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A 22-kg female in early childhood with a history of reactive airway disease presented to a paediatric emergency department with acute shortness of breath, tachypnoea and wheezing. Despite treatment with albuterol and corticosteroids, her bronchospasm persisted, prompting the administration of terbutaline. The patient received 220 mcg (10 mcg/kg) terbutaline intravenously, followed immediately by an inadvertent supratherapeutic intravenous dose of 10 000 mcg (454.5 mcg/kg). The patient's laboratory results obtained minutes after the medication error were notable for: potassium, 3.1 mmol/L, lactate, 2.6 mmol/L and troponin I, 0.30 ng/mL (normal <0.03 ng/mL). Over the next 48 hours, serial serum troponin values decreased. The patient was discharged home approximately 72 hours after the initial presentation and she remained well based on follow-up calls over the next several months. Given the timing and trend of troponin concentrations, we do not believe the terbutaline overdose to be responsible for the myocardial injury.
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Overdose de Drogas , Terbutalina , Humanos , Terbutalina/administração & dosagem , Feminino , Broncodilatadores/administração & dosagem , Administração Intravenosa , Troponina I/sangue , Pré-EscolarRESUMO
OBJECTIVE: Assess the use of video otoscopy (VO) as a tool for teaching Emergency Department (ED) residents and remote Otolaryngology consultation. STUDY DESIGN: Survey and retrospective chart review. SETTING: Tertiary care center. METHODS: Emergency Medicine resident physicians completed an otologic skill self-assessment and pathology followed by an interactive training on VO and postintervention assessment after 9 months of use. Outcomes compared change in pre- to posttraining scores. ED consultations using VO during this time period were reviewed to detect differences between the presumed diagnosis/treatment based only on phone consultation and VO image compared to the final diagnosis/treatment after in-person Otolaryngology consultation. RESULTS: Forty-six (63.1%) ED residents participated. Diagnostic accuracy improved by 20.7% overall. The most improved diagnoses were of a normal ear canal (+75%), tympanosclerosis (+58.4%), and ear canal foreign body (+57.1%); most challenging were external auditory canal cyst (-13.6%), hemotympanum (-11.3%), and cerumen (-1.9%). Cholesteatoma did not improve because all responses were incorrect; neither did tympanic membrane perforation because all were correct. Confidence in the otologic exam and anatomy also increased (P < .01). Thirteen consults used VO and 3 (23.1%) had a change in diagnosis/treatment after in-person Otolaryngology evaluation. CONCLUSION: Training on the use of VO significantly improves the confidence and diagnostic skills of ED providers for many pathologies. This application suggests the efficacy of an otologic e-consultation model.
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CASE REPORT: A 12-month-old (former 24 week gestational age), 8.7 kg male was hospitalized after an uneventful colostomy reversal. In the postoperative unit, the patient unintentionally received 1000 mg IV (114.9 mg/kg) acetaminophen instead of the intended 100 mg IV. Serial acetaminophen concentrations were drawn. The patient received IV Nacetylcysteine and ultimately had no adverse outcomes. DISCUSSION: This case report adds to the existing literature regarding toxicokinetics of IV APAP in infants. Our patient had a calculated ke of 0.263 h-1, correlating with a half-life of 2.63 hours. Based on current available data, the half-life of IV APAP in infants varies (2.6 to 4.9 hours). The reason for this variation is unknown and further research is needed in this area.
