The effect of antimalarials on the safety and persistence of treatment with biologic agents or Janus kinase inhibitors in rheumatoid arthritis.

OBJECTIVES: To test the association of use of antimalarials with the overall safety of treatment in RA patients receiving one or multiple courses of biologic (b)DMARDs or a Janus kinase inhibitor (JAKi). METHODS: BiobadaBrasil is a multicentric registry-based cohort study of Brazilian patients with rheumatic diseases starting their first bDMARD or JAKi. The present analysis includes RA patients recruited from January 2009 to October 2019, followed up over one or multiple (up to six) courses of treatment (latest date, 19 November 2019). The primary outcome was the incidence of serious adverse events (SAEs). Total and system-specific adverse events (AEs) and treatment interruption served as secondary outcomes. Negative binomial regression with generalized estimating equations (to estimate multivariate incidence rate ratios, mIRR) and frailty Cox proportional hazards models were used for statistical analyses. RESULTS: The number of patients enrolled was 1316 (2335 treatment courses, 6711 patient-years [PY]; 1254.5 PY on antimalarials). The overall incidence of SAEs was 9.2/100 PY. Antimalarials were associated with reduced risk of SAEs (mIRR: 0.49; 95% CI: 0.36, 0.68; P < 0.001), total AEs (0.68; 95% CI: 0.56, 0.81; P < 0.001), serious infections (0.53; 95% CI: 0.34, 0.84; P = 0.007) and total hepatic AEs (0.21; 95% CI: 0.05, 0.85; P = 0.028). Antimalarials were also related to better survival of treatment course (P = 0.003). There was no significant increase in the risk of cardiovascular AEs. CONCLUSION: Among RA patients on treatment with bDMARDs or JAKi, concomitant use of antimalarials was associated with reduced the incidence of serious and total AEs and with longer treatment course survival.

Nickel-Catalyzed NO Group Transfer Coupled with NOx Conversion.

Nitrogen oxide (NOx) conversion is an important process for balancing the global nitrogen cycle. Distinct from the biological NOx transformation, we have devised a synthetic approach to this issue by utilizing a bifunctional metal catalyst for producing value-added products from NOx. Here, we present a novel catalysis based on a Ni pincer system, effectively converting Ni-NOx to Ni-NO via deoxygenation with CO(g). This is followed by transfer of the in situ generated nitroso group to organic substrates, which favorably occurs at the flattened Ni(I)-NO site via its nucleophilic reaction. Successful catalytic production of oximes from benzyl halides using NaNO2 is presented with a turnover number of >200 under mild conditions. In a key step of the catalysis, a nickel(I)-•NO species effectively activates alkyl halides, which is carefully evaluated by both experimental and theoretical methods. Our nickel catalyst effectively fulfills a dual purpose, namely, deoxygenating NOx anions and catalyzing C-N coupling.

Mono- and dinuclear zinc complexes bearing identical bis(thiosemicarbazone) ligand that exhibit alkaline phosphatase-like catalytic reactivity.

Mono- and dinuclear zinc(II) complexes bearing bis(thiosemicarbazone) (bTSC) ligand were employed in the cleavage of phosphoester bonds. Comparative kinetic studies combined with theory suggested that the P-O bond cleavage is much accelerated by dinuclear zinc(II) complex in the presence of base. Based on the DFT-optimized structures of the proposed intermediates, it is plausible that (1) the removal of sulfur atoms of bTSC ligand from the zinc center provides two vacant sites for the binding of water (or hydroxide ion) and phosphoester and (2) the H-bonding between water (or hydroxide ion) and phosphoester, through several water molecules, may also assist the P-O bond cleavage and facilitate the nucleophilic attack. The kinetic and catalytic studies on the hydrolysis of phosphoester by dinuclear zinc complex showed a much-enhanced reactivity under basic reaction conditions, reaching over 95% conversion yield within 4 h. The currently presented compounds are arguably one of the faster synthetic Zn-based model performing phosphatase-like activity presented so far.

Performance and ruminal and intestinal morphometry of Santa Inês sheep submitted to feed restriction and refeeding.

