Burden assessment of antimicrobial use and resistance in livestock in data-scarce contexts.

Misuse and overuse of antimicrobials in livestock production are identified as drivers for antimicrobial resistance (AMR). To improve decision-making concerning livestock health, it is important to understand the impact of AMR in livestock and aquaculture, within and beyond farm level, as well as expenditure on antimicrobial use (AMU). Such understanding provides grounds for systematic disease prioritisation and establishes a baseline for understanding the value of different strategies to mitigate animal health problems and for the monitoring and evaluation of the impact of those strategies. Yet limited data availability and quality surrounding AMU and AMR create barriers to furthering the knowledge of such impact. These data constraints are also more prevalent in contexts that lack the necessary resources to develop and maintain systematic and centralised data collection and collation systems. Even in regions with robust AMU and AMR monitoring systems in place, data limitations remain, such that the expenditure on antimicrobials and impacts of AMR remain unclear. Additionally, the current research funding strategies have been less focused on primary data collection, adding further barriers to filling the data void and reducing the global AMU/AMR knowledge gap. To work around the data scarcity and leverage previous and ongoing research efforts, it is vital to gain comprehensive knowledge of the people, projects and research consortia dedicated to the topic of AMU/AMR.

Les utilisations incorrecte et excessive d'agents antimicrobiens dans la production animale figurent parmi les facteurs connus de développement de résistances aux agents antimicrobiens (RAM). Pour améliorer la prise de décision relative à la santé des cheptels, il est essentiel de comprendre l'impact de la RAM chez les animaux d'élevage terrestres et aquatiques, aussi bien au niveau des élevages qu'au-delà, et de pouvoir quantifier les dépenses consacrées à l'utilisation d'agents antimicrobiens (UAM). Cette compréhension apporte les éléments d'information pour la priorisation systématique des maladies et établit un cadre de référence pour comprendre la valeur respective des différentes stratégies d'atténuation des problèmes de santé animale et pour assurer le suivi et l'évaluation d'impact de ces stratégies. Cependant, la disponibilité et la qualité limitées des données relatives à l'UAM et à la RAM font obstacle à une connaissance plus poussée de cet impact. Ces contraintes liées aux données sont plus répandues dans les contextes dépourvus des ressources nécessaires pour élaborer et entretenir des systèmes de collecte de données systématiques et centralisés. Même dans les régions où des systèmes robustes de suivi de l'UAM et de la RAM sont en place, le problème de l'insuffisance de données reste posé de sorte que la réalité des coûts induits par les agents antimicrobiens et l'impact de la RAM demeurent incertains. De plus, les stratégies actuelles de financement de la recherche ont été moins axées sur la collecte de données primaires, ce qui ajoute des obstacles supplémentaires pour l'obtention des données manquantes et compromet les efforts visant à réduire les écarts de connaissances sur l'UAM et la RAM à l'échelle mondiale. Afin de remédier à la pénurie de données et de mettre à profit les recherches antérieures et en cours, il est indispensable de savoir quels sont les acteurs, les projets et les consortiums de recherche qui travaillent sur l'UAM et la RAM.

El uso incorrecto y excesivo de antimicrobianos en la producción ganadera se considera un impulsor de la resistencia a los antimicrobianos (RAM). Para mejorar la toma de decisiones relativas a la sanidad del ganado, es importante comprender el impacto de la RAM en la ganadería y la acuicultura, a nivel de las granjas y más allá, así como el coste con el uso de antimicrobianos (UAM). Tal comprensión permite una priorización sistemática de enfermedades y establece una línea base para comprender el valor de las distintas estrategias destinadas a mitigar los problemas de sanidad animal, así como para supervisar y evaluar el impacto de esas estrategias. Sin embargo, la limitada disponibilidad y calidad de los datos en torno al UAM y a la RAM crean barreras que impiden ampliar la comprensión de dicho impacto. Estas limitaciones de datos también son más frecuentes en contextos que carecen de los recursos necesarios para desarrollar y mantener sistemas sistemáticos y centralizados de recopilación y cotejo de datos. Incluso en las regiones que cuentan con sistemas sólidos de seguimiento del UAM y la RAM, los datos siguen siendo limitados, de modo que los costes con antimicrobianos y las repercusiones de la resistencia a estos siguen sin estar claros. Además, las actuales estrategias de financiación de la investigación se han centrado menos en la recopilación de datos primarios, lo que añade más obstáculos a la hora de llenar el vacío de datos y reducir la brecha mundial de conocimientos sobre el UAM y la RAM. Para superar la escasez de datos y aprovechar las iniciativas de investigación previas y en curso, es fundamental adquirir un conocimiento detallado de las personas, los proyectos y los consorcios de investigación dedicados al tema del uso de antimicrobianos y la resistencia a estos.

