RESUMEN
Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon, and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR, ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.
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Evolución Clonal/genética , Colitis/genética , Enfermedades Inflamatorias del Intestino/genética , Tasa de Mutación , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Evolución Clonal/inmunología , Colitis/metabolismo , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Proteínas de Unión al ADN/genética , Células Epiteliales/metabolismo , Células Epiteliales/patología , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Femenino , Humanos , Mutación INDEL , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Interleucina-17/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Filogenia , Mutación Puntual , Receptores de Superficie Celular/genética , Ribonucleasas/genética , Receptores Toll-Like/genética , Factores de Transcripción/genética , Secuenciación Completa del GenomaRESUMEN
A complete, 52-protein, 2.5 million dalton, Mediator-RNA polymerase II pre-initiation complex (Med-PIC) was assembled and analyzed by cryo-electron microscopy and by chemical cross-linking and mass spectrometry. The resulting complete Med-PIC structure reveals two components of functional significance, absent from previous structures, a protein kinase complex and the Mediator-activator interaction region. It thereby shows how the kinase and its target, the C-terminal domain of the polymerase, control Med-PIC interaction and transcription.
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Complejo Mediador/química , Complejo Mediador/metabolismo , Modelos Moleculares , ARN Polimerasa II/química , ARN Polimerasa II/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Microscopía por Crioelectrón , Regulación de la Expresión Génica , Espectrometría de Masas , Fosforilación , Estructura Terciaria de Proteína , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
The ontogeny of the human haematopoietic system during fetal development has previously been characterized mainly through careful microscopic observations1. Here we reconstruct a phylogenetic tree of blood development using whole-genome sequencing of 511 single-cell-derived haematopoietic colonies from healthy human fetuses at 8 and 18 weeks after conception, coupled with deep targeted sequencing of tissues of known embryonic origin. We found that, in healthy fetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 weeks after conception. We used these mutations as barcodes and timed the divergence of embryonic and extra-embryonic tissues during development, and estimated the number of blood antecedents at different stages of embryonic development. Our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans.
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Linaje de la Célula/genética , Desarrollo Embrionario/genética , Sistema Hematopoyético/embriología , Sistema Hematopoyético/metabolismo , Mutación , Células Sanguíneas/citología , Células Sanguíneas/metabolismo , Células Clonales/citología , Células Clonales/metabolismo , Análisis Mutacional de ADN , Feto/citología , Feto/embriología , Feto/metabolismo , Estratos Germinativos/citología , Estratos Germinativos/metabolismo , Salud , Sistema Hematopoyético/citología , Humanos , Cariotipificación , Masculino , Mesodermo/citología , Mesodermo/embriología , Mesodermo/metabolismo , Tasa de Mutación , Especificidad de Órganos/genética , Factores de Tiempo , Secuenciación Completa del Genoma , Flujo de TrabajoRESUMEN
Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.
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Linaje de la Célula/genética , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario/genética , Mutación , Encéfalo/metabolismo , Cromosomas Humanos Y/genética , Células Clonales/metabolismo , Mutación de Línea Germinal/genética , Humanos , Masculino , Mosaicismo , Especificidad de Órganos/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes1-8. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease9-13 than in normal liver13-16, which enables positive selection to shape the genomic landscape9-13. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes17-19, and GPAM, which produces storage triacylglycerol from free fatty acids20,21, also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease.
