Streptomyces cell-free systems for natural product discovery and engineering.

Streptomyces bacteria are a major microbial source of natural products, which are encoded within so-called biosynthetic gene clusters (BGCs). This highlight discusses the emergence of native Streptomyces cell-free systems as a new tool to accelerate the study of the fundamental chemistry and biology of natural product biosynthesis from these bacteria. Cell-free systems provide a prototyping platform to study plug-and-play reactions in microscale reactions. So far, Streptomyces cell-free systems have been used to rapidly characterise gene expression regulation, access secondary metabolite biosynthetic enzymes, and catalyse cell-free transcription, translation, and biosynthesis of example natural products. With further progress, we anticipate the development of more complex systems to complement existing experimental tools for the discovery and engineering of natural product biosynthesis from Streptomyces and related high G + C (%) bacteria.

Elucidation of the biosynthesis of the methane catalyst coenzyme F430.

Methane biogenesis in methanogens is mediated by methyl-coenzyme M reductase, an enzyme that is also responsible for the utilization of methane through anaerobic methane oxidation. The enzyme uses an ancillary factor called coenzyme F430, a nickel-containing modified tetrapyrrole that promotes catalysis through a methyl radical/Ni(ii)-thiolate intermediate. However, it is unclear how coenzyme F430 is synthesized from the common primogenitor uroporphyrinogen iii, incorporating 11 steric centres into the macrocycle, although the pathway must involve chelation, amidation, macrocyclic ring reduction, lactamization and carbocyclic ring formation. Here we identify the proteins that catalyse the biosynthesis of coenzyme F430 from sirohydrochlorin, termed CfbA-CfbE, and demonstrate their activity. The research completes our understanding of how the repertoire of tetrapyrrole-based pigments are constructed, permitting the development of recombinant systems to use these metalloprosthetic groups more widely.

Alcohol affordability: implications for alcohol price policies. A cross-sectional analysis in middle and older adults from UK Biobank.

BACKGROUND: Increasing the price of alcohol reduces alcohol consumption and harm. The role of food complementarity, transaction costs and inflation on alcohol demand are determined and discussed in relation to alcohol price policies. METHODS: UK Biobank (N = 502,628) was linked by region to retail price quotes for the years 2007 to 2010. The log residual food and alcohol prices, and alcohol availability were regressed onto log daily alcohol consumption. Model standard errors were adjusted for clustering by region. RESULTS: Associations with alcohol consumption were found for alcohol price (ß = -0.56, 95% CI, -0.92 to -0.20) and availability (ß = 0.06, 95% CI, 0.04 to 0.07). Introducing, food price reduced the alcohol price consumption association (ß = -0.26, 95% CI, -0.50 to -0.03). Alcohol (B = 0.001, 95% CI, 0.0004 to 0.001) and food (B = 0.001, 95% CI, 0.0005 to 0.0006) price increased with time and were associated (ρ = 0.57, P < 0.001). CONCLUSION: Alcohol and food are complements, and the price elasticity of alcohol reduces when the effect of food price is accounted for. Transaction costs did not affect the alcohol price consumption relationship. Fixed alcohol price policies are susceptible to inflation.

PEER simplified chronic pain guideline: Management of chronic low back, osteoarthritic, and neuropathic pain in primary care.

