Is the 1-day surprise question a useful screening tool for predicting prognosis in patients with advanced cancer?—a multicenter prospective observational study

Introduction

Accurate survival prediction of cancer patients is critical (1). It is essential for determining the goals of care among physicians, patients, and their families because many important decisions, such as those determining care plans and advance care planning depend on expected survival time (2,3). Therefore, if the responsible physicians’ prognosis is inaccurate or wrong, patients may receive unwanted and harmful treatments (4). It is even more important to predict the prognosis of cancer patients with impending death because their conditions change rapidly, and individualized care that incorporates predicting prognosis is key for providing better care to patients and their families (5). Several prognostic tools such as prognosis in palliative care study predictor models (PiPS), palliative prognostic index (PPI), and palliative prognosis (PaP) Score have been utilized to predict the prognosis of cancer patients on a weekly or monthly basis (6-10). However, these tools have not been validated as tools for predicting prognosis on daily basis.

The surprise question (SQ), “Would I be surprised if this patient died in the next 12 months?” is widely known as a practicable, simple, and helpful tool for identifying cancer patients who are at increased risk of one year mortality and would respond well to hospice and palliative care (11,12). Previous studies have shown that the 7-day SQ (7DSQ), “Would I be surprised if this patient died in the next 7 days?” is a highly sensitive and feasible way to predict the prognosis (13). Our study group had previously reported that the 3-Day SQ (3DSQ), “Would I be surprised if this patient died in the next 3 days?” was also highly sensitive in cancer patients with impending death (14).

There are few screening tools to identify cancer patients who die within one day, and we examined the possibility that the 1-Day Surprise Question (1DSQ), “Would I be surprised if this patient died in the next 1 day?” may be as helpful as the 3DSQ to predict the prognosis of cancer patients with impending death. It has been previously reported that family members were most stressed during the unpredictable death of the patient (15). If the sensitivity of the 1DSQ was as high as that of the 3DSQ, physicians and family members would be able to better prepare for rapidly changing conditions at the time of ending, and allow patients and their family members to be together at the time of death.

Therefore, our aims were to elucidate the usefulness of the 1DSQ in cancer patients with impending death, and to identify the characteristics of patients who ultimately died among those whose physicians answered “not surprised” to the 1DSQ.

We present the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/apm-21-1718).

Methods

Participants

The current study was a sub-analysis using Japanese domestic data as a part of the East-Asian collaborative cross-cultural Study to Elucidate the Dying process (EASED) data. The EASED was a multicenter, prospective, observational study conducted to better understand the process of death and terminal care in patients with advanced cancer admitted to palliative care units (PCUs) in Japan, Korea, and Taiwan.

Adult patients over 18 years old who were diagnosed with metastatic or locally extensive cancer and were newly admitted to PCUs were included. Patients who refused to be enrolled in this study or were scheduled to be discharged within 1 week were excluded. Consecutive patients were registered if they had been referred to the participating PCUs during the study duration.

The observations were conducted in daily clinical practice. The responsible physicians prospectively reported data on a data-collecting sheet created for this study, which was piloted prior to study initiation.

Data collection

We collected data regarding the characteristics of the patients and medical care received during the PCUs admission. The characteristics of the patients were sex, primary cancer site, metastasis, and past medical treatment as examples. The medical care received during the PCUs admission were oxygen and opioid administration, corticosteroid medication, infusion therapy, sedative therapy, administration of benzodiazepines, and administration of airway secretion inhibitors. Furthermore, we also collected data on patients’ vital signs, physical signs, and clinical symptoms on the first day, when the patient had palliative performance scale (PPS) ≤20. The vital signs were respiratory rate, oxygen saturation of peripheral artery, urine output, and body temperature. The physical signs were modified Richmond Agitation Sedation Scale score (modified RASS), pulse of radial artery, peripheral cyanosis, bronchial secretions, respiration with mandibular movement, Eastern Cooperative Oncology Group Performance Status, dysphagia of liquids, response to visual stimuli, hyperextension of neck, response to verbal stimuli, grunting of vocal cords, inability to close eyelids, apnea periods, and Cheyne-Stokes breathing. The modified RASS has been validated as a tool for assessing the severity of agitation and sedation levels in cancer patients (16). The clinical symptoms were dyspnea, pain, fatigue, delirium, and edema. The clinical symptoms were assessed using the integrated palliative care outcome scale (IPOS). The IPOS of Japanese version has been demonstrated to be valid for assessing the physical and psychological status of patients with cancer (17).

