The SUMMIT trial: a field comparison of buprenorphine versus methadone maintenance treatment.

This prospective patient-preference study examined the effectiveness in practice of methadone versus buprenorphine maintenance treatment and the beliefs of subjects regarding these drugs. A total of 361 opiate-dependent individuals (89% of those eligible, presenting for treatment over 2 years at a drug service in England) received rapid titration then flexible dosing with methadone or buprenorphine; 227 patients chose methadone (63%) and 134 buprenorphine (37%). Participants choosing methadone had more severe substance abuse and psychiatric and physical problems but were more likely to remain in treatment. Survival analysis indicated those prescribed methadone were over twice as likely to be retained (hazard ratio for retention was 2.08 and 95% confidence interval [CI] = 1.49-2.94 for methadone vs. buprenorphine), However, those retained on buprenorphine were more likely to suppress illicit opiate use (odds ratio = 2.136, 95% CI = 1.509-3.027, p < .001) and achieve detoxification. Buprenorphine may also recruit more individuals to treatment because 28% of those choosing buprenorphine (10% of the total sample) stated they would not have accessed treatment with methadone

Eutectic Colony Formation: A Stability Analysis

Experiments have widely shown that a steady-state lamellar eutectic solidification front is destabilized on a scale much larger than the lamellar spacing by the rejection of a dilute ternary impurity and forms two-phase cells commonly referred to as `eutectic colonies'. We extend the stability analysis of Datye and Langer for a binary eutectic to include the effect of a ternary impurity. We find that the expressions for the critical onset velocity and morphological instability wavelength are analogous to those for the classic Mullins-Sekerka instability of a monophase planar interface, albeit with an effective surface tension that depends on the geometry of the lamellar interface and, non-trivially, on interlamellar diffusion. A qualitatively new aspect of this instability is the occurence of oscillatory modes due to the interplay between the destabilizing effect of the ternary impurity and the dynamical feedback of the local change in lamellar spacing on the front motion. In a transient regime, these modes lead to the formation of large scale oscillatory microstructures for which there is recent experimental evidence in a transparent organic system. Moreover, it is shown that the eutectic front dynamics on a scale larger than the lamellar spacing can be formulated as an effective monophase interface free boundary problem with a modified Gibbs-Thomson condition that is coupled to a slow evolution equation for the lamellar spacing. This formulation provides additional physical insights into the nature of the instability and a simple means to calculate an approximate stability spectrum. Finally, we investigate the influence of the ternary impurity on a short wavelength oscillatory instability that is already present at off-eutectic compositions in binary eutectics.Comment: 26 pages RevTex, 14 figures (28 EPS files); some minor changes; references adde

Scaling up the effects of inbreeding depression from individuals to metapopulations

Abstract Inbreeding is common in nature, and many laboratory studies have documented that inbreeding depression can reduce the fitness of individuals. Demonstrating the consequences of inbreeding depression on the growth and persistence of populations is more challenging because populations are often regulated by density- or frequency-dependent selection and influenced by demographic and environmental stochasticity. A few empirical studies have shown that inbreeding depression can increase extinction risk of local populations. The importance of inbreeding depression at the metapopulation level has been conjectured based on population-level studies but has not been evaluated. We quantified the impact of inbreeding depression affecting the fitness of individuals on metapopulation persistence in heterogeneous habitat networks of different sizes and habitat configuration in a context of natural butterfly metapopulations. We developed a spatial individual-based simulation model of metapopulations with explicit genetics. We used Approximate Bayesian Computation to fit the model to extensive demographic, genetic, and life-history data available for the well-studied Glanville fritillary butterfly (Melitaea cinxia) metapopulations in the Åland islands in SW Finland. We compared 18 semi-independent habitat networks differing in size and fragmentation. The results show that inbreeding is more frequent in small habitat networks, and consequently, inbreeding depression elevates extinction risks in small metapopulations. Metapopulation persistence and neutral genetic diversity maintained in the metapopulations increase with the total habitat amount in and mean patch size of habitat networks. Dispersal and mating behavior interact with landscape structure to determine how likely it is to encounter kin while looking for mates. Inbreeding depression can decrease the viability of small metapopulations even when they are strongly influenced by stochastic extinction-colonization dynamics and density-dependent selection. The findings from this study support that genetic factors, in addition to demographic factors, can contribute to extinctions of small local populations and also of metapopulations. This article is protected by copyright. All rights reserved.Peer reviewe

