New and emerging treatments for fungal infections

Although several new antifungal drugs have been licensed in the last 5 years, some patients remain difficult to treat. The main reasons for this include intrinsic or acquired antifungal resistance, organ dysfunction preventing the use of some agents and drug interactions. In addition, some drugs pene-trate poorly into sanctuary sites including eye and urine, and others are associated with considerable adverse events. Here, we review the preclinical and clinical development progress with four new anti-fungal agents: isavuconazole, ravuconazole, albaconazole and aminocandin. Isavuconazole and ravu-conazole are extremely similar, with a broad spectrum of activity, a very long half-life and large volume of distribution and good in vivo data supporting their efficacy in invasive aspergillosis and candidosis. Both compounds are in early Phase 3 development. Albaconazole has also shown very potent activity against species of Candida, Cryptococcus and Aspergillus. It was well tolerated and effective in women with vaginal candidosis. Aminocandin is an intravenous-only echinocandin with in vivo activity against Candida spp. and Aspergillus spp. Its extended half-life probably permits dosing less fre-quently than once a day. Overall these new antifungal agents in development offer extended half-lives, possibly reduced drug interaction profiles and good tolerance. Their antifungal spectrum is narrower than posaconazole and probably similar to voriconazole (isavuconazole and ravuconazole) and caspo-fungin (aminocandin). Licensure and determination of their place in clinical practice requires random-ized clinical studies, which are or will be underway

Test of ID carbon-carbon composite prototype tiles for the SPIDER diagnostic calorimeter

Additional heating will be provided to the thermonuclear fusion experiment ITER by injection of neutral beams from accelerated negative ions. In the SPIDER test facility, under construction at Consorzio RFX in Padova (Italy), the production of negative ions will be studied and optimised. To this purpose the STRIKE (Short-Time Retractable Instrumented Kalorimeter Experiment) diagnostic will be used to characterise the SPIDER beam during short operation (several seconds) and to verify if the beam meets the ITER requirement regarding the maximum allowed beam non-uniformity (below \ub110%). The most important measurements performed by STRIKE are beam uniformity, beamlet divergence and stripping losses. The major components of STRIKE are 16 1D-CFC (Carbon matrix-Carbon Fibre reinforced Composite) tiles, observed at the rear side by a thermal camera. The requirements of the 1D CFC material include a large thermal conductivity along the tile thickness (at least 10 times larger than in the other directions); low specific heat and density; uniform parameters over the tile surface; capability to withstand localised heat loads resulting in steep temperature gradients. So 1D CFC is a very anisotropic and delicate material, not commercially available, and prototypes are being specifically realised. This contribution gives an overview of the tests performed on the CFC prototype tiles, aimed at verifying their thermal behaviour. The spatial uniformity of the parameters and the ratio between the thermal conductivities are assessed by means of a power laser at Consorzio RFX. Dedicated linear and non-linear simulations are carried out to interpret the experiments and to estimate the thermal conductivities; these simulations are described and a comparison of the experimental data with the simulation results is presented

Development of a Disposable Gold Electrodes-Based Sensor for Electrochemical Measurements of cDNA Hybridization

AbstractThis work deals with the development of a disposable electrochemical biosensor for the specific detection of short DNA sequences. The sensor is an amperometric transducer with three planar electrodes, comprising a working, a counter and a pseudo-reference electrode, all made of a gold layer over a polycarbonate substrate. For the development of the genosensor, the working electrode was modified using thiol-tethered 33-mer DNA probe by chemisorptions, in a concentration range from 0.1 μM to 5 μM. Immobilization of ssDNA on gold surface was monitored with electrochemical impedance spectroscopy (EIS) and differential pulse voltammetry (DPV) in Fe(CN)64−/13− and Ruthenium(II)/(III) solutions. The time dependence of ssDNA probe immobilization was also studied. The hybridization detection is then compared with EIS and DPV measurements

Subchondroplasty in the treatment of bone marrow lesions of the knee: Preliminary experience on first 15 patients