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Analgésicos não Narcóticos , Overdose de Drogas , Humanos , Masculino , Lactente , Acetaminofen/toxicidade , Analgésicos não Narcóticos/toxicidade , Toxicocinética , Acetilcisteína , Estudos Retrospectivos , Overdose de Drogas/diagnóstico , Overdose de Drogas/tratamento farmacológicoRESUMO
Importance: A patient's belief in the likely success of a treatment may influence outcomes, but this has been understudied in surgical trials. Objective: To examine the association between patients' baseline beliefs about the likelihood of treatment success with outcomes of antibiotics for appendicitis in the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial. Design, Setting, and Participants: This was a secondary analysis of the CODA randomized clinical trial. Participants from 25 US medical centers were enrolled between May 3, 2016, and February 5, 2020. Included in the analysis were participants with appendicitis who were randomly assigned to receive antibiotics in the CODA trial. After informed consent but before randomization, participants who were assigned to receive antibiotics responded to a baseline survey including a question about how successful they believed antibiotics could be in treating their appendicitis. Interventions: Participants were categorized based on baseline survey responses into 1 of 3 belief groups: unsuccessful/unsure, intermediate, and completely successful. Main Outcomes and Measures: Three outcomes were assigned at 30 days: (1) appendectomy, (2) high decisional regret or dissatisfaction with treatment, and (3) persistent signs and symptoms (abdominal pain, tenderness, fever, or chills). Outcomes were compared across groups using adjusted risk differences (aRDs), with propensity score adjustment for sociodemographic and clinical factors. Results: Of the 776 study participants who were assigned antibiotic treatment in CODA, a total of 425 (mean [SD] age, 38.5 [13.6] years; 277 male [65%]) completed the baseline belief survey before knowing their treatment assignment. Baseline beliefs were as follows: 22% of participants (92 of 415) had an unsuccessful/unsure response, 51% (212 of 415) had an intermediate response, and 27% (111 of 415) had a completely successful response. Compared with the unsuccessful/unsure group, those who believed antibiotics could be completely successful had a 13-percentage point lower risk of appendectomy (aRD, -13.49; 95% CI, -24.57 to -2.40). The aRD between those with intermediate vs unsuccessful/unsure beliefs was -5.68 (95% CI, -16.57 to 5.20). Compared with the unsuccessful/unsure group, those with intermediate beliefs had a lower risk of persistent signs and symptoms (aRD, -15.72; 95% CI, -29.71 to -1.72), with directionally similar results for the completely successful group (aRD, -15.14; 95% CI, -30.56 to 0.28). Conclusions and Relevance: Positive patient beliefs about the likely success of antibiotics for appendicitis were associated with a lower risk of appendectomy and with resolution of signs and symptoms by 30 days. Pathways relating beliefs to outcomes and the potential modifiability of beliefs to improve outcomes merit further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT02800785.
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Apendicite , Humanos , Masculino , Adulto , Apendicite/tratamento farmacológico , Apendicite/cirurgia , Apendicite/complicações , Antibacterianos/uso terapêutico , Apendicectomia , Resultado do Tratamento , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The management of patients with acetaminophen (APAP) toxicity is largely informed by the blood concentration. We sought to assess the analytical characteristics of past and current commercial APAP assays in the United States. METHODS: We systematically reviewed the analytical characteristics of APAP assays cleared by the Food and Drug Administration's (FDA) 510(k) premarket notification process by searching the Clinical Laboratory Improvement Amendments (CLIA) database. We collected the following data where available: test principle, precision near 10â mg/L, precision near 150â mg/L, limits of detection, and limits of quantitation. RESULTS: For all assays, absolute analytical precision decreased as analyte concentration increased. Near [APAP] = 10â mg/L, the most precise assays had a standard deviation (SD) of 0.2â mg/L or coefficient of variation (CV) of 1% and the least precise assays had a SD of 1.8â mg/L or a CV of 10%. Near [APAP] = 150â mg/L, the most precise assay had a SD of 1.4â mg/L or CV of 0.9% and the least precise assays had a SD of 7.4â mg/L or a CV of 4.9%. CONCLUSIONS: Commercially available APAP assays had good analytical precision with improvement over time. The failure of some manufacturers to validate precision near treatment thresholds is concerning. Newer APAP assays can measure a wider range of [APAP], which likely improves the risk stratification of overdose patients but also carries a risk of overdiagnosis when minuscule quantities are detected.
