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3.
Stomatologiia (Mosk) ; 102(2): 34-39, 2023.
Artigo em Russo | MEDLINE | ID: mdl-37144766

RESUMO

OBJECTIVE: The study level of patient satisfaction with interaction with doctors of various specialties in the municipal dental clinic. MATERIAL AND METHODS: 596 patients who received dental care at the Severodvinsk Dental Polyclinic State Autonomous Healthcare Institution participated in the cross-sectional study. Satisfaction was studied across 10 domains using a questionnaire. The average values of the scores obtained for different specialties of the doctor were compared using a variance analysis for each of the domains. The relationship between patient satisfaction and factor characteristics - specialty and age of the doctor, gender and age of the patient or legal representative was evaluated using multivariate linear regression analysis with the calculation of regression coefficients and 95% confidence intervals (CI). RESULTS: At least a good level of satisfaction was found in all 10 domains for doctors of all specialties. The age of the doctor was inversely related to the domains "Communication on equal terms" and "Active listening". Respondents were statistically significantly less satisfied with interaction with dental therapists, dental surgeons and pediatric dentists in all domains compared to interaction with orthodontists, except for the domain "Prognosis". Satisfaction did not depend on the gender and age of the patients. CONCLUSIONS: Lower satisfaction in different domains can be explained by limited time for patient admission and/or insufficient training of dentists in terms of communication with patients. The assessment of satisfaction with the doctor's appointment is an important indicator for determining the ways of developing the education of specialists and the organization of medical care in dentistry.


Assuntos
Odontólogos , Satisfação do Paciente , Criança , Humanos , Estudos Transversais , Inquéritos e Questionários , Satisfação Pessoal
4.
Acta Paediatr ; 112(7): 1548-1554, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37038729

RESUMO

AIM: To determine the effects of obesity in childhood on SARS-CoV-2 infection. METHODS: A population-based, cross-sectional study combining the Israeli Growth Survey and COVID-19 data for children with at least one SARS-CoV-2 test from 16 February 2020 to 20 December 2021. Overweight and obesity status were based on body mass index and the Center for Disease Control criteria. Multivariate logistics regression was performed to validate reliability for weight categories at the age of approximately 6 years compared with weights at approximately 12 years. RESULTS: A total of 444 868 records for children with an overall positivity rate of 22% were studied. The mean age was 9.5 years. The odds ratios of children with obesity or overweight after controlling for sex at 6 years to test positive were 1.07-1.12 and 1.06-1.08 (depending on the model), respectively, compared to those with healthy range body mass index. CONCLUSION: Excess weight appears to increase the risk of SARS-CoV-2 infection. This finding should be considered for public health planning. For example, children with overweight and obesity should be prioritised for vaccination. Excess weight in childhood can be harmful at a young age and not only for long-term health.


Assuntos
COVID-19 , Obesidade Infantil , Humanos , Criança , Sobrepeso/complicações , Sobrepeso/epidemiologia , SARS-CoV-2 , Obesidade Infantil/epidemiologia , COVID-19/epidemiologia , Estudos Transversais , Reprodutibilidade dos Testes , Aumento de Peso
5.
Int J Radiat Oncol Biol Phys ; 115(4): 1012-1013, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36822778
6.
J Occup Environ Hyg ; 18(10-11): 522-531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34491879

