Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity

BACKGROUND: Controlled clinical trials of health care interventions are either explanatory or pragmatic. Explanatory trials test whether an intervention is efficacious; that is, whether it can have a beneficial effect in an ideal situation. Pragmatic trials measure effectiveness; they measure the degree of beneficial effect in real clinical practice. In pragmatic trials, a balance between external validity (generalizability of the results) and internal validity (reliability or accuracy of the results) needs to be achieved. The explanatory trial seeks to maximize the internal validity by assuring rigorous control of all variables other than the intervention. The pragmatic trial seeks to maximize external validity to ensure that the results can be generalized. However the danger of pragmatic trials is that internal validity may be overly compromised in the effort to ensure generalizability. We are conducting two pragmatic randomized controlled trials on interventions in the management of hypertension in primary care. We describe the design of the trials and the steps taken to deal with the competing demands of external and internal validity. DISCUSSION: External validity is maximized by having few exclusion criteria and by allowing flexibility in the interpretation of the intervention and in management decisions. Internal validity is maximized by decreasing contamination bias through cluster randomization, and decreasing observer and assessment bias, in these non-blinded trials, through baseline data collection prior to randomization, automating the outcomes assessment with 24 hour ambulatory blood pressure monitors, and blinding the data analysis. SUMMARY: Clinical trials conducted in community practices present investigators with difficult methodological choices related to maintaining a balance between internal validity (reliability of the results) and external validity (generalizability). The attempt to achieve methodological purity can result in clinically meaningless results, while attempting to achieve full generalizability can result in invalid and unreliable results. Achieving a creative tension between the two is crucial

Are different groups of patients with stroke more likely to be excluded from the new UK general medical services contract? A cross-sectional retrospective analysis of a large primary care population

Peer reviewedPublisher PD

Robust and Fast Whole Brain Mapping of the RF Transmit Field B1 at 7T

In-vivo whole brain mapping of the radio frequency transmit field B1+ is a key aspect of recent method developments in ultra high field MRI. We present an optimized method for fast and robust in-vivo whole-brain B1+ mapping at 7T. The method is based on the acquisition of stimulated and spin echo 3D EPI images and was originally developed at 3T. We further optimized the method for use at 7T. Our optimization significantly improved the robustness of the method against large B1+ deviations and off-resonance effects present at 7T. The mean accuracy and precision of the optimized method across the brain was high with a bias less than 2.6 percent unit (p.u.) and random error less than 0.7 p.u. respectively

Loss of expression of FANCD2 protein in sporadic and hereditary breast cancer

Fanconi anemia (FA) is a recessive disorder associated with progressive pancytopenia, multiple developmental defects, and marked predisposition to malignancies. FA is genetically heterogeneous, comprising at least 12 complementation groups (A–M). Activation of one of the FA proteins (FANCD2) by mono-ubiquitination is an essential step in DNA damage response. As FANCD2 interacts with BRCA1, is expressed in proliferating normal breast cells, and FANCD2 knockout mice develop breast tumors, we investigated the expression of FANCD2 in sporadic and hereditary invasive breast cancer patients to evaluate its possible role in breast carcinogenesis. Two tissue microarrays of 129 and 220 sporadic breast cancers and a tissue microarray containing 25 BRCA1 germline mutation-related invasive breast cancers were stained for FANCD2. Expression results were compared with several clinicopathological variables and tested for prognostic value. Eighteen of 96 (19%) sporadic breast cancers and two of 21 (10%) BRCA1-related breast cancers were completely FANCD2-negative, which, however, still showed proliferation. In the remaining cases, the percentage of FANCD2-expressing cells correlated strongly with mitotic index and percentage of cells positive for the proliferation markers Ki-67 and Cyclin A. In immunofluorescence double staining, coexpression of FANCD2 and Ki-67 was apparent. In survival analysis, high FANCD2 expression appeared to be prognostically unfavorable for overall survival (p = 0.03), independent from other major prognosticators (p = 0.026). In conclusion, FANCD2 expression is absent in 10–20% of sporadic and BRCA1-related breast cancers, indicating that somatic inactivating (epi)genetic events in FANCD2 may be important in both sporadic and hereditary breast carcinogenesis. FANCD2 is of independent prognostic value in sporadic breast cancer

Nutritional strategies of high level natural bodybuilders during competition preparation

Background Competitive bodybuilders employ a combination of resistance training, cardiovascular exercise, calorie reduction, supplementation regimes and peaking strategies in order to lose fat mass and maintain fat free mass. Although recommendations exist for contest preparation, applied research is limited and data on the contest preparation regimes of bodybuilders are restricted to case studies or small cohorts. Moreover, the influence of different nutritional strategies on competitive outcome is unknown. Methods Fifty-one competitors (35 male and 16 female) volunteered to take part in this project. The British Natural Bodybuilding Federation (BNBF) runs an annual national competition for high level bodybuilders; competitors must qualify by winning at a qualifying events or may be invited at the judge’s discretion. Competitors are subject to stringent drug testing and have to undergo a polygraph test. Study of this cohort provides an opportunity to examine the dietary practices of high level natural bodybuilders. We report the results of a cross-sectional study of bodybuilders competing at the BNBF finals. Volunteers completed a 34-item questionnaire assessing diet at three time points. At each time point participants recorded food intake over a 24-h period in grams and/or portions. Competitors were categorised according to contest placing. A “placed” competitor finished in the top 5, and a “Non-placed” (DNP) competitor finished outside the top 5. Nutrient analysis was performed using Nutritics software. Repeated measures ANOVA and effect sizes (Cohen’s d) were used to test if nutrient intake changed over time and if placing was associated with intake. Results Mean preparation time for a competitor was 22 ± 9 weeks. Nutrient intake of bodybuilders reflected a high-protein, high-carbohydrate, low-fat diet. Total carbohydrate, protein and fat intakes decreased over time in both male and female cohorts (P < 0.05). Placed male competitors had a greater carbohydrate intake at the start of contest preparation (5.1 vs 3.7 g/kg BW) than DNP competitors (d = 1.02, 95% CI [0.22, 1.80]). Conclusions Greater carbohydrate intake in the placed competitors could theoretically have contributed towards greater maintenance of muscle mass during competition preparation compared to DNP competitors. These findings require corroboration, but will likely be of interest to bodybuilders and coaches. Keywords BodybuildersCaloriesCompetitionContest preparationDietingEnergy restrictionNaturalNutritionSupplementationPhysiqu

