RESUMEN
Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community.
Asunto(s)
Antígenos de Neoplasias/inmunología , Epítopos/inmunología , Neoplasias/inmunología , Alelos , Presentación de Antígeno/inmunología , Estudios de Cohortes , Humanos , Péptidos/inmunología , Receptor de Muerte Celular Programada 1 , Reproducibilidad de los ResultadosRESUMEN
Although current immune-checkpoint therapy (ICT) mainly targets lymphoid cells, it is associated with a broader remodeling of the tumor micro-environment. Here, using complementary forms of high-dimensional profiling, we define differences across all hematopoietic cells from syngeneic mouse tumors during unrestrained tumor growth or effective ICT. Unbiased assessment of gene expression of tumor-infiltrating cells by single-cell RNA sequencing (scRNAseq) and longitudinal assessment of cellular protein expression by mass cytometry (CyTOF) revealed significant remodeling of both the lymphoid and myeloid intratumoral compartments. Surprisingly, we observed multiple subpopulations of monocytes/macrophages, distinguishable by the markers CD206, CX3CR1, CD1d, and iNOS, that change over time during ICT in a manner partially dependent on IFNγ. Our data support the hypothesis that this macrophage polarization/activation results from effects on circulatory monocytes and early macrophages entering tumors, rather than on pre-polarized mature intratumoral macrophages.
Asunto(s)
Linfocitos/inmunología , Células Mieloides/inmunología , Neoplasias/inmunología , Análisis de la Célula Individual , Transcriptoma , Animales , Línea Celular Tumoral , Citometría de Flujo , Inmunoterapia/métodos , Interferón gamma/inmunología , Activación de Macrófagos , Masculino , Espectrometría de Masas , Ratones , Células Precursoras de Monocitos y Macrófagos/inmunología , Neoplasias/terapiaRESUMEN
CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1-5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.
Asunto(s)
Antígenos de Neoplasias , Linfocitos T CD4-Positivos , Citotoxicidad Inmunológica , Inmunoterapia , Neoplasias , Linfocitos T Reguladores , Animales , Femenino , Humanos , Masculino , Ratones , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Línea Celular Tumoral , Quimiocina CCL5/metabolismo , Células Dendríticas/inmunología , Granzimas/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Interleucina-10/metabolismo , Interleucina-10/inmunología , Ratones Endogámicos C57BL , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T Reguladores/inmunología , Receptores Inmunológicos/antagonistas & inhibidores , Glicoproteínas de Membrana/antagonistas & inhibidores , Tolerancia Inmunológica , Linfocitos T CD8-positivos/inmunologíaRESUMEN
The ability of the immune system to eliminate and shape the immunogenicity of tumours defines the process of cancer immunoediting1. Immunotherapies such as those that target immune checkpoint molecules can be used to augment immune-mediated elimination of tumours and have resulted in durable responses in patients with cancer that did not respond to previous treatments. However, only a subset of patients benefit from immunotherapy and more knowledge about what is required for successful treatment is needed2-4. Although the role of tumour neoantigen-specific CD8+ T cells in tumour rejection is well established5-9, the roles of other subsets of T cells have received less attention. Here we show that spontaneous and immunotherapy-induced anti-tumour responses require the activity of both tumour-antigen-specific CD8+ and CD4+ T cells, even in tumours that do not express major histocompatibility complex (MHC) class II molecules. In addition, the expression of MHC class II-restricted antigens by tumour cells is required at the site of successful rejection, indicating that activation of CD4+ T cells must also occur in the tumour microenvironment. These findings suggest that MHC class II-restricted neoantigens have a key function in the anti-tumour response that is nonoverlapping with that of MHC class I-restricted neoantigens and therefore needs to be considered when identifying patients who will most benefit from immunotherapy.
