Coupling Matrix Representation of Nonreciprocal Filters Based on Time Modulated Resonators

This paper addresses the analysis and design of non-reciprocal filters based on time modulated resonators. We analytically show that time modulating a resonator leads to a set of harmonic resonators composed of the unmodulated lumped elements plus a frequency invariant element that accounts for differences in the resonant frequencies. We then demonstrate that harmonic resonators of different order are coupled through non-reciprocal admittance inverters whereas harmonic resonators of the same order couple with the admittance inverter coming from the unmodulated filter network. This coupling topology provides useful insights to understand and quickly design non-reciprocal filters and permits their characterization using an asynchronously tuned coupled resonators network together with the coupling matrix formalism. Two designed filters, of orders three and four, are experimentally demonstrated using quarter wavelength resonators implemented in microstrip technology and terminated by a varactor on one side. The varactors are biased using coplanar waveguides integrated in the ground plane of the device. Measured results are found to be in good agreement with numerical results, validating the proposed theory

Discovery of a wide companion near the deuterium burning mass limit in the Upper Scorpius association

We present the discovery of a companion near the deuterium burning mass limit located at a very wide distance, at an angular separation of 4.6+/-0.1 arcsec (projected distance of ~ 670 AU) from UScoCTIO108, a brown dwarf of the very young Upper Scorpius association. Optical and near-infrared photometry and spectroscopy confirm the cool nature of both objects, with spectral types of M7 and M9.5, respectively, and that they are bona fide members of the association, showing low gravity and features of youth. Their masses, estimated from the comparison of their bolometric luminosities and theoretical models for the age range of the association, are 60+/-20 and 14^{+2}_{-8} MJup, respectively. The existence of this object around a brown dwarf at this wide orbit suggests that the companion is unlikely to have formed in a disk based on current planet formation models. Because this system is rather weakly bound, they did not probably form through dynamical ejection of stellar embryos.Comment: 10 pages, including 4 figures and 2 table

3D Printed Punctal Plugs for Controlled Ocular Drug Delivery

Dry eye disease is a common ocular disorder that is characterised by tear deficiency or excessive tear evaporation. Current treatment involves the use of eye drops; however, therapeutic efficacy is limited because of poor ocular bioavailability of topically applied formulations. In this study, digital light processing (DLP) 3D printing was employed to develop dexamethasone-loaded punctal plugs. Punctal plugs with different drug loadings were fabricated using polyethylene glycol diacrylate (PEGDA) and polyethylene glycol 400 (PEG 400) to create a semi-interpenetrating network (semi-IPN). Drug-loaded punctal plugs were characterised in terms of physical characteristics (XRD and DSC), potential drug-photopolymer interactions (FTIR), drug release profile, and cytocompatibility. In vitro release kinetics of the punctal plugs were evaluated using an in-house flow rig model that mimics the subconjunctival space. The results showed sustained release of dexamethasone for up to 7 days from punctal plugs made with 20% w/w PEG 400 and 80% w/w PEGDA, while punctal plugs made with 100% PEGDA exhibited prolonged releases for more than 21 days. Herein, our study demonstrates that DLP 3D printing represents a potential manufacturing platform for fabricating personalised drug-loaded punctal plugs with extended release characteristics for ocular administration

Stereolithography (SLA) 3D printing of a bladder device for intravesical drug delivery

Intravesical instillation therapy is an alternative approach to oral medications for the treatment of severe bladder diseases, offering high drug concentrations at the site of action while minimising systemic side effects. However, therapeutic efficacy is often limited because of the short residence time of the drug in the bladder and the need for repeated instillations. This study reports, for the first time, the use of stereolithography (SLA) 3D printing to manufacture novel indwelling bladder devices using an elastic polymer to achieve extended and localised delivery of lidocaine hydrochloride. The devices were designed to be inserted into and retrieved from the bladder using a urethral catheter. Two types of bladder devices (hollow and solid) were prepared with a resilient material (Elastic Resin) incorporating three drug loads of lidocaine hydrochloride (10% w/w, 30% w/w and 50% w/w); a drug frequently used to treat interstitial cystitis and bladder pain. All of the devices showed acceptable blood compatibility, good resistance to compressive and stretching forces and were able to recover their original shape immediately once external forces were removed. In vitro drug release studies showed that a complete release of lidocaine was achieved within 4 days from the hollow devices, whereas the solid devices enabled sustained drug release for up to 14 days. SLA 3D printing therefore provides a new manufacturing route to produce bladder-retentive drug delivery devices using elastic polymers, and offers a revolutionary and personalised approach for clinical intravesical drug delivery

Prevention and management of idiosyncratic drug-induced liver injury: Systematic review and meta-analysis of randomised clinical trials

