Background. Propensity score usage seems to be growing in popularity leading researchers to question the possible role of propensity scores in prediction modeling, despite the lack of a theoretical rationale. It is suspected that such requests are due to the lack of differentiation regarding the goals of predictive modeling versus causal inference modeling. Therefore, the purpose of this study is to formally examine the effect of propensity scores on predictive performance. Our hypothesis is that a multivariable regression model that adjusts for all covariates will perform as well as or better than those models utilizing propensity scores with respect to model discrimination and calibration.
Methods. The most commonly encountered statistical scenarios for medical prediction (logistic and proportional hazards regression) were used to investigate this research question. Random cross-validation was performed 500 times to correct for optimism. The multivariable regression models adjusting for all covariates were compared with models that included adjustment for or weighting with the propensity scores. The methods were compared based on three predictive performance measures: (1) concordance indices; (2) Brier scores; and (3) calibration curves.
Results. Multivariable models adjusting for all covariates had the highest average concordance index, the lowest average Brier score, and the best calibration. Propensity score adjustment and inverse probability weighting models without adjustment for all covariates performed worse than full models and failed to improve predictive performance with full covariate adjustment.
Conclusion. Propensity score techniques did not improve prediction performance measures beyond multivariable adjustment. Propensity scores are not recommended if the analytical goal is pure prediction modeling.
Prediction; Propensity score; Calibration curve; Concordance index; Multivariable regression
For a randomized trial, the primary publication is usually the one which reports the results of the primary outcome and provides consolidated data from all study centers. Other aspects of a randomized trial’s findings (that is, non-primary results) are often reported in subsequent publications.
We carried out a cross-sectional review of the characteristics and type of information reported in non-primary reports (n = 69) of randomized trials (indexed in PubMed core clinical journals in 2009) and whether they report pre-specified or exploratory analyses. We also compared consistency of information in non-primary publications with that reported in the primary publication.
The majority (n = 56; 81%) of non-primary publications were large, multicenter trials, published in specialty journals. Most reported subgroup analyses (n = 27; 39%), analyzing a specific subgroup of patients from the randomized trial, or reported on secondary outcomes (n = 29; 42%); 19% (n = 13) reported extended follow-up. Less than half reported details of trial registration (n = 30; 43%) or the trial protocol (n = 27; 39%) and in 41% (n = 28) it was unclear from reading the abstract that the report was not the primary publication for the trial. Non-primary publications often analyzed and reported multiple different outcomes (16% reported >20 outcomes) and in 10% (n = 7) it was unclear how many outcomes had actually been assessed; in 42% (n = 29) it was unclear whether the analyses reported were pre-specified or exploratory. Only 39% (n = 27) of non-primary publications described the primary outcome of the randomized trial, 6% (n = 4) reported its numerical results and 9% (n = 6) details of how participants were randomized.
Non-primary publications often lack important information about the randomized trial and the type of analyses conducted and whether these were pre-specified or exploratory to enable readers to accurately identify and assess the validity and reliably of the study findings. We provide recommendations for what information authors should include in non-primary reports of randomized trials.
Randomized controlled trial; Non-primary publication; Subgroup analyses; Secondary outcomes
Background. Psychodynamic psychotherapy is a psychological treatment approach that has a growing empirical base. Research has indicated an association between therapist-facilitated affective experience and outcome in psychodynamic therapy. Affect-phobia therapy (APT), as outlined by McCullough et al., is a psychodynamic treatment that emphasizes a strong focus on expression and experience of affect. This model has neither been evaluated for depression nor anxiety disorders in a randomized controlled trial. While Internet-delivered psychodynamic treatments for depression and generalized anxiety disorder exist, they have not been based on APT. The aim of this randomized controlled trial was to investigate the efficacy of an Internet-based, psychodynamic, guided self-help treatment based on APT for depression and anxiety disorders.
Methods. One hundred participants with diagnoses of mood and anxiety disorders participated in a randomized (1:1 ratio) controlled trial of an active group versus a control condition. The treatment group received a 10-week, psychodynamic, guided self-help treatment based on APT that was delivered through the Internet. The treatment consisted of eight text-based treatment modules and included therapist contact (9.5 min per client and week, on average) in a secure online environment. Participants in the control group also received online therapist support and clinical monitoring of symptoms, but received no treatment modules. Outcome measures were the 9-item Patient Health Questionnaire Depression Scale (PHQ-9) and the 7-item Generalized Anxiety Disorder Scale (GAD-7). Process measures were also included. All measures were administered weekly during the treatment period and at a 7-month follow-up.
Results. Mixed models analyses using the full intention-to-treat sample revealed significant interaction effects of group and time on all outcome measures, when comparing treatment to the control group. A large between-group effect size of Cohen’s d = 0.77 (95% CI: 0.37–1.18) was found on the PHQ-9 and a moderately large between-group effect size d = 0.48 (95% CI: 0.08–0.87) was found on the GAD-7. The number of patients who recovered (had no diagnoses of depression and anxiety, and had less than 10 on both the PHQ-9 and the GAD-7) were at post-treatment 52% in the treatment group and 24% in the control group. This difference was significant, χ2(N = 100, d
f = 1) = 8.3, p < .01. From post-treatment to follow-up, treatment gains were maintained on the PHQ-9, and significant improvements were seen on the GAD-7.
