Trial Protocol: Randomised controlled trial of the effects of very low calorie diet, modest dietary restriction, and sequential behavioural programme on hunger, urges to smoke, abstinence and weight gain in overweight smokers stopping smoking

Background\ud Weight gain accompanies smoking cessation, but dieting during quitting is controversial as hunger may increase urges to smoke. This is a feasibility trial for the investigation of a very low calorie diet (VLCD), individual modest energy restriction, and usual advice on hunger, ketosis, urges to smoke, abstinence and weight gain in overweight smokers trying to quit. \ud \ud Methods\ud This is a 3 armed, unblinded, randomized controlled trial in overweight (BMI > 25 kg/$m^2$), daily smokers (CO > 10 ppm); with at least 30 participants in each group. Each group receives identical behavioural support and NRT patches (25 mg(8 weeks),15 mg(2 weeks),10 mg(2 weeks)). The VLCD group receive a 429-559 kcal/day liquid formula beginning 1 week before quitting and continuing for 4 weeks afterwards. The modest energy restricted group (termed individual dietary and activity planning(IDAP)) engage in goal-setting and receive an energy prescription based on individual basal metabolic rate(BMR) aiming for daily reduction of 600 kcal. The control group receive usual dietary advice that accompanies smoking cessation i.e. avoiding feeling hungry but eating healthy snacks. After this, the VLCD participants receive IDAP to provide support for changing eating habits in the longer term; the IDAP group continues receiving this support. The control group receive IDAP 8 weeks after quitting. This allows us to compare IDAP following a successful quit attempt with dieting concurrently during quitting. It also aims to prevent attrition in the unblinded, control group by meeting their need for weight management. Follow-up occurs at 6 and 12 months. \ud \ud Outcome measures include participant acceptability, measured qualitatively by semi-structured interviewing and quantitatively by recruitment and attrition rates. Feasibility of running the trial within primary care is measured by interview and questionnaire of the treatment providers. Adherence to the VLCD is verified by the presence of urinary ketones measured weekly. Daily urges to smoke, hunger and withdrawal are measured using the Mood and Physical Symptoms Scale-Combined (MPSS-C) and a Hunger Craving Score (HCS). 24 hour, 7 day point prevalence and 4-week prolonged abstinence (Russell Standard) is confirmed by CO < 10 ppm. Weight, waist and hip circumference and percentage body fat are measured at each visit. \ud \ud Trial Registration\ud Current controlled trials ISRCTN83865809\ud \u

Effect on Adherence to Nicotine Replacement Therapy of Informing Smokers Their Dose Is Determined by Their Genotype: A Randomised Controlled Trial

BACKGROUND: The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA. METHODS AND FINDINGS: We conducted an RCT with smokers in smoking cessation clinics (N = 633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference = 5.0%, 95% CI -0.9,10.8, p = 0.098). Motivation to make another quit attempt among those (n = 331) not abstinent at six months was not significantly different between groups (p = 0.23). Abstinence at 28 days was not different between groups (p = 0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference = 5.8%, 95% CI 1.0,10.7, p = 0.018). CONCLUSIONS: Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN14352545.</p

Examining the effectiveness of general practitioner and nurse promotion of electronic cigarettes versus standard care for smoking reduction and abstinence in hardcore smokers with smoking-related chronic disease:protocol for a randomised controlled trial

BACKGROUND: Despite the clear harm associated with smoking tobacco, many people with smoking-related chronic diseases or serious mental illnesses (SMI) are unwilling or unable to stop smoking. In many cases, these smokers have tried and exhausted all methods to stop smoking and yet clinicians are repeatedly mandated to offer them during routine consultations. Providing nicotine through electronic cigarettes (e-cigarettes) may reduce the adverse health consequences associated with tobacco smoking, but these are not currently offered. The aim of this study is to examine the feasibility, acceptability and effectiveness of general practitioners (GPs) and nurses delivering a brief advice intervention on e-cigarettes and offering an e-cigarette starter pack and patient support resources compared with standard care in smokers with smoking-related chronic diseases or SMI who are unwilling to stop smoking. METHODS/DESIGN: This is an individually randomised, blinded, two-arm trial. Smokers with a smoking-related chronic condition or SMI with no intention of stopping smoking will be recruited through primary care registers. Eligible participants will be randomised to one of two groups if they decline standard care for stopping smoking: a control group who will receive no additional support beyond standard care; or an intervention group who will receive GP or nurse-led brief advice about e-cigarettes, an e-cigarette starter pack with accompanying practical support booklet, and telephone support from experienced vapers and online video tutorials. The primary outcome measures will be smoking reduction, measured through changes in cigarettes per day and 7-day point-prevalence abstinence at 2 months. Secondary outcomes include smoking reduction, 7-day point-prevalence abstinence and prolonged abstinence at 8 months. Other outcomes include patient recruitment and follow-up, patient uptake and use of e-cigarettes, nicotine intake, contamination of randomisation and practitioner adherence to the delivery of the intervention. Qualitative interviews will be conducted in a subsample of practitioners, patients and the vape team to garner their reactions to the programme. DISCUSSION: This is the first randomised controlled trial to investigate whether e-cigarette provision alongside a brief intervention delivered by practitioners leads to reduced smoking and abstinence among smokers with smoking-related chronic diseases or SMI. TRIAL REGISTRATION: ISRCTN registry, ISRCTN59404712. Registered 28/11/17

