Precision of jaw‐closing movements for different jaw gaps

Jaw‐closing movements are basic components of physiological motor actions precisely achieving intercuspation without significant interference. The main purpose of this study was to test the hypothesis that, despite an imperfect intercuspal position, the precision of jaw‐closing movements fluctuates within the range of physiological closing movements indispensable for meeting intercuspation without significant interference. For 35 healthy subjects, condylar and incisal point positions for fast and slow jaw‐closing, interrupted at different jaw gaps by the use of frontal occlusal plateaus, were compared with uninterrupted physiological jaw closing, with identical jaw gaps, using a telemetric system for measuring jaw position. Examiner‐guided centric relation served as a clinically relevant reference position. For jaw gaps ≤4 mm, no significant horizontal or vertical displacement differences were observed for the incisal or condylar points among physiological, fast, and slow jaw‐closing. However, the jaw positions under these three closing conditions differed significantly from guided centric relation for nearly all experimental jaw gaps. The findings provide evidence of stringent neuromuscular control of jaw‐closing movements in the vicinity of intercuspation. These results might be of clinical relevance to occlusal intervention with different objectives.     

Analytical and simulation methods for estimating the potential predictive ability of genetic profiling: a comparison of methods and results

Various modeling methods have been proposed to estimate the potential predictive ability of polygenic risk variants that predispose to various common diseases. However, it is unknown whether differences between them affect their conclusions on predictive ability. We reviewed input parameters, assumptions and output of the five most common methods and compared their estimates of the area under the receiver operating characteristic (ROC) curve (AUC) using hypothetical data representing effect sizes and frequencies of genetic variants, population disease risk and number of variants. To assess the accuracy of the estimated AUCs, we aimed to reproduce the AUCs of published empirical studies. All methods assumed that the combined effect of genetic variants on disease risk followed a multiplicative risk model of independent genetic effects, but they either assumed per allele, per genotype or dominant/recessive effects for the genetic variants. Modeling strategy and input parameters differed. Methods used simulation analysis or analytical formulas with effect sizes quantified by odds ratios (ORs) or relative risks. Estimated AUC values were similar for lower ORs (<1.2). When AUCs were larger (>0.7) due to variants with strong effects, differences in estimated AUCs between methods increased. The simulation methods accurately reproduced the AUC values of empirical studies, but the analytical methods did not. We conclude that despite differences in input parameters, the modeling methods estimate similar AUC for realistic values of the ORs. When one or more variants have stronger effects and AUC values are higher, the simulation methods tend to be more accurate.     

Using electronic medical record data to report laboratory adverse events

Despite the importance of adverse event (AE) reporting, AEs are under‐reported on clinical trials. We hypothesized that electronic medical record (EMR) data can ascertain laboratory‐based AEs more accurately than those ascertained manually. EMR data on 12 AEs for patients enrolled on two Children's Oncology Group (COG) trials at one institution were extracted, processed and graded. When compared to gold standard chart data, COG AE report sensitivity and positive predictive values (PPV) were 0–21·1% and 20–100%, respectively. EMR sensitivity and PPV were >98·2% for all AEs. These results demonstrate that EMR‐based AE ascertainment and grading substantially improves laboratory AE reporting accuracy.     

Coronary sinus lead delay index for optimization of coronary sinus lead placement

Aim

Optimization of coronary sinus (CS) lead position to the latest activated left ventricular (LV) area is important to increase cardiac resynchronization therapy (CRT) response. We aimed to detect the relationship between coronary sinus lead delay index (CSDI) and echocardiographic, electrocardiographic response to CRT treatment.

Methods

We prospectively included 137 consecutive patients with heart failure (HF) diagnosis, QRS ≥ 120 ms, left bundle branch block (LBBB), New York Heart Association score (NYHA) II–IV, LV ejection fraction (LVEF) <35% and scheduled for CRT (84 male, 53 female; mean age 65.1 ± 10.1 years). Echocardiographic CRT response was defined as ≥15% reduction in LV end‐systolic volume (LVESV). CS lead sensing delay was calculated as the time interval from the onset of surface QRS wave to the onset of depolarization wave recorded from the CS lead by using the CS pacing lead as a bipolar electrode. CSDI was calculated by dividing the CS lead sensing delay by the QRS duration.

Results

LVESV reduction was associated with baseline QRS width (r = .257, p = .002), QRS narrowing (r = .396, p < .001), CSDI (r = .357, p < .001), and NT‐proBNP (r = ?0.213, p = .022) in bivariate analysis. In logistic regression analysis, CSDI was found to be only independent parameter for predicting significant LVESV reduction (Beta = 0.318, p < .001). CSDI was also found to be significantly associated with LVEF increase (r = .244, p = .004) and QRS narrowing (r = .178, p = .046).

