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Background: The effect of COVID-19 on treatment outcomes in the literature remains limited and is mostly reported either as predictive survival using prioritization and modeling techniques. We aimed to quantify the effect of COVID-19 on lung cancer survival using real-world data collected at the Jewish General Hospital, Montreal. Methods: This is a retrospective chart review study of patients diagnosed between March 2019 and March 2022. We compared three cohorts: pre-COVID-19, and 1st and 2nd year of the pandemic. Results: 417 patients were diagnosed and treated with lung cancer at our centre: 130 in 2019, 103 in 2020 and 184 in 2021. Although the proportion of advanced/metastatic-stage lung cancer remained the same, there was a significant increase in the late-stage presentation during the pandemic. The proportion of M1c (multiple extrathoracic sites) cases in 2020 and 2021 was 57% and 51%, respectively, compared to 31% in 2019 (p < 0.05). Median survival for early stages of lung cancer was similar in the three cohorts. However, patients diagnosed in the M1c stage had a significantly increased risk of death. The 6-month mortality rate was 53% in 2021 compared to 47% in 2020 and 29% in 2019 (p = 0.004). The median survival in this subgroup of patients decreased significantly from 13 months in 2019 to 6 months in 2020 and 5 months in 2021 (p < 0.001). Conclusions: This study is, to our knowledge, the largest single-institution study in Canada looking at lung cancer survival during the COVID-19 pandemic. Our study looks at overall survival in the advanced/metastatic setting of NSCLC during the COVID-19 pandemic. We have previously reported on treatment pattern changes and increased wait times for NSCLC patients during the pandemic. In this study, we report that the advanced/metastatic subgroup had both an increase in the 6-month mortality rate and worsening overall survival during this same time period. Although there was no statistical difference in the proportion of patients with advanced disease, there was a concerning trend of increased M1c disease in cohorts 2 and 3. The higher M1c disease during the COVID-19 pandemic (cohorts 2 and 3) likely played a crucial role in increasing the 6-month mortality rate and leading to a reduced overall survival of lung cancer patients during the pandemic. These findings are more likely to be better identified with longer follow-up.
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COVID-19 , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Pandemias , Estudios Retrospectivos , Canadá , Carcinoma de Pulmón de Células no Pequeñas/patologíaRESUMEN
Radiometric Terrain Corrected (RTC) gamma nought backscatter, which was introduced around a decade ago, has evolved into the standard for analysis-ready Synthetic Aperture Radar (SAR) data. While working with RTC backscatter data is particularly advantageous over undulated terrain, it requires substantial computing resources given that the terrain flattening is more computationally demanding than simple orthorectification. The extra computation may become problematic when working with large SAR datasets such as the one provided by the Sentinel-1 mission. In this study, we examine existing Sentinel-1 RTC pre-processing workflows and assess ways to reduce processing and storage overheads by considering the satellite's high orbital stability. By propagating Sentinel-1's orbital deviations through the complete pre-processing chain, we show that the local contributing area and the shadow mask can be assumed to be static for each relative orbit. Providing them as a combined external static layer to the pre-processing workflow, and streamlining the transformations between ground and orbit geometry, reduces the overall processing times by half. We conducted our experiments with our in-house developed toolbox named wizsard, which allowed us to analyse various aspects of RTC, specifically run time performance, oversampling, and radiometric quality. Compared to the Sentinel Application Platform (SNAP) this implementation allowed speeding up processing by factors of 10-50. The findings of this study are not just relevant for Sentinel-1 but for all SAR missions with high spatio-temporal coverage and orbital stability.
