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Covering 1986 to presentNatural product drug discovery at Novartis has a long and successful history of delivering life saving medicines to millions of patients. In this viewpoint, we are presenting the tools we use and challenges we face as we advance natural products from early research into development and beyond. We are leveraging our collection of 90 000 microbial strains and 20 000 isolated natural products to find new medications in an interdisciplinary approach that requires expertise in microbiology, computational biology, synthetic biology, chemistry, and process development. Technological advances, particularly in genome engineering and data science have transformed our field, accelerating discovery and facilitating sustainable compound supply. Emerging new modalities such as antibody drug conjugates, radioligand therapies and xRNA-based medications offer new opportunities for natural product-derived drugs. By taking advantage of these new modalities and the most recent research technologies, natural products will significantly contribute to the medicines of the future.
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The natural product FR900359 (FR) has generated significant attention lately, due to its characteristics as potent and selective inhibitor of Gq/11 mediated signal transduction of associated G protein-coupled receptors (GPCRs). This makes FR both a widely used pharmacological tool compound and a lead molecule for targeted cancer therapy. The exploration of structure-activity-relationship (SAR) of the scaffold by total synthesis has been complicated by its structural complexity and its incompatibility with standard approaches of solid-phase peptide synthesis. Options for late-stage functionalization of FR are limited due to a lack of tractable functional groups. Here we present a mixed approach combining i) genetic engineering of the FR-assembly line in Chromobacterium vaccinii, to obtain a novel FR analog featuring a primary amine, with ii) its subsequent synthetic modification and biological profiling for further SAR exploration of the FR scaffold.
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For a potential application of FK506 in the treatment of acute kidney failure only the FKBP12 binding capability of the compound is required, while the immunosuppressive activity via calcineurin binding is considered as a likely risk to the patients. The methoxy groups at C13 and C15 are thought to have significant influence on the immunosuppressive activity of the molecule. Consequently, FK506 analogs with different functionalities at C13 and C15 were generated by targeted CRISPR editing of the AT domains in moduleâ 7 and 8 of the biosynthetic assembly line in Streptomyces tsukubaensis. In addition, the corresponding FK520 (C21 ethyl derivative of FK506) analogs could be obtained by media adjustments. The compounds were tested for their bioactivity in regards to FKBP12 binding, BMP potentiation and calcineurin sparing. 15-desmethoxy FK506 was superior to the other tested analogs as it did not inhibit calcineurin but retained high potency towards FKBP12 binding and BMP potentiation.
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Calcineurina , Streptomyces , Tacrolimo , Humanos , Tacrolimo/farmacologia , Tacrolimo/metabolismo , Calcineurina/metabolismo , Proteína 1A de Ligação a Tacrolimo/genética , Proteína 1A de Ligação a Tacrolimo/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Imunossupressores/farmacologia , Imunossupressores/químicaRESUMO
Per- and polyfluoroalkyl substances (PFASs) have been detected in an array of environmental media due to their ubiquitous use in industrial and consumer products as well as potential release from fluorochemical manufacturing facilities. During their manufacture, many fluorotelomer (FT) facilities rely on neutral intermediates in polymer production including the FT-alcohols (FTOHs). These PFAS are known to transform to the terminal acids (perfluoro carboxylic acids; PFCAs) at rates that vary with environmental conditions. In the current study on soils from a FT facility, we employed gas chromatography coupled with conventional- and high-resolution mass spectrometry (GC-MS and GC-HRMS) to investigate the profile of these precursor compounds, the intermediary secondary alcohols (sFTOHs), FT-acrylates (FTAcr), and FT-acetates (FTAce) in soils around the former FT-production facility. Of these precursors, the general trend in detection intensity was [FTOHs] > [sFTOHs] > [FTAcrs], while for the FTOHs, homologue intensities generally were [12:2 FTOH] > [14:2 FTOH] > [16:2 FTOH] > [10:2 FTOH] > [18:2 FTOH] > [20:2 FTOH] > [8:2 FTOH] â¼ [6:2 FTOH]. The corresponding terminal acids were also detected in all soil samples and positively correlated with the precursor concentrations. GC-HRMS confirmed the presence of industrial manufacturing byproducts such as FT-ethers and FT-esters and aided in the tentative identification of previously unreported dimers and other compounds. The application of GC-HRMS to the measurement and identification of precursor PFAS is in its infancy, but the methodologies described here will help refine its use in tentatively identifying these compounds in the environment.