Conclusion. This study provides initial support for the efficacy of Internet-delivered psychodynamic therapy based on the affect-phobia model in the treatment of depression and anxiety disorders. The results support the conclusion that psychodynamic treatment approaches may be transferred to the guided self-help format and delivered via the Internet.
Depression; Anxiety; Psychotherapy; Psychodynamic therapy; Internet; Affect; Emotion; Internet-delivered treatments; e-health
Chronic kidney disease is a major health concern that, if left untreated, may progress to end-stage kidney failure (ESKF). Identifying individuals at an increased risk of kidney disease and who might benefit from a therapeutic or preventive intervention is an important challenge.
To evaluate the performance of the QKidney® scores for predicting 5-year risk of developing moderate-severe kidney disease and ESKF in an independent UK cohort of patients from general practice records.
Design and setting
Prospective cohort study to evaluate the performance of two risk scores for kidney disease in 364 practices from the UK, contributing to The Health Improvement Network (THIN) database.
Data were obtained from 1.6 million patients registered with a general practice surgery between 1 January 2002 and 1 July 2008, aged 35–74 years, with 43 186 incident cases of moderate-severe kidney disease and 2663 incident cases of ESKF. This is the first recorded evidence of moderate-severe chronic kidney and ESKF as recorded in general practice records.
The results from this independent and external validation of QKidney scores indicate that both scores showed good performance data for both moderate-severe kidney disease and ESKF, on a large cohort of general practice patients. Discrimination and calibration statistics were better for models including serum creatinine; however, there were considerable amounts of missing data for serum creatinine. QKidney scores both with and without serum creatinine were well calibrated.
QKidney scores have been shown to be useful tools to predict the 5-year risk of moderate-severe kidney disease and ESKF in the UK.
kidney disease; primary care; risk prediction; validation
Chlorthalidone (CTD) reduces 24-hour blood pressure more effectively than hydrochlorothiazide (HCTZ), but whether this influences electrocardiographic left ventricular hypertrophy (LVH) is uncertain. One source of comparative data is the Multiple Risk Factor Intervention Trial (MRFIT), which randomly assigned 8,012 hypertensive men to special intervention (SI) or usual care (UC). SI participants could use CTD or HCTZ initially; previous analyses have grouped clinics by their main diuretic used (C-clinics: CTD; H-clinics: HCTZ). After 48 months, SI participants receiving HCTZ were recommended to switch to CTD, in part, because higher mortality was observed for SI compared to UC participants in H-clinics, while the opposite was found in C-clinics. In this analysis, we examined change in continuous measures of electrocardiographic LVH using both an ecologic analysis by previously-reported C- or H-clinic groupings, and an individual participant analysis where use of CTD or HCTZ by SI participants was considered and updated annually. Through 48 months, differences between SI and UC in LVH were larger for C-clinics compared to H-clinics (Sokolow-Lyon: −93.9 vs −54.9 μV, P=0.049; Cornell voltage: −68.1 vs −35.9 μV, P=0.019; Cornell voltage product: −4.6 vs −2.2 μV/ms, P=0.071; left ventricular mass: −4.4 vs −2.8 gm, P=0.002). At the individual participant level, Sokolow-Lyon and left ventricular mass were significantly lower for SI men receiving CTD compared to HCTZ through 48 months and 84 months of follow-up. Our findings on LVH support the idea that greater blood pressure reduction with CTD than HCTZ may have led to differences in mortality observed in MRFIT.
hydrochlorothiazide; chlorthalidone; left ventricular hypertrophy; hypertension; blood pressure; electrocardiography
During in vitro fertilization (IVF), fertility patients are expected to self-administer many injections as part of this treatment. While newer medications have been developed to substantially reduce the number of these injections, such agents are typically much more expensive. Considering these differences in both cost and number of injections, this study compared patient preferences between GnRH-agonist and GnRH-antagonist based protocols in IVF.
Data were collected by voluntary, anonymous questionnaire at first consultation appointment. Patient opinion concerning total number of s.c. injections as a function of non-reimbursed patient cost associated with GnRH-agonist [A] and GnRH-antagonist [B] protocols in IVF was studied.
Completed questionnaires (n = 71) revealed a mean +/− SD patient age of 34 +/− 4.1 yrs. Most (83.1%) had no prior IVF experience; 2.8% reported another medical condition requiring self-administration of subcutaneous medication(s). When out-of-pocket cost for [A] and [B] were identical, preference for [B] was registered by 50.7% patients. The tendency to favor protocol [B] was weaker among patients with a health occupation. Estimated patient costs for [A] and [B] were $259.82 +/− 11.75 and $654.55 +/− 106.34, respectively (p < 0.005). Measured patient preference for [B] diminished as the cost difference increased.