Linking animal and human health burden: challenges and opportunities.

Quantifying the impact of poor animal health outcomes on human health represents a complex challenge. Using the disability-adjusted life year (DALY) metric as an endpoint, this article discusses how animal health outcomes can impact humans through three key processes: directly through zoonotic disease, indirectly via changes in yields and their impacts on nutrition and wealth, and finally, through indirect features associated with the agricultural industry, such as pharmaceuticals and climate change. For each process, the current state of the art and feasibility of global DALY-associated estimates are discussed. Existing frameworks for zoonoses already consider some key pathogens; ensuring completeness in the pathogens considered and consistency in methodological decisions is an important next step. For diet, risk factor frameworks enable a calculation of attributable DALYs; however, significant economic methodological developments are needed to ensure that local production changes are appropriately mapped to both local and global changes in dietary habits. Concerning wealth-related impacts, much work needs to be done on method development. Industry-related impacts require a focus on key research topics, such as attribution studies for animal antimicrobial resistance contributing to human outcomes. For climate change, a critical next step is identifying to what extent associated industry emissions are amenable to change should animal health outcomes improve. Allocation of finite funds to improve animal health must also consider the downstream impact on humans. Leveraging DALYs enables comparisons with other human health-related decisions and would represent a transformative way of approaching animal health decision-making should the obstacles in this article be addressed and new methods be developed.

La quantification de l'impact des problèmes de santé animale sur la santé humaine constitue un défi d'une grande complexité. En se servant de l'indicateur des années de vie ajustées sur l'incapacité (DALY) comme critère d'évaluation, les auteurs examinent trois processus essentiels illustrant l'impact que la situation zoosanitaire peut avoir sur la santé humaine : impact direct résultant des maladies zoonotiques, impact indirect résultant des mauvaises performances des animaux et de leurs conséquences sur la nutrition et la création de richesses, et enfin, effets indirects résultant de facteurs en lien avec le secteur agricole, par exemple l'utilisation de produits pharmaceutiques et le changement climatique. Pour chacun de ces processus, les auteurs font le point sur l'état actuel des connaissances et sur l'applicabilité des évaluations mondiales basées sur l'indicateur DALY. Les cadres existants relatifs aux zoonoses recouvrent déjà certains agents pathogènes majeurs ; la prochaine étape importante consistera à assurer une couverture complète des agents pathogènes et à veiller à la cohérence des décisions méthodologiques. S'agissant de l'alimentation, les cadres basés sur l'analyse des facteurs de risque permettent de calculer les DALY imputables à l'alimentation ; toutefois, d'importantes avancées méthodologiques sur les aspects économiques de cette corrélation seront nécessaires pour s'assurer que tout changement intervenant localement en matière de production animale est correctement mis en correspondance avec les modifications des habitudes alimentaires dans ce même contexte local mais aussi à l'échelle mondiale. S'agissant des impacts liés à la création de richesses, il reste beaucoup à faire dans le domaine méthodologique. La détermination des impacts liés aux filières d'élevage requiert des travaux axés sur des sujets précis, par exemple des études visant à déceler les sources de la résistance aux agents antimicrobiens qui contribuent à l'apparition d'antibiorésistances chez l'être humain. Enfin, pour ce qui concerne le changement climatique, une étape cruciale consistera à déterminer dans quelle mesure les émissions associées à l'élevage sont susceptibles de changer en cas d'amélioration de la situation zoosanitaire. Dans un contexte de ressources limitées, l'affectation de fonds à l'amélioration de la santé animale doit également prendre en compte l'impact en aval sur la santé humaine. L'utilisation de l'indicateur DALY permet des comparaisons avec d'autres décisions de santé publique et représenterait une approche transformative de la prise de décision en santé animale, dès lors que les obstacles mentionnés dans cet article sont surmontés et que de nouvelles méthodes sont mises au point.