A study was carried out to evaluate the performance and ruminal and intestinal morphology of Santa Inês sheep subjected to feed restriction followed by refeeding. A total of 40 uncastrated lambs with an approximate age of 120 ± 15 days and mean body weight (BW) of 17.04 ± 1.18 kg were randomly divided into two groups of BW (20 and 25 kg of BW), which were subjected to different levels of feed restriction (0%, 25%, and 40% of feed restriction). For performance variables, six treatments were considered (0, 25%, and 40% of feed restriction for both groups (20 and 25 kg of BW)) and five treatments for morphometric variables (ad libitum, 25% and 40% for both groups (20 and 25 kg of BW)). All animals were slaughtered with 14 weeks of experimentation. During the feed restriction phase, the dry matter intake (DMI), feed efficiency (FE), and average daily gain (ADG) decreased (P < 0.05) as the level of restriction increased. During the refeeding phase, lambs with 20 kg of body weight subjected to restriction presented lower (P < 0.05) DMI in the ad libitum treatment. However, lambs with 25 kg of body weight under feed restriction presented DMI, FE, and ADG similar (P > 0.05) to the group ad libitum. The final body weight of restricted lambs after refeeding (both groups 20 and 25 kg of body weight) was lower (P < 0.05) than lambs feed ad libitum. In relation to morphology, restricted lambs showed greater height ruminal papillae and larger (P < 0.05) area of ruminal absorption and intestinal absorption, especially the lambs under treatment 40% of feed restriction. The feed restriction followed by refeeding in sheep provided partial compensatory gain, in addition, caused morphological changes in the rumen and intestine that allowed greater absorption and possibly compensatory gain in periods of greater refeeding.

High-protein intake and early exercise in adult intensive care patients: a prospective, randomized controlled trial to evaluate the impact on functional outcomes.

BACKGROUND: We evaluated the efficacy of high protein intake and early exercise versus standard nutrition care and routine physiotherapy on the outcome of critically ill patients. METHODS: We randomized mechanically ventilated patients expected to stay in the intensive care unit (ICU) for 4 days. We used indirect calorimetry to determine energy expenditure and guide caloric provision to the patients randomized to the high protein and early exercise (HPE) group and the control group. Protein intakes were 1.48 g/kg/day and 1.19 g/kg/day medians respectively; while the former was submitted to two daily sessions of cycle ergometry exercise, the latter received routine physiotherapy. We evaluated the primary outcome physical component summary (PCS) score at 3 and 6 months) and the secondary outcomes (handgrip strength at ICU discharge and ICU and hospital mortality). RESULTS: We analyzed 181 patients in the HPE (87) and control (94) group. There was no significant difference between groups in relation to calories received. However, the amount of protein received by the HPE group was significantly higher than that received by the control group (p < 0.0001). The PCS score was significantly higher in the HPE group at 3 months (p = 0.01) and 6 months (p = 0.01). The mortality was expressively higher in the control group. We found an independent association between age and 3-month PCS and that between age and group and 6-month PCS. CONCLUSION: This study showed that a high-protein intake and resistance exercise improved the physical quality of life and survival of critically ill patients. TRIAL REGISTRATION: Research Ethics Committee of Hospital São Domingos: Approval number 1.487.683, April 09, 2018. The study protocol was registered in ClinicalTrials.gov ( NCT03469882 , March 19,2018).

Infrared Spectroelectrochemistry of Iron-Nitrosyl Triarylcorroles. Implications for Ligand Noninnocence.

Recent DFT calculations have suggested that iron nitrosyl triarylcorrole complexes have substantial {FeNO}7-corrole•2- character. With this formulation, reduction of Fe(C)(NO) complexes, where C = triarylcorrole, should be centered on the corrole macrocycle rather than on the {FeNO}7 moiety. To verify this proposition, visible and infrared spectroelectrochemical studies of Fe(C)(NO) were carried out and the results were interpreted using DFT (B3LYP/STO-TZP) calculations. The first reduction of Fe(C)(NO) led to significant changes in the Soret and Q-band regions of the visible spectrum as well as to a significant downshift in the νNO and changes in the corrole vibrational frequencies. DFT calculations, which showed that the electron was mostly added to the corrole ligand (85%), were also able to predict the observed shifts in the νNO and corrole bands upon reduction. These results underscore the importance of monitoring both the corrole and nitrosyl vibrations in ascertaining the site of reduction. By contrast, the visible spectroelectrochemistry of the second reduction revealed only minor changes in the Soret band upon reduction, consistent with the reduction of the FeNO moiety.

