Carbodiimide and Isocyanate Hydroboration by a Cyclic Carbodiphosphorane Catalyst.

We report hydroboration of carbodiimide and isocyanate substrates catalyzed by a cyclic carbodiphosphorane catalyst. The cyclic carbodiphosphorane outperformed the other Lewis basic carbon species tested, including other zerovalent carbon compounds, phosphorus ylides, an N-heterocyclic carbene, and an N-heterocyclic olefin. Hydroborations of seven carbodiimides and nine isocyanates were performed at room temperature to form N-boryl formamidine and N-boryl formamide products. Intermolecular competition experiments demonstrated the selective hydroboration of alkyl isocyanates over carbodiimide and ketone substrates. DFT calculations support a proposed mechanism involving activation of pinacolborane by the carbodiphosphorane catalyst, followed by hydride transfer and B-N bond formation.

Autologous Blood-Derived Products (ABDPs) for the Treatment of Chronic Wounds.

Autologous blood-derived therapies have emerged as a unique and promising treatment option for chronic wounds. From whole blood clots to spun-down clot constituents, these therapies are highly versatile and tend to have a lower cost profile, allow for point-of-service preparation, and inherently carry minimal to no risk of rejection or allergic reaction when compared to many alternative cellular and matrix-like products. Subsequently, a diversity of processing systems, devices, and kits have surfaced on the market for preparing autologous blood-derived products (ABDPs) and many have demonstrated preclinical and clinical efficacy in facilitating chronic wound healing. However, not all ABDPs are created equal, and the lack of standardization among product formulations and cell concentrations as well as varying complexities in preparation protocols has led to unreliable substrate viabilities and overall inconsistent conclusions on efficacy. Additionally, external factors, such as the ease of drawing blood, the health of a patient's blood, and the reimbursement landscape have dissuaded some practitioners from incorporating ABDPs into an algorithm of care for recalcitrant wounds. Here, we attempt to categorize ABDPs into "classes" and examine their efficacy, advantages, and limitations when used as both a primary therapy and an adjunct for treating chronic wounds as well as comment on some potential considerations that may help gear future product development and application.

Barriers and motivators to women's cancer screening: A qualitative study of a sample of diverse women.

INTRODUCTION: Cancer is an enormous public health challenge in the United States and around the world. Early detection through screening can identify cancer when it is most treatable and can result in greater survival rates; however, racial and ethnic disparities in breast and cervical screening result in late diagnosis and a higher risk of poor outcomes and death for women of color. PURPOSE: The purpose of this study was to examine barriers that a diverse sample of women in Rhode Island face related to breast and cervical cancer screening, as well as motivators that encourage women to obtain screening services. DESIGN AND METHODS: Women, most of whom self-identified as Black or Hispanic, who were aged 40 years and older, were recruited to participate in focus groups via Zoom. The main topics of the discussions included thoughts, attitudes, beliefs, and prior experiences with screening. RESULTS: Forty-seven women from Rhode Island participated in a total of six focus groups. The following themes emerged: (1) fear, lack of knowledge, cultural beliefs, and the role of women as caretakers are personal barriers; (2) communication challenges, a shortage of primary care providers and negative health experiences are system barriers; and (3) family history of cancer, encouragement from providers, and clinic reminders are motivators that encourage women to get screened. CONCLUSIONS: Results suggest that communities must focus on eliminating barriers, promoting motivators, and expanding access to supportive screening services to reduce the number of cases and deaths due to breast and cervical cancer.

The Shift to Synthetics: A Review of Novel Synthetic Matrices for Wound Closure.

Since the late 1990s, a growing number of "skin substitutes" have become available to practitioners seeking to heal large surface wounds. These extracellular matrices were originally from xenograft sources, and then from very highly engineered living human cellular tissues. More recently, they consist of biosynthetic materials that are combinations of silicone, collagen and chondroitin. The list of xenograft materials as well as minimally manipulated human tissues, such as human skin-, amniotic- and placental-based products, has grown exponentially. Over the last 5 years, truly synthetic materials have become part of the armamentarium available for closing large wounds. The first notable product in this category was made of polyurethane. These purely synthetic products do not have any components made of naturally occurring structures, such as collagen. In this review, we seek to create a rudimentary framework in which to understand these synthetic products and to review the current literature that supports the use of these novel yet intriguing therapies.

