Why unidimensional pain measurement prevails in the pediatric acute pain context and what multidimensional self-report methods can offer

Although pain is widely recognized to be a multidimensional experience and defined as such, unidimensional pain measurement focusing on pain intensity prevails in the pediatric acute pain context. Unidimensional assessments fail to provide a comprehensive picture of a child’s pain experience and commonly do little to shape clinical interventions. The current review paper overviews the theoretical and empirical literature supporting the multidimensional nature of pediatric acute pain. Literature reporting concordance data for children’s self-reported sensory, affective and evaluative pain scores in the acute pain context has been reviewed and supports the distinct nature of these dimensions. Multidimensional acute pain measurement holds particular promise for identifying predictive markers of chronicity and may provide the basis for tailoring clinical management. The current paper has described key reasons contributing to the widespread use of unidimensional, rather than multidimensional, acute pediatric pain assessment protocols. Implications for clinical practice, education and future research are considered

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Protocol and rationale for the international lung screening trial

: The NLST (National Lung Screening Trial) reported a 20% reduction in lung cancer mortality with low-dose computed tomography screening; however, important questions on how to optimize screening remain, including which selection criteria are most accurate at detecting lung cancers and what nodule management protocol is most efficient. The PLCO (Prostate, Lung, Colorectal and Ovarian) Cancer Screening Trial 6-year and PanCan (Pan-Canadian Early Detection of Lung Cancer) nodule malignancy risk models are two of the better validated risk prediction models for screenee selection and nodule management, respectively. Combined use of these models for participant selection and nodule management could significantly improve screening efficiency.: The ILST (International Lung Screening Trial) is a prospective cohort study with two primary aims: ) Compare the accuracy of the PLCO model against U.S. Preventive Services Task Force (USPSTF) criteria for detecting lung cancers and ) evaluate nodule management efficiency using the PanCan nodule probability calculator-based protocol versus Lung-RADS.: ILST will recruit 4,500 participants who meet USPSTF and/or PLCO risk ≥1.51%/6-year selection criteria. Participants will undergo baseline and 2-year low-dose computed tomography screening. Baseline nodules are managed according to PanCan probability score. Participants will be followed up for a minimum of 5 years. Primary outcomes for aim 1 are the proportion of individuals selected for screening, proportion of lung cancers detected, and positive predictive values of either selection criteria, and outcomes for aim 2 include comparing distributions of individuals and the proportion of lung cancers in each of three management groups: next surveillance scan, early recall scan, or diagnostic evaluation recommended. Statistical powers to detect differences in the four components of primary study aims were ≥82%.: ILST will prospectively evaluate the comparative accuracy and effectiveness of two promising multivariable risk models for screenee selection and nodule management in lung cancer screening.Clinical trial registered with www.clinicaltrials.gov (NCT02871856)

Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells

An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD+ leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used