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BACKGROUND: The outbreak of the COVID-19 pandemic has had a profound impact on the circulation of seasonal respiratory viruses. This study aimed to compare the outcomes of SARS-CoV-2 and seasonal viruses in adults hospitalized with severe acute respiratory infection (SARI) during the COVID-19 pandemic. METHODS: This population-based cohort study included patients aged > 18 years hospitalized for SARI in Brazil between February 2020 and February 2023. The primary outcome was in-hospital mortality. A competing risk analysis was used to account for competing events. RESULTS: In total, 2,159,171 patients were included in the study. SARS-CoV-2 was the predominant virus (98.7%). The cumulative incidence of in-hospital mortality was 33.1%, 31.5%, 21.0%, 18.7%, and 18.6%, for patients positive for SARS-CoV-2, adenovirus, RSV, influenza, and other viruses, respectively. SARS-CoV-2 accounted for 99.3% of the deaths. Older age, male sex, comorbidities, hospitalization in the northern region, and oxygen saturation <95% were the common risk factors for death among all viruses. CONCLUSIONS: In this large cohort study, individuals infected with SARS-CoV-2 or adenovirus had the highest risk of mortality. Irrespective of the virus type, older age, male sex, comorbidities, hospitalization in vulnerable regions, and low oxygen saturation were associated with an increased risk of fatality.
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OBJECTIVE: The objective of this study was to estimate the vaccine effectiveness (VE) against hospitalization and severe illness in adolescents due to infection with SARS-CoV-2 variants (gamma, delta, and omicron). STUDY DESIGN: A test-negative, case-control analysis was conducted in Brazil from July 2021 to March 2022. We enrolled 8458 eligible individuals (12-19 years of age) hospitalized with an acute respiratory syndrome, including 3075 cases with laboratory-proven COVID-19 and 4753 controls with negative tests for COVID-19. The primary exposure of interest was vaccination status. The primary outcome was SARS-CoV-2 infection during gamma/delta vs omicron-predominant periods. The aOR for the association of prior vaccination and outcomes was used to estimate VE. RESULTS: In the pre-omicron period, VE against COVID-19 hospitalization was 88% (95% CI, 83%-92%) and has dropped to 59% (95% CI, 49%-66%) during the omicron period. For hospitalized cases of COVID-19, considering the entire period of the analysis, 2-dose schedule was moderately effective against intensive care unit admission (46%, [95% CI, 27-60]), need of mechanical ventilation (49%, [95% CI, 32-70]), severe COVID-19 (42%, [95% CI, 17-60]), and death (46%, [95% CI, 8-67]). There was a substantial reduction of about 40% in the VE against all end points, except for death, during the omicron-predominant period. Among cases, 240 (6.6%) adolescents died; of fatal cases, 224 (93.3%) were not fully vaccinated. CONCLUSION: Among adolescents, the VE against all end points was substantially reduced during the omicron-predominant period. Our findings suggest that the 2-dose regimen may be insufficient for SARS-CoV-2 variants and support the need for updated vaccines to provide better protection against severe COVID-19.
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COVID-19 , SARS-CoV-2 , Adolescente , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Eficacia de las Vacunas , Estudios de Casos y ControlesRESUMEN
Global nocturnal temperatures are rising more rapidly than daytime temperatures and have a large effect on crop productivity. In particular, stomatal conductance at night (gsn ) is surprisingly poorly understood and has not been investigated despite constituting a significant proportion of overall canopy water loss. Here, we present the results of 3 yr of field data using 12 spring Triticum aestivum genotypes which were grown in NW Mexico and subjected to an artificial increase in night-time temperatures of 2°C. Under nocturnal heating, grain yields decreased (1.9% per 1°C) without significant changes in daytime leaf-level physiological responses. Under warmer nights, there were significant differences in the magnitude and decrease in gsn , values of which were between 9 and 33% of daytime rates while respiration appeared to acclimate to higher temperatures. Decreases in grain yield were genotype-specific; genotypes categorised as heat tolerant demonstrated some of the greatest declines in yield in response to warmer nights. We conclude the essential components of nocturnal heat tolerance in wheat are uncoupled from resilience to daytime temperatures, raising fundamental questions for physiological breeding. Furthermore, this study discusses key physiological traits such as pollen viability, root depth and irrigation type may also play a role in genotype-specific nocturnal heat tolerance.