Disentangling Ligand Effects on Metathesis Catalyst Activity: Experimental and Computational Studies of Ruthenium-Aminophosphine Complexes.

Second-generation ruthenium olefin metathesis catalysts bearing aminophosphine ligands were investigated with systematic variation of the ligand structure. The rates of phosphine dissociation ( k1; initiation rate) and relative phosphine reassociation ( k-1) were determined for two series of catalysts bearing cyclohexyl(morpholino)phosphine and cyclohexyl(piperidino)phosphine ligands. In both cases, incorporating P-N bonds into the architecture of the dissociating phosphine accelerates catalyst initiation relative to the parent [Ru]-PCy3 complex; however, this effect is muted for the tris(amino)phosphine-ligated complexes, which exhibit higher ligand binding constants in comparison to those with phosphines containing one or two cyclohexyl substituents. These results, along with X-ray crystallographic data and DFT calculations, were used to understand the influence of ligand structure on catalyst activity. Especially noteworthy is the application of phosphines containing incongruent substituents (PR1R'2); detailed analyses of factors affecting ligand dissociation, including steric effects, inductive effects, and ligand conformation, are presented. Computational studies of the reaction coordinate for ligand dissociation reveal that ligand conformational changes contribute to the rapid dissociation for the fastest-initiating catalyst of these series, which bears a cyclohexyl-bis(morpholino)phosphine ligand. Furthermore, the effect of amine incorporation was examined in the context of ring-opening metathesis polymerization, and reaction rates were found to correlate well with catalyst initiation rates. The combined experimental and computational studies presented in this report reveal important considerations for designing efficient ruthenium olefin metathesis catalysts.

Control of Grafting Density and Distribution in Graft Polymers by Living Ring-Opening Metathesis Copolymerization.

Control over polymer sequence and architecture is crucial to both understanding structure-property relationships and designing functional materials. In pursuit of these goals, we developed a new synthetic approach that enables facile manipulation of the density and distribution of grafts in polymers via living ring-opening metathesis polymerization (ROMP). Discrete endo,exo-norbornenyl dialkylesters (dimethyl DME, diethyl DEE, di-n-butyl DBE) were strategically designed to copolymerize with a norbornene-functionalized polystyrene (PS), polylactide (PLA), or polydimethylsiloxane (PDMS) macromonomer mediated by the third-generation metathesis catalyst (G3). The small-molecule diesters act as diluents that increase the average distance between grafted side chains, generating polymers with variable grafting density. The grafting density (number of side chains/number of norbornene backbone repeats) could be straightforwardly controlled by the macromonomer/diluent feed ratio. To gain insight into the copolymer sequence and architecture, self-propagation and cross-propagation rate constants were determined according to a terminal copolymerization model. These kinetic analyses suggest that copolymerizing a macromonomer/diluent pair with evenly matched self-propagation rate constants favors randomly distributed side chains. As the disparity between macromonomer and diluent homopolymerization rates increases, the reactivity ratios depart from unity, leading to an increase in gradient tendency. To demonstrate the effectiveness of our method, an array of monodisperse polymers (PLAx-ran-DME1-x)n bearing variable grafting densities (x = 1.0, 0.75, 0.5, 0.25) and total backbone degrees of polymerization (n = 167, 133, 100, 67, 33) were synthesized. The approach disclosed in this work therefore constitutes a powerful strategy for the synthesis of polymers spanning the linear-to-bottlebrush regimes with controlled grafting density and side chain distribution, molecular attributes that dictate micro- and macroscopic properties.

Design, Synthesis, and Self-Assembly of Polymers with Tailored Graft Distributions.

