Bridging the gap between clinical research and clinical practice: introduction to the special section

This Special Section, developed by the American Psychology Association's Division 12 (Clinical) 2011 Committee on Science and Practice, highlights different ideas to help bridge the gap between clinical research and clinical practice, and notes recent innovations that help make research-practice integration feasible. The articles consider how to break down the barriers to enhance researcher-practitioner dialogue, as well as how to make ongoing outcome assessment feasible for clinicians. Moreover, the articles address how to promote training in evidence-based practice, and how to translate efficacy research into clinical practice and clinical insight into empirical study to better establish a two-way bridge between research and practice. Ultimately, we hope this series can speak to many different types of psychologists, whether they work mainly as researchers or practitioners, so they can see new ways to integrate and learn from both research and practice.     

Factors associated with mortality in under-five children with severe anemia in Ebonyi,Nigeria

Objective  

To determine the risk factors associated with poor outcome among under-five children with severe anemia in sub Saharan Africa.     

Correlative BOLD MR imaging of stages of synovitis in a rabbit model of antigen-induced arthritis

Background

Because of the ability of blood-oxygen-level-dependent (BOLD) MRI to assess blood oxygenation changes within the microvasculature, this technique holds potential for evaluating early perisynovial changes in inflammatory arthritis.

Objective

To evaluate the feasibility of BOLD MRI to detect interval perisynovial changes in knees of rabbits with inflammatory arthritis.

Materials and methods

Rabbit knees were injected with albumin (n?=?9) or saline (n?=?6) intra-articularly, or were not injected (control knees, n?=?9). Except for two rabbits (albumin-injected, n?=?2 knees; saline-injected, n?=?2 knees) that unexpectedly died on days 7 and 21 of the experiment, respectively, all other animals were scanned with BOLD MRI on days 0, 1, 7, 14, 21 and 28 after induction of arthritis. T2*-weighted gradient-echo MRI was performed during alternate 30?s of normoxia/hyperoxia. BOLD MRI measurements were compared with clinical, laboratory and histological markers.

Results

Percentage of activated voxels was significantly greater in albumin-injected knees than in contralateral saline-injected knees (P?=?0.04). For albumin-injected knees (P?P?=?0.009), the percentage of activated BOLD voxels varied over time. A quadratic curve for on-and-off BOLD difference was delineated for albumin- and saline-injected knees over time (albumin-injected, P?=?0.047; saline-injected, P?=?0.009). A trend toward a significant difference in synovial histological scores between albumin-injected and saline-injected knees was noted only for acute scores (P?=?0.07).

Conclusion

As a proof of concept, BOLD MRI can depict perisynovial changes during progression of experimental arthritis.     

Clinical implications of anterolateral thigh flap shrinkage

OBJECTIVE: To evaluate anterolateral thigh flap shrinkage after elevation and to develop a predictive model for flap design. METHOD: A prospective study was conducted in a university teaching hospital. The skin islands from anterolateral thigh flaps were outlined on a transparent sheet before and after the reconstruction procedure. Dimensions of the stretched flaps were also recorded. These three outlines were scanned and the surface areas computed and compared by tracing and use of AutoCAD. Age, sex, flap dimension, and flap thickness were investigated for association with flap shrinkage. RESULTS: Forty-five anterolateral thigh flaps harvested for head and neck soft tissue reconstruction after tumor resection were studied. Flap size ranged from 4 to 14 cm in width and 8 to 22 cm in length; flap area ranged from 30.6 to 151.0 cm. On average, the flaps shrunk by 25.0% (6.2%-52.6%), a highly significant change (P < .01). Flap width and thickness correlated with the reduction in flap size. The average stretched-flap area was 10.1% (0.4%-29.4%) less than the preflap area, a significant reduction (P < .01). The difference between stretched-flap and preflap areas was independent of all variables. We developed a predictive model using a stepwise multiple linear regression method with a coefficient of determination of 0.495. CONCLUSIONS: Anterolateral thigh flaps shrink after harvesting, and flap width and thickness are significant contributing variables. These findings indicate that flap size must take shrinkage into account to ensure sufficient coverage.     

Synergy of Caspofungin with Human Polymorphonuclear Granulocytes for Killing Candida albicans

