Use of Real-World Data Sources for Canadian Drug Pricing and Reimbursement Decisions: Stakeholder Views and Lessons for Other Countries.

BACKGROUND: Canada has a long history of the use of clinical evidence to support healthcare decision making. Given improvements in data holdings and analytic capacity in Canada and stakeholder interest, the purpose of this study is to reflect on perceptions of the value of real-world evidence in pricing and reimbursement decisions, barriers to its optimal use in pricing and reimbursement, current initiatives that may lead to its increased use, and what role the pharmaceutical industry may play in this.Methods/ResultsTo capture stakeholder perceptions, ninety-one participants identified as key stakeholders were identified according to background roles and geography and invited to participate in four round table discussions conducted under Chatham House rule. Important themes emerging from these discussions included: (i) the need to understand what "real world" evidence means; (ii) barriers to using real world evidence from differences in access, governance, inter-operability, system structures, expertise, and quality across Canadian health systems; (iii) differing views on industry's role. CONCLUSIONS: The use of real-world data in Canada to inform pricing and reimbursement decisions is far from routine but nascent and slowly increasing. Barriers, including interoperability concerns, may also apply to other federated health systems that need to focus on the networking of healthcare administrative data across provincial jurisdictional boundaries. There also appears to be a desire to see better use of pragmatic trials linked to these administrative data sets. Emerging initiatives are under way to use real world evidence more broadly, and include identification of common data elements and approaches to networking data.

Is radiograph glenopolar angle accurate for extraarticular scapular neck fractures?

BACKGROUND: Plain radiographs still play a role in management of extraarticular scapular neck fractures. Glenopolar angle (GPA) is one of the radiograph measurements that is used to determine the necessity for surgery. Our aim was to establish reliability of GPA on plain radiograph in patients with extraarticular scapular neck fractures. METHODS: We performed a multicentre retrospective study including all patients with extraarticular scapular neck fractures with available imaging between 2006 and 2012. We excluded intra-articular glenoid fractures, scapular blade fractures, acromion fractures, and scapular spine fractures. We compared GPA on plain radiograph with three dimensional computed tomography (3D CT) measurement, as well as contribution of radiograph rotational error, glenoid inclination, and medial shortening of glenoid fragment towards GPA measurement. RESULTS: One hundred patients met the inclusion criteria. The mean difference between the GPA measurements on radiographs and 3D CT was 6.1±0.85° (95% confidence interval) as an absolute value. In terms of contribution to GPA values, GPA changed by one degree with ten degrees of radiograph rotational error, three degrees of glenoid inclination, and three millimetres of glenoid fragment medial shortening. CONCLUSION: Plain radiograph can provide a clinician with a reasonable estimation of the GPA. Glenoid inclination has a greater influence on GPA compared to medial shortening.

Endodontic Management of a Mandibular Central Incisor with Type IV Canal Pattern: A Case Report.

The success of endodontic treatment requires the knowledge of tooth morphology and its variations. Mandibular incisor's anatomy presents a challenge when an endodontic access is made, because of its small size and high prevalence of two canals. We are describing a Weine's Type IV root canal configuration that was detected in a mandibular central incisor, which was demonstrated by a radiographic examination. This article also focuses on the successful endodontic treatment of a mandibular central incisor with a single canal at the pulp chamber, which divided into two distinct and separate canals (buccolingual) at the middle third of the root.

A rare case of extrafollicular adenomatoid odontogenic tumour in the posterior region of the mandible: misdiagnosed as residual cyst.

Adenomatoid odontogenic tumor is a relatively uncommon distinct odontogenic neoplasm. It is an uncommon tumor of odontogenic origin with varying number of ductlike structures and inductive changes in the stroma. It is a benign and slow growing epithelial tumor and represents 3% of all odontogenic tumors. Its occurrence is more common in anterior region of the maxilla than mandible. Most of the adenomatoid odontogenic tumors occur intra-osseously but few peripheral variant have been reported which are attached to the gingival structures. The intra-osseous Adenomatoid odontogenic tumor may be related to unerrupted tooth (follicular varient) or may not (extrafollicular varient) be related to unerrupted tooth. This paper is to present a rare case of an extrafollicular Adenomatoid odontogenic tumor occurring in the body of the mandible in a male patient which is distinct and secondly it was clinically and radiographically diagnosed as residual cyst. The diagnosis of Adenomatoid odontogenic tumor was confirmed by Histopathological investigation. How to cite this article: Shivali V, Khanna VD, Khanna P, Singh A, Pandey A, Ahuja T. A Rare Case of Extrafollicular Adenomatoid Odontogenic Tumour in the Posterior Region of the Mandible: Misdiagnosed as Residual Cyst. J Int Oral Health 2013; 5(5):124-8.

Hemangioma: review of literature.