Asunto(s)
Antígenos de Neoplasias/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Neoplasias Experimentales/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunoterapia , Ratones , Neoplasias Experimentales/terapiaRESUMEN
OBJECTIVE: Throughout the COVID-19 pandemic, there have been concerns about the mental health of health care workers (HCW). Although numerous studies have investigated the level of distress among HCW, few studies have explored programs to improve their mental well-being. In this paper, we describe the implementation and evaluation of a program to support the mental health of HCW at University Health Network (UHN), Canada's largest healthcare network. METHODS: Using a quality improvement approach, we conducted a needs assessment and then created and evaluated a modified stepped-care model to address HCW mental health during the pandemic. This included: online resources focused on psychoeducation and self-management, access to online support and psychotherapeutic groups, and self-referral for individual care from a psychologist or psychiatrist. We used ongoing mixed-methods evaluation, combining quantitative and qualitative analysis, to improve program quality. RESULTS: The program is ongoing, running continuously throughout the pandemic. We present data up to November 30, 2021. There were over 12,000 hits to the UHN's COVID mental health intranet web page, which included self-management resources and information on group support. One hundred and sixty-six people self-referred for individual psychological or psychiatric care. The mean wait time from referral to initial appointment was 5.4 days, with an average of seven appointments for each service user. The majority had moderate to severe symptoms of depression and anxiety at referral, with over 20% expressing thoughts of self-harm or suicide. Post-care user feedback, collected through self-report surveys and semistructured interviews, indicated that the program is effective and valued. CONCLUSIONS: Development of a high-quality internal mental health support for HCW program is feasible, effective, and highly valued. By using early and frequent feedback from multiple perspectives and stakeholders to address demand and implement changes responsively, the program was adjusted to meet HCW mental health needs as the pandemic evolved.
Asunto(s)
COVID-19 , Salud Mental , Humanos , Pandemias , Personal de Salud , Derivación y ConsultaRESUMEN
BACKGROUND: The mental health of healthcare workers (HCWs) has been at the forefront throughout the COVID-19 pandemic. While workplace-based support programs have been developed in hospitals globally, few systematically collected data. While critical to their success, information on these programs and the experience of mental healthcare providers (MHP) who support colleagues is limited. The objective of this study was to explore the experiences of MHP caring for HCW colleagues within a novel workplace-based mental health support program during the COVID-19 pandemic, to provide insights on facilitators, areas for improvement and barriers to program sustainability. METHODS: This qualitative study used semi-structured interviews conducted by videoconference between September 2020 to October 2021. UHN CARES (University Health Network Coping and Resilience for Employees and Staff) Program was developed during the first wave of the COVID-19 pandemic in March 2020. It supports over 21,000 staff members within the UHN, Canada's largest academic health research institution, in Toronto, Canada. Purposive sampling was used to select 10 of the 22 MHP in the UHN CARES Program (n = 10). Using a critical realism framework, key components required to sustain a successful workplace-based mental health support program for HCWs and balance the needs of MHP were determined. RESULTS: Six psychiatrists and four psychologists (n = 10) with varying roles at UHN participated in 17 interviews, including seven repeat interviews exploring changes over time within the pandemic and program. Components which facilitated the success of the program included flexibility in scheduling, confidential health record storage, comprehensive administrative support, availability of resources and adaptive quality improvement approach. Recommendations for improvement included opportunities for peer supervision, triaging of cases, and managing HCW expectations. MHP found caring for HCWs to be meaningful and they utilized existing clinical skills during sessions. Challenges included working in a virtual setting, navigating boundaries when caring for colleagues, and managing the range of service users and their needs. CONCLUSIONS: These findings suggest how support programs can be structured for HCWs, how to provide support, and how to sustain this support, allowing health systems to balance the needs of HCWs and MHPs in preparation for future public health emergencies.
Asunto(s)
COVID-19 , Desastres , Humanos , Pandemias , Salud Pública , Urgencias Médicas , Personal de Salud/psicologíaRESUMEN
Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-ß (IFN-ß knockout [IFN-ß-KO] mice or mice treated with an IFN-ß-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-α-blocking antibody). Mice lacking either IFN-α or IFN-ß developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-α sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-ß-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-ß had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-ß-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-α limiting early viral replication and dissemination and IFN-ß modulating neutrophil-mediated inflammation.IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-α and IFN-ß both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-α limits CHIKV replication and dissemination, whereas IFN-ß protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response.