All factors were chosen as representative factors, which we considered to be prognostic in daily clinical practice.

Measurements

We defined “day 0” as the first day on which each patient had PPS ≤20; physicians’ answers to the 1DSQ, “Would I be surprised if this patient died in the next 1 day?” were collected on this day. The same responsible physician, who collected the patient information, including physical signs and clinical symptoms, answered the 1DSQ. The response was categorized as “surprised” or “not surprised”. We followed up the patients until death, and defined “died in the next 1 day” as death having occurred between day 0 and day 1.

Data analysis and statistics

First, to summarize the patients’ baseline characteristics, we performed descriptive analyses.

Second, the patients were placed in the “surprised” and “not surprised” groups according to the 1DSQ answers of responsible physicians. We also added the patients’ state: alive or dead, on day 1 and created a 2×2 contingency table based on these results. We used simple statistical analysis to compute the sensitivity, specificity, positive predictive value and negative predictive value based on this table.

Third, to clarify factors of patients who died within the next 1 day as those whom the physicians answered “not surprised” to the 1DSQ, we categorized the patients into two groups. Patients whose physicians answered “not surprised” and died within the next 1 day were categorized group A and defined as the “predictable death group”. Patients whose physicians answered “not surprised” but did not die within the next 1 day were categorized as group B.

Fourth, we performed a Fisher’s exact test for categorical variables and a Cochran-Armitage trend test for ordinal variables to clarify patients’ factors related to the “Predictable death group”.

Fifth, we put variables with P˂0.05 derived from univariate analyses into a multivariate logistic regression analysis to identify the patients’ factors related to the “predictable death group”.

We performed statistical analyses using JMP Pro version 14 (SAS, Cary, NC, USA).

Ethical statement

The present study was conducted in accordance with the ethical standards of the Declaration of Helsinki (as revised in 2013) and the ethical guidelines for medical and health research involving human subjects presented by the Ministry of Health, Labour, and Welfare in Japan, and was approved by the local institutional review boards of all participating institutions. All procedures were in accordance with the ethical standards of the independent ethics committee of Tohoku University School of Medicine (approval No. 2016-1-689). Japanese law does not require individual informed consent from participants in a non-invasive observational trial, such as in the present study. Therefore, we used an opt-out method rather than acquiring written or oral informed consent.

Results

A total of 1,896 patients were enrolled from 22 PCUs in Japan between January and December 2017. Among these, 485 patients were excluded: 245 patients were discharged from the hospital alive and 240 patients had missing data on day 0. The remaining 1,411 patients were analyzed (Figure 1).

Figure 1 Patient selection for this study.

We summarized the baseline characteristics of 1,411 patients in Table 1. The mean (standard deviation) age was 72.6 (12.2) years, and the most common primary cancer site was the lungs (17.1%).

We indicate a 2×2 contingency table (Table 2). The responsible physicians answered “not surprised” for 847 (60.0%) patients. This prediction showed a sensitivity of 82.0% [95% confidence interval (CI): 77.5–85.8%] and specificity of 45.5% (95% CI: 44.4–46.4%). The positive predictive value was 27.4% (95% CI: 25.9–28.7%), and the negative predictive value was 91.0% (95% CI: 88.7–92.9%).

Table S1 showed the results of all variables for which univariate analysis was performed to clarify factors related to the “predictable death group”, and Table 3 summarizes 17 variables with P˂0.05. The 17 variables were urine output over last 12 h <100 mL (P<0.01), decreased response to verbal stimuli (P<0.01), oxygen administration (P<0.01), decreased response to visual stimuli (P<0.01), radial artery (P<0.01), dysphagia of liquids (P<0.01), peripheral cyanosis (P<0.01), respiration with mandibular movement (P<0.01), saturation of percutaneous oxygen (SpO₂) (P<0.01), hyperextension of neck (P=0.02), grunting of vocal cords (P=0.02), dyspnea (P=0.02), infusion therapy (P=0.02), age (P=0.03), sex (P=0.04), inability to close eyelids (P=0.04), and opioid administration (P=0.04).