This investigation found consistently higher non-reimbursed direct medication costs for GnRH-antagonist IVF vs. GnRH-agonist IVF protocols. A conditional preference to minimize downregulation (using GnRH-antagonist) was noted among some, but not all, IVF patient sub-groups. Compared to IVF patients with a health occupation, the preference for GnRH-antagonist was weaker than for other patients. While reducing total number of injections by using GnRH-antagonist is a desirable goal, it appears this advantage is not perceived equally by all IVF patients and its utility is likely discounted heavily by patients when nonreimbursed medication costs reach a critical level.
GnRH-antagonist; IVF; Preference; Patient cost; Health economics
Thalassemia is a common disorder worldwide with a predominant incidence in Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia. Whilst substantial progress has been made towards the improvement of Health related quality of life (HRQoL) in western countries, scarce evidence-based data exists on HRQol of thalassemia children and adolescents living in developing countries.
We studied 60 thalassemia children from Middle Eastern countries with a median age of 10 years (range 5 to 17 years). HRQoL was assessed with the Pediatric Quality of Life Inventory (PedsQL) 4.0. The Questionnaire was completed at baseline by all patients and their parents. The agreement between child-self and parent-proxy HRQoL reports and the relationship between HRQoL profiles and socio-demographic and clinical factors were investigated.
The scores of parents were generally lower than those of their children for Emotional Functioning (mean 75 vs 85; p = 0.002), Psychosocial Health Summary (mean 70.3 vs 79.1; p = 0.015) and the Total Summary Score (mean 74.3 vs 77.7 p = 0.047). HRQoL was not associated with ferritin levels, hepatomegaly or frequency of transfusions or iron chelation therapy. Multivariate analysis showed that a delayed start of iron chelation had a negative impact on total PedsQL scores of both children (p = 0.046) and their parents (p = 0.007).
The PedsQL 4.0 is a useful tool for the measurement of HRQoL in pediatric thalassemia patients. This study shows that delayed start of iron chelation has a negative impact on children’s HRQoL.
Quality of life; Thalassemia; PEDsQL 4.0
During IVF, non-transferred embryos are usually selected for cryopreservation on the basis of morphological criteria. This investigation evaluated an application for array comparative genomic hybridization (aCGH) in assessment of surplus embryos prior to cryopreservation.
First-time IVF patients undergoing elective single embryo transfer and having at least one extra non-transferred embryo suitable for cryopreservation were offered enrollment in the study. Patients were randomized into two groups: Patients in group A (n=55) had embryos assessed first by morphology and then by aCGH, performed on cells obtained from trophectoderm biopsy on post-fertilization day 5. Only euploid embryos were designated for cryopreservation. Patients in group B (n=48) had embryos assessed by morphology alone, with only good morphology embryos considered suitable for cryopreservation.
Among biopsied embryos in group A (n=425), euploidy was confirmed in 226 (53.1%). After fresh single embryo transfer, 64 (28.3%) surplus euploid embryos were cryopreserved for 51 patients (92.7%). In group B, 389 good morphology blastocysts were identified and a single top quality blastocyst was selected for fresh transfer. All group B patients (48/48) had at least one blastocyst remaining for cryopreservation. A total of 157 (40.4%) blastocysts were frozen in this group, a significantly larger proportion than was cryopreserved in group A (p=0.017, by chi-squared analysis).
While aCGH and subsequent frozen embryo transfer are currently used to screen embryos, this is the first investigation to quantify the impact of aCGH specifically on embryo cryopreservation. Incorporation of aCGH screening significantly reduced the total number of cryopreserved blastocysts compared to when suitability for freezing was determined by morphology only. IVF patients should be counseled that the benefits of aCGH screening will likely come at the cost of sharply limiting the number of surplus embryos available for cryopreservation.
Fertilization in vitro; Comparative genomic hybridization; Preimplantation genetic diagnosis; Cryopreservation
Single embryo transfer (SET) remains underutilized as a strategy to reduce multiple gestation risk in IVF, and its overall lower pregnancy rate underscores the need for improved techniques to select one embryo for fresh transfer. This study explored use of comprehensive chromosomal screening by array CGH (aCGH) to provide this advantage and improve pregnancy rate from SET.
First-time IVF patients with a good prognosis (age <35, no prior miscarriage) and normal karyotype seeking elective SET were prospectively randomized into two groups: In Group A, embryos were selected on the basis of morphology and comprehensive chromosomal screening via aCGH (from d5 trophectoderm biopsy) while Group B embryos were assessed by morphology only. All patients had a single fresh blastocyst transferred on d6. Laboratory parameters and clinical pregnancy rates were compared between the two groups.
For patients in Group A (n = 55), 425 blastocysts were biopsied and analyzed via aCGH (7.7 blastocysts/patient). Aneuploidy was detected in 191/425 (44.9%) of blastocysts in this group. For patients in Group B (n = 48), 389 blastocysts were microscopically examined (8.1 blastocysts/patient). Clinical pregnancy rate was significantly higher in the morphology + aCGH group compared to the morphology-only group (70.9 and 45.8%, respectively; p = 0.017); ongoing pregnancy rate for Groups A and B were 69.1 vs. 41.7%, respectively (p = 0.009). There were no twin pregnancies.
