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Showing papers by "University of Dundee published in 2017"


Journal ArticleDOI
TL;DR: This systematic review of interventions to improve antibiotic prescribing to hospital inpatients showed interventions to be associated with improvement in prescribing according to antibiotic policy in routine clinical practice, with 70% of interventions being hospital-wide compared with 31% for RCTs.
Abstract: BACKGROUND: Antibiotic resistance is a major public health problem. Infections caused by multidrug-resistant bacteria are associated with prolonged hospital stay and death compared with infections caused by susceptible bacteria. Appropriate antibiotic use in hospitals should ensure effective treatment of patients with infection and reduce unnecessary prescriptions. We updated this systematic review to evaluate the impact of interventions to improve antibiotic prescribing to hospital inpatients. OBJECTIVES: To estimate the effectiveness and safety of interventions to improve antibiotic prescribing to hospital inpatients and to investigate the effect of two intervention functions: restriction and enablement. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library), MEDLINE, and Embase. We searched for additional studies using the bibliographies of included articles and personal files. The last search from which records were evaluated and any studies identified incorporated into the review was January 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies (NRS). We included three non-randomised study designs to measure behavioural and clinical outcomes and analyse variation in the effects: non- randomised trials (NRT), controlled before-after (CBA) studies and interrupted time series (ITS) studies. For this update we also included three additional NRS designs (case control, cohort, and qualitative studies) to identify unintended consequences. Interventions included any professional or structural interventions as defined by the Cochrane Effective Practice and Organisation of Care Group. We defined restriction as 'using rules to reduce the opportunity to engage in the target behaviour (or increase the target behaviour by reducing the opportunity to engage in competing behaviours)'. We defined enablement as 'increasing means/reducing barriers to increase capability or opportunity'. The main comparison was between intervention and no intervention. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed study risk of bias. We performed meta-analysis and meta-regression of RCTs and meta-regression of ITS studies. We classified behaviour change functions for all interventions in the review, including those studies in the previously published versions. We analysed dichotomous data with a risk difference (RD). We assessed certainty of evidence with GRADE criteria. MAIN RESULTS: This review includes 221 studies (58 RCTs, and 163 NRS). Most studies were from North America (96) or Europe (87). The remaining studies were from Asia (19), South America (8), Australia (8), and the East Asia (3). Although 62% of RCTs were at a high risk of bias, the results for the main review outcomes were similar when we restricted the analysis to studies at low risk of bias.More hospital inpatients were treated according to antibiotic prescribing policy with the intervention compared with no intervention based on 29 RCTs of predominantly enablement interventions (RD 15%, 95% confidence interval (CI) 14% to 16%; 23,394 participants; high-certainty evidence). This represents an increase from 43% to 58% .There were high levels of heterogeneity of effect size but the direction consistently favoured intervention.The duration of antibiotic treatment decreased by 1.95 days (95% CI 2.22 to 1.67; 14 RCTs; 3318 participants; high-certainty evidence) from 11.0 days. Information from non-randomised studies showed interventions to be associated with improvement in prescribing according to antibiotic policy in routine clinical practice, with 70% of interventions being hospital-wide compared with 31% for RCTs. The risk of death was similar between intervention and control groups (11% in both arms), indicating that antibiotic use can likely be reduced without adversely affecting mortality (RD 0%, 95% CI -1% to 0%; 28 RCTs; 15,827 participants; moderate-certainty evidence). Antibiotic stewardship interventions probably reduce length of stay by 1.12 days (95% CI 0.7 to 1.54 days; 15 RCTs; 3834 participants; moderate-certainty evidence). One RCT and six NRS raised concerns that restrictive interventions may lead to delay in treatment and negative professional culture because of breakdown in communication and trust between infection specialists and clinical teams (low-certainty evidence).Both enablement and restriction were independently associated with increased compliance with antibiotic policies, and enablement enhanced the effect of restrictive interventions (high-certainty evidence). Enabling interventions that included feedback were probably more effective than those that did not (moderate-certainty evidence).There was very low-certainty evidence about the effect of the interventions on reducing Clostridium difficile infections (median -48.6%, interquartile range -80.7% to -19.2%; 7 studies). This was also the case for resistant gram-negative bacteria (median -12.9%, interquartile range -35.3% to 25.2%; 11 studies) and resistant gram-positive bacteria (median -19.3%, interquartile range -50.1% to +23.1%; 9 studies). There was too much variance in microbial outcomes to reliably assess the effect of change in antibiotic use. Heterogeneity of intervention effect on prescribing outcomesWe analysed effect modifiers in 29 RCTs and 91 ITS studies. Enablement and restriction were independently associated with a larger effect size (high-certainty evidence). Feedback was included in 4 (17%) of 23 RCTs and 20 (47%) of 43 ITS studies of enabling interventions and was associated with greater intervention effect. Enablement was included in 13 (45%) of 29 ITS studies with restrictive interventions and enhanced intervention effect. AUTHORS' CONCLUSIONS: We found high-certainty evidence that interventions are effective in increasing compliance with antibiotic policy and reducing duration of antibiotic treatment. Lower use of antibiotics probably does not increase mortality and likely reduces length of stay. Additional trials comparing antibiotic stewardship with no intervention are unlikely to change our conclusions. Enablement consistently increased the effect of interventions, including those with a restrictive component. Although feedback further increased intervention effect, it was used in only a minority of enabling interventions. Interventions were successful in safely reducing unnecessary antibiotic use in hospitals, despite the fact that the majority did not use the most effective behaviour change techniques. Consequently, effective dissemination of our findings could have considerable health service and policy impact. Future research should instead focus on targeting treatment and assessing other measures of patient safety, assess different stewardship interventions, and explore the barriers and facilitators to implementation. More research is required on unintended consequences of restrictive interventions.

