Development and Evaluation of an NTM-IGRA to Guide Pediatric Lymphadenitis Diagnosis.

BACKGROUND: Diagnosis of nontuberculous mycobacteria (NTM) infections remains a challenge. In this study, we describe the evaluation of an immunological NTM-interferon (IFN)-γ release assay (IGRA) that we developed using glycopeptidolipids (GPLs) as NTM-specific antigens. METHODS: We tested the NTM-IGRA in 99 samples from pediatric patients. Seventy-five were patients with lymphadenitis: 25 were NTM confirmed, 45 were of unknown etiology but compatible with mycobacterial infection and 5 had lymphadenitis caused by an etiologic agent other than NTM. The remaining 24 samples were from control individuals without lymphadenitis (latently infected with M. tuberculosis , uninfected controls and active tuberculosis patients). Peripheral blood mononuclear cells were stimulated overnight with GPLs. Detection of IFN-γ producing cells was evaluated by enzyme-linked immunospot assay. RESULTS: NTM culture-confirmed lymphadenitis patient samples had a significantly higher response to GPLs than the patients with lymphadenitis of unknown etiology but compatible with mycobacterial infection ( P < 0.001) and lymphadenitis not caused by NTM ( P < 0.01). We analyzed the response against GPLs in samples from unknown etiology lymphadenitis but compatible with mycobacterial infection cases according to the tuberculin skin test (TST) response, and although not statistically significant, those with a TST ≥5 mm had a higher response to GPLs when compared with the TST <5 mm group. CONCLUSIONS: Stimulation with GPLs yielded promising results in detecting NTM infection in pediatric patients with lymphadenitis. Our results indicate that the test could be useful to guide the diagnosis of pediatric lymphadenitis. This new NTM-IGRA could improve the clinical handling of NTM-infected patients and avoid unnecessary misdiagnosis and treatments.

Boronic ester functionalised 1,8-diboryl-naphthalene scaffolds: fluoride versus oxide chelation.

1,8-Bis(boronic ester) derivatives of naphthalene, 1,8-C10H6{B(OR)2}2, present an attractive target as receptors for the fluoride ion via B-F-B chelation, but are synthetically challenging to access due to the competing formation of a very stable anhydride containing a B-O-B motif. By contrast, unsymmetrical systems of the type 1,8-C10H6{B(OR)2}(BR'2) can be synthesized for (OR)2 = 1,2-O2C6H4 (i.e. Cat) and R' = Mes. This system is shown to be competent for the uptake of F-, making use of a chelating mode of action and the formation of a bridging B-F-B motif between the two boron centres. However, both experimental and quantum chemical studies indicate that the µ2-F adduct is the kinetic product of fluoride uptake, with an alternative structural motif featuring a terminal B-F bond and a B-O-B bridge using one of the catechol oxygens being (marginally) more favourable thermodynamically.

Copper-Catalyzed Dehydrogenative Amidation of Light Alkanes.

The functionalization of C-H bonds in light alkanes, particularly to form C-N bonds, remains a challenge. We report the dehydrogenative coupling of amides with C1-C4 hydrocarbons to form N-alkyl amide products with tBuOOtBu as oxidant, and a copper complex of a phenanthroline-type ligand as catalyst. The reactions occurred in good yields in benzene or supercritical carbon dioxide as solvents. This strategy allowed for the determination of the relative reactivity of these alkane C-H bonds toward this amination process and showed, in contrast to prior work with larger alkanes, that the reactivity correlated with bond dissociation energies.

Reactions of a diborylstannylene with CO2 and N2O: diboration of carbon dioxide by a main group bis(boryl) complex.

