Fully automated flow protocol for C(sp3)–C(sp3) bond formation from tertiary amides and alkyl halides

Herein, we present a novel C(sp3)–C(sp3) bond-forming protocol via the reductive coupling of abundant tertiary amides with organozinc reagents prepared in situ from their corresponding alkyl halides. Using a multistep fully automated flow protocol, this reaction could be used for both library synthesis and target molecule synthesis on the gram-scale starting from bench-stable reagents. Additionally, excellent chemoselectivity and functional group tolerance make it ideal for late-stage diversification of druglike molecules

Current clinical spectrum of common variable immunodeficiency in Spain: The multicentric nationwide GTEM-SEMI-CVID registry

Common variable immunodeficiency (CVID) constitutes a heterogenic group of primary immunodeficiency disorders with a wide-ranging clinical spectrum. CVID-associated non-infectious morbidity constitutes a major challenge requiring a full understanding of its pathophysiology and its clinical importance and global variability, especially considering the broad clinical, genetic, and regional heterogeneity of CVID disorders. This work aimed to develop a nationwide, multicenter, retrospective study over a 3-year period describing epidemiological, clinical, laboratory, therapeutic, and prognostic features of 250 CVID patients in Spain. The mean diagnostic delay was around 10 years and most patients initially presented with infectious complications followed by non-infectious immune disorders. However, infectious diseases were not the main cause of morbimortality. Non-infectious lung disease was extraordinarily frequent in our registry affecting approximately 60% of the patients. More than one-third of the patients in our cohort showed lymphadenopathies and splenomegaly in their follow-up, and more than 33% presented immune cytopenias, especially Evans' syndrome. Gastrointestinal disease was observed in more than 40% of the patients. Among biopsied organs in our cohort, benign lymphoproliferation was the principal histopathological alteration. Reaching 15.26%, the global prevalence of cancer in our registry was one of the highest reported to date, with non-Hodgkin B lymphoma being the most frequent. These data emphasize the importance of basic and translational research delving into the pathophysiological pathways involved in immune dysregulation and diffuse lymphocytic infiltration. This would reveal new tailored strategies to reduce immune complications, and the associated healthcare burden, and ensure a better quality of life for CVID patients

Trends in the epidemiology of catheter-related bloodstream infections; towards a paradigm shift, Spain, 2007 to 2019

Altres ajuts: Departament de Salut. Generalitat de Catalunya ("Pla estratègic de recerca i innovació en salut (PERIS) 2019-2021"); Ministerio de Asuntos Económicos y Transformación Digital; Red Española de Investigación en Patología Infecciosa (REIPI).Background: Catheter-related bloodstream infections (CRBSI) are frequent healthcare-associated infections and an important cause of death. Aim: To analyse changes in CRBSI epidemiology observed by the Infection Control Catalan Programme (VINCat). Methods: A cohort study including all hospital-acquired CRBSI episodes diagnosed at 55 hospitals (2007-2019) in Catalonia, Spain, was prospectively conducted. CRBSI incidence rates were adjusted per 1,000patientdays. To assess the CRBSI rate trend per year, negative binomial models were used, with the number of events as the dependent variable, and the year as the main independent variable. From each model, the annual rate of CRBSI diagnosed per 1,000patientdays and the incidence rate ratio (IRR) with its 95% confidence intervals (CI) were reported. Results: During the study, 9,290 CRBSI episodes were diagnosed (mean annual incidence rate:0.20episodes/1,000patientdays). Patients' median age was 64.1years; 36.6% (3,403/9,290) were female. In total, 73.7% (n=6,845) of CRBSI occurred in non-intensive care unit (ICU) wards, 62.7% (n=5,822) were related to central venous catheter (CVC), 24.1% (n=2,236) to peripheral venous catheters (PVC) and 13.3% (n=1,232) to peripherally-inserted central venous catheters (PICVC). Incidence rate fell over the study period (IRR:0.94;95%CI:0.93-0.96), especially in the ICU (IRR:0.88;95%CI:0.87-0.89). As a whole, while episodes of CVC CRBSI fell significantly (IRR:0.88;95%CI:0.87-0.91), peripherally-inserted catheter CRBSI (PVC and PICVC) rose, especially in medical wards (IRR PICVC:1.08;95%CI:1.05-1.11; IRR PVC: 1.03; 95% 1.00-1.05). Conclusions: Over the study, CRBSIs associated with CVC and diagnosed in ICUs decreased while episodes in conventional wards involving peripherally-inserted catheters increased. Hospitals should implement preventive measures in conventional wards