Conclusion

CSDI may be used as a marker to predict the favorable response to CRT. It may be useful to integrate CSDI to CRT implantation procedure in order to minimize nonresponders.

     

Quality control despite mistranslation caused by an ambiguous genetic code

A high level of accuracy during protein synthesis is considered essential for life. Aminoacyl-tRNA synthetases (aaRSs) translate the genetic code by ensuring the correct pairing of amino acids with their cognate tRNAs. Because some aaRSs also produce misacylated aminoacyl-tRNA (aa-tRNA) in vivo, we addressed the question of protein quality within the context of missense suppression by Cys-tRNA(Pro), Ser-tRNA(Thr), Glu-tRNA(Gln), and Asp-tRNA(Asn). Suppression of an active-site missense mutation leads to a mixture of inactive mutant protein (from translation with correctly acylated aa-tRNA) and active enzyme indistinguishable from the wild-type protein (from translation with misacylated aa-tRNA). Here, we provide genetic and biochemical evidence that under selective pressure, Escherichia coli not only tolerates the presence of misacylated aa-tRNA, but can even require it for growth. Furthermore, by using mass spectrometry of a reporter protein not subject to selection, we show that E. coli can survive the ambiguous genetic code imposed by misacylated aa-tRNA tolerating up to 10% of mismade protein. The editing function of aaRSs to hydrolyze misacylated aa-tRNA is not essential for survival, and the EF-Tu barrier against misacylated aa-tRNA is not absolute. Rather, E. coli copes with mistranslation by triggering the heat shock response that stimulates nonoptimized polypeptides to achieve a native conformation or to be degraded. In this way, E. coli ensures the presence of sufficient functional protein albeit at a considerable energetic cost.     

Dosing Accuracy of Two Disposable Insulin Pens According to New ISO 11608-1: 2012 Requirements

Objective:

The aim was to compare 2 disposable insulin pens, FlexTouch® (Novo Nordisk, insulin aspart) and SoloSTAR® (Sanofi, insulin glulisine), according to new ISO 11608-1:2012 requirements for dosing accuracy.

Methods:

Sixty pens of each type were tested at 1, 40, and 80 U doses. Following the new ISO requirements, each dose was delivered from the front, middle, and rear one-third of the pen. Statistical analysis was performed using Student’s t test.

Results:

Both pens delivered all doses within ISO limits. The difference between the average measured dose and the target dose was significantly smaller for SoloSTAR than FlexTouch at 40 U (P = .009) and 80 U (P = .008), but not at 1 U (P = .417).

Conclusion:

Both insulin pens fulfilled the dosing accuracy requirements defined by ISO 11608-1:2012 at all 3 dosage levels.     

Mast cell degranulation during abdominal surgery initiates postoperative ileus in mice

BACKGROUND & AIMS: Inflammation of the intestinal muscularis following manipulation during surgery plays a crucial role in the pathogenesis of postoperative ileus. Here, we evaluate the role of mast cell activation in the recruitment of infiltrates in a murine model. METHODS: Twenty-four hours after control laparotomy or intestinal manipulation, gastric emptying was determined. Mast cell degranulation was determined by measurement of mast cell protease-I in peritoneal fluid. Intestinal inflammation was assessed by determination of tissue myeloperoxidase activity and histochemical staining. RESULTS: Intestinal manipulation elicited a significant increase in mast cell protease-I levels in peritoneal fluid and resulted in recruitment of inflammatory infiltrates to the intestinal muscularis. This infiltrate was associated with a delay in gastric emptying 24 hours after surgery. Pretreatment with mast cell stabilizers ketotifen (1 mg/kg, p.o.) or doxantrazole (5 mg/kg, i.p.) prevented both manipulation-induced inflammation and gastroparesis. Reciprocally, in vivo exposure of an ileal loop to the mast cell secretagogue compound 48/80 (0.2 mg/mL for 1 minute) induced muscular inflammation and delayed gastric emptying. The manipulation-induced inflammation was dependent on the presence of mast cells because intestinal manipulation in mast cell-deficient Kit/Kitv mice did not elicit significant leukocyte recruitment. Reconstitution of Kit/Kitv mice with cultured bone marrow-derived mast cells from congenic wild types restored the manipulation-induced inflammation. CONCLUSIONS: Our results show that degranulation of connective tissue mast cells is a key event for the establishment of the intestinal infiltrate that mediates postoperative ileus following abdominal surgery.