Barriers and facilitators to the dissemination of national movement behavior guidelines among health-promoting organizations: a qualitative study.

Background: National movement behavior guidelines offer evidence-informed recommendations for how to obtain health benefits. However, their impact on practice and policy has been limited. Factors at multiple levels determine the effective mobilization of knowledge into practice.

Consensus on managing open ankle fractures in the frail patient.

Aims: Ankle fractures are common injuries and the third most common fragility fracture. In all, 40% of ankle fractures in the frail are open and represent a complex clinical scenario, with morbidity and mortality rates similar to hip fracture patients. They have a higher risk of complications, such as wound infections, malunion, hospital-acquired infections, pressure sores, veno-thromboembolic events, and significant sarcopaenia from prolonged bed rest.

Therapeutic enzyme engineering using a generative neural network.

Enhancing the potency of mRNA therapeutics is an important objective for treating rare diseases, since it may enable lower and less-frequent dosing. Enzyme engineering can increase potency of mRNA therapeutics by improving the expression, half-life, and catalytic efficiency of the mRNA-encoded enzymes. However, sequence space is incomprehensibly vast, and methods to map sequence to function (computationally or experimentally) are inaccurate or time-/labor-intensive.

Effectiveness of an Online Course on Fracture-Related Infections.

This study aims to evaluate the effectiveness of an online course to enable orthopaedic surgeons to acquire the core competencies necessary to prevent and treat fracture-related infections (FRI). This study included orthopaedic surgeons and residents from Latin American countries who attended an online course focused on FRI. The online course included: didactic lectures, small-group clinical case discussions, and panel case discussions.

mRNA structure regulates protein expression through changes in functional half-life.

Messenger RNAs (mRNAs) encode information in both their primary sequence and their higher order structure. The independent contributions of factors like codon usage and secondary structure to regulating protein expression are difficult to establish as they are often highly correlated in endogenous sequences. Here, we used 2 approaches, global inclusion of modified nucleotides and rational sequence design of exogenously delivered constructs, to understand the role of mRNA secondary structure independent from codon usage.

Human 5' UTR design and variant effect prediction from a massively parallel translation assay.

The ability to predict the impact of cis-regulatory sequences on gene expression would facilitate discovery in fundamental and applied biology. Here we combine polysome profiling of a library of 280,000 randomized 5' untranslated regions (UTRs) with deep learning to build a predictive model that relates human 5' UTR sequence to translation. Together with a genetic algorithm, we use the model to engineer new 5' UTRs that accurately direct specified levels of ribosome loading, providing the ability to tune sequences for optimal protein expression.

Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines.

mRNA vaccines have the potential to tackle many unmet medical needs that are unable to be addressed with conventional vaccine technologies. A potent and well-tolerated delivery technology is integral to fully realizing the potential of mRNA vaccines. Pre-clinical and clinical studies have demonstrated that mRNA delivered intramuscularly (IM) with first-generation lipid nanoparticles (LNPs) generates robust immune responses.

Analysis of RNA nearest neighbor parameters reveals interdependencies and quantifies the uncertainty in RNA secondary structure prediction.

RNA secondary structure prediction is often used to develop hypotheses about structure-function relationships for newly discovered RNA sequences, to identify unknown functional RNAs, and to design sequences. Secondary structure prediction methods typically use a thermodynamic model that estimates the free energy change of possible structures based on a set of nearest neighbor parameters. These parameters were derived from optical melting experiments of small model oligonucleotides.

A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates.

The success of mRNA-based therapies depends on the availability of a safe and efficient delivery vehicle. Lipid nanoparticles have been identified as a viable option. However, there are concerns whether an acceptable tolerability profile for chronic dosing can be achieved.

Fracture-related infection: A consensus on definition from an international expert group.

Fracture-related infection (FRI) is a common and serious complication in trauma surgery. Accurately estimating the impact of this complication has been hampered by the lack of a clear definition. The absence of a working definition of FRI renders existing studies difficult to evaluate or compare.

A sensitivity analysis of RNA folding nearest neighbor parameters identifies a subset of free energy parameters with the greatest impact on RNA secondary structure prediction.

Nearest neighbor parameters for estimating the folding energy changes of RNA secondary structures are used in structure prediction and analysis. Despite their widespread application, a comprehensive analysis of the impact of each parameter on the precision of calculations had not been conducted. To identify the parameters with greatest impact, a sensitivity analysis was performed on the 291 parameters that compose the 2004 version of the free energy nearest neighbor rules.

Demystifying damage control in musculoskeletal trauma.

Trauma care has evolved rapidly over the past decade. The benefits of operative fracture management in major trauma patients are well recognised. Concerns over early total care arose when applied broadly.

Temporal variation in major trauma admissions.

Introduction: Trauma is a significant cause of morbidity and mortality in the UK. Since the inception of the trauma networks, little is known of the temporal pattern of trauma admissions.

Methods: Trauma Audit and Research Network data for 1 April 2011 to 31 March 2013 were collated from two large major trauma centres (MTCs) in the South East of England: Brighton and Sussex University Hospitals NHS Trust (BSUH) and St George's University Hospitals NHS Foundation Trust (SGU).

Ionising radiation exposure in paediatric trauma.

Introduction: Trauma remains the highest cause of paediatric morbidity and mortality. These trauma patients incur radiation exposure during intraoperative management. Medical personnel have the responsibility to ensure observation of the 'as low as reasonably achievable' principle, a practice mandate that minimises ionising radiation exposure.