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Hepatopatías/genética , Hepatopatías/metabolismo , Hígado/metabolismo , Mutación/genética , Transporte Activo de Núcleo Celular/genética , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular Tumoral , Enfermedad Crónica , Estudios de Cohortes , Ácidos Grasos no Esterificados/metabolismo , Femenino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Resistencia a la Insulina , Hepatopatías Alcohólicas/genética , Hepatopatías Alcohólicas/metabolismo , Masculino , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Triglicéridos/metabolismoRESUMEN
BACKGROUND: Nursing home residents are at high risk for infection, hospitalization, and colonization with multidrug-resistant organisms. METHODS: We performed a cluster-randomized trial of universal decolonization as compared with routine-care bathing in nursing homes. The trial included an 18-month baseline period and an 18-month intervention period. Decolonization entailed the use of chlorhexidine for all routine bathing and showering and administration of nasal povidone-iodine twice daily for the first 5 days after admission and then twice daily for 5 days every other week. The primary outcome was transfer to a hospital due to infection. The secondary outcome was transfer to a hospital for any reason. An intention-to-treat (as-assigned) difference-in-differences analysis was performed for each outcome with the use of generalized linear mixed models to compare the intervention period with the baseline period across trial groups. RESULTS: Data were obtained from 28 nursing homes with a total of 28,956 residents. Among the transfers to a hospital in the routine-care group, 62.2% (the mean across facilities) were due to infection during the baseline period and 62.6% were due to infection during the intervention period (risk ratio, 1.00; 95% confidence interval [CI], 0.96 to 1.04). The corresponding values in the decolonization group were 62.9% and 52.2% (risk ratio, 0.83; 95% CI, 0.79 to 0.88), for a difference in risk ratio, as compared with routine care, of 16.6% (95% CI, 11.0 to 21.8; P<0.001). Among the discharges from the nursing home in the routine-care group, transfer to a hospital for any reason accounted for 36.6% during the baseline period and for 39.2% during the intervention period (risk ratio, 1.08; 95% CI, 1.04 to 1.12). The corresponding values in the decolonization group were 35.5% and 32.4% (risk ratio, 0.92; 95% CI, 0.88 to 0.96), for a difference in risk ratio, as compared with routine care, of 14.6% (95% CI, 9.7 to 19.2). The number needed to treat was 9.7 to prevent one infection-related hospitalization and 8.9 to prevent one hospitalization for any reason. CONCLUSIONS: In nursing homes, universal decolonization with chlorhexidine and nasal iodophor led to a significantly lower risk of transfer to a hospital due to infection than routine care. (Funded by the Agency for Healthcare Research and Quality; Protect ClinicalTrials.gov number, NCT03118232.).
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Antiinfecciosos Locales , Infecciones Asintomáticas , Clorhexidina , Infección Hospitalaria , Casas de Salud , Povidona Yodada , Humanos , Administración Cutánea , Administración Intranasal , Antiinfecciosos Locales/administración & dosificación , Antiinfecciosos Locales/uso terapéutico , Baños , Clorhexidina/administración & dosificación , Clorhexidina/uso terapéutico , Infección Hospitalaria/epidemiología , Infección Hospitalaria/prevención & control , Infección Hospitalaria/terapia , Hospitalización/estadística & datos numéricos , Casas de Salud/estadística & datos numéricos , Transferencia de Pacientes/estadística & datos numéricos , Povidona Yodada/administración & dosificación , Povidona Yodada/uso terapéutico , Cuidados de la Piel/métodos , Infecciones Asintomáticas/terapiaRESUMEN
Proteins entering the secretory pathway need to attain native disulfide pairings to fold correctly. For proteins with complex disulfides, this process requires the reduction and isomerisation of non-native disulfides. Two key members of the protein disulfide isomerase (PDI) family, ERp57 and ERdj5 (also known as PDIA3 and DNAJC10, respectively), are thought to be required for correct disulfide formation but it is unknown whether they act as a reductase, an isomerase or both. In addition, it is unclear how reducing equivalents are channelled through PDI family members to substrate proteins. Here, we show that neither enzyme is required for disulfide formation, but ERp57 is required for isomerisation of non-native disulfides within glycoproteins. In addition, alternative PDIs compensate for the absence of ERp57 to isomerise glycoprotein disulfides, but only in the presence of a robust reductive pathway. ERdj5 is required for this alternative pathway to function efficiently indicating its role as a reductase. Our results define the essential cellular functions of two PDIs, highlighting a distinction between formation, reduction and isomerisation of disulfide bonds.
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Oxidorreductasas , Proteína Disulfuro Isomerasas , Proteína Disulfuro Isomerasas/genética , Proteína Disulfuro Isomerasas/química , Proteína Disulfuro Isomerasas/metabolismo , Oxidorreductasas/metabolismo , Pliegue de Proteína , Glicoproteínas/metabolismo , Disulfuros/metabolismo , Oxidación-ReducciónRESUMEN
The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.