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Fluorocarbonos , Poluentes do Solo , Solo , Poluentes do Solo/análise , Solo/química , Fluorocarbonos/análise , Cromatografia Gasosa-Espectrometria de Massas , Monitoramento Ambiental , Instalações Industriais e de ManufaturaRESUMO
BACKGROUND: Pain assessment and proper evaluation of pain is a prerequisite for treatment of acute and chronic pain. Until now, most evaluations use only resting pain intensity and a unidimensional scale, although multidimensional pain assessment and especially assessment of functional pain impact on activities is recommended. The "Defense and Veterans Pain Rating Scale" (DVPRS) permits this multidimensional assessment, but no validated French translation exists. OBJECTIVES: To validate the French translation of the multidimensional DVPRS, called Functional Pain Scale (FPS) in multiple settings of acute and chronic pain. STUDY DESIGN: Prospective observational study. SETTING: Two large hospitals in the French-speaking region of Switzerland. METHODS: We recruited 232 patients from February 2022 to January 2023. Patients with acute or chronic pain in different settings received a paper questionnaire with both the NRS and the Functional Pain Scale and a customized evaluation questionnaire. Correlation of FPS and NRS, psychometric properties and patient preferences were analysed. RESULTS: For the whole group of 232 patients, correlation of FPS and NRS was high, as well for all subgroups. The multi-item FPS scale showed excellent internal consistency. A large majority of patients, even those >75 years old, preferred FPS over NRS and stated that the FPS was easy to use. CONCLUSIONS: The study confirms that the French translation of the DVPRS (= Functional Pain Scale) is a valid measurement instrument for acute and chronic pain evaluation in a wide range of patient groups, and easy to use by patients.
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Microbial secondary metabolites continue to provide a valuable source of both chemical matter and inspiration for drug discovery in a broad range of therapeutic areas. Beyond this, the corresponding microorganisms represent a sustainable modality for biotechnological production of structurally complex molecules at the quantities required for drug development or even commercial manufacturing. Chromobacterium vaccinii, which has recently been reported as a producer of the pharmacologically highly important Gq inhibitor FR900359 (FR), represents such an example. The characterization of an orphan biosynthetic gene cluster (BGC) located directly downstream of the frs BCG led to the discovery of eight new lipopeptides, valhidepsins A-H (1-8), produced by C. vaccinii. Their chemical structures were elucidated through analysis of 1D and 2D NMR data and high-resolution MS/MS fragmentation methods. The valhidepsins did not display significant antibiotic nor cytotoxic activities but showed surfactant properties. The cluster-compound correlation was demonstrated by generation of a knockout mutant, which abolished production of valhidepsins. This knockout mutant yielded a significantly increased isolated yield of FR.
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Depsipeptídeos , Lipopeptídeos , Lipopeptídeos/química , Espectrometria de Massas em Tandem , Depsipeptídeos/química , Família MultigênicaRESUMO
Population estimates are critical for government services, development projects, and public health campaigns. Such data are typically obtained through a national population and housing census. However, population estimates can quickly become inaccurate in localized areas, particularly where migration or displacement has occurred. Some conflict-affected and resource-poor countries have not conducted a census in over 10 y. We developed a hierarchical Bayesian model to estimate population numbers in small areas based on enumeration data from sample areas and nationwide information about administrative boundaries, building locations, settlement types, and other factors related to population density. We demonstrated this model by estimating population sizes in every 10- m grid cell in Nigeria with national coverage. These gridded population estimates and areal population totals derived from them are accompanied by estimates of uncertainty based on Bayesian posterior probabilities. The model had an overall error rate of 67 people per hectare (mean of absolute residuals) or 43% (using scaled residuals) for predictions in out-of-sample survey areas (approximately 3 ha each), with increased precision expected for aggregated population totals in larger areas. This statistical approach represents a significant step toward estimating populations at high resolution with national coverage in the absence of a complete and recent census, while also providing reliable estimates of uncertainty to support informed decision making.
