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Mutations in KRAS are some of the most common across multiple cancer types and are thus attractive targets for therapy. Recent studies demonstrated that mutant KRAS generates immunogenic neoantigens that are targetable by adoptive T-cell therapy in metastatic diseases. To expand mutant KRAS-specific immunotherapies, it is critical to identify additional HLA-I allotypes that can present KRAS neoantigens and their cognate T-cell receptors (TCR). Here, we identified a murine TCR specific to a KRAS-G12V neoantigen (7VVVGAVGVGK16) using a vaccination approach with transgenic mice expressing HLA-A*03:01 (HLA-A3). This TCR demonstrated exquisite specificity for mutant G12V and not WT KRAS peptides. To investigate the molecular basis for neoantigen recognition by this TCR, we determined its structure in complex with HLA-A3(G12V). G12V-TCR CDR3ß and CDR1ß formed a hydrophobic pocket to interact with p6 Val of the G12V but not the WT KRAS peptide. To improve the tumor sensitivity of this TCR, we designed rational substitutions to improve TCR:HLA-A3 contacts. Two substitutions exhibited modest improvements in TCR binding avidity to HLA-A3 (G12V) but did not sufficiently improve T-cell sensitivity for further clinical development. Our study provides mechanistic insight into how TCRs detect neoantigens and reveals the challenges in targeting KRAS-G12V mutations.
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BACKGROUND AND OBJECTIVE: Chest x-ray (CXR) remains a core component of health monitoring guidelines for workers at risk of exposure to crystalline silica. There has however been a lack of evidence regarding the sensitivity of CXR to detect silicosis in artificial stone benchtop industry workers. METHODS: Paired CXR and high-resolution computed tomography (HRCT) images were acquired from 110 artificial stone benchtop industry workers. Blinded to the clinical diagnosis, each CXR and HRCT was independently read by two thoracic radiologists from a panel of seven, in accordance with International Labour Office (ILO) methodology for CXR and International Classification of HRCT for Occupational and Environmental Respiratory Diseases. Accuracy of screening positive (ILO major category 1, 2 or 3) and negative (ILO major category 0) CXRs were compared with identification of radiological features of silicosis on HRCT. RESULTS: CXR was positive for silicosis in 27/110 (24.5%) workers and HRCT in 40/110 (36.4%). Of the 83 with a negative CXR (ILO category 0), 15 (18.1%) had silicosis on HRCT. All 11 workers with ILO category 2 or 3 CXRs had silicosis on HRCT. In 99 workers ILO category 0 or 1 CXRs, the sensitivity of screening positive CXR compared to silicosis identified by HRCT was 48% (95%CI 29-68) and specificity 97% (90-100). CONCLUSION: Compared to HRCT, sensitivity of CXR was low but specificity was high. Reliance on CXR for health monitoring would provide false reassurance for many workers, delay management and underestimate the prevalence of silicosis in the artificial stone benchtop industry.
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Exposición Profesional , Radiografía Torácica , Sensibilidad y Especificidad , Silicosis , Tomografía Computarizada por Rayos X , Humanos , Silicosis/diagnóstico por imagen , Silicosis/etiología , Masculino , Adulto , Exposición Profesional/efectos adversos , Persona de Mediana Edad , Femenino , Enfermedades Profesionales/diagnóstico por imagen , Enfermedades Profesionales/etiología , Enfermedades Profesionales/diagnósticoRESUMEN
BACKGROUND: The Perceived Stress Scale (PSS-10) has been used in a range of occupational cohorts, but only recently in stone benchtop workers undergoing screening for silicosis. The aim of this study was to compare psychometric properties of the PSS-10 in stone benchtop workers amongst those born overseas or who used an interpreter. METHODS: Stone benchtop workers in Melbourne, Australia completed the PSS-10 as part of their occupational screening for silicosis. Internal consistency was assessed with Cronbach's α for the total score and the positive and negative subscales. Validity was assessed using confirmatory factor analysis (CFA). Analysis was performed for the total group and for subgroups according to sex, interpreter use, overseas-born, and language spoken at home. RESULTS: The results of 682 workers with complete PSS-10 scores were included in analysis. Most participants were male (93%), with mean age 36.9 years (SD 11.4), with just over half (51.6%) born in Australia, 10.1% using an interpreter, and 17.5% using a language other than English at home. Cronbach's α for the overall group (α = 0.878) suggested good internal consistency. DISCUSSION: CFA analysis for validity testing suggested PSS-10 performance was good for both sexes, moderate for country of birth and language spoken at home categories, but poorer for those who used an interpreter. Whilst professional interpreters provide a range of benefits in the clinical setting, the use of translated and validated instruments are important, particularly in cohorts with large numbers of migrant workers. CONCLUSION: This study describes the psychometric properties of the PSS-10 in a population of stone benchtop workers, with good internal consistency, and mixed performance from validity testing across various subgroups.
