RESUMO
BACKGROUND: Training future clinicians in safe opioid prescribing (SOP) and treatment of opioid use disorder (OUD) is critical to address the opioid epidemic. The Accreditation Council on Graduate Medical Education requires all programs to provide instruction and experience in pain management and will mandate addiction medicine clinical experiences for internal medicine trainees. OBJECTIVE: Assess residents' training in SOP and treatment of OUD and identify training barriers. DESIGN: Cross-sectional nationally representative survey was emailed in 2019. PARTICIPANTS: Four hundred twenty-two Association of Program Directors in Internal Medicine members in US internal medicine residency programs. MAIN MEASURES: Program opportunities and challenges to developing or implementing training in SOP, treatment of OUD, and buprenorphine waiver training, and perceived curricular effectiveness. KEY RESULTS: The response rate was 69.4% (293/422). Most programs required didactics in SOP (94.2%) and treatment of OUD (71.7%). Few programs required clinical experiences including addiction medicine clinics (28/240, 11.7%), inpatient consult services (11/240, 4.6%), or offsite treatment rotations (8/240, 3.3%). Lack of trained faculty limited developing or implementing curricula (61.5%). Few respondents reported that their program was "very effective" in teaching SOP (80/285, 28.1%) or treatment of OUD (43/282, 15.3%). Some programs offered buprenorphine waiver training to residents (83/286, 29.0%) and faculty (94/286, 32.9%) with few mandating training (11.7% (28/240) and 5.4% (13/240) respectively). Only 60 of 19,466 (0.3%) residents completed buprenorphine waiver training. Primary care programs/tracks were more likely to offer waiver training to residents (odds ratio [OR], 3.07; 95% CI, 1.68-5.60; P < 0.001) and faculty (OR, 1.08; 95% CI, 1.01-3.22; P = 0.05). CONCLUSIONS: In this nationally representative survey, few internal medicine residency programs provided clinical training in SOP and treatment of OUD, and training was not viewed as very effective. Lack of effective training may have adverse implications for patients, clinicians, and society.
Assuntos
Buprenorfina , Internato e Residência , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides/uso terapêutico , Buprenorfina/uso terapêutico , Estudos Transversais , Humanos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Padrões de Prática MédicaRESUMO
BACKGROUND: The learning and working environment for resident physicians shifted dramatically over the past two decades, with increased focus on work hours, resident wellness, and patient safety. Following two multi-center randomized trials comparing 16-h work limits for PGY-1 trainees to more flexible rules, the ACGME implemented new flexible work hours standards in 2017. OBJECTIVE: We sought to determine program directors' (PDs) support for the work hour changes and programmatic response. DESIGN: In 2017, US Internal Medicine PDs were surveyed about their degree of support for extension of PGY-1 work hour limits, whether they adopted the new maximum continuous work hours permitted, and reasons for their decisions. KEY RESULTS: The response rate was 70% (266/379). Fifty-seven percent of PDs (n = 151) somewhat/strongly support the new work hour rules for PGY-1 residents, while only 25% of programs (N = 66) introduced work periods greater than 16-h on any rotation. Higher rates of adopting change were seen in PDs who strongly/somewhat supported the change (56/151 [37%], P < 0.001), had tenure of 6+ years (33/93 [35%], P = 0.005), were of non-general internal medicine subspecialty (30/80 [38%], P = 0.003), at university-based programs (35/101 [35%], P = 0.009), and with increasing number of approved positions (< 38, 10/63 [16%]; 38-58, 13/69 [19%]; 59-100, 15/64 [23%]; > 100, 28/68 [41%], P = 0.005). Areas with the greatest influence for PDs not extending work hours were the 16-h rule working well (56%) and risk to PGY1 well-being (47%). CONCLUSIONS: Although the majority of PDs support the ACGME 2017 work hours rules, only 25% of programs made immediate changes to extend hours. These data reveal that complex, often competing, forces influence PDs' decisions to change trainee schedules.