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Modelos Estatísticos , Densidade Demográfica , Teorema de Bayes , Humanos , IncertezaRESUMO
Access to the cyclic depsipeptide FR900359 (FR), a selective Gq/11 protein inhibitor of high pharmacological interest and a potential lead molecule for targeted therapy of cancers with oncogenic GNAQ or GNA11 mutations (encoding Gq and G11 respectively), has been challenging ever since its initial discovery more than three decades ago. The recent discovery of Chromobacterium vaccinii as a cultivable FR producer enables the development of approaches leading to a high-yielding, scalable and sustainable biotechnological process for production of FR, thereby removing this bottleneck. Here we characterize different promoters in exchange of the native promoter of the FR assembly line, resulting in an overexpression mutant with significantly increased production of FR. Thereby, the isolation and structure elucidation of novel FR analogs of low abundance is enabled. Further, we explore the antiproliferative activities of fifteen chromodepsins against uveal melanoma cell lines harboring Gq/11 mutations and characterize the major metabolite of FR formed in plasma.
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Chromobacterium , Depsipeptídeos , Linhagem Celular Tumoral , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/antagonistas & inibidores , Humanos , Mutação , Regiões Promotoras Genéticas , Neoplasias UveaisRESUMO
Although next-generation per- and polyfluorinated substances (PFAS) were designed and implemented as safer and environmentally degradable alternatives to "forever" legacy PFAS, there is little evidence to support the actual transformation of these compounds and less evidence of the safety of transformed products in the environment. Multiple congeners of one such PFAS alternative, the chloro-perfluoropolyether carboxylates (Cl-PFPECAs), have been found in New Jersey soils surrounding a manufacturing facility. These compounds are ideal candidates for investigating environmental transformation due to the existence of potential reaction centers including a chlorinated carbon and ether linkages. Transformation products of the chemical structures of this class of compounds were predicted based on analogous PFAS transformation pathways documented in peer-reviewed literature. Potential reaction products were used as the basis for high-resolution mass-spectrometric suspect screening of the soils. Suspected transformation products of multiple congeners, the Cl-PFPECAs, including H-PFPECAs, epox-PFPECAs, and diOH-PFPECAs, were tentatively observed in these screenings. Although ether linkages have been hypothesized as potential reaction centers under environmental conditions, to date, no documentation of ether scission has been identified. Despite exhaustive scrutiny of the high-resolution data for our Cl-PFPECA-laden soils, we found no evidence of ether scission.
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Fluorocarbonos , Ácidos Carboxílicos , Éter , Éteres , Fluorocarbonos/análise , New Jersey , SoloRESUMO
The United States Environmental Protection Agency's Chemical Transformation Simulator (CTS) platform implemented the first freely available reaction library to predict direct photolysis products of organic contaminants in aquatic systems. However, the initial version of the reaction library did not differentiate the formation likelihood of each predicted product, and therefore, the number of predicted products that are not observed tended to exponentially increase with the prediction generation. To alleviate this problem, we first employed relative reasoning algorithms to remove unlikely products. We then ranked different reaction schemes according to their transformation kinetics and removed slowly forming products. Applying the two strategies improved the precision (the percentage of correctly predicted products over all predicted products) by 34% and 53% for the internal evaluation set and the external evaluation set, respectively, when products from three generations were considered. This improved library also revealed new research directions to improve predictions of the dominant phototransformation products.
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Poluentes Químicos da Água , Cinética , Fotólise , Poluentes Químicos da Água/análiseRESUMO
Cheminformatics-based applications to predict transformation pathways of environmental contaminants are useful to quickly prioritize contaminants with potentially toxic/persistent products. Direct photolysis can be an important degradation pathway for sunlight-absorbing compounds in aquatic systems. In this study, we developed the first freely available direct phototransformation pathway predictive tool, which uses a rule-based reaction library. Journal publications studying diverse contaminants (such as pesticides, pharmaceuticals, and energetic compounds) were systematically compiled to encode 155 reaction schemes into the reaction library. The execution result of this predictive tool was internally evaluated against 390 compounds from the compiled journal publications and externally evaluated against 138 compounds from the regulatory reports. The recall (sensitivity) and precision (selectivity) were 0.62 and 0.35, respectively, for internal evaluation, and 0.56 and 0.20, respectively, for external evaluation, when only the products formed from the first reaction step were counted. This predictive tool could help to narrow the data gaps in chemical registration/evaluation and inform future experimental studies.
