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When compared with other phylogroups (PGs) of the Pseudomonas syringae species complex, P. syringae pv. syringae (Pss) strains within PG2 have a reduced repertoire of type III effectors (T3Es) but produce several phytotoxins. Effectors within the cherry pathogen Pss 9644 were grouped based on their frequency in strains from Prunus as the conserved effector locus (CEL) common to most P. syringae pathogens; a core of effectors common to PG2; a set of PRUNUS effectors common to cherry pathogens; and a FLEXIBLE set of T3Es. Pss 9644 also contains gene clusters for biosynthesis of toxins syringomycin, syringopeptin and syringolin A. After confirmation of virulence gene expression, mutants with a sequential series of T3E and toxin deletions were pathogenicity tested on wood, leaves and fruits of sweet cherry (Prunus avium) and leaves of ornamental cherry (Prunus incisa). The toxins had a key role in disease development in fruits but were less important in leaves and wood. An effectorless mutant retained some pathogenicity to fruit but not wood or leaves. Striking redundancy was observed amongst effector groups. The CEL effectors have important roles during the early stages of leaf infection and possibly acted synergistically with toxins in all tissues. Deletion of separate groups of T3Es had more effect in P. incisa than in P. avium. Mixed inocula were used to complement the toxin mutations in trans and indicated that strain mixtures may be important in the field. Our results highlight the niche-specific role of toxins in P. avium tissues and the complexity of effector redundancy in the pathogen Pss 9644.
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Prunus avium , Prunus , Virulência/genética , Pseudomonas syringae , Prunus avium/metabolismo , Frutas/metabolismo , Mutação/genética , Prunus/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismoRESUMO
INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.
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Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Colite Ulcerativa/terapia , Doença de Crohn/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Medicina de Precisão , Estudos Prospectivos , Qualidade de VidaRESUMO
Murine intraepithelial γδ T cells include distinct tissue-protective cells selected by epithelial butyrophilin-like (BTNL) heteromers. To determine whether this biology is conserved in humans, we characterized the colonic γδ T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor Vγ4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103+γδ T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103+Vγ4+cell dysregulation and loss were also displayed by humans with germline BTNL3/BTNL8 hypomorphism, which we identified as a risk factor for penetrating Crohn's disease (CD). Thus, BTNL-dependent selection and/or maintenance of distinct tissue-intrinsic γδ T cells appears to be an evolutionarily conserved axis limiting the progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.
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Butirofilinas , Doenças Inflamatórias Intestinais , Receptores de Antígenos de Linfócitos T gama-delta , Subpopulações de Linfócitos T , Animais , Humanos , Camundongos , Butirofilinas/genética , Colo/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Subpopulações de Linfócitos T/imunologia , Mucosa Intestinal/imunologiaRESUMO
Effectors play a central role in determining the outcome of plant-pathogen interactions. As key virulence proteins, effectors are collectively indispensable for disease development. By understanding the virulence mechanisms of effectors, fundamental knowledge of microbial pathogenesis and disease resistance have been revealed. Effectors are also considered double-edged swords because some of them activate immunity in disease resistant plants after being recognized by specific immune receptors, which evolved to monitor pathogen presence or activity. Characterization of effector recognition by their cognate immune receptors and the downstream immune signaling pathways is instrumental in implementing resistance. Over the past decades, substantial research effort has focused on effector biology, especially concerning their interactions with virulence targets or immune receptors in plant cells. A foundation of this research is robust identification of the effector repertoire from a given pathogen, which depends heavily on bioinformatic prediction. In this review, we summarize methodologies that have been used for effector mining in various microbial pathogens which use different effector delivery mechanisms. We also discuss current limitations and provide perspectives on how recently developed analytic tools and technologies may facilitate effector identification and hence generation of a more complete vision of host-pathogen interactions. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.
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Doenças das Plantas , Plantas , Resistência à Doença , Proteínas de Plantas , Virulência , Imunidade VegetalRESUMO
BACKGROUND: The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG4 for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions. METHODS: This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30-90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort). RESULTS: The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 µg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients. CONCLUSION: Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic. TRIAL REGISTRATION NUMBER: NCT02749630.
