ToxR activates the Vibrio cholerae virulence genes by tethering DNA to the membrane through versatile binding to multiple sites.

ToxR, a Vibrio cholerae transmembrane one-component signal transduction factor, lies within a regulatory cascade that results in the expression of ToxT, toxin coregulated pilus, and cholera toxin. While ToxR has been extensively studied for its ability to activate or repress various genes in V. cholerae, here we present the crystal structures of the ToxR cytoplasmic domain bound to DNA at the toxT and ompU promoters. The structures confirm some predicted interactions, yet reveal other unexpected promoter interactions with implications for other potential regulatory roles for ToxR. We show that ToxR is a versatile virulence regulator that recognizes diverse and extensive, eukaryotic-like regulatory DNA sequences, that relies more on DNA structural elements than specific sequences for binding. Using this topological DNA recognition mechanism, ToxR can bind both in tandem and in a twofold inverted-repeat-driven manner. Its regulatory action is based on coordinated multiple binding to promoter regions near the transcription start site, which can remove the repressing H-NS proteins and prepares the DNA for optimal interaction with the RNA polymerase.

Patient-centered care in Coronary Heart Disease: what do you want to measure? A systematic review of reviews on patient-reported outcome measures.

BACKGROUND: The number of published articles on Patient-Reported Outcomes Measures (PROMs) in Coronary Heart Disease (CHD), a leading cause of disability-adjusted life years lost worldwide, has been growing in the last decades. The aim of this study was to identify all the disease-specific PROMs developed for or used in CHD and summarize their characteristics (regardless of the construct), to facilitate the selection of the most adequate one for each purpose. METHODS: A systematic review of reviews was conducted in MEDLINE, Scopus, and the Cochrane Database of Systematic Reviews. PROQOLID and BiblioPRO libraries were also checked. PROMs were classified by construct and information was extracted from different sources regarding their main characteristics such as aim, number of items, specific dimensions, original language, and metric properties that have been assessed. RESULTS: After title and abstract screening of 1224 articles, 114 publications were included for full text review. Finally, we identified 56 PROMs: 12 symptoms scales, 3 measuring functional status, 21 measuring Health-Related Quality of Life (HRQL), and 20 focused on other constructs. Three of the symptoms scales were specifically designed for a study (no metric properties evaluated), and only five have been included in a published study in the last decade. Regarding functional status, reliability and validity have been assessed for Duke Activity Index and Seattle Angina Questionnaire, which present multiple language versions. For HRQL, most of the PROMs included physical, emotional, and social domains. Responsiveness has only been evaluated for 10 out the 21 HRQL PROMs identified. Other constructs included psychological aspects, self-efficacy, attitudes, perceptions, threats and expectations about the treatment, knowledge, adjustment, or limitation for work, social support, or self-care. CONCLUSIONS: There is a wide variety of instruments to assess the patients' perspective in CHD, covering several constructs. This is the first systematic review of specific PROMs for CHD including all constructs. It has practical significance, as it summarizes relevant information that may help clinicians, researchers, and other healthcare stakeholders to choose the most adequate instrument for promoting shared decision making in a trend towards value-based healthcare.

Molecular Approach to Alkali-Metal Encapsulation by a Prussian Blue Analogue FeII/CoIII Cube in Aqueous Solution: A Kineticomechanistic Exchange Study.

The preparation of a series of alkali-metal inclusion complexes of the molecular cube [{CoIII(Me3-tacn)}4{FeII(CN)6}4]4- (Me3-tacn = 1,4,7-trimethyl-1,4,7-triazacyclononane), a mixed-valent Prussian Blue analogue bearing bridging cyanido ligands, has been achieved by following a redox-triggered self-assembly process. The molecular cubes are extremely robust and soluble in aqueous media ranging from 5 M [H+] to 2 M [OH-]. All the complexes have been characterized by the standard mass spectometry, UV-vis, inductively coupled plasma, multinuclear NMR spectroscopy, and electrochemistry. Furthermore, X-ray diffraction analysis of the sodium and lithium salts has also been achieved, and the inclusion of moieties of the form {M-OH2}+ (M = Li, Na) is confirmed. These inclusion complexes in aqueous solution are rather inert to cation exchange and are characterized by a significant decrease in acidity of the confined water molecule due to hydrogen bonding inside the cubic cage. Exchange of the encapsulated cationic {M-OH2}+ or M+ units by other alkali metals has also been studied from a kineticomechanistic perspective at different concentrations, temperatures, ionic strengths, and pressures. In all cases, the thermal and pressure activation parameters obtained agree with a process that is dominated by differences in hydration of the cations entering and exiting the cage, although the size of the portal enabling the exchange also plays a determinant role, thus not allowing the large Cs+ cation to enter. All the exchange substitutions studied follow a thermodynamic sequence that relates with the size and polarizing capability of the different alkali cations; even so, the process can be reversed, allowing the entry of {Li-OH2}+ units upon adsorption of the cube on an anion exchange resin and subsequent washing with a Li+ solution.