Grafting density and graft distribution impact the chain dimensions and physical properties of polymers. However, achieving precise control over these structural parameters presents long-standing synthetic challenges. In this report, we introduce a versatile strategy to synthesize polymers with tailored architectures via grafting-through ring-opening metathesis polymerization (ROMP). One-pot copolymerization of an ω-norbornenyl macromonomer and a discrete norbornenyl comonomer (diluent) provides opportunities to control the backbone sequence and therefore the side chain distribution. Toward sequence control, the homopolymerization kinetics of 23 diluents were studied, representing diverse variations in the stereochemistry, anchor groups, and substituents. These modifications tuned the homopolymerization rate constants over 2 orders of magnitude (0.36 M-1 s-1 < khomo < 82 M-1 s-1). Rate trends were identified and elucidated by complementary mechanistic and density functional theory (DFT) studies. Building on this foundation, complex architectures were achieved through copolymerizations of selected diluents with a poly(d,l-lactide) (PLA), polydimethylsiloxane (PDMS), or polystyrene (PS) macromonomer. The cross-propagation rate constants were obtained by nonlinear least-squares fitting of the instantaneous comonomer concentrations according to the Mayo-Lewis terminal model. In-depth kinetic analyses indicate a wide range of accessible macromonomer/diluent reactivity ratios (0.08 < r1/r2 < 20), corresponding to blocky, gradient, or random backbone sequences. We further demonstrated the versatility of this copolymerization approach by synthesizing AB graft diblock polymers with tapered, uniform, and inverse-tapered molecular "shapes." Small-angle X-ray scattering analysis of the self-assembled structures illustrates effects of the graft distribution on the domain spacing and backbone conformation. Collectively, the insights provided herein into the ROMP mechanism, monomer design, and homo- and copolymerization rate trends offer a general strategy for the design and synthesis of graft polymers with arbitrary architectures. Controlled copolymerization therefore expands the parameter space for molecular and materials design.

Application of Bottlebrush Block Copolymers as Photonic Crystals.

Brush block copolymers are a class of comb polymers that feature polymeric side chains densely grafted to a linear backbone. These polymers display interesting properties due to their dense functionality, low entanglement, and ability to rapidly self-assemble to highly ordered nanostructures. The ability to prepare brush polymers with precise structures has been enabled by advancements in controlled polymerization techniques. This Feature Article highlights the development of brush block copolymers as photonic crystals that can reflect visible to near-infrared wavelengths of light. Fabrication of these materials relies on polymer self-assembly processes to achieve nanoscale ordering, which allows for the rapid preparation of photonic crystals from common organic chemical feedstocks. The characteristic physical properties of brush block copolymers are discussed, along with methods for their preparation. Strategies to induce self-assembly at ambient temperatures and the use of blending techniques to tune photonic properties are emphasized.

Electrophilic Activation of Silicon-Hydrogen Bonds in Catalytic Hydrosilations.

Hydrosilation reactions represent an important class of chemical transformations and there has been considerable recent interest in expanding the scope of these reactions by developing new catalysts. A major theme to emerge from these investigations is the development of catalysts with electrophilic character that transfer electrophilicity to silicon by Si-H activation. This type of mechanism has been proposed for catalysts ranging from Group 4 transition metals to Group 15 main group species. Additionally, other electrophilic silicon species, such as silylene complexes and η3 -H2 SiRR' complexes, have been identified as intermediates in hydrosilation reactions. In this Review, different types of catalysts are compared to highlight the range of hydrosilation mechanisms that feature electrophilic silicon centers. The importance of these catalysts to the development of new hydrosilation reactions is also discussed.

Significant Cooperativity Between Ruthenium and Silicon in Catalytic Transformations of an Isocyanide.