Assuntos
Internato e Residência , Admissão e Escalonamento de Pessoal , Humanos , Medicina Interna , Inquéritos e Questionários , Estados Unidos , Carga de TrabalhoRESUMO
BACKGROUND: Consider the problem of designing a panel of complex biomarkers to predict a patient's health or disease state when one can pair his or her current test sample, called a target sample, with the patient's previously acquired healthy sample, called a reference sample. As contrasted to a population averaged reference this reference sample is individualized. Automated predictor algorithms that compare and contrast the paired samples to each other could result in a new generation of test panels that compare to a person's healthy reference to enhance predictive accuracy. This paper develops such an individualized predictor and illustrates the added value of including the healthy reference for design of predictive gene expression panels. RESULTS: The objective is to predict each subject's state of infection, e.g., neither exposed nor infected, exposed but not infected, pre-acute phase of infection, acute phase of infection, post-acute phase of infection. Using gene microarray data collected in a large scale serially sampled respiratory virus challenge study we quantify the diagnostic advantage of pairing a person's baseline reference with his or her target sample. The full study consists of 2886 microarray chips assaying 12,023 genes of 151 human volunteer subjects under 4 different inoculation regimes (HRV, RSV, H1N1, H3N2). We train (with cross-validation) reference-aided sparse multi-class classifier algorithms on this data to show that inclusion of a subject's reference sample can improve prediction accuracy by as much as 14 %, for the H3N2 cohort, and by at least 6 %, for the H1N1 cohort. Remarkably, these gains in accuracy are achieved by using smaller panels of genes, e.g., 39 % fewer for H3N2 and 31 % fewer for H1N1. The biomarkers selected by the predictors fall into two categories: 1) contrasting genes that tend to differentially express between target and reference samples over the population; 2) reinforcement genes that remain constant over the two samples, which function as housekeeping normalization genes. Many of these genes are common to all 4 viruses and their roles in the predictor elucidate the function that they play in differentiating the different states of host immune response. CONCLUSIONS: If one uses a suitable mathematical prediction algorithm, inclusion of a healthy reference in biomarker diagnostic testing can potentially improve accuracy of disease prediction with fewer biomarkers.
Assuntos
Marcadores Genéticos , Análise em Microsséries , Viroses/diagnóstico , Algoritmos , Expressão Gênica , Genes Essenciais , Humanos , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Modelos Moleculares , Vírus Sinciciais Respiratórios , RhinovirusRESUMO
CONTEXT: Graduate medical trainees have a critical role in the teaching of other trainees. Improving their teaching requires an understanding of their attitudes towards teaching and their motivation to teach. Both have been incompletely explored in this population. We aimed to better understand graduate medical trainees' attitudes towards teaching and motivation to teach in the clinical setting in order to inform modifications to resident-as-teacher (RAT) programmes and enhance teaching practices. METHODS: We applied Q methodology, an established sorting method, to identify and quantify the factors that have an impact on trainees' engagement in teaching. We invited house officers at our institution to rank-order 47 statements regarding their attitudes to and motivation for teaching. Respondents explained their Q-sort rankings in writing and completed a demographic questionnaire. By-person factor analysis yielded groups of individuals with similar attitudes. RESULTS: One hundred and seven trainees completed the Q-sort. We found three primary groups of attitudes towards teaching in the clinical setting: enthusiasm, reluctance and rewarded. Enthusiastic teachers are committed and make time to teach. Teaching increases their job satisfaction. Reluctant teachers have enthusiasm but are earlier in training and feel limited by clinical workload and unprepared. Rewarded teachers feel teaching is worthwhile and derive satisfaction from the rewards and recognition they receive for teaching. CONCLUSIONS: This improved understanding of common attitudes shared by groups of residents will help curriculum designers create RAT programmes to further reinforce and encourage attitudes that promote teaching as well as improve trainees' motivation to teach. Designing RAT programmes that acknowledge the attitudes to and motivations for teaching should help develop effective teachers to improve educational outcomes. Directed efforts to enhance motivation for reluctant teachers and encourage more positive attitudes in rewarded teachers may lead to improved teaching behaviours among residents.
