Mortality Benefit Among Primary Prevention Implantable Cardioverter-Defibrillator Recipients on Contemporary Heart Failure Treatment.

BACKGROUND: Past clinical trials have shown the benefit of implantable cardioverter-defibrillators (ICDs) for reducing sudden cardiac death in at-risk patients. However, heart failure management and ICD technology have changed since these trials were first published. An updated assessment of ICD mortality benefit is needed. OBJECTIVES: The purpose of this study was to compare mortality rates between patients with a primary prevention (PP) indication for an ICD who did or did not receive an ICD using a contemporary, real-world data set. METHODS: Data was obtained from a large electronic health record data set covering patients in the United States from 2012 through 2020 who had a PP indication for an ICD and survived at least 1-year postindication. RESULTS: A total of 25,296 patients were identified as having a PP indication for ICD implantation, of which 2,118 (8.4%) were treated with an ICD within a year. Treated patients were younger than nontreated patients (age 63.4 years vs 66.1 years) with a smaller proportion of women (25.0% vs 36.7%). After 4-to-1 propensity matching, treated patients had similar clinical characteristics to nontreated patients. A Cox proportional hazard model estimated a 24.3% lower risk of all-cause mortality in patients when treated vs not treated with an ICD (HR: 0.757; 95% CI: 0.678-0.835; P <0.001). There was no detectable difference in ICD benefit between patients with ischemic and nonischemic heart disease (P = 0.50). CONCLUSIONS: ICD treatment of patients with a PP indication is associated with improved mortality even in the context of evolving adjunctive HF treatment, consistent with earlier landmark trials.

Nucleophile responsive charge-reversing polycations for pDNA transfection.

Polycationic carriers promise low cost and scalable gene therapy treatments, however inefficient intracellular unpacking of the genetic cargo has limited transfection efficiency. Charge-reversing polycations, which transition from cationic to neutral or negative charge, can offer targeted intracellular DNA release. We describe a new class of charge-reversing polycation which undergoes a cationic-to-neutral conversion by a reaction with cellular nucleophiles. The deionization reaction is relatively slow with primary amines, and much faster with thiols. In mammalian cells, the intracellular environment has elevated concentrations of amino acids (∼10×) and the thiol glutathione (∼1000×). We propose this allows for decationization of the polymeric carrier slowly in the extracellular space and then rapidly in the intracellular milleu for DNA release. We demonstrate that in a lipopolyplex formulation this leads to both improved transfection and reduced cytotoxicity when compared to a non-responsive polycationic control.

Chemical signal regulated injectable coacervate hydrogels.

In the quest for stimuli-responsive materials with specific, controllable functions, coacervate hydrogels have become a promising candidate, featuring sensitive responsiveness to environmental signals enabling control over sol-gel transitions. However, conventional coacervation-based materials are regulated by relatively non-specific signals, such as temperature, pH or salt concentration, which limits their possible applications. In this work, we constructed a coacervate hydrogel with a Michael addition-based chemical reaction network (CRN) as a platform, where the state of coacervate materials can be easily tuned by specific chemical signals. We designed a pyridine-based ABA triblock copolymer, whose quaternization can be regulated by an allyl acetate electrophile and an amine nucleophile, leading to gel construction and collapse in the presence of polyanions. Our coacervate gels showed not only highly tunable stiffness and gelation times, but excellent self-healing ability and injectability with different sized needles, and accelerated degradation resulting from chemical signal-induced coacervation disruption. This work is expected to be a first step in the realization of a new class of signal-responsive injectable materials.

Temporally programmed polymer - solvent interactions using a chemical reaction network.

