RESUMO
A previously healthy 1-year-old boy presented with a right lower eyelid abscess. Oral and topical antibiotics were initiated, and the lesion was drained and explored. Despite medical and surgical treatment, the abscess failed to resolve completely and formed again 1 month later. A second incision and drainage procedure was performed, and Candida albicans grew in cultures. Additional workup revealed severe neutropenia with an absolute neutrophil count of 0.18 k/µl (1.19-7.21 k/µl). The abscess resolved after 2 weeks of oral fluconazole. C. albicans eyelid abscess may be the presenting sign of systemic immunodeficiency.
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Abscesso/diagnóstico , Candidíase/diagnóstico , Infecções Oculares Fúngicas/diagnóstico , Doenças Palpebrais/diagnóstico , Neutropenia/diagnóstico , Abscesso/tratamento farmacológico , Abscesso/microbiologia , Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Drenagem , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Doenças Palpebrais/tratamento farmacológico , Doenças Palpebrais/microbiologia , Fluconazol/uso terapêutico , Humanos , Lactente , Masculino , Neutropenia/tratamento farmacológico , Neutropenia/microbiologiaRESUMO
OBJECTIVE: To assess central venous catheter (CVC) harm in pediatric oncology patients, we explored risks for central-line-associated bloodstream infections (CLABSIs) and central-line-associated non-CLABSI complications (CLANCs). DESIGN: Retrospective cohort study. SETTING: Midwestern US pediatric oncology program. PATIENTS: The study cohort comprised 592 pediatric oncology patients seen between 2006 and 2016. METHODS: CLABSIs were defined according to Centers for Disease Control and Prevention (CDC)/National Health Safety Network (NHSN) definitions. CLANCs were classified using a novel definition requiring CVC removal. Patient-level and central-line-level risks were calculated using a negative binomial model to adjust for correlations between total events and line numbers. RESULTS: CVCs were inserted in 62% of patients, with 175,937 total catheter days. The inpatient CLABSI and CLANC rates were 5.8 and 8.5 times higher than outpatient rates. At the patient level, shared risks included acute myeloid leukemia (AML) and age <1 year at diagnosis. At the line level, shared risks included age <1 year at diagnosis, non-mediports, and >1 lumen. AML was a CLABSI-specific risk. CLANC-specific risks included non-brain-tumor diagnosis, younger age at diagnosis or central-line placement, and age <1 year at diagnosis or line placement. Multivariable risks were for CLABSI >1 lumen and for CLANC age <1 year at placement. CONCLUSIONS: Among patients with CVCs, CLABSI and CLANC rates were similar, higher among inpatients than outpatients. For both CLABSIs and CLANCs, infants and patients with AML were at higher risk. In both univariate and multivariate models, lines with >1 lumen were associated with CLABSIs and placement during infancy with CLANCs.
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Bacteriemia , Infecções Relacionadas a Cateter , Cateterismo Venoso Central , Cateteres Venosos Centrais , Neoplasias , Sepse , Criança , Lactente , Humanos , Infecções Relacionadas a Cateter/prevenção & controle , Estudos Retrospectivos , Cateterismo Venoso Central/efeitos adversos , Cateteres Venosos Centrais/efeitos adversos , Neoplasias/complicações , Sepse/etiologia , Bacteriemia/prevenção & controleRESUMO
BACKGROUND: Syphilis screening during pregnancy helps prevent congenital syphilis. The harms associated with false positive (FP) screens and whether screening leads to correct treatments has not been well determined. METHODS: The population included mothers and infants from 75 056 pregnancies. Using laboratory-based criteria we classified initial positive syphilis screens as FP or true positive (TP) and calculated false discovery rates. For mothers and infants we determined treatments, clinical characteristics, and syphilis classifications. RESULTS: There were 221 positive screens: 183 FP and 38 TP. The false discovery rate was 0.83 (95% confidence interval [CI], 0.78-0.88). False discovery rates were similar for traditional 0.83 [95% CI, 0.72-0.94] and reverse algorithms 0.83 (95% CI, 0.77-0.88), and for syphilis Immunoglobin (Ig) G 0.79 (95% CI, 0.71-0.86) and total 0.90 (95% CI, 0.82-0.97) assays. FP screens led to treatment in 2 women and 1 infant. Two high-risk women were not rescreened at delivery and were diagnosed after hospital discharge; 1 infant developed congenital syphilis. Among 15 TP women with new syphilis, the diagnosis was before the late third trimester in 14 (93%). In one-half of these women, there was concern for reinfection, treatment failure, inadequate treatment or follow-up care, or late treatment, and their infants did not achieve an optimal syphilis classification. CONCLUSIONS: Syphilis screening identifies maternal syphilis, but limitations include FP screens, which occasionally lead to unnecessary treatment, inconsistent risk-based rescreening, and among TP mothers failure to optimize care to prevent birth of infants at higher risk for congenital syphilis.
