Tandem High-Pressure Crystallography-Optical Spectroscopy Unpacks Noncovalent Interactions of Piezochromic Fluorescent Molecular Rotors.

To develop luminescent molecular materials with predictable and stimuli-responsive emission, it is necessary to correlate changes in their geometries, packing structures, and noncovalent interactions with the associated changes in their optical properties. Here, we demonstrate that high-pressure single-crystal X-ray diffraction can be combined with high-pressure UV-visible absorption and fluorescence emission spectroscopies to elucidate how subtle changes in structure influence optical outputs. A piezochromic aggregation-induced emitter, sym-heptaphenylcycloheptatriene (Ph7C7H), displays bathochromic shifts in its absorption and emission spectra at high pressure. Parallel X-ray measurements identify the pressure-induced changes in specific phenyl-phenyl interactions responsible for the piezochromism. Pairs of phenyl rings from neighboring molecules approach the geometry of a stable benzene dimer, while conformational changes alter intramolecular phenyl-phenyl interactions correlated with a relaxed excited state. This tandem crystallographic and spectroscopic analysis provides insights into how subtle structural changes relate to the photophysical properties of Ph7C7H and could be applied to a library of similar compounds to provide general structure-property relationships in fluorescent organic molecules with rotor-like geometries.

Extended Conjugation Attenuates the Quenching of Aggregation-Induced Emitters by Photocyclization Pathways.

Herein, we expose how the antagonistic relationship between solid-state luminescence and photocyclization of oligoaryl alkene chromophores is modulated by the conjugation length of their alkenyl backbones. Heptaaryl cycloheptatriene molecular rotors exhibit aggregation-induced emission characteristics. We show that their emission is turned off upon breaking the conjugation of the cycloheptatriene by epoxide formation. While this modification is deleterious to photoluminescence, it enables formation of extended polycyclic frameworks by Mallory reactions. We exploit this dichotomy (i) to manipulate emission properties in a controlled manner and (ii) as a synthetic tool to link together pairs of phenyl rings in a specific sequence. This method to alter the tendency of oligoaryl alkenes to undergo photocyclization can inform the design of solid-state emitters that avoid this quenching mechanism, while also allowing selective cyclization in syntheses of polycyclic aromatic hydrocarbons.

Leadless left ventricular endocardial pacing for CRT upgrades in previously failed and high-risk patients in comparison with coronary sinus CRT upgrades.

AIMS: Cardiac resynchronization therapy (CRT) upgrades may be less likely to improve following intervention. Leadless left ventricular (LV) endocardial pacing has been used for patients with previously failed CRT or high-risk upgrades. We compared procedural and long-term outcomes in patients undergoing coronary sinus (CS) CRT upgrades with high-risk and previously failed CRT upgrades undergoing LV endocardial upgrades. METHOD AND RESULTS: Prospective consecutive CS upgrades between 2015 and 2019 were compared with those undergoing WiSE-CRT implantation. Cardiac resynchronization therapy response at 6 months was defined as improvement in clinical composite score (CCS) and a reduction in LV end-systolic volume (LVESV) ≥15%. A total of 225 patients were analysed; 121 CS and 104 endocardial upgrades. Patients receiving WiSE-CRT tended to have more comorbidities and were more likely to have previous cardiac surgery (30.9% vs. 16.5%; P = 0.012), hypertension (59.2% vs. 34.7%; P < 0.001), chronic obstructive airways disease (19.4% vs. 9.9%; P = 0.046), and chronic kidney disease (46.4% vs. 21.5%; P < 0.01) but similar LV ejection fraction (30.0 ± 8.3% vs. 29.5 ± 8.6%; P = 0.678). WiSE-CRT upgrades were successful in 97.1% with procedure-related mortality in 1.9%. Coronary sinus upgrades were successful in 97.5% of cases with a 2.5% rate of CS dissection and 5.6% lead malfunction/displacement. At 6 months, 91 WiSE-CRT upgrades and 107 CS upgrades had similar improvements in CCS (76.3% vs. 68.5%; P = 0.210) and reduction in LVESV ≥15% (54.2% vs. 56.3%; P = 0.835). CONCLUSION: Despite prior failed upgrades and high-risk patients with more comorbidities, WiSE-CRT upgrades had high rates of procedural success and similar improvements in CCS and LV remodelling with CS upgrades.

