Prognostic significance of nailfold capillary microscopy in patients with Raynaud's phenomenon and scleroderma-pattern abnormalities. A six-year follow-up study.

The aim of this study was to assess the prognostic significance of scleroderma capillary pattern (SD-pattern) in patients with Raynaud's phenomenon. Thirty patients with a capillaroscopy examination suggestive of scleroderma (megacapillaries and/or avascularity) but without clinical criteria of scleroderma (ARA criteria) were reevaluated 6 years after the initial clinical and capillaroscopy examinations. SD-pattern abnormalities were classified according to a semiquantitative method. Eight out of the 28 evaluated patients (28%) developed a scleroderma spectrum disorder (SDS). The presence of avascularity and/or a mean of more than two megacapillaries digit greatly enhanced the percentage of evolution toward SDS (70%/88% respectively). Most of the patients with few enlarged capillaries and no capillary rarefaction at entry had primary acrocyanosis (11/15). None of them developed SDS. The microangiopathy disappeared during the follow-up period in most of these patients (14/15). These results confirm the prognostic value of SD-pattern capillary abnormalities for SDS. Primary acrocyanosis, a benign clinical entity should be considered in presence of few megacapillaries and without capillary rarefaction.

Feasibility of Therapeutic Drug Monitoring (TDM) for Imatinib: Preliminary considerations on the dosage adjustment approach for CML patients enrolled in the Imatinib Concentration Monitoring (I-COME) study

Background: As imatinib pharmacokinetics are highly variable, plasma levels differ largely between patients under the same dosage. Retrospective studies in chronic myeloid leukemia (CML) patients showed significant correlations between low levels and suboptimal response, and between high levels and poor tolerability. Monitoring of plasma levels is thus increasingly advised, targeting trough concentrations of 1000 μg/L and above. Objectives: Our study was launched to assess the clinical usefulness of systematic imatinib TDM in CML patients. The present preliminary evaluation questions the appropriateness of dosage adjustment following plasma level measurement to reach the recommended trough level, while allowing an interval of 4-24 h after last drug intake for blood sampling. Methods: Initial blood samples from the first 9 patients in the intervention arm were obtained 4-25 h after last dose. Trough levels in 7 patients were predicted to be significantly away from the target (6 <750 μg/L, and 1 >1500 μg/L with poor tolerance), based on a Bayesian approach using a population pharmacokinetic model. Individual dosage adjustments were taken up in 5 patients, who had a control measurement 1-4 weeks after dosage change. Predicted trough levels were confronted to anterior model-based extrapolations. Results: Before dosage adjustment, observed concentrations extrapolated at trough ranged from 359 to 1832 μg/L (median 710; mean 804, CV 53%) in the 9 patients. After dosage adjustment they were expected to target between 720 and 1090 μg/L (median 878; mean 872, CV 13%). Observed levels of the 5 recheck measurements extrapolated at trough actually ranged from 710 to 1069 μg/L (median 1015; mean 950, CV 16%) and had absolute differences of 21 to 241 μg/L to the model-based predictions (median 175; mean 157, CV 52%). Differences between observed and predicted trough levels were larger when intervals between last drug intake and sampling were very short (~4 h). Conclusion: These preliminary results suggest that TDM of imatinib using a Bayesian interpretation is able to bring trough levels closer to 1000 μg/L (with CV decreasing from 53% to 16%). While this may simplify blood collection in daily practice, as samples do not have to be drawn exactly at trough, the largest possible interval to last drug intake yet remains preferable. This encourages the evaluation of the clinical benefit of a routine TDM intervention in CML patients, which the randomized Swiss I-COME study aims to.