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Acetaminofen , Overdose de Drogas , Humanos , Estados Unidos , Acetaminofen/uso terapêutico , Overdose de Drogas/diagnóstico , Overdose de Drogas/tratamento farmacológicoRESUMO
Importance: In the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial, which found antibiotics to be noninferior, approximately half of participants randomized to receive antibiotics had outpatient management with hospital discharge within 24 hours. If outpatient management is safe, it could increase convenience and decrease health care use and costs. Objective: To assess the use and safety of outpatient management of acute appendicitis. Design, Setting, and Participants: This cohort study, which is a secondary analysis of the CODA trial, included 776 adults with imaging-confirmed appendicitis who received antibiotics at 25 US hospitals from May 1, 2016, to February 28, 2020. Exposures: Participants randomized to antibiotics (intravenous then oral) could be discharged from the emergency department based on clinician judgment and prespecified criteria (hemodynamically stable, afebrile, oral intake tolerated, pain controlled, and follow-up confirmed). Outpatient management and hospitalization were defined as discharge within or after 24 hours, respectively. Main Outcomes and Measures: Outcomes compared among patients receiving outpatient vs inpatient care included serious adverse events (SAEs), appendectomies, health care encounters, satisfaction, missed workdays at 7 days, and EuroQol 5-dimension (EQ-5D) score at 30 days. In addition, appendectomy incidence among outpatients and inpatients, unadjusted and adjusted for illness severity, was compared. Results: Among 776 antibiotic-randomized participants, 42 (5.4%) underwent appendectomy within 24 hours and 8 (1.0%) did not receive their first antibiotic dose within 24 hours, leaving 726 (93.6%) comprising the study population (median age, 36 years; range, 18-86 years; 462 [63.6%] male; 437 [60.2%] White). Of these participants, 335 (46.1%; site range, 0-89.2%) were discharged within 24 hours, and 391 (53.9%) were discharged after 24 hours. Over 7 days, SAEs occurred in 0.9 (95% CI, 0.2-2.6) per 100 outpatients and 1.3 (95% CI, 0.4-2.9) per 100 inpatients; in the appendicolith subgroup, SAEs occurred in 2.3 (95% CI, 0.3-8.2) per 100 outpatients vs 2.8 (95% CI, 0.6-7.9) per 100 inpatients. During this period, appendectomy occurred in 9.9% (95% CI, 6.9%-13.7%) of outpatients and 14.1% (95% CI, 10.8%-18.0%) of inpatients; adjusted analysis demonstrated a similar difference in incidence (-4.0 percentage points; 95% CI, -8.7 to 0.6). At 30 days, appendectomies occurred in 12.6% (95% CI, 9.1%-16.7%) of outpatients and 19.0% (95% CI, 15.1%-23.4%) of inpatients. Outpatients missed fewer workdays (2.6 days; 95% CI, 2.3-2.9 days) than did inpatients (3.8 days; 95% CI, 3.4-4.3 days) and had similar frequency of return health care visits and high satisfaction and EQ-5D scores. Conclusions and Relevance: These findings support that outpatient antibiotic management is safe for selected adults with acute appendicitis, with no greater risk of complications or appendectomy than hospital care, and should be included in shared decision-making discussions of patient preferences for outcomes associated with nonoperative and operative care. Trial Registration: ClinicalTrials.gov Identifier: NCT02800785.