OBJECTIVE: To develop a clinical practice guideline to support the management of chronic pain, including low back, osteoarthritic, and neuropathic pain in primary care. METHODS: The guideline was developed with an emphasis on best available evidence and shared decision-making principles. Ten health professionals (4 generalist family physicians, 1 pain management-focused family physician, 1 anesthesiologist, 1 physical therapist, 1 pharmacist, 1 nurse practitioner, and 1 psychologist), a patient representative, and a nonvoting pharmacist and guideline methodologist comprised the Guideline Committee. Member selection was based on profession, practice setting, and lack of financial conflicts of interest. The guideline process was iterative in identification of key questions, evidence review, and development of guideline recommendations. Three systematic reviews, including a total of 285 randomized controlled trials, were completed. Randomized controlled trials were included only if they reported a responder analysis (eg, how many patients achieved a 30% or greater reduction in pain). The committee directed an Evidence Team (composed of evidence experts) to address an additional 11 complementary questions. Key recommendations were derived through committee consensus. The guideline and shared decision-making tools underwent extensive review by clinicians and patients before publication. RECOMMENDATIONS: Physical activity is recommended as the foundation for managing osteoarthritis and chronic low back pain; evidence of benefit is unclear for neuropathic pain. Cognitive-behavioural therapy or mindfulness-based stress reduction are also suggested as options for managing chronic pain. Treatments for which there is clear, unclear, or no benefit are outlined for each condition. Treatments for which harms likely outweigh benefits for all or most conditions studied include opioids and cannabinoids. CONCLUSION: This guideline for the management of chronic pain, including osteoarthritis, low back pain, and neuropathic pain, highlights best available evidence including both benefits and harms for a number of treatment interventions. A strong recommendation for exercise as the primary treatment for chronic osteoarthritic and low back pain is made based on demonstrated long-term evidence of benefit. This information is intended to assist with, not dictate, shared decision making with patients.

Refactoring of a synthetic raspberry ketone pathway with EcoFlex.

BACKGROUND:  A key focus of synthetic biology is to develop microbial or cell-free based biobased routes to value-added chemicals such as fragrances. Originally, we developed the EcoFlex system, a Golden Gate toolkit, to study genes/pathways flexibly using Escherichia coli heterologous expression. In this current work, we sought to use EcoFlex to optimise a synthetic raspberry ketone biosynthetic pathway. Raspberry ketone is a high-value (~ £20,000 kg-1) fine chemical farmed from raspberry (Rubeus rubrum) fruit. RESULTS:  By applying a synthetic biology led design-build-test-learn cycle approach, we refactor the raspberry ketone pathway from a low level of productivity (0.2 mg/L), to achieve a 65-fold (12.9 mg/L) improvement in production. We perform this optimisation at the prototype level (using microtiter plate cultures) with E. coli DH10ß, as a routine cloning host. The use of E. coli DH10ß facilitates the Golden Gate cloning process for the screening of combinatorial libraries. In addition, we also newly establish a novel colour-based phenotypic screen to identify productive clones quickly from solid/liquid culture. CONCLUSIONS:  Our findings provide a stable raspberry ketone pathway that relies upon a natural feedstock (L-tyrosine) and uses only constitutive promoters to control gene expression. In conclusion we demonstrate the capability of EcoFlex for fine-tuning a model fine chemical pathway and provide a range of newly characterised promoter tools gene expression in E. coli.

Review of the Technical, Toxicological, and PKPD Considerations for Conducting Inhalation Toxicity Studies on Biologic Pharmaceuticals-The Outcome of a Cross-Industry Working Group Survey.

The inhaled route is still a relatively novel route for delivering biologics and poses additional challenges to those encountered with inhaled small molecules, further complicating the design and interpretation of toxicology studies. A working group formed to summarize the current knowledge of inhaled biologics across industry and to analyze data collated from an anonymized cross-industry survey comprising 12 inhaled biologic case studies (18 individual inhalation toxicity studies on monoclonal antibodies, fragment antibodies, domain antibodies, oligonucleotides, and proteins/peptides). The output of this working group provides valuable insights into the issues faced when conducting toxicology studies with inhaled biologics, including common technical considerations on aerosol generation, use of young and sexually mature nonhuman primates, pharmacokinetic/pharmacodynamic modeling, exposure and immunogenicity assessment, maximum dose setting, and no observed adverse effect levels determination. Although the current data set is too small to allow firm conclusions, testing of novel biologics remains an active area and is likely to remain so for molecules where delivery via the inhaled route is beneficial. In the future, it is hoped others will continue to share their experiences and build on the conclusions of this review to further improve our understanding of these complex issues and, ultimately, facilitate the safe introduction of inhaled biologics into clinical use.

The "beauty in the beast"-the multiple uses of Priestia megaterium in biotechnology.