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Colon/citología , Células Epiteliales/citología , Células Epiteliales/metabolismo , Mutación , Síntomas Prodrómicos , Recto/citología , Adenoma/genética , Adenoma/patología , Anciano , Proteína Axina/genética , Carcinoma/genética , Carcinoma/patología , Transformación Celular Neoplásica , Células Clonales/citología , Células Clonales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Femenino , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Células Madre/citología , Células Madre/metabolismoRESUMEN
The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.
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Tratamiento Farmacológico de COVID-19 , Pandemias , Vacunas contra la COVID-19 , Desarrollo de Medicamentos , Humanos , Pandemias/prevención & control , SARS-CoV-2RESUMEN
BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500â ng/L (vs <200â ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000â copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000â copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8â ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8â ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.
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Antivirales , COVID-19 , Hospitalización , Interleucina-6 , SARS-CoV-2 , Humanos , COVID-19/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Anciano , Interleucina-6/sangre , Adulto , Antivirales/uso terapéutico , ARN Viral/sangre , Tratamiento Farmacológico de COVID-19 , Anticuerpos Antivirales/sangre , Antígenos Virales/sangreRESUMEN
OBJECTIVES: Inaugural axial muscle involvement, defined as dropped head syndrome (DHS) and/or camptocormia (CC), is poorly described in inflammatory myopathies (IM). This study aimed to further characterize IM patients with inaugural DHS/CC, their outcome and care management. METHODS: This retrospective study included IM patients diagnosed between 2000 and 2021. The main inclusion criterion was IM revealed by axial muscle deficit (DHS/CC). RESULTS: Twenty-seven patients were included; median (IQR) age at first symptoms was 66.0 years (55.5-75.0); 21 were female (77.8%). There were nine IBM, 33.3%, nine overlap myositis (OM, 33.3%), five DM, 18.5%, two immune checkpoint inhibitor-related myositis (7.4%), one focal myositis (3.7%) and one myositis with anti-Hu antibodies (3.7%). Age at first symptoms was ≤70 years in 16 patients (59.3%), including all DM patients and 8/9 OM patients (88.9%). In this group, partial remission of the disease was obtained in 9/16 (56.3%) and complete remission in 1/16 patients (6.3%); regression of DHS/CC was achieved in 3/16 patients (18.8%). Conversely, in the group of 11 patients aged >70 years at first symptoms, there were eight IBM (72.7%). Partial remission was obtained in 5/11 patients (45.5%), the disease was stable in 6/11 patients (54.5%); no complete remission was obtained nor regression of DHS/CC. CONCLUSION: The analysis of IM patients with inaugural DHS/CC delineates two groups of patients according to the age at first symptoms in terms of clinical and outcome specificities, and proposes an adapted diagnostic and care management approach to prevent long-term complications.
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Atrofia Muscular Espinal , Miositis , Curvaturas de la Columna Vertebral , Humanos , Femenino , Masculino , Estudios Retrospectivos , Síndrome de Cabeza Caída , Miositis/complicaciones , Atrofia Muscular Espinal/complicacionesRESUMEN
OBJECTIVES: The revised European Society of Musculoskeletal Radiology (ESSR) consensus guidelines on soft tissue tumor imaging represent an update of 2015 after technical advancements, further insights into specific entities, and revised World Health Organization (2020) and AJCC (2017) classifications. This second of three papers covers algorithms once histology is confirmed: (1) standardized whole-body staging, (2) special algorithms for non-malignant entities, and (3) multiplicity, genetic tumor syndromes, and pitfalls. MATERIALS AND METHODS: A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries. Statements that had undergone interdisciplinary revision were scored online by the level of agreement (0 to 10) during two iterative rounds, that could result in 'group consensus', 'group agreement', or 'lack of agreement'. RESULTS: The three sections contain 24 statements with comments. Group consensus was reached in 95.8% and group agreement in 4.2%. For whole-body staging, pulmonary MDCT should be performed in all high-grade sarcomas. Whole-body MRI is preferred for staging bone metastasis, with [18F]FDG-PET/CT as an alternative modality in PET-avid tumors. Patients with alveolar soft part sarcoma, clear cell sarcoma, and angiosarcoma should be screened for brain metastases. Special algorithms are recommended for entities such as rhabdomyosarcoma, extraskeletal Ewing sarcoma, myxoid liposarcoma, and neurofibromatosis type 1 associated malignant peripheral nerve sheath tumors. Satisfaction of search should be avoided in potential multiplicity. CONCLUSION: Standardized whole-body staging includes pulmonary MDCT in all high-grade sarcomas; entity-dependent modifications and specific algorithms are recommended for sarcomas and non-malignant soft tissue tumors. CLINICAL RELEVANCE STATEMENT: These updated ESSR soft tissue tumor imaging guidelines aim to provide support in decision-making, helping to avoid common pitfalls, by providing general and entity-specific algorithms, techniques, and reporting recommendations for whole-body staging in sarcoma and non-malignant soft tissue tumors. KEY POINTS: An early, accurate, diagnosis is crucial for the prognosis of patients with soft tissue tumors. These updated guidelines provide best practice expert consensus for standardized imaging algorithms, techniques, and reporting. Standardization can improve the comparability examinations and provide databases for large data analysis.
