Use and Misuse of Multivariable Approaches in Interventional Cardiology Studies on Drug‐Eluting Stents: A Systematic Review

Aims: Randomized clinical trials (RCTs) are the most reliable evidence, even if they require important resource and logistic efforts. Large, cost‐free and real‐world datasets may be easily accessed yielding to observational studies, but such analyses often lead to problematic results in the absence of careful methods, especially from a statistic point of view. We aimed to appraise the performance of current multivariable approaches in the estimation of causal treatment and effects in studies focusing on drug‐eluting stents (DES). Methods and Results: Pertinent studies published in the literature were searched, selected, abstracted, and appraised for quality and validity features. Six studies with a logistic regression were included, all of them reporting more than 10 events for covariates and different length of follow‐up, with an overall low risk of bias. Most of the 15 studies with a Cox proportional hazard analysis had a different follow‐up, with less than 10 events for covariates, yielding an overall low or moderate risk of bias. Sixteen studies with propensity score were included: the most frequent method for variable selection was logistic regression, with underlying differences in follow‐up and less than 10 events for covariate in most of them. Most frequently, calibration appraisal was not reported in the studies, on the contrary of discrimination appraisal, which was more frequently performed. In seventeen studies with propensity and matching, the latter was most commonly performed with a nearest neighbor‐matching algorithm yet without appraisal in most of the studies of calibration or discrimination. Balance was evaluated in 46% of the studies, being obtained for all variables in 48% of them. Conclusions: Better exploitation and methodological appraisal of multivariable analysis is needed to improve the clinical and research impact and reliability of nonrandomized studies. (J Interven Cardiol 2012;25:611–621)     

All-trans retinoic acid shows multiple effects on the survival, proliferation and differentiation of human fetal CD34+ haemopoietic progenitor cells

Summary. To evaluate the effect of all-trans retinoic acid (RA) on fetal haemopoiesis, we performed serum-free liquid and semisolid cultures using CD34⁺ cells purified from mid-trimester human fetal blood samples. RA, at both physiological (10^-n and 10^-12M) and pharmacological (10^-6 and l(r⁷M) concentrations, significantly (P<0.01) promoted the survival of fetal CD34⁺ cells in liquid cultures from day 3 onwards, by suppressing apoptosis induced by serum and growth factor deprivation. On the other hand, RA alone had no significant effect on the proliferation and differentiation of fetal haemopoietic progenitors. In the presence of optimal concentrations of recombinant interleukin-3 (IL-3), stem cell factor (SCF), granulocyte/ macrophage-colony stimulating factor (GM-CSF), and erythropoietin (Epo), low and high doses of RA induced striking differential effects on CD34⁺ cell proliferation in liquid cultures and colony formation in semisolid assays. In fact, 1CT^U M and 1CT¹²M RA were able to: (i) significantly (P<0.05) increase ³H-thymidine uptake by fetal CD34⁺ cells in liquid cultures, and (ii) variably promote the growth of pluripotent (CFU-GEMM, P<0.05), early (BFU-meg) and late (CFU-meg, P<0.01) megakaryocyte, granulocyte/macrophage (CFU-GM. P<001) and erythroid (BFU-E) progenitors in semisolid cultures. On the contrary, 10^-6 and 10^-7 M RA induced: (i) an overall inhibition (P<0.01) of CD34⁺ cell growth in liquid cultures; (ii) a marked suppression of BFU-E colony formation (P<0.01) at all Epo concentrations examined (0-002-4IU/ml); and (iii) a significant (P<0.()1) stimulation of CFU-GM with a shift from mixed granulocyte/ macrophage to pure granulocyte colonies, whereas it had little effect on the growth of CFU-GEMM, BFU-meg and CFU-meg. Our data, as a whole, demonstrate that RA has direct complex effects on the survival, growth and clonal expansion of fetal haemopoietic progenitor cells, mainly depending on the presence of recombinant cytokines, the type of progenitor and the concentrations of RA.     

Supernormal Conduction in the Left Bundle Branch

Supernormal Conduction. This report describes a patient with tachycardia-dependent left bundle branch block (LBBB) and atrial extrasystoles, some of which were followed by an unexpectedly narrow QRS complex. His-bundle recordings and premature atrial stimulation were performed to analyze the mechanism underlying the normalized intraventricular conduction of some of the early atrial impulses. The results suggested the presence of supernormal conduction in the left bundle branch (LBB), because(1) the HV interval was identical in LBBB complexes and in early narrow QRS complexes; (2) during single lest stimulation using different paced atrial cycle lengths, there was a well-defined range of H₁, H₂, intervals resulting in normalization of intraventricular conduction; and (3) atrial pacing with a cycle length of 500 msec resulted in alternation between wide and narrow QRS complexes. These findings rule out alternative mechanisms that could explain the unexpectedly normal intraventricular conduction of early impulses.     

