Intracellular islatravir-triphosphate half-life supports extended dosing intervals.

Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t½) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 study was performed to evaluate the pharmacokinetics and safety of islatravir in plasma and the pharmacokinetics of islatravir-TP in peripheral blood mononuclear cells after administration of a single oral dose of islatravir 30 mg. Eligible participants were healthy adult males without HIV infection between the ages of 18 and 65 years. Fourteen participants were enrolled. The median time to maximum plasma islatravir concentration was 1 hour. Plasma islatravir concentrations decreased in a biphasic manner, with a t½ of 73 hours. The t½ (percentage geometric coefficient of variation) of islatravir-TP in peripheral blood mononuclear cells through 6 weeks (~1008 hours) after dosing was 8.1 days or 195 hours (25.6%). Islatravir was generally well tolerated with no drug-related adverse events observed. Islatravir-TP has a long intracellular t½, supporting further clinical investigation of islatravir administered at an extended dosing interval.

Thorough QT/QTc study to evaluate the effect of a single supratherapeutic dose of islatravir on QTc interval prolongation in healthy adults.

Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly. In multiple previous clinical studies, islatravir was generally well tolerated, with no clear trend in cardiac adverse events. A trial was conducted to evaluate the effect of islatravir on cardiac repolarization. A randomized, double-blind, active- and placebo-controlled phase 1 trial was conducted, in which a single dose of islatravir 0.75 mg, islatravir 240 mg (supratherapeutic dose), moxifloxacin 400 mg (active control), or placebo was administered. Continuous 12-lead electrocardiogram monitoring was performed before dosing through 24 hours after dosing. QT interval measurements were collected, and safety and pharmacokinetics were evaluated. Sixty-three participants were enrolled, and 59 completed the study. Fridericia's QT correction for heart rate was inadequate; therefore, a population-specific correction was applied (QTcP). The placebo-corrected change from baseline in QTcP (ΔΔQTcP) interval at the observed geometric mean maximum plasma concentration associated with islatravir 0.75 mg and islatravir 240 mg was <10 ms at all time points. Assay sensitivity was confirmed because the use of moxifloxacin 400 mg led to a ΔΔQTcP >10 ms. The pharmacokinetic profile of islatravir was consistent with that of previous studies, and islatravir was generally well tolerated. Results from the current trial suggest that single doses of islatravir as high as 240 mg do not lead to QTc interval prolongation.

Effects of Structural Constraints on Excited-State Properties in Dimeric Cu(I) Diimine Complexes.

Copper(I) bis-diimine complexes have played important roles in light-activated processes that can lead to their potential applications in photocatalysis and chemical sensing. Their metal-to-ligand charge-transfer (MLCT) excited-state properties are tunable by various structural factors. Dimeric Cu(I) complexes with connecting diimine derivative ligands offer another structural tuning platform for the excited-state properties. Here, we investigate excited-state properties in two covalently connected dimeric Cu(I)'s with varying structural constraints exerted by the number of carbons in the polyethylene bridge (C0 and C4) connecting the two copper(I) diimine moieties. An interesting feature of Cu(I) diimine complexes is their ability to flatten following a photoinduced structural change. Herein, we observe larger structural constraints and more structural rearrangement required upon excitation of the longer bridged complex C4 to achieve a conformation toward a more flattened tetrahedral coordination geometry compared to the shorter bridged C0. Vibrational wavepacket analysis of these complexes further supports the effect of these structural constraints where we observe a more rapid dephasing of the C0 complex, as opposed to the C4 complex, despite similar normal mode vibrations. The experimental results were supplemented by TDDFT calculations. The studies provide insight into using metal-metal interactions through constraints to tune excited-state dynamics and pathways.

Solvent effects on the photooxidation of indolepyrazines.

Photodestruction of 2-(pyrazin-2'-yl)-1H-indole and 2,5-di(1H-indol-2'-yl)pyrazine involves singlet oxygen generation and its rapid insertion into the indole ring with the formation of benzoxazinone derivatives: 2-(pyrazin-2-yl)-4H-3,1-benzoxazin-4-one and 2-[5-(1H-indol-2-yl)pyrazin-2-yl]-4H-3,1-benzoxazin-4-one. The quantum yield of this reaction strongly depends on the environment. It is definitely smaller in protic methanol than in aprotic acetonitrile or n-hexane. The observed effect of photostabilization is explained by formation of hydrogen bonded complexes between the chromophore and alcohol, which results in lower triplet formation efficiency and, in consequence, decrease of singlet oxygen formation quantum yield.