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Praguicidas , Poluentes Químicos da Água , Fotólise , Luz Solar , Poluentes Químicos da Água/análiseRESUMO
BACKGROUND: Regional anaesthesia for upper limb surgery is routinely performed with brachial plexus blocks. A retroclavicular brachial plexus block has recently been described, but has not been adequately compared with another approach. This randomised controlled single-blinded trial tested the hypothesis that the retroclavicular approach, when compared with the supraclavicular approach, would increase the success rate. METHODS: One hundred and twenty ASA physical status 1-3 patients undergoing distal upper limb surgery were randomised to receive an ultrasound-guided retroclavicular or supraclavicular brachial plexus block with 30 mL of a 1:1 mixture of mepivacaine 1% and ropivacaine 0.5%, using a single-injection technique without needle tip repositioning. The primary outcome was block success rate 30 min after local anaesthetic injection, defined as a composite score of 14 of 16 points, inclusive of sensory and motor components. Secondary outcomes included needling time, time to first opioid request, oxycodone consumption, and pain scores (numeric rating scale, 0-10) at 24 h postoperatively. RESULTS: Success rates were 98.3% [95% confidence interval (CI): 90.8%, 99.9%] and 98.3% [95% CI: 90.9%, 99.9%] in the supraclavicular and retroclavicular groups, respectively (P=0.99). The mean needling time was reduced in the supraclavicular group [supraclavicular: 5.0 (95% CI: 4.7, 5.4) min; retroclavicular: 6.0 (95% CI: 5.4, 6.6) min; P=0.006]. The mean time to first opioid request was similar between groups [supraclavicular: 439 (95% CI: 399, 479) min; retroclavicular: 447 (95% CI: 397, 498) min; P=0.19] as were oxycodone consumption [supraclavicular: 10.0 (95% CI: 6.5, 13.5 mg; retroclavicular: 7.9 (95% CI: 4.8, 11.0) mg; P=0.80] and pain scores at 24 h postoperatively [supraclavicular: 1.2 (95% CI: 2.1, 2.7); retroclavicular: 1.5 (95% CI: 1.6, 2.4); P=0.09]. CONCLUSIONS: Ultrasound-guided retroclavicular and supraclavicular brachial plexus blocks share identical success rates, while providing similar pain relief. Reduced needling time in the supraclavicular approach is not clinically relevant. CLINICAL TRIAL REGISTRATION: NCT02641613.
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Anestésicos Locais/administração & dosagem , Bloqueio do Plexo Braquial/métodos , Extremidade Superior/cirurgia , Adulto , Idoso , Anestésicos Combinados/administração & dosagem , Plexo Braquial/diagnóstico por imagem , Feminino , Humanos , Masculino , Mepivacaína/administração & dosagem , Pessoa de Meia-Idade , Dor Pós-Operatória/prevenção & controle , Ropivacaina/administração & dosagem , Método Simples-Cego , Ultrassonografia de Intervenção/métodosRESUMO
Although remote sensing has long been used to aid in the estimation of population, it has usually been in the context of spatial disaggregation of national census data, with the census counts serving both as observational data for specifying models and as constraints on model outputs. Here we present a framework for estimating populations from the bottom up, entirely independently of national census data, a critical need in areas without recent and reliable census data. To make observations of population density, we replace national census data with a microcensus, in which we enumerate population for a sample of small areas within the states of Kano and Kaduna in northern Nigeria. Using supervised texture-based classifiers with very high resolution satellite imagery, we produce a binary map of human settlement at 8-meter resolution across the two states and then a more refined classification consisting of 7 residential types and 1 non-residential type. Using the residential types and a model linking them to the population density observations, we produce population estimates across the two states in a gridded raster format, at approximately 90-meter resolution. We also demonstrate a simulation framework for capturing uncertainty and presenting estimates as prediction intervals for any region of interest of any size and composition within the study region. Used in concert with previously published demographic estimates, our population estimates allowed for predictions of the population under 5 in ten administrative wards that fit strongly with reference data collected during polio vaccination campaigns.