RESUMO

The objective of this paper was to estimate the inter-rater reliability of expert assessments of occupational exposures. An inter-rater reliability sub-study was conducted within a population-based case-control study of postmenopausal breast cancer. Detailed information on lifetime occupational histories was obtained from participants and two industrial hygienists assigned exposures to 185 jobs using a checklist of 293 agents. Experts rated exposure for each job-agent combination according to exposure status (unexposed/exposed), confidence that the exposure occurred (possible/probable/definite), intensity (low/medium/high), and frequency (% time per week). The statistical unit of observation was each job-agent assessment (185 jobs × 293 agents = 54,205 assessments per expert). Crude agreement, Gwet AC1/2 statistics, and Cohen's Kappa were used to estimate inter-rater agreement for confidence and intensity; for frequency, the intra-class correlation coefficient (ICC) was used. The majority of job-agent combinations were evaluated by the two experts to be not exposed (crude agreement >98% of decisions). The degree of agreement between the experts for the confidence of exposure status was Gwet AC1/2 = 0.99 (95% CI: 0.99-0.99), and for intensity, a Gwet AC2 = 0.99 (95% CI: 0.99-0.99). For frequency, an ICC of 0.31 (95% CI: 0.26-0.35) was found. A sub-analysis restricted to job-agent combinations for which the two experts agreed on exposure status revealed a moderate agreement for confidence of exposure (Gwet AC2 = 0.66) and high agreement for intensity (Gwet AC2 = 0.96). For frequency, the ICC was 0.52 (95% CI: 0.47-0.57). A high level of inter-rater agreement was found for identifying exposures and for coding intensity, but agreement was lower for the coding of frequency of exposure.


Assuntos
Neoplasias da Mama , Exposição Ocupacional , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Variações Dependentes do Observador , Ocupações , Reprodutibilidade dos Testes
7.
J Dent Res ; 100(3): 318-325, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33078669

RESUMO

The presence of periodontal diseases (PDs) often strongly correlates with other severe chronic inflammatory conditions, including cardiovascular disease, diabetes, and arthritis. However, the mechanisms through which these diseases interact are unclear. In PD, tissue and bone destruction in the mouth is driven by elevated recruitment of polymorphonuclear neutrophils (PMNs), which are primed and recruited from the circulation to sites of inflammation. We predicted that systemic effects on PMN mobilization or priming could account for the interaction between PD and other inflammatory conditions. We tested this using a mouse model of ligature-induced PD and found elevated PMN counts specifically in bone marrow, supporting a systemic effect of periodontal tissue inflammation on PMN production. In contrast, mice with induced peritonitis had elevated PMN counts in the blood, peritoneum, and colon. These elevated counts were further significantly increased when acute peritonitis was induced after ligature-induced PD in mice, revealing a synergistic effect of multiple inflammatory events on PMN levels. Flow cytometric analysis of CD marker expression revealed enhanced priming of PMNs from mice with both PD and peritonitis compared to mice with peritonitis alone. Thus, systemic factors associated with PD produce hyperinflammatory PMN responses during a secondary infection. To analyze this systemic effect in humans, we induced gingival inflammation in volunteers and also found significantly increased activation of blood PMNs in response to ex vivo stimulation, which reverted to normal following resolution of gingivitis. Together, these results demonstrate that periodontal tissue inflammation has systemic effects that predispose toward an exacerbated innate immune response. This indicates that peripheral PMNs can respond synergistically to simultaneous and remote inflammatory triggers and therefore contribute to the interaction between PD and other inflammatory conditions. This suggests larger implications of PD beyond oral health and reveals potential new approaches for treating systemic inflammatory diseases that interact with PD.


Assuntos
Gengivite , Peritonite , Animais , Imunidade Inata , Inflamação , Neutrófilos
8.
Front Public Health ; 8: 605133, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363097

RESUMO

"General-purpose cohorts" in epidemiology and public health are designed to cover a broad scope of determinants and outcomes, in order to answer several research questions, including those not defined at study inception. In this context, the general objective of the CONSTANCES project is to set up a large population-based cohort that will contribute to the development of epidemiological research by hosting ancillary projects on a wide range of scientific domains, and to provide public health information. CONSTANCES was designed as a randomly selected sample of French adults aged 18-69 years at study inception; 202,045 subjects were included over an 8-year period. At inclusion, the selected participants are invited to attend one of the 24 participating Health Prevention Centers (HPCs) for a comprehensive health examination. The follow-up includes a yearly self-administered questionnaire, and a periodic visit to an HPC. Procedures have been developed to use the national healthcare databases to allow identification and validation of diseases over the follow-up. The biological collection (serum, lithium heparinized plasma, EDTA plasma, urine and buffy coat) began gradually in June 2018. At the end of the inclusions, specimens from 83,000 donors will have been collected. Specimens are collected according to a standardized protocol, identical in all recruitment centers. All operations relating to bio-banking have been entrusted by Inserm to the Integrated Biobank of Luxembourg (IBBL). A quality management system has been put in place. Particular attention has been paid to the traceability of all operations. The nature of the biological samples stored has been deliberately limited due to the economic and organizational constraints of the inclusion centers. Some research works may require specific collection conditions, and can be developed on request for a limited number of subjects and in specially trained centers. The biological specimens that are collected will allow for a large spectrum of biomarkers studies and genetic and epigenetic markers through candidate or agnostic approaches. By linking the extensive data on personal, lifestyle, environmental, occupational and social factors with the biomarker data, the CONSTANCES cohort offers the opportunity to study the interplays between these factors using an integrative approach and state-of-the-art methods.


