Challenges and practical recommendations for successfully recruiting inactive, statin-free older adults to clinical trials

Objectives: To outline the challenges and provide practical recommendations for recruiting inactive, statin-free older adults to facilitate feasible study designs. Data was obtained from a double-blind randomised-controlled clinical trial investigating the effects of acipimox versus placebo on muscle function and metabolism in older (65-75 years), inactive, statin-free males. The initial recruitment target was 20 volunteers within 12 months (November 2016-November 2017). Results: Recruitment occurred via the Exeter 10,000 database containing 236 'eligible' males, a Facebook campaign reaching > 8000 ≥ 65 years old males, 400 directly-addressed letters to ≥ 66 year old males, > 1500 flyers distributed within the community, > 40 emails to local community groups, 4 recruitment talks, 2 magazine adverts and 1 radio advert. Widespread recruitment efforts reaching > 120,000 people led to the recruitment of 20 volunteers (18 completed the clinical trial) within a 25-month timeframe, highlighting the challenge of the timely recruitment of inactive, statin-free older adults for clinical trials. We recommend recruitment for future clinical trials should take a multi-pronged approach from the outset, prioritising the use of volunteer databases, Facebook campaigns and delivering recruitment talks.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by a grant from Dunhill Medical Trust (R492/0516) and the NIHR Exeter CRF. CS Deane is a funded Medical Research Council Skills Development Fellow (MR/T026014/1). The funders had no role in study design, data analysis or outcome of the study.published version, accepted versio

A record of carbonyl sulfide from Antarctic ice over the last 1000 years

Carbonyl sulfide (COS) is a trace gas, present in the troposphere, and also in the stratosphere, where it contributes to the stratospheric sulfate aerosol layer. It has both natural and anthropogenic sources. Natural processes include uptake by plants, while oceans, wetlands, volcanism and biomass burning all contribute to natural COS emissions. We have measured COS in Antarctic ice cores from Dronning Maud Land, drilled in 1998, the DE08 core drilled at Law Dome in 1987, and the DSS0506 core drilled in 2006. Ice samples with COS gas ages between about 1050 AD and the early 20th centrury have been examined. A large volume ice crusher at the CSIRO Marine and Atmospheric Research laboratory was used to extract air from bubbles occluded in the ice cores. These air samples were analysed for CO2, CH4, CO and 13CO2 at CSIRO, and then for COS and several halocarbons at the University of East Anglia on a high sensitivity gas chromatograph/tri-sector mass spectrometer system. Initial results indicate that good sample integrity can be achieved. Measurements from the DML samples indicate low and uniform abundances across the last few hundred years, and at concentrations significantly below those in the modernday atmosphere. Measurements in more recent ice from DE08 show the start of increasing concentrations in the early 1900s, confirming earlier evidence that the global atmospheric abundance of COS has increased as a result of industrial activity during the 20th century

Atmospheric CO2 and d13C-CO2 reconstruction of the little ice age from antarctic ice cores

The decrease of atmospheric CO2 concentration recorded in Antarctic ice around 1600 AD is one of the most significant atmospheric changes to have occurred during the last millennia, before the onset of the industrial period.Together with the temperature decrease, the CO2 drop has been used to derive the sensitivity of carbon stores to climate. However, the cause of it is still under debate because models are not yet able to reproduce either its magnitude, or its timing. Here we present new measurements of the CO2 concentration decrease recorded in an ice core from a medium accumulation rate site in Antarctica (DML). We show that the new record is compatible(differences <2 ppm) with the CO2 record from the high accumulation rate DSS site on Law Dome (East Antarctica), when the different age distributions are taken into account. We have also measured the d13C-CO2 change in DML ice, filling a gap around 1600 AD in the DSS d13C record. We use a double deconvolution of the CO2 and d13C records together to provide quantitative evidence that the CO2 decrease was caused by a change in the net flux to the terrestrial biosphere. Finally, we provide a new interpretation of a published record showing increasing atmospheric carbonyl sulphide during the CO2 decrease, suggesting that cooler LIA climate affected terrestrial biospheric fluxes. Altogether our findings support the hypothesis that reduced soil heterotrophic respiration is likely to have given the most significant contribution to the LIA CO2 decrease implying a positive CO2-climate feedback. © 2015, Authors