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Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Voluntários Saudáveis , Administração Intravenosa , BiomarcadoresRESUMO
Many strains of Pseudomonas colonise plant surfaces, including the cherry canker pathogens, Pseudomonas syringae pathovars syringae and morsprunorum. We have examined the genomic diversity of P. syringae in the cherry phyllosphere and focused on the role of prophages in transfer of genes encoding Type 3 secreted effector (T3SE) proteins contributing to the evolution of virulence. Phylogenomic analysis was carried out on epiphytic pseudomonads in the UK orchards. Significant differences in epiphytic populations occurred between regions. Nonpathogenic strains were found to contain reservoirs of T3SE genes. Members of P. syringae phylogroups 4 and 10 were identified for the first time from Prunus. Using bioinformatics, we explored the presence of the gene encoding T3SE HopAR1 within related prophage sequences in diverse P. syringae strains including cherry epiphytes and pathogens. Results indicated that horizontal gene transfer (HGT) of this effector between phylogroups may have involved phage. Prophages containing hopAR1 were demonstrated to excise, circularise and transfer the gene on the leaf surface. The phyllosphere provides a dynamic environment for prophage-mediated gene exchange and the potential for the emergence of new more virulent pathotypes. Our results suggest that genome-based epidemiological surveillance of environmental populations will allow the timely application of control measures to prevent damaging diseases.
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Bacteriófagos , Prunus avium , Pseudomonas syringae/genética , Transferência Genética Horizontal , Bacteriófagos/genética , Genômica , Genoma Bacteriano , Doenças das Plantas/genéticaRESUMO
Bacterial canker is a major disease of stone fruits and is a critical limiting factor to sweet cherry (Prunus avium) production worldwide. One important strategy for disease control is the development of resistant varieties. Partial varietal resistance in sweet cherry is discernible using shoot or whole tree inoculations; however, these quantitative differences in resistance are not evident in detached leaf assays. To identify novel sources of resistance to canker, we used a rapid leaf pathogenicity test to screen a range of wild cherry, ornamental Prunus species and sweet cherry × ornamental cherry hybrids with the canker pathogens, Pseudomonas syringae pvs syringae, morsprunorum races 1 and 2, and avii. Several Prunus accessions exhibited limited symptom development following inoculation with each of the pathogens, and this resistance extended to 16 P. syringae strains pathogenic on sweet cherry and plum. Resistance was associated with reduced bacterial multiplication after inoculation, a phenotype similar to that of commercial sweet cherry towards nonhost strains of P. syringae. Progeny resulting from a cross of a resistant ornamental species Prunus incisa with susceptible sweet cherry (P. avium) exhibited resistance indicating it is an inherited trait. Identification of accessions with resistance to the major bacterial canker pathogens is the first step towards characterizing the underlying genetic mechanisms of resistance and introducing these traits into commercial germplasm.
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Inflectional affixes expressing the same grammatical category (e.g., subject agreement) tend to appear in the same morphological position in the word. We hypothesize that this cross-linguistic tendency toward category clustering is at least partly the result of a learning bias, which facilitates the transmission of morphology from one generation to the next if each inflectional category has a consistent morphological position. We test this in an online artificial language experiment, teaching adult English speakers a miniature language consisting of noun stems representing shapes and suffixes representing the color and number features of each shape. In one experimental condition, each suffix category has a fixed position, with color in the first position and number in the second position. In a second condition, each specific combination of suffixes has a fixed order, but some combinations have color in the first position, and some have number in the first position. In a third condition, suffixes are randomly ordered on each presentation. While the language in the first condition is consistent with the category clustering principle, those in the other conditions are not. Our results indicate that category clustering of inflectional affixes facilitates morphological learning, at least in adult English speakers. Moreover, we found that languages that violate category clustering but still follow fixed affix ordering patterns are more learnable than languages with random ordering. Altogether, our results provide evidence for individual biases toward category clustering; we suggest that this bias may play a causal role in shaping the typological regularities in affix order we find in natural language.
