Profiles of mathematical deficits in children with dyslexia.

Despite a high rate of concurrent mathematical difficulties among children with dyslexia, we still have limited information regarding the prevalence and severity of mathematical deficits in this population. To address this gap, we developed a comprehensive battery of cognitive tests, known as the UCSF Mathematical Cognition Battery (MCB), with the aim of identifying deficits in four distinct mathematical domains: number processing, arithmetical procedures, arithmetic facts retrieval, and geometrical abilities. The mathematical abilities of a cohort of 75 children referred to the UCSF Dyslexia Center with a diagnosis of dyslexia, along with 18 typically developing controls aged 7 to 16, were initially evaluated using a behavioral neurology approach. A team of professional clinicians classified the 75 children with dyslexia into five groups, based on parents' and teachers' reported symptoms and clinical history. These groups included children with no mathematical deficits and children with mathematical deficits in number processing, arithmetical procedures, arithmetic facts retrieval, or geometrical abilities. Subsequently, the children underwent evaluation using the MCB to determine concordance with the clinicians' impressions. Additionally, neuropsychological and cognitive standardized tests were administered. Our study reveals that within a cohort of children with dyslexia, 66% exhibit mathematical deficits, and among those with mathematical deficits, there is heterogeneity in the nature of these deficits. If these findings are confirmed in larger samples, they can potentially pave the way for new diagnostic approaches, consistent subtype classification, and, ultimately personalized interventions.

The prevalence of atopic dermatitis beyond childhood: A systematic review and meta-analysis of longitudinal studies.

BACKGROUND: There are sparse and conflicting data regarding the long-term clinical course of atopic dermatitis (AD). Although often described as a childhood disease, newer population-based estimates suggest the prevalence of pediatric and adult disease may be similar. METHODS: Our objective was to determine whether there is a decline in the prevalence of AD in population-based cohorts of patients followed longitudinally beyond childhood. We conducted a systematic review and meta-analysis including studies assessing AD prevalence across 3 or more points in time. The primary outcome was weighted overall risk difference (percentage decrease in AD prevalence). RESULTS: Of 2080 references reviewed, 7 studies with 13 515 participants were included. Participants were assessed at 3-6 time points, ranging from age 3 months to 26 years. The percentage decrease in prevalence after age 12 was 1%, which was not significantly different from zero (95% confidence interval -2%-5%). Similar results were found with other age cut-offs. CONCLUSION: The prevalence of AD in longitudinal birth cohort studies is similar in childhood and adolescence/early adulthood.

Preliminary evidence supports circulating microRNAs as prognostic biomarkers for type 2 diabetes.

Background: Circulating microRNAs are emerging as potential prognostic biomarkers for the development of type 2 diabetes. However, microRNAs are also associated with complications from impaired glucose metabolism (e.g. endothelial cell function). Prior studies have not evaluated for associations between trajectories of circulating microRNAs with trajectories of fasting blood glucose over time and the responses to behavioral interventions to reduce risk. This study performed longitudinal assessment of microRNAs and fasting blood glucose and identified relationships between microRNAs and behavioral risk reduction interventions. Methods: MicroRNAs (n = 353) were measured in subsets (n = 10, n = 8) of participants from previously completed clinical trials that studied behavioral risk reduction interventions. Fasting blood glucose trajectories were associated with changes in 45 microRNAs over 12 months. Results: Following a 3-month physical activity and dietary intervention compared with baseline, 13 microRNAs were differentially expressed. Seven microRNAs (i.e. miR-106b, miR-20b, miR-363, miR-486, miR-532, miR-92a and miR-93) were commonly identified between the two analyses. Conclusions: Further studies are needed to determine which microRNAs are prognostic biomarkers of risk for type 2 diabetes versus consequences of impaired glucose metabolism. Additional future directions of this research are to differentiate whether microRNAs are prognostic and/or diagnostic biomarkers for risk for type 2 diabetes and predictive biomarkers of responses to risk reduction interventions.

Diagnostic accuracy of C-reactive protein for active pulmonary tuberculosis: a meta-analysis.

