Predictive Modeling for Diagnostic Tests with High Specificity, but Low Sensitivity: A Study of the Glycerol Test in Patients with Suspected Menière’s Disease

A high specificity does not ensure that the expected benefit of a diagnostic test outweighs its cost. Problems arise, in particular, when the investigation is expensive, the prevalence of a positive test result is relatively small for the candidate patients, and the sensitivity of the test is low so that the information provided by a negative result is virtually negligible. The consequence may be that a potentially useful test does not gain broader acceptance. Here we show how predictive modeling can help to identify patients for whom the ratio of expected benefit and cost reaches an acceptable level so that testing these patients is reasonable even though testing all patients might be considered wasteful. Our application example is based on a retrospective study of the glycerol test, which is used to corroborate a suspected diagnosis of Menière’s disease. Using the pretest hearing thresholds at up to 10 frequencies, predictions were made by K-nearest neighbor classification or logistic regression. Both methods estimate, based on results from previous patients, the posterior probability that performing the considered test in a new patient will have a positive outcome. The quality of the prediction was evaluated using leave-one-out cross-validation, making various assumptions about the costs and benefits of testing. With reference to all 356 cases, the probability of a positive test result was almost 0.4. For subpopulations selected by K-nearest neighbor classification, which was clearly superior to logistic regression, this probability could be increased up to about 0.6. Thus, the odds of a positive test result were more than doubled

Cells as delivery vehicles for cancer therapeutics

Cell-based therapeutics have advanced significantly over the past decade and are poised to become a major pillar of modern medicine. Three cell types in particular have been studied in detail for their ability to home to tumors and to deliver a variety of different payloads. Neural stem cells, mesenchymal stem cells and monocytes have each been shown to have great potential as future delivery systems for cancer therapy. A variety of other cell types have also been studied. These results demonstrate that the field of cell-based therapeutics will only continue to grow

Metastatic rhabdomyosarcoma of the thyroid gland, a case report

The thyroid gland is a known but an unusual site for metastatic tumors from various primary sites. Despite the fact that it is one of the largest vascular organs in the body, clinical and surgical cases have given an incidence of 3 % of secondary malignances of the organ. Nevertheless, thyroid metastases are not an exceptional finding at autopsy, they are encountered in 2 % to 24 % of the patients with malignant neoplasm. Soft tissue sarcomas metastatic to the thyroid are extremely rare as the majority of thyroid metastasis are caused by tumors of the kidneys, lungs, mammary glands, ovaries , and colon or by melanomas. We report a case of 22-years-old woman with right leg rhabdomyosarcoma metastatic to the thyroid gland

Phosphorylation and translocation of heat shock protein 27 and αB-crystallin in human myocardium after cardioplegia and cardiopulmonary bypass

ObjectivesCardiac surgery using cardioplegia and cardiopulmonary bypass subjects myocardium to hypothermic reversible ischemic injury that can impair cardiac function. Research in animal and cell models demonstrates that acute myocardial ischemia/reperfusion injury causes phosphorylation of heat shock protein 27 and αB-crystallin. Phosphorylation of heat shock protein 27 and αB-crystallin is implicated in the regulation of both beneficial and detrimental responses to ischemic injury. The phosphorylation status of these proteins in human myocardium after ischemic insults associated with cardioplegia and cardiopulmonary bypass is unknown.MethodsRight atrial appendage and chest wall skeletal muscle samples were collected from patients before and after cardioplegia and cardiopulmonary bypass. Cardioplegia and cardiopulmonary bypass-induced changes in phosphorylation and localization of heat shock protein 27 and αB-crystallin were determined using immunoblot and confocal microscopy with total and phospho-specific antibodies.ResultsCardioplegia and cardiopulmonary bypass increased the phosphorylation of heat shock protein 27 on serine 15, 78, and 82, and αB-crystallin on serine 59 and 45, but not serine 19. The majority of heat shock protein 27 and αB-crystallin localized to I-bands of cardiac myofilaments and shifted to a detergent insoluble fraction after cardioplegia and cardiopulmonary bypass. Cardioplegia and cardiopulmonary bypass–induced phosphorylation of specific heat shock protein 27 and αB-crystallin residues were associated with additional subcellular locations. Increases in phosphorylation of heat shock protein 27 and αB-crystallin were negatively correlated with cardiac function after surgery.ConclusionCardiac surgery using cardioplegia and cardiopulmonary bypass is associated with phosphorylation and myofilament translocation of heat shock protein 27 and αB-crystallin in human myocardium. Phosphorylation of specific heat shock protein 27 and αB-crystallin serine residues is associated with distinct localization. Understanding the human myocardial small heat shock protein response may have significant implications for surgical myocardial protection