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Pruebas Psicológicas , Autoinforme , Dióxido de Silicio , Silicosis , Femenino , Masculino , Humanos , Adulto , Psicometría , LingüísticaRESUMEN
OBJECTIVES: Lower tidal volume ventilation (targeting 3 mL/kg predicted body weight, PBW) facilitated by extracorporeal carbon dioxide removal (ECCO2R) has been investigated as a potential therapy for acute hypoxemic respiratory failure (AHRF) in the pRotective vEntilation with veno-venouS lung assisT in respiratory failure (REST) trial. We investigated the effect of this strategy on cardiac function, and in particular the right ventricle. DESIGN: Substudy of the REST trial. SETTING: Nine U.K. ICUs. PATIENTS: Patients with AHRF (Pao2/Fio2 < 150 mm Hg [20 kPa]). INTERVENTION: Transthoracic echocardiography and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements were collected at baseline and postrandomization in patients randomized to ECCO2R or usual care. MEASUREMENTS: The primary outcome measures were a difference in tricuspid annular plane systolic excursion (TAPSE) on postrandomization echocardiogram and difference in NT-proBNP postrandomization. RESULTS: There were 21 patients included in the echocardiography cohort (ECCO2R, n = 13; usual care, n = 8). Patient characteristics were similar in both groups at baseline. Median (interquartile range) tidal volumes were lower in the ECCO2R group compared with the usual care group postrandomization; 3.6 (3.1-4.2) mL/kg PBW versus 5.2 (4.9-5.7) mL/kg PBW, respectively (p = 0.01). There was no difference in the primary outcome measure of mean (sd) TAPSE in the ECCO2R and usual care groups postrandomization; 21.3 (5.4) mm versus 20.1 (3.2) mm, respectively (p = 0.60). There were 75 patients included in the NT-proBNP cohort (ECCO2R, n = 36; usual care, n = 39). Patient characteristics were similar in both groups at baseline. Median (interquartile range [IQR]) tidal volumes were lower in the ECCO2R group than the usual care group postrandomization; 3.8 (3.3-4.2) mL/kg PBW versus 6.7 (5.8-8.1) mL/kg PBW, respectively (p < 0.0001). There was no difference in median (IQR) NT-proBNP postrandomization; 1121 (241-5370) pg/mL versus 1393 (723-4332) pg/mL in the ECCO2R and usual care groups, respectively (p = 0.30). CONCLUSIONS: In patients with AHRF, a reduction in tidal volume facilitated by ECCO2R, did not modify cardiac function.
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Background: Acute kidney injury commonly occurs in patients admitted to ICU. After acute kidney injury, kidney function may not completely recover leading to increased risk of future cardiovascular events. We sought to ascertain the rates of cardiovascular events in ICU survivors and if these rates were affected by the presence of acute kidney injury whilst in ICU. Methods: This retrospective observational cohort study utilised routinely collected data to identify patients who had survived an admission to one of two ICUs between July 2015 and June 2018. Baseline serum creatinine and subsequent values were used to identify acute kidney injury. Major adverse cardiovascular events described were myocardial injury, coronary artery intervention, or radiological evidence of stroke. Results: Of the 3994 ICU survivors, major adverse cardiovascular events were identified in 385 patients (9.6%; 95% confidence interval [CI] 8.8-10.6%). Presence of acute kidney injury whilst in ICU was significantly associated with future major adverse cardiovascular events (hazard ratio=1.38; 95% CI 1.12-1.70; P-value=0.003) and future biochemical myocardial injury (hazard ratio=1.48; 95% CI 1.16-1.89; P-value=0.001). Acute kidney injury did not have a statistically significant association with future coronary artery interventions or future cerebrovascular events. Conclusions: One in 10 ICU survivors experiences a major adverse cardiovascular event after discharge. Acute kidney injury whilst in ICU was associated with an increased risk of major adverse cardiovascular events and specifically myocardial injury. Further research is warranted on whether ICU survivors with acute kidney injury merit enhanced strategies for cardiovascular protection.