New Tridentate Ligand Affords a Long-Lived 3MLCT Excited State in a Ru(II) Complex: DNA Photocleavage and 1O2 Production.

Two new complexes, [Ru(tpy)(qdppz)](PF6)2 (1; qdppz = 2-(quinolin-8-yl)dipyrido[3,2-a:2',3'-c]phenazine, tpy = 2,2':6',2″-terpyridine) and [Ru(qdppz)2](PF6)2 (2), were investigated for their potential use as phototherapeutic agents through their ability to photosensitize the production of singlet oxygen, 1O2, upon irradiation with visible light. The complexes exhibit strong Ru(dπ) → qdppz(π*) metal-to-ligand charge transfer (MLCT) absorption with maxima at 485 and 495 nm for 1 and 2 in acetone, respectively, red-shifted from the Ru(dπ) → tpy(π*) absorption at 470 nm observed for [Ru(tpy)2]2+ (3) in the same solvent. Complexes 1 and 3 are not luminescent at room temperature, but 3MLCT emission is observed for 2 with maximum at 690 nm (λexc = 480 nm) in acetone. The lifetimes of the 3MLCT states of 1 and 2 were measured using transient absorption spectroscopy to be ∼9 and 310 ns in methanol, respectively, at room temperature (λexc = 490 nm). The bite angle of the qdppz ligand is closer to octahedral geometry than that of tpy, resulting in the longer lifetime of 2 as compared to those of 1 and 3. Arrhenius treatment of the temperature dependence of the luminescence results in similar activation energies, Ea, from the 3MLCT to the 3LF (ligand-field) state for the two complexes, 2520 cm-1 in 1 and 2400 cm-1 in 2. However, the pre-exponential factors differ by approximately two orders of magnitude, 2.3 × 1013 s-1 for 1 and 1.4 × 1011 s-1 for 2, which, together with differences in the Huang-Rhys factors, lead to markedly different 3MLCT lifetimes. Although both 1 and 2 intercalate between the DNA bases, only 2 is able to photocleave DNA owing to its 1O2 production upon irradiation with ΦΔ = 0.69. The present work highlights the profound effect of the ligand bite angle on the electronic structure, providing guidelines for extending the lifetime of 3MLCT Ru(II) complexes with tridentate ligands, a desired property for a number of applications.

Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency.

Islatravir (MK-8591) is a high-potency reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. Data from preclinical and clinical studies suggest that ~30% to 60% of islatravir is excreted renally and that islatravir is not a substrate of renal transporters. To assess the impact of renal impairment on the pharmacokinetics of islatravir, an open-label phase 1 trial was conducted with individuals with severe renal insufficiency (RI). A single dose of islatravir 60 mg was administered orally to individuals with severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and to healthy individuals without renal impairment (matched control group; eGFR ≥90 mL/min/1.73 m2). Safety and tolerability were assessed, and blood samples were collected to measure the pharmacokinetics of islatravir and its major metabolite 4'-ethynyl-2-fluoro-2'deoxyinosine (M4) in plasma, as well as active islatravir-triphosphate (TP) in peripheral blood mononuclear cells (PBMCs). Plasma islatravir and M4 area under the concentration-time curve from zero to infinity (AUC0-∞) were ~2-fold and ~5-fold higher, respectively, in participants with severe RI relative to controls, whereas islatravir-TP AUC0-∞ was ~1.5-fold higher in the RI group than in the control group. The half-lives of islatravir in plasma and islatravir-TP in PBMCs were longer in participants with severe RI than in controls. These findings are consistent with renal excretion playing a major role in islatravir elimination. A single oral dose of islatravir 60 mg was generally well tolerated. These data provide guidance regarding administration of islatravir in individuals with impaired renal function. (This study has been registered at ClinicalTrials.gov under registration no. NCT04303156.).

