Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common manifestation of SSc and a leading cause of death.
All ...patients newly diagnosed with SSc should receive a comprehensive clinical evaluation, including assessment of respiratory symptoms, a high-resolution computed tomography (HRCT) scan of the chest, and pulmonary function tests. ILD can develop in any patient with SSc, including those with pulmonary hypertension, but the risk is increased in those with diffuse (rather than limited) cutaneous SSc, those with anti-Scl-70/anti-topoisomerase I antibody, and in the absence of anti-centromere antibody. While it can occur at any time, the risk of developing ILD is greatest early in the course of SSc, so patients should be monitored closely in the first few years after diagnosis. An increased extent of lung fibrosis on HRCT and a low forced vital capacity (FVC) are predictors of early mortality. While not all patients will require treatment, current approaches to the treatment of progressive SSc-ILD focus on immunosuppressant therapies, including cyclophosphamide and mycophenolate mofetil. In patients with severe and/or rapidly progressive disease, both haematopoietic stem cell transplantation (HSCT) and lung transplantation have been successfully used. A number of medications, including the two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF), are under active investigation as potential new therapies for SSc-ILD.
Physicians managing patients with SSc should maintain a high level of suspicion and regularly monitor for ILD, particularly in the first few years after diagnosis.
Stocks of soil organic carbon represent a large component of the carbon cycle that may participate in climate change feedbacks, particularly on decadal and centennial timescales. For Earth system ...models (ESMs), the ability to accurately represent the global distribution of existing soil carbon stocks is a prerequisite for accurately predicting future carbon-climate feedbacks. We compared soil carbon simulations from 11 model centers to empirical data from the Harmonized World Soil Database (HWSD) and the Northern Circumpolar Soil Carbon Database (NCSCD). Model estimates of global soil carbon stocks ranged from 510 to 3040 Pg C, compared to an estimate of 1260 Pg C (with a 95% confidence interval of 890-1660 Pg C) from the HWSD. Model simulations for the high northern latitudes fell between 60 and 820 Pg C, compared to 500 Pg C (with a 95% confidence interval of 380-620 Pg C) for the NCSCD and 290 Pg C for the HWSD. Global soil carbon varied 5.9 fold across models in response to a 2.6-fold variation in global net primary productivity (NPP) and a 3.6-fold variation in global soil carbon turnover times. Model-data agreement was moderate at the biome level (R super(2) values ranged from 0.38 to 0.97 with a mean of 0.75); however, the spatial distribution of soil carbon simulated by the ESMs at the 1 degree scale was not well correlated with the HWSD (Pearson correlation coefficients less than 0.4 and root mean square errors from 9.4 to 20.8 kg C m super(-2)). In northern latitudes where the two data sets overlapped, agreement between the HWSD and the NCSCD was poor (Pearson correlation coefficient 0.33), indicating uncertainty in empirical estimates of soil carbon. We found that a reduced complexity model dependent on NPP and soil temperature explained much of the 1 degree spatial variation in soil carbon within most ESMs (R super(2) values between 0.62 and 0.93 for 9 of 11 model centers). However, the same reduced complexity model only explained 10% of the spatial variation in HWSD soil carbon when driven by observations of NPP and temperature, implying that other drivers or processes may be more important in explaining observed soil carbon distributions. The reduced complexity model also showed that differences in simulated soil carbon across ESMs were driven by differences in simulated NPP and the parameterization of soil heterotrophic respiration (inter-model R super(2) = 0.93), not by structural differences between the models. Overall, our results suggest that despite fair global-scale agreement with observational data and moderate agreement at the biome scale, most ESMs cannot reproduce grid-scale variation in soil carbon and may be missing key processes. Future work should focus on improving the simulation of driving variables for soil carbon stocks and modifying model structures to include additional processes.
Nutrient enrichment alters plant community structure and function at a global scale. Coastal plant systems are expected to experience increased rates of nitrogen and phosphorus deposition by 2100, ...caused mostly by anthropogenic activity. Despite high density of studies investigating connections between plant community structure and ecosystem function in response to nutrient addition, inconsistencies in system response based on the ecosystem in question calls for more detailed analyses of nutrient impacts on community organization and resulting productivity response. Here, we focus on nutrient addition impacts on community structure and organization as well as productivity of different lifeforms in a coastal grassland. We established long-term nutrient enrichment plots in 2015 consisting of control (C), nitrogen (N), phosphorus (P), and nitrogen + phosphorus (NP) treatments. In 2017 we collected graminoid and forb productivity, root productivity, and community composition for each plot. We found no N x P interaction, but N enrichment was a significant main effect on productivity, highlighting N limitation in coastal systems. Importantly, nutrient enrichment treatments did not alter root productivity. However, all treatments caused significant differences in community composition. Using rank abundance curves, we determined that community composition differences were driven by increased dominance of nitrophilous graminoids, re-organization of subordinate species, and species absences in N and NP plots. Results of this study highlight how coastal grassland communities are impacted by nutrient enrichment. We show that community re-organization, increased dominance, and absence of critical species are all important mechanisms that reflect community-level impacts of nutrient enrichment in our coastal grassland site.