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Aprendizagem , Linguística , Adulto , Análise por Conglomerados , Humanos , Idioma , Desenvolvimento da LinguagemRESUMO
Pain that develops in the coccyx or surrounding tissues is known as coccydynia, which occurs as a result of many etiologies both traumatic and nontraumatic. Although coccydynia most commonly affects middle-aged women, it may be found in both sexes and in all age groups. The aim of this article is to provide an overview of the presentation, diagnostic imaging, and pathophysiology of coccydynia, and to comprehensively review the current treatment options. A review of publications from 1990 to 2020 using search words related to the treatment of coccydynia in PubMed and Google Scholar was completed. Level II evidence was found supporting stretching, manipulation, and extracorporeal shock wave therapy. There are no data from high-quality studies to support injection-based therapy including corticosteroids, prolotherapy, nerve blocks, and radiofrequency ablation, although there are small retrospective and prospective observational studies suggesting benefit. Level III evidence was found supporting coccygectomy for chronic/refractory coccydynia. There are no data from randomized controlled trials to support the use of neuromodulation (sacral burst and dorsal root ganglion stimulation), although there are case reports suggesting benefit. High-level, comparative studies are lacking to guide the treatment of coccydynia and should be a focus for future research studies.
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Dor Lombar , Dor Musculoesquelética , Dor nas Costas , Cóccix/cirurgia , Feminino , Humanos , Dor Lombar/diagnóstico , Dor Lombar/etiologia , Dor Lombar/terapia , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Dor Pélvica , Estudos RetrospectivosRESUMO
Context: Osteoporosis is a known complication in spinal cord injury patients and can result in an increased risk of fractures and associated morbidity. Bone demineralization is most common in long bones below the level of injury. The pathogenesis is complex and not fully understood.Findings: We present the case of a 65-year-old male with chronic spinal cord injury who was found to have multiple vertebral compression fractures causing autonomic dysreflexia and new onset spasticity.Conclusion/Clinical Relevance: This case illustrates the need for improved awareness, diagnosis, and prevention for this disease process.
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Disreflexia Autonômica , Fraturas por Compressão , Fraturas de Estresse , Traumatismos da Medula Espinal , Fraturas da Coluna Vertebral , Idoso , Disreflexia Autonômica/diagnóstico , Disreflexia Autonômica/etiologia , Fraturas de Estresse/complicações , Humanos , Masculino , Quadriplegia/complicações , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/patologia , Fraturas da Coluna Vertebral/complicaçõesRESUMO
Targeting interactions between α4ß7 integrin and endothelial adhesion molecule MAdCAM-1 to inhibit lymphocyte migration to the gastrointestinal tract is an effective therapy in inflammatory bowel disease (IBD). Following lymphocyte entry into the mucosa, a subset of these cells expresses αEß7 integrin, which is expressed on proinflammatory lymphocytes, to increase cell retention. The factors governing lymphocyte migration into the intestinal mucosa and αE integrin expression in healthy subjects and IBD patients remain incompletely understood. We evaluated changes in factors involved in lymphocyte migration and differentiation within tissues. Both ileal and colonic tissue from active IBD patients showed upregulation of ICAM-1, VCAM-1, and MAdCAM-1 at the gene and protein levels compared with healthy subjects and/or inactive IBD patients. ß1 and ß7 integrin expression on circulating lymphocytes was similar across groups. TGF-ß1 treatment induced expression of αE on both ß7+ and ß7- T cells, suggesting that cells entering the mucosa independently of MAdCAM-1/α4ß7 can become αEß7+ ITGAE gene polymorphisms did not alter protein induction following TGF-ß1 stimulation. Increased phospho-SMAD3, which is directly downstream of TGF-ß, and increased TGF-ß-responsive gene expression were observed in the colonic mucosa of IBD patients. Finally, in vitro stimulation experiments showed that baseline ß7 expression had little effect on cytokine, chemokine, transcription factor, and effector molecule gene expression in αE+ and αE- T cells. These findings suggest cell migration to the gut mucosa may be altered in IBD and α4ß7-, and α4ß7+ T cells may upregulate αEß7 in response to TGF-ß once within the gut mucosa.
