Safety and quality of cystectomy and pelvic lymph node dissection after neoadjuvant durvalumab and cisplatin/gemcitabine.

OBJECTIVE: To report on the surgical safety and quality of pelvic lymph node dissection (PLND) in patients treated with radical cystectomy (RC) and PLND for muscle-invasive bladder cancer (MIBC) after neoadjuvant chemo-immunotherapy. PATIENTS AND METHODS: The Swiss Group for Clinical Cancer Research (SAKK) 06/17 was an open-label single-arm phase II trial including 61 cisplatin-fit patients with clinical stage (c)T2-T4a cN0-1 operable urothelial MIBC or upper urinary tract cancer. Patients received neoadjuvant cisplatin/gemcitabine and durvalumab followed by surgery. Prospective quality assessment of surgeries was performed via central review of intraoperative photographs. Postoperative complications were assessed using the Clavien-Dindo Classification. Data were analysed descriptively. RESULTS: A total of 50 patients received RC and PLND. All patients received neoadjuvant chemo-immunotherapy. The median (interquartile range) number of lymph nodes removed was 29 (23-38). No intraoperative complications were registered. Grade ≥III postoperative complications were reported in 12 patients (24%). Complete nodal dissection (100%) was performed at the level of the obturator fossa (bilaterally) and of the left external iliac region; in 49 patients (98%) at the internal iliac region and at the right external iliac region; in 39 (78%) and 38 (76%) patients at the right and left presacral level, respectively. CONCLUSION: This study supports the surgical safety of RC and PLND following neoadjuvant chemo-immunotherapy in patients with MIBC. The extent and completeness of protocol-defined PLND varies between patients, highlighting the need to communicate and monitor the surgical template.

Development of a certified reference material for the determination of polycyclic aromatic hydrocarbons (PAHs) in rubber toy.

Polycyclic aromatic hydrocarbons (PAHs) are a large group of priority organic pollutants, which contaminate environmental compartments, food, and consumer products as well. Due to their frequent occurrence associated with elevated levels of PAHs, plastic and rubber parts of consumer products and toys are particular sources of exposure. Although European maximum levels exist for eight carcinogenic PAHs in consumer products and toys according to REACH Regulation (EC) No. 1907/2006, certified reference materials (CRM) are still not available. To overcome this lack, the first CRM for the determination of PAHs in rubber toys (BAM-B001) was developed according to the requirements of ISO Guide 35. The whole process of CRM development including preparation, homogeneity and stability studies, and value assignment is presented. The assignment of the certified mass fractions was based upon in-house study at BAM using stable isotope dilution analysis (SIDA) gas chromatography mass spectrometry (GC-MS). The obtained values were confirmed by the results of two interlaboratory comparison (ILC) studies with more than 50 expert laboratories from Germany and China. The mass fractions of 14 PAHs including all REACH and GS mark regulated compounds were certified ranging between 0.2 and 15.4 mg/kg accompanied by expanded uncertainties (coverage factor k = 2). In addition, informative values were determined for 4 PAHs, mainly due to higher uncertainties and/or lack of ILC data for confirmation. BAM-B001 is intended for analytical quality control particularly based on the AfPS GS 2019:01 PAK method and contributes to improve the chemical safety of consumer products including toys.

A Deep Residual Neural Network for Image Reconstruction in Biomedical 3D Magnetic Induction Tomography.

In recent years, it has become increasingly popular to solve inverse problems of various tomography methods with deep learning techniques. Here, a deep residual neural network (ResNet) is introduced to reconstruct the conductivity distribution of a biomedical, voluminous body in magnetic induction tomography (MIT). MIT is a relatively new, contactless and noninvasive tomography method. However, the ill-conditioned inverse problem of MIT is challenging to solve, especially for voluminous bodies with conductivities in the range of biological tissue. The proposed ResNet can reconstruct up to two cuboid perturbation objects with conductivities of 0.0 and 1.0 S/m in the whole voluminous body, even in the difficult-to-detect centre. The dataset used for training and testing contained simulated signals of cuboid perturbation objects with randomised lengths and positions. Furthermore, special care went into avoiding the inverse crime while creating the dataset. The calculated metrics showed good results over the test dataset, with an average correlation coefficient of 0.87 and mean squared error of 0.001. Robustness was tested on three special test cases containing unknown shapes, conductivities and a real measurement that showed error results well within the margin of the metrics of the test dataset. This indicates that a good approximation of the inverse function in MIT for up to two perturbation objects was achieved and the inverse crime was avoided.

Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia.

Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1-90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63-80 Hz) in occipital regions and upregulated low frequency (5-28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.

Impairment in predictive processes during auditory mismatch negativity in ScZ: Evidence from event-related fields.

Patients with schizophrenia (ScZ) show pronounced dysfunctions in auditory perception but the underlying mechanisms as well as the localization of the deficit remain unclear. To examine these questions, the current study examined whether alterations in the neuromagnetic mismatch negativity (MMNm) in ScZ-patients could involve an impairment in sensory predictions in local sensory and higher auditory areas. Using a whole-head MEG-approach, we investigated the MMNm as well as P300m and N100m amplitudes during a hierarchical auditory novelty paradigm in 16 medicated ScZ-patients and 16 controls. In addition, responses to omitted sounds were investigated, allowing for a critical test of the predictive coding hypothesis. Source-localization was performed to identify the generators of the MMNm, omission responses as well as the P300m. Clinical symptoms were examined with the positive and negative syndrome scale. Event-related fields (ERFs) to standard sounds were intact in ScZ-patients. However, the ScZ-group showed a reduction in the amplitude of the MMNm during both local (within trials) and global (across trials) conditions as well as an absent P300m at the global level. Importantly, responses to sound omissions were reduced in ScZ-patients which overlapped both in latency and generators with the MMNm sources. Thus, our data suggest that auditory dysfunctions in ScZ involve impaired predictive processes that involve deficits in both automatic and conscious detection of auditory regularities. Hum Brain Mapp 38:5082-5093, 2017. © 2017 Wiley Periodicals, Inc.

Salt-free reducing reagent of bis(trimethylsilyl)cyclohexadiene mediates multielectron reduction of chloride complexes of W(VI) and W(IV).

We developed a salt-free reduction of WCl6 using 1-methyl-3,6-bis(trimethylsilyl)-1,4-cyclohexadiene (MBTCD) in toluene to give a low-valent trinulcear tungsten complex involving W(II) and W(III) centers, while in the presence of redox active ligands such as α-diketone and α-diimine the same reduction produced W(IV) complexes with the corresponding redox-active ligands, (α-diketone)WCl4 and (α-diimine)WCl4. A W(VI) complex with two α-diketone ligands, (α-diketone)2WCl2, was found to be synthetically equivalent to low-valent W(IV) species that trapped azopyridine to give (α-diketone)WCl2(azopyridine).

Stability and intrinsic dissolution of vacuum compression molded amorphous solid dispersions of efavirenz.

In this study, the stability and intrinsic dissolution of vacuum compression molded (VCM) amorphous solid dispersions (ASDs) of efavirenz (EFV) were investigated in relation to its solubility limits in seven polymers determined by the melting point depression (MPD) method. The extrapolated solubility limits of EFV at 22 °C ranged from 3 to 68% (w/w) with PVOH being the only polymer suggesting immiscibility with EFV according to both MPD and Hansen solubility parameters (HSPs). All ASDs with EFV loadings below or close to their calculated solubility limit did not show any signs of crystallization upon conditioning for 7 months at either 22 or 37 °C and 23 or 75% relative humidity. However, all ASDs with EFV loading above the solubility limit crystallized at high humidity, while the ASDs with cellulose derived carrier polymers proved kinetically stable at low humidity over 7 months. While the EFV intrinsic dissolution rates from the VCM ASDs were partly depending on the polymer dissolution rate, no correlation was observed between EFV matrix crystallization and its miscibility in the polymer. Altogether, the observations of the study underline the importance of combining preformulation miscibility determination and dissolution studies to rationally decide on both stability and viability of ASD formulations.

Retrospective Evaluation of a Single Surgeon's Learning Curve of Robot-Assisted Radical Cystectomy with Intracorporeal Urinary Diversion via Ileal Conduit.

Robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) is increasingly being performed instead of open surgery. A criticism of this technique is the long learning curve, but limited data are available on this topic. At our center, the transition from open radical cystectomy (ORC) to iRARC began in May 2017. A retrospective analysis was conducted on the initial 53 cases of robot-assisted cystectomy with intracorporeal urinary diversion via ileal conduit, which were performed by one single surgeon. The patients were divided into four consecutive groups according to the surgeon's increasing experience, and perioperative parameters were analyzed as a surrogate for the learning curve. Over the course of the learning curve, a decline in median operation time from 415 to 361 min (p = 0.02), blood loss from 400 to 200 mL (p = 0.01), and minor complications from 71% to 15% (p = 0.02) was observed. No significant difference in overall and major complications, length of hospital stay, and total lymph node yield was shown. During the initial period of the learning curve, only the less complex cases were operated on using robotic surgery, while the more challenging ones were handled through open surgery. After experience with 28 cases, no more cystectomies were performed through open surgery. This led to an increase in operation time and length of hospital stay, as well as a higher incidence of both minor and overall complications among cases 28-40. After 40 cases, a significant decrease in these parameters was observed again. Our analysis demonstrated that operation time, blood loss, and minor complications decrease with increasing surgical experience in iRARC, while suggesting that technically challenging cases should be operated on after experience with 40 robotic cystectomies.

Spectral and phase-coherence correlates of impaired auditory mismatch negativity (MMN) in schizophrenia: A MEG study.

BACKGROUND: Reduced auditory mismatch negativity (MMN) is robustly impaired in schizophrenia. However, mechanisms underlying dysfunctional MMN generation remain incompletely understood. This study aimed to examine the role of evoked spectral power and phase-coherence towards deviance detection and its impairments in schizophrenia. METHODS: Magnetoencephalography data was collected in 16 male schizophrenia patients and 16 male control participants during an auditory MMN paradigm. Analyses of event-related fields (ERF), spectral power and inter-trial phase-coherence (ITPC) focused on Heschl's gyrus, superior temporal gyrus, inferior/medial frontal gyrus and thalamus. RESULTS: MMNm ERF amplitudes were reduced in patients in temporal, frontal and subcortical regions, accompanied by decreased theta-band responses, as well as by a diminished gamma-band response in auditory cortex. At theta/alpha frequencies, ITPC to deviant tones was reduced in patients in frontal cortex and thalamus. Patients were also characterized by aberrant responses to standard tones as indexed by reduced theta-/alpha-band power and ITPC in temporal and frontal regions. Moreover, stimulus-specific adaptation was decreased at theta/alpha frequencies in left temporal regions, which correlated with reduced MMNm spectral power and ERF amplitude. Finally, phase-reset of alpha-oscillations after deviant tones in left thalamus was impaired, which correlated with impaired MMNm generation in auditory cortex. Importantly, both non-rhythmic and rhythmic components of spectral activity contributed to the MMNm response. CONCLUSIONS: Our data indicate that deficits in theta-/alpha- and gamma-band activity in cortical and subcortical regions as well as impaired spectral responses to standard sounds could constitute potential mechanisms for dysfunctional MMN generation in schizophrenia, providing a novel perspective towards MMN deficits in the disorder.

In vitro-in vivo relationship for amorphous solid dispersions using a double membrane dissolution-permeation setup.

The use of amorphous solid dispersions (ASDs) is one commonly applied formulation strategy to improve the oral bioavailability of poorly water-soluble drugs by overcoming dissolution rate and/or solubility limitations. While bioavailability enhancement of ASDs is well documented, it has often been a challenge to establish a predictive model describing in vitro-in vivo relationship (IVIVR). In this study, it is hypothesized that drug absorption might be overestimated by in vitro dissolution-permeation (D/P)-setups, when drug in suspension has the possibility of directly interacting with the permeation barrier. This is supported by the overprediction of drug absorption from neat crystalline efavirenz compared to four ASDs in a D/P-setup based on the parallel artificial membrane permeability assay (PAMPA). However, linear IVIVR (R2 = 0.97) is established in a modified D/P-setup in which the addition of a hydrophilic PVDF-filter acts as a physical boundary between the donor compartment and the PAMPA-membrane. Based on microscopic visualization, the improved predictability of the modified D/P-setup is due to the avoidance of direct dissolution of drug particles in the lipid components of the PAMPA-membrane. In general, this principle might aid in providing a more reliable evaluation of formulations of poorly water-soluble drugs before initiating animal models.

Synthesis, characterization, and lactide polymerization activity of group 4 metal complexes containing two bis(phenolate) ligands.

