Predictors of in-hospital surgical site infections in surgically managed acetabular fractures: A nationwide analysis.

Background: A surgical site infection (SSI) rate of 4%-8% has been reported in patients who undergo open reduction and internal fixation (ORIF) for acetabular fractures. Studies have identified risk factors for SSI, but none have performed a nationwide analysis of SSI in surgically managed acetabular fracture patients.

Methods: The National Inpatient Sample (NIS) database was queried for patients who underwent ORIF for acetabular fractures from 2016 to 2019.

A Structured Benefit-Risk Assessment Operating Model for Investigational Medicinal Products in the Pharmaceutical Industry.

Robust and transparent formal benefit-risk (BR) analyses for medicinal products represent a means to better understand the appropriate use of medicinal products, and to maximize their value to prescribers and patients. Despite regulatory and social imperatives to conduct structured BR (sBR) assessments, and the availability of a plethora of methodological tools, there exists large variability in the uptake and execution of sBR assessments among pharmaceutical companies. As such, in this paper we present an sBR assessment framework developed and implemented within a large global pharmaceutical company that aims to guide the systematic assessment of BR across the continuum of drug development activities, from first-time-in-human studies through to regulatory submission.

A Structured Methodology to Assess Safety Signal Strength and Inform Causality Assessment.

Causality assessment of safety signals observed with medicinal products is a foundational element of pharmacovigilance and regulatory practice, typically performed by a global introspection process. We have developed a novel, structured methodological framework to support the global introspection process for safety signal causality assessment. This Signal Assessment Guide (SAGe) tool was developed by AstraZeneca and is used internally, both to assess safety signal strength and to inform causality decisions related to safety signals.

Practical considerations for creating a strategic and proactive clinical safety and pharmacovigilance organization for the future.

Background: In 2012, Patient Safety (PS) in AstraZeneca was facing a situation with multiple challenges, scientifically and structurally.

Objective: To meet these and support AstraZeneca's ambition to return to growth after years of patent expiry, we undertook a project to fundamentally revisit ways of working to create an organisation set up to provide strategic safety in support of drug project decision-making.

Method: In this paper, we describe the challenges we faced, the project to deliver changes to respond to them, and the methodology used.

IMO-8400, a toll-like receptor 7, 8, and 9 antagonist, demonstrates clinical activity in a phase 2a, randomized, placebo-controlled trial in patients with moderate-to-severe plaque psoriasis.

Background: Aberrant toll-like receptors (TLRs) 7, 8, and 9 activation by self-nucleic acids is implicated in immune-mediated inflammatory diseases (IMIDs) such as psoriasis. In preclinical IMID models, blocking TLR-activation reduced disease severity. IMO-8400 is a first-in-class, oligonucleotide-based antagonist of TLRs 7, 8, and 9.

Carotid extramedial thickness is associated with local arterial stiffness in children.

Objectives: Experimental evidence suggests that structural changes to the arterial adventitia may be a key vascular determinant of early arterial stiffening, although this has not been directly studied. Accordingly, we hypothesized that in young children, in whom this relationship would not be altered by atheroma, carotid extramedial thickness (EMT), a measure that incorporates the thickness of the arterial adventitia, perivascular tissues and the internal jugular venous wall, would be associated with localized arterial stiffness of the same arterial region.

Methods: We studied 248 healthy prepubescent children (aged 8 years).

Weight gain in infancy is associated with carotid extra-medial thickness in later childhood.

Objective: Early life is an important period for determining future risk of cardiovascular disease. Carotid extra-medial thickness is a novel noninvasive measure that estimates arterial adventitial thickness, information concerning vascular health not captured by assessment of arterial intima-media thickness alone. We sought to determine whether fetal growth and early postnatal growth are associated with carotid extra-medial thickness in 8 year old children.

Suppression of molecular inflammatory pathways by Toll-like receptor 7, 8, and 9 antagonists in a model of IL-23-induced skin inflammation.