Although aCGH followed by frozen embryo transfer has been used to screen at risk embryos (e.g., known parental chromosomal translocation or history of recurrent pregnancy loss), this is the first description of aCGH fully integrated with a clinical IVF program to select single blastocysts for fresh SET in good prognosis patients. The observed aneuploidy rate (44.9%) among biopsied blastocysts highlights the inherent imprecision of SET when conventional morphology is used alone. Embryos randomized to the aCGH group implanted with greater efficiency, resulted in clinical pregnancy more often, and yielded a lower miscarriage rate than those selected without aCGH. Additional studies are needed to verify our pilot data and confirm a role for on-site, rapid aCGH for IVF patients contemplating fresh SET.
Reporting of the flow of participants through each stage of a randomized trial is essential to assess the generalisability and validity of its results. We assessed the type and completeness of information reported in CONSORT (Consolidated Standards of Reporting Trials) flow diagrams published in current reports of randomized trials.
A cross sectional review of all primary reports of randomized trials which included a CONSORT flow diagram indexed in PubMed core clinical journals (2009). We assessed the proportion of parallel group trial publications reporting specific items recommended by CONSORT for inclusion in a flow diagram.
Of 469 primary reports of randomized trials, 263 (56%) included a CONSORT flow diagram of which 89% (237/263) were published in a CONSORT endorsing journal. Reports published in CONSORT endorsing journals were more likely to include a flow diagram (62%; 237/380 versus 29%; 26/89). Ninety percent (236/263) of reports which included a flow diagram had a parallel group design, of which 49% (116/236) evaluated drug interventions, 58% (137/236) were multicentre, and 79% (187/236) compared two study groups, with a median sample size of 213 participants. Eighty-one percent (191/236) reported the overall number of participants assessed for eligibility, 71% (168/236) the number excluded prior to randomization and 98% (231/236) the overall number randomized. Reasons for exclusion prior to randomization were more poorly reported. Ninety-four percent (223/236) reported the number of participants allocated to each arm of the trial. However, only 40% (95/236) reported the number who actually received the allocated intervention, 67% (158/236) the number lost to follow up in each arm of the trial, 61% (145/236) whether participants discontinued the intervention during the trial and 54% (128/236) the number included in the main analysis.
Over half of published reports of randomized trials included a diagram showing the flow of participants through the trial. However, information was often missing from published flow diagrams, even in articles published in CONSORT endorsing journals. If important information is not reported it can be difficult and sometimes impossible to know if the conclusions of that trial are justified by the data presented.
To report on relationships among baseline serum anti-Müllerian hormone (AMH) measurements, blastocyst development and other selected embryology parameters observed in non-donor oocyte IVF cycles.
Pre-treatment AMH was measured in patients undergoing IVF (n = 79) and retrospectively correlated to in vitro embryo development noted during culture.
Mean (+/- SD) age for study patients in this study group was 36.3 ± 4.0 (range = 28-45) yrs, and mean (+/- SD) terminal serum estradiol during IVF was 5929 +/- 4056 pmol/l. A moderate positive correlation (0.49; 95% CI 0.31 to 0.65) was noted between basal serum AMH and number of MII oocytes retrieved. Similarly, a moderate positive correlation (0.44) was observed between serum AMH and number of early cleavage-stage embryos (95% CI 0.24 to 0.61), suggesting a relationship between serum AMH and embryo development in IVF. Of note, serum AMH levels at baseline were significantly different for patients who did and did not undergo blastocyst transfer (15.6 vs. 10.9 pmol/l; p = 0.029).
While serum AMH has found increasing application as a predictor of ovarian reserve for patients prior to IVF, its roles to estimate in vitro embryo morphology and potential to advance to blastocyst stage have not been extensively investigated. These data suggest that baseline serum AMH determinations can help forecast blastocyst developmental during IVF. Serum AMH measured before treatment may assist patients, clinicians and embryologists as scheduling of embryo transfer is outlined. Additional studies are needed to confirm these correlations and to better define the role of baseline serum AMH level in the prediction of blastocyst formation.
serum AMH; IVF; embryo development; blastocyst transfer
Clinical Prediction Rules (CPRs) are tools that quantify the contribution of symptoms, clinical signs and available diagnostic tests, and in doing so stratify patients according to the probability of having a target outcome or need for a specified treatment. Most focus on the derivation stage with only a minority progressing to validation and very few undergoing impact analysis. Impact analysis studies remain the most efficient way of assessing whether incorporating CPRs into a decision making process improves patient care. However there is a lack of clear methodology for the design of high quality impact analysis studies.
We have developed a sequential four-phased framework based on the literature and the collective experience of our international working group to help researchers identify and overcome the specific challenges in designing and conducting an impact analysis of a CPR.