A series of group 4 metal complexes Zr-(1)(2), Zr-(2)(2), Zr-(3)(2), Zr-(4)(2), Zr-(5)(2), Hf-(1)(2), and Hf-(4)(2) containing two bridged bis(phenolate) ligands of the (OSSO)-type were prepared by the reaction of the corresponding bis(phenol) and group 4 metal precursor MX(4) (X = O(i)Pr, CH(2)Ph) and isolated as robust, colorless crystals. NMR spectra indicate D(2) symmetry, in agreement with the solid state structure determined by single crystal X-ray diffraction study of the complexes Zr-(1)(2), Hf-(1)(2), Zr-(3)(2), Zr-(4)(2), and Zr-(5)(2). The complexes with the 1,4-dithiabutanediyl bridged ligands exhibit a highly symmetric coordination around the metal center. The introduction of the rigid trans-1,2-cyclohexanediyl bridged ligands led to a distorted coordination around the metal center in Zr-(4)(2) and Zr-(5)(2) when the ortho substituent is tert-butyl and the para substituent is larger than methyl. The complexes Zr-(1)(2), Zr-(2)(2), Zr-(3)(2), Zr-(4)(2) as well as Hf-(1)(2) and Hf-(4)(2) initiated the ring-opening polymerization of meso-lactide at 100 °C to give heterotactic polylactide with pronounced heterotacticity (>70%) and varying polydispersity (1.05 < M(w)/M(n) < 1.61). As shown by kinetic studies, zirconium complex Zr-(1)(2) polymerized meso-lactide faster than the homologous hafnium complex Hf-(1)(2).

Downstream Processing of Itraconazole:HPMCAS Amorphous Solid Dispersion: From Hot-Melt Extrudate to Tablet Using a Quality by Design Approach.

The downstream processing of hot-melt extruded amorphous solid dispersions (ASDs) into tablets is challenging due to the low tabletability of milled ASDs. Typically, the extrudate strand is sized before milling, as the strand cannot be fed directly into the milling system. At the lab scale, the strand can be sized by hand-cutting before milling. For scaling up, pelletizers or chill roll and flaker systems can be used to break strands. Due to the different techniques used, differences in milling and tablet compaction are to be expected. We present a systematic study of the milling and tableting of an extruded ASD of itraconazole with hypromellose acetate succinate (HPMCAS) as a carrier polymer. The strand was sized using different techniques at the end of the extruder barrel (hand-cutting, pelletizer, or chill roll and flaker) before being milled at varying milling speeds with varying screen sizes. The effects of these variables (sizing technology, milling speed, and screen size) on the critical quality attributes (CQAs) of the milled ASD, such as yield, mean particle size (D50), tablet compaction characteristics, and tablet dissolution, were established using response surface methodology. It was found that the CQAs varied according to sizing technology, with chill roll flakes showing the highest percentage yield, the lowest D50, and the highest tabletability and dissolution rate for itraconazole. Pearson correlation coefficient tests indicated D50 as the most important CQA related to tabletability and dissolution. For certain milling conditions, the milling of hand-cut filaments results in similar particle size distributions (PSDs) to the milling of pellets or chill roll flakes.

Downstream processing of spray-dried ASD with hypromellose acetate succinate - Roller compaction and subsequent compression into high ASD load tablets.

Despite wide commercial application of hypromellose acetate succinate (HPMCAS) in spray-dried amorphous solid dispersion (ASD) drug products, little information is available in the references on downstream processing of spray-dried dispersions with HPMCAS. Poor flow and high dilution factor are a challenge in formulating spray-dried ASDs into tablets, leaving little space for other excipients facilitating binding and disintegration. Direct compression is not possible due to the poor powder flow of spray-dried ASDs. Moisture has to be avoided due to the plasticizing properties of water on the ASD, resulting in reduced stability of the amorphous state. Thus, dry granulation by roller compaction and subsequent tablet compression is the preferred downstream process. We report the investigation of downstream processing by roller compaction and tablet compression of a high load formulation with 75% of spray-dried amorphous solid dispersion (Nifedipine:HPMCAS 1:2). A head to head comparison of microcrystalline cellulose/croscarmellose (MCC/cl-NaCMC) as binder/disintegrant vs. MCC and low-substituted hydroxypropyl cellulose (L-HPC) as excipient for binding and disintegration showed improved re-workability of the formulation with MCC/L-HPC after roller compaction. Upon transfer to the rotary press, a 45% higher tensile strength of tablets is observed after dry granulation with MCC/L-HPC.