Relativistic Effects on a Metal-Metal Bond: Osmium Corrole Dimers.

A series of metal-metal bonded osmium corrole dimers, {Os[T pXPC]}2, were synthesized in reasonably good yields (35-46%) via the interaction of the corresponding free-base meso-tris( p-X-phenyl)corroles (H3[T pXPC], X = CF3, H, CH3, and OCH3), Os3(CO)12, and potassium carbonate in 1,2,4-trichlorobenzene under an inert atmosphere at 180 °C over several hours. The complexes are only the second class of Os corroles reported to date (the first being OsVIN corroles) and also the second class of metal-metal bonded metallocorrole dimers (the other being Ru corrole dimers). Comparison of the X-ray structures, redox potentials, and optical spectra of analogous Ru and Os corrole dimers, along with scalar-relativistic DFT calculations, has provided an experimentally calibrated account of relativistic effects in these complexes. Three of the Os corrole dimers (X = CF3, H, and OCH3) were analyzed with single-crystal X-ray diffraction analysis, revealing inversion-related corrole rings with eclipsed Os-N bonds and Os-Os distances of ∼2.24 Å that are ∼0.06 Å longer than the Ru-Ru distances in the analogous Ru corrole dimers. Interestingly, a comparison of scalar-relativistic and nonrelativistic DFT calculations indicates that this difference in metal-metal bond distance does not, in fact, reflect a differential relativistic effect. For a given corrole ligand, the Ru and Os corrole dimers exhibit nearly identical oxidation potentials but dramatically different reduction potentials, with the Os values ∼0.5 V lower relative to Ru, suggesting that whereas oxidation occurs in a ligand-centered manner, reduction is substantially metal-centered, which indeed was confirmed by scalar-relativistic calculations. The calculations further indicate that approximately a third of the ∼0.5 V difference in reduction potentials can be ascribed to relativity. The somewhat muted value of this relativistic effect appears to be related to the finding that reduction of an Os corrole dimer is not exclusively metal-based but that a significant amount of spin density is delocalized over to the corrole ligand; in contrast, reduction of an Ru corrole dimer occurs exclusively on the Ru-Ru linkage. For isoelectronic complexes, the Ru and Os corrole dimers exhibit substantially different UV-vis spectra. A key difference is a strong near-UV feature of the Os series, which in energy terms is blue-shifted by ∼0.55 V relative to the analogous feature of the Ru series. TDDFT calculations suggest that this difference may be related to higher-energy Os(5d)-based LUMOs in the Os case relative to analogous MOs for Ru.

Ovines submitted to diets containing cassava foliage hay and spineless cactus forage: histological changes in the digestive and renal systems.

The aim of this study was to evaluate the histological alterations in the digestive and renal systems of 35 male ovines in Paraíba, Brazil, at around 16 ± 1.87 kg submitted to the following treatments for 90 days (15 of adaptation + 75 of experimental period): 1- Tifton hay (TH); 2- Cassava foliage hay (CH); 3-35% TH and 35% CH; 4-35% TH and 35% forage palm (FP), and 5-35% CH and 35% FP, based on dry matter (DM). Samples of the liver, kidney, rumen, and small intestine were histomorphometrically evaluated and the data were submitted to ANOVA analysis and Tukey post test at p ≤ 0.05. The use of alternative foods in the voluminous fraction (CH + FP) in the ovine diets did not compromise the performance of the animals; on the contrary, promoted better gain when compared with TH treatment (18.55 kg vs 9.42 kg). The CH + FP diet had a positive effect on papilla height. The papilla width decreased with the diets CH + FP and TH + FP. The thickness of the ruminal muscular layer were higher in the diets containing TH + CH and CH + FP. The keratinized layer of the ruminal epithelium was larger in the diet containing CH and FP. The villi of the intestinal crypts were deeper in the diets with FP and the villus/crypt ratio was the same in all diets. Goblet cells decreased with the CH or FP diet. Some renal changes were observed according to the diets, mainly when using FP. It is recommended to use CH and FP as a large fraction of the ovines diet, which will not alter animal performance.