Hemangiomas are tumors identifed by rapid endothelial cell proliferation in early infancy, followed by involution over time. All other abnormalities are malformations resulting from anomalous development of vascular plexuses. The malformations have a normal endothelial cell growth cycle that affects the veins, the capillaries or the lymphatics and they do not involute. Hemangiomas are the most common tumors of infancy and are characterized by a proliferating and involuting phase. They are seen more commonly in whites than in blacks, more in females than in males in a ratio of 3:1.

Second-line therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a systematic review and mixed-treatment comparison meta-analysis.

BACKGROUND: Although there is general agreement that metformin should be used as first-line pharmacotherapy in patients with type 2 diabetes, uncertainty remains regarding the choice of second-line therapy once metformin is no longer effective. We conducted a systematic review and meta-analysis to assess the comparative safety and efficacy of all available classes of antihyperglycemic therapies in patients with type 2 diabetes inadequately controlled on metformin monotherapy. METHODS: MEDLINE, EMBASE, BIOSIS Previews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published in English from 1980 to October 2009. Additional citations were obtained from grey literature and conference proceedings and through stakeholder feedback. Two reviewers independently selected studies, extracted data and assessed risk of bias. Key outcomes of interest were hemoglobin A1c, body weight, hypoglycemia, quality of life, long-term diabetes-related complications, serious adverse drug events and mortality. Mixed-treatment comparison and pairwise meta-analyses were conducted to pool trial results, when appropriate. RESULTS: We identified 49 active and non-active controlled randomized trials that compared 2 or more of the following classes of antihyperglycemic agents and weight-loss agents: sulfonylureas, meglitinides, thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, insulins, alpha-glucosidase inhibitors, sibutramine and orlistat. All classes of second-line antihyperglycemic therapies achieved clinically meaningful reductions in hemoglobin A1c (0.6% to 1.0%). No significant differences were found between classes. Insulins and insulin secretagogues were associated with significantly more events of overall hypoglycemia than the other agents, but severe hypoglycemia was rarely observed. An increase in body weight was observed with the majority of second-line therapies (1.8 to 3.0 kg), the exceptions being DPP-4 inhibitors, alpha-glucosidase inhibitors and GLP-1 analogues (0.6 to -1.8 kg). There were insufficient data available for diabetes complications, mortality or quality of life. INTERPRETATION: DPP-4 inhibitors and GLP-1 analogues achieved improvements in glycemic control similar to those of other second-line therapies, although they may have modest benefits in terms of weight gain and overall hypoglycemia. Further long-term trials of adequate power are required to determine whether newer drug classes differ from older agents in terms of clinically meaningful outcomes.

Choline-mediated depression of hippocampal synaptic transmission.

Choline is a micronutrient essential for the structural integrity of cellular membranes, and its presence at synapses follows either depolarization-induced pre-synaptic release or degradation of acetylcholine. Previous studies using whole-cell recording have shown that choline can modulate inhibitory input to hippocampal pyramidal neurons by acting upon nicotinic acetylcholine receptors (nAChRs) found on interneurons. However, little is known about how choline affects neuronal activity at the population level; therefore, we used extracellular recordings to assess its influence upon synaptic transmission in acutely prepared hippocampal slices. Choline caused a reversible depression of evoked field excitatory post-synaptic potentials (fEPSPs) in a concentration-dependent manner (10, 500, and 1000 µM). When applied after the induction of long-term potentiation, choline-mediated depression (CMD) was still observed, and potentiation returned on wash-out. Complete blockade of CMD could not be achieved with antagonists for the α7 nAChR, to which choline is a full agonist, but was possible with a general nAChR antagonist. The ability of choline to increase paired-pulse facilitation, and the inability of applied gamma-aminobutyric acid (GABA) to mediate further depression of fEPSPs, suggests that the principal mechanism of choline's action was on the facilitation of neurotransmitter release. Our study provides evidence that choline can depress population-level activity, quite likely by facilitating the release of GABA from interneurons, and may thereby influence hippocampal function.

A novel silicon patch-clamp chip permits high-fidelity recording of ion channel activity from functionally defined neurons.

We report on a simple and high-yield manufacturing process for silicon planar patch-clamp chips, which allow low capacitance and series resistance from individually identified cultured neurons. Apertures are etched in a high-quality silicon nitride film on a silicon wafer; wells are opened on the backside of the wafer by wet etching and passivated by a thick deposited silicon dioxide film to reduce the capacitance of the chip and to facilitate the formation of a high-impedance cell to aperture seal. The chip surface is suitable for culture of neurons over a small orifice in the substrate with minimal leak current. Collectively, these features enable high-fidelity electrophysiological recording of transmembrane currents resulting from ion channel activity in cultured neurons. Using cultured Lymnaea neurons we demonstrate whole-cell current recordings obtained from a voltage-clamp stimulation protocol, and in current-clamp mode we report action potentials stimulated by membrane depolarization steps. Despite the relatively large size of these neurons, good temporal and spatial control of cell membrane voltage was evident. To our knowledge this is the first report of recording of ion channel activity and action potentials from neurons cultured directly on a planar patch-clamp chip. This interrogation platform has enormous potential as a novel tool to readily provide high-information content during pharmaceutical assays to investigate in vitro models of disease, as well as neuronal physiology and synaptic plasticity.

