Impact of cardiovascular risk factors and related comorbid conditions and medical therapy reported at baseline on the treatment response to tadalafil 5 mg once-daily in men with lower urinary tract symptoms associated with benign prostatic hyperplasia: an integrated analysis of four randomised, double-blind, placebo-controlled, clinical trials.

PURPOSE: The influence of cardiovascular risk factors/comorbidities on response to oral once-daily tadalafil 5 mg was explored in men with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). METHODS: This post hoc analysis pooled data from four double-blind studies in which 1498 men with > 6-mo history of LUTS/BPH were randomised and received either once-daily placebo (n = 746) or tadalafil 5 mg (n = 752) for 12 weeks. Descriptive statistics were reported for changes in total International Prostate Symptom Score (IPSS), IPSS voiding and storage subscores, and IPSS quality-of-life (QoL) index. Treatment group differences by baseline clinical and cardiovascular factors and medical therapies were examined using analysis of covariance. RESULTS: Tadalafil was effective in men with LUTS/BPH and cardiovascular risk factors/comorbidities except for patients receiving > 1 antihypertensive medication. Placebo-adjusted least squares (LS) mean improvements in total IPSS were -1.2 (95% CI: -2.5 to -0.0) in men taking > 1 antihypertensive medication vs. -3.3 (95% CI: -4.4 to -2.1) in men taking one medication (interaction p = 0.020). In addition, placebo-adjusted LS mean improvements in total IPSS were -0.2 (95% CI, -2.1 to 1.7) in men who reported use of diuretics vs. -2.8 (95% CI, -3.7 to -1.9) in men who reported taking other antihypertensive medications vs. -2.3 (95% CI, -3.2 to -1.5) in men who reported not using any antihypertensive drug (p-value for interaction = 0.053). CONCLUSIONS: Once-daily tadalafil 5 mg improved LUTS/BPH, regardless of severity, in men with coexisting cardiovascular risk factors/comorbidities, except for patients with history of > 1 drug for arterial hypertension. Use of diuretics may contribute to patients' perception of a negated efficacy of tadalafil on LUTS/BPH. Comorbidities should be considered when choosing the optimal medicine to treat men with LUTS/BPH.

Defining in Detail and Evaluating Reliability of DSM-5 Criteria for Autism Spectrum Disorder (ASD) Among Children.

This paper describes a process to define a comprehensive list of exemplars for seven core Diagnostic and Statistical Manual (DSM) diagnostic criteria for autism spectrum disorder (ASD), and report on interrater reliability in applying these exemplars to determine ASD case classification. Clinicians completed an iterative process to map specific exemplars from the CDC Autism and Developmental Disabilities Monitoring (ADDM) Network criteria for ASD surveillance, DSM-5 text, and diagnostic assessments to each of the core DSM-5 ASD criteria. Clinicians applied the diagnostic exemplars to child behavioral descriptions in existing evaluation records to establish initial reliability standards and then for blinded clinician review in one site (phase 1) and for two ADDM Network surveillance years (phase 2). Interrater reliability for each of the DSM-5 diagnostic categories and overall ASD classification was high (defined as very good .60-.79 to excellent ≥ .80 Kappa values) across sex, race/ethnicity, and cognitive levels for both phases. Classification of DSM-5 ASD by mapping specific exemplars from evaluation records by a diverse group of clinician raters is feasible and reliable. This framework provides confidence in the consistency of prevalence classifications of ASD and may be further applied to improve consistency of ASD diagnoses in clinical settings.

Estimation of normal lumbar flexion with surface inclinometry. A comparison of three methods.

The purpose of this study was to determine the magnitude and clinical significance of surface measurement error in the determination of lumbar spinal flexion. Intrarater, inter-rater and intermethod reliability estimates were obtained using single inclinometry, double inclinometry and back range-of-motion inclinometry methods. Eight healthy subjects were examined independently by two experienced observers and three replicates of each measurement were obtained by each observer in a random sequence. In addition, three replicates of lumbar flexion angles were obtained for each subject by a single observer using the B-200. Reliability estimates were determined by intraclass correlation coefficients and were further compared by paired t tests between observation series. The median range of error was 8.5 degrees using the single inclinometer, 10.5 degrees using the double inclinometer and 16 degrees using the back range-of-motion. The intrarater reliability was generally higher than inter-rater reliability and intermethod reliability was low in most cases reflecting the poor cross-validity across inclinometry methods and between each inclinometry method and the B-200. In conclusion, significant measurement error in estimating lumbar flexion by inclinometry may be expected to occur even in a "controlled" setting using experienced observers, standard examination techniques and asymptomatic healthy subjects. These findings appear to undermine the expectation that the clinician can reliably apply surface inclinometry to estimate loss of spinal mobility for purposes of impairment determination.

Glucose suppression of insulin secretion in chronically hyperglycemic fetal sheep.