Cuantificar el impacto de una mala sanidad animal en la salud humana es un desafío complejo. Utilizando el parámetro de años de vida ajustados en función de la discapacidad (AVAD o DALY) como criterio de valoración, en este artículo se examina cómo la sanidad animal puede repercutir en los seres humanos a través de tres procesos clave: directamente, a través de las zoonosis; indirectamente, a través de cambios en los rendimientos y sus repercusiones en la nutrición y la riqueza; y, por último, a través de factores indirectos asociados a la industria agropecuaria, como los fármacos y el cambio climático. Para cada uno de estos procesos, se examinan el estado actual y la viabilidad de estimar AVAD a escala mundial. Los marcos existentes para la zoonosis ya tienen en cuenta algunos patógenos claves; garantizar la exhaustividad de los patógenos considerados y la coherencia en las decisiones metodológicas es un próximo paso importante. En lo que respecta a la alimentación, aunque los marcos de factores de riesgo permiten calcular los AVAD atribuibles, se necesitan importantes avances metodológicos en el ámbito económico para asegurar que los cambios en la producción local se correspondan adecuadamente con los cambios locales y mundiales en los hábitos alimentarios. En cuanto a las repercusiones en la riqueza, queda mucho trabajo por hacer en el desarrollo de métodos. Para abordar las repercusiones relacionadas con la industria, es necesario centrarse en temas clave de investigación, como los estudios de atribución relativos al impacto en la salud humana de la resistencia a los antimicrobianos en los animales. En lo que se refiere al cambio climático, un próximo paso crucial es determinar en qué medida las emisiones de la industria podrían cambiar, en función de la mejora de los resultados en materia de sanidad animal. Al asignar fondos limitados para la mejora de la sanidad animal también se deben tener en cuenta las repercusiones correspondientes en los seres humanos. Utilizar los AVAD permite hacer comparaciones con otras decisiones importantes relacionadas con la salud humana y representaría una forma transformadora de enfocar la toma de decisiones en materia de sanidad animal, en caso de que se aborden los obstáculos presentados en ese artículo y se desarrollen nuevos métodos.

Discovery of N-X anomeric amides as electrophilic halogenation reagents.

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N-X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up).

Comprehensive portrait of stroke fellowship training in Brazil: A national survey study.

BACKGROUND AND OBJECTIVES: The field of vascular neurology has undergone significant advances over the last decade, and care has become more complex. However, vascular neurology training programs remain underdeveloped in many countries, despite stroke impact on health care. There are efforts towards building a nationally regulated curricula in some countries. Still, comprehensive planning and implementation of these programs may be needed on a global scale, especially in countries where stroke treatment is not fully implemented. We aim to comprehensively analyze vascular neurology trainees' profiles in Brazil to describe training program contents from trainees and program directors' perspectives. METHODS: We performed an observational, cross-sectional, web-based survey study to describe trainee and program-specific characteristics at vascular neurology fellowship training programs in Brazil. The study was conducted from June to September 2023 using a secure web-based survey sent to active fellows and program directors from all known vascular neurology fellowship programs in the country. All respondents were required to provide informed consent. RESULTS: We obtained a 100 % response rate of a total of 12 programs distributed in 7 federal states. Notably, 57 % of the 28 surveyed fellows were women, 60 % were aged 25-30, and 70 % self-identified as White. All fellows had prior neurology training, and 60 % engaged in the program just following residency. Exposure to various training experiences was favorable, except for simulation-based learning and telestroke training. Program directors perceived exposure to be sufficient for most components but similarly found deficiencies in telestroke and simulation-based learning. Scientific productivity was low, with about two-thirds of fellows having no publications or abstracts. Most fellows (92.6 %) reported performing non-fellowship medical activities to supplement their incomes. DISCUSSION: In conclusion, the number of vascular neurology training programs and trainees in Brazil is currently insufficient and exhibits an uneven geographic distribution. Despite this, the clinical training provided is extensive, and there is generally some funding available for fellows. These insights highlight the need for strategic improvements in Brazil's stroke education and could inform similar developments in other nations.

