Iatrogenic Spinal Cord Injury Resulting From Cervical Spine Surgery.

STUDY DESIGN: Retrospective cohort study of prospectively collected data. OBJECTIVE: To examine the incidence of iatrogenic spinal cord injury following elective cervical spine surgery. METHODS: A retrospective multicenter case series study involving 21 high-volume surgical centers from the AOSpine North America Clinical Research Network was conducted. Medical records for 17 625 patients who received cervical spine surgery (levels from C2 to C7) between January 1, 2005, and December 31, 2011, were reviewed to identify occurrence of iatrogenic spinal cord injury. RESULTS: In total, 3 cases of iatrogenic spinal cord injury following cervical spine surgery were identified. Institutional incidence rates ranged from 0.0% to 0.24%. Of the 3 patients with quadriplegia, one underwent anterior-only surgery with 2-level cervical corpectomy, one underwent anterior surgery with corpectomy in addition to posterior surgery, and one underwent posterior decompression and fusion surgery alone. One patient had complete neurologic recovery, one partially recovered, and one did not recover motor function. CONCLUSION: Iatrogenic spinal cord injury following cervical spine surgery is a rare and devastating adverse event. No standard protocol exists that can guarantee prevention of this complication, and there is a lack of consensus regarding evaluation and treatment when it does occur. Emergent imaging with magnetic resonance imaging or computed tomography myelography to evaluate for compressive etiology or malpositioned instrumentation and avoidance of hypotension should be performed in cases of intraoperative and postoperative spinal cord injury

Orthopedic in-training examination question metrics and resident test performance

First administered in November 1963, the orthopedic in-training examination (OITE) is now distributed to more than 4000 residents in over 20 countries and has become important for evaluation of resident fund of knowledge. Several studies have assessed the effect of didactic programs on resident performance, but only recently has it become possible to assess detailed testtaking metrics such as time spent per question. Here, we report the first assessment of resident OITE performance utilizing this full electronic dataset from two large academic institutions. Full 2015 OITE score reports for all orthopedic surgery residents at two institutions were anonymized and compiled. For every question answered by each resident, the resident year, question content or domain, question result (correct or incorrect), and answer speed were recorded. Data were then analyzed to determine whether resident year, result, or domain affected answer speed and whether performance in each subspecialty domain varied based on resident year in training. Data was available for 46 residents and 12,650 questions. Mean answer speed for questions answered correctly, 54.0±48.1 s, was significantly faster than for questions answered incorrectly, 72.2±61.2 s (P<0.00001). When considering both correct and incorrect answers, PGY-1s were slower than all other years (P<0.02). Residents spent a mean of nearly 80 seconds on foot and ankle and shoulder and elbow questions, compared to only 40 seconds on basic science questions (P<0.05). In education, faster answer speed for questions is often considered a sign of mastery of the material and more confidence in the answer. Though faster answer speed was strongly associated with correct answers, this study demonstrates that answer speed is not reliably associated with resident year. While answer speed varies between domains, it is likely that the majority of this variation is due to question type as opposed to confidence. Nevertheless, it is possible that in domains with more tiered experience such as shoulder, answer speed correlates strongly with resident year and percentage correct

LEADER 3—Lipase and Amylase Activity in Subjects With Type 2 Diabetes: Baseline Data From Over 9000 Subjects in the LEADER Trial

Objectives: This report from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial describes baseline lipase and amylase activity in type 2 diabetic subjects without acute pancreatitis symptoms before randomization to the glucagonlike peptide analog liraglutide or placebo. Methods: The LEADER is an international randomized placebo-controlled trial evaluating the cardiovascular safety of liraglutide in 9340 type 2 diabetic patients at high cardiovascular risk. Fasting lipase and amylase activity was assessed at baseline, before receiving liraglutide or placebo, using a commercial assay (Roche) with upper limit of normal values of 63 U/L for lipase and 100 U/L for amylase. Results: Either or both enzymes were above the upper limit of normal in 22.7% of subjects; 16.6% (n = 1540) had an elevated lipase level (including 1.2% >3-fold elevated), and 11.8% (n = 1094) had an elevated amylase level (including 0.2% >3-fold elevated). In multivariable regression models, severely reduced kidney function was associated with the largest effect on increasing activity of both. However, even among subjects with normal kidney function, 12.2% and 7.7% had elevated lipase and amylase levels. Conclusions: In this large study of type 2 diabetic patients, nearly 25% had elevated lipase or amylase levels without symptoms of acute pancreatitis. The clinician must take these data into account when evaluating abdominal symptoms in type 2 diabetic patients