SETTING: Systematic screening for active pulmonary tuberculosis (PTB) is recommended for high-risk populations, including people living with the human immunodeficiency virus (PLHIV); however, currently recommended TB screening tools are inadequate for most high-burden settings. OBJECTIVE: To determine whether C-reactive protein (CRP) possesses the necessary test characteristics to screen individuals for active PTB. DESIGN: We performed a systematic review and meta-analysis of studies evaluating the diagnostic accuracy of CRP (10 mg/l cut-off point) for culture-positive PTB. Pooled diagnostic accuracy estimates were generated using random-effects meta-analysis for out-patients and in-patients, and for pre-specified subgroups based on HIV status and test indication. RESULTS: We identified nine unique studies enrolling 1793 adults from out-patient (five studies, 1121 patients) and in-patient settings (five studies, 672 patients), 72% of whom had confirmed HIV infection. Among out-patients, CRP had high sensitivity (93%, 95%CI 88-98) and moderate specificity (60%, 95%CI 40-75) for active PTB. Specificity was lowest among in-patients (21%, 95%CI 6-52) and highest among out-patients undergoing TB screening (range 58-81%). There was no difference in summary estimates by HIV status. CONCLUSION: CRP, which is available as a simple, inexpensive and point-of-care test, can be used to screen PLHIV presenting for routine HIV/AIDS (acquired immune-deficiency syndrome) care for active TB.

Determinants of practice patterns in pediatric UTI management.

INTRODUCTION: Urinary tract infection (UTI) affects 10% of girls and 3% of boys by age 16. Both the American Academy of Pediatrics and National Institute for Health and Clinical Excellence Guidelines recommend urine testing prior to initiation of antibiotic treatment and the use of local antibiograms to guide empiric antibiotic therapy. Urine culture results not only provide the opportunity to halt empiric therapy if there is no bacterial growth, but also allow for tailoring of broad-spectrum therapy. Additionally, the use of antiobiograms improves empiric antibiotic selection based on local resistance patterns. However, execution of guideline recommendations has proved challenging. Understanding barriers in implementation is critical to developing targeted interventions aimed to improve adherence to these guidelines. OBJECTIVES: The present study sought to investigate practice patterns and factors that influence urine testing and antibiogram use in the setting of empiric antibiotic treatment of UTI in children to ultimately improve adherence to UTI management guidelines. STUDY DESIGN: A random, national sample of physicians caring for children was surveyed from the American Medical Association Masterfile. Participants were queried regarding practice type, length of time in practice, factors influencing urine testing, urine specimen collection method, and antibiogram utilization. Logistic regression was used to assess factors associated with use of urine testing, bagged specimens, and antibiograms. RESULTS: Of respondents who acknowledged contact by surveyors, 47% completed the survey (n = 366). Most respondents (84%) obtain urinalysis and culture prior to treatment for UTI. Physicians report they would more likely order testing if the specimen were easier to collect (46%) and if results were available immediately (48%) (Table). Urine collection by bag was more common in circumcised boys (>30%) compared with girls (20%) and uncircumcised boys (20%) (P = 0.02). The most common reasons for collection by bag were parental refusal for (49%) and difficulty with (42%) catheterization (Table). Of the 70% of respondents reporting antibiogram access (n = 256), 50% report its use the majority of the time with empiric prescription (n = 128). DISCUSSION: While most practitioners report following guidelines to obtain urine testing prior to antibiotic prescription for UTI, urine collection by bag is common. Additionally, <50% of practitioners adhere to guideline recommendations for empiric antibiotic selection based on local antibiograms. Interventions to improve adherence to UTI management guidelines should focus on (1) improving catheterization practices, (2) educating parents regarding the value of catheterization, and (3) incorporating local antibiograms into electronic medical records.

Meta-analysis to assess the efficacy of interferon-alpha in patients with follicular non-Hodgkin's lymphoma.

The authors wanted to determine whether adding interferon-alpha (IFN-alpha) to chemotherapy regimens, in either induction or maintenance settings, provides additional survival benefits in follicular non-Hodgkin's lymphoma (NHL). A meta-analysis was performed based on published data from randomized controlled clinical trials involving nine separate study populations. Patients receiving IFN-alpha (in either induction or maintenance therapy) had significantly increased 5-year and progression-free survival rates at 3 and 5 years compared with concurrent controls. The advantages of IFN-alpha therapy were most marked in studies using anthracycline-containing induction chemotherapy; in these studies, patients who received IFN-alpha had approximately 20% increased progression-free survival rates compared with controls and a lesser survival advantage. The available literature did not allow a determination of the relative benefit of IFN-alpha in induction or maintenance treatments for NHL or a determination of the optimum duration of IFN-alpha treatment. Although questions remain about its optimal use. IFN-alpha appears to prolong survival time in patients with follicular NHL.