Asunto(s)
Fiebre Chikungunya/genética , Virus Chikungunya/patogenicidad , Factor 7 Regulador del Interferón/genética , Interferón-alfa/genética , Interferón beta/genética , Neutrófilos/inmunología , Animales , Anticuerpos Neutralizantes/farmacología , Huesos/inmunología , Huesos/patología , Huesos/virología , Fiebre Chikungunya/inmunología , Fiebre Chikungunya/patología , Fiebre Chikungunya/virología , Virus Chikungunya/inmunología , Femenino , Expresión Génica , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata , Inflamación , Factor 7 Regulador del Interferón/deficiencia , Factor 7 Regulador del Interferón/inmunología , Interferón-alfa/antagonistas & inhibidores , Interferón-alfa/deficiencia , Interferón-alfa/inmunología , Interferón beta/antagonistas & inhibidores , Interferón beta/deficiencia , Interferón beta/inmunología , Masculino , Ratones , Ratones Noqueados , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Músculo Esquelético/virología , Infiltración Neutrófila , Neutrófilos/patología , Neutrófilos/virología , Tarso Animal/inmunología , Tarso Animal/patología , Tarso Animal/virología , Replicación ViralRESUMEN
BACKGROUND: Improving brain tumor survival rates have drawn increasing focus on neuropsychiatric and psychological outcomes. OBJECTIVE: This review characterizes the literature on neuropsychiatric sequelae after neurosurgical resection of adult brain tumors. METHODS: Using a scoping method, we reviewed articles describing patients with adult brain tumor who underwent partial or total brain resection and examined major neuropsychiatric domains after intervention. RESULTS: The initial search yielded 9903 articles. After duplicate removal, abstract screening, review, and hand searching, 81 articles were found: 63 empirical and 18 nonempirical. Most articles centered on survivorship within the first year. Cognition was most widely studied with a transient worsening during the first month and usually recovery or improvement thereafter. Depression increased in frequency during survivorship and was associated with frontotemporal location, time to survival, quality of life, cognitive and physical parameters, and functional status. Anxiety, independent of depression, related to tumor histology and grading and had a weaker association with cognition and quality of life. Obsessive-compulsive symptoms, psychosis, mania, and delirium received little attention. Most studies did not include preoperative neuropsychiatric assessment, and treatment was poorly addressed. CONCLUSION: This review highlights key gaps, including preoperative and postoperative neuropsychiatric assessment and a short follow-up. A better understanding of postresection neuropsychiatric outcomes can inform our ability to prognosticate and tailor management for patients at risk for these life-impairing conditions.
Asunto(s)
Neoplasias Encefálicas/psicología , Complicaciones Posoperatorias/psicología , Adulto , Ansiedad/etiología , Neoplasias Encefálicas/cirugía , Cognición , Disfunción Cognitiva/etiología , Depresión/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Psicóticos/etiología , Calidad de VidaRESUMEN
Although IFN-γ is required for resolution of Listeria monocytogenes infection, the identities of the IFN-γ-responsive cells that initiate the process remain unclear. We addressed this question using novel mice with conditional loss of IFN-γR (IFNGR1). Itgax-cre(+)Ifngr1(f/f) mice with selective IFN-γ unresponsiveness in CD8α(+) dendritic cells displayed increased susceptibility to infection. This phenotype was due to the inability of IFN-γ-unresponsive CD8α(+) dendritic cells to produce the initial burst of IL-12 induced by IFN-γ from TNF-α-activated NK/NKT cells. The defect in early IL-12 production resulted in increased IL-4 production that established a myeloid cell environment favoring Listeria growth. Neutralization of IL-4 restored Listeria resistance in Itgax-cre(+)Ifngr1(f/f) mice. We also found that Itgax-cre(+)Ifngr1(f/f) mice survived infection with low-dose Listeria as the result of a second wave of IL-12 produced by Ly6C(hi) monocytes. Thus, an IFN-γ-driven cascade involving CD8α(+) dendritic cells and NK/NKT cells induces the rapid production of IL-12 that initiates the anti-Listeria response.