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Apendicite , Doença Aguda , Adulto , Antibacterianos/uso terapêutico , Apendicectomia/efeitos adversos , Apendicite/complicações , Apendicite/cirurgia , Estudos de Coortes , Feminino , Humanos , Masculino , Pacientes AmbulatoriaisRESUMO
INTRODUCTION: The training practices and the level of medical oversight of search and rescue (SAR) organizations in the US National Park Service (NPS) Pacific west region is not known. METHODS: A database of SAR teams in the NPS Pacific west region was assembled using public sources. SAR team leaders received an electronic survey between May and December 2019. A descriptive analysis characterizing team size, technical and medical training protocols, and medical oversight was completed. Results are reported as median (interquartile range, range). RESULTS: Of the 250 SAR teams contacted, 39% (n=97) completed our survey. Annual mission volume was 25 (10-50, 1-200). Team size was 30 members (22-58, 1-405). SAR teams most frequently trained in helicopter operations (77%), low-angle rope rescue (75%), and avalanche rescue (43%). Nearly all teams (99%) had members with some medical training: first aid or cardiopulmonary resuscitation (89%), emergency medical technicians (75%), registered nurses or midlevel providers (52%), and physicians (40%). SAR members administered field medical care (84%), often in coordination with EMS (77%). Medical direction was present on a minority of teams (45%), most frequently by a provider specialized in emergency medicine (68%). Expanded medical procedures were permitted on 21% of SAR teams. CONCLUSIONS: SAR teams across the NPS Pacific west region had composition and training standards similar to those surveyed previously in the US intermountain states. Healthcare professionals were present on most teams, typically as team members, not as medical directors. Few SAR teams use medical protocols in remote care environments.
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Serviços Médicos de Emergência , Medicina de Emergência , Aeronaves , Humanos , Parques Recreativos , Trabalho de ResgateRESUMO
STUDY OBJECTIVE: Enterobacteriaceae resistant to ceftriaxone, mediated through extended-spectrum ß-lactamases (ESBLs), commonly cause urinary tract infections worldwide, but have been less prevalent in North America. Current US rates are unknown. We determine Enterobacteriaceae antimicrobial resistance rates among US emergency department (ED) patients hospitalized for urinary tract infection. METHODS: We prospectively enrolled adults hospitalized for urinary tract infection from 11 geographically diverse university-affiliated hospital EDs during 2018 to 2019. Among participants with culture-confirmed infection, we evaluated prevalence of antimicrobial resistance, including that caused by ESBL-producing Enterobacteriaceae, resistance risk factors, and time to in vitro-active antibiotics. RESULTS: Of 527 total participants, 444 (84%) had cultures that grew Enterobacteriaceae; 89 of 435 participants (20.5%; 95% confidence interval 16.9% to 24.5%; 4.6% to 45.4% by site) whose isolates had confirmatory testing had bacteria that were ESBL producing. The overall prevalence of ESBL-producing Enterobacteriaceae infection among all participants with urinary tract infection was 17.2% (95% confidence interval 14.0% to 20.7%). ESBL-producing Enterobacteriaceae infection risk factors were hospital, long-term care, antibiotic exposure within 90 days, and a fluoroquinolone- or ceftriaxone-resistant isolate within 1 year. Enterobacteriaceae resistance rates for other antimicrobials were fluoroquinolone 32.3%, gentamicin 13.7%, amikacin 1.3%, and meropenem 0.3%. Ceftriaxone was the most common empirical antibiotic. In vitro-active antibiotics were not administered within 12 hours of presentation to 48 participants (53.9%) with ESBL-producing Enterobacteriaceae infection, including 17 (58.6%) with sepsis. Compared with other Enterobacteriaceae infections, ESBL infections were associated with longer time to in vitro-active treatment (17.3 versus 3.5 hours). CONCLUSION: Among adults hospitalized for urinary tract infection in many US locations, ESBL-producing Enterobacteriaceae have emerged as a common cause of infection that is often not initially treated with an in vitro-active antibiotic.
