searches were conducted in September 2013. SELECTION CRITERIA: We included randomised controlled trials of adults and children with a diagnosis of asthma. We separately considered trials in which participants had received a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma). Trials comparing vitamin C and E supplementation versus placebo were included. We included trials in which asthma management for treatment and control groups included similar background therapy. Short-term use of vitamins C and E at the time of exacerbation or for cold symptoms in people with asthma is outside the scope of this review. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of potential studies and subsequently screened full-text study reports for inclusion. We used standard methods as expected by The Cochrane Collaboration. MAIN RESULTS: It was not possible to aggregate the five included studies (214 participants). Four studies (206 participants) addressed the question of whether differences in outcomes were seen when vitamin C and E supplementation versus placebo was provided for participants with asthma, and only one of those studies (160 children) included a paediatric population; the remaining three studies included a combined total of just 46 adults. An additional study considered the question of whether differences in outcomes were noted when vitamin C and E supplementation was compared with placebo for exercise-induced asthma; this trial included only eight participants. The randomisation process of the trials were unclear leading us to downgrade the quality of the evidence. Four of the studies were double blind while the other study was single blind.None of these studies provided data on our two prespecified primary outcome measures: exacerbations and HRQL. Lung function data obtained from the studies were inconclusive. The only studies that provided any suggestion of an effect, and only with some outcomes, were the paediatric study, especially for children with moderate to severe asthma, and the small study on exercise-induced asthma. Even so, this evidence was judged to be at moderate/low quality. Only one study contributed data on asthma symptoms and adverse events, reporting no evidence of an effect of the intervention for symptoms and that one participant in the treatment group dropped out due to cystitis. AUTHORS' CONCLUSIONS: It is not possible to draw firm conclusions from this review with respect to the comparison of vitamin C and E supplementation versus placebo in the management of asthma or exercise-induced bronchoconstriction. We found only one study relevant to exercise-induced bronchoconstriction; most included participants came from studies designed to assess the effect of vitamin supplementation on the impact of atmospheric pollutants (such as ozone). Evidence is lacking on the comparison of vitamin C and E supplementation versus placebo for asthma with respect to outcomes such as HRQL and exacerbations, which were not addressed by any of the included studies.When compared with lung function tests alone, HRQL scores and exacerbation frequency are better indicators of the severity of asthma, its impact on daily activities and its response to treatment in a patient population. These end points are well recognised in good quality studies of asthma management. However, clinical studies of vitamins C and E in the management of asthma using these important end points of exacerbations and effects on quality of life are not available, and evidence is insufficient to support robust conclusions on the role of vitamin C and E supplementation in asthma and exercise-induced breathlessness.

Inhaled hyperosmolar agents for bronchiectasis.