Over 30 years, the Gram-positive bacterium Priestia megaterium (previously known as Bacillus megaterium) was systematically developed for biotechnological applications ranging from the production of small molecules like vitamin B12, over polymers like polyhydroxybutyrate (PHB) up to the in vivo and in vitro synthesis of multiple proteins and finally whole-cell applications. Here we describe the use of the natural vitamin B12 (cobalamin) producer P. megaterium for the elucidation of the biosynthetic pathway and the subsequent systematic knowledge-based development for production purposes. The formation of PHB, a natural product of P. megaterium and potential petro-plastic substitute, is covered and discussed. Further important biotechnological characteristics of P. megaterium for recombinant protein production including high protein secretion capacity and simple cultivation on value-added carbon sources are outlined. This includes the advanced system with almost 30 commercially available expression vectors for the intracellular and extracellular production of recombinant proteins at the g/L scale. We also revealed a novel P. megaterium transcription-translation system as a complementary and versatile biotechnological tool kit. As an impressive biotechnology application, the formation of various cytochrome P450 is also critically highlighted. Finally, whole cellular applications in plant protection are completing the overall picture of P. megaterium as a versatile giant cell factory. KEY POINTS: • The use of Priestia megaterium for the biosynthesis of small molecules and recombinant proteins through to whole-cell applications is reviewed. • P. megaterium can act as a promising alternative host in biotechnological production processes.

Rapid acquisition and model-based analysis of cell-free transcription-translation reactions from nonmodel bacteria.

Native cell-free transcription-translation systems offer a rapid route to characterize the regulatory elements (promoters, transcription factors) for gene expression from nonmodel microbial hosts, which can be difficult to assess through traditional in vivo approaches. One such host, Bacillus megaterium, is a giant Gram-positive bacterium with potential biotechnology applications, although many of its regulatory elements remain uncharacterized. Here, we have developed a rapid automated platform for measuring and modeling in vitro cell-free reactions and have applied this to B. megaterium to quantify a range of ribosome binding site variants and previously uncharacterized endogenous constitutive and inducible promoters. To provide quantitative models for cell-free systems, we have also applied a Bayesian approach to infer ordinary differential equation model parameters by simultaneously using time-course data from multiple experimental conditions. Using this modeling framework, we were able to infer previously unknown transcription factor binding affinities and quantify the sharing of cell-free transcription-translation resources (energy, ribosomes, RNA polymerases, nucleotides, and amino acids) using a promoter competition experiment. This allows insights into resource limiting-factors in batch cell-free synthesis mode. Our combined automated and modeling platform allows for the rapid acquisition and model-based analysis of cell-free transcription-translation data from uncharacterized microbial cell hosts, as well as resource competition within cell-free systems, which potentially can be applied to a range of cell-free synthetic biology and biotechnology applications.

Controlled observational study and economic evaluation of the effect of city-centre night-time alcohol intoxication management services on the emergency care system compared with usual care.

BACKGROUND: Alcohol intoxication management services (AIMS) provide an alternative care pathway for alcohol-intoxicated adults otherwise requiring emergency department (ED) services and at times of high incidence. We estimate the effectiveness and cost-effectiveness of AIMS on ED attendance rates with ED and ambulance service performance indicators as secondary outcomes. METHODS: A controlled longitudinal retrospective observational study in English and Welsh towns, six with AIMS and six without. Control and intervention cities were matched by sociodemographic characteristics. The primary outcome was ED attendance rate per night, secondary analyses explored hospital admission rates and ambulance response times. Interrupted time series analyses compared control and matched intervention sites pre-AIMS and post-AIMS. Cost-effectiveness analyses compared the component costs of AIMS to usual care before with results presented from the National Health Service and social care prospective. The number of diversions away from ED required for a service to be cost neutral was determined. RESULTS: Analyses found considerable variation across sites, only one service was associated with a significant reduction in ED attendances (-4.89, p<0.01). The services offered by AIMS varied. On average AIMS had 7.57 (mean minimum=1.33, SD=1.37 to mean maximum=24.66, SD=12.58) in attendance per session, below the 11.02 diversions away from ED at which services would be expected to be cost neutral. CONCLUSIONS: AIMSs have variable effects on the emergency care system, reflecting variable structures and processes, but may be associated with modest reductions in the burden on ED and ambulance services. The more expensive model, supported by the ED, was the only configuration likely to divert patients away from ED. AIMS should be regarded as fledgling services that require further work to realise benefit. TRIAL REGISTRATION NUMBER: ISRCTN63096364.