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Grano Comestible , Fitomejoramiento , Grano Comestible/genética , Hojas de la Planta/fisiología , Temperatura , CalorRESUMEN
BACKGROUND: Patients with kidney diseases (KD) appear to be at particularly high risk for severe COVID-19. This study aimed to characterize the clinical outcomes and risk factors for COVID-19-related death in a large cohort of hospitalized pediatric patients with KD. METHODS: We performed an analysis of all pediatric patients with KD and COVID-19 registered in SIVEP-Gripe, a Brazilian nationwide surveillance database, between February 16, 2020, and May 29, 2021. The primary outcome was time to death, which was evaluated considering discharge as a competitive risk by using cumulative incidence function. RESULTS: Among 21,591 hospitalized patients with COVID-19, 290 cases (1.3%) had KD. Of these, 59 (20.8%) had a fatal outcome compared with 7.5% of the non-KD cohort (P < 0.001). Pediatric patients with KD had an increased hazard of death compared with the non-KD cohort (Hazard ratio [HR] = 2.85, 95% CI 2.21-3.68, P < 0.0001). After adjustment, the factors associated with the death among KD patients were living in Northeast (HR 2.16, 95% CI 1.13-4.31) or North regions (HR 3.50, 95% CI 1.57-7.80), oxygen saturation < 95% at presentation (HR 2.31, 95% CI 1.30-4.10), and presence of two or more associated comorbidities (HR 2.10, 95% CI 1.08-4.04). CONCLUSIONS: Children and adolescents with KD had a higher risk of death compared with the non-KD cohort. The higher risk was associated with low oxygen saturation at admission, living in socioeconomically disadvantaged regions, and presence of other pre-existing comorbidities. A higher resolution version of the Graphical abstract is available as Supplementary information.
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COVID-19 , Enfermedades Renales , Humanos , Adolescente , Niño , COVID-19/epidemiología , SARS-CoV-2 , Niño Hospitalizado , Factores de Riesgo , Enfermedades Renales/epidemiologíaRESUMEN
This study aimed to evaluate the risk factors for COVID-19-related death in a large cohort of hospitalized children with hematological disorders. We performed an analysis of all pediatric patients with COVID-19 registered in a Brazilian nationwide surveillance database between February 2020 and May 2021. The primary outcome was time to death, which was evaluated considering discharge as a competitive risk by using the cumulative incidence function. Among 21,591 hospitalized pediatric patients with COVID-19, 596 cases (2.8%) had hematological diseases. Sixty-one children (27.4%) with malignant hematological diseases had a fatal outcome as compared with 4.2% and 7.4% of nonmalignant hematological and nonhematological cohorts, respectively ( P <0.0001). Children with hematological diseases had a significant increased hazard of death compared with those without these conditions (hazard ratio [HR],=2.40, 95% confidence interval, 1.98 - 2.91). In multivariable analysis, the factors associated with death were the presence of malignant hematological disease (HR, 2.22, 95% CI 1.47 - 3.36), age >10 years (HR 2.19, 95% CI 1.46 - 3.19), male (HR 1.52, 95% CI 1.02 - 2.27), oxygen saturation <95% (HR 2.02, 95% CI 1.38 - 2.96), and abdominal pain at admission (HR 2.75, 95% CI 1.76 - 4.27). Children with malignant hematological diseases had a higher risk of death compared with those without these disorders.