Adverse drug reactions in hospitalized patients: A critique of a meta-analysis.

OBJECTIVE: To replicate and to critique a recently published meta-analysis[1] of the incidence of nonpreventable serious and fatal adverse drug reactions (ADRs) in hospitalized patients, to better understand its results and conclusions. METHODS: The published methods described in the meta-analysis of Lazarou and colleagues were followed.[1] This meta-analysis reviewed 30 original publications describing 39 prospective studies. In each study, the numbers of patients with nonpreventable ADRs, probably or definitely related to drugs, were sought to allow calculation of the incidence of "all-severities," serious and fatal, ADRs. In the original meta-analysis, these ADR incidences were then pooled to provide estimates of the incidence in all hospitalized patients. In our analysis, the original studies were examined by 2 investigators for consistency with the study search and inclusion criteria of the meta-analysis by Lazarou and colleagues, as well as accuracy and appropriateness of data extraction, meta-analysis, and conclusions. RESULTS: Multiple sources of heterogeneity among studies and data were found and include important differences in populations and hospital wards monitored, surveillance techniques, ADR definitions, determination of preventability of ADRs, distinguishing relationship to drugs, and in formats of reporting ADRs (by numbers of events or by patients). Imputations of event numerators made by the authors of the original meta-analysis were questionable and may overestimate the results of any individual study. With regard to fatal ADRs, the problem of small numbers of events is likely to introduce large errors in incidence estimates. Simple pooling of fatal event frequencies from only those studies specifically reporting the number of fatal ADRs, as was done in the meta-analysis of Lazarou and colleagues, is likely to dramatically overestimate the death rate. CONCLUSION: Meta-analysis was invalid because of heterogeneity of the studies. Most of these studies did not report the data needed for incidence calculations. The methodology used was seriously flawed, and no conclusions regarding ADR incidence rates in the hospitalized population in the United States should be made on the basis of the original meta-analysis.

Effect of postmenopausal hormone replacement therapy on dental outcomes: systematic review of the literature and pharmacoeconomic analysis.

A systematic review and economic analysis of clinical trials evaluating the effect of hormone replacement therapy (HRT) on dental outcomes in postmenopausal women were conducted. Twenty published studies involving more than 13,735 postmenopausal women were summarized and analyzed. In prospective studies, the effect of HRT on osteoporosis (OP) has been well documented. The effect of OP on mandibular bone density has also been examined in some observational studies. Few studies, however, have examined the effect of HRT directly on mandibular bone density or on dental outcomes. From these studies, the effect of HRT on costs of dental treatment and prophylaxis was estimated directly and indirectly. It was determined that HRT use was associated with reduction in adverse dental outcomes and the associated costs of dental care. Annualized excess cost in a cohort of 1,000 untreated women averaged $100,000. From this analysis, it is clear that postmenopausal women with OP who do not receive HRT have a greater incidence of adverse dental outcomes and higher dental care costs than those who do.

Systematic review and meta-analysis of the literature regarding the diagnosis of sleep apnea.

To establish the evidence base for the diagnosis of sleep apnea (SA) in adult patients, a systematic review of the literature from 1980 through November 1, 1997 was performed. Diagnostic studies were included if they reported results of any test to establish or support a diagnosis of SA, in comparison to a diagnosis from a full polysomnogram (PSG). Test results were meta-analyzed using fixed effects models and summary receiver operating characteristic curves (ROCs) to examine consistency of tests within and between diagnostics vs. the "gold standard" of PSG. From a total of 937 studies, 249 fit the broad eligibility criteria for inclusion in the clinical trial database and its data were extracted from these reports; useable data for statistical analyses were reported in 71 studies (7,572 patients). The sensitivity and specificity of partial channel and partial time PSGs appeared most promising as replacements for full PSG in patients suspected of obstructive SA. Clinical prediction rules (multivariate models) were also promising. Studies of portable sleep monitors, radiologic or morphologic features, and focused questionnaires were too heterogeneous to be meta-analyzed. In general, the diversity of study designs and objectives were very high and the methodological rigor of these studies as assessments of diagnostic tests was very low. Thus, we are still not in a position to recommend standardization of diagnostic methodology for sleep apnea. Instead, our recommendations for future research include standardization of terms and diagnostic criteria, and consistently reported statistics to enhance the utility of this literature.