Asunto(s)
Interferón gamma/inmunología , Interleucina-12/inmunología , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Receptores de Interferón/inmunología , Animales , Antígenos Ly/metabolismo , Antígenos CD8/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Interleucina-12/biosíntesis , Interleucina-4/biosíntesis , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Receptores de Interferón/deficiencia , Receptores de Interferón/genética , Factor de Necrosis Tumoral alfa/metabolismo , Receptor de Interferón gammaRESUMEN
OBJECTIVE: To determine whether presence of a psychiatric comorbidity impacts use of inpatient imaging tests and subsequent wait times. METHODS: This was a retrospective cohort study of all patients admitted to General Internal Medicine (GIM) at five academic hospitals in Toronto, Ontario from 2010 to 2019. Exposure was presence of a coded psychiatric comorbidity on admission. Primary outcome was time to test, as calculated from the time of test ordering to time of test completion, for computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, or peripherally inserted central catheter (PICC) insertion. Multilevel mixed-effects models were used to identify predictors of time to test, and marginal effects were used to calculate differences in absolute units (h). Secondary outcome was the rate of each type of test included. Subgroup analyses were performed according to type of psychiatric comorbidity: psychotic, mood/anxiety, or substance use disorder. RESULTS: There were 196,819 GIM admissions from 2010to 2019. In 77,562 admissions, ≥1 advanced imaging test was performed. After adjusting for all covariates, presence of any psychiatric comorbidity was associated with increased time to test for MRI (adjusted difference: 5.3 h, 95% confidence interval [CI]: 3.9-6.8), PICC (adjusted difference: 3.7 h, 95% CI: 1.6-5.8), and ultrasound (adjusted difference: 3.0 h, 95% CI: 2.3-3.8), but not for CT (adjusted difference: 0.1 h, 95% CI: -0.3 to 0.5). Presence of any psychiatric comorbidity was associated with lower rate of ordering for all test types (adjusted difference: -17.2 tests per 100 days hospitalization, interquartile range: -18.0 to -16.3). CONCLUSIONS: There was a lower rate of ordering of advanced imaging among patients with psychiatric comorbidity. Once ordered, time to test completion was longer for MRI, ultrasound, and PICC. Further exploration, such as quantifying rates of cancelled tests and qualitative studies evaluating hospital, provider, and patient barriers to timely advanced imaging, will be helpful in elucidating causes for these disparities.
Asunto(s)
Pacientes Internos , Trastornos Relacionados con Sustancias , Humanos , Estudios Retrospectivos , Comorbilidad , AnsiedadRESUMEN
BACKGROUND: People with schizophrenia are less likely than those without to be treated for cardiovascular disease. We aimed to evaluate the association between schizophrenia and secondary preventive care after ischemic stroke. METHODS AND RESULTS: In this retrospective cohort study, we used linked population-based administrative data to identify adults who survived 1 year after ischemic stroke hospitalization in Ontario, Canada between 2004 and 2017. Outcomes were screening, treatment, and control of risk factors, and receipt of outpatient physician services. We used modified Poisson regression to model the relative risk of each outcome among people with and without schizophrenia, adjusting for age and other factors. Among 81 163 people with ischemic stroke, 844 (1.04%) had schizophrenia. Schizophrenia was associated with lower rates of screening for hyperlipidemia (60.5% versus 66.0%, adjusted relative risk [aRR] 0.88 [95% CI, 0.84-0.93]) and diabetes (69.4% versus 73.9%, aRR 0.93 [95% CI, 0.89-0.97]), prescription of antihypertensive medications (91.2% versus 94.7%, aRR 0.96 [95% CI, 0.93-0.99]), achievement of target lipid levels (low-density lipoprotein <2 mmol/L) (30.6% versus 34.6%, aRR 0.86 [95% CI, 0.78-0.96]), and outpatient specialist visits (55.3% versus 67.8%, aRR 0.78 [95% CI, 0.74-0.83]) or primary care physician visits (94.5% versus 98.5%; aRR 0.96 [95% CI, 0.95-0.98]) within 1 year. There were no differences in prescription of antilipemic, antiglycemic, or anticoagulant medications, or in achievement of target hemoglobin A1c ≤7%. CONCLUSIONS: People with stroke and schizophrenia are less likely than those without to receive secondary preventive care. This may inform interventions to improve poststroke care and outcomes in those with schizophrenia.
