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Autologous T-cell-based therapies, such as CAR-T-cell therapy, exhibit low success rates in chronic lymphocytic leukemia (CLL) which correlates with a dysfunctional T-cell phenotype observed in patients. Despite various proposed mechanisms of T-cell dysfunction in CLL, the specific CLL-derived factors responsible remain unidentified. This study aims to investigate mechanisms by which CLL cells suppress (CAR) T-cell activation and function. We found that CLL-derived T cells get activated, albeit in a delayed fashion and that specifically re-stimulation of (CAR-) T cells in presence of CLL cells causes impaired cytokine production and reduced proliferation. Notably, co-culture of T cells with CD40-activated CLL cells did not result in T-cell dysfunction and this required direct cell contact between the CD40-stimulated CLL cells and T cells. Inhibition of kinases involved in the CD40-signaling cascade revealed that the SRC-kinase inhibitor dasatinib prevented rescue of T-cell function independent of CD40-mediated increased levels of costimulatory and adhesion ligands on CLL cells. Transcriptome profiling of CD40-stimulated CLL cells with or without dasatinib identified widespread differential gene expression. Selecting for surface receptor genes revealed CD40-mediated downregulation of SIGLEC-10-ligands CD24 and CD52, which was prevented by dasatinib; suggesting a role for these ligands in functional T-cell suppression in CLL. Indeed, blocking CD24 and/or CD52 markedly reduced (CAR) T-cell dysfunction upon co-culture with resting CLL cells. These results demonstrate that T cells derived from CLL patients can be reinvigorated by manipulating CLL-T cell interactions. Targeting CD24- and CD52-mediated CLL-T cell interaction could be a promising therapeutic strategy to enhance T-cell function in CLL.
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In 2017, the British Society for Children's Orthopaedic Surgery engaged the profession and all relevant stakeholders in two formal research prioritization processes. In this editorial, we describe the impact of this prioritization on funding, and how research in children's orthopaedics, which was until very recently a largely unfunded and under-investigated area, is now flourishing. Establishing research priorities was a crucial step in this process.
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Pesquisa Biomédica , Ortopedia , Pediatria , Apoio à Pesquisa como Assunto , Humanos , Ortopedia/economia , Pesquisa Biomédica/economia , Criança , Reino Unido , Pediatria/economia , Prioridades em SaúdeRESUMO
Studies in preclinical models suggest that complex lipids, such as phospholipids, play a role in the regulation of longevity. However, identification of universally conserved complex lipid changes that occur during aging, and how these respond to interventions, is lacking. Here, to comprehensively map how complex lipids change during aging, we profiled ten tissues in young versus aged mice using a lipidomics platform. Strikingly, from >1,200 unique lipids, we found a tissue-wide accumulation of bis(monoacylglycero)phosphate (BMP) during mouse aging. To investigate translational value, we assessed muscle tissue of young and older people, and found a similar marked BMP accumulation in the human aging lipidome. Furthermore, we found that a healthy-aging intervention consisting of moderate-to-vigorous exercise was able to lower BMP levels in postmenopausal female research participants. Our work implicates complex lipid biology as central to aging, identifying a conserved aging lipid signature of BMP accumulation that is modifiable upon a short-term healthy-aging intervention.