Halterman Corroles and Their Use as a Probe of the Conformational Dynamics of the Inherently Chiral Copper Corrole Chromophore.

Halterman corroles have been synthesized for the first time from pyrrole and Halterman's aldehyde via Gryko's "water-methanol method". These were derivatized to the corresponding copper complexes and subsequently to the ß-octabromo complexes. Electronic circular dichroism spectra were recorded for the enantiopure copper complexes, affording the first such measurements for the inherently chiral Cu corrole chromophore. Interestingly, for a given configuration of the Halterman substituents, X-ray crystallographic studies revealed both P and M conformations of the Cu-corrole core, proving that the substituents, even in conjunction with ß-octabromination, are unable to lock the Cu-corrole core into a given chirality. The overall body of evidence strongly indicates a dynamic equilibrium between the P and M conformations. Such an interconversion, which presumably proceeds via saddling inversion, provides a rationale for our failure so far to resolve sterically hindered Cu corroles into their constituent enantiomers by means of chiral HPLC.

Stepwise Deoxygenation of Nitrite as a Route to Two Families of Ruthenium Corroles: Group 8 Periodic Trends and Relativistic Effects.

Given the many applications of ruthenium porphyrins, the rarity of ruthenium corroles and the underdeveloped state of their chemistry are clearly indicative of an area ripe for significant breakthroughs. The tendency of ruthenium corroles to form unreactive metal-metal-bonded dimers has been recognized as a key impediment in this area. Herein, by exposing free-base meso-tris(p-X-phenyl)corroles, H3[TpXPC] (X = CF3, H, Me, and OMe), and [Ru(COD)Cl2]x in refluxing 2-methoxyethanol to nitrite, we have been able to reliably intercept the series Ru[TpXPC](NO) in a matter of seconds to minutes and subsequently RuVI[TpXPC](N), the products of a second deoxygenation, over some 16 h. Two of the RuVIN complexes and one ruthenium corrole dimer could be crystallographically analyzed; the Ru-Nnitrido distance was found to be ∼1.61 Å, consistent with the triple-bonded character of the RuVIN units and essentially identical with the Os-Nnitrido distance in analogous osmium corroles. Spectroscopic and density functional theory (DFT) calculations suggest that the RuNO corroles are best viewed as innocent {RuNO}6 complexes, whereas the analogous FeNO corroles are noninnocent, i.e., best viewed as {FeNO}7-corrole•2-. Both RuVIN and OsVIN corroles exhibit sharp Soret bands, suggestive of an innocent macrocycle. A key difference between the two metals is that the Soret maxima of the OsVIN corroles are red-shifted some 25 nm relative to those of the RuVIN complexes. Careful time-dependent DFT studies indicate that this difference is largely attributable to relativistic effects in OsVIN corroles. The availability of two new classes of mononuclear ruthenium corroles potentially opens the door to new applications, in such areas as catalysis and cancer therapy.

Stabilization and Structure of the cis†Tautomer of a Free-Base Porphyrin.

Single-crystal X-ray analysis of the ß-heptakis(trifluoromethyl)-meso-tetrakis(p-fluorophenyl)porphyrin, H2 [(CF3 )7 TpFPP], has revealed the first example of a stable cis tautomer of a free-base porphyrin, the long-postulated intermediate of porphyrin tautomerism. The stability of the unique molecule appears to reflect a dual origin: a strongly saddled porphyrin skeleton, which alleviates electrostatic repulsion between the two NH protons, and two polarization-enhanced, transannular N-H⋅⋅⋅O-H⋅⋅⋅N hydrogen bond chains, each involving a molecule of water. DFT calculations suggest that the observed tautomer has a lower energy than the alternative, doubly hydrated trans tautomer by some 8.3 kcal mol-1 . A fascinating prospect thus exists that H2 [(CF3 )7 TpFPP]⋅2 H2 O and cognate structures may act as supramolecular synthons, which, given their chirality, may even be amenable to resolution into optically pure enantiomers.

Wolves in Sheep's Clothing: µ-Oxo-Diiron Corroles Revisited.