Assuntos
Atitude do Pessoal de Saúde , Internato e Residência , Motivação , Estudantes de Medicina/psicologia , Ensino/psicologia , Feminino , Humanos , Masculino , North Carolina , Satisfação PessoalRESUMO
Pneumococcal pneumonia is a leading cause of bacterial infection and death worldwide. Current diagnostic tests for detecting Streptococcus pneumoniae can be unreliable and can mislead clinical decision-making and treatment. To address this concern, we developed a preclinical model of pneumococcal pneumonia in nonhuman primates useful for identifying novel biomarkers, diagnostic tests, and therapies for human S. pneumoniae infection. Adult colony-bred baboons (n = 15) were infected with escalating doses of S. pneumoniae (Serotype 19A-7). We characterized the pathophysiological and serological profiles of healthy and infected animals over 7 days. Pneumonia was prospectively defined by the presence of three criteria: (1) change in white blood cell count, (2) isolation of S. pneumoniae from bronchoalveolar lavage fluid (BALF) or blood, and (3) concurrent signs/symptoms of infection. Animals given 10(9) CFU consistently met our definition and developed a phenotype of tachypnea, tachycardia, fever, hypoxemia, and radiographic lobar infiltrates at 48 hours. BALF and plasma cytokines, including granulocyte colony-stimulating factor, IL-6, IL-10, and IL-1ra, peaked at 24 to 48 hours. At necropsy, there was lobar consolidation with frequent pleural involvement. Lung histopathology showed alveolar edema and macrophage influx in areas of organizing pneumonia. Hierarchical clustering of peripheral blood RNA data at 48 hours correctly identified animals with and without pneumonia. Dose-dependent inoculation of baboons with S. pneumoniae produces a host response ranging from spontaneous clearance (10(6) CFU) to severe pneumonia (10(9) CFU). Selected BALF and plasma cytokine levels and RNA profiles were associated with severe pneumonia and may provide clinically useful parameters after validation.
Assuntos
Modelos Animais de Doenças , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/microbiologia , Primatas/imunologia , Primatas/microbiologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Fator Estimulador de Colônias de Granulócitos/imunologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Interleucinas/imunologia , Interleucinas/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Papio/imunologia , Papio/metabolismo , Papio/microbiologia , Pneumonia Pneumocócica/metabolismo , Primatas/metabolismo , Streptococcus pneumoniae/imunologiaRESUMO
Exposure to influenza viruses is necessary, but not sufficient, for healthy human hosts to develop symptomatic illness. The host response is an important determinant of disease progression. In order to delineate host molecular responses that differentiate symptomatic and asymptomatic Influenza A infection, we inoculated 17 healthy adults with live influenza (H3N2/Wisconsin) and examined changes in host peripheral blood gene expression at 16 timepoints over 132 hours. Here we present distinct transcriptional dynamics of host responses unique to asymptomatic and symptomatic infections. We show that symptomatic hosts invoke, simultaneously, multiple pattern recognition receptors-mediated antiviral and inflammatory responses that may relate to virus-induced oxidative stress. In contrast, asymptomatic subjects tightly regulate these responses and exhibit elevated expression of genes that function in antioxidant responses and cell-mediated responses. We reveal an ab initio molecular signature that strongly correlates to symptomatic clinical disease and biomarkers whose expression patterns best discriminate early from late phases of infection. Our results establish a temporal pattern of host molecular responses that differentiates symptomatic from asymptomatic infections and reveals an asymptomatic host-unique non-passive response signature, suggesting novel putative molecular targets for both prognostic assessment and ameliorative therapeutic intervention in seasonal and pandemic influenza.