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OBJECTIVE: To identify and characterise COVID-19 workers' compensation claims in healthcare and other industries during the pandemic in Victoria, Australia. METHODS: We used workers' compensation claims identified as COVID-19 infection related from 1 January 2020 to 31 July 2022 to compare COVID-19 infection claims and rates of claims by industry and occupation, and in relation to Victorian COVID-19 epidemiology. A Cox proportional hazards model assessed risk factors for extended claim duration. RESULTS: Of the 3313 direct and indirect COVID-19-related claims identified, 1492 (45.0%) were classified as direct COVID-19 infection accepted time-loss claims and were included in analyses. More than half (52.9%) of COVID-19 infection claims were made by healthcare and social assistance industry workers, with claims for this group peaking in July-October 2020. The overall rate of claims was greater in the healthcare and social assistance industry compared with all other industries (16.9 vs 2.4 per 10 000 employed persons) but industry-specific rates were highest in public administration and safety (23.0 per 10 000 employed persons). Workers in healthcare and social assistance were at increased risk of longer incapacity duration (median 26 days, IQR 16-61 days) than in other industries (median 17 days, IQR 11-39.5 days). CONCLUSIONS: COVID-19 infection claims differed by industry, occupational group, severity and timing and changes coincided with different stages of the COVID-19 pandemic. Occupational surveillance for COVID-19 cases is important and monitoring of worker's compensation claims and incapacity duration can contribute to understanding the impacts of COVID-19 on work absence.
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COVID-19 , Traumatismos Ocupacionales , Humanos , Victoria/epidemiología , Indemnización para Trabajadores , Pandemias , Traumatismos Ocupacionales/epidemiología , COVID-19/epidemiología , Atención a la SaludRESUMEN
Genetic studies associate killer cell immunoglobulin-like receptors (KIRs) and their HLA class I ligands with a variety of human diseases. The basis for these associations and the relative contribution of inhibitory and activating KIR to NK cell responses are unclear. Because KIR binding to HLA-I is peptide dependent, we performed systematic screens, which totaled more than 3500 specific interactions, to determine the specificity of five KIR for peptides presented by four HLA-C ligands. Inhibitory KIR2DL1 was largely peptide sequence agnostic and could bind ~60% of hundreds of HLA-peptide complexes tested. Inhibitory KIR2DL2, KIR2DL3, and activating KIR2DS1 and KIR2DS4 bound only 10% and down to 1% of HLA-peptide complexes tested, respectively. Activating KIR2DS1, previously described as weak, had high binding affinity for HLA-C, with high peptide sequence specificity. Our data revealed MHC-restricted peptide recognition by germline-encoded NK receptors and suggest that NK cell responses can be shaped by HLA-I-bound immunopeptidomes in the context of disease or infection.
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Antígenos HLA-C , Péptidos , Humanos , Ligandos , Secuencia de Aminoácidos , Células GerminativasRESUMEN
INTRODUCTION: Heat and moisture exchanger (HME) filters are commonly used as passive circuit humidifiers during mechanical ventilation, however, are only ~80% efficient. As a result, patients that undergo mechanical ventilation in critical care with HME filter circuits will be exposed to partial airway humidification. This is associated with detrimental effects including increased secretion load which has been shown to be an independent predictor of failed extubation. Nebulised normal saline is commonly utilised to supplement circuit humidification in ventilated patients with high secretion loads, although there are no randomised control trials evaluating its use. Novel vibrating mesh nebulisers generate a fine aerosol resulting in deeper lung penetration, potentially offering a more effective means of nebulisation in comparison to jet nebulisers. The primary aim of this study is to compare the viscosity of respiratory secretions after treatment with nebulised normal saline administered via vibrating mesh nebuliser or jet nebuliser. METHODS AND ANALYSIS: This randomised controlled trial is enrolling 60 mechanically ventilated adult critical care patients breathing on HME filter circuits with high secretion loads. Recruited patients will be randomised to receive nebulised saline via 3 modalities: 1) Continuous vibrating mesh nebuliser; 2) Intermittent vibrating mesh nebuliser or 3) Intermittent jet nebuliser. Over the 72-hr study period, the patients' sputum viscosity (measured using a validated qualitative sputum assessment tool) and physiological parameters will be recorded by an unblinded assessor. A median reduction in secretion viscosity of ≥0.5 on the qualitative sputum assessment score will be deemed as a clinically significant improvement between treatment groups at analysis. DISCUSSION: At the conclusion of this trial, we will provisionally determine if nebulised normal saline administered via vibrating mesh nebulisation is superior to traditional jet nebulisation in terms of reduced respiratory secretion viscosity in intubated patients. Results from this pilot study will provide information to power a definitive clinical study. TRIAL REGISTRATION: ClinicalTrails.Gov Registry (NCT05635903).