LEADER 3: Lipase and amylase activity in subjects with type 2 diabetes

Objectives: This report from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial describes baseline lipase and amylase activity in type 2 diabetic subjects without acute pancreatitis symptoms before randomization to the glucagonlike peptide analog liraglutide or placebo. Methods: The LEADER is an international randomized placebo-controlled trial evaluating the cardiovascular safety of liraglutide in 9340 type 2 diabetic patients at high cardiovascular risk. Fasting lipase and amylase activity was assessed at baseline, before receiving liraglutide or placebo, using a commercial assay (Roche) with upper limit of normal values of 63 U/L for lipase and 100 U/L for amylase. Results: Either or both enzymes were above the upper limit of normal in 22.7% of subjects; 16.6% (n = 1540) had an elevated lipase level (including 1.2% \u3e3-fold elevated), and 11.8% (n = 1094) had an elevated amylase level (including 0.2% \u3e3-fold elevated). In multivariable regression models, severely reduced kidney function was associated with the largest effect on increasing activity of both. However, even among subjects with normal kidney function, 12.2% and 7.7% had elevated lipase and amylase levels. Conclusions: In this large study of type 2 diabetic patients, nearly 25% had elevated lipase or amylase levels without symptoms of acute pancreatitis. The clinician must take these data into account when evaluating abdominal symptoms in type 2 diabetic patients

A Signature in HIV-1 Envelope Leader Peptide Associated with Transition from Acute to Chronic Infection Impacts Envelope Processing and Infectivity

Mucosal transmission of the human immunodeficiency virus (HIV) results in a bottleneck in viral genetic diversity. Gnanakaran and colleagues used a computational strategy to identify signature amino acids at particular positions in Envelope that were associated either with transmitted sequences sampled very early in infection, or sequences sampled during chronic infection. Among the strongest signatures observed was an enrichment for the stable presence of histidine at position 12 at transmission and in early infection, and a recurrent loss of histidine at position 12 in chronic infection. This amino acid lies within the leader peptide of Envelope, a region of the protein that has been shown to influence envelope glycoprotein expression and virion infectivity. We show a strong association between a positively charged amino acid like histidine at position 12 in transmitted/founder viruses with more efficient trafficking of the nascent envelope polypeptide to the endoplasmic reticulum and higher steady-state glycoprotein expression compared to viruses that have a non-basic position 12 residue, a substitution that was enriched among viruses sampled from chronically infected individuals. When expressed in the context of other viral proteins, transmitted envelopes with a basic amino acid position 12 were incorporated at higher density into the virus and exhibited higher infectious titers than did non-signature envelopes. These results support the potential utility of using a computational approach to examine large viral sequence data sets for functional signatures and indicate the importance of Envelope expression levels for efficient HIV transmission

Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial.

BACKGROUND: Diabetes is a multisystem disorder associated with a nearly twofold excess risk for a broad range of adverse cardiovascular outcomes including coronary heart disease, stroke, and cardiovascular death. Liraglutide is a human glucagon-like peptide receptor analog approved for use in patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: To formally assess the cardiovascular safety of liraglutide, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial was commenced in 2010. LEADER is a phase 3B, multicenter, international, randomized, double-blind, placebo-controlled clinical trial with long-term follow-up. Patients with T2DM at high risk for cardiovascular disease (CVD) who were either drug naive or treated with oral antihyperglycemic agents or selected insulin regimens (human NPH, long-acting analog, or premixed) alone or in combination with oral antihyperglycemics were eligible for inclusion. Randomized patients are being followed for up to 5 years. The primary end point is the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. CONCLUSIONS: LEADER commenced in September 2010, and enrollment concluded in April 2012. There were 9,340 patients enrolled at 410 sites in 32 countries. The mean age of patients was 64.3 ± 7.2 years, 64.3% were men, and mean body mass index was 32.5 ± 6.3 kg/m2. There were 7,592 (81.3%) patients with prior CVD and 1,748 (18.7%) who were high risk but without prior CVD. It is expected that LEADER will provide conclusive data regarding the cardiovascular safety of liraglutide relative to the current standard of usual care for a global population of patients with T2DM

