The Role of Self-Assembled Monolayers in the Surface Modification and Interfacial Contact of Copper Fillers in Electrically Conductive Adhesives.

Printing of electrical circuits and interconnects using isotropic conductive adhesives (ICAs) is of great interest due to their low-temperature processing and compatibility with substrates for applications in sensors, healthcare, and flexible devices. As a lower cost alternative to silver (Ag), copper (Cu)-filled ICAs are desirable but limited by the formation of high-resistivity Cu surface oxides. To overcome this limitation, self-assembled monolayers (SAMs) of octadecanethiol (ODT) have been demonstrated to reduce the oxidation of micrometer-scale Cu powder particles for use in ICAs. However, the deposition and function of the SAM require further investigation, as described in this paper. As part of this work, the stages of the SAM deposition process, which included etching with hydrochloric acid to remove pre-existing oxides, were studied using X-ray photoelectron spectroscopy (XPS), which showed low levels of subsequent Cu oxidation when ODT coated. The treated Cu powders were combined with one- or two-part epoxy resins to make Cu-ICAs, and the effect of the Cu surface condition and weight loading on electrical conductivity was examined. When thermally cured in an inert argon atmosphere, ICAs filled with Cu protected by ODT achieved electrical conductivity up to 20 × 105 S·m-1, comparable to Ag-ICAs, and were used to make a functional circuit. To understand the function of the SAM in these Cu-ICAs, scanning and transmission electron microscopy were used to examine the internal micro- and nano-structures along with the elemental distribution at the interfaces within sections taken from cured samples. Sulfur (S), indicative of the ODT, was still detected at the internal polymer-metal interface after curing, and particle-to-particle contacts were also examined. XPS also identified S on the surface of cured Cu-ICAs even after thermal treatment. Based on the observations, electrical contact and conduction mechanisms for these Cu-filled ICAs are proposed and discussed.

sSPhos: A General Ligand for Enantioselective Arylative Phenol Dearomatization via Electrostatically-Directed Palladium Catalysis.

Arylative phenol dearomatization affords complex, cyclohexanone-based scaffolds from simple starting materials, and asymmetric versions allow access to valuable enantioenriched structures. However, bespoke chiral ligands must typically be identified for each new scaffold variation. We have addressed this limitation by applying the concept of electrostatically-directed palladium catalysis whereby the chiral sulfonated ligand sSPhos engages in electrostatic interactions with a phenolate substrate via its associated alkali metal cation. This approach allows access to highly enantioenriched spirocyclohexadienones, a process originally reported by Buchwald and co-workers in a predominantly racemic manner. In addition, sSPhos is proficient at forming two other distinct scaffolds, which had previously required fundamentally different chiral ligands, as well as a novel oxygen-linked scaffold. We envisage that the broad generality displayed by sSPhos will facilitate the expansion of this important reaction type and highlight the potential of this unusual design principle, which harnesses attractive electrostatic interactions.

Prospective observational study on the accuracy of predictors of high-grade atrioventricular conduction block after transcatheter aortic valve implantation (CONDUCT-TAVI): study protocol, background and significance.

INTRODUCTION: Aortic stenosis is the most common cardiac valve pathology worldwide and has a mortality rate of over 50% at 5 years if left untreated. Transcatheter aortic valve implantation (TAVI) is a minimally invasive and highly effective alternative treatment option to open-heart surgery. High-grade atrioventricular conduction block (HGAVB) is one of the most common complications after TAVI and requires a permanent pacemaker. Due to this, patients are typically monitored for 48 hours post TAVI, however up to 40% of HGAVB may delayed, and occur after discharge. Delayed HGAVB can cause syncope or sudden unexplained cardiac death in a vulnerable population, and no accurate methods currently exist to identify patients at risk. METHODS AND ANALYSIS: The prospective observational study on the accuracy of predictors of high-grade atrioventricular conduction block after transcatheter aortic valve implantation (CONDUCT-TAVI) trial is an Australian-led, multicentre, prospective observational study, aiming to improve the prediction of HGAVB, after TAVI. The primary objective of the trial is to assess whether published and novel invasive electrophysiology predictors performed immediately before and after TAVI can help predict HGAVB after TAVI. The secondary objective aims to further evaluate the accuracy of previously published predictors of HGAVB after TAVI, including CT measurements, 12-lead ECG, valve characteristics, percentage oversizing and implantation depth. Follow-up will be for 2 years, and detailed continuous heart rhythm monitoring will be obtained by inserting an implantable loop recorder in all participants. ETHICS AND DISSEMINATION: Ethics approval has been obtained for the two participating centres. Results of the study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN12621001700820.