BACKGROUND: Mucus retention in the lungs is a prominent feature of bronchiectasis. The stagnant mucus becomes chronically colonised with bacteria, which elicit a host neutrophilic response. This fails to eliminate the bacteria, and the large concentration of host-derived protease may contribute to the airway damage. The sensation of retained mucus is itself a cause of suffering, and the failure to maintain airway sterility probably contributes to the frequent respiratory infections experienced by many patients.Hypertonic saline inhalation is known to accelerate tracheobronchial clearance in many conditions, probably by inducing a liquid flux into the airway surface, which alters mucus rheology in a way favourable to mucociliary clearance. Inhaled dry powder mannitol has a similar effect. Such agents are an attractive approach to the problem of mucostasis, and deserve further clinical evaluation. OBJECTIVES: To determine whether inhaled hyperosmolar substances are effective in the treatment of bronchiectasis. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register, trials registries, and the reference lists of included studies and review articles. Searches are current up to April 2014. SELECTION CRITERIA: Any randomised controlled trial (RCT) using hyperosmolar inhalation in patients with bronchiectasis not caused by cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two review authors assessed studies for suitability. We used standard methods recommended by The Cochrane Collaboration. MAIN RESULTS: Eleven studies met the inclusion criteria of the review (1021 participants).Five studies on 833 participants compared inhaled mannitol with placebo but poor outcome reporting meant we could pool very little data and most outcomes were reported by only one study. One 12-month trial on 461 participants provided results for exacerbations and demonstrated an advantage for mannitol in terms of time to first exacerbation (median time to exacerbation 165 versus 124 days for mannitol and placebo respectively (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.63 to 0.96, P = 0.022) and number of days on antibiotics for bronchiectasis exacerbations was significantly better with mannitol (risk ratio (RR) 0.76, 95%CI 0.58 to 1.00, P = 0.0496). However, exacerbation rate per year was not significantly different between mannitol and placebo (RR 0.92 95% CI 0.78 to 1.08). The quality of this evidence was rated as moderate. There was also an indication, from only three trials, again based on moderate quality evidence, that mannitol improves health-related quality of life (mean difference (MD) -2.05; 95% CI -3.69 to -0.40). An analysis of adverse events data, also based on moderate quality evidence, revealed no difference between mannitol and placebo (OR 0.96; 95% CI 0.61 to 1.51). Two additional small trials on 25 participants compared mannitol versus no treatment and the data from these studies were inconclusive.Four studies (combined N = 113) compared hypertonic saline versus isotonic saline. On most outcomes there were conflicting results and the opportunities for the statistical aggregation of data from studies was very limited. It is not possible to draw robust conclusions for this comparison and judgments should be reserved until further data are available. AUTHORS' CONCLUSIONS: There is an indication from a single, large, unpublished study that inhaled mannitol increases time to first exacerbation in patients with bronchiectasis. In patients with near normal lung function, spirometry does not change dramatically with mannitol and adverse events are not more frequent than placebo. Further investigation is required in a patient population with impaired lung function.It is not possible to draw firm conclusions regarding the effect of nebulised hypertonic saline due to significant differences in the methodology, patient groups, and findings amongst the limited data available. The data suggest that it is unlikely to have benefit over isotonic saline in patients with milder disease, and hence future studies should test its use in those with more severe disease.

Mucolytics for bronchiectasis.