Comparison of the Airtraq® and Truview® laryngoscopes to the Macintosh laryngoscope for use by Advanced Paramedics in easy and simulated difficult intubation in manikins

<p>Abstract</p> <p>Background</p> <p>Paramedics are frequently required to perform tracheal intubation, a potentially life-saving manoeuvre in severely ill patients, in the prehospital setting. However, direct laryngoscopy is often more difficult in this environment, and failed tracheal intubation constitutes an important cause of morbidity. Novel indirect laryngoscopes, such as the Airtraq^®and Truview^®laryngoscopes may reduce this risk.</p> <p>Methods</p> <p>We compared the efficacy of these devices to the Macintosh laryngoscope when used by 21 Paramedics proficient in direct laryngoscopy, in a randomized, controlled, manikin study. Following brief didactic instruction with the Airtraq^®and Truview^®laryngoscopes, each participant took turns performing laryngoscopy and intubation with each device, in an easy intubation scenario and following placement of a hard cervical collar, in a SimMan^®manikin.</p> <p>Results</p> <p>The Airtraq^®reduced the number of optimization manoeuvres and reduced the potential for dental trauma when compared to the Macintosh, in both the normal and simulated difficult intubation scenarios. In contrast, the Truview^®increased the duration of intubation attempts, and required a greater number of optimization manoeuvres, compared to both the Macintosh and Airtraq^®devices.</p> <p>Conclusion</p> <p>The Airtraq^®laryngoscope performed more favourably than the Macintosh and Truview^®devices when used by Paramedics in this manikin study. Further studies are required to extend these findings to the clinical setting.</p

Comparison of the Airtraq® and Truview® laryngoscopes to the Macintosh laryngoscope for use by Advanced Paramedics in easy and simulated difficult intubation in manikins

<p>Abstract</p> <p>Background</p> <p>Paramedics are frequently required to perform tracheal intubation, a potentially life-saving manoeuvre in severely ill patients, in the prehospital setting. However, direct laryngoscopy is often more difficult in this environment, and failed tracheal intubation constitutes an important cause of morbidity. Novel indirect laryngoscopes, such as the Airtraq^®and Truview^®laryngoscopes may reduce this risk.</p> <p>Methods</p> <p>We compared the efficacy of these devices to the Macintosh laryngoscope when used by 21 Paramedics proficient in direct laryngoscopy, in a randomized, controlled, manikin study. Following brief didactic instruction with the Airtraq^®and Truview^®laryngoscopes, each participant took turns performing laryngoscopy and intubation with each device, in an easy intubation scenario and following placement of a hard cervical collar, in a SimMan^®manikin.</p> <p>Results</p> <p>The Airtraq^®reduced the number of optimization manoeuvres and reduced the potential for dental trauma when compared to the Macintosh, in both the normal and simulated difficult intubation scenarios. In contrast, the Truview^®increased the duration of intubation attempts, and required a greater number of optimization manoeuvres, compared to both the Macintosh and Airtraq^®devices.</p> <p>Conclusion</p> <p>The Airtraq^®laryngoscope performed more favourably than the Macintosh and Truview^®devices when used by Paramedics in this manikin study. Further studies are required to extend these findings to the clinical setting.</p

Indications for implant removal after fracture healing: a review of the literature