Adaptation and psychometric validation of Diabetes Health Profile (DHP-18) in patients with type 2 diabetes in Quito, Ecuador: a cross-sectional study.

INTRODUCTION: The Diabetes Health Profile (DHP-18), structured in three dimensions (psychological distress (PD), barriers to activity (BA) and disinhibited eating (DE)), assesses the psychological and behavioural burden of living with type 2 diabetes. The objectives were to adapt the DHP-18 linguistically and culturally for use with patients with type 2 DM in Ecuador, and to evaluate its psychometric properties. METHODS: Participants were recruited using purposive sampling through patient clubs at primary health centres in Quito, Ecuador. The DHP-18 validation consisted in the linguistic validation made by two Ecuadorian doctors and eight patient interviews. And in the psychometric validation, where participants provided clinical and sociodemographic data and responded to the SF-12v2 health survey and the linguistically and culturally adapted version of the DHP-18. The original measurement model was evaluated with confirmatory factor analysis (CFA). Reliability was assessed through internal consistency using Cronbach's alpha and test-retest reproducibility by administering DHP-18 in a random subgroup of the participants two weeks after (n = 75) using intraclass correlation coefficient (ICC). Convergent validity was assessed by establishing previous hypotheses of the expected correlations with the SF12v2 using Spearman's coefficient. RESULTS: Firstly, the DHP-18 was linguistically and culturally adapted. Secondly, in the psychometric validation, we included 146 participants, 58.2% female, the mean age was 56.8 and 31% had diabetes complications. The CFA indicated a good fit to the original three factor model (χ2 (132) = 162.738, p < 0.001; CFI = 0.990; TLI = 0.989; SRMR = 0.086 and RMSEA = 0.040. The BA dimension showed the lowest standardized factorial loads (λ) (ranging from 0.21 to 0.77), while λ ranged from 0.57 to 0.89 and from 0.46 to 0.73, for the PD and DE dimensions respectively. Cronbach's alphas were 0.81, 0.63 and 0.74 and ICCs 0.70, 0.57 and 0.62 for PD, BA and DE, respectively. Regarding convergent validity, we observed weaker correlations than expected between DHP-18 dimensions and SF-12v2 dimensions (r > -0.40 in two of three hypotheses). CONCLUSIONS: The original three factor model showed good fit to the data. Although reliability parameters were adequate for PD and DE dimensions, the BA presented lower internal consistency and future analysis should verify the applicability and cultural equivalence of some of the items of this dimension to Ecuador.

Self-Assembled, Highly Positively Charged, Allyl-Pd Crowns: Cavity-Pocket-Driven Interactions of Fluoroanions.

A series of dodecanuclear highly positively charged homo- and heterometallamacrocycles [{Pd(η3 -2-Me-C3 H4 )}6 (4-PPh2 py)12 {M2 (tpbz)}3 ]18+ (M=Pd, Pt; tpbz=1,2,4,5-tetrakis(diphenylphosphanyl)benzene were synthesized by the quantitative self-assembly of {Pd(η3 -2-Me-C3 H4 )}+ , {M2 (tpbz)}4+ and 4-PPh2 py moieties in 2:1:4 molar ratio. The cationic assemblies were obtained as salts of different fluorinated anions with diverse sizes and electronic properties, namely BF4 - , PF6 - , SbF6 - and CF3 SO3 - . The new crown-like metallamacrocycles showed remarkable differences in their NMR spectra due to the presence of the different counteranions. On the basis of the observed variations, the metallacycles have been tested as catalytic precursors in allylic alkylation reactions. The anion-dependent activity and selectivity has been analysed and compared with that of the corresponding monometallic allylic corners [Pd(η3 -2-Me-C3 H4 )(4-PPh2 py)2 ]X (X=BF4 - , PF6 - , SbF6 - , CF3 SO3 - ). DFT calculations have been employed in order to help to the interpretation of the experimental data and to model the anion-crown interactions.

