Efficacy and safety of once daily oral administration of sodium-glucose cotransporter-2 inhibitor velagliflozin compared with twice daily insulin injection in diabetic cats.

BACKGROUND: Options for treatment of diabetes mellitus in cats are limited to insulin injections and monitoring for hypoglycemia. HYPOTHESIS: Once daily sodium-glucose cotransporter-2 inhibitor velagliflozin PO is noninferior to insulin injections. ANIMALS: Client-owned diabetic cats (127 safety; 116 efficacy assessment). METHODS: Prospective, randomized (1 mg/kg velagliflozin), positive controlled (titrated Caninsulin), open label, noninferiority field trial, comparing number of cats with treatment success in ≥1 clinical variable and ≥1 glycemic variable (margin Δ: 15%) on Day 45; secondary endpoints included glycemic and clinical assessments during 91 days. RESULTS: On Day 45, 29/54 (54%) velagliflozin-treated cats and 26/62 (42%) Caninsulin-treated cats showed treatment success, demonstrating noninferiority (difference -11.8%; upper 1-sided 97.5% confidence interval, -∞ to 6.3%). By Day 91, quality of life (QoL), polyuria, and polydipsia had improved in 81%, 54% and 61% (velagliflozin); on blood glucose (BG) curves, mean BG was <252 mg/dL in 42/54 (78%; velagliflozin) and 37/62 (60%; Caninsulin); minimum BG was <162 mg/dL in 41/54 (76%; velagliflozin) and 41/62 (66%; Caninsulin); serum fructosamine was <450 µmol/L in 41/54 (76%; velagliflozin) and 38/62 (61%; Caninsulin). Velagliflozin's most frequent adverse events were loose feces/diarrhea (n = 23/61, 38%), positive urine culture (n = 19/61, 31%), and nonclinical hypoglycemia (BG <63 mg/dL; n = 8/61, 13%); Caninsulin's: clinical and nonclinical hypoglycemia (n = 35/66, 53%), positive urine culture (n = 18/66, 27%), and loose feces/diarrhea (n = 10/66, 15%). Diabetic ketoacidosis occurred in 4/61 (7%; velagliflozin) and 0/66 (Caninsulin). CONCLUSIONS AND CLINICAL IMPORTANCE: Once daily oral administration of velagliflozin was noninferior to insulin injections, showed good QoL and glycemia without clinical hypoglycemia.

Dunnett-type inference in the frailty Cox model with covariates.

A frequent objective in medical research is the investigation of differences in patient survival between several experimental treatments and one standard treatment. In order to assess these differences statistically, we have to apply adjustments for multiple comparisons to prevent an increased number of false-positive findings. The most prominent procedure of this type is the Bonferroni correction, which maintains the error level but leads to conservative results. On the basis of a general statistical framework for simultaneous inference, we propose a new statistical procedure for many-to-one comparisons of treatments with adjustment for covariates for clustered survival data modeled by a frailty Cox model. In contrast to the Bonferroni method, dependencies between estimated effects are taken into account. The resulting simultaneous confidence intervals for the hazard ratios of the experimental treatments compared with a control can be interpreted in terms of both statistical significance and clinical importance. The quality of the new procedure is judged by the coverage probability for the simultaneous confidence intervals. Simulation results show an acceptable performance in balanced and various unbalanced designs. The practical merits are demonstrated by a reanalysis of a chronic myelogeneous leukemia clinical trial. The procedure presented here works well for multiple comparisons with a control with adjustment for covariates for survival data from multicenter clinical trials.

Statistical evaluation of mortality in long-term carcinogenicity bioassays using a Williams-type procedure.

Several doses and a control group can be compared under order restriction using the Williams procedure for normally distributed endpoints assuming variance homogeneity. Comparison of the survival functions represents a secondary endpoint in long-term in vivo bioassays of carcinogenicity. Therefore, a Williams-type procedure for the comparison of survival functions is proposed for the assumption of the Cox proportional hazards model or the general frailty Cox model to allow a joint analysis over sex and strains. Interpretation according to both statistical significance and biological relevance is possible with simultaneous confidence intervals for hazard ratios. Related survival data can be analyzed using the R packages survival, coxme, and multcomp. Together with the R packages MCPAN and nparcomp, Dunnett- or Williams-type procedures are now available for the statistical analysis of the following endpoint types in toxicology: (i) normally distributed, (ii) non-normally distributed, (iii) score (ordered categorical) data, (iv) crude proportions, (v) survival functions, and (vi) time-to-tumor data with and without cause-of-death information.

Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease.

BACKGROUND: The discovery of filaggrin (FLG) null mutations as a major risk factor for eczema represents a milestone toward the understanding of an important mechanism in this complex disease. However, published studies demonstrate differences concerning design and effect size, and conflicting results for asthma have been reported. OBJECTIVES: We sought to provide a more accurate estimate of FLG effect sizes and to better refine FLG risk profiles within the broad and inclusive eczema diagnosis. We also sought to provide a more detailed and conclusive estimate of the risk for asthma associated with FLG null alleles. METHODS: We performed a meta-analysis of 24 studies on FLG mutations and eczema involving 5,791 cases, 26,454 control subjects, and 1,951 families as well as 17 studies on asthma involving 3,138 cases, 17,164 control subjects, and 1,511 offspring. RESULTS: Both case-control and family studies showed strong associations with eczema. Case-control studies were heterogeneous, whereas family studies yielded more homogeneous results. Combined analysis showed that FLG haploinsufficiency strongly increases the eczema risk (odds ratio [OR], 3.12; 95% CI, 2.57-3.79) and is associated with more severe and dermatologist-diagnosed disease. FLG mutations are also significantly associated with asthma (OR, 1.48; 95% CI, 1.32-1.66). However, although strong effects for the compound phenotype asthma plus eczema (OR, 3.29; 95% CI, 2.84-3.82) were observed, there appears to be no association with asthma in the absence of eczema. CONCLUSIONS: This meta-analysis summarizes the strong evidence for a high eczema risk conferred by FLG mutations and refines their risk profiles, suggesting an association with more severe and secondary care disease. FLG mutations are also a robust risk factor for asthma and might help define the asthma endophenotype linked with eczema.

Auditory evoked potentials compared with bispectral index for monitoring of midazolam and propofol sedation during colonoscopy.

OBJECTIVES: The purpose of this study was to evaluate and compare Bispectral index (BIS) and A-line auditory evoked potential index (AAI) for monitoring depth of low-dose midazolam and propofol sedation during colonoscopy. METHODS: A total of 115 consecutive patients (ASA I-IV), receiving low-dose midazolam and propofol sedation for colonoscopy, were evaluated. BIS and AAI levels, Observer's Assessment of Alertness/Sedation (OAA/S) scores, blood pressure, heart rate, oxygen saturation, as well as the presence or absence of eyelash reflex, patient reaction to an external noxious stimulus and to procedure-related pain were recorded every 1-3 min by a single trained observer. RESULTS: There was a positive correlation between BIS and OAA/S scores (correlation coefficient=0.77) and to a lesser extent AAI and OAA/S scores (correlation coefficient=0.47). BIS and AAI showed significant differences between subsequent levels of sedation (P<0.001). The clustered receiver operating characteristic curve estimate of BIS for the detection of deep sedation was significantly better than that of AAI (P<0.001). Regarding the presence or absence of eyelash reflex and patient reaction to an external noxious stimulus and to procedure-related pain, significant different levels were found for BIS as well as AAI, respectively. Only small changes were observed in hemodynamic variables and oxygen saturation. Overall, our data suggest target BIS levels of slightly above 73 for moderate sedation (defined as OAA/S scores 2 and 3). CONCLUSIONS: BIS and AAI correlated with the level of sedation. Hemodynamic variables were poor indicators of the hypnotic-anesthetic status of the patient. BIS discriminated best between moderate and deep sedation and could complement clinical observation for guidance of moderate sedation.

Efficacy of long-term oral telmisartan treatment in cats with hypertension: Results of a prospective European clinical trial.

