An automated treatment planning strategy for highly noncoplanar radiotherapy arc trajectories

Radiation therapy is a technology-driven cancer treatment modality that has experienced significant advances over the last decades, due to multidisciplinary contributions that include engineering and computing. Recent technological developments allow the use of noncoplanar volumetric modulated arc therapy (VMAT), one of the most recent photon treatment techniques, in clinical practice. In this work, an automated noncoplanar arc trajectory optimization framework designed in two modular phases is presented. First, a noncoplanar beam angle optimization algorithm is used to obtain a set of noncoplanar irradiation directions. Then, anchored in these directions, an optimization strategy is proposed to compute an optimal arc trajectory. The computational experiments considered a pool of twelve difficult head-and-neck tumor cases. It was possible to observe that, for some of these cases, the optimized noncoplanar arc trajectories led to significant treatment planning quality improvements, when compared with coplanar VMAT treatment plans. Although these experiments were done in a research environment treatment planning software (matRad), the conclusions can be of interest for a clinical setting: automated procedures can simplify the current treatment workflow, produce high-quality treatment plans, making better use of human resources and allowing for unbiased comparisons between different treatment techniques.     

Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC₅₀) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC₅₀ shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.     

Numerical analysis of Augmented Lagrangian algorithms in complementary elastoplasticity

The main subject of the paper is the investigation of Augmented Lagrangian algorithms and update formulas in the solution of elastoplastic problems. A stress rate formulation for elastoplastic models with internal variables and its finite increment form is employed to state the mechanical problem. In this formulation the Augmented Lagrangian is used to enforce the constraint of plastic admissibility directly on the stresses and thermodynamic forces. This is not a limitation of the Augmented Lagrangian approach, and the same framework can be built on more classical displacement formulations as well. The meaning and the derivation of various first and second order Lagrangian multipliers update formulas and iterative schemes is shown. A new diagonal iteration algorithm and the introduction of a scale factor for the Augmented Lagrangian term are proposed. Numerical examples compare the efficiency of several forms of Augmented Lagrangian algorithms and illustrate the influence of the scale factor and of the penalty parameter. Copyright © 2004 John Wiley & Sons, Ltd.     

Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q

The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.     

Physiology of spinal anaesthesia and practical suggestions for successful spinal anaesthesia

There are numerous physiological effects of spinal anaesthesia. This chapter focuses on the physiological effects that are of clinical relevance to the anaesthesiologist, and provides suggestions for successful management of this simple and popular technique. The mechanisms and clinical significance of spinal-anaesthesia-induced hypotension, bradycardia and cardiac arrest are reviewed. The increasing popularity of ambulatory spinal anaesthesia requires knowledge that long-acting local anaesthetics, such as bupivacaine, impair the ability to void far longer than short-acting local anaesthetics, such as lidocaine. The importance of thermoregulation during spinal anaesthesia, and the clinical consequences of spinal-anaesthesia-induced hypothermia are reviewed. Effects of spinal anaesthesia on ventilatory mechanics are also highlighted. Lastly, the sedative and minimum-alveolar-concentration-sparing effects of spinal anaesthesia are discussed to reinforce the need for the judicious use of sedation in the perioperative setting.     

Alagille syndrome: family studies

Alagille syndrome (AGS) is one of the major forms of chronic liver disease in childhood with severe morbidity and a mortality of 10 to 20%. It is characterised by cholestasis of variable severity with paucity of interlobular bile ducts and anomalies of the cardiovascular system, skeleton, eyes, and face. Previous studies suggest a wide variation in the expression of the disease and a high incidence of new mutations. To determine more accurately the rate of new mutations and to develop criteria for detecting the disorder in parents we systematically investigated parents in 14 families with an affected child. Clinical examination was supplemented by liver function tests, echocardiography, radiographic examination of the spine and forearm, ophthalmological assessment, and chromosome analysis. Six parents had typical anomalies in two or more systems pointing to the presence of autosomal dominant inheritance. Systematic screening of parents for the features defined in this study should improve the accuracy of genetic counselling.     

Evaluation of Textile Bobbins Drying Processes: Experimental and Modelling Studies

Drying of textile bobbins was carried out on two kinds of laboratory-scale dryers: in a cross circulation drying rig, atmospheric pressure heating air is used, while in the through circulation drying apparatus, the heating air is pressurized before the drying process takes place. In both cases, a bobbin was fitted with seven thermocouples, placed in a plane normal to the bobbin axis but at different radial distances, in order to provide temperature data during the drying process. In cross circulation drying, plots of temperature against time indicated the presence of two moving fronts, one starting from inside the bobbin, another from the outside, while in through circulation drying, similar plots showed the presence of an evaporation front, moving from inside the bobbin to the outside. In both canes, numerical models were developed to simulate the drying processes.     

Pseudomonas aeruginosa as a cause of infectious diarrhea successfully treated with oral ciprofloxacin

OBJECTIVE: To describe an immunocompromised patient (without AIDS) with nosocomial infectious diarrhea caused by Pseudomonas aeruginosa. Oral ciprofloxacin therapy proved to be effective. CASE SUMMARY: An 80-year-old woman with type II diabetes mellitus and hypertension developed progressive renal insufficiency, was hospitalized because of uremia, and underwent hemodialysis. When the patient developed hematochezia, Duke's C sigmoid colon cancer was detected and successfully resected. She received broad-spectrum antibiotics in the perioperative period. The patient then developed profuse diarrhea associated with abdominal cramping, a low-grade fever, prostration, and headache. The patient then started to received vancomycin 500 mg po qid empirically. Four days later, the diarrhea continued unabated, the Clostridium difficile titer was negative, and the vancomycin therapy was stopped. However, the stool culture was positive for heavy growth of P. aeruginosa sensitive to ciprofloxacin. The patient then began to receive ciprofloxacin 500 mg po bid. Within 3 days the diarrhea stopped. Oral ciprofloxacin therapy was continued for 10 days and the patient remained free of symptoms with formed stools thereafter. DISCUSSION: Diarrhea following the use of broad-spectrum antibiotics implicates pseudomembranous colitis as the cause. The patient did not respond to oral vancomycin therapy and had a negative stool assay for C. difficile toxin. This patient was believed to have Pseudomonas enteritis, which was confirmed by 2 positive stool cultures. The administration of oral ciprofloxacin therapy stopped her diarrhea with a rapid resolution of symptoms. CONCLUSIONS: P. aeruginosa as a cause of infectious diarrhea is unusual. When it occurs, it usually represents a nosocomial infection in an immunocompromised host. This report illustrates that oral ciprofloxacin therapy is effective for Pseudomonas enteritis, with rapid resolution of symptoms.