An Enantioselective Suzuki-Miyaura Coupling To Form Axially Chiral Biphenols.

Axial chirality features prominently in molecules of biological interest as well as chiral catalyst designs, and atropisomeric 2,2'-biphenols are particularly prevalent. Atroposelective metal-catalyzed cross-coupling is an attractive and modular approach to access enantioenriched biphenols, and yet existing protocols cannot achieve this directly. We address this challenge through the use of enantiopure, sulfonated SPhos (sSPhos), an existing ligand that has until now been used only in racemic form and that derives its chirality from an atropisomeric axis that is introduced through sulfonation. We believe that attractive noncovalent interactions involving the ligand sulfonate group are responsible for the high levels of asymmetric induction that we obtain in the 2,2'-biphenol products of Suzuki-Miyaura coupling, and we have developed a highly practical resolution of sSPhos via diastereomeric salt recrystallization.

Truce-Smiles Rearrangements by Strain Release: Harnessing Primary Alkyl Radicals for Metal-Free Arylation.

The ring-opening of 3-aminocyclobutanone oximes enables easy generation of primary alkyl radicals, capable of undergoing an unprecedented strain-release, desulfonylative radical Truce-Smiles rearrangement, providing divergent access to valuable 1,3 diamines and unnatural ß-amino acids. Characterized by mild conditions and wide scope of migrating species, this protocol allows the modular assembly of sp3 -aryls under transition metal-free, room-temperature conditions.

Clinical screening tools for obstructive sleep apnea in a population with atrial fibrillation: a diagnostic accuracy trial.

STUDY OBJECTIVES: Although obstructive sleep apnea (OSA) is a known risk factor for atrial fibrillation (AF), there is a paucity of data around its diagnosis and management in patients with AF. The objectives of this study were to compare the diagnostic accuracy of commonly used OSA screening tools in an AF population, including a level 3 portable sleep study device, and to examine the epidemiology of OSA in a hospital cohort with AF. METHODS: One hundred seven patients with AF recruited from 2 tertiary centers underwent a panel of OSA screening tools and in-laboratory polysomnography in randomized order. RESULTS: Oxygen desaturation index derived from a level 3 portable sleep study device performed best for moderate to severe and severe OSA, with excellent diagnostic accuracy (area under the curve, 0.899; 95% confidence interval, 0.838-0.960 and area under the curve, 0.925; 95% confidence interval, 0.859-0.991, respectively). Sixty-seven patients (62.6%) were newly diagnosed with OSA (31.8% mild, 18.7% moderate, 12.1% severe). CONCLUSIONS: Undiagnosed OSA is highly prevalent in a hospital AF cohort. However, it is characterized by a relative paucity of symptoms, markedly limiting the usefulness of history or screening questionnaires. This is the first study to find that a level 3 home sleep study device shows excellent diagnostic accuracy in patients with AF. This finding may inform AF management guidelines. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: The validity and reliability of a portable device for the diagnosis of Obstructive Sleep Apnoea in patients with Atrial Fibrillation; URL:https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371024; Identifier: ACTRN12616001016426.

Targeting Cardiac Myocyte Na+-K+ Pump Function With ß3 Adrenergic Agonist in Rabbit Model of Severe Congestive Heart Failure.

BACKGROUND: Abnormally high cytosolic Na+ concentrations in advanced heart failure impair myocardial contractility. Stimulation of the membrane Na+-K+ pump should lower Na+ concentrations, and the ß3 adrenoceptor (ß3 AR) mediates pump stimulation in myocytes. We examined if ß3 AR-selective agonists given in vivo increase myocyte Na+-K+ pump activity and reverse organ congestion in severe heart failure (HF). METHODS: Indices for HF were lung-, heart-, and liver: body weight ratios and ascites after circumflex coronary artery ligation in rabbits. Na+-K+ pump current, Ip, was measured in voltage-clamped myocytes from noninfarct myocardium. Rabbits were treated with the ß3 AR agonists CL316,243 or ASP9531, starting 2 weeks after coronary ligation. RESULTS: Coronary ligation caused ascites in most rabbits, significantly increased lung-, heart-, and liver: body weight ratios, and decreased Ip relative to that for 10 sham-operated rabbits. Treatment with CL316,243 for 3 days significantly reduced lung-, heart-, and liver: body weight ratios and prevalence of ascites in 8 rabbits with HF relative to indices for 13 untreated rabbits with HF. It also increased Ip significantly to levels of myocytes from sham-operated rabbits. Treatment with ASP9531 for 14 days significantly reduced indices of organ congestion in 6 rabbits with HF relative to indices of 6 untreated rabbits, and it eliminated ascites. ß3 AR agonists did not significantly change heart rates or blood pressures. CONCLUSIONS: Parallel ß3 AR agonists-induced reversal of Na+-K+ pump inhibition and indices of congestion suggest pump inhibition is a useful target for treatment with ß3 AR agonists in congestive HF.