BACKGROUND: Bronchiectasis is predominantly an acquired disease process that represents the end stage of a variety of unrelated pulmonary insults. It is defined as persistent irreversible dilatation and distortion of medium-sized bronchi. It has been suggested that with widespread use of high-resolution computed tomography, more bronchiectasis diagnoses are being made. Patients diagnosed with bronchiectasis frequently have difficulty expectorating sputum. Sputum therefore is retained in the lungs and may become infected, leading to further lung damage. Mucolytic agents target hypersecretion or changed physiochemical properties of sputum to make it easier to clear. One drug, recombinant human DNase, breaks down the DNA that is released at the site of infection by neutrophils.Mucus clearance along with antimicrobial therapy remains an integral part of bronchiectasis management. Chest physiotherapy along with mucolytic agents is commonly used in practice without clear supportive evidence. OBJECTIVES: To determine whether ingested or inhaled mucolytics are effective in the treatment of patients with bronchiectasis. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register and reference lists of relevant articles. We contacted experts in the field and drug companies. Searches were current as of June 2013. SELECTION CRITERIA: Randomised trials of mucolytic treatment in people with bronchiectasis but not cystic fibrosis. DATA COLLECTION AND ANALYSIS: Data extraction was performed independently by two review authors. Study authors were contacted for confirmation. MAIN RESULTS: Four trials (with a combined total of 528 adult participants) were included, but almost none of the data from these studies could be aggregated in a meta-analysis.One trial (with 88 participants) compared bromhexine versus placebo. Compared with placebo, high doses of bromhexine with antibiotics eased difficulty in expectoration (mean difference (MD) -0.53, 95% confidence interval (CI) -0.81 to -0.25 at 16 days); the quality of the evidence was rated as low. A reduction in sputum production was noted with bromhexine (MD -21.5%, 95% CI -38.9 to -4.1 at day 16); again the quality of the evidence was rated as low. No significant differences between bromhexine and placebo were observed with respect to reported adverse events (odds ratio (OR) 2.93; 95% CI 0.12 to 73.97), and again the quality of the evidence was rated as low.In a single small, blinded but not placebo-controlled trial of older (> 55 years) participants with stable bronchiectasis and mucus hypersecretion, erdosteine combined with physiotherapy over a 15-day period improved spirometry and sputum purulence more effectively compared with physiotherapy alone. The spirometric improvement was small (MD 200 mL in forced expiratory volume in one second (FEV1) and 300 mL in forced vital capacity (FVC)) and was apparent only at day 15, not at earlier time points.The remaining two studies (with a combined total of 410 participants) compared recombinant human DNase (RhDNase) versus placebo. These two studies were very different (one was a two-week study of 61 participants, and the other ran for 24 weeks and included 349 participants), and the opportunity for combining data from the two studies was very limited. Compared with placebo, recombinant human DNase showed no difference in FEV1 or FVC in the smaller study but showed a significant negative effect on FEV1 in the larger and longer study. For reported adverse events, no significant differences between recombinant human DNase and placebo were noted. In all of the above comparisons of recombinant human DNase versus placebo, the quality of the evidence was judged to be low. AUTHORS' CONCLUSIONS: Given the harmful effects of recombinant human DNase in one trial and no evidence of benefit, this drug should be avoided in non-cystic fibrosis bronchiectasis, except in the context of clinical trials. Evidence is insufficient to permit evaluation of the routine use of other mucolytics for bronchiectasis. High doses of bromhexine coupled with antibiotics may help with sputum production and clearance, but long-term data and robust clinical outcomes are lacking. Similarly, erdosteine may be a useful adjunct to physiotherapy in stable patients with mucus hypersecretion, but robust longer-term trials are required.Generally, clinical trials in children on the use of various mucolytic agents are lacking. As the number of agents available on the market, such as RhDNase, acetylcysteine and bromhexine, is increasing, improvement of the evidence base is needed.

An investigation of factors affecting the outcome of the clinical skills assessment (CSA) in general practice specialty training.

Identifying general practice trainees at risk of failing the CSA early in their training is important so that supportive measures can be put in place to ensure training progression. The aim of this study was to determine aspects of the trainee's learning portfolio activity which might predict performance in the CSA. From the Mersey School of General Practice records, details were obtained for trainees who had completed their ST3 year between 1 August and 31 December 2012 with respect to the numbers of entries for the Mini Clinical Evaluation Exercise (Mini-CEX), case-based discussions (CBDs), directly observed procedures (DOPS), learning logs and personal development plans (PDPs) that they had carried out in each of their ST1 and ST2 years. Gender, university of qualification and years since qualification were also recorded. Records were obtained for 116 trainees (94 had passed their CSA). ST1 number of CBD and ST1 number of DOPS, university of qualification, gender, and shorter time since qualification were significantly associated with CSA pass. A multivariate model indicated that graduation from a European university and being female were both associated with an increased chance of passing. Longer time since qualification, non-European university graduation and male gender are the strongest predictors of failing the CSA. Portfolio activity is not a predictor of CSA outcome.

Postnatal head growth in preterm infants: a randomized controlled parenteral nutrition study.