Assuntos
Infecções Assintomáticas , Interações Hospedeiro-Patógeno , Vírus da Influenza A Subtipo H3N2 , Influenza Humana/metabolismo , Adolescente , Adulto , Citocinas/biossíntese , Citocinas/metabolismo , Perfilação da Expressão Gênica , Humanos , Influenza Humana/genética , Influenza Humana/virologia , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Estresse FisiológicoRESUMO
BACKGROUND: Pneumonia due to typical bacterial, atypical bacterial and viral pathogens can be difficult to clinically differentiate. Host response-based diagnostics are emerging as a complementary diagnostic strategy to pathogen detection. METHODS: We used murine models of typical bacterial, atypical bacterial and viral pneumonia to develop diagnostic signatures and understand the host's response to these types of infections. Mice were intranasally inoculated with Streptococcus pneumoniae, Mycoplasma pneumoniae, influenza or saline as a control. Peripheral blood gene expression analysis was performed at multiple time points. Differentially expressed genes were used to perform gene set enrichment analysis and generate diagnostic signatures. These murine-derived signatures were externally validated in silico using human gene expression data. The response to S. pneumoniae was the most rapid and robust. RESULTS: Mice infected with M. pneumoniae had a delayed response more similar to influenza-infected animals. Diagnostic signatures for the three types of infection had 0.94-1.00 area under the receiver operator curve (auROC). Validation in five human gene expression datasets revealed auROC of 0.82-0.96. DISCUSSION: This study identified discrete host responses to typical bacterial, atypical bacterial and viral aetiologies of pneumonia in mice. These signatures validated well in humans, highlighting the conserved nature of the host response to these pathogen classes.
Assuntos
Modelos Animais de Doenças , Mycoplasma pneumoniae , Pneumonia por Mycoplasma , Streptococcus pneumoniae , Animais , Humanos , Camundongos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/isolamento & purificação , Pneumonia por Mycoplasma/diagnóstico , Mycoplasma pneumoniae/genética , Mycoplasma pneumoniae/isolamento & purificação , Feminino , Pneumonia Pneumocócica/microbiologia , Infecções por Orthomyxoviridae/imunologia , Curva ROC , Perfilação da Expressão Gênica , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Camundongos Endogâmicos C57BL , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/diagnóstico , Interações Hospedeiro-PatógenoRESUMO
BACKGROUND: This paper introduces a new constrained model and the corresponding algorithm, called unsupervised Bayesian linear unmixing (uBLU), to identify biological signatures from high dimensional assays like gene expression microarrays. The basis for uBLU is a Bayesian model for the data samples which are represented as an additive mixture of random positive gene signatures, called factors, with random positive mixing coefficients, called factor scores, that specify the relative contribution of each signature to a specific sample. The particularity of the proposed method is that uBLU constrains the factor loadings to be non-negative and the factor scores to be probability distributions over the factors. Furthermore, it also provides estimates of the number of factors. A Gibbs sampling strategy is adopted here to generate random samples according to the posterior distribution of the factors, factor scores, and number of factors. These samples are then used to estimate all the unknown parameters. RESULTS: Firstly, the proposed uBLU method is applied to several simulated datasets with known ground truth and compared with previous factor decomposition methods, such as principal component analysis (PCA), non negative matrix factorization (NMF), Bayesian factor regression modeling (BFRM), and the gradient-based algorithm for general matrix factorization (GB-GMF). Secondly, we illustrate the application of uBLU on a real time-evolving gene expression dataset from a recent viral challenge study in which individuals have been inoculated with influenza A/H3N2/Wisconsin. We show that the uBLU method significantly outperforms the other methods on the simulated and real data sets considered here. CONCLUSIONS: The results obtained on synthetic and real data illustrate the accuracy of the proposed uBLU method when compared to other factor decomposition methods from the literature (PCA, NMF, BFRM, and GB-GMF). The uBLU method identifies an inflammatory component closely associated with clinical symptom scores collected during the study. Using a constrained model allows recovery of all the inflammatory genes in a single factor.
