A natural experiment to assess how urban interventions in lower socioeconomic areas influence health behaviors: the UrbASanté study.

BACKGROUND: Mechanisms underlying the associations between changes in the urban environment and changes in health-related outcomes are complex and their study requires specific approaches. We describe the protocol of the interdisciplinary UrbASanté study, which aims to explore how urban interventions can modify environmental exposures (built, social, and food environments; air quality; noise), health-related behaviors, and self-reported health using a natural experiment approach. METHODS: The study is based on a natural experiment design using a before/after protocol with a control group to assess changes in environmental exposures, health-risk behaviors, and self-reported health outcomes of a resident adult population before and after the implementation of a time series of urban interventions in four contiguous neighborhoods in Paris (France). The changes in environmental exposures, health-related behaviors, and self-reported health outcomes of a resident adult population will be concurrently monitored in both intervention and control areas. We will develop a mixed-method framework combining substantial fieldwork with quantitative and qualitative analytical approaches. This study will make use of (i) data relating to exposures and health-related outcomes among all participants and in subsamples and (ii) interviews with residents regarding their perceptions of their neighborhoods and with key stakeholders regarding the urban change processing, and (iii) existing geodatabases and field observations to characterize the built, social, and food environments. The data collected will be analyzed with a focus on interrelationships between environmental exposures and health-related outcomes using appropriate approaches (e.g., interrupted time series, difference-in-differences method). DISCUSSION: Relying on a natural experiment approach, the research will provide new insights regarding issues such as close collaboration with urban/local stakeholders, recruitment and follow-up of participants, identification of control and intervention areas, timing of the planned urban interventions, and comparison of subjective and objective measurements. Through the collaborative work of a consortium ensuring complementarity between researchers from different disciplines and stakeholders, the UrbASanté study will provide evidence-based guidance for designing future urban planning and public health policies. TRIAL REGISTRATION: This research was registered at the ClinicalTrial.gov (NCT05743257).

Trends in guideline implementation: an updated scoping review.

BACKGROUND: Guidelines aim to support evidence-informed practice but are inconsistently used without implementation strategies. Our prior scoping review revealed that guideline implementation interventions were not selected and tailored based on processes known to enhance guideline uptake and impact. The purpose of this study was to update the prior scoping review. METHODS: We searched MEDLINE, EMBASE, AMED, CINAHL, Scopus, and the Cochrane Database of Systematic Reviews for studies published from 2014 to January 2021 that evaluated guideline implementation interventions. We screened studies in triplicate and extracted data in duplicate. We reported study and intervention characteristics and studies that achieved impact with summary statistics. RESULTS: We included 118 studies that implemented guidelines on 16 clinical topics. With regard to implementation planning, 21% of studies referred to theories or frameworks, 50% pre-identified implementation barriers, and 36% engaged stakeholders in selecting or tailoring interventions. Studies that employed frameworks (n=25) most often used the theoretical domains framework (28%) or social cognitive theory (28%). Those that pre-identified barriers (n=59) most often consulted literature (60%). Those that engaged stakeholders (n=42) most often consulted healthcare professionals (79%). Common interventions included educating professionals about guidelines (44%) and information systems/technology (41%). Most studies employed multi-faceted interventions (75%). A total of 97 (82%) studies achieved impact (improvements in one or more reported outcomes) including 10 (40% of 25) studies that employed frameworks, 28 (47.45% of 59) studies that pre-identified barriers, 22 (52.38% of 42) studies that engaged stakeholders, and 21 (70% of 30) studies that employed single interventions. CONCLUSIONS: Compared to our prior review, this review found that more studies used processes to select and tailor interventions, and a wider array of types of interventions across the Mazza taxonomy. Given that most studies achieved impact, this might reinforce the need for implementation planning. However, even studies that did not plan implementation achieved impact. Similarly, even single interventions achieved impact. Thus, a future systematic review based on this data is warranted to establish if the use of frameworks, barrier identification, stakeholder engagement, and multi-faceted interventions are associated with impact. TRIAL REGISTRATION: The protocol was registered with Open Science Framework ( https://osf.io/4nxpr ) and published in JBI Evidence Synthesis.

Tandem mass spectrometry for the direct assay of lysosomal enzymes in dried blood spots: application to screening newborns for mucopolysaccharidosis II (Hunter Syndrome).