UK multicenter retrospective comparison of novel active versus conventional passive fixation coronary sinus leads.

BACKGROUND: A novel active fixation coronary sinus (CS) lead, Attain Stability (AS), has been released aiming to improve targeted lead positioning. Rather than being wedged into the distal vessel, it relies on a side helix for fixation. We aimed to compare implant procedure parameters and electromechanical stability of the AS lead with passive CS leads. METHODS: A retrospective study involving six major UK cardiac centers. Patients who received active fixation leads were compared with passive fixation lead recipients in a 1:2 ratio. The primary outcome was total lead displacements (combined macrodisplacement/microdisplacement, defined as displacements requiring repositioning procedures, an increase in threshold ≥0.5 V or pulse width ≥0.5 ms, or a change in pacing polarity). RESULTS: A total of 761 patients were included (253 AS leads and 508 passive fixation leads), of which 736 had follow-up data. The primary endpoint rate was 31% (75/241) in the active and 43% (214/495) in the passive group (p = .002). Six patients (2.5%) in the active group and 14 patients (2.8%) in the passive group required CS lead repositioning procedures (p = 0.981). On multivariable analysis, active leads were associated with a reduction in lead displacements, odds ratio 0.66 (95% confidence interval: 0.46-0.95), p = .024. There were differences in favor of passive leads in procedure duration, 120 (96-149) versus 127 (105-155) min (p = .008), and fluoroscopy time, 17 (11-26) versus 18.5 (13-27) min (p = .0022). The median follow-up duration was similar (active vs. passive): 31 (17-47) versus 34 (16-71) weeks, (p = .052). CONCLUSION: AS CS leads had improved electromechanical stability compared with passive fixation leads, with only minimal increases in implant procedure and fluoroscopy times.

Local introduction and heterogeneous spatial spread of dengue-suppressing Wolbachia through an urban population of Aedes aegypti.

Dengue-suppressing Wolbachia strains are promising tools for arbovirus control, particularly as they have the potential to self-spread following local introductions. To test this, we followed the frequency of the transinfected Wolbachia strain wMel through Ae. aegypti in Cairns, Australia, following releases at 3 nonisolated locations within the city in early 2013. Spatial spread was analysed graphically using interpolation and by fitting a statistical model describing the position and width of the wave. For the larger 2 of the 3 releases (covering 0.97 km2 and 0.52 km2), we observed slow but steady spatial spread, at about 100-200 m per year, roughly consistent with theoretical predictions. In contrast, the smallest release (0.11 km2) produced erratic temporal and spatial dynamics, with little evidence of spread after 2 years. This is consistent with the prediction concerning fitness-decreasing Wolbachia transinfections that a minimum release area is needed to achieve stable local establishment and spread in continuous habitats. Our graphical and likelihood analyses produced broadly consistent estimates of wave speed and wave width. Spread at all sites was spatially heterogeneous, suggesting that environmental heterogeneity will affect large-scale Wolbachia transformations of urban mosquito populations. The persistence and spread of Wolbachia in release areas meeting minimum area requirements indicates the promise of successful large-scale population transformation.

Control of Porphyrin Planarity and Aggregation by Covalent Capping: Bissilyloxy Porphyrin Silanes.