Previous observations in fetal sheep indicate that glucose may inhibit as well as enhance insulin secretion. To study conditions involved in inhibition of insulin secretion, we compared changes in plasma insulin concentration in response to acute increases in glucose and arginine concentrations in a group of normal, late gestation fetal sheep (euglycemic controls, EC) and a comparable group made chronically hyperglycemic by constant maternal glucose infusion (hyperglycemics, HG). After 7-10 d of maternal and fetal hyperglycemia, fetal glucose concentrations (G) were significantly increased in the HG group (0.98 +/- 0.07 mM EC, 2.00 +/- 0.11 mM HG, p < 0.001) but fetal plasma insulin concentrations (I) were not significantly different (57 +/- 7 pM EC, 71 +/- 9 pM HG, p = 0.2). Furthermore, the I/G ratio was significantly decreased in the HG group (60 +/- 9 EC, 40 +/- 4 HG, p = 0.03) and during a hyperglycemic glucose clamp (delta G approximately equal to 1.4 mM), glucose-stimulated increase in steady state I was less in the HG than in the EC fetuses (mean delta I/delta G = 106 +/- 15 EC, 61 +/- 10 HG, p = 0.01). An arginine infusion at the end of the clamp produced similar increases in I in the EC and HG groups (delta I = 824 +/- 116 pM EC, 906 +/- 131 pM HG, p = 0.45). There were no differences between groups for blood oxygen saturation and content, pH, or lactate concentration. After 14-17 d of hyperglycemia, glucose-stimulated increase in I was even more reduced in the HG fetuses than observed at 7-10 d. Decreased insulin response to arginine also was present, although pancreatic insulin concentration was not decreased. Glucose-stimulated increase in I returned to normal after 7 d of no glucose infusion and euglycemia. These data indicate that glucose-stimulated insulin secretion is reversibly decreased by marked, chronic hyperglycemia. Because pharmacologic inhibitors of insulin secretion (e.g. streptozotocin or alloxan) were not used, and oxygenation, pH, and lactate values were similar between the two groups, this decrease of insulin secretion appears to be glucose-specific, although mechanisms involved can include both glucose and amino acid (arginine) stimulation processes. Such decrease in fetal insulin secretion may limit the rate of fetal glucose utilization during chronic hyperglycemia and thereby modulate the rate of fetal growth.

Spontaneous versus extraction related injuries associated with Accufix J-wire atrial pacemaker lead: tracking changes in patient management.

UNLABELLED: To make recommendations for management of potentially fatal failure of the Accufix series of atrial J-wire permanent pacemaker leads, we closely monitored the number of injuries and fatalities resulting either from spontaneous fracture of the J-wire or from attempts to extract the lead. In a population of 30,357 patients, 2,298 patients are enrolled in a prospective follow-up Multicenter Study, the remainder are patients with known clinical status from voluntary reporting, and 2,992 patients died following implant. In the remaining 27,365 patients, 6 deaths have been attributed to J-wire related injury (J-inj) while 13 were complications (E-inj) associated with 4,076 lead extraction procedures (3,974 intravascular (intra)/102 primary thoracotomy (PT). The date of occurrences were from 1994 to November 1997. CONCLUSIONS: (1) Since lead extractions were not conducted in a controlled study, it is not known whether the deaths associated with lead extraction is in excess of what would have occurred if these leads had not been removed in this specific subset. (2) Awareness of the procedure related complication rate appears to have moderated the rate of lead extraction and may ultimately lead to management that reasonably balances the risks of patient injury.

Kaplan-Meier analysis of freedom from extraction or death in patients with an Accufix J retention wire atrial permanent pacemaker lead: a potential management tool.

UNLABELLED: Morbidity (36 cases) and mortality (6 cases) have been reported in patients with Accufix J retention wire atrial leads. This has resulted in ongoing patient fluoroscopic monitoring as well as lead extractions. The estimated implanted worldwide population is 40,860. Estimating the size of the remaining population at risk is an important tool for assessing patient management guidelines. RESULTS: The Kaplan-Meier method can be used to calculate the cumulative probability of remaining free of extraction and death for patients based on implant duration. The individual Kaplan-Meier curves for lead extraction and patient survival can also be computed. Based on the Multicenter Study (MCS) population of 2,298 patients, the probability that a patient is alive with the lead still implanted at 5 years implant duration is 52.5%. The event-free survival rate at 5 years implant duration is 81.3%. The corresponding probability of remaining free from injury due to the J-wire is 99.9% at 5 years implant duration. Assuming similar rates of death and extraction, these results can be extrapolated to the world wide population. CONCLUSIONS: The management of Accufix patients must consider patient longevity, the probability of J-wire morbidity/mortality, and the probability of extraction complication morbidity/mortality. The probability of remaining at risk as a function of time from implant can be calculated from the events known in the MCS patient population. These event-free survival estimates can be used to identify subsets of the population at greater or lesser risk based on various clinical parameters.

Cumulative hazard analysis of J-wire fracture in the Accufix series of atrial permanent pacemaker leads.

UNLABELLED: To permit a more complete analysis of J-wire fracture in the Accufix series of atrial permanent pacemaker leads, the time to occurrence of all known fractures and injuries has been redefined relative to the duration of risk exposure, that is, according to the interval of time between implant and occurrence of the event. This redefinition permits application of a cumulative hazards model to the data, which previously has not been explored. Predictors of J-wire fracture can be tested using this method. This also permits parametric curve-fitting for determination of linearity or constancy of risk of events over time. RESULTS: Among 2,063 Multicenter Study (MCS) leads analyzed, 381 fractures of the J-wire were identified. Stratified analysis based on cumulative hazard curves identified a more open shape of the J-wire as predictive of fracture, which supports the results previously reported based on logistic regression analysis. Fitting a Weibull curve to the cumulative hazard of J-wire fracture gives a shape parameter equal to 0.85. This value indicates that the instantaneous hazard of J-wire fracture decreased over time from implant. CONCLUSIONS: (1) The cumulative hazard function can be used to examine predictors of J-wire fracture and preliminary findings support the previously identified predictor of J shape; (2) Based on these analyses, the rate of J-wire fracture appears to decrease slightly as time from implant increases.