Assuntos
Bancos de Espécimes Biológicos , Adolescente , Adulto , Idoso , Estudos de Coortes , Bases de Dados Factuais , Humanos , Luxemburgo , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
9.
Compr Psychiatry ; 102: 152203, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32927368

RESUMO

BACKGROUND: The role of alcohol, tobacco and cannabis use in social differences in terms of depression is poorly understood. METHOD: We have applied mediation and moderated-mediation models stratified by gender to a population-based sample (N = 37,192) of French men and women from the Constances cohort with baseline and follow-up measures of depressive states. We have examined whether socioeconomic status (SES, measured by education and income) differences in the prevalence of depressive states may be explained by both differences in prevalence of substance use according to SES (mediating effects) and differential effects of substance use on depressive state according to SES (moderating effects). RESULTS: In the mediation models, substance use only explained 5.3% and 2.4% of the association between low education and depressive state in men and women respectively, and was not a significant mediator for income. Moderated mediation models showed robust moderation effects of education and income in both men and women. The association of tobacco use with depressive symptoms, which was the only substance for which a mediation effect remained and for which the moderation effect of SES was the strongest, was significantly higher in participants with low SES. LIMITATIONS: The partially cross-sectional nature of the data restricts the possibility of drawing causality with regards to associations between SES and substance use. CONCLUSION: Targeting substance use, particularly tobacco, can especially reduce depression risk in individuals of low SES.


Assuntos
Depressão , Transtornos Relacionados ao Uso de Substâncias , Estudos de Coortes , Estudos Transversais , Depressão/diagnóstico , Depressão/epidemiologia , Feminino , Humanos , Masculino , Classe Social , Transtornos Relacionados ao Uso de Substâncias/epidemiologia
10.
Bioact Mater ; 5(3): 644-658, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32420515

RESUMO

Calcium phosphate cements are of great interest for researchers and their applications in medical practice expanded. Nevertheless, they have a number of drawbacks including the insufficient level of mechanical properties and low degradation rate. Struvite (MgNH4PO4) -based cements, which grew in popularity in recent years, despite their neutral pH and acceptable mechanical performance, release undesirable NH4 + ions during their resorption. This issue could be avoided by replacement of ammonia ions in the cement liquid with sodium, however, such cements have a pH values of 9-10, leading to cytotoxicity. Thus, the main goal of this investigation is to optimize the composition of cements to achieve the combination of desirable properties: neutral pH, sufficient mechanical properties, and the absence of cytotoxicity, applying Na2HPO4-based cement liquid. For this purpose, cement powders precursors in the CaO-MgO-P2O5 system were synthesized by one-pot process in a wide composition range, and their properties were investigated. The optimal performance was observed for the cements with (Ca + Mg)/P ratio of 1.67, which are characterized by newberyite phase formation during setting reaction, pH values close to 7, sufficient compressive strength up to 22 ± 3 MPa (for 20 mol.% of Mg), dense microstructure and adequate matrix properties of the surface. This set of features make those materials promising candidates for medical applications.

