Mild Strategy for the Preparation of Alkyl Sulfonyl Fluorides from Alkyl Bromides and Alcohols Using Photoredox Catalysis and Flow Chemistry.

Facile access to sp3-rich scaffolds containing a sulfonyl fluoride group is still limited. Herein, we describe a mild and scalable strategy for the preparation of alkyl sulfonyl fluorides from readily available alkyl bromides and alcohols using photoredox catalysis. This approach is based on halogen atom transfer (XAT), followed by SO2 capture and fluorination. The method features mild conditions enabling fast access to high-value derivatives and has been scaled up to 5 g using a continuous stirred tank reactor cascade.

Ruthenium-catalyzed intermolecular alkene-alkyne couplings in biologically relevant media.

Cationic cyclopentadienyl Ru(ii) catalysts can efficiently promote mild intermolecular alkyne-alkene couplings in aqueous media, even in the presence of different biomolecular components, and in complex media like DMEM. The method can also be used for the derivatization of amino acids and peptides, therefore proposing a new way to label biomolecules with external tags. This C-C bond-forming reaction, based on simple alkene and alkyne reactants, can now be added to the toolbox of bioorthogonal reactions promoted by transition metal catalysts.

C-H Insertion via Ruthenium Catalyzed gem-Hydrogenation of 1,3-Enynes.

gem-Hydrogenation of an internal alkyne with the aid of [Cp*RuCl]4 as the precatalyst is a highly unorthodox transformation, in which one C atom of the triple bond is transformed into a methylene group, whereas the second C atom gets converted into a ruthenium carbene. In the case of 1,3-enynes bearing a propargylic steering substituent as the substrates, the reaction occurs regioselectively, giving rise to vinyl carbene complexes that adopt interconverting η1/η3-binding modes in solution; a prototypical example of such a reactive intermediate was characterized in detail by spectroscopic means. Although both forms are similarly stable, only the η3-vinyl carbene proved kinetically competent to insert into primary, secondary, or tertiary C-H bonds on the steering group itself or another suitably placed ether, acetal, orthoester, or (sulfon)amide substituent. The ensuing net hydrogenative C-H insertion reaction is highly enabling in that it gives ready access to spirocyclic as well as bridged ring systems of immediate relevance as building blocks for medicinal chemistry. Moreover, the reaction scales well and lends itself to the formation of partly or fully deuterated isotopologues. Labeling experiments in combination with PHIP NMR spectroscopy (PHIP = parahydrogen induced polarization) confirmed that the reactions are indeed triggered by gem-hydrogenation, whereas kinetic data provided valuable insights into the very nature of the turnover-limiting transition state of the actual C-H insertion step.

Altered cardiometabolic profile in girls with central precocious puberty and adipokines: A propensity score matching analysis.

OBJECTIVE: To compare cardiometabolic factors and adipokines between patients with recently diagnosed CPP and controls without CPP, paired by BMI Z scores (BMIz) and classified into girls with adequate nutritional status and girls who are overweight or obese. METHODS: This cross-sectional study was performed from January 2012 to May 2015 at two tertiary care pediatric centers in Mexico City. We included female patients with idiopathic CPP without other chronic pathology and healthy controls. Patients were divided into groups, BMI < 85th and BMI ≥ 85th percentile, according to 2000 CDC Growth Charts. Anthropometric data and fasting plasma concentrations of lipids, glucose, insulin, and leptin were assessed. RESULTS: There were 73 patients with CPP and 82 without CPP. Sixty-six patients were matched between the groups; no significant difference was noted between the groups according to zBMI. However, differences in the bone/chronological age relationship, birth weight and proportions in different Tanner stages were observed. Among girls with normal BMI, the percentage of body fat (24.6% vs 18.9%, p < 0.001), serum triglycerides (102.9 vs 54.3 mg/dl, p < 0.001), leptin (7.46 vs 5.4 ng/ml, p = 0.010) and free leptin (0.44 vs 0.29 ng/ml, p = 0.044) were higher in those with CPP; additionally, girls with CPP presented a higher proportion of hypertriglyceridemia. In the overweight/obese group, adiponectin levels were lower in girls with CPP (6.23 vs 7.28 pg/ml, p = 0.011). CONCLUSIONS: Girls with CPP and normal BMI at diagnosis had a worse cardiometabolic profile, as reflected by higher levels of free leptin, and higher proportion of hypertriglyceridemia than girls without CPP.

