101 research outputs found
Wigmore Hall 2022/2023 Season, September-December 2022: Performance Notes by David Owen Norris
No full textDavid Owen Norris provides commentary and added performance during the Wigmore Hall 2022/23 Season September-December 2022, in person and online.Thursday 22 September 2022 07:30 PMAngela Hewitt, piano – performing Bach, Mozart, and ChopinTuesday 11 October 2022 07:30 PMBeatrice Rana, piano – performing Skryabin, Chopin, and BeethovenFriday 14 October 2022 07:30 PMAndreas Haefliger, piano – performing Copland, R. Schumann, and BeethovenMonday 14 November 2022 07:30 PMTakács Quartet – performing BeethovenWednesday 16 November 2022 07:30 PMTakács Quartet – performing Britten, Bartók, and DvořákThursday 22 December 2022 07:30 PMPavel Kolesnikov, piano – performing Schubert, Bach, and R. Schumann<br/
Morphisms between complete Riemannian pseudogroups
No full textAbstractWe introduce the concept of morphism of pseudogroups generalizing the étalé morphisms of Haefliger. With our definition, any continuous foliated map induces a morphism between the corresponding holonomy pseudogroups. The main theorem states that any morphism between complete Riemannian pseudogroups is complete, has a closure and its maps are C∞ along the orbit closures. Here, completeness and closure are versions for morphisms of concepts introduced by Haefliger for pseudogroups. This result is applied to approximate foliated maps by smooth ones in the case of transversely complete Riemannian foliations, yielding the foliated homotopy invariance of their spectral sequence. This generalizes the topological invariance of their basic cohomology, shown by El Kacimi-Alaoui–Nicolau. A different proof of the spectral sequence invariance was also given by the second author
Individualization of Piperacillin Dosage based on Therapeutic Drug Monitoring With or Without Model-Informed Precision Dosing: a Scenario Analysis
No full text« Individualisaton de la posologie de la pipéracilline basée sur le suivi thérapeutque
pharmacologique avec ou sans dosage de précision renseigné par des modèles : une analyse
de scénarios »
Résumé :
La pipéracilline, un antbiotque β-lactamine à large spectre, présente une actvité antmicrobienne
dépendante du temps : la fracton de l’intervalle de dosage pendant laquelle les concentratons libres
restent au-dessus de la concentraton minimale inhibitrice des bactéries (%fT>CMI) est l’indice qui relie
l’expositon à l’efet antbactérien. Au CHUV, on dispose depuis de nombreuses années du suivi
thérapeutque pharmacologique (therapeutc drug monitoring, TDM) de la pipéracilline, sur la base
duquel on peut ajuster sa posologie pour maximiser son efcacité et minimiser son risque de toxicité.
La cible visée est une concentraton résiduelle entre 8 et 32 mg/L, assurant la couverture de la majorité
des bactéries isolées au CHUV, tout en limitant sa toxicité dose-dépendante. Les modèles de
pharmacocinétque de populaton (popPK) prédisent rigoureusement l'expositon circulante moyenne
et sa variabilité inter-individuelle. L’approche du dosage de précision renseigné par des modèles
(Model-Informed Precision Dosing, MIPD) consiste à combiner les informatons issues des modèles
popPK et les données individuelles issues du TDM : une estmaton bayésienne permet alors d’établir
le profl pharmacocinétque de vraisemblance maximale d’un patent spécifque. TUCUXI est un logiciel
qui calcule ces prédictons individuelles a priori et a posteriori sur la base de modèles popPK, en
intégrant respectvement les caractéristques connues des patents et les concentratons observées au
TDM. Notre étude visait à évaluer les bénéfces du TDM avec et sans MIPD en termes de probabilité
d’ateinte d’une cible thérapeutque prédéfnie.
Les données TDM issues de 80 cures de pipéracilline en perfusions intermitentes ont été analysées
rétrospectvement à l’aide du logiciel TUCUXI. Six scénarios d’ajustement posologique ont été
considérés : une posologie uniforme pour tous les patents (4000 mg q8h = scenario 1U), la posologie
initale réelle (scénario 1A), l’ajustement empirique réel après une 1ère mesure de TDM (scénario 2A),
une posologie MIPD a priori (scénario 1P), la posologie MIPD a posteriori après une 1ère mesure de
TDM (scénario 2T) et une posologie MIPD a posteriori après une 2ème mesure de TDM (scénario 3T).