We have developed a tandem mass spectrometry based assay of iduronate-2-sulfatase (IdS) activity for the neonatal detection of mucopolysaccharidosis II (MPS-II, Hunter Syndrome). The assay uses a newly designed synthetic substrate (IdS-S) consisting of α-L-iduronate-2-sulfate, which is glycosidically conjugated to a coumarin and a linker containing a tert-butyloxycarbamido group. A short synthesis of the substrate has been developed that has the potential of being scaled to multigram quantities. Sulfate hydrolysis of IdS-S by IdS found within a 3 mm dried blood spot specifically produces a nonsulfated product (IdS-P) which is detected by electrospray tandem mass spectrometry and quantified using a deuterium-labeled internal standard, both carried out in positive ion mode. Analysis of DBS from 75 random human newborns showed IdS activities in the range of 4.8-16.2 (mean 9.1) µmol/(h L of blood), which were clearly distinguished from the activities measured for 14 MPS-II patients at 0.17-0.52 (mean 0.29) µmol/(h L of blood). The assay shows low blank activity, 0.15 ± 0.03 µmol/(h L of blood). The within-assay coefficient of variation (CV) was 3.1% while the interassay CV was 15%.

Comparison of weight gain and energy intake after subthalamic versus pallidal stimulation in Parkinson's disease.

To compare body mass index (BMI) and daily energy intake (DEI) after subthalamic versus pallidal deep brain stimulation (DBS). Weight gain following DBS in Parkinson's disease patients remains largely unexplained and no comparison of subthalamic and pallidal (GPi) stimulation has yet been performed. BMI and DEI, dopaminergic drug administration and motor scores were recorded in 46 patients with PD before STN (n = 32) or GPi (n = 14) DBS and 3 and 6 months after. At M6, BMI had increased by an average of 8.4% in the STN group and 3.2% in the GPi group. BMI increased in 28 STN and 9 GPi patients. This increase was significantly higher in the STN group (P < 0.048) and the difference remained significant after adjustment for reduced dopaminergic medication; 28.6% of GPi patients were overweight at 6 months (14.3% preoperatively) versus 37.5% of STN patients (21.9% preoperatively). Changes in BMI were negatively correlated with changes in dyskinesia in the GPi-DBS group. Food intake did not change in the two groups, either quantitatively or qualitatively. Frequent weight gain, inadequately explained by motor improvement or reduced dopaminergic drug dosage, occurred in subthalamic DBS patients. The difference between groups suggests additional factors in the STN group, such as homeostatic control center involvement.

Diversity of ring-hydroxylating dioxygenases in pristine and oil contaminated microbial mats at genomic and transcriptomic levels.

The aim of this work was to characterize bacterial ring-hydroxylating dioxygenase (RHD) diversity in a pristine microbial mat and follow their diversity changes in response to heavy fuel oil contamination. In order to describe the RHDs diversity, new degenerate primers were designed and a nested-PCR approach was developed to gain sensitivity and wider diversity. RHD diversity in artificially contaminated mats maintained in microcosms and in chronically contaminated mats was analysed by clone libraries and terminal restriction fragment length polymorphism (T-RFLP) at genomic and transcriptomic levels. The RHD diversity in the pristine microbial mat was represented by Pseudomonas putida nahAc-like genes and no increase of diversity was detected after 1 year of oil contamination. The diversity observed in a 30 year chronically polluted microbial mat was represented by four main RHD clusters and two new genes revealing higher polyaromatic hydrocarbon (PAH) degradation capacity. This study illustrates that a single petroleum contamination (such as oil spill) is not enough to involve a detectable modification of RHD diversity. The new degenerate primers described here allowed RHD gene amplification from pristine and contaminated samples thereby showing their diversity. The proposed approach solves one of the main problems of functional gene analysis providing effective amplification of the environmental diversity of the targeted genes.

Tandem mass spectrometry for the direct assay of lysosomal enzymes in dried blood spots: application to screening newborns for mucopolysaccharidosis I.