Clinical outcomes in statin treatment trials: a meta-analysis.

OBJECTIVE: To determine the risk of cardiovascular events and death in patients receiving statin treatment for cholesterol regulation. METHODS: Systematic review and meta-analysis of all randomized controlled trials that were published as of April 15, 1997. Primary or secondary prevention trials or regression trials were eligible. MAIN OUTCOME MEASURES: All-cause mortality, fatal myocardial infarction (MI) or stroke, nonfatal MI or stroke, angina, and withdrawal from the studies. Both random- and fixed-effects models were run for the outcomes of interests, and results are expressed as odds ratios (ORs). Sensitivity analyses tested the impact of the study type and duration, statin treatment type, and control arm event rates. Intent-to-treat denominators were used whenever they were available, and the number needed to treat was calculated when appropriate. RESULTS: Seventeen studies (21 303 patients) were included (2 secondary prevention studies, 5 mixed primary-secondary prevention population studies, and 10 regression trials). Treatment groups included lovastatin (t = 5), pravastatin (t = 10), and simvastatin (t = 3). For all-cause mortality, the OR was 0.76 (95% confidence interval [CI], 0.67-0.86) in favor of receiving statin treatment; for fatal MI, the OR was 0.61 (95% CI, 0.48-0.78); for nonfatal MI, the OR was 0.69 (0.54-0.88); for fatal stroke, the OR was 0.77 (95% CI, 0.57-1.04); for nonfatal stroke, the OR was 0.69 (95% CI, 0.54-0.88); and for angina, the OR was 0.70 (95% CI, 0.65-0.76). CONCLUSIONS: Patients who received statin treatment demonstrated a 20% to 30% reduction in death and major cardiovascular events compared with patients who received placebo. This advantage was generally present across study types and statin treatment types and for patients with less severe dyslipidemias. The benefit in clinical outcomes was noticeable as early as 1 year.

Risk of serious adverse events in hypertensive patients receiving isradipine: a meta-analysis.

A meta-analysis was performed to compare the risk of serious adverse events associated with the use of all formulations of isradipine, when used as monotherapy in hypertension, to active drug or placebo controls. Eligible studies totalled 65 published and unpublished randomised controlled trials involving 9903 subjects and 10,675 treatment exposures: 4492 to isradipine, 1473 to isradipine sustained release, 2768 to other active drugs, and 1942 to placebo. Mortality, cardiovascular outcomes, other serious incident illnesses, such as cancer, and withdrawals were sought. Seventy-five per cent of the isradipine exposures were to standard-release formulations and 25% were to sustained-release formulations. Overall, isradipine therapy shows no difference in risk of major adverse events or withdrawals compared to other active controls or placebo (odds ratios [OR] 0.9; 95% CI 0.7-1.46 and 0.5; 95% CI 0.2-1.3). These major adverse events included angina, fatal and non-fatal myocardial infarction, stroke and overall mortality. Isradipine sustained release could be compared only to placebo, based on available data, and shows a lower risk of withdrawals (OR 0.5; 95% CI 0.3-0.9), and a similar trend was observed for major adverse events, (OR 0.8; 95% CI 0.3-2.5). Published and unpublished randomised controlled trials were analysed in separate meta-analyses and later combined when this sensitivity analysis of risk showed no differences between the groups. In conclusion, we find no evidence for increased risk of serious adverse events in patients receiving isradipine as monotherapy for hypertension.

Rapid infarct imaging with a technetium-99m-labeled antimyosin recombinant single-chain Fv: evaluation in a canine model of acute myocardial infarction.

