Increased Risk of Incident Chronic Obstructive Pulmonary Disease and Related Hospitalizations in Tuberculosis Survivors: A Population-Based Matched Cohort Study.

BACKGROUND: Tuberculosis (TB) survivors have an increased risk of developing chronic obstructive pulmonary disease (COPD). This study assessed the risk of COPD development and COPD-related hospitalization in TB survivors compared to controls. METHODS: We conducted a population-based cohort study of TB survivors and 1:1 age- and sex-matched controls using data from the Korean National Health Insurance Service database collected from 2010 to 2017. We compared the risk of COPD development and COPD-related hospitalization between TB survivors and controls. RESULTS: Of the subjects, 9.6% developed COPD, and 2.8% experienced COPD-related hospitalization. TB survivors had significantly higher COPD incidence rates (36.7/1,000 vs. 18.8/1,000 person-years, P < 0.001) and COPD-related hospitalization (10.7/1,000 vs. 4.3/1,000 person-years, P < 0.001) than controls. Multivariable Cox regression analyses revealed higher risks of COPD development (adjusted hazard ratio [aHR], 1.63; 95% confidence interval [CI], 1.54-1.73) and COPD-related hospitalization (aHR, 2.03; 95% CI, 1.81-2.27) in TB survivors. Among those who developed COPD, the hospitalization rate was higher in individuals with post-TB COPD compared to those with non-TB COPD (10.7/1,000 vs. 4.9/1,000 person-years, P < 0.001), showing an increased risk of COPD-related hospitalization (aHR, 1.84; 95% CI, 1.17-2.92). CONCLUSION: TB survivors had higher risks of incident COPD and COPD-related hospitalization compared to controls. These results suggest that previous TB is an important COPD etiology associated with COPD-related hospitalization.

Increased Lung Cancer Risk and Associated Risk Factors in Tuberculosis Survivors: A Korean Population-Based Study.

BACKGROUND: Few studies have comprehensively evaluated the risk of lung cancer in tuberculosis survivors with consideration of smoking status and chronic obstructive pulmonary disease (COPD). Furthermore, little is known about lung cancer risk factors in tuberculosis survivors. METHODS: This population-based cohort study enrolled tuberculosis survivors (n = 75 467) between 2010 and 2017 and 1:1 age- and sex-matched controls. Subjects were followed up for 1 year from the date of tuberculosis diagnosis to the date of the incident lung cancer, death, or December 2018, whichever came first. The risk of lung cancer was evaluated according to smoking and COPD status. We also evaluated the risk factors for lung cancer and developed an individualized lung cancer prediction model for tuberculosis survivors. RESULTS: During a median follow-up duration of 4.8 years, the incident lung cancer risk was 1.72-fold higher in tuberculosis survivors than in the controls. Among tuberculosis survivors, those who were current smokers with ≥20 pack-years showed the highest risk of lung cancer (adjusted hazard ratio, 6.78) compared with never-smoker, non-tuberculosis-infected controls. tuberculosis survivors with COPD had a higher risk (2.43) than non-COPD, non-tuberculosis-infected controls. Risk factors for lung cancer in tuberculosis survivors were pulmonary tuberculosis, age >60 years, smoking, and the presence of COPD or asthma. The individualized lung cancer risk model showed good discrimination (concordance statistic = 0.827). CONCLUSIONS: Previous tuberculosis infection is an independent risk factor regardless of smoking status or amount and COPD. Closer monitoring of tuberculosis survivors, especially heavy smokers or those with COPD, is needed for early lung cancer diagnosis.

Association between non-cystic fibrosis bronchiectasis and the risk of incident dementia: A nationwide cohort study.