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Complicações Infecciosas na Gravidez , Sífilis Congênita , Sífilis , Feminino , Humanos , Lactente , Programas de Rastreamento , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Terceiro Trimestre da Gravidez , Sífilis/diagnóstico , Sífilis/epidemiologia , Sífilis Congênita/diagnóstico , Sífilis Congênita/epidemiologia , Sífilis Congênita/prevenção & controleRESUMO
Importance: Blood culture overuse in the pediatric intensive care unit (PICU) can lead to unnecessary antibiotic use and contribute to antibiotic resistance. Optimizing blood culture practices through diagnostic stewardship may reduce unnecessary blood cultures and antibiotics. Objective: To evaluate the association of a 14-site multidisciplinary PICU blood culture collaborative with culture rates, antibiotic use, and patient outcomes. Design, Setting, and Participants: This prospective quality improvement (QI) collaborative involved 14 PICUs across the United States from 2017 to 2020 for the Bright STAR (Testing Stewardship for Antibiotic Reduction) collaborative. Data were collected from each participating PICU and from the Children's Hospital Association Pediatric Health Information System for prespecified primary and secondary outcomes. Exposures: A local QI program focusing on blood culture practices in the PICU (facilitated by a larger QI collaborative). Main Outcomes and Measures: The primary outcome was blood culture rates (per 1000 patient-days/mo). Secondary outcomes included broad-spectrum antibiotic use (total days of therapy and new initiations of broad-spectrum antibiotics ≥3 days after PICU admission) and PICU rates of central line-associated bloodstream infection (CLABSI), Clostridioides difficile infection, mortality, readmission, length of stay, sepsis, and severe sepsis/septic shock. Results: Across the 14 PICUs, the blood culture rate was 149.4 per 1000 patient-days/mo preimplementation and 100.5 per 1000 patient-days/mo postimplementation, for a 33% relative reduction (95% CI, 26%-39%). Comparing the periods before and after implementation, the rate of broad-spectrum antibiotic use decreased from 506 days to 440 days per 1000 patient-days/mo, respectively, a 13% relative reduction (95% CI, 7%-19%). The broad-spectrum antibiotic initiation rate decreased from 58.1 to 53.6 initiations/1000 patient-days/mo, an 8% relative reduction (95% CI, 4%-11%). Rates of CLABSI decreased from 1.8 to 1.1 per 1000 central venous line days/mo, a 36% relative reduction (95% CI, 20%-49%). Mortality, length of stay, readmission, sepsis, and severe sepsis/septic shock were similar before and after implementation. Conclusions and Relevance: Multidisciplinary diagnostic stewardship interventions can reduce blood culture and antibiotic use in the PICU. Future work will determine optimal strategies for wider-scale dissemination of diagnostic stewardship in this setting while monitoring patient safety and balancing measures.
Assuntos
Sepse , Choque Séptico , Antibacterianos/uso terapêutico , Hemocultura , Criança , Estado Terminal , Humanos , Unidades de Terapia Intensiva Pediátrica , Estudos Prospectivos , Sepse/diagnóstico , Sepse/tratamento farmacológico , Estados UnidosRESUMO
E-consults replace "curbside" interactions, facilitate provider-specialist communication, document within the medical record, and track relative value units (RVUs). Pediatric infectious diseases (PID) E-consults commonly relate to vaccines, exposures, diagnoses, and treatments. The documented RVU effort of 197 consecutive PID E-consults was equivalent to 70 level 4 new outpatient consults.