When Subterranean Termites Challenge the Rules of Fungal Epizootics

Over the past 50 years, repeated attempts have been made to develop biological control technologies for use against economically important species of subterranean termites, focusing primarily on the use of the entomopathogenic fungus Metarhizium anisopliae. However, no successful field implementation of biological control has been reported. Most previous work has been conducted under the assumption that environmental conditions within termite nests would favor the growth and dispersion of entomopathogenic agents, resulting in an epizootic. Epizootics rely on the ability of the pathogenic microorganism to self-replicate and disperse among the host population. However, our study shows that due to multilevel disease resistance mechanisms, the incidence of an epizootic within a group of termites is unlikely. By exposing groups of 50 termites in planar arenas containing sand particles treated with a range of densities of an entomopathogenic fungus, we were able to quantify behavioral patterns as a function of the death ratios resulting from the fungal exposure. The inability of the fungal pathogen M. anisopliae to complete its life cycle within a Coptotermes formosanus (Isoptera: Rhinotermitidae) group was mainly the result of cannibalism and the burial behavior of the nest mates, even when termite mortality reached up to 75%. Because a subterranean termite colony, as a superorganism, can prevent epizootics of M. anisopliae, the traditional concepts of epizootiology may not apply to this social insect when exposed to fungal pathogens, or other pathogen for which termites have evolved behavioral and physiological means of disrupting their life cycle

Nicotinic Receptors Underlying Nicotine Dependence: Evidence from Transgenic Mouse Models.

Nicotine underlies the reinforcing properties of tobacco cigarettes and e-cigarettes. After inhalation and absorption, nicotine binds to various nicotinic acetylcholine receptor (nAChR) subtypes localized on the pre- and postsynaptic membranes of cells, which subsequently leads to the modulation of cellular function and neurotransmitter signaling. In this chapter, we begin by briefly reviewing the current understanding of nicotine's actions on nAChRs and highlight considerations regarding nAChR subtype localization and pharmacodynamics. Thereafter, we discuss the seminal discoveries derived from genetically modified mouse models, which have greatly contributed to our understanding of nicotine's effects on the reward-related mesolimbic pathway and the aversion-related habenulo-interpeduncular pathway. Thereafter, emerging areas of research focusing on modulation of nAChR expression and/or function are considered. Taken together, these discoveries have provided a foundational understanding of various genetic, neurobiological, and behavioral factors underlying the motivation to use nicotine and related dependence processes, which are thereby advancing drug discovery efforts to promote long-term abstinence

Relapse prevention for addictive behaviors

The Relapse Prevention (RP) model has been a mainstay of addictions theory and treatment since its introduction three decades ago. This paper provides an overview and update of RP for addictive behaviors with a focus on developments over the last decade (2000-2010). Major treatment outcome studies and meta-analyses are summarized, as are selected empirical findings relevant to the tenets of the RP model. Notable advances in RP in the last decade include the introduction of a reformulated cognitive-behavioral model of relapse, the application of advanced statistical methods to model relapse in large randomized trials, and the development of mindfulness-based relapse prevention. We also review the emergent literature on genetic correlates of relapse following pharmacological and behavioral treatments. The continued influence of RP is evidenced by its integration in most cognitive-behavioral substance use interventions. However, the tendency to subsume RP within other treatment modalities has posed a barrier to systematic evaluation of the RP model. Overall, RP remains an influential cognitive-behavioral framework that can inform both theoretical and clinical approaches to understanding and facilitating behavior change

Lethal and Pre-Lethal Effects of a Fungal Biopesticide Contribute to Substantial and Rapid Control of Malaria Vectors