The influence of caspofungin on polymorphonuclear leukocyte (PMN) phagocytosis and intracellular killing of Candida albicans was investigated. Caspofungin, at all of the concentrations tested (2, 3.2, and 8 μg/ml), significantly increased intracellular killing by PMNs through its direct action on both yeast cells and PMNs, indicating the potential ability of caspofungin to synergize with phagocytes for candidal killing. Caspofungin may therefore constitute an effective therapeutic option for the treatment of invasive fungal infections, including those refractory to conventional treatment with azole agents.Echinocandins, such as caspofungin, are new drugs that broaden the available therapeutic arsenal for invasive fungal infection (IFI) treatment (6, 7, 11). Caspofungin displays favorable pharmacodynamic and pharmacokinetic characteristics and has an excellent toxicological profile and antifungal activity against Candida spp., Aspergillus spp., Histoplasma spp., Blastomyces spp., and Coccidioides spp. (3, 7, 11, 12, 15). As the current trend in therapy requires drugs with high in vitro activity associated with the capacity to potentiate host defense mechanisms, especially in immunocompromised hosts (2, 19), the interaction of caspofungin with human polymorphonuclear leukocytes (PMNs) was evaluated, focusing on both the phagocytosis and intracellular killing of Candida albicans.(This study was presented in part at the Congress of the Italian Society of Pharmaceutical Microbiology, Turin, Italy, 20 to 22 June 2008.)A clinical C. albicans strain isolated from blood and identified by biochemical methods was subcultured on Sabouraud dextrose agar (Oxoid S.p.A., Milan, Italy) to ensure viability and purity. Yeast cultures consisted entirely of blastoconidia and had a slight tendency to differentiate into pseudohyphae during the course of the experiments.Caspofungin acetate (Merck Sharp & Dohme Ltd., Hoddesdon, United Kingdom) was dissolved in pyrogen-free water and stored at −20°C. Antifungal susceptibility testing was performed with an inoculum of 10³ CFU/ml, in accordance with CLSI M27-A3 (4), and an inoculum of 10⁶ CFU/ml was used to perform tests with phagocytes.PMNs were separated from lithium heparinized venous blood using Ficoll-Paque (Pharmacia S.p.A., Milan, Italy) and adjusted to 10⁶ cells/ml in RPMI 1640 medium (Gibco Laboratories, Grand Island, NY) (1, 5). Viability, determined by trypan blue exclusion, was greater than 95%.The effect of caspofungin on the phagocytosis of radiolabeled C. albicans ([³H]uracil [specific activity, 1,270 GBq/mmol; NEN Life Science Products, Milan, Italy]) by PMNs was investigated by incubating the yeast cells (10⁶ invasive fungal cells/ml) and PMNs (10⁶ cells/ml) at 37°C in a shaking water bath in the presence of 2 μg/ml (MIC), 3.2 μg/ml, or 8 μg/ml caspofungin; the last two concentrations were within the range achieved clinically (8, 9). Caspofungin-free controls were included. After 30, 60, or 90 min, phagocytosis was assessed (18, 19). PMNs were centrifuged twice at 200 × g for 5 min to remove free blastoconidia and suspended in sterile water for 5 min; 100-μl samples were placed in scintillation fluid (Atomlight; NEN) and counted by spectrophotometry. Radioactivity was expressed as counts per minute (cpm) per sample. The percentage of phagocytosis at a given sampling time was calculated as follows: % phagocytosis = [(cpm in PMN pellet)/(cpm in total fungal pellet)]×100 (18, 19). Intracellular killing was investigated by incubating yeast cells and PMNs (1:1 ratio) for 30 min to allow phagocytosis to proceed. The PMN-yeast cell mixtures were centrifuged at 200 × g for 5 min and washed to remove extracellular blastoconidia. An aliquot of PMNs was lysed by adding sterile water, and intracellular viable yeast cell counting was performed (time zero). PMNs were incubated further with 2, 3.2, or 8 μg/ml caspofungin, and at time x (30, 60, and 90 min), the viable counts were measured in the same way. Killing values were expressed as a survival index (SI), which was calculated by adding the number of surviving yeast cells at time zero to the number of survivors at time x and dividing by the number of survivors at time zero. According to this formula, if fungal killing was 100% effective, the SI would be 1 (18, 19). To differentiate between any separate effect of caspofungin on the yeast cells and PMNs, the experiments were conducted after the exposure of each of them to 2, 3.2, or 8 μg/ml caspofungin for 1 h, before they were incubated together (16, 17). After the withdrawal of caspofungin, preexposed blastoconidia were added to PMNs and blastoconidia were added to preexposed PMNs. Drug-free controls were included. Intracellular killing was determined as described above. Results were expressed as the mean ± the standard error of the mean (SEM) of 10 separate experiments, each performed in quadruplicate. Statistical evaluation of the differences between test and control results was performed by Tukey''s test.The majority of systemic antifungal drugs do not significantly influence the phagocytic activity of PMNs against Candida spp. (8, 13, 14). We reported that fluconazole enhances the in vitro killing activity of phagocytes against C. albicans, without improving phagocytosis (18, 19). We observed a similar pattern for caspofungin (data not shown), probably owing to the altered expression of surface molecules that link to cleavage products of complement (13). On the contrary, under the same experimental conditions, caspofungin showed a marked effect on the survival of blastoconidia, with SI values that ranged from 1.25 to 1.29, 1.14 to 1.28, and 1.17 to 1.26 for the three drug concentrations tested, compared with those for the caspofungin-free controls (P < 0.01; Table ​Table11).

TABLE 1.