Studies of monoclonal antibody-based imaging agents show that blood clearance is inversely proportional to molecular size, i.e., Fab or Fab' > F(ab')2 > IgG. Indium-111-antimyosin Fab-DTPA is a highly specific and sensitive marker for myocardial necrosis. An improvement on current antibody diagnostic imaging may result from the use of smaller labeled fragments. We report the first in vivo targeting of acute myocardial infarction with a novel recombinant single-chain Fv (sFv) antimyosin protein. The sFv (MW = 27,594) is approximately one-half the size of the Fab and is comprised of the heavy and light chain variable regions from the myosin-specific murine monoclonal antibody R11D10 which were joined by a 15-amino-acid linker and expressed as a fusion protein (sFv) in E. coli. The binding affinity of the sFv for cardiac myosin was similar to the affinity observed for the Fab fragment. Technetium-99m labeling of the sFv was accomplished by the attachment of a cleavable, ester-linked bifunctional chelator (RP-1). Comparative studies in mice showed 99mTc-sFv-RP-1 cleared significantly faster (p < 0.001) than 99mTc-Fab'-RP-1 and 111In-Fab-DTPA antimyosin fragments. Furthermore, measurement of 99mTc-sFv-RP-1 blood clearance in a canine model of acute myocardial infarction gave a mean T1/2 of 0.54 +/- 0.13 hr versus 2.80 +/- 0.57 and 2.58 +/- 0.64 hr for Fab-DTPA and Fab'-RP-1 (p < 0.05), respectively. Despite its comparatively rapid clearance, 99mTc sFv-RP-1 had similar uptake in the infarct compared to the Fab'-RP-1. In addition, infarct visualization was more rapid with the sFv. Thus, these data demonstrate antimyosin sFv possesses characteristics necessary for rapid imaging of myocardial necrosis.

Effectiveness of a human monoclonal anti-endotoxin antibody (HA-1A) in gram-negative sepsis: relationship to endotoxin and cytokine levels.

Gram-negative sepsis is caused by endotoxin-induced release of tumor necrosis factor (TNF) and other cytokines. HA-1A is a human monoclonal antibody that binds specifically to endotoxin. HA-1A should prevent death in endotoxemic patients and reduce serum levels of TNF and interleukin-6 (IL-6). This hypothesis was tested in 82 septic patients who were randomly allocated to receive a single intravenous 100-mg dose of HA-1A or placebo. Pretreatment endotoxemia was detected in 27 patients (33%). Death occurred within 28 days of treatment in 8 (73%) of 11 placebo recipients and in 5 (31%) of 16 HA-1A recipients (P = .02). The median decrease in serum TNF level 24 h after treatment was 12 ng/L in patients given HA-1A and 0 ng/L in placebo recipients (n = 65; P = .04). For IL-6, this was 204 ng/L in patients given HA-1A and 44 ng/L in placebo recipients (n = 67; P = .4). Thus, HA-1A reduces mortality in septic patients with endotoxemia and lowers serum TNF levels.

Limited sampling models for HA-1A IgM monoclonal antibody.

In this study, limited sampling models for HA-1A human IgM monoclonal antibody were developed to predict the area under the concentration time curve from timed serum concentrations. Patients were administered 15 minute infusions of 25 mg (11 patients), 100 mg (15 patients), and 250 mg (2 patients). A detailed pharmacokinetic analysis (eight time points) was performed to obtain the area under the curve for each of the 28 patients using a one-compartment model with the values normalized to a dose of 100 mg. Various models were then developed to estimate the area under the curve from one and two timed concentrations using regression analysis methodology. Of these models, four were determined to be of interest with coefficients of determinations ranging from 0.92 to 0.97. They performed quite well in predicting the area under the curve values with relative root mean squared predictive error of 7.1 to 10.8% and relative mean predictive error of -4.5 to + 6.9%. These models should be extremely useful in larger scale, Phase II/III studies of HA-1A in correlating the estimated area under the curve with various demographic data, toxicity, and efficacy.

Antihypertensive therapy with indoramin in the elderly.

The antihypertensive efficacy and safety of indoramin, an alpha 1-adrenergic antagonist, were evaluated in 215 elderly patients. Data were collected from patients aged 60 years and older who were treated under similar protocols with indoramin administered alone (n = 58) or in combination with a thiazide diuretic (n = 157). After at least 6 months of treatment, the mean daily dosage of indoramin was higher among patients who received indoramin alone (122 mg/day) than among those who received indoramin plus a diuretic (92 mg/day). Mean supine blood pressure decreased (p less than 0.001) from 174/105 to 152/191 mm Hg in indoramin-treated patients and from 179/101 to 150/91 mm Hg in patients who were treated with indoramin plus a diuretic. Clinically satisfactory blood pressure decreases occurred in the majority of the patients who received indoramin, either alone (69%) or with a diuretic (75%). Both treatments were well tolerated by elderly patients; only 15 patients (7%) discontinued therapy because of adverse effects. Drowsiness, fatigue, and dizziness were the most frequently reported side effects. The results of this analysis indicate that indoramin, administered alone or in combination with a thiazide diuretic, is a safe and effective therapeutic regimen for elderly hypertensive patients.