Complexes [PhBP3]RuH(η(3)-H2SiRR') (RR' = Me,Ph, 1a; RR' = Ph2, 1b; RR' = Et2, 1c) react with XylNC to form carbene complexes [PhBP3]Ru(H)═[C(H)(N(Xyl)(η(2)-H-SiRR'))] (2a-c; previously reported for 2a,b). Reactions of 1a-c with XylNC were further investigated to assess how metal complexes with multiple M-H-Si bonds can mediate transformations of unsaturated substrates. Complex 2a eliminates an N-methylsilacycloindoline product (3a) that results from hydrosilylation, hydrogenation, and benzylic C-H activation of XylNC. Turnover was achieved in a pseudocatalytic manner by careful control of the reaction conditions. Complex 1c mediates a catalytic isocyanide reductive coupling to furnish an alkene product (4) in a transformation that has precedent only in stoichiometric processes. The formations of 3a and 4 were investigated with deuterium labeling experiments, KIE and other kinetic studies, and by examining the reactivity of XylNC with an η(3)-H2SiMeMes complex (1d) to form a C-H activated complex (6). Complex 6 serves as a model for an intermediate in the formation of 3a, and NMR investigations at -30 °C reveal that 6 forms via a carbene complex (1d) that isomerizes to aminomethyl complex 7d. These investigations reveal that the formations of 3a and 4 involve multiple 4-, 5-, and 6-coordinate silicon species with 0, 1, 2, or 3 Ru-H-Si bonds. These mechanisms demonstrate exceptionally intricate roles for silicon in transition-metal-catalyzed reactions with a silane reagent.

Lewis Acidity of Bis(perfluorocatecholato)silane: Aldehyde Hydrosilylation Catalyzed by a Neutral Silicon Compound.

Bis(perfluorocatecholato)silane Si(cat(F))2 was prepared, and stoichiometric binding to Lewis bases was demonstrated with fluoride, triethylphosphine oxide, and N,N'-diisopropylbenzamide. The potent Lewis acidity of Si(cat(F))2 was suggested from catalytic hydrosilylation and silylcyanation reactions with aldehydes. Mechanistic studies of hydrosilylation using an optically active silane substrate, R-(+)-methyl-(1-naphthyl)phenylsilane, proceeded with predominant stereochemical retention at silicon, consistent with a carbonyl activation pathway. The enantiospecificity was dependent on solvent and salt effects, with increasing solvent polarity or addition of NBu4BAr(F)4 leading to a diminished enantiomeric ratio. The medium effects are consistent with an ionic mechanism, wherein hydride transfer occurs prior to silicon-oxygen bond formation.

Arterial Leg Ulcers in the Octogenarian.

Arterial leg ulcers are a debilitating sequela of chronic ischemia, and their management, particularly in the octogenarian, is an immense challenge. ALUs are frequently a manifestation of end-stage peripheral arterial disease, and their presence portends a high morbidity and mortality. Management primarily relies on restoration of flow, but in the geriatric population, interventions may carry undue risk and pathologies may not be amenable. Adjunctive therapies that improve quality of life and decrease morbidity and mortality are therefore essential, and understanding their benefits and limitations is crucial in developing a multimodal treatment algorithm of care for the uniquely challenging octogenarian population.

A remote Lewis acid trigger dramatically accelerates biaryl reductive elimination from a platinum complex.

A strategy for the control of electron density at a metal center is reported, which uses a remote chemical switch involving second-sphere Lewis acid binding that modulates electron density in the first coordination sphere. Binding of the Lewis acid B(C6F5)3 at remote nitrogen positions of a bipyrazine-diarylplatinum(II) complex accelerates biaryl reductive elimination by a factor of 64,000.

The mechanism of action of doxofylline is unrelated to HDAC inhibition, PDE inhibition or adenosine receptor antagonism.

Xanthines such as theophylline have been used in the treatment of lung diseases since the early 1900's, but have a major drawback of a very narrow therapeutic window and many drug/drug interactions. This means that plasma levels have to be measured regularly and can make the use of theophylline problematic. With the increasing availability of other classes of drugs for the treatment of respiratory diseases, this has limited the use of xanthines, despite their clear clinical benefit in the treatment of patients with asthma and COPD. Doxofylline is a xanthine molecule having both bronchodilator and anti-inflammatory activity with an improved therapeutic window over conventional xanthines such as theophylline. However, the mechanistic basis of this improved therapeutic window is not understood. The present study has investigated some pharmacological activities of doxofylline in comparison with theophylline. Doxofylline does not directly inhibit any of the known HDAC enzymes, and did not inhibit any PDE enzyme sub types or act as an antagonist at any of the known adenosine receptors, except for PDE2A(1), and adenosine A(2A) and only at the highest tested concentration (10(-4) M). These results may explain the improved tolerability profile of doxofylline compared with theophylline.

