HIV-1 fitness landscape models for indinavir treatment pressure using observed evolution in longitudinal sequence data are predictive for treatment failure

We previously modeled the in vivo evolution of human immunodeficiency virus-1 (HIV-1) under drug selective pressure from cross-sectional viral sequences. These fitness landscapes (FLs) were made by using first a Bayesian network (BN) to map epistatic substitutions, followed by scaling the fitness landscape based on an HIV evolution simulator trying to evolve the sequences from treatment naïve patients into sequences from patients failing treatment. In this study, we compared four FLs trained with different sequence populations. Epistatic interactions were learned from three different cross-sectional BNs, trained with sequence from patients experienced with indinavir (BNT), all protease inhibitors (PIs) (BNP) or all PI except indinavir (BND). Scaling the fitness landscape was done using cross-sectional data from drug naïve and indinavir experienced patients (Fcross using BNT) and using longitudinal sequences from patients failing indinavir (FlongT using BNT, FlongP using BNP, FlongD using BND). Evaluation to predict the failing sequence and therapy outcome was performed on independent sequences of patients on indinavir. Parameters included estimated fitness (LogF), the number of generations (GF) or mutations (MF) to reach the fitness threshold (average fitness when a major resistance mutation appeared), the number of generations (GR) or mutations (MR) to reach a major resistance mutation and compared to genotypic susceptibility score (GSS) from Rega and HIVdb algorithms. In pairwise FL comparisons we found significant correlation between fitness values for individual sequences, and this correlation improved after correcting for the subtype. Furthermore, FLs could predict the failing sequence under indinavir-containing combinations. At 12 and 48 weeks, all parameters from all FLs and indinavir GSS (both for Rega and HIVdb) were predictive of therapy outcome, except MR for FlongT and FlongP. The fitness landscapes have similar predictive power for treatment response under indinavir-containing regimen as standard rules-based algorithms, and additionally allow predicting genetic evolution under indinavir selective pressure

A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors

The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices.Confining plasma and managing disruptions in tokamak devices is a challenge. Here the authors demonstrate a method predicting and possibly preventing disruptions and macroscopic instabilities in tokamak plasma using data from JET

Long term operation of the radiation-hard Hall probes system and the path toward a high performance hybrid magnetic field sensor

The paper reports a systematic assessment of the radiation-hard Hall probes (RHP) magnetic diagnostic system of the JET tokamak, which is based on InSb semiconductor thin films, and describes the path that lead to the proposal of an innovative magnetic probe concept. A relevant account of RHP operation during the recent deuterium–tritium experimental campaign is also provided, showing correct operation under ITER-like intense neutron flux. The period considered for the systematic assessment of the RHP system ranges from October 2009 to March 2021, during which the machine produced more than 19 000 pulses. The RHP system consists of six three-dimensional Hall probes, which have built-in recalibration capability, thanks to the presence of microsolenoids that produce a local known field during a tailored automatic pre-pulse calibration sequence, that can also be initiated manually. During pulses, the microsolenoids can also be used as inductive sensors as their signals are recorded as well. Moreover, the system provides temperature measurements at the location of the probes, which are continuously recorded too. The assessment demonstrates accurate long-term operation of the RHP system. All the diagnostic channels reliably provide pre-pulse calibration data and pulse signals and the original sensitivities of the Hall sensors are preserved. Integration considerations and a data fusion analysis lead to the proposal of a high performance, compact, broadband, hybrid field probe, consisting of the combination of an inductive coil and a Hall sensor, to be manufactured by means of the coil technology developed for ITER or an alternative concept with improved radiation-hardness. The hybrid probe is expected to deliver the advantages of both inductive and Hall sensing technologies, essentially in the same package size of a single ITER magnetic discrete probe. In particular, it would solve the problem of the drift of the integrator for long lasting burning plasma discharges. The signals produced by the coil and the Hall sensor, processed by means of a Luenberger–Kalman observer, provide a magnetic field measurement which is non-drifting and low-noise. For these reasons, the hybrid probe has been proposed as the potential primary magnetic diagnostic sensor for future burning plasma experiments and demonstration fusion power plants

One-stage vs two-stage bilateral THA in Lombardy: a cost-effectiveness analysis

Abstract Background Total hip arthroplasty (THA) is the most common treatment for primary and secondary end-stage hip osteoarthritis (OA). Almost 20% of all patients undergoing primary THA suffer from bilateral hip OA and, consequently, will need a contralateral procedure to be performed in the following years. The aim of this study is to evaluate the cost-effectiveness and the reliability of one-stage bilateral THA (1-BTHA) compared to two-stage bilateral THA (2-BTHA), in low-risk patients, performed with anterior minimally invasive surgery (AMIS). Methods Single patient’s costs were obtained by dividing the annual costs report by the number of hospitalizations, considering the diagnosis related group (DRG) of the two procedures. Then, 16 patients undergoing 1-BTHA and 8 undergoing 2-BTHA were examined. Hemoglobin (Hb) values before surgery and before discharge, transfusion rate and the occurrence of post-operative complications were observed. Results Procedural costs were divided in different subgroups: pre-hospitalization, operating room, hospital stay, post-operative follow-up and other costs. 1-BTHA total costs amount to 5.754,82€, while performing 2-BTHA costs 7.624,32€. However, considering DRG reimbursement, the hospital’s profit margin following 1-BTHA is lower than that following 2-BTHA (6.346,18€ versus 9.261,68€). Surgical time was found not to be significantly different between 1-BTHA and 2-BTHA (141,13 ± 26,1 min vs 164,8 ± 44,3 min; p = 0,111). The two groups showed a statistically significant difference in Hb decrease (4,8 ± 1,3 g/dl vs 3,3 ± 0,9; p = 0,001), despite no variances in transfusion rate. No further complications were observed in either group. Conclusions This study demonstrates how, in carefully selected patients, 1-BTHA performed with AMIS is a cost-effective and safe technique compared to 2-BTHA, resulting in a shorter OR time, LOS and lower overall costs. Level of evidence II