Porphyrins are cornerstone functional materials that are useful in a wide variety of settings, ranging from molecular electronics to biology and medicine. Their applications are often hindered, however, by poor solubilities that result from their extended, solvophobic aromatic surfaces. Attempts to counteract this problem by functionalizing their peripheries have been met with only limited success. Here, we demonstrate a versatile strategy to tune the physical and electronic properties of porphyrins using an axial functionalization approach. Porphyrin silanes (PorSils) and bissilyloxy PorSils (SOPS) are prepared from porphyrins by operationally simple κ4N-silylation protocols, introducing bulky silyloxy "caps" that are central and perpendicular to the planar porphyrin. While porphyrins typically form either J- or H-aggregates, SOPS do not self-associate in the same manner: the silyloxy axial substituents dramatically improve the solubility by inhibiting aggregation. Moreover, axial porphyrin functionalization offers convenient handles through which optical, electronic, and structural properties of the porphyrin core can be modulated. We observe that the identity of the silyloxy substituent impacts the degree of planarity of the porphyrin in the solid state as well as the redox potentials.

Leadless left ventricular endocardial pacing in nonresponders to conventional cardiac resynchronization therapy.

BACKGROUND: Endocardial pacing may be beneficial in patients who fail to improve following conventional epicardial cardiac resynchronization therapy (CRT). The potential to pace anywhere inside the left ventricle thus avoiding myocardial scar and targeting the latest activating segments may be particularly important. The WiSE-CRT system (EBR systems, Sunnyvale, CA) reliably produces wireless, endocardial left ventricular (LV) pacing. The purpose of this analysis was to determine whether this system improved symptoms or led to LV remodeling in patients who were nonresponders to conventional CRT. METHOD: An international, multicenter registry of patients who were nonresponders to conventional CRT and underwent implantation with the WiSE-CRT system was collected. RESULTS: Twenty-two patients were included; 20 patients underwent successful implantation with confirmation of endocardial biventricular pacing and in 2 patients, there was a failure of electrode capture. Eighteen patients proceeded to 6-month follow-up; endocardial pacing resulted in a significant reduction in QRS duration compared with intrinsic QRS duration (26.6 ± 24.4 ms; P = .002) and improvement in left ventricular ejection fraction (LVEF) (4.7 ± 7.9%; P = .021). The mean reduction in left ventricular end-diastolic volume was 8.3 ± 42.3 cm3 (P = .458) and left ventricular end-systolic volume (LVESV) was 13.1 ± 44.3 cm3 (P = .271), which were statistically nonsignificant. Overall, 55.6% of patients had improvement in their clinical composite score and 66.7% had a reduction in LVESV ≥15% and/or absolute improvement in LVEF ≥5%. CONCLUSION: Nonresponders to conventional CRT have few remaining treatment options. We have shown in this high-risk patient group that the WiSE-CRT system results in improvement in their clinical composite scores and leads to LV remodeling.

Novel experience of laser-assisted 'inside-out' central venous access in a patient with bilateral subclavian vein occlusion requiring pacemaker implantation.

AIM: This new laser facilitated 'inside-out' technique was used for transvenous pacemaker insertion in a pacemaker-dependent patient with bilateral subclavian occlusion and a failed epicardial system who is not suitable for a transfemoral approach. METHOD AND RESULTS: Procedure was undertaken under general anaesthesia with venous access obtained from right femoral vein and left axillary vein. 7F multipurpose catheter was used to enter proximal edge of the occluded segment of subclavian vein via femoral approach, which then supported stiff angioplasty wires and microcatheters to tunnel into the body of occlusion. When encountered with impenetrable resistance, 1.4 mm Excimer laser helped delivery of a Pilot 200 wire, which then progressed towards the distal edge of occlusion. Serial balloon dilatations allowed wire tracked into subintimal plane, advanced towards left clavicle using knuckle wire technique, which was then externalized with blunt dissection from infraclavicular pocket area. It was later changed to Amplatz superstiff wire exiting from both ends to form a rail, which ultimately allowed passage of pacing leads after serial balloon dilatation from clavicular end. CONCLUSION: Our hybrid 'inside-out' technique permitted transvenous pacemaker insertion without complication and this is, to our knowledge, the first case using laser in this context.