Metalloimmunotherapy with Rhodium and Ruthenium Complexes: Targeting Tumor-Associated Macrophages.

Tumor associated macrophages (TAMs) suppress the cancer immune response and are a key target for immunotherapy. The effects of ruthenium and rhodium complexes on TAMs have not been well characterized. To address this gap in the field, a panel of 22 dirhodium and ruthenium complexes were screened against three subtypes of macrophages, triple-negative breast cancer and normal breast tissue cells. Experiments were carried out in 2D and biomimetic 3D co-culture experiments with and without irradiation with blue light. Leads were identified with cell-type-specific toxicity toward macrophage subtypes, cancer cells, or both. Experiments with 3D spheroids revealed complexes that sensitized the tumor models to the chemotherapeutic doxorubicin. Cell surface exposure of calreticulin, a known facilitator of immunogenic cell death (ICD), was increased upon treatment, along with a concomitant reduction in the M2-subtype classifier arginase. Our findings lay a strong foundation for the future development of ruthenium- and rhodium-based chemotherapies targeting TAMs.

Electrocatalytic Hydrogen Evolution by Cobalt Complexes with a Redox Non-Innocent Polypyridine Ligand.

Novel cobalt and zinc complexes with the tetradentate ppq (8-(1″,10″-phenanthrol-2″-yl)-2-(pyrid-2'-yl)quinoline) ligand have been synthesized and fully characterized. Electrochemical measurements have shown that the formal monovalent complex [Co(ppq)(PPh3)]+ (2) undergoes two stepwise ligand-based electroreductions in DMF, affording a [Co(ppq)DMF]-1 species. Theoretical calculations have described the electronic structure of [Co(ppq)DMF]-1 as a low-spin Co(II) center coupling with a triple-reduced ppq radical ligand. In the presence of triethylammonium as the proton donor, the cobalt complex efficiently drives electrocatalytic hydrogen evolution with a maximum turnover frequency of thousands per second. A mechanistic investigation proposes an EECC H2-evolving pathway, where the second ligand-based redox process (E), generating the [Co(ppq)DMF]-1 intermediate, initiates proton reduction, and the second proton transfer process (C) is the rate-determining step. This work provides a unique example for understanding the role of redox-active ligands in electrocatalytic H2 evolution by transition metal sites.

Revisiting Dinuclear Ruthenium Water Oxidation Catalysts: Effect of Bridging Ligand Architecture on Catalytic Activity.

An attractive catalytic pathway for the conversion of water to oxygen would involve two metal oxide centers combining in a constructive sense to make O═O. This prospect makes the study of certain dinuclear transition metal complexes particularly attractive. In this work, we describe the design and synthesis of two symmetrical bis-tridentate polypyridine ligands 6 and 12 that bind two RuII centers at a separation of 3.6 Šin 7 and 5.7 Šin 13. In the presence of CeIV at pH = 1, these systems oxidize water with the system having the more proximal metals being more reactive. In the case of the more proximal metal centers, the bridging ligand is a 3,6-disubstituted pyridazine which, under the influence of CeIV, cleaves into two [Ru(bpc)(pic)2CH3CN]+ fragments (14) which then function as the actual catalyst (bpc = 2,2'-bipyridine-6-carboxylate, pic = 4-methylpyridine). The second dinuclear catalyst contains a central pyrimidine ring which is less sensitive to oxidative decay and hence less reactive. Caution is advised in the use of CeIV as a sacrificial electron acceptor due to unexpected oxidative decay of the catalyst.

Transition Metal Complexes and Photodynamic Therapy from a Tumor-Centered Approach: Challenges, Opportunities, and Highlights from the Development of TLD1433.