Assuntos
Algoritmos , Perfilação da Expressão Gênica/métodos , Análise em Microsséries/métodos , Teorema de Bayes , Humanos , Vírus da Influenza A Subtipo H3N2 , Influenza Humana/genética , Influenza Humana/metabolismo , MasculinoRESUMO
Fungal pathogens exploit diverse mechanisms to survive exposure to antifungal drugs. This poses concern given the limited number of clinically useful antifungals and the growing population of immunocompromised individuals vulnerable to life-threatening fungal infection. To identify molecules that abrogate resistance to the most widely deployed class of antifungals, the azoles, we conducted a screen of 1,280 pharmacologically active compounds. Three out of seven hits that abolished azole resistance of a resistant mutant of the model yeast Saccharomyces cerevisiae and a clinical isolate of the leading human fungal pathogen Candida albicans were inhibitors of protein kinase C (PKC), which regulates cell wall integrity during growth, morphogenesis, and response to cell wall stress. Pharmacological or genetic impairment of Pkc1 conferred hypersensitivity to multiple drugs that target synthesis of the key cell membrane sterol ergosterol, including azoles, allylamines, and morpholines. Pkc1 enabled survival of cell membrane stress at least in part via the mitogen activated protein kinase (MAPK) cascade in both species, though through distinct downstream effectors. Strikingly, inhibition of Pkc1 phenocopied inhibition of the molecular chaperone Hsp90 or its client protein calcineurin. PKC signaling was required for calcineurin activation in response to drug exposure in S. cerevisiae. In contrast, Pkc1 and calcineurin independently regulate drug resistance via a common target in C. albicans. We identified an additional level of regulatory control in the C. albicans circuitry linking PKC signaling, Hsp90, and calcineurin as genetic reduction of Hsp90 led to depletion of the terminal MAPK, Mkc1. Deletion of C. albicans PKC1 rendered fungistatic ergosterol biosynthesis inhibitors fungicidal and attenuated virulence in a murine model of systemic candidiasis. This work establishes a new role for PKC signaling in drug resistance, novel circuitry through which Hsp90 regulates drug resistance, and that targeting stress response signaling provides a promising strategy for treating life-threatening fungal infections.
Assuntos
Calcineurina/genética , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Proteínas de Choque Térmico HSP90/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Proteína Quinase C/metabolismo , Animais , Antifúngicos/farmacologia , Calcineurina/metabolismo , Candida albicans/genética , Candida albicans/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Immunoblotting , Camundongos , Testes de Sensibilidade Microbiana , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N(2) backcross mice (F(1) [C18A]xC57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus-challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 beta and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.
Assuntos
Cromossomos de Mamíferos/genética , Predisposição Genética para Doença , Locos de Características Quantitativas/genética , Sepse/genética , Infecções Estafilocócicas/genética , Staphylococcus aureus/genética , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores/metabolismo , Western Blotting , Quimiocinas/metabolismo , Mapeamento Cromossômico , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sepse/microbiologia , Sepse/patologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/patogenicidadeRESUMO
Invasive fungal infections are a leading cause of mortality among immunocompromised individuals. Treatment is notoriously difficult with the limited armamentarium of antifungal drugs, whose efficacy is compromised by host toxicity, a limited activity spectrum, or the emergence of drug resistance. We previously established that the molecular chaperone Hsp90 enables the emergence and maintenance of fungal drug resistance. For the most prevalent fungal pathogen of humans, Candida albicans, Hsp90 mediates resistance to azoles, which inhibit ergosterol biosynthesis and are the most widely deployed antifungals in the clinic. For the emerging opportunistic pathogen Aspergillus terreus, Hsp90 is required for basal resistance to echinocandins, which inhibit beta(1, 3)-glucan synthesis and are the only new class of antifungals to reach the clinic in decades. Here, we explore the therapeutic potential of Hsp90 inhibitors in fungal disease using a tractable host-model system, larvae of the greater wax moth Galleria mellonella, and a murine model of disseminated disease. Combination therapy with Hsp90 inhibitors that are well tolerated in humans and an azole rescued larvae from lethal C. albicans infections. Combination therapy with an Hsp90 inhibitor and an echinocandin rescued larvae from infections with the most lethal mold, Aspergillus fumigatus. In a murine model of disseminated candidiasis, genetic compromise of C. albicans HSP90 expression enhanced the therapeutic efficacy of an azole. Thus, harnessing Hsp90 provides a much-needed strategy for improving the treatment of fungal disease because it enhances the efficacy of existing antifungals, blocks the emergence of drug resistance, and exerts broad-spectrum activity against diverse fungal pathogens.