Anti-circumsporozoite protein antibodies measure age related exposure to malaria in Kataragama, Sri Lanka

Antibodies to two peptides DDAAD and (NANP)40 representing the repetitive sequence of circumsporozoite antigens (CS protein) of P. vivax and P. falciparum respectively were measured in a cohort of 149 and 107 individuals respectively at four, 6 monthly blood surveys performed on residents of Kataragama, a P. vivax malaria endemic region in southern Sri Lanka. The prevalence of antibodies to the CS protein of both species was relatively low being less than 20% to either peptide in the population as a whole, this being consistent with the low entomological inoculation rates in the area. A marked age related prevalence pattern was evident, with the prevalence of antibodies increasing with age to reach between 25 to 30% in the 25-50 year age group in both P. vivax and P. falciparum. The population had had a life long exposure to P. vivax malaria but not to P. falciparum, an epidemic of which occurred in this region a few months prior to the beginning of this study. Nevertheless, the age-related prevalence of these antibodies was identical with respect to the two species. This suggests that the age-related prevalence pattern reflected differences in inoculation rates between the age groups due to differences in exposure to inoculation rather than an age acquired response resulting from a cumulative experience over several years. An analysis of antibody prevalence in individuals showed first, that sporozoite inoculations must have been clustered rather than homogeneously distributed in the population and secondly, that sero-conversion did not correlate with malaria infections in these individuals.     

Rhythm Discrimination by Rate Branch and QRS Morphology in Dual Chamber Implantable Cardioverter Defibrillators

BORIANI, G., et al. : Rhythm Discrimination by Rate Branch and QRS Morphology in Dual Chamber Implantable Cardioverter Defibrillators. Morphology Discrimination is a discriminator based on QRS morphology analysis that has been recently implemented in dual chamber implantable cardioverter defibrillators (ICDs). Detected events are initially classified according to median atrial and ventricular rates (Rate Branch). Then, a series of discriminators (Morphology Discrimination, Stability, Sudden Onset) analyze the rhythm according to specific criteria and the number of discriminators required for VT diagnosis (i.e., requiring "any" or "all" of the specific discriminators to indicate VT). The discriminating accuracy of the algorithm was evaluated in 645 detections recorded during the follow-up of 25 patients. The overall specificity for 397 supraventricular arrhythmias was 73.5% (292/397) with the tachycardia diagnosis criteria set to "any" and 90.9% (361/397) with the tachycardia diagnosis criteria set to "all." Sensitivity for VT was 100% and 98.7% (231/234) with the tachycardia diagnosis criteria set to "any" and "all," respectively. With the tachycardia diagnosis criteria set to "any," specificity for atrial fibrillation was 88.6%, for atrial flutter 40.3%, for atrial tachycardia 0%, and for sinus tachycardia 97.0%. With the tachycardia diagnosis criteria set to "all," specificity for atrial fibrillation was 92.40%, for atrial flutter 93.5%, for atrial tachycardia 54.7%, and for sinus tachycardia 99.0%. The contribution of Morphology Discrimination was crucial to improve the specificity of the Rate Branch algorithm. The implementation of Morphology Discrimination in a dual chamber ICD with Rate Branch rhythm classification allows the attainment of high specificity and high sensitivity for ventricular tachyarrhythmias. (PACE 2003; 26[Pt. II]:466–470)     

Brief Report: Graft-Versus-Host Reaction in F1 Hybrid Mice Injected with Pre-Immunized Parental Thymus Cells

Dissociated thymus cells are capable of initiating graft-versus-host reactionin (C3Hf/Gs x DBA/2)F₁ hybrids only when derived from parental donorspreviously sensitized against the antigens of the other parental strain. Thelower immunologic activity of thymus cells as compared with other lymphoidcells is presumably due to quantitative rather than qualitative differences inimmunologically competent cells.