BACKGROUND: Chronic lung diseases, such as chronic obstructive pulmonary disease or asthma, are associated with an increased risk of dementia. However, few data are available regarding the risk of dementia in individuals with bronchiectasis. OBJECTIVES: To explore the association between bronchiectasis and the risk of incident dementia using a longitudinal population-based cohort. METHODS: A total of 4,068,560 adults older than 50 years without previous dementia were enrolled from the Korean National Health Insurance Service database in 2009. They were followed up until the date of the diagnosis of dementia or December 31, 2020. The study exposure was the diagnosis of bronchiectasis, and the primary outcome was incident dementia comprising Alzheimer's disease and vascular dementia. RESULTS: During the median follow-up duration of 9.3 years, the incidence of all-cause dementia was 1.6-fold higher in individuals with bronchiectasis than in those without bronchiectasis (15.0 vs. 9.3/1000 person-years, p < .001). In the multivariable Cox regression analysis, the risk of all dementia was significantly higher in individuals with bronchiectasis than in those without bronchiectasis (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 1.04-1.14). In a subgroup analysis by dementia type, individuals with bronchiectasis had an increased risk of Alzheimer's disease compared to those without bronchiectasis (aHR 1.07, 95% CI 1.01-1.12); the risk of vascular dementia did not significantly differ between the two groups (aHR 1.05, 95% CI 0.90-1.21). CONCLUSION: Bronchiectasis was associated with an increased risk of dementia, especially Alzheimer's disease.

Association between exercise and risk of cardiovascular diseases in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: Although cardiovascular comorbidities negatively impact survival in patients with bronchiectasis, there is limited evidence to recommend exercise in this population. We aimed to evaluate whether exercise habit changes are related to reduced cardiovascular disease risk and explore an optimal exercise amount. METHODS: This study identified 165,842 patients with newly diagnosed bronchiectasis during 2010-2016 who underwent two health examinations and were followed up until December 2020. The exposure was the change in weekly habits of moderate- or vigorous-intensity physical activity between the two examinations, classified into non-exercisers and exercisers (further classified into new exercisers, exercise dropouts, and exercise maintainers). The amount of exercise was measured using metabolic equivalents of task (MET). The outcome was the incidence of myocardial infarction (MI) or stroke. RESULTS: During a mean of 6.2 ± 2.1 follow-up years, 4,233 (2.6%) and 3,745 (2.3%) of patients with bronchiectasis had MI or stroke, respectively. Compared to non-exercisers, exercisers had a significantly lower risk of MI or stroke by 9-28% (p < 0.001 for both). Among exercisers, exercise maintainers showed the lowest risk of MI (adjusted hazard ratio [aHR], 0.72; 95% confidence interval [CI], 0.64-0.81) and stroke (aHR, 0.72; 95% CI, 0.64-0.82) compared to non-exercisers. Regarding exercise amount, a significant risk reduction was observed only in patients with bronchiectasis who exercised for ≥ 500 MET-min/wk. CONCLUSION: Exercise was associated with a reduced risk of cardiovascular diseases in patients with bronchiectasis. In particular, the risk was lowest in exercise maintainers, and cardiovascular risk reduction was significant when exercising more than 500 MET-min/wk.

Chronic Obstructive Pulmonary Disease is Associated with a More Symptomatic Burden and Severe Presentation of COVID-19: A Korean National COVID-19 Cohort Study.

Insufficient data are available on comprehensive evaluation of demographics, symptoms or signs, laboratory findings, and disease course in patients with coronavirus disease 2019 (COVID-19) and chronic obstructive pulmonary disease (COPD). We aimed to evaluate whether COPD patients are more prone to severe COVID-19 compared with those without COPD. We also investigate the clinical characteristics and disease course of COVID-19 in patients with COPD versus those without COPD. Patients were selected from a Korean nationwide cohort of 5,628 patients with confirmed COVID-19 and who had completed treatment or quarantine by April 30, 2020; 3,673 patients aged 40 years or older were included in this study. COPD was diagnosed using patient reports of physician-diagnosed COPD. During the study period, all patients with COVID-19 in Korea were hospitalized following the national health policy. Of the study participants, 38 (1.0%) had COPD. Regarding initial symptoms, COPD patients with COVID-19 showed greater sputum production (50.0% vs. 29.8%, p < 0.01) and dyspnea (36.8% vs. 14.9%, p < 0.01) than those without COPD. In addition, patients with COPD were more likely to receive oxygen therapy or non-invasive ventilation (29.0% vs. 13.7%, p = 0.01) and had a higher mortality (21.1% vs. 6.4%, p < 0.01) than those without COPD. After adjusting for age, sex, body mass index, and comorbidities, COPD patients showed increased risk of severe COVID-19 compared with those without COPD. Our nationwide study showed that COVID-19 patients with COPD have higher symptomatic burden and more severe disease course than those without COPD.