Out of equilibrium operation of chemical reaction networks (CRNs) enables artificial materials to autonomously respond to their environment by activation and deactivation of intermolecular interactions. Generally, their activation can be driven by various chemical conversions, yet their deactivation to non-interacting building blocks remains largely limited to hydrolysis and internal pH change. To achieve control over deactivation, we present a new, modular CRN that enables reversible formation of positive charges on a tertiary amine substrate, which are removed using nucleophilic signals that control the deactivation kinetics. The modular nature of the CRN enables incorporation in diverse polymer materials, leading to a temporally programmed transition from collapsed and hydrophobic to solvated, hydrophilic polymer chains by controlling polymer-solvent interactions. Depending on the layout of the CRN, we can create stimuli-responsive or autonomously responding materials. This concept will not only offer new opportunities in molecular cargo delivery but also pave the way for next-generation interactive materials.

Thioanisole ester based logic gate cascade to control ROS-triggered micellar degradation.

In certain tumor and diseased tissues, reactive oxygen species (ROS), such as H2O2, are produced in higher concentrations than in healthy cells. Drug delivery and release systems that respond selectively to the presence of ROS, while maintaining their stability in "healthy" biological conditions, have great potential as on-site therapeutics. This study presents polymer micelles with 4-(methylthio)phenyl ester functionalities as a ROS-responsive reactivity switch. Oxidation of the thioether moieties triggers ester hydrolysis, exposing a hydrophylic carboxylate and leading to micellar disassembly. At 37 °C, the micelles fall apart on a timescale of days in the presence of 2 mM H2O2 and within hours at higher concentrations of H2O2 (60-600 mM). In the same time frame, the nanocarriers show no hydrolysis in oxidant-free physiological or mildly acidic conditions. This logic gate cascade behavior represents a step forward to realize drug delivery materials capable of selective response to a biomarker input.

Fuel-driven macromolecular coacervation in complex coacervate core micelles.

Fuel-driven macromolecular coacervation is an entry into the transient formation of highly charged, responsive material phases. In this work, we used a chemical reaction network (CRN) to drive the coacervation of macromolecular species readily produced using radical polymerisation methods. The CRN enables transient quaternization of tertiary amine substrates, driven by the conversion of electron deficient allyl acetates and thiol or amine nucleophiles. By incorporating tertiary amine functionality into block copolymers, we demonstrate chemical triggered complex coacervate core micelle (C3M) assembly and disassembly. In contrast to most dynamic coacervate systems, this CRN operates at constant physiological pH without the need for complex biomolecules. By varying the allyl acetate fuel, deactivating nucleophile and reagent ratios, we achieved both sequential signal-induced C3M (dis)assembly, as well as transient non-equilibrium (dis)assembly. We expect that timed and signal-responsive control over coacervate phase formation at physiological pH will find application in nucleic acid delivery, nano reactors and protocell research.

Linear Coordination Polymer Synthesis from Bis-Catechol Functionalized RAFT Polymers.

Catechol-Fe(III) complexes contain some of the strongest known metal-chelate coordination bonds. Despite this, they have until now not been utilized in (polymeric linker) linear coordination polymer (LCP) synthesis. With the view of generating catechol end-functional polymers, a new, symmetrical bis-catechol functionalized trithiocarbonate reversible addition fragmentation chain transfer (RAFT) agent is synthesized (CatDMAT). Acrylamide (AM) and dimethylacrylamide (DMA) polymerizations are conducted with CatDMAT using direct photoactivation RAFT polymerization to yield bis-catechol end-functionalized homo- and block-copolymers of molecular weight 10-15 kDa. Catechol-Fe(III) LCPs are successfully formed from the telechelic catechol polymers by bis-complexation to Fe(III). The tetrahedral bis-complex is detected by UV-vis spectroscopy (λmax  = 570 nm), while increases in relative viscosity and Mn,GPC over their respective uncomplexed polymers confirm the occurrence of supramolecular polymerization. The catechol-LCPs are shown to undergo oxidation and crosslinking in aqueous solution after 24 h.

Ultra-high molecular weight linear coordination polymers with terpyridine ligands.