Enzymatic Method for the Synthesis of Long DNA Sequences with Multiple Repeat Units.

A polymerase chain reaction (PCR) derived method for preparing long DNA, consisting of multiple repeat units of one to ten base pairs, is described. Two seeding oligodeoxynucleotides, so-called oligoseeds, which encode the repeat unit and produce a duplex with 5'-overhangs, are extended using a thermostable archaeal DNA polymerase. Multiple rounds of heat-cool extension cycles, akin to PCR, rapidly elongate the oligoseed. Twenty cycles produced long DNA with uniformly repeating sequences to over 20 kilobases (kb) in length. The polynucleotides prepared include [A]n /[T]n , [AG]n /[TC]n , [A2 G]n /[T2 C]n , [A3 G]n /[T3 C]n , [A4 G]n /[T4 C]n , [A9 G]n /[T9 C]n , [GATC]n /[CTAG]n , and [ACTGATCAGC]n /[TGACTAGTCG]n , indicating that the method is extremely flexible with regard to the repeat length and base sequence of the initial oligoseeds. DNA of this length (20 kb≈7 µm) with strictly defined base reiterations should find use in nanomaterial applications.

Balloon venoplasty of subclavian vein and brachiocephalic junction to enable left ventricular lead placement for cardiac resynchronisation therapy.

This report describes the successful implantation of a LV lead using balloon venoplasty to overcome a very tight stenosis of the right subclavian vein / brachiocephalic junction for cardiac resynchronisation therapy (CRT-P) in a patient with a right sided CRT-P system and a failed epicardial LV lead. It is important for device implanters to be familiar with interventional equipments and techniques such as balloon venoplasty to overcome difficult venous access.

Rupturing aromaticity by periphery overcrowding.

The balance between strain relief and aromatic stabilization dictates the form and function of non-planar π-aromatics. Overcrowded systems are known to undergo geometric deformations, but the energetically favourable π-electron delocalization of their aromatic ring(s) is typically preserved. In this study we incremented the strain energy of an aromatic system beyond its aromatic stabilization energy, causing it to rearrange and its aromaticity to be ruptured. We noted that increasing the steric bulk around the periphery of π-extended tropylium rings leads them to deviate from planarity to form contorted conformations in which aromatic stabilization and strain are close in energy. Under increasing strain, the aromatic π-electron delocalization of the system is broken, leading to the formation of a non-aromatic, bicyclic analogue referred to as 'Dewar tropylium'. The aromatic and non-aromatic isomers have been found to exist in rapid equilibrium with one another. This investigation demarcates the extent of steric deformation tolerated by an aromatic carbocycle and thus provides direct experimental insights into the fundamental nature of aromaticity.

Control of dynamic sp3-C stereochemistry.

Stereogenic sp3-hybridized carbon centres are fundamental building blocks of chiral molecules. Unlike dynamic stereogenic motifs, such as sp3-nitrogen centres or atropisomeric biaryls, sp3-carbon centres are usually fixed, requiring intermolecular reactions to undergo configurational changes. Here we report the internal enantiomerization of fluxional carbon cages and the consequences of their adaptive configurations for the transmission of stereochemical information. The sp3-carbon stereochemistry of the rigid tricyclic cages is inverted through strain-assisted Cope rearrangements, emulating the low-barrier configurational dynamics typical for sp3-nitrogen inversion or conformational isomerism. This dynamic enantiomerization can be stopped, restarted or slowed by external reagents, while the configuration of the cage is controlled by neighbouring, fixed stereogenic centres. As part of a phosphoramidite-olefin ligand, the fluxional cage acts as a conduit to transmit stereochemical information from the ligand while also transferring its dynamic properties to chiral-at-metal coordination environments, influencing catalysis, ion pairing and ligand exchange energetics.

Catalysis enabled synthesis, structures, and reactivities of fluorinated S8-corona[n]arenes (n = 8-12).