Psoriasis is a complex inflammatory disease resulting from the activation of T helper (Th) 1 and Th17 cells. Recent evidence suggests that abnormal activation of Toll-like receptors (TLRs) 7, 8 and 9 contributes to the initiation and maintenance of psoriasis. We have evaluated the effects of TLR antagonists on the gene expression profile in an IL-23-induced skin inflammation model in mice.

Nrf2 activation: a potential strategy for the prevention of acute mountain sickness.

Reactive oxygen species (ROS) formed during acute high altitude exposure contribute to cerebral vascular leak and development of acute mountain sickness (AMS). Nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) is a transcription factor that regulates expression of greater than 90% of antioxidant genes, but prophylactic treatment with Nrf2 activators has not yet been tested as an AMS therapy. We hypothesized that prophylactic activation of the antioxidant genome with Nrf2 activators would attenuate high-altitude-induced ROS formation and cerebral vascular leak and that some drugs currently used to treat AMS symptoms have an additional trait of Nrf2 activation.

Design, synthesis and biological evaluation of novel antagonist compounds of Toll-like receptors 7, 8 and 9.

Oligonucleotides containing an immune-stimulatory motif and an immune-regulatory motif act as antagonists of Toll-like receptor (TLR)7 and TLR9. In the present study, we designed and synthesized oligonucleotide-based antagonists of TLR7, 8 and 9 containing a 7-deaza-dG or arabino-G modification in the immune-stimulatory motif and 2'-O-methylribonucleotides as the immune-regulatory motif. We evaluated the biological properties of these novel synthetic oligoribonucleotides as antagonists of TLRs 7, 8 and 9 in murine and human cell-based assays and in vivo in mice and non-human primates.

Design of synthetic oligoribonucleotide-based agonists of Toll-like receptor 3 and their immune response profiles in vitro and in vivo.

Double-stranded RNA of viral origin and enzymatically synthesized poly I:C act as agonists of TLR3 and induce immune responses. We have designed and synthesized double-stranded synthetic oligoribonucleotides (dsORNs) which act as agonists of TLR3. Each strand of dsORN contains two distinct segments, namely an alignment segment composed of a heteronucleotide sequence and an oligo inosine (I) or an oligo cytidine (C) segment.

Free hemoglobin induction of pulmonary vascular disease: evidence for an inflammatory mechanism.

Cell-free hemoglobin (Hb) exposure may be a pathogenic mediator in the development of pulmonary arterial hypertension (PAH), and when combined with chronic hypoxia the potential for exacerbation of PAH and vascular remodeling is likely more pronounced. We hypothesized that Hb may contribute to hypoxia-driven PAH collectively as a prooxidant, inflammatory, and nitric oxide (NO) scavenger. Using programmable micropump technology, we exposed male Sprague-Dawley rats housed under room air or hypoxia to 12 or 30 mg per day Hb for 3, 5, and 7 wk.

Carotid extra-medial thickness in childhood: early life effects on the arterial adventitia.

Objective: Structural modification of the arterial adventitia may be an early event in atherosclerosis. Carotid extra-medial thickness is a new measure of arterial adventitial thickness. We examined the association of cardiovascular risk factors with extra-medial thickness, in childhood.

Discovery of potent and specific CXCR3 antagonists.

The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay.

An old friend in a new light: the role of osteocalcin in energy metabolism.

Accumulating evidence suggests interactions between bone and energy metabolism, which may affect the risk of cardiovascular disease. Recent animal studies indicate that osteocalcin (OC) plays a key role in the coordinated regulation of glucose and insulin metabolism while insulin receptors on osteoblasts may regulate bone turnover and circulating OC levels. Association studies, weight loss interventions, and observational data lend some support to the existence and relevance of these mechanisms in humans.

Reducing maternal mortality: a review of progress and evidence-based strategies to achieve millennium development goal 5.

Maternal mortality represents a major global health challenge. Millennium Development Goal 5 (MDG 5) set a range of targets pertaining to maternal mortality and universal access to reproductive health care. While the realization of these targets seems unlikely, cost-effective population-level approaches in combination with evidence-based interventions targeting the acute management of the major causes of maternal mortality present the potential for considerable progress as the 2015 deadline approaches.