Putrescine Depletion Affects Arabidopsis Root Meristem Size by Modulating Auxin and Cytokinin Signaling and ROS Accumulation.

Polyamines (PAs) dramatically affect root architecture and development, mainly by unknown mechanisms; however, accumulating evidence points to hormone signaling and reactive oxygen species (ROS) as candidate mechanisms. To test this hypothesis, PA levels were modified by progressively reducing ADC1/2 activity and Put levels, and then changes in root meristematic zone (MZ) size, ROS, and auxin and cytokinin (CK) signaling were investigated. Decreasing putrescine resulted in an interesting inverted-U-trend in primary root growth and a similar trend in MZ size, and differential changes in putrescine (Put), spermidine (Spd), and combined spermine (Spm) plus thermospermine (Tspm) levels. At low Put concentrations, ROS accumulation increased coincidently with decreasing MZ size, and treatment with ROS scavenger KI partially rescued this phenotype. Analysis of double AtrbohD/F loss-of-function mutants indicated that NADPH oxidases were not involved in H2O2 accumulation and that elevated ROS levels were due to changes in PA back-conversion, terminal catabolism, PA ROS scavenging, or another pathway. Decreasing Put resulted in a non-linear trend in auxin signaling, whereas CK signaling decreased, re-balancing auxin and CK signaling. Different levels of Put modulated the expression of PIN1 and PIN2 auxin transporters, indicating changes to auxin distribution. These data strongly suggest that PAs modulate MZ size through both hormone signaling and ROS accumulation in Arabidopsis.

Endorsement of clinical practice guidelines: Criteria from the College of Family Physicians of Canada.

OBJECTIVE: To refine the process for endorsement of guidelines and establish the expectations of the College of Family Physicians of Canada (CFPC) regarding the quality and relevance of clinical practice guidelines targeting family physicians and their patients. COMPOSITION OF THE COMMITTEE: Initially, a group of 6 CFPC staff and selected College members reviewed the previous process for endorsement with the aim of providing a new direction, if needed. The work was then assumed by the Guideline and Knowledge Translation Expert Working Group, a purposefully selected group of 9 family physicians from across Canada with expertise in research, evidence, guidelines, knowledge translation, and continuing professional development and education. METHODS: The initial task force reviewed the endorsement process and identified areas for improvement. A draft new process and core criteria for high-quality guidelines were developed. This was approved by the CFPC board. A Guideline and Knowledge Translation Expert Working Group was then formed to further refine the process and the criteria. Multiple resources were used to inform the criteria. The Guideline and Knowledge Translation Expert Working Group will manage the endorsement process of external submitted guidelines, as well as provide high-level guidance to the CFPC regarding in-house guidelines and continuing professional development content. REPORT: This article provides the expectations of the CFPC regarding clinical practice guidelines and describes in detail the process and criteria for endorsement. Key principles include family physician involvement and guideline funding unlikely to introduce bias, with most criteria falling under 4 themed areas: relation to family medicine, CFPC values, patient engagement and decision making, and scientific rigour. The Guideline and Knowledge Translation Expert Working Group will report to the CFPC board at least once a year. It is hoped that this fully transparent process and these criteria will help advance the quality and standards of clinical practice guideline production in Canada. CONCLUSION: A comprehensive but reasonable list has been provided that reflects the best standards and recommendations and is consistent with the CFPC's values while recognizing the landscape of guideline development for its national partners and colleagues. As with all processes, careful consideration and evaluation will be essential.

The Enduring Effects of Parental Alcohol, Tobacco, and Drug Use on Child Well-being: A Multilevel Meta-Analysis.