RESUMEN
As per recommendations from the European Society of Radiology and the European Union of Medical Specialists, upon completion of level 3 radiology training, an objective assessment of the attained standards, aligned with national customs and practices, should take place. A subspecialty exam should ideally be an integral part of the training completion process. Among 10 of 13 European subspecialty societies currently offering a European subspecialty diploma, the European Society of Musculoskeletal Radiology (ESSR) diploma program was formally introduced by the ESSR in 2003. This article describes the evolution of the ESSR diploma, encompassing the current diploma program, validation procedures, endorsements, and future perspectives. Additionally, insights from a brief survey among ESSR diploma holders is shared, offering valuable tips for prospective candidates aiming to navigate the examination process successfully.
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Radiología , Humanos , Radiología/educación , Europa (Continente) , Educación de Postgrado en Medicina/métodos , Sociedades Médicas , Enfermedades Musculoesqueléticas/diagnóstico por imagen , Certificación/métodos , Competencia Clínica , Evaluación Educacional/métodosRESUMEN
OBJECTIVE: To determine differences in prevalence and diagnostic accuracy of MRI findings between asymptomatic athletes and athletes with longstanding groin pain. MATERIALS AND METHODS: One hundred twenty-three adult male athletes were approached with 85 consecutive athletes recruited. Group 1 (symptomatic, n = 34) athletes referred for longstanding groin pain (insidious onset, > 3 weeks duration). Group 2 (control, n = 51) athletes referred for injuries remote from the pelvis and no groin pain in the last 12 weeks. All referrers completed a clinical examination proforma documenting absence or presence of pelvis and hip abnormality. All patients completed the Copenhagen Hip and Groin Outcome Score (HAGOS) questionnaire and underwent a 3T MRI groin and hip protocol. MRIs were scored independently by two musculoskeletal radiologists blinded to clinical details. Statistical analysis was performed to evaluate associations between MRI findings, inter-reader reliability, clinical examination and HAGOS scores. RESULTS: Pubic body subchondral bone oedema, capsule/aponeurosis junction tear and soft tissue oedema were more prevalent in the symptomatic group (p = 0.0003, 0.0273 and 0.0005, respectively) and in athletes with clinical abnormality at symphysis pubis, adductor insertion, rectus abdominis, psoas and inguinal canal (p = 0.0002, 0.0459 and 0.00002, respectively). Pubic body and subchondral oedema and capsule/aponeurosis tear and oedema significantly correlated with lower (worse) HAGOS scores (p = 0.004, 0.00009, 0.0004 and 0.002, respectively). Inter-reader reliability was excellent, 0.87 (range 0.58-1). Symphyseal bone spurring, disc protrusion and labral tears were highly prevalent in both groups. CONCLUSION: Clinical assessment and MRI findings of pubic subchondral bone oedema and capsule/aponeurosis abnormality appear to be the strongest correlators with longstanding groin pain.