Introduction: The aim of this review was to collect and summarize published data on the indications for implant removal after fracture healing, since these are not well defined and guidelines hardly exist. Methods: A literature search was performed. Results: Though there are several presumed benefits of implant removal, such as functional improvement and pain relief, the surgical procedure can be very challenging and may lead to complications or even worsening of the complaints. Research has focused on the safety of metal implants (e.g., risk of corrosion, allergy, and carcinogenesis). For these reasons, implants have been removed routinely for decades. Along with the introduction of titanium alloy implants, the need for implant removal became a subject of debate in view of potential (dis)advantages since, in general, implants made of titanium alloys are more difficult to remove. Currently, the main indications for removal from both the upper and lower extremity are mostly 'relative' and patient-driven, such as pain, prominent material, or simply the request for removal. True medical indications like infection or intra-articular material are minor reasons. Conclusion: This review illustrates the great variety of view points in the literature, with large differences in opinions and practices about the indications for implant removal after fracture healing. Since some studies have described asymptomatic patients developing complaints after removal, the general advice nowadays is to remove implants after fracture healing only in symptomatic patients and after a proper informed consent. Well-designed prospective studies on this subject are urgently needed in order to form guidelines based on scientific evidence

Reduced Cortisol and Metabolic Responses of Thin Ewes to an Acute Cold Challenge in Mid-Pregnancy: Implications for Animal Physiology and Welfare

Background: Low food availability leading to reductions in Body Condition Score (BCS; 0 indicates emaciation and 5 obesity) in sheep often coincides with low temperatures associated with the onset of winter in New Zealand. The ability to adapt to reductions in environmental temperature may be impaired in animals with low BCS, in particular during pregnancy when metabolic demand is higher. Here we assess whether BCS affects a pregnant animal’s ability to cope with cold challenges. Methods: Eighteen pregnant ewes with a BCS of 2.760.1 were fed to attain low (LBC: BCS2.360.1), medium (MBC: BCS3.260.2) or high BCS (HBC: BCS3.660.2). Shorn ewes were exposed to a 6-h acute cold challenge in a climate-controlled room (wet and windy conditions, 4.460.1uC) in mid-pregnancy. Blood samples were collected during the BCS change phase, acute cold challenge and recovery phase. Results: During the BCS change phase, plasma glucose and leptin concentrations declined while free fatty acids (FFA) increased in LBC compared to MBC (P,0.01, P,0.01 and P,0.05, respectively) and HBC ewes (P,0.05, P,0.01 and P,0.01, respectively). During the cold challenge, plasma cortisol concentrations were lower in LBC than MBC (P,0.05) and HBC ewes (P,0.05), and FFA and insulin concentrations were lower in LBC than HBC ewes (P,0.05 and P,0.001, respectively). Leptin concentrations declined in MBC and HBC ewes while remaining unchanged in LBC ewes (P,0.01). Glucose concentrations and internal body temperature (Tcore) increased in all treatments, although peak Tcore tended to be higher in HBC ewes (P,0.1). During the recovery phase, T4 concentrations were lower in LBC ewes (P,0.05). Conclusion: Even though all ewes were able to increase Tcore and mobilize glucose, low BCS animals had considerably reduced cortisol and metabolic responses to a cold challenge in mid-pregnancy, suggesting that their ability to adapt to cold challenges through some of the expected pathways was reduced

PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in lymphoma cells

PRMT5, which regulates gene expression by symmetric dimethylation of histones and non-histone target proteins, is overexpressed and plays a pathogenic role in many cancers. In diffuse large B cell lymphoma (DLBCL), the mechanisms of PRMT5 dysregulation and its role in lymphomagenesis remain largely unknown. Here we demonstrate that B cell receptor (BCR) signaling regulates PRMT5 expression in DLBCL cells. Immunohistochemical analysis reveals elevated levels of PRMT5 expression in DLBCL cases and in germinal center (GC) B cells when compared to naive B cells. PRMT5 can be induced in naive B cells by BCR stimulation. We discovered that BTK-NF-κB signaling induces PRMT5 transcription in activated B cell-like (ABC) DLBCL cells while BCR downstream PI3K-AKT-MYC signaling upregulates PRMT5 expression in both ABC and GCB DLBCL cells. PRMT5 inhibition inhibits the growth of DLBCL cells in vitro and patient derived xenografts. Genomic and biochemical analysis demonstrate that PRMT5 promotes cell cycle progression and activates PI3K-AKT signaling, suggesting a feedback regulatory mechanism to enhance cell survival and proliferation. Co-targeting PRMT5 and AKT by their specific inhibitors is lethal to DLBCL cell lines and primary cancer cells. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate PRMT5 and AKT inhibitors for DLBCL