Self-Assembly and Properties of a Discrete Water-Soluble Prussian Blue Analogue FeII/CoIII Cube: Confinement of a Water Molecule in Aqueous Solution.

Novel types of water-soluble anionic cubic cages, K4[{CoIII(Me3-Tacn)}4{FeII(CN)6}4] and Na4[{CoIII(Me3-Tacn)}4{FeII(CN)6}4] (Me3-Tacn = 1,4,7-trimethyl-1,4,7-triazacyclononane), were prepared by means of a mechanistically designed self-assembly process between [Co(Me3-Tacn)Cl3] and A4[FeII(CN)6] (M = Na or K), consisting of a rate-limiting outer-sphere redox step, followed by a fast substitution/inner-sphere redox reaction sequence. These compounds show remarkable stability in aqueous solution at different pH ranges, displaying neat protonation processes and reversible oxidation with peroxodisulfate to its neutral {FeIII4CoIII4} form. Furthermore, the cages behave as a robust and water-soluble molecular Prussian Blue analogue capable of encapsulating {Na-OH2}+ pairs and K+ cations in aqueous solution, with the cubic structure of the complex being preserved. Substitution of the {Na-OH2}+ pairs by K+ is easily accomplished, and the electrochemical properties of the sodium and potassium salts of the new cages have been found to be dramatically dependent on the encapsulated units.

Bond Dissociation Energies of Metallo-supramolecular Building Blocks: Insight from Fragmentation of Selectively Self-Assembled Heterometallic Metallo-supramolecular Aggregates.

A series of selectively self-assembled metallo-supramolecular square-like macrocycles with unsymmetric ditopic linkers and two different types of metal corners, i.e., {Pd(η3-2-Me-C3H4)} and {M(dppp)} with dppp = 1,3-bis(diphenylphosphino)propane and M = Pd2+ or Pt2+, have been studied in the gas phase using collision-induced dissociation. The aggregates show distinct fragmentation patterns determined by ligand length, i.e, aggregate size, and type of metal corner. Information on relative binding strength can be deduced. This is of particular interest for (methylallyl)Pd as a relatively new building block in metallo-supramolecular chemistry. The phosphane end of the unsymmetric ligand connected to (η3-2-Me-C3H4)Pd is bound significantly stronger than its pyridine end to (dppp)Pt and (dppp)Pd. These results are corroborated by DFT calculations.

Kineticomechanistic Study of the Redox pH Cycling Processes Occurring on a Robust Water-Soluble Cyanido-Bridged Mixed-Valence {CoIII/FeII}2 Square.

A kineticomechanistic study of reversible electron-transfer processes undergone by the water-soluble, cyanido-bridged mixed-valence [{CoIII{(Me)2(µ-ET)cyclen}}2{(µ-NC)2FeII(CN)4}2]2- square has been carried out. The oxidation reaction consists of a two-step process with the participation of a solvent-assisted outer-sphere complex, as a result of the establishment of hydrogen bonds that involve the oxo groups of the oxidant (peroxodisulfate) and the terminal cyanido ligands of the tetrametallic square. The formally endergonic reduction reaction of the fully oxidized ([{CoIII{(Me)2(µ-ET)cyclen}}2{(µ-NC)2FeIII(CN)4}2]) core by water, producing hydrogen peroxide from water even at low pH values, is also a two-step process. Each one of these processes requires a set of two preequilibria involving the association of OH- and its subsequent deprotonation by a further OH- anion. The structure of the square compound in its fully protonated form has also been determined by X-ray diffraction and shows the existence of strong hydrogen-bonding interactions, in agreement with the rather high basicity of the terminal cyanido ligands. Likewise, density functional theory calculations on the tetrametallic complex showed zones with negative electrostatic potential around the FeII centers of the square that would account for the establishment of the hydrogen bonds found in the solid state. Spectroelectrochemistry experiments demonstrated the singular stability of the {CoIII/FeII}22- complex, as well as that of their partially, {Co2III/FeIIIFeII}-, and fully, {CoIII/FeIII}2, oxidized counterparts because no hysteresis was observed in these measurements.

