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Conducting organic materials, such as doped organic polymers1, molecular conductors2,3 and emerging coordination polymers4, underpin technologies ranging from displays to flexible electronics5. Realizing high electrical conductivity in traditionally insulating organic materials necessitates tuning their electronic structure through chemical doping6. Furthermore, even organic materials that are intrinsically conductive, such as single-component molecular conductors7,8, require crystallinity for metallic behaviour. However, conducting polymers are often amorphous to aid durability and processability9. Using molecular design to produce high conductivity in undoped amorphous materials would enable tunable and robust conductivity in many applications10, but there are no intrinsically conducting organic materials that maintain high conductivity when disordered. Here we report an amorphous coordination polymer, Ni tetrathiafulvalene tetrathiolate, which displays markedly high electronic conductivity (up to 1,200 S cm-1) and intrinsic glassy-metallic behaviour. Theory shows that these properties are enabled by molecular overlap that is robust to structural perturbations. This unusual set of features results in high conductivity that is stable to humid air for weeks, pH 0-14 and temperatures up to 140 °C. These findings demonstrate that molecular design can enable metallic conductivity even in heavily disordered materials, raising fundamental questions about how metallic transport can exist without periodic structure and indicating exciting new applications for these materials.
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Powassan virus is an emerging tick-borne virus of concern for public health, but very little is known about its transmission patterns and ecology. Here, we expanded the genomic dataset by sequencing 279 Powassan viruses isolated from Ixodes scapularis ticks from the northeastern United States. Our phylogeographic reconstructions revealed that Powassan virus lineage II was likely introduced or emerged from a relict population in the Northeast between 1940 and 1975. Sequences strongly clustered by sampling location, suggesting a highly focal geographical distribution. Our analyses further indicated that Powassan virus lineage II emerged in the northeastern United States mostly following a south-to-north pattern, with a weighted lineage dispersal velocity of ~3 km/y. Since the emergence in the Northeast, we found an overall increase in the effective population size of Powassan virus lineage II, but with growth stagnating during recent years. The cascading effect of population expansion of white-tailed deer and I. scapularis populations likely facilitated the emergence of Powassan virus in the northeastern United States.
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Cervos , Vírus da Encefalite Transmitidos por Carrapatos , Ixodes , Animais , New EnglandRESUMO
West Nile virus (WNV) is the most common arthropod-borne flavivirus in the United States; however, the vector ligand(s) that participate in infection are not known. We now show that an Aedes aegypti C-type lectin, mosGCTL-1, is induced by WNV, interacts with WNV in a calcium-dependent manner, and facilitates infection in vivo and in vitro. A mosquito homolog of human CD45 in A. aegypti, designated mosPTP-1, recruits mosGCTL-1 to enable viral attachment to cells and to enhance viral entry. In vivo experiments show that mosGCTL-1 and mosPTP-1 function as part of the same pathway and are critical for WNV infection of mosquitoes. A similar phenomenon was also observed in Culex quinquefasciatus, a natural vector of WNV, further demonstrating that these genes participate in WNV infection. During the mosquito blood-feeding process, WNV infection was blocked in vivo with mosGCTL-1 antibodies. A molecular understanding of flaviviral-arthropod interactions may lead to strategies to control viral dissemination in nature.
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Aedes/virologia , Culex/virologia , Proteínas de Insetos/metabolismo , Lectinas Tipo C/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Internalização do Vírus , Vírus do Nilo Ocidental/fisiologia , Animais , Humanos , Antígenos Comuns de Leucócito/químicaRESUMO
High-valent cobalt oxides play a pivotal role in alternative energy technology as catalysts for water splitting and as cathodes in lithium-ion batteries. Despite this importance, the properties governing the stability of high-valent cobalt oxides and specifically possible oxygen evolution pathways are not clear. One root of this limited understanding is the scarcity of high-valent Co(IV)-containing model complexes; there are no reports of stable, well-defined complexes with multiple Co(IV) centers. Here, an oxidatively robust fluorinated ligand scaffold enables the isolation and crystallographic characterization of a Co(IV)2-bis-µ-oxo complex. This complex is remarkably stable, in stark contrast with previously reported Co(IV)2 species that are highly reactive, which demonstrates that oxy-Co(IV)2 species are not necessarily unstable with respect to oxygen evolution. This example underscores a new design strategy for highly oxidizing transition-metal fragments and provides detailed data on a previously inaccessible chemical unit of relevance to O-O bond formation and oxygen evolution.