Differential photosynthetic plasticity of Amazonian tree species in response to light environments.

To investigate how and to what extent there are differences in the photosynthetic plasticity of trees in response to different light environments, six species from three successional groups (late successional, mid-successional, and pioneers) were exposed to three different light environments [deep shade - DS (5% full sunlight - FS), moderate shade - MS (35% FS) and full sunlight - FS]. Maximum net photosynthesis (Amax), leaf N partitioning, stomatal, mesophile, and biochemical limitations (SL, ML, and BL, respectively), carboxylation velocity (Vcmax), and electron transport (Jmax) rates, and the state of photosynthetic induction (IS) were evaluated. Higher values of Amax, Vcmax, and Jmax in FS were observed for pioneer species, which invested the largest amount of leaf N in Rubisco. The lower IS for pioneer species reveals its reduced ability to take advantage of sunflecks. In general, the main photosynthetic limitations are diffusive, with SL and ML having equal importance under FS, and ML decreasing along with irradiance. The leaf traits, which are more determinant of the photosynthetic process, respond independently in relation to the successional group, especially with low light availability. An effective partitioning of leaf N between photosynthetic and structural components played a crucial role in the acclimation process and determined the increase or decrease of photosynthesis in response to the light conditions.

Simplified Modular Access to Enantiopure 1,2-Aminoalcohols via Ni-Electrocatalytic Decarboxylative Arylation.

Chiral aminoalcohols are omnipresent in bioactive compounds. Conventional strategies to access this motif involve multiple-step reactions to install the requisite functionalities stereoselectively using conventional polar bond analysis. This study reveals that a simple chiral oxazolidine-based carboxylic acid can be readily transformed to substituted chiral aminoalcohols with high stereochemical control by Ni-electrocatalytic decarboxylative arylation. This general, robust, and scalable coupling can be used to synthesize a variety of medicinally important compounds, avoiding protecting and functional group manipulations, thereby dramatically simplifying their preparation.

Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology.

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion of cytokines IL-6, IL-1ß, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed.

Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology.

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.

Simplifying Access to Targeted Protein Degraders via Nickel Electrocatalytic Cross-Coupling.

C-C linked glutarimide-containing structures with direct utility in the preparation of cereblon-based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial α-bromoglutarimide through a unique Brønsted-acid assisted Ni-electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multi-step sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time-consuming aspect of reaction setup is weighing out the starting materials.

Nickel-Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers.

There is a pressing need, particularly in the field of drug discovery, for general methods that will enable direct coupling of tertiary alkyl fragments to (hetero)aryl halides. Herein a uniquely powerful and simple set of conditions for achieving this transformation with unparalleled generality and chemoselectivity is disclosed. This new protocol is placed in context with other recently reported methods, applied to simplify the routes of known bioactive building blocks molecules, and scaled up in both batch and flow. The role of pyridine additive as well as the mechanism of this reaction are interrogated through Cyclic Voltammetry studies, titration experiments, control reactions with Ni(0) and Ni(II)-complexes, and ligand optimization data. Those studies indicate that the formation of a BINAPNi(0) is minimized and the formation of an active pyridine-stabilized Ni(I) species is sustained during the reaction. Our preliminary mechanistic studies ruled out the involvement of Ni(0) species in this electrochemical cross-coupling, which is mediated by Ni(I) species via a Ni(I)-Ni(II)-Ni(III)-Ni(I) catalytic cycle.

Smokers who were seen by a doctor or other healthcare provider for any health concern in Brazil: what a missed opportunity to encourage smoking cessation!