The reactions of the boryl-substituted stannylene Sn{B(NDippCH)2}2 (1) with carbon dioxide have been investigated and shown to proceed via pathways involving insertion into the Sn-B bond(s). In the first instance this leads to formation of the (boryl)tin(ii) borylcarboxylate complex Sn{B(NDippCH)2}{O2CB(NDippCH)2} (2), which has been structurally characterized and shown to feature a κ2 mode of coordination of the [(HCDippN)2BCO2]- ligand at the metal centre. 2 undergoes B-O reductive elimination in hexane solution (in the absence of further CO2) to give the boryl(borylcarboxylate)ester {(HCDippN)2B}O2C{B(NDippCH)2} (3) i.e. the product of formal diboration of carbon dioxide. Alternatively, 2 can assimilate a second equivalent of CO2 to give the homoleptic bis(borylcarboxylate) Sn{O2CB(NDippCH)2}2 (4), which can be prepared via an alternative route from SnBr2 and the potassium salt of [(HCDippN)2BCO2]-, and structurally characterized as its DMAP (N,N-dimethylaminopyridine) adduct. Structural and reactivity studies also point to the possibility for extrusion of CO from the [(HCDippN)2BCO2]- fragment to generate the boryloxy system [(HCDippN)2BO]-, a ligand which can be generated directly from 1via reaction with N2O. The initially formed unsymmetrical species Sn{B(NDippCH)2}{OB(NDippCH)2} has been shown to be amenable to crystallographic study in the solid state, but to undergo ligand redistribution in solution to generate a mixture of 1 and the bis(boryloxy) complex Sn{OB(NDippCH)2}2.

Approaching a "Naked" Boryl Anion: Amide Metathesis as a Route to Calcium, Strontium, and Potassium Boryl Complexes.

Amide metathesis has been used to generate the first structurally characterized boryl complexes of calcium and strontium, {(Me3 Si)2 N}M{B(NDippCH)2 }(thf)n (M=Ca, n=2; M=Sr, n=3), through the reactions of the corresponding bis(amides), M{N(SiMe3 )2 }2 (thf)2 , with (thf)2 Li- {B(NDippCH)2 }. Most notably, this approach can also be applied to the analogous potassium amide K{N(SiMe3 )2 }, leading to the formation of the solvent-free borylpotassium dimer [K{B(NDippCH)2 }]2 , which is stable in the solid state at room temperature for extended periods (48 h). A dimeric structure has been determined crystallographically in which the K+ cations interact weakly with both the ipso-carbons of the flanking Dipp groups and the boron centres of the diazaborolyl heterocycles, with K⋅⋅⋅B distances of >3.1 Å. These structural features, together with atoms in molecules (QTAIM) calculations imply that the boron-containing fragment closely approaches a limiting description as a "free" boryl anion in the condensed phase.

Evaluación del Programa Integrado de Investigación en Tuberculosis promovido por la sociedad española de Neumología y Cirugía Torácica tras 11 años de funcionamiento / Evaluation of the Integrated Tuberculosis Research Program Sponsored by the Spanish Society of Pulmonology and Thoracic Surgery: 11 Years on

OBJETIVO: El objetivo del estudio fue conocer la tendencia de las variables relacionadas con la tuberculosis (TB) en España a partir del registro del Programa Integrado de Investigación en Tuberculosis (PII-TB) de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) y evaluar el PII-TB mediante indicadores relacionados con sus objetivos científicos. MÉTODO: Estudio transversal multicéntrico de base poblacional de casos nuevos de TB registrados prospectivamente por el PII-TB entre 2006 y 2016. La tendencia temporal de variables cuantitativas se realizó mediante un modelo de regresión lineal y las cualitativas mediante la prueba de χ2 de tendencia lineal. RESULTADOS: Se analizaron 6.892 casos de TB con una mediana anual de 531. La tendencia general fue significativamente decreciente en mujeres, inmigrantes, privados de libertad y en tratados inicialmente con 3 fármacos. Se incrementaron significativamente la tendencia de grupos de 40 -50 años y > 50 años, primera atención por especialista de zona, hospitalización, retraso diagnóstico, localización diseminada y extrapulmonar única, cultivo (+), realización de antibiogramas, resistencia a fármacos, tratamiento directamente observado, prolongación del tratamiento y muerte por otra causa. Los objetivos científicos del PII-TB que incrementaron significativamente fueron las publicaciones alcanzando un máximo de 8 en 2016 y con un factor de impacto total de 49,664, y también mejoraron los proyectos iniciados anualmente, presentaciones en congresos y las tesis o tesinas. CONCLUSIONES: El PII-TB proporciona información relevante sobre la TB y sus factores asociados en España. Se ha formado un amplio equipo de investigadores y se han detectado aspectos científicos positivos y otros mejorables