Reversible Self-Assembly of Water-Soluble Gold(I) Complexes.

The reaction of the gold polymers containing bipyridyl and terpyridyl units, [Au(C≡CC15H10N3)]n and [Au(C≡CC10H7N2)]n, with the water-soluble phosphines 1,3,5-triaza-7-phosphatricyclo[3.3.1.13.7]decane and 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane gives rise to the formation of four gold(I) alkynyl complexes that self-assemble in water (H2O) and dimethyl sulfoxide (DMSO), through different intermolecular interactions, with an impact on the observed luminescence displayed by the supramolecular assemblies. A detailed analysis carried out by NMR studies performed in different DMSO/deuterated H2O mixtures indicates the presence of two different assembly modes in the aggregates: (i) chain assemblies, which are based mainly on aurophilic interactions, and (ii) stacked assemblies, which are based on Au···π and π···π interactions. These different supramolecular environments can also be detected by their intrinsic optical properties (differences in absorption and emission spectra) and are predicted by the changes in the relative binding energy from density functional theory calculations carried out in DMSO and H2O. Small-angle X-ray scattering (SAXS) experiments performed in the same mixture of solvents are in agreement with the formation of aggregates in all cases. The aromatic units chosen, bipyridine and terpyridine, allow the use of external stimuli to reversibly change the aggregation state of the supramolecular assemblies. Interaction with the Zn2+ cation is observed to disassemble the aggregates, while encapsulating agents competing for Zn2+ complexation revert the process to the aggregation stage, as verified by SAXS and NMR. The adaptive nature of the supramolecular assemblies to the metal-ion content is accompanied by significant changes in the absorption and emission spectra, signaling the aggregation state and also the content on Zn2+.

Relief of Urinary Symptom Burden after Primary Prostate Cancer Treatment.

PURPOSE: Harms of prostate cancer treatment on urinary health related quality of life have been thoroughly studied. In this study we evaluated not only the harms but also the potential benefits of prostate cancer treatment in relieving the pretreatment urinary symptom burden. MATERIALS AND METHODS: In American (1,021) and Spanish (539) multicenter prospective cohorts of men with localized prostate cancer we evaluated the effects of radical prostatectomy, external radiotherapy or brachytherapy in relieving pretreatment urinary symptoms and in inducing urinary symptoms de novo, measured by changes in urinary medication use and patient reported urinary bother. RESULTS: Urinary symptom burden improved in 23% and worsened in 28% of subjects after prostate cancer treatment in the American cohort. Urinary medication use rates before treatment and 2 years after treatment were 15% and 6% with radical prostatectomy, 22% and 26% with external radiotherapy, and 19% and 46% with brachytherapy, respectively. Pretreatment urinary medication use (OR 1.4, 95% CI 1.0-2.0, p = 0.04) and pretreatment moderate lower urinary tract symptoms (OR 2.8, 95% CI 2.2-3.6) predicted prostate cancer treatment associated relief of baseline urinary symptom burden. Subjects with pretreatment lower urinary tract symptoms who underwent radical prostatectomy experienced the greatest relief of pretreatment symptoms (OR 4.3, 95% CI 3.0-6.1), despite the development of deleterious de novo urinary incontinence in some men. The magnitude of pretreatment urinary symptom burden and beneficial effect of cancer treatment on those symptoms were verified in the Spanish cohort. CONCLUSIONS: Men with pretreatment lower urinary tract symptoms may experience benefit rather than harm in overall urinary outcome from primary prostate cancer treatment. Practitioners should consider the full spectrum of urinary symptom burden evident before prostate cancer treatment in treatment decisions.

Short Physical Performance Battery and all-cause mortality: systematic review and meta-analysis.

