Mild and Low-Pressure fac-Ir(ppy)3 -Mediated Radical Aminocarbonylation of Unactivated Alkyl Iodides through Visible-Light Photoredox Catalysis.

A novel, mild and facile preparation of alkyl amides from unactivated alkyl iodides employing a fac-Ir(ppy)3 -catalyzed radical aminocarbonylation protocol has been developed. Using a two-chambered system, alkyl iodides, fac-Ir(ppy)3 , amines, reductants, and CO gas (released ex situ from Mo(CO)6 ), were combined and subjected to an initial radical reductive dehalogenation generating alkyl radicals, and a subsequent aminocarbonylation with amines affording a wide range of alkyl amides in moderate to excellent yields.

Ventromedial prefrontal cortex encodes emotional value.

The ventromedial prefrontal cortex (vmPFC) plays a critical role in processing appetitive stimuli. Recent investigations have shown that reward value signals in the vmPFC can be altered by emotion regulation processes; however, to what extent the processing of positive emotion relies on neural regions implicated in reward processing is unclear. Here, we investigated the effects of emotion regulation on the valuation of emotionally evocative images. Two independent experimental samples of human participants performed a cognitive reappraisal task while undergoing fMRI. The experience of positive emotions activated the vmPFC, whereas the regulation of positive emotions led to relative decreases in vmPFC activation. During the experience of positive emotions, vmPFC activation tracked participants' own subjective ratings of the valence of stimuli. Furthermore, vmPFC activation also tracked normative valence ratings of the stimuli when participants were asked to experience their emotions, but not when asked to regulate them. A separate analysis of the predictive power of vmPFC on behavior indicated that even after accounting for normative stimulus ratings and condition, increased signal in the vmPFC was associated with more positive valence ratings. These results suggest that the vmPFC encodes a domain-general value signal that tracks the value of not only external rewards, but also emotional stimuli.

Synthesis and labeling of a piperazine-based library of ¹¹C-labeled ligands for imaging of the vesicular acetylcholine transporter.

The cholinergic system is involved in neurodegenerative diseases, and visualization of cholinergic innervations with positron emission tomography (PET) would be a useful tool in understanding these diseases. A ligand for the vesicular acetylcholine transporter (VAChT), acknowledged as a marker for cholinergic neurons, could serve as such a PET tracer. The aim was to find a VAChT PET tracer using a library concept to create a small but diverse library of labeled compounds. From the same precursor and commercially available aryl iodides 6a-f, six potential VAChT PET tracers, [(11)C]-(±)5a-f, were (11)C-labeled by a palladium (0)-mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [(11)C]-(±)5a-f were obtained in radiochemical purities >95% with decay-corrected radiochemical yields and specific radioactivities between 4-25% and 124-597 GBq/µmol, respectively. Autoradiography studies were then conducted to assess the compounds binding selectivity for VAChT. Labeled compounds [(11)C]-(±)5d and [(11)C]-(±)5e showed specific binding but not enough to permit further preclinical studies. To conclude, a general method for a facile synthesis and labeling of a small piperazine-based library of potential PET tracers for imaging of VAChT was shown, and in upcoming work, another scaffold will be explored using this approach.

Fast-track care for pertrochanteric hip fracture: What impact on function and autonomy after discharge?