Transition metal complexes are of increasing interest as photosensitizers in photodynamic therapy (PDT) and, more recently, for photochemotherapy (PCT). In recent years, Ru(II) polypyridyl complexes have emerged as promising systems for both PDT and PCT. Their rich photochemical and photophysical properties derive from a variety of excited-state electronic configurations accessible with visible and near-infrared light, and these properties can be exploited for both energy- and electron-transfer processes that can yield highly potent oxygen-dependent and/or oxygen-independent photobiological activity. Selected examples highlight the use of rational design in coordination chemistry to control the lowest-energy triplet excited-state configurations for eliciting a particular type of photoreactivity for PDT and/or PCT effects. These principles are also discussed in the context of the development of TLD1433, the first Ru(II)-based photosensitizer for PDT to enter a human clinical trial. The design of TLD1433 arose from a tumor-centered approach, as part of a complete PDT package that includes the light component and the protocol for treating non-muscle invasive bladder cancer. Briefly, this review summarizes the challenges to bringing PDT into mainstream cancer therapy. It considers the chemical and photophysical solutions that transition metal complexes offer, and it puts into context the multidisciplinary effort needed to bring a new drug to clinical trial.

NIR-Absorbing RuII Complexes Containing α-Oligothiophenes for Applications in Photodynamic Therapy.

The design of near-infrared (NIR)-active photosensitizers (PSs) for light-based cancer treatments such as photodynamic therapy (PDT) has been a challenge. While several NIR-RuII scaffolds have been reported, this approach has not been proven in cells. This is the first report of NIR-RuII PSs that are phototoxic to cancer cells, including highly pigmented B16F10 melanoma cells. The PS family incorporated a bis(1,8-naphthyridine)-based ligand (tpbn), a bidentate thiophene-based ligand (nT; n=0-4), and a monodentate 4-picoline ligand (4-pic). All compounds absorbed light >800 nm with maxima near 730 nm. Transient absorption (TA) measurements indicated that n=4 thiophene rings (4T) positioned the PDT-active triplet intraligand charge transfer (3 ILCT) excited state in energetic proximity to the lowest-lying triplet metal-to-ligand charge transfer (3 MLCT). 4T had low-micromolar phototoxicity with PIvis and PI733nm values as large as 90 and 12, respectively. Spectroscopic studies suggested that the longer-lived (τTA =3-6 µs) 3 ILCT state was accessible from the 3 MLCT state, but energetically uphill in the overall photophysics. The study highlights that phototoxic effects can be achieved with NIR-absorbing RuII PSs as long as the reactive 3 ILCT states are energetically accessible from the low-energy 3 MLCT states. It also demonstrates that tissue-penetrating NIR light can be used to activate the PSs in highly pigmented cells where melanin attenuates shorter wavelengths of light.

Fluorescence and Metal-Binding Properties of the Highly Preorganized Tetradentate Ligand 2,2'-Bi-1,10-phenanthroline and Its Remarkable Affinity for Cadmium(II).

The metal-ion-complexing properties of the tetradentate ligand 2,2'-bi-1,10-phenanthroline (BIPHEN) in 50% CH3OH/H2O are reported for a variety of metal ions. BIPHEN (with two reinforcing benzo groups in the backbone) was compared to other tetrapyridyls, 2,9-di(pyrid-2-yl)-1,10-phenanthroline (DPP; with one benzo group) and 2,2':6',2″:6″,2‴- quaterpyridine (QPY; with no benzo groups), with levels of preorganization BIPHEN > DPP > QPY. Formation constants were determined by following the variation of the intense π → π* transitions in the absorbance spectra of BIPHEN in the presence of metal ion as a function of the pH. The log K1 values show that the increased level of preorganization produced by the two benzo groups, reinforcing the backbone of the BIPHEN ligand, leads to increased complex stability with large metal ions (an ionic radius greater than 0.9 Å) compared to the less preorganized tetrapyridines DPP and QPY. In particular, the large CdII ion [log K1(BIPHEN) = 12.7] shows unusual selectivity over the small ZnII ion [log K1(BIPHEN) = 7.78]. The order of levels of preorganization BIPHEN > DPP > QPY leads to enhanced selectivity for SmIII over GdIII with increased preorganization, which is of interest in relation to separating AmIII from GdIII in the treatment of radioactive waste. AmIII is very close in ionic radius to SmIII, so that the size-based selectivity produced by the enhanced preorganization of BIPHEN should translate into enhanced AmIII/GdIII selectivity. The chelation-enhanced fluorescence (CHEF) effect in BIPHEN complexes is discussed. The CHEF effect in the ZnII complex is somewhat smaller than that for CdII, which is discussed in terms of decreased overlap in the Zn-N bonds formed by the too small ZnII, leading to a partial photoinduced-electron-transfer quenching of fluorescence. The structure of the complex [Cd(BIPHEN)2](ClO4)2 is reported and shows that the Cd-N bonds are largely normal for the unusual 8-coordination observed, except that steric clashes between the terminal pyridyl groups of each of the BIPHEN ligands, and the rest of the orthogonal BIPHEN ligand, lead to some stretching of the outer Cd-N bonds.