1,480 citations


Journal ArticleDOI
TL;DR: Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut.
Abstract: Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration. Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving the lysosome. In the last 10 years, we have moved from a simple picture, that metformin improves glycaemia by acting on the liver via AMPK activation, to a much more complex picture reflecting its multiple modes of action. More work is required to truly understand how this drug works in its target population: individuals with type 2 diabetes.

1,302 citations


Journal ArticleDOI
27 Apr 2017-Nature
TL;DR: The importance of the barley reference sequence for breeding is demonstrated by inspecting the genomic partitioning of sequence variation in modern elite germplasm, highlighting regions vulnerable to genetic erosion.
Abstract: Cereal grasses of the Triticeae tribe have been the major food source in temperate regions since the dawn of agriculture. Their large genomes are characterized by a high content of repetitive elements and large pericentromeric regions that are virtually devoid of meiotic recombination. Here we present a high-quality reference genome assembly for barley (Hordeum vulgare L.). We use chromosome conformation capture mapping to derive the linear order of sequences across the pericentromeric space and to investigate the spatial organization of chromatin in the nucleus at megabase resolution. The composition of genes and repetitive elements differs between distal and proximal regions. Gene family analyses reveal lineage-specific duplications of genes involved in the transport of nutrients to developing seeds and the mobilization of carbohydrates in grains. We demonstrate the importance of the barley reference sequence for breeding by inspecting the genomic partitioning of sequence variation in modern elite germplasm, highlighting regions vulnerable to genetic erosion.

1,105 citations


Journal ArticleDOI
TL;DR: The results show that interventions to improve antibiotic prescribing to hospital inpatients are successful, and can reduce antimicrobial resistance or hospital acquired infections.
Abstract: This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: Aim: To systematically review the literature to identify interventions that alone, or in combination, are effective in improving antibiotic prescribing to hospital inpatients. Research questions: What is the evidence that exposure of hospital inpatients to antibiotics can be reduced safely, without compromising clinical outcomes? What is the evidence that changing the antibiotic choice, dose or route can be achieved without compromising clinical outcomes? Are interventions that include goal setting, feedback and action planning more effective than interventions that only include one or two of these components? Do interventions that include behaviour change techniques to enhance capability have greater initial effect (Michie 2011)? Do interventions that include behaviour change techniques to enhance capability have more sustained effectiveness (Michie 2011)? What is the relationship between change in antibiotic use or choice and microbial outcomes? Withdrawal from publication: this protocol was written with the express purpose of updating the methodology for the review, and has now been superseded by the updated review (Davey 2017).

1,030 citations


Posted Content
TL;DR: A quadruplet deep network using a margin-based online hard negative mining is proposed based on the quadruplet loss for the person ReID, which can lead to the model output with a larger inter- class variation and a smaller intra-class variation compared to the triplet loss.
Abstract: Person re-identification (ReID) is an important task in wide area video surveillance which focuses on identifying people across different cameras. Recently, deep learning networks with a triplet loss become a common framework for person ReID. However, the triplet loss pays main attentions on obtaining correct orders on the training set. It still suffers from a weaker generalization capability from the training set to the testing set, thus resulting in inferior performance. In this paper, we design a quadruplet loss, which can lead to the model output with a larger inter-class variation and a smaller intra-class variation compared to the triplet loss. As a result, our model has a better generalization ability and can achieve a higher performance on the testing set. In particular, a quadruplet deep network using a margin-based online hard negative mining is proposed based on the quadruplet loss for the person ReID. In extensive experiments, the proposed network outperforms most of the state-of-the-art algorithms on representative datasets which clearly demonstrates the effectiveness of our proposed method.