Systemic gene delivery protects the photoreceptors in the retinal degeneration slow mouse.

The retinal degeneration slow (rds/rds) mouse was used to test photoreceptor protection by systemic gene delivery of non-erythropoietic forms of erythropoietin (EPO). Two Epo mutants were generated and packaged into recombinant adeno-associated virus (rAAV) serotype 2/5, controls included rAAV2/5.Epo and rAAV2/5.

Discovery and optimization of CRTH2 and DP dual antagonists.

A series of phenylacetic acid derivatives was discovered as CRTH2 antagonists. Modification of the series led to compounds that are also antagonists of DP. Since activation of CRTH2 and DP are believed to play key roles in mediating responses of asthma and other immune diseases, this series was optimized to increase the dual antagonistic activities and improve pharmacokinetic properties.

Prevalence of acute repetitive seizures (ARS) in the United Kingdom.

Introduction: "Acute repetitive seizures" (ARS) is a term to describe a condition manifest by multiple seizures occurring over a relatively brief period of time -generally 24 hours- in patients with epilepsy. There is limited information regarding the epidemiology of ARS in the general population.

Methods: We performed a historical cohort study using data from the United Kingdom General Practice Research Database (GPRD) to identify all incident and prevalent cases of active epilepsy in 2005.

Optimization of a series of quinazolinone-derived antagonists of CXCR3.

The evaluation of the CXCR3 antagonist AMG 487 in clinic trials was complicated due to the formation of an active metabolite. In this Letter, we will discuss the further optimization of the quinazolinone series that led to the discovery of compounds devoid of the formation of the active metabolite that was seen with AMG 487. In addition, these compounds also feature increased potency and good pharmacokinetic properties.

A potential role for reactive oxygen species and the HIF-1alpha-VEGF pathway in hypoxia-induced pulmonary vascular leak.

Acute hypoxia causes pulmonary vascular leak and is involved in the pathogenesis of pulmonary edema associated with inflammation, acute altitude exposure, and other critical illnesses. Reactive oxygen species, HIF-1, and VEGF have all been implicated in various hypoxic pathologies, yet the ROS-HIF-1-VEGF pathway in pulmonary vascular leak has not been defined. We hypothesized that the ROS-HIF-1-VEGF pathway has an important role in producing hypoxia-induced pulmonary vascular leak.

An antibody to IP-10 is a potent antagonist of cell migration in vitro and in vivo and does not affect disease in several animal models of inflammation.

IP-10 secretion is induced by pro-inflammatory cytokines and mediates the migration of CXCR3+ cells. Its elevation in clinical samples has been associated with multiple inflammatory diseases and its antagonism has been reported to be effective in several animal models of inflammatory disease. We generated a mouse anti-mouse IP-10 monoclonal antibody (mAb; Clone 20A9) that specifically bound murine IP-10 with high affinity and inhibited in vitro IP-10 induced BaF3/mCXCR3 cell migration with an IC(50) of approximately 4 nM.

Orbital arteriovenous malformations.

Objective: To present the clinical features, management, and outcomes in a series of patients with orbital arteriovenous malformations (AVMs).

Methods: Clinical records of patients with orbital AVMs confirmed using angiography were reviewed as a retrospective, noncomparative, interventional case series.

Results: Eight patients (3 women and 5 men) with unilateral AVMs and a mean age of 39 years (median, 36.

Impact of secondary structure of toll-like receptor 9 agonists on interferon alpha induction.

Oligodeoxynucleotides containing a CpG motif and double- or multistranded structure-forming sequences act as agonists of Toll-like receptor 9 (TLR9) and induce high levels of interferon alpha (IFN-alpha) in addition to other Th1-type cytokines. In the present study, we evaluated three highly effective IFN-alpha-inducing agonists of TLR9 to determine the type of duplex structures formed and the agonist's ability to induce immune responses, including IFN-alpha induction, in human cell-based assays and in vivo in mice and nonhuman primates. Thermal melting studies showed that two of the agonists evaluated had a single melting transition with similar hyperchromicity in both heating and cooling cycles, suggesting the formation of intermolecular duplexes.