Adenosine 5′-diphosphate (ADP) inducible aggregation is used to assess platelet response to thienopyridines. Thrombin receptor-activating peptide-6 (TRAP-6) inducible aggregation may serve as a positive control because it acts via the thrombin receptor protease-activating receptor-1, which is not blocked by thienopyridines. We therefore investigated if TRAP-6 is suitable as a positive control when assessing residual platelet reactivity to ADP. Platelet response to clopidogrel was assessed in 200 patients on dual antiplatelet therapy using ADP inducible platelet aggregation by light transmission aggregometry (LTA), multiple electrode aggregometry (MEA), and the shear-dependent Impact-R. Test specificities were monitored by TRAP-6 inducible platelet aggregation. The aggregation-independent vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay served for comparisons. ADP inducible aggregation was correlated to that by TRAP-6 (r = 0.33 to 0.72; p < 0.001 for all assays). A linear correlation was seen within MEA (r = 0.72). LTA TRAP-6 correlated weakly with the VASP assay (r = 0.19; p = 0.01), while there were no correlations of TRAP-6 responses by MEA or the Impact-R with the VASP assay (r = 0.03 and −0.09; p > 0.05). In all three assays, differences between ADP and TRAP-6 inducible aggregation varied considerably. Within MEA, TRAP-6 inducible aggregation was almost always stronger than ADP inducible aggregation, while within LTA and the Impact-R, weak responses to ADP were associated with both, weak and strong responses to TRAP-6. In conclusion, the application of TRAP-6 as a positive control for platelet reactivity has major limitations and results need to be cautiously interpreted on an individual basis.
Cytokines have been found to be elevated in cancer patients and have been associated with worse prognosis in single tumour entities. We investigated the association of eight different cytokines with venous thromboembolism (VTE) and prognosis in cancer patients. The Vienna Cancer and Thrombosis Study (CATS), a prospective study, includes patients with newly diagnosed tumour or disease progression. Patients with an overt infection are excluded. Study end-points are VTE, death, loss to follow-up or study completion. Interleukin (IL) serum levels were measured using the xMAP technology developed by Luminex. Among 726 included patients, no associations between IL levels and VTE were found, with the exception of a trend for IL-1β and IL-6 in pancreatic cancer. Elevated levels of IL-6 [as continuous variable per double increase hazard ratio (HR) = 1·07, 95% confidence interval (CI) = 1·027-1·114, P = 0·001, IL-8 (HR = 1·12, 95% CI = 1·062-1·170, P < 0·001) and IL-11 (HR = 1·37, 95% CI = 1·103-1·709, P = 0·005] were associated with worse survival. In subgroup analyses based on tumour type, colon carcinoma patients, who had higher IL-6 levels, showed a shorter survival (HR = 2·405, 95% CI = 1·252-4·618, P = 0·008). A significant association of elevated IL-10 levels with a decrease in survival (HR = 1·824, 95% CI = 1·098-3·031, P = 0·020) was seen among patients with lung cancer. No correlation between VTE and IL levels was found, but higher IL-6, IL-8 and IL-11 levels were associated with worse survival in cancer patients. Further, elevated IL-6 levels might be a prognostic marker in colorectal cancer and elevated IL-10 levels in lung cancer patients.