Assuntos
Proteínas de Choque Térmico HSP90/fisiologia , Micoses/terapia , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Fungos/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/genética , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Micoses/microbiologia , Micoses/fisiopatologiaRESUMO
PURPOSE: To quantify the extent to which internal medicine (IM) residents provided care for patients with COVID-19 and examine characteristics of residency programs with or without plans (at some point) to exclude residents from COVID-19 care during the first 6 months of the pandemic. METHOD: The authors used data from a nationally representative, annually recurring survey of U.S. IM program directors (PDs) to quantify early (March-August 2020) resident participation in COVID-19 care. The survey was fielded from August to December 2020. PDs reported whether they had planned to exclude residents from COVID-19 care (i.e., PTE status). PTE status was tested for association with program and COVID-19 temporal characteristics, resident schedule accommodations, and resident COVID-19 cases. RESULTS: The response rate was 61.5% (264/429). Nearly half of PDs (45.4%, 118/260) reported their program had planned at some point to exclude residents from COVID-19 care. Northeastern U.S. programs represented a smaller percentage of PTE than non-PTE programs (26.3% vs 36.6%; P = .050). PTE programs represented a higher percentage of programs with later surges than non-PTE programs (33.0% vs 13.6%, P = .048). Median percentage of residents involved in COVID-19 care was 75.0 (interquartile range [IQR]: 22.5-100.0) for PTE programs, compared with 95.0 (IQR: 60.0-100.0) for non-PTE programs ( P < .001). Residents participated most in intensive care units (87.6%, 227/259) and inpatient wards (80.8%, 210/260). Accommodations did not differ by PTE status. PTE programs reported fewer resident COVID-19 cases than non-PTE programs (median percentage = 2.7 [IQR: 0.0-8.6] vs 5.1 [IQR: 1.6-10.7]; P = .011). CONCLUSIONS: IM programs varied widely in their reported plans to exclude residents from COVID-19 care during the early pandemic. A high percentage of residents provided COVID-19 care, even in PTE programs. Thus, the pandemic highlighted the tension as to whether residents are learners or employees.
Assuntos
COVID-19 , Internato e Residência , Humanos , Estados Unidos/epidemiologia , COVID-19/epidemiologia , Pandemias , Inquéritos e QuestionáriosRESUMO
Background: Burnout is common among physicians and physician leaders, including residency program directors (PDs). The effects of the COVID-19 pandemic and other stressors in 2020 on PDs is unknown. Objective: To measure the prevalence of burnout among internal medicine (IM) residency PDs 6 months into the COVID-19 pandemic. Methods: A total of 429 IM PDs, representing 83% of accredited residency programs, were surveyed from August to December 2020. Burnout, using a 2-item screening tool, and self-reported consideration of resigning in 2020, were compared to their annual prevalence since 2012 and tested for possible associations with pandemic stressors and program characteristics. Results: The survey response rate was 61.5% (264 of 429). One-third (33.6%, 87 of 259) of PD respondents met burnout criteria, and 45.1% (110 of 244) reported considering resigning in the past year, which were within the range of preceding years. PDs who reported feeling highly supported by institutional leadership were less likely to meet burnout criteria and to have considered resigning. There were no associations between burnout or consideration of resigning and the amount of clinical time PDs spent in their roles, duration of maximum stress on programs, budget cuts to programs, or geographic region. Conclusions: The prevalence of burnout among PDs in fall 2020 was similar to the prevalence of burnout in pre-pandemic years despite uniquely extreme stressors. PDs' perception of being highly supported by institutional leadership was associated with lower prevalence of burnout and consideration of resigning. Perceived leadership support may be a protective factor against burnout during periods of high stress.
Assuntos
Esgotamento Profissional , COVID-19 , Internato e Residência , Esgotamento Profissional/epidemiologia , Esgotamento Psicológico , Humanos , Pandemias , Inquéritos e QuestionáriosRESUMO
Many aspects of the host response to invasive cryptococcal infections remain poorly understood. In order to explore the pathobiology of infection with common clinical strains, we infected BALB/cJ mice with Cryptococcus neoformans, Cryptococcus gattii, or sham control, and assayed host transcriptomic responses in peripheral blood. Infection with C. neoformans resulted in markedly greater fungal burden in the CNS than C. gattii, as well as slightly higher fungal burden in the lungs. A total of 389 genes were significantly differentially expressed in response to C. neoformans infection, which mainly clustered into pathways driving immune function, including complement activation and TH2-skewed immune responses. C. neoformans infection demonstrated dramatic up-regulation of complement-driven genes and greater up-regulation of alternatively activated macrophage activity than seen with C gattii. A 27-gene classifier was built, capable of distinguishing cryptococcal infection from animals with bacterial infection due to Staphylococcus aureus with 94% sensitivity and 89% specificity. Top genes from the murine classifiers were also differentially expressed in human PBMCs following infection, suggesting cross-species relevance of these findings. The host response, as manifested in transcriptional profiles, informs our understanding of the pathophysiology of cryptococcal infection and demonstrates promise for contributing to development of novel diagnostic approaches.