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Importance: Infections due to multidrug-resistant organisms (MDROs) are associated with increased morbidity, mortality, length of hospitalization, and health care costs. Regional interventions may be advantageous in mitigating MDROs and associated infections. Objective: To evaluate whether implementation of a decolonization collaborative is associated with reduced regional MDRO prevalence, incident clinical cultures, infection-related hospitalizations, costs, and deaths. Design, Setting, and Participants: This quality improvement study was conducted from July 1, 2017, to July 31, 2019, across 35 health care facilities in Orange County, California. Exposures: Chlorhexidine bathing and nasal iodophor antisepsis for residents in long-term care and hospitalized patients in contact precautions (CP). Main Outcomes and Measures: Baseline and end of intervention MDRO point prevalence among participating facilities; incident MDRO (nonscreening) clinical cultures among participating and nonparticipating facilities; and infection-related hospitalizations and associated costs and deaths among residents in participating and nonparticipating nursing homes (NHs). Results: Thirty-five facilities (16 hospitals, 16 NHs, 3 long-term acute care hospitals [LTACHs]) adopted the intervention. Comparing decolonization with baseline periods among participating facilities, the mean (SD) MDRO prevalence decreased from 63.9% (12.2%) to 49.9% (11.3%) among NHs, from 80.0% (7.2%) to 53.3% (13.3%) among LTACHs (odds ratio [OR] for NHs and LTACHs, 0.48; 95% CI, 0.40-0.57), and from 64.1% (8.5%) to 55.4% (13.8%) (OR, 0.75; 95% CI, 0.60-0.93) among hospitalized patients in CP. When comparing decolonization with baseline among NHs, the mean (SD) monthly incident MDRO clinical cultures changed from 2.7 (1.9) to 1.7 (1.1) among participating NHs, from 1.7 (1.4) to 1.5 (1.1) among nonparticipating NHs (group × period interaction reduction, 30.4%; 95% CI, 16.4%-42.1%), from 25.5 (18.6) to 25.0 (15.9) among participating hospitals, from 12.5 (10.1) to 14.3 (10.2) among nonparticipating hospitals (group × period interaction reduction, 12.9%; 95% CI, 3.3%-21.5%), and from 14.8 (8.6) to 8.2 (6.1) among LTACHs (all facilities participating; 22.5% reduction; 95% CI, 4.4%-37.1%). For NHs, the rate of infection-related hospitalizations per 1000 resident-days changed from 2.31 during baseline to 1.94 during intervention among participating NHs, and from 1.90 to 2.03 among nonparticipating NHs (group × period interaction reduction, 26.7%; 95% CI, 19.0%-34.5%). Associated hospitalization costs per 1000 resident-days changed from $64â¯651 to $55â¯149 among participating NHs and from $55â¯151 to $59â¯327 among nonparticipating NHs (group × period interaction reduction, 26.8%; 95% CI, 26.7%-26.9%). Associated hospitalization deaths per 1000 resident-days changed from 0.29 to 0.25 among participating NHs and from 0.23 to 0.24 among nonparticipating NHs (group × period interaction reduction, 23.7%; 95% CI, 4.5%-43.0%). Conclusions and Relevance: A regional collaborative involving universal decolonization in long-term care facilities and targeted decolonization among hospital patients in CP was associated with lower MDRO carriage, infections, hospitalizations, costs, and deaths.