Table 4 lists the results of the multivariate analysis. We found that five factors associated with the “predictable death group”. The five factors were urine output over the last 12 hours [<100 vs. ≥100 mL; odds ratio (OR) 2.11; 95% CI: 1.41–3.12; P<0.01], decreased response to visual stimuli (present vs. absent; OR 1.71; 95% CI: 1.03–2.82; P=0.04), respiration with mandibular movement (present vs. absent; OR 2.69; 95% CI: 1.28–5.63; P=0.01), radial artery (pulselessness vs. palpable; OR 2.32; 95% CI: 1.21–4.46; P=0.01), and SpO₂ (<89% vs. ≥90%; OR 3.20; 95% CI: 1.95–5.26; P<0.01).

Discussion

This is the first study to verify the usefulness of the 1DSQ as a tool for estimating the prognosis of cancer patients with impending death using a large group.

Our analyses revealed that the 1DSQ has a high sensitivity in predicting death in cancer patients within 1 day and may be useful as a screening tool in this context. White et al. reported the mean sensitivity of SQs to predict the prognosis cancer patients within 12 months was 77.1% (18). In comparison, the 1DSQ has a higher sensitivity (82.0%). This may be attributed to the standardization of the question when a patient had PPS ≤20. Most of palliative physicians recognize that patients with PPS ≤20 have a poorer prognosis, which may have caused a physician to respond with “not surprised”. When physicians answered “not surprised” to the 1DSQ, the physicians should carefully explain to the family member the possibility of the patient dying within 1 day. We believe that using the 1DSQ to carefully explain the prognosis to the patient’s family will significantly improve psychological care for those affected.

However, compared to other studies that used SQs for short-term prognosis, the 1DSQ had a slightly lower sensitivity; Hamano et al. reported that the sensitivity and specificity of the 30-day surprise question were 95.6% and 37.0%, respectively, and 7-day surprise question were 84.7% and 68.0%, respectively (13). In addition, our previous findings revealed a sensitivity and specificity of 94.3% and 26.3% for the 3DSQ, respectively (14). One possible explanation for the discrepancy in sensitivity may be that physicians could not confidently answer “not surprised” to cancer patients who died within 1 day. It is known that physicians refer to the physical signs and clinical symptoms of cancer patients with impending death when predicting their prognosis (5). Hui et al. reported on 16 clinical signs that often occur between 1.5 and 5.5 days prior to death in cancer patients (19). Among them, the clinical sign that occurred most often within 1 day before death was only “pulselessness of radial artery (19-21)”. The lack of clarity in the physical signs and clinical symptoms of cancer patients who die within 1 day may cause physicians to hesitate in making their decisions. However, we believe that the 1DSQ is a valuable screening tools to identify cancer patients who die within one day, as it has a high sensitivity while there are few accurate physical signs and clinical symptoms that can predict death within one day. In addition, the 1DSQ can be conveniently performed at a patient’s bedside. The usefulness of the 1DSQ may be further enhanced as more research is conducted on the clinical signs and symptoms that often occur immediately before death.

We identified five variables associated with the factors of patients who were likely to die within 1 day, as the physicians predicted. These were urine output over last 12 hours <100 mL, decreased response to visual stimuli, respiration with mandibular movement, pulselessness of radial artery, and SpO₂ <90%. These signs have been previously reported to occur in cancer patients 3 days before death (5,19-22). In particular, urine output over last 12 hours <100 mL, respiration with mandibular movement, and pulselessness of radial artery have been shown to be the signs that most likely occur 1-1.5 days before death (20). If physicians answer the 1DSQ with “not surprised” and notice these clinical signs, the patients’ condition should be observed more carefully.