OBJECTIVE: The objective of the study was to determine the trend of variables related to tuberculosis (TB) from the Integrated Tuberculosis Research Program (PII-TB) registry of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), and to evaluate the PII-TB according to indicators related to its scientific objectives. METHOD: Cross-sectional, population-based, multicenter study of new TB cases prospectively registered in the PII-TB between 2006 and 2016. The time trend of quantitative variables was calculated using a lineal regression model, and qualitative variables using the χy test for lineal trend. RESULTS: A total of 6,892 cases with an annual median of 531 were analyzed. Overall, a significant downward trend was observed in women, immigrants, prisoners, and patients initially treated with 3 drugs. Significant upward trends were observed in patients aged 40-50 and > 50 years, first visit conducted by a specialist, hospitalization, diagnostic delay, disseminated disease and single extrapulmonary location, culture (+), sensitivity testing performed, drug resistance, directly observed treatment, prolonged treatment, and death from another cause. The scientific objectives of the PII-TB that showed a significant upward trend were publications, which reached a maximum of 8 in 2016 with a total impact factor of 49,664, numbers of projects initiated annually, presentations at conferences, and theses. CONCLUSIONS: PII-TB provides relevant information on TB and its associated factors in Spain. A large team of researchers has been created; some scientific aspects of the registry were positive, while others could have been improved

Cooperative N-H bond activation by amido-Ge(ii) cations.

N-heterocyclic carbene (NHC) and tertiary phosphine-stabilized germylium-ylidene cations, [R(L)Ge:]+, featuring tethered amido substituents at R have been synthesized via halide abstraction. Characterization in the solid state by X-ray crystallography shows these systems to be monomeric, featuring a two-coordinate C,N- or P,N-ligated germanium atom. The presence of the strongly Lewis acidic cationic germanium centre and proximal amide function allows for facile cleavage of N-H bonds in 1,2-fashion: the products resulting from reactions with carbazole feature a tethered secondary amine donor bound to a three-coordinate carbazolyl-GeII centre. In each case, addition of the components of the N-H bond occurs to the same face of the germanium amide function, consistent with a coordination/proton migration mechanism. Such as sequence is compatible with the idea that substrate coordination via the pπ orbital at germanium reduces the extent of N-to-Ge π donation from the amide, thereby enhancing the basicity of the proximal N-group.

Probing the non-innocent nature of an amino-functionalised ß-diketiminate ligand in silylene/iminosilane systems.

Electron-rich ß-diketiminate ligands, featuring amino groups at the backbone ß positions ("N-nacnac" ligands) have been employed in the synthesis of a range of silylene (SiII) complexes of the type (N-nacnac)SiX (where X = H, Cl, N(SiMe3)2, P(SiMe3)2 and Si(SiMe3)3). A combination of experimental and quantum chemical approaches reveals (i) that in all cases rearrangement to give an aza-butadienyl SiIV imide featuring a contracted five-membered heterocycle is thermodynamically favourable (and experimentally viable); (ii) that the kinetic lability of systems of the type (N-nacnac)SiX varies markedly as a function of X, such that compounds of this type can be isolated under ambient conditions for X = Cl and P(SiMe3)2, but not for X = H, N(SiMe3)2 and Si(SiMe3)3; and (iii) that the ring contraction process is most facile for systems bearing strongly electron-donating and sterically less encumbered X groups, since these allow most ready access to a transition state accessed via intramolecular nucleophilic attack by the SiII centre at the ß-carbon position of the N-nacnac ligand backbone.

N-H cleavage vs. Werner complex formation: reactivity of cationic group 14 tetrelenes towards amines.