Interstitial lung disease increases susceptibility to and severity of COVID-19.

BACKGROUND: There are limited data regarding the relationship between interstitial lung disease (ILD) and the natural course of COVID-19. In this study, we investigate whether patients with ILD are more susceptible to COVID-19 than those without ILD and evaluate the impact of ILD on disease severity in patients with COVID-19. METHODS: A nationwide cohort of patients with COVID-19 (n=8070) and a 1:15 age-, sex- and residential area-matched cohort (n=121 050) were constructed between 1 January 2020 and 30 May 2020 in Korea. We performed a nested case-control study to compare the proportions of patients with ILD between the COVID-19 cohort and the matched cohort. Using the COVID-19 cohort, we also evaluated the risk of severe COVID-19 in patients with ILD versus those without ILD. RESULTS: The proportion of patients with ILD was significantly higher in the COVID-19 cohort than in the matched cohort (0.8% versus 0.4%; p<0.001). The odds of having ILD was significantly higher in the COVID-19 cohort than in the matched cohort (adjusted OR 2.02, 95% CI 1.54-2.61). Among patients in the COVID-19 cohort, patients with ILD were more likely to have severe COVID-19 than patients without ILD (47.8% versus 12.6%), including mortality (13.4% versus 2.8%) (all p<0.001). The risk of severe COVID-19 was significantly higher in patients with ILD than in those without ILD (adjusted OR 2.23, 95% CI 1.24-4.01). CONCLUSION: The risks of COVID-19 and severe presentation were significantly higher in patients with ILD than in those without ILD.

A case report of allergic bronchopulmonary mycosis caused by Alternaria alternata in colonization of Aspergillus.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease caused by a complex hypersensitivity reaction to colonization of the airways with various fungi. ABPA caused by Alternaria alternata, other than Aspergillus spp., is named Allergic bronchopulmonary mycosis (ABPM). OBJECTIVE: To describe the first case of ABPM caused by Alternaria alternata in East Asia. METHODS: Case report. RESULTS: A 58-year-old female visited our hospital due to an abnormal chest x-ray, following chest computed tomography (CT) revealed consolidation in the left lower lobe. On laboratory finding, eosinophil count and total IgE level were high. The skin prick test and specific IgE for Alternaria alternata were positive. After diagnosis of ABPM, the patient was treated with prednisolone without antifungal agents, and her chest image was much improved. CONCLUSIONS: Aspergillus is most common etiology of allergic pulmonary disease, however, Alternaria should be considered even though positive culture of Aspergillus spp.

Burden of male hardcore smokers and its characteristics among those eligible for lung cancer screening.

BACKGROUND: There are few data available about hardcore smokers and their behavioral characteristics among the lung cancer screening (LCS) population. The study investigated the burden of hardcore smokers within the LCS population, and determine the characteristics of hardcore smokers using nationally representative data in South Korea. METHODS: We used data from 2007 to 2012 from the Korean National Health and Nutrition Examination Survey. This study enrolled current male smokers aged 55-74 years. Among them, subjects eligible for LCS were defined as these populations with smoking histories of at least 30 PY. Hardcore smoking was defined as smoking >15 cigarettes per day, with no plan to quit, and having made no attempt to quit. Multivariate logistic regression analyses were used to estimate associations between hardcore smokers and various sociodemographic and other variables. RESULTS: The proportion of hardcore smokers among those who met LCS eligibility criteria decreased from 2007 to 2012 (from 39.07 to 29.47% of the population) but did not change significantly thereafter (P = 0.2770), and that proportion was consistently 10-15% higher than that of hardcore smokers among all male current smokers. The proportion without any plan to quit smoking decreased significantly from 54.35% in 2007 to 38.31% in 2012. However, the smokers who had made no intentional quit attempt in the prior year accounted for more than half of those eligible for LCS, and the proportion of such smokers did not change significantly during the study period (50.83% in 2007 and 51.03% in 2012). Multivariate logistic regression analyses showed that hardcore smokers were older (OR = 1.05, 95% confidence interval [CI] 1.01-1.09) than non-hardcore smokers. Hardcore smokers exhibited higher proportion of depression (OR = 6.55, 95% CI 1.75-24.61) and experienced extreme stress more frequently (OR = 1.93, 95% CI 1.13-3.29). Smokers who did not receive smoking cessation education within the past year were significantly more likely to be hardcore smokers (OR = 4.15, 95% CI 1.30-13.22). CONCLUSIONS: It is important to identify a subset of smokers unwilling or minimally motivated to quit within the context of lung cancer screening. Anti-smoking education should be enhanced to influence hardcore smokers' behavior.

