Mortality among Hospitalized Dengue Patients with Comorbidities in Mexico, Brazil, and Colombia.

Dengue patients with comorbidities may be at higher risk of death. In this cross-sectional study, healthcare databases from Mexico (2008-2014), Brazil (2008-2015), and Colombia (2009-2017) were used to identify hospitalized dengue cases and their comorbidities. Case fatality rates (CFRs), relative risk, and odds ratios (OR) for in-hospital mortality were determined. Overall, 678,836 hospitalized dengue cases were identified: 68,194 from Mexico, 532,821 from Brazil, and 77,821 from Colombia. Of these, 35%, 5%, and 18% were severe dengue, respectively. Severe dengue and age ≥ 46 years were associated with increased risk of in-hospital mortality. Comorbidities were identified in 8%, 1%, and 4% of cases in Mexico, Brazil, and Colombia, respectively. Comorbidities increased hospitalized dengue CFRs 3- to 17-fold; CFRs were higher with comorbidities regardless of dengue severity or age. The odds of in-hospital mortality were significantly higher in those with pulmonary disorders (11.6 [95% CI 7.4-18.2], 12.7 [95% CI 9.3-17.5], and 8.0 [95% CI 4.9-13.1] in Mexico, Brazil, and Colombia, respectively), ischemic heart disease (23.0 [95% CI 6.6-79.6], 5.9 [95% CI 1.4-24.6], and 7.0 [95% CI 1.9-25.5]), and renal disease/failure (8.3 [95% CI 4.8-14.2], 8.0 [95% CI 4.5-14.4], and 9.3 [95% CI 3.1-28.0]) across the three countries; the odds of in-hospital mortality from dengue with comorbidities was at least equivalent or higher than severe dengue alone (4.5 [95% CI 3.4-6.1], 9.6 [95% CI 8.6-10.6], and 9.0 [95% CI 6.8-12.0). In conclusion, the risk of death because of dengue increases with comorbidities independently of age and/or disease severity.

Comorbidities increase in-hospital mortality in dengue patients in Brazil.

Dengue remains an unmet public health burden. We determined risk factors for dengue in-hospital mortality in Brazil. Of 326,380 hospitalised dengue cases in 9-45-year-old individuals, there were 971 deaths. Risk of dying was 11-times higher in the presence of underlying common comorbidities (renal, infectious, pulmonary disease and diabetes), similar to the risk of dying from severe dengue and much higher with the combination. Ensuring access to integrated dengue preventative measures in individuals aged ≥ 9 years including those with comorbidities may help achieve the WHO objective of 50% reduction in mortality and 25% reduction in morbidity due to dengue by 2020.

Comorbidities increase in-hospital mortality in dengue patients in Brazil

Dengue remains an unmet public health burden. We determined risk factors for dengue in-hospital mortality in Brazil. Of 326,380 hospitalised dengue cases in 9-45-year-old individuals, there were 971 deaths. Risk of dying was 11-times higher in the presence of underlying common comorbidities (renal, infectious, pulmonary disease and diabetes), similar to the risk of dying from severe dengue and much higher with the combination. Ensuring access to integrated dengue preventative measures in individuals aged ≥ 9 years including those with comorbidities may help achieve the WHO objective of 50% reduction in mortality and 25% reduction in morbidity due to dengue by 2020.

Multi-scale tracking reveals scale-dependent chromatin dynamics after DNA damage.

The dynamic organization of genes inside the nucleus is an important determinant for their function. Using fast DNA tracking microscopy in S. cerevisiae cells and improved analysis of mean square displacements, we quantified DNA motion at time scales ranging from 10 milliseconds to minute and found that following DNA damage, DNA exhibits distinct sub-diffusive regimes. In response to double-strand breaks, chromatin is more mobile at large time scales but, surprisingly, its mobility is reduced at short time scales. This effect is even more pronounced at the site of damage. Such a pattern of dynamics is consistent with a global increase in chromatin persistence length in response to DNA damage. Scale-dependent nuclear exploration is regulated by the Rad51 repair protein, both at the break and throughout the genome. We propose a model in which stiffening of the damaged ends by the repair complex, combined with global increased stiffness, act like a "needle in a ball of yarn", enhancing the ability of the break to traverse the chromatin meshwork.

Intra-Nuclear Single-Particle Tracking (I-SPT) to Reveal the Functional Architecture of Chromosomes.

Chromosome architecture needs to be investigated in relation with the chemical function of DNA. The kinetics of gene expression, DNA replication, and repair are driven by the mechanisms by which a functional nuclear protein finds its substrate in the nucleus. Single-particle tracking (SPT) is a method to quantify fluorescent molecules dynamics from the tracks of the single molecules recorded by high-resolution microscopes. SPT offers direct observation of the movement and single-molecule resolution. Usually SPT is performed on membranes because of higher contrast. Here, we introduce a novel method to record the trajectories of weakly fluorescent molecules in the nucleus of living cells. I-SPT uses some specific detection and analysis tools to enable the computation of reliable statistics on nuclear particle movement.

Single-molecule tracking in live cells reveals distinct target-search strategies of transcription factors in the nucleus.

Gene regulation relies on transcription factors (TFs) exploring the nucleus searching their targets. So far, most studies have focused on how fast TFs diffuse, underestimating the role of nuclear architecture. We implemented a single-molecule tracking assay to determine TFs dynamics. We found that c-Myc is a global explorer of the nucleus. In contrast, the positive transcription elongation factor P-TEFb is a local explorer that oversamples its environment. Consequently, each c-Myc molecule is equally available for all nuclear sites while P-TEFb reaches its targets in a position-dependent manner. Our observations are consistent with a model in which the exploration geometry of TFs is restrained by their interactions with nuclear structures and not by exclusion. The geometry-controlled kinetics of TFs target-search illustrates the influence of nuclear architecture on gene regulation, and has strong implications on how proteins react in the nucleus and how their function can be regulated in space and time.

Single cell correlation fractal dimension of chromatin: a framework to interpret 3D single molecule super-resolution.

Chromatin is a major nuclear component, and it is an active matter of debate to understand its different levels of spatial organization, as well as its implication in gene regulation. Measurements of nuclear chromatin compaction were recently used to understand how DNA is folded inside the nucleus and to detect cellular dysfunctions such as cancer. Super-resolution imaging opens new possibilities to measure chromatin organization in situ. Here, we performed a direct measure of chromatin compaction at the single cell level. We used histone H2B, one of the 4 core histone proteins forming the nucleosome, as a chromatin density marker. Using photoactivation localization microscopy (PALM) and adaptive optics, we measured the three-dimensional distribution of H2B with nanometric resolution. We computed the distribution of distances between every two points of the chromatin structure, namely the Ripley K(r) distribution. We found that the K(r) distribution of H2B followed a power law, leading to a precise measurement of the correlation fractal dimension of chromatin of 2.7. Moreover, using photoactivable GFP fused to H2B, we observed dynamic evolution of chromatin sub-regions compaction. As a result, the correlation fractal dimension of chromatin reported here can be interpreted as a dynamically maintained non-equilibrium state.