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Antígenos CD/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Cadeias alfa de Integrinas/metabolismo , Cadeias beta de Integrinas/metabolismo , Mucosa Intestinal/imunologia , Receptores de Retorno de Linfócitos/metabolismo , Linfócitos T/imunologia , Adulto , Idoso , Movimento Celular , Feminino , Humanos , Cadeias beta de Integrinas/genética , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND AND AIMS: Altering dietary ferrous sulphate (FS) consumption exacerbates a murine model of colitis and alters the intestinal microbiome. We investigated the impact of oral ferric maltol (FM) and FS on mice with dextran sodium sulphate (DSS) induced colitis, and the microbiome of patients with iron deficiency. METHODS: Mice had acute colitis induced, with 2% DSS for 5 days, followed by water. During this period, groups of mice were fed standard chow (200 ppm iron, SC, n = 8), or SC with 200ppm FS supplementation (n = 16, FSS), or SC with 200 ppm FM supplementation (n = 16, FMS). Clinical, pathological and microbiome assessments were compared at days 1 and 10. Fecal bacterial gDNA was extracted and the microbiome assessed by sequencing. Statistical inferences were made using MacQIIME. Principal Coordinates Analysis were used to visualize beta-diversity cluster analysis. Ten patients with IDA were treated with FS, and six with inactive inflammatory bowel disease received FM, supplements for four weeks: pre- and mid-treatment fecal samples were collected: the microbiome was assessed (see above). RESULTS: In mice, after DSS treatment, there was a decrease in many genera in the SC and FSS groups: Lactobacillales increased in mice that received FMS. In humans, FS treatment led to an increase in five genera, but FM was not associated with any measurable change. The severity of DSS-induced colitis was greater with FSS than FMS. CONCLUSIONS: This study demonstrates differential and unique influences of ferric maltol and ferrous sulphate supplements on intestinal microbiota. These differences might contribute to the different side effects associated with these preparations.
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Compostos Férricos/administração & dosagem , Compostos Férricos/farmacologia , Compostos Ferrosos/farmacologia , Pironas/administração & dosagem , Pironas/farmacologia , Administração Oral , Animais , Biodiversidade , Peso Corporal/efeitos dos fármacos , Colite/induzido quimicamente , Colite/microbiologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/patologia , Sulfato de Dextrana , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Ferro/metabolismo , Camundongos Endogâmicos C57BL , FilogeniaRESUMO
BACKGROUND: Increased mucosa-associated E. coli are present in Crohn's disease, but their role in pathogenesis is uncertain. AIMS: To assess efficacy and safety of an antibiotic/hydroxychloroquine combination effective against E. coli inside macrophages. METHODS: Adults with moderately active disease (CDAI > 220-450 plus C reactive protein ≥ 5 mg/l and/or fecal calprotectin > 250 µg/g) were randomized to receive (open-label) oral budesonide (Entocort CR 9 mg/day 8 weeks, 6 mg/day 2 weeks, 3 mg/day 2 weeks) or oral ciprofloxacin 500 mg bd, doxycycline 100 mg bd, hydroxychloroquine 200 mg tds for 4 weeks, followed by doxycycline 100 mg bd and hydroxychloroquine 200 mg tds for 20 weeks. Primary endpoints were remission (CDAI ≤ 150) at 10 weeks, remission maintained to 24 weeks, and remission maintained to 52 weeks. Patients not responding (CDAI fall by > 70) by 10 weeks were invited to crossover onto the alternative therapy. RESULTS: Fifty-nine patients were recruited across 8 sites. Including crossover, 39 patients received antibiotics/hydroxychloroquine and 39 received budesonide. At 10 weeks, 24 weeks, and 52 weeks on initial therapy, only 2/27, 2/27, and 1/27 were in remission on antibiotics/hydroxychloroquine compared with 8/32, 1/32, and 1/32 on budesonide (P = 0.092 at 10 weeks). Withdrawals by 10 weeks due to adverse events were seen in 15 receiving antibiotics/hydroxychloroquine and 6 budesonide. Results including crossover were more promising with 9/24 patients receiving antibiotics/hydroxychloroquine per protocol in remission by 24 weeks. No correlation was seen between response to antibiotics/hydroxychloroquine and ASCA/OmpC antibody status or disease location. CONCLUSION: Overall results with this antibiotic/hydroxychloroquine combination were unimpressive, but long-term remission is seen in some patients and justifies further study.