In our previous study investigating the 3DSQ, adjunctive medical treatment, such as opioid administration and continuous deep sedation, was identified as a factor to assist in predicting prognosis (14). However, this study only presented the patients’ physical signs. The result of this study suggests that the physical signs may be more important for predicting which patients will die within 1 day.

This study has some limitations. First, physical signs and clinical symptoms of patients might influence the physician’s answer to the 1DSQ. However, as the SQ is a tool that relies on the physician’s intuition, we believe that it is unavoidable in this study and in clinical practice. We consider that the 1DSQ is not a screening tool to be used alone, but rather should be used in conjunction with physical signs and symptoms. Among these, we revealed the five signs that may be more helpful when combined in this study. Second, the 1DSQ was answered by palliative care physicians; non-palliative care physicians may have provided different answers and thus yielded different results. Further studies involving non-palliative care physicians should be conducted to clarify this possibility. Third, the physicians may have been influenced by other prognostic tools such as PiPS models, PPI, or PaP score when answering the 1DSQ. However, we considered this effect to be unclear as these tools have not been optimized for predicting the prognosis of cancer patients with impending death (6-8). Fourth, the medical care provided in PCUs may differ from that provided in a general ward. However, the medical care provided to patients with PPS ≤20 was expected to be almost identical, and thus, it might not be a determining factor for this study. Fifth, we lack information regarding the attending physicians, such as age, gender, and years of experience, which might have influenced our results.

