Plasma as endothelial rescue in septic shock: A randomized, phase 2a pilot trial.

Background: Septic shock is associated with high morbidity and mortality, the endothelium plays an important role. Crystalloids is standard of care to maintain intravascular volume. Plasma is associated with improved endothelial integrity and restoration of the glycocalyx layer.

Mild induced hypothermia and coagulation and platelet function in patients with septic shock: Secondary outcome of a randomized trial.

Coagulation abnormalities and microthrombi contribute to septic shock, but the impact of body temperature regulation on coagulation in patients with sepsis is unknown. We tested the hypothesis that mild induced hypothermia reduces coagulation and platelet aggregation in patients with septic shock. Secondary analysis of randomized controlled trial.

Early Biomarker-Guided Prediction of Bloodstream Infection in Critically Ill Patients: C-Reactive Protein, Procalcitonin, and Leukocytes.

Background: Bloodstream infections (BSIs) often lead to critical illness and death. The primary aim of this study was to determine the diagnostic accuracy of the biomarkers C-reactive protein (CRP), procalcitonin (PCT), and leukocyte count for the diagnosis of BSI in critically ill patients.

Methods: This was a nested case-control study based on the Procalcitonin And Survival Study (PASS) trial (n = 1200).

ABO blood types and sepsis mortality.

Background: We aimed to determine if the ABO blood types carry different risks of 30-day mortality, acute kidney injury (AKI), and endothelial damage in critically ill patients with sepsis. This was a retrospective cohort study of three independent cohorts of critically ill patients from the United States and Scandinavia consisting of adults with septic shock. We compared the 30-day mortality across the blood types within each cohort and pooled the results in a meta-analysis.

Clinical impact of frailty among patients with severe vital sign derangement: An observational study.

Background: Frailty is associated with increased morbidity and mortality and frail patients may have reduced ability to tolerate severe vital sign derangement such as estimated by a high National Early Warning Score (NEWS). The clinical impact of frailty among patients that develop high NEWS during hospital admissions is sparsely studied. The aim of this study was to investigate the association between clinical frailty and admission to intensive care unit (ICU) among these patients.

Copper-catalyzed and additive free decarboxylative trifluoromethylation of aromatic and heteroaromatic iodides.

A copper-catalyzed decarboxylative trifluoromethylation of (hetero)aromatic iodides has been developed. Importantly, this new copper-catalyzed reaction operates in the absence of any ligands and metal additives. The protocol shows good functional group tolerance and is compatible with heteroaromatic systems.

COtab: Expedient and Safe Setup for Pd-Catalyzed Carbonylation Chemistry.

Bench-stable tablets (COtabs) have been developed for the rapid and safe production of carbon monoxide. The tablets can be made in less than 5 min without the use of a glovebox and only require a stock solution of an amine base to liberate a specific quantity of CO in a two-chamber system. The COtabs were tested in five different carbonylation reactions and provided similar yields compared to literature procedures.

[Psychodynamic psychotherapy of patients with schizophrenia spectrum psychosis].

This Danish review is a description of the relevance and importance of psychodynamic psychotherapy in the understanding and treatment of patients with schizophrenia spectrum psychosis. Previous research is included, and the results of a recently published, large-scale, prospective comparative study showing good results of adding psychodynamic psychotherapy to treatment as usual are summarised. Concrete examples are given to demonstrate the specificity of the dynamics and the supportive characteristics of the effective interventions in the relationship between patient and therapist.

Recent developments in carbonylation chemistry using [ C]CO, [ C]CO, and [ C]CO.

Carbon monoxide represents the most important C1-building block for the chemical industry, both for the production of bulk and fine chemicals, but also for synthetic fuels. Yet its toxicity and subsequently its cautious handling have limited its applications in medicinal chemistry research and in particular for the synthesis of pharmaceutically relevant molecules. Recent years have nevertheless witnessed a considerable headway on the development of carbon monoxide surrogates and reactor systems, which provide an ideal setting for performing carbonylation chemistry with stoichiometric and substoichiometric carbon monoxide.

generation of stoichiometric HCN and its application in the Pd-catalysed cyanation of aryl bromides: evidence for a transmetallation step between two oxidative addition Pd-complexes.

A protocol for the Pd-catalysed cyanation of aryl bromides using near stoichiometric and gaseous hydrogen cyanide is reported for the first time. A two-chamber reactor was adopted for the safe liberation of generated HCN in a closed environment, which proved highly efficient in the Ni-catalysed hydrocyanation as the test reaction. Subsequently, this setup was exploited for converting a range of aryl and heteroaryl bromides (28 examples) directly into the corresponding benzonitriles in high yields, without the need for cyanide salts.

Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial.

Background: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock.

Methods: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America.

Nucleophilic fluorination facilitated by a CsF-CaF packed bed reactor in continuous flow.

A simple to prepare, dry and handle packed bed reactor carrying CsF on CaF, towards nucleophilic fluorinations in continuous flow, is reported. The reactor also proved adaptable for silyl-ether deprotection and trifluoromethylations with Ruppert's reagent. The study includes reactor stability and scale-up investigations.

Organocatalyzed Decarboxylative Trichloromethylation of Morita-Baylis-Hillman Adducts in Batch and Continuous Flow.