BACKGROUND: The Short Physical Performance Battery (SPPB) is a well-established tool to assess lower extremity physical performance status. Its predictive ability for all-cause mortality has been sparsely reported, but with conflicting results in different subsets of participants. The aim of this study was to perform a meta-analysis investigating the relationship between SPPB score and all-cause mortality. METHODS: Articles were searched in MEDLINE, the Cochrane Library, Google Scholar, and BioMed Central between July and September 2015 and updated in January 2016. Inclusion criteria were observational studies; >50 participants; stratification of population according to SPPB value; data on all-cause mortality; English language publications. Twenty-four articles were selected from available evidence. Data of interest (i.e., clinical characteristics, information after stratification of the sample into four SPPB groups [0-3, 4-6, 7-9, 10-12]) were retrieved from the articles and/or obtained by the study authors. The odds ratio (OR) and/or hazard ratio (HR) was obtained for all-cause mortality according to SPPB category (with SPPB scores 10-12 considered as reference) with adjustment for age, sex, and body mass index. RESULTS: Standardized data were obtained for 17 studies (n = 16,534, mean age 76 ± 3 years). As compared to SPPB scores 10-12, values of 0-3 (OR 3.25, 95%CI 2.86-3.79), 4-6 (OR 2.14, 95%CI 1.92-2.39), and 7-9 (OR 1.50, 95%CI 1.32-1.71) were each associated with an increased risk of all-cause mortality. The association between poor performance on SPPB and all-cause mortality remained highly consistent independent of follow-up length, subsets of participants, geographic area, and age of the population. Random effects meta-regression showed that OR for all-cause mortality with SPPB values 7-9 was higher in the younger population, diabetics, and men. CONCLUSIONS: An SPPB score lower than 10 is predictive of all-cause mortality. The systematic implementation of the SPPB in clinical practice settings may provide useful prognostic information about the risk of all-cause mortality. Moreover, the SPPB could be used as a surrogate endpoint of all-cause mortality in trials needing to quantify benefit and health improvements of specific treatments or rehabilitation programs. The study protocol was published on PROSPERO (CRD42015024916).

Redox-Assisted Self-Assembly of a Water-Soluble Cyanido-Bridged Mixed Valence {CoIII /FeII }2 Square.

The facile redox-assisted assembly of a water-soluble, extremely robust, cyanide-bridged mixed-valence [{CoIII {(Me)2 (µ-ET)cyclen}}2 {(µ-NC)2 FeII (CN)4 }2 ]2- square is reported. The preparation process involved the use of the enhanced lability of inert CoIII synthons triggered by outer-sphere redox processes. Characterization of the final compounds has been carried out by NMR, UV/Vis, electrochemistry, and ICP analyses. DFT calculations have been conducted to optimize a structure that has the same hydrodynamic radius as that obtained from DOSY experiments. The new compound is extremely robust, surviving in aqueous solution within the 0-12 pH range for months. The species shows a high affinity for both protons and hydroxo ions in aqueous medium.

Lower limb function and 10-year survival in population aged 75 years and older.

BACKGROUND: Scientific societies recommend assessing lower limb function in usual clinical practice. The Short Physical Performance Battery (SPPB) is one of the most validated tools to assess this, but its capacity to predict long-term mortality in very old population attending primary care has not been studied. OBJECTIVE: To assess the ability of the SPPB to predict 10-year survival in individuals aged 75 and over. METHODS: Prospective cohort study with a 10-year follow-up. A representative sample of people aged 75 years or older without severe dependence (Barthel Index > 20) treated at a Spanish primary care centre (n = 315). Baseline evaluation included geriatric assessment with most well-known death predictors. The three SPPB subtasks (standing balance, walking speed and chair stand tests) were administered. Kaplan-Meier curves and Cox proportional hazard models were calculated for all-cause mortality. RESULTS: Mean age was 81.9 years (60.6% female). Ten-year survival of elders with SPPB score <7 and ≥7 was 0.23 and 0.37 (P < 0.001), respectively. This difference remained statistically significant in the Cox model adjusted by age, gender, number of drugs prescribed, cognitive status, body mass index and visual sharpness (adjusted hazard ratio = 1.37; 95% confidence interval: 1.01-1.86). Also, walking speed and chair stand subtasks were both individual-independent predictors of 10-year survival. CONCLUSIONS: Our findings indicate that SPPB is an independent predictor of long-term survival. The chair stand subtask could be a predictor as useful as the full performance battery, becoming a good alternative for primary care where the burden of performing all three subtasks could be excessive.