Conclusions

Based on our findings, the 1DSQ has proven to be a helpful screening tool for identifying cancer patients with impending death.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing. This study was performed in the East-Asian collaborative cross-cultural Study to Elucidate the Dying process (EASED). The participating study sites and site investigators in Japan were as follows: Satoshi Inoue, MD (Seirei Hospice, Seirei Mikatahara General Hospital), Naosuke Yokomichi, MD, PhD (Department of Palliative and Supportive Care, Seirei Mikatahara General Hospital), Kengo Imai, MD (Seirei Hospice, Seirei Mikatahara General Hospital), Tatsuya Morita, MD (Department of Palliative and Supportive Care, Seirei Mikatahara General Hospital), Hiroaki Tsukuura, MD, PhD (Department of Palliative Care, TUMS Urayasu Hospital), Toshihiro Yamauchi, MD (Seirei Hospice, Seirei Mikatahara General Hospital), Akemi Shirado Naito, MD (Department of palliative care Miyazaki Medical Association Hospital), Akira Yoshioka, MD, PhD (Department of Oncology and Palliative Medicine, Mitsubishi Kyoto Hospital), Shuji Hiramoto, MD (Department of Oncology and Palliative Medicine, Mitsubishi Kyoto Hospital), Ayako Kikuchi, MD (Department of Oncology and Palliative Medicine, Mitsubishi Kyoto Hospital), Tetsuo Hori, MD (Department of Respiratory surgery, Mitsubishi Kyoto Hospital), Hiroyuki Kohara, MD, PhD (Hiroshima Prefectural Hospital), Hiromi Funaki, MD (Hiroshima Prefectural Hospital), Keiko Tanaka, MD, PhD (Department of Palliative Care Tokyo Metropolitan Cancer & Infectious Diseases Center Komagome Hospital), Kozue Suzuki, MD (Department of Palliative Care Tokyo Metropolitan Cancer & Infectious Diseases Center Komagome Hospital), Tina Kamei, MD (Department of Palliative Care, NTT Medical Center Tokyo), Yukari Azuma, MD (Home Care Clinic Aozora Shin-Matsudo), Teruaki Uno, MD (Department of Palliative Medicine, Osaka City General Hospital), Jiro Miyamoto, MD (Department of Palliative Medicine, Osaka City General Hospital), Hirofumi Katayama, MD (Department of Palliative Medicine, Osaka City General Hospital), Hideyuki Kashiwagi, MD, MBA (Aso Iizuka Hospital/Transitional and Palliative Care), Eri Matsumoto, MD (Aso Iizuka Hospital/Transitional and Palliative Care), Takeya Yamaguchi, MD (Japan Community Health care Organization Kyushu Hospital/Palliative Care), Tomonao Okamura, MD, MBA. (Aso Iizuka Hospital/Transitional and Palliative Care), Hoshu Hashimoto, MD, MBA. (Inoue Hospital/Internal Medicine), Shunsuke Kosugi, MD (Department of General Internal Medicine, Aso Iizuka Hospital), Nao Ikuta, MD (Department of Emergency Medicine, Osaka Red Cross Hospital), Yaichiro Matsumoto, MD (Department of Transitional and Palliative Care, Aso Iizuka Hospital), Takashi Ohmori, MD (Department of Transitional and Palliative Care, Aso Iizuka Hospital), Takehiro Nakai, MD (Immuno-Rheumatology Center, St Luke‘s International Hospital), Takashi Ikee, MD (Department of Cardiorogy, Aso Iizuka Hospital), Yuto Unoki, MD (Department of General Internal Medicine, Aso Iizuka Hospital), Kazuki Kitade, MD (Department of Orthopedic Surgery, Saga-Ken Medical Centre Koseikan), Shu Koito, MD (Department of General Internal Medicine, Aso Iizuka Hospital), Nanao Ishibashi, MD (Environmental Health and Safety Division, Environmental Health Department, Ministry of the Environment), Masaya Ehara, MD (TOSHIBA), Kosuke Kuwahara, MD (Department of General Internal Medicine, Aso Iizuka Hospital), Shohei Ueno, MD (Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital), Shunsuke Nakashima, MD (Oshima Clinic), Yuta Ishiyama, MD (Department of Transitional and Palliative Care, Aso Iizuka Hospital), Akihiro Sakashita, MD, PhD (Department of Palliative Medicine, Kobe University School of Medicine), Ryo Matsunuma, MD (Department of Palliative Medicine, Kobe University Graduate School of Medicine), Hana Takatsu, MD (Division of Palliative Care, Konan Medical Center), Takashi Yamaguchi, MD, PhD (Division of Palliative Care, Konan Medical Center), Satoko Ito, MD (Hospice, The Japan Baptist Hospital), Toru Terabayashi, MD (Hospice, The Japan Baptist Hospital), Jun Nakagawa, MD (Hospice, The Japan Baptist Hospital), Tetsuya Yamagiwa, MD, PhD (Hospice, The Japan Baptist Hospital), Akira Inoue, MD, PhD (Department of Palliative Medicine Tohoku University School of Medicine), Mitsunori Miyashita, R.N., PhD (Department of Palliative Nursing, Health Sciences, Tohoku University Graduate School of Medicine), Saran Yoshida, PhD (Graduate School of Education, Tohoku University), Hiroaki Watanabe, MD (Department of Palliative Care, Komaki City Hospital), Takuya Odagiri, MD (Department of Palliative Care, Komaki City Hospital), Tetsuya Ito, MD, PhD (Department of Palliative Care, Japanese Red Cross Medical Center), Masayuki Ikenaga, MD (Hospice, Yodogawa Christian Hospital), Keiji Shimizu, MD, PhD (Department of Palliative Care Internal Medicine, Osaka General Hospital of West Japan Railway Company), Akira