Ligan-controlled α- and β-arylation of acyclic N-Boc amines

International audienceThe palladium‐catalyzed ligand‐controlled arylation of α‐zincated acyclic amines, obtained by directed α‐lithiation and transmetalation, is described. Whereas PtBu3 gave rise to α‐arylated Boc‐protected amines, more flexible N‐phenylazole‐based phosphine ligands induced major β‐arylation through migrative cross‐coupling.All manner of control: The arylation of α‐zincated acyclic Boc‐protected amines was selectively performed at the α‐ or β‐position in a ligand‐controlled manner. α‐Arylation occurs by direct reductive elimination of the α‐palladated intermediate whereas β‐arylation involves palladium migration along the alkyl chain. Boc=tert‐butoxycarbonyl

A 4 day-clinical microdialysis monitoring in a patient with traumatic brain injury (tbi) suggests a possible link between brain serotonin and cerebral energy metabolism

International audienceWhile the continuous microdialysis monitoring of cerebral biomarkers of energy metabolism is frequently used in neurocritical care, very few data on monoamine neurotransmitters, such as serotonin (5-HT), have been reported using clinical microdialysis. Consequently, taking the opportunity of a feasibility study for a project on TBI, we sought to determine 5-HT levels in the brain microdialysis samples obtained from a TBI patient, concomitantly with biomarkers of energy metabolism

Divergent Synthesis of Bioactive Dithiodiketopiperazine Natural Products Based on a Double C(sp 3

This article provides a detailed report of our efforts to synthesize the dithiodiketopiperazine (DTP) natural products (−)‐epicoccin G and (−)‐rostratin A using a double C(sp3)−H activation strategy. The strategy's viability was first established on a model system lacking the C8/C8’ alcohols. Then, an efficient stereoselective route including an organocatalytic epoxidation was secured to access a key bis‐triflate substrate. This bis‐triflate served as the functional handles for the key transformation of the synthesis: a double C(sp3)−H activation. The successful double activation opened access to a common intermediate for both natural products in high overall yield and on a multigram scale. After several unsuccessful attempts, this intermediate was efficiently converted to (−)‐epicoccin G and to the more challenging (−)‐rostratin A via suitable oxidation/reduction and protecting group sequences, and via a final sulfuration that occurred in good yield and high diastereoselectivity. These efforts culminated in the synthesis of (−)‐epicoccin G and (−)‐rostratin A in high overall yields (19.6 % over 14 steps and 12.7 % over 17 steps, respectively), with the latter being obtained on a 500 mg scale. Toxicity assessments of these natural products and several analogues (including the newly synthesized epicoccin K) in the leukemia cell line K562 confirmed the importance of the disulfide bridge for activity and identified dianhydrorostratin A as a 20x more potent analogue

Prognostic factors of long-term outcome in cases of severe traumatic brain injury

AbstractIntroductionThe purpose of this monocentric study was to assess the long-term outcome of a group of severe traumatic brain-injured patients and explore the prognostic values of some clinical and paraclinical parameters available at the initial stage.MethodologyThe patients included were victims of severe traumatic brain injuries in 2007 or 2008. A standardized assessment was performed for each patient including clinical, radiological, and electrophysiological data collected at the initial stage, The outcomes were assessed at least 2 years after injury. Depending on the patients’ availability and ability to communicate, the assessments included measures of dependency for activities of daily living (ADL), cognitive functions, behaviour, mood, and quality of life.ResultsEighteen patients were included, of whom ten were autonomous for ADL at the time of assessment. Memory complaints, attentional deficits, anxiety, and irritability were the main long-term impairments observed. A correlation analysis showed significant correlations between the dependency level (as rated by the Functional Independence Measure) and each of length of coma, length of the post-traumatic amnesia, and the N100 auditory evoked potentials.DiscussionThese results confirm the uniqueness of each patient regarding the long-term consequences of a traumatic brain injury and the multi-determined nature of each prognosis

Assessment of White Matter Injury and Outcome in Severe Brain Trauma: A Prospective Multicenter Cohort

BACKGROUND:: Existing methods to predict recovery after severe traumatic brain injury lack accuracy. The aim of this study is to determine the prognostic value of quantitative diffusion tensor imaging (DTI). METHODS:: In a multicenter study, the authors prospectively enrolled 105 patients who remained comatose at least 7 days after traumatic brain injury. Patients underwent brain magnetic resonance imaging, including DTI in 20 preselected white matter tracts. Patients were evaluated at 1 yr with a modified Glasgow Outcome Scale. A composite DTI score was constructed for outcome prognostication on this training database and then validated on an independent database (n = 38). DTI score was compared with the International Mission for Prognosis and Analysis of Clinical Trials Score. RESULTS:: Using the DTI score for prediction of unfavorable outcome on the training database, the area under the receiver operating characteristic curve was 0.84 (95% CI: 0.75-0.91). The DTI score had a sensitivity of 64% and a specificity of 95% for the prediction of unfavorable outcome. On the validation-independent database, the area under the receiver operating characteristic curve was 0.80 (95% CI: 0.54-0.94). On the training database, reclassification methods showed significant improvement of classification accuracy (P < 0.05) compared with the International Mission for Prognosis and Analysis of Clinical Trials score. Similar results were observed on the validation database. CONCLUSIONS:: White matter assessment with quantitative DTI increases the accuracy of long-term outcome prediction compared with the available clinical/radiographic prognostic score

Nurse-to-Nurse Familiarity and Mortality in the Critically Ill. A Multicenter Observational Study

RATIONALE: Nurse-to-nurse familiarity at work should strengthen the components of team working and enhance its efficiency. However, its impact on patient outcomes in critical care remains poorly investigated. OBJECTIVES: To explore the role of nurse-to-nurse familiarity on inpatient deaths during intensive care unit stay. METHODS: Retrospective observational study in eight adult academic intensive care units between 01/01/2011 and 31/12/2016. MEASUREMENTS AND MAIN RESULTS: Nurse-to-nurse familiarity was measured across day and night 12-hour daily shifts as the mean number of previous collaborations between each nursing team member during previous shifts within the given Intensive Care Unit (suboptimal if\textless50). Primary outcome was a shift with at least one inpatient death, excluding death of patients with a decision to forego life-sustaining therapy. A multiple modified Poisson regression was computed to identify the determinants of mortality per shift, taking into account intensive care unit, patients' characteristics, patient-to-nurse and patient-to-assistant nurse ratios, nurse experience length and workload. A total of 43,479 patients were admitted of whom 3,311 (8%) died. Adjusted model showed a lower risk of a shift with mortality when nurse-to-nurse familiarity increased in the shift (relative risk 0.90 [0.82-0.98] 95%confidence intervals per 10 shifts, p=0.012). Low nurse-to-nurse familiarity during the shift combined with suboptimal patient-to-nurse and assistant-nurse ratios (suboptimal if \textgreater2.5 and \textgreater4, respectively) were associated with increased risk of shift with mortality (1.84 [1.15-2.96], p\textless0.001). CONCLUSIONS: Shifts with low nurse-to-nurse familiarity were associated with an increased risk of patient deaths