BACKGROUND: Treatments now available for mucopolysaccharidosis I require early detection for optimum therapy. Therefore, we have developed an assay appropriate for newborn screening of the activity of the relevant enzyme, alpha-L-iduronidase. METHODS: We synthesized a new alpha-L-iduronidase substrate that can be used to assay the enzyme by use of tandem mass spectrometry together with an internal standard or by fluorometry. The assay uses a dried blood spot on a newborn screening card as the enzyme source. The assay protocol uses a simple liquid-liquid extraction step before mass spectrometry. We optimized enzyme reaction conditions and procedures for the assay, including the concentration of substrate, the reaction pH, the incubation time, and mass spectrometer operation. We also assessed inter- and intraassay imprecision. RESULTS: When the assay was tested on dried blood spots, the alpha-L-iduronidase activity measured for 5 patients with mucopolysaccharidosis I was well below the interval found for 10 randomly chosen newborns. Inter- and intraassay imprecision were <10%. The synthesis of the alpha-L-iduronidase substrate is practical for use on a scale needed to support newborn screening demands. CONCLUSIONS: This newly developed tandem mass spectrometry assay has the potential to be adopted for newborn screening of mucopolysaccharidosis I. This assay has advantages over a previously reported assay also developed in this laboratory and has the potential to be performed in a multiplex fashion to measure several lysosomal enzymes relevant to treatable lysosomal storage diseases.

University Sports Rivalries Provide Insights on Coalitional Psychology : Territorial Context Influences Reactions to Vocal Signals of Allegiance.

Sports are an excellent venue for demonstrating evolutionary principles to audiences not familiar with academic research. Team sports and sports fandom feature dynamics of in-group loyalty and intergroup competition, influenced by our evolved coalitional psychology. We predicted that reactions to expressions signaling mutual team/group allegiance would vary as a function of the territorial context. Reactions should become more prevalent, positive, and enthusiastic as one moves from the home territory to a contested area, and from a contested area to a rival's territory during active rival engagement. We also predicted that men would be more responsive than women based on sex differences in evolved coalitional psychology. The research team visited public places immediately prior to 2016-2017 collegiate football and basketball games. A male research confederate wore a sweatshirt displaying the logo of one of the competing university teams and vocalized the team's most popular slogan when he saw a fan displaying similar logos. Observers followed 5 m behind, recording reactions (N = 597) and response positivity/enthusiasm. Reaction tone was most positive in the rival territory, least positive in the home territory, and intermediate in the periphery and contested territory. Rates of "no reaction" were lowest in the rival territory but were highest in the periphery. Men had higher reaction rates and more positive and enthusiastic reaction tones than women. Reactions generally followed predictions based on expected signal value. This project provides evidence that coalitional psychology influences dynamics related to university sports team rivalries and that context matters for expressions of alliance.

Enzymatic tools for engineering natural product glycosylation.

Glycosylated natural products have served as reliable platforms for the development of many existing front-line drugs. In an effort to explore the contribution of the sugar constituents of these compounds, research groups have focused upon the development of chemical and enzymatic tools to diversify natural product glycosylation. Among the complementary routes available, in vivo pathway engineering, also referred to as 'combinatorial biosynthesis', is an emerging method that relies upon the co-expression of sugar biosynthetic gene cassettes and glycosyltransferases in a host organism to generate novel glycosylated natural products. An overview of recent progress in combinatorial biosynthesis is highlighted in this review, emphasizing the elucidation of nucleotide-sugar biosynthetic pathways and recent developments on glycosyltransferases.

Deciphering indolocarbazole and enediyne aminodideoxypentose biosynthesis through comparative genomics: insights from the AT2433 biosynthetic locus.

AT2433, an indolocarbazole antitumor antibiotic, is structurally distinguished by its aminodideoxypentose-containing disaccharide and asymmetrically halogenated N-methylated aglycon. Cloning and sequence analysis of AT2433 gene cluster and comparison of this locus with that encoding for rebeccamycin and the gene cluster encoding calicheamicin present an opportunity to study the aminodideoxypentose biosynthesis via comparative genomics. The locus was confirmed via in vitro biochemical characterization of two methyltransferases--one common to AT2433 and rebeccamycin, the other unique to AT2433--as well as via heterologous expression and in vivo bioconversion experiments using the AT2433 N-glycosyltransferase. Preliminary studies of substrate tolerance for these three enzymes reveal the potential to expand upon the enzymatic diversification of indolocarbazoles. Moreover, this work sets the stage for future studies regarding the origins of the indolocarbazole maleimide nitrogen and indolocarbazole asymmetry.