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Envelhecimento , Exercício Físico , Músculo Esquelético , Humanos , Animais , Envelhecimento/metabolismo , Feminino , Camundongos , Músculo Esquelético/metabolismo , Exercício Físico/fisiologia , Masculino , Lipidômica , Lisofosfolipídeos/metabolismo , Condicionamento Físico Animal/fisiologia , Idoso , Metabolismo dos Lipídeos/fisiologia , Monoglicerídeos/metabolismo , Adulto , Pessoa de Meia-IdadeRESUMO
Some individuals show a discrepancy between cognition and the amount of neuropathological changes characteristic for Alzheimer's disease (AD). This phenomenon has been referred to as 'resilience'. The molecular and cellular underpinnings of resilience remain poorly understood. To obtain an unbiased understanding of the molecular changes underlying resilience, we investigated global changes in gene expression in the superior frontal gyrus of a cohort of cognitively and pathologically well-defined AD patients, resilient individuals and age-matched controls (n = 11-12 per group). 897 genes were significantly altered between AD and control, 1121 between resilient and control and 6 between resilient and AD. Gene set enrichment analysis (GSEA) revealed that the expression of metallothionein (MT) and of genes related to mitochondrial processes was higher in the resilient donors. Weighted gene co-expression network analysis (WGCNA) identified gene modules related to the unfolded protein response, mitochondrial processes and synaptic signaling to be differentially associated with resilience or dementia. As changes in MT, mitochondria, heat shock proteins and the unfolded protein response (UPR) were the most pronounced changes in the GSEA and/or WGCNA, immunohistochemistry was used to further validate these processes. MT was significantly increased in astrocytes in resilient individuals. A higher proportion of the mitochondrial gene MT-CO1 was detected outside the cell body versus inside the cell body in the resilient compared to the control group and there were higher levels of heat shock protein 70 (HSP70) and X-box-binding protein 1 spliced (XBP1s), two proteins related to heat shock proteins and the UPR, in the AD donors. Finally, we show evidence for putative sex-specific alterations in resilience, including gene expression differences related to autophagy in females compared to males. Taken together, these results show possible mechanisms involving MTs, mitochondrial processes and the UPR by which individuals might maintain cognition despite the presence of AD pathology.
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Doença de Alzheimer , Perfilação da Expressão Gênica , Metalotioneína , Mitocôndrias , Resposta a Proteínas não Dobradas , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Metalotioneína/genética , Metalotioneína/metabolismo , Feminino , Masculino , Idoso , Resposta a Proteínas não Dobradas/genética , Resposta a Proteínas não Dobradas/fisiologia , Mitocôndrias/metabolismo , Mitocôndrias/genética , Mitocôndrias/patologia , Idoso de 80 Anos ou mais , Resiliência PsicológicaRESUMO
Microglia nodules (HLA-DR+ cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion formation. We show that microglia nodules are associated with more severe MS pathology. Compared to microglia nodules in stroke, those in MS show enhanced expression of genes previously found upregulated in MS lesions. Furthermore, genes associated with lipid metabolism, presence of T and B cells, production of immunoglobulins and cytokines, activation of the complement cascade, and metabolic stress are upregulated in microglia nodules in MS. Compared to stroke, they more frequently phagocytose oxidized phospholipids and possess a more tubular mitochondrial network. Strikingly, in MS, some microglia nodules encapsulate partially demyelinated axons. Taken together, we propose that activation of microglia nodules in MS by cytokines and immunoglobulins, together with phagocytosis of oxidized phospholipids, may lead to a microglia phenotype prone to MS lesion formation.
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Esclerose Múltipla , Doenças do Sistema Nervoso , Acidente Vascular Cerebral , Humanos , Esclerose Múltipla/patologia , Microglia/metabolismo , Doenças do Sistema Nervoso/patologia , Acidente Vascular Cerebral/patologia , Citocinas/metabolismo , Imunoglobulinas/metabolismoRESUMO
Chronic lymphocytic leukemia (CLL) cells are highly dependent on microenvironmental cells and signals. The lymph node (LN) is the critical site of in vivo CLL proliferation and development of resistance to both chemotherapy and targeted agents. We present a new model that incorporates key aspects of the CLL LN, which enables investigation of CLL cells in the context of a protective niche. We describe a three-dimensional (3D) in vitro culture system using ultra-low attachment plates to create spheroids of CLL cells derived from peripheral blood. Starting from CLL:T cell ratios as observed in LN samples, CLL activation was induced by either direct stimulation and/or indirectly via T cells. Compared with two-dimensional cultures, 3D cultures promoted CLL proliferation in a T cell-dependent manner, and enabled expansion for up to 7 weeks, including the formation of follicle-like structures after several weeks of culture. This model enables high-throughput drug screening, of which we describe response to Btk inhibition, venetoclax resistance, and T cell-mediated cytotoxicity as examples. In summary, we present the first LN-mimicking in vitro 3D culture for primary CLL, which enables readouts such as real-time drug screens, kinetic growth assays, and spatial localization. This is the first in vitro CLL system that allows testing of response and resistance to venetoclax and Bruton's tyrosine kinase inhibitors in the context of the tumor microenvironment, thereby opening up new possibilities for clinically useful applications.