Asthma inhaler adherence determinants in adults: systematic review of observational data.

Nonadherence to inhaled medication leads to poor asthma control and increased healthcare utilisation. Many studies exploring adherence determinants have been conducted, but summaries of the evidence are scarce. We performed a systematic review of observational research on determinants of asthma inhaler adherence among adults. We searched for articles in English reporting quantitative observational studies on inhaler adherence correlates among adults in developed countries, published in EMBASE, Medline, PsychInfo and PsychArticles in 1990-2014. Two coders independently assessed eligibility and extracted data, and assessed study quality. Results were summarised qualitatively into social and economic, and healthcare-, therapy-, condition- and patient-related factors. The 51 studies included mainly examined patient-related factors and found consistent links between adherence and stronger inhaler-necessity beliefs, and possibly older age. There was limited evidence on the relevance of other determinants, partly due to study heterogeneity regarding the types of determinants examined. Methodological quality varied considerably and studies performed generally poorly on their definitions of variables and measures, risk of bias, sample size and data analysis. A broader adoption of common methodological standards and health behaviour theories is needed before cumulative science on the determinants of adherence to asthma inhalers among adults can develop further.

The EULAR Outcome Measures Library: development and an example from a systematic review for systemic lupus erythematous instruments.

OBJECTIVES: Patient reported outcomes (PROs) are relevant in rheumatology. Variable accessibility and validity of commonly used PROs are obstacles to homogeneity in evidence synthesis. The objective of this project was to provide a comprehensive library of "validated PROs". METHODS: A launch meeting with rheumatologists, PROs methodological experts, and patients, was held to define the library's aims and scope, and basic requirements. To feed the library we performed systematic reviews on selected diseases and domains. Relevant information on PROs was collected using standardised data collection forms based on the COSMIN checklist. RESULTS: The EULAR Outcomes Measures Library (OML), whose aims are to provide and to advise on PROs on a user-friendly manner albeit based on scientific grounds, has been launched and made accessible to all. PROs currently included cover any domain and, are generic or specifically target to the following diseases: rheumatoid arthritis, osteoarthritis, spondyloarthritis, low back pain, systemic lupus erythematosus, gout, osteoporosis, juvenile idiopathic arthritis, and fibromyalgia. Up to 236 instruments (106 generic and 130 specific) have been identified, evaluated, and included. The systematic review for SLE, which yielded 10 specific instruments, is presented here as an example. The OML website includes, for each PRO, information on the construct being measured and the extent of validation, recommendations for use, and available versions; it also contains a glossary on common validation terms. CONCLUSIONS: The OML is an in progress library led by rheumatologists, related professionals and patients, that will help to better understand and apply PROs in rheumatic and musculoskeletal diseases.

Validation of the Spanish-language version of the Prolapse Quality of Life questionnaire in Chilean women.

INTRODUCTION AND HYPOTHESIS: The Prolapse Quality of Life (P-QOL) questionnaire is a specific health-related quality of life (HRQL) instrument to assess the impact of POP on women. It has been validated in English-speaking women and to date has been translated into several other languages. However, currently there is no Spanish translation of the P-QOL questionnaire. The aim of this study was to translate the P-QOL questionnaire into Spanish and to assess its feasibility, validity, and reliability. METHODS: Following a forward- and back-translation of the original English P-QOL questionnaire into Spanish language, the translated questionnaire was reviewed by a group of patients as well as an expert panel to assess its comprehensibility. In this cross-sectional study women with POP symptoms were recruited from a tertiary referral teaching hospital. Women were defined as symptomatic if they report feeling a lump/bulge/pressure in the vagina. The Spanish translated P-QOL questionnaire was self-administered to all women. Reliability, content, and construct validity were evaluated using the Cronbach's alpha coefficient, ANOVA, and Spearman's correlation tests. RESULTS: One hundred and twenty-eight women were studied. There were no missing items. The Cronbach's alpha ranged from 0.626 to 0.866 across domains, demonstrating the good reliability of the Spanish P-QOL. The severity of symptoms was related to the worst quality of life, but the severity of POP was not related to poorer QoL. CONCLUSIONS: The Spanish translated version of the P-QOL is a reliable, consistent and valid instrument to assess symptom severity and QoL impact in Chilean women with POP.