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Doenças Transmissíveis , Médicos , Consulta Remota , Criança , Doenças Transmissíveis/diagnóstico , Humanos , Infectologia , EspecializaçãoRESUMO
Two infants treated for syphilis born to at risk mothers who screened negative at their first prenatal visit but were not rescreened at delivery are described. The first presented with classic, but unrecognized, features of congenital syphilis. In the second case, possible early maternal syphilis was diagnosed soon after delivery using the treponemal first reverse-screening algorithm. Although the child's physical exam was normal and the maternal rapid plasma reagin (RPR) negative, the child was treated for syphilis because maternal confirmatory treponemal tests suggested recent seroconversion. Given the re-emergence of congenital syphilis, our report aims to demonstrate the importance of rescreening women at increased risk and improve awareness of common manifestations of the syphilis disease in the newborn. For women at increased risk, repeat syphilis testing early in the third trimester and again at delivery in communities and populations with a high prevalence of syphilis is recommended.
RESUMO
BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) are a leading cause of health care-associated infection. Catheter insertion bundles (IBs) and maintenance bundles (MBs) have been developed to prevent CAUTIs but have not been extensively validated for use in pediatric populations. We report the CAUTI prevention efforts of a large network of children's hospitals. METHODS: Children's hospitals joined the Children's Hospitals' Solutions for Patient Safety engagement network from 2011 to 2017, using an open start time engagement approach, and elected to participate in CAUTI prevention efforts, with 26 submitting data initially and 128 at the end. CAUTI prevention recommendations were first released in May 2012, and IBs and MBs were released in May 2014. Hospitals reported on CAUTIs, patient-days, and urinary catheter-line days and tracked reliability to each bundle. For the network, run charts or control charts were used to plot CAUTI rates, urinary catheter use, and reliability to each bundle component. RESULTS: After the introduction of the pediatric CAUTI IBs and MBs, CAUTI rates across the network decreased 61.6%, from 2.55 to 0.98 infections per 1000 catheter-line days. Centerline shifts occurred both before and after the 2015 Centers for Disease Control and Prevention CAUTI definition change. Urinary catheter use rates did not decline during the intervention period. Network reliability to the IBs and MBs increased to 95.4% and 86.9%, respectively. CONCLUSIONS: IBs and MBs aimed at preventing CAUTIs were introduced across a large network of children's hospitals. Across the network, the rate of urinary tract infections among hospitalized children with indwelling urinary catheters decreased 61.6%.
Assuntos
Infecções Relacionadas a Cateter/prevenção & controle , Cateteres de Demora/efeitos adversos , Infecção Hospitalar/prevenção & controle , Pacotes de Assistência ao Paciente , Cateterismo Urinário/efeitos adversos , Infecções Urinárias/prevenção & controle , Infecções Relacionadas a Cateter/epidemiologia , Criança , Infecção Hospitalar/epidemiologia , Hospitais Pediátricos , Humanos , Segurança do Paciente , Melhoria de Qualidade/organização & administração , Reprodutibilidade dos Testes , Estados Unidos/epidemiologia , Infecções Urinárias/epidemiologiaRESUMO
Tuberculosis (TB) in the health care worker demands orchestrated efforts from health care institutions to promptly identify cases and address community risk. We describe a pediatric intensive care unit nurse with latent TB infection who developed hemoptysis and a lung infiltrate concerning for active TB. Her evaluation and contact investigation were facilitated by our institution's command center. Although TB was ultimately ruled out, this case tested our team-based care in response to a suspected high-consequence pathogen.
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Busca de Comunicante/métodos , Transmissão de Doença Infecciosa do Profissional para o Paciente/prevenção & controle , Tuberculose Latente/transmissão , Infecções por Mycobacterium não Tuberculosas/transmissão , Micobactérias não Tuberculosas , Diagnóstico Diferencial , Feminino , Pessoal de Saúde , Humanos , Tuberculose Latente/diagnóstico , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/diagnósticoRESUMO
OBJECTIVE: To summarize risk factors for Clostridioides (formerly Clostridium) difficile infection (CDI) in hospitalized pediatric patients as determined by previous observational studies. DESIGN: Meta-analysis and systematic review. PATIENTS: Studies evaluating risk factors for CDI in pediatric inpatients were eligible for inclusion. METHOD: We systematically searched MEDLINE, Web of Science, Scopus, and EMBASE for subject headings and text words related to CDI and pediatrics from 1975 to 2017. Two of the investigators independently screened studies, extracted and compiled data, assessed study quality, and performed the meta-analysis. RESULTS: Of the 2,033 articles screened, 14 studies reporting 10,531,669 children met the inclusion criteria. Prior antibiotic exposure (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.31-3.52) and proton pump inhibitor (PPI) use (OR, 1.33; 95% CI, 1.07-1.64) were associated with an increased risk of CDI in children. Subgroup analyses using studies reporting only adjusted results suggested that prior antibiotic exposure is not a significant risk factor for CDI. H2 receptor antagonist (H2RA) use (OR, 1.36; 95% CI, 0.31-5.98) and that female gender (OR, 0.87; 95% CI, 0.74-1.03) did not play a significant role as a risk factor for developing CDI. CONCLUSION: Prior antibiotic exposure appears to be an important risk factor for CDI based on the combined analysis but not significant using adjusted studies. PPI use was associated with an increased risk of CDI. Judicious and appropriate use of antibiotics and PPIs may help reduce the risk of CDI in this vulnerable population.
Assuntos
Infecções por Clostridium/epidemiologia , Adolescente , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Clostridioides difficile , Humanos , Pediatria , Inibidores da Bomba de Prótons/efeitos adversos , Fatores de RiscoRESUMO
BACKGROUND AND OBJECTIVES: Respiratory tract infections (RTIs) are a common reason for direct-to-consumer (DTC) telemedicine consultation. Antibiotic prescribing during video-only DTC telemedicine encounters was explored for pediatric RTIs. METHODS: Encounter data were obtained from a nationwide DTC telemedicine platform. Mixed-effects regression was used to assess variation in antibiotic receipt by patient and physician factors as well as the association between antibiotic receipt and visit length or patient satisfaction. RESULTS: Of 12 842 RTI encounters with 560 physicians, antibiotics were prescribed in 55%. The provider was more likely to receive a 5-star rating from the parent when an antibiotic was prescribed (93.4% vs 80.8%). A 5-star rating was associated with a prescription for an antibiotic (odds ratio [OR] 3.38; 95% confidence interval [CI] 2.84 to 4.02), an antiviral (OR 2.56; 95% CI 1.81 to 3.64), or a nonantibiotic (OR 1.93; 95% CI 1.58 to 2.36). Visit length was associated with higher odds of a 5-star rating only when no antibiotic was prescribed (OR 1.03 per 6 seconds; 95% CI 1.01 to 1.06). Compared with nonpediatricians, pediatric providers were less likely to prescribe antibiotics (OR 0.44; 95% CI 0.29 to 0.68); however, pediatricians received higher encounter satisfaction ratings (OR 1.50; 95% CI 1.11 to 2.03). CONCLUSIONS: During DTC telemedicine consultations for RTIs, pediatric patients were frequently prescribed antibiotics, which correlated with visit satisfaction. Although pediatricians prescribed antibiotics at a lower rate than other physicians, their satisfaction scores were higher. Further work is required to ensure that antibiotic use during DTC telemedicine encounters is guideline concordant.