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CRB1 gene mutations can cause early- or late-onset retinitis pigmentosa, Leber congenital amaurosis, or maculopathy. Recapitulating human CRB1 phenotypes in animal models has proven challenging, necessitating the development of alternatives. We generated human induced pluripotent stem cell (iPSC)-derived retinal organoids of patients with retinitis pigmentosa caused by biallelic CRB1 mutations and evaluated them against autologous gene-corrected hiPSCs and hiPSCs from healthy individuals. Patient organoids show decreased levels of CRB1 and NOTCH1 expression at the retinal outer limiting membrane. Proximity ligation assays show that human CRB1 and NOTCH1 can interact via their extracellular domains. CRB1 patient organoids feature increased levels of WDFY1+ vesicles, fewer RAB11A+ recycling endosomes, decreased VPS35 retromer complex components, and more degradative endolysosomal compartments relative to isogenic control organoids. Taken together, our data demonstrate that patient-derived retinal organoids enable modeling of retinal degeneration and highlight the importance of CRB1 in early endosome maturation receptor recycling in the retina.
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Células-Tronco Pluripotentes Induzidas , Degeneração Retiniana , Retinose Pigmentar , Animais , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Retina/metabolismo , Degeneração Retiniana/genética , Retinose Pigmentar/genética , Mutação , Organoides/metabolismo , Proteínas do Olho/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismoRESUMO
OBJECTIVE: Rectangular collimation is a popular method used in intraoral radiography to reduce patient exposure to ionizing radiation. One of the perceived drawbacks of rectangular collimation is the possibility of an increase in cone cut errors ultimately impacting the diagnostic value of the radiographs. Thus, the aim of this study was to explore the frequency of cone cut errors in radiographs taken using a rectangular collimator. MATERIALS AND METHODS: Radiographs taken using PSP plates at Academic Center for Dentistry Amsterdam in the Netherlands by staff and students from January to December 2015 were assessed for cone cut errors. The radiographs were grouped as bitewings, front teeth, inferior premolars and molars, and superior premolars and molars and categorized as no cone cut, cone cut but diagnostically usable, and cone cut but diagnostically not usable. The results were entered into Microsoft Excel and analyzed thereafter. RESULTS: A total of 53,684 radiographs were assessed, 79% had no cone cut errors and consequently 21% had some degree of cone cut. However, the diagnostic value was unaffected in 18% of the radiographs with cone cut. Only 3% of the radiographs were deemed diagnostically unusable due to cone cut. The most common area of cone cut was in the premolar and molar areas while cone cut in the front teeth was least likely to be diagnostically unusable. CONCLUSION: Cone cut from the use of a rectangular collimator does not seem to result in an increase of diagnostically unusable radiographs. Thus, rectangular collimation should be preferred as it decreases the amount of radiation exposure to the patient while producing diagnostically usable radiographs and thus allowing the dental professional to adhere to the ALADA principle and practice radiation stewardship. CLINICAL RELEVANCE: Scientific rationale for the study: rectangular collimation is a method used to reduce patient exposure to ionizing radiation; however, this benefit is negligible if radiographs must be retaken due to cone cut errors that make the radiograph diagnostically unusable. Therefore, the aim of this study was to explore the frequency of cone cut in radiographs taken using a rectangular collimator. PRINCIPAL FINDINGS: cone cut was observed in 21% of the radiographs; however, only 3% of the radiographs were considered diagnostically unusable. PRACTICAL IMPLICATIONS: rectangular collimation does not result in a high number of diagnostically unusable radiographs and should be used to reduce patient exposure to ionizing radiation.