11.
Disabil Rehabil Assist Technol ; 15(2): 225-237, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30729844

RESUMO

Purpose: To provide empirical evidence on learning barriers and facilitators in instructional science and engineering laboratory settings from a national survey on students with physical disabilities (SwD-P).Methods: A nationwide self-report survey, the Full Participation Science and Engineering Accessibility (FPSEA), was disseminated online via Qualtrics. Approximately 1200 organizations and universities across the United States were contacted through purposive sampling. Descriptive statistics were primarily used for the analysis of the results.Results: Survey findings reveal that students experience a wide range of limitations to full participation in the laboratory, from entering the laboratory (25%) to being given passive roles (50%). Additionally, while 66% of respondents indicated that instructors were willing to help SwD-P participate in science and engineering (S&E) laboratories, 16.8% were not willing to do so, and 47% SwD-P felt that practices were not in place to provide accommodations. The survey also reveals a range of facilitators such as elevators, ramps, accessible course materials and peer assistance. Most respondents (74%) also indicated that peers were helpful in completing laboratory tasks.Conclusion: This survey provides empirical evidence that was previously voiced through non-empirical information in the literature. Participants cited barriers such as inappropriate accommodations and instructors' negative viewpoints, as well as gaining access to facilities even after the enactment of the Americans with Disabilities Act (ADA). These findings suggest that while ADA has lessened some barriers to SwD-P, barriers remain in using the laboratory space. The FPSEA survey fills the gap in finding barriers and facilitators to using S&E laboratories from the SwD-P's perspective.Implications for RehabiliationBarriers students with disabilities encounter in science and engineering (S&E) laboratory environments remain unclear.The FPSEA survey fills the gap in finding barriers and facilitators to using S&E laboratories from the SwD-P's perspective.The FPSEA survey allows former and current SwD-P to share their experiences using a postsecondary S&E instructional laboratory.


Assuntos
Acessibilidade Arquitetônica , Pessoas com Deficiência , Engenharia/educação , Laboratórios , Estudantes , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Estados Unidos , Universidades , Adulto Jovem
12.
J Nutr Health Aging ; 23(5): 466-473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31021364

RESUMO

OBJECTIVES: To assess the relationship between changes of frailty status and intervening hospitalizations, using information of the GAZEL cohort, matched with the data of the French National Health Data System. DESIGN: Observational cohort study. PARTICIPANTS: Community-dwelling adults of the GAZEL cohort (n = 12145; aged between 58 and 73 years in 2012). MEASUREMENTS: Frailty was determined with the Strawbridge questionnaire in 2012, 2013 and 2014. Data regarding hospitalizations (notably their number, length of stay, emergency department use, and main diagnosis) were collected from the French National Health Data System. The relationship between intervening hospitalizations and changes of frailty status over time was assessed with multivariate Markov models. RESULTS: The prevalence of frailty was 14% in 2012 and 2013 and 17% in 2014. A total of 2715 changes in frailty status were observed from 2012 to 2014. At least one hospitalization was recorded for 1453 people (12%) between the 2012 and 2013 questionnaires, and 1472 (13%) between the 2013 and 2014 questionnaires. No association was found between intervening hospitalizations and changes of frailty status (aHR 1.14 [0.97-1.35] for robust to frail transition and aHR 0.89 [0.73-1.08] for frail to robust transition). However, repeated hospitalizations, hospitalizations after emergency department use, surgery and several diagnosis groups were significantly associated with transitions towards frailty or its recovery. CONCLUSION: Hospitalizations encompass a wide range of clinical situations, some of them being associated with incident frailty. An early recognition of these situations could help to better prevent and manage frailty in the early old age.


Assuntos
Idoso Fragilizado/estatística & dados numéricos , Fragilidade/complicações , Hospitalização/estatística & dados numéricos , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino
13.
Disabil Rehabil Assist Technol ; 14(7): 692-709, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30317937