Extending enzyme molecular recognition with an expanded amino acid alphabet

Natural enzymes are constructed from the twenty proteogenic amino acids, which may then require post-translational modification or the recruitment of coenzymes or metal ions to achieve catalytic function. Here, we demonstrate that expansion of the alphabet of amino acids can also enable the properties of enzymes to be extended. A chemical mutagenesis strategy allowed a wide range of non-canonical amino acids to be systematically incorporated throughout an active site to alter enzymic substrate specificity. Specifically, 13 different non-canonical side chains were incorporated at 12 different positions within the active site of N-acetylneuraminic acid lyase (NAL), and the resulting chemically-modified enzymes were screened for activity with a range of aldehyde substrates. A modified enzyme containing a 2,3-dihydroxypropyl cysteine at position 190 was identified that had significantly increased activity for the aldol reaction of erythrose with pyruvate compared with the wild-type enzyme. Kinetic investigation of a saturation library of the canonical amino acids at the same position showed that this increased activity was not achievable with any of the 20 proteogenic amino acids. Structural and modelling studies revealed that the unique shape and functionality of the non-canonical side chain enabled the active site to be remodelled to enable more efficient stabilisation of the transition state of the reaction. The ability to exploit an expanded amino acid alphabet can thus heighten the ambitions of protein engineers wishing to develop enzymes with new catalytic properties

Biomarkers Enhance Discrimination and Prognosis of Type 2 Myocardial Infarction

Background: The observed incidence of type 2 myocardial infarction (T2MI) is expected to increase with the implementation of increasingly sensitive cardiac troponin (cTn) assays. However, it remains to be determined how to diagnose, risk stratify and treat patients with T2MI. We aimed to discriminate and risk-stratify T2MI using biomarkers. Methods: Patients presenting to the Emergency Department with chest pain, enrolled in the CHOPIN study, were retrospectively analyzed. Two cardiologists adjudicated type 1 MI (T1MI) and T2MI. The prognostic ability of several biomarkers alone or in combination to discriminate T2MI from T1MI was investigated using receiver operating characteristic (ROC) curve analysis. The biomarkers analyzed were cTnI, copeptin, mid-regional pro-atrial natriuretic peptide (MRproANP), C-terminal pro-endothelin-1 (CT-proET1), mid-regional pro-adrenomedullin (MRproADM) and procalcitonin. Prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular event (MACE: a composite of acute MI, unstable angina pectoris, reinfarction, heart failure, and stroke) at 180-day follow-up was also investigated. Results: Among the 2071 patients, T1MI and T2MI were adjudicated in 94 and 176 patients, respectively. Patients with T1MI had higher levels of baseline cTnI, while those with T2MI had higher baseline levels of MR-proANP, CT-proET1, MR-proADM, and procalcitonin. The area under the ROC curve (AUC) for the diagnosis of T2MI was higher for CT-proET1, MRproADM and MR-proANP (0.765, 0.750, and 0.733, respectively) than for cTnI (0.631). Combining all biomarkers resulted in a similar accuracy to a model using clinical variables and cTnI (0.854 versus 0.884, p = 0.294). Addition of biomarkers to the clinical model yielded the highest AUC (0.917). Other biomarkers, but not cTnI, were associated with mortality and MACE at 180-day among all patients, with no interaction between the diagnosis of T1MI or T2MI. Conclusions: Assessment of biomarkers reflecting pathophysiologic processes occurring with T2MI might help differentiate it from T1MI. Additionally, all biomarkers measured, except cTnI, were significant predictors of prognosis, regardless of type of MI

Use of procalcitonin for the diagnosis of pneumonia in patients presenting with a chief complaint of dyspnoea: results from the BACH (Biomarkers in Acute Heart Failure) trial

Biomarkers have proven their ability in the evaluation of cardiopulmonary diseases.We investigated the utility of concentrations of the biomarker procalcitonin (PCT) alone and with clinical variables for the diagnosis of pneumonia in patients presenting to emergency departments (EDs) with a chief complaint of shortness of breath. The BACH trial was a prospective, international, study of 1641 patients presenting to EDs with dyspnoea. Blood samples were analysed for PCT and other biomarkers. Relevant clinical data were also captured. Patient outcomes were assessed at 90 days. The diagnosis of pneumonia was made using strictly validated guidelines. A model using PCT was more accurate [area under the curve (AUC) 72.3%] than any other individual clinical variable for the diagnosis of pneumonia in all patients, in those with obstructive lung disease, and in those with acute heart failure (AHF). Combining physician estimates of the probability of pneumonia with PCT values increased the accuracy to .86% for the diagnosis of pneumonia in all patients. Patients with a diagnosis of AHF and an elevated PCT concentration (.0.21 ng/mL) had a worse outcome if not treated with antibiotics (P ¼ 0.046), while patients with low PCT values (,0.05 ng/mL) had a better outcome if they did not receive antibiotic therapy (P ¼ 0.049). Procalcitonin may aid in the diagnosis of pneumonia, particularly in cases with high diagnostic uncertainty. Importantly, PCT may aid in the decision to administer antibiotic therapy to patients presenting with AHF in which clinical uncertainty exists regarding a superimposed bacterial infection