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Cheminformatics-based software tools can predict the molecular structure of transformation products using a library of transformation reaction schemes. This paper presents the development of such a library for abiotic hydrolysis of organic chemicals under environmentally relevant conditions. The hydrolysis reaction schemes in the library encode the process science gathered from peer-reviewed literature and regulatory reports. Each scheme has been ranked on a scale of one to six based on the median half-life in a data set compiled from literature-reported hydrolysis rates. These ranks are used to predict the most likely transformation route when more than one structural fragment susceptible to hydrolysis is present in a molecule of interest. Separate rank assignments are established for pH 5, 7, and 9 to represent standard conditions in hydrolysis studies required for registration of pesticides in Organisation for Economic Co-operation and Development (OECD) member countries. The library is applied to predict the likely hydrolytic transformation products for two lists of chemicals, one representative of chemicals used in commerce and the other specific to pesticides, to evaluate which hydrolysis reaction pathways are most likely to be relevant for organic chemicals found in the natural environment.
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Compostos Orgânicos , Praguicidas , Meia-Vida , Concentração de Íons de Hidrogênio , HidróliseRESUMO
Non-organic visual loss (NOVL), defined as a decrease in visual acuity or field without an identifiable organic cause, can be challenging to diagnose, especially in patients whose NOVL is superimposed on some component of true organic pathology. Exposure to combat puts soldiers at risk of emotional distress and physical trauma, which can contribute to the development of NOVL with conversion disorder or malingering. This case series describes six patients with NOVL who sustained ocular or non-ocular injuries while serving in combat operations in Iraq and Afghanistan, and highlights diagnostic pearls and components of inter-disciplinary management in the unique military context.
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A pair of homologous series of polyfluorinated degradation products have been identified, both having structures similar to perfluorocarboxylic acids but (i) having a H substitution for F on the α carbon for 2H polyfluorocarboxylic acids (2HPFCAs) and (ii) bearing a double bond between the α-ß carbons for the unsaturated PFCAs (2uPFCAs). Obtaining an authentic sample containing 2uPFOA and 2HPFOA, we optimized a mass-spectrometric multiple-reaction-monitoring (MS/MS) technique and then identified uPFCA and HPFCA homologous series in sludge-applied agricultural soils and fodder grasses for cattle grazing. Analysis of samples from a degradation experiment of commercial fluorotelomer-based polymers (FTPs), the dominant product of the fluorotelomer industry, confirmed that commercial FTPs are a potential source of uPFCAs and HPFCAs to the environment. We further confirmed the identity of the uPFCAs by imposing high-energy ionization to decarboxylate the uPFCAs then focused on the fluorinated chains in the first MS quadrupole. We also employed this high-energy ionization to decarboxylate and analyze PFCAs by MS/MS (for the first time, to our knowledge). In exploratory efforts, we report the possible detection of unsaturated perfluorooctanesulfonate in environmental samples, having a conceptual double-bond structure analogous to uPFOA. Using microcosms spiked with fluorotelomer compounds, we found 2uPFOA and 2HPFOA to be generated from unsaturated 8:2 fluorotelomer acid (8:2 FTUCA) and propose ß- and α-oxidation mechanisms for generation of these compounds from 8:2 FTUCA. In light of these experimental results, we also reexamined the proposed biodegradation pathways of 8:2 fluorotelomer alcohol.
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Biodegradação Ambiental , Fluorocarbonos/análise , Poluentes do Solo/análise , Álcoois/química , Ácidos Alcanossulfônicos/análise , Ácidos Alcanossulfônicos/química , Ração Animal/análise , Animais , Carbono/química , Bovinos , Fluorocarbonos/química , Hidrocarbonetos Fluorados/análise , Hidrocarbonetos Fluorados/química , Polímeros/química , Esgotos , Solo/química , Poluentes do Solo/química , Espectrometria de Massas em TandemRESUMO
Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factorâ 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti-fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF-1α) as the primary target for this compound class. Nannocystinâ A (1) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site of 1 with the anti-cancer compound didemninâ B on EF-1α. This myxobacterial chemotype thus offers an interesting starting point for further investigations of the potential of therapeutics targeting elongation factorâ 1.