Asunto(s)
Esquizofrenia , Prevención Secundaria , Humanos , Esquizofrenia/complicaciones , Esquizofrenia/epidemiología , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Prevención Secundaria/métodos , Ontario/epidemiología , Anciano , Factores de Riesgo , Accidente Cerebrovascular Isquémico/prevención & control , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/diagnóstico , Adulto , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiologíaRESUMEN
BACKGROUND: Delirium is a major cause of preventable mortality and morbidity in hospitalized adults, but accurately determining rates of delirium remains a challenge. OBJECTIVE: To characterize and compare medical inpatients identified as having delirium using two common methods, administrative data and retrospective chart review. METHODS: We conducted a retrospective study of 3881 randomly selected internal medicine hospital admissions from six acute care hospitals in Toronto and Mississauga, Ontario, Canada. Delirium status was determined using ICD-10-CA codes from hospital administrative data and through a previously validated chart review method. Baseline sociodemographic and clinical characteristics, processes of care and outcomes were compared across those without delirium in hospital and those with delirium as determined by administrative data and chart review. RESULTS: Delirium was identified in 6.3% of admissions by ICD-10-CA codes compared to 25.7% by chart review. Using chart review as the reference standard, ICD-10-CA codes for delirium had sensitivity 24.1% (95%CI: 21.5-26.8%), specificity 99.8% (95%CI: 99.5-99.9%), positive predictive value 97.6% (95%CI: 94.6-98.9%), and negative predictive value 79.2% (95%CI: 78.6-79.7%). Age over 80, male gender, and Charlson comorbidity index greater than 2 were associated with misclassification of delirium. Inpatient mortality and median costs of care were greater in patients determined to have delirium by ICD-10-CA codes (5.8% greater mortality, 95% CI: 2.0-9.5 and $6824 greater cost, 95%CI: 4713-9264) and by chart review (11.9% greater mortality, 95%CI: 9.5-14.2% and $4967 greater cost, 95%CI: 4415-5701), compared to patients without delirium. CONCLUSIONS: Administrative data are specific but highly insensitive, missing most cases of delirium in hospital. Mortality and costs of care were greater for both the delirium cases that were detected and missed by administrative data. Better methods of routinely measuring delirium in hospital are needed.
Asunto(s)
Delirio , Clasificación Internacional de Enfermedades , Humanos , Delirio/diagnóstico , Delirio/epidemiología , Masculino , Femenino , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Anciano de 80 o más Años , Ontario/epidemiología , Hospitalización , Estudios de CohortesRESUMEN
OBJECTIVE: Current scores for predicting sepsis outcomes are limited by generalizability, complexity, and electronic medical record (EMR) integration. Here, we validate a simple EMR-based score for sepsis outcomes in a large multi-centre cohort. DESIGN: A simple electronic medical record-based predictor of illness severity in sepsis (SEPSIS) score was developed (4 additive lab-based predictors) using a population-based retrospective cohort study. SETTING: Internal medicine services across four academic teaching hospitals in Toronto, Canada from April 2010-March 2015 (primary cohort) and 2015-2019 (secondary cohort). PATIENTS: We identified patients admitted with sepsis based upon receipt of antibiotics and positive cultures. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital mortality and secondary outcomes were ICU admission at 72 hours, and hospital length of stay (LOS). We calculated the area under the receiver operating curve (AUROC) for the SEPSIS score, qSOFA, and NEWS2. We then evaluated the SEPSIS score in a secondary cohort (2015-2019) of hospitalized patients receiving antibiotics. Our primary cohort included 1,890 patients with a median age of 72 years (IQR: 56-83). 9% died during hospitalization, 18.6% were admitted to ICU, and mean LOS was 12.7 days (SD: 21.5). In the primary and secondary (2015-2019, 4811 patients) cohorts, the AUROCs of the SEPSIS score for predicting in-hospital mortality were 0.63 and 0.64 respectively, which were similar to NEWS2 (0.62 and 0.67) and qSOFA (0.62 and 0.68). AUROCs for predicting ICU admission at 72 hours, and length of stay > 14 days, were similar between scores, in the primary and secondary cohorts. All scores had comparable calibration for predicting mortality. CONCLUSIONS: An EMR-based SEPSIS score shows a similar ability to predict important clinical outcomes compared with other validated scores (qSOFA and NEWS2). Because of the SEPSIS score's simplicity, it may prove a useful tool for clinical and research applications.