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Alkyne semihydrogenation is a broadly important transformation in chemical synthesis. Here, we introduce an electrochemical method for the selective semihydrogenation of terminal alkynes using a dihydrazonopyrrole Ni complex capable of storing an H2 equivalent (2H+ + 2e-) on the ligand backbone. This method is chemoselective for the semihydrogenation of terminal alkynes over internal alkynes or alkenes. Mechanistic studies reveal that the transformation is concerted and Z-selective. Calculations support a ligand-based hydrogen-atom transfer pathway instead of a hydride mechanism, which is commonly invoked for transition metal hydrogenation catalysts. The synthesis of the proposed intermediates demonstrates that the catalytic mechanism proceeds through a reduced formal Ni(I) species. The high yields for terminal alkene products without over-reduction or oligomerization are among the best reported for any homogeneous catalyst. Furthermore, the metal-ligand cooperative hydrogen transfer enabled with this system directs the efficient flow of H atom equivalents toward alkyne reduction rather than hydrogen evolution, providing a blueprint for applying similar strategies toward a wide range of electroreductive transformations.
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Despite the broad importance of hydrogen peroxide (H2O2) in oxidative transformations, there are comparatively few viable routes for its production. The majority of commercial H2O2 is currently produced by the stepwise reduction of dioxygen (O2) via the anthraquinone process, but direct electrochemical formation from water (H2O) would have several advantagesânamely, avoiding flammable gases or stepwise separations. However, the selective oxidation of H2O to form H2O2 over the thermodynamically favored product of O2 is a difficult synthetic challenge. Here, we present a molecular H2O oxidation system with excellent selectivity for H2O2 that functions both stoichiometrically and catalytically. We observe high efficiency for electrocatalytic H2O2 production at low overpotential with no O2 observed under any conditions. Mechanistic studies with both calculations and kinetic analyses from isolated intermediates suggest that H2O2 formation occurs in a bimolecular fashion via a dinuclear H2O2-bridged intermediate with an important role for a redox non-innocent ligand. This system showcases the ability of metal-ligand cooperativity and strategic design of the secondary coordination sphere to promote kinetically and thermodynamically challenging selectivity in oxidative catalysis.
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Near-infrared (NIR) lumiphores are promising candidates for numerous imaging, communication, and sensing applications, but they typically require large, conjugated scaffolds to achieve emission in this low-energy region. Due to the extended conjugation and synthetic complexity required, it is extremely difficult to tune the photophysical properties of these systems for desired applications. Here, we report facile tuning of deep NIR-emitting diradicaloid complexes through simple modification of peripheral ligands. These new lumiphores are rare examples of air-, acid-, and water-stable emissive diradicaloids. We apply a simple Hammett parameter-based strategy to tune the electron donation of the capping ligand across a series of commercially available triarylphosphines. This minor peripheral modification significantly alters the electronic structure, and consequently, the electrochemical, photophysical, and magnetic properties of the tetrathiafulvalene tetrathiolate (TTFtt)-based lumiphores. The resultant â¼100 nm absorption and emission range spans common laser lines and the desirable telecom region (ca. 1260-1550 nm). Furthermore, these lumiphores are sensitive to local dielectrics, distinguishing them as promising candidates for ratiometric imaging and/or barcoding in the deep NIR region.
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Two-dimensional conductive metal-organic frameworks have emerged as promising electronic materials for applications in (opto)electronic, thermoelectric, magnetic, electrocatalytic, and energy storage devices. Many bottom-up or postsynthetic protocols have been developed to isolate these materials or further modulate their electronic properties. However, some methodologies commonly used in classic semiconductors, notably, aliovalent substitution, are conspicuously absent. Here, we demonstrate how aliovalent Fe(III) to Ni(II) substitution enables the isolation of a Ni bis(dithiolene) material from a previously reported Fe analogue. Detailed characterization supports the idea that aliovalent substitution of Fe(III) to Ni(II) results in an in situ oxidation of the organic dithiolene linker. This substitution-induced redox tuning modulates the electronic properties in the system, leading to higher electrical conductivity and Hall mobility but slightly lower carrier densities and weaker antiferromagnetic interactions. Moreover, this aliovalent substitution improves the material's electrochemical stability and thus enables pseudocapacitive behavior in the Ni material. These results demonstrate how classic aliovalent substitution strategies in semiconductors can also be leveraged in conductive MOFs and add further support to this class of compounds as emerging electronic materials.