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Serviço Hospitalar de Emergência/estatística & dados numéricos , Estados Unidos/epidemiologia , Infecções Urinárias/tratamento farmacológico , Resistência beta-Lactâmica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Enterobacteriaceae/efeitos dos fármacos , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Infecções Urinárias/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Antibiotic therapy has been proposed as an alternative to surgery for the treatment of appendicitis. METHODS: We conducted a pragmatic, nonblinded, noninferiority, randomized trial comparing antibiotic therapy (10-day course) with appendectomy in patients with appendicitis at 25 U.S. centers. The primary outcome was 30-day health status, as assessed with the European Quality of Life-5 Dimensions (EQ-5D) questionnaire (scores range from 0 to 1, with higher scores indicating better health status; noninferiority margin, 0.05 points). Secondary outcomes included appendectomy in the antibiotics group and complications through 90 days; analyses were prespecified in subgroups defined according to the presence or absence of an appendicolith. RESULTS: In total, 1552 adults (414 with an appendicolith) underwent randomization; 776 were assigned to receive antibiotics (47% of whom were not hospitalized for the index treatment) and 776 to undergo appendectomy (96% of whom underwent a laparoscopic procedure). Antibiotics were noninferior to appendectomy on the basis of 30-day EQ-5D scores (mean difference, 0.01 points; 95% confidence interval [CI], -0.001 to 0.03). In the antibiotics group, 29% had undergone appendectomy by 90 days, including 41% of those with an appendicolith and 25% of those without an appendicolith. Complications were more common in the antibiotics group than in the appendectomy group (8.1 vs. 3.5 per 100 participants; rate ratio, 2.28; 95% CI, 1.30 to 3.98); the higher rate in the antibiotics group could be attributed to those with an appendicolith (20.2 vs. 3.6 per 100 participants; rate ratio, 5.69; 95% CI, 2.11 to 15.38) and not to those without an appendicolith (3.7 vs. 3.5 per 100 participants; rate ratio, 1.05; 95% CI, 0.45 to 2.43). The rate of serious adverse events was 4.0 per 100 participants in the antibiotics group and 3.0 per 100 participants in the appendectomy group (rate ratio, 1.29; 95% CI, 0.67 to 2.50). CONCLUSIONS: For the treatment of appendicitis, antibiotics were noninferior to appendectomy on the basis of results of a standard health-status measure. In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days. Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith. (Funded by the Patient-Centered Outcomes Research Institute; CODA ClinicalTrials.gov number, NCT02800785.).
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Antibacterianos/uso terapêutico , Apendicectomia , Apendicite/tratamento farmacológico , Apendicite/cirurgia , Apêndice/cirurgia , Absenteísmo , Administração Intravenosa , Adulto , Antibacterianos/efeitos adversos , Apendicectomia/estatística & dados numéricos , Apendicite/complicações , Apêndice/patologia , Impacção Fecal , Feminino , Nível de Saúde , Hospitalização/estatística & dados numéricos , Humanos , Laparoscopia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Qualidade de Vida , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Neural tube defects (NTDs) are common birth defects in humans and show an unexplained female bias. Female mice lacking the tumor suppressor p53 display NTDs with incomplete penetrance. We found that the combined loss of pro-apoptotic BIM and p53 caused 100% penetrant, female-exclusive NTDs, which allowed us to investigate the female-specific functions of p53. We report that female p53-/- embryonic neural tube samples show fewer cells with inactive X chromosome markers Xist and H3K27me3 and a concomitant increase in biallelic expression of the X-linked genes, Huwe1 and Usp9x. Decreased Xist and increased X-linked gene expression was confirmed by RNA sequencing. Moreover, we found that p53 directly bound response elements in the X chromosome inactivation center (XIC). Together, these findings suggest p53 directly activates XIC genes, without which there is stochastic failure in X chromosome inactivation, and that X chromosome inactivation failure may underlie the female bias in neural tube closure defects.
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Defeitos do Tubo Neural/genética , Proteína Supressora de Tumor p53/deficiência , Animais , Células-Tronco Embrionárias/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Defeitos do Tubo Neural/patologia , Gravidez , Processos Estocásticos , Proteína Supressora de Tumor p53/genética , Inativação do Cromossomo XRESUMO
Somatically acquired mutations in PHF6 (plant homeodomain finger 6) frequently occur in hematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumorigenesis. Similarly, the role of PHF6 in hematopoiesis is unknown. We report here that Phf6 deletion in mice resulted in a reduced number of hematopoietic stem cells (HSCs), an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased and sustained hematopoietic reconstitution in serial transplantation experiments. Interferon-stimulated gene expression was upregulated in the absence of PHF6 in hematopoietic stem and progenitor cells. The numbers of hematopoietic progenitor cells and cycling hematopoietic stem and progenitor cells were restored to normal by combined loss of PHF6 and the interferon α and ß receptor subunit 1. Ectopic expression of TLX3 alone caused partially penetrant leukemia. TLX3 expression and loss of PHF6 combined caused fully penetrant early-onset leukemia. Our data suggest that PHF6 is a hematopoietic tumor suppressor and is important for fine-tuning hematopoietic stem and progenitor cell homeostasis.