Rapidly emerging insecticide resistance is creating an urgent need for new active ingredients to control the adult mosquitoes that vector malaria. Biopesticides based on the spores of entomopathogenic fungi have shown considerable promise by causing very substantial mortality within 7–14 days of exposure. This mortality will generate excellent malaria control if there is a high likelihood that mosquitoes contact fungi early in their adult lives. However, where contact rates are lower, as might result from poor pesticide coverage, some mosquitoes will contact fungi one or more feeding cycles after they acquire malaria, and so risk transmitting malaria before the fungus kills them. Critics have argued that ‘slow acting’ fungal biopesticides are, therefore, incapable of delivering malaria control in real-world contexts. Here, utilizing standard WHO laboratory protocols, we demonstrate effective action of a biopesticide much faster than previously reported. Specifically, we show that transient exposure to clay tiles sprayed with a candidate biopesticide comprising spores of a natural isolate of Beauveria bassiana, could reduce malaria transmission potential to zero within a feeding cycle. The effect resulted from a combination of high mortality and rapid fungal-induced reduction in feeding and flight capacity. Additionally, multiple insecticide-resistant lines from three key African malaria vector species were completely susceptible to fungus. Thus, fungal biopesticides can block transmission on a par with chemical insecticides, and can achieve this where chemical insecticides have little impact. These results support broadening the current vector control paradigm beyond fast-acting chemical toxins

Mediterranean-climate streams and rivers: geographically separated but ecologically comparable freshwater systems

Streams and rivers in mediterranean-climate regions (med-rivers in med-regions) are ecologically unique, with flow regimes reflecting precipitation patterns. Although timing of drying and flooding is predictable, seasonal and annual intensity of these events is not. Sequential flooding and drying, coupled with anthropogenic influences make these med-rivers among the most stressed riverine habitat worldwide. Med-rivers are hotspots for biodiversity in all med-regions. Species in med-rivers require different, often opposing adaptive mechanisms to survive drought and flood conditions or recover from them. Thus, metacommunities undergo seasonal differences, reflecting cycles of river fragmentation and connectivity, which also affect ecosystem functioning. River conservation and management is challenging, and trade-offs between environmental and human uses are complex, especially under future climate change scenarios. This overview of a Special Issue on med-rivers synthesizes information presented in 21 articles covering the five med-regions worldwide: Mediterranean Basin, coastal California, central Chile, Cape region of South Africa, and southwest and southern Australia. Research programs to increase basic knowledge in less-developed med-regions should be prioritized to achieve increased abilities to better manage med-rivers

P-31 magnetic resonance spectroscopy in skeletal muscle: Experts' consensus recommendations

Skeletal muscle phosphorus-31 31P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31P MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1H MRS measurements) can help in the physiological/metabolic interpretation of 31P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology

Genome Sequencing and Comparative Transcriptomics of the Model Entomopathogenic Fungi Metarhizium anisopliae and M. acridum

Metarhizium spp. are being used as environmentally friendly alternatives to chemical insecticides, as model systems for studying insect-fungus interactions, and as a resource of genes for biotechnology. We present a comparative analysis of the genome sequences of the broad-spectrum insect pathogen Metarhizium anisopliae and the acridid-specific M. acridum. Whole-genome analyses indicate that the genome structures of these two species are highly syntenic and suggest that the genus Metarhizium evolved from plant endophytes or pathogens. Both M. anisopliae and M. acridum have a strikingly larger proportion of genes encoding secreted proteins than other fungi, while ∼30% of these have no functionally characterized homologs, suggesting hitherto unsuspected interactions between fungal pathogens and insects. The analysis of transposase genes provided evidence of repeat-induced point mutations occurring in M. acridum but not in M. anisopliae. With the help of pathogen-host interaction gene database, ∼16% of Metarhizium genes were identified that are similar to experimentally verified genes involved in pathogenicity in other fungi, particularly plant pathogens. However, relative to M. acridum, M. anisopliae has evolved with many expanded gene families of proteases, chitinases, cytochrome P450s, polyketide synthases, and nonribosomal peptide synthetases for cuticle-degradation, detoxification, and toxin biosynthesis that may facilitate its ability to adapt to heterogenous environments. Transcriptional analysis of both fungi during early infection processes provided further insights into the genes and pathways involved in infectivity and specificity. Of particular note, M. acridum transcribed distinct G-protein coupled receptors on cuticles from locusts (the natural hosts) and cockroaches, whereas M. anisopliae transcribed the same receptor on both hosts. This study will facilitate the identification of virulence genes and the development of improved biocontrol strains with customized properties