Natural and anthropogenic changes in atmospheric greenhouse gases over the past 2 millennia

Millennial changes in atmospheric trace gas composition are best determined from air enclosed in ice sheets. Air extracted from the open pores in firn and the bubbles in ice is measured to derive the past concentrations and isotopic ratios of the long lived trace gases. The significant increases observed in CO2, CH4 and N2O since about 1750 and the more recent appearance of synthetic gases such as the CFCs in the atmosphere are a key feature of the anthropocene. The millennia preceding the anthropocene, the Late Pre-Industrial Holocene (LPIH), show evidence of natural changes in trace gases that can be used to constrain models and improve their ability to predict future changes under scenarios of anthropogenic emissions and climate change. Precise measurements and ice core air samples that are accurately dated and highly resolved in time are required to record the small and rapid trace gas signals of this period. The atmospheric composition records produced by CSIRO and collaborators using the Law Dome, Antarctica ice cores are widely used in models of climate, atmospheric chemistry and the carbon cycle over the anthropocene and the LPIH. Results from these studies have been influential in informing global policies, including the Montreal and Kyoto Protocols. We will present the recently revised trace gas records from Law Dome and new measurements of tracers from these and other ice sites that reveal the causes of atmospheric changes over the anthropocene and the LPIH

COMPETITIVE OR WEAK COOPERATIVE STOCHASTIC LOTKA-VOLTERRA SYSTEMS CONDITIONED TO NON-EXTINCTION

International audienceWe are interested in the long time behavior of a two-type density-dependent biological population conditioned to non-extinction, in both cases of competition or weak cooperation between the two species. This population is described by a stochastic Lotka-Volterra system, obtained as limit of renormalized interacting birth and death processes. The weak cooperation assumption allows the system not to blow up. We study the existence and uniqueness of a quasi-stationary distribution, that is convergence to equilibrium conditioned to non extinction. To this aim we generalize in two-dimensions spectral tools developed for one-dimensional generalized Feller diffusion processes. The existence proof of a quasi-stationary distribution is reduced to the one for a $d$-dimensional Kolmogorov diffusion process under a symmetry assumption. The symmetry we need is satisfied under a local balance condition relying the ecological rates. A novelty is the outlined relation between the uniqueness of the quasi-stationary distribution and the ultracontractivity of the killed semi-group. By a comparison between the killing rates for the populations of each type and the one of the global population, we show that the quasi-stationary distribution can be either supported by individuals of one (the strongest one) type or supported by individuals of the two types. We thus highlight two different long time behaviors depending on the parameters of the model: either the model exhibits an intermediary time scale for which only one type (the dominant trait) is surviving, or there is a positive probability to have coexistence of the two species

Extinction threshold in the spatial stochastic logistic model: space homogeneous case

We consider the extinction regime in the spatial stochastic logistic model in R^d (a.k.a. Bolker–Pacala–Dieckmann–Law model of spatial populations) using the first-order perturbation beyond the mean-field equation. In space homogeneous case (i.e. when the density is non-spatial and the covariance is translation invariant), we show that the perturbation converges as time tends to infinity; that yields the first-order approximation for the stationary density. Next, we study the critical mortality – the smallest constant death rate which ensures the extinction of the population – as a function of the mean-field scaling parameter ε>0. We find the leading term of the asymptotic expansion (as ε→0) of the critical mortality which is apparently different for the cases d≥3, d = 2, and d = 1

High Throughput Selection of Effective Serodiagnostics for Trypanosoma cruzi infection

The diagnosis of Trypanosoma cruzi infection (the cause of human Chagas disease) is difficult because the symptoms of the infection are often absent or non-specific, and because the parasites themselves are usually below the level of detection in the infected subjects. Therefore, diagnosis generally depends on the measurement of T. cruzi–specific antibodies produced in response to the infection. However, current methods to detect anti–T. cruzi antibodies are relatively poor. In this study, we have conducted a broad screen of >400 T. cruzi proteins to identify those proteins which are best able to detect anti–T. cruzi antibodies. Using a set of proteins selected by this screen, we were able to detect 100% of >100 confirmed positive human cases of T. cruzi infection, as well as suspect cases that were negative using existing tests. This protein panel was also able to detect apparent changes in infection status following drug treatment of individuals with chronic T. cruzi infection. The results of this study should allow for significant improvements in the detection of T. cruzi infection and better screening methods to avoid blood transfusion–related transmission of the infection, and offer a crucial tool for determining the success or failure of drug treatment and other intervention strategies to limit the impact of Chagas disease