Ultra-high molecular weight (UHMW, M n > 1000 kDa) polymeric drift control adjuvants (DCAs) for agricultural spraying are prone to mechanical degradation and rapidly lose performance. To overcome this, we have designed linear coordination polymers (LCPs) composed of 400 kDa telechelic bis-terpyridine end-functionalised polyacrylamide units, which 'self-heal' upon shearing through reformation of coordination bonds. After addition of Fe(ii) to dilute aqueous solutions of the terpyridine telechelics, UHMW LCPs were obtained as demonstrated by UV-vis spectroscopy, MALS GPC and intrinsic viscosity measurements. Importantly, these UHMW LCPs were shown to function as effective DCAs, reducing the formation of fine 'driftable' droplets during spray testing at concentrations as low as 100 ppm. Following mechanically-induced coordination bond-scission, the UHMW LCPs were found to recover up to 90% of their performance compared to un-sheared samples, at a rate dependent on the transition metal ion used to form the complex.

Light-Induced RAFT Single Unit Monomer Insertion in Aqueous Solution-Toward Sequence-Controlled Polymers.

First report on the sequential, visible light-initiated, single unit monomer insertion (SUMI) of N,N-dimethylacrylamide (DMAm) into the reversible addition fragmentation chain transfer (RAFT) agent, 4-((((2-carboxyethyl)thio)carbonothioyl)thio)-4-cyanopentanoic acid (CTA1 ), in aqueous solution is provided. The specificity for SUMI over formation of higher oligomers and/or RAFT agent-derived by-products is higher for longer irradiation wavelengths. Red light provides the cleanest product (selective SUMI), showing a linear pseudo-first order kinetic profile to high (>80%) conversion, but also the slowest reaction rate. Blue light provides a relatively rapid reaction, but also gives some by-products (<2%) and the kinetic profile displays a conversion plateau at >65% conversion. Higher specificity with red light is attributed to CTA1 absorbing at longer wavelengths than the SUMI product, which allows selective excitation of CTA1 . The use of a higher reaction temperature (65 °C vs ambient) results in a higher reaction rate and a reduction in oligomer formation.

Compliance with remote monitoring of ICDS/CRTDS in a real-world population.

BACKGROUND: Remote monitoring (RM) of defibrillators (implantable cardioverter defibrillators [ICDs]) and cardiac resynchronization therapy devices (CRTDs) has been shown to be cost effective, convenient, and associated with reduced mortality and a reduction in the time to physician intervention for actionable events. However, patient compliance with monitoring over time and what factors might influence such compliance have not been well described. This study sought to identify factors contributing to patient noncompliance with RM of ICDs and CRTDs in a large real-world population. METHODS: Deidentified data on U.S. patients enrolled in the Medtronic CareLink RM system were used to compare patients with no (noncompliant, n = 14,848) and with ≥ 2 RM transmissions (compliant, n = 103,284) during a 14-month period. RESULTS: Overall noncompliance with RM was 21%. Younger age (≤ 40), female sex, wanded device, Medicare Census Division, and small clinic size all predicted patient noncompliance (P < 0.01). Device type (ICD vs CRTD) did not (P = 0.52). Multivariate analysis suggested clinically important predictors of noncompliance to be: age ≤ 40, odds ratio (OR) 2.64 (95% confidence interval, 2.42-2.88); Medicare Census Division (Mountain vs West North Central), OR 2.15 (1.96-2.37); and small clinic size (1-4 vs >100 patients), OR 4.38 (3.92-4.91). CONCLUSIONS: There is room for improvement in RM usage among enrolled patients. Younger patients, smaller clinics, and certain geographic areas may be targets for research into interventions to further improve the use of RM.

Detection system built from commercial integrated circuits for real-time measurement of radiation dose and quality using the variance method.