In Brief Objectives: The aim of the present study was to compare two novel fine structure strategies “FS4” and “FS4-p” with the established fine structure processing (FSP) strategy. FS4 provides fine structure information on the apical four-electrode channels. With FS4-p, these electrodes may be stimulated in a parallel manner. The authors evaluated speech perception, sound quality, and subjective preference. Design: A longitudinal crossover study was done on postlingually deafened adults (N = 33) who were using FSP as their default strategy. Each participant was fitted with FS4, FS4-p, and FSP, for 4 months in a randomized and blinded order. After each run, an Adaptive Sentence test in noise (Oldenburger Sentence Test [OLSA]) and a Monosyllable test in quiet (Freiburger Monosyllables) were performed, and subjective sound quality was determined with a Visual Analogue Scale. At the end of the study the preferred strategy was noted. Results: Scores of the OLSA did not reveal any significant differences among the three strategies, but the Freiburger test showed a statistically significant effect (p = 0.03) with slightly worse scores for FS4 (49.7%) compared with FSP (54.3%). Performance of FS4-p (51.8%) was comparable with the other strategies. Both audiometric tests depicted a high variability among subjects. The number of best-performing strategies for each participant individually was as follows: (a) for the OLSA: FSP, N = 10.5; FS4, N = 10.5; and FS4-p, N = 12; and (b) for the Freiburger test: FSP, N = 14; FS4, N = 9; and FS4-p, N = 10. A moderate agreement was found in the best-performing strategies of the Speech tests within the participants. For sound quality, speech in quiet, classical, and pop music were assessed. No significant effects of strategy were found for speech in quiet and classical music, but auditory impression of pop music was rated as more natural in FSP compared with FS4 (p = 0.04). It is interesting that at the end of the study, a majority of the participants favored the new coding strategies over their previous default FSP (FSP, N = 13; FS4, N = 13; FS4-p, N = 7). Conclusions: In summary, FS4 and FS4-p offer new and further options in audio processor fitting, with similar levels of speech understanding in noise as FSP. This is an interesting result, given that the strategies’ presentation of temporal fine structure differs from FSP. At the end of the study, 20 of 33 subjects chose either FS4 or FS4-p over their previous default strategy FSP. This study with cochlear implant patients is a long-term, blinded, crossover comparison of 3 fine structure sound-coding strategies (FS4, FS4-p, and FSP). Every participant used each strategy for 4 months in a randomized sequence. Overall, no difference was found in speech perception in noise. Speech perception in quiet showed slightly better scores with FSP compared to FS4. Interestingly, differences in scores between strategies within each participant were rather large. This indicates that it is worthwhile to determine the best individual strategy for optimal performance.
Abstract The current standard of care treatment for severe hemophilia A and B (SHA and SHB) is the prophylactic intravenous replacement of coagulation factor VIII or IX (FVIII/FIX) to prevent spontaneous bleeding. Persons with hemophilia without prophylactic treatment receive therapy in case of bleeding, i.e., on demand. To assess treatment patterns, utilization of products, and bleeding outcomes in a real-world cohort of persons with SHA and SHB, defined as FVIII or FIX activity < 1%, data was retrospectively collected from hemophilia-specific patient diaries used for home treatment, medical records, and entries into the Austrian Hemophilia Registry from the year 2012 to 2017. Fifty-three male persons with SHA ( n = 47) and SHB ( n = 6) were included; 26 with SHA and 5 with SHB were on prophylaxis, 8 and 1 switched therapy regimen, and 13 and 0 received on-demand therapy. Persons on prophylaxis used a mean factor FVIII or FIX dose of 71.7 and 40.1 IU/kg/week. Median (IQR) annualized bleeding rates (ABR) in SHA were 28.0 (23.4–31.3) in the on-demand, 4.9 (1.6–13.5) in the prophylaxis group, and 3.0 (2.0–6.8) in the prophylactic group of SHB. Three persons with SHA had zero bleeds during the observation period. On-demand therapy and hepatitis B and C were associated with higher ABR but not age, weight, and HIV positivity. Bleeding rates and the proportion of on-demand therapy in persons with hemophilia were high in our real-world cohort. Further improvement is needed, which might be facilitated with the advent of factor products with extended half-life or non-factor therapies.
The aim was to evaluate the association of molecular-level human leukocyte antigen (HLA) mismatching with post-transplant graft survival, rejection, and cardiac allograft vasculopathy (CAV). We retrospectively analyzed all primary cardiac transplant recipients between 01/1984-06/2016. 1167 patients fulfilled inclusion criteria and had HLA typing information available. In 312 donor-recipient pairs, typing at serological split antigen level was available. We used the Epitope MisMatch Algorithm to calculate the number of amino acid differences in antibody-verified HLA eplets (amino acid mismatch load (AAMM)) between donor and recipient. Patients with a higher HLA-DR AAMM load had inferior 1-year graft survival (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.01–1.28). The HLA-AB AAMM load showed no impact on graft survival. In the subgroup with available split-level information, we observed an inferior graft survival for a higher HLA-DR AAMM load 3 months after transplantation (HR, 1.22; 95% CI, 1.04–1.44) and a higher risk for rejection for an increasing HLA-AB (HR, 1.70; 95% CI, 1.29–2.24) and HLA-DR (HR, 1.32; 95% CI, 1.09–1.61) AAMM load. No impact on the development of CAV was found. Molecular-level HLA mismatch analysis could serve as a tool for risk stratification after heart transplantation and might take us one step further into precision medicine.