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COVID-19 , Enfermedades Hematológicas , Humanos , Masculino , Adolescente , Niño , COVID-19/epidemiología , Niño Hospitalizado , Estudios Retrospectivos , Mortalidad Hospitalaria , Factores de Riesgo , Enfermedades Hematológicas/complicacionesRESUMEN
OBJECTIVE: To evaluate the severity and clinical outcomes of the SARS-CoV-2 gamma variant in children and adolescents hospitalized with COVID-19 in Brazil. STUDY DESIGN: In this observational retrospective cohort study, we performed an analysis of all 21 591 hospitalized patients aged <20 years with confirmed SARS-CoV-2 infection registered in a national database in Brazil. The cohort was divided into 2 groups according to the predominance of SARS-CoV-2 lineages (WAVE1, n = 11 574; WAVE2, n = 10 017). The characteristics of interest were age, sex, geographic region, ethnicity, clinical presentation, and comorbidities. The primary outcome was time to death, which was evaluated by competing-risks analysis, using cumulative incidence functions. A predictive Fine and Gray competing-risks model was developed based on the WAVE1 cohort with temporal validation in the WAVE2 cohort. RESULTS: Compared with children and adolescents admitted during the first wave, those admitted during the second wave had significantly more hypoxemia (52.5% vs 41.1%; P < .0001) and intensive care unit admissions (28.3% vs 24.9%; P < .0001) and needed more noninvasive ventilatory support (37.3% vs 31.6%; P < .0001). In-hospital deaths and death rates were 896 (7.7%) in the first wave and 765 (7.6%) in the second wave (P = .07). The prediction model of death included age, ethnicity, region, respiratory symptoms, and comorbidities. In the validation set (WAVE2), the C statistic was 0.750 (95% CI, 0.741-0.758; P < .0001). CONCLUSIONS: This large national study found a more severe spectrum of risk for pediatric patients with COVID-19 caused by the gamma variant. However, there was no difference regarding the probability of death between the waves.
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COVID-19 , SARS-CoV-2 , Adolescente , COVID-19/epidemiología , Niño , Hospitalización , Humanos , Pandemias , Estudios RetrospectivosRESUMEN
Joint range of motion (RoM) analyses are fundamental to our understanding of how an animal moves throughout its ecosystem. Recent technological advances allow for more detailed quantification of this RoM (e.g. including interaction of degrees of freedom) both in ex vivo joints and in vivo experiments. Both types of data have been used to draw comparisons with fossils to reconstruct locomotion. Salamanders are often used as analogues for early tetrapod locomotion; testing such hypotheses requires an in-depth analysis of salamander joint RoM. Here, we provide a detailed dataset of the ex vivo ligamentous rotational joint RoM in the hindlimb of the fire salamander Salamandra salamandra, using a new method for collecting and visualising joint RoM. We also characterise in vivo joint RoM used during walking, via scientific rotoscoping and compare the in vivo and ex vivo data. In summary, we provide (1) a new method for joint RoM data experiments and (2) a detailed analysis of both in vivo and ex vivo data of salamander hindlimbs, which can be used for comparative studies.
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Salamandra , Animales , Ecosistema , Rango del Movimiento Articular , Urodelos , CaminataRESUMEN
Quantifying joint range of motion (RoM), the reachable poses at a joint, has many applications in research and clinical care. Joint RoM measurements can be used to investigate the link between form and function in extant and extinct animals, to diagnose musculoskeletal disorders and injuries or monitor rehabilitation progress. However, it is difficult to visually demonstrate how the rotations of the joint axes interact to produce joint positions. Here, we introduce the spherical frame projection (SFP), which is a novel 3D visualisation technique, paired with a complementary data collection approach. SFP visualisations are intuitive to interpret in relation to the joint anatomy because they 'trace' the motion of the coordinate system of the distal bone at a joint relative to the proximal bone. Furthermore, SFP visualisations incorporate the interactions of degrees of freedom, which is imperative to capture the full joint RoM. For the collection of such joint RoM data, we designed a rig using conventional motion capture systems, including live audio-visual feedback on torques and sampled poses. Thus, we propose that our visualisation and data collection approach can be adapted for wide use in the study of joint function.