Total biosynthesis of hydrocortisone from a simple carbon source in yeast.

We report on the production of hydrocortisone, the major adrenal glucocorticoid of mammals and an important intermediate of steroidal drug synthesis, from a simple carbon source by recombinant Saccharomyces cerevisiae strains. An artificial and fully self-sufficient biosynthetic pathway involving 13 engineered genes was assembled and expressed in a single yeast strain. Endogenous sterol biosynthesis was rerouted to produce compatible sterols to serve as substrates for the heterologous part of the pathway. Biosynthesis involves eight mammalian proteins (mature forms of CYP11A1, adrenodoxin (ADX), and adrenodoxin reductase (ADR); mitochondrial forms of ADX and CYP11B1; 3beta-HSD, CYP17A1, and CYP21A1). Optimization involved modulating the two mitochondrial systems and disrupting of unwanted side reactions associated with ATF2, GCY1, and YPR1 gene products. Hydrocortisone was the major steroid produced. This work demonstrates the feasibility of transfering a complex biosynthetic pathway from higher eukaryotes into microorganisms.

Unexpected regioselectivity of Humicola insolens Cel7B glycosynthase mutants.

Four Humicola insolens Cel7B glycoside hydrolase mutants have been evaluated for the coupling of lactosyl fluoride on O-allyl N(I)-acetyl-2(II)-azido-beta-chitobioside. Double mutants Cel7B E197A H209A and Cel7B E197A H209G preferentially catalyze the formation of a beta-(1-->4) linkage between the two disaccharides, while single mutant Cel7B E197A and triple mutant Cel7B E197A H209A A211T produce predominantly the beta-(1-->3)-linked tetrasaccharide. This result constitutes the first report of the modulation of the regioselectivity through site-directed mutagenesis for an endoglycosynthase.

Short synthetic sequence for 2-sulfation of alpha-L-iduronate glycosides.

Hunter syndrome (mucopolysaccharidosis-II) is caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase. The assay of this sulfatase requires the use of alpha-L-iduronate glycosides containing a sulfate at the 2-position. We report a simple, three-step procedure for the introduction of sulfate at the 2-position starting with the methyl ester of alpha-L-iduronate glycosides. The procedure involves protection of the 2- and 4-hydroxyl groups of the iduronate moiety as the dibutyl stannylene acetal, selective sulfation with sulfur trioxide-trimethylamine, and deprotection of the methyl ester to afford the desired 2-sulfate in 61% overall yield.

Model for antibiotic optimization via neoglycosylation: synthesis of liponeoglycopeptides active against VRE.

The neoglycosylation of a methoxyamine-appended vancomycin aglycon with all possible N'-decanoylglucopyranose and N'-biphenoylglucopyranose regioisomers led to the production of a focused set of liponeoglycopeptide variants in good yields and with excellent stereoselectivity. High-throughput antibacterial assays employing a unique set of vancomycin-resistant Enterococci faecalis and Enterococci faecium clinical isolates revealed that the nature and regiochemistry of glycosyl lipidation modulated vancomycin-resistent Enterococci potency. In contrast to prior work with lipoglycopeptides, this study reveals the glucose C3' or C4' as the optimal position for neoglycopeptide lipidation. This purely chemical method for the diversification of the glycolipid portion of lipoglycopeptide antibiotics is simple to perform on a large scale, requires minimal synthetic effort in sugar donor preparation, and provides access to highly active antibiotics that are not easily prepared by other state-of-the-art methods.

A novel synthesis of D-galactofuranosyl, D-glucofuranosyl and D-mannofuranosyl 1-phosphates based on remote activation of new and free hexofuranosyl donors.

The selective synthesis of 1,2-cis-hexofuranosyl 1-phosphates was readily accomplished according to a procedure based on the 'Remote Activation Concept'. This approach required (i) the preparation of suitable 1,2-trans-hexofuranosyl donors, so that new heterocyclic thiofuranosides were designed and synthesized, (ii) the stereocontrolled phosphorylation of the corresponding unprotected donors and (iii) the simple and fast purification of the resulting anomeric phosphates. This approach showed to be equally efficient in the galactose, glucose and mannose series.