Accelerated inbreeding depression suggests synergistic epistasis for deleterious mutations in Drosophila melanogaster

Epistasis may have important consequences for a number of issues in quantitative genetics and evolutionary biology. In particular, synergistic epistasis for deleterious alleles is relevant to the mutation load paradox and the evolution of sex and recombination. Some studies have shown evidence of synergistic epistasis for spontaneous or induced deleterious mutations appearing in mutation-accumulation experiments. However, many newly arising mutations may not actually be segregating in natural populations because of the erasing action of natural selection. A demonstration of synergistic epistasis for naturally segregating alleles can be achieved by means of inbreeding depression studies, as deleterious recessive allelic effects are exposed in inbred lines. Nevertheless, evidence of epistasis from these studies is scarce and controversial. In this paper, we report the results of two independent inbreeding experiments carried out with two different populations of Drosophila melanogaster. The results show a consistent accelerated inbreeding depression for fitness, suggesting synergistic epistasis among deleterious alleles. We also performed computer simulations assuming different possible models of epistasis and mutational parameters for fitness, finding some of them to be compatible with the results observed. Our results suggest that synergistic epistasis for deleterious mutations not only occurs among newly arisen spontaneous or induced mutations, but also among segregating alleles in natural populationsWe acknowledge the support by Uvigo Marine Research Centre funded by the “Excellence in Research (INUGA)” Programme from the Regional Council of Culture, Education and Universities, with co-funding from the European Union through the ERDF Operational Programme Galicia 2014-2020. This work was funded by Agencia Estatal de Investigación (AEI) (CGL2016-75904-C2-1-P), Xunta de Galicia (ED431C 2016-037) and Fondos Feder: “Unha maneira de facer Europa.” SD was founded by a predoctoral (FPI) grant from Ministerio de Economía y Competitividad, SpainS

Weekly Intra-Amniotic IGF-1 Treatment Increases Growth of Growth-Restricted Ovine Fetuses and Up-Regulates Placental Amino Acid Transporters

Frequent treatment of the growth-restricted (IUGR) ovine fetus with intra-amniotic IGF-1 increases fetal growth. We aimed to determine whether increased growth was maintained with an extended dosing interval and to examine possible mechanisms. Pregnant ewes were allocated to three groups: Control, and two IUGR groups (induced by placental embolization) treated with weekly intra-amniotic injections of either saline (IUGR) or 360 µg IGF-1 (IGF1). IUGR fetuses were hypoxic, hyperuremic, hypoglycemic, and grew more slowly than controls. Placental glucose uptake and SLC2A1 (GLUT2) mRNA levels decreased in IUGR fetuses, but SLC2A3 (GLUT3) and SLC2A4 (GLUT4) levels were unaffected. IGF-1 treatment increased fetal growth rate, did not alter uterine blood flow or placental glucose uptake, and increased placental SLC2A1 and SLC2A4 (but not SLC2A3) mRNA levels compared with saline-treated IUGR animals. Following IGF-1 treatment, placental mRNA levels of isoforms of the system A, y+, and L amino acid transporters increased 1.3 to 5.0 fold, while the ratio of phosphorylated-mTOR to total mTOR also tended to increase. Weekly intra-amniotic IGF-1 treatment provides a promising avenue for intra-uterine treatment of IUGR babies, and may act via increased fetal substrate supply, up-regulating placental transporters for neutral, cationic, and branched-chain amino acids, possibly via increased activation of the mTOR pathway