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Omadacycline is a new antimicrobial that is related to tetracyclines and is active against a broad range of pathogens. In this randomized, controlled trial involving 774 adults, omadacycline was found to be noninferior to moxifloxacin in the treatment of community-acquired bacterial pneumonia.

Treatment for acute bacterial skin and skin-structure infections is becoming more challenging as organisms with antimicrobial resistance become more prevalent. In this randomized trial involving 655 adults with bacterial skin and skin-structure infections, omadacycline was noninferior to linezolid regardless of the causative pathogen, including MRSA.

An important question in representative democracies is how to determine the optimal parliament size of a given country. According to an old conjecture, known as the cubic root law, there is a fairly universal power-law relation, with an exponent equal to 1/3, between the size of an elected parliament and the country’s population. Empirical data in modern European countries support such universality but are consistent with a larger exponent. In this work, we analyse this intriguing regularity using tools from complex networks theory. We model the population of a democratic country as a random network, drawn from a growth model, where each node is assigned a constituency membership sampled from an available set of size D . We calculate analytically the modularity of the population and find that its functional relation with the number of constituencies is strongly non-monotonic, exhibiting a maximum that depends on the population size. The criterion of maximal modularity allows us to predict that the number of representatives should scale as a power-law in the size of the population, a finding that is qualitatively confirmed by the empirical analysis of real-world data.

Impaired capacity to increase heart rate (HR) during exercise (ΔHR ex ), and a reduced rate of recovery post-exercise (ΔHR rec ) are associated with higher cardiovascular mortality rates. Currently, the genetic basis of both phenotypes remains to be elucidated. We conduct genome-wide association studies (GWASs) for ΔHR ex and ΔHR rec in ~40,000 individuals, followed by replication in ~27,000 independent samples, all from UK Biobank. Six and seven single-nucleotide polymorphisms for ΔHR ex and ΔHR rec , respectively, formally replicate. In a full data set GWAS, eight further loci for ΔHR ex and nine for ΔHR rec are genome-wide significant ( P  ≤ 5 × 10 −8 ). In total, 30 loci are discovered, 8 being common across traits. Processes of neural development and modulation of adrenergic activity by the autonomic nervous system are enriched in these results. Our findings reinforce current understanding of HR response to exercise and recovery and could guide future studies evaluating its contribution to cardiovascular risk prediction. Genome-wide association studies have identified multiple loci for resting heart rate (HR) but the genetic factors associated with HR increase during and HR recovery after exercise are less well studied. Here, the authors examine both traits in a two-stage GWAS design in up to 67,257 individuals from UK Biobank.

Background: legislation.gov.uk is a platform that enables users to explore and navigate the many sections of the UK's legal corpus through its well-designed searching and browsing features. However, there is room for improvement as it lacks the ability to easily move between related sections or Acts and only presents a text-only rendering of provisions. With Graphie, our novel navigational tool (graphie.quantlaw.co.uk), we aim to address this limitation by presenting alternative visualizations of legal documents using both text and graphs. Methods: The building block of Graphie is Sofia, an offline data pipeline designed to support different data visualizations by parsing and modelling data provided by legislation.gov.uk in open access form. Results: Graphie provides a network representation of the hierarchical structure of an Act of Parliament, which is typically organized in a tree-like fashion according to the content and information contained in each sub-branch. Nodes in Graphie represent sections of an Act (or individual provisions), while links embody the hierarchical connections between them. The legal map provided by Graphie is easily navigable by hovering on nodes, which are also color-coded and numbered to provide easily accessible information about the underlying content. The full textual content of each node is also available on a dedicated hyperlinked canvas. Conclusions: While we focus on the Housing Act 2004 for illustrative purposes, our platform is scalable, versatile, and provides users with a unified toolbox to visualize and explore the UK legal corpus in a fast and user-friendly way.