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Respiración Artificial , Esputo , Adulto , Humanos , Proyectos Piloto , Estudios Prospectivos , Solución Salina , Viscosidad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
INTRODUCTION: The costs of global warming are substantial. These include expenses from occupational illnesses and injuries (OIIs), which have been associated with increases during heatwaves. This study estimated retrospective and projected future heatwave-attributable OIIs and their costs in Australia. MATERIALS AND METHODS: Climate and workers' compensation claims data were extracted from seven Australian capital cities representing OIIs from July 2005 to June 2018. Heatwaves were defined using the Excess Heat Factor. OIIs and associated costs were estimated separately per city and pooled to derive national estimates. Results were projected to 2030 (2016-2045) and 2050 (2036-2065). RESULTS: The risk of OIIs and associated costs increased during heatwaves, with the risk increasing during severe and particularly extreme heatwaves. Of all OIIs, 0.13% (95% empirical confidence interval [eCI]: 0.11-0.16%) were heatwave-attributable, equivalent to 120 (95%eCI:70-181) OIIs annually. 0.25% of costs were heatwave-attributable (95%eCI: 0.18-0.34%), equal to $AU4.3 (95%eCI: 1.4-7.4) million annually. Estimates of heatwave-attributable OIIs by 2050, under Representative Concentration Pathway [RCP]4.5 and RCP8.5, were 0.17% (95%eCI: 0.10-0.27%) and 0.23% (95%eCI: 0.13-0.37%), respectively. National costs estimates for 2030 under RCP4.5 and RCP8.5 were 0.13% (95%eCI: 0.27-0.46%) and 0.04% (95%eCI: 0.66-0.60), respectively. These estimates for extreme heatwaves were 0.04% (95%eCI: 0.02-0.06%) and 0.04% (95%eCI: 0.01-0.07), respectively. Cost-AFs in 2050 were, under RCP4.5, 0.127% (95%eCI: 0.27-0.46) for all heatwaves and 0.04% (95%eCI: 0.01-0.09%) for extreme heatwaves. Attributable fractions were approximately similar to baseline when assuming theoretical climate adaptation. DISCUSSION: Heatwaves represent notable and preventable portions of preventable OIIs and economic burden. OIIs are likely to increase in the future, and costs during extreme heatwaves in 2030. Workplace and public health policies aimed at heat adaptation can reduce heat-attributable morbidity and costs.
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PURPOSE: Survivors of critical illness frequently experience long-term symptoms including physical symptoms such as pain and emotional symptoms such as anxiety and depression. These symptoms frequently co-exist, however, at present there is limited understanding of these relationships. The aim of this study was to quantify the relationship between pain, anxiety and depression across the recovery trajectory. METHODS: This study is a secondary analysis of data from a multi-centre, prospective, cohort study which followed-up patients recovering from critical illness. Data was available at multiple time points and for 3 distinct cohorts. Structural equation modelling was used to investigate the relationship between outcome measures of pain, anxiety and depression. RESULTS: Data from 414 patients was analysed. Pain was significantly associated with both anxiety and depression in all cohorts and at all time points sampled. Path coefficients for the covariances between pain and depression ranged between 0.39 and 0.72 (p < 0.01). Path coefficients for the covariances between pain and anxiety ranged between 0.39 and 0.65 (p < 0.01). CONCLUSIONS: Pain, anxiety and depression are highly correlated in survivors of critical illness. Pharmacological treatments for pain management may be ineffective alone and further research is required to assess interventions targeting these symptoms in combination.
