Complexity and line of critical points in a short-range spin-glass model

We investigate the critical behavior of a three-dimensional short-range spin glass model in the presence of an external field \eps conjugated to the Edwards-Anderson order parameter. In the mean-field approximation this model is described by the Adam-Gibbs-DiMarzio approach for the glass transition. By Monte Carlo numerical simulations we find indications for the existence of a line of critical points in the plane (\eps,T) which separates two paramagnetic phases and terminates in a critical endpoint. This line of critical points appears due to the large degeneracy of metastable states present in the system (configurational entropy) and is reminiscent of the first-order phase transition present in the mean-field limit. We propose a scenario for the spin-glass transition at \eps=0, driven by a spinodal point present above $T_c$, which induces strong metastability through Griffiths singularities effects and induces the absence of a two-step shape relaxation curve characteristic of glasses.Comment: 5 pages, 4 postscript figure, revte

Constraint methods for determining pathways and free energy of activated processes

Activated processes from chemical reactions up to conformational transitions of large biomolecules are hampered by barriers which are overcome only by the input of some free energy of activation. Hence, the characteristic and rate-determining barrier regions are not sufficiently sampled by usual simulation techniques. Constraints on a reaction coordinate r have turned out to be a suitable means to explore difficult pathways without changing potential function, energy or temperature. For a dense sequence of values of r, the corresponding sequence of simulations provides a pathway for the process. As only one coordinate among thousands is fixed during each simulation, the pathway essentially reflects the system's internal dynamics. From mean forces the free energy profile can be calculated to obtain reaction rates and insight in the reaction mechanism. In the last decade, theoretical tools and computing capacity have been developed to a degree where simulations give impressive qualitative insight in the processes at quantitative agreement with experiments. Here, we give an introduction to reaction pathways and coordinates, and develop the theory of free energy as the potential of mean force. We clarify the connection between mean force and constraint force which is the central quantity evaluated, and discuss the mass metric tensor correction. Well-behaved coordinates without tensor correction are considered. We discuss the theoretical background and practical implementation on the example of the reaction coordinate of targeted molecular dynamics simulation. Finally, we compare applications of constraint methods and other techniques developed for the same purpose, and discuss the limits of the approach

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion

Background: Metastasis is a leading cause of death among cancer patients. In the tumor microenvironment, altered levels of extracellular matrix proteins, such as collagens, can facilitate the first steps of cancer cell metastasis, including invasion into surrounding tissue and intravasation into the blood stream. However, the degree of misexpression of collagen genes in tumors remains understudied, even though this knowledge could greatly facilitate the development of cancer treatment options aimed at preventing metastasis. Methods: We systematically evaluate the expression of all 44 collagen genes in breast cancer and assess whether their misexpression provides clinical prognostic significance. We use immunohistochemistry on 150 ductal breast cancers and 361 cervical cancers and study DNA methylation in various epithelial cancers. Results: In breast cancer, various tests show that COL4A1 and COL4A2 overexpression and COL17A1 (BP180, BPAG2) underexpression provide independent prognostic strength (HR = 1.25, 95% CI = 1.17–1.34, p = 3.03 × 10; HR = 1.18, 95% CI = 1.11–1.25, p = 8.11 × 10; HR = 0.86, 95% CI = 0.81–0.92, p = 4.57 × 10; respectively). Immunohistochemistry on ductal breast cancers confirmed that the COL17A1 protein product, collagen XVII, is underexpressed. This strongly correlates with advanced stage, increased invasion, and postmenopausal status. In contrast, immunohistochemistry on cervical tumors showed that collagen XVII is overexpressed in cervical cancer and this is associated with increased local dissemination. Interestingly, consistent with the opposed direction of misexpression in these cancers, the COL17A1 promoter is hypermethylated in breast cancer and hypomethylated in cervical cancer. We also find that the COL17A1 promoter is hypomethylated in head and neck squamous cell carcinoma, lung squamous cell carcinoma, and lung adenocarcinoma, in all of which collagen XVII overexpression has previously been shown. Conclusions: Paradoxically, collagen XVII is underexpressed in breast cancer and overexpressed in cervical and other epithelial cancers. However, the COL17A1 promoter methylation status accurately predicts both the direction of misexpression and the increased invasive nature for five out of five epithelial cancers. This implies that aberrant epigenetic control is a key driver of COL17A1 gene misexpression and tumor cell invasion. These findings have significant clinical implications, suggesting that the COL17A1 promoter methylation status can be used to predict patient outcome. Moreover, epigenetic targeting of COL17A1 could represent a novel strategy to prevent metastasis in patients