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Exposição à Radiação , Humanos , Doses de Radiação , Radiografia , Países Baixos , Radiografia Dentária/métodosRESUMO
Background: Clostridioides difficile infection (CDI) is a leading cause of health care-associated infection and may result in organ dysfunction, colectomy, and death. Published risk scores to predict severe complications from CDI demonstrate poor performance upon external validation. We hypothesized that building and validating a model using geographically and temporally distinct cohorts would more accurately predict risk for complications from CDI. Methods: We conducted a multicenter retrospective cohort study of adults diagnosed with CDI. After randomly partitioning the data into training and validation sets, we developed and compared 3 machine learning algorithms (lasso regression, random forest, stacked ensemble) with 10-fold cross-validation to predict disease-related complications (intensive care unit admission, colectomy, or death attributable to CDI) within 30 days of diagnosis. Model performance was assessed using the area under the receiver operating curve (AUC). Results: A total of 3646 patients with CDI were included, of whom 217 (6%) had complications. All 3 models performed well (AUC, 0.88-0.89). Variables of importance were similar across models, including albumin, bicarbonate, change in creatinine, non-CDI-related intensive care unit admission, and concomitant non-CDI antibiotics. Sensitivity analyses indicated that model performance was robust even when varying derivation cohort inclusion and CDI testing approach. However, race was an important modifier, with models showing worse performance in non-White patients. Conclusions: Using a large heterogeneous population of patients, we developed and validated a prediction model that estimates risk for complications from CDI with good accuracy. Future studies should aim to reduce the disparity in model accuracy between White and non-White patients and to improve performance overall.
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T-cell dysregulation in chronic lymphocytic leukemia (CLL) associates with low response rates to autologous T cell-based therapies. How CLL affects antigen-specific T-cell responses remains largely unknown. We investigated (epi)genetic and functional consequences of antigen-specific T-cell responses in presence of CLL in vitro and in an adoptive-transfer murine model. Already at steady-state, antigen-experienced patient-derived T cells were skewed towards short-lived effector cells (SLEC) at the expense of memory-precursor effector cells (MPEC). Stimulation of these T cells in vitro showed rapid induction of effector genes and suppression of key memory transcription factors only in presence of CLL cells, indicating epigenetic regulation. This was investigated in vivo by following antigen-specific responses of naïve OT-I CD8+ cells to mCMV-OVA in presence/absence of TCL1 B-cell leukemia. Presence of leukemia resulted in increased SLEC formation, with disturbed inflammatory cytokine production. Chromatin and transcriptome profiling revealed strong epigenetic modifications, leading to activation of an effector and silencing of a memory profile through presence of CLL cells. Secondary challenge in vivo confirmed dysfunctional memory responses by antigen-experienced OT-I cells generated in presence of CLL. Altogether, we show that presence of CLL induces a short-lived effector phenotype and impaired memory responses by epigenetic reprogramming during primary responses.
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Leucemia Linfocítica Crônica de Células B , Camundongos , Animais , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/terapia , Epigênese Genética , Linfócitos T CD8-Positivos , Antígenos , Fatores de Transcrição/genéticaRESUMO
The human brain is populated by perivascular T cells with a tissue-resident memory T (TRM)-cell phenotype, which in multiple sclerosis (MS) associate with lesions. We investigated the transcriptional and functional profile of freshly isolated T cells from white and gray matter. RNA sequencing of CD8+ and CD4+ CD69+ T cells revealed TRM-cell signatures. Notably, gene expression hardly differed between lesional and normal-appearing white matter T cells in MS brains. Genes up-regulated in brain TRM cells were MS4A1 (CD20) and SPP1 (osteopontin, OPN). OPN is also abundantly expressed by microglia and has been shown to inhibit T cell activity. In line with their parenchymal localization and the increased presence of OPN in active MS lesions, we noticed a reduced production of inflammatory cytokines IL-2, TNF, and IFNγ by lesion-derived CD8+ and CD4+ T cells ex vivo. Our study reports traits of brain TRM cells and reveals their tight control in MS lesions.