Clinical intervals and diagnostic characteristics in a cohort of prostate cancer patients in Spain: a multicentre observational study.

BACKGROUND: Little is known about the healthcare process for patients with prostate cancer, mainly because hospital-based data are not routinely published. The main objective of this study was to determine the clinical characteristics of prostate cancer patients, the, diagnostic process and the factors that might influence intervals from consultation to diagnosis and from diagnosis to treatment. METHODS: We conducted a multicentre, cohort study in seven hospitals in Spain. Patients' characteristics and diagnostic and therapeutic variables were obtained from hospital records and patients' structured interviews from October 2010 to September 2011. We used a multilevel logistic regression model to examine the association between patient care intervals and various variables influencing these intervals (age, BMI, educational level, ECOG, first specialist consultation, tumour stage, PSA, Gleason score, and presence of symptoms) and calculated the odds ratio (OR) and the interquartile range (IQR). To estimate the random inter-hospital variability, we used the median odds ratio (MOR). RESULTS: 470 patients with prostate cancer were included. Mean age was 67.8 (SD: 7.6) years and 75.4% were physically active. Tumour size was classified as T1 in 41.0% and as T2 in 40% of patients, their median Gleason score was 6.0 (IQR:1.0), and 36.1% had low risk cancer according to the D'Amico classification. The median interval between first consultation and diagnosis was 89 days (IQR:123.5) with no statistically significant variability between centres. Presence of symptoms was associated with a significantly longer interval between first consultation and diagnosis than no symptoms (OR:1.93, 95%CI 1.29-2.89). The median time between diagnosis and first treatment (therapeutic interval) was 75.0 days (IQR:78.0) and significant variability between centres was found (MOR:2.16, 95%CI 1.45-4.87). This interval was shorter in patients with a high PSA value (p = 0.012) and a high Gleason score (p = 0.026). CONCLUSIONS: Most incident prostate cancer patients in Spain are diagnosed at an early stage of an adenocarcinoma. The period to complete the diagnostic process is approximately three months whereas the therapeutic intervals vary among centres and are shorter for patients with a worse prognosis. The presence of prostatic symptoms, PSA level, and Gleason score influence all the clinical intervals differently.

Long-acting beta-agonists plus inhaled corticosteroids safety: a systematic review and meta-analysis of non-randomized studies.

BACKGROUND: Although several systematic reviews investigated the safety of long-acting beta-agonists (LABAs) in asthma, they mainly addressed randomized clinical trials while evidence from non-randomized studies has been mostly neglected. We aim to assess the risk of serious adverse events in adults and children with asthma treated with LABAs and Inhaled Corticosteroids (ICs), compared to patients treated only with ICs, from published non-randomized studies. METHODS: The protocol registration number was CRD42012003387 (http://www.crd.york.ac.uk/Prospero). Literature search for articles published since 1990 was performed in MEDLINE and EMBASE. Two authors selected studies independently for inclusion and extracted the data. A third reviewer resolved discrepancies. To assess the risk of serious adverse events, meta-analyses were performed calculating odds ratio summary estimators using random effect models when heterogeneity was found, and fixed effect models otherwise. RESULTS: Of 4,415 candidate articles, 1,759 abstracts were reviewed and 220 articles were fully read. Finally, 19 studies met the inclusion criteria. Most of them were retrospective observational cohorts. Sample sizes varied from 50 to 514,216. The meta-analyses performed (69,939-624,303 participants according to the outcome considered) showed that odds ratio of the LABAs and ICs combined treatment when compared with ICs alone was: 0.88 (95% CI 0.69-1.12) for asthma-related hospitalization; 0.75 (95% CI 0.66-0.84) for asthma-related emergency visits; 1.02 (95% CI 0.94-1.10) for systemic corticosteroids; and 0.95 (95% CI 0.9-1.0) for the combined outcome. CONCLUSIONS: Evidence from observational studies shows that the combined treatment of LABAs and ICs is not associated with a higher risk of serious adverse events, compared to ICs alone. Major gaps identified were prospective design, paediatric population and inclusion of mortality as a primary outcome.

Kinetico-mechanistic insights on the assembling dynamics of allyl-cornered metallacycles: the Pt-Npy bond is the keystone.

