Predictors of mortality in HIV-associated hospitalizations in Portugal: a hierarchical survival model

<p>Abstract</p> <p>Background</p> <p>The beneficial effects of highly active antiretroviral therapy, increasing survival and the prevention of AIDS defining illness development are well established. However, the annual Portuguese hospital mortality is still higher than expected. It is crucial to understand the hospitalization behaviour to better allocate resources. This study investigates the predictors of mortality in HIV associated hospitalizations in Portugal through a hierarchical survival model.</p> <p>Methods</p> <p>The study population consists of 12,078 adult discharges from patients with HIV infection diagnosis attended at Portuguese hospitals from 2005–2007 that were registered on the diagnosis-related groups' database.</p> <p>We used discharge and hospital level variables to develop a hierarchical model. The discharge level variables were: age, gender, type of admission, type of diagnoses-related group, related HIV complication, the region of the patient's residence, the number of diagnoses and procedures, the Euclidean distance from hospital to the centroid of the patient's ward, and if patient lived in the hospital's catchment area. The hospital characteristics include size and hospital classification according to the National Health System. Kaplan-Meier plots were used to examine differences in survival curves. Cox proportional hazard models with frailty were applied to identify independent predictors of hospital mortality and to calculate hazard ratios (HR).</p> <p>Results</p> <p>The Cox proportional model with frailty showed that male gender, older patient, great number of diagnoses and pneumonia increased the hazard of HIV related hospital mortality. On the other hand tuberculosis was associated with a reduced risk of death. Central hospital discharge also presents less risk of mortality.</p> <p>The frailty variance was small but statistically significant, indicating hazard ratio heterogeneity among hospitals that varied between 0.67 and 1.34, and resulted in two hospitals with HR different from the average risk.</p> <p>Conclusion</p> <p>The frailty model suggests that there are unmeasured factors affecting mortality in HIV associated hospitalizations. Consequently, for healthcare policy purposes, hospitals should not all be treated in an equal manner.</p

Egg Production in a Coastal Seabird, the Glaucous-Winged Gull (Larus glaucescens), Declines during the Last Century

Seabirds integrate information about oceanic ecosystems across time and space, and are considered sensitive indicators of marine conditions. To assess whether hypothesized long-term foodweb changes such as forage fish declines may be reflected in a consumer's life history traits over time, I used meta-regression to evaluate multi-decadal changes in aspects of egg production in the glaucous-winged gull (Larus glaucescens), a common coastal bird. Study data were derived from literature searches of published papers and unpublished historical accounts, museum egg collections, and modern field studies, with inclusion criteria based on data quality and geographic area of the original study. Combined historical and modern data showed that gull egg size declined at an average of 0.04 cc y−1 from 1902 (108 y), equivalent to a decline of 5% of mean egg volume, while clutch size decreased over 48 y from a mean of 2.82 eggs per clutch in 1962 to 2.25 in 2009. There was a negative relationship between lay date and mean clutch size in a given year, with smaller clutches occurring in years where egg laying commenced later. Lay date itself advanced over time, with commencement of laying presently (2008–2010) 7 d later than in previous studies (1959–1986). This study demonstrates that glaucous-winged gull investment in egg production has declined significantly over the past ∼50–100 y, with such changes potentially contributing to recent population declines. Though gulls are generalist feeders that should readily be able to buffer themselves against food web changes, they are likely nutritionally constrained during the early breeding period, when egg production requirements are ideally met by consumption of high-quality prey such as forage fish. This study's results suggest a possible decline in the availability of such prey, and the incremental long-term impoverishment of a coastal marine ecosystem bordering one of North America's rapidly growing urban areas

Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells

BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naive cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGF beta/SMAD (transforming growth factor-beta/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naive cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients.Fapesp-grant number 2012/04194-1, 2013/05172-4, 2014/24400-0 and 2015/10821-7, CNPq-grant number 150447/2013-2 and 471512/2013-3 and PRODOC-grant no 3193-32/2010. Work in the lab of KS Smalley was supported by the National Institutes of Health grants R01 CA161107, R21 CA198550, and Skin SPORE grant P50 CA168536info:eu-repo/semantics/publishedVersio

Deregulation of CREB Signaling Pathway Induced by Chronic Hyperglycemia Downregulates NeuroD Transcription