Assuntos
Antibacterianos/uso terapêutico , Prescrições de Medicamentos , Satisfação do Paciente , Padrões de Prática Médica , Infecções Respiratórias/tratamento farmacológico , Telemedicina , Adolescente , Criança , Pré-Escolar , Feminino , Fidelidade a Diretrizes , Humanos , Lactente , Recém-Nascido , Medicina Interna , Masculino , Pediatras , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Epidemiologic and animal studies provide evidence for a chemopreventive effect of selenium on colorectal cancer, which may be mediated by the antioxidative and anti-inflammatory properties of selenoenzymes. We therefore investigated whether genetic variants in selenoenzymes abundantly expressed in the colon are associated with advanced colorectal adenoma, a cancer precursor. METHODS: Cases with a left-sided advanced adenoma (n = 772) and matched controls (n = 777) screen negative for polyps based on sigmoidoscopy examination were randomly selected from participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The underlying genetic variation was determined by resequencing. We genotyped 44 tagging single nucleotide polymorphisms (SNP) in six genes [glutathione peroxidase 1-4 (GPX1, GPX2, GPX3, and GPX4), selenoprotein P (SEPP1), and thioredoxin reductase 1 (TXNRD1)] to efficiently predict common variation across these genes. RESULTS: Four variants in SEPP1 were significantly associated with advanced adenoma risk. A rare variant in the 5' region of SEPP1 (-4166C>G) was present in nine cases but in none of the controls (exact P = 0.002). Three SNPs located in the 3' region of SEPP1, which is overlapping with the promoter region of an antisense transcript, were significantly associated with adenoma risk: homozygotes at two SEPP1 loci (31,174 bp 3' of STP A>G and 43,881 bp 3' of STP G>A) were associated with increased adenoma risk [odds ratio (OR), 1.48; 95% confidence interval (95% CI), 1.00-2.19 and OR, 1.53; 95% CI, 1.05-2.22, respectively] and the variant SEPP1 44,321 bp 3' of STP C>T was associated with a reduced adenoma risk (CT versus CC OR, 0.85; 95% CI, 0.63-1.15). Furthermore, we observed a significant 80% reduction for advanced colorectal adenoma risk for carriers of the variant allele at TXNRD1 IVS1-181C>G (OR, 0.20; 95% CI, 0.07-0.55; P trend = 0.004). Consistent with the individual SNP results, we observed a significant overall association with adenoma risk for SEPP1 and TXNRD1 (global P = 0.02 and 0.008, respectively) but not for the four GPX genes. CONCLUSION: Our study suggests that genetic variants at or near the SEPP1 and TXNRD1 loci may be associated with advanced colorectal adenoma. As this is the first study to comprehensively investigate this hypothesis, confirmation in independent study populations is needed.
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Adenoma/enzimologia , Adenoma/genética , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Variação Genética , Selênio , Idoso , Estudos de Casos e Controles , Genótipo , Glutationa Peroxidase/genética , Haplótipos , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Polimorfismo de Nucleotídeo Único , Risco , Selenoproteína P/genética , Inquéritos e Questionários , Tiorredoxina Redutase 1/genética , Glutationa Peroxidase GPX1RESUMO
BACKGROUND: Selenium is a potential chemopreventive agent against prostate cancer, whose chemoprotective effects are possibly mediated through the antioxidative properties of selenoenzymes. Interrelations with other antioxidative agents and oxidative stressors, such as smoking, are poorly understood. OBJECTIVES: The aims were to investigate the association between serum selenium and prostate cancer risk and to examine interactions with other antioxidants and tobacco use. DESIGN: A nested case-control study was performed within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Serum selenium in prospectively collected samples was compared between 724 incident prostate cancer case subjects and 879 control subjects, frequency-matched for age, time since initial screen, and year of blood draw. The men were followed for up to 8 y. RESULTS: Overall, serum selenium was not associated with prostate cancer risk (P for trend = 0.70); however, higher serum selenium was associated with lower risks in men reporting a high (more than the median: 28.0 IU/d) vitamin E intake [odds ratio (OR) for the highest compared with the lowest quartile of selenium: 0.58; 95% CI: 0.37, 0.91; P for trend = 0.05; P for interaction = 0.01] and in multivitamin users (OR for highest compared with the lowest quartile of selenium: 0.61; 95% CI: 0.36, 1.04; P for trend = 0.06; P for interaction = 0.05). Furthermore, among smokers, high serum selenium concentrations were related to reduced prostate cancer risk (OR for the highest compared with the lowest quartile of selenium: 0.65; 95% CI: 0.44, 0.97; P for trend = 0.09; P for interaction = 0.007). CONCLUSION: Greater prediagnostic serum selenium concentrations were not associated with prostate cancer risk in this large cohort, although greater concentrations were associated with reduced prostate cancer risks in men who reported a high intake of vitamin E, in multivitamin users, and in smokers.
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Micronutrientes/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Selênio/sangue , Vitaminas/administração & dosagem , Idoso , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Estudos de Casos e Controles , Intervalos de Confiança , Humanos , Masculino , Micronutrientes/metabolismo , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Selênio/metabolismo , Fumar/sangue , Vitamina E/administração & dosagem , Vitaminas/sangueRESUMO
We report a significantly higher occurrence of adverse events associated with prolonged courses of piperacillin-tazobactam compared with other antibacterial agents used for pediatric outpatient parenteral antimicrobial therapy. These adverse events were characterized by a constellation of clinical findings including fever, hematologic abnormalities and transaminitis. Adverse events related to piperacillin-tazobactam should be considered in patients who develop a febrile illness associated with a prolonged course of therapy.