Bioorthogonal Azide-Thioalkyne Cycloaddition Catalyzed by Photoactivatable Ruthenium(II) Complexes.

Tailored ruthenium sandwich complexes bearing photoresponsive arene ligands can efficiently promote azide-thioalkyne cycloaddition (RuAtAC) when irradiated with UV light. The reactions can be performed in a bioorthogonal manner in aqueous mixtures containing biological components. The strategy can also be applied for the selective modification of biopolymers, such as DNA or peptides. Importantly, this ruthenium-based technology and the standard copper-catalyzed azide-alkyne cycloaddition (CuAAC) proved to be compatible and mutually orthogonal.

The Impact of a History of Pre-maturity on Viral Respiratory Infections in Children Under 2 Years of Age: A Propensity Score-Matching Analysis of in-hospital Complications and Mortality.

Introduction: A history of pre-maturity may be a risk factor for complications in patients under 24 months of age hospitalized for viral respiratory infections (VRIs). Objective: To identify the impact of a history of pre-maturity on in-hospital complications and mortality in patients under 24 months of age who were hospitalized for VRIs over a period of 5 years. Material and Methods: This was a propensity score-matched study. The database was compiled by physicians, electronically validated by engineers, and analyzed by statisticians. Patients diagnosed with VRIs (based on International Classification of Diseases [ICD-10]) codes B974, J12, J120-J129X, J168, J17, J171, J178, J20, J203-J209, J21, J210, J211, J218, J219, J22X, and J189) from 2013 to 2017 were enrolled in the study. The subjects were classified into two groups according to the absence or presence of a history of pre-maturity (P070, P072, P073). Patients with congenital heart disease (CHD) (Q20-Q26) were excluded. Length of hospital stay, in-hospital complications, surgical procedures, and mortality were analyzed. Statistical Analysis: Patients were matched according to age. For comparisons between groups, Student's t-tests and chi2 tests were applied. A logistic regression model was constructed to identify factors related to in-hospital complications and mortality. Results: In total, 5,880 patients were eligible for inclusion in the analysis. The average patient age was 14.25 weeks. The presence of pre-maturity (coefficient = 1.16), male sex, bronchopulmonary dysplasia (BPD), in-hospital infectious complications (coefficient = 11.31), and invasive medical procedures (coefficient = 18.4) increased the number of days of hospitalization. Invasive medical procedures (OR = 6.13), a history of pre-maturity (OR = 2.54), and male sex (OR = 1.78) increased the risk for in-hospital complications. In-hospital infectious complications (OR = 84.2) and invasive medical procedures (OR = 58.4) were risk factors for mortality. Conclusions: A history of pre-maturity increased the length of hospital stay and the rate of in-hospital complications but did not increase mortality in patients under 24 months of age hospitalized for VRIs.

Hospitalizations for viral respiratory infections in children under 2 years of age: epidemiology and in-hospital complications.