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Early data suggested that CC-115, a clinical molecule, already known to inhibit the mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK) may have additional targets beyond TORK and DNA-PK. Therefore, we aimed to identify such target(s) and investigate a potential therapeutic applicability. Functional profiling of 141 cancer cell lines revealed inhibition of kinase suppressor of morphogenesis in genitalia 1 (SMG1), a key regulator of the RNA degradation mechanism nonsense-mediated mRNA decay (NMD), as an additional target of CC-115. CC-115 treatment showed a dose-dependent increase of SMG1-mediated NMD transcripts. A subset of cell lines, including multiple myeloma (MM) cell lines sensitive to the endoplasmic reticulum stress-inducing compound thapsigargin, were highly susceptible to SMG1 inhibition. CC-115 caused the induction of UPR transcripts and cell death by mitochondrial apoptosis, requiring the presence of BAX/BAK and caspase activity. Superior antitumor activity of CC-115 over TORK inhibitors in primary human MM cells and three xenograft mouse models appeared to be via inhibition of SMG1. Our data support further development of SMG1 inhibitors as possible therapeutics in MM.
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Mieloma Múltiplo , Degradação do RNAm Mediada por Códon sem Sentido , Animais , Humanos , Camundongos , Linhagem Celular , DNA/metabolismo , Mamíferos/genética , Mamíferos/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Degradação do RNAm Mediada por Códon sem Sentido/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
AIMS: CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-tumour necrosis factor receptor associated factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice. METHOD AND RESULTS: Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe-/- background were generated (CD40wt and CD40mac-/-, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40mac-/- compared to CD40wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac-/- atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses. Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206+CD209b- macrophages in the atherosclerotic aorta of CD40mac-/- compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40mac-/- mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1, and Tns1). CONCLUSIONS: We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.
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Aterosclerose , Placa Aterosclerótica , Animais , Camundongos , Aterosclerose/genética , Aterosclerose/prevenção & controle , Aterosclerose/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Transdução de Sinais , Aorta/patologia , Antígenos CD40/genéticaRESUMO
Delineating the origins and properties of antibodies elicited by SARS-CoV-2 infection and vaccination is critical for understanding their benefits and potential shortcomings. Therefore, we investigate the SARS-CoV-2 spike (S)-reactive B cell repertoire in unexposed individuals by flow cytometry and single-cell sequencing. We show that â¼82% of SARS-CoV-2 S-reactive B cells harbor a naive phenotype, which represents an unusually high fraction of total human naive B cells (â¼0.1%). Approximately 10% of these naive S-reactive B cells share an IGHV1-69/IGKV3-11 B cell receptor pairing, an enrichment of 18-fold compared to the complete naive repertoire. Following SARS-CoV-2 infection, we report an average 37-fold enrichment of IGHV1-69/IGKV3-11 B cell receptor pairing in the S-reactive memory B cells compared to the unselected memory repertoire. This class of B cells targets a previously undefined non-neutralizing epitope on the S2 subunit that becomes exposed on S proteins used in approved vaccines when they transition away from the native pre-fusion state because of instability. These findings can help guide the improvement of SARS-CoV-2 vaccines.