Conducting randomised clinical trials (RCTs) in idiosyncratic drug-induced liver injury (DILI) is challenging. This systematic review aims to summarise the design and findings of RCTs in the prevention and management of idiosyncratic DILI. A systematic literature search up to January 31st, 2020 was performed. Recognised scales were used to assess methodological bias and quality of the studies. Quantitative and qualitative analyses were performed. Heterogeneity was assessed with I2 statistic. Overall, 22 RCTs were included: 12 on prevention (n = 2,471 patients) and 10 in management (n = 797) of DILI/non-acetaminophen DILI-related acute liver failure (ALF). Silymarin (eight studies), bicyclol (four), magnesium isoglycyrrhizinate (three), N-acetylcysteine (three), tiopronin (one), L-carnitine (one), and traditional Chinese medicines (two) were tested in the intervention arm, while control arm mostly received standard supportive care or placebo. Main efficacy criteria in the prevention RCTs was DILI incidence or peak of liver enzymes value. In management RCTs, the efficacy parameter was usually 50 % decrease or normalisation of liver enzymes, or survival rate in DILI-related ALF patients. Overall, 15 trials described the randomisation method, eight were double-blind (n = 672) and nine had sample size esti- mation (n = 880). Four RCTs involving 377 patients used an intention-to-treat analysis. Based on the scarce number of trials available, tested agents showed limited efficacy in DILI prevention and management and a favourable safety profile. In conclusion, heterogeneity among studies in DILI case qualification and methodologic quality was evident, and the RCTs performed demonstrated limited efficacy of specific interventions. Interna- tional research networks are needed to establish a framework on RCTs design and therapeutic endpoints.This work was supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional - FEDER (contract numbers: PI18/00901; PI18/01804; PT17/0017/0020; PT 20/00127) and Agencia Espan ̃ola del Medicamento. Plataforma de Investigacio ́n Clínica and CIBERehd are funded by ISCIII. MRD holds a Joan Rodes (JR16/00015)/Accio ́n B clinicos investigadores (B-0002-2019), JSC a Rio Hortega (CM17/00243) and IAA a Sara Borrell (CD20/00083) research contract from ISCIII and Consejería de Salud de Andalucía. This publication is based upon work from COST Action “CA17112 - Pro- spective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology). www.cost.e

Carotid Body-Mediated Chemoreflex Drive in The Setting of low and High Output Heart Failure.

Enhanced carotid body (CB) chemoreflex function is strongly related to cardiorespiratory disorders and disease progression in heart failure (HF). The mechanisms underlying CB sensitization during HF are not fully understood, however previous work indicates blood flow per se can affect CB function. Then, we hypothesized that the CB-mediated chemoreflex drive will be enhanced only in low output HF but not in high output HF. Myocardial infarcted rats and aorto-caval fistulated rats were used as a low output HF model (MI-CHF) and as a high output HF model (AV-CHF), respectively. Blood flow supply to the CB region was decreased only in MI-CHF rats compared to Sham and AV-CHF rats. MI-CHF rats exhibited a significantly enhanced hypoxic ventilatory response compared to AV-CHF rats. However, apnea/hypopnea incidence was similarly increased in both MI-CHF and AV-CHF rats compared to control. Kruppel-like factor 2 expression, a flow sensitive transcription factor, was reduced in the CBs of MI-CHF rats but not in AV-CHF rats. Our results indicate that in the setting of HF, potentiation of the CB chemoreflex is strongly associated with a reduction in cardiac output and may not be related to other pathophysiological consequences of HF

Top-squark searches at the Tevatron in models of low-energy supersymmetry breaking

We study the production and decays of top squarks (stops) at the Tevatron collider in models of low-energy supersymmetry breaking. We consider the case where the lightest Standard Model (SM) superpartner is a light neutralino that predominantly decays into a photon and a light gravitino. Considering the lighter stop to be the next-to-lightest Standard Model superpartner, we analyze stop signatures associated with jets, photons and missing energy, which lead to signals naturally larger than the associated SM backgrounds. We consider both 2-body and 3-body decays of the top squarks and show that the reach of the Tevatron can be significantly larger than that expected within either the standard supergravity models or models of low-energy supersymmetry breaking in which the stop is the lightest SM superpartner. For a modest projection of the final Tevatron luminosity, L = 4 fb-1, stop masses of order 300 GeV are accessible at the Tevatron collider in both 2-body and 3-body decay modes. We also consider the production and decay of ten degenerate squarks that are the supersymmetric partners of the five light quarks. In this case we find that common squark masses up to 360 GeV are easily accessible at the Tevatron collider, and that the reach increases further if the gluino is light.Comment: 32 pages, 9 figures; references adde