Impact of a silver layer on the membrane of tap water filters on the microbiological quality of filtered water

<p>Abstract</p> <p>Background</p> <p>Bacteria in the hospital's drinking water system represent a risk for the acquisition of a nosocomial infection in the severely immunocompromised host. Terminal tap water filters may be used to prevent nosocomial Legionnaires' disease. We present data from water samples using an improved kind of tap water filters.</p> <p>Methods</p> <p>In a blinded study on an intermediate care unit of the thoracic surgery department, a modified type of the Germlyser water filter (Aqua-Free Membrane Technology) with a newly-introduced silver layer on the filtration membrane was compared to its preceding type without such a layer on 15 water outlets. We determined growth of <it>Legionella</it>, other pathogenic bacteria, and the total heterotrophic plate count in unfiltered water and filtered water samples after filter usage intervals of 1 through 4 weeks.</p> <p>Results</p> <p>A total of 299 water samples were tested. Twenty-nine of the 60 unfiltered water samples contained <it>Legionella </it>of various serogroups (baseline value). In contrast, all samples filtered by the original water filter and all but one of the water samples filtered by the modified filter type remained <it>Legionella</it>-free. No other pathogenic bacteria were detected in any filtered sample. The total plate count in water samples increased during use of both kinds of filters over time. However, for the first 7 days of use, there were significantly fewer water samples containing >100 CFU per mL when using the new filter device compared with the older filters or taps with no filter. No advantage was seen thereafter.</p> <p>Conclusion</p> <p>The use of this type of terminal water filter is an appropriate method to protect immunocompromised patients from water-borne pathogens such as <it>Legionella</it>.</p

Predator foraging altitudes reveal the structure of aerial insect communities

The atmosphere is populated by a diverse array of dispersing insects and their predators. We studied aerial insect communities by tracking the foraging altitudes of an avian insectivore, the Purple Martin (Progne subis). By attaching altitude loggers to nesting Purple Martins and collecting prey delivered to their nestlings, we determined the flight altitudes of ants and other insects. We then tested hypotheses relating ant body size and reproductive ecology to flight altitude. Purple Martins flew up to 1,889 meters above ground, and nestling provisioning trips ranged up to 922 meters. Insect communities were structured by body size such that species of all sizes flew near the ground but only light insects flew to the highest altitudes. Ant maximum flight altitudes decreased by 60% from the lightest to the heaviest species. Winged sexuals of social insects (ants, honey bees, and termites) dominated the Purple Martin diet, making up 88% of prey individuals and 45% of prey biomass. By transferring energy from terrestrial to aerial food webs, mating swarms of social insects play a substantial role in aerial ecosystems. Although we focus on Purple Martins and ants, our combined logger and diet method could be applied to a range of aerial organisms.This work was funded by US NSF award IDBR-1014891 to ESB, and a US NSF Graduate Research Fellowship, OU Alumni Fellowship, OU Biological Station Graduate Summer Research Fellowship, and George Miksch Sutton Avian Research Scholarship to JAH.Ye

Effectiveness of joint mobilisation after cast immobilisation for ankle fracture: a protocol for a randomised controlled trial [ACTRN012605000143628]

BACKGROUND: Passive joint mobilisation is a technique frequently used by physiotherapists to reduce pain, improve joint movement and facilitate a return to activities after injury, but its use after ankle fracture is currently based on limited evidence. The primary aim of this trial is to determine if adding joint mobilisation to a standard exercise programme is effective and cost-effective after cast immobilisation for ankle fracture in adults. METHODS/DESIGN: Ninety participants will be recruited from the physiotherapy departments of three teaching hospitals and randomly allocated to treatment or control groups using a concealed procedure. All participants will perform an exercise programme. Participants in the treatment group will also receive joint mobilisation twice a week for four weeks. Blinded follow-up assessments will be conducted four, 12 and 24 weeks after randomisation. The primary outcome measures will be the Lower Extremity Functional Scale and the Assessment of Quality of Life. Secondary outcomes will include measures of impairments, activity limitation and participation. Data on the use of physiotherapy services and participants' out-of-pocket costs will be collected for the cost-effective and cost-utility analyses. To test the effects of treatment, between-group differences will be examined with analysis of covariance using a regression approach. The primary conclusions will be based on the four-week follow-up data. DISCUSSION: This trial incorporates features known to minimise bias. It uses a pragmatic design to reflect clinical practice and maximise generalisability. Results from this trial will contribute to an evidence-based approach for rehabilitation after ankle fracture