Pathogen resistance and safety concerns limit oral antibiotic options for the treatment of acute bacterial skin and skin structure infections (ABSSSI). We aimed to compare the efficacy and safety of once-daily oral omadacycline, an aminomethylcycline antibiotic, versus twice-daily oral linezolid for treatment of ABSSSI. In this phase 3, double-blind, randomised, non-inferiority study, eligible adults with ABSSSI at 33 sites in the USA were randomly assigned (1:1) to receive omadacycline (450 mg orally every 24 h over the first 48 h then 300 mg orally every 24 h) or linezolid (600 mg orally every 12 h) for 7–14 days. Randomisation was done via an interactive response system using a computer-generated schedule, and stratified by type of infection (wound infection, cellulitis or erysipelas, or major abscess) and receipt (yes or no) of allowed previous antibacterial treatment. Investigators, funders, and patients were masked to treatment assignments. Primary endpoints were early clinical response, 48–72 h after first dose, in the modified intention-to-treat (mITT) population (randomised patients without solely Gram-negative ABSSSI pathogens at baseline), and investigator-assessed clinical response at post-treatment evaluation, 7–14 days after the last dose, in the mITT population and clinically evaluable population (ie, mITT patients who had a qualifying infection as per study-entry criteria, received study drug, did not receive a confounding antibiotic, and had an assessment of outcome during the protocol-defined window). The safety population included randomised patients who received any amount of study drug. We set a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, NCT02877927, and is complete. Between Aug 11, 2016, and June 6, 2017, 861 participants were assessed for eligibility. 735 participants were randomly assigned, of whom 368 received omadacycline and 367 received linezolid. Omadacycline (315 [88%] of 360) was non-inferior to linezolid (297 [83%] of 360) for early clinical response (percentage-point difference 5·0, 95% CI −0·2 to 10·3) in the mITT population. For investigator-assessed clinical response at post-treatment evaluation, omadacycline was non-inferior to linezolid in the mITT (303 [84%] of 360 vs 291 [81%] of 360; percentage-point difference 3·3, 95% CI −2·2 to 9·0) and clinically evaluable (278 [98%] of 284 vs 279 [96%] of 292; 2·3, −0·5 to 5·8) populations. Mild to moderate nausea and vomiting were the most frequent treatment-emergent adverse events in omadacycline (111 [30%] of 368 and 62 [17%] of 368, respectively) and linezolid (28 [8%] of 367 and 11 [3%] of 367, respectively) groups. Once-daily oral omadacycline was non-inferior to twice-daily oral linezolid in adults with ABSSSI, and was safe and well tolerated. Oral-only omadacycline represents a new treatment option for ABSSSI, with potential for reduction in hospital admissions and cost savings. Paratek Pharmaceuticals.

Omadacycline is a semisynthetic tetracycline antibiotic. Phase III clinical trial results have shown that omadacycline has an acceptable safety profile in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Similar to most tetracyclines, transient nausea and vomiting and low-magnitude increases in liver aminotransferases were the most frequent treatment-emergent adverse events in phase III studies but were not treatment limiting. Package insert warnings and precautions for omadacycline include tooth discoloration; enamel hypoplasia; inhibition of bone growth following use in late pregnancy, infancy, or childhood up to 8 years of age; an imbalance in mortality (2%, compared with 1% in moxifloxacin-treated patients) was observed in the phase III study in patients with community-acquired bacterial pneumonia. Omadacycline has no effect on the QT interval, and its affinity for muscarinic M2 receptors resulted in transient heart rate increases following dosing.