ß-Diketiminate ligands featuring backbone NMe2 groups have been exploited to access a series of two-coordinate cations of the type [(N-nacnac)E]+ (E = Si, Ge, Sn), whose reactivity towards N-H bonds has been investigated. While the heavier group 14 systems react via simple adduct formation, N-H oxidative addition occurs for E = Si consistent with differences in EII/EIV redox potentials. The structurally characterized Ge/Sn adducts can be viewed as models for the corresponding (transient) Si systems [(N-nacnac)Si·(NH2R)]+ (R = H, tBu) - which are potential intermediates in the formation of [(N-nacnac)Si(H)(NHR)]+via a proton-shuttling mechanism.

Evaluation of the Integrated Tuberculosis Research Program Sponsored by the Spanish Society of Pulmonology and Thoracic Surgery: 11 Years on. / Evaluación del Programa Integrado de Investigación en Tuberculosis promovido por la sociedad española de Neumología y Cirugía Torácica tras 11 años de funcionamiento.

OBJECTIVE: The objective of the study was to determine the trend of variables related to tuberculosis (TB) from the Integrated Tuberculosis Research Program (PII-TB) registry of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), and to evaluate the PII-TB according to indicators related to its scientific objectives. METHOD: Cross-sectional, population-based, multicenter study of new TB cases prospectively registered in the PII-TB between 2006 and 2016. The time trend of quantitative variables was calculated using a lineal regression model, and qualitative variables using the χy test for lineal trend. RESULTS: A total of 6,892 cases with an annual median of 531 were analyzed. Overall, a significant downward trend was observed in women, immigrants, prisoners, and patients initially treated with 3 drugs. Significant upward trends were observed in patients aged 40-50 and > 50 years, first visit conducted by a specialist, hospitalization, diagnostic delay, disseminated disease and single extrapulmonary location, culture(+), sensitivity testing performed, drug resistance, directly observed treatment, prolonged treatment, and death from another cause. The scientific objectives of the PII-TB that showed a significant upward trend were publications, which reached a maximum of 8 in 2016 with a total impact factor of 49,664, numbers of projects initiated annually, presentations at conferences, and theses. CONCLUSIONS: PII-TB provides relevant information on TB and its associated factors in Spain. A large team of researchers has been created; some scientific aspects of the registry were positive, while others could have been improved.

An Acid-Free Anionic Oxoborane Isoelectronic with Carbonyl: Facile Access and Transfer of a Terminal B═O Double Bond.

We disclose the synthesis and structural characterization of the first acid-free anionic oxoborane, [K(2.2.2-crypt)][(HCDippN)2BO] (1) (Dipp = 2,6- iPr2C6H3), which is isoelectronic with classical carbonyl compounds. 1 can readily be accessed from its borinic acid by a simple deprotonation/sequestration sequence. Crystallographic and density functional theory (DFT) analyses support the presence of a polarized terminal B═O double bond. Subsequent π bond metathesis converts the B═O bond to a heavier B═S containing system, affording the first anionic thioxoborane [K(2.2.2-crypt)][(HCDippN)2BS] (2), isoelectronic with thiocarbonyls. Facile B═O bond cleavage can also be achieved to access B-H and B-Cl bonds and, via a remarkable oxide (O2-) ion abstraction, to generate a borenium cation [(HCDippN)2B(NC5H5)][OTf] (4). By extension, 1 can act as an oxide transfer agent to organic substrates, a synthetic role traditionally associated with transition-metal compounds. Hence we show that B-O linkages, which are often considered to be thermodynamic sinks, can be activated under mild conditions toward bond cleavage and transfer, by exploiting the higher reactivity inherent in the B═O double bond.

Reversible borohydride formation from aluminium hydrides and {H(9-BBN)}2: structural, thermodynamic and reactivity studies.

A series of novel ß-diketiminate stabilised aluminium borohydrides of the type (Nacnac)Al(R){H2(9-BBN)} has been synthesised offering variation in both the auxiliary R substituent and in the Nacnac backbone itself. A number of these complexes show unusual dissociation of the borane from the aluminium hydride in solution under ambient conditions. The lability of the borane is shown (by variable temperature NMR analyses) to be influenced by the electronic character of both the aluminium-bound R substituent and the Nacnac ligand itself, such that electron-withdrawing substituents lead to greater dissociation of the borane. Comparison of these complexes with related systems featuring the tetrahydroborate [BH4]- ligand illustrates the impact of the boron-bound substituents on the ability of the borane fragment to dissociate from the aluminium hydride. This dissociative behaviour is shown to be highly influential on the ability of the borohydride complexes to reduce carbon dioxide in a stoichiometric manner.