Neutrophil Gelatinase-Associated Lipocalin for Predicting Intensive Care Unit Admission and Mortality in Patients with Pneumonia.

Pneumonia is one of the most common causes of hospital admissions and mortality, and it is responsible for significant socioeconomic burden worldwide. Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein, which is involved in iron trafficking and has chemostatic and bacteriostatic effects. NGAL is also known as an early marker of many inflammatory diseases. However, little is known about the role of NGAL in the management of pneumonia. Thus, this study aimed to investigate whether plasma NGAL levels can predict intensive care unit (ICU) admission and in-hospital mortality in patients with pneumonia. This retrospective observational study included 241 adults hospitalized with pneumonia who underwent NGAL measurement. We compared the prognostic values of plasma NGAL with pneumonia severity index (PSI) for prediction of ICU admission and in-hospital mortality. Of 241 patients, 47 (19.5%) died during hospital admission. There was no significant difference between NGAL and PSI for predicting ICU admission (area under the receiver operating characteristic curve [AUC] of log NGAL vs. PSI, P > 0.999). Although log NGAL was useful in predicting in-hospital mortality, its ability was inferior to that of PSI (AUC of log NGAL vs. PSI, P = 0.008). Multivariable analysis revealed that log NGAL was significantly associated with ICU admission (adjusted odds ratio = 10.76, P < 0.001) and in-hospital mortality (adjusted odds ratio = 5.04, P = 0.004). These results suggest that plasma NGAL level is a useful biomarker for predicting ICU admission and mortality in hospitalized patients with pneumonia.

Increased mortality in patients with corticosteroid-dependent asthma: a nationwide population-based study.

INTRODUCTION: Chronic systemic corticosteroid (CS) therapy is associated with an increased risk of mortality in patients with many chronic diseases. However, it has not been elucidated whether chronic systemic CS therapy is associated with increased mortality in patients with asthma. The aim of this study was to determine the effects of chronic systemic CS therapy on long-term mortality in adult patients with asthma. METHODS: A population-based matched cohort study of males and females aged ≥18 years with asthma was performed using the Korean National Health Insurance Service database from 2005 to 2015. Hazard ratio (HR) with 95% confidence interval for all-cause mortality among patients in the CS-dependent cohort (CS use ≥6 months during baseline period) relative to those in the CS-independent cohort (CS use <6 months during baseline period) was evaluated. RESULTS: The baseline cohort included 466 941 patients with asthma, of whom 8334 were CS-dependent and 458 607 were CS-independent. After 1:1 matching, 8334 subjects with CS-independent asthma were identified. The HR of mortality associated with CS-dependent asthma relative to CS-independent asthma was 2.17 (95% CI 2.04-2.31). In patients receiving low-dose CS, the HR was 1.84 (95% CI 1.69-2.00); in patients receiving high-dose CS, the HR was 2.56 (95% CI 2.35-2.80). CONCLUSIONS: In this real-world, clinical practice, observational study, chronic use of systemic CS was associated with increased risk of mortality in patients with asthma, with a significant dose-response relationship between systemic CS use and long-term mortality.

Robotic cholecystectomy using Revo-i Model MSR-5000, the newly developed Korean robotic surgical system: a preclinical study.