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Antiinfecciosos Locales , Infecciones Bacterianas , Infección Hospitalaria , Farmacorresistencia Bacteriana Múltiple , Instituciones de Salud , Control de Infecciones , Anciano , Humanos , Administración Intranasal , Antiinfecciosos Locales/administración & dosificación , Antiinfecciosos Locales/uso terapéutico , Infecciones Bacterianas/economía , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/mortalidad , Infecciones Bacterianas/prevención & control , Baños/métodos , California/epidemiología , Clorhexidina/administración & dosificación , Clorhexidina/uso terapéutico , Infección Hospitalaria/economía , Infección Hospitalaria/microbiología , Infección Hospitalaria/mortalidad , Infección Hospitalaria/prevención & control , Instituciones de Salud/economía , Instituciones de Salud/normas , Instituciones de Salud/estadística & datos numéricos , Hospitalización/economía , Hospitalización/estadística & datos numéricos , Hospitales/normas , Hospitales/estadística & datos numéricos , Control de Infecciones/métodos , Yodóforos/administración & dosificación , Yodóforos/uso terapéutico , Casas de Salud/economía , Casas de Salud/normas , Casas de Salud/estadística & datos numéricos , Transferencia de Pacientes , Mejoramiento de la Calidad/economía , Mejoramiento de la Calidad/estadística & datos numéricos , Cuidados de la Piel/métodos , Precauciones UniversalesRESUMEN
BACKGROUND AND OBJECTIVES: Pompe disease is a rare hereditary glycogen storage disorder due to lysosomal acid alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) is the only available treatment. Infusion-associated reactions (IAR) are challenging since there are no guidelines for ERT rechallenge after a drug hypersensitivity reaction (DHR) in Pompe disease. The objective of the present study was to describe IAR and their management in late-onset Pompe disease (LOPD) patients in France, and to discuss the various possibilities of ERT rechallenge. METHODS: An exhaustive screening of LOPD patients receiving ERT between 2006 and 2020 from the 31-participating hospital-based or reference centers was performed. The patients who had presented at least one hypersensitivity IAR (=DHR) episode were included. Demographic characteristics of the patients, IAR onset and timing, were retrospectively collected from the French Pompe Registry. RESULTS: Fifteen patients among 115 treated LOPD patients in France presented at least 1 IAR; 80.0% were women. Twenty-nine IAR were reported; 18 (62.1%) IAR were Grade I reactions, 10 (34.5%) IAR were Grade II, and 1 (3.4%) IAR was Grade III. IgE-mediated hypersensitivity was found in 2/15 patients (13.3%). The median [IQR] time from ERT introduction to the first IAR was 15.0 months [11.0-24.0]. ERT was safely and effectively re-introduced either with premedication alone, or in combination with either modified regimen or desensitization protocol, in all 9 rechallenged patients; including in patients with IgE-mediated hypersensitivity, in the patient with the Grade III reaction, as well as in patients with very high anti-GAA titer. DISCUSSION: Based on the results herein and previous reports, we discuss premedication and modified regimen for Grade I reactions, and desensitization in Grade II and III reactions. In conclusion, ERT-induced IAR can be safely and effectively managed with a modified regimen or desensitization protocol in LOPD patients.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Hipersensibilidad Inmediata , Hipersensibilidad , Humanos , Femenino , Masculino , Enfermedad del Almacenamiento de Glucógeno Tipo II/terapia , Estudios Retrospectivos , Terapia de Reemplazo Enzimático/efectos adversos , Sistema de Registros , Hipersensibilidad Inmediata/inducido químicamente , Hipersensibilidad Inmediata/tratamiento farmacológico , alfa-Glucosidasas/efectos adversosRESUMEN
OBJECTIVES: To determine COVID-19 vaccine hesitancy rates in inflammatory arthritis patients and identify factors associated with changing vaccine hesitancy over time. METHODS: This investigation was a prospective cohort study of inflammatory arthritis patients from community and public hospital outpatient rheumatology clinics enrolled in the Australian Rheumatology Association Database (ARAD). Two surveys were conducted, one immediately prior to (pre-pandemic) and another approximately 1 year after the start of the pandemic (follow-up). Coronavirus disease 2019 (COVID-19) vaccine hesitancy was measured at follow-up, and general vaccine hesitancy was inferred pre-pandemic; these were used to identify factors associated with fixed and changing vaccine beliefs, including sources of information and broader beliefs about medication. RESULTS: Of the 594 participants who completed both surveys, 74 (12%) were COVID-19 vaccine hesitant. This was associated with pre-pandemic beliefs about medications being harmful (P < 0.001) and overused (P = 0.002), with stronger beliefs resulting in vaccine hesitancy persistent over two time points (P = 0.008, P = 0.005). For those not vaccine hesitant pre-pandemic, the development of COVID-19 vaccine hesitancy was associated with a lower likelihood of seeking out vaccine information from health-care professionals (P < 0.001). COVID-19 vaccine hesitancy was not associated with new influenza vaccine hesitancy (P = 0.138). CONCLUSION: In this study of vaccine beliefs before and during the COVID-19 pandemic, factors associated with COVID-19 vaccine hesitancy in inflammatory arthritis patients varied, depending on vaccine attitudes immediately prior to the start of the pandemic. Fixed beliefs reflected broader views about medications, while fluid beliefs were highly influenced by whether they sought out information from health-care professionals, including rheumatologists.