INTRODUCTION: Fast-track treatment of pertrochanteric fracture is being developed in traumatology. The present study hypothesis was that fast-track treatment of pertrochanteric fracture does not jeopardize patient autonomy. MATERIAL AND METHOD: A single-center prospective comparative observational study, conducted from 2014 to 2016 in the University Hospital of Angers, France, included patients presenting with isolated A1 or A2 pertrochanteric fracture on the AO classification, managed by intramedullary nailing and requiring transfer to Post-acute Recovery (PAR). The fast-track exposure group were transferred directly on postoperative day 1, while the non-exposure group received postoperative care in the surgery department before transfer to PAR. The main endpoint was difference in Parker score between admission and discharge. Secondary endpoints comprised type of walking aid at discharge and destination of discharge from PAR. RESULTS: 109 patients were initially included, with 54 patients (27 pairs) after matching. There was a significant difference in reduction in Parker score in favor of fast-track: -1.27 (95% CI: -2.27; -0.32) (p=0.012). There were no differences in amount or type of aid at discharge or discharge destination, although there was a trend toward greater discharge to the initial place of residence with fast-track. DISCUSSION: Orthopedics is heading to the fast-track. Previous studies reported shorter hospital stay, comparable survival and complications rates, and significant cost-saving. The present study addressed progression: fast-track patients showed significantly less loss of walking autonomy. CONCLUSION: Fast-track management of pertrochanteric fracture significantly reduced loss of walking autonomy, without significant impact on discharge destination or walking aids. LEVEL OF EVIDENCE: IIB, exposure/non-exposure cohort.

Fast track care for pertrochanteric hip fractures: How does it impact length of stay and complications?

INTRODUCTION: The medical and economic impact of treating pertrochanteric hip fractures is growing. We hypothesized that fast track surgery of pertrochanteric fractures would reduce the length of stay (LOS) without compromising the quality of care. MATERIALS AND METHODS: This was a prospective, observational, single-center cohort study conducted between 2014 and 2016 at the Angers Teaching Hospital in France. The enrolled patients had an isolated A1 or A2 proximal femur fracture (AO classification) that was treated surgically by intramedullary nailing and required post-acute rehabilitation (PAR) care. The exposed FT cohort was transferred into the PAR pathway on postoperative day 1. The non-exposed (control) group was provided with postoperative care in the surgery unit before transfer to PAR. The primary outcome was the total LOS (LOS in surgery+LOS in PAR). The secondary objectives were to determine the immediate survival, 1-year survival, postoperative complications and average cost of hospitalization. RESULTS: The study enrolled 109 patients initially, with 54 patients eligible for analysis after matching (27 pairs). The LOS in PAR and total LOS were 45.85±19.24 days and 48.56±19.36 days in the FT group (n=27), and 68.41±48.77 days and 77.85±48.80 days in the control group (n=27). Thus the LOS in PAR and total LOS were significantly lower in the FT group (p=0.022, p=0.003). There was no significant difference in the number of early deaths, complications, and 1-year survival without rehospitalization between cohorts. The mean cost per patient was lower in the FT cohort. DISCUSSION: The FT pathway has already been adopted in orthopedics. For patient who suffer a hip fracture, it contributes to reducing the total LOS without negatively impacting the quality of care. Early health economics studies support this care pathway. CONCLUSION: The FT approach to treating pertrochanteric fractures reduces total LOS without increasing mortality or complication rates. The 1-year survival is comparable. LEVEL OF EVIDENCE: IIB, Exposed/Unexposed cohort.

Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2-P1' Region.

Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1' 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with K i-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2-P1'. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1' 4-(trifluoromethyl)phenyl side chain.

Neural mechanisms of risky decision-making and reward response in adolescent onset cannabis use disorder.