821 citations


Proceedings ArticleDOI
06 Apr 2017
TL;DR: In this article, a quadruplet deep network using a margin-based online hard negative mining is proposed based on the quadruplet loss for person ReID, which can lead to the model output with a larger interclass variation and a smaller intra-class variation compared to the triplet loss.
Abstract: Person re-identification (ReID) is an important task in wide area video surveillance which focuses on identifying people across different cameras. Recently, deep learning networks with a triplet loss become a common framework for person ReID. However, the triplet loss pays main attentions on obtaining correct orders on the training set. It still suffers from a weaker generalization capability from the training set to the testing set, thus resulting in inferior performance. In this paper, we design a quadruplet loss, which can lead to the model output with a larger inter-class variation and a smaller intra-class variation compared to the triplet loss. As a result, our model has a better generalization ability and can achieve a higher performance on the testing set. In particular, a quadruplet deep network using a margin-based online hard negative mining is proposed based on the quadruplet loss for the person ReID. In extensive experiments, the proposed network outperforms most of the state-of-the-art algorithms on representative datasets which clearly demonstrates the effectiveness of our proposed method.

760 citations


Journal ArticleDOI
TL;DR: The quality of evidence was low due to participant numbers, length of intervention and follow‐up, and the evidence for any adverse effects or harm associated with physical activity and exercise interventions, though even these statistically significant results had only small‐to‐moderate effect sizes.
Abstract: Background Chronic pain is defined as pain lasting beyond normal tissue healing time, generally taken to be 12 weeks. It contributes to disability, anxiety, depression, sleep disturbances, poor quality of life, and healthcare costs. Chronic pain has a weighted mean prevalence in adults of 20%. For many years, the treatment choice for chronic pain included recommendations for rest and inactivity. However, exercise may have specific benefits in reducing the severity of chronic pain, as well as more general benefits associated with improved overall physical and mental health, and physical functioning. Physical activity and exercise programmes are increasingly being promoted and offered in various healthcare systems, and for a variety of chronic pain conditions. It is therefore important at this stage to establish the efficacy and safety of these programmes, and furthermore to address the critical factors that determine their success or failure. Objectives To provide an overview of Cochrane Reviews of adults with chronic pain to determine (1) the effectiveness of different physical activity and exercise interventions in reducing pain severity and its impact on function, quality of life, and healthcare use; and (2) the evidence for any adverse effects or harm associated with physical activity and exercise interventions. Methods We searched theCochrane Database of Systematic Reviews (CDSR) on the Cochrane Library (CDSR 2016, Issue 1) for systematic reviews of randomised controlled trials (RCTs), after which we tracked any included reviews for updates, and tracked protocols in case of full review publication until an arbitrary cut-off date of 21 March 2016 (CDSR 2016, Issue 3). We assessed the methodological quality of the reviews using the AMSTAR tool, and also planned to analyse data for each painful condition based on quality of the evidence. We extracted data for (1) self-reported pain severity, (2) physical function (objectively or subjectively measured), (3) psychological function, (4) quality of life, (5) adherence to the prescribed intervention, (6) healthcare use/attendance, (7) adverse events, and (8) death. Due to the limited data available, we were unable to directly compare and analyse interventions, and have instead reported the evidence qualitatively. Main results We included 21 reviews with 381 included studies and 37,143 participants. Of these, 264 studies (19,642 participants) examined exercise versus no exercise/minimal intervention in adults with chronic pain and were used in the qualitative analysis. Pain conditions included rheumatoid arthritis, osteoarthritis, fibromyalgia, low back pain, intermittent claudication, dysmenorrhoea, mechanical neck disorder, spinal cord injury, postpolio syndrome, and patellofemoral pain. None of the reviews assessed 'chronic pain' or 'chronic widespread pain' as a general term or specific condition. Interventions included aerobic, strength, flexibility, range of motion, and core or balance training programmes, as well as yoga, Pilates, and tai chi. Reviews were well performed and reported (based on AMSTAR), and included studies had acceptable risk of bias (with inadequate reporting of attrition and reporting biases). However the quality of evidence was low due to participant numbers (most included studies had fewer than 50 participants in total), length of intervention and follow-up (rarely assessed beyond three to six months). We pooled the results from relevant reviews where appropriate, though results should be interpreted with caution due to the low quality evidence. Pain severity: several reviews noted favourable results from exercise: only three reviews that reported pain severity found no statistically significant changes in usual or mean pain from any intervention. However, results were inconsistent across interventions and follow-up, as exercise did not consistently bring about a change (positive or negative) in self-reported pain scores at any single point. Physical function: was the most commonly reported outcome measure. Physical function was significantly improved as a result of the intervention in 14 reviews, though even these statistically significant results had only small-to-moderate effect sizes (only one review reported large effect sizes). Psychological function and quality of life: had variable results: results were either favourable to exercise (generally small and moderate effect size, with two reviews reporting significant, large effect sizes for quality of life), or showed no difference between groups. There were no negative effects. Adherence to the prescribed intervention: could not be assessed in any review. However, risk of withdrawal/dropout was slightly higher in the exercising group (82.8/1000 participants versus 81/1000 participants), though the group difference was non-significant. Healthcare use/attendance: was not reported in any review. Adverse events, potential harm, and death: only 25% of included studies (across 18 reviews) actively reported adverse events. Based on the available evidence, most adverse events were increased soreness or muscle pain, which reportedly subsided after a few weeks of the intervention. Only one review reported death separately to other adverse events: the intervention was protective against death (based on the available evidence), though did not reach statistical significance. Authors' conclusions The quality of the evidence examining physical activity and exercise for chronic pain is low. This is largely due to small sample sizes and potentially underpowered studies. A number of studies had adequately long interventions, but planned follow-up was limited to less than one year in all but six reviews. There were some favourable effects in reduction in pain severity and improved physical function, though these were mostly of small-to-moderate effect, and were not consistent across the reviews. There were variable effects for psychological function and quality of life. The available evidence suggests physical activity and exercise is an intervention with few adverse events that may improve pain severity and physical function, and consequent quality of life. However, further research is required and should focus on increasing participant numbers, including participants with a broader spectrum of pain severity, and lengthening both the intervention itself, and the follow-up period.