There is a need to shift emphasis from deriving new CPRs to validating and implementing existing CPRs. The proposed framework provides a structured approach to this topical and complex area of research.
The World Health Organisation estimates that by 2030 there will be approximately 350 million people with type 2 diabetes. Associated with renal complications, heart disease, stroke and peripheral vascular disease, early identification of patients with undiagnosed type 2 diabetes or those at an increased risk of developing type 2 diabetes is an important challenge. We sought to systematically review and critically assess the conduct and reporting of methods used to develop risk prediction models for predicting the risk of having undiagnosed (prevalent) or future risk of developing (incident) type 2 diabetes in adults.
We conducted a systematic search of PubMed and EMBASE databases to identify studies published before May 2011 that describe the development of models combining two or more variables to predict the risk of prevalent or incident type 2 diabetes. We extracted key information that describes aspects of developing a prediction model including study design, sample size and number of events, outcome definition, risk predictor selection and coding, missing data, model-building strategies and aspects of performance.
Thirty-nine studies comprising 43 risk prediction models were included. Seventeen studies (44%) reported the development of models to predict incident type 2 diabetes, whilst 15 studies (38%) described the derivation of models to predict prevalent type 2 diabetes. In nine studies (23%), the number of events per variable was less than ten, whilst in fourteen studies there was insufficient information reported for this measure to be calculated. The number of candidate risk predictors ranged from four to sixty-four, and in seven studies it was unclear how many risk predictors were considered. A method, not recommended to select risk predictors for inclusion in the multivariate model, using statistical significance from univariate screening was carried out in eight studies (21%), whilst the selection procedure was unclear in ten studies (26%). Twenty-one risk prediction models (49%) were developed by categorising all continuous risk predictors. The treatment and handling of missing data were not reported in 16 studies (41%).
We found widespread use of poor methods that could jeopardise model development, including univariate pre-screening of variables, categorisation of continuous risk predictors and poor handling of missing data. The use of poor methods affects the reliability of the prediction model and ultimately compromises the accuracy of the probability estimates of having undiagnosed type 2 diabetes or the predicted risk of developing type 2 diabetes. In addition, many studies were characterised by a generally poor level of reporting, with many key details to objectively judge the usefulness of the models often omitted.
Background & Aims
Liver disease is a major cause of morbidity and mortality among HIV-infected persons. We evaluated the prevalence, etiology, and factors associated with liver dysfunction in patients during the highly active antiretroviral therapy (HAART) era.
We performed tests for liver function (baseline and after a 6-month follow-up period) in HIV-infected patients treated at a large clinic. Comprehensive laboratory and ultrasound analyses were performed. Factors associated with liver test abnormalities were assessed using multivariate logistic regression models.
Eighty of 299 HIV-positive patients (27%) had abnormal liver test results during the 6-month study period. The majority of abnormalities were grade 1. Of those with liver test abnormalities, the most common diagnosis was nonalcoholic fatty liver disease (NAFLD, 30%), followed by excessive alcohol use (13%), chronic hepatitis B (9%), chronic active hepatitis C (5%), and other (hemochromatosis and autoimmune hepatitis, 2%); 8 participants (10%) had more than 1 diagnosis. In total, 39 HIV patients with abnormal liver tests (49%) had a defined underlying liver disease. Despite laboratory tests and ultrasound examination, 41 abnormal liver test results (51%) were unexplained. Multivariate analyses of this group found that increased total cholesterol levels (odds ratio 1.6 per 40 mg/dl increase, p=0.01) were associated with liver abnormalities.
Liver test abnormalities are common among HIV patients during the HAART era. The most common diagnosis was NAFLD. Despite laboratory and radiologic investigations into the cause of liver dysfunction, 51% were unexplained, but might be related to unrecognized fatty liver disease.
HIV; liver test abnormalities; liver disease; NAFLD; antiretroviral medications
Objective To evaluate the performance of the QFractureScores for predicting the 10 year risk of osteoporotic and hip fractures in an independent UK cohort of patients from general practice records.
Design Prospective cohort study.
Setting 364 UK general practices contributing to The Health Improvement Network (THIN) database.
Participants 2.2 million adults registered with a general practice between 27 June 1994 and 30 June 2008, aged 30-85 (13 million person years), with 25 208 osteoporotic fractures and 12 188 hip fractures.
Main outcome measures First (incident) diagnosis of osteoporotic fracture (vertebra, distal radius, or hip) and incident hip fracture recorded in general practice records.
Results Results from this independent and external validation of QFractureScores indicated good performance data for both osteoporotic and hip fracture end points. Discrimination and calibration statistics were comparable to those reported in the internal validation of QFractureScores. The hip fracture score had better performance data for both women and men. It explained 63% of the variation in women and 60% of the variation in men, with areas under the receiver operating characteristic curve of 0.89 and 0.86, respectively. The risk score for osteoporotic fracture explained 49% of the variation in women and 38% of the variation in men, with corresponding areas under the receiver operating characteristic curve of 0.82 and 0.74. QFractureScores were well calibrated, with predicted risks closely matching those across all 10ths of risk and for all age groups.