The effects of psychoactive substance abuse are not limited to the user, but extend to the entire family system, with children of substance abusers being particularly at risk. This meta-analysis attempted to quantify the longitudinal relationship between parental alcohol, tobacco, and drug use and child well-being, investigating variation across a range of substance and well-being indices and other potential moderators. We performed a literature search of peer-reviewed, English language, longitudinal observational studies that reported outcomes for children aged 0 to 18 years. In total, 56 studies, yielding 220 dependent effect sizes, met inclusion criteria. A multilevel random-effects model revealed a statistically significant, small detriment to child well-being for parental substance abuse over time (r = .15). Moderator analyses demonstrated that the effect was more pronounced for parental drug use (r = .25), compared with alcohol use (r = .13), tobacco use (r = .13), and alcohol use disorder (r = .14). Results highlight a need for future studies that better capture the effect of parental psychoactive substance abuse on the full breadth of childhood well-being outcomes and to integrate substance abuse into models that specify the precise conditions under which parental behavior determines child well-being.Registration: PROSPERO CRD42017076088.

Drinking beer, wine or spirits - does it matter for inequalities in alcohol-related hospital admission? A record-linked longitudinal study in Wales.

BACKGROUND: Alcohol-related harm has been found to be higher in disadvantaged groups, despite similar alcohol consumption to advantaged groups. This is known as the alcohol harm paradox. Beverage type is reportedly socioeconomically patterned but has not been included in longitudinal studies investigating record-linked alcohol consumption and harm. We aimed to investigate whether and to what extent consumption by beverage type, BMI, smoking and other factors explain inequalities in alcohol-related harm. METHODS: 11,038 respondents to the Welsh Health Survey answered questions on their health and lifestyle. Responses were record-linked to wholly attributable alcohol-related hospital admissions (ARHA) eight years before the survey month and until the end of 2016 within the Secure Anonymised Information Linkage (SAIL) Databank. We used survival analysis, specifically multi-level and multi-failure Cox mixed effects models, to calculate the hazard ratios of ARHA. In adjusted models we included the number of units consumed by beverage type and other factors, censoring for death or moving out of Wales. RESULTS: People living in more deprived areas had a higher risk of admission (HR 1.75; 95% CI 1.23-2.48) compared to less deprived. Adjustment for the number of units by type of alcohol consumed only reduced the risk of ARHA for more deprived areas by 4% (HR 1.72; 95% CI 1.21-2.44), whilst adding smoking and BMI reduced these inequalities by 35.7% (HR 1.48; 95% CI 1.01-2.17). These social patterns were similar for individual-level social class, employment, housing tenure and highest qualification. Inequalities were further reduced by including either health status (16.6%) or mental health condition (5%). Unit increases of spirits drunk were positively associated with increasing risk of ARHA (HR 1.06; 95% CI 1.01-1.12), higher than for other drink types. CONCLUSIONS: Although consumption by beverage type was socioeconomically patterned, it did not help explain inequalities in alcohol-related harm. Smoking and BMI explained around a third of inequalities, but lower socioeconomic groups had a persistently higher risk of (multiple) ARHA. Comorbidities also explained a further proportion of inequalities and need further investigation, including the contribution of specific conditions. The increased harms from consumption of stronger alcoholic beverages may inform public health policy.

A Longitudinal Study of European Students' Alcohol Use and Related Behaviors as They Travel Abroad to Study.

BACKGROUND: Travelling away from home can be associated with fewer limits on behavior, particularly for students who participate in exchange programs. AIMS: To examine the effects of eight moderators on change in alcohol use and related negative outcomes, drug use and unprotected sexual behavior in European study abroad students before, during, and after their time abroad. METHODS: A three wave (before departure, while abroad, and after their return) longitudinal design collecting data on the frequency and volume of alcohol consumed, heavy episodic drinking, alcohol-related outcomes, drug use, and unprotected casual sex. RESULTS: The baseline survey was completed by 1145 students participating in one or two semester exchange programs (67.5% spent up to a semester abroad), of which 906 participated in two or more waves, representing 42 and 33 countries of origin and destination, respectively. Mean age was 22.2 years (SD = 2.28) and 72.7% were female. Students increased the amount of alcohol consumed by 35% (B = 0.32; 95% CI 0.287-0.349) and experienced more alcohol-related consequences (B = 0.15; 95% CI 0.089-0.219) during the study abroad experience, though levels fell below pre-departure levels when they returned home. Factors related to greater alcohol use while abroad include pre-departure expectations about alcohol use during the study abroad experience, psychological adjustment to the host country, academic involvement, and host country living costs. No statistically meaningful change in drug use and unprotected sexual behavior was observed. CONCLUSIONS: Studying abroad exposes European students to additional time-limited alcohol-related health risks.