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Iron-sulfur clusters play essential roles in biological systems, and thus synthetic [Fe4S4] clusters have been an area of active research. Recent studies have demonstrated that soluble [Fe4S4] clusters can serve as net H atom transfer mediators, improving the activity and selectivity of a homogeneous Mn CO2 reduction catalyst. Here, we demonstrate that incorporating these [Fe4S4] clusters into a coordination polymer enables heterogeneous H atom transfer from an electrode surface to a Mn complex dissolved in solution. A previously reported solution-processable Fe4S4-based coordination polymer was successfully deposited on the surfaces of different electrodes. The coated electrodes serve as H atom transfer mediators to a soluble Mn CO2 reduction catalyst displaying good product selectivity for formic acid. Furthermore, these electrodes are recyclable with a minimal decrease in activity after multiple catalytic cycles. The heterogenization of the mediator also enables the characterization of solution-phase and electrode surface species separately. Surface enhanced infrared absorption spectroscopy (SEIRAS) reveals spectroscopic signatures for an in situ generated active Mn-H species, providing a more complete mechanistic picture for this system. The active species, reaction mechanism, and the protonation sites on the [Fe4S4] clusters were further confirmed by density functional theory calculations. The observed H atom transfer reactivity of these coordination polymer-coated electrodes motivates additional applications of this composite material in reductive H atom transfer electrocatalysis.
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BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema. METHODS: VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418. FINDINGS: Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00-0·31) for garadacimab and 1·35 (1·00-3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events. INTERPRETATION: Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults. FUNDING: CSL Behring.
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Angioedemas Hereditários , Adulto , Adolescente , Humanos , Masculino , Feminino , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Resultado do Tratamento , Anticorpos Monoclonais , Método Duplo-CegoRESUMO
The gram-negative bacterium Shigella is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine candidates are in late stages of clinical development against this increasingly antibiotic-resistant pathogen. However, considering the increasingly crowded and costly paediatric immunization schedule, and likely advent of other important new vaccines, it is unclear whether introduction of a Shigella vaccine would represent a high priority for international agencies or health ministries in low- and middle-income countries. To determine whether there is a compelling public health value proposition for a Shigella vaccine, we used the World Health Organization's Full Value of Vaccine Assessment analytic framework and formulated five broad scientific, policy, economic and commercial-related propositions regarding the development of a Shigella vaccine. We also explored the current regulatory, clinical, policy and commercial challenges to a Shigella-containing combination vaccine development and adoption. Through a series of literature reviews, expert consultations, social science field studies and model-based analyses, we addressed each of these propositions. As described in a series of separate publications that are synthesized here, we concluded that the economic and public health value of a Shigella vaccine may be greater than previously recognized, particularly if it is found to also be effective against less severe forms of diarrheal disease and childhood stunting. The decision by pharmaceutical companies to develop a standalone vaccine or a multipathogen combination will be a key factor in determining its relative prioritization by various stakeholders in low- and middle-income countries.