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Movimiento , Animales , Fenómenos Biomecánicos , Rango del Movimiento ArticularRESUMEN
BACKGROUND: Diabetes has been recognized as a major comorbidity for COVID-19 severity in adults. This study aimed to characterize the clinical outcomes and risk factors for COVID-19-related death in a large cohort of hospitalized pediatric patients with diabetes. METHODS: We performed an analysis of all pediatric patients with diabetes and COVID-19 registered in SIVEP-Gripe, a Brazilian nationwide surveillance database, between February 2020 and May 2021. The primary outcome was time to death, which was evaluated considering discharge as a competitive risk by using cumulative incidence function. RESULTS: Among 21,591 hospitalized pediatric patients with COVID-19, 379 (1.8%) had diabetes. Overall, children and adolescents with diabetes had a higher prevalence of ICU admission (46.6% vs. 26%), invasive ventilation (16.9% vs. 10.3%), and death (15% vs. 7.6%) (all P < 0.0001). Children with diabetes had twice the hazard of death compared with pediatric patients without diabetes (Hazard ratio [HR] = 2.0, 95% CI, 1.58-2.66). Among children with diabetes, four covariates were independently associated with the primary outcome, living in the poorest regions of the country (Northeast, HR, 2.17, 95% CI 1.18-4.01, and North, (HR 4.0, 95% CI 1.79-8.94), oxygen saturation < 95% at admission (HR 2.97, 95% CI 1.64-5.36), presence of kidney disorders (HR 3.39, 95% CI 1.42-8.09), and presence of obesity (HR 3.77, 95% CI 1.83-7.76). CONCLUSION: Children and adolescents with diabetes had a higher risk of death compared with patients without diabetes. The higher risk of death was associated with clinical and socioeconomic factors.
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COVID-19 , Diabetes Mellitus , Adolescente , Adulto , COVID-19/complicaciones , Niño , Niño Hospitalizado , Comorbilidad , Diabetes Mellitus/epidemiología , Hospitalización , Humanos , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2RESUMEN
BACKGROUND: The grading of urinary tract dilatation (UTD) on postnatal sonography is a fundamental step to establish rational management for infants with antenatal hydronephrosis (ANH). The aim of this study was to compare the prediction accuracy of UTD grading systems for relevant clinical outcomes. In addition, we propose a refinement of the UTD classification by adding quantitative measurements and evaluate its impact on accuracy. METHODS: Between 1989 and 2019, 447 infants diagnosed with isolated AHN were prospectively followed. The events of interest were surgical interventions and kidney injury. Comparison of performance of the grading systems and the impact on the accuracy of a modified UTD classification (including the size of the kidney parenchyma) was assessed by the area under the receiver-operating characteristic curve (AUC). RESULTS: Of 447 infants, 131 (29%) underwent surgical intervention and 26 (5.8%) had developed kidney injury. The median follow-up time was 9 years (IQ range, 7-12 years). The performance for detecting the need for surgical intervention was excellent for all grading systems (AUC > 0.90). However, for predicting kidney injury, the modified UTD classification exhibited significant improvement in accuracy (AUC = 0.913, 95%CI, 0.883-0.937) as compared with UTD classification (AUC = 0.887, 95%CI, 0.854-0.915) (P = 0.027). CONCLUSIONS: Our study confirms that the hydronephrosis grading systems provide excellent accuracy in discriminating patients who need surgical intervention among infants with AHN. Our findings suggest that the inclusion of kidney parenchymal thickness to UTD classification might increase the accuracy for predicting infants who may develop kidney injury. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Hidronefrosis , Sistema Urinario , Dilatación , Femenino , Humanos , Hidronefrosis/diagnóstico por imagen , Hidronefrosis/etiología , Lactante , Riñón/diagnóstico por imagen , Masculino , Embarazo , Estudios Retrospectivos , Ultrasonografía Prenatal , Sistema Urinario/diagnóstico por imagenRESUMEN
Based on an extensive analysis of public databases, we provide an overview of the global scientific output and describe the dynamics of the profound changes in the scientific enterprise during the last decades. The analysis included the scientific production of 53 countries over the 1996-2018 period. During this period, the production of articles per year has tripled. There was a strong correlation between the growth of the global gross domestic product and the increase in the number of articles (R2 = 0.973, P<0.001). Six countries showed a robust increment of their scientific production and are currently among the top 20 in the ranking of world scientific production (China, India, South Korea, Brazil, Turkey, and Iran). The mean annual growth rate was about 12.7% for these six countries. The share of the global scientific production of these countries increased from 7% in 1996 to 27.8% in 2018. Conversely, the participation of the 10 most traditional countries has dropped from 73% to 45% during the same period. In conclusion, we believe that our findings may contribute to further studies aiming to evaluate the impact and changes of the scientific endeavor over the next years in light of the forthcoming new world framework.