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Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Compostos Macrocíclicos/farmacologia , Myxococcales/fisiologia , Neoplasias/patologia , Fator 1 de Elongação de Peptídeos/antagonistas & inibidores , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Genômica/métodos , Humanos , Compostos Macrocíclicos/química , Estrutura Molecular , Neoplasias/tratamento farmacológico , Fator 1 de Elongação de Peptídeos/genética , Fator 1 de Elongação de Peptídeos/metabolismo , Proteômica/métodos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
BACKGROUND: This article aims to describe the implementation and initial results of an audit-feedback quality improvement initiative in Belgian diabetic foot clinics. METHODS: Using self-developed software and questionnaires, diabetic foot clinics collected data in 2005, 2008 and 2011, covering characteristics, history and ulcer severity, management and outcome of the first 52 patients presenting with a Wagner grade ≥ 2 diabetic foot ulcer or acute neuropathic osteoarthropathy that year. Quality improvement was encouraged by meetings and by anonymous benchmarking of diabetic foot clinics. RESULTS: The first audit-feedback cycle was a pilot study. Subsequent audits, with a modified methodology, had increasing rates of participation and data completeness. Over 85% of diabetic foot clinics participated and 3372 unique patients were sampled between 2005 and 2011 (3312 with a diabetic foot ulcer and 111 with acute neuropathic osteoarthropathy). Median age was 70 years, median diabetes duration was 14 years and 64% were men. Of all diabetic foot ulcers, 51% were plantar and 29% were both ischaemic and deeply infected. Ulcer healing rate at 6 months significantly increased from 49% to 54% between 2008 and 2011. Management of diabetic foot ulcers varied between diabetic foot clinics: 88% of plantar mid-foot ulcers were off-loaded (P10-P90: 64-100%), and 42% of ischaemic limbs were revascularized (P10-P90: 22-69%) in 2011. CONCLUSIONS: A unique, nationwide quality improvement initiative was established among diabetic foot clinics, covering ulcer healing, lower limb amputation and many other aspects of diabetic foot care. Data completeness increased, thanks in part to questionnaire revision. Benchmarking remains challenging, given the many possible indicators and limited sample size. The optimized questionnaire allows future quality of care monitoring in diabetic foot clinics.
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Instituições de Assistência Ambulatorial/normas , Pé Diabético/terapia , Neuropatias Diabéticas/terapia , Úlcera do Pé/terapia , Melhoria de Qualidade , Idoso , Amputação Cirúrgica/estatística & dados numéricos , Bélgica/epidemiologia , Pé Diabético/epidemiologia , Pé Diabético/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Retroalimentação , Feminino , Humanos , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Projetos Piloto , Inquéritos e QuestionáriosRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0293848.].
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Introduction: Lower limb orthoses (LLOs) and assistive devices (ADs) can be used together or separately to improve mobility when performing daily activities. The goal of this study was to examine utilization of LLOs and ADs in a national sample of adult LLO users. Methods: A survey was designed to ask participants whether they typically use their LLOs and/or ADs to perform 20 daily activities. LLO users from orthotic clinics across the United States were invited to complete the survey. Descriptive statistics were used to examine utilization trends. Results: Survey responses from 1036 LLO users were analyzed. Community-based activities were performed with LLOs by at least 80% of participants. Activities that involved walking short distances in the home were more often performed without LLOs or ADs. Among participants with the four most prevalent health conditions, LLO use in the community was greatest among participants with Charcot-Marie-Tooth disease. Conclusions: LLOs were frequently used for a wide range of community-based activities. Simultaneous use of ADs and LLOs may be most beneficial for LLO users when performing activities outside of the home. Clinicians can discuss LLO and AD use with patients to optimize their functional outcomes at home and in the community.