Harmonic priming in an amusic patient: the power of implicit tasks

Our study investigated with an implicit method (i.e., priming paradigm) whether I.R. - a brain-damaged patient exhibiting severe amusia - processes implicitly musical structures. The task consisted in identifying one of two phonemes (Experiment 1) or timbres (Experiment 2) on the last chord of eight-chord sequences (i.e., target). The targets were harmonically related or less related to the prior chords. I.R. displayed harmonic priming effects: Phoneme and timbre identification was faster for related than for less related targets (Experiments 1 and 2). However, I.R.'s explicit judgements of completion for the same sequences did not differ between related and less related contexts (Experiment 3). Her impaired performance in explicit judgements was not due to general difficulties with task demands since she performed like controls for completion judgements on spoken sentences (Experiment 4). The findings indicate that implicit knowledge of musical structures might remain intact and accessible, even when explicit judgements and overt recognition have been lost.     

Developing a quality by design approach to model tablet dissolution testing: an industrial case study

Abstract

This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a quality control strategy to model dissolution testing of solid oral dose products according to International Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk analysis to identify the material- and process-related parameters impacting the critical quality attributes of dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship between design factors and dissolution profiles. Results show that (a) in the case studied, the two parameters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tablet hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing such an approach systematically in industrial pharmaceutical production would reduce the need for tablet dissolution testing.     

Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: Practical recommendations for the laboratory

There is a laboratory and clinical need to know the impact of direct oral anticoagulants (DOACs) on diagnostic tests to avoid misinterpretation of results. Although the regulatory labelling documents provide some information about the influences of each DOAC on diagnostic tests, these are usually limited to some of the most common tests and no head to head comparison is available. In this paper, we report the impact of DOACs on several thrombophilia tests, including assessment of antithrombin, protein S and protein C activity assays, detection of activated protein C resistance and assays used for lupus anticoagulant. Results are compared and discussed with data obtained from literature. The final goal of this comprehensive review is to provide practical recommendations for laboratories to avoid misdiagnosis due to oral direct factor Xa (FXa) or IIa (FIIa) inhibitors. Overall, oral direct FXa (apixaban, betrixaban, edoxaban and rivaroxaban) and FIIa (dabigatran) antagonists may affect clot-based thrombophilia diagnostic tests resulting in false-positive or false-negative results. An effect on FIIa-based thrombophilia diagnostic tests is observed with dabigatran but not with anti-FXa DOACs and conversely for FXa-based thrombophilia diagnostic tests. No impact was observed with antigenic/chromogenic methods for the assessment of protein S and C activity. In conclusion, interpretation of thrombophilia diagnostic tests results should be done with caution in patients on DOACs. The use of a device/chemical compound able to remove or antagonize the effect of DOACs or the development of new diagnostic tests insensitive to DOACs should be considered to minimize the risk of false results.     

Review of coagulation preanalytical variables with update on the effect of direct oral anticoagulants

There are many preanalytical variables (PAV) that are known to affect coagulation testing. The more commonly acknowledged PAV addressed by the clinical laboratory tend to start with their influence on blood collection, but realistically coagulation PAV starts with the patient, where the laboratory has less influence or control. Patient selection and appropriate timing for blood collection may be integral for assuring proper diagnosis and management. Laboratory control and assurance for ideal phlebotomy practice would mitigate most PAVs related to blood collection to minimize suboptimal sample collection. Laboratory oversight of sample transportation, processing and storage will assure sample integrity until testing can be facilitated. The purpose of this document is to review common PAV that should be taken into consideration when ordering, performing and interpreting a coagulation test result, with additional attention to the effect of direct oral anticoagulants (DOACs).     

Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation

We report here on a preliminary human autologous transplantation study of retroviral gene transfer to bone marrow (BM) and peripheral blood (PB)-derived CD34-enriched cells. Eleven patients with multiple myeloma or breast cancer had cyclophosphamide and filgrastim-mobilized PB cells CD34-enriched and transduced with a retroviral marking vector containing the neomycin resistance gene, and CD34-enriched BM cells transduced with a second marking vector also containing a neomycin resistance gene. After high-dose conditioning therapy, both transduced cell populations were reinfused and patients were followed over time for the presence of the marker gene and any adverse effects related to the gene-transfer procedure. All 10 evaluable patients had the marker gene detected at the time of engraftment, and 3 of 9 patients had persistence of the marker gene for greater than 18 months posttransplantation. The marker gene was detected in multiple lineages, including granulocytes, T cells, and B cells. The source of the marking was both the transduced PB graft and the BM graft, with a suggestion of better long-term marking originating from the PB graft. The steady- state levels of marking were low, with only 1:1000 to 1:10,000 cells positive. There was no toxicity noted, and patients did not develop detectable replication-competent helper virus at any time posttransplantation. These results suggest that mobilized PB cells may be preferable to BM for gene therapy applications and that progeny of mobilized peripheral blood cells can contribute long-term to engraftment of multiple lineages.     

Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4- one iron chelators in overloaded and nonoverloaded mice

Five orally effective iron chelators of the 3-hydroxypyridin-4-one series have been administered intraperitoneally to iron-overloaded and nonoverloaded male mice at a dose of 200 mg/kg/24 h for a total of 60 days to investigate the effect on iron loading and toxicity. There was a significant reduction in hepatic iron at the end of the study in the iron-overloaded mice with all compounds studied using chemical iron quantitation (P less than .001) and with Perls' stain (P less than .01). Liver iron removal with the hydroxypyridinones ranged from 37% with CP20 to 63% with CP51, compared with 46% removal for desferrioxamine (DFO). There was no significant reduction in splenic or cardiac iron with any chelator. There were no deaths in iron-overloaded animals receiving any of the hydroxypyridin-4-ones, but significantly more deaths in the nonoverloaded groups as a whole (P less than .03). No weight loss was observed with any chelator. Significant reductions in hemoglobin and white cell count were observed with CP20(L1). No histologic abnormalities of kidney, spleen, bone marrow, or stifle joints were observed. Intracytoplasmic inclusion bodies were observed in the centrilobular hepatocytes of animals administered each of the hydroxypyridin-4-ones, while the DFO-treated and control groups showed no such changes.     

Tablet formulation of Famotidine-loaded P-gp inhibiting nanoparticles using PLA-g-PEG grafted polymer

Our work aimed at evaluating the use of permeability glycoprotein (P-gp) inhibiting nanoparticles (NPs) as a part of a suitable oral solid dosage to improve bioavailability. Famotidine (Pepcid^®), a stomach acid production inhibitor, was used as a drug model to test our hypothesis. Famotidine-loaded NPs were prepared by solvent emulsion evaporation using PEG grafted on a polylactide acid (PLA) polymer backbone (PLA-g-PEG), with a 5% molar ratio of PEG versus lactic acid monomer and PEG of either 750 or 2000?Da molecular weight. Tablet formulation was composed of 40% Famotidine-loaded NPs, 52.5% microcrystalline cellulose as filler, 7% pre-gelatinized starch as binder/disintegrant, and 0.5% magnesium stearate as lubricant. Tablets containing 1.6?mg of Famotidine were prepared at an average weight of 500?mg, thickness of 6.2–6.5?mm, hardness of 5–8?kp, and disintegration time of <1?min. Our results suggest that Famotidine-loaded NPs using grafted PEG-g-PLA polymers can be formulated as an oral solid dosage form while effectively inhibiting P-gp mediated Famotidine efflux, irrespective of PEG molecular weights. This could therefore represent an attractive formulation alternative to enhance oral permeability and bioavailability of drugs that are P-gp substrates.     

Canadian Cardiovascular Society Guidelines for the Diagnosis and Management of Stable Ischemic Heart Disease

This overview provides a guideline for the management of stable ischemic heart disease. It represents the work of a primary and secondary panel of participants from across Canada who achieved consensus on behalf of the Canadian Cardiovascular Society. The suggestions and recommendations are intended to be of relevance to primary care and specialist physicians with an emphasis on rational deployment of diagnostic tests, expedited implementation of long- and short-term medical therapy, timely consideration of revascularization, and practical follow-up measures.