La bactérie à Gram négatif Shigella est l'une des principales causes de morbidité et de mortalité diarrhéiques chez les enfants des pays à revenu faible et intermédiaire. Plusieurs candidats vaccins prometteurs sont en phase avancée de conception clinique contre cet agent pathogène qui connaît une antibiorésistance croissante. Toutefois, compte tenu du calendrier de vaccination pédiatrique de plus en plus chargé et coûteux et de l'arrivée probable d'autres nouveaux vaccins importants, il n'est pas certain que la mise sur le marché d'un vaccin contre Shigella constitue une priorité élevée pour les agences internationales ou les ministères de la Santé des pays à revenu faible ou intermédiaire. Pour déterminer l'existence d'un intérêt convaincant en matière de santé publique pour un vaccin contre Shigella, nous avons utilisé le cadre analytique du cadre d'évaluation de la valeur totale des vaccins de l'Organisation mondiale de la santé et formulé cinq propositions scientifiques, politiques, économiques et commerciales générales concernant la conception d'un vaccin contre Shigella. Nous avons également étudié les défis en matière réglementaire, clinique, politique et commerciale qui se posent actuellement à la mise au point et à l'adoption d'un vaccin combiné contenant des Shigella. Nous avons abordé chacune de ces propositions au moyen d'une série d'analyses documentaires, de consultations d'experts, d'études de terrain en sciences sociales et d'analyses basées sur des modèles. Comme décrit dans une série de publications distinctes résumées ici, nous avons conclu que la valeur économique et sur le plan de la santé publique d'un vaccin contre Shigella pourrait être plus importante que ce qui était considéré précédemment, en particulier s'il s'avère que ce vaccin s'avère également efficace contre les formes moins sévères de maladies diarrhéiques et de retard de croissance chez l'enfant. La décision d'entreprises pharmaceutiques de mettre au point un vaccin autonome ou une combinaison de plusieurs agents pathogènes sera un facteur clé dans la détermination de sa priorité relative par les différentes parties prenantes dans les pays à revenu faible et intermédiaire.
La bacteria gramnegativa Shigella es una de las principales causas de morbilidad y mortalidad por diarrea en niños de países de ingresos bajos y medios. Varias vacunas candidatas y prometedoras se encuentran en las últimas fases de desarrollo clínico contra este patógeno cada vez más resistente a los antibióticos. Sin embargo, teniendo en cuenta el esquema de inmunización pediátrica, cada vez más saturado y costoso, y la probable llegada de otras vacunas nuevas importantes, no está claro si la introducción de una vacuna contra la Shigella representaría una alta prioridad para los organismos internacionales o los ministerios de salud de los países de ingresos bajos y medios. Para determinar si existe una propuesta de valor de salud pública convincente para una vacuna contra la Shigella, utilizamos el marco de análisis Full Value of Vaccine Assessment de la Organización Mundial de la Salud y formulamos cinco amplias propuestas científicas, políticas, económicas y comerciales relacionadas con el desarrollo de una vacuna contra la Shigella. También exploramos los actuales desafíos reglamentarios, clínicos, políticos y comerciales para el desarrollo y la adopción de una vacuna combinada que contenga Shigella. Mediante una serie de revisiones bibliográficas, consultas a expertos, estudios de campo de ciencias sociales y análisis basados en modelos, abordamos cada una de estas proposiciones. Como se describe en una serie de publicaciones separadas que se sintetizan aquí, llegamos a la conclusión de que el valor económico y de salud pública de una vacuna contra la Shigella puede ser mayor de lo que se reconocía anteriormente, en particular si se descubre que también es eficaz contra formas menos graves de enfermedad diarreica y retraso del crecimiento infantil. La decisión de las empresas farmacéuticas de desarrollar una vacuna independiente o una combinación multipatógena será un factor clave a la hora de determinar su prioridad relativa por parte de las diversas partes interesadas en los países de ingresos bajos y medios.
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Vacinas contra Shigella , Shigella , Vacinas , Criança , Humanos , Diarreia/prevenção & controle , Diarreia/microbiologia , Saúde GlobalRESUMO
Due to its increased safety over ultraviolet light, there is interest in the development of antimicrobial violet-blue light technologies for infection control applications. To ensure compatibility with exposed materials and tissue, the light irradiances and dose regimes used must be suitable for the target application. This study investigates the antimicrobial dose responses and germicidal efficiency of 405 nm violet-blue light when applied at a range of irradiance levels, for inactivation of surface-seeded and suspended bacteria. Bacteria were seeded onto agar surfaces (101-108 CFUplate-1) or suspended in PBS (103-109 CFUmL-1) and exposed to increasing doses of 405-nm light (≤ 288 Jcm-2) using various irradiances (0.5-150 mWcm-2), with susceptibility at equivalent light doses compared. Bacterial reductions ≥ 96% were demonstrated in all cases for lower irradiance (≤ 5 mWcm-2) exposures. Comparisons indicated, on a per unit dose basis, that significantly lower doses were required for significant reductions of all species when exposed at lower irradiances: 3-30 Jcm-2/0.5 mWcm-2 compared to 9-75 Jcm-2/50 mWcm-2 for low cell density (102 CFUplate-1) surface exposures and 22.5 Jcm-2/5 mWcm-2 compared to 67.5 Jcm-2/150 mWcm-2 for low density (103 CFUmL-1) liquid exposures (P ≤ 0.05). Similar patterns were observed at higher densities, excluding S. aureus exposed at 109 CFUmL-1, suggesting bacterial density at predictable levels has minimal influence on decontamination efficacy. This study provides fundamental evidence of the greater energy efficacy of 405-nm light for inactivation of clinically-significant pathogens when lower irradiances are employed, further supporting its relevance for practical decontamination applications.