Population Pharmacokinetics and Pharmacodynamics of Bezlotoxumab in Adults with Primary and Recurrent Clostridium difficile Infection.

The fully human monoclonal antibody bezlotoxumab is indicated for preventing the recurrence of Clostridioides difficile (formerly Clostridium difficile) infection (CDI) in adults who receive antibacterial treatment for CDI and who are at high risk for a CDI recurrence. The efficacy and safety of 10-mg/kg of body weight bezlotoxumab were demonstrated in two phase 3 trials: the MODIFY I (ClinicalTrials.gov registration number NCT01241552) and MODIFY II (ClinicalTrials.gov registration number NCT01513239) trials. Here, a population pharmacokinetic (popPK) analysis, performed using data from the MODIFY I and II trials (n = 1,515) and from three phase 1 trials (n = 72) to characterize bezlotoxumab pharmacokinetics (PK) in phase 3 clinical trial participants and in healthy subjects, is reported. A stepwise covariate search was conducted to identify factors influencing PK. Post hoc-estimated bezlotoxumab exposures from the popPK model were used to conduct an exposure-response analysis for CDI recurrence. Bezlotoxumab PK were described by a two-compartment model with linear elimination and allometric scaling for clearance and the volume of distribution by body weight. Although the final popPK model included gender, ethnicity (Japanese descent), race (black versus nonblack), and albumin level as significant covariates, the impact of these factors was not clinically meaningful, based on the totality of the PK and clinical experience. Exposure-response analysis of CDI recurrence demonstrated a similar low rate of CDI recurrence over the entire range of exposures achieved in the phase 3 trials, indicating that exposures were on the maximal response plateau of the exposure-response curve. Overall, the analyses confirmed the appropriateness of the 10-mg/kg dose across the phase 3 trial population with no dose adjustments necessary over a broad demographic background.

Photoinduced oxidation of an indole derivative: 2-(1'H-indol-2'-yl)-[1,5]naphthyridine.

The UV-induced oxidation of 2-(1'H-indol-2'-yl)-[1,5]naphthyridine acetonitrile solution in the presence of air leads to the formation of 2-(1,5-naphthyridin-2-yl)-4H-3,1-benzoxazin-4-one as a major product and N-(2-formylphenyl)-1,5-naphthyridine-2-carboxamide as a minor one. The probable reaction mechanisms are different for the two photoproducts and may involve both the reaction with singlet oxygen generated by the excited substrate or the reaction of the excited substrate with the ground state oxygen molecule. Electronic absorption and IR spectra indicate that both photoproducts are formed as mixtures of syn and anti-rotameric forms. The obtained results indicate an efficient and easy method for the synthesis of molecules with a benzoxazinone structure.

Early photophysical events of a ruthenium(ii) molecular dyad capable of performing photochemical water oxidation and of its model compounds.