BACKGROUND: Efficacy of telmisartan in treating hypertension (HT) in cats has not been largely investigated. OBJECTIVE: Telmisartan oral solution effectively controls systolic arterial blood pressure (SABP) in hypertensive cats. ANIMALS: Two-hundred eighty-five client-owned cats with systemic HT. METHODS: Prospective, multicenter, placebo-controlled, randomized, double-blinded study. Hypertensive cats diagnosed with SABP ≥160 mmHg and ≤200 mmHg without target-organ-damage were randomized (2 : 1 ratio) to receive 2 mg/kg telmisartan or placebo q24 PO. A 28-day efficacy phase was followed by a 120-day extended use phase. Efficacy was defined as significant difference in mean SABP reduction between telmisartan and placebo on Day 14 and group mean reduction in SABP of > 20 mmHg by telmisartan on Day 28 compared to baseline. RESULTS: Two-hundred fifty-two cats completed the efficacy and 144 cats the extended use phases. Mean SABP reduction at Day 14 differed significantly between groups (P < .001). Telmisartan reduced baseline SABP of 179 mmHg by 19.2 (95% confidence interval [CI]: 15.92-22.52) and 24.6 (95% CI: 21.11-28.14) mmHg at Days 14 and 28. The placebo group baseline SABP of 177 mmHg was reduced by 9.0 (95% CI: 5.30-12.80) and 11.4 (95% CI: 7.94-14.95) mmHg, respectively. Of note, 52% of telmisartan-treated cats had SABP <150 mmHg at Day 28. Mean SABP reduction by telmisartan in severe (≥180 mmHg) and moderate HT (160-179 mmHg) was comparable and persistent over time. CONCLUSIONS AND CLINICAL IMPORTANCE: Telmisartan solution (PO) was effective in reducing SABP in hypertensive cats with SABP ≥160 mmHg and ≤200 mmHg.

Multiple curve comparisons with an application to the formation of the dorsal funiculus of mutant mice.

Much biological experimental data are represented as curves, including measurements of growth, hormone, or enzyme levels, and physical structures. Here we consider the multiple testing problem of comparing two or more nonlinear curves. We model smooth curves of unknown form nonparametrically using penalized splines. We use random effects to model subject-specific deviations from the group-level curve. We present an approach that allows examination of overall differences between the curves of multiple groups and detection of sections in which the curves differ. Adjusted p-values for each single comparison can be obtained by exploiting the connection between semiparametric mixed models and linear mixed models and employing an approach for multiple testing in general parametric models. In simulations, we show that the probability of false-positive findings of differences between any two curves in at least one position can be controlled by a pre-specified error level. We apply our method to compare curves describing the form of the mouse dorsal funiculus - a morphological curved structure in the spinal cord - in mice wild-type for the gene encoding EphA4 or heterozygous with one of two mutations in the gene.

A robust procedure for comparing multiple means under heteroscedasticity in unbalanced designs.

Investigating differences between means of more than two groups or experimental conditions is a routine research question addressed in biology. In order to assess differences statistically, multiple comparison procedures are applied. The most prominent procedures of this type, the Dunnett and Tukey-Kramer test, control the probability of reporting at least one false positive result when the data are normally distributed and when the sample sizes and variances do not differ between groups. All three assumptions are non-realistic in biological research and any violation leads to an increased number of reported false positive results. Based on a general statistical framework for simultaneous inference and robust covariance estimators we propose a new statistical multiple comparison procedure for assessing multiple means. In contrast to the Dunnett or Tukey-Kramer tests, no assumptions regarding the distribution, sample sizes or variance homogeneity are necessary. The performance of the new procedure is assessed by means of its familywise error rate and power under different distributions. The practical merits are demonstrated by a reanalysis of fatty acid phenotypes of the bacterium Bacillus simplex from the "Evolution Canyons" I and II in Israel. The simulation results show that even under severely varying variances, the procedure controls the number of false positive findings very well. Thus, the here presented procedure works well under biologically realistic scenarios of unbalanced group sizes, non-normality and heteroscedasticity.

Prognostic factors for survival in patients with unresectable pancreatic cancer.

OBJECTIVES: In patients with unresectable pancreatic cancer, estimation of individual prognosis is essential to provide the most suitable biliary stent (self-expanding metal stent or plastic stent). The aim of the current study was to determine prognostic factors for survival in patients with unresectable pancreatic cancer after initial biliary drainage. PATIENTS AND METHODS: The current study included 278 patients with unresectable pancreatic cancer. Prognostic factors for survival were analyzed using the Cox proportional hazards model, the Kaplan-Meier survival estimator, and the Wilcoxon test for difference in survival. RESULTS: In univariate analysis, advanced T stage according to the TNM classification (P = 0.021, Wald test) and the presence of distant metastases (P = 0.001, Wald test) were predictive factors for shorter survival. However, in multivariate analysis, the presence of distant metastasis was the only independent prognostic factor. The median survival time after initial biliary drainage was 3.1 and 6.6 months in patients with and without the presence of distant metastases, respectively. CONCLUSIONS: The presence of distant metastases was identified as the only independent prognostic factor for survival after initial biliary drainage. A self-expanding metal stent should be systematically chosen for patient without distant metastases, whereas polyethylene plastic stents should be preferred in patients with distant metastases.