Perceptual Gains and Losses in Synesthesia and Schizophrenia.

Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in, eg, perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Perceptual variability may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients (N = 20), synesthetes (N = 20), and controls (N = 26). Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors-introduced during the hysteresis experiment-lowered thresholds but did not normalize perception. Our results imply that perceptual variability might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.

In Vitro Evaluation of Enteric-Coated HPMC Capsules-Effect of Formulation Factors on Product Performance.

A comparative study on different enteric-coated hard capsules was performed. The influence of different formulation factors like choice of enteric polymer, triethyl citrate (TEC) concentration (plasticizer), talc concentrations (anti-tacking agent), and different coating process parameters on the sealing performance of the capsule and the disintegration time were investigated. Furthermore, the influence of different disintegration test methods (with disc vs. without disc and 50 mM U.S. Pharmacopoeia (USP) buffer pH 6.8 vs. biopredictive 15 mM phosphate buffer pH 6.5) was evaluated. All formulations showed sufficient but not equivalent acid resistance when tested. Polymer type was the main factor influencing the capsule sealing and disintegration time. In addition, TEC and talc could affect the performance of the formulation. Regarding the choice of the disintegration test method, the presence of a disc had for the most part only limited influence on the results. The choice of disintegration buffer was found to be important in identifying differences between the formulations.

A MEG Study of Visual Repetition Priming in Schizophrenia: Evidence for Impaired High-Frequency Oscillations and Event-Related Fields in Thalamo-Occipital Cortices.

Background: Cognitive dysfunctions represent a core feature of schizophrenia and a predictor for clinical outcomes. One possible mechanism for cognitive impairments could involve an impairment in the experience-dependent modifications of cortical networks. Methods: To address this issue, we employed magnetoencephalography (MEG) during a visual priming paradigm in a sample of chronic patients with schizophrenia (n = 14), and in a group of healthy controls (n = 14). We obtained MEG-recordings during the presentation of visual stimuli that were presented three times either consecutively or with intervening stimuli. MEG-data were analyzed for event-related fields as well as spectral power in the 1-200 Hz range to examine repetition suppression and repetition enhancement. We defined regions of interest in occipital and thalamic regions and obtained virtual-channel data. Results: Behavioral priming did not differ between groups. However, patients with schizophrenia showed prominently reduced oscillatory response to novel stimuli in the gamma-frequency band as well as significantly reduced repetition suppression of gamma-band activity and reduced repetition enhancement of beta-band power in occipital cortex to both consecutive repetitions as well as repetitions with intervening stimuli. Moreover, schizophrenia patients were characterized by a significant deficit in suppression of the C1m component in occipital cortex and thalamus as well as of the late positive component (LPC) in occipital cortex. Conclusions: These data provide novel evidence for impaired repetition suppression in cortical and subcortical circuits in schizophrenia. Although behavioral priming was preserved, patients with schizophrenia showed deficits in repetition suppression as well as repetition enhancement in thalamic and occipital regions, suggesting that experience-dependent modification of neural circuits is impaired in the disorder.

MEG-measured visually induced gamma-band oscillations in chronic schizophrenia: Evidence for impaired generation of rhythmic activity in ventral stream regions.

BACKGROUND: Gamma-band oscillations are prominently impaired in schizophrenia, but the nature of the deficit and relationship to perceptual processes is unclear. METHODS: 16 patients with chronic schizophrenia (ScZ) and 16 age-matched healthy controls completed a visual paradigm while magnetoencephalographic (MEG) data was recorded. Participants had to detect randomly occurring stimulus acceleration while viewing a concentric moving grating. MEG data were analyzed for spectral power (1-100Hz) at sensor- and source-level to examine the brain regions involved in aberrant rhythmic activity, and for contribution of differences in baseline activity towards the generation of low- and high-frequency power. RESULTS: Our data show reduced gamma-band power at sensor level in schizophrenia patients during stimulus processing while alpha-band and baseline spectrum were intact. Differences in oscillatory activity correlated with reduced behavioral detection rates in the schizophrenia group and higher scores on the "Cognitive Factor" of the Positive and Negative Syndrome Scale. Source reconstruction revealed that extra-striate (fusiform/lingual gyrus), but not striate (cuneus), visual cortices contributed towards the reduced activity observed at sensor-level in ScZ patients. Importantly, differences in stimulus-related activity were not due to differences in baseline activity. CONCLUSIONS: Our findings highlight that MEG-measured high-frequency oscillations during visual processing can be robustly identified in ScZ. Our data further suggest impairments that involve dysfunctions in ventral stream processing and a failure to increase gamma-band activity in a task-context. Implications of these findings are discussed in the context of current theories of cortical-subcortical circuit dysfunctions and perceptual processing in ScZ.