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Descontaminação , Luz , Descontaminação/métodos , Bactérias/efeitos da radiação , Bactérias/efeitos dos fármacos , Desinfecção/métodos , Viabilidade Microbiana/efeitos da radiação , Staphylococcus aureus/efeitos da radiação , Staphylococcus aureus/efeitos dos fármacosRESUMO
BACKGROUND: Lanadelumab was well-tolerated and effective in preventing hereditary angioedema (HAE) attacks in the phase 3, double-blind, placebo-controlled HELP Study and subsequent open-label extension study, HELP OLE (NCT02741596). OBJECTIVE: To evaluate outcomes from HELP OLE for adolescent patients aged 12 to 17 years. METHODS: HELP OLE comprised patients who completed the HELP Study (rollovers) and new eligible (lanadelumab-naive) patients. Rollovers received a single dose of lanadelumab 300 mg at the last HELP Study visit (day 0). Treatment was then paused until patients experienced their first investigator-confirmed HAE attack, following which lanadelumab 300 mg was administered every 2 weeks (Q2W) for up to 33 months (4 weeks/month). Lanadelumab-naive patients received lanadelumab 300 mg Q2W from day 0. Patient-reported outcomes included Angioedema Quality of Life Questionnaire (AE-QoL). Safety was monitored throughout the study. RESULTS: The subgroup analysis included 21 patients (8 rollovers, 13 lanadelumab-naive patients); 95.2% completed ≥ 30 months on study. Mean (SD) monthly attack rates decreased from 1.58 (1.0) at baseline to 0.11 (0.2) during treatment (mean 94.7% reduction). Eight (38.1%) patients were attack-free during treatment and, on average, 99.1% of days were attack-free (mean 27.7 days/month). Patients reported a mean (SD) AE-QoL total score of 27.5 (17.5) at baseline vs 7.5 (13.2) at end of study. Twelve (57.1%) patients reported treatment-related treatment-emergent adverse events; however, there were no treatment-related serious adverse events. CONCLUSION: Lanadelumab provided long-term efficacy in preventing HAE attacks, was associated with clinically meaningful improvements in health-related quality of life and high levels of treatment satisfaction, and was well-tolerated in adolescent patients.
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Contemporary conservation science requires mediating conflicts among nonhuman species, but the grounds for favoring one species over another can be unclear. We examined the premises through which wildlife managers picked sides in an interspecies conflict: seabird conservation in the Gulf of Maine (GOM). Managers in the GOM follow a simple narrative dubbed the gull problem. This narrative assumes Larus gulls are overpopulated and unnatural in the region. In turn, these assumptions make gulls an easy target for culling and lethal control when the birds come into conflict with other seabirds, particularly Sterna terns. Surveying historical, natural historical, and ecological evidence, we found no scientific support for the claim that Larus gulls are overpopulated in the GOM. Claims of overpopulation originated from a historical context in which rising gull populations became a nuisance to humans. Further, we found only limited evidence that anthropogenic subsidies make gulls unnatural in the region, especially when compared with anthropogenic subsidies provided for other seabirds. The risks and consequences of leveraging precarious assumptions include cascading plans to cull additional gull populations, obfuscation of more fundamental environmental threats to seabirds, and the looming paradox of gull conservation-even if one is still inclined to protect terns in the GOM. Our close look at the regional history of a conservation practice thus revealed the importance of not only conservation decisions, but also conservation decision-making.