Ces scénarios ont été comparées selon la dose quotdienne, la distributon des concentratons
résiduelles et la probabilité d’ateinte de la cible (probability of target atainment, PTA, c’est-à-dire une
concentraton résiduelle entre 8 et 32 mg/L).
La concentraton résiduelle médiane se situait entre 8 et 32 mg/L pour tous les scénarios, sauf pour la
posologie basée sur le MIPD a priori (42 mg/L). Les distributons de concentratons résiduelles prédites
par les six scénarios diféraient signifcatvement, les deux scénarios basés sur le MIPD a posteriori
réduisant au mieux leur dispersion (p<0.001). Entre les scénarios, l’écart-type des doses journalières
se corrélait de façon inverse avec l’écart-type des concentratons. Les PTA estmées ateignaient
respectvement 32%, 32%, 55%, 29%, 83% et 94 % pour les six scénarios (p<0.001). La mauvaise
performance du scénario MIPD a priori n’a pas empêché les stratégies basées sur le MIPD a posteriori
d’améliorer le mieux l’ateinte de la cible.
En conclusion, nos observatons et simulatons de schémas posologiques ont montré une meilleure
ateinte de la cible avec le TDM classique par rapport à l’absence de TDM. L’ajout d’une approche
bayésienne (MIPD) devrait permetre d’améliorer signifcatvement l’ateinte précise de la cible
thérapeutque. Des essais cliniques prospectfs restent nécessaires pour confrmer les bénéfces du
MIPD, en termes non seulement d’ateinte d’une cible pharmacologique, mais aussi de résultats
cliniques
The rational classification of links of codimension > 2
No full textLet m and p1,.,pr < m - 2 be positive integers. The set of links of codimension > 2, Em(∐k=1 rSPk), is the set of smooth isotopy classes of smooth embeddings ∐k=1 rSPk → Sm. Haefliger showed that Em(∐k=1 rSPk) is a finitely generated abelian group with respect to embedded connected summation and computed its rank in the case of knots, i.e. r = 1. For r > 1 and for restrictions on p1,.,pr the rank of this group can be computed using results of Haefliger or Nezhinsky. Our main result determines the rank of the group Em(∐k=1 rSPk) in general. In particular we determine precisely when Em(∐k=1 rSPk) is finite. We also accomplish these tasks for framed links. Our proofs are based on the Haefliger exact sequence for groups of links and the theory of Lie algebras. © de Gruyter 2014.The third author was supported in part by INTAS grant 06-1000014-6277, Moebius Contest Foundation for Young Scientists and Euler Foundation
Synthetic Biology Platform for Sensing and Integrating Endogenous Transcriptional Inputs in Mammalian Cells
No full textSummaryOne of the goals of synthetic biology is to develop programmable artificial gene networks that can transduce multiple endogenous molecular cues to precisely control cell behavior. Realizing this vision requires interfacing natural molecular inputs with synthetic components that generate functional molecular outputs. Interfacing synthetic circuits with endogenous mammalian transcription factors has been particularly difficult. Here, we describe a systematic approach that enables integration and transduction of multiple mammalian transcription factor inputs by a synthetic network. The approach is facilitated by a proportional amplifier sensor based on synergistic positive autoregulation. The circuits efficiently transduce endogenous transcription factor levels into RNAi, transcriptional transactivation, and site-specific recombination. They also enable AND logic between pairs of arbitrary transcription factors. The results establish a framework for developing synthetic gene networks that interface with cellular processes through transcriptional regulators
Connexin 43 expression in human hypertrophied heart due to pressure and volume overload
No full textLeft ventricular hypertrophy (LVH) is due to pressure overload or mechanical stretch and is thought to be associated with remodeling of gap-junctions. We investigated whether the expression of connexin 43 (Cx43) is altered in humans in response to different degrees of LVH. The expression of Cx43 was analyzed by quantitative polymerase chain reaction, Western blot analysis and immunohistochemistry on left ventricular biopsies from patients undergoing aortic or mitral valve replacement. Three groups were analyzed: patients with aortic stenosis with severe LVH (n=9) versus only mild LVH (n=7), and patients with LVH caused by mitral regurgitation (n=5). Cx43 mRNA expression and protein expression were similar in the three groups studied. Furthermore, immunohistochemistry revealed no change in Cx43 distribution. We can conclude that when compared with mild LVH or with LVH due to volume overload, severe LVH due to chronic pressure overload is not accompanied by detectable changes of Cx43 expression or spatial distribution
Clinically relevant bidirectional drug-drug interaction between midostaurin and voriconazole.