Abstract Background Within the last decade, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a frequent cause of purulent skin and soft tissue infections. New therapeutic options are being investigated for these infections. Methods We report an integrated analysis of 2 randomized, controlled studies involving omadacycline, a novel aminomethylcycline, and linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Omadacycline in Acute Skin and Skin Structure Infections Study 1 (OASIS-1) initiated patients on intravenous omadacycline or linezolid, with the option to transition to an oral formulation after day 3. OASIS-2 was an oral-only study of omadacycline versus linezolid. Results In total, 691 patients received omadacycline and 689 patients received linezolid. Infection types included wound infection in 46.8% of patients, cellulitis/erysipelas in 30.5%, and major abscess in 22.7%. Pathogens were identified in 73.2% of patients. S. aureus was detected in 74.7% and MRSA in 32.4% of patients in whom a pathogen was identified. Omadacycline was noninferior to linezolid using the Food and Drug Administration primary endpoint of early clinical response (86.2% vs 83.9%; difference 2.3, 95% confidence interval –1.5 to 6.2) and using the European Medicines Agency primary endpoint of investigator-assessed clinical response at the posttreatment evaluation. Clinical responses were similar across different infection types and infections caused by different pathogens. Treatment-emergent adverse events, mostly described as mild or moderate, were reported by 51.1% of patients receiving omadacycline and 41.2% of those receiving linezolid. Conclusions Omadacycline was effective and safe in ABSSSI. Clinical Trials Registration NCT02378480 and NCT02877927.

Arterial stiffness index (ASI) is a non-invasive measure of arterial stiffness using infra-red finger sensors (photoplethysmography). It is a well-suited measure for large populations as it is relatively inexpensive to perform, and data can be acquired within seconds. These features raise interest in using ASI as a tool to estimate cardiovascular disease risk as prior work demonstrates increased arterial stiffness is associated with elevated systolic blood pressure, and ASI is predictive of cardiovascular disease and mortality. We conducted genome-wide association studies (GWASs) for ASI in 127,121 UK Biobank participants of European-ancestry. Our primary analyses identified variants at four loci reaching genome-wide significance ( P  < 5 × 10 −8 ): TEX41 (rs1006923; P  = 5.3 × 10 −12 ), FOXO1 (rs7331212; P  = 2.2 × 10 −11 ), C1orf21 (rs1930290, P  = 1.1 × 10 −8 ) and MRVI1 (rs10840457, P  = 3.4 × 10 −8 ). Gene-based testing revealed three significant genes, the most significant gene was COL4A2 ( P  = 1.41 × 10 −8 ) encoding type IV collagen. Other candidate genes at associated loci were also involved in smooth muscle tone regulation. Our findings provide new information for understanding the development of arterial stiffness.

Abstract Background Early clinical response (ECR) is a new endpoint to determine whether a drug should be approved for community-acquired bacterial pneumonia in the United States. The Omadacycline for Pneumonia Treatment In the Community (OPTIC) phase III study demonstrated noninferiority of omadacycline to moxifloxacin using this endpoint. This study describes the performance of the ECR endpoint and clinical stability relative to a posttreatment evaluation (PTE) of clinical success. Methods ECR was defined as symptom improvement 72–120 hours after the first dose of study drug (ECR window), no use of rescue antibiotics, and patient survival. Clinical success at PTE was an investigator assessment of success. Clinical stability was defined based on vital sign stabilization, described in the American Thoracic Society and Infectious Diseases Society of America community-acquired pneumonia treatment guidelines. Results During the ECR window, ECR was achieved in 81.1% and 82.7% of omadacycline and moxifloxacin patients, respectively. Similar numbers of patients achieved clinical stability in each treatment group (omadacycline 74.6%, moxifloxacin 77.6%). The proportion of patients with improved symptoms who were considered clinically stable increased across the ECR window (69.2–77.6% for omadacycline; 68.0–79.7% for moxifloxacin). There was high concordance (>70%) and high positive predictive value (>90%) of ECR and clinical stability with overall clinical success at PTE. Conclusions Omadacycline was noninferior to moxifloxacin, based on a new ECR endpoint. Clinical stability was similarly high when measured in the same time frame as ECR. Both ECR and clinical stability showed high concordance and high positive predictive value with clinical success at PTE. Clinical Trials Registration NCT02531438.