Performance of mutation pathogenicity prediction methods on missense variants

Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation in humans. The number of SNPs identified in the human genome is growing rapidly, but attaining experimental knowledge about the possible disease association of variants is laborious and time-consuming. Several computational methods have been developed for the classification of SNPs according to their predicted pathogenicity. In this study, we have evaluated the performance of nine widely used pathogenicity prediction methods available on the Internet. The evaluated methods were MutPred, nsSNPAnalyzer, Panther, PhD-SNP, PolyPhen, PolyPhen2, SIFT, SNAP, and SNPs&GO. The methods were tested with a set of over 40,000 pathogenic and neutral variants. We also assessed whether the type of original or substituting amino acid residue, the structural class of the protein, or the structural environment of the amino acid substitution, had an effect on the prediction performance. The performances of the programs ranged from poor (MCC 0.19) to reasonably good (MCC 0.65), and the results from the programs correlated poorly. The overall best performing methods in this study were SNPs&GO and MutPred, with accuracies reaching 0.82 and 0.81, respectively.     

Primary omental infarct: conservative vs operative management in the era of ultrasound, computerized tomography, and laparoscopy

Purpose

Primary omental infarct is a rare condition in children. The preoperative diagnosis can be accurately accomplished using ultrasound (US) and computerized tomography (CT). This study aimed to elucidate the efficacy of conservative vs operative management.

Methods

Cases of omental infarction in children diagnosed preoperatively in our institution since laparoscopy became the standard of care were reviewed.

Results

Ten cases of omental infarction in children were treated. There were 6 males and 4 females (age, 5-14 years). The diagnosis was made preoperatively by CT in all cases; in 2 cases, US was also diagnostic. Conservative nonoperative management was successful in 4 cases, and laparoscopic omentectomy and appendectomy done in the other 6. There was no mortality. All children recovered uneventfully. Average hospital stay was 4 days for patients treated nonoperatively. Average postoperative stay was 2 days for children treated with laparoscopy. Three patients initially treated conservatively had surgery because of intractable pain. The preoperative stay was 3 days in these patients.

Conclusions

Children with omental infarct can be treated conservatively, and a short trial period is warranted. The indications for surgery are uncertain diagnosis, intractable relentless pain, and persistent peritoneal findings. Children treated with laparoscopy have a shorter length of stay and decreased use of narcotics.     

Quantifying cardiac‐induced brain tissue expansion using DENSE

Brain tissue undergoes viscoelastic deformation and volumetric strain as it expands over the cardiac cycle due to blood volume changes within the underlying microvasculature. Volumetric strain measurements may therefore provide insights into small vessel function and tissue viscoelastic properties. Displacement encoding via stimulated echoes (DENSE) is an MRI technique that can quantify the submillimetre displacements associated with brain tissue motion. Despite previous studies reporting brain tissue displacements using DENSE and other MRI techniques, a complete picture of brain tissue volumetric strain over the cardiac cycle has not yet been obtained. To address this need we implemented 3D cine‐DENSE at 7 T and 3 T to investigate the feasibility of measuring cardiac‐induced volumetric strain as a marker for small vessel blood volume changes. Volumetric strain over the entire cardiac cycle was computed for the whole brain and for grey and white matter tissue separately in six healthy human subjects. Signal‐to‐noise ratio (SNR) measurements were used to determine the voxel‐wise volumetric strain noise. Mean peak whole brain volumetric strain at 7 T (mean ± SD) was (4.5 ± 1.0) × 10^?4 (corresponding to a volume expansion of 0.48 ± 0.1 mL), which is in agreement with literature values for cerebrospinal fluid that is displaced into the spinal canal to maintain a stable intracranial pressure. The peak volumetric strain ratio of grey to white matter was 4.4 ± 2.8, reflecting blood volume and tissue stiffness differences between these tissue types. The mean peak volumetric strains of grey and white matter tissue were found to be significantly different (p < 0.001). The mean SNR at 7 T and 3 T of the DENSE measurements was 22.0 ± 7.3 and 7.0 ± 2.8 respectively, which currently limits a voxel‐wise strain analysis at both field strengths. We demonstrate that tissue specific quantification of volumetric strain is feasible with DENSE. This metric holds potential for studying blood volume pulsations in the ageing brain in healthy and diseased states.     

Proteases and protease inhibitors in infectious diseases

There are numerous proteases of pathogenic organisms that are currently targeted for therapeutic intervention along with many that are seen as potential drug targets. This review discusses the chemical and biological makeup of some key druggable proteases expressed by the five major classes of disease causing agents, namely bacteria, viruses, fungi, eukaryotes, and prions. While a few of these enzymes including HIV protease and HCV NS3‐4A protease have been targeted to a clinically useful level, a number are yet to yield any clinical outcomes in terms of antimicrobial therapy. A significant aspect of this review discusses the chemical and pharmacological characteristics of inhibitors of the various proteases discussed. A total of 25 inhibitors have been considered potent and safe enough to be trialed in humans and are at different levels of clinical application. We assess the mechanism of action and clinical performance of the protease inhibitors against infectious agents with their developmental strategies and look to the next frontiers in the use of protease inhibitors as anti‐infective agents.     

Baseline breath alcohol concentration in Nigerian commercial drivers and motorcyclists

Objective: We sought to determine breath alcohol concentration (BrAC) in a sample of consenting Nigerian commercial drivers and motorcyclists and relate values obtained to some social parameters and practices.

Method: A cross-sectional study of randomly selected, consenting commercial drivers, and motorcyclists in two Nigerian cities was undertaken. We obtained data on subjects’ sociodemographics, driving/riding related experiences and practices with the aid of a pretested structured questionnaire. We determined their BrAC and analyzed data using SPSS version 17.0. Statistical significance was inferred at p ≤ 0.05.

Result: One hundred ninety respondents aged 20–65 years mean (SD) 40 (11.28) were studied. They were 112 (58.9%) drivers, 78 (41.1%) motorcyclists, and predominantly males (98.9%). A significant proportion of motorcyclists were aged <40 years and most drivers >40 years (p < 0.001). Respondents’ educational attainment did not differ significantly with age groups and status; however, 6.8% had no formal education.

Alcohol use decreased significantly with increasing years of experience (p < 0.001). Note that 68.9% of respondents tested positive with the breathalyzer with blood alcohol concentration (BAC) levels 0.01–1.8 mg/ml with mean (SD) at 0.16 (0.32) mg/ml. In total, 51.1% of respondents had BAC values ≥0.1% while 7.9% had BAC ≥0.5 mg/ml. A total of 92.6% admitted use of various measures to enhance their performances and overcome fatigue.

Conclusion: The drink driving/riding law in Nigeria needs to be revised to suit prevailing circumstance and enforced.