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Antibacterianos/efeitos adversos , Infusões Parenterais/estatística & dados numéricos , Ácido Penicilânico/análogos & derivados , Adolescente , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pacientes Ambulatoriais/estatística & dados numéricos , Ácido Penicilânico/administração & dosagem , Ácido Penicilânico/efeitos adversos , Ácido Penicilânico/uso terapêutico , Piperacilina/administração & dosagem , Piperacilina/efeitos adversos , Piperacilina/uso terapêutico , Combinação Piperacilina e TazobactamRESUMO
BACKGROUND: During the Fall of 2014, numerous children were hospitalized with asthma or respiratory distress related to Enterovirus D68 (EV-D68). A large proportion initially tested positive for rhinovirus. During this period our laboratory noted a cross-reactivity between EV-D68 and the rhinovirus component of the GenMark multiplex respiratory viral panel. Many other laboratories used assays not designed to distinguish these Picornoviridae. METHODS: To compare the presentation and outcomes of patients with rhinovirus and EV-D68, 103 GenMark rhinovirus positive nasopharyngeal swabs from hospitalized children were retested for EV-D68. RESULTS: EV-D68 positive patients versus EV-D68 negative patients were more likely to have a history of asthma (33.3% vs. 11.0%, P = 0.02) and to present with acute respiratory illness (66.7% vs. 40.2%, P = 0.048), especially status asthmaticus (47.6% vs. 2.4%, P < 0.001). On admission they had more wheezing, respiratory distress, and lower respiratory tract involvement, and were more likely to be treated with steroids and discharged home on asthma medications. Respiratory viral coinfection was less common in EV-D68 positive vs EV-D68 negative patients. In patients without a respiratory viral coinfection the overall findings were similar. CONCLUSION: Patients with EV-D68 versus rhinovirus were more likely to have a history of asthma, to present with status asthmaticus, to wheeze on admission, and to receive treatment with asthma medications in hospital and at discharge. The inability of common assays to distinguish EV-D68 from rhinoviruses raises the possibility that the role of EV-D68 as a viral trigger of asthma has been under appreciated. Pediatr Pulmonol. 2017;52:827-832. © 2017 Wiley Periodicals, Inc.
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Criança Hospitalizada/estatística & dados numéricos , Enterovirus Humano D , Infecções por Enterovirus/epidemiologia , Infecções por Picornaviridae/epidemiologia , Rhinovirus , Adolescente , Asma/epidemiologia , Criança , Pré-Escolar , Dispneia/epidemiologia , Feminino , Humanos , Lactente , Masculino , Sons Respiratórios , Estações do AnoRESUMO
The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases defined by chronic muscle inflammation and weakness associated with autoimmunity. We have performed low to high resolution molecular typing to assess the genetic variability of major histocompatibility complex loci (HLA-A, -B, -Cw, -DRB1, and -DQA1) in a large population of European American patients with IIM (n = 571) representing the major myositis autoantibody groups. We established that alleles of the 8.1 ancestral haplotype (8.1 AH) are important risk factors for the development of IIM in patients producing anti-synthetase/anti-Jo-1, -La, -PM/Scl, and -Ro autoantibodies. Moreover, a random forests classification analysis suggested that 8.1 AH-associated alleles B*0801 and DRB1*0301 are the principal HLA risk markers. In addition, we have identified several novel HLA susceptibility factors associated distinctively with particular myositis-specific (MSA) and myositis-associated autoantibody (MAA) groups of the IIM. IIM patients with anti-PL-7 (anti-threonyl-tRNA synthetase) autoantibodies have a unique HLA Class I risk allele, Cw*0304 (pcorr = 0.046), and lack the 8.1 AH markers associated with other anti-synthetase autoantibodies (for example, anti-Jo-1 and anti-PL-12). In addition, HLA-B*5001 and DQA1*0104 are novel potential risk factors among anti-signal recognition particle autoantibody-positive IIM patients (pcorr = 0.024 and p = 0.010, respectively). Among those patients with MAA, HLA DRB1*11 and DQA1*06 alleles were identified as risk factors for myositis patients with anti-Ku (pcorr = 0.041) and anti-La (pcorr = 0.023) autoantibodies, respectively. Amino acid sequence analysis of the HLA DRB1 third hypervariable region identified a consensus motif, 70D (hydrophilic)/71R (basic)/74A (hydrophobic), conferring protection among patients producing anti-synthetase/anti-Jo-1 and -PM/Scl autoantibodies. Together, these data demonstrate that HLA signatures, comprising both risk and protective alleles or motifs, distinguish IIM patients with different myositis autoantibodies and may have diagnostic and pathogenic implications. Variations in associated polymorphisms for these immune response genes may reflect divergent pathogenic mechanisms and/or responses to unique environmental triggers in different groups of subjects resulting in the heterogeneous syndromes of the IIM.