Asunto(s)
Registros Electrónicos de Salud , Mortalidad Hospitalaria , Sepsis , Índice de Severidad de la Enfermedad , Humanos , Sepsis/mortalidad , Sepsis/diagnóstico , Masculino , Anciano , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano de 80 o más Años , Tiempo de Internación , Unidades de Cuidados Intensivos , Curva ROCRESUMEN
A genetic absence of the common IFN-α/ß signaling receptor (IFNAR) in mice is associated with enhanced viral replication and altered adaptive immune responses. However, analysis of IFNAR(-/-) mice is limited for studying the functions of type I IFN at discrete stages of viral infection. To define the temporal functions of type I IFN signaling in the context of infection by West Nile virus (WNV), we treated mice with MAR1-5A3, a neutralizing, non cell-depleting anti-IFNAR antibody. Inhibition of type I IFN signaling at or before day 2 after infection was associated with markedly enhanced viral burden, whereas treatment at day 4 had substantially less effect on WNV dissemination. While antibody treatment prior to infection resulted in massive expansion of virus-specific CD8(+) T cells, blockade of type I IFN signaling starting at day 4 induced dysfunctional CD8(+) T cells with depressed cytokine responses and expression of phenotypic markers suggesting exhaustion. Thus, only the later maturation phase of anti-WNV CD8(+) T cell development requires type I IFN signaling. WNV infection experiments in BATF3(-/-) mice, which lack CD8-α dendritic cells and have impaired priming due to inefficient antigen cross-presentation, revealed a similar effect of blocking IFN signaling on CD8(+) T cell maturation. Collectively, our results suggest that cell non-autonomous type I IFN signaling shapes maturation of antiviral CD8(+) T cell response at a stage distinct from the initial priming event.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Interferón Tipo I/inmunología , Fiebre del Nilo Occidental/inmunología , Virus del Nilo Occidental/inmunología , Enfermedad Aguda , Animales , Anticuerpos Neutralizantes/farmacología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Antígenos CD8/genética , Antígenos CD8/inmunología , Células Dendríticas/inmunología , Interferón Tipo I/genética , Ratones , Ratones Noqueados , Receptor de Interferón alfa y beta/antagonistas & inhibidores , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/inmunología , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Factores de Tiempo , Fiebre del Nilo Occidental/genéticaRESUMEN
Importance: The COVID-19 pandemic caused large disruptions to health care for hospitalized older adults. The incidence and management of delirium may have been affected by high rates of COVID-19 infection, staffing shortages, overwhelmed hospital capacity, and changes to visitor policies. Objective: To measure changes in rates of delirium and related medication prescribing during the COVID-19 pandemic among hospitalized older adults. Design, Setting, and Participants: This population-based, repeated cross-sectional study used linked databases to measure rates of delirium and related medication prescriptions among adults aged 66 years or older hospitalized before and during the COVID-19 pandemic (January 1, 2017, to March 31, 2022) in Ontario, Canada. Exposure: The first 2 years of the COVID-19 pandemic (March 1, 2020, to March 31, 2022). Main Outcomes and Measures: The main outcomes were weekly rates of delirium per 1000 admitted population and monthly rates of new antipsychotic and benzodiazepine prescriptions per 1000 discharged population. Observed rates were compared with projected rates based on modeling from 3 years before pandemic onset. Results: Among 2â¯128â¯411 hospitalizations of older adults over the 5-year study period (50.7% female; mean [SD] age, 78.9 [8.3] years), absolute rates of delirium increased from 35.9 per 1000 admitted population during the prepandemic period to 41.5 per 1000 admitted population throughout the pandemic. The adjusted rate ratio (ARR) of delirium during the pandemic compared with the projected rate was 1.15 (95% CI, 1.11-1.19). Monthly rates of new antipsychotic prescriptions increased from 6.9 to 8.8 per 1000 discharged population and new benzodiazepine prescriptions from 4.4 to 6.0 per 1000 discharged population and were significantly higher during the pandemic compared with projected rates (antipsychotics: ARR, 1.28; 95% CI, 1.19-1.38; benzodiazepines: ARR, 1.37; 95% CI, 1.20-1.57). Rates were highest during pandemic waves 1 (March to June 2020), 3 (March to June 2021), and 5 (December 2021 to February 2022) and remained elevated above projected levels throughout the first 2 years of the pandemic. Conclusions and Relevance: In this repeated cross-sectional study of hospitalized older adults, there was a temporal association between COVID-19 pandemic onset and significant increases in rates of delirium in the hospital and new antipsychotic and benzodiazepine prescriptions after hospital discharge. Rates remained elevated over 2 years. Pandemic-related changes such as visitor restrictions, staff shortages, isolation practices, and reduced staff time at the bedside may have contributed to these trends.