Conflicto interespecífico, razonamiento precario y el problema de las gaviotas en el Golfo de Maine Resumen La ciencia de la conservación actual requiere mediar conflictos entre las especies no humanas, pero los fundamentos para favorecer a una especie por encima de otra pueden ser poco claros. Analizamos las premisas mediante las cuales los gestores de fauna eligen bandos en un conflicto interespecífico: la conservación de aves marinas en el Golfo de Maine (GDM). Los gestores en el GDM siguen una narrativa simple llamada el problema de las gaviotas. Esta narrativa asume que las gaviotas del género Larus no son nativas y tienen una sobrepoblación en la región. En cambio, estas suposiciones hacen que las gaviotas sean un objetivo fácil para el sacrificio y el control letal cuando las aves entran en conflicto con otras aves marinas, en particular con los charranes del género Sterna. Censamos la evidencia histórica, ecológica y de historia natural y no encontramos respaldo científico alguno para la afirmación de que hay una sobrepoblación de gaviotas Larus en el GDM. Esta afirmación se originó a partir de un contexto histórico en el que el incremento poblacional de las gaviotas se volvió una molestia para los humanos. Además, encontramos evidencia limitada de que los subsidios antropogénicos hacen que las gaviotas no sean nativas en la región, en especial cuando los comparamos con los subsidios antropogénicos proporcionados a otras aves marinas. Los riesgos y consecuencias de impulsar suposiciones precarias incluyen los planes en cascada para sacrificar poblaciones adicionales de gaviotas, la ofuscación de amenazas ambientales más fundamentales para las aves marinas y la paradoja inminente de la conservación de las gaviotasincluso si todavía se inclinan por proteger a los charranes en el GDM. Esta mirada detallada de la historia regional de una práctica de conservación nos reveló la importancia no sólo de las decisiones de conservación, sino también de la toma de decisiones de conservación.
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OBJECTIVES: Endoscopy teaching practice is variable, which inevitably affects the training provided. There is only one Train the Paediatric Colonoscopy Trainer (TPCT) course in the UK. Informal feedback has been positive, but its practical value has never been formally assessed. We aim to assess the practical value of the TPCT course and how attendees perceive their teaching practice compared to nonattendees. METHODS: A questionnaire based on the TPCT course learning aims and objectives was distributed to two groups of consultant paediatric gastroenterologists who teach colonoscopy in the UK; those who had attended the course (participants) and those who had not (controls). RESULTS: The 41 completed responses were received. Overall, responses indicated participants of the TPCT course rated their confidence and knowledge in teaching practices as higher than controls (4.27 vs. 3.56 p = < 0.001). There was a statistically significant difference in all areas: set (4.21 vs. 3.71 p = 0.011), dialogue (4.29 vs. 3.55 p = < 0.001) and closure (4.37 vs. 3.6 p = < 0.001) with those who attended the TPCT course giving higher ratings. There was evidence of increased understanding of key concepts such as using standardised language, conscious competence, dual task interference and performance enhancing feedback. CONCLUSION: Attending a TPCT course results in a higher perceived level of knowledge in fundamental teaching principles and confidence in colonoscopy teaching skills.
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Colonoscopia , Endoscopia Gastrointestinal , Humanos , Criança , Colonoscopia/educação , Inquéritos e Questionários , Ensino , Competência Clínica , CurrículoRESUMO
Background: A diagnosis of hereditary angioedema (HAE) with normal C1 esterase inhibitor (HAE-nl-C1-INH) can be challenging and pharmacologic management is not well defined. Objective: The objective was to discuss practical considerations in the clinical management of HAE-nl-C1-INH by using illustrative clinical vignettes to highlight and/or address select challenges. Methods: This was a narrative review. Results: Symptoms of HAE-nl-C1-INH overlap with HAE types I and II; the heterogeneity of presentation and symptom burden are diagnostic challenges. A patient history, with particular attention to whether urticaria or other symptoms of mast cell mediator release are present, is important because such symptoms would strongly suggest a mast cell-mediated pathway. A family history of angioedema is informative but a lack thereof does not rule out diagnosis. Expected laboratory findings would be normal for C4, C1-INH level and function, and Complement 1q; a genetic mutational analysis may be helpful, but current assays do not include all known mutations; most cases are categorized as unknown. To align with guideline-directed treatment approaches, the following stepwise approach is suggested for suspected HAE-nl-C1-INH: (1) thoroughly investigate the possibility of response to histaminergic and/or mast cell-targeting treatments; (2) if patients with normal C4, C1-INH level and/or function fail adequate trials with histamine/mast cell-directed therapy or have a mutation that suggests bradykinin pathway involvement, follow HAE type I and II treatment guidelines. Response to medications approved for HAE types I/II provides compelling support for a high clinical suspicion of HAE-nl-C1-INH. De-labeling an HAE-nl-C1-INH diagnosis may be appropriate if the initial diagnosis was made without adequate evaluation or if new information and/or testing indicates that the patient does not actually have HAE. Conclusion: Key unmet needs in HAE-nl-C1-INH include lack of confirmatory biomarker(s) for diagnosis and lack of prospective controlled clinical studies of pharmacologic products in this patient population.