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Enfermedad Crítica , Depresión , Humanos , Enfermedad Crítica/psicología , Estudios de Cohortes , Estudios Prospectivos , Depresión/epidemiología , Depresión/psicología , Ansiedad/epidemiología , Ansiedad/psicología , DolorRESUMEN
OBJECTIVES: High silica content artificial stone has been found to be associated with silicosis among stone benchtop industry (SBI) workers. The objectives of this study were to determine the prevalence of and risk factors for silicosis among a large cohort of screened SBI workers, and determine the reliability of respiratory function testing (RFT) and chest x-ray (CXR) as screening tests in this industry. METHODS: Subjects were recruited from a health screening programme available to all SBI workers in Victoria, Australia. Workers undertook primary screening, including an International Labour Office (ILO) classified CXR, and subject to prespecified criteria, also underwent secondary screening including high-resolution CT (HRCT) chest and respiratory physician assessment. RESULTS: Among 544 SBI workers screened, 95% worked with artificial stone and 86.2% were exposed to dry processing of stone. Seventy-six per cent (414) required secondary screening, among whom 117 (28.2%) were diagnosed with silicosis (median age at diagnosis 42.1 years (IQR 34.8-49.7)), and all were male. In secondary screening, silicosis was associated with longer SBI career duration (12 vs 8 years), older age, lower body mass index and smoking. In those with silicosis, forced vital capacity was below the lower limit of normal in only 14% and diffusion capacity for carbon monoxide in 13%. Thirty-six (39.6%) of those with simple silicosis on chest HRCT had an ILO category 0 CXR. CONCLUSION: Screening this large cohort of SBI workers identified exposure to dry processing of stone was common and the prevalence of silicosis was high. Compared with HRCT chest, CXR and RFTs had limited value in screening this high-risk population.
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Exposición Profesional , Silicosis , Humanos , Masculino , Adulto , Persona de Mediana Edad , Femenino , Prevalencia , Reproducibilidad de los Resultados , Silicosis/diagnóstico por imagen , Silicosis/epidemiología , Silicosis/etiología , Dióxido de Silicio/efectos adversos , Factores de Riesgo , Victoria , Exposición Profesional/efectos adversos , Exposición Profesional/análisisRESUMEN
OBJECTIVES: To assess the mental health and wellbeing of health and aged care workers in Australia during the second and third years of the coronavirus disease 2019 (COVID-19) pandemic, overall and by occupation group. DESIGN, SETTING, PARTICIPANTS: Longitudinal cohort study of health and aged care workers (ambulance, hospitals, primary care, residential aged care) in Victoria: May-July 2021 (survey 1), October-December 2021 (survey 2), and May-June 2022 (survey 3). MAIN OUTCOME MEASURES: Proportions of respondents (adjusted for age, gender, socio-economic status) reporting moderate to severe symptoms of depression (Patient Health Questionnaire-9, PHQ-9), anxiety (Generalized Anxiety Disorder scale, GAD-7), or post-traumatic stress (Impact of Event Scale-6, IES-6), burnout (abbreviated Maslach Burnout Inventory, aMBI), or high optimism (10-point visual analogue scale); mean scores (adjusted for age, gender, socio-economic status) for wellbeing (Personal Wellbeing Index-Adult, PWI-A) and resilience (Connor Davidson Resilience Scale 2, CD-RISC-2). RESULTS: A total of 1667 people responded to at least one survey (survey 1, 989; survey 2, 1153; survey 3, 993; response rate, 3.3%). Overall, 1211 survey responses were from women (72.6%); most respondents were hospital workers (1289, 77.3%) or ambulance staff (315, 18.9%). The adjusted proportions of respondents who reported moderate to severe symptoms of depression (survey 1, 16.4%; survey 2, 22.6%; survey 3, 19.2%), anxiety (survey 1, 8.8%; survey 2, 16.0%; survey 3, 11.0%), or post-traumatic stress (survey 1, 14.6%; survey 2, 35.1%; survey 3, 14.9%) were each largest for survey 2. The adjusted proportions of participants who reported moderate to severe symptoms of burnout were higher in surveys 2 and 3 than in survey 1, and the proportions who reported high optimism were smaller in surveys 2 and 3 than in survey 1. Adjusted mean scores for wellbeing and resilience were similar at surveys 2 and 3 and lower than at survey 1. The magnitude but not the patterns of change differed by occupation group. CONCLUSION: Burnout was more frequently reported and mean wellbeing and resilience scores were lower in mid-2022 than in mid-2021 for Victorian health and aged care workers who participated in our study. Evidence-based mental health and wellbeing programs for workers in health care organisations are needed. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12621000533897 (observational study; retrospective).