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Células-Tronco Hematopoéticas/citologia , Proteínas de Homeodomínio/metabolismo , Leucemia/etiologia , Proteínas Repressoras/fisiologia , Animais , Carcinogênese , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Receptores de Interferon , Proteínas Repressoras/genética , Proteínas Supressoras de TumorRESUMO
Apoptotic cell death removes unwanted cells and is regulated by interactions between pro-survival and pro-apoptotic members of the BCL-2 protein family. The regulation of apoptosis is thought to be crucial for normal embryonic development. Accordingly, complete loss of pro-survival MCL-1 or BCL-XL (BCL2L1) causes embryonic lethality. However, it is not known whether minor reductions in pro-survival proteins could cause developmental abnormalities. We explored the rate-limiting roles of MCL-1 and BCL-XL in development and show that combined loss of single alleles of Mcl-1 and Bcl-x causes neonatal lethality. Mcl-1+/-;Bcl-x+/- mice display craniofacial anomalies, but additional loss of a single allele of pro-apoptotic Bim (Bcl2l11) restores normal development. These findings demonstrate that the control of cell survival during embryogenesis is finely balanced and suggest that some human craniofacial defects, for which causes are currently unknown, may be due to subtle imbalances between pro-survival and pro-apoptotic BCL-2 family members.
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Proteína 11 Semelhante a Bcl-2/genética , Anormalidades Craniofaciais/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína bcl-X/genética , Animais , Apoptose , Proteína 11 Semelhante a Bcl-2/metabolismo , Células Cultivadas , Feminino , Heterozigoto , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteína bcl-X/metabolismoRESUMO
Staphylococcus aureus is an opportunistic pathogen that causes a range of serious infections associated with significant morbidity, by strains increasingly resistant to antibiotics. However, to date all candidate vaccines have failed to induce protective immune responses in humans. We need a more comprehensive understanding of the antigenic targets important in the context of human infection. To investigate infection-associated immune responses, patients were sampled at initial presentation and during convalescence from three types of clinical infection; skin and soft tissue infection (SSTI), prosthetic joint infection (PJI) and pediatric hematogenous osteomyelitis (PHO). Reactivity of serum IgG was tested with an array of recombinant proteins, representing over 2,652 in-vitro-translated open reading frames (ORFs) from a community-acquired methicillin-resistant S. aureus USA300 strain. High-level reactivity was demonstrated for 104 proteins with serum IgG in all patient samples. Overall, high-level IgG-reactivity was most commonly directed against a subset of secreted proteins. Although based on limited surveys, we found subsets of S. aureus proteins with differential reactivity with serum samples from patients with different clinical syndromes. Together, our studies have revealed a hierarchy within the diverse proteins of the S. aureus "immunome", which will help to advance efforts to develop protective immunotherapeutic agents.