Previously inaccessible large S8-corona[n]arene macrocycles (n = 8-12) with alternating aryl and 1,4-C6F4 subunits are easily prepared on up to gram scales, without the need for chromatography (up to 45% yield, 10 different examples) through new high acceleration SNAr substitution protocols (catalytic NR4F in pyridine, R = H, Me, Bu). Macrocycle size and functionality are tunable by precursor and catalyst selection. Equivalent simple NR4F catalysis allows facile late-stage SNAr difunctionalisation of the ring C6F4 units with thiols (8 derivatives, typically 95+% yields) providing two-step access to highly functionalised fluoromacrocycle libraries. Macrocycle host binding supports fluoroaryl catalytic activation through contact ion pair binding of NR4F and solvent inclusion. In the solid-state, solvent inclusion also intimately controls macrocycle conformation and fluorine-fluorine interactions leading to spontaneous self-assembly into infinite columns with honeycomb-like lattices.

Modulation of charge transfer by N-alkylation to control photoluminescence energy and quantum yield.

Charge transfer in organic fluorophores is a fundamental photophysical process that can be either beneficial, e.g., facilitating thermally activated delayed fluorescence, or detrimental, e.g., mediating emission quenching. N-Alkylation is shown to provide straightforward synthetic control of the charge transfer, emission energy and quantum yield of amine chromophores. We demonstrate this concept using quinine as a model. N-Alkylation causes changes in its emission that mirror those caused by changes in pH (i.e., protonation). Unlike protonation, however, alkylation of quinine's two N sites is performed in a stepwise manner to give kinetically stable species. This kinetic stability allows us to isolate and characterize an N-alkylated analogue of an 'unnatural' protonation state that is quaternized selectively at the less basic site, which is inaccessible using acid. These materials expose (i) the through-space charge-transfer excited state of quinine and (ii) the associated loss pathway, while (iii) developing a simple salt that outperforms quinine sulfate as a quantum yield standard. This N-alkylation approach can be applied broadly in the discovery of emissive materials by tuning charge-transfer states.

Shared decision-making for ICDs: a regional collaborative initiative.

The National Institute for Health and Care Excellence (NICE) and NHS England have shown a commitment to embedding shared decision-making (SDM) in clinical practice and developing decision aids based on clinical guidelines. Healthcare policy makers are keen to enhance the engagement of patients in SDM in the belief that it improves the benefits accrued from healthcare interventions. This may be important for interventions such as implantable cardioverter-defibrillator (ICD) implantation, where cost-effectiveness is under scrutiny. NHS England invited the ICD implanters in the north of England to participate in a regional commissioning quality incentive (CQUIN) project to improve decision- making around a primary prevention ICD implant. A collaborative project included the development of a specific SDM tool, the first of its kind in the UK, followed by training and education of the clinical teams. The project illustrates that this approach is practical and deliverable and could be applied and used in other regions, and considered in additional clinical areas.

Aggregate Science: From Structures to Properties.

Molecular science entails the study of structures and properties of materials at the level of single molecules or small interacting complexes of molecules. Moving beyond single molecules and well-defined complexes, aggregates (i.e., irregular clusters of many molecules) serve as a particularly useful form of materials that often display modified or wholly new properties compared to their molecular components. Some unique structures and phenomena such as polymorphic aggregates, aggregation-induced symmetry breaking, and cluster excitons are only identified in aggregates, as a few examples of their exotic features. Here, by virtue of the flourishing research on aggregation-induced emission, the concept of "aggregate science" is put forward to fill the gaps between molecules and aggregates. Structures and properties on the aggregate scale are also systematically summarized. The structure-property relationships established for aggregates are expected to contribute to new materials and technological development. Ultimately, aggregate science may become an interdisciplinary research field and serves as a general platform for academic research.

Stable establishment of wMel Wolbachia in Aedes aegypti populations in Yogyakarta, Indonesia.