Asunto(s)
Antipsicóticos , COVID-19 , Delirio , Humanos , Femenino , Anciano , Masculino , Benzodiazepinas/uso terapéutico , COVID-19/epidemiología , Antipsicóticos/uso terapéutico , Pandemias , Estudios Transversales , Ontario/epidemiología , Delirio/tratamiento farmacológico , Delirio/epidemiologíaRESUMEN
OBJECTIVE: To examine how project Extension for Community Healthcare Outcomes-Integrated Mental and Physical Health (ECHO-IMPH) influences the attitudes and approaches of primary care providers and other participants towards patients. METHODS: An exploratory qualitative approach was undertaken using semistructured interviews conducted between August 2020 and March 2021. One hundred and sixty-four individuals from two cycles of ECHO-IMPH were invited to participate, and 22 (n = 22) agreed to participate. Data were analyzed using the Braun and Clarke method for thematic analysis. RESULTS: Three major themes were identified: 1) enhanced knowledge and skills; 2) changes in attitude and approach; 3) space for reflection and exploration. When participants were asked about areas for improvement, suggestions were focused on the structure of the sessions. Participants identified that ECHO-IMPH helped them to view patients more holistically, which led to greater patient-centered care in their practice. Additionally, skills gained in ECHO-IMPH gave participants the concrete tools needed to have more empathetic interactions with patients with complex needs. CONCLUSIONS: ECHO-IMPH created a safe space for participants to reflect on their practice with patients with complex needs. Participants applied newly acquired knowledge and skills to provide more empathetic and patient-centered care for patients with complex needs. Based on the shift in perspectives described by participants, transformative learning theory was proposed as a model for how ECHO-IMPH created change in participants' practice.
Asunto(s)
Atención Dirigida al Paciente , Humanos , OntarioRESUMEN
BACKGROUND: There is increasing interest in collecting sociodemographic and social needs data in hospital settings to inform patient care and health equity. However, few studies have examined inpatients' views on this data collection and what should be done to address social needs. This study describes internal medicine inpatients' perspectives on the collection and use of sociodemographic and social needs information. METHODS: A qualitative interpretive description methodology was used. Semi-structured interviews were conducted with 18 patients admitted to a large academic hospital in Toronto, Canada. Participants were recruited using maximum variation sampling for diverse genders, races, and those with and without social needs. Interviews were coded using a predominantly inductive approach and a thematic analysis was conducted. RESULTS: Patients expressed that sociodemographic and social needs data collection is important to offer actionable solutions to address their needs. Patients described a gap between their ideal care which would attend to social needs, versus the reality that hospital-based teams are faced with competing priorities and pressures that make it unfeasible to provide such care. They also believed that this data collection could facilitate more holistic, integrated care. Patients conveyed a need to have a trusting and transparent relationship with their provider to alleviate concerns surrounding bias, discrimination, and confidentiality. Lastly, they indicated that sociodemographic and social needs data could be useful to inform care, support research to inspire social change, and assist them with navigating community resources or creating in-hospital programs to address unmet social needs. CONCLUSIONS: While the collection of sociodemographic and social needs information in hospital settings is generally acceptable, there were varied views on whether hospital staff should intervene, as their priority is medical care. The results can inform the implementation of social data collection and interventions in hospital settings.