BACKGROUND: Viral respiratory infections (VRIs) are a frequent cause of hospitalization in children under 24 months of age. A history of prematurity or heart disease may be a risk factor for complications in patients hospitalized for VRI. The objective was to describe epidemiological data for children hospitalized for IRV and aged 1 to 24 months and to identify risk factors for the presence of in-hospital complications and mortality over a period of 5 years. METHODS: This was a cross-sectional study. Patients registered with VRI codes B974, J12, J120-J129X, J168, J17, J171, J178, J20, J203-J209, J21, J210, J211, J218, J219 (based on International Classification of Diseases [ICD-10]) from 2013 to 2017 were included. Three subanalyses were performed to compare [1] patients with pathological history (prematurity, bronchopulmonary dysplasia [BPD] and congenital heart disease [CHD]), [2] diagnoses (pneumonia, acute bronchitis, and acute bronchiolitis), and [3] admission to the pediatric intensive care unit. Days of hospital stay, in-hospital complications, invasive medical procedure and mortality were analyzed. STATISTICAL ANALYSIS: VRI hospitalization prevalence was described. For comparison between groups, Student's t-test, ANOVA and the Chi2 test were applied. To identify factors related to days of hospital stay, in-hospital complications and mortality, a linear and logistic regression model was performed. RESULTS: A total of 66,304 hospitalizations were reported. The average age was 14.7 weeks; hospitalization events were higher in winter (39%), followed by autumn (27.3%). A total of 371 (0.56%) patients died. A total of 7068 (10.6%) hospitalized patients with pathological histories were identified. The presence of BPD (coefficient = 1.6), CHD (coefficient = 1.2), diagnosis of pneumonia (coefficient = 1.2), in-hospital complications (coefficient = 2.1) and invasive medical procedures (coefficient = 15.7) were the most common factors that increased the length of hospital stay. Risk factors for in-hospital complications and mortality were invasive medical procedure (OR = 3.3 & 11.7), BPD (OR = 1.8 & 1.6), CHD (OR = 4.6 & 3.4) and diagnosis of pneumonia (OR = 1.8 & 4.2). CONCLUSIONS: Risk factors for morbidity and mortality in patients hospitalized for VRIs are BPD and CHD, diagnosis of pneumonia and invasive medical procedure.

Intracellular Reactions Promoted by Bis(histidine) Miniproteins Stapled Using Palladium(II) Complexes.

The generation of catalytically active metalloproteins inside living mammalian cells is a major research challenge at the interface between catalysis and cell biology. Herein we demonstrate that basic domains of bZIP transcription factors, mutated to include two histidine residues at i and i+4 positions, react with palladium(II) sources to generate catalytically active, stapled pallado-miniproteins. The resulting constrained peptides are efficiently internalized into living mammalian cells, where they perform palladium-promoted depropargylation reactions without cellular fixation. Control experiments confirm the requirement of the peptide scaffolding and the palladium staple for attaining the intracellular reactivity.

Ruthenium-Catalyzed Redox Isomerizations inside Living Cells.

Tailored ruthenium(IV) complexes can catalyze the isomerization of allylic alcohols into saturated carbonyl derivatives under physiologically relevant conditions, and even inside living mammalian cells. The reaction, which involves ruthenium-hydride intermediates, is bioorthogonal and biocompatible, and can be used for the "in cellulo" generation of fluorescent and bioactive probes. Overall, our research reveals a novel metal-based tool for cellular intervention, and comes to further demonstrate the compatibility of organometallic mechanisms with the complex environment of cells.

Resistin levels are not associated with obesity in central precocious puberty.