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Radar , Radiometría , Rayos gamma , Flujo de TrabajoRESUMEN
BACKGROUND: We have recently reported a 35% drop in new lung cancer diagnoses and a 64% drop in lung cancer surgeries during the first year of the pandemic. METHODS: The target population was divided into three cohorts: pre-COVID-19 (2019), first year of COVID-19 (2020), and second year of COVID-19 (2021). RESULTS: The number of new lung cancer diagnoses during the second year of the pandemic increased by 75%, with more than 50% being in the advanced/metastatic stage. There was a significant increase in cases with multiple extrathoracic sites of metastases during the pandemic. During the first year of the pandemic, significantly more patients were treated with radiosurgery compared to the pre-COVID-19 year. During the second year, the number of radiosurgery and surgical cases returned to pre-COVID-19 levels. No significant changes were observed in systemic chemotherapy and targeted therapy. No statistical difference was identified in the mean wait time for diagnosis and treatment during the three years of observation. However, the wait time for surgery was prolonged compared to the pre-COVID-19 cohort. CONCLUSIONS: The significant drop in new diagnoses of lung cancer during the first year of the pandemic was followed by an almost two-fold increase in the second year, with the increased rate of metastatic disease with multiple extra-thoracic site metastases. Limited access to surgery resulted in the more frequent use of radiosurgery.
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COVID-19 , Neoplasias Pulmonares , Radiocirugia , Humanos , Canadá/epidemiología , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Terapia CombinadaRESUMEN
We demonstrate reactivity between a ß-diketiminate-supported niobium(III) imido complex and alkyl azides to form niobatetrazene complexes (BDI)Nb(NtBu)(RNNNNR) (BDI = N,N-bis(2,6-diisopropylphenyl)-3,5-dimethyl-ß-diketiminate; R = cyclohexyl (1), benzyl (2)). Intriguingly, niobatetrazene complexes 1 and 2 can be interconverted via addition of an appropriate alkyl azide, likely through a series of concerted [3 + 2] cycloaddition and retrocycloaddition reactions in which π-loaded bis(imido) intermediates are formed. The bis(imido) intermediates were trapped upon addition of alkyl isocyanides to yield five-coordinate bis(imido) complexes (BDI)Nb(NtBu)(NCy)(CNR) (R = tert-butyl (4a), cyclohexyl (4b)). Two computational methodsâdensity functional theory and density functional tight binding (DFTB)âwere employed to calculate the lowest energy pathway across the potential energy surface for this multistep transformation. Reaction path calculations for individual cycloaddition or retrocycloaddition processes along the multistep reaction pathway showed that these transformations occur via a concerted, yet highly asynchronous mechanism, in which the two bond-breaking or -making events do not occur simultaneously. The use of the DFTB method in this work highlights its advantages and utility for studying transition metal systems.
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INTRODUCTION: People who experience social disadvantage including homelessness suffer from numerous ill health effects when compared to the general public. Use of patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) enables collection of information from the point of view of the person receiving care. Involvement in research and health care decision-making, a process that can be facilitated by the use of PROMs and PREMs, is one way to promote equity in care. METHODS: This article reports on a codevelopment and consultation study investigating the use of PROMs and PREMs with people who experience homelessness and chronic illness. Data were analysed according to interpretative phenomenological analysis. RESULTS: Committee members with lived experience identified three themes for the role of PROMs and PREMs in health care measurement: trust and relationship-building; health and quality of life; and equity, alongside specific recommendations for the design and administration of PROMs and PREMs. The codevelopment process is reported to demonstrate the meaningful investment in time, infrastructure and relationship-building required for successful partnership between researchers and people with lived experience of homelessness. CONCLUSION: PROMs and PREMs can be meaningful measurement tools for people who experience social disadvantage, but can be alienating or reproduce inequity if they fail to capture complexity or rely on hidden assumptions of key concepts. PATIENT OR PUBLIC CONTRIBUTION: This study was conducted in active partnership between researchers and people with experience of homelessness and chronic illness, including priority setting for study design, data construction, analysis and coauthorship on this article.