Reversible O-H bond activation by an intramolecular frustrated Lewis pair.

The interactions of the O-H bonds in alcohols, water and phenol with dimethylxanthene-derived frustrated Lewis pairs (FLPs) have been probed. Within the constraints of this backbone framework, the preference for adduct formation or O-H bond cleavage to give the corresponding zwitterion is largely determined by pKa considerations. In the case of the PPh2/B(C6F5)2 system and p-tBuC6H4OH, an equilibrium is established between the two isomeric forms which allows the thermodynamic parameters associated with zwitterion formation via O-H bond cleavage to be probed.

Reduction of Carbon Oxides by an Acyclic Silylene: Reductive Coupling of CO.

Reactions of a boryl-substituted acyclic silylene with carbon dioxide and monoxide are reported. The former proceeds through oxygen atom abstraction, generating CO (with rearrangement of the putative silanone product through silyl-group transfer). The latter is characterized by reductive coupling of CO to give an ethynediolate fragment, which undergoes formal insertion into the Si-B bond. The net conversion of carbon dioxide with two equivalents of silylene offers a route for the three-electron reduction of CO2 to [C2 O2 ]2- .

Borylated N-Heterocyclic Carbenes: Rearrangement and Chemical Trapping.

This study details attempts to access N-heterocyclic carbenes (NHCs) featuring the diazaborolyl group, {(HCNDipp)2 B}, as one or both of the N-bound substituents, to generate strongly electron-donating and sterically imposing new carbene ligands. Attempts to isolate N-heterocyclic carbenes based around imidazolylidene or related heterocycles, are characterized by facile N-to-C migration of the boryl substituent. In the cases of imidazolium precursors bearing one N-bound diazaborolyl group and one methyl substituent, deprotonation leads to the generation of the target carbenes, which can be characterized in situ by NMR measurements, and trapped by reactions with metal fragments and elemental selenium. The half-lives of the free carbenes at room temperature range from 4-50 h (depending on the pattern of ancillary substituents) with N-to-C2 migration of the boryl function being shown to be the predominant rearrangement pathway. Kinetic studies show this to be a first-order process that occurs with an entropy of activation close to zero. DFT calculations imply that an intramolecular 1,2-shift is mechanistically feasible, with calculated activation energies of the order of 90-100 kJ mol-1 , reflecting the retention of significant aromatic character in the imidazole ring in the transition state. Trapping of the carbene allows for evaluation of steric and electronic properties through systems of the type LAuCl, LRh(CO)2 Cl, and LSe. A highly unsymmetrical (but nonetheless bulky) steric profile and moderately enhanced σ-donor capabilities (compared with IMes) are revealed.

Comparing Neutral (Monometallic) and Anionic (Bimetallic) Aluminum Complexes in Hydroboration Catalysis: Influences of Lithium Cooperation and Ligand Set.

Bimetallic lithium aluminates and neutral aluminum counterparts are compared as catalysts in hydroboration reactions with aldehydes, ketones, imines and alkynes. Possessing Li-Al cooperativity, ate catalysts are found to be generally superior. Catalytic activity is also influenced by the ligand set, alkyl and/or amido. Devoid of an Al-H bond, iBu2 Al(TMP) operates as a masked hydride reducing benzophenone through a ß-Η transfer process. This catalyst library therefore provides an entry point into the future design of Al catalysts targeting substrate specific transformations.

Molecular Manipulations of a Utility Nitrogen-Heterocyclic Carbene by Sodium Magnesiate Complexes and Transmetallation Chemistry with Gold Complexes.