Innovations in soft material synthesis and fabrication technologies have led to the development of integrated soft electronic devices. Such soft devices offer opportunities to interact with ...biological cells, mimicking their soft environment. However, existing fabrication technologies cannot create the submicron-scale, soft transducers needed for healthcare and medical applications involving single cells. This work presents a nanofabrication strategy to create submicron-scale, all-soft electronic devices based on eutectic gallium-indium alloy (EGaIn) using a hybrid method utilizing electron-beam lithography and soft lithography. The hybrid lithography process is applied to a biphasic structure, comprising a metallic adhesion layer coated with EGaIn, to create soft nano/microstructures embedded in elastomeric materials. Submicron-scale EGaIn thin-film patterning with feature sizes as small as 180 nm and 1 μm line spacing was achieved, resulting in the highest resolution EGaIn patterning technique to date. The resulting soft and stretchable EGaIn patterns offer a currently unrivaled combination of resolution, electrical conductivity, and electronic/wiring density.
Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib ...has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown.
In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia UIP or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern.
A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval CI, 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group.
In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).
Genomic microarrays used to assess DNA copy number are now recommended as first-tier tests for the postnatal evaluation of individuals with intellectual disability, autism spectrum disorders, and/or ...multiple congenital anomalies. Application of this technology has resulted in the discovery of widespread copy number variation in the human genome, both polymorphic variation in healthy individuals and novel pathogenic copy number imbalances. To assist clinical laboratories in the evaluation of copy number variants and to promote consistency in interpretation and reporting of genomic microarray results, the American College of Medical Genetics has developed the following professional guidelines for the interpretation and reporting of copy number variation. These guidelines apply primarily to evaluation of constitutional copy number variants detected in the postnatal setting.
The whitefly Bemisia tabaci sibling species (sibsp.) group comprises morphologically indiscernible lineages of well-known exemplars referred to as biotypes. It is distributed throughout tropical and ...subtropical latitudes and includes the contemporary invasive haplotypes, termed B and Q. Several well-studied B. tabaci biotypes exhibit ecological and biological diversity, however, most members are poorly studied or completely uncharacterized. Genetic studies have revealed substantial diversity within the group based on a fragment of the mitochondrial cytochrome oxidase I (mtCOI) sequence (haplotypes), with other tested markers being less useful for deep phylogenetic comparisons. The view of global relationships within the B. tabaci sibsp. group is largely derived from this single marker, making assessment of gene flow and genetic structure difficult at the population level. Here, the population structure was explored for B. tabaci in a global context using nuclear data from variable microsatellite markers. Worldwide collections were examined representing most of the available diversity, including known monophagous, polyphagous, invasive, and indigenous haplotypes. Well-characterized biotypes and other related geographic lineages discovered represented highly differentiated genetic clusters with little or no evidence of gene flow. The invasive B and Q biotypes exhibited moderate to high levels of genetic diversity, suggesting that they stemmed from large founding populations that have maintained ancestral variation, despite homogenizing effects, possibly due to human-mediated among-population gene flow. Results of the microsatellite analyses are in general agreement with published mtCOI phylogenies; however, notable conflicts exist between the nuclear and mitochondrial relationships, highlighting the need for a multifaceted approach to delineate the evolutionary history of the group. This study supports the hypothesis that the extant B. tabaci sibsp. group contains ancient genetic entities and highlights the vast cryptic diversity throughout the genome in the group.
Background
Involvement of the lateral compartment remains a relative or absolute contraindication to pelvic exenteration in most units. Initial experience with exenteration in the authors' unit ...produced a 21 per cent clear margin rate (R0), which improved to 53 per cent by adopting a novel technique for en bloc resection of the iliac vessels and other side‐wall structures. The objective of this study was to report morbidity and oncological outcomes in consecutive exenterations involving the lateral compartment.
Methods
Patients undergoing pelvic exenteration between 1994 and 2014 were eligible for review.
Results
Two hundred consecutive patients who had en bloc resection of the lateral compartment were included. R0 resection was achieved in 66·5 per cent of 197 patients undergoing surgery for cancer and 68·9 per cent of planned curative resections. For patients with colorectal cancer, a clear resection margin was associated with a significant overall survival benefit (P = 0·030). Median overall and disease‐free survival in this group was 41 and 27 months respectively. Overall 1‐, 3‐ and 5‐year survival rates were 86, 46 and 35 per cent respectively. No predictors of survival were identified on univariable analysis other than margin status and operative intent. Excision of the common or external iliac vessels or sciatic nerve did not confer a survival disadvantage.
Conclusion
The continuing evolution of radical pelvic exenteration techniques has seen an improvement in R0 margin status from 21 to 66·5 per cent over a 20‐year interval by routine adoption of a more lateral anatomical plane. Five‐year overall survival rates are comparable with those for more centrally based tumours.
Extension of excision confers survival advantage
Cancer chemoprevention involves the chronic administration of a synthetic, natural or biological agent to reduce or delay the occurrence of malignancy. The potential value of this approach has been ...demonstrated with trials in breast, prostate and colon cancer. The paradigm for developing new chemopreventive agents has changed markedly in the last decade and now involves extensive preclinical mechanistic evaluation of agents before clinical trials are instituted and a focus on defining biomarkers of activity that can be used as early predictors of efficacy. This review will summarise the current status of the field of chemoprevention and highlight potential new developments.
Forkhead box O (FOXO) transcription factors are central regulators of cellular homeostasis. FOXOs respond to a wide range of external stimuli, including growth factor signaling, oxidative stress, ...genotoxic stress, and nutrient deprivation. These signaling inputs regulate FOXOs through a number of posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and methylation. Covalent modifications can affect localization, DNA binding, and interactions with other cofactors in the cell. FOXOs integrate the various modifications to regulate cell type-specific gene expression programs that are essential for metabolic homeostasis, redox balance, and the stress response. Together, these functions are critical for coordinating a response to environmental fluctuations in order to maintain cellular homeostasis during development and to support healthy aging.
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