The early photophysical events occurring in the dinuclear metal complex [(ttb-terpy)(I)Ru(µ-dntpz)Ru(bpy)2]3+ (2; ttb-terpy = 4,4',4''-tri-tert-butyl-terpy; bpy = 2,2'-bipyridine; dntpz = 2,5-di-(1,8-dinaphthyrid-2-yl)pyrazine) - a species containing the chromophoric {(bpy)2Ru(µ-dntpz)}2+ subunit and the catalytic {(I)(ttb-terpy)Ru(µ-dntpz)}+ unit, already reported to be able to perform photocatalytic water oxidation - have been studied by ultrafast pump-probe spectroscopy in acetonitrile solution. The model species [Ru(bpy)2(dntpz)]2+ (1), [(bpy)2Ru(µ-dntpz)Ru(bpy)2]4+ (3), and [(ttb-terpy)(I)Ru((µ-dntpz)Ru[(ttb-terpy)(I)]2+ (4) have also been studied. For completeness, the absorption spectra, redox behavior of 1-4 and the spectroelectrochemistry of the dinuclear species 2-4 have been investigated. The usual 3MLCT (metal-to-ligand charge transfer) decay, characterized by relatively long lifetimes on the ns timescale, takes place in 1 and 3, whose lowest-energy level involves a {(bpy)2Ru(dntpz)}2+ unit, whereas for 2 and 4, whose lowest-energy excited state involves a 3MLCT centered on the {(I)(ttb-terpy)Ru(µ-dntpz)}+ subunit, the excited-state lifetimes are on the ps timescale, possibly involving population of a low-lying 3MC (metal-centered) level. Compound 2 also exhibits a fast process, with a time constant of 170 fs, which is attributed to intercomponent energy transfer from the MLCT state centered in the {(bpy)2Ru(µ-dntpz)}2+ unit to the MLCT state involving the {(I)(ttb-terpy)Ru(µ-dntpz)}+ unit. Both the intercomponent energy transfer and the MLCT-to-MC activation process take place from non-equilibrated MLCT states.

Combined effect of hydrogen bonding interactions and freezing of rotameric equilibrium on the enhancement of photostability.

The photophysics and photostability of 12,13-dihydro-5H-indolo[3,2-c]acridine (IA), a rigid bifunctional indole derivative with proton donor/acceptor functionalities, can be drastically changed by the environment. The formation of hydrogen bonds with alcohols leads to a significant decrease of the triplet formation efficiency and an increase of photostability. The photodegradation yield was found to be about two hundred times lower in methanol and 1-propanol than in n-hexane or acetonitrile. A similar effect has been reported for two indole-naphthyridines, molecules that can exist in syn and anti rotameric forms. We demonstrate that IA, which can exist only in the syn form, is more photostable in alcohols than similar, but non-rigid molecules. This additional photostability enhancement is due to the elimination of a slower channel of excited state deactivation in alcohol complexes, S0 ← S1 internal conversion. The dominant, faster channel of S1 depopulation is the excited state double proton transfer, manifested by the presence of low energy tautomeric fluorescence.

Photochemical and Photobiological Activity of Ru(II) Homoleptic and Heteroleptic Complexes Containing Methylated Bipyridyl-type Ligands.

Light-activated compounds are powerful tools and potential agents for medical applications, as biological effects can be controlled in space and time. Ruthenium polypyridyl complexes can induce cytotoxic effects through multiple mechanisms, including acting as photosensitizers for singlet oxygen (1O2) production, generating other reactive oxygen species (ROS), releasing biologically active ligands, and creating reactive intermediates that form covalent bonds to biological molecules. A structure-activity relationship (SAR) study was performed on a series of Ru(II) complexes containing isomeric tetramethyl-substituted bipyridyl-type ligands. Three of the ligand systems studied contained strain-inducing methyl groups and created photolabile metal complexes, which can form covalent bonds to biomolecules upon light activation, while the fourth was unstrained and resulted in photostable complexes, which can generate 1O2. The compounds studied included both bis-heteroleptic complexes containing two bipyridine ligands and a third, substituted ligand and tris-homoleptic complexes containing only the substituted ligand. The photophysics, electrochemistry, photochemistry, and photobiology were assessed. Strained heteroleptic complexes were found to be more photoactive and cytotoxic then tris-homoleptic complexes, and bipyridine ligands were superior to bipyrimidine. However, the homoleptic complexes exhibited an enhanced ability to inhibit protein production in live cells. Specific methylation patterns were associated with improved activation with red light, and photolabile complexes were generally more potent cytotoxic agents than the photostable 1O2-generating compounds.

Effect of biochars produced from solid organic municipal waste on soil quality parameters.