RESUMO

Purpose: The purpose of this study is to address the development of the Full Participation Science and Engineering Accessibility (FPSEA) self-report survey that gathers experiences from students with physical disabilities (SwD-P) using a postsecondary laboratory and to evaluate the survey's stability. Methods: Survey items were generated from an extensive literature review and recommendations articulated by experts. Think-aloud sessions and content validity index (CVI) were used to determine survey content validity and help finalize survey items. Individuals with physical disabilities (n = 20) who have taken a postsecondary science or engineering laboratory course completed the survey and took it again 10-14 days apart. The test-retest reliability was assessed using Spearman Rho coefficients for Likert-scale items, Chi-square and Fisher's exact test for the dichotomous items. Missing data completely at random (MCAR) test was computed before reliability data analysis. Results: Each sub-item passed the MCAR test, indicating that the data are missing completely at random and can be imputed to perform the analysis. Reliability analysis was completed on 20 individuals. The FPSEA had good content reliability: the item-level CVI of items kept ranged from 0.86 to 1. The scale-level CVI was 0.94. Stability was demonstrated with adequate Spearman correlation ranged from 0.56 to 0.86. Conclusions: No previous survey had been developed linking SwD-P and the postsecondary science and engineering (S&E) laboratory setting prior to this work. Overall, FPSEA is reliable and stable for reporting the barriers and facilitators to use S&E laboratories from the SwD-P's perspective. Implications for rehabilitation The barriers students with disabilities encounter in S&E laboratory environments are largely unknown. The FPSEA survey may help identify barriers and facilitators to using S&E laboratories for SwD-P. The FPSEA Survey allows former and current SwD-P to share their experiences using a postsecondary S&E instructional laboratory.


Assuntos
Acessibilidade Arquitetônica , Pessoas com Deficiência/psicologia , Engenharia/educação , Laboratórios , Ciência/educação , Humanos , Psicometria , Reprodutibilidade dos Testes , Inquéritos e Questionários
14.
Eur J Neurol ; 26(5): 786-793, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30575234

RESUMO

BACKGROUND AND PURPOSE: Neuropsychological testing plays a key role in various clinical contexts. Even though a substantial number of adults suffer neurological disorders such as early-onset dementia, stroke, traumatic brain injury or multiple sclerosis, most normative data do not include persons below 65. The aim of this study was to produce updated norms for the Mini-Mental State Examination, the Free and Cued Selective Reminding Test, the Trail Making Test, verbal fluency tasks and the Digit Symbol Substitution Test for middle-aged and older adults. METHODS: The sample consisted of 51 879 participants aged 45-70 years from the CONSTANCES study. Norms are presented in percentiles stratified on age, education and gender. RESULTS: The results illustrated the effect of age in all tests considered. For tests involving speed processing, the impact of age was observed including in tight age range categories (5 years). The results also showed the well-known effect of education and an effect of gender in tests involving verbal memory and speed processing. CONCLUSIONS: The norms provided allow the variability of the cognitive performances of middle-aged to older populations to be understood, with a high precision in age categories. The tests considered are broadly used in neuropsychological practice and should be helpful in a variety of clinical contexts.


Assuntos
Testes Neuropsicológicos/normas , Fatores Etários , Idoso , Estudos de Coortes , Sinais (Psicologia) , Escolaridade , Feminino , França , Humanos , Masculino , Memória , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Desempenho Psicomotor , Tempo de Reação , Valores de Referência , Fatores Sexuais , Teste de Sequência Alfanumérica , Comportamento Verbal
15.
J Am Med Dir Assoc ; 19(11): 967-973.e3, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30172683

RESUMO

OBJECTIVES: High-risk prescribing can have deleterious effects on the health of older people. This study aimed to assess the role of inappropriate prescribing on changes in frailty status over 3 years of follow-up. DESIGN, SETTING: This is a prospective observational study nested in the GAZEL cohort. PARTICIPANTS: The study sample included 12,405 community-dwelling people aged 58 to 73 in 2012, and followed for 3 years. MEASUREMENT: Polypharmacy and potentially inappropriate medications (PIMs) were assessed from reimbursement data by the French National Health Insurance. Frailty was evaluated each year with the Strawbridge questionnaire. PIMs were defined according to the Laroche list plus additional criteria dealing with inappropriate prolonged use of medications. The relationship between PIMs and changes in frailty status (incident frailty and recovery) was analyzed with Markov multistate modeling. RESULTS: The prevalence of frailty increased from 14% in 2012 to 17% in 2014, whereas the frequency of PIMs was 29% in 2012 and 23% in 2014. Polypharmacy (5-9 drugs: aHR 1.31, 95% CI 1.14-1.50; and 10 drugs or more: aHR 1.57, 95% CI 1.28-1.92) and potentially inappropriate use of nonsteroidal anti-inflammatory drugs (aHR 1.33, 95% CI 1.04-1.71) were significantly associated with incident frailty, when the presence of at least 1 PIM presented a small association with the risk of becoming frail (aHR 1.15, 95% CI 1.01-1.32). CONCLUSIONS/IMPLICATIONS: This study brings new elements to our knowledge regarding the association between inappropriate prescribing and frailty in older adults, which support research development to alert on inappropriate prescribing and to improve drug prescribing among old people, especially with polypharmacy.