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Budesonida/uso terapêutico , Ciprofloxacina/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doxiciclina/uso terapêutico , Hidroxicloroquina/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Budesonida/administração & dosagem , Ciprofloxacina/administração & dosagem , Estudos Cross-Over , Doxiciclina/administração & dosagem , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidroxicloroquina/administração & dosagemRESUMO
BACKGROUND: Multiple investigations are available to aid the diagnosis and monitoring of disease activity in inflammatory bowel disease (IBD). Fecal calprotectin (FC) is an established surrogate for intestinal inflammatory activity. Therapeutic drug monitoring (TDM) including thiopurine metabolites, anti-tumor necrosis factor (TNF) levels and antidrug antibody measurements are a step toward personalized medicine in IBD, but face access barriers. We aimed to assess test availability and barriers for these investigations in European practice. METHODS: Five-hundred questionnaires were distributed to workshop participants at the 11th Congress of the European Crohn's and Colitis Organisation (ECCO). Access to FC, TDM for thiopurines and anti-tumor necrosis factor agents, as well as factors associated with usage and barriers to access were recorded. RESULTS: Responses were obtained from 195 attendees from 38 countries across a range of practices, healthcare settings and levels of experience. FC was available to 92.3% while access to anti-TNF (78.9%, P = 0.02 vs. thiopurine TDM, P = 0.0002 vs. FC) and thiopurine TDM (67.7%, P = 0.0001) were less widespread. Cost was a frequently cited barrier to test access or usage, with access having a significant West-East and North-South divide across all three investigations. The strongest independent predictor of access to all tests was healthcare spending per capita (P = 0.005 for FC; P < 0.0001 for both TDM). CONCLUSION: FC, anti-TNF and thiopurine TDM are increasingly incorporated as part of routine practice in IBD care across Europe and have the potential to impact positively on patient care. However, access barriers remain of which we found test cost the most significant with the investment required to reduce these barriers.
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Doença de Crohn , Doenças Inflamatórias Intestinais , Doença Crônica , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Complexo Antígeno L1 Leucocitário , Inquéritos e Questionários , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfaRESUMO
The Merit-based Incentive Payment System (MIPS) is a requirement for all physicians for value-based reporting. Medicare has approved registries as a mechanism for MIPS reporting. Concurrently, residencies continue to abide by the Accreditation Council for Graduate Medical Education's (ACGME's) curriculum requirement of utilizing/practicing quality improvement (QI).The objectives of this study were as follows: (1) incorporate a meaningful functional outcome measure into an electronic health record (EHR) to track spine functional outcomes; (2) generate a report containing covariables extracted from the EHR system to provide trackable data for current and future resident QI projects/investigations; and (3) establish an infrastructure to align ACGME QI initiatives with the MIPS requirements. This pilot study and retrospective analysis successfully demonstrates how a meaningful functional outcome measure can be incorporated into the EHR system for QI. Moreover, it demonstrates successful establishment of infrastructure for alignment of QI projects for ACGME residency requirements with MIPS requirements.
