Are stentless valves hemodynamically superior to stented valves? Long-term follow-up of a randomized trial comparing Carpentier–Edwards pericardial valve with the Toronto Stentless Porcine Valve

ObjectiveThe benefit of stentless valves remains in question. In 1999, a randomized trial comparing stentless and stented valves was unable to demonstrate any hemodynamic or clinical benefits at 1 year after implantation. This study reviews long-term outcomes of patients randomized in the aforementioned trial.MethodsBetween 1996 and 1999, 99 patients undergoing aortic valve replacement were randomized to receive either a stented Carpentier–Edwards pericardial valve (CE) (Edwards Lifesciences, Irvine, Calif) or a Toronto Stentless Porcine Valve (SPV) (St Jude Medical, Minneapolis, Minn). Among these, 38 patients were available for late echocardiographic follow-up (CE, n = 17; SPV, n = 21). Echocardiographic analysis was undertaken both at rest and with dobutamine stress, and functional status (Duke Activity Status Index) was compared at a mean of 9.3 years postoperatively (range, 7.5–11.1 years). Clinical follow-up was 82% complete at a mean of 10.3 years postoperatively (range, 7.5–12.2 years).ResultsPreoperative characteristics were similar between groups. Effective orifice areas increased in both groups over time. Although there were no differences in effective orifice areas at 1 year, at 9 years, effective orifice areas were significantly greater in the SPV group (CE, 1.49 ± 0.59 cm2; SPV, 2.00 ± 0.53 cm2; P = .011). Similarly, mean and peak gradients decreased in both groups over time; however, at 9 years, gradients were lower in the SPV group (mean: CE, 10.8 ± 3.8 mm Hg; SPV, 7.8 ± 4.8 mm Hg; P = .011; peak: CE, 20.4 ± 6.5 mm Hg; SPV, 14.6 ± 7.1 mm Hg; P = .022). Such differences were magnified with dobutamine stress (mean: CE, 22.7 ± 6.1 mm Hg; SPV, 15.3 ± 8.4 mm Hg; P = .008; peak: CE, 48.1 ± 11.8 mm Hg; SPV, 30.8 ± 17.7 mm Hg; P = .001). Ventricular mass regression occurred in both groups; however, no differences were demonstrated between groups either on echocardiographic, magnetic resonance imaging, or biochemical (plasma B-type [brain] natriuretic peptide) assessment (P = .74). Similarly, Duke Activity Status Index scores of functional status improved in both groups over time; however, no differences were noted between groups (CE, 27.5 ± 19.1; SPV, 19.9 ± 12.0; P = .69). Freedom from reoperation at 12 years was 92% ± 5% in patients with CEs and 75% ± 5% in patients with SPVs (P = .65). Freedom from valve-related morbidity at 12 years was 82% ± 7% in patients with CEs and 55% ± 7% in patients with SPVs (P = .05). Finally, 12-year actuarial survival was 35% ± 7% in patients with CEs and 52% ± 7% in patients with SPVs (P = .37).ConclusionAlthough offering improved hemodynamic outcomes, the SPV did not afford superior mass regression or improved clinical outcomes up to 12 years after implantation

Multifactorial Patterns of Gene Expression in Colonic Epithelial Cells Predict Disease Phenotypes in Experimental Colitis

Background— The pathogenesis of inflammatory bowel disease (IBD) is complex and the need to identify molecular biomarkers is critical. Epithelial cells play a central role in maintaining intestinal homeostasis. We previously identified five “signature” biomarkers in colonic epithelial cells (CEC) that are predictive of disease phenotype in Crohn\u27s disease. Here we investigate the ability of CEC biomarkers to define the mechanism and severity of intestinal inflammation. Methods— We analyzed the expression of RelA, A20, pIgR, tumor necrosis factor (TNF), and macrophage inflammatory protein (MIP)-2 in CEC of mice with dextran sodium sulfate (DSS) acute colitis or T-cell-mediated chronic colitis. Factor analysis was used to combine the five biomarkers into two multifactorial principal components (PCs). PC scores for individual mice were correlated with disease severity. Results— For both colitis models, PC1 was strongly weighted toward RelA, A20, and pIgR, and PC2 was strongly weighted toward TNF and MIP-2, while the contributions of other biomarkers varied depending on the etiology of inflammation. Disease severity was correlated with elevated PC2 scores in DSS colitis and reduced PC1 scores in T-cell transfer colitis. Downregulation of pIgR was a common feature observed in both colitis models and was associated with altered cellular localization of pIgR and failure to transport IgA. Conclusions— A multifactorial analysis of epithelial gene expression may be more informative than examining single gene responses in IBD. These results provide insight into the homeostatic and proinflammatory functions of CEC in IBD pathogenesis and suggest that biomarker analysis could be useful for evaluating therapeutic options for IBD patients