A small, specialised amplifier using commercial integrated circuits (ICs) was developed to measure radiation dose and quality in real time using a microdosimetric ion chamber and the variance method. The charges from a microdosimetric ion chamber, operated in the current mode, were repeatedly collected for a fixed period of time for 20 cycles of 100 integrations, and processed by this specialised amplifier to produce signal pulse heights between 0 and 10 V. These signals were recorded by a multi-channel analyser coupled to a computer. FORTRAN programs were written to calculate the dose and dose variance. The dose variance produced in the ion chamber is a microdosimetric measure of radiation quality. Benchmark measurements of different brands of ICs were conducted. Results demonstrate that this specialised amplifier is capable of distinguishing differences of radiation quality in various high-dose-rate radiation fields including X rays, gamma rays and mixed neutron-gamma radiation from the research reactor at Texas A&M University Nuclear Science Center.

Acid-base balance of the domestic turkey during thermal panting.

The objectives of this research were to evaluate the effects of thermal panting in domestic turkeys on arterial blood values for the acid-base variables, pH(a), bicarbonate concentration ([HCO(-) (3)](a)), partial pressure of carbon dioxide (P(a)CO(2)), and hemoglobin concentration [Hb]. In addition, body temperature and partial pressure of oxygen (P(a)O(2)) were measured to determine the effectiveness of panting in their control. Nine adult (23 wk) broad-breasted white turkey toms, all from the same hatch and reared contemporaneously in the same facility, were acclimated to room conditions of 19 degrees C and 65% RH. After a 1-wk control period, a 3-wk heat-stress period (32 degrees C, 65% RH) was induced, for a heat-stress group of 9 turkeys. Thermal panting began at this time and continued to its end. A 1-wk recovery period followed (19 degrees C, 65% RH) during which panting ceased. An age-matched group of 8 turkeys was similarly acclimated (19 degrees C, 65% RH) but was continued at this level to the end of the experiment. During the heat-stress period, the bicarbonate concentration increased, whereas pH(a) and P(a)CO(2) did not change significantly. Body temperature changes were not significant. Parabronchial ventilation was not compromised by panting, as noted by a significant increase in P(a)O(2). Hemoglobin concentration decreases were significant. The only significant change that occurred for the age-matched group was an increase in [Hb]. Domestic turkeys, reared in confinement, have the ability to resist changes in blood pH and prevent the development of respiratory alkalosis while panting in response to thermal stress. Normal body temperature and oxygenation of the blood are also maintained.

Gemcitabine with a specific conformal 3D 5FU radiochemotherapy technique is safe and effective in the definitive management of locally advanced pancreatic cancer.

The aim of this phase II study was to assess the feasibility and efficacy of a specific three-dimensional conformal radiotherapy technique with concurrent continuous infusion of 5-fluorouracil (CI 5FU) sandwiched between gemcitabine chemotherapy in patients with locally advanced pancreatic cancer. Patients with inoperable cancer in the pancreatic head or body without metastases were given gemcitabine at 1000 mg m(-2) weekly for 3 weeks followed by a 1-week rest and a 6-week period of radiotherapy and concurrent CI 5FU (200 mg m(-2) day(-1)). The defined target volume was treated to 54 Gy in 30 daily fractions of 1.8 Gy. After 4 weeks' rest, gemcitabine treatment was re-initiated for three cycles (days 1, 8, 15, q28). Forty-one patients were enrolled. At the end of radiotherapy, one patient (2.4%) had a complete response and four patients (9.6%) had a partial response; at the end of treatment, three patients (7.3%) had a complete response and two patients (4.9%) had a partial response. Median survival time was 11.7 months, median time to progression was 7.1 months, and median time to failure of local control was 11.9 months. The 1- and 2-year survival rates were 46.3 and 9.8%, respectively. Treatment-related grade 3 and 4 toxicities were reported by 16 (39.0%) and four (9.8%) patients, respectively. Sixteen out of 41 patients did not complete the planned treatment and nine due to disease progression. This approach to treatment of locally advanced pancreatic cancer is safe and promising, with good local control for a substantial proportion of patients, and merits testing in a randomised trial.