No full textMidostaurin is often prescribed with azole antifungals in patients with leukemia, either for aspergillosis prophylaxis or treatment. Midostaurin is extensively metabolized by cytochrome (CYP) 3A4. In addition it inhibits and induces various CYPs at therapeutic concentrations. Thus midostaurin is associated with a high potential for drug-drug interactions (DDIs), both as a substrate (victim) and as a perpetrator. However, data on midostaurin as a perpetrator of DDIs are scarce, as most pharmacokinetic studies have focused on midostaurin as a victim drug. We report a clinically relevant bidirectional DDI between midostaurin and voriconazole during induction treatment. A 49-year-old woman with acute myeloid leukemia developed invasive pulmonary aspergillosis after induction chemotherapy. She was treated with voriconazole at standard dosage. Six days after starting midostaurin, she developed visual hallucinations with a concurrent sharp increase in voriconazole blood concentration (Ctrough 10.3 mg L-1 , target Ctrough 1-5 mg L-1 ). Neurotoxicity was considered to be related to voriconazole overexposure. The concentration of midostaurin was concomitantly six-fold above the average expected level, however without safety issues. Midostaurin was stopped and the dosage of voriconazole was adjusted with therapeutic drug monitoring. The evolution was favorable with quick resolution and no recurrence of visual hallucinations. To our knowledge, this is the first case suggesting that midostaurin and voriconazole reciprocally inhibit each other's metabolism leading to increased exposure of both. This case highlights the knowledge gap regarding drug-drug interactions between midostaurin and azole antifungals. Close clinical and therapeutic drug monitoring is advised in such cases
1.1 First Order Dehn Functions and their isoperimetric spectrum... 57
No full textBibliography [12] Martin R. Bridson. The geometry of the word problem. In Invitations to geometry and topology, volume 7 of Oxf. Grad. Texts Math., pages 29--91. Oxford Univ. Press, Oxford, 2002. [13] Martin R. Bridson and Andre Haefliger. Metric spaces of non-positive curvature, volume 319 of Grundlehren der Mathematischen Wissenschaften [Fundamental Principles of Mathematical Sciences]. Springer-Verlag, Berlin, 1999. [14] Kenneth S. Brown. Cohomology of groups, volume 87 of Graduate Texts in Mathematics. Springer-Verlag, New York, 1982. [15] Kai-Uwe Bux and Carlos Gonzalez. The Bestvina-Brady construction revisited: geometric computation of #-invariants for right-angled Artin groups. J. London Math. Soc. (2), 60(3):793--801, 1999. [16] Michael W. Davis. Nonpositive curvature and reflection groups. In Handbook of geometric topology, pages 373--422. North-Holland, Amsterdam, 2002. [17] David B. A. Epstein, James W. Cannon, Derek F. Holt, Silvio V. F. Levy, Michael S. Paterso
Antipsychotiques atypiques et dysfonction sexuelle: à propos de cinq cas associés à la rispéridone [Atypical antipsychotics and sexual dysfunction: five case-reports associated with risperidone]
No full textSexual and reproductive function side effects of atypical antipsychotics are frequent, often underestimated and badly tolerated. They contribute to the 50% rate of non-compliance reported for treated patients. Prevalence of sexual dysfunction associated with atypical antipsychotic treatment is high, varying from 18 to 96%. Atypical antipsychotics aren't, as a group, much better than typical antipsychotics, and among them, risperidone seems to induce more and quetiapine less sexual dysfunction. Most atypicals are non-selective, and have actions on multiple central and peripheral receptors. Among these, dopaminergic blockade could have a direct - altering motivation (desire) and reward (orgasm) - and an indirect negative influence on sexuality. Actually, the secondary hyperprolactinemia induced by some antipsychotics (typical antipsychotics, risperidone and amisulpiride), is dose-dependent, more pronounced for female patients, and may have a detrimental effect on sexual function. It also may result in hypogonadism, particularly for female patients. The long-term consequences of this secondary hypogonadism are subject to debate but potentially severe. Furthermore, the blocking and/or modulating actions of atypical antipsychotics on adrenaline, serotonine, histamine