A visible light-mediated, decarboxylative, desulfonylative Smiles rearrangement for general arylethylamine syntheses.

A decarboxylative, desulfonylative Smiles rearrangement is presented that employs activated-ester/energy transfer catalysis to decarboxylate ß-amino acid derived starting materials at room-temperature under visible light irradiation. The radical Smiles rearrangement gives a range of biologically active arylethylamine products highly relevant to the pharmaceutical industry, chemical biology and materials science. The reaction is then applied to the synthesis of a chiral unnatural amino acid, 2-thienylalanine, used in the treatment of phenylketonuria. We also show how the reaction can proceed under metal-free and catalyst-free conditions.

Relative Contributions of Packaging Elements to the Thermal Hysteresis of a MEMS Pressure Sensor.

Piezoresistive silicon pressure sensor samples were thermally cycled after being consecutively packaged to three different levels. These started with the absolute minimum to allow measurement of the output and with each subsequent level incorporating additional packaging elements within the build. Fitting the data to a mathematical function was necessary both to correct for any testing uncertainties within the pressure and temperature controllers, and to enable the identification and quantification of any hysteresis. Without being subjected to any previous thermal preconditioning, the sensors were characterized over three different temperature ranges and for multiple cycles, in order to determine the relative contributions of each packaging level toward thermal hysteresis. After reaching a stabilised hysteretic behaviour, 88.5% of the thermal hysteresis was determined to be related to the bond pads and wire bonds, which is likely to be due to the large thermal mismatch between the silicon and bond pad metallisation. The fluid-fill and isolation membrane contributed just 7.2% of the total hysteresis and the remaining 4.3% was related to the adhesive used for attachment of the sensing element to the housing. This novel sequential packaging evaluation methodology is independent of sensor design and is useful in identifying those packaging elements contributing the most to hysteresis.

Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency, selectivity and structural novelty.

Focussed studies on imidazopyridine inhibitors of Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG) have significantly advanced the series towards desirable in vitro property space. LLE-based approaches towards combining improvements in cell potency, key physicochemical parameters and structural novelty are described, and a structure-based design hypothesis relating to substituent regiochemistry has directed efforts towards key examples with well-balanced potency, ADME and kinase selectivity profiles.

A randomised controlled trial evaluating arrhythmia burden, risk of sudden cardiac death and stroke in patients with Fabry disease: the role of implantable loop recorders (RaILRoAD) compared with current standard practice.

BACKGROUND: Fabry disease (FD) is a genetic disorder caused by a deficiency in the enzyme alpha-galactosidase A, leading to an accumulation of glycosphingolipids in tissues across the body. Cardiac disease is the leading cause of morbidity and mortality. Advanced disease, characterised by extensive left ventricular hypertrophy, ventricular dysfunction and fibrosis, is known to be associated with an increase in arrhythmia. Data identifying risk factors for arrhythmia are limited, and no Fabry-specific risk stratification tool is available to select those who may benefit from initiation of medical or device therapy (implantable cardiac defibrillators). Current monitoring strategies have a limited diagnostic yield, and implantable loop recorders (ILRs) have the potential to change treatment and clinical outcomes. AIM: The aim of this study is to determine whether ILRs can (1) improve arrhythmia detection in FD and (2) identify risk predictors of arrhythmia. METHODS: A prospective, 5-year, open-label, international, multi-centre randomised controlled trial of a minimum of 164 participants with genetically or enzymatically confirmed FD (or both) who have evidence of cardiac disease will be recruited from five centres: Queen Elizabeth Hospital, Birmingham, UK; Salford Royal Hospital, Salford, UK; Royal Free Hospital, London, UK; Addenbrookes Hospital, Cambridge, UK; and Westmead Hospital, Sydney, Australia. Participants will be block-randomised (1:1) to two study arms for cardiac monitoring (i) control arm: standard of care with annual 24 h or 5-day Holter monitor or (ii) treatment arm: continuous cardiac monitoring with ILR implantation plus standard of care. Participants will undergo multiple investigations-blood/urine biomarkers, 12-lead and advanced electrocardiogram (ECG) recording, echocardiography and cardiovascular magnetic resonance (CMR) imaging-at baseline and 6-12 monthly follow-up visits. The primary endpoint is identification of arrhythmia requiring initiation or alteration in therapy. Secondary outcome measures include characterising the risk factors associated with arrhythmia and outcome data in the form of imaging, ECG and blood biomarkers. DISCUSSION: This is the first study evaluating arrhythmia burden and the use of ILR across the spectrum of risk profiles in Fabry cardiomyopathy. This will enable detailed characterisation of arrhythmic risk predictors in FD and ultimately support formulation of Fabry-specific guidance in this high-risk population. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03305250 ). Registered on 9 October 2017.

