Rapid reduction versus abrupt quitting for smokers who want to stop soon: a randomised controlled non-inferiority trial

Background: The standard way to stop smoking is to stop abruptly on a quit day with no prior reduction in consumption of cigarettes. Many smokers feel that reduction is natural and if reduction programmes were offered, many more might take up treatment. Few trials of reduction versus abrupt cessation have been completed. Most are small, do not use pharmacotherapy, and do not meet the standards necessary to obtain a marketing authorisation for a pharmacotherapy.\ud Design/Methods: We will conduct a non-inferiority andomised trial of rapid reduction versus standard abrupt cessation among smokers who want to stop smoking. In the reduction arm,participants will be advised to reduce smoking consumption by half in the first week and to 25% of baseline in the second, leading up to a quit day at which participants will stop smoking completely.This will be assisted by nicotine patches and an acute form of nicotine replacement therapy. In the abrupt arm participants will use nicotine patches only, whilst smoking as normal, for two weeks prior to a quit day, at which they will also stop smoking completely. Smokers in either arm will have standard withdrawal orientated behavioural support programme with a combination of nicotine patches and acute nicotine replacement therapy post-cessation.\ud Outcomes/Follow-up: The primary outcome of interest will be prolonged abstinence from smoking, with secondary trial outcomes of point prevalence, urges to smoke and withdrawal\ud symptoms. Follow up will take place at 4 weeks, 8 weeks and 6 months post-quit day

Infection of the malaria mosquito, Anopheles gambiae, with two species of entomopathogenic fungi: effects of concentration, co-formulation, exposure time and persistence

<p>Abstract</p> <p>Background</p> <p>Entomopathogenic fungi <it>Metarhizium anisopliae </it>and <it>Beauveria bassiana </it>isolates have been shown to infect and reduce the survival of mosquito vectors.</p> <p>Methods</p> <p>Here four different bioassays were conducted to study the effect of conidia concentration, co-formulation, exposure time and persistence of the isolates <it>M. anisopliae </it>ICIPE-30 and <it>B. bassiana </it>I93-925 on infection and survival rates of female <it>Anopheles gambiae sensu stricto</it>. Test concentrations and exposure times ranged between 1 × 10⁷- 4 × 10¹⁰conidia m^-2and 15 min - 6 h. In co-formulations, 2 × 10¹⁰conidia m^-2of both fungus isolates were mixed at ratios of 4:1, 2:1, 1:1,1:0, 0:1, 1:2 and 1:4. To determine persistence, mosquitoes were exposed to surfaces treated 1, 14 or 28 d previously, with conidia concentrations of 2 × 10⁹, 2 × 10¹⁰or 4 × 10¹⁰.</p> <p>Results</p> <p>Mosquito survival varied with conidia concentration; 2 × 10¹⁰conidia m^-2was the concentration above which no further reductions in survival were detectable for both isolates of fungus. The survival of mosquitoes exposed to single and co-formulated treatments was similar and no synergistic or additive effects were observed. Mosquitoes were infected within 30 min and longer exposure times did not result in a more rapid killing effect. Fifteen min exposure still achieved considerable mortality rates (100% mortality by 14 d) of mosquitoes, but at lower speed than with 30 min exposure (100% mortality by 9 d). Conidia remained infective up to 28 d post-application but higher concentrations did not increase persistence.</p> <p>Conclusion</p> <p>Both fungus isolates are effective and persistent at low concentrations and short exposure times.</p

Changing atmospheric CO2 concentration was the primary driver of early Cenozoic climate

The Early Eocene Climate Optimum (EECO, which occurred about 51 to 53 million years ago)1, was the warmest interval of the past 65 million years, with mean annual surface air temperature over ten degrees Celsius warmer than during the pre-industrial period2–4. Subsequent global cooling in the middle and late Eocene epoch, especially at high latitudes, eventually led to continental ice sheet development in Antarctica in the early Oligocene epoch (about 33.6 million years ago). However, existing estimates place atmospheric carbon dioxide (CO2) levels during the Eocene at 500–3,000 parts per million5–7, and in the absence of tighter constraints carbon–climate interactions over this interval remain uncertain. Here we use recent analytical and methodological developments8–11 to generate a new high-fidelity record of CO2 concentrations using the boron isotope (δ11Β) composition of well preserved planktonic foraminifera from the Tanzania Drilling Project, revising previous estimates6. Although species-level uncertainties make absolute values difficult to constrain, CO2 concentrations during the EECO were around 1,400 parts per million. The relative decline in CO2 concentration through the Eocene is more robustly constrained at about fifty per cent, with a further decline into the Oligocene12. Provided the latitudinal dependency of sea surface temperature change for a given climate forcing in the Eocene was similar to that of the late Quaternary period13, this CO2 decline was sufficient to drive the well documented high- and low-latitude cooling that occurred through the Eocene14. Once the change in global temperature between the pre-industrial period and the Eocene caused by the action of all known slow feedbacks (apart from those associated with the carbon cycle) is removed2–4, both the EECO and the late Eocene exhibit an equilibrium climate sensitivity relative to the pre-industrial period of 2.1 to 4.6 degrees Celsius per CO2 doubling (66 per cent confidence), which is similar to the canonical range (1.5 to 4.5 degrees Celsius15), indicating that a large fraction of the warmth of the early Eocene greenhouse was driven by increased CO2 concentrations, and that climate sensitivity was relatively constant throughout this period

Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates

β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as ‘transition state analogue’ inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs

Analisis Kekuatan Massa Batugamping Dengan Menggunakan Kaidah Hoek-Brown Failure Criterion-Roclab Di Daerah Gunung Sudo Kabupaten Gunung Kidul YOGYAKARTA

The research area is a limestone quarry region prospect, located in Gunung Sudo, Gunung Kidul Regency, Special Region of Yogyakarta Province. Safety factor of bench in limestone quarry is extremely determined by rock mass quality. The aim of this research is analyzing of rock mass strength of limestone in the quarry prospect using the Hoek-Brown failure criterion. The research used quantitative method. To obtain rock mass strength analysis of limestone needs some parameters. The main parameters are uniaxial compressive strength of intact rock, GSI, lithology, disturbance factor, unit weight and application for slope (height).To solve this analysis is assisted by Roclab software. The Roclab is a software program for determining rock mass strength parameters based on the generalized Hoek-Brown failure criterion. Final result of the research will be used for safely mine design of the limestone quarry

Thrombospondin-4 is a putative tumour-suppressor gene in colorectal cancer that exhibits age-related methylation

<p>Abstract</p> <p>Background</p> <p><it>Thrombospondin-4 </it>(<it>THBS4</it>) is a member of the extracellular calcium-binding protein family and is involved in cell adhesion and migration. The aim of this study was to evaluate the potential role of deregulation of <it>THBS4 </it>expression in colorectal carcinogenesis. Of particular interest was the possible silencing of expression by methylation of the CpG island in the gene promoter.</p> <p>Methods</p> <p>Fifty-five sporadic colorectal tumours stratified for the CpG Island Methylator Phenotype (CIMP) were studied. Immunohistochemical staining of THBS4 protein was assessed in normal and tumour specimens. Relative levels of <it>THBS4 </it>transcript expression in matched tumours and normal mucosa were also determined by quantitative RT-PCR. Colony forming ability was examined in 8 cell lines made to overexpress THBS4. Aberrant promoter hypermethylation was investigated as a possible mechanism of gene disruption using MethyLight. Methylation was also assessed in the normal colonic tissue of 99 patients, with samples biopsied from four regions along the length of the colon.</p> <p>Results</p> <p><it>THBS4 </it>expression was significantly lower in tumour tissue than in matched normal tissue. Immunohistochemical examination demonstrated that THBS4 protein was generally absent from normal epithelial cells and tumours, but was occasionally expressed at low levels in the cytoplasm towards the luminal surface in vesicular structures. Forced THBS4 over-expression caused a 50-60% repression of tumour colony growth in all eight cell lines examined compared to control cell lines. Tumours exhibited significantly higher levels of methylation than matched normal mucosa, and <it>THBS4 </it>methylation correlated with the CpG island methylator phenotype. There was a trend towards decreased gene expression in tumours exhibiting high <it>THBS4 </it>methylation, but the correlation was not significant. <it>THBS4 </it>methylation was detectable in normal mucosal biopsies where it correlated with increasing patient age and negatively with the occurrence of adenomas elsewhere in the colon.</p> <p>Conclusions</p> <p><it>THBS4 </it>shows increased methylation in colorectal cancer, but this is not strongly associated with altered gene expression, either because methylation has not always reached a critical level or because other factors influence <it>THBS4 </it>expression. <it>THBS4 </it>may act as a tumour suppressor gene, demonstrated by its suppression of tumour colony formation <it>in vitro</it>. <it>THBS4 </it>methylation is detectable in normal colonic mucosa and its level may be a biomarker for the occurrence of adenomas and carcinoma.</p

Global comparison of warring groups in 2002–2007: fatalities from targeting civilians vs. fighting battles