OBJECTIVES: This study aimed to examine changes in the proportion of smokers who were advised to quit smoking by health professionals as part of routine consultations or interactions with their patients between 2008 and 2019. STUDY DESIGN: Serial cross-sectional study. METHODS: Data from two nationally representative cross-sectional surveys were used to examine changes over time in the proportions of smokers who were seen by a doctor or other healthcare provider for any health concern and were advised to quit smoking ('Advice_HP'). An additional dichotomous variable ('AdviceAccess_HP') was created and included smokers who were not seen by a doctor or other healthcare provider in the past 12 months in the 'no advice' received category. Crude and adjusted absolute differences in prevalence rates of smokers who were advised to quit smoking by health professionals as part of routine consultations or interactions with their patients between 2008 and 2019 were evaluated using a generalised linear model. RESULTS: The proportion of smokers who were seen by a health professional for any health concern increased from 58.8% in 2008 to 88.7% in 2019. The proportion of 'AdviceAccess_HP' increased from 33.6% in 2008 to 45.2% in 2019; however, the proportion of 'Advice_HP' decreased from 57.1% in 2008 to 51.0% in 2019. After adjustment for sociodemographic and smoking behaviour characteristics, differences remained virtually unchanged. In 2019, health professionals missed the opportunity to provide around 10 million smokers with brief advice to stop smoking. CONCLUSIONS: Monitoring the actions needed to encourage smoking cessation is critical for achieving the United Nations sustainable development goals. Primary healthcare workers should serve as role models for patients and provide brief advice that increases the likelihood of successfully quitting tobacco use, particularly in low- and middle-income countries.

Complex molecule synthesis by electrocatalytic decarboxylative cross-coupling.

Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes1. This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges2-4. Although this approach forms the basis of undergraduate curriculum in organic chemistry5 and strategic applications of most synthetic methods6, the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography3,4,7. Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed.

A Paradigm Shift in Catalysis: Electro- and Photomediated Nickel-Catalyzed Cross-Coupling Reactions.

ConspectusTransition-metal catalyzed cross-coupling reactions are fundamental reactions in organic chemistry, facilitating strategic bond formations for accessing natural products, organic materials, agrochemicals, and pharmaceuticals. Redox chemistry enables access to elusive cross-coupling mechanisms through single-electron processes as an alternative to classical two-electron strategies predominated by palladium catalysis. The seminal reports of Baran, MacMillan, Doyle, Molander, Weix, Lin, Fu, Reisman, and others in merging redox perturbation (photochemical, electrochemical, and purely chemical) with catalysis are pivotal to the current resurgence and mechanistic understanding of first-row transition metal-based catalysis. The hallmark of this redox platform is the systematic modulation of transition-metal oxidation states by a photoredox catalyst or at a heterogeneous electrode surface. Electrocatalysis and photocatalysis enhance transition metal catalysis' capacity for bond formation through electron- or energy-transfer processes that promote otherwise challenging elementary steps or elusive mechanisms. Cross-coupling conditions promoted by electrocatalysis and photocatalysis are mild, and bond formation proceeds with exceptionally high chemoselectivity and wide functional group tolerance. The interfacing of abundant first-row transition-metal catalysis with electrocatalysis and photocatalysis has brought about a paradigm shift in cross-coupling technology as practitioners are quickly applying these tools in synthesizing fine chemicals and pharmaceutically relevant motifs. In particular, the merger of Ni catalysis with electro- and photochemistry ushered in a new era for carbon-carbon and carbon-heteroatom cross-couplings with expanded generality compared to their thermally driven counterparts. Over the past decade, we have developed enabling photo- and electrochemical methods throughout our combined research experience in industry (BMS, AstraZeneca) and academia (Professor Baran, Scripps Research) in cross-disciplinary collaborative environments. In this Account, we will outline recent progress from our past and present laboratories in photo- and electrochemically mediated Ni-catalyzed cross-couplings. By highlighting these cross-coupling methodologies, we will also compare mechanistic features of both electro- and photochemical strategies for forging C(sp2)-C(sp3), C(sp3)-C(sp3), C-O, C-N, and C-S bonds. Through these side-by-side comparisons, we hope to demystify the subtle differences between the two complementary tools to enact redox control over transition metal catalysis. Finally, building off the collective experience of ourselves and the rest of the community, we propose a tactical user guide to photo- and electrochemically driven cross-coupling reactions to aid the practitioner in rapidly applying such tools in their synthetic designs.

Imidazophenothiazine-Based Thermally Activated Delayed Fluorescence Materials with Ultra-Long-Lived Excited States for Energy Transfer Photocatalysis.