CREB mediates the transcriptional effects of glucose and incretin hormones in insulin-target cells and insulin-producing β-cells. Although the inhibition of CREB activity is known to decrease the β-cell mass, it is still unknown what factors inversely alter the CREB signaling pathway in β-cells. Here, we show that β-cell dysfunctions occurring in chronic hyperglycemia are not caused by simple inhibition of CREB activity but rather by the persistent activation of CREB due to decreases in protein phophatase PP2A. When freshly isolated rat pancreatic islets were chronically exposed to 25 mM (high) glucose, the PP2A activity was reduced with a concomitant increase in active pCREB. Brief challenges with 15 mM glucose or 30 µM forskolin after 2 hour fasting further increased the level of pCREB and consequently induced the persistent expression of ICER. The excessively produced ICER was sufficient to repress the transcription of NeuroD, insulin, and SUR1 genes. In contrast, when islets were grown in 5 mM (low) glucose, CREB was transiently activated in response to glucose or forskolin stimuli. Thus, ICER expression was transient and insufficient to repress those target genes. Importantly, overexpression of PP2A reversed the adverse effects of chronic hyperglycemia and successfully restored the transient activation of CREB and ICER. Conversely, depletion of PP2A with siRNA was sufficient to disrupt the negative feedback regulation of CREB and induce hyperglycemic phenotypes even under low glucose conditions. Our findings suggest that the failure of the negative feedback regulation of CREB is the primary cause for β-cell dysfunctions under conditions of pathogenic hyperglycemia, and PP2A can be a novel target for future therapies aiming to protect β-cells mass in the late transitional phase of non-insulin dependent type 2 diabetes (NIDDM)

Climate simulations for 1880-2003 with GISS modelE

We carry out climate simulations for 1880-2003 with GISS modelE driven by ten measured or estimated climate forcings. An ensemble of climate model runs is carried out for each forcing acting individually and for all forcing mechanisms acting together. We compare side-by-side simulated climate change for each forcing, all forcings, observations, unforced variability among model ensemble members, and, if available, observed variability. Discrepancies between observations and simulations with all forcings are due to model deficiencies, inaccurate or incomplete forcings, and imperfect observations. Although there are notable discrepancies between model and observations, the fidelity is sufficient to encourage use of the model for simulations of future climate change. By using a fixed well-documented model and accurately defining the 1880-2003 forcings, we aim to provide a benchmark against which the effect of improvements in the model, climate forcings, and observations can be tested. Principal model deficiencies include unrealistically weak tropical El Nino-like variability and a poor distribution of sea ice, with too much sea ice in the Northern Hemisphere and too little in the Southern Hemisphere. The greatest uncertainties in the forcings are the temporal and spatial variations of anthropogenic aerosols and their indirect effects on clouds.Comment: 44 pages; 19 figures; Final text accepted by Climate Dynamic

Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema

<p>Abstract</p> <p>Background</p> <p>Smoking is a known cause of the outcomes COPD, chronic bronchitis (CB) and emphysema, but no previous systematic review exists. We summarize evidence for various smoking indices.</p> <p>Methods</p> <p>Based on MEDLINE searches and other sources we obtained papers published to 2006 describing epidemiological studies relating incidence or prevalence of these outcomes to smoking. Studies in children or adolescents, or in populations at high respiratory disease risk or with co-existing diseases were excluded. Study-specific data were extracted on design, exposures and outcomes considered, and confounder adjustment. For each outcome RRs/ORs and 95% CIs were extracted for ever, current and ex smoking and various dose response indices, and meta-analyses and meta-regressions conducted to determine how relationships were modified by various study and RR characteristics.</p> <p>Results</p> <p>Of 218 studies identified, 133 provide data for COPD, 101 for CB and 28 for emphysema. RR estimates are markedly heterogeneous. Based on random-effects meta-analyses of most-adjusted RR/ORs, estimates are elevated for ever smoking (COPD 2.89, CI 2.63-3.17, n = 129 RRs; CB 2.69, 2.50-2.90, n = 114; emphysema 4.51, 3.38-6.02, n = 28), current smoking (COPD 3.51, 3.08-3.99; CB 3.41, 3.13-3.72; emphysema 4.87, 2.83-8.41) and ex smoking (COPD 2.35, 2.11-2.63; CB 1.63, 1.50-1.78; emphysema 3.52, 2.51-4.94). For COPD, RRs are higher for males, for studies conducted in North America, for cigarette smoking rather than any product smoking, and where the unexposed base is never smoking any product, and are markedly lower when asthma is included in the COPD definition. Variations by sex, continent, smoking product and unexposed group are in the same direction for CB, but less clearly demonstrated. For all outcomes RRs are higher when based on mortality, and for COPD are markedly lower when based on lung function. For all outcomes, risk increases with amount smoked and pack-years. Limited data show risk decreases with increasing starting age for COPD and CB and with increasing quitting duration for COPD. No clear relationship is seen with duration of smoking.</p> <p>Conclusions</p> <p>The results confirm and quantify the causal relationships with smoking.</p

Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway

Loss and Damage in the Rapidly Changing Arctic

Arctic climate change is happening much faster than the global average. Arctic change also has global consequences, in addition to local ones. Scientific evidence shows that meltwater of Arctic sources contributes to sea-level rise significantly while accounting for 35% of current global sea-level rise. Arctic communities have to find ways to deal with rapidly changing environmental conditions that are leading to social impacts such as outmigration, similarly to the global South. International debates on Loss and Damage have not addressed the Arctic so far. We review literature to show what impacts of climate change are already visible in the Arctic, and present local cases in order to provide empirical evidence of losses and damages in the Arctic region. This evidence is particularly well presented in the context of outmigration and relocation of which we highlight examples. The review reveals a need for new governance mechanisms and institutional frameworks to tackle Loss and Damage. Finally, we discuss what implications Arctic losses and damages have for the international debate