The all-hazards willingness to respond (WTR) of local public health personnel is critical to emergency preparedness. This study applied a threat-and efficacy-centered framework to characterize these ...workers' scenario and jurisdictional response willingness patterns toward a range of naturally-occurring and terrorism-related emergency scenarios.
Eight geographically diverse local health department (LHD) clusters (four urban and four rural) across the U.S. were recruited and administered an online survey about response willingness and related attitudes/beliefs toward four different public health emergency scenarios between April 2009 and June 2010 (66% response rate). Responses were dichotomized and analyzed using generalized linear multilevel mixed model analyses that also account for within-cluster and within-LHD correlations.
Comparisons of rural to urban LHD workers showed statistically significant odds ratios (ORs) for WTR context across scenarios ranging from 1.5 to 2.4. When employees over 40 years old were compared to their younger counterparts, the ORs of WTR ranged from 1.27 to 1.58, and when females were compared to males, the ORs of WTR ranged from 0.57 to 0.61. Across the eight clusters, the percentage of workers indicating they would be unwilling to respond regardless of severity ranged from 14-28% for a weather event; 9-27% for pandemic influenza; 30-56% for a radiological 'dirty' bomb event; and 22-48% for an inhalational anthrax bioterrorism event. Efficacy was consistently identified as an important independent predictor of WTR.
Response willingness deficits in the local public health workforce pose a threat to all-hazards response capacity and health security. Local public health agencies and their stakeholders may incorporate key findings, including identified scenario-based willingness gaps and the importance of efficacy, as targets of preparedness curriculum development efforts and policies for enhancing response willingness. Reasons for an increased willingness in rural cohorts compared to urban cohorts should be further investigated in order to understand and develop methods for improving their overall response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study examines the attitudinal impact of an Extended Parallel Process Model (EPPM)-based training curriculum on local public health department (LHD) workers' willingness to respond to ...representative public health emergency scenarios. Data are from 71 U.S. LHDs in urban and rural settings across nine states. The study explores changes in response willingness and EPPM threat and efficacy appraisals between randomly assigned control versus intervention health departments, at baseline and 1 week post curriculum, through an EPPM-based survey/resurvey design. Levels of response willingness and emergency response-related attitudes/beliefs are measured. Analyses focus on two scenario categories that have appeared on a U.S. government list of scenarios of significant concern: a weather-related emergency and a radiological "dirty" bomb event (U.S. Department of Homeland Security, 2007). The greatest impact from the training intervention on response willingness was observed among LHD workers who had low levels of EPPM-related threat and efficacy perceptions at baseline. Self-efficacy and response efficacy and response willingness increased in intervention LHDs for both scenarios, with greater response willingness increases observed for the radiological "dirty" bomb terrorism scenario. Findings indicate the importance of building efficacy versus enhancing threat perceptions as a path toward greater response willingness, and suggest the potential applicability of such curricular interventions for boosting emergency response willingness among other cadres of health providers.
This study evaluated the impact of a novel multimethod curricular intervention using a train-the-trainer model: the Public Health Infrastructure Training (PHIT). PHIT was designed to 1) modify ...perceptions of self-efficacy, response efficacy, and threat related to specific hazards and 2) improve the willingness of local health department (LHD) workers to report to duty when called upon.
Between June 2009 and October 2010, eight clusters of US LHDs (n = 49) received PHIT. Two rounds of focus groups at each intervention site were used to evaluate PHIT. The first round of focus groups included separate sessions for trainers and trainees, 3 weeks after PHIT. The second round of focus groups combined trainers and trainees in a single group at each site 6 months following PHIT. During the second focus group round, participants were asked to self-assess their preparedness before and after PHIT implementation.
Focus groups were conducted at eight geographically representative clusters of LHDs.
Focus group participants included PHIT trainers and PHIT trainees within each LHD cluster.
Focus groups were used to assess attitudes toward the curricular intervention and modifications of willingness to respond (WTR) to an emergency; self-efficacy; and response efficacy.