New value-added uses for solid municipal waste are needed for environmental and economic sustainability. Fortunately, value-added biochars can be produced from mixed solid waste, thereby addressing solid waste management issues, and enabling long-term carbon sequestration. We hypothesize that soil deficiencies can be remedied by the application of municipal waste-based biochars. Select municipal organic wastes (newspaper, cardboard, woodchips and landscaping residues) individually or in a 25% blend of all four waste streams were used as feedstocks of biochars. Three sets of pyrolysis temperatures (350, 500, and 750 °C) and 3 sets of pyrolysis residence time (2, 4 and 6 h) were used for biochar preparation. The biochar yield was in the range of 21-62% across all feedstocks and pyrolysis conditions. We observed variations in key biochar properties such as pH, electrical conductivity, bulk density and surface area depending on the feedstocks and production conditions. Biochar increased soil pH and improved its electrical conductivity, aggregate stability, water retention and micronutrient contents. Similarly, leachate from the soil amended with biochar showed increased pH and electrical conductivity. Some elements such as Ca and Mg decreased while NO3-N increased in the leachates of soils incubated with biochars. Overall, solid waste-based biochar produced significant improvements to soil fertility parameters indicating that solid municipal wastes hold promising potential as feedstocks for manufacturing value-added biochars with varied physicochemical characteristics, allowing them to not only serve the needs for solid waste management and greenhouse gas mitigation, but also as a resource for improving the quality of depleted soils.

Feasibility and Tolerability of Daily Pulse Consumption in Individuals with Peripheral Artery Disease.

The present study investigated the feasibility, tolerability, and adherence of daily consumption of whole pulses (dried beans, peas, lentils, chickpeas) by individuals with peripheral artery disease participating in an 8-week study. Study questionnaires and semi-structured interviews for 26 participants were used to determine prestudy pulse consumption and participants' experiences with respect to adherence, positive and negative effects, bowel routine, satiety, and enjoyment of the foods. Although the majority of participants rarely consumed pulses prior to the study, there was a high rate of adherence to daily consumption of the study foods for 8 weeks despite comments regarding study fatigue during the latter part of the study. Participants had no gastrointestinal side effects (42%) or experienced flatulence that resolved by week 4 (23%), whereas 62% reported improvements in their bowel pattern. By week 8 greater satiety was noted by some participants (19%), with the categories "less afternoon snacking" and "not snacking" receiving more responses. The key finding of this study was that consumption of pulses is a viable approach for this population; however, the frequency of consumption that is tolerable in the long term should be integrated with the dose and timeframe required to achieve and maintain health benefits.

Practice gaps in the care of mitral valve regurgitation: Insights from the American College of Cardiology mitral regurgitation gap analysis and advisory panel.

BACKGROUND: The revised 2014 American College of Cardiology (ACC)/American Heart Association valvular heart disease guidelines provide evidenced-based recommendations for the management of mitral regurgitation (MR). However, knowledge gaps related to our evolving understanding of critical MR concepts may impede their implementation. METHODS: The ACC conducted a multifaceted needs assessment to characterize gaps, practice patterns, and perceptions related to the diagnosis and treatment of MR. A key project element was a set of surveys distributed to primary care and cardiovascular physicians (cardiologists and cardiothoracic surgeons). Survey and other gap analysis findings were presented to a panel of 10 expert advisors from specialties of general cardiology, cardiac imaging, interventional cardiology, and cardiac surgeons with expertise in valvular heart disease, especially MR, and cardiovascular education. The panel was charged with assessing the relative importance and potential means of remedying identified gaps to improve care for patients with MR. RESULTS: The survey results identified several knowledge and practice gaps that may limit implementation of evidence-based recommendations for MR care. Specifically, half of primary care physicians reported uncertainty regarding timing of intervention for patients with severe primary or functional MR. Physicians in all groups reported that quantitative indices of MR severity were frequently not reported in clinical echocardiographic interpretations, and that these measurements were not consistently reviewed when provided in reports. In the treatment of MR, nearly 30% of primary care physician and general cardiologists did not know the volume of mitral valve repair surgeries by their reference cardiac surgeons and did not have a standard source to obtain this information. After review of the survey results, the expert panel summarized practice gaps into 4 thematic areas and offered proposals to address deficiencies and promote better alignment with the 2014 ACC/American Heart Association valvular disease guidelines. CONCLUSION: Important knowledge and skill gaps exist that may impede optimal care of the patient with MR. Focused educational and practice interventions should be developed to reduce these gaps.