Brain perfusion imaging with voxel-based analysis in secondary progressive multiple sclerosis patients with a moderate to severe stage of disease: a boon for the workforce

Background: The present study was carried out to evaluate cerebral perfusion in multiple sclerosis (MS) patients with a moderate to severe stage of disease. Some patients underwent hyperbaric oxygen therapy (HBOT) and brain perfusion between before and after that was compared. Methods: We retrospectively reviewed 25 secondary progressive (SP)-MS patients from the hospital database. Neurological disability evaluated by Expanded Disability Status Scale Score (EDSS). Brain perfusion was performed by (99 m) Tc-labeled bicisate (ECD) brain SPECT and the data were compared using statistical parametric mapping (SPM). In total, 16 patients underwent HBOT. Before HBOT and at the end of 20 sessions of oxygen treatment, 99mTc-ECD brain perfusion single photon emission computed tomography (SPECT) was performed again then the results were evaluated and compared. Brain perfusion was performed by (99 m) Tc-labeled bicisate (ECD) brain SPECT and the data were compared using statistical parametric mapping (SPM). Results: A total of 25 SP-MS patients, 14 females (56 %) and 11 males (44 %) with a mean age of 38.92 ± 11. 28 years included in the study. The mean disease duration was 8.70 ± 5.30 years. Of the 25 patients, 2 (8 %) had a normal SPECT and 23 (92 %) had abnormal brain perfusion SPECT studies. The study showed a significant association between severity of perfusion impairment with disease duration and also with EDSS (P <0.05). There was a significant improvement in pre- and post-treatment perfusion scans (P <0.05), but this did not demonstrate a significant improvement in the clinical subjective and objective evaluation of patients (P >0.05). Conclusions: This study depicted decreased cerebral perfusion in SP-MS patients with a moderate to severe disability score and its association with clinical parameters. Because of its accessibility, rather low price, practical ease, and being objective quantitative information, brain perfusion SPECT can be complementing to other diagnostic modalities such as MRI and clinical examinations in disease surveillance and monitoring. The literature on this important issue is extremely scarce, and follow up studies are required to assess these preliminary results

Earth stewardship: Shaping a sustainable future through interacting policy and norm shifts

This is the final version. Available on open access from Springer via the DOI in this recordTransformation toward a sustainable future requires an earth stewardship approach to shift society from its current goal of increasing material wealth to a vision of sustaining built, natural, human, and social capital-equitably distributed across society, within and among nations. Widespread concern about earth's current trajectory and support for actions that would foster more sustainable pathways suggests potential social tipping points in public demand for an earth stewardship vision. Here, we draw on empirical studies and theory to show that movement toward a stewardship vision can be facilitated by changes in either policy incentives or social norms. Our novel contribution is to point out that both norms and incentives must change and can do so interactively. This can be facilitated through leverage points and complementarities across policy areas, based on values, system design, and agency. Potential catalysts include novel democratic institutions and engagement of non-governmental actors, such as businesses, civic leaders, and social movements as agents for redistribution of power. Because no single intervention will transform the world, a key challenge is to align actions to be synergistic, persistent, and scalable

The role of organisms in hyporheic processes : gaps in current knowledge, needs for future research and applications

