[Guided discontinuation of antidepressants: approach and first results of a Dutch multidisciplinary outpatient clinic]. / Werkwijze en eerste resultaten van multidisciplinaire afbouwpoli anti-depressiva.

BACKGROUND: Discontinuation of antidepressant medication can be difficult due to withdrawal symptoms and relapse risk. Scientific evidence on the questions of who, when, and how to stop antidepressants is limited. In Amsterdam a multidisciplinary outpatient clinic was started to provide advice and guidance. AIM: To substantiate the design of the clinic. Central questions relate to knowing which patients are referred, the background of their request, and their experiences with the outpatient clinic. METHOD: The first 51 patients of the clinic were described on the basis of file research, in addition a survey was conducted into patient experiences. RESULTS: Half of the patients (55%) actually started discontinuation, 39% were advised not to do so (yet). Patients at the clinic had used antidepressants for an average of 10 years, and 76% had previously attempted to stop. 21% had now successfully stopped and 25% were satisfied with a lower dose. One patient relapsed during tapering. CONCLUSION: So far, patients with long-term antidepressant use and multiple quit attempts have been referred. Our experiences are aimed at helping individual patients but can also result in more knowledge about who can stop at what moment, and how this should be done.

MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial.

Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.

Elaboration and validation of the method for the quantification of the emetic toxin of Bacillus cereus as described in EN-ISO 18465 - Microbiology of the food chain - Quantitative determination of emetic toxin (cereulide) using LC-MS/MS.

A method for the quantification of the Bacillus cereus emetic toxin (cereulide) was developed and validated. The method principle is based on LC-MS as this is the most sensitive and specific method for cereulide. Therefore the study design is different from the microbiological methods validated under this mandate. As the method had to be developed a two stage validation study approach was used. The first stage (pre-study) focussed on the method applicability and the experience of the laboratories with the method. Based on the outcome of the pre-study and comments received during voting at CEN and ISO level a final method was agreed to be used for the second stage the (final) validation of the method. In the final (validation) study samples of cooked rice (both artificially contaminated with cereulide or contaminated with B. cereus for production of cereulide in the rice) and 6 other food matrices (fried rice dish, cream pastry with chocolate, hotdog sausage, mini pancakes, vanilla custard and infant formula) were used. All these samples were spiked by the participating laboratories using standard solutions of cereulide supplied by the organising laboratory. The results of the study indicate that the method is fit for purpose. Repeatability values were obtained of 0.6 µg/kg at low level spike (ca. 5 µg/kg) and 7 to 9.6 µg/kg at high level spike (ca. 75 µg/kg). Reproducibility at low spike level ranged from 0.6 to 0.9 µg/kg and from 8.7 to 14.5 µg/kg at high spike level. Recovery from the spiked samples ranged between 96.5% for mini-pancakes to 99.3% for fries rice dish.

Cues to speech segmentation: evidence from juncture misperceptions and word spotting.

The question of whether Dutch listeners rely on the rhythmic characteristics of their native language to segment speech was investigated in three experiments. In Experiment 1, listeners were induced to make missegmentations of continuous speech. The results showed that word boundaries were inserted before strong syllables and deleted before weak syllables. In Experiment 2, listeners were required to spot real CVC or CVCC words (C = consonant, V = vowel) embedded in bisyllabic nonsense strings. For CVCC words, fewer errors were made when the second syllable of the nonsense string was weak rather than strong, whereas for CVC words the effect was reversed. Experiment 3 ruled out an acoustic explanation for this effect. It is argued that these results are in line with an account in which both metrical segmentation and lexical competition play a role.

Explicit speech segmentation and syllabic onset structure: developmental trends.

Recent applications of the hierarchical theory of the syllable to the development of explicit speech segmentation are critically examined. One particular prediction, that an initial consonant is more easily isolated when it constitutes the complete onset of a syllable than when it is part of a cluster onset, was tested on children with grade levels ranging from kindergarten to second grade. At each level, two independent groups of children worked with either CVCC (first consonant complete onset) or CCVC (part of cluster onset) syllables. First- and second-graders performed better on the CVCC than on the CCVC material in an initial consonant deletion task, but not when the task was comparison on the basis of that consonant. With the same instructions as the older children, kindergarten children performed at floor level on both tasks with both materials. However, in a new experiment in which the deletion task was presented as a puppet game, and with pretraining and selection on vowel deletion, a significantly higher level of success was achieved by the children working with the CVCC material. These results are consistent with the notion of developmental precedence of onset segmentation on phoneme segmentation. On the other hand, the results of the first and second graders show that onset superiority is not specific for the pre-reading stage.