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COVID-19 , Humanos , Brasil , China , Bases de Datos Factuales , IndiaRESUMEN
The cure fraction models are intended to analyze lifetime data from populations where some individuals are immune to the event under study, and allow a joint estimation of the distribution related to the cured and susceptible subjects, as opposed to the usual approach ignoring the cure rate. In situations involving small sample sizes with many censored times, the detection of nonfinite coefficients may arise via maximum likelihood. This phenomenon is commonly known as monotone likelihood (ML), occurring in the Cox and logistic regression models when many categorical and unbalanced covariates are present. An existing solution to prevent the issue is based on the Firth correction, originally developed to reduce the estimation bias. The method ensures finite estimates by penalizing the likelihood function. In the context of mixture cure models, the ML issue is rarely discussed in the literature; therefore, this topic can be seen as the first contribution of our paper. The second major contribution, not well addressed elsewhere, is the study of the ML issue in cure mixture modeling under the flexibility of a semiparametric framework to handle the baseline hazard. We derive the modified score function based on the Firth approach and explore finite sample size properties of the estimators via a Monte Carlo scheme. The simulation results indicate that the performance of coefficients related to the binary covariates are strongly affected to the imbalance degree. A real illustration, in the melanoma dataset, is discussed using a relatively novel data set collected in a Brazilian university hospital.
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Algoritmos , Modelos Estadísticos , Sesgo , Simulación por Computador , Humanos , Funciones de Verosimilitud , Método de Montecarlo , Análisis de SupervivenciaRESUMEN
Background and Objectives: Perilipins 1-5 (PLIN) are lipid droplet-associated proteins that participate in regulating lipid storage and metabolism, and the PLIN5 isoform is known to form a nuclear complex with peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) to regulate lipid metabolism gene expression. However, the changes in PLIN isoforms' expression in response to pregnancy-induced cardiac hypertrophy are not thoroughly studied. The aim of this study was to quantify the mRNA expression of PLIN isoforms and PGC-1α along with total triacylglycerol (TAG) and cholesterol levels during late pregnancy and the postpartum period in the rat left ventricle. Materials and Methods: Female Sprague-Dawley rats were divided into three groups: non-pregnant, late pregnancy, and postpartum. The mRNA and protein levels were evaluated using quantitative RT-PCR and Western blotting, respectively. TAG and total cholesterol content were evaluated using commercial colorimetric methods. Results: The expression of mRNAs for PLIN1, 2, and 5 increased during pregnancy and the postpartum period. PGC-1α mRNA and protein expression increased during pregnancy and the postpartum period. Moreover, TAG and total cholesterol increased during pregnancy and returned to basal levels after pregnancy. Conclusions: Our results demonstrate that pregnancy upregulates differentially the expression of PLIN isoforms along with PGC-1α, suggesting that together they might be involved in the regulation of the lipid metabolic shift induced by pregnancy.