Fifty years after the hyporheic zone was first defined (Orghidan, 1959), there are still gaps in the knowledge regarding the role of biodiversity in hyporheic processes. First, some methodological questions remained unanswered regarding the interactions between biodiversity and physical processes, both for the study of habitat characteristics and interactions at different scales. Furthermore, many questions remain to be addressed to help inform our understanding of invertebrate community dynamics, especially regarding the trophic niches of organisms, the functional groups present within sediment, and their temporal changes. Understanding microbial community dynamics would require investigations about their relationship with the physical characteristics of the sediment, their diversity, their relationship with metabolic pathways, their inter- actions with invertebrates, and their response to environmental stress. Another fundamental research question is that of the importance of the hyporheic zone in the global metabolism of the river, which must be explored in relation to organic matter recycling, the effects of disturbances, and the degradation of contaminants. Finally, the application of this knowledge requires the development of methods for the estimation of hydro- logical exchanges, especially for the management of sediment clogging, the optimization of self-purification, and the integration of climate change in environmental policies. The development of descriptors of hyporheic zone health and of new metrology is also crucial to include specific targets in water policies for the long-term management of the system and a clear evaluation of restoration strategies

Measuring the availability of human resources for health and its relationship to universal health coverage for 204 countries and territories from 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Human resources for health (HRH) include a range of occupations that aim to promote or improve human health. The UN Sustainable Development Goals (SDGs) and the WHO Health Workforce 2030 strategy have drawn attention to the importance of HRH for achieving policy priorities such as universal health coverage (UHC). Although previous research has found substantial global disparities in HRH, the absence of comparable cross-national estimates of existing workforces has hindered efforts to quantify workforce requirements to meet health system goals. We aimed to use comparable and standardised data sources to estimate HRH densities globally, and to examine the relationship between a subset of HRH cadres and UHC effective coverage performance. Methods: Through the International Labour Organization and Global Health Data Exchange databases, we identified 1404 country-years of data from labour force surveys and 69 country-years of census data, with detailed microdata on health-related employment. From the WHO National Health Workforce Accounts, we identified 2950 country-years of data. We mapped data from all occupational coding systems to the International Standard Classification of Occupations 1988 (ISCO-88), allowing for standardised estimation of densities for 16 categories of health workers across the full time series. Using data from 1990 to 2019 for 196 of 204 countries and territories, covering seven Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) super-regions and 21 regions, we applied spatiotemporal Gaussian process regression (ST-GPR) to model HRH densities from 1990 to 2019 for all countries and territories. We used stochastic frontier meta-regression to model the relationship between the UHC effective coverage index and densities for the four categories of health workers enumerated in SDG indicator 3.c.1 pertaining to HRH: physicians, nurses and midwives, dentistry personnel, and pharmaceutical personnel. We identified minimum workforce density thresholds required to meet a specified target of 80 out of 100 on the UHC effective coverage index, and quantified national shortages with respect to those minimum thresholds. Findings: We estimated that, in 2019, the world had 104·0 million (95% uncertainty interval 83·5–128·0) health workers, including 12·8 million (9·7–16·6) physicians, 29·8 million (23·3–37·7) nurses and midwives, 4·6 million (3·6–6·0) dentistry personnel, and 5·2 million (4·0–6·7) pharmaceutical personnel. We calculated a global physician density of 16·7 (12·6–21·6) per 10 000 population, and a nurse and midwife density of 38·6 (30·1–48·8) per 10 000 population. We found the GBD super-regions of sub-Saharan Africa, south Asia, and north Africa and the Middle East had the lowest HRH densities. To reach 80 out of 100 on the UHC effective coverage index, we estimated that, per 10 000 population, at least 20·7 physicians, 70·6 nurses and midwives, 8·2 dentistry personnel, and 9·4 pharmaceutical personnel would be needed. In total, the 2019 national health workforces fell short of these minimum thresholds by 6·4 million physicians, 30·6 million nurses and midwives, 3·3 million dentistry personnel, and 2·9 million pharmaceutical personnel. Interpretation: Considerable expansion of the world's health workforce is needed to achieve high levels of UHC effective coverage. The largest shortages are in low-income settings, highlighting the need for increased financing and coordination to train, employ, and retain human resources in the health sector. Actual HRH shortages might be larger than estimated because minimum thresholds for each cadre of health workers are benchmarked on health systems that most efficiently translate human resources into UHC attainment