BACKGROUND: Laparoscopic surgery has become the standard option for gastrointestinal surgeries. However, laparoscopic procedures require extended training times and are difficult for inexperienced surgeons. Robot-assisted laparoscopic surgery facilitates easy adaptation of laparoscopic procedures, but robotic surgical systems are expensive. In addition, their cost has remained high because there is currently only one manufacturer of commercially available systems. Recently, a new Korean robotic surgical system, Revo-i, has been developed. The aim of this study was to evaluate the feasibility and safety of Revo-i by performing robotic cholecystectomy in a porcine model. METHODS: After approval by the Institutional Animal Care and Use Committee of Yonsei University Health System, cholecystectomy was performed in four pigs using the Revo-i robotic surgical system. Operative time and perioperative complications were recorded, and all animals were observed for postoperative complications for 2 weeks after surgery RESULTS: Robotic cholecystectomy was completed successfully and without gallbladder perforation in all cases. The mean operative time was 78 ± 12 min, the mean docking time was 4.5 ± 2.52 min, and the mean console time was 49.8 ± 14.17 min. There were no perioperative complications, and none of the animal used for the in vivo models exhibited abnormal behavior during the postoperative observation period. CONCLUSIONS: These preliminary results verify the safety and efficacy of robotic cholecystectomy using the Revo-i robotic surgical system. Human trials are slated to begin accordingly.

Prevalence and Risk Factors of Respiratory Viral Infections in Exacerbations of Chronic Obstructive Pulmonary Disease.

Exacerbations of chronic obstructive pulmonary disease (COPD) lead to high morbidity and mortality. Respiratory virus infection is considered as one of the important causes of COPD exacerbations. The aim of this study was to assess the prevalence of respiratory virus infection in COPD exacerbations and to find the factors associated with susceptibility to viral infections. Furthermore, we tried to examine if COPD exacerbations caused by viral infections have more severe clinical outcomes in comparison with those with non-viral causes. We enrolled the patients with acute exacerbations of COPD who were hospitalized in a university hospital, over a 2-year period. Nasopharyngeal swabs were taken and viruses were identified by multiplex polymerase chain reaction. A total of 278 episodes of COPD exacerbations were recorded in 213 patients with COPD (number of females = 73). Among the COPD exacerbations, viral infection was detected in 78 episodes (28.1%) from 67 subjects. The most common virus was rhinovirus (38.8%), followed by respiratory syncytial virus, coronavirus, influenza A, parainfluenza, adenovirus and metapneumovirus. In multivariate regression analysis adjusting for sex, age, BMI, lung function and history of exacerbations, female subjects were found to be significantly associated with viral infections in COPD exacerbations (Odds ratio 2.58, 95%CI 1.25-5.31, P = 0.010). The severity of COPD exacerbations were not different between positive and negative viral detections. In conclusion, the prevalence of viral infection was 28.1% in the hospitalized patients with COPD exacerbations. Moreover, female subjects are at significantly higher risk for viral infections in COPD exacerbations.

The Association of Fever with Total Mechanical Ventilation Time in Critically Ill Patients.

This research aims to investigate the impact of fever on total mechanical ventilation time (TVT) in critically ill patients. Subgroup analysis was conducted using a previous prospective, multicenter observational study. We included mechanically ventilated patients for more than 24 hours from 10 Korean and 15 Japanese intensive care units (ICU), and recorded maximal body temperature under the support of mechanical ventilation (MAX(MV)). To assess the independent association of MAX(MV) with TVT, we used propensity-matched analysis in a total of 769 survived patients with medical or surgical admission, separately. Together with multiple linear regression analysis to evaluate the association between the severity of fever and TVT, the effect of MAX(MV) on ventilator-free days was also observed by quantile regression analysis in all subjects including non-survivors. After propensity score matching, a MAX(MV) ≥ 37.5°C was significantly associated with longer mean TVT by 5.4 days in medical admission, and by 1.2 days in surgical admission, compared to those with MAX(MV) of 36.5°C to 37.4°C. In multivariate linear regression analysis, patients with three categories of fever (MAX(MV) of 37.5°C to 38.4°C, 38.5°C to 39.4°C, and ≥ 39.5°C) sustained a significantly longer duration of TVT than those with normal range of MAX(MV) in both categories of ICU admission. A significant association between MAX(MV) and mechanical ventilator-free days was also observed in all enrolled subjects. Fever may be a detrimental factor to prolong TVT in mechanically ventilated patients. These findings suggest that fever in mechanically ventilated patients might be associated with worse mechanical ventilation outcome.

Ethical issues recognized by critical care nurses in the intensive care units of a tertiary hospital during two separate periods.