Conclusion QFractureScores are useful tools for predicting the 10 year risk of osteoporotic and hip fractures in patients in the United Kingdom.
The PELICAN Multidisciplinary Team Total Mesorectal Excision (MDT-TME) Development Programme aimed to improve clinical outcomes for rectal cancer by educating colorectal cancer teams in precision surgery and related aspects of multidisciplinary care. The Programme reached almost all colorectal cancer teams across England. We took the opportunity to assess the impact of participating in this novel team-based Development Programme on the working lives of colorectal cancer team members.
The impact of participating in the programme on team members' self-reported job stress, job satisfaction and team performance was assessed in a pre-post course study. 333/568 (59%) team members, from the 75 multidisciplinary teams who attended the final year of the Programme, completed questionnaires pre-course, and 6-8 weeks post-course.
Across all team members, the main sources of job satisfaction related to working in multidisciplinary teams; whilst feeling overloaded was the main source of job stress. Surgeons and clinical nurse specialists reported higher levels of job satisfaction than team members who do not provide direct patient care, whilst MDT coordinators reported the lowest levels of job satisfaction and job stress. Both job stress and satisfaction decreased after participating in the Programme for all team members. There was a small improvement in team performance.
Participation in the Development Programme had a mixed impact on the working lives of team members in the immediate aftermath of attending. The decrease in team members' job stress may reflect the improved knowledge and skills conferred by the Programme. The decrease in job satisfaction may be the consequence of being unable to apply these skills immediately in clinical practice because of a lack of required infrastructure and/or equipment. In addition, whilst the Programme raised awareness of the challenges of teamworking, a greater focus on tackling these issues may have improved working lives further.
Objective To evaluate the performance of the QRISK2 score for predicting 10-year cardiovascular disease in an independent UK cohort of patients from general practice records and to compare it with the NICE version of the Framingham equation and QRISK1.
Design Prospective cohort study to validate a cardiovascular risk score.
Setting 365 practices from United Kingdom contributing to The Health Improvement Network (THIN) database.
Participants 1.58 million patients registered with a general practice between 1 January 1993 and 20 June 2008, aged 35-74 years (9.4 million person years) with 71 465 cardiovascular events.
Main outcome measures First diagnosis of cardiovascular disease (myocardial infarction, angina, coronary heart disease, stroke, and transient ischaemic stroke) recorded in general practice records.
Results QRISK2 offered improved prediction of a patient’s 10-year risk of cardiovascular disease over the NICE version of the Framingham equation. Discrimination and calibration statistics were better with QRISK2. QRISK2 explained 33% of the variation in men and 40% for women, compared with 29% and 34% respectively for the NICE Framingham and 32% and 38% respectively for QRISK1. The incidence rate of cardiovascular events (per 1000 person years) among men in the high risk group was 27.8 (95% CI 27.4 to 28.2) with QRISK2, 21.9 (21.6 to 22.2) with NICE Framingham, and 24.8 (22.8 to 26.9) with QRISK1. Similarly, the incidence rate of cardiovascular events (per 1000 person years) among women in the high risk group was 24.3 (23.8 to 24.9) with QRISK2, 20.6 (20.1 to 21.0) with NICE Framingham, and 21.8 (18.9 to 24.6) with QRISK1.
Conclusions QRISK2 is more accurate in identifying a high risk population for cardiovascular disease in the United Kingdom than the NICE version of the Framingham equation. Differences in performance between QRISK2 and QRISK1 were marginal.
This study sought to describe patient features before beginning fertility treatment, and to ascertain their perceptions relative to risk of twin pregnancy outcomes associated with such therapy.
Data on readiness for twin pregnancy outcome from in vitro fertilisation (IVF) was gathered from men and women before initiating fertility treatment by anonymous questionnaire.
A total of 206 women and 204 men were sampled. Mean (± SD) age for women and men being 35.5 ± 5 and 37.3 ± 7 yrs, respectively. At least one IVF cycle had been attempted by 27.2% of patients and 33.9% of this subgroup had initiated ≥3 cycles, reflecting an increase in previous failed cycles over five years. Good agreement was noted between husbands and wives with respect to readiness for twins from IVF (77% agreement; Cohen's K = 0.61; 95% CI 0.53 to 0.70).
Most patients contemplating IVF already have ideas about particular outcomes even before treatment begins, and suggests that husbands & wives are in general agreement on their readiness for twin pregnancy from IVF. However, fertility patients now may represent a more refractory population and therefore carry a more guarded prognosis. Patient preferences identified before IVF remain important, but further studies comparing pre- and post-treatment perceptions are needed.