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Personas con Mala Vivienda , Calidad de Vida , Humanos , Atención a la Salud , Medición de Resultados Informados por el Paciente , Enfermedad CrónicaRESUMEN
BACKGROUND: Recent studies have demonstrated the utility of cell-free tumor DNA (ctDNA) from plasma as an alternative source of genomic material for detection of sensitizing and resistance mutations in NSCLC. We hypothesized that the plasma level of ctDNA is an effective biomarker to provide a non-invasive and thus a less risky method to determine new resistance mutations and to monitor response to treatment and tumor progression in lung cancer patients. METHODS: This prospective cohort study was approved and conducted at the Peter Brojde Lung Cancer Centre, Montreal. Blood was collected in STRECK tubes at four time points. DNA was extracted from plasma, and ctDNA was analyzed for the presence of mutations in the EGFR gene using the COBAS® EGFR v2 qPCR (Roche) test. RESULTS: Overall, 75 pts were enrolled in the study. In total, 23 pts were TKI-naïve, and 52 were already receiving first-line TKI treatment. ctDNA detected the original mutations (OM) in 35/75 (48%) patients. Significantly higher detection rates were observed in TKI-naïve patients compared to the TKI-treated group, 70% versus 37%, respectively (p = 0.012). The detection of the original mutation at the study baseline was a negative predictor of progression-free survival (PFS) and overall survival (OS). The resistance mutation (T790M) was detected in 32/74 (43%) patients. In 27/32 (84%), the T790M was detected during treatment with TKI: in 25/27 patients, T790M was detected at the time of radiologic progression, in one patient, T790M was detected before radiologic progression, and in one patient, T790M was detected four weeks after starting systemic chemotherapy post progression on TKI. At the time of progression, the detection of T790M significantly correlates with the re-appearance of OM (p = 0.001). CONCLUSION: Plasma ctDNA is a noninvasive patient-friendly test that can be used to monitor response to treatment, early progression, and detection of acquired resistant mutations. Monitoring of clearance and re-emergence of driver mutations during TKI treatment effectively identifies progression of the disease. As larger NGS panels are available for ctDNA testing, these findings may also have implications for other biomarkers. The results from ongoing and prospective studies will further determine the utility of plasma testing to diagnose, monitor for disease progression, and guide treatment decisions in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Tumoral Circulante/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Tadalafil 40 mg once daily is approved for adult patients with pulmonary arterial hypertension (PAH). To investigate and potentially fulfill an unmet need in pediatric patients with PAH, pharmacokinetic (PK) data were explored in a pediatric phase Ib/II study and pooled with prior phase III (pulmonary arterial hypertension and response to tadalafil [PHIRST-1]) adult data to develop the first population PK model for tadalafil in pediatric patients with PAH. METHODS: H6D-MC-LVIG (NCT01484431) was an open-label, multicenter, multiple ascending dose study in pediatric patients with PAH, while PHIRST-1 was a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel design study in adults with PAH who received one of five treatments (tadalafil 2.5, 10, 20, or 40 mg, or placebo orally, once daily). PK data from the studies were pooled to develop a pediatric population PK model for tadalafil that characterized relationships among dose, exposure, and the effects of covariates with an aim to develop a population PK model that could simulate concentration-time profiles and assess exposure-matched dosing strategies in a pediatric PAH population. RESULTS: In line with the observed data, modeling and simulation demonstrated that the doses studied in the pediatric population produced area under the concentration-time curves (AUCs) within the range of those associated with improved exercise ability in adults with PAH. The analyses included 1430 observations from 305 adult patients (PHIRST-1: 69 males and 236 females, 1102 observations) and 19 pediatric patients (LVIG: 6 males and 13 females, 328 observations) who received tadalafil once daily at different dose levels. The best-fit base model retained an effect of weight on apparent volume of distribution (V/F), fixed to the allometric scaling value of 1, and did not include an effect of weight on apparent clearance (CL/F). Other covariate effects were that bosentan increased CL/F, V/F decreased with decreasing body weight, and bioavailability (F) decreased with increasing dose and decreasing age. The PK model reliably predicted the observed concentrations and overall variability evident from the overlap of the individual observed concentrations with the distributions of simulated concentrations. CONCLUSIONS: A one-compartment model parameterized in terms of F, absorption rate constant, CL/F, and V/F described the data well. The model demonstrated that plasma tadalafil concentrations in pediatric patients aged 2 to < 18 years were similar to those in adults at similar doses, and confirmed that dosing of 40 mg once daily in pediatric patients with a bodyweight ≥ 40 kg, and a dose of 20 mg once daily in patients with a body weight < 40 kg and aged ≥ 2 years are suitable for phase III evaluation. TRIAL REGISTRATION NUMBER (DATE OF REGISTRATION): LVIG: ClinicalTrials.gov identifier: NCT01484431 (2 December 2011). PHIRST-1: ClinicalTrials.gov identifier: NCT00125918 (2 August 2005).