Preliminary Air Quality and Microclimatic Conditions Study in the <i>Santuario della Beata Vergine dei Miracoli</i> in Saronno (VA)

In the present work, the microclimatic conditions (temperature (T), relative humidity (RH), and illuminance (I)), together with the air quality (both aerosol particulate matter (PM) and gaseous pollutants), were monitored to evaluate the environmental conditions inside the Santuario della Beata Vergine dei Miracoli in Saronno (VA), a masterpiece of the Italian Renaissance. For this purpose, dataloggers were used to carry out the T, RH, and I measurements, whereas an optical particle counter (OPC) was employed to perform the particle count and determine the concentration of the aerosol PM. Finally, diffusive passive samplers were used to determine the concentration of nitrogen dioxide (NO2) and BTEX (benzene, toluene, ethylbenzene, and xylenes). To identify possible spatial variations, the studies were conducted at different sites and different heights in the Sanctuary. Particular focus was given to the Easter week during which liturgical services attracting large numbers of people were carried out. Additionally, a comparison with the outdoor values was performed to highlight the accumulation phenomena and other variations in the concentrations of the species. Despite the indoor concentrations of pollutants and variations in the thermohygrometric parameters being generally lower compared to the outdoors (e.g., 5.2–15.0 µg m−3 versus 17.7–45.3 µg m−3 for NO2), the microclimatic conditions were often not in line with the Italian legislation and technical standards

Knee cooled radiofrequency vs continuous radiofrequency for genicular neurotomy: preliminary experience - Crio-radiofrequenza vs radiofrequenza continua per neurotomia dei nervi genicolati: esperienza preliminare

Radiofrequency neurotomy of genicular nerves has been often used as an efficacious treatment option in all patients suffering from chronic osteoarthritis pain to provide long-term pain relief. After providing informed written consent, 80 patients with severe knee chronic osteoarthritis pain had been enrolled; patients had been divided into two groups (Group C, crioneurolysis, vs Group R, traditional radiofrequency, 40 patients for each group). Pain relief in C group was poorer and with shorter time in duration (median NRS reducing from 8 to 5). Radiofrequency can be considered as an effective, minimally invasive treat­ment for these kinds of conditions, and offers the benefit of being a fast procedure with long-term pain relief

Craniofacial pain and high frequency stimulation - Dolore cranio faciale e neurostimolazione ad alta frequenza

Neuromodulation is a treatment modality that shows promise and so far case reports have used peripheral approaches to the trigeminal ganglion and its branches. We describe the use of high frequency spinal cord stimulation at the cervical spine as a novel approach to management of refractory trigeminal neuralgia. We have enrolled 3 patients, suffering from trigeminal neuralgia involving the first branch of nerve. All the patients had been implanted with one octopolar electrode such that the stimulating contacts were placed at the C2-C3 vertebral level; electrodes had been connected to an external trial lead extension, which was removed at the end of the trial with subsequent implantation of the definitive IPG. All the patients completed trial period with successful implantation because pain relief was about 70%. All the patients decreased analgesics consumption, especially for opioids.The application of electrical pulses directly onto the dorsal columns at the C2-C3 vertebral level provide a neuromodulatory effect on the Trigemino-Cervical Complex (TCC) greater than peripheral trigeminal branches stimulation

Isotopic analysis of black crust samples from the Monza Cathedral (Italy): a preliminary study

The degradation of historical buildings surfaces through the formation of black crusts is a process mainly related to air pollution. The origin of air pollutants can be determined by measuring the stable isotope ratio of their main elements. In this study, the results obtained from the isotopic analysis of BCs taken from the historical Monza cathedral, an important monument placed in Monza, a highly polluted city of Northen Italy, are discussed. In particular, stable isotope ratios of carbon, sulphur and oxygen of two black crust samples (namely MD and MS) were measured by Isotope Ratio Mass Spectroscopy. The obtained deltaC, deltaS and deltaO values suggest that anthropogenic pollution is responsible for the formation of black crusts on the façade of this cathedral

The Application of Trichoderma Strains or Metabolites Alters the Olive Leaf Metabolome and the Expression of Defense-Related Genes

Biocontrol fungal strains of the genus Trichoderma can antagonize numerous plant pathogens and promote plant growth using different mechanisms of action, including the production of secondary metabolites (SMs). In this work we analyzed the effects of repeated applications of selected Trichoderma strains or SMs on young olive trees on the stimulation of plant growth and on the development of olive leaf spot disease caused by Fusicladium oleagineum. In addition, metabolomic analyses and gene expression profiles of olive leaves were carried out by LC-MS Q-TOF and real-time RT-PCR, respectively. A total of 104 phenolic compounds were detected from olive leave extracts and 20 were putatively identified. Targeted and untargeted approaches revealed significant differences in both the number and type of phenolic compounds accumulated in olive leaves after Trichoderma applications, as compared to water-treated plants. Different secoiridoids were less abundant in treated plants than in controls, while the accumulation of flavonoids (including luteolin and apigenin derivatives) increased following the application of specific Trichoderma strain. The induction of defense-related genes, and of genes involved in the synthesis of the secoiridoid oleuropein, was also analyzed and revealed a significant variation of gene expression according to the strain or metabolite applied