In mice and in rats, reduced levels of the growth hormone secretagogue receptor (GHS-R1a) results in reduced body weight and lower levels of serum insulin-like growth factor I (IGF-I). However, the mechanism leading to these impairments has not been elucidated. Studies in primary cultures of pituitary cells from very young mice have shown that GHS-R1a agonists, including ghrelin, increase expression of the pituitary-specific transcription factor (Pit-1) that is critical for differentiation of pituitary cells into somatotrophs, lactotrophs and thyrotrophs. Hence, we hypothesized that ablation of Ghsr would reduce Pit-1 expression and as a consequence reduce growth hormone (GH) production explaining the lower body weight of Ghsr-/- mice. Here, we now show that Pit-1 mRNA levels are significantly lower in the pituitary gland of Ghsr-/- mice compared to wild type littermates and also with advancing age. This Pit-1 loss is associated with reduced GH mRNA and fewer GH producing cells. To determine whether reduced GH is caused by reduced expression of Pit-1 in Ghsr-/- mice, we also measured prolactin (PRL) expression in the pituitary gland and in the circulation. PRL mRNA was significantly reduced in Ghsr-/- mice compared to wild-type littermates and fewer cells expressed PRL. The reduction in expression of both GH and PRL is consistent with a Pit-1 regulated pathway and demonstrates that the GHS-R has an important role in the pituitary gland as a modulator of Pit-1 expression and provides a possible mechanism to explain the lower plasma IGF-1 and modestly reduced body weight exhibited by Ghsr-/- mice. We also believe that lower systemic and lymphoid hormone expression may also account, in part, for the enhanced thymic involution and reduced thymic output in Ghsr-/- mice.
Ghrelin; GHS-R; Aging; Pituitary; GH; IGF-1; Prolactin; Pit-1; thymus
To describe the prevalence and factors associated with nonalcoholic fatty liver disease (NAFLD) among HIV-infected persons not infected with hepatitis C virus (HCV).
A cross-sectional study among HIV-infected patients in a large HIV clinic.
NAFLD was defined as steatosis among patients without viral hepatitis (B or C) co-infection or excessive alcohol use. The prevalence of NAFLD was identified by ultrasound examination evaluated by two radiologists blinded to the clinic information; liver biopsies were performed on a subset of the study population. Factors associated with NAFLD evaluated by proportional odds logistic regression models.
Sixty-seven (31%) of 216 patients had NAFLD based on ultrasound evaluation. Among those with NAFLD, steatosis was graded as mild in 60%, moderate in 28%, and severe/ marked in 12%. Factors associated with the degree of steatosis on ultrasound examination in the multivariate model included increased waist circumference (odds ratio [OR] 2.1 per 10 cm, p<0.001), elevated triglycerides (OR= 1.2 per 100 mg/dl, p=0.03), and lower HDL levels (OR 0.7, p=0.03). African Americans were less likely to have NAFLD compared to Caucasians (14% vs. 35%), although this did not reach statistical significance (OR= 0.4, p=0.08). Similar associations were noted for the subset of patients diagnosed by liver biopsy. CD4 cell count, HIV viral load, duration of HIV infection, and antiretroviral medications were not independent risk factors associated with NAFLD after adjustment for dyslipidemia or waist circumference.
NAFLD was common among this cohort of HIV-infected, HCV-seronegative patients. NAFLD was associated with a greater waist circumference, low HDL and high triglyceride levels. Antiretroviral medications were not associated with NAFLD; prospective studies are needed to confirm this finding.
HIV; NAFLD; steatosis; liver disease; antiretroviral medication
Objective To independently evaluate the performance of the QRISK score for predicting 10 year risk of cardiovascular disease in an independent UK cohort of patients from general practice and compare the performance with Framingham equations.
Design Prospective open cohort study.
Setting 274 practices from England and Wales contributing to the THIN database.
Participants 1.07 million patients, registered between 1 January 1995 and 1 April 2006, aged 35-74 years (5.4 million person years) with 43 990 cardiovascular events.
Main outcome measures First diagnosis of cardiovascular disease (myocardial infarction, coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records.
Results This independent validation indicated that QRISK offers an improved performance in predicting the 10 year risk of cardiovascular disease in a large cohort of UK patients over the Anderson Framingham equation. Discrimination and calibration statistics were better with QRISK. QRISK explained 32% of the variation in men and 37% in women, compared with 27% and 31% respectively for Anderson Framingham. QRISK underpredicted risk by 13% for men and 10% for women, whereas Anderson Framingham overpredicted risk by 32% for men and 10% for women. In total, 85 010 (8%) of patients would be reclassified from high risk (≥20%) with Anderson Framingham to low risk with QRISK, with an observed 10 year cardiovascular disease risk of 17.5% (95% confidence interval 16.9% to 18.1%) for men and 16.8% (15.7% to 18.0%) for women. The incidence rate of cardiovascular disease events among men was 30.5 per 1000 person years (95% confidence interval 29.9 to 31.2) in high risk patients identified with QRISK and 23.7 per 1000 person years (23.2 to 24.1) in high risk patients identified with Anderson Framingham. Similarly, the incidence rate of cardiovascular disease events among women was 26.7 per 1000 person years (25.8 to 27.7) in high risk patients identified with QRISK compared with 22.2 per 1000 person years (21.4 to 23.0) in high risk patients identified with Anderson Framingham.