Mitochondrial hydrogen sulfide supplementation improves health in the C. elegans Duchenne muscular dystrophy model

This is the final version. Available on open access from the National Academy of Sciences via the DOI in this record. Data Availability: All study data are included in the article.Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle degeneration and weakness due to mutations in the dystrophin gene. The symptoms of DMD share similarities with those of accelerated aging. Recently, hydrogen sulfide (H2S) supplementation has been suggested to modulate the effects of age-related decline in muscle function, and metabolic H2S deficiencies have been implicated in affecting muscle mass in conditions such as phenylketonuria. We therefore evaluated the use of sodium GYY4137 (NaGYY), a H2S-releasing molecule, as a possible approach for DMD treatment. Using the dys-1(eg33) Caenorhabditis elegans DMD model, we found that NaGYY treatment (100 µM) improved movement, strength, gait, and muscle mitochondrial structure, similar to the gold-standard therapeutic treatment, prednisone (370 µM). The health improvements of either treatment required the action of the kinase JNK-1, the transcription factor SKN-1, and the NAD-dependent deacetylase SIR-2.1. The transcription factor DAF-16 was required for the health benefits of NaGYY treatment, but not prednisone treatment. AP39 (100 pM), a mitochondria-targeted H2S compound, also improved movement and strength in the dys-1(eg33) model, further implying that these improvements are mitochondria-based. Additionally, we found a decline in total sulfide and H2S-producing enzymes in dystrophin/utrophin knockout mice. Overall, our results suggest that H2S deficit may contribute to DMD pathology, and rectifying/overcoming the deficit with H2S delivery compounds has potential as a therapeutic approach to DMD treatment.Medical Research Council (MRC)NASABiotechnology and Biological Sciences Research Council (BBSRC)Medical Research Council (MRC)United Mitochondrial Disease FoundationMRC Versus Arthritis Centre for Musculoskeletal Ageing ResearchNational Health and Medical Research CouncilUniversity of Nottingham School of MedicineFulbright U.S. Student ProgramGermanistic Society of AmericaBrian Ridge ScholarshipUniversity of ExeterUniversity of New South WalesUniversity of MelbourneRebecca L. Cooper Medical Research FoundationOsteopathic Heritage Foundatio

Calpains Mediate Integrin Attachment Complex Maintenance of Adult Muscle in Caenorhabditis elegans

Two components of integrin containing attachment complexes, UNC-97/PINCH and UNC-112/MIG-2/Kindlin-2, were recently identified as negative regulators of muscle protein degradation and as having decreased mRNA levels in response to spaceflight. Integrin complexes transmit force between the inside and outside of muscle cells and signal changes in muscle size in response to force and, perhaps, disuse. We therefore investigated the effects of acute decreases in expression of the genes encoding these multi-protein complexes. We find that in fully developed adult Caenorhabditis elegans muscle, RNAi against genes encoding core, and peripheral, members of these complexes induces protein degradation, myofibrillar and mitochondrial dystrophies, and a movement defect. Genetic disruption of Z-line– or M-line–specific complex members is sufficient to induce these defects. We confirmed that defects occur in temperature-sensitive mutants for two of the genes: unc-52, which encodes the extra-cellular ligand Perlecan, and unc-112, which encodes the intracellular component Kindlin-2. These results demonstrate that integrin containing attachment complexes, as a whole, are required for proper maintenance of adult muscle. These defects, and collapse of arrayed attachment complexes into ball like structures, are blocked when DIM-1 levels are reduced. Degradation is also blocked by RNAi or drugs targeting calpains, implying that disruption of integrin containing complexes results in calpain activation. In wild-type animals, either during development or in adults, RNAi against calpain genes results in integrin muscle attachment disruptions and consequent sub-cellular defects. These results demonstrate that calpains are required for proper assembly and maintenance of integrin attachment complexes. Taken together our data provide in vivo evidence that a calpain-based molecular repair mechanism exists for dealing with attachment complex disruption in adult muscle. Since C. elegans lacks satellite cells, this mechanism is intrinsic to the muscles and raises the question if such a mechanism also exists in higher metazoans