Hayakawa, MD, PhD (Hospice, Yodogawa Christian Hospital), Rena Kamura, MD (Hospice, Yodogawa Christian Hospital), Takeru Okoshi, MD, PhD (Okoshi Nagominomori Clinic), Tomohiro Nishi, MD (Kawasaki Municipal Ida Hospital, Kawasaki Comprehensive Care Center), Kazuhiro Kosugi, MD (Department of Palliative Medicine, National Cancer Center Hospital East), Yasuhiro Shibata, MD (Kawasaki Municipal Ida Hospital, Kawasaki Comprehensive Care Center), Takayuki Hisanaga, MD (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Takahiro Higashibata, MD, PhD (Department of General Medicine and Primary Care, Palliative Care Team, University of Tsukuba Hospital), Ritsuko Yabuki, MD (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Shingo Hagiwara, MD, PhD (Department of Palliative Medicine, Yuai Memorial Hospital), Miho Shimokawa, MD (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Satoshi Miyake, MD, PhD (Professor, Department of Clinical Oncology Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU)), Junko Nozato, MD (Specially Appointed Assistant Professor, Department of Internal Medicine, Palliative Care, Medical Hospital, Tokyo Medical and Dental University), Hiroto Ishiki, MD (Department of Palliative Medicine, National Cancer Center Hospital), Tetsuji Iriyama, MD (Specially Appointed Assistant Professor, Department of Internal Medicine, Palliative Care, Medical Hospital, Tokyo Medical and Dental University), Keisuke Kaneishi, MD, PhD (Department of Palliative Care Unit, JCHO Tokyo Shinjuku Medical Center), Mika Baba, MD, PhD (Department of Palliative medicine Suita Tokushukai Hospital), Tomofumi Miura, MD, PhD (Department of Palliative Medicine, National Cancer Center Hospital East), Yoshihisa Matsumoto, MD, PhD (Department of Palliative Medicine, National Cancer Center Hospital East), Ayumi Okizaki, PhD (Department of Palliative Medicine, National Cancer Center Hospital East), Yuki Sumazaki Watanabe, MD (Department of Palliative Medicine, National Cancer Center Hospital East), Yuko uehara, MD (Department of Palliative Medicine, National Cancer Center Hospital East), Eriko Satomi, MD (Department of palliative medicine, National Cancer Center Hospital), Kaoru Nishijima, MD (Department of Palliative Medicine, Kobe University Graduate School of Medicine), Junichi Shimoinaba, MD (Department of Hospice Palliative Care, Eikoh Hospital), Ryoichi Nakahori, MD (Department of Palliative Care, Fukuoka Minato Home Medical Care Clinic), Takeshi Hirohashi, MD (Eiju General Hospital), Jun Hamano, MD, PhD (Assistant Professor, Faculty of Medicine, University of Tsukuba), Natsuki Kawashima, MD (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Takashi Kawaguchi, PhD (Tokyo University of Pharmacy and Life Sciences Department of Practical Pharmacy), Megumi Uchida, MD, PhD (Department of Psychiatry and Cognitive-Behavioral Medicine, Nagoya City University Graduate School of Medical Sciences), Ko Sato, MD, PhD (Hospice, Ise Municipal General Hospital), Yoichi Matsuda, MD, PhD (Department of Anesthesiology & Intensive Care Medicine/Osaka University Graduate School of Medicine), Yutaka Hatano, MD, PhD (Hospice, Gratia Hospital), Satoru Tsuneto, MD, PhD (Professor, Department of Human Health Sciences, Graduate School of Medicine, Kyoto University Department of Palliative Medicine, Kyoto University Hospital), Sayaka Maeda, MD (Department of Palliative Medicine, Kyoto University Hospital), Yoshiyuki Kizawa, MD, PhD, FJSIM, DSBPMJ (Designated Professor and Chair, Department of Palliative Medicine, Kobe University School of Medicine), Hiroyuki Otani, MD (Palliative Care Team, and Palliative and Supportive Care, National Kyushu Cancer Center), Isseki Maeda, MD, PhD (Department of Palliative Care, Senri-Chuo Hospital).

Funding: This work was supported in part by a Grant-in-Aid from the Japanese Hospice Palliative Care Foundation (Grant Numbers 16H05212 and 16KT0007).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-1718

Data Sharing Statement: Available at https://dx.doi.org/10.21037/apm-21-1718

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-1718). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The present study was conducted in accordance with the ethical standards of the Declaration of Helsinki (as revised in 2013) and the ethical guidelines for medical and health research involving human subjects presented by the Ministry of Health, Labour, and Welfare in Japan, and was approved by the local institutional review boards of all participating institutions. All procedures were in accordance with the ethical standards of the independent ethics committee of Tohoku University School of Medicine (approval No. 2016-1-689). Japanese law does not require individual informed consent from participants in a non-invasive observational trial, such as in the present study. Therefore, we used an opt-out method rather than acquiring written or oral informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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