For well over 20 years, µ-oxo-diiron corroles, first reported by Vogel and co-workers in the form of µ-oxo-bis[(octaethylcorrolato)iron] (Mössbauer δ 0.02 mm s(-1) , ΔEQ 2.35 mm s(-1) ), have been thought of as comprising a pair antiferromagnetically coupled low-spin Fe(IV) centers. The remarkable stability of these complexes, which can be handled at room temperature and crystallographically analyzed, present a sharp contrast to the fleeting nature of enzymatic, iron(IV)-oxo intermediates. An array of experimental and theoretical methods have now shown that the iron centers in these complexes are not Fe(IV) but intermediate-spin Fe(III) coupled to a corrole(.2-) . The intramolecular spin couplings in {Fe[TPC]}2 (µ-O) were analyzed via DFT(B3LYP) calculations in terms of the Heisenberg-Dirac-van Vleck spin Hamiltonian H=JFe-corrole (SFe ⋅Scorrole )+JFe-Fe' (SFe ⋅SFe' )+JFe'-corrole (SFe' ⋅Scorrole' ), which yielded JFe-corrole =JFe'-corrole' =0.355 eV (2860 cm(-1) ) and JFe-Fe' =0.068 eV (548 cm(-1) ). The unexpected stability of µ-oxo-diiron corroles thus appears to be attributable to charge delocalization via ligand noninnocence.

Synthesis and Molecular Structure of 99 Tc Corroles.

The first 99 Tc corroles have been synthesized and fully characterized. A single-crystal X-ray structure of a 99 TcO triarylcorrole revealed nearly identical geometry parameters as the corresponding ReO structure. A significant spectral shift between the Soret maxima of TcO (410-413 nm) and ReO (438-441 nm) corroles was observed and, based on two-component spin-orbit ZORA TDDFT calculations, ascribed to relativistic effects in the Re case. The syntheses reported herein potentially pave the way toward 99m Tc-porphyrinoid-based radiopharmaceuticals.

Tungsten Biscorroles: New Chiral Sandwich Compounds.

The oxidative metalation method, involving the interaction of free-base meso-triarylcorroles and W(CO)6 in refluxing decalin, led to a set of three tungsten(VI) biscorroles, the first homoleptic sandwich compounds involving corroles. Single-crystal X-ray structures of two of the complexes revealed square-antiprismatic coordination and strongly domed corroles with long W-N distances of 2.15-2.22 Šand a substantial displacement of ∼1.17 Šof the metal relative to the mean N4 planes of the ligands. The structures correspond to approximate C2 symmetry and are thus chiral. DFT calculations strongly indicate that the enantiomers are configurationally stable and hence amenable to chiral resolution. Their other notable properties include a strongly blueshifted Soret band at (357±2) nm, a relatively intense π→W(dz2 ) near-IR feature at (781±3) nm, and a low electrochemical HOMO-LUMO gap of approximately 1.3 V. The results obtained herein suggest that metallobiscorroles may emerge as a new class of inherently chiral chromophores with novel optical and electrochemical properties.

Metallocorrole Interactions with Carbon Monoxide, Nitric Oxide, and Nitroxyl-A DFT Study of Low-Energy Bound States.

Presented herein is a first DFT survey of metallocorrole (M = Mn, Fe, Co) adducts of CO, NO, NO(-), and HNO. Bound states with relatively short M-N(O) distances <1.9 Å are predicted for both [M(Cor)(NO)](-) and [M(Cor)(HNO)] derivatives for all three metals. The calculations also confirm the existence of moderately stable charge-neutral CoCO corrole adducts.

Effect of urinary incontinence on the quality of life of asthmatic women.

OBJECTIVES: Urinary incontinence (UI) has been associated with chronic respiratory symptoms, and it affects quality of life. This study evaluated the quality of life of asthmatic patients from the Assistance Program for Asthmatic Patients (PAPA) with and without UI. METHODS: This is an analytical descriptive cross-sectional study using a sample of 358 women with asthma. Data were collected via the International Consultation Incontinence Questionnaire-Simplified Form (ICIQ-SF), Quality of Life in Asthma Questionnaire (QLAQ-ASTHMA) and Short Form 36 Health Survey (SF-36). RESULTS: We found a general prevalence of UI of 55.3%. Overall quality of life scores in the SF-36 and QLAQ-ASTHMA were not related to the presence of UI. However, the amount of urine lost was significantly correlated with the subdomains physical aspects, general health, social functioning and mental health of the SF-36 and with socioeconomic and psychosocial domains of the QLAQ-ASTHMA. CONCLUSIONS: Urinary incontinence may affect a large proportion of older women with asthma. This study demonstrates the importance of routinely evaluating the occurrence of UI in order to improve the quality of life of asthmatic patients.