The successful establishment of the wMel strain of Wolbachia for the control of arbovirus transmission by Aedes aegypti has been proposed and is being implemented in a number of countries. Here we describe the successful establishment of the wMel strain of Wolbachia in four sites in Yogyakarta, Indonesia. We demonstrate that Wolbachia can be successfully introgressed after transient releases of wMel-infected eggs or adult mosquitoes. We demonstrate that the approach is acceptable to communities and that Wolbachia maintains itself in the mosquito population once deployed. Finally, our data show that spreading rates of Wolbachia in the Indonesian setting are slow which may reflect more limited dispersal of Aedes aegypti than seen in other sites such as Cairns, Australia.

Real-world experience of leadless left ventricular endocardial cardiac resynchronization therapy: A multicenter international registry of the WiSE-CRT pacing system.

BACKGROUND: Biventricular endocardial pacing (BiV ENDO) is a therapy for heart failure patients who cannot receive transvenous epicardial cardiac resynchronization therapy (CRT) or have not responded adequately to CRT. BiV ENDO CRT can be delivered by a new wireless LV ENDO pacing system (WiSE-CRT system; EBR Systems, Sunnyvale, CA), without the requirement for lifelong anticoagulation. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of the WiSE-CRT system during real-world clinical use in an international registry. METHODS: Data were prospectively collected from 14 centers implanting the WiSE-CRT system as part of the WiCS-LV Post Market Surveillance Registry. (ClinicalTrials.gov Identifier: NCT02610673). RESULTS: Ninety patients from 14 European centers underwent implantation with the WiSE-CRT system. Patients were predominantly male, age 68.2 ± 10.5 years, left ventricular ejection fraction 30.6% ± 8.9%, mean QRS duration 180.7 ± 27.0 ms, and 40% with ischemic etiology. Successful implantation and delivery of BiV ENDO pacing was achieved in 94.4% of patients. Acute (<24 hours), 1- to 30-day, and 1- to 6-month complications rates were 4.4%, 18.8%, and 6.7%, respectively. Five deaths (5.6%) occurred within 6 months (3 procedure related). Seventy percent of patients had improvement in heart failure symptoms. CONCLUSION: BiV ENDO pacing with the WiSE-CRT system seems to be technically feasible, with a high success rate. Three procedural deaths occurred during the study. Procedural complications mandate adequate operator training and implantation at centers with immediately available cardiothoracic and vascular surgical support.

Time to manual activation of implantable loop recorders--implications for programming recording period: a 10-year single-centre experience.

AIM: A new generation of commercially available implantable loop recorders (ILRs) has improved arrhythmia detection algorithms but reduced manually activated ECG storage duration. We investigated the effect that this would have had on symptom-arrhythmia correlation in a retrospective patient cohort. METHOD AND RESULTS: Retrospective review of all patients receiving a Medtronic Reveal 9525/9526 for the investigation of unexplained syncope or pre-syncope in our centre between 1998 and 2008. All ILRs were programmed for a single manual activation with 40 min retrospective ECG recording. We identified all patients who subsequently underwent permanent pacemaker implantation and analysed the time delay between bradycardia onset and manual ILR activation. Five hundred and sixty-four patients underwent implantation of an ILR during the study period. Of these, 57 (10%) subsequently underwent the implantation of a pacemaker (31 male, median age 66 years, range 9-86 years). In this group, 35 of 57 (61%) bradycardia diagnoses were made in patients (18 male, median age 65 years, range 9-86 years) after manual activation of the ILR. The median time from bradycardia onset to ILR activation was 136 s (0-488 s). Nineteen recordings showed high-grade atrio-ventricular block and 16 sinus node disease. CONCLUSION: Ten-year experience with the ILR confirms its utility in establishing a pacemaker indication as the cause for syncope or pre-syncope in 6% (34 of 564) of recipients following manual activation. This requires a recording loop of sufficient duration to reliably include both symptoms and activation.