Despite considerable advances in process understanding, numerical modeling, and the observational record of ice sheet contributions to global mean sea-level rise (SLR) since the Fifth Assessment ...Report (AR5) of the Intergovernmental Panel on Climate Change, severe limitations remain in the predictive capability of ice sheet models. As a consequence, the potential contributions of ice sheets remain the largest source of uncertainty in projecting future SLR. Here, we report the findings of a structured expert judgement study, using unique techniques for modeling correlations between interand intra-ice sheet processes and their tail dependences. We find that since the AR5, expert uncertainty has grown, in particular because of uncertain ice dynamic effects. For a +2 °C temperature scenario consistent with the Paris Agreement, we obtain a median estimate of a 26 cm SLR contribution by 2100, with a 95th percentile value of 81 cm. For a +5 °C temperature scenario more consistent with unchecked emissions growth, the corresponding values are 51 and 178 cm, respectively. Inclusion of thermal expansion and glacier contributions results in a global total SLR estimate that exceeds 2 m at the 95th percentile. Our findings support the use of scenarios of 21st century global total SLR exceeding 2 m for planning purposes. Beyond 2100, uncertainty and projected SLR increase rapidly. The 95th percentile ice sheet contribution by 2200, for the +5 °C scenario, is 7.5 m as a result of instabilities coming into play in both West and East Antarctica. Introducing process correlations and tail dependences increases estimates by roughly 15%.
Objective To evaluate the effectiveness of multifactorial assessment and intervention programmes to prevent falls and injuries among older adults recruited to trials in primary care, community, or ...emergency care settings.Design Systematic review of randomised and quasi-randomised controlled trials, and meta-analysis.Data sources Six electronic databases (Medline, Embase, CENTRAL, CINAHL, PsycINFO, Social Science Citation Index) to 22 March 2007, reference lists of included studies, and previous reviews.Review methods Eligible studies were randomised or quasi-randomised trials that evaluated interventions to prevent falls that were based in emergency departments, primary care, or the community that assessed multiple risk factors for falling and provided or arranged for treatments to address these risk factors.Data extraction Outcomes were number of fallers, fall related injuries, fall rate, death, admission to hospital, contacts with health services, move to institutional care, physical activity, and quality of life. Methodological quality assessment included allocation concealment, blinding, losses and exclusions, intention to treat analysis, and reliability of outcome measurement. Results 19 studies, of variable methodological quality, were included. The combined risk ratio for the number of fallers during follow-up among 18 trials was 0.91 (95% confidence interval 0.82 to 1.02) and for fall related injuries (eight trials) was 0.90 (0.68 to 1.20). No differences were found in admissions to hospital, emergency department attendance, death, or move to institutional care. Subgroup analyses found no evidence of different effects between interventions in different locations, populations selected for high risk of falls or unselected, and multidisciplinary teams including a doctor, but interventions that actively provide treatments may be more effective than those that provide only knowledge and referral.Conclusions Evidence that multifactorial fall prevention programmes in primary care, community, or emergency care settings are effective in reducing the number of fallers or fall related injuries is limited. Data were insufficient to assess fall and injury rates.
Recurrent vulvovaginal candidiasis (RVVC) is a problematic form of mucosal Candida infection, characterized by repeated episodes per year. Candida albicans is the most common cause of RVVC. ...Currently, there are no immunotherapeutic treatments for RVVC.
This exploratory randomized, double-blind, placebo-controlled trial evaluated an immunotherapeutic vaccine (NDV-3A) containing a recombinant C. albicans adhesin/invasin protein for prevention of RVVC.
The study in 188 women with RVVC (n = 178 evaluable) showed that 1 intramuscular dose of NDV-3A was safe and generated rapid and robust B- and T-cell immune responses. Post hoc exploratory analyses revealed a statistically significant increase in the percentage of symptom-free patients at 12 months after vaccination (42% vaccinated vs 22% placebo; P = .03) and a doubling in median time to first symptomatic episode (210 days vaccinated vs 105 days placebo) for the subset of patients aged <40 years (n = 137). The analysis of evaluable patients, which combined patients aged <40 years (77%) and ≥40 years (23%), trended toward a positive impact of NDV-3A versus placebo (P = .099).
In this unprecedented study of the effectiveness of a fungal vaccine in humans, NDV-3A administered to women with RVVC was safe and highly immunogenic and reduced the frequency of symptomatic episodes of vulvovaginal candidiasis for up to 12 months in women aged <40 years. These results support further development of NDV-3A vaccine and provide guidance for meaningful clinical endpoints for immunotherapeutic management of RVVC.
NCT01926028.
Fluoroalkylation reactions of (hetero)aromatics have been accomplished through the low-power illumination from red LEDs (
λ
max
= 635 nm) of commercially available perfluoroalkyl iodides R
F
-I and ...phthalocyanine zinc salt as photocatalyst in MeCN : DMF solvent mixture. This methodology has been extended to the perfluorobutylation of sulfides. As far as we are concerned, this is the first report on a perfluoroalkylation reaction of (hetero)aromatics and sulfides under red-light photocatalysis.
The use of Zn-phthalocyanine in a red-light-driven process for the perfluoroalkylation reactions of (hetero)arenes and sufides represents a friendlier environmental alternative.