BACKGROUND: Early postnatal head growth failure is well recognized in very preterm infants (VPIs). This coincides with the characteristic nutritional deficits that occur in these parenteral nutrition (PN) dependent infants in the first month of life. Head circumference (HC) is correlated with brain volume and later neurodevelopmental outcome. We hypothesized that a Standardized, Concentrated With Added Macronutrients Parenteral (SCAMP) nutrition regimen would improve early head growth. The aim was to compare the change in HC (ΔHC) and HC SD score (ΔSDS) achieved at day 28 in VPIs randomly assigned to receive SCAMP nutrition or a control standardized, concentrated PN regimen. METHODS: Control PN (10% glucose, 2.8 g/kg per day protein/lipid) was started within 6 hours of birth. VPIs (birth weight <1200 g; gestation <29 weeks) were randomly assigned to either start SCAMP (12% glucose, 3.8 g/kg per day protein/lipid) or remain on the control regimen. HC was measured weekly. Actual daily nutritional intake data were collected for days 1 to 28. RESULTS: There were no differences in demographic data between SCAMP (n = 74) and control (n = 76) groups. Comparing cumulative 28-day intakes, the SCAMP group received 11% more protein and 7% more energy. The SCAMP group had a greater ΔHC at 28 days (P < .001). The difference between the means (95% confidence interval) for ΔHC was 5 mm (2 to 8), and ΔSDS was 0.37 (0.17 to 0.58). HC differences are still apparent at 36 weeks' corrected gestational age. CONCLUSIONS: Early postnatal head growth failure in VPIs can be ameliorated by optimizing PN.

The other genome: a systematic review of studies of mitochondrial DNA haplogroups and outcomes of HIV infection and antiretroviral therapy.

Mitochondrial toxicity is implicated in some treatment-limiting antiretroviral therapy complications, and reports of mitochondrial dysfunction in untreated HIV infection suggest antiretroviral therapy independent effects of HIV. Several studies have explored associations between mtDNA haplogroups (patterns of mtDNA polymorphisms) and outcomes of HIV infection and/or antiretroviral therapy, but findings have been inconsistent. We systematically reviewed published studies examining mtDNA haplogroups in HIV-infected persons to summarize reported outcome associations, and to highlight potential future research directions. We identified 21 articles published from 2005-2013. Multiple different phenotypes were studied; most were antiretroviral therapy associated metabolic outcomes (e.g. lipodystrophy, insulin resistance, and dyslipidemia). Haplogroup H was associated with the most outcomes, including AIDS progression, CD4 T-cell recovery, cirrhosis (in hepatitis C coinfection), and metabolic outcomes. This review is the first to focus on the emerging area of mtDNA haplogroups in HIV, and summarizes the published literature on associations between mtDNA haplogroups and clinical outcomes in populations of European and African descent. Several reported associations require replication and ideally biological verification before definitive conclusions can be drawn, but research in this area has the potential to explain outcome disparities and impact clinical management of patients.

Vitamin C for asthma and exercise-induced bronchoconstriction.