The square-like homo- and heterometallamacrocycles [{Pd(η(3) -2-Me-C3 H4 )(L(n) )2 }2 {M(dppp)}2 ](CF3 SO3 )6 (dppp=1,3-bis(diphenylphosphino)propane) and [{Pd(η(3) -2-Me-C3 H4 )(L(1) )2 }2 {M(PPh3 )2 }2 ](CF3 SO3 )6 [py=pyridine, M=Pd, Pt, L(n=) 4-PPh2 py (L(1) ), 4-C6 F4 PPh2 py (L(2) )] containing allyl corners were synthesised by antisymbiotic self-assembly of the different palladium and platinum metallic corners and the ambidentate N,P ligands. All the synthesised assemblies displayed a complex dynamic behaviour in solution, the rate of which is found to be dependent on the electronic and/or steric nature of the different building blocks. A kinetico-mechanistic study by NMR line shape analysis of the dynamics of some of these assemblies was undertaken in order to determine the corresponding thermal activation parameters. Both an enhanced thermodynamic stability and slower dynamics were observed for platinum-pyridine-containing species when compared with their palladium analogues. Time-dependent NMR spectroscopy in combination with ESI mass spectrometry was used to study the exchange between the assemblies and their building blocks, as well as that occurring between different metallamacrocycles. Preliminary studies were carried out on the activity of some of the metallamacrocyclic compounds as catalytic precursors in the allylic substitution reaction, and the results compared with that of the monometallic allylic corner [Pd(η(3) -2-Me-C3 H4 )(L(1) )2 ](+) .

Dinuclear pyridine-4-thiolate-bridged rhodium and iridium complexes as ditopic building blocks in molecular architecture.

A series of dinuclear pyridine-4-thiolate (4-Spy)-bridged rhodium and iridium compounds [M(µ-4-Spy)(diolef)]2 [diolef = 1,5-cyclooctadiene (cod), M = Rh (1), Ir (2); diolef = 2,5-norbornadiene (nbd), M = Rh (3)] were prepared by the reaction of Li(4-Spy) with the appropriate compound [M(µ-Cl)(diolef)]2 (M = Rh, Ir). The dinuclear compound [Rh(µ-4-Spy)(CO)(PPh3)]2 (4) was obtained by the reaction of [Rh(acac)(CO)(PPh3)] (acac = acetylacetonate) with 4-pySH. Compounds 1-4 were assessed as metalloligands in self-assembly reactions with the cis-blocked acceptors [M(cod)(NCCH3)2](BF4) [M = Rh (a), Ir (b)] and [M(H2O)2(dppp)](OTf)2 [M = Pd (c), Pt (d); dppp = 1,3-bis(diphenylphosphino)propane]. The homometallic hexanuclear metallomacrocycles [{M2(µ-4-Spy)2(cod)2}2{M(cod)}2](BF4)2 (M = Rh [(1a)2], Ir [(2b)2]) and the heterometallic hexanuclear metallomacrocycles [{Rh2(µ-4-Spy)2(cod)2}2{Ir(cod)}2](BF4)2 [(1b)2], [{Rh2(µ-4-Spy)2(cod)2}2{M'(dppp)}2](OTf)4 (M' = Pd [(1c)2], Pt [(1d)2]), and [{Ir2(µ-4-Spy)2(cod)2}2{M'(dppp)}2](OTf)4 (M' = Pd [(2c)2], Pt [(2d)2]) were obtained. NMR spectroscopy in combination with electrospray ionization mass spectrometry was used to elucidate the nature of the metalloligands and their respective supramolecular assemblies. Most of the synthesized species were found to be nonrigid in solution, and their fluxional behavior was studied by variable-temperature (1)H NMR spectroscopy. An X-ray diffraction study of the assemblies (1a)2 and (1d)2 revealed the formation of rectangular (9.6 Å × 6.6 Å) hexanuclear metallomacrocycles with alternating dinuclear (Rh2) and mononuclear (Rh or Pt) corners. The hexanuclear core is supported by four pyridine-4-thiolate linkers, which are bonded through the thiolate moieties to the dinuclear rhodium units, exhibiting a bent-anti arrangement, and through the peripheral pyridinic nitrogen atoms to the mononuclear corners.