The Caldera. No. 16

Cuando hablamos de paz, generalmente asociamos el vocablo con adjetivos, momentos, experiencias que nos produzcan un estado de relajación, de calma, de quietud; es decir, la zozobra, la inquietud e incluso, el debate, serían antónimos de paz: Este año nuestra querida Institución Educativa se ha propuesto marcar la pauta en este tema; por tal razón, se ha implementado, dentro de los diferentes espacios pedagógicos que disfrutan nuestros educandos, la “CÁTEDRA DE LA PAZ”, como una alternativa viable, que les permita a nuestros estudiantes, desde los primeros años de preescolar, hasta los últimos de bachillerato, lograr acercamientos a distintas situaciones cotidianas, que hacen parte de nuestra condición humana y permanente de seres comunicativos y sociales; por tanto, las aulas de clase, los distintos escenarios en los que nos movemos deben convertirse en espacios en los que se deben llegar a establecer acuerdos que nos permitan ambientes, de estudio, de trabajo, de recreación, aún más agradables y cordiales.Biografías: Steve Jobs, John Lennon; Por: Javier Felipe Molina Salazar e Isabella Polo García…04 II Concurso Intercolegiado de Oratoria “Literatura y paz” “El arte de leer”; Por: Mariana Alejandra Galvis M. …08 Deporte en el Instituto Caldas Instituto Caldas: Subcampeón Departamental de Baloncesto…10 El pequeño gran ajedrecista; Por: Sebastián Felipe Blanco…11 Escritores memorables, Kafka; Por: Daniel José Galvis Jaimes…12 Proyectos Pedagógicos (Preescolar); Por: Slendy Pinzón González…15 Talentos caldistas…16 Reloj Solar 2014…20 Expresiones caldistas…22 Galería de Imágenes…29When we speak of peace, we generally associate the word with adjectives, moments, experiences that produce us a state of relaxation, calm, and stillness; that is to say, anxiety, concern and even debate, would be antonyms for peace: This year our beloved Educational Institution has proposed to set the standard on this issue; For this reason, the "CHAIR OF PEACE" has been implemented within the different pedagogical spaces that our students enjoy, as a viable alternative that allows our students, from the first years of preschool, to the last years of high school, achieve approaches to different daily situations, which are part of our human and permanent condition of communicative and social beings; therefore, the classrooms, the different settings in which we move, must become spaces in which agreements must be reached that allow us environments, study, work, recreation, even more pleasant and cordial

Automated One-pot Library Synthesis with Aldehydes as Radical Precursors

The increased demand for the synthesis of enriched hybridized Csp3 motifs and the urgency of discovering new drug molecules require the development of more efficient technologies and synthetic tools to accelerate drug discovery processes. Herein, we report a fully automated strategy for the addition of Csp3 enriched building blocks onto olefins via Giese addition to forge Csp3-Csp3 bonds. The developed fully automated protocol allowed the conversion of aldehydes (non-redox-active species) in-situ to electroactive imidazolidines and to employ them as precursors of C-centered radicals under photoredox catalyzed conditions for the synthesis of enriched fraction sp3 (Fsp3) character building blocks and bioactive compound libraries

Assembly line library synthesis in flow: A multistep and multivectorial approach

In drug discovery, traditional automated library synthesis has typically involved single-step synthetic procedures targeting a single vector of interest. However, achieving greater structural diversity requires exploring multistep and multivectorial approaches. These methodologies enable the preparation of compounds with varying structures in a single experiment. Here, we present a novel method for multistep library synthesis in continuous flow. This approach offers unique opportunities, such as exploring linkers between two defined vectors or rapidly mapping synergistic structure-activity relationship (SAR) by concurrently exploring multiple vectors. Our method incorporates up to eight different synthetic methodologies, including established chemistries, metal-catalysed transformations, and modern metallaphotoredox couplings. This broad range of synthetic methodologies ensures a high level of diversity in the compounds generated, providing a powerful tool to accelerate exploration of the chemical space in drug discovery programs

Late-Stage C(sp2)–C(sp3) Diversification via Nickel Oxidative Addition Complexes

Nickel catalysis has emerged as a powerful technique for streamlining the access to exceedingly complex organic molecules from simple precursors. However, nickel-catalyzed cross-couplings with advanced synthetic intermediates still remain a considerable challenge. Herein, we describe a technique based on the utilization of nickel oxidative addition complexes (Ni-OAC) of drug-like molecules as a platform to rapidly and reliably generate lead candidates with enhanced C(sp3) fraction. The potential of Ni-OACs to access new chemical space has been assessed in three different C(sp2)–C(sp3) bond-forming events without recourse to specialized ligand backbones. Reactions with Ni-OACs proceed under exceptionally mild conditions and with improved generality when compared to nickel-catalyzed reactions. The development of an automated process for forging C(sp2)–C(sp3) architectures further illustrates the robustness and generality of Ni-OACs, thus offering a new gateway to expedite the design-make-test-analyze (DMTA) cycle in drug discover

End-to-End Automated Synthesis of C(sp³)‑Enriched Drug-like Molecules <i>via</i> Negishi Coupling and Novel, Automated Liquid–Liquid Extraction

Herein, we report an end-to-end process including synthesis, work-up, purification, and post-purification with minimal human intervention using Negishi coupling as a key transformation to increase Fsp3 in bioactive molecules. The main advantages of this protocol are twofold. First, the automated sequential generation of organozinc reagents from readily available alkyl halides offers a large diversity of alkyl groups to functionalize (hetero)aryl halide scaffolds via Pd-catalyzed Negishi coupling in continuous flow. Second, a fully automated liquid–liquid extraction has been developed and successfully applied for unattended operations. The workflow was completed with mass-triggered preparative high-performance liquid chromatography HPLC, providing an efficient production line of compounds with enriched sp3 character and better drug-like properties. The modular nature allows a smooth adaptation to a wide variety of synthetic methods and protocols and makes it applicable to any medchem laboratory