Conclusions The QRISK cardiovascular disease risk equation offers an improvement over the long established Anderson Framingham equation in terms of identifying a high risk population for cardiovascular disease in the United Kingdom. QRISK underestimates 10 year cardiovascular disease risk, but the magnitude of underprediction is smaller than the overprediction with Anderson Framingham.
We have recently demonstrated that all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cis RA) promote IL-4, IL-5 and IL-13 synthesis, while decreasing IFN-γ and TNF-α expression by activated human T cells and reduces the synthesis of IL-12p70 from accessory cells. Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-α (RAR-α)-selective agonist, AM580 but not with the RAR-β/γ ligand, 4-hydroxyphenylretinamide (4-HPR).
The increase in type 2 cytokine production by these retinoids correlated with the expression of the T cell activation markers, CD69 and CD38. The RAR-α-selective agonist, AM580 recapitulated all of the T cell activation and type 2 cytokine-inducing effects of ATRA and 9-cis-RA, while the RAR-α-selective antagonist, RO 41–5253, inhibited these effects.
These results strongly support a role for RAR-α engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production.
Previous health research has often explicitly excluded individuals from minority ethnic backgrounds due to perceived cultural and communication difficulties, including studies where there might be language/literacy problems in obtaining informed consent. This study addressed these difficulties by developing audio-recorded methods of obtaining informed consent and recording data. This report outlines 1) our experiences with securing recruitment to a qualitative study investigating alternative methods of data collection, and 2) the development of a standardised process for obtaining informed consent from individuals from minority ethnic backgrounds whose main language does not have an agreed written form.
Two researchers from South Asian backgrounds recruited adults with Type 2 diabetes whose main language was spoken and not written, to attend a series of focus groups. A screening tool was used at recruitment in order to assess literacy skills in potential participants. Informed consent was obtained using audio-recordings of the patient information and recording patients' verbal consent. Participants' perceptions of this method of obtaining consent were recorded.
Recruitment rates were improved by using telephone compared to face-to-face methods. The screening tool was found to be acceptable by all potential participants. Audio-recorded methods of obtaining informed consent were easy to implement and accepted by all participants. Attrition rates differed according to ethnic group. Snowballing techniques only partly improved participation rates.
Audio-recorded methods of obtaining informed consent are an acceptable alternative to written consent in study populations where literacy skills are variable. Further exploration of issues relating to attrition is required, and a range of methods may be necessary in order to maximise response and participation rates.
Lipid rafts play an important role in signal integration and in the cellular activation of a number of cytokine and growth factor receptors. It has recently been demonstrated that flotillin proteins are recruited to lipid raft microdomains upon cellular activation and play a role in neural cell regeneration, receptor signaling and lymphocyte activation. However, little is known about the relevance of the flotillin proteins during T cell responses to chemoattractant stimulation. To this end, cytoplasmic and lipid raft fractions from human T cells were analyzed for flotillin protein redistribution prior to and after CXCL12 stimulation. Flotillin-1, but not flotillin-2, redistributes to lipid rafts upon CXCR4 ligation. Moreover, in CXCL12-treated T cells, flotillin-1 also associates with several raft proteins including LAT, CD48 and CD11a but not Lck. In addition, an increase in CXCR4 association with flotillin-1 in lipid rafts was observed after chemokine treatment. RNAi technology was also utilized to inhibit the expression of flotillin-1, resulting in an inhibition of CXCL12-mediated signaling, function and CXCR4 recruitment into lipid rafts. Together, these data suggest that the increased association of cellular flotillin-1 with lipid raft microdomains during chemokine exposure may play an important role in chemokine receptor signaling and receptor partitioning with lipid rafts.
Chemotaxis; CXCL12; CXCR4; Flotillin-1; Lipid rafts
Vitamin A (VA) deficiency induces a type 1 cytokine response and exogenously provided retinoids can induce a type 2 cytokine response both in vitro and in vivo. The precise mechanism(s) involved in this phenotypic switch are inconsistent and have been poorly characterized in humans. In an effort to determine if retinoids are capable of inducing Th2 cytokine responses in human T cell cultures, we stimulated human PBMCs with immobilized anti-CD3 mAb in the presence or absence of all-trans retinoic acid (ATRA) or 9-cis-RA.
Stimulation of human PBMCs and purified T cells with ATRA and 9-cis-RA increased mRNA and protein levels of IL-4, IL-5, and IL-13 and decreased levels of IFN-γ, IL-2, IL-12p70 and TNF-α upon activation with anti-CD3 and/or anti-CD28 mAbs. These effects were dose-dependent and evident as early as 12 hr post stimulation. Real time RT-PCR analysis revealed a dampened expression of the Th1-associated gene, T-bet, and a time-dependent increase in the mRNA for the Th2-associated genes, GATA-3, c-MAF and STAT6, upon treatment with ATRA. Besides Th1 and Th2 cytokines, a number of additional proinflammatory and regulatory cytokines including several chemokines were also differentially regulated by ATRA treatment.
These data provide strong evidence for multiple inductive roles for retinoids in the development of human type-2 cytokine responses.