Embedded 3D Printing of Novel Bespoke Soft Dosage Form Concept for Pediatrics

Embedded three-dimensional printing (e-3DP) is an emerging method for additive manufacturing where semi-solid materials are extruded within a solidifying liquid matrix. Here, we present the first example of employing e-3DP in the pharmaceutical field and demonstrate the fabrication of bespoke chewable dosage forms with dual drug loading for potential use in pediatrics. LegoTM-like chewable bricks made of edible soft material (gelatin-based matrix) were produced by directly extruding novel printing patterns of model drug ink (embedded phase) into a liquid gelatin-based matrix (embedding phase) at an elevated temperature (70 °C) to then solidify at room temperature. Dose titration of the two model drugs (paracetamol and ibuprofen) was possible by using specially designed printing patterns of the embedded phase to produce varying doses. A linearity [R2 = 0.9804 (paracetamol) and 0.9976 (ibuprofen)] was achieved between percentage of completion of printing patterns and achieved doses using a multi-step method. The impact of embedded phase rheological behavior, the printing speed and the needle size of the embedded phase were examined. Owning to their appearance, modular nature, ease of personalizing dose and geometry, and tailoring and potential inclusion of various materials, this new dosage form concept holds a substantial promise for novel dosage forms in pediatrics

Insulin treatment enhances the myocardial angiogenic response in diabetes

ObjectiveGrowth factor and cell-based angiogenesis are attractive therapeutic options for diabetic patients with end-stage coronary disease. Reduced collateral vessel formation observed in diabetes is associated with increased expression of anti-angiogenic proteins, angiostatin and endostatin. The aim of this study was to determine the effects of insulin treatment on the diabetic angiogenic response to chronic myocardial ischemia.MethodsYucatan miniswine were treated with alloxan (pancreatic β-cell specific toxin, 150 mg/kg) and divided into two groups. In the diabetic group (DM, n = 8), blood glucose levels were kept greater than 250 mg/dL, and in the insulin-treated group (IDM, n = 6), intramuscular insulin was administered daily to keep blood glucose less than 150 mg/dL. A third group of age-matched swine served as nondiabetic controls (ND; n = 8). Eight weeks later, all animals underwent circumflex artery ameroid constrictor placement to induce chronic ischemia. Myocardial perfusion was assessed at 3 and 7 weeks after ameroid placement using microspheres. Microvascular function, capillary density, and myocardial expression of anti-angiogenic mediators were evaluated.ResultsDiabetic animals exhibited significant impairments in endothelium-dependent microvessel relaxation to adenosine diphosphate and substance P, which were reversed in insulin-treated animals. Collateral-dependent perfusion in the ischemic circumflex territory, which was profoundly reduced in diabetic animals (−0.18 ± 0.02 vs +0.23 ± 0.07 mL · min−1 · g−1; P < .001), improved significantly with insulin treatment (0.12 ± 0.05 mL · min−1 · g−1; P < .01). Myocardial expression of anti-angiogenic proteins, angiostatin and endostatin, showing a 4.3- and 3.6-fold increase in diabetic animals respectively (both P < .01 vs ND), was markedly reduced in insulin-treated animals (2.3- and 1.8-fold vs ND; both P < .01).ConclusionsInsulin treatment successfully reversed diabetic coronary endothelial dysfunction and significantly improved the endogenous angiogenic response. These pro-angiogenic effects may be mediated through downregulation of anti-angiogenic mediators. Insulin therapy appears to be a promising modality to enhance the angiogenic response in diabetic patients

Robust Estimators in Generalized Pareto Models

This paper deals with optimally-robust parameter estimation in generalized Pareto distributions (GPDs). These arise naturally in many situations where one is interested in the behavior of extreme events as motivated by the Pickands-Balkema-de Haan extreme value theorem (PBHT). The application we have in mind is calculation of the regulatory capital required by Basel II for a bank to cover operational risk. In this context the tail behavior of the underlying distribution is crucial. This is where extreme value theory enters, suggesting to estimate these high quantiles parameterically using, e.g. GPDs. Robust statistics in this context offers procedures bounding the influence of single observations, so provides reliable inference in the presence of moderate deviations from the distributional model assumptions, respectively from the mechanisms underlying the PBHT.Comment: 26pages, 6 figure