Assuntos
Fragilidade/epidemiologia , Prescrição Inadequada/estatística & dados numéricos , Polimedicação , Idoso , Estudos de Coortes , França/epidemiologia , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Lista de Medicamentos Potencialmente Inapropriados , Prevalência
17.
Clin Exp Allergy ; 48(8): 1025-1034, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29758103

RESUMO

BACKGROUND: The prevalence of sesame food allergy (SFA) has increased over recent years, with the potential of anaphylactic reactions upon exposure. Oral food challenge (OFC) remains the diagnostic standard, yet its implementation may be risky. Commercial skin prick tests (SPT) have a low sensitivity. Investigation of alternate diagnostic methods is warranted. OBJECTIVE: To evaluate the utility of SPT and the basophil activation test (BAT) for SFA diagnosis. METHODS: Eighty-two patients with suspected SFA completed an open OFC to sesame or reported a recent confirmed reaction. Patients were administered skin prick tests (SPT) with commercial sesame seed extract (CSSE) and a high protein concentration sesame extract (HPSE) (100 mg/mL protein). Whole blood from 80 patients was stimulated with sesame seed extract (40-10 000 ng/mL protein) for BAT), assessing CD63 and CD203c as activation markers. RESULTS: Sixty patients (73%) had IgE-mediated reactions to sesame, and 22 (27%) did not react. Receiver operating characteristic (ROC) curve analysis demonstrated an area under the curve (AUC) of 0.87 for HPSE-SPT and 0.66 for CSSE-SPT. At 1000 ng/mL of sesame protein, induction of CD63 and CD203c was weakly but significantly associated with OFC eliciting dose by rank (Spearman's rho = -.42 (P < .01) and -.35 (P < .05) for CD63 and CD203c, respectively). By ROC analysis, the AUC was 0.86 for CD63 and was 0.81 for CD203c sesame-induced basophil expression. Using HPSE-SPT as a first test to definitively diagnose (n = 24) or rule-out (n = 5) SFA and BAT as a second test to diagnose the remainder results in the correct classification of 73 of 80 (91%) patients, leaving one false negative and 4 false positive patients. Two BAT non-responders remain unclassified by this algorithm. CONCLUSIONS & CLINICAL RELEVANCE: While prospective cohort validation is necessary, joint utilization of BAT and SPT with HPSE extract may obviate the need for OFC in most SFA patients.


Assuntos
Alérgenos/imunologia , Basófilos/imunologia , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/imunologia , Sesamum/efeitos adversos , Testes Cutâneos , Teste de Degranulação de Basófilos , Basófilos/metabolismo , Biomarcadores , Feminino , Humanos , Masculino , Fenótipo , Curva ROC , Sensibilidade e Especificidade
18.
Ann Oncol ; 29(4): 872-880, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29360925

RESUMO

Background: Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. Patients and methods: To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. Results: We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Conclusions: Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Metástase Neoplásica , Proteínas Recombinantes de Fusão/genética
19.
JDR Clin Trans Res ; 3(1): 65-75, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-30938653