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Receptores Activados del Proliferador del Peroxisoma , Factores de Transcripción , Ratas , Femenino , Animales , Embarazo , Perilipina-1 , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Ratas Sprague-Dawley , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Cardiomegalia/genética , Cardiomegalia/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Triglicéridos , ColesterolRESUMEN
Gram-negative bacteria release nanovesicles, called outer membrane vesicles (OMVs), from their outer membrane. Proteomics has been used to determine their composition. OMVs contain proteins able to elicit an immune response, so they have been proposed as a model to develop acellular vaccines. In this study, OMVs of Brucella suis, B. ovis, B. canis, and B. neotomae were purified and analyzed by SDS-PAGE, transmission electron microscopy and liquid chromatography coupled to mass spectrometry to determine the pan-proteome of these vesicles. In addition, antigenic proteins were detected by western blot with anti-Brucella sera. The in silico analysis of the pan-proteome revealed many homologous proteins, such as Omp16, Omp25, Omp31, SodC, Omp2a, and BhuA. Proteins contained in the vesicles from different Brucella species were detected by anti-Brucella sera. The occurrence of previously described immunogenic proteins derived from OMVs supports the use of these vesicles as candidates to be evaluated as an acellular brucellosis vaccine.
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Antígenos Bacterianos , Proteínas Bacterianas , Brucella , Proteoma , Animales , Antígenos Bacterianos/genética , Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Brucella/genética , Brucella/metabolismo , Brucella canis , Brucella ovis , Brucella suis , Electroforesis en Gel de Poliacrilamida , Proteoma/genética , ProteómicaRESUMEN
Theories attempting to explain species coexistence in plant communities have argued in favour of species' capacities to occupy a multidimensional niche with spatial, temporal and biotic axes. We used the concept of hydrological niche segregation to learn how ecological niches are structured both spatially and temporally and whether small scale humidity gradients between adjacent niches are the main factor explaining water partitioning among tree species in a highly water-limited semiarid forest ecosystem. By combining geophysical methods, isotopic ecology, plant ecophysiology and anatomical measurements, we show how coexisting pine and oak species share, use and temporally switch between diverse spatially distinct niches by employing a set of functionally coupled plant traits in response to changing environmental signals. We identified four geospatial niches that turned into nine, when considering the temporal dynamics of the wetting/drying cycles in the substrate and the particular plant species adaptations to garner, transfer, store and use water. Under water scarcity, pine and oak exhibited water use segregation from different niches, yet under maximum drought when oak trees crossed physiological thresholds, niche overlap occurred. The identification of niches and mechanistic understanding of when and how species use them will help unify theories of plant coexistence and competition.
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Ecosistema , Árboles/fisiología , Deshidratación , Ambiente , Pinus/metabolismo , Pinus/fisiología , Fenómenos Fisiológicos de las Plantas , Tallos de la Planta/metabolismo , Quercus/metabolismo , Quercus/fisiología , Lluvia , Árboles/metabolismo , Xilema/metabolismoRESUMEN
Muscle force-length dynamics are governed by intrinsic contractile properties, motor stimulation and mechanical load. Although intrinsic properties are well characterised, physiologists lack in vitro instrumentation to account for combined effects of limb inertia, musculoskeletal architecture and contractile dynamics. We introduce in vitro virtual reality (in vitro-VR) which enables in vitro muscle tissue to drive a musculoskeletal jumping simulation. In hardware, muscle force from a frog plantaris was transmitted to a software model where joint torques, inertia and ground reaction forces were computed to advance the simulation at 1â kHz. To close the loop, simulated muscle strain was returned to update in vitro length. We manipulated (1) stimulation timing and (2) the virtual muscle's anatomical origin. This influenced interactions among muscular, inertial, gravitational and contact forces dictating limb kinematics and jump performance. We propose that in vitro-VR can be used to illustrate how neuromuscular control and musculoskeletal anatomy influence muscle dynamics and biomechanical performance.
