Pharmacists Improve Door to Needle Times in the Emergency Department

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Probing the molecular and structural basis of voltage sensor gating in Kv11.1 ion channels

Congenital mutations in the cardiac Kv11.1 channel can cause long QT syndrome type 2 (LQTS2), a heart rhythm disorder associated with sudden cardiac death. Mutations act either by reducing protein expression at the membrane, and/or by perturbing the intricate gating properties of Kv11.1 channels. A number of clinical LQTS2-associated mutations have been reported in the first transmembrane segment (S1) of Kv11.1 channels but the role of this region of the channel is largely unexplored. In part this is due to problems defining the extent of the S1 helix, as a consequence of its low sequence homology with other Kv family members. Here we used NMR spectroscopy and electrophysiological characterization to show that the S1 of Kv11.1 channels extends seven helical turns, from Pro405 to Phe431, and is flanked by unstructured loops. Functional analysis suggests that pre-S1 loop residues His402 and Tyr403 play an important role in regulating the kinetics and voltage dependence of channel activation and deactivation. Multiple residues within the S1 helix also play an important role in fine-tuning the voltage dependence of activation, regulating slow deactivation, and modulating C-type inactivation of Kv11.1 channels. We demonstrate that for Kv11.1, activation and deactivation processes are not simple reversal transitions, but rather deactivation and inactivation processes are likely to be coupled. Analyses of LQTS2-associated mutations in the pre-S1 loop or S1 helix of Kv11.1 channels demonstrate perturbations to both protein expression and most gating transitions. Thus S1 region mutations would reduce both the action potential repolarizing current passed by Kv11.1 channels in cardiac myocytes, as well as the current passed in response to premature depolarizations that normally helps protect against the formation of ectopic beats

A personalised approach to spine surgery

Background: Anterior lumbar interbody fusion (ALIF) remains one of the mainstay surgical approaches in treating painful degenerative disc disease with or without segmental instability in the lower spine. The risk factors and complication profile for ALIF differs significantly from other established fusion techniques. Objectives: The goal of the first part of this thesis is to establish the factors associated with long-term clinical outcome (Chapter 2) and short-term perioperative outcomes (Chapter 3) following ALIF. Chapter 4 focuses on the long-term radiographic evidence for biomaterial alternatives for ALIF implants, namely titanium (Ti)-coated PEEK integrated cages. Methods and Results: From a prospective cohort analysis of 147 patients undergoing ALIF, elderly age (≥64 years old) was associated with an increased rate of subsidence but does not affect clinical outcomes. Obesity was not associated with postoperative complications or follow-up patient-reported outcomes. Failed fusion was significantly higher for smokers, and they were significantly more likely than non-smokers to experience postoperative complications such as pseudoarthrosis. To assess risk factors for perioperative complications and readmissions after ALIF, the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was analysed. ALIF was associated with prolonged length of stay and higher rate of return to operating theatre compared to posterior lumbar fusion. Obesity and alcohol intake increased the risk of 30-day readmissions. Discharge to non-home destination following ALIF was independently associated with wound complications and venous thromboembolism. Finally, a prospective follow-up study was performed to determine the long-term radiographic outcome following ALIF using Ti-coated PEEK cages with allograft and INFUSE. Effective fusion was achieved at up to 24-month follow-up for various indications including degenerative spine/disc disease, low grade lumbar isthmic spondylolisthesis, spondylotic radiculopathy and discogenic low back pain. Conclusions: Collectively, this thesis highlights the importance of personalising the care of an ALIF surgery patient, through identification and optimization of individual risk factors for short-term and long-term outcomes, as well as through choice of implant biomaterial and design

Cardiac interventions in patients with achondroplasia: a systematic review.

Patients with achondroplasia and other causes of dwarfism suffer from increased rates of cardiovascular disease relative to the remainder of the population. Few studies have examined these patients when undergoing cardiac surgery or percutaneous intervention. This systematic review examines the literature to determine outcomes following cardiac intervention in this unique population. An electronic search was performed in the English literature to identify all reports of achondroplasia, dwarfism, and cardiac intervention. Of the 5,274 articles identified, 14 articles with 14 cases met inclusion criteria. Patient-level data was extracted and analyzed. Median patient age was 55.5 [interquartile ranges (IQR), 43.8, 59.8] years, median height 102.0 [98.8, 112.5] cm, median BMI 32.1 [27.0, 45.9], and 57.1% (8/14) were male. Of these 14 patients, nine had the following documented skeletal abnormalities: 66.7% (6/9) had scoliosis, 66.7% (6/9) had kyphosis, 11.1% (1/9) had lordosis, 11.1% (1/9) pectus carinatum and 11.1% (1/9) spinal stenosis. Coronary artery disease was present in 53.8% (7/13), and 30.8% (4/13) patients previously suffered a myocardial infarction. Of the eight patients who underwent cardiac surgery, 37.5% (3/8) underwent multivessel coronary artery bypass grafting, 37.5% (3/8) underwent aortic valve replacement, 25.0% (2/8) underwent type A aortic dissection repair, and the remaining 12.5% (1/8) underwent pulmonary thromboendarterectomy. Six patients underwent percutaneous intervention. Median cardiopulmonary bypass time was 136.5 [110.0, 178.8] minutes. Median arterial cannula size was 20.0 [20.0, 24.0] Fr. Bicaval cannulation was performed in all cases describing cannulation strategy (5/5). Median superior vena cava cannula size was 28.0 [28.0, 28.0] Fr, and inferior vena cava cannula size was 28.0 [28.0, 28.0] Fr. No mortality was reported with a median follow up time of 6.0 [6.0, 10.5] months. In conclusion, Common cardiac procedures can be performed with reasonable safety in this patient population. Operative adjustments may need to be made with respect to equipment to accommodate patient-specific needs

Aberrant Reward Center Response To Partner Reputation During A Social Exchange Game In Generalized Social Phobia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97533/1/da22091.pd