758 citations


Journal ArticleDOI
TL;DR: The ERS guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature, using the GRADE approach to define the quality of the evidence and the level of recommendations.
Abstract: Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines.The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature.A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy.These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes.

701 citations


Journal ArticleDOI
Nasim Azani1, Marielle Babineau2, C. Donovan Bailey3, Hannah Banks4, Ariane R. Barbosa5, Rafael Barbosa Pinto6, James S. Boatwright7, Leonardo Maurici Borges8, Gillian K. Brown9, Anne Bruneau2, Elisa Silva Candido6, Domingos Cardoso10, Kuo-Fang Chung11, Ruth Clark4, Adilva de Souza Conceição, Michael D. Crisp12, Paloma Cubas13, Alfonso Delgado-Salinas14, Kyle G. Dexter, Jeff J. Doyle15, Jérôme Duminil16, Ashley N. Egan17, Manuel de la Estrella4, Marcus J. Falcao, Dmitry A. Filatov18, Ana Paula Fortuna-Perez19, Renee Hersilia Fortunato20, Edeline Gagnon2, Peter Gasson4, Juliana Gastaldello Rando21, Ana Maria Goulart de Azevedo Tozzi6, Bee F. Gunn12, David Harris22, Elspeth Haston22, Julie A. Hawkins23, Patrick S. Herendeen, Colin E. Hughes24, João Ricardo Vieira Iganci25, Firouzeh Javadi26, Sheku Alfred Kanu27, Shahrokh Kazempour-Osaloo28, Geoffrey C. Kite4, Bente B. Klitgaard4, Fabio J. Kochanovski6, Erik J. M. Koenen24, Lynsey Kovar3, Matt Lavin29, M. Marianne le Roux30, Gwilym P. Lewis4, Haroldo Cavalcante de Lima, Maria Cristina Lopez-Roberts5, Barbara A. Mackinder22, Vitor Hugo Maia31, Valéry Malécot32, Vidal de Freitas Mansano, Brigitte Marazzi, Sawai Mattapha23, Joseph T. Miller33, Chika Mitsuyuki26, Tania M. Moura34, Daniel J. Murphy4, Madhugiri Nageswara-Rao3, Bruno Nevado18, Danilo M. Neves4, Dario I. Ojeda16, R. Toby Pennington22, Darirn E. Prado35, Gerhard Prenner4, Luciano Paganucci de Queiroz5, Gustavo Ramos10, Fabiana L. Ranzato Filardi, Pétala Gomes Ribeiro5, María de Lourdes Rico-Arce4, Michael J. Sanderson36, Juliana Santos-Silva, Wallace M. B. São-Mateus37, Marcos J. S. Silva38, Marcelo F. Simon39, Carole Sinou2, Cristiane Snak5, Élvia R. de Souza, Janet I. Sprent40, Kelly P. Steele41, Julia E. Steier42, Royce Steeves2, Charles H. Stirton43, Shuichiro Tagane26, Benjamin M. Torke44, Hironori Toyama26, Daiane Trabuco da Cruz5, Mohammad Vatanparast17, Jan J. Wieringa45, Michael Wink46, Martin F. Wojciechowski42, Tetsukazu Yahara26, Ting-Shuang Yi47, Erin Zimmerman2 
01 Feb 2017-Taxon
TL;DR: The classification of the legume family proposed here addresses the long-known non-monophyly of the traditionally recognised subfamily Caesalpinioideae, by recognising six robustly supported monophyletic subfamilies and reflects the phylogenetic structure that is consistently resolved.
Abstract: The classification of the legume family proposed here addresses the long-known non-monophyly of the traditionally recognised subfamily Caesalpinioideae, by recognising six robustly supported monophyletic subfamilies. This new classification uses as its framework the most comprehensive phylogenetic analyses of legumes to date, based on plastid matK gene sequences, and including near-complete sampling of genera (698 of the currently recognised 765 genera) and ca. 20% (3696) of known species. The matK gene region has been the most widely sequenced across the legumes, and in most legume lineages, this gene region is sufficiently variable to yield well-supported clades. This analysis resolves the same major clades as in other phylogenies of whole plastid and nuclear gene sets (with much sparser taxon sampling). Our analysis improves upon previous studies that have used large phylogenies of the Leguminosae for addressing evolutionary questions, because it maximises generic sampling and provides a phylogenetic tree that is based on a fully curated set of sequences that are vouchered and taxonomically validated. The phylogenetic trees obtained and the underlying data are available to browse and download, facilitating subsequent analyses that require evolutionary trees. Here we propose a new community-endorsed classification of the family that reflects the phylogenetic structure that is consistently resolved and recognises six subfamilies in Leguminosae: a recircumscribed Caesalpinioideae DC., Cercidoideae Legume Phylogeny Working Group (stat. nov.), Detarioideae Burmeist., Dialioideae Legume Phylogeny Working Group (stat. nov.), Duparquetioideae Legume Phylogeny Working Group (stat. nov.), and Papilionoideae DC. The traditionally recognised subfamily Mimosoideae is a distinct clade nested within the recircumscribed Caesalpinioideae and is referred to informally as the mimosoid clade pending a forthcoming formal tribal and/or cladebased classification of the new Caesalpinioideae. We provide a key for subfamily identification, descriptions with diagnostic charactertistics for the subfamilies, figures illustrating their floral and fruit diversity, and lists of genera by subfamily. This new classification of Leguminosae represents a consensus view of the international legume systematics community; it invokes both compromise and practicality of use.

697 citations


Journal ArticleDOI
TL;DR: Glucose sensing at the lysosome, in which AMPK and other components of the activation complex act antagonistically with another key nutrient sensor, mTORC1, may have been one of the ancestral roles of AMPK.

680 citations


Journal ArticleDOI
TL;DR: The results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.
Abstract: Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation.

Journal ArticleDOI
Robert A. Scott1, Laura J. Scott2, Reedik Mägi3, Letizia Marullo4  +213 moreInstitutions (66)
01 Nov 2017-Diabetes
TL;DR: This article conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel.
Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects) We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology

Journal ArticleDOI
TL;DR: The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
Abstract: The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13877/full. Enzymes are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Journal ArticleDOI
TL;DR: The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
Abstract: The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13878/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Journal ArticleDOI
TL;DR: All forms of extra support analyzed together showed a decrease in cessation of 'any breastfeeding', which includes partial and exclusive breastfeeding, and substantial heterogeneity for within-group heterogeneity remained high for all of these analyses, so advise caution when making specific conclusions based on subgroup results.
Abstract: BACKGROUND: There is extensive evidence of important health risks for infants and mothers related to not breastfeeding. In 2003, the World Health Organization recommended that infants be breastfed exclusively until six months of age, with breastfeeding continuing as an important part of the infant's diet until at least two years of age. However, current breastfeeding rates in many countries do not reflect this recommendation. OBJECTIVES: To describe forms of breastfeeding support which have been evaluated in controlled studies, the timing of the interventions and the settings in which they have been used.To examine the effectiveness of different modes of offering similar supportive interventions (for example, whether the support offered was proactive or reactive, face-to-face or over the telephone), and whether interventions containing both antenatal and postnatal elements were more effective than those taking place in the postnatal period alone.To examine the effectiveness of different care providers and (where information was available) training.To explore the interaction between background breastfeeding rates and effectiveness of support. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (29 February 2016) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing extra support for healthy breastfeeding mothers of healthy term babies with usual maternity care. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: This updated review includes 100 trials involving more than 83,246 mother-infant pairs of which 73 studies contribute data (58 individually-randomised trials and 15 cluster-randomised trials). We considered that the overall risk of bias of trials included in the review was mixed. Of the 31 new studies included in this update, 21 provided data for one or more of the primary outcomes. The total number of mother-infant pairs in the 73 studies that contributed data to this review is 74,656 (this total was 56,451 in the previous version of this review). The 73 studies were conducted in 29 countries. Results of the analyses continue to confirm that all forms of extra support analyzed together showed a decrease in cessation of 'any breastfeeding', which includes partial and exclusive breastfeeding (average risk ratio (RR) for stopping any breastfeeding before six months 0.91, 95% confidence interval (CI) 0.88 to 0.95; moderate-quality evidence, 51 studies) and for stopping breastfeeding before four to six weeks (average RR 0.87, 95% CI 0.80 to 0.95; moderate-quality evidence, 33 studies). All forms of extra support together also showed a decrease in cessation of exclusive breastfeeding at six months (average RR 0.88, 95% CI 0.85 to 0.92; moderate-quality evidence, 46 studies) and at four to six weeks (average RR 0.79, 95% CI 0.71 to 0.89; moderate quality, 32 studies). We downgraded evidence to moderate-quality due to very high heterogeneity.We investigated substantial heterogeneity for all four outcomes with subgroup analyses for the following covariates: who delivered care, type of support, timing of support, background breastfeeding rate and number of postnatal contacts. Covariates were not able to explain heterogeneity in general. Though the interaction tests were significant for some analyses, we advise caution in the interpretation of results for subgroups due to the heterogeneity. Extra support by both lay and professionals had a positive impact on breastfeeding outcomes. Several factors may have also improved results for women practising exclusive breastfeeding, such as interventions delivered with a face-to-face component, high background initiation rates of breastfeeding, lay support, and a specific schedule of four to eight contacts. However, because within-group heterogeneity remained high for all of these analyses, we advise caution when making specific conclusions based on subgroup results. We noted no evidence for subgroup differences for the any breastfeeding outcomes. AUTHORS' CONCLUSIONS: When breastfeeding support is offered to women, the duration and exclusivity of breastfeeding is increased. Characteristics of effective support include: that it is offered as standard by trained personnel during antenatal or postnatal care, that it includes ongoing scheduled visits so that women can predict when support will be available, and that it is tailored to the setting and the needs of the population group. Support is likely to be more effective in settings with high initiation rates. Support may be offered either by professional or lay/peer supporters, or a combination of both. Strategies that rely mainly on face-to-face support are more likely to succeed with women practising exclusive breastfeeding.

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TL;DR: The timely recognition and treatment of children with ADHD-type difficulties provides an opportunity to improve long-term outcomes, including educational underachievement, difficulties with employment and relationships, and criminality.

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Christopher P. Nelson1, Christopher P. Nelson2, Anuj Goel3, Anuj Goel4, Adam S. Butterworth5, Stavroula Kanoni6, Tom R. Webb1, Tom R. Webb2, Eirini Marouli6, Lingyao Zeng7, Ioanna Ntalla6, Florence Lai1, Florence Lai2, Jemma C. Hopewell3, Olga Giannakopoulou6, Tao Jiang5, Stephen E. Hamby2, Stephen E. Hamby1, Emanuele Di Angelantonio5, Themistocles L. Assimes8, Erwin P. Bottinger9, John C. Chambers10, John C. Chambers11, John C. Chambers12, Robert Clarke3, Colin N. A. Palmer13, Richard M Cubbon14, Patrick T. Ellinor15, Raili Ermel16, Evangelos Evangelou17, Evangelos Evangelou10, Paul W. Franks18, Paul W. Franks19, Paul W. Franks20, Christopher Grace3, Christopher Grace4, Dongfeng Gu21, Aroon D. Hingorani22, Joanna M. M. Howson5, Erik Ingelsson8, Adnan Kastrati7, Thorsten Kessler7, Theodosios Kyriakou4, Theodosios Kyriakou3, Terho Lehtimäki23, Xiangfeng Lu8, Yingchang Lu9, Yingchang Lu24, Winfried März25, Winfried März26, Winfried März27, Ruth McPherson28, Andres Metspalu29, Mar Pujades-Rodriguez14, Arno Ruusalepp16, Eric E. Schadt9, Amand F. Schmidt22, Michael J. Sweeting5, Pierre Zalloua19, Pierre Zalloua30, Kamal Alghalayini31, Bernard Keavney32, Bernard Keavney33, Jaspal S. Kooner34, Jaspal S. Kooner11, Jaspal S. Kooner12, Ruth J. F. Loos9, Riyaz S. Patel35, Martin K. Rutter33, Martin K. Rutter32, Maciej Tomaszewski33, Maciej Tomaszewski36, Ioanna Tzoulaki10, Ioanna Tzoulaki17, Eleftheria Zeggini37, Jeanette Erdmann38, George Dedoussis39, Johan L.M. Björkegren40, Johan L.M. Björkegren9, CARDIoGRAMplusC D3, Heribert Schunkert7, Martin Farrall4, Martin Farrall3, John Danesh37, John Danesh5, Nilesh J. Samani2, Nilesh J. Samani1, Hugh Watkins3, Hugh Watkins4, Panos Deloukas31, Panos Deloukas6 
TL;DR: This approach identified 13 new loci at genome-wide significance, 12 of which were on the previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals.
Abstract: Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10-8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

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TL;DR: This Review provides an up-to-date consensus on exercise management for individuals with type 1 diabetes who exercise regularly, including glucose targets for safe and effective exercise, and nutritional and insulin dose adjustments to protect against exercise-related glucose excursions.

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Dajiang J. Liu1, Gina M. Peloso2, Gina M. Peloso3, Haojie Yu4  +285 moreInstitutions (91)
TL;DR: It is found that beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD), and only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and TG-lowering alleles involved in hepatic production of TG-rich lipoproteins tracked with higher liver fat, higher risk for T2D, and lower risk for CAD.
Abstract: We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

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15 Jun 2017-Nature
TL;DR: This study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer.
Abstract: Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

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TL;DR: In this paper, the authors report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci.
Abstract: Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

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TL;DR: The complex pattern of upstream pathways that converge on ULK1 suggests that this complex acts as a node, converting multiple signals into autophagosome formation, and what happens downstream, once the ULK 1 complex becomes activated.
Abstract: Autophagy is a vital lysosomal degradation pathway that serves as a quality control mechanism. It rids the cell of damaged, toxic or excess cellular components, which if left to persist could be detrimental to the cell. It also serves as a recycling pathway to maintain protein synthesis under starvation conditions. A key initial event in autophagy is formation of the autophagosome, a unique double-membrane organelle that engulfs the cytosolic cargo destined for degradation. This step is mediated by the serine/threonine protein kinase ULK1 (unc-51-like kinase 1), which functions in a complex with at least three protein partners: FIP200 (focal adhesion kinase family interacting protein of 200 kDa), ATG (autophagy-related protein) 13 (ATG13), and ATG101. In this artcile, we focus on the regulation of the ULK1 complex during autophagy initiation. The complex pattern of upstream pathways that converge on ULK1 suggests that this complex acts as a node, converting multiple signals into autophagosome formation. Here, we review our current understanding of this regulation and in turn discuss what happens downstream, once the ULK1 complex becomes activated.

Journal ArticleDOI
19 Jul 2017-Nature
TL;DR: An AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease is described.
Abstract: The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

Journal ArticleDOI
10 Nov 2017-eLife
TL;DR: The results implicate LRRK2 in primary ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to L RRK2-dependent pathologies.
Abstract: We previously reported that Parkinson’s disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43). Affinity enrichment mass spectrometry revealed that the primary ciliogenesis regulator, RILPL1 specifically interacts with the LRRK2-phosphorylated forms of Rab8A and Rab10, whereas RILPL2 binds to phosphorylated Rab8A, Rab10, and Rab12. Induction of primary cilia formation by serum starvation led to a two-fold reduction in ciliogenesis in fibroblasts derived from pathogenic LRRK2-R1441G knock-in mice. These results implicate LRRK2 in primary ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to LRRK2-dependent pathologies.

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TL;DR: This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial.

Journal ArticleDOI
09 Feb 2017-Nature
TL;DR: The data indicate that intestinal epithelial cells serve as gatekeepers for the supply of AHR ligands to the host and emphasize the importance of feedback control in modulating AHR pathway activation.
Abstract: The aryl hydrocarbon receptor (AHR) recognizes xenobiotics as well as natural compounds such as tryptophan metabolites, dietary components and microbiota-derived factors, and it is important for maintenance of homeostasis at mucosal surfaces. AHR activation induces cytochrome P4501 (CYP1) enzymes, which oxygenate AHR ligands, leading to their metabolic clearance and detoxification. Thus, CYP1 enzymes have an important feedback role that curtails the duration of AHR signalling, but it remains unclear whether they also regulate AHR ligand availability in vivo. Here we show that dysregulated expression of Cyp1a1 in mice depletes the reservoir of natural AHR ligands, generating a quasi AHR-deficient state. Constitutive expression of Cyp1a1 throughout the body or restricted specifically to intestinal epithelial cells resulted in loss of AHR-dependent type 3 innate lymphoid cells and T helper 17 cells and increased susceptibility to enteric infection. The deleterious effects of excessive AHR ligand degradation on intestinal immune functions could be counter-balanced by increasing the intake of AHR ligands in the diet. Thus, our data indicate that intestinal epithelial cells serve as gatekeepers for the supply of AHR ligands to the host and emphasize the importance of feedback control in modulating AHR pathway activation.

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TL;DR: This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.
Abstract: Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10-23). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.

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TL;DR: The International Hypoglycaemia Study Group recommends that the frequency of detection of a glucose concentration <3.0 mmol/l (<54 mg/dl), which it considers to be clinically significant biochemical hypoglycaemic, be included in reports of clinical trials of glucoselowering drugs evaluated for the treatment of diabetes mellitus.
Abstract: Position Statement The International Hypoglycaemia Study Group recommends that the frequency of detection of a glucose concentration <3.0 mmol/l (<54 mg/dl), which it considers to be clinically significant biochemical hypoglycaemia, be included in reports of clinical trials of glucose-lowering drugs evaluated for the treatment of diabetes mellitus.

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TL;DR: The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.
Abstract: The WHO recognizes human African trypanosomiasis, Chagas disease and the leishmaniases as neglected tropical diseases. These diseases are caused by parasitic trypanosomatids and range in severity from mild and self-curing to near invariably fatal. Public health advances have substantially decreased the effect of these diseases in recent decades but alone will not eliminate them. In this Review, we discuss why new drugs against trypanosomatids are required, approaches that are under investigation to develop new drugs and why the drug discovery pipeline remains essentially unfilled. In addition, we consider the important challenges to drug discovery strategies and the new technologies that can address them. The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.