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Agotamiento Profesional , COVID-19 , Adulto , Humanos , Femenino , Anciano , COVID-19/epidemiología , Salud Mental , Estudios Longitudinales , Estudios Retrospectivos , Personal de Salud/psicología , Ansiedad , Encuestas y Cuestionarios , Agotamiento Profesional/psicología , Victoria/epidemiología , Depresión/epidemiologíaRESUMEN
OBJECTIVES: Malignant mesothelioma is an uncommon cancer associated with asbestos exposure, predominantly occupational. Asbestos has been banned in Australia since 2003 but mesothelioma has a long latency and incident cases continue to present. The Australian Mesothelioma Registry was incepted to collect systematic data about incidence and mortality alongside asbestos exposure. METHODS: Benefiting from the Australian national system of cancer notification, all incident cases of mesothelioma in all states and territories are fast-tracked and notified regularly. Notified patients are contacted asking for consent to collect exposure information, initially by postal questionnaire and subsequently by telephone interview. Age-standardised annual incidence rates and mortality rates were calculated. Asbestos exposure was categorised as occupational, non-occupational, neither or, both; and as low, or high, probability of exposure. RESULTS: Mesothelioma incidence appears to have peaked. The age-standardised incidence rates have declined steadily since the early 2000s (peaking in males at 5.9/100 000 and in all-persons at 3.2/100 000), driven by rates in males, who comprise the majority of diagnosed cases. Rates in women have remained fairly stable since that time. Age-standardised mortality rates have followed similar trends. Mesothelioma remains the most common in those aged over 80 years. Nearly all (94%) cases were linked with asbestos exposure (78% occupational in men; 6.8% in women). CONCLUSIONS: With effective control of occupational asbestos use, the decline in age-standardised incidence and death rates has occurred. Incidence rates among women, in whom occupational asbestos exposure is rarely detectable, remain unchanged, pointing to the role of household and /or environmental asbestos exposure.
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Amianto , Mesotelioma Maligno , Mesotelioma , Exposición Profesional , Masculino , Humanos , Femenino , Anciano de 80 o más Años , Mesotelioma Maligno/inducido químicamente , Mesotelioma Maligno/complicaciones , Incidencia , Australia/epidemiología , Mesotelioma/etiología , Amianto/efectos adversos , Exposición Profesional/efectos adversos , Sistema de RegistrosRESUMEN
BACKGROUND: In 2014, wildfires ignited a coal mine in Australia, burning for 6 weeks, releasing large amounts of fine particulate matter ≤2.5 µm in diameter (PM2.5). We investigated the association between individual PM2.5 exposure and emergency department presentations (EDPs) within 5 years post-fire. METHODS: Survey and exposure data for 2725 residents from an exposed and unexposed town were linked with ED administrative data from 2009 to 2019. The association between individual PM2.5 and EDPs was assessed using recurrent survival analysis. RESULTS: A 10 µg/m3 increase in PM2.5 was associated with a 10% increase in respiratory EDPs (HR = 1.10; 95%CI:1.00-1.22) over 5 years post-fire. Increased risks of EDPs for ischaemic heart disease (HR = 1.39; 95%CI:1.12-1.73), atherothrombotic disease (HR = 1.27; 95%CI:1.08-1.50), and cardiovascular disease (HR = 1.10, 95%CI:0.99-1.22) were evident within 2.5 years. CONCLUSION: PM2.5 exposure from a 6-week mine fire increased the 5-year risk of respiratory conditions. An increased risk of CVD within 2.5 years post-fire subsided after this time.