BACKGROUND: Dietary antioxidants, such as vitamin C, in the epithelial lining and lining fluids of the lung may be beneficial in the reduction of oxidative damage (Arab 2002). They may therefore be of benefit in reducing symptoms of inflammatory airway conditions such as asthma, and may also be beneficial in reducing exercise-induced bronchoconstriction, which is a well-recognised feature of asthma and is considered a marker of airways inflammation. However, the association between dietary antioxidants and asthma severity or exercise-induced bronchoconstriction is not fully understood. OBJECTIVES: To examine the effects of vitamin C supplementation on exacerbations and health-related quality of life (HRQL) in adults and children with asthma or exercise-induced bronchoconstriction compared to placebo or no vitamin C. SEARCH METHODS: We identified trials from the Cochrane Airways Group's Specialised Register (CAGR). The Register contains trial reports identified through systematic searches of a number of bibliographic databases, and handsearching of journals and meeting abstracts. We also searched trial registry websites. The searches were conducted in December 2012. SELECTION CRITERIA: We included randomised controlled trials (RCTs). We included both adults and children with a diagnosis of asthma. In separate analyses we considered trials with a diagnosis of exercise-induced bronchoconstriction (or exercise-induced asthma). We included trials comparing vitamin C supplementation with placebo, or vitamin C supplementation with no supplementation. We included trials where the asthma management of both treatment and control groups provided similar background therapy. The primary focus of the review is on daily vitamin C supplementation to prevent exacerbations and improve HRQL. The short-term use of vitamin C at the time of exacerbations or for cold symptoms in people with asthma are outside the scope of this review. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of potential studies, and subsequently screened full text study reports for inclusion. We used standard methods expected by The Cochrane Collaboration. MAIN RESULTS: A total of 11 trials with 419 participants met our inclusion criteria. In 10 studies the participants were adults and only one was in children. Reporting of study design was inadequate to determine risk of bias for most of the studies and poor availability of data for our key outcomes may indicate some selective outcome reporting. Four studies were parallel-group and the remainder were cross-over studies. Eight studies included people with asthma and three studies included 40 participants with exercise-induced asthma. Five studies reported results using single-dose regimes prior to bronchial challenges or exercise tests. There was marked heterogeneity in vitamin C dosage regimes used in the selected studies, compounding the difficulties in carrying out meaningful analyses.One study on 201 adults with asthma reported no significant difference in our primary outcome, health-related quality of life (HRQL), and overall the quality of this evidence was low. There were no data available to evaluate the effects of vitamin C supplementation on our other primary outcome, exacerbations in adults. One small study reported data on asthma exacerbations in children and there were no exacerbations in either the vitamin C or placebo groups (very low quality evidence). In another study conducted in 41 adults, exacerbations were not defined according to our criteria and the data were not available in a format suitable for evaluation by our methods. Lung function and symptoms data were contributed by single studies. We rated the quality of this evidence as moderate, but further research is required to assess any clinical implications that may be related to the changes in these parameters. In each of these outcomes there was no significant difference between vitamin C and placebo. No adverse events at all were reported; again this is very low quality evidence.Studies in exercise-induced bronchoconstriction suggested some improvement in lung function measures with vitamin C supplementation, but theses studies were few and very small, with limited data and we judged the quality of the evidence to be low. AUTHORS' CONCLUSIONS: Currently, evidence is not available to provide a robust assessment on the use of vitamin C in the management of asthma or exercise-induced bronchoconstriction. Further research is very likely to have an important impact on our confidence in the estimates of effect and is likely to change the estimates. There is no indication currently that vitamin C can be recommended as a therapeutic agent in asthma. There was some indication that vitamin C was helpful in exercise-induced breathlessness in terms of lung function and symptoms; however, as these findings were provided only by small studies they are inconclusive. Most published studies to date are too small and inconsistent to provide guidance. Well-designed trials with good quality clinical endpoints, such as exacerbation rates and health-related quality of life scores, are required.

Normative values for the Bath Ankylosing Spondylitis Metrology Index in a UK population.

OBJECTIVE: Spinal mobility is assessed frequently in patients with AS/axial SpA using the BASMI to provide baseline measurement and monitor change over time. The interpretation of BASMI scores has been hindered by the absence of normative values. We aimed to obtain normative values for the BASMI in healthy men and women in a UK population. METHODS: A cross-sectional study of 168 volunteers stratified by gender and age was completed. Exclusion criteria comprised factors potentially influencing spinal mobility. Each component of the BASMI was assessed, with the total score computed using the 10-point scoring system. Measurements were taken by physiotherapists following an agreed protocol. Data were summarized and analysed with age-specific centiles and CIs calculated. RESULTS: Total BASMI scores ranged from 0 to 4.4, with only 1.2% of the sample having a score of 0. The estimated median score for an individual age 25 years was 0.9, increasing with age to 2.1 for an individual age 65 years. There was a corresponding increase in component BASMI scores, which was more pronounced for some components than others. CONCLUSION: Our data indicate that it is unusual for healthy individuals to score zero on the BASMI, which has implications for the interpretation of scores, especially at baseline. The generation of normative values has the potential to inform clinical assessment of spinal mobility and assist patients in understanding how their spinal mobility compares with that of a healthy age-matched population.

Effect of partogram use on outcomes for women in spontaneous labour at term.