Effects of storage time and temperature after blood sampling from turkeys on plasma concentrations of potassium, sodium, and chloride.

The objectives of this research were to study the effect of several time intervals of turkey blood storage from sampling to centrifugation on plasma K, Na, and Cl concentrations and to study the effect of ambient temperature of turkey blood storage on these same variables. In the first study, 6 consecutive blood samples were obtained from each turkey. The first sample was centrifuged immediately (control), and each of the others was respectively stored for 20, 40, 60, 120, or 360 min at 22 degrees C before centrifugation and plasma harvest. In the second study, 4 consecutive blood samples were obtained from each turkey. The first sample was centrifuged immediately (control), and each of the others was respectively stored at ambient temperatures of 9, 22, and 30 degrees C for 120 min before centrifugation and plasma harvest. Plasma K concentration declines and is significant (P < 0.01) for each of the 20, 40, 60, 120, and 360 min values. Plasma Na concentration increases and Cl decreases were not significant (P < 0.01) until 360 and 120 min, respectively. Significant (P < 0.01) reductions occurred for plasma K concentration for each of the ambient temperature values but were the least at 9 degrees C and greatest when stored at 30 degrees C. Plasma Na concentration decreased (P < 0.01) when stored at 9 degrees C. Though increased (P < 0.01) when stored at 22 and 30 degrees C, the difference was not significant (P < 0.01) between samples stored at either 22 or 30 degrees C. Plasma Cl concentration was decreased (P < 0.01) from control values, but there was no significant difference (P < 0.01) among samples stored at 9, 22, and 30 degrees C. Clot formation and its retraction from serum are unduly delayed after blood is withdrawn from turkeys because birds lack the intrinsic mechanism for blood coagulation. Accordingly, serum is not appropriate for the determination of K concentration in turkeys, and plasma harvested immediately after blood sampling is the fluid of choice for K analysis.

GE PETtrace cyclotron as a neutron source for boron neutron capture therapy.

This paper discusses the use of a General Electric PETtrace cyclotron as a neutron source for boron neutron capture therapy. In particular, the standard PETtrace (18)O target is considered. The resulting dose from the neutrons emitted from the target is evaluated using the Monte Carlo radiation transport code MCNP at different depths in a brain phantom. MCNP-simulated results are presented at 1, 2, 3, 4, 5, 6, 7, and 8 cm depth inside this brain phantom. Results showed that using a PETtrace cyclotron in the current configuration allows treating tumors at a depth of up to 4 cm with reasonable treatment times. Further increase of a beam current should significantly improve the treatment time and allow treating tumors at greater depths.

Cellular immunity induced by the recombinant Plasmodium falciparum malaria vaccine, RTS,S/AS02, in semi-immune adults in The Gambia.

Vaccination of malaria-naive humans with recombinant RTS,S/AS02, which includes the C-terminus of the circumsporozoite protein (CS), has been shown to induce strong T cell responses to both the whole protein antigen and to peptides from CS. Here we show that strong T cell responses were also observed in a semi-immune population in The Gambia, West Africa. In a Phase I study, 20 adult male volunteers, lifelong residents in a malaria-endemic region, were given three doses of RTS,S/AS02 at 0, 1 and 6 months. Responses to RTS,S, hepatitis B surface antigen and peptides from CS were tested using lymphocyte proliferation, interferon (IFN)-gamma production in microcultures, and IFN-gamma ex vivo and cultured ELISPOT, before and after vaccination. Cytotoxic responses were tested only after vaccination and none were detected. Before vaccination, the majority of the volunteers (15/20) had detectable responses in at least one of the tests. After vaccination, responses increased in all assays except cytotoxicity. The increase was most marked for proliferation; all donors responded to RTS,S after the third dose and all except one donor responded to at least one peptide after the second or third dose. There was a lack of close association of peptide responses detected by the different assays, although in microcultures IFN-gamma responses were found only when proliferative responses were high, and responses by cultured ELISPOT and proliferation were found together more frequently after vaccination. We have therefore identified several peptide-specific T cell responses induced by RTS,S/AS02 which provides a mechanism to investigate potentially protective immune responses in the field.