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COVID-19 , SARS-CoV-2 , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , Epitopos , Humanos , Isotipos de Imunoglobulinas , Receptores de Antígenos de Linfócitos B , Glicoproteína da Espícula de CoronavírusRESUMO
Background Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the currently available biomarkers have limited diagnostic value in long-term childhood cancer survivors. This study sought to identify diagnostic plasma biomarkers for ACMP in childhood cancer survivors. Methods and Results We measured 275 plasma proteins in 28 ACMP cases with left ventricular ejection fraction <45%, 29 anthracycline-treated controls with left ventricular ejection fraction ≥53% matched on sex, time after cancer, and anthracycline dose, and 29 patients with genetically determined dilated cardiomyopathy with left ventricular ejection fraction <45%. Multivariable linear regression was used to identify differentially expressed proteins. Elastic net model, including clinical characteristics, was used to assess discrimination of proteins diagnostic for ACMP. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the inflammatory markers CCL19 (C-C motif chemokine ligands 19) and CCL20, PSPD (pulmonary surfactant protein-D), and PTN (pleiotrophin) were significantly upregulated in ACMP compared with controls. An elastic net model selected 45 proteins, including NT-proBNP, CCL19, CCL20 and PSPD, but not PTN, that discriminated ACMP cases from controls with an area under the receiver operating characteristic curve (AUC) of 0.78. This model was not superior to a model including NT-proBNP and clinical characteristics (AUC=0.75; P=0.766). However, when excluding 8 ACMP cases with heart failure, the full model was superior to that including only NT-proBNP and clinical characteristics (AUC=0.75 versus AUC=0.50; P=0.022). The same 45 proteins also showed good discrimination between dilated cardiomyopathy and controls (AUC=0.89), underscoring their association with cardiomyopathy. Conclusions We identified 3 specific inflammatory proteins as candidate plasma biomarkers for ACMP in long-term childhood cancer survivors and demonstrated protein overlap with dilated cardiomyopathy.
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Sobreviventes de Câncer , Cardiomiopatias , Cardiomiopatia Dilatada , Neoplasias , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Biomarcadores , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Estudos de Casos e Controles , Criança , Humanos , Peptídeo Natriurético Encefálico , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos , Volume Sistólico , Função Ventricular EsquerdaRESUMO
BACKGROUND: Childhood fractures can have a significant impact on the daily lives of families affecting children's normal activities and parent's work. Wrist fractures are the most common childhood fracture. The more serious wrist fractures, that can look visibly bent, are often treated with surgery to realign the bones; but this may not be necessary as bent bones straighten in growing children. The children's radius acute fracture fixation trial (CRAFFT) is a multicentre randomised trial of surgery versus a cast without surgery for displaced wrist fractures. Little is known about how families experience these wrist fractures and how they manage treatment uncertainty. This study aimed to understand families' experience of this injury and what it is like to be asked to include their child in a clinical trial. METHODS: Nineteen families (13 mothers, 7 fathers, 2 children) from across the UK participated in telephone interviews. Interviews were audio recorded, transcribed and analysed using reflexive thematic analysis. RESULTS: Our findings highlight parents' desire to be a good parent through the overarching theme "protecting my injured child". To protect their child after injury, parents endeavoured to make the right decisions about treatment and provide comfort to their child but they experienced ongoing worry about their child's recovery. Our findings show that parents felt responsible for the decision about their child's treatment and their child's recovery. They also reveal the extent to which parents worried about the look of their child's wrist and their need for reassurance that the wrist was healing. CONCLUSION: Our findings show that protecting their child after injury can be challenging for parents who need support to make decisions about treatment and confidently facilitate their child's recovery. They also highlight the importance of providing information about treatments, acknowledging parents' concerns and their desire to do the right thing for their child, reassuring parents that their child's wrist will heal and ensuring parents understand what to expect as their child recovers.
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Fraturas do Rádio , Criança , Emoções , Feminino , Humanos , Mães , Pais , Pesquisa Qualitativa , Fraturas do Rádio/terapiaRESUMO
BACKGROUND: The aim of this study was to determine the accuracy of clinical and radiographic measurements of infrabony periodontal defects. METHODS: The MEDLINE-Pubmed and Cochrane-CENTRAL electronic databases were searched from initiation to May 2020. The inclusion criteria were clinical trials, human subjects with at least one infrabony defect, measurements of clinical attachment level (CAL), radiographic bone level (rBL), and intraoperative bone level (iBL) used as the reference standard. RESULTS: In total, 11 studies including 17 comparisons were included in this meta-analysis. All 17 comparisons showed that the values of the CAL and rBL measurements underestimated the iBL values. For CAL, the analysis showed a significant difference of means of -1.22 (P < .00001; 95%CI: [-1.49; -0.95]) and for rBL -1.10 (P < .00001; 95%CI: [-1.34; -0.85]). No significant DiffM were observed between the CAL and rBL measurements (DiffM -0.05; Pâ¯=â¯.76; 95%CI: [-0.39; 0.28]). CONCLUSION: The results of this systematic review and meta-analysis show that both clinical and radiographic measurements substantially underestimate the bone level when compared to intraoperative level measurements. However, there was no significant difference in the results between the clinical attachment level measurements and the radiographic observation.