Purpose The aim of this prospective study was to assess the effectiveness in terms of pain relief and functional improvement of the Subchondroplasty procedure in the treatment of osteoarthritis-related bone marrow lesions (BMLs) of the knee. Methods The study included first 15 consecutive patients undergone to Subchon-droplasty procedure for the treatment of chronic degenerative BMLs in which previous conservative treatment have failed. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, Knee Injury and Osteoarthritis Outcome Scores (KOOS), and visual analog scale (VAS) pain scores were obtained preoperatively and at 1, 6, and 12 months of follow-up. Results WOMAC scores significantly improved from 39.7 \ub1 20.2 before surgery to 26.8 \ub1 16.1 at the 1-month follow-up (p = 0.045). A further significant improvement to 15.5 \ub1 12.7 (p = 0.02) and to 8.6 \ub1 3.1 (p <0.01) was obtained both at 6-month and at 1-year follow-up. KOOS scores improved significantly from 47.5 \ub1 16.6 before surgery to 65.4 \ub1 14.9 at 1 month (p = 0.013) and to 80.4 \ub1 15.1 at 6-month follow-up (p = 0.01). A further improvement to 85.6 \ub1 15.1 was recorded 1 year postoperatively, although nonsignificant. VAS score showed a significant improvement from 55.8 \ub1 20.5 preoperatively to 36.2 \ub1 16.9 at 1 month (p = 0.008) and to 18.2 \ub1 17.3 at 6-month follow-up (p = 0.005). This further improved to 12.8 \ub1 17.9 at 1-year follow-up, although not significantly. Conclusion Subchondroplasty procedure represents a safe and valid surgical option in the treatment of osteoarthritis-related BMLs of the knee, providing an improvement in terms of pain relief and functional recovery. Longer studies are required to evaluate how long these improvements may last. Level of Evidence Therapeutic case-series, Level IV study

Il piano educativo individualizzato su base ICF. Strumenti e prospettive per la scuola

Il piano educativo individualizzato (PEI) \ue8 il dispositivo pedagogico su cui si fonda l\u2019inclusione degli alunni con disabilit\ue0. Esso deve definire un percorso educativo e didattico che chiama a corresponsabilit\ue0 gli insegnanti, la famiglia e gli attori extrascolastici. Il D.Lgs. 66/2017 sull\u2019inclusione scolastica offre l\u2019occasione per ripensare il PEI alla luce del paradigma biopsicosociale della Classificazione internazionale del funzionamento della disabilit\ue0 e della salute (ICF). Il libro offre agli insegnanti una prospettiva culturale e metodologica aggiornata, a partire dall\u2019ICF, nonch\ue9 strumenti per la programmazione e la valutazione degli alunni con bisogni educativi speciali secondo l\u2019approccio della evidence based education. Arricchito da esemplificazioni e risorse disponibili sul sito www.icf-scuola.it, il volume costituisce una valida guida per elaborare un profilo biopsicosociale funzionale alla redazione del PEI secondo le disposizioni legislative.The individualized educational plan (IEP) is the pedagogical device on which the inclusion of pupils with disabilities is based. It must define an educational and didactic path that calls teachers, family and extracurricular actors to co-responsibility. The Legislative Decree 66/2017 on school inclusion offers the opportunity to rethink the IEP in the light of the biopsychosocial paradigm of the International Classification of the Functioning of Disability and Health (ICF). The book offers teachers an updated cultural and methodological perspective, starting from the ICF, as well as tools for programming and evaluating pupils with special educational needs according to the evidence based education approach. Enriched with examples and resources available on the website www.icf-scuola.it, the volume is a valid guide for developing a functioning profile and drawing up the PEI according to the legislative provisions

An automated method for detection of layer activation order in information processing pathway of rat barrel cortex under mechanical whisker stimulation

Rodents perform object localization, texture and shape discrimination very precisely through whisking. During whisking, microcircuits in corresponding barrel columns get activated to segregate and integrate tactile information through the information processing pathway. Sensory signals are projected through the brainstem and thalamus to the corresponding ‘barrel columns’ where different cortical layers are activated during signal projection. Therefore, having precise information about the layer activation order is desirable to better understand this signal processing pathway. This work proposes an automated, computationally efficient and easy to implement method to determine the cortical layer activation from intracortically recorded local field potentials (LFPs) and derived current source density (CSD) profiles: 1. Barrel cortex LFPs are represented by a template of four subsequent events: small positive/negative (E1) → large negative (E2) → slow positive (E3)→ slow long negative (E4). The method exploits the layer specific characteristics of LFPs to obtain latencies of the individual events (E1–E4), then taking the latency of E2 for calculating the layer activation order. 2. The corresponding CSD profile is calculated from the LFPs and the first sink’s peak is considered as a reference point to calculate latencies and evaluate the layer activation order. Other reference points require manual calculation. Similar results of layer activation sequence are found using LFPs and CSDs. Extensive tests on LFPs recorded using standard borosilicate micropipettes demonstrated the method’s workability. An interpretation of layer activation order and CSD profiles on the basis of a simplified interacortical barrel column architecture is also provided