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Autoanticorpos/análise , Antígenos HLA/genética , Antígenos HLA/imunologia , Miosite/genética , Miosite/imunologia , Alelos , Motivos de Aminoácidos , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Antígenos HLA/classificação , Antígenos HLA-A/genética , Antígenos HLA-A/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Cadeias alfa de HLA-DQ , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Cadeias HLA-DRB1 , Haplótipos , Humanos , Imunidade Inata , Masculino , Miosite/patologia , Ligação Proteica , Fatores de Risco , População Branca/genéticaRESUMO
BACKGROUND: Epidemiologic and animal studies suggest that selenium may reduce risk of colorectal cancer. However, the epidemiologic data is mainly from relatively small investigations, limiting their interpretation. Although substantial evidence suggests that smoking is a strong effect modifier for other antioxidative nutrients, little is known about smoking-selenium interactions in colorectal tumors. METHODS: We studied the association of serum selenium and advanced colorectal adenoma, a cancer precursor, in 758 cases and 767 sex- and race-matched controls, randomly selected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases had at least one verified advanced adenoma (> or = 1 cm or villous elements, or high-grade dysplasia) of the distal colon, and controls had a negative sigmoidoscopy. RESULTS: The multivariable odds ratio (OR) comparing participants in the highest quintile of serum selenium with those in the lowest quintile was 0.76 [95% confidence interval (95% CI), 0.53-1.10; P(trend) = 0.01]. The inverse association between serum selenium and advanced colorectal adenoma was significant among recent smokers (OR, 0.53; 95% CI, 0.27-1.01 for highest versus lowest tertile; P(trend) = 0.008). Serum selenium was unrelated to adenoma risk in nonsmokers and former smokers who quit smoking > or = 10 years ago. CONCLUSION: Selenium may reduce the risk of developing advanced colorectal adenoma, particularly among the high-risk group of recent smokers.
Assuntos
Adenoma/epidemiologia , Neoplasias Colorretais/epidemiologia , Selênio/sangue , Fumar/sangue , Adenoma/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
BACKGROUND: There are at least 25 human selenoproteins, each characterized by the incorporation of selenium into the primary sequence as the amino acid selenocysteine. Since many selenoproteins have antioxidant properties, it is plausible that inter-individual differences in selenoprotein expression or activity could influence risk for a range of complex diseases, such as cancer, infectious diseases as well as deleterious responses to oxidative stressors like cigarette smoke. To capture the common genetic variants for 6 important selenoprotein genes (GPX1, GPX2, GPX3, GPX4, TXNRD1, and SEPP1) known to contribute to antioxidant host defenses, a re-sequence analysis was conducted across these genes with particular interest directed at the coding regions, intron-exon borders and flanking untranslated regions (UTR) for each gene in an 102 individual population representative of 4 major ethnic groups found within the United States. RESULTS: For 5 of the genes there was no strong evidence for selection according to the expectations of the neutral equilibrium model of evolution; however, at the GPX1 locus (3p21) there was evidence for positive selection. Strong confirmatory evidence for recent positive selection at the genomic region 3p21 in Asian populations is provided by data from the International HapMap project. CONCLUSION: The SNPs and fine haplotype maps described in this report will be valuable resources for future functional studies, for population specific genetic studies designed to comprehensively explore the role of selenoprotein genetic variants in the etiology of various human diseases, and to define the forces responsible for a recent selective sweep in the vicinity of the GPX1 locus.