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Perda do Osso Alveolar , Testes Diagnósticos de Rotina , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/cirurgia , Regeneração Tecidual Guiada Periodontal/métodos , HumanosRESUMO
Legionella is an opportunistic premise plumbing pathogen and causative agent of a severe pneumonia called Legionnaires' Disease (LD). Cases of LD have been on the rise in the U.S. and globally. Although Legionella was first identified 45 years ago, it remains an 'emerging pathogen." Legionella is part of the normal ecology of a public water system and is frequently detected in regulatory-compliant drinking water. Drinking water utilities, regulators and public health alike are increasingly required to have a productive understanding of the evolving issues and complex discussions of the contribution of the public water utility to Legionella exposure and LD risk. This review provides a brief overview of scientific considerations important for understanding this complex topic, a review of findings from investigations of public water and LD, including data gaps, and recommendations for professionals interested in investigating public water utilities. Although the current literature is inconclusive in identifying a public water utility as a sole source of an LD outbreak, the evidence is clear that minimizing growth of Legionella in public water utilities through proper maintenance and sustained disinfectant residuals, throughout all sections of the water utility, will lead to a less conducive environment for growth of the bacteria in the system and the buildings they serve.
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Água Potável , Legionella pneumophila , Legionella , Doença dos Legionários , Surtos de Doenças/prevenção & controle , Água Potável/microbiologia , Humanos , Doença dos Legionários/epidemiologia , Engenharia Sanitária , Microbiologia da ÁguaRESUMO
PURPOSE: Late radiation toxicity is a major dose-limiting factor in curative cancer radiation therapy. Previous studies identified several risk factors for late radiation toxicity, including both dose-volume factors and genetic predisposition. Herein, we investigated the contribution of genetic predisposition, particularly compared with dose-volume factors, to the risk of late radiation toxicity in patients treated with highly conformal radiation therapy. METHODS AND MATERIALS: We included 179 patients with prostate cancer who underwent treatment with curative external beam radiation therapy between 2009 and 2013. Toxicity was graded according to the Common Terminology Criteria for Adverse Events version 4.0. Transcriptional responsiveness of homologous recombination repair genes and γ-H2AX foci decay ratios (FDRs) were determined in ex vivo irradiated lymphocytes in a previous analysis. Dose-volume parameters were retrieved by delineating the organs at risk (OARs) on CT planning images. Associations between risk factors and grade ≥2 urinary and bowel late radiation toxicities were assessed using univariable and multivariable logistic regression analyses. The analyses were performed using the highest toxicity grade recorded during the follow-up per patient. RESULTS: The median follow-up period was 31 months. One hundred and one patients (56%) developed grade ≥2 late radiation toxicity. Cumulative rates for urinary and bowel grade ≥2 late toxicities were 46% and 17%, respectively. In the multivariable analysis, factors significantly associated with grade ≥2 late toxicity were transurethral resection of the prostate (P = .013), γ-H2AX FDR <3.41 (P = .008), and rectum V70 >11.52% (P = .017). CONCLUSIONS: Our results suggest that impaired DNA double-strand break repair in lymphocytes, as quantified by γ-H2AX FDR, is the most critical determining factor of late radiation toxicity. The limited influence of dose-volume parameters could be due to the use of increasingly conformal techniques, leading to improved dose-volume parameters of the organs at risk.