Effect of caspofungin on intracellular killing of C. albicans by human PMNs

Impact of positive hepatitis B surface antigen on the outcome of IVF treatment

There has been controversy about the effect of hepatitis B virus (HBV) infection on pregnancy outcome after IVF treatment. A total of 1676 couples undergoing their first IVF cycle were included in this study. The prevalence of HBV infection in the female partners of the subfertile population seeking treatment with assisted reproductive technology was 7.8-9.6% during the study period. The ongoing pregnancy rate was not significantly different between couples with HBV-seropositive wives and seronegative ones (26.7% versus 30.2%). The ongoing pregnancy rate and the live-birth rate of couples with both partners being HBV surface antigen positive was not significantly different from couples with discordant HBV serostatus and those couples with both partners being HBV surface antigen negative (23% versus 29% versus 30%, respectively; 23% versus 27% versus 27%, respectively). The percentage of normal sperm morphology in HBV-seropositive husbands was significantly lower than that of seronegative counterparts (5.0% versus 10.0%, P=0.009). In conclusion, there was no adverse effect of HBV infection on the assisted reproduction outcomes. This study was the first report on the live-birth rate of hepatitis B (HBV) seropositive couples, revealing the effect on the pregnancy outcome of IVF. The prevalence of HBV infection in the female partners of subfertile population seeking treatment with ART was 7.8-9.6%. Both the ongoing pregnancy rate and live-birth rate were not significantly different among couples with both partners being positive for HBV surface antigen, couples with discordant HBV serostatus and those couples with both partners being negative for HBV surface antigen. The percentage of normal sperm morphology in HBV-seropositive husbands was significantly lower than that of seronegative counterparts.     

Effect of Intensive Compared With Standard Glycemia Treatment Strategies on Mortality by Baseline Subgroup Characteristics: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial

OBJECTIVE

To determine if baseline subgroups in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial can be identified for whom intensive compared with standard glycemia treatment had different effects on all-cause mortality.

RESEARCH DESIGN AND METHODS

Exploratory post hoc intention-to-treat comparisons were made between intensive and standard glycemia groups on all-cause mortality by subgroups defined by baseline characteristics.

RESULTS

There were few significant interactions between baseline characteristics and effects of intensive versus standard glycemia treatment on mortality: self-reported history of neuropathy (hazard ratio [HR] 1.95, 95% CI 1.41–2.69) versus no history of neuropathy (0.99, 0.79–1.26; P value for interaction 0.0008), higher A1C (A1C >8.5%: HR 1.64, 95% CI 1.22–2.22; A1C 7.5–8.4%: 1.00, 0.75–1.34; A1C <7.5%: 1.00, 0.67–1.50; P value for interaction 0.04), and aspirin use (HR 1.45, 95% CI 1.13–1.85, compared with 0.96, 0.72–1.27, in nonusers; P value for interaction 0.03).

CONCLUSIONS

We found a remarkable similarity of effect from intensive compared with standard glycemia treatment on mortality across most baseline subgroups. No differential effect was found in subgroups defined by variables anticipated to have an interaction: age, duration of diabetes, and previous history of cardiovascular disease. The three baseline characteristics that defined subgroups for which there was a differential effect on mortality may help identify patients with type 2 diabetes at higher risk of mortality from intensive regimens for glycemic control. Further research is warranted.Numerous epidemiological studies have demonstrated a relationship between elevated A1C and a greater risk of cardiovascular (CVD) events and mortality in type 2 diabetes (1–3). Therefore, it has been hypothesized that a reduction to near-normal levels of A1C in patients with type 2 diabetes would reduce the risk of these adverse outcomes. Three large randomized controlled clinical trials testing this hypothesis in individuals with longstanding type 2 diabetes reported their main results in the past 2 years (4–6).The Data Safety Monitoring Board of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial discontinued the intensive glycemia arm because of an increase in all-cause mortality in the intensive glycemia arm compared with the standard glycemia arm. The finding of excess mortality in the intensive arm of the ACCORD trial has led to controversy about implementation of intensive glucose control in patients with type 2 diabetes (7,8). Adding to the controversy were results of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) and Veterans Affairs Diabetes Trial (VADT), demonstrating that although there was no significant reduction in the primary end point of CVD events, there was no increase in mortality with the intensive glycemia arm compared with the standard glycemia arm (4,6), which has raised questions about reasons for these discrepancies (9–12).A critical question relates to the applicability and generalizability of the conclusions of the ACCORD trial to the broader population or to specific subgroups of patients with type 2 diabetes. Indeed, prespecified subgroup analyses in ACCORD did suggest a significant benefit of intensive glycemic control on CVD events in those participants with lower A1C at entry or absence of CVD event by history, but there was no suggestion of a differential effect on mortality (5). However, these observations are based on only a few subgroup analyses at the time of the primary publication. The effect on mortality of intensive compared with standard glycemia treatment may have been modified by other possible characteristics of patients at entry. We have therefore carried out exploratory post hoc analyses of the effects of intensive compared with standard glycemia treatment in ACCORD participants categorized by various baseline characteristics on all-cause mortality at the time of discontinuation of the intensive glycemia treatment of ACCORD, with the goal to determine if particular subgroups at higher or lower risk from the intensive intervention can be identified.