This research aimed to investigate the changes in ethical issues in everyday clinical practice recognized by critical care nurses during two observation periods. We conducted a retrospective analysis of data obtained by prospective questionnaire surveys of nurses in the intensive care units (ICU) of a tertiary university-affiliated hospital in Seoul, Korea. Data were collected prospectively during two different periods, February 2002-January 2003 (Period 1) and August 2011-July 2012 (Period 2). Significantly fewer cases with ethical issues were reported in Period 2 than in Period 1 (89 cases [2.1%] of 4,291 ICU admissions vs. 51 [0.5%] of 9,302 ICU admissions, respectively; P < 0.001). The highest incidence of cases with identified ethical issues in both Periods occurred in MICU. The major source of ethical issues in Periods 1 and 2 was behavior-related. Among behaviorrelated issues, inappropriate healthcare professional behavior was predominant in both periods and mainly involved resident physicians. Ethical issue numbers regarding end-oflife (EOL) care significantly decreased in the proportion with respect to ethical issues during Period 2 (P = 0.044). In conclusion, the decreased incidence of cases with identified ethical issues in Period 2 might be associated with ethical enhancement related with EOL and improvements in the ICU care environment of the studied hospital. However, behaviorrelated issues involving resident physicians represent a considerable proportion of ethical issues encountered by critical care nurses. A systemic approach to solve behavior-related issues of resident physicians seems to be required to enhance an ethical environment in the studied ICU.

Predicting postoperative lung function using ventilation SPECT/CT in patients with lung cancer.

Background: Single-photon emission computed tomography/computed tomography (SPECT/CT) has the advantage of assessing regional lung function. We aimed to investigate the potential of ventilation (SPECT/CT) for predicting postoperative lung function in patients with lung cancer. Methods: This retrospective study included consecutive patients with lung cancer who underwent lobectomy, preoperative ventilation, and perfusion SPECT/CT between January 2020 and December 2021. The percentage of predicted postoperative forced expiratory volume in 1 s (ppoFEV1%) and the percentage of predicted postoperative diffusion capacity of the lung for carbon monoxide (ppoDLCO%) were calculated from the % counts of each scan based on anatomical segments for lobar function. Correlation tests were performed between the predicted lung function values and actual ppoFEV1% and ppoDLCO%. Results: Among the 47 patients, 29 men and 18 women aged 67.5±9.6 years were included. Moreover, 46 ventilation and 41 perfusion SPECT/CT scans were obtained. The pulmonary function on ventilation SPECT/CT strongly correlated with perfusion SPECT/CT (correlation coefficient r=0.939 for ppoFEV1%, P<0.001; r=0.938 for ppoDLCO%, P<0.001). Both ppoFEV1% and ppoDLCO% values obtained from the ventilation and perfusion scans strongly correlated with postoperative FEV1% and DLCO% (correlation coefficient, r=0.774 and r=0.768 for ventilation; r=0.795 and r=0.751 for perfusion, each P<0.001). Conclusions: Ventilation SPECT/CT was comparable to perfusion SPECT/CT in predicting postoperative lung function.

Determination of contamination sources and geochemical reactions in groundwater of a mine area using Cu, Zn, and S-O isotopes.

To determine contamination sources and pathways, the use of multiple isotopes, including metal isotopes, can increase the reliability of environmental forensic techniques. This study differentiated contamination sources in groundwater of a mine area and elucidated geochemical processes using Cu, Zn, S-O, and O-H isotopes. Sulfate reduction and sulfide precipitation were elucidated using concentrations of dissolved sulfides, δ34SSO4, δ18OSO4, and δ66Zn. The overlying contaminated soil was possibly responsible for the contamination of groundwater at <5 mbgl, which was suggested by low δ65Cu values (0.419-1.120‰) reflecting those of soil (0.279-1.115‰). The existence of dissolved Cu as Cu(I) may prevent the increase in δ65Cu during leaching of contaminated soil in the sulfate-reducing environment. In contrast, the groundwater at >5 mbgl seemed to be highly affected by the contamination plume from the adit water, which was suggested by high SO42- concentrations (407-447 mg L-1) and δ65Cu (0.252-2.275‰) and δ66Zn (-0.105‰-0.362‰) values at a multilevel sampler approaching those of the adit seepages. Additionally, the O-H isotopic ratios were distinguished between <5 mbgl and >5 mbgl. Using δ65Cu and δ66Zn to support the determination of groundwater contamination sources may be encouraged, particularly where the isotopic signatures are distinct for each source.