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Imunoglobulina G/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/imunologia , Adulto , Idoso , Antibacterianos/uso terapêutico , Criança , Feminino , Antígenos HLA-D/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Masculino , Staphylococcus aureus Resistente à Meticilina/imunologia , Pessoa de Meia-Idade , Osteomielite/imunologia , Osteomielite/microbiologia , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Relacionadas à Prótese/imunologia , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções dos Tecidos Moles/imunologia , Infecções Estafilocócicas/metabolismo , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Infecções Cutâneas Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/metabolismo , Staphylococcus aureus/patogenicidadeRESUMO
Staphylococcus aureus is a Gram-positive opportunistic pathogen that causes superficial and invasive infections in the hospital and community. High mortality from infection emphasizes the need for improved methods for prevention and treatment. Although S. aureus possesses an arsenal of virulence factors that contribute to evasion of host defenses, few studies have examined long-term humoral and B-cell responses. Adults with acute-phase skin and soft tissue infections were recruited; blood samples were obtained; and S. aureus isolates, including methicillin-resistant strains, were subjected to genomic sequence analysis. In comparisons of acute-phase sera with convalescent-phase sera, a minority (37.5%) of patients displayed 2-fold or greater increases in antibody titers against three or more S. aureus antigens, whereas nearly half exhibited no changes, despite the presence of toxin genes in most infecting strains. Moreover, enhanced antibody responses waned over time, which could reflect a defect in B-cell memory or long-lived plasma cells. However, memory B cells reactive with a range of S. aureus antigens were prevalent at both acute-phase and convalescent-phase time points. While some memory B cells exhibited toxin-specific binding, those cross-reactive with structurally related leucocidin subunits were dominant across patients, suggesting the targeting of conserved epitopes. Memory B-cell reactivity correlated with serum antibody levels for selected S. aureus exotoxins, suggesting a relationship between the cellular and humoral compartments. Overall, although there was no global defect in the representation of anti-S. aureus memory B cells, there was evidence of restrictions in the range of epitopes recognized, which may suggest potential therapeutic approaches for augmenting host defenses.IMPORTANCE The contribution of B-cell memory and long-term antibody responses to host defenses against S. aureus exotoxins remains poorly understood. Our studies confirmed that infection did not commonly lead to enhanced long-term humoral responses. Whereas circulating memory B cells against S. aureus secreted exotoxins were prevalent, they were dominated by cross-reactivity with structurally related leucocidin subunits, consistent with recognition of conserved epitopes. These findings also provide the first evidence of a relationship between the reactivity of antistaphylococcal circulating memory B cells and serum antibody levels. In general, infection was not associated with a global defect in B-cell memory for S. aureus secreted factors, and responses were highly dominated by cross-reactivity to structurally related exotoxins, which arguably may alone be suboptimal in providing host defenses. Our studies illuminate aspects of the S. aureus-host relationship that may better inform strategies for the development of an effective protective vaccine.
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Linfócitos B/imunologia , Exotoxinas/imunologia , Memória Imunológica , Infecções dos Tecidos Moles/imunologia , Infecções Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Anticorpos Antibacterianos/sangue , Humanos , Cidade de Nova IorqueRESUMO
BACKGROUND: Hepatitis C virus (HCV) is responsible for the most common chronic bloodborne infection in the United States. The Centers for Disease Control (CDC) recently recommended screening all patients born between 1945-1965 (baby boomers) at least once for HCV infection. New York State has since mandated screening of baby boomers for HCV in nearly all patient care settings and encouraged it in the emergency department (ED). OBJECTIVES: This pilot study aimed to ascertain acceptability of an HCV screening test among the 1945-1965 birth cohort presenting to the ED in advance of a study investigating the prevalence of HCV infection in this birth cohort in the ED setting. METHODS: We conducted a cross-sectional study of health knowledge about HCV and government recommendations regarding HCV testing using a convenience sample of baby boomers in an ED in a large public hospital in the New York metropolitan area. Surveys were administered via a series of semistructured interviews. RESULTS: There were 81 patient participants. Fifty-two percent of patients were born outside of the United States, 69% had a high school diploma level of education or lower, and 37% were unemployed. Patients demonstrated misconceptions about HCV transmission and curability and poor knowledge about the necessity of testing in their age cohort. Knowledge that "HCV can cause the liver to stop working" was significantly associated with acceptance of testing. CONCLUSIONS: Baby boomers showed limited knowledge about the necessity of HCV screening in their age group, but testing for HCV infection in the ED was acceptable for the majority.