Savannas constitute the most fire-prone biome on Earth and annual emissions from savanna-burning activities are a globally important source of greenhouse-gas (GHG) emissions. Here, we describe the ...application of a commercial fire-management program being implemented over 28 000 km
2
of savanna on Aboriginal lands in northern Australia. The project combines the reinstatement of Aboriginal traditional approaches to savanna fire management - in particular a strategic, early dry-season burning program - with a recently developed emissions accounting methodology for savanna burning. Over the first 7 years of implementation, the project has reduced emissions of accountable GHGs (methane, nitrous oxide) by 37.7%, relative to the pre-project 10-year emissions baseline. In addition, the project is delivering social, biodiversity, and long-term biomass sequestration benefits. This methodological approach may have considerable potential for application in other fire-prone savanna settings.
A new graphical model, called a vine, for dependent random variables is introduced. Vines generalize the Markov trees often used in modelling high-dimensional distributions. They differ from Markov ...trees and Bayesian belief nets in that the concept of conditional independence is weakened to allow for various forms of conditional dependence. Vines can be used to specify multivariate distributions in a straightforward way by specifying various marginal distributions and the ways in which these marginals are to be coupled. Such distributions have applications in uncertainty analysis where the objective is to determine the sensitivity of a model output with respect to the uncertainty in unknown parameters. Expert information is frequently elicited to determine some quantitative characteristics of the distribution such as (rank) correlations. We show that it is simple to construct a minimum information vine distribution, given such expert information. Sampling from minimum information distributions with given marginals and (conditional) rank correlations specified on a vine can be performed almost as fast as independent sampling. A special case of the vine construction generalizes work of Joe and allows the construction of a multivariate normal distribution by specifying a set of partial correlations on which there are no restrictions except the obvious one that a correlation lies between - 1 and 1.
We know little about on how frequently transitions into new habitats occur, especially the colonization of novel environments that are the most likely to instigate adaptive evolution. One of the most ...extreme ecological transitions has been the shift in habitat associated with the move from water to land by amphibious fish. We provide the first phylogenetic investigation of these transitions for living fish. Thirty-three families have species reported to be amphibious and these are likely independent evolutionary origins of fish emerging onto land. Phylogenetic reconstructions of closely related taxa within one of these families, the Blenniidae, inferred as many as seven convergences on a highly amphibious lifestyle. Taken together, there appear to be few constraints on fish emerging onto land given amphibious behavior has evolved repeatedly many times across ecologically diverse families. The colonization of novel habitats by other taxa resulting in less dramatic changes in environment should be equally, if not, more frequent in nature, providing an important prerequisite for subsequent adaptive differentiation.
Military trainees are at increased risk for Staphylococcus aureus colonization and infection. Disease prevention strategies are needed, but a S. aureus vaccine does not currently exist.
We enrolled ...US Army Infantry trainees (Fort Benning, GA) in a phase 2, randomized, double-blind, placebo-controlled trial of NDV-3A, a vaccine containing a recombinant adhesin/invasion protein of Candida albicans that has structural similarity to the S. aureus protein clumping factor A. Study participants received one intramuscular dose of NDV-3A or placebo (adjuvant alone) within 72 h of arrival on base. Longitudinal nasal and oral (throat) swabs were collected throughout the 14-week Infantry training cycle. Safety, immunogenicity, and efficacy of NDV-3A against S. aureus nasal / oral acquisition were the endpoints.
The NDV-3A candidate had minimal reactogenicity and elicited robust antigen-specific B- and T-cell responses. During the 56-day post-vaccination period, there was no difference in the incidence of S. aureus nasal acquisition between those who were randomized to receive NDV-3A vs. placebo (25.6% vs. 29.1%; vaccine efficacy VE: 12.1%; p = 0.31). In time-to-event analysis, there was no difference between study groups with respect to the S. aureus colonization-free interval (VE: 13%; p = 0.29). Similarly, the efficacy of NDV-3A against S. aureus oral acquisition was poor (VE: 2.4%; p = 0.52).
A single dose of NDV-3A did not prevent nasal nor oral acquisition of S. aureus in a population of military trainees at high risk for colonization.
Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus ...providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.
The complement system is a crucial component of the host response to infection and tissue damage. Activation of the complement cascade generates anaphylatoxins including C5a and C3a. C5a exerts a ...pro-inflammatory effect via the G-protein-coupled receptor C5a anaphylatoxin chemotactic receptor 1 (C5aR1, also known as CD88) that is expressed on cells of myeloid origin. Inhibitors of the complement system have long been of interest as potential drugs for the treatment of diseases such as sepsis, rheumatoid arthritis, Crohn's disease and ischaemia-reperfusion injuries. More recently, a role of C5a in neurodegenerative conditions such as Alzheimer's disease has been identified. Peptide antagonists based on the C5a ligand have progressed to phase 2 trials in psoriasis and rheumatoid arthritis; however, these compounds exhibited problems with off-target activity, production costs, potential immunogenicity and poor oral bioavailability. Several small-molecule competitive antagonists for C5aR1, such as W-54011 and NDT9513727, have been identified by C5a radioligand-binding assays. NDT9513727 is a non-peptide inverse agonist of C5aR1, and is highly selective for the primate and gerbil receptors over those of other species. Here, to study the mechanism of action of C5a antagonists, we determine the structure of a thermostabilized C5aR1 (known as C5aR1 StaR) in complex with NDT9513727. We found that the small molecule bound between transmembrane helices 3, 4 and 5, outside the helical bundle. One key interaction between the small molecule and residue Trp213
seems to determine the species selectivity of the compound. The structure demonstrates that NDT9513727 exerts its inverse-agonist activity through an extra-helical mode of action.
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