The Smoker’s Paradox Revisited: A Patient-Level Pooled Analysis of 18 Randomized Controlled Trials

ObjectivesThis study examined the smoker’s paradox using patient-level data from 18 prospective, randomized trials of patients undergoing percutaneous coronary intervention (PCI) with stent implantation.BackgroundStudies on the effects of smoking and outcomes among patients undergoing PCI have reported conflicting results.MethodsData from the RAVEL, E-SIRIUS, SIRIUS, C-SIRIUS, TAXUS IV and V, ENDEAVOR II to IV, SPIRIT II to IV, HORIZONS-AMI, COMPARE I and II, PLATINUM, and TWENTE I and II randomized trials were pooled. Patients were stratified by smoking status at time of enrollment. The 1- and 5-year ischemic outcomes were compared.ResultsAmong 24,354 patients with available data on smoking status, 6,722 (27.6%) were current smokers. Smokers were younger and less likely to have diabetes mellitus; hypertension; hyperlipidemia; or prior myocardial infarction (MI), PCI, or coronary artery bypass grafting. Angiographically, smokers had longer lesions, more complex lesions, and more occlusions, but were less likely to have moderate or severe calcification or tortuosity. At 5 years, smokers had significantly higher rates of MI (7.8% vs. 5.6%; p < 0.0001) and definite or probable stent thrombosis (3.5% vs. 1.8%; p < 0.0001); however, there were no differences in the rates of death, cardiac death, target lesion revascularization, or composite endpoints (cardiac death, target vessel MI, or ischemic target lesion revascularization). After multivariable adjustment for potential confounders, smoking was a strong independent predictor of death (hazard ratio [HR]: 1.86; 95% confidence interval [CI]: 1.63 to 2.12; p < 0.0001), cardiac death (HR: 1.68; 95% CI: 1.38 to 2.05; p < 0.0001), MI (HR: 1.38; 95% CI: 1.20 to 1.58; p < 0.0001), stent thrombosis (HR: 1.60; 95% CI: 1.28 to 1.99; p < 0.0001), and target lesion failure (HR: 1.17; 95% CI: 1.05 to 1.30; p = 0.005).ConclusionsThe present large, patient-level, pooled analysis with 5-year follow-up clearly demonstrates smoking to be an important predictor of adverse outcomes after PCI.     

Attenuation of Replication-Competent Adenovirus Serotype 26 Vaccines by Vectorization

Replication-competent adenovirus (rcAd)-based vaccine vectors may theoretically provide immunological advantages over replication-incompetent Ad vectors, but they also raise additional potential clinical and regulatory issues. We produced replication-competent Ad serotype 26 (rcAd26) vectors by adding the E1 region back into a replication-incompetent Ad26 vector backbone with the E3 or E3/E4 regions deleted. We assessed the effect of vectorization on the replicative capacity of the rcAd26 vaccines. Attenuation occurred in a stepwise fashion, with E3 deletion, E4 deletion, and human immunodeficiency virus type 1 (HIV-1) envelope (Env) gene insertion all contributing to reduced replicative capacity compared to that with the wild-type Ad26 vector. The rcAd26 vector with E3 and E4 deleted and containing the Env transgene exhibited 2.7- to 4.4-log-lower replicative capacity than that of the wild-type Ad26 in vitro. This rcAd26 vector is currently being evaluated in a phase 1 clinical trial. Attenuation as a result of vectorization and transgene insertion has implications for the clinical development of replication-competent vaccine vectors.     

Multimodality Screening for Lower Genital Tract Infections Between 18 and 24 Weeks of Pregnancy and its Efficacy in Predicting Spontaneous Preterm Delivery

Background

Predicting spontaneous preterm birth (SPTB) during mid-trimester would be very useful. We used a multimodality screening approach mainly focusing on urogenital infections among unselected obstetric population between 18 and 24 weeks in a tertiary center.

Method

Diagnosis of lower genital tract infection (LGTI) was attempted among 228 pregnant women using several factors—symptom of vaginal discharge, characteristic appearance of discharge on speculum, point of care tests using Amsel’s criteria and gram staining of vaginal swab. Nugent’s scoring was taken as gold standard. Urine microscopy/culture was obtained. Serum inflammatory markers were done. Total leukocyte count, neutrophil/lymphocyte ratio and C-reactive protein were obtained. Data on cervical length were obtained from mid-trimester scan.

Results

Thirty patients complained of vaginal discharge. Speculum examination revealed discharge in 221 (96.92%), appearing pathological in 192 (86.87%). Amsel’s criteria showed poor sensitivity to detect full (57%) and partial (24%) bacterial vaginosis (BV). On gram staining, 104 (45.61%) showed evidence of LGTI; 14 full BV (6.1%); 45 partial BV (19.5%); 40 candidiasis (17.5%); and two each of trichomoniasis and aerobic vaginitis. Appearance of vaginal discharge and microscopic diagnosis of LGTI were poorly correlated. Forty women (17.5%) had SPTB, 24 following membrane rupture and 16 following spontaneous labor. The presence of BV (specifically partial) increased the likelihood of SPTB with OR of 3.347 (CI 1.642, 6.823). Three of seven women with short cervix delivered preterm. No other screening modality was associated with SPTB.

Conclusion

Active screening for LGTI between 18 and 24 weeks shows high prevalence of BV in Indian setting. There is a strong link between partial BV and SPTB.

     

New drugs for type 2 diabetes mellitus: what is their place in therapy?

Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulfonylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women.Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on beta cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator-activated receptor-alpha/gamma agonists, or glitazars, is presently uncertain following concerns about their safety.In conclusion, several new classes of drugs have recently become available in some countries that offer new options for treating type 2 diabetes. Beneficial or neutral effects on bodyweight are an attractive feature of the new drugs. However, the higher cost of these agents, coupled with an absence of long-term safety and clinical outcome data, need to be taken into consideration by clinicians and healthcare organizations.     

Deriving high contrast fluorescence microscopy images through low contrast noisy image stacks

Contrast in fluorescence microscopy images allows for the differentiation between different structures by their difference in intensities. However, factors such as point-spread function and noise may reduce it, affecting its interpretability. We identified that fluctuation of emitters in a stack of images can be exploited to achieve increased contrast when compared to the average and Richardson-Lucy deconvolution. We tested our methods on four increasingly challenging samples including tissue, in which case results were comparable to the ones obtained by structured illumination microscopy in terms of contrast.