Prospective randomised phase II study of gemcitabine at standard or fixed dose rate schedule in unresectable hepatocellular carcinoma.

The present randomised phase II study was an effort to evaluate single-agent gemcitabine as a first-line systemic treatment of Asian patients with unresectable hepatocellular carcinoma (HCC). Gemcitabine was given via intravenous infusion at 1250 mg m(-2) on days 1 and 8 of 3-week cycles. Patients were randomised to receive gemcitabine as a 30-min intravenous infusion (standard schedule) or at a fixed dose rate (FDR) of 10 mg m(-2) min(-1). A total of 50 patients were enrolled in the study, of whom 48 received study therapy. One patient on standard schedule had a partial response, for an overall response rate of 2.1% (95% CI: 0.05-11.1%). The median time to progression and survival time were 46 and 97 days, respectively. The overall rates of Grade 3 or 4 haematological and nonhaematological toxicities were 39.6 and 64.6%, respectively, with no significant difference between the two treatment arms. There were no drug-related deaths and severe clinical toxicities were rare. Both schedules of gemcitabine were safe and toxicity was well manageable in this patient population. However, gemcitabine seems no more active than other cytotoxic agents when used alone for systemic treatment of advanced HCC.

Effect of torso adipose tissue thickness on effective dose in a broad parallel photon beam.

The effect of torso adipose tissue thickness on effective dose was studied for external broad parallel photon beams using the MCNP code and a mathematical anthropomorphic phantom. The variation of torso adipose tissue thickness was modeled by adding a layer of soft tissue (1-7 cm) around the torso of the phantom. This study found that effective dose varies almost linearly with the thickness of the adipose tissue layer. For most irradiation geometries (i.e., antero-posterior, postero-anterior, and lateral), effective dose decreases with the thickness of the adipose tissue layer due to the shielding effect of the layer. Effective dose decreases by 11-35% when the thickness of the adipose tissue layer increases from 0 to 7 cm considering all photon energies (0.08, 0.3, and 1.0 MeV) and irradiation geometries in this study. For overhead irradiation geometry, however, an increase of adipose tissue layer thickness results in an increase of effective dose. This is because the organs and tissues in the body are additionally exposed by the photons that are scattered from the added adipose tissue layer. For the overhead irradiation geometry, effective dose increases by 13-27% when the adipose tissue thickness increases from 0 to 7 cm.

Monte Carlo simulation of single and two-dosimeter approaches in a steam generator channel head.

In a steam generator channel head, it was not unusual to see radiation workers wearing as many as twelve dosimeters over the surface of the body to avoid a possible underestimation of effective dose equivalent (H(E)) or effective dose (E). This study shows that only one or two dosimeters can be used to estimate H(E) and E without a significant underestimation. MCNP and a point-kernel approach were used to model various exposure situations in a steam generator channel head. The single-dosimeter approach (on the chest) was found to underestimate H(E) and E significantly for a few exposure situations, i.e., when the major portion of radiation source is located in the backside of a radiation worker. In this case, the photons from the source pass through the body and are attenuated before reaching the dosimeter on the chest. To assure that a single dosimeter provides a good estimate of worker dose, these few exposure situations cannot dominate a worker's exposure. On the other hand, the two-dosimeter approach (on the chest and back) predicts H(E) and E very well, hardly ever underestimating these quantities by more than 4% considering all worker positions and contamination situations in a steam generator channel head. This study shows that two dosimeters are adequate for an accurate estimation of H(E) and E in a steam generator channel head.