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Angioedemas Hereditários , Proteína Inibidora do Complemento C1 , Humanos , Proteína Inibidora do Complemento C1/uso terapêutico , Proteína Inibidora do Complemento C1/genética , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Diagnóstico Diferencial , FemininoRESUMO
Background: Hereditary angioedema (HAE) is a rare genetic condition characterized by painful and often debilitating swelling attacks. Little is known about the differences in outcomes between patients with HAE types I or II (type I: HAE caused by C1 esterase inhibitor deficiency; type II: HAE caused by C1 esterase inhibitor dysfunction), with decreased or dysfunctional C1 esterase inhibitor (C1-INH), and those with normal C1-INH (nC1-INH-HAE). Objective: To compare physician- and patient-reported real-world outcomes in patients with HAE types I/II versus patients with nC1-INH-HAE. Methods: Data were drawn from the Adelphi HAE Disease Specific ProgrammeTM a real-world, cross-sectional survey of HAE-treating physicians and their patients in the United States conducted between July and November 2021. Physicians reported patient disease activity and severity, and recent attack history. Patient-reported outcomes were collected. Bivariate tests used were either the Student's t-test, the Fisher exact test, or Mann-Whitney U test. Results: Physicians (N = 67) provided data on 368 patients (92.4% HAE types I/II and 7.6% nC1-INH-HAE). Physicians reported that a higher proportion of patients with nC1-INH-HAE had moderate or high disease activity and moderate or severe disease severity both at diagnosis and at data collection versus those with HAE types I/II. Patients with nC1-INH-HAE versus patients with HAE types I/II experienced increased attack severity (34.6% versus 4.4%) and hospitalization rate during the most recent attack (39.3% versus 6.6%), and reported lower health status and quality of life, via the European Quality of Life 5 Dimension 5 Level (US tariff) and Angioedema Quality of Life, respectively. On average, 25% of the patients with nC1-INH-HAE reported absenteeism and work or activity impairment due to HAE compared with 2.7% of patients with HAE types I/II. Both patient groups reported improvements in disease activity and severity from diagnosis to the time of data collection. Conclusion: These real-world findings suggest that patients with nC1-INH-HAE have increased disease activity and severity, and experience greater impairment to their quality of life, work, and daily functioning than patients with HAE types I/II. Powered statistical analyses are required to confirm these findings.
Assuntos
Angioedemas Hereditários , Proteína Inibidora do Complemento C1 , Medidas de Resultados Relatados pelo Paciente , Médicos , Humanos , Feminino , Masculino , Estudos Transversais , Adulto , Pessoa de Meia-Idade , Proteína Inibidora do Complemento C1/genética , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/epidemiologia , Índice de Gravidade de Doença , Angioedema Hereditário Tipos I e II/diagnóstico , Adulto Jovem , Qualidade de Vida , Estados Unidos/epidemiologia , Idoso , AdolescenteRESUMO
BACKGROUND: To lessen surgical times for patients with adolescent idiopathic scoliosis (AIS) undergoing posterior spinal instrumentation and fusion (PSIF), our department developed a quality improvement initiative where 2 AIS cases were completed in 1 day by the same 2 surgeons operating together in 1 operating room (OR). We describe the results of this initiative, comparing operative times and outcomes to cases of these surgeons operating individually. METHODS: From 2017 to 2023, patients aged 10 to 18 years with AIS undergoing PSIF were prospectively enrolled for "Two Spine Tuesday." Patients were matched by age, sex, curve severity, and number of levels fused to historical AIS controls. Outcomes included surgery time, total OR time, estimated blood loss (EBL), volume of cell saver transfused, allogenic blood transfusion, length of stay, 90-day readmissions, Clavien-Dindo-Sink Complication Classification System complication rates, and percentage who achieved the minimal clinically important difference (MCID) for SRS-22. RESULTS: Fifty-five patients composing the 2-spine group (group 2) were compared with 55 historical sex-matched and age-matched controls (group 1). Major coronal curve and average number of levels fused were similar between groups. Overall surgery time (203 vs. 296 min, P <0.001), total OR time ( P <0.001), and EBL (400 vs. 550 mL, P <0.001) were lower for group 2. Group 2 had fewer complications [n=17 (31%) vs. n=28 (51%), P =0.03]. CONCLUSIONS: Performing 2 AIS cases in 1 OR by 2 surgeons the same day resulted in shorter surgery times, less total time in the operating room, lower complication rates, and less blood loss compared with single-surgeon matched controls. LEVEL OF EVIDENCE: Level III-retrospective comparative study.