Assuntos
Cromossomos Humanos Par 3 , Glutationa Peroxidase/genética , Polimorfismo de Nucleotídeo Único , Selenoproteínas/genética , Povo Asiático/genética , Mapeamento Cromossômico , Etnicidade , Frequência do Gene , Haplótipos , Humanos , Desequilíbrio de Ligação , Reação em Cadeia da Polimerase , Estados Unidos , Regiões não Traduzidas/genética , Glutationa Peroxidase GPX1RESUMO
Most individual cystic fibrosis transmembrane conductance regulator (CFTR) mutations appear not to correlate directly with severity of lung damage in cystic fibrosis (CF). Components of innate immunity, namely, mannose-binding lectin (MBL2), and surfactant protein A1 and A2 genes (SFTPA1 and SFTPA2), were shown to be critical in pulmonary host defenses. A pilot association study was conducted to identify genetic modifiers of lung disease in adult patients with CF. The structural and promoter (-221x/y) variants of MBL2, variants at codons 19, 50, 62, and 219 of SFTPA1, and at codons 9, 91, and 223 for SFTPA2, were studied in 135 adults with CF and compared to their forced expired volume in 1 sec (FEV1), diffusion of CO (DLCO), and other pulmonary scores. Predicted FEV1 was significantly lower in adults with the SFTPA1 6A3 allele and SFTPA2 1A1) allele (P = 0.01 and 0.009, respectively). The extended haplotype 6A3/1A1, which includes SFTPA1 and SFTPA2, was associated with lower pulmonary function, using FEV1 (P = 0.005) and poor pulmonary scores which were determined by American Medical Association, American Thoracic Society, and modified Shwachman-Kulczycki scores. Lower FEV1 and DLCO values were associated with MBL2 coding variants in those who had the DeltaF508 CFTR mutation (P = 0.03 and 0.004, respectively). These results support the current hypothesis that variants in pulmonary host defense molecules are potentially genetic modifiers of pulmonary disease in CF. Further work in larger populations is required to provide important new insights into the pathogenesis of CF.
Assuntos
Fibrose Cística/genética , Haplótipos/genética , Pneumopatias/imunologia , Proteínas Associadas a Surfactantes Pulmonares/genética , Adulto , Idoso , Sequência de Bases , Distribuição de Qui-Quadrado , Fibrose Cística/imunologia , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Marcadores Genéticos/genética , Genótipo , Humanos , Imunidade Inata/genética , Pneumopatias/genética , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Projetos Piloto , Reação em Cadeia da Polimerase , Probabilidade , Estudos Retrospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Estatísticas não ParamétricasAssuntos
Bacteriemia/prevenção & controle , Infecções Relacionadas a Cateter/prevenção & controle , Infecção da Ferida Cirúrgica/prevenção & controle , Bacteriemia/tratamento farmacológico , Bacteriemia/etiologia , Pesquisa Biomédica/tendências , Infecções Relacionadas a Cateter/tratamento farmacológico , Infecções Relacionadas a Cateter/etiologia , Criança , Pré-Escolar , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/etiologia , Infecção Hospitalar/prevenção & controle , Suscetibilidade a Doenças , Política de Saúde , Humanos , Doença Iatrogênica/prevenção & controle , Lactente , Unidades de Terapia Intensiva Pediátrica , Guias de Prática Clínica como Assunto , Infecção da Ferida Cirúrgica/tratamento farmacológico , Infecção da Ferida Cirúrgica/etiologia , Estados UnidosRESUMO
Low serum selenium or selenoprotein P (SePP) levels have been repetitively observed in severe sepsis. The role of SePP in sepsis is incompletely characterized. To test the hypothesis that lipopolysaccharide (LPS) interacts with SePP, we investigated the interaction between LPS and the histidine-rich (His-rich) regions of SePP. We demonstrate that both purified SePP and synthetic peptides corresponding to the His-rich motifs neutralized LPS. In addition, we used a hepatocyte model to study the fate of SePP in response to LPS or endoplasmic reticulum (ER) stress. Our findings indicate that ER stress increases the cellular level of SePP and promotes its nuclear localization.