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Hipertensión Arterial Pulmonar , Adulto , Área Bajo la Curva , Peso Corporal , Bosentán , Niño , Femenino , Humanos , Masculino , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Tadalafilo/efectos adversos , Tadalafilo/farmacocinéticaRESUMEN
The discovery of EGFR tyrosine kinase inhibitors (TKI) for the treatment of EGFR mutant (EGFRm) metastatic NSCLC is regarded as a landmark in lung cancer. EGFR-TKIs have now become a standard first-line treatment for EGFRm NSCLC. The aim of this retrospective cohort study is to describe real-world patterns of treatment and treatment outcomes in patients with EGFRm metastatic NSCLC who received EGFR-TKI therapy outside of clinical trials. One hundred and seventy EGFRm metastatic NSCLC patients were diagnosed and initiated on first-line TKI therapy between 2004 and 2018 at the Peter Brojde Lung Cancer Centre in Montreal. Following progression of the disease, 137 (80%) patients discontinued first-line treatment. Moreover, 80/137 (58%) patients received second-line treatment, which included: EGFR-TKIs, platinum-based, or single-agent chemotherapy. At the time of progression on first-line treatment, 73 patients were tested for the T790M mutation. Moreover, 30/73 (41%) patients were found to be positive for the T790M mutation; 62/80 patients progressed to second-line treatment and 20/62 were started on third-line treatment. The median duration of treatment was 11.5 (95% CI; 9.62-13.44) months for first-line treatment, and 4.4 (95% CI: 1.47-7.39) months for second-line treatment. Median OS from the time of diagnosis of metastatic disease was 23.5 months (95% CI: 16.9-30.1) and median OS from the initiation of EGFR-TKI was 20.6 months (95% CI: 13.5-27.6). We identified that ECOG PS ≤ 2, presence of exon 19 deletion mutation, and absence of brain metastases were associated with better OS. A significant OS benefit was observed in patients treated with osimertinib in second-line treatment compared to those who never received osimertinib. Overall, our retrospective observational study suggests that treatment outcomes in EGFRm NSCLC in real-world practice, such as OS and PFS, reflect the result of RCTs. However, given the few observational studies on real-world treatment patterns of EGFR-mutant NSCLC, this study is important for understanding the potential impact of EGFR-TKIs on survival outside of clinical trials. Further real-world studies are needed to characterize patient outcomes for emerging therapies, including first-line osimertinib use and combination of osimertinib with chemotherapy and potential future combination of osimertinib and novel anticancer drug, outside of a clinical trial setting.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quebec , Estudios RetrospectivosRESUMEN
Since the opening of Earth Observation (EO) archives (USGS/NASA Landsat and EC/ESA Sentinels), large collections of EO data are freely available, offering scientists new possibilities to better understand and quantify environmental changes. Fully exploiting these satellite EO data will require new approaches for their acquisition, management, distribution, and analysis. Given rapid environmental changes and the emergence of big data, innovative solutions are needed to support policy frameworks and related actions toward sustainable development. Here we present the Swiss Data Cube (SDC), unleashing the information power of Big Earth Data for monitoring the environment, providing Analysis Ready Data over the geographic extent of Switzerland since 1984, which is updated on a daily basis. Based on a cloud-computing platform allowing to access, visualize and analyse optical (Sentinel-2; Landsat 5, 7, 8) and radar (Sentinel-1) imagery, the SDC minimizes the time and knowledge required for environmental analyses, by offering consistent calibrated and spatially co-registered satellite observations. SDC derived analysis ready data supports generation of environmental information, allowing to inform a variety of environmental policies with unprecedented timeliness and quality.