BoBo mixing meseasurement at Belle using dilepton events tagged with a soft pion

L'expérience Belle, située dans le centre de recherche du KEK, au Japon, est consacrée principalement à l'étude de la violation de CP dans le système des mésons B. Elle est placée sur le collisionneur KEKB, qui produit des paires Banti-B. KEKB, l'une des deux « usines à B » actuellement en fonction, détient le record du nombre d'événements produits avec plus de 150 millions de paires. Cet échantillon permet des mesures d'une grande précision dans le domaine de la physique du méson B. C'est dans le cadre de ces mesures de précision que s'inscrit cette analyse. L'un des phénomènes remarquables de la physique des hautes énergies est la faculté qu'a l'interaction faible de coupler un méson neutre avec son anti-méson. Dans le présent travail, nous nous intéressons au méson B neutre couplé à l'anti-méson B neutre, avec une fréquence d'oscillation _md mesurable précisément. Outre la beauté de ce phénomène lui-même, une telle mesure trouve sa place dans la quête de l'origine de la violation de CP. Cette dernière n'est incluse que d'une façon peu satisfaisante dans le modèle standard des interactions électro-faibles. C'est donc la recherche de phénomènes physiques encore inexpliqués qui motive en premier lieu la collaboration Belle. Il existe déjà de nombreuses mesures de _md antérieures. Celle que nous présentons ici est cependant d'une précision encore jamais atteinte grâce, d'une part, à l'excellente performance de KEKB et, d'autre part, à une approche originale qui permet de réduire considérablement la contamination de la mesure par des événements indésirés. Cette approche fut déjà mise à profit par d'autres expériences, dans des conditions quelque peu différentes de celles de Belle. La méthode utilisée consiste à reconstruire partiellement l'un des mésons dans le canal ___D*(D0_)l_l, en n'utilisant que les informations relatives au lepton l et au pion _. L'information concernant l'autre méson de la paire Banti-B initiale n'est tirée que d'un seul lepton de haute énergie. Ainsi, l'échantillon à disposition ne souffre pas de grandes réductions dues à une reconstruction complète, tandis que la contamination due aux mésons B chargés, produits par KEKB en quantité égale aux B0, est fortement diminuée en comparaison d'une analyse inclusive. Nous obtenons finalement le résultat suivant : _md = 0.513±0.006±0.008 ps^-1, la première erreur étant l'erreur statistique et la deuxième, l'erreur systématique.<br/><br/>The Belle experiment is located in the KEK research centre (Japan) and is primarily devoted to the study of CP violation in the B meson sector. Belle is placed on the KEKB collider, one of the two currently running "B-meson factories", which produce Banti-B pairs. KEKB has created more than 150 million pairs in total, a world record for this kind of colliders. This large sample allows very precise measurements in the physics of beauty mesons. The present analysis falls within the framework of these precise measurements. One of the most remarkable phenomena in high-energy physics is the ability of weak interactions to couple a neutral meson to its anti-meson. In this work, we study the coupling of neutral B with neutral anti-B meson, which induces an oscillation of frequency _md we can measure accurately. Besides the interest of this phenomenon itself, this measurement plays an important role in the quest for the origin of CP violation. The standard model of electro-weak interactions does not include CP violation in a fully satisfactory way. The search for yet unexplained physical phenomena is, therefore, the main motivation of the Belle collaboration. Many measurements of _md have previously been performed. The present work, however, leads to a precision on _md that was never reached before. This is the result of the excellent performance of KEKB, and of an original approach that allows to considerably reduce background contamination of pertinent events. This approach was already successfully used by other collaborations, in slightly different conditions as here. The method we employed consists in the partial reconstruction of one of the B mesons through the decay channel ___D*(D0_)l_l, where only the information on the lepton l and the pion _ are used. The information on the other B meson of the initial Banti-B pair is extracted from a single high-energy lepton. The available sample of Banti-B pairs thus does not suffer from large reductions due to complete reconstruction, nor does it suffer of high charged B meson background, as in inclusive analyses. We finally obtain the following result: _md = 0.513±0.006±0.008 ps^-1, where the first error is statistical, and the second, systematical.<br/><br/>De quoi la matière est-elle constituée ? Comment tient-elle ensemble ? Ce sont là les questions auxquelles la recherche en physique des hautes énergies tente de répondre. Cette recherche est conduite à deux niveaux en constante interaction. D?une part, des modèles théoriques sont élaborés pour tenter de comprendre et de décrire les observations. Ces dernières, d?autre part, sont réalisées au moyen de collisions à haute énergie de particules élémentaires. C?est ainsi que l?on a pu mettre en évidence l?existence de quatre forces fondamentales et de 24 constituants élémentaires, classés en « quarks » et « leptons ». Il s?agit là de l?une des plus belles réussites du modèle en usage aujourd?hui, appelé « Modèle Standard ». Il est une observation fondamentale que le Modèle Standard peine cependant à expliquer, c?est la disparition quasi complète de l?anti-matière (le « négatif » de la matière). Au niveau fondamental, cela doit correspondre à une asymétrie entre particules (constituants de la matière) et antiparticules (constituants de l?anti-matière). On l?appelle l?asymétrie (ou violation) CP. Bien qu?incluse dans le Modèle Standard, cette asymétrie n?est que partiellement prise en compte, semble-t-il. En outre, son origine est inconnue. D?intenses recherches sont donc aujourd?hui entreprises pour mettre en lumière cette asymétrie. L?expérience Belle, au Japon, en est une des pionnières. Belle étudie en effet les phénomènes physiques liés à une famille de particules appelées les « mésons B », dont on sait qu?elles sont liées de près à l?asymétrie CP. C?est dans le cadre de cette recherche que se place cette thèse. Nous avons étudié une propriété remarquable du méson B neutre : l?oscillation de ce méson avec son anti-méson. Cette particule est de se désintégrer pour donner l?antiparticule associée. Il est clair que cette oscillation est rattachée à l?asymétrie CP. Nous avons ici déterminé avec une précision encore inégalée la fréquence de cette oscillation. La méthode utilisée consiste à caractériser une paire de mésons B à l?aide de leur désintégration comprenant un lepton chacun. Une plus grande précision est obtenue en recherchant également une particule appelée le pion, et qui provient de la désintégration d?un des mésons. Outre l?intérêt de ce phénomène oscillatoire en lui-même, cette mesure permet d?affiner, directement ou indirectement, le Modèle Standard. Elle pourra aussi, à terme, aider à élucider le mystère de l?asymétrie entre matière et anti-matière.