Visual experience facilitates allocentric spatial representation

Representing the position of the objects independently from our own position is a fundamental cognitive ability. Here we investigated whether this ability depends on visual experience. Congenitally blind, late blind and blindfolded sighted participants haptically learnt a room-sized regularly shaped array of objects, and their spatial memory was tested to determine which spatial reference frame was used. Crucially, the use of an object-based reference frame requires representing the regular structure of the array. We found that blindfolded sighted and late blind participants, that is those with visual experience, showed a preferential use of the object-based or ‘allocentric’ reference frame. On the contrary, congenitally blind participants preferred a self-based, or egocentric, reference frame. This suggests that, due to its developmental effect on the multisensory brain areas involved in spatial cognition, visual experience is necessary to develop a preference for an object-based, allocentric reference frame

Polymorphisms in toll-like receptor genes and susceptibility to pulmonary aspergillosis

Toll-like receptors (TLRs) are important components of innate immunity. We investigated the association between polymorphisms in the TLR2, TLR4, and TLR9 genes and susceptibility to noninvasive forms of pulmonary aspergillosis. A significant association was observed between allele G on Asp299Gly (TLR4) and chronic cavitary pulmonary aspergillosis (odds ratio [OR], 3.46; P =.003). Susceptibility to allergic bronchopulmonary aspergillosis was associated with allele C on T-1237C (TLR9) (OR, 2.49; P =. 043). No particular polymorphism was associated with severe asthma with fungal sensitization. These findings reinforce the importance of innate immunity in the pathogenesis of different forms of aspergillosis.Fundação para a Ciência e Tecnologia, Portugal (POCI/SAU-ESP/61080/ 2004 and fellowship to A.C., contract SFRH/BD/11837/2003); CAPES (Brazilian government) (grant to A.P); and the Fungal Research Trust, United Kingdom

Development and first operation of a Cavity Ring Down Spectroscopy diagnostic in the negative ion source SPIDER

The Neutral Beam Injectors of the ITER experiment will rely on negative ion sources to produce 16.7 MW beams of H/D particles accelerated at 1 MeV. The prototype of these sources was built and is currently operated in the SPIDER experiment (Source for the Production of Ions o Deuterium Extracted from an RF plasma), part of the Neutral Beam Test Facility of Consorzio RFX, Padua. In SPIDER, the H-/D- ion source is coupled to a three grids 100 kV acceleration system. One of the main targets of the experimentation in SPIDER is to uniformly maximize the extracted current density; to achieve this it is important to study the density of negative ions available in proximity of the ion acceleration system. In SPIDER, line-integrated measurements of negative ion density are performed by a Cavity Ring Down Spectroscopy (CRDS) diagnostic. Its principle of operation is based on the absorption of the photons of a laser beam pulse by H-/D- photo-detachment; the absorption detection is enhanced by trapping the laser pulse in an optical cavity, containing the absorbing medium (i.e. negative ions). The paper presents and discusses the CRDS diagnostic setup in SPIDER, including the first measurements of negative ion density, correlated to the main source parameters.Comment: 5 pages, 7 figures. Contributer paper for the HTPD 2020 conference. Accepted manuscrip

Characterization of cesium and H-/D- density in the negative ion source SPIDER

The Heating Neutral Beam Injectors (HNBs) for ITER will have to deliver 16.7 MW beams of H/D particles at 1 MeV energy. The beams will be produced from H-/D- ions, generated by a radiofrequency plasma source coupled to an ion acceleration system. A prototype of the ITER HNB ion source is being tested in the SPIDER experiment, part of the ITER Neutral Beam Test Facility at Consorzio RFX. Reaching the design targets for beam current density and fraction of coextracted electrons is only possible by evaporating cesium in the source, in particular on the plasma facing grid (PG) of the acceleration system. In this way the work function of the surfaces decreases, significantly increasing the amount of surface reactions that convert neutrals and positive ions into H-/D-. It is then of paramount importance to monitor the density of negative ions and the density of Cs in the proximity of the PG. Monitoring the Cs spatial distribution along the PG is also essential to guarantee the uniformity of the beam current. In SPIDER, this is possible thanks to the Cavity Ringdown Spectroscopy (CRDS) and the Laser absorption Spectroscopy diagnostics (LAS), which provide line-integrated measurements of negative ion density and neutral, ground state Cs density, respectively. The paper discusses the CRDS and LAS measurements as a function of input power and of the magnetic and electric field used to reduce the coextraction of electrons. Negative ion density data are in qualitative agreement with the results in Cs-free conditions. In agreement with simulations, Cs density is peaked in the center of the source; a top/bottom non uniformity is however present. Several effects of plasma on Cs deposition are presented.Comment: 17 pages, 9 figures. Paper (Preprint) following the poster contribution at the SOFT 2022 conference. The destination journal is Fusion Engineering and Desig