Participants reported that despite challenges in administering the training, PHIT was well designed and appropriate for multiple management levels and disciplines. Positive mean changes were observed for all nine self-rated preparedness factors (p < 0.001). The findings show PHIT's benefit in improving self-efficacy and WTR among participants.
The PHIT has the potential to enhance emergency response willingness and related self-efficacy among LHD workers.
Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy
. The pathogenesis ...of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1
Ctla4
mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration
. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1
Ctla4
mice, we identify clonal effector CD8
T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1
Ctla4
mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8
T cells. The cardiac-specific protein α-myosin, which is absent from the thymus
, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8
T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.
Immunotherapies targeting the PD-1 pathway produce durable responses in many cancers, but the tumor-intrinsic factors governing response and resistance are largely unknown. MHC-II expression on tumor ...cells can predict response to anti-PD-1 therapy. We therefore sought to determine how MHC-II expression by tumor cells promotes PD-1 dependency. Using transcriptional profiling of anti-PD-1-treated patients, we identified unique patterns of immune activation in MHC-II+ tumors. In patients and preclinical models, MHC-II+ tumors recruited CD4+ T cells and developed dependency on PD-1 as well as Lag-3 (an MHC-II inhibitory receptor), which was upregulated in MHC-II+ tumors at acquired resistance to anti-PD-1. Finally, we identify enhanced expression of FCRL6, another MHC-II receptor expressed on NK and T cells, in the microenvironment of MHC-II+ tumors. We ascribe this to what we believe to be a novel inhibitory function of FCRL6 engagement, identifying it as an immunotherapy target. These data suggest a MHC-II-mediated context-dependent mechanism of adaptive resistance to PD-1-targeting immunotherapy.
Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large ...drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression.
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•Amplified MYCN is synthetic lethal with the BCL-2 inhibitor ABT-199 in neuroblastoma•MYCN upregulates the MCL-1 inhibitor, NOXA•MYCN-amplified neuroblastomas are further sensitized to ABT-199 with MLN8237•ABT-199 with MLN8237 induce tumor regressions in MYCN-amplified neuroblastoma mice
Ham et al. show that MYCN-amplified neuroblastomas are sensitive to treatment with the BCL-2 inhibitor ABT-199 due to MYCN-driven increase of NOXA. Combination treatment with the Aurora Kinase A inhibitor MLN8237 and ABT-199 is synergistic in xenograft models of this tumor type, in part via reducing MCL-1.
Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and ...safety of olutasidenib in 18 patients with m
AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1-2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with m
AML previously treated with venetoclax.
Background
Pediatric hematology/oncology (PHO) patients receiving therapy or undergoing hematopoietic stem cell transplantation (HSCT) often require a central line and are at risk for bloodstream ...infections (BSI). There are limited data describing outcomes of BSI in PHO and HSCT patients.
Methods
This is a multicenter (n = 17) retrospective analysis of outcomes of patients who developed a BSI. Centers involved participated in a quality improvement collaborative referred to as the Childhood Cancer and Blood Disorder Network within the Children's Hospital Association. The main outcome measures were all‐cause mortality at 3, 10, and 30 days after positive culture date; transfer to the intensive care unit (ICU) within 48 hours of positive culture; and central line removal within seven days of the positive blood culture.
Results
Nine hundred fifty‐seven BSI were included in the analysis. Three hundred fifty‐four BSI (37%) were associated with at least one adverse outcome. All‐cause mortality was 1% (n = 9), 3% (n = 26), and 6% (n = 57) at 3, 10, and 30 days after BSI, respectively. In the 165 BSI (17%) associated with admission to the ICU, the median ICU stay was four days (IQR 2‐10). Twenty‐one percent of all infections (n = 203) were associated with central line removal within seven days of positive blood culture.
Conclusions
BSI in PHO and HSCT patients are associated with adverse outcomes. These data will assist in defining the impact of BSI in this population and demonstrate the need for quality improvement and research efforts to decrease them.
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