or acetyl-choline receptors all have the potential to contribute to secondary sexual problems. The pharmacological profile of risperidone, characterized by a strong affinity for D2 and alpha1 receptors, correlates with his tendency to significantly elevate prolactin levels and to produce ejaculatory disturbances. FIVE CASE-REPORTS: We describe five case-reports of sexual or hormonal disturbances associated with risperidone treatment: two cases of ejaculatory disturbance, one case of galactorrhea and two cases of amenorrhea. Alberto and David are two young male schizophrenic patients, treated with risperidone, and complaining of a total absence of ejaculation despite a preserved orgasm. Many recent case-reports describe the occurrence of retrograde ejaculation associated with risperidone but the exact prevalence is unknown. Retrograde ejaculation is thought to be related to the strong adrenolytic activity of risperidone. Alberto refused his medication because the ejaculatory dysfunction was unbearable for him. A switch to haloperidol depot was eventually well tolerated, without any sexual complaints. His case emphasizes the importance of sexual function for self-esteem and how this may amplify the intolerance to side-effects. David is on depot-risperidone in a setting of a legally forced treatment. Though he - reluctantly - accepts his medication, this side effect exacerbates his pre-existing delusions, strongly focused on sexual themes. His case illustrates how intolerance to sexual side-effects may be amplified by nature of delusions. Mireille is a 58 year old psychotic female patient, whose 2 mg risperidone treatment produced a unilateral galactorrhea. This sign became problematic because potentially visible at a time when Mireille started an activity in a sheltered occupation in town. Lowering dosage of antipsychotic allowed disappearance of the problem. Subjective responses to galactorrhea have been reported to be highly individual. Apart being a potentially visible side-effect, it may be misinterpreted as evidence of pregnancy or of a tumoral process. The cases of Ermina and Denise illustrate two contrasted situations in terms of subjective tolerability of reproductive function side-effects. Both were pre-menopausal patients with hyperprolactinemia secondary to risperidone treatment, resulting in amenorrhea. This was unbearable for Ermina. A switch to olanzapine allowed, one month later, the menses to resume. For Denise, on the other hand, the amenorrhea was a positive event, freeing her of unpleasant menses.
Amenorrhea occurs in about 30% of pre-menopausal women treated with risperidone. It is a consequence of hyperprolactinemia, which, although often silent, is not devoid of potential negative consequences (ie increased risk of osteoporosis or neoplasia, worsening of psychopathology) (34). When hyperprolactinemia is symptomatic, lowering of the dose of the antipsychotic, or switching to a prolactin-sparing agent (olanzapine, quetiapine, aripiprazole and clozapine) is recommended. Before this, women with amenorrhea secondary to antipsychotic-induced hyperprolactinemia should be advised that menses may resume. Especially after long-standing amenorrhea they may assume being menopaused, hence may believe birth control measures are no longer required. The prevalence of antipsychotic-induced sexual and reproductive function side-effects is high. Clinicians should be aware of them, because they are often badly tolerated, are associated with a low satisfaction and may therefore result in low adherence with treatment. This implies for the clinician to overtly discuss with the patient of his sexuality and the potential negative impact of antipsychotic treatment on it. The recognition of these problems allows the searching together for a solution.
The described cases indicate that solving the problem is often possible, provided that individual preferences and subjective impact are taken in account. Antipsychotic treatment is often prescribed for very long periods. A better knowledge of - and attention to - the associated side effects, particularly on the sexual and reproductive functions, is necessary in order to reduce some potentially negative long-term effects and to improve the adherence to treatment of our patients
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