Elevated synaptic activity preconditions neurons against an in vitro model of ischemia.

Tolerance to otherwise lethal cerebral ischemia in vivo or to oxygen-glucose deprivation (OGD) in vitro can be induced by prior transient exposure to N-methyl-D-aspartic acid (NMDA): preconditioning in this manner activates extrasynaptic and synaptic NMDA receptors and can require bringing neurons to the "brink of death." We considered if this stressful requirement could be minimized by the stimulation of primarily synaptic NMDA receptors. Subjecting cultured cortical neurons to prolonged elevations in electrical activity induced tolerance to OGD. Specifically, exposing cultures to a K(+)-channel blocker, 4-aminopyridine (20-2500 microm), and a GABA(A) receptor antagonist, bicuculline (50 microm) (4-AP/bic), for 1-2 days resulted in potent tolerance to normally lethal OGD applied up to 3 days later. Preconditioning induced phosphorylation of ERK1/2 and CREB which, along with Ca(2+) spiking and OGD tolerance, was eliminated by tetrodotoxin. Antagonists of NMDA receptors or L-type voltage-gated Ca(2+) channels (L-VGCCs) applied during preconditioning decreased Ca(2+) spiking, phosphorylation of ERK1/2 and CREB, and OGD tolerance more effectively when combined, particularly at the lowest 4-AP concentration. Inhibiting ERK1/2 or Ca(2+)/calmodulin-dependent protein kinases (CaMKs) also reduced Ca(2+) spiking and OGD tolerance. Preconditioning resulted in altered neuronal excitability for up to 3 days following 4-AP/bic washout, based on field potential recordings obtained from neurons cultured on 64-channel multielectrode arrays. Taken together, the data are consistent with action potential-driven co-activation of primarily synaptic NMDA receptors and L-VGCCs, resulting in parallel phosphorylation of ERK1/2 and CREB and involvement of CaMKs, culminating in a potent, prolonged but reversible, OGD-tolerant phenotype.

Synaptic activity and triphenyltetrazolium chloride metabolism are correlated after oxygen-glucose deprivation in acute, but not cultured, hippocampal slices.

The importance of the hippocampus to learning and memory has attracted significant attention to how the structure responds to damage. Although many studies have used either the acute hippocampal slice preparation or organotypic hippocampal slice cultures, little work has been done to determine if the choice of model is an important variable. The present study examined whether differences exist in how each model responds to a commonly studied ischemic-like paradigm, oxygen-glucose deprivation. Following the insult, synaptic activity was examined by recording orthodromically evoked CA1 subfield responses, while mitochondrial activity was assessed by spectrophotometric measurement of formazan produced by metabolism of 2,3,5-triphenyltetrazolium chloride. The insult significantly decreased both synaptic and mitochondrial activity within acutely prepared slices, but a disparity existed between these measures in cultured slices. While evoked activity was greatly reduced by an insult of moderate duration, a much longer period was required to cause a comparable decrease in formazan production. Quantitative immunoblotting revealed that one possible explanation for the discrepancy was an elevated expression of astrocytes, which display resistance to hypoxia-aglycemia. Our data indicate that acutely prepared and cultured slices respond differently to ischemic-like challenge; therefore, assays examining viability in these models must consider their innate differences.

Longitudinal study of the effects of a high-fat diet on glucose regulation, hippocampal function, and cerebral insulin sensitivity in C57BL/6 mice.

Although the increasing rate of obesity has stimulated interest in the effects of diet composition on peripheral systems, comparatively little work has been done to examine effects upon the brain. A diet high in fat is one of many factors that can promote obesity, and previous research has shown that such a diet can produce learning and memory impairment in rodents. In the present study, C57BL/6 mice were placed on either a high-fat (45% kcal fat) or regular (5% kcal fat) diet, and examined at different points during the subsequent year. The high-fat diet led to increased weight gain, significant impairment in glucoregulation, and altered insulin-mediated signaling within the hippocampus, an area of the brain believed to be important for the acquisition of memory. Following ten months on either diet, synaptic function in ex vivo hippocampal slices was examined, and neither stimulus-response curves nor electrically induced long-term potentiation were found to be different. As well, performance in the Morris water maze, a hippocampal-dependent test of spatial memory, was not influenced by diet. However, mice consuming a high-fat diet failed to perform an operant bar-pressing task, indicating a significant impairment to procedural learning and consolidation processes. Despite causing broad peripheral changes in C57BL/6 mice, consuming a large proportion of calories from saturated fat had only a limited effect upon learning and memory, which suggests that certain aspects of brain function are selectively vulnerable to the influences of diet.