Nasal filters in prevention of seasonal rhinitis induced by allergenic pollen grains. Open clinical study.

Nasal filters (Sanispira) might represent a novel approach in preventing exacerbations of symptoms of seasonal allergic rhinitis by reducing pollen access to nasal cavities. Female and male voluntary patients between the ages of 18 and 64 years living in Naples area and affected by allergic rhinitis were recruited in an open clinical study. All were allergic to Parietaria pollen as assessed by skin-prick and/or RAST test with or without associated sensitization to other pollens such as Gramineae and Olea europaea. A pollen count was also carried out from 10th April until 30th of June 2011. The results of our study show positive statistical differences between the scores of common nasal symptoms and the reduced use of antihistaminic drugs in patients using nasal filters in comparison to non users. Nasal filters constitute a useful mean to reduce symptoms of seasonal allergic rhinitis in patients suffering from pollen allergy.

Crystal structure of 2-(2,6-diiso-propyl-phen-yl)-N,N-diethyl-3,3-dimethyl-2-aza-spiro-[4.5]decan-1-amine: a di-ethyl-amine adduct of a cyclic(alk-yl)(amino)-carbene (CAAC).

The structure of the title compound, C27H46N2, at 93 K has monoclinic (P21/n) symmetry. The title compound was prepared by treatment of 2-(2,6-diiso-propyl-phenyl)-3,3-dimethyl-2-aza-spiro-[4.5]dec-1-en-2-ium hydrogen dichloride with two equivalents of lithium di-ethyl-amide. Characterization of the title compound by single-crystal X-ray diffraction and 1H and 13C NMR spectroscopy is presented. Formation of the di-ethyl-amine adduct of the cyclic(alk-yl)(amino)-carbene (CAAC) was unexpected, as deprotonation using lithium diiso-propyl-amide results in free CAAC formation.

Processing Effects on the Self-Assembly of Brush Block Polymer Photonic Crystals.

The self-assembly of poly(dimethylsiloxane)-b-poly(trimethylene carbonate) (PDMS-b-PTMC) bottlebrush block polymers was investigated under different processing conditions. Small-angle X-ray scattering (SAXS) and UV/Visible spectroscopy provided insight into the self-assembly and structure in response to heating and applied pressure. In the absence of applied pressure (i.e., before annealing), the PDMS-b-PTMC bottlebrush block polymers are white solids and adopt small, randomly oriented lamellar grains. Heating the materials to 140 °C in the absence of applied pressure appears to "lock in" the isotropic, short-range-ordered state, preventing the formation of the long-range-ordered lamellar structure responsible for photonic properties. Applying modest anisotropic pressure (3 psi) between parallel plates at ambient temperature orients the short-range lamellar grains; however, applied pressure alone does not produce long-range order. Only when the bottlebrush block polymers were heated (>100 °C) under modest pressure (3 psi) were long-range-ordered photonic crystals formed. Analysis of the SAXS data motivated analogies to liquid crystals and revealed the potential self-assembly pathway. These results provide insight into the structure and self-assembly of bottlebrush block polymers with low glass transition temperature side chains in response to different processing conditions.

Standards of care and clinical predictors in patients hospitalised for a COPD exacerbation--the Italian SOS (Stratification Observational Study).