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Optogenetic effectors and sensors provide a novel real-time window into complex physiological processes, enabling determination of molecular signaling processes within functioning cellular networks. However, the combination of these optical tools in mice is made practical by construction of genetic lines that are optically compatible and genetically tractable. We present a new toolbox of 21 mouse lines with lineage-specific expression of optogenetic effectors and sensors for direct biallelic combination, avoiding the multiallelic requirement of Cre recombinase -mediated DNA recombination, focusing on models relevant for cardiovascular biology. Optogenetic effectors (11 lines) or Ca2+ sensors (10 lines) were selectively expressed in cardiac pacemaker cells, cardiomyocytes, vascular endothelial and smooth muscle cells, alveolar epithelial cells, lymphocytes, glia, and other cell types. Optogenetic effector and sensor function was demonstrated in numerous tissues. Arterial/arteriolar tone was modulated by optical activation of the second messengers InsP3 (optoα1AR) and cAMP (optoß2AR), or Ca2+-permeant membrane channels (CatCh2) in smooth muscle (Acta2) and endothelium (Cdh5). Cardiac activation was separately controlled through activation of nodal/conducting cells or cardiac myocytes. We demonstrate combined effector and sensor function in biallelic mouse crosses: optical cardiac pacing and simultaneous cardiomyocyte Ca2+ imaging in Hcn4BAC-CatCh2/Myh6-GCaMP8 crosses. These experiments highlight the potential of these mice to explore cellular signaling in vivo, in complex tissue networks.
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Expresión Génica , Ratones/genética , Optogenética/métodos , Animales , Ratones TransgénicosRESUMEN
We investigate the interaction between a molecule and a pore mouth-a critical step in adsorption processes-by characterizing the conformation of a macrocyclic calix[4]arene-TiIV complex, which is grafted on the external surface of a zeotype (*-SVY). X-ray absorption and 13 C{1 H} CPMAS NMR spectroscopies independently detect a unique conformation of this complex when it is grafted at crystallographically equivalent locations that lie at the interface of 7â Å hemispherical microporous cavities and the external surface. Electronic structure calculations support the presence of this unique conformation, and suggest that it is brought about by a specific orientation of the macrocycle that maximizes non-covalent interactions between calix[4]arene upper-rim tert-butyl substituents and the microporous-cavity walls. Our comparative study provides a rare "snapshot" of a molecule partially confined at a pore mouth, an essential intermediate for adsorption into micropores, and demonstrates how surrounding environment controls this confinement in a sensitive fashion.
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Calixarenos/química , Compuestos Macrocíclicos/química , Compuestos Organometálicos/química , Fenoles/química , Titanio/química , Teoría Funcional de la Densidad , Modelos Moleculares , Estructura Molecular , Tamaño de la Partícula , Porosidad , Propiedades de SuperficieRESUMEN
Electron paramagnetic resonance (EPR) studies of the rhenium(II) complex Re(η5-Cp)(BDI) (1; BDI = N,N'-bis(2,6-diisopropylphenyl)-3,5-dimethyl-ß-diketiminate) have revealed that this species reversibly binds N2 in solution: flash frozen toluene solutions of 1 disclose entirely different EPR spectra at 10 K when prepared under N2 versus Ar atmospheres. This observation was additionally verified by the synthesis of stable CO and 2,6-xylylisocyanide (XylNC) adducts of 1, which display EPR features akin to those observed in the putative N2 complex. While we found that 1 displays an extremely large gmax value of 3.99, the binding of an additional ligand leads to substantial decreases in this value, displaying gmax values of ca. 2.4. Following the generation of isotopically enriched 15N2 and 13CO adducts of 1, HYSCORE experiments allowed for the measurement of the corresponding hyperfine couplings associated with spin delocalization onto the electron-accepting ligands in these species, which proved to be small. A cumulative assessment of the EPR data, when combined with insights provided by near-infrared (NIR) spectroscopy and time-dependent density functional theory (TDDFT) calculations, indicated that while the binding of electron acceptors to 1 does lead to decreases in gmax in relative accord with the field strength (i.e., π-acidity) of the variable ligand, the magnitude of these decreases is primarily due to the changes in electronic structure at the Re center.