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Internato e Residência , Motivação , Idoso , Educação de Pós-Graduação em Medicina , Humanos , Medicare , Avaliação de Resultados em Cuidados de Saúde , Projetos Piloto , Melhoria de Qualidade , Estudos Retrospectivos , Estados UnidosRESUMO
BACKGROUND AND AIMS: Historical and emerging data implicate fungi in Crohn's disease [CD] pathogenesis. However, a causal link between mycobiota, dysregulated immunity, and any impact of NOD2 variants remains elusive. This study aims to evaluate associations between NOD2 variants and faecal mycobiota in CD patients and non-CD subjects. METHODS: Faecal samples were obtained from 34 CD patients [18 NOD2 mutant, 16 NOD2 wild-type] identified from the UK IBD Genetics Consortium. To avoid confounding influence of mucosal inflammation, CD patients were in clinical remission and had a faecal calprotectinâ <250 µg/g; 47 non-CD subjects were included as comparator groups, including 22 matched household [four NOD2 mutant] and 25 non-household subjects with known NOD2 genotype [14 NOD2 mutant] identified by the NIHR BioResource Cambridge. Faecal mycobiota composition was determined using internal transcribed spacer 1 [ITS1] sequencing and was compared with 16S rRNA gene sequences and volatile organic compounds. RESULTS: CD was associated with higher numbers of fungal observed taxonomic units [OTUs] [pâ =â 0.033]. Principal coordinates analysis using Jaccard index [pâ =â 0.018] and weighted Bray-Curtis dissimilarities [pâ =â 0.01] showed Candida spp. clustered closer to CD patients whereas Cryptococcus spp. clustered closer to non-CD. In CD, we found higher relative abundance of Ascomycota [pâ =â 0.001] and lower relative abundance Basidiomycota [pâ =â 0.019] phyla. An inverse relationship was found between bacterial and fungal Shannon diversity in NOD2 wild-type which was independent of CD [râ =â -0.349; pâ =â 0.029]. CONCLUSIONS: This study confirms compositional changes in the gut mycobiota in CD and provides evidence that fungi may play a role in CD pathogenesis. No NOD2 genotype-specific differences were observed in the faecal mycobiota.
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Doença de Crohn/genética , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Micoses/genética , Micoses/microbiologia , Proteína Adaptadora de Sinalização NOD2/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Indução de RemissãoRESUMO
In order to achieve saturating transposon mutagenesis of the genome of plant pathogenic strains of Pseudomonas syringae we needed to improve plasmid conjugation frequency. Manipulation of the growth stage of donor and recipient cells allowed the required increase in frequency and facilitated conjugation of otherwise recalcitrant strains.
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Técnicas Bacteriológicas/métodos , Conjugação Genética , Pseudomonas syringae/genética , DNA Bacteriano , Técnicas Genéticas , Recombinação GenéticaRESUMO
Bacterial canker disease is a major limiting factor in the growing of cherry and other Prunus species worldwide. At least five distinct clades within the bacterial species complex Pseudomonas syringae are known to be causal agents of the disease. The different pathogens commonly coexist in the field. Reducing canker is a challenging prospect as the efficacy of chemical controls and host resistance may vary against each of the diverse clades involved. Genomic analysis has revealed that the pathogens use a variable repertoire of virulence factors to cause the disease. Significantly, strains of P. syringae pv. syringae possess more genes for toxin biosynthesis and fewer encoding type III effector proteins. There is also a shared pool of key effector genes present on mobile elements such as plasmids and prophages that may have roles in virulence. By contrast, there is evidence that absence or truncation of certain effector genes, such as hopAB, is characteristic of cherry pathogens. Here we highlight how recent research, underpinned by the earlier epidemiological studies, is allowing significant progress in our understanding of the canker pathogens. This fundamental knowledge, combined with emerging insights into host genetics, provides the groundwork for development of precise control measures and informed approaches to breed for disease resistance.
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BACKGROUND: Prevention and management of postoperative recurrence (POR) is a controversial field in Crohn's disease. The aim of this survey was to report common practice in real-life settings. METHODS: An 11-question survey was distributed among gastroenterologists attending the 14th European Crohn's and Colitis Organisation (ECCO) congress. RESULTS: Postoperative endoscopy to assess recurrence was routinely performed within 12 months by 87% of respondents. Forty-six percent of clinicians reported to maintain endoscopic assessment in routine follow-up even after first negative colonoscopy. Most respondents (60%) considered starting postoperative immunoprophylaxis in naïve patients if one or more known risk factors were present. The number of risk factors was an important driver for prescribing biologics over immunosuppressants for 60% of respondents.In case of fistulizing phenotype, perianal disease, or concomitant colonic involvement, the majority of physicians reported to start an immediate prophylaxis in 85, 98 and 88% of patients, respectively. A significant percentage of clinicians were more prone to an endoscopy-driven treatment in long-standing disease after failure of thiopurines (51%) and elderly (43%). CONCLUSION: Endoscopy within the first year after surgery to assess POR has become routine in most centres. The high rate of early prophylaxis with expensive biologics despite missing solid evidence highlights the need for more randomized trials.