Ligand Noninnocence in Coinage Metal Corroles: A Silver Knife-Edge.

A silver ß-octabromo-meso-triarylcorrole has been found to exhibit a strongly saddled geometry, providing the first instance of a strongly saddled corrole complex involving a metal other than copper. The Soret maxima of the Ag octabromocorroles also redshift markedly in response to increasingly electron-donating para substituents on the meso-aryl groups. In both these respects, the Ag octabromocorroles differ from simple Ag triarylcorrole derivatives, which exhibit only mild saddling and substituent-insensitive Soret maxima. These results have been rationalized in terms of an innocent M(III)-corrole(3-) description for the simple Ag corroles and a noninnocent M(II)-corrole(·2-) description for the Ag octabromocorroles. In contrast, all copper corroles are thought to be noninnocent, while all gold corroles are innocent. Uniquely among metallocorroles, silver corroles thus seem poised on a knife-edge, so to speak, between innocent and noninnocent electronic structures and may tip either way, depending on the exact nature of the corrole ligand.

Octaiodoporphyrin.

Interaction of 3,4-diiodopyrrole with 4-trifluoromethylbenzaldeyde under carefully optimized, Lindsey-type conditions at -10 °C has led to the synthesis of the first ß-octaiodoporphyrin, H2[I8TpCF3PP]. The free ligand readily yielded Ni, Cu, and Zn complexes, which all proved amenable to single-crystal X-ray structure analyses. The zinc complex Zn[I8TpCF3PP] exhibits the most saddled porphyrin core for any simple porphyrin known to date and a dramatically red-shifted optical spectrum with a Soret maximum at 495 nm.

Synthesis and reactivity studies of a tin(II) corrole complex.

A series of tris(pentafluorophenyl)corrole (TPFC) tin(IV) and tin(II) complexes were prepared and studied by various characterization techniques including (1)H, (19)F, and (119)Sn NMR and UV-vis spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. The unusual 4-coordinate, monomeric, divalent tin(II) complex [(TPFC)Sn(II)](-) (2a) showed highly efficient reactivity toward alkenes and alkyl halides via a nucleophilic addition pathway leading to the quantitative formation of alkyl stannyl corrole compounds. DFT calculations confirmed the divalent nature of the tin center in 2a, and an NBO analysis showed about 99.99% Sn lone pair character, of which 83.6% was Sn 5s and 16.35% was Sn 5p character.

Understanding the mechanism of polymerization of ε-caprolactone catalyzed by aluminum salen complexes.

Studies of the kinetics of polymerization of ε-caprolactone (CL) by salen-aluminum catalysts comprising ligands with similar steric profiles but different electron donating characteristics (R = OMe, Br, or NO2) were performed using high initial monomer concentrations (2 M < [CL]0 < 2.6 M) in toluene-d8 at temperatures ranging from 20 to 90 °C. Saturation behavior was observed, enabling determination of monomer equilibrium constants (Keq) and catalytic rate constants (k2) as a function of R and temperature. While Keq varied only slightly with the electron donating properties of R (Hammett ρ = +0.16(8)), k2 showed a more significant dependence reflected by ρ = +1.4(1). Thermodynamic parameters ΔG° (associated with Keq) and ΔG(‡) (associated with k2) were determined, with the former being ∼0 kcal/mol for all catalysts and the latter exhibiting the trend R = OMe > Br > NO2. Density functional theory (DFT) calculations were performed to characterize mechanistic pathways at a microscopic level of detail. Lowest energy transition-state structures feature incipient bonding of the nucleophile to the lactone carbonyl that is approaching the metal ion, but a distinct CL adduct is not an energy minimum on the reaction pathway, arguing against Keq being associated with coordination of monomer according to the typical coordination-insertion mechanism. An alternative hypothesis is presented associating Keq with "nonproductive" coordination of substrate in a manner that inhibits the polymerization reaction at high substrate concentrations.