Two protocols for the organocatalyzed decarboxylative trichloromethylation of Morita-Baylis-Hillman (MBH) substrates have been developed. Applying sodium trichloroacetate, as the trichloromethyl anion precursor, in combination with an organocatalyst and acetylated MBH-alcohols, the desired trichloromethylated products were obtained in good yields at room temperature in batch. The method was next extrapolated into a two-step continuous flow protocol, starting directly from the MBH alcohols, in combination with tributylamine acting both as base and catalyst.

Self-Rated Health as a Predictor of Death after Two Years: The Importance of Physical and Mental Wellbeing Postintensive Care.

Introduction: The objective of this study is, among half-year intensive care survivors, to determine whether self-assessment of health can predict two-year mortality.

Methods: The study is a prospective cohort study based on the Procalcitonin and Survival Study trial. Half-year survivors from this 1200-patient multicenter intensive care trial were sent the SF-36 questionnaire.

Cooperative redox activation for carbon dioxide conversion.

A longstanding challenge in production chemistry is the development of catalytic methods for the transformation of carbon dioxide into useful chemicals. Silane and borane promoted reductions can be fined-tuned to provide a number of C1-building blocks under mild conditions, but these approaches are limited because of the production of stoichiometric waste compounds. Here we report on the conversion of CO with diaryldisilanes, which through cooperative redox activation generate carbon monoxide and a diaryldisiloxane that actively participate in a palladium-catalysed carbonylative Hiyama-Denmark coupling for the synthesis of an array of pharmaceutically relevant diarylketones.

Synthesis and selective H-, C-, and N-labeling of the Tau protein binder THK-523.

A new synthetic route to the Tau binder, THK-523, is disclosed herein, which can easily be adapted to C- and D-isotope labeling. The synthesis proceeds via two key reactions, namely, a Pd-catalyzed carbonylative Sonogashira coupling and a reductive ring-closing step with hydrogen or deuterium gas. By carrying out these reactions in a 2-chamber reactor we reported previously, ex situ-generated carbon monoxide and hydrogen/deuterium can be applied in stoichiometric quantities, thereby facilitating isotope labeling of this Tau-binding compound.

The Development and Application of Two-Chamber Reactors and Carbon Monoxide Precursors for Safe Carbonylation Reactions.

Low molecular weight gases (e.g., carbon monoxide, hydrogen, and ethylene) represent vital building blocks for the construction of a wide array of organic molecules.

Palladium-Catalyzed Carbonylative α-Arylation of tert-Butyl Cyanoacetate with (Hetero)aryl Bromides.

A three-component coupling protocol has been developed for the generation of 3-oxo-3-(hetero)arylpropanenitriles via a carbonylative palladium-catalyzed α-arylation of tert-butyl 2-cyanoacetates with (hetero)aryl bromides followed by an acid-mediated decarboxylation step. Through the combination of only a stoichiometric loading of carbon monoxide and mild basic reaction conditions such as MgCl2 and dicyclohexylmethylamine for the deprotonation step, an excellent functional group tolerance was ensured for the methodology. Through the use of (13)C-labeled carbon monoxide generated from (13)COgen, the corresponding (13)C-isotopically labeled β-ketonitriles were obtained, and these products could subsequently be converted into cyanoalkynes and 3-cyanobenzofurans with site specific (13)C-isotope labeling.

Palladium-catalyzed carbonylative couplings of vinylogous enolates: application to statin structures.

The first Pd-catalyzed carbonylative couplings of aryl and vinyl halides with vinylogous enolates are reported generating products derived from C-C bond formation exclusively at the γ-position. Good results were obtained with a dienolate derivative of acetoacetate (1,3-dioxin-4-one). These transformations occurred at room temperature and importantly with only stoichiometric carbon monoxide in a two-chamber reactor.

Decarboxylative Reissert type trifluoro- and trichloro-methylation of (iso)quinoline derivatives in batch and continuous flow.

Two decarboxylative methods providing access to N-alkylated α-trihalomethylated heterocyclic amines have been developed. A batch protocol in which methyl trifluoroacetate acts both as a methylating reagent and subsequently as a nucleophilic trifluoromethyl anion precursor upon its addition to (iso)quinoline derivatives. Next, a telescoped continuous flow process, forming the corresponding α-trichloromethylated heterocyclic amines, utilizing a similar decarboxylation of trichloroacetic acid, was developed and taken to scale-up.

Access to 2-(Het)aryl and 2-Styryl Benzoxazoles via Palladium-Catalyzed Aminocarbonylation of Aryl and Vinyl Bromides.

A sequential one-pot procedure for the synthesis of either 2-(hetero)aryl or 2-styryl benzoxazoles is reported, starting from aryl and vinyl bromides, respectively, involving an initial aminocarbonylation with 2-aminophenols as nucleophiles followed by an acid mediated ring closure to generate the heterocycle. The methodology displays a broad substrate scope in moderate to excellent yields and can be exploited for (13)C-isotope labeling. Finally, this carbonylative protocol was applied to the synthesis of a potential Alzheimer's plaque binder and a selective PPAR antagonist including site-specific labeling with (13)C-carbon monoxide.