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Realidad Virtual , Fenómenos Biomecánicos , Simulación por Computador , Modelos Biológicos , Contracción Muscular , Músculo Esquelético , Programas InformáticosRESUMEN
Standard inference procedures for the Cox model involve maximizing the partial likelihood function. Monotone partial likelihood is an issue that frequently happens in the analysis of health science studies. Monotone likelihood mainly occurs in samples with substantial censoring of survival times and is associated with categorical covariates. In particular, and more frequently, it usually happens when one level of a categorical covariate has just experienced censoring times. In order to overcome this problem, Heinze and Schemper proposed an adjusted partial likelihood score function obtained by suitably adapting the general approach of Firth for mean bias reduction. The procedure is effective in preventing infinite estimates. As an alternative solution, we propose an approach based on the adjusted score function recently suggested by Kenne Pagui et al for median bias reduction. This procedure also solves the infinite estimate problem and has an additional advantage of being invariant under componentwise reparameterizations. This latter fact is fundamental under Cox model since hazards ratio interpretation is obtained by exponentiating parameter estimates. Numerical studies of the proposed method suggest better inference properties than those of the mean bias reduction. A real-data application related to a melanoma skin dataset is used as illustration for a comparison basis of the methods.
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Modelos de Riesgos Proporcionales , Sesgo , Humanos , Funciones de VerosimilitudRESUMEN
Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering cAMP in cystic tissues through the inhibition of the type-2 vasopressin receptor (V2R) constitutes a validated strategy to reduce disease progression. We identified a peptide from green mamba venom that exhibits nanomolar affinity for the V2R without any activity on 155 other G-protein-coupled receptors or on 15 ionic channels. Mambaquaretin-1 is a full antagonist of the V2R activation pathways studied: cAMP production, beta-arrestin interaction, and MAP kinase activity. This peptide adopts the Kunitz fold known to mostly act on potassium channels and serine proteases. Mambaquaretin-1 interacts selectively with the V2R through its first loop, in the same manner that aprotinin inhibits trypsin. Injected in mice, mambaquaretin-1 increases in a dose-dependent manner urine outflow with concomitant reduction of urine osmolality, indicating a purely aquaretic effect associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of PKD, daily treated with 13 [Formula: see text]g of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts than control mice. Neither tachyphylaxis nor apparent toxicity has been noted. Mambaquaretin-1 represents a promising therapeutic agent against PKDs.
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Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Dendroaspis , Péptidos Natriuréticos/farmacología , Péptidos/farmacología , Enfermedades Renales Poliquísticas/tratamiento farmacológico , Receptores de Vasopresinas/genética , Venenos de Serpiente/farmacología , Animales , Benzazepinas/farmacología , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , AMP Cíclico/metabolismo , Femenino , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Enfermedades Renales Poliquísticas/metabolismo , Transducción de Señal , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Factores de Tiempo , Tolvaptán , Tripsina/químicaRESUMEN
Recent migrants to the United States face various stressors, including adjustment to new community norms and practices. To ease this transition, migrant groups have traditionally formed enclaves where they might live in close proximity and access institutions designed to serve their cultural interests. For newer migrant groups, such as Brazilians residing in New England, neighborhood social cohesion may therefore be particularly important for buffering against serious psychological distress. We use representative data from the 2007 Boston Metropolitan Immigrant Health and Legal Status Survey to estimate the association of serious psychological distress with neighborhood-level social cohesion among foreign-born Brazilian adults. We find that serious psychological distress is inversely related to neighborhood social cohesion (OR 0.66, 95% CI 0.46, 0.94). Annual earnings were also negatively associated with distress (OR 0.97, 95% CI 0.93, 0.99). Our findings suggest that neighborhood social ties may buffer against serious psychological distress for Brazilian migrants in New England.