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Artritis , COVID-19 , Humanos , Vacunas contra la COVID-19/uso terapéutico , Pandemias , Estudios Prospectivos , COVID-19/epidemiología , COVID-19/prevención & control , Australia/epidemiología , Artritis/tratamiento farmacológico , VacunaciónRESUMEN
OBJECTIVES: Early, accurate diagnosis is crucial for the prognosis of patients with soft tissue sarcomas. To this end, standardization of imaging algorithms, technical requirements, and reporting is therefore a prerequisite. Since the first European Society of Musculoskeletal Radiology (ESSR) consensus in 2015, technical achievements, further insights into specific entities, and the revised WHO-classification (2020) and AJCC staging system (2017) made an update necessary. The guidelines are intended to support radiologists in their decision-making and contribute to interdisciplinary tumor board discussions. MATERIALS AND METHODS: A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries. Statements were scored online by level of agreement (0 to 10) during two iterative rounds. Either "group consensus," "group agreement," or "lack of agreement" was achieved. RESULTS: Eight sections were defined that finally contained 145 statements with comments. Overall, group consensus was reached in 95.9%, and group agreement in 4.1%. This communication contains the first part consisting of the imaging algorithm for suspected soft tissue tumors, methods for local imaging, and the role of tumor centers. CONCLUSION: Ultrasound represents the initial triage imaging modality for accessible and small tumors. MRI is the modality of choice for the characterization and local staging of most soft tissue tumors. CT is indicated in special situations. In suspicious or likely malignant tumors, a specialist tumor center should be contacted for referral or teleradiologic second opinion. This should be done before performing a biopsy, without exception. CLINICAL RELEVANCE: The updated ESSR soft tissue tumor imaging guidelines aim to provide best practice expert consensus for standardized imaging, to support radiologists in their decision-making, and to improve examination comparability both in individual patients and in future studies on individualized strategies. KEY POINTS: ⢠Ultrasound remains the best initial triage imaging modality for accessible and small suspected soft tissue tumors. ⢠MRI is the modality of choice for the characterization and local staging of soft tissue tumors in most cases; CT is indicated in special situations. Suspicious or likely malignant tumors should undergo biopsy. ⢠In patients with large, indeterminate or suspicious tumors, a tumor reference center should be contacted for referral or teleradiologic second opinion; this must be done before a biopsy.
RESUMEN
Ankle impingement syndromes are a well-recognized cause of chronic ankle symptoms in both the elite athletic and general population. They comprise several distinct clinical entities with associated radiologic findings. Originally described in the 1950s, advances in magnetic resonance imaging (MRI) and ultrasonography have allowed musculoskeletal (MSK) radiologists to further their understanding of these syndromes and the range of imaging-associated features. Many subtypes of ankle impingement syndromes have been described, and precise terminology is critical to carefully separate these conditions and thus guide treatment options. These are divided broadly into intra-articular and extra-articular types, as well as location around the ankle. Although MSK radiologists should be aware of these conditions, the diagnosis remains largely clinical, with plain film or MRI used to confirm the diagnosis or assess a surgical/treatment target. The ankle impingement syndromes are a heterogeneous group of conditions, and care must be taken not to overcall findings. The clinical context remains paramount. Treatment considerations are patient symptoms, examination, and imaging findings, in addition to the patient's desired level of physical activity.
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Traumatismos del Tobillo , Tobillo , Humanos , Traumatismos del Tobillo/diagnóstico por imagen , Articulación del Tobillo/diagnóstico por imagen , Extremidad Inferior , Imagen por Resonancia Magnética/métodosRESUMEN
BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection. OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone. DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multinational, multicenter trial. PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: Intravenous ensovibep, 600 mg, or placebo. MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90. RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep). LIMITATION: The trial was prematurely stopped because of futility, limiting power for the primary outcome. CONCLUSION: Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified. PRIMARY FUNDING SOURCE: National Institutes of Health.