RESUMO
Candida albicans is a fungal pathogen that causes severe disseminated infections that can be lethal in immunocompromised patients. Genetic factors are known to alter the initial susceptibility to and severity of C. albicans infection. We developed a next-generation computational genetic mapping program with advanced features to identify genetic factors affecting survival in a murine genetic model of hematogenous C. albicans infection. This computational tool was used to analyze the median survival data after inbred mouse strains were infected with C. albicans, which provides a useful experimental model for identification of host susceptibility factors. The computational analysis indicated that genetic variation within early classical complement pathway components (C1q, C1r, and C1s) could affect survival. Consistent with the computational results, serum C1 binding to this pathogen was strongly affected by C1rs alleles, as was survival of chromosome substitution strains. These results led to a combinatorial, conditional genetic model, involving an interaction between C5 and C1r/s alleles, which accurately predicted survival after infection. Beyond applicability to infectious disease, this information could increase our understanding of the genetic factors affecting susceptibility to autoimmune and neurodegenerative diseases.
Assuntos
Alelos , Candidíase/imunologia , Mapeamento Cromossômico , Ativação do Complemento/genética , Biologia Computacional/métodos , Predisposição Genética para Doença , Animais , Candidíase/genética , Candidíase/mortalidade , Haplótipos , Camundongos , Camundongos Endogâmicos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Candida albicans is the leading fungal pathogen of humans, causing life-threatening disease in immunocompromised individuals. Treatment of candidiasis is hampered by the limited number of antifungal drugs whose efficacy is compromised by host toxicity, fungistatic activity, and the emergence of drug resistance. We previously established that the molecular chaperone Hsp90, which regulates the form and function of diverse client proteins, potentiates resistance to the azoles in C. albicans and in the model yeast Saccharomyces cerevisiae. Genetic studies in S. cerevisiae revealed that Hsp90's role in azole resistance is to enable crucial cellular responses to the membrane stress exerted by azoles via the client protein calcineurin. Here, we demonstrate that Hsp90 governs cellular circuitry required for resistance to the only new class of antifungals to reach the clinic in decades, the echinocandins, which inhibit biosynthesis of a critical component of the fungal cell wall. Pharmacological or genetic impairment of Hsp90 function reduced tolerance of C. albicans laboratory strains and resistance of clinical isolates to the echinocandins and created a fungicidal combination. Compromising calcineurin function phenocopied compromising Hsp90 function. We established that calcineurin is an Hsp90 client protein in C. albicans: reciprocal co-immunoprecipitation validated physical interaction; Hsp90 inhibition blocked calcineurin activation; and calcineurin levels were depleted upon genetic reduction of Hsp90. The downstream effector of calcineurin, Crz1, played a partial role in mediating calcineurin-dependent stress responses activated by echinocandins. Hsp90's role in echinocandin resistance has therapeutic potential given that genetic compromise of C. albicans HSP90 expression enhanced the efficacy of an echinocandin in a murine model of disseminated candidiasis. Our results identify the first Hsp90 client protein in C. albicans, establish an entirely new role for Hsp90 in mediating resistance to echinocandins, and demonstrate that targeting Hsp90 provides a promising therapeutic strategy for the treatment of life-threatening fungal disease.
Assuntos
Antifúngicos/farmacologia , Calcineurina/metabolismo , Candida albicans/metabolismo , Equinocandinas/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Análise de Variância , Animais , Azóis/farmacologia , Calcineurina/genética , Candida albicans/efeitos dos fármacos , Candida albicans/genética , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Farmacorresistência Fúngica , Proteínas Fúngicas/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/genética , Lipopeptídeos/farmacologia , Masculino , Micafungina , Camundongos , Estresse Fisiológico , Fatores de Transcrição/metabolismoRESUMO
Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection.