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Background: Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight loss-induced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain. Methods: In a randomized controlled trial, 52 healthy obese individuals were, after a diet-induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor plasma levels and decrease in free leptin index after 52 weeks weight loss maintenance. Results: Soluble leptin receptor increase was 59% lower; 2.1±0.7 vs 5.1±0.8 ng ml −1 (−3.0 (95% confidence interval (CI)=−0.5 to −5.5)), P <0.001 and free leptin index decrease was 43% smaller; −62±15 vs −109±20 (−47 (95% CI=−11 to −83)), P <0.05 with administration of GLP-1RA compared with control group. The 12% weight loss was successfully maintained in both the groups with no significant change in weight after 52 weeks follow-up. The GLP-1RA group had greater weight loss during the weight maintenance period (−2.3 kg (95% CI=−0.6 to −4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI=−0.6 to −1)), P <0.001. Fasting glucose was decreased by an additional −0.2±0.1 mmol l −1 in the GLP-1RA group in contrast to the control group, where glucose increased 0.3±0.1 mmol l −1 to the level before weight loss (−0.5mmol l −1 (95% CI=−0.1 to −0.9)), P <0.005. Meal response of peptide PYY 3–36 was higher at week 52 in the GLP-1RA group compared with the control group, P <0.05. Conclusions: The weight maintaining effect of GLP-1RAs may be mediated by smaller decrease in free leptin and higher PYY 3–36 response. Low dose GLP-1RA therapy maintained 12% weight loss for 1 year and may prevent pre-diabetes in obesity.

يعاني الوطن العربي من عجز في مصادره المائية لوقوعه ضمن المناطق الجافة وشبه الجافة، علاوة على الاستنزاف الجائر لمياهه المتاحة نتيجة الممارسات الخاطئة في تطبيقاته وغياب وسوء إدارته، أضف إلى ذلك السلب الذي يتعرض له هذا المصدر الحيوي أو جزء منه من بعض الدول المجاورة دون مراعاة القوانين الدولية أو حسن الجوار مما زاد من مشاطل شح المياة. لذا أصبح لزاما علينا كأمة بكافة شرائحها الاجتماعية والمهنية والزراعية العمل على ترشيد استخدام المياة خاصة في المجال الزراعي واتباع كافة الوسائل والتقنيات الحديثة لتحقيق هذه الغايات.

Research in international trade has changed dramatically over the last twenty years, as attention has shifted from countries and industries towards the firms actually engaged in international trade. The now-standard heterogeneous firm model posits measure-zero firms that compete under monopolistic competition and decide whether to export to foreign markets. However, much of international trade is dominated by a few “global firms,” which participate in the international economy along multiple margins and account for substantial shares of aggregate trade. We develop a new theoretical framework that allows firms to have large market shares and decide simultaneously on the set of production locations, export markets, input sources, products to export, and inputs to import. Using US firm and trade transactions data, we provide strong evidence in support of this framework’s main predictions of interdependencies and complementarities between these margins of firm international participation. Global firms participate more intensively along each margin, magnifying the impact of underlying differences in firm characteristics and increasing their shares of aggregate trade.

Key Points Electronic health record (EHR) systems are increasingly being implemented all over the world, but represent a vast, underused data resource for biomedical research. Structured EHR data, such as encoded diagnosis and medication information, are the easiest data sources to process, but advances in text-mining methods has made it possible to also use the narrative parts of patient records. Statistical studies of the distribution and co-occurrence of clinical features in large collections of patient records enables identification of correlations between, for example, diseases (comorbidities) or between medications and adverse drug reactions. Knowledge-discovery and machine-learning methods can be used both for discovering novel patterns in patient data and for classification and predictive purposes, such as outcome or risk assessment. This has the potential to extend current EHR decision support systems, which integrate available patient data with clinical guidelines to provide assistance to the physician at the point of care. Research platforms built on EHR data, alone or coupled to genotype data, provide an inexpensive and timely way to sample relevant case and control cohorts based on relevant clinical features. As EHR and DNA databases become increasingly interlinked, genotype–phenotype association studies may be designed and conducted by re-using existing data. The growing political focus on the adoption of EHR systems must be accompanied by funding and strategic research into data standards, interoperability and security. Legal matters such as data ownership, privacy and consent need to be addressed to find the right balance between public demands for autonomy and privacy, and manageable procedures for researchers to access data. Fulfilling the full potential of electronic health data for scientific discovery and improved public health will require collaboration across stakeholders and research groups. The adoption of electronic health records will provide a rich resource for biomedical researchers. This Review discusses the potential for their use in informed decision making in the clinic, for a finer understanding of genotype–phenotype relationships and for selection of research cohorts, along with the current challenges for their mining and use. Clinical data describing the phenotypes and treatment of patients represents an underused data source that has much greater research potential than is currently realized. Mining of electronic health records (EHRs) has the potential for establishing new patient-stratification principles and for revealing unknown disease correlations. Integrating EHR data with genetic data will also give a finer understanding of genotype–phenotype relationships. However, a broad range of ethical, legal and technical reasons currently hinder the systematic deposition of these data in EHRs and their mining. Here, we consider the potential for furthering medical research and clinical care using EHR data and the challenges that must be overcome before this is a reality.

Type VI secretion systems are bacterial virulence-associated nanomachines composed of proteins that are evolutionarily related to components of bacteriophage tails. Here we show that protein secretion by the type VI secretion system of Vibrio cholerae requires the action of a dynamic intracellular tubular structure that is structurally and functionally homologous to contractile phage tail sheath. Time-lapse fluorescence light microscopy reveals that sheaths of the type VI secretion system cycle between assembly, quick contraction, disassembly and re-assembly. Whole-cell electron cryotomography further shows that the sheaths appear as long tubular structures in either extended or contracted conformations that are connected to the inner membrane by a distinct basal structure. These data support a model in which the contraction of the type VI secretion system sheath provides the energy needed to translocate proteins out of effector cells and into adjacent target cells. Microscopy reveals the dynamics of the type VI secretion system of Vibrio cholerae and its structural and functional resemblance to the contractile tail sheath of bacteriophages. Phage-like secretory system Bacteria use a variety of secretion systems for intercellular interactions. The type VI secretion system, made up of proteins evolutionarily related to bacteriophage tail components, has been implicated in competitive bacteria–bacteria interactions. An in vivo analysis of the dynamics of the type VI secretion system of Vibrio cholerae now shows that the resemblance to bacteriophage tails extends to function as well as to structure and evolutionary links. Type VI secretion acts as a dynamic nanomachine, cycling morphological states that are directly analogous to extended and contracted sheath components of tailed bacteriophages. The data suggest that energy captured from conformational changes in polymeric structures can drive the rapid transport of proteins through cell membranes.

Summary Pain medication has been associated with fractures. We found higher weight in paracetamol and non-steroidal anti-inflammatory drugs (NSAID) users and lower vitamin D levels in opioid and acetylsalicylic acid users. None of the pain medications influenced bone mineral density or loss. NSAID were associated with an increased fracture risk. Introduction To study the effects of use of paracetamol, non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA), and opioids on bone mineral density (BMD) and risk of fractures. Methods Two-thousand sixteen perimenopausal women followed for 10 years as part of a partly randomised comprehensive cohort study on hormone therapy (HT). BMD was measured at baseline and after 10 years by DXA (Hologic). Results Paracetamol users were heavier (70.4 ± 13.4 vs. 67.7 ± 11.9 kg, 2 p  < 0.01) than non-users. NSAID users were heavier (71.6 ± 15.6 vs. 67.8 ± 11.9 kg, 2 p  = 0.04) than non-users. ASA users had lower 25-hydroxy-vitamin D (25OHD) levels (21.9 ± 9.3 vs. 25.3 ± 12.4 ng/ml, 2 p  < 0.01) than non-users. Opioid users had lower 25OHD (21.4 ± 8.4 vs. 25.2 ± 12.3 ng/ml) and lower intake of vitamin D (2.2 ± 1.1 vs. 3.1 ± 3.0 μg/day, 2 p  < 0.01) than non-users. Despite these differences, no baseline differences were present in spine, hip, forearm or whole body BMD. Over 10 years, no differences were present in BMD alterations except a small trend towards a higher BMD gain in the spine in users of paracetamol, NSAID, ASA, and opioids compared to non-exposed. After adjustment, NSAID exposed sustained more fractures (HR = 1.44, 95% CI 1.07–1.93) than non-users. For users of paracetamol and opioids, a non-significant trend towards more fractures was present after adjustment. For ASA users, no excess risk of fractures was present. Conclusion Significant differences exist between subjects exposed to pain medications and non-users. Despite an absence of an effect over time on BMD, users of NSAID experienced more fractures than expected. The reasons for this have to be explored in further studies.