The relationship between alcohol use and long-term cognitive decline in middle and late life: a longitudinal analysis using UK Biobank.

Background: Using UK Biobank data, this study sought to explain the causal relationship between alcohol intake and cognitive decline in middle and older aged populations. Methods: Data from 13 342 men and women, aged between 40 and 73 years were used in regression analysis that tested the functional relationship and impact of alcohol on cognitive performance. Performance was measured using mean reaction time (RT) and intra-individual variation (IIV) in RT, collected in response to a perceptual matching task. Covariates included body mass index, physical activity, tobacco use, socioeconomic status, education and baseline cognitive function. Results: A restricted cubic spline regression with three knots showed how the linear (ß1 = -0.048, 95% CI: -0.105 to -0.030) and non-linear effects (ß2 = 0.035, 95% CI: 0.007-0.059) of alcohol use on mean RT and IIV in RT (ß1 = -0.055, 95% CI: -0.125 to -0.034; ß2 = 0.034, 95% CI: 0.002-0.064) were significant adjusting for covariates. Cognitive function declined as alcohol use increased beyond 10 g/day. Decline was more apparent as age increased. Conclusions: The relationship between alcohol use and cognitive function is non-linear. Consuming more than one UK standard unit of alcohol per day is detrimental to cognitive performance and is more pronounced in older populations.

Managing alcohol-related attendances in emergency care: can diversion to bespoke services lessen the burden?

Acute alcohol intoxication (AAI) has a long history of burdening emergency care services. Healthcare systems around the world have explored a variety of different services that divert AAI away from EDs to better manage their condition. Little formal evaluation has been undertaken, particularly in the UK where alcohol misuse is one of the highest in the world. In this article, we outline a brief history of diversionary services, introduce the concept of Alcohol Intoxication Management Services (AIMS) and describe examples of AIMS in the UK. We then describe Evaluating the Diversion of Alcohol-Related Attendances, a natural experiment including six cities with AIMS compared with six cities without, that involves an ethnographic study, records patient experiences in both AIMS and EDs, assesses impact on key performance indicators in healthcare and evaluates the cost-effectiveness of AIMS.

Cell-free synthetic biology for in vitro prototype engineering.

Cell-free transcription-translation is an expanding field in synthetic biology as a rapid prototyping platform for blueprinting the design of synthetic biological devices. Exemplar efforts include translation of prototype designs into medical test kits for on-site identification of viruses (Zika and Ebola), while gene circuit cascades can be tested, debugged and re-designed within rapid turnover times. Coupled with mathematical modelling, this discipline lends itself towards the precision engineering of new synthetic life. The next stages of cell-free look set to unlock new microbial hosts that remain slow to engineer and unsuited to rapid iterative design cycles. It is hoped that the development of such systems will provide new tools to aid the transition from cell-free prototype designs to functioning synthetic genetic circuits and engineered natural product pathways in living cells.

Lignes directrices simplifiées de PEER sur la douleur chronique: Gestion de la douleur chronique lombaire, arthrosique et neuropathique en première ligne.