Triplet-triplet energy transfer (EnT) is a powerful activation pathway in photocatalysis that unlocks new organic transformations and improves the sustainability of organic synthesis. Many current examples, however, still rely on platinum-group metal complexes as photosensitizers, with associated high costs and environmental impacts. Photosensitizers that exhibit thermally activated delayed fluorescence (TADF) are attractive fully organic alternatives in EnT photocatalysis. However, TADF photocatalysts incorporating heavy atoms remain rare, despite their utility in inducing efficient spin-orbit-coupling, intersystem-crossing, and consequently a high triplet population. Here, we describe the synthesis of imidazo-phenothiazine (IPTZ), a sulfur-containing heterocycle with a locked planar structure and a shallow LUMO level. This acceptor is used to prepare seven TADF-active photocatalysts with triplet energies up to 63.9 kcal mol-1. We show that sulfur incorporation improves spin-orbit coupling and increases triplet lifetimes up to 3.64 ms, while also allowing for tuning of photophysical properties via oxidation at the sulfur atom. These IPTZ materials are applied as photocatalysts in five seminal EnT reactions: [2 + 2] cycloaddition, the disulfide-ene reaction, and Ni-mediated C-O and C-N cross-coupling to afford etherification, esterification, and amination products, outcompeting the industry-standard TADF photocatalyst 2CzPN in four of the five studied scenarios. Detailed photophysical and theoretical studies are used to understand structure-activity relationships and to demonstrate the key role of the heavy atom effect in the design of TADF materials with superior photocatalytic performance.

Stereocontrolled Radical Thiophosphorylation.

The first practical, fully stereoselective P(V)-radical hydrophosphorylation is presented herein by using simple, limonene-derived reagent systems. A set of reagents have been developed that upon radical initiation react smoothly with olefins and other radical acceptors to generate P-chiral products, which can be further diversified (with conventional 2e- chemistry) to a range of underexplored bioisosteric building blocks. The reactions have a wide scope with excellent chemoselectivity, and the unexpected stereochemical outcome has been supported computationally and experimentally. Initial ADME studies are suggestive of the promising properties of this rarely explored chemical space.

Influence of Deep Sedation in Intensive Care Medicine Memories of Critical COVID-19 Survivors.

Introduction: Critical care survivors sustain a variety of sequelae after intensive care medicine (ICM) admission, and the Coronavirus Disease 2019 (COVID-19) pandemic has added further challenges. Specifically, ICM memories play a significant role, and delusional memories are associated with poor outcomes post-discharge including a delayed return to work and sleep problems. Deep sedation has been associated with a greater risk of perceiving delusional memories, bringing a move toward lighter sedation. However, there are limited reports on post-ICM memories in COVID-19, and influence of deep sedation has not been fully defined. Therefore, we aimed to evaluate ICM-memory recall in COVID-19 survivors and their relation with deep sedation. Materials/Methods: Adult COVID-19 ICM survivors admitted to a Portuguese University Hospital between October 2020 and April 2021 (second/third "waves") were evaluated 1 to 2 months post-discharge using "ICU Memory Tool," to assess real, emotional, and delusional memories. Results: The study included 132 patients (67% male; median age = 62 years, Acute Physiology and Chronic Health Evaluation [APACHE]-II = 15, Simplified Acute Physiology Score [SAPS]-II = 35, ICM stay = 9 days). Approximately 42% received deep sedation (median duration = 19 days). Most participants reported real (87%) and emotional (77%) recalls, with lesser delusional memories (36.4%). Deeply sedated patients reported significantly fewer real memories (78.6% vs 93.4%, P = .012) and increased delusional memories (60.7% vs 18.4%, P < .001), with no difference in emotional memories (75% vs 80.4%, P = .468). In multivariate analysis, deep sedation had a significant, independent association with delusional memories, increasing their likelihood by a factor of approximately 6 (OR = 6.274; 95% confidence interval = 1.165-33.773, P = .032), without influencing real (P = .545) or emotional (P = .133) memories. Conclusions: This study contributes to a better understanding of the potential adverse effects of deep sedation on ICM memories in critical COVID-19 survivors, indicating a significant, independent association with the incidence of delusional recalls. Although further studies are needed to support these findings, they suggest that strategies targeted to minimize sedation should be favored, aiming to improve long-term recovery.