High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men

Elucidating virus-host interactions responsible for HIV-1 transmission is important for advancing HIV-1 prevention strategies. To this end, single genome amplification (SGA) and sequencing of HIV-1 within the context of a model of random virus evolution has made possible for the first time an unambiguous identification of transmitted/founder viruses and a precise estimation of their numbers. Here, we applied this approach to HIV-1 env analyses in a cohort of acutely infected men who have sex with men (MSM) and found that a high proportion (10 of 28; 36%) had been productively infected by more than one virus. In subjects with multivariant transmission, the minimum number of transmitted viruses ranged from 2 to 10 with viral recombination leading to rapid and extensive genetic shuffling among virus lineages. A combined analysis of these results, together with recently published findings based on identical SGA methods in largely heterosexual (HSX) cohorts, revealed a significantly higher frequency of multivariant transmission in MSM than in HSX [19 of 50 subjects (38%) versus 34 of 175 subjects (19%); Fisher's exact p = 0.008]. To further evaluate the SGA strategy for identifying transmitted/founder viruses, we analyzed 239 overlapping 5′ and 3′ half genome or env-only sequences from plasma viral RNA (vRNA) and blood mononuclear cell DNA in an MSM subject who had a particularly well-documented virus exposure history 3–6 days before symptom onset and 14–17 days before peak plasma viremia (47,600,000 vRNA molecules/ml). All 239 sequences coalesced to a single transmitted/founder virus genome in a time frame consistent with the clinical history, and a molecular clone of this genome encoded replication competent virus in accord with model predictions. Higher multiplicity of HIV-1 infection in MSM compared with HSX is consistent with the demonstrably higher epidemiological risk of virus acquisition in MSM and could indicate a greater challenge for HIV-1 vaccines than previously recognized

An instrument to determine the technological literacy levels of upper secondary school students

In this article, an instrument for assessing upper secondary school students’ levels of technological literacy is presented. The items making up the instrument emerged from a previous study that employed a phenomenographic research approach to explore students’ conceptions of technology in terms of their understanding of the nature of technology and their interaction with technological artefacts. The instrument was validated through administration to 1,245 students on completion of their 12 years of formal schooling. A factor analysis was conducted on the data and Cronbach alpha reliability coefficients determined. The results show that a five-dimension factor structure (namely, artefact, process, direction/instruction, tinkering, and engagement) strongly supported the dimensions as developed during the original phenomenographic study. The Cronbach alpha reliability co-efficient of each dimension was satisfactory. Based on these findings, the instrument has been shown to be valid and reliable and can be used with confidence

Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection

Identification of full-length transmitted HIV-1 genomes could be instrumental in HIV-1 pathogenesis, microbicide, and vaccine research by enabling the direct analysis of those viruses actually responsible for productive clinical infection. We show in 12 acutely infected subjects (9 clade B and 3 clade C) that complete HIV-1 genomes of transmitted/founder viruses can be inferred by single genome amplification and sequencing of plasma virion RNA. This allowed for the molecular cloning and biological analysis of transmitted/founder viruses and a comprehensive genome-wide assessment of the genetic imprint left on the evolving virus quasispecies by a composite of host selection pressures. Transmitted viruses encoded intact canonical genes (gag-pol-vif-vpr-tat-rev-vpu-env-nef) and replicated efficiently in primary human CD4+ T lymphocytes but much less so in monocyte-derived macrophages. Transmitted viruses were CD4 and CCR5 tropic and demonstrated concealment of coreceptor binding surfaces of the envelope bridging sheet and variable loop 3. 2 mo after infection, transmitted/founder viruses in three subjects were nearly completely replaced by viruses differing at two to five highly selected genomic loci; by 12–20 mo, viruses exhibited concentrated mutations at 17–34 discrete locations. These findings reveal viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses

A Live-Attenuated HSV-2 ICP0− Virus Elicits 10 to 100 Times Greater Protection against Genital Herpes than a Glycoprotein D Subunit Vaccine

Glycoprotein D (gD-2) is the entry receptor of herpes simplex virus 2 (HSV-2), and is the immunogen in the pharmaceutical industry's lead HSV-2 vaccine candidate. Efforts to prevent genital herpes using gD-2 subunit vaccines have been ongoing for 20 years at a cost in excess of $100 million. To date, gD-2 vaccines have yielded equivocal protection in clinical trials. Therefore, using a small animal model, we sought to determine if a live-attenuated HSV-2 ICP0− virus would elicit better protection against genital herpes than a gD-2 subunit vaccine. Mice immunized with gD-2 and a potent adjuvant (alum+monophosphoryl lipid A) produced high titers of gD-2 antibody. While gD-2-immunized mice possessed significant resistance to HSV-2, only 3 of 45 gD-2-immunized mice survived an overwhelming challenge of the vagina or eyes with wild-type HSV-2 (MS strain). In contrast, 114 of 115 mice immunized with a live HSV-2 ICP0− virus, 0ΔNLS, survived the same HSV-2 MS challenges. Likewise, 0ΔNLS-immunized mice shed an average 125-fold less HSV-2 MS challenge virus per vagina relative to gD-2-immunized mice. In vivo imaging demonstrated that a luciferase-expressing HSV-2 challenge virus failed to establish a detectable infection in 0ΔNLS-immunized mice, whereas the same virus readily infected naïve and gD-2-immunized mice. Collectively, these results suggest that a HSV-2 vaccine might be more likely to prevent genital herpes if it contained a live-attenuated HSV-2 virus rather than a single HSV-2 protein

Relapse prevention for addictive behaviors

The Relapse Prevention (RP) model has been a mainstay of addictions theory and treatment since its introduction three decades ago. This paper provides an overview and update of RP for addictive behaviors with a focus on developments over the last decade (2000-2010). Major treatment outcome studies and meta-analyses are summarized, as are selected empirical findings relevant to the tenets of the RP model. Notable advances in RP in the last decade include the introduction of a reformulated cognitive-behavioral model of relapse, the application of advanced statistical methods to model relapse in large randomized trials, and the development of mindfulness-based relapse prevention. We also review the emergent literature on genetic correlates of relapse following pharmacological and behavioral treatments. The continued influence of RP is evidenced by its integration in most cognitive-behavioral substance use interventions. However, the tendency to subsume RP within other treatment modalities has posed a barrier to systematic evaluation of the RP model. Overall, RP remains an influential cognitive-behavioral framework that can inform both theoretical and clinical approaches to understanding and facilitating behavior change

Opportunistic Detection of Type 2 Diabetes Using Deep Learning From Frontal Chest Radiographs

Deep learning (DL) models can harness electronic health records (EHRs) to predict diseases and extract radiologic findings for diagnosis. With ambulatory chest radiographs (CXRs) frequently ordered, we investigated detecting type 2 diabetes (T2D) by combining radiographic and EHR data using a DL model. Our model, developed from 271,065 CXRs and 160,244 patients, was tested on a prospective dataset of 9,943 CXRs. Here we show the model effectively detected T2D with a ROC AUC of 0.84 and a 16% prevalence. The algorithm flagged 1,381 cases (14%) as suspicious for T2D. External validation at a distinct institution yielded a ROC AUC of 0.77, with 5% of patients subsequently diagnosed with T2D. Explainable AI techniques revealed correlations between specific adiposity measures and high predictivity, suggesting CXRs\u27 potential for enhanced T2D screening

Significance testing as perverse probabilistic reasoning

Truth claims in the medical literature rely heavily on statistical significance testing. Unfortunately, most physicians misunderstand the underlying probabilistic logic of significance tests and consequently often misinterpret their results. This near-universal misunderstanding is highlighted by means of a simple quiz which we administered to 246 physicians at two major academic hospitals, on which the proportion of incorrect responses exceeded 90%. A solid understanding of the fundamental concepts of probability theory is becoming essential to the rational interpretation of medical information. This essay provides a technically sound review of these concepts that is accessible to a medical audience. We also briefly review the debate in the cognitive sciences regarding physicians' aptitude for probabilistic inference