Sernbo score predicts survival after intracapsular hip fracture in the elderly.

Introduction: The Sernbo score uses four factors (age, social situation, mobility and mental state) to divide patients into a high-risk and a low-risk group. This study sought to assess the use of the Sernbo score in predicting mortality after an intracapsular hip fracture.

Methods: A total of 259 patients with displaced intracapsular hip fractures were included in the study.

Intramedullary nailing for pathological fractures of the ulna.

Pathological lesions of long bones increase the morbidity of many common cancers. The orthopedic management of metastatic skeletal lesions can be challenging. The ultimate aim is to provide patients with a painless, functional limb.

Towards ambient temperature-stable vaccines: the identification of thermally stabilizing liquid formulations for measles virus using an innovative high-throughput infectivity assay.

As a result of thermal instability, some live attenuated viral (LAV) vaccines lose substantial potency from the time of manufacture to the point of administration. Developing regions lacking extensive, reliable refrigeration ("cold-chain") infrastructure are particularly vulnerable to vaccine failure, which in turn increases the burden of disease. Development of a robust, infectivity-based high throughput screening process for identifying thermostable vaccine formulations offers significant promise for vaccine development across a wide variety of LAV products.

Application of a high-throughput screening procedure with PEG-induced precipitation to compare relative protein solubility during formulation development with IgG1 monoclonal antibodies.

Protein solubility is a critical attribute in monoclonal antibody (mAb) formulation development as insolubility issues can negatively impact drug stability, activity, bioavailability, and immunogenicity. A high-throughput adaptation of an experimental method previously established in the literature to determine apparent protein solubility is described, where polyethylene glycol (PEG) is used to reduce protein solubility in a quantitatively definable manner. Utilizing an automated, high-throughput system, an immunoglobulin G (IgG)1 mAb in a variety of buffer conditions was exposed to increasing concentrations of PEG and the amount of protein remaining in solution was determined.

Should unstable extra-articular distal radial fractures be treated with fixed-angle volar-locked plates or percutaneous Kirschner wires? A prospective randomised controlled trial.

Fractures of the distal radius are commonly treated with cast immobilisation; however, those potentially unstable injuries with dorsal comminution may need operative intervention. This intervention is usually with manipulation and Kirschner wires but advances in locking-plate technology have enabled surgeons to achieve anatomical reconstruction of complex fracture patterns, even in poor-quality osteoporotic bone.To ascertain if fixed-angle volar-locked plates confer a significant benefit over manipulation and Kirschner-wire stabilisation, we prospectively randomised 56 adult patients with isolated, closed,unilateral, unstable extra-articular fractures into two treatment groups, one fixed with K-wires and the other fixed with a volar locking plate.

A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): discovery of (S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid (MMP408).

Matrix metalloprotease 12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been found in the lung of human COPD patients. MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metalloprotease 2 and 13 inhibitor via lead optimization and has good physical properties and bioavailability.

Computer hexapod assisted orthopaedic surgery (CHAOS) in the correction of long bone fracture and deformity.

We describe a surgical technique using the Taylor Spatial Frame intraoperatively to correct complex multiplanar deformities of the distal femur prior to definitive internal fixation using minimally invasive stabilization techniques. Eight procedures were done in 7 patients. All deformities were complex oblique plane deformities, often with a rotational component, and ranged from 10 degrees valgus to 35 degrees varus; up to 45 degrees of external rotation; 10 mm of translation and in 1 case, 100 mm of shortening.

Scaphoid bone bruising--probably not the precursor of asymptomatic non-union of the scaphoid.

The MRI finding of bone marrow oedema, without fracture, following trauma to the scaphoid has been called a 'bone bruise'. A similar injury is found in the knee, considered benign and managed conservatively. In the scaphoid, there is the concern that this lesion may lead to scaphoid non-union.

Use of structure-based drug design approaches to obtain novel anthranilic acid acyl carrier protein synthase inhibitors.

Acyl carrier protein synthase (AcpS) catalyzes the transfer of the 4'-phosphopantetheinyl group from the coenzyme A to a serine residue in acyl carrier protein (ACP), thereby activating ACP, an important step in cell wall biosynthesis. The structure-based design of novel anthranilic acid inhibitors of AcpS, a potential antibacterial target, is presented. An initial high-throughput screening lead and numerous analogues were modeled into the available AcpS X-ray structure, opportunities for synthetic modification were identified, and an iterative process of synthetic modification, X-ray complex structure determination with AcpS, biological testing, and further modeling ultimately led to potent inhibitors of the enzyme.

A randomized double blind-cross over trial of soya protein for the treatment of cyclical breast pain.

Twenty patients with cyclical breast pain were enrolled in a double-blind cross-over trial in which either a soy protein drink or a flavoured cow's milk was taken orally each day for 3 months before crossing over to the alternate drink for a further 3 months. Records of pain scores were taken throughout the study. Blood was also taken before and after 3 and 6 months for the measurement of phytoestrogents to assess compliance.

Anthranilate 4H-oxazol-5-ones: novel small molecule antibacterial acyl carrier protein synthase (AcpS) inhibitors.

D-optimal design and Projection to Latent Structures (PLS) analysis were used to optimize screening hit 5 (B. subtilis AcpS IC(50): 15 microM, B. subtilis MIC: >200 microM) into a series of 4H-oxazol-5-one, small molecule, antibacterial, AcpS inhibitors.