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Contaminantes Atmosféricos , Contaminación del Aire , Enfermedades Cardiovasculares , Humanos , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Material Particulado/análisis , Australia/epidemiología , Enfermedades Cardiovasculares/inducido químicamente , Servicio de Urgencia en Hospital , Carbón Mineral , Exposición a Riesgos Ambientales/análisis , Contaminación del Aire/análisis , Humo/análisisRESUMEN
In supervised learning model development, domain experts are often used to provide the class labels (annotations). Annotation inconsistencies commonly occur when even highly experienced clinical experts annotate the same phenomenon (e.g., medical image, diagnostics, or prognostic status), due to inherent expert bias, judgments, and slips, among other factors. While their existence is relatively well-known, the implications of such inconsistencies are largely understudied in real-world settings, when supervised learning is applied on such 'noisy' labelled data. To shed light on these issues, we conducted extensive experiments and analyses on three real-world Intensive Care Unit (ICU) datasets. Specifically, individual models were built from a common dataset, annotated independently by 11 Glasgow Queen Elizabeth University Hospital ICU consultants, and model performance estimates were compared through internal validation (Fleiss' κ = 0.383 i.e., fair agreement). Further, broad external validation (on both static and time series datasets) of these 11 classifiers was carried out on a HiRID external dataset, where the models' classifications were found to have low pairwise agreements (average Cohen's κ = 0.255 i.e., minimal agreement). Moreover, they tend to disagree more on making discharge decisions (Fleiss' κ = 0.174) than predicting mortality (Fleiss' κ = 0.267). Given these inconsistencies, further analyses were conducted to evaluate the current best practices in obtaining gold-standard models and determining consensus. The results suggest that: (a) there may not always be a "super expert" in acute clinical settings (using internal and external validation model performances as a proxy); and (b) standard consensus seeking (such as majority vote) consistently leads to suboptimal models. Further analysis, however, suggests that assessing annotation learnability and using only 'learnable' annotated datasets for determining consensus achieves optimal models in most cases.
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Despite their long-known photochemical properties and their industrial value, the use of nitroarenes as a productive photochemical handle in organic synthesis has remained relatively unexplored. More specifically, the photochemical formation of nitrogen-sulfur bonds from nitroarenes remains to be demonstrated. Herein, we report the design and application of a sulfinate-nitroarene electron donor-acceptor (EDA) complex and its subsequent use in the first light mediated catalyst-free synthesis of N-hydroxy-sulfonamides. The presence of the EDA was assessed spectroscopically and studied via DFT and TD-DFT calculations. A total of 32 examples including both electron withdrawing and electron donating groups were synthesized under our oxygen- and water-tolerant conditions.
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INTRODUCTION: Pain is a common and debilitating symptom in survivors of critical illness. The 'Core Outcome Set for Survivors of Acute Respiratory Failure' proposes that the pain and discomfort question of the EuroQol 5 Dimension 5 Level (EQ-5D-5L) could be used to assess pain in this group, however, it was recognised that further research is required to evaluate how this single question compares to other more detailed pain tools. This study aims to evaluate the relationship between the pain and discomfort question of the EQ-5D-5L and the Brief Pain Inventory (BPI) in survivors of critical illness. METHODS: This study retrospectively analysed paired EQ-5D-5L and BPI data extracted from a prospective, multicentre study evaluating the impact of a critical care recovery programme. 172 patients who received a complex recovery intervention and 108 patients who did not receive this intervention were included. Data were available for the intervention cohort at multiple time points, namely, baseline, 3 months and 12 months. While, data were available for the usual care cohort at a single time point (12 months). We assessed the correlation between the pain and discomfort question of the EQ-5D-5L and two separate components of the BPI: severity of pain and pain interference. RESULTS: Correlation coefficients comparing the pain and discomfort question of the EQ-5D-5L and the BPI pain severity score ranged between 0.73 (95% CI 0.63 to 0.80) and 0.80 (95% CI 0.72 to 0.86). Correlation coefficients comparing the pain and discomfort question of the EQ-5D-5L and the BPI pain interference score ranged between 0.71 (95% CI 0.62 to 0.79) and 0.83 (95% CI 0.76 to 0.88) across the various time points. CONCLUSIONS: The pain and discomfort question of the EQ-5D-5L correlates moderately well with a more detailed pain tool and may help to streamline assessments in survivorship studies. More in-depth tools may be of use where pain is the primary study outcome or a patient-reported concern.