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Monóxido de Carbono/química , Complejos de Coordinación/química , Cianuros/química , Iminas/química , Nitrógeno/química , Rutenio/química , Teoría Funcional de la Densidad , Espectroscopía de Resonancia por Spin del Electrón , Electrones , Estructura MolecularRESUMEN
The focus of this work is OS-CCSD-SPT(2), which is a second-order similarity transformed perturbation theory correction to opposite spin coupled cluster singles doubles, where in the latter the same-spin amplitudes are removed and the opposite-spin ones are solved self-consistently. OS-CCSD-SPT(2) is free of empirical parameters, has an instrinsic scaling of O(N6), and makes no use of triples. We demonstrate that, for non-multireference molecules, OS-CCSD-SPT(2) produces relative energies whose accuracy is significantly higher than what is generally expected of a triples-free model. For example, using PBE0 orbitals in the reference, OS-CCSD-SPT(2) exhibits a mean absolute deviation (MAD) of 1.13 kcal/mol with respect to CCSD(2F) benchmark values for the non-multireference subset of W4-08 atomization energies (cf. a MAD > 6.5 kcal/mol for CCSD) and a MAD of 0.68 kcal/mol for the energies of reactions generated from the W4-08 molecules. These MADs are reduced to 0.61 and 0.63 kcal/mol, respectively, by a simple one-parameter spin-component scaling of the OS-CCSD-SPT(2) same-spin correlation energy. OS-CCSD is also naturally amenable to higher order corrections: the associated third-order correction, OS-CCSD-SPT(3), which does involve connected triples and quadruples, exhibits a MAD of 0.44 kcal/mol for the same atomization-energy benchmark.
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Machine learning (ML) approximations to density functional theory (DFT) potential energy surfaces (PESs) are showing great promise for reducing the computational cost of accurate molecular simulations, but at present, they are not applicable to varying electronic states, and in particular, they are not well suited for molecular systems in which the local electronic structure is sensitive to the medium to long-range electronic environment. With this issue as the focal point, we present a new machine learning approach called "BpopNN" for obtaining efficient approximations to DFT PESs. Conceptually, the methodology is based on approaching the true DFT energy as a function of electron populations on atoms; in practice, this is realized with available density functionals and constrained DFT (CDFT). The new approach creates approximations to this function with neural networks. These approximations thereby incorporate electronic information naturally into a ML approach, and optimizing the model energy with respect to populations allows the electronic terms to self-consistently adapt to the environment, as in DFT. We confirm the effectiveness of this approach with a variety of calculations on LinHn clusters.
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INTRODUCTION: One of the major neuropathological features of Alzheimer's disease (AD) is the accumulation of amyloid-ß (Aß) protein in the brain. Evidence suggests that the low-density lipoprotein receptor-associated protein (RAP) binds strongly to Aß and enhances its cellular uptake and that decreased RAP expression correlates with increased Aß production in animal models of AD. METHODS: The current study examined whether RAP levels change in AD human brain tissue and whether they are related to the amount of AD pathology. RAP and NeuN levels were determined by Western blot, while low-density lipoprotein receptor-related protein 1 (LRP1), tau and Aß levels were determined by ELISA in the temporal cortex of 17 AD and 16 control cases. RESULTS: An increase in total Aß and insoluble and soluble tau protein was observed in AD brain tissue. In contrast, RAP levels were significantly decreased in AD brain tissue compared to controls. Correlation analysis revealed that levels of RAP correlated with both total Aß and soluble and insoluble tau levels. Neither LRP1 nor NeuN levels were significantly altered in AD brain tissue homogenates and did not correlate with Aß or tau protein levels. CONCLUSION: Reduction in RAP may contribute to the accumulation and aggregation of Aß in the AD brain.