Background Warring groups that compete to dominate a civilian population confront contending behavioral options: target civilians or battle the enemy. We aimed to describe degrees to which combatant groups concentrated lethal behavior into intentionally targeting civilians as opposed to engaging in battle with opponents in contemporary armed conflict. Methodology/Principal Findings We identified all 226 formally organized state and non-state groups (i.e. actors) that engaged in lethal armed conflict during 2002–2007: 43 state and 183 non-state. We summed civilians killed by an actor's intentional targeting with civilians and combatants killed in battles in which the actor was involved for total fatalities associated with each actor, indicating overall scale of armed conflict. We used a Civilian Targeting Index (CTI), defined as the proportion of total fatalities caused by intentional targeting of civilians, to measure the concentration of lethal behavior into civilian targeting. We report actor-specific findings and four significant trends: 1.) 61% of all 226 actors (95% CI 55% to 67%) refrained from targeting civilians. 2.) Logistic regression showed actors were more likely to have targeted civilians if conflict duration was three or more years rather than one year. 3.) In the 88 actors that targeted civilians, multiple regressions showed an inverse correlation between CTI values and the total number of fatalities. Conflict duration of three or more years was associated with lower CTI values than conflict duration of one year. 4.) When conflict scale and duration were accounted for, state and non-state actors did not differ. We describe civilian targeting by actors in prolonged conflict. We discuss comparable patterns found in nature and interdisciplinary research. Conclusions/Significance Most warring groups in 2002–2007 did not target civilians. Warring groups that targeted civilians in small-scale, brief conflict concentrated more lethal behavior into targeting civilians, and less into battles, than groups in larger-scale, longer conflict

Minimum joint space width and tibial cartilage morphology in the knees of healthy individuals: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>The clinical use of minimum joint space width (mJSW) and cartilage volume and thickness has been limited to the longitudinal measurement of disease progression (i.e. change over time) rather than the diagnosis of OA in which values are compared to a standard. This is primarily due to lack of establishment of normative values of joint space width and cartilage morphometry as has been done with bone density values in diagnosing osteoporosis. Thus, the purpose of this pilot study is to estimate reference values of medial joint space width and cartilage morphometry in healthy individuals of all ages using standard radiography and peripheral magnetic resonance imaging.</p> <p>Design</p> <p>For this cross-sectional study, healthy volunteers underwent a fixed-flexion knee X-ray and a peripheral MR (pMR) scan of the same knee using a 1T machine (ONI OrthOne™, Wilmington, MA). Radiographs were digitized and analyzed for medial mJSW using an automated algorithm. Only knees scoring ≤1 on the Kellgren-Lawrence scale (no radiographic evidence of knee OA) were included in the analyses. All 3D SPGRE fat-sat sagittal pMR scans were analyzed for medial tibial cartilage morphometry using a proprietary software program (Chondrometrics GmbH).</p> <p>Results</p> <p>Of 119 healthy participants, 73 were female and 47 were male; mean (SD) age 38.2 (13.2) years, mean BMI 25.0 (4.4) kg/m². Minimum JSW values were calculated for each sex and decade of life. Analyses revealed mJSW did not significantly decrease with increasing decade (p > 0.05) in either sex. Females had a mean (SD) medial mJSW of 4.8 (0.7) mm compared to males with corresponding larger value of 5.7 (0.8) mm. Cartilage morphometry results showed similar trends with mean (SD) tibial cartilage volume and thickness in females of 1.50 (0.19) μL/mm²and 1.45 (0.19) mm, respectively, and 1.77 (0.24) μL/mm²and 1.71 (0.24) mm, respectively, in males.</p> <p>Conclusion</p> <p>These data suggest that medial mJSW values do not decrease with aging in healthy individuals but remain fairly constant throughout the lifespan with "healthy" values of 4.8 mm for females and 5.7 mm for males. Similar trends were seen for cartilage morphology. Results suggest there may be no need to differentiate a t-score and a z-score in OA diagnosis because cartilage thickness and JSW remain constant throughout life in the absence of OA.</p

Label-free cell separation and sorting in microfluidic systems

Cell separation and sorting are essential steps in cell biology research and in many diagnostic and therapeutic methods. Recently, there has been interest in methods which avoid the use of biochemical labels; numerous intrinsic biomarkers have been explored to identify cells including size, electrical polarizability, and hydrodynamic properties. This review highlights microfluidic techniques used for label-free discrimination and fractionation of cell populations. Microfluidic systems have been adopted to precisely handle single cells and interface with other tools for biochemical analysis. We analyzed many of these techniques, detailing their mode of separation, while concentrating on recent developments and evaluating their prospects for application. Furthermore, this was done from a perspective where inertial effects are considered important and general performance metrics were proposed which would ease comparison of reported technologies. Lastly, we assess the current state of these technologies and suggest directions which may make them more accessible