OBJECTIVE: To compare serum resistin concentrations between prepubertal girls with a BMI > 85th percentile and girls with precocious puberty (CPP) who have and have not undergone GnRH analog treatment. PATIENTS AND METHODS: This is a cross-sectional study in girls with a BMI > 85th percentile and a median age of 8 years. We included 31 girls with CPP who did not receive treatment (CPPoT), 23 girls with CPP who were treated with leuprolide (CPPT), 22 prepubertal girls and 24 pubertal girls. Anthropometric data and the fasting plasma concentrations of lipids, glucose, insulin, and resistin were measured. RESULTS: The z-BMI scores were similar among the groups (p = 0.344), and body fat percentage (BF%) was similar among CPPT, CPPoT and prepubertal girls (p = 0.151). Resistin and insulin levels were lower in girls with CPP (CPPT and CPPoT) than in prepubertal and pubertal girls (median resistin level: CPPT 11.8 pg/ml vs CPPoT 11 pg/ml vs prepubertal 16 pg/ml vs pubertal 16 pg/ml, p = 0.001; median insulin level: CPPT 10.7 µUI/mL vs CPPoT 10.2 µUI/mL vs prepubertal 14.4 µUI/mL vs pubertal 32 µUI/mL p = 0.02). ANCOVA analysis, after adjustments for pubertal stage, BF% and z-BMI, showed that CPP modifies resistin levels (F = 31.4; p = 0.0001) independently of these parameters (p < 0.05). CONCLUSIONS: In the group of girls with overweight or obesity, the resistin level was lower in girls with CPP than in prepubertal and pubertal girls. More studies are needed to understand the role of resistin in CPP patients.

Health and quality of life outcomes impairment of quality of life in type 2 diabetes mellitus: a cross-sectional study.

BACKGROUND: Type 2 diabetes mellitus (DM2) is a chronic disease, and for treatment to succeed, it is necessary to harmonize the mental health of the patient with the environment, which impacts quality of life and adherence to medical regimens. The objetive of this study is describe the quality of life of patients with DM2 and the factors relates to its modification. METHODS: This investigation was a cross-sectional study. Patients over 18 years of age with DM2 were selected. The following variables related to quality of life were studied: age, sex, occupation, marital status, years of DM2 evolution, comorbidities and presence of depression (Beck Depression Inventory). Perceived quality of life was measured with a health-related quality of life (HRQoL) scale, the 36-Item Short-Form Survey (SF-36). Patients were classified according to SF-36 HRQoL score (< 50, 51-75 and > 76 points). RESULTS: Among the 1394 patients included, the median age was 62 years. Global HRQoL had a median of 50.1 points. Bivariate analysis showed that age, marital status, sex, occupation, comorbidities, duration of DM2 and comorbidities had impacts on HRQoL. The logistic regression model identified age (odds ratio [OR] 1.04) and depression (OR 4.4) as independent factors that influenced overall quality of life. CONCLUSIONS: Patients with DM2 have poor HRQoL, which is associated with a high frequency of depression. Older age and the presence of depression impair patient HRQoL. TRIAL REGISTRATION: R-2013-781-052. Registered 20 December 2014.

RELATIONSHIP BETWEEN SERUM LEPTIN LEVELS AND WEIGHT GAIN IN GIRLS WITH CENTRAL PRECOCIOUS PUBERTY AT 1-YEAR FOLLOW-UP.

OBJECTIVE: Patients with central precocious puberty (CPP) may have increased serum leptin levels; however, it is not well known whether this increase differs between patients with and without obesity. Our objectives were to describe the changes in serum leptin in girls with CPP in the first 12 months after diagnosis based on body mass index (BMI) and to explore whether serum leptin level at CPP diagnosis is related to BMI z-score (BMIz) after a 1-year follow-up. METHODS: A prospective cohort study was performed. We included 42 girls with idiopathic CPP in Tanner stages II and III. Anthropometric measurements were performed, and serum leptin was measured at study initiation and after 12 months. Patients were stratified according to BMI category (30 with a BMI in the <94th percentile and 12 with a BMI in the >95th percentile). Study variables were compared. Correlations among leptin, BMIz, and body fat were assessed. RESULTS: Leptin increased gradually during the first year of treatment. In girls with a BMI in the <94th percentile at diagnosis, body fat percentage increased gradually during the first year of follow-up. CONCLUSION: Girls with a BMI in the <94th percentile have a greater risk of weight increase. Leptin level >10.5 ng/dL at diagnosis is a risk factor for weight gain after 1 year. ABBREVIATIONS: BMI = body mass index BMIz = BMI z-score CPP = central precocious puberty GnRHa = gonadotropin-releasing hormone analogue.