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Enfermedad de Alzheimer , Encéfalo/metabolismo , Proteínas tau , Péptidos beta-Amiloides/metabolismo , Animales , Humanos , Proteína Asociada a Proteínas Relacionadas con Receptor de LDL , Proteínas tau/metabolismoRESUMEN
Cardiovascular disease is the leading cause of worldwide mortality. Intravital microscopy has provided unprecedented insight into leukocyte biology by enabling the visualization of dynamic responses within living organ systems at the cell-scale. The heart presents a uniquely dynamic microenvironment driven by periodic, synchronous electrical conduction leading to rhythmic contractions of cardiomyocytes, and phasic coronary blood flow. In addition to functions shared throughout the body, immune cells have specific functions in the heart including tissue-resident macrophage-facilitated electrical conduction and rapid monocyte infiltration upon injury. Leukocyte responses to cardiac pathologies, including myocardial infarction and heart failure, have been well-studied using standard techniques, however, certain questions related to spatiotemporal relationships remain unanswered. Intravital imaging techniques could greatly benefit our understanding of the complexities of in vivo leukocyte behavior within cardiac tissue, but these techniques have been challenging to apply. Different approaches have been developed including high frame rate imaging of the beating heart, explantation models, micro-endoscopy, and mechanical stabilization coupled with various acquisition schemes to overcome challenges specific to the heart. The field of cardiac science has only begun to benefit from intravital microscopy techniques. The current focused review presents an overview of leukocyte responses in the heart, recent developments in intravital microscopy for the murine heart, and a discussion of future developments and applications for cardiovascular immunology.
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Lesiones Cardíacas/inmunología , Microscopía Intravital/métodos , Animales , Leucocitos , Ratones , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Infarto del Miocardio , Miocitos CardíacosRESUMEN
A dicopper complex featuring a symmetrically bridging nitrile ligand and supported by a binucleating naphthyridine-based ligand, [Cu2(µ-η 1 :η 1 -MeCN)DPFN](NTf2)2, was treated with phosphaalkynes (RC[triple bond, length as m-dash]P, isoelectronic analogues of nitriles) to yield dicopper complexes that exhibit phosphaalkynes in rare µ-η 2:η 2 binding coordination modes. X-ray crystallography revealed that these unusual "tilted" structures exist in two isomeric forms (R "up" vs. R "sideways"), depending on the steric profile of the phosphaalkyne's alkyl group (R = Me, Ad, or t Bu). Only one isomer is observed in both solution and the solid state for R = Me (sideways) and t Bu (up). With intermediate steric bulk (R = Ad), the energy difference between the two geometries is small enough that both are observed in solution, and NMR spectroscopy and computations indicate that the solid-state structure corresponds to the minor isomer observed in solution. Meanwhile, treatment of [Cu2(µ-η 1:η 1-MeCN)DPFN](NTf2)2 with 2-butyne affords [Cu2(µ-η 2:η 2-(MeC[triple bond, length as m-dash]CMe))DPFN](NTf2)2: its similar ligand geometry demonstrates that the tilted µ-η 2:η 2 binding mode is not limited to phosphaalkynes but reflects a more general trend, which can be rationalized via an NBO analysis showing maximization of π-backbonding.