Ketamine Dysregulates the Amplitude and Connectivity of High-Frequency Oscillations in Cortical-Subcortical Networks in Humans: Evidence From Resting-State Magnetoencephalography-Recordings.

Hypofunctioning of the N-methyl-D-aspartate receptor (NMDA-R) has been prominently implicated in the pathophysiology of schizophrenia (ScZ). The current study tested the effects of ketamine, a dissociative anesthetic and NMDA-R antagonist, on resting-state activity recorded with magnetoencephalography (MEG) in healthy volunteers. In a single-blind cross-over design, each participant (n = 12) received, on 2 different sessions, a subanesthetic dose of S-ketamine (0.006 mg/Kg) and saline injection. MEG-data were analyzed at sensor- and source-level in the beta (13-30 Hz) and gamma (30-90 Hz) frequency ranges. In addition, connectivity analysis at source-level was performed using transfer entropy (TE). Ketamine increased gamma-power while beta-band activity was decreased. Specifically, elevated 30-90 Hz activity was pronounced in subcortical (thalamus and hippocampus) and cortical (frontal and temporal cortex) regions, whilst reductions in beta-band power were localized to the precuneus, cerebellum, anterior cingulate, temporal and visual cortex. TE analysis demonstrated increased information transfer in a thalamo-cortical network after ketamine administration. The findings are consistent with the pronounced dysregulation of high-frequency oscillations following the inhibition of NMDA-R in animal models of ScZ as well as with evidence from electroencephalogram-data in ScZ-patients and increased functional connectivity during early illness stages. Moreover, our data highlight the potential contribution of thalamo-cortical connectivity patterns towards ketamine-induced neuronal dysregulation, which may be relevant for the understanding of ScZ as a disorder of disinhibition of neural circuits.

Effects of gaze direction, head orientation and valence of facial expression on amygdala activity.

There is increasing evidence for a role of the amygdala in processing gaze direction and emotional relevance of faces. In this event-related functional magnetic resonance study we investigated amygdala responses while we orthogonally manipulated head direction, gaze direction and facial expression (angry, happy and neutral). This allowed us to investigate effects of stimulus ambiguity, low-level factors and non-emotional factors on amygdala activation. Averted vs direct gaze induced increased activation in the right dorsal amygdala regardless of facial expression and head orientation. Furthermore, valence effects were found in the ventral amygdala and strongly dependent on head orientation. We observed enhanced activation to angry and neutral vs happy faces for observer-directed faces in the left ventral amygdala while the averted head condition reversed this pattern resulting in increased activation to happy as compared to angry and neutral faces. These results suggest that gaze direction drives specifically dorsal amygdala activation regardless of facial expression, low-level perceptual factors or stimulus ambiguity. The role of the amygdala is thus not restricted to the detection of potential threat, but has a more general role in attention processes. Furthermore, valence effects are associated with activation of the ventral amygdala and strongly influenced by non-emotional factors.

Structurally well-defined group 4 metal complexes as initiators for the ring-opening polymerization of lactide monomers.

Polylactide (PLA) is an attractive polymeric material due to its origin from annually renewable resources and its biodegradability. The ring-opening polymerization (ROP) of lactide initiated by Lewis acidic and oxophilic metal-based catalysts constitutes the method of choice to access PLA in a controlled and stereoselective manner. The design and synthesis of ligand-supported metal complexes to act as effective ROP initiators of lactide monomers have been the subject of numerous investigations over the past decades. In view of their oxophilic nature, well-defined group 4 metal complexes supported by polydentate supporting ligands have appeared as active initiators for lactide ROP. This perspective summarizes various classes of structurally well-defined group 4 metal initiators developed for lactide ROP. It also provides observed trends regarding their catalytic performance. Whenever appropriate and possible, catalyst structure-ROP performance (i.e. activity, control and stereoselectivity) relationships are rationalized.