Submitted on May 6, 1964 Accepted on July 14, 1964     

Postnatal development of intestinal endocrine cell populations in the water buffalo

The frequency and distribution of 11 endocrine cell populations were studied in the intestine of differently aged buffalo, grouped on the basis of diet: 2-d-olds (suckling), 5-mo-olds (weaning) and 5-y-olds (ruminant adult diet). The endocrine cell populations were identified immunocytochemically using antisera against 5-hydroxytryptamine (5-HT), somatostatin, gastrin, cholecystokinin (CCK), COOH-terminal octapeptide of gastrin/CCK, neurotensin, motilin, gastric inhibitory polypeptide (GIP), secretin, glucagon/glicentin (GLU/GLI) and polypeptide YY (PYY). In adult buffalos the regional distribution of endocrine cells is similar to that of other adult ruminants. During postnatal development, these cell types showed the following changes in their frequency and distribution: (1) 5-HT, neurotensin and gastrin/CCK immunoreactive cells (i.c.) showed a decrease in frequency with age; (2) somatostatin i.c. frequency remained stable with age; (3) motilin, GIP, secretin and CCK i.c. showed a slight increase in frequency with age; (4) GLU/GLI and PYY i.c. decreased in frequency with age in the small intestine, caecum and proximal colon and an increase in frequency in the rectum. It was hypothesised that the endocrine cell types, whose presence and localisation is substantially stable in all examined ages, probably contain substances that are strictly necessary for intestinal function. In contrast the hormones contained in the cell populations that decreased with age, are probably involved in physiological needs during the milk and weaning diet or play a role in intestinal growth.     

Oral Loading with Propafenone: A Placebo-Controlled Study in Elderly and Nonelderly Patients with Recent Onset Atrial Fibrillation

The efficacy and safety of propafenone as an oral loading dose (600-mg single oral dose) in converting recent-onset atrial fibrillation (≤ 7 days duration) to sinus rhythm were evaluated in a single-blind, placebo-controlled study according to patients' age. Overall, 240 hospitalized patients, NYHA Class ≤ 2 without signs or symptoms of heart failure were enrolled: among patients aged ≤ 60 years, 55 were allocated to propafenone treatment and 59 to placebo, respectively, and among patients aged > 60 years, 64 were allocated to propafenone treatment and 62 to placebo, respectively. Results: In each age group, the likelihood of conversion to sinus rhythm was significantly greater after propafenone compared with plocebo at 3 and 8 hours. For patients aged ≤ 60 years, corresponding odd ratios were 3.78 (95% CI = 1.80–7.92, P = 0.04) at 3 hours and 4.74 (95% CI = 2.12–10.54, P = 0.02) at 8 hours; for patients aged > 60 years odd ratios were 5.03 (95% CI = 2.08–12.12, P = 0.02) at 3 hours and 6.75 (95% CI = 3.28–73.86, P = 0.01) at 8 hours, respectively. Logistic regression analysis showed that conversion to sinus rhythm within 3 hours was predicted by age ≤ 60 years (P = 0.0064) and by propafenone treatment (P < 0.0001), and conversion to sinus rhythm within 8 hours was predicted by age ≤ 60 years (P = 0.0467) and by propafenone treatment (P < 0.0001). The occurrence of adverse effects was observed in 14%-16% of propafenone treated patients and in 8% of placebo treated patients without significant differences according to age. In conclusion, in patients with recent-onset atrial fibrillation without signs of heart failure, propafenone as a single oral loading dose is effective. It is also effective in selected elderly subjects with a favorable safety profile. Moreover, spontaneous conversion to sinus rhythm appears to occur less frequently in elderly patients.     

Multigenetic lesions in infant acute leukaemias: correlations with ALL-1 gene status

The large majority of childhood B-precursor cell acute lymphoblastic leukaemia cases present IgH and TCRδ gene rearrangements. These rearrangements have been widely used as specific markers for monitoring minimal residual disease. However, their prognostic value still remains unclear. In order to determine whether IgH and TCRδ gene rearrangements have any influence on relapse and event-free survival (EFS), we analysed the clinical impact of these genetic characteristics in 51 B-precursor acute lymphoblastic leukaemia patients. 46/51 patients (90.2%) showed IgH gene rearrangements by Southern blot and/or polymerase chain reaction (PCR) analysis. No statistically significant associations were found between IgH gene rearrangement pattern and age, sex, WBC count, immunophenotype, risk factor, relapse or EFS. 27/41 patients (66%) showed Vδ₂Dδ₃ recombination by Southern blot and/or PCR analysis. At a median follow-up of 53 months the estimated 5-year EFS probability was 78 ± 3% for the whole group. The EFS probability among patients with a Vδ₂Dδ₃ recombination pattern in the TCRδ locus was 90 ± 3%, whereas for patients without Vδ₂Dδ₃ recombination was 39 ± 13% ( P  < 0.005).
IgH rearrangement patterns do not appear to influence relapse or EFS probability. However, TCRδ gene rearrangement patterns have a relevant impact on the relapse rate and the EFS probability. Patients with Vδ₂Dδ₃ recombination have better clinical outcome than patients without this recombination, independent of any other prognostic factors.