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Anti-Markovnikov additions to alkenes have been a longstanding goal of catalysis, and anti-Markovnikov addition of arenes to alkenes would produce alkylarenes that are distinct from those formed by acid-catalysed processes. Existing hydroarylations are either directed or occur with low reactivity and low regioselectivity for the n-alkylarene. Herein, we report the first undirected hydroarylation of unactivated alkenes with unactivated arenes that occurs with high regioselectivity for the anti-Markovnikov product. The reaction occurs with a nickel catalyst ligated by a highly sterically hindered N-heterocyclic carbene. Catalytically relevant arene- and alkene-bound nickel complexes have been characterized, and the rate-limiting step was shown to be reductive elimination to form the C-C bond. Density functional theory calculations, combined with second-generation absolutely localized molecular orbital energy decomposition analysis, suggest that the difference in activity between catalysts containing large and small carbenes results more from stabilizing intramolecular non-covalent interactions in the secondary coordination sphere than from steric hindrance.
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Alquenos/química , Complejos de Coordinación/química , Hidrocarburos Aromáticos/química , Níquel/química , Alquilación , Catálisis , Calor , Metano/análogos & derivados , Metano/química , Estructura Molecular , Oxidación-Reducción , Estereoisomerismo , TermodinámicaRESUMEN
OBJECTIVE: This study sought to describe the incidence inadequate prenatal care (IPNC) at an urban level II hospital in Hamilton, Ontario, and to compare the characteristics and outcomes of mothers who received IPNC and their newborns with those who received adequate prenatal care (APNC). This study is the first part of a mixed-methods research program aimed at informing the development of an interdisciplinary, patient-centred, prenatal care program for people who struggle to access conventional modes of care. METHODS: This retrospective cohort study compared mothers and neonates born at St. Joseph's Health Care Hamilton in 2016 with IPNC (fewer than or equal to four antenatal visits, or first visit in third trimester) with those born with APNC (five or more prenatal visits and initial visit before the third trimester). Cases and controls matched 3:1 for age and parity were identified through a retrospective chart review. RESULTS: In total 3235 charts were reviewed, and 69 cases of IPNC were identified (2.1%). The IPNC group had lower education and higher unemployment levels, as well as higher rates of smoking and drug use. Our primary and secondary outcomes of newborn custody loss, neonatal intensive care unit admission, and neonatal length of stay were significantly higher in the IPNC group. CONCLUSION: Patients delivering with IPNC represent a high-risk group with increased rates of adverse neonatal outcomes and newborn custody loss. This quantitative study will inform future research and innovative interdisciplinary program development aimed at increasing access to prenatal care in an effort to improve maternal and neonatal outcomes.
Asunto(s)
Complicaciones del Embarazo , Atención Prenatal/estadística & datos numéricos , Determinantes Sociales de la Salud , Desempleo/estadística & datos numéricos , Adolescente , Adulto , Custodia del Niño , Femenino , Humanos , Incidencia , Recién Nacido , Persona de Mediana Edad , Ontario/epidemiología , Paridad , Embarazo , Resultado del Embarazo , Estudios Retrospectivos , Población Urbana , Adulto JovenRESUMEN
In this work, we revisited the idea of using the coupled-cluster (CC) ground state formalism to target excited states. Our main focus was targeting doubly excited states and double core hole states. Typical equation-of-motion (EOM) approaches for obtaining these states struggle without higher-order excitations than doubles. We showed that by using a non-Aufbau determinant optimized via the maximum overlap method, the CC ground state solver can target higher energy states. Furthermore, just with singles and doubles (i.e., CCSD), we demonstrated that the accuracy of ΔCCSD and ΔCCSD(T) (triples) far surpasses that of EOM-CCSD for doubly excited states. The accuracy of ΔCCSD(T) is nearly exact for doubly excited states considered in this work. For double core hole states, we used an improved ansatz for greater numerical stability by freezing core hole orbitals. The improved methods, core valence separation (CVS)-ΔCCSD and CVS-ΔCCSD(T), were applied to the calculation of the double ionization potential of small molecules. Even without relativistic corrections, we observed qualitatively accurate results with CVS-ΔCCSD and CVS-ΔCCSD(T). Remaining challenges in ΔCC include the description of open-shell singlet excited states with the single-reference CC ground state formalism as well as excited states with genuine multireference character. The tools and intuition developed in this work may serve as a stepping stone toward directly targeting arbitrary excited states using ground state CC methods.