OBJECTIF: Formuler des lignes directrices de pratique clinique pour soutenir la prise en charge de la douleur chronique, y compris la douleur lombaire, arthrosique et neuropathique, dans les soins primaires. MÉTHODES: Ces lignes directrices ont été élaborées en mettant l'accent sur les meilleures données probantes disponibles et sur les principes de décision partagée. Dix professionnels de la santé (4 omnipraticiens, 1 médecin de famille spécialisée en gestion de la douleur, 1 anesthésiste, 1 physiothérapeute, 1 pharmacienne, 1 infirmière praticienne et 1 psychologue), 1 représentant des patients, et 1 pharmacienne et spécialiste de la méthodologie des lignes directrices sans droit de vote composaient le comité des lignes directrices. Les membres ont été sélectionnés en fonction de leur profession, de leur milieu de pratique, et de l'absence d'un conflit d'intérêts de nature financière. Les lignes directrices sont le fruit d'un processus itératif incluant la détermination des questions clés, l'examen des données probantes et la formulation des recommandations des lignes directrices. Trois revues systématiques, totalisant 285 études avec répartition aléatoire et contrôlées ont été réalisées. Ces études n'étaient incluses que si elles avaient rapporté une analyse des répondants (p. ex. combien de patients ont obtenu un soulagement d'au moins 30% de la douleur). Le comité a confié à une équipe d'examen des données (composée de spécialistes des données probantes) la tâche de répondre à 11 autres questions complémentaires. Les principales recommandations découlent d'un consensus au sein du comité. Des cliniciens et des patients ont minutieusement examiné les lignes directrices et les outils de décision partagée avant leur publication. RECOMMANDATIONS: L'activité physique est recommandée comme fondement de la gestion de la douleur arthrosique et lombaire chronique; les données probantes étayant un bienfait ne sont pas concluantes dans le cas de la douleur neuropathique. La thérapie cognitivo-comportementale ou la réduction du stress basée sur la pleine conscience sont également suggérées comme des options pour gérer la douleur chronique. Les traitements pour lesquels le bienfait est clair, non concluant ou absent sont décrits sous chaque affection. Les traitements dont les préjudices surpassent probablement les bienfaits pour toutes les affections étudiées, ou la plupart d'entre elles, sont les opioïdes et les cannabinoïdes. CONCLUSION: Ces lignes directrices sur la gestion de la douleur chronique, y compris la douleur arthrosique, lombaire et neuropathique, met en lumière les meilleures données probantes disponibles, y compris les bienfaits et préjudices pour un certain nombre d'interventions thérapeutiques. Une forte recommandation en faveur de l'exercice comme principal traitement de la douleur arthrosique et lombaire chronique repose sur des données probantes ayant démontré un bienfait depuis longtemps. Cette information vise à contribuer au processus de décision partagée avec le patient et non à le dicter.

Feasibility of alcohol misuse screening and treatment in the dental setting.

BACKGROUND: Dental specialists treat conditions such as facial trauma and oral cancer that can result from alcohol misuse. Visits to primary dental care professionals are oriented towards prevention. Interventions coordinated by specialist services but delivered strategically in primary care could therefore potentially help to reduce burdens on secondary care services. The aim of this study was to determine the feasibility of screening for alcohol misuse and providing brief intervention in a primary dental care setting. METHODS: In this randomised controlled trial, patients aged 18-65 years were recruited from a local general dental practice. Patients were stratified according to appointment (with a dentist or hygienist). Reception staff administered envelope packs containing screening materials (the Modified Single Alcohol Screening Question [M-SASQ]), consent forms, and a short survey collecting contact details to patients who agreed to take part in the study. Packs were randomly pre-allocated to control and intervention groups by strata using block randomisation before the start of the study. Consenting patients scoring positively on the M-SASQ for drinking hazardously and allocated to the intervention group received a motivational intervention to reduce alcohol intake from either the hygienist or dentist. Patients in the control group received usual care. The outcome assessor and patients were masked to allocations. The outcome measure at 3 months was M-SASQ score. This trial is registered with the ISRCTN registry, number ISRCTN18745862. FINDINGS: One hygiene patient and 106 dental patients were recruited. The hygiene patient did not score positively on the M-SASQ for alcohol misuse. Of the 106 dental patients, 46 (43%) scored positively, with 26 allocated to the intervention group and 20 to the control group. Follow-up data were available for 22 (48%) of the 46 patients (12 intervention, 10 control). M-SASQ scores changed from positive to negative for two patients in the intervention and five in the control group. INTERPRETATION: Alcohol misuse screening and treatment was feasible in a primary dental care setting; this suggests a new approach involving the general dental team, which could potentially reduce burdens on specialist dental services. Overall, in this practice, the dentist was best placed to deliver the intervention rather than the hygienist since these health-care professionals saw most of the patients recruited into the trial. Contamination might have been a problem because more patients in the control group changed M-SASQ score. Building on these findings, a multicentre, cluster randomised controlled trial is planned. FUNDING: Royal College of Surgeons of England.