Accuracy and economic evaluation of screening tests for undiagnosed COPD among hypertensive individuals in Brazil.

In Brazil, prevalence of diagnosed COPD among adults aged 40 years and over is 16% although over 70% of cases remain undiagnosed. Hypertension is common and well-recorded in primary care, and frequently co-exists with COPD because of common causes such as tobacco smoking, therefore we conducted a cross-sectional screening test accuracy study in nine Basic Health Units in Brazil, among hypertensive patients aged ≥40 years to identify the optimum screening test/combinations to detect undiagnosed COPD. We compared six index tests (four screening questionnaires, microspirometer and peak flow) against the reference test defined as those below the lower limit of normal (LLN-GLI) on quality diagnostic spirometry, with confirmed COPD at clinical review. Of 1162 participants, 6.8% (n = 79) had clinically confirmed COPD. Peak flow had a higher specificity but lower sensitivity than microspirometry (sensitivity 44.3% [95% CI 33.1, 55.9], specificity 95.5% [95% CI 94.1, 96.6]). SBQ performed well compared to the other questionnaires (sensitivity 75.9% [95% CI 65.0, 84.9], specificity 59.2% [95% CI 56.2, 62.1]). A strategy requiring both SBQ and peak flow to be positive yielded sensitivity of 39.2% (95% CI 28.4, 50.9) and specificity of 97.0% (95% CI 95.7, 97.9). The use of simple screening tests was feasible within the Brazilian primary care setting. The combination of SBQ and peak flow appeared most efficient, when considering performance of the test, cost and ease of use (costing £1690 (5554 R$) with 26.7 cases detected per 1,000 patients). However, the choice of screening tests depends on the clinical setting and availability of resources.ISRCTN registration number: 11377960.

Overcoming Limitations in Decarboxylative Arylation via Ag-Ni Electrocatalysis.

A useful protocol for achieving decarboxylative cross-coupling (DCC) of redox-active esters (RAE, isolated or generated in situ) and halo(hetero)arenes is reported. This pragmatically focused study employs a unique Ag-Ni electrocatalytic platform to overcome numerous limitations that have plagued this strategically powerful transformation. In its optimized form, coupling partners can be combined in a surprisingly simple way: open to the air, using technical-grade solvents, an inexpensive ligand and Ni source, and substoichiometric AgNO3, proceeding at room temperature with a simple commercial potentiostat. Most importantly, all of the results are placed into context by benchmarking with state-of-the-art methods. Applications are presented that simplify synthesis and rapidly enable access to challenging chemical space. Finally, adaptation to multiple scale regimes, ranging from parallel milligram-based synthesis to decagram recirculating flow is presented.

Evaluation of miRNAs regulation of BDNF and IGF1 genes in T2DM insulin resistance in experimental models: bioinformatics based approach.

microRNAs (miRNAs) are recognized as diabetes mellitus type 2 (T2DM) biomarkers useful for disease metabolism comprehension and have great potential as therapeutics targets. BDNF and IGF1 increased expression are highly involved in the benefits of insulin and glucose paths, however, they are down-regulated in insulin resistance conditions, while their expression increase is correlated to the improvement of glucose and insulin metabolism. Studies suggest the microRNA regulation of these genes in several different contexts, providing a novel investigation approach for comprehending T2DM metabolism and revealing potential therapeutic targets. In the present study, we investigate in different animal models (human, rat, and mouse) miRNAs that target BDNF and IGF1 in skeletal muscle tissue with T2DM physiological conditions. Bioinformatics tools and databases were used to miRNA prediction, molecular homology, experimental validation of interactions, expression in the studied physiological condition, and network interaction. The findings showed three miRNAs candidates for IGF1(miR-29a, miR-29b, and miR-29c) and one for BDNF (miR-206). The experimental evaluations and the search for the expression in skeletal muscle from T2DM subjects confirmed the predicted interaction between miRNA-mRNA for miR-29b and miR-206 through human, rat, and mouse models. This interaction was reaffirmed in multiple network analyses. In conclusion, our results show the regulation relationship between miR-29b and miR-206 with the investigated genes, in several tissues, suggesting an inhibition pattern. Nevertheless, these data show a large number of possible interaction physiological processes, for future biotechnological prospects.