Expanding the scope and applications of anionic N-heterocyclic carbenes (NHCs), a novel series of magnesium NHC complexes is reported using a mixed sodium-magnesium approach. Sequential reactivity of classical imidazol- 2-ylidene carbene IPr with NaR and MgR2 (R=CH2 SiMe3 ) affords [(THF)3 Na(µ-IPr- )MgR2 (THF)] (2) [IPr- =:C{[N(2,6-iPr2 C6 H3 )]2 CHC] containing an anionic NHC ligand, whereas surprisingly sodium magnesiate [NaMgR3 ] fails to deprotonate IPr affording instead the redistribution coordination adduct [IPr2 Na2 MgR4 ] (1). Compound 2 undergoes selective C2-methylation when treated with MeOTf furnishing novel abnormal NHC complex [{aIPrMe MgR2 }2 ] (3). Dissolving 3 in THF led to the dissociation of this complex into MgR2 and aIPrMe with the latter isomerizing to the olefinic NHC IPr=CH2 . The ability of 2 and 3 to transfer their anionic and abnormal NHC ligands, respectively to AuI metal fragments has been investigated allowing the isolation and structural characterization of [RAu(µ-IPr- )MgR(THF)2 ] (4) and [aIPrMe AuR] (5) respectively. In both cases transfer of an alkyl R group is observed. However while 3 can also transfer its abnormal NHC ligand to give 5, in 4 the anionic NHC still remains coordinated to Mg via its C4 position, whereas the {AuR} fragment occupies the C2 position previously filled by a donor-solvated {Na(THF)3 }+ cation.

Reversible C-H Activation, Facile C-B/B-H Metathesis and Apparent Hydroboration Catalysis by a Dimethylxanthene-Based Frustrated Lewis Pair.

A dimethylxanthene-based phosphine/borane frustrated Lewis pair (FLP) is shown to effect reversible C-H activation, cleaving phenylacetylene, PhCCH, to give an equilibrium mixture of the free FLP and phosphonium acetylide in CD2 Cl2 solution at room temperature. This system also reacts with B-H bonds although in a different fashion: reactions with HBpin and HBcat proceed via C-B/B-H metathesis, leading to replacement of the -B(C6 F5 )2 Lewis acid component by -Bpin/-Bcat, and transfer of HB(C6 F5 )2 to the phosphine Lewis base. This transformation underpins the ability of the FLP to catalyze the hydroboration of alkynes by HBpin: the active species is derived from the HB(C6 F5 )2 fragment generated in this exchange process.

Revealing the remarkable structural diversity of the alkali metal transfer agents of the trans-calix[2]benzene[2]pyrrolide ligand.

Excellent reagents for transferring their heterocalix[4]arene ligand to f-block organometallic complexes, lithium, sodium and potassium trans-calix[2]benzene[2]pyrrolides have been found to adopt a fascinating series of structures in their own right.

Structural Diversity in Alkali Metal and Alkali Metal Magnesiate Chemistry of the Bulky 2,6-Diisopropyl-N-(trimethylsilyl)anilino Ligand.

Bulky amido ligands are precious in s-block chemistry, since they can implant complementary strong basic and weak nucleophilic properties within compounds. Recent work has shown the pivotal importance of the base structure with enhancement of basicity and extraordinary regioselectivities possible for cyclic alkali metal magnesiates containing mixed n-butyl/amido ligand sets. This work advances alkali metal and alkali metal magnesiate chemistry of the bulky arylsilyl amido ligand [N(SiMe3 )(Dipp)]- (Dipp=2,6-iPr2 -C6 H3 ). Infinite chain structures of the parent sodium and potassium amides are disclosed, adding to the few known crystallographically characterised unsolvated s-block metal amides. Solvation by N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDETA) or N,N,N',N'-tetramethylethylenediamine (TMEDA) gives molecular variants of the lithium and sodium amides; whereas for potassium, PMDETA gives a molecular structure, TMEDA affords a novel, hemi-solvated infinite chain. Crystal structures of the first magnesiate examples of this amide in [MMg{N(SiMe3 )(Dipp)}2 (µ-nBu)]∞ (M=Na or K) are also revealed, though these breakdown to their homometallic components in donor solvents as revealed through NMR and DOSY studies.