BACKGROUND AND AIMS: Hospitalisations for chronic obstructive pulmonary disease (COPD) exacerbations are major events in the natural history of the disease in terms of survival, quality of life and risk of further episodes of exacerbation. The aims of study were to evaluate: 1. adherence to recommended standards of care; and 2. clinical factors influencing major outcomes during hospitalisation for an episode of COPD exacerbation and within a 6-month follow-up. METHODS: An observational, prospective study was conducted in 68 centres. Assessment of standards of care included diagnostic procedures (such as pulmonary function tests and microbiology) and management options (such as drug therapies, vaccinations and rehabilitation). Outcome measures relevant to the hospitalisation were: survival, need for mechanical ventilation, and length of stay (LOS). Outcomes at 6-months were: survival, exacerbations and hospitalisations for an exacerbation. Multivariate logistic regression was applied to evaluate the relation between clinical factors and outcomes. RESULTS: 931 patients were enrolled. Only 556 patients (59.7%) were diagnosed COPD and stratified for severity with the support of spirometry (FEV1/VC < or = 0.7) and were considered for outcome analysis. Among treatments, pulmonary rehabilitation and anti-smoking counselling were applied infrequently (14.5 and 8.1% of patients, respectively). Within six months 63 COPD patients (17.7%) had at least one episode of exacerbation prompting a further hospitalisation and 19 died (5.3%). Predictor of mortality was the co-morbidity Charlson index (odds ratio, OR 10.3, p=0.03 CI: 1.25-84.96). A further hospitalisation was predicted by hospitalisation for an exacerbation in the previous 12 months (OR 3.59, p=0.003 CI: 1.54-8.39). CONCLUSIONS: Standards of care were far lower than recommended, in particular 40% of patients were labelled as COPD without spirometry. COPD patients with a second hospitalisation in 12 months for an exacerbation had about 3 times the risk of suffering a new episode and hospitalisation in the following six months.

Lewis acid-base interactions between platinum(ii) diaryl complexes and bis(perfluorophenyl)zinc: strongly accelerated reductive elimination induced by a Z-type ligand.

Z-type interactions between bis(perfluorophenyl)zinc and platinum(ii) diaryl complexes supported by 1,10-phenanthroline (phen), 2,2'-bipyridine (bpy), and bis(dimethylphosphino)ethane (dmpe) ligands are reported. In the solid state, the nature of the Pt-Zn interaction depends on the bidentate ligand; the phen-supported complex exhibits an unsupported Pt-Zn bond, while the dmpe derivative features additional bridging aryl interactions. A strongly accelerated rate of reductive elimination is observed for phen- and bpy-supported complexes, while aryl exchange between Pt and Zn is observed for the dmpe complex.

Combination therapy in COPD: different response of COPD stages and predictivity of functional parameters.

BACKGROUND: Inhaled corticosteroids reduce exacerbations in patients with chronic obstructive pulmonary disease (COPD) but they do not affect disease progression. FEV1, as single parameter, showed limits in describing the heterogeneity of COPD population. Combination therapy, with long-acting Beta2-agonist and corticosteroid, showed a more beneficial effect on lung function, exacerbations, and health status than single inhaled drug. The aim of this study was to assess, in stable COPD, which stage (mild, moderate, severe) shows the best response after 12 weeks inhaled treatment, and which starting functional parameters show a correlation with the response. METHODS: 170 stable COPD patients (38 mild, 66 moderate, 66 severe) were enrolled. Patients received salmeterol/fluticasone 50/500 microg Metered Dose Inhaler (MDI) bid for 12 weeks. Pulmonary function tests and clinical data were performed. Results were subdivided, on functional and clinical data, in "responders (R)" and "no-responders (NR)". RESULTS: A FEV1 improvement (+ 12% and 200 ml) was achieved in 21 mild, 28 moderate and 17 severe COPD patients, respectively 55.3%, 45.9%, and 30.9% of each group. Statistical analysis of starting functional parameters showed a correlation with the therapeutic response for FEV1/FVC, MEF50 and DLCO/VA% (p < 0.05). CONCLUSIONS: Salmeterol/fluticasone improves FEV1% in mild and moderate more than in severe COPD patients. The study confirmed the difference in response between early and advanced stage. Starting FEV1/FVC and MEF50 were significant predictors in mild and moderate stages, and starting DLCO/VA% resulted a significant predictor in moderate and severe stages.