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TL;DR: Assessment of the effectiveness of chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for the control of gingivitis and plaque in children and adults finds that further research is very unlikely to change confidence in the estimate of effect.
Abstract: Background Dental plaque associated gingivitis is a reversible inflammatory condition caused by accumulation and persistence of microbial biofilms (dental plaque) on the teeth. It is characterised by redness and swelling of the gingivae (gums) and a tendency for the gingivae to bleed easily. In susceptible individuals, gingivitis may lead to periodontitis and loss of the soft tissue and bony support for the tooth. It is thought that chlorhexidine mouthrinse may reduce the build-up of plaque thereby reducing gingivitis. Objectives To assess the effectiveness of chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for the control of gingivitis and plaque compared to mechanical oral hygiene procedures alone or mechanical oral hygiene procedures plus placebo/control mouthrinse. Mechanical oral hygiene procedures were toothbrushing with/without the use of dental floss or interdental cleaning aids and could include professional tooth cleaning/periodontal treatment. To determine whether the effect of chlorhexidine mouthrinse is influenced by chlorhexidine concentration, or frequency of rinsing (once/day versus twice/day). To report and describe any adverse effects associated with chlorhexidine mouthrinse use from included trials. Search methods Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 28 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 28 September 2016); MEDLINE Ovid (1946 to 28 September 2016); Embase Ovid (1980 to 28 September 2016); and CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 28 September 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. Selection criteria We included randomised controlled trials assessing the effects of chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for at least 4 weeks on gingivitis in children and adults. Mechanical oral hygiene procedures were toothbrushing with/without use of dental floss or interdental cleaning aids and could include professional tooth cleaning/periodontal treatment. We included trials where participants had gingivitis or periodontitis, where participants were healthy and where some or all participants had medical conditions or special care needs. Data collection and analysis Two review authors independently screened the search results extracted data and assessed the risk of bias of the included studies. We attempted to contact study authors for missing data or clarification where feasible. For continuous outcomes, we used means and standard deviations to obtain the mean difference (MD) and 95% confidence interval (CI). We combined MDs where studies used the same scale and standardised mean differences (SMDs) where studies used different scales. For dichotomous outcomes, we reported risk ratios (RR) and 95% CIs. Due to anticipated heterogeneity we used random-effects models for all meta-analyses. Main results We included 51 studies that analysed a total of 5345 participants. One study was assessed as being at unclear risk of bias, with the remaining 50 being at high risk of bias, however, this did not affect the quality assessments for gingivitis and plaque as we believe that further research is very unlikely to change our confidence in the estimate of effect. Gingivitis After 4 to 6 weeks of use, chlorhexidine mouthrinse reduced gingivitis (Gingival Index (GI) 0 to 3 scale) by 0.21 (95% CI 0.11 to 0.31) compared to placebo, control or no mouthrinse (10 trials, 805 participants with mild gingival inflammation (mean score 1 on the GI scale) analysed, high-quality evidence). A similar effect size was found for reducing gingivitis at 6 months. There were insufficient data to determine the reduction in gingivitis associated with chlorhexidine mouthrinse use in individuals with mean GI scores of 1.1 to 3 (moderate or severe levels of gingival inflammation). Plaque Plaque was measured by different indices and the SMD at 4 to 6 weeks was 1.45 (95% CI 1.00 to 1.90) standard deviations lower in the chlorhexidine group (12 trials, 950 participants analysed, high-quality evidence), indicating a large reduction in plaque. A similar large reduction was found for chlorhexidine mouthrinse use at 6 months. Extrinsic tooth staining There was a large increase in extrinsic tooth staining in participants using chlorhexidine mouthrinse at 4 to 6 weeks. The SMD was 1.07 (95% CI 0.80 to 1.34) standard deviations higher (eight trials, 415 participants analysed, moderate-quality evidence) in the chlorhexidine mouthrinse group. There was also a large increase in extrinsic tooth staining in participants using chlorhexidine mouthrinse at 7 to 12 weeks and 6 months. Calculus Results for the effect of chlorhexidine mouthrinse on calculus formation were inconclusive. Effect of concentration and frequency of rinsing There were insufficient data to determine whether there was a difference in effect for either chlorhexidine concentration or frequency of rinsing. Other adverse effects The adverse effects most commonly reported in the included studies were taste disturbance/alteration (reported in 11 studies), effects on the oral mucosa including soreness, irritation, mild desquamation and mucosal ulceration/erosions (reported in 13 studies) and a general burning sensation or a burning tongue or both (reported in nine studies). Authors' conclusions There is high-quality evidence from studies that reported the Loe and Silness Gingival Index of a reduction in gingivitis in individuals with mild gingival inflammation on average (mean score of 1 on the 0 to 3 GI scale) that was not considered to be clinically relevant. There is high-quality evidence of a large reduction in dental plaque with chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for 4 to 6 weeks and 6 months. There is no evidence that one concentration of chlorhexidine rinse is more effective than another. There is insufficient evidence to determine the reduction in gingivitis associated with chlorhexidine mouthrinse use in individuals with mean GI scores of 1.1 to 3 indicating moderate or severe levels of gingival inflammation. Rinsing with chlorhexidine mouthrinse for 4 weeks or longer causes extrinsic tooth staining. In addition, other adverse effects such as calculus build up, transient taste disturbance and effects on the oral mucosa were reported in the included studies.