BACKGROUND: Neural mechanisms of decision-making and reward response in adolescent cannabis use disorder (CUD) are underexplored. METHODS: Three groups of male adolescents were studied: CUD in full remission (n=15); controls with psychopathology without substance use disorder history (n=23); and healthy controls (n=18). We investigated neural processing of decision-making and reward under conditions of varying risk and uncertainty with the Decision-Reward Uncertainty Task while participants were scanned using functional magnetic resonance imaging. RESULTS: Abstinent adolescents with CUD compared to controls with psychopathology showed hyperactivation in one cluster that spanned left superior parietal lobule/left lateral occipital cortex/precuneus while making risky decisions that involved uncertainty, and hypoactivation in left orbitofrontal cortex to rewarded outcomes compared to no-reward after making risky decisions. Post hoc region of interest analyses revealed that both control groups significantly differed from the CUD group (but not from each other) during both the decision-making and reward outcome phase of the Decision-Reward Uncertainty Task. In the CUD group, orbitofrontal activations to reward significantly and negatively correlated with total number of individual drug classes the CUD patients experimented with prior to treatment. CUD duration significantly and negatively correlated with orbitofrontal activations to no-reward. CONCLUSIONS: The adolescent CUD group demonstrated distinctly different activation patterns during risky decision-making and reward processing (after risky decision-making) compared to both the controls with psychopathology and healthy control groups. These findings suggest that neural differences in risky decision-making and reward processes are present in adolescent addiction, persist after remission from first CUD treatment, and may contribute to vulnerability for adolescent addiction.

Structural integrity of the uncinate fasciculus and resting state functional connectivity of the ventral prefrontal cortex in late life depression.

BACKGROUND: Neuroimaging studies in late life depression have reported decreased structural integrity of white matter tracts in the prefrontal cortex. Functional studies have identified changes in functional connectivity among several key areas involved in mood regulation. Few studies have combined structural and functional imaging. In this study we sought to examine the relationship between the uncinate fasciculus, a key fronto-temporal tract and resting state functional connectivity between the ventral prefrontal cortex ((PFC) and limbic and striatal areas. METHODS: The sample consisted of 24 older patients remitted from unipolar major depression. Each participant had a magnetic resonance imaging brain scan using standardized protocols to obtain both diffusion tensor imaging and resting state functional connectivity data. Our statistical approach compared structural integrity of the uncinate fasciculus and functional connectivity data. RESULTS: We found positive correlations between left uncinate fasciculus (UF) fractional anisotropy (FA) and resting state functional connectivity (rsFC) between the left ventrolateral PFC and left amygdala and between the left ventrolateral PFC and the left hippocampus. In addition, we found a significant negative correlation between left ventromedial PFC-caudate rsFC and left UF FA. The right UF FA did not correlate with any of the seed region based connectivity. CONCLUSIONS: These results support the notion that resting state functional connectivity reflects structural integrity, since the ventral PFC is structurally connected to temporal regions by the UF. Future studies should include larger samples of patients and healthy comparison subjects in which both resting state and task-based functional connectivity are examined.

Behavioral risk elicits selective activation of the executive system in adolescents: clinical implications.

We investigated adolescent brain processing of decisions under conditions of varying risk, reward, and uncertainty. Adolescents (n = 31) preformed a Decision-Reward Uncertainty task that separates decision uncertainty into behavioral and reward risk, while they were scanned using functional magnetic resonance imaging. Behavioral risk trials involved uncertainty about which action to perform to earn a fixed monetary reward. In contrast, during reward risk the decision that might lead to a reward was known, but the likelihood of earning a reward was probabilistically determined. Behavioral risk trials evoked greater activation than the reward risk and no risk conditions in the anterior cingulate, medial frontal gyrus, bilateral frontal poles, bilateral inferior parietal lobe, precuneus, bilateral superior-middle frontal gyrus, inferior frontal gyrus, and insula. Our results were similar to those of young adults using the same task (Huettel, 2006) except that adolescents did not show significant activation in the posterior supramarginal gyrus during behavioral risk. During the behavioral risk condition regardless of reward outcome, overall mean frontal pole activity showed a positive correlation with age during the behavioral and reward risk conditions suggesting a developmental difference of this region of interest. Additionally, reward response to the Decision-Reward Uncertainty task in adolescents was similar to that seen in young adults (Huettel, 2006). Our data did not show a correlation between age and mean ventral striatum activity during the three conditions. While our results came from a healthy high functioning non-maltreated sample of adolescents, this method can be used to address types of risks and reward processing in children and adolescents with predisposing vulnerabilities and add to the paucity of imaging studies of risk and reward processing during adolescence.