BACKGROUND: The partogram (sometimes known as partograph) is usually a pre-printed paper form on which labour observations are recorded. The aim of the partogram is to provide a pictorial overview of labour, to alert midwives and obstetricians to deviations in maternal or fetal wellbeing and labour progress. Charts often contain pre-printed alert and action lines. An alert line represents the slowest 10% of primigravid women's labour progress. An action line is placed a number of hours after the alert line (usually two or four hours) to prompt effective management of slow progress of labour. OBJECTIVES: To determine the effect of use of partogram on perinatal and maternal morbidity and mortality.To determine the effect of partogram design on perinatal and maternal morbidity and mortality. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013). SELECTION CRITERIA: Randomised and quasi-randomised controlled trials involving a comparison of partogram with no partogram, or comparison between different partogram designs. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed eligibility, quality and extracted data. When one review author was also the trial author, the two remaining authors assessed the studies independently. MAIN RESULTS: We have included six studies involving 7706 women in this review; two studies assessed partogram versus no partogram and the remainder assessed different partogram designs. There was no evidence of any difference between partogram and no partogram in caesarean section (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.24 to 1.70); instrumental vaginal delivery (RR 1.00, 95% CI 0.85 to 1.17) or Apgar score less than seven at five minutes (RR 0.77, 95% CI 0.29 to 2.06) between the groups. When compared to a four-hour action line, women in the two-hour action line group were more likely to require oxytocin augmentation (RR 1.14, 95% CI 1.05 to 1.22). When the three- and four-hour action line groups were compared, caesarean section rate was lowest in the four-hour action line group and this difference was statistically significant (RR 1.70, 95% CI 1.07 to 2.70, n = 613, one trial). When a partogram with a latent phase (composite) and one without (modified) were compared, the caesarean section rate was lower in the partograph without a latent phase (RR 2.45, 95% CI 1.72 to 3.50, n = 743, one trial). AUTHORS' CONCLUSIONS: On the basis of the findings of this review, we cannot recommend routine use of the partogram as part of standard labour management and care. Given the fact that the partogram is currently in widespread use and generally accepted, it appears reasonable, until stronger evidence is available, that partogram use should be locally determined. Further trial evidence is required to establish the efficacy of partogram use.

Bridging the gap between the economic evaluation literature and daily practice in occupational health: a qualitative study among decision-makers in the healthcare sector.

BACKGROUND: Continued improvements in occupational health can only be ensured if decisions regarding the implementation and continuation of occupational health and safety interventions (OHS interventions) are based on the best available evidence. To ensure that this is the case, scientific evidence should meet the needs of decision-makers. As a first step in bridging the gap between the economic evaluation literature and daily practice in occupational health, this study aimed to provide insight into the occupational health decision-making process and information needs of decision-makers. METHODS: An exploratory qualitative study was conducted with a purposeful sample of occupational health decision-makers in the Ontario healthcare sector. Eighteen in-depth interviews were conducted to explore the process by which occupational health decisions are made and the importance given to the financial implications of OHS interventions. Twenty-five structured telephone interviews were conducted to explore the sources of information used during the decision-making process, and decision-makers' knowledge on economic evaluation methods. In-depth interview data were analyzed according to the constant comparative method. For the structured telephone interviews, summary statistics were prepared. RESULTS: The occupational health decision-making process generally consists of three stages: initiation stage, establishing the need for an intervention; pre-implementation stage, developing an intervention and its business case in order to receive senior management approval; and implementation and evaluation stage, implementing and evaluating an intervention. During this process, information on the financial implications of OHS interventions was found to be of great importance, especially the employer's costs and benefits. However, scientific evidence was rarely consulted, sound ex-post program evaluations were hardly ever performed, and there seemed to be a need to advance the economic evaluation skill set of decision-makers. CONCLUSIONS: Financial information is particularly important at the front end of implementation decisions, and can be a key deciding factor of whether to go forward with a new OHS intervention. In addition, it appears that current practice in occupational health in the healthcare sector is not solidly grounded in evidence-based decision-making and strategies should be developed to improve this.