RESUMO

Polymorphonuclear neutrophils (PMNs) are the primary leukocytes present in the healthy and inflamed oral cavity. While unique PMN activation states have been shown to differentiate health and periodontitis, little is known about the changes in PMN activation states that occur during the transition from periodontal health to gingivitis. The objective of this study was to characterize oral and circulatory PMNs during induction and resolution of experimental gingivitis. Healthy volunteers were recruited to undergo experimental gingivitis. Clinical assessment of pocket depths, bleeding on probing, gingival index, and plaque index, as well as flow cytometric analysis of CD (cluster of differentiation) activation markers on blood and oral PMNs, was performed weekly. All clinical parameters increased significantly during the induction period and returned to baseline levels during the resolution phase. During the induction phase, while oral PMN counts increased, oral PMN activation state based on surface expression of CD63, CD11b, CD16, and CD14 was diminished compared to those seen in health and during the resolution phase. PMNs in circulation during onset showed increased activation based on CD55, CD63, CD11b, and CD66a. Using clinical parameters and oral PMN counts assessed at day 21, we noted 2 unique disease patterns where one-third of subjects displayed an exaggerated influx of oral PMNs with severe inflammation compared to the majority of the population who experienced a moderate level of inflammation and PMN influx. This supports the notion that PMN influx and severe inflammatory changes during gingivitis could identify subjects at risk for the development of severe gingival inflammation and progression toward destructive periodontitis. This study demonstrates that oral PMN activation states are reduced in gingivitis and suggest that only in periodontitis do PMNs become hyperactivated and tissue damaging. Knowledge Transfer Statement: Our article creates a paradigm for future studies of the evolution of essential oral and circulatory biomarkers to identify individuals at risk to develop periodontitis at an early stage of periodontal disease, which is reversible upon proper oral hygiene practices and dental treatments.


Assuntos
Gengivite/imunologia , Boca/imunologia , Ativação de Neutrófilo , Neutrófilos/fisiologia , Adolescente , Adulto , Biofilmes , Biomarcadores , Sangue/imunologia , Índice de Placa Dentária , Feminino , Citometria de Fluxo , Bolsa Gengival , Voluntários Saudáveis , Humanos , Contagem de Leucócitos , Masculino , Modelos Biológicos , Índice Periodontal , Adulto Jovem
20.
J Hosp Infect ; 98(1): 21-28, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28712548

RESUMO

BACKGROUND: The impact of Clostridium difficile infection (CDI) on mortality is controversial. AIM: To assess excess mortality due to CDI in France. METHOD: Two cohorts of patients with CDI and a cohort of matched controls were extracted from a 1% representative sample of subjects covered by the general health insurance system in France (Echantillon Généraliste de Bénéficiaires database, 660,000 patients). The CDI patients were hospitalized with CDI as a principal diagnosis or an associated diagnosis between 2007 and 2014, but not in 2006. Controls were patients hospitalized between 2007 and 2014 but not hospitalized with CDI between 2006 and 2014. The one-year incidence of deaths between 2007 and 2014 was estimated and compared with that of a propensity score (PS)-matched control group with no CDI (two controls per case). The PS was calculated with the following variables: age; sex; Charlson Comorbidity Index score; duration of stay; year of index stay; and main comorbidities. Cox and Poisson models were used to estimate the increased risk of death while adjusting for PS. Sensitivity analyses (timeframe, diarrhoea, recurrent hospitalization for CDI) were used to explore the robustness of the results. FINDINGS: In total, 482 patients who had been infected with C. difficile were matched with 964 controls. A significantly higher risk of death was observed among the subjects with CDI, with a non-adjusted hazard ratio of 1.65 [95% confidence interval (CI) 1.33-2.04] and an adjusted ratio of 1.58 (95% CI 1.27-1.97). The adjusted relative risk of death was 1.78 (95% CI 1.18-2.70]) at 28 days, 1.52 (95% CI 1.17-1.98) at three months, 1.52 (95% CI 1.20-1.93) at six months and 1.64 (95% CI 1.32-2.03) at 12 months. Sensitivity analyses produced similar results; the hazard ratio ranged from 1.53 to 1.86, and was always statistically significant. CONCLUSION: CDI is responsible for excess mortality after taking age, sex, comorbidities and length of hospital stay into account.


Assuntos
Infecções por Clostridium/mortalidade , Mortalidade , Fatores Etários , França/epidemiologia , Humanos , Incidência , Tempo de Internação , Fatores Sexuais , Análise de Sobrevida
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