Transferring control demands across incidental learning tasks - Stronger sequence usage in serial reaction task after shortcut option in letter string checking

After incidentally learning about a hidden regularity, participants can either continue to solve the task as instructed or, alternatively, apply a shortcut. Past research suggests that the amount of conflict implied by adopting a shortcut seems to bias the decision for vs. against continuing instruction-coherent task processing. We explored whether this decision might transfer from one incidental learning task to the next. Theories that conceptualize strategy change in incidental learning as a learning-plus-decision phenomenon suggest that high demands to adhere to instruction-coherent task processing in Task 1 will impede shortcut usage in Task 2, whereas low control demands will foster it. We sequentially applied two established incidental learning tasks differing in stimuli, responses and hidden regularity (the alphabet verification task followed by the serial reaction task, SRT). While some participants experienced a complete redundancy in the task material of the alphabet verification task (low demands to adhere to instructions), for others the redundancy was only partial. Thus, shortcut application would have led to errors (high demands to follow instructions). The low control demand condition showed the strongest usage of the fixed and repeating sequence of responses in the SRT. The transfer results are in line with the learning-plus-decision view of strategy change in incidental learning, rather than with resource theories of self-control.

Partial cricotracheal resection for paediatric subglottic stenosis: update of the Lausanne experience with 129 cases.

OBJECTIVES: Partial cricotracheal resection (PCTR) is widely accepted for treating severe paediatric laryngotracheal stenosis (LTS). However, it remains limited to a few experienced centres. Here we report an update of the Lausanne experience in paediatric PCTR performed or supervised by a senior surgeon (Philippe Monnier). METHODS: An ongoing database of 129 paediatric patients who underwent PCTR for benign LTS between March 1978 and July 2012 at our hospital was retrospectively reviewed. Demographic characteristics and information on preoperative status, stenosis and surgery were collected. Primary outcomes were measured as overall and operation-specific decannulation rates (ODR and OSDR, respectively), and secondary outcomes as morbidity, mortality and postoperative functional results. RESULTS: A total of 129 paediatric patients [79 males and 50 females; mean age, 4.1 years (1 month-16 years, median age of 2 years old)] underwent PCTR during the study period. ODR and OSDR were 90 and 81%, respectively. The decannulation rates were significantly superior for single-stage PCTR compared with double-stage PCTR in both ODR and OSDR. Eight patients died postoperatively for reasons unrelated to surgery. Partial anastomotic dehiscence was seen in 13 patients, 9 of whom were successfully treated by revision surgery. Respiratory, voice and swallowing functions were near normal or only minimally impaired in 86, 65 and 81% of patients, respectively. CONCLUSIONS: PCTR is effective and feasible with good ODR and OSDR for highgrade / severe LTS. Glottic involvement and the presence of comorbidities were negative predictive factors of decannulation. Early detection and reintervention of postoperative incipient dehiscence contribute to avoiding the progress to late restenosis; however, voice improvement remains a challenge.

Mild guanidinoacetate increase under partial guanidinoacetate methyltransferase deficiency strongly affects brain cell development.

Among cerebral creatine deficiency syndromes, guanidinoacetate methyltransferase (GAMT) deficiency can present the most severe symptoms, and is characterized by neurocognitive dysfunction due to creatine deficiency and accumulation of guanidinoacetate in the brain. So far, every patient was found with negligible GAMT activity. However, GAMT deficiency is thought under-diagnosed, in particular due to unforeseen mutations allowing sufficient residual activity avoiding creatine deficiency, but enough guanidinoacetate accumulation to be toxic. With poorly known GAA-specific neuropathological mechanisms, we developed an RNAi-induced partial GAMT deficiency in organotypic rat brain cell cultures. As expected, the 85% decrease of GAMT protein was insufficient to cause creatine deficiency, but generated guanidinoacetate accumulation causing axonal hypersprouting and decrease in natural apoptosis, followed by induction of non-apoptotic cell death. Specific guanidinoacetate-induced effects were completely prevented by creatine co-treatment. We show that guanidinoacetate accumulation without creatine deficiency is sufficient to affect CNS development, and suggest that additional partial GAMT deficiencies, which may not show the classical brain creatine deficiency, may be discovered through guanidinoacetate measurement.

On the Adoption of Partial Least Squares in Psychological Research: Caveat Emptor

The partial least squares technique (PLS) has been touted as a viable alternative to latent variable structural equation modeling (SEM) for evaluating theoretical models in the differential psychology domain. We bring some balance to the discussion by reviewing the broader methodological literature to highlight: (1) the misleading characterization of PLS as an SEM method; (2) limitations of PLS for global model testing; (3) problems in testing the significance of path coefficients; (4) extremely high false positive rates when using empirical confidence intervals in conjunction with a new "sign change correction" for path coefficients; (5) misconceptions surrounding the supposedly superior ability of PLS to handle small sample sizes and non-normality; and (6) conceptual and statistical problems with formative measurement and the application of PLS to such models. Additionally, we also reanalyze the dataset provided by Willaby et al. (2015; doi:10.1016/j.paid.2014.09.008) to highlight the limitations of PLS. Our broader review and analysis of the available evidence makes it clear that PLS is not useful for statistical estimation and testing.