Pharmacological Therapy for Ventricular Arrhythmias: A State-of-the Art Review.

While implantable cardioverter defibrillators decrease mortality in high risk groups of patients who have ventricular arrhythmias, antiarrhythmic drugs are still required to reduce the burden of both benign and life-threatening arrhythmias. This review will address the available medical therapy for ventricular arrhythmias in Australia and their use in different clinical situations.

Potent inhibitors of malarial P. Falciparum protein kinase G: Improving the cell activity of a series of imidazopyridines.

Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels of inhibitory activity against the recombinant kinase and in vitro activity against the parasite. Key examples were shown to possess encouraging in vitro ADME properties, and computational analysis provided valuable insight into the origins of the observed activity profiles.

Alkene Carboarylation through Catalyst-Free, Visible Light-Mediated Smiles Rearrangement.

A light-mediated Truce-Smiles arylative rearrangement is described that proceeds in the absence of any photocatalyst. The protocol creates two C-C bonds from simple starting materials, with the installation of an aryl ring and a difluoroacetate moiety across unactivated alkenes. The reaction proceeds via a radical mechanism, utilizing a light-mediated reduction of ethyl bromodifluoroacetate by N,N,N',N'-tetramethylethylenediamine (TMEDA) to set up intermolecular addition to an unactivated alkene, followed by Truce-Smiles rearrangement.

Trisubstituted thiazoles as potent and selective inhibitors of Plasmodium falciparum protein kinase G (PfPKG).

A series of trisubstituted thiazoles have been identified as potent inhibitors of Plasmodium falciparum (Pf) cGMP-dependent protein kinase (PfPKG) through template hopping from known Eimeria PKG (EtPKG) inhibitors. The thiazole series has yielded compounds with improved potency, kinase selectivity and good in vitro ADME properties. These compounds could be useful tools in the development of new anti-malarial drugs in the fight against drug resistant malaria.

Pulmonary Vein Isolation for Atrial Fibrillation Can Be Achieved With Low Radiation Exposure.

BACKGROUND: Atrial fibrillation is common and management by pharmacotherapy is limited by modest efficacy and significant toxicities. Pulmonary vein isolation (PVI) is a safe and effective alternative in select patients with atrial fibrillation. However, prolonged procedure time raises concerns of health risks from radiation exposure. This study aims to determine the significance of radiation exposure from PVI. METHODS: In this study, we retrospectively reviewed patient demographics, fluoroscopy time, entrance skin dose and dose area product in 80 cases of PVI, radiofrequency ablation for atrial flutter and diagnostic coronary angiogram performed in our institution. RESULTS: Compared to other procedures, patients who underwent PVI were younger (age, mean±standard error of mean, 59.4±1.1 years old, p<0.0001) and were more likely to be male (82%, p<0.001). Body mass index was similar between the three groups. The median (and interquartile range) fluoroscopy time was similar between PVI (20.8 and 13.1-30.7mins) and flutter ablation (17.6 and 11.1-26.1mins) but longer than diagnostic angiography (4.2 and 2.3-6.7mins, p<0.0001). Entrance skin dose was similar between PVI and flutter ablation groups but significantly higher in the diagnostic angiography group, with median and IQR for PVI vs. flutter ablation vs. diagnostic angiography, 100.4 (52.8-179.9) vs. 73.2 (37.0-142.1) vs. 393.5 (276.1-555.6) mGy (p<0.0001). Dose area product in PVI (1831.2 and 887.7-3460.8cGycm2) was higher than flutter ablation (1077.8 and 452.9-2410.2cGycm2, p<0.05) but lower than the diagnostic angiography group (3446.8 and 2341.9-5283.1cGycm2, p<0.0001). The fluoroscopy time and entrance skin dose for PVI decreased over time, likely due to increased operator experience. CONCLUSIONS: Despite prolonged procedure time, radiation exposure from PVI was comparable to, or lower than, other fluoroscopy-guided cardiac procedures.