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by reduced lacrimal and salivary secretion. Sicca symptoms together with fatigue and musculoskeletal pain can significantly reduce the patients' quality of life. Furthermore, low salivary secretion may disrupt the oral microbial homeostasis. The aim of this study was to compare the salivary microbiota from pSS patients with patients with sicca symptoms not fulfilling the classification criteria for pSS (non-SS), and with healthy controls without sicca complaints. Pellets from centrifuged chewing-stimulated whole saliva from pSS patients (n = 15), non-SS sicca patients (n = 15) and healthy controls (n = 15) were prepared. DNA was extracted and analyzed by 16S rRNA gene sequencing. The acquired sequencing data were performed using the human oral microbiome database (HOMD). We detected 42, 45, and 34 bacterial genera in saliva samples from pSS patients, non-SS sicca patients, and healthy controls, respectively. The most abundant genera in all samples were Prevotella, Veillonella, Streptococcus, and Haemophilus. At species level Streptococcus intermedius, Prevotella intermedia, Fusobacterium nucleatum subsp. vincentii, Porphyromonas endodontalis, Prevotella nancensis, Tannerella spp., and Treponema spp. were detected in the samples from pSS and non-SS only, while Porphyromonas pasteri was mostly found among the healthy controls. Our study indicated dysbiosis in the salivary microbiota from pSS and non-SS patients compared to healthy controls. Additionally, the results showed that the salivary microbiome in the pSS group differed significantly from the non-SS group.

Since the mid-1990s, researchers have used micro datasets to study countries' production and trade at the firm level and have found that exporting firms differ substantially from firms that solely serve the domestic market. Across a wide range of countries and industries, exporting firms have been shown to be larger, more productive, more skill- and capital-intensive, and to pay higher wages than nonexporting firms. These differences exist even before exporting begins and have important consequences for evaluating the gains from trade and their distribution across factors of production. The new empirical research challenges traditional models of international trade and, as a result, the focus of the international trade field has shifted from countries and industries towards firms and products. Recently available transaction-level U.S. trade data reveal new stylized facts about firms' participation in international markets, and recent theories of international trade incorporating the behavior of heterogenous firms have made substantial progress in explaining patterns of trade and productivity growth.

Knowledge transfer can be facilitated through the judicious timing of transfer methods. Yet, extant research has neglected the impact of the timing of transfer methods. Departing from this observation, we theorize the existence of two knowledge transfer modes—“front-loading” and “back-loading”—based on whether the affordance for tacit knowledge exchange provided by the transfer methods used is higher during the initiation or during the implementation phase of a transfer. We suggest that the impact of front-loading and back-loading on transfer difficulty is contingent on the causal ambiguity of the knowledge being transferred and on the arduousness of the relationship between the source and the recipient of knowledge. We operationalize front-loading and back-loading and test our propositions using primary data on 2,711 instances of method use in 116 transfers of 37 organizational practices in 8 companies. We hypothesize and find empirical support for the claim that front-loading affordance for tacit knowledge exchange reduces transfer difficulty when the causal ambiguity of the knowledge to be transferred is high, whereas it increases difficulty when the relationship between the source and recipient of knowledge is arduous.