Assuntos
Salas Cirúrgicas , Duração da Cirurgia , Escoliose , Fusão Vertebral , Humanos , Escoliose/cirurgia , Feminino , Fusão Vertebral/métodos , Fusão Vertebral/efeitos adversos , Masculino , Adolescente , Criança , Estudos Prospectivos , Melhoria de Qualidade , Tempo de Internação/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos de Casos e Controles , Perda Sanguínea Cirúrgica/estatística & dados numéricosRESUMO
Cognitive Reserve (CR) refers to the preservation of cognitive function in the face of age- or disease-related neuroanatomical decline. While bilingualism has been shown to contribute to CR, the extent to which, and what particular aspect of, second language experience contributes to CR are debated, and the underlying neural mechanism(s) unknown. Intrinsic functional connectivity reflects experience-dependent neuroplasticity that occurs across timescales ranging from minutes to decades, and may be a neural mechanism underlying CR. To test this hypothesis, we used voxel-based morphometry and resting-state functional connectivity analyses of MRI data to compare structural and functional brain integrity between monolingual and bilingual older adults, matched on cognitive performance, and across levels of second language proficiency measured as a continuous variable. Bilingualism, and degree of second language proficiency specifically, were associated with lower gray matter integrity in a hub of the default mode network - a region that is particularly vulnerable to decline in aging and dementia - but preserved intrinsic functional network organization. Bilingualism moderated the association between neuroanatomical differences and cognitive decline, such that lower gray matter integrity was associated with lower executive function in monolinguals, but not bilinguals. Intrinsic functional network integrity predicted executive function when controlling for group differences in gray matter integrity and language status. Our findings confirm that lifelong bilingualism is a CR factor, as bilingual older adults performed just as well as their monolingual peers on tasks of executive function, despite showing signs of more advanced neuroanatomical aging, and that this is a consequence of preserved intrinsic functional network organization.
Assuntos
Reserva Cognitiva , Multilinguismo , Humanos , Idoso , Testes Neuropsicológicos , Encéfalo/diagnóstico por imagem , IdiomaRESUMO
Transition metal-oxo complexes are key intermediates in a variety of oxidative transformations, notably C-H bond activation. The relative rate of C-H bond activation mediated by transition metal-oxo complexes is typically predicated on substrate bond dissociation free energy in cases with a concerted proton-electron transfer (CPET). However, recent work has demonstrated that alternative stepwise thermodynamic contributions such as acidity/basicity or redox potentials of the substrate/metal-oxo may dominate in some cases. In this context, we have found basicity-governed concerted activation of C-H bonds with the terminal CoIII-oxo complex PhB(tBuIm)3CoIIIO. We have been interested in testing the limits of such basicity-dependent reactivity and have synthesized an analogous, more basic complex, PhB(AdIm)3CoIIIO, and studied its reactivity with H-atom donors. This complex displays a higher degree of imbalanced CPET reactivity than PhB(tBuIm)3CoIIIO with C-H substrates, and O-H activation of phenol substrates displays mechanistic crossover to stepwise proton transfer-electron transfer (PTET) reactivity. Analysis of the thermodynamics of proton transfer (PT) and electron transfer (ET) reveals a distinct thermodynamic crossing point between concerted and stepwise reactivity. Furthermore, the relative rates of stepwise and concerted reactivity suggest that maximally imbalanced systems provide the fastest CPET rates up to the point of mechanistic crossover, which results in slower product formation.