Browsing Over 29 Presentations
Presentation Topic- Palliative care
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- Palliative care
1278P - How do hospitalized patients with chronic liver disease, with and without hepatocellular carcinoma, die? End-of-life quality analysis
- Ana Catarina Bravo (Lisbon, Portugal)
Abstract
Background
Chronic liver disease (CLD) is a major cause of morbidity and mortality. However, they are poorly established metrics to assess the quality of end-of-life (EOL) care in this context. Offering better care to who is dying is an important mission of health professionals, but EOL interventions can be futile, prolong suffering and consume resources better allocated to other needs. We aimed to characterize and compare the EOL of patients with CLD, with and without hepatocellular carcinoma (HCC).
Methods
Retrospective cohort study including all patients who died with CLD between 2012-2021 in charge of Gastroenterology, in a tertiary hospital.
Results
72 patients, 89% male, with a mean age of 64±11 years, 68% Child-Pugh C and 50% with HCC. In the last 6 months of life, patients had a median of 2 (IQR 1-6) hospitalizations, and they were hospitalized a median of 21.5 (IQR 13.25-38.5) days, 15 (IQR 9.25-24.5) in the last month. Only 38% were referred to palliative care (PC), with a median of 5 (IQR 2-15) days between referral and death. 86% had prescribed do-not-resuscitate order, with a median of 3 (IQR 1-9) days between this and death. In 42%, endoscopic procedures were performed in the last hospitalization. In 58% and 17%, it was documented, in the clinical process, discussion of the prognosis with the family and the patient, respectively. There was a significant difference between patients with and without HCC in their referral to PC (53% vs 22%, p-value 0.007) and sharing the prognosis with the patient (31% vs 3%, p-value 0.002).
Conclusions
In this cohort, there was a late referral to PC in general, being lower in the group of patients without HCC. It is imperative to select and apply quality of death metrics in patients with CLD, with and without HCC, aiming to improve care, manage expectations and resources.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1279P - Changes in vital signs of end-of-life patients with advanced cancer: A prospective cohort study
- Shuji Hiramoto (Kyoto, Japan)
Abstract
Background
Changes in vital signs in end-of-life (EOL) cancer patients near impending death are relatively common. However, there are few reports indicate that the timing of death can be predicted by changes in vital signs is unclear. The aim of this study was to clarify the role of changes in vital signs in patients with advanced cancer near impending death.
Methods
In this pre-planned secondary analysis of a multicenter, prospective East Asian cross-cultural collaborative cohort study in palliative care units (PCU) between January and December 2017 had their vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation, and temperature) documented once a day serially from a palliative performance scale (PPS) of <20 to death. We divided the timeframes into Segment 1 (Seg 1): days 14–3 and Segment 2 (Seg 2): days 2–1 from date of death, and measured changes in vital signs. We calculated respective sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) for death in two days.
Results
The 1,221 study patients (633 men, 588 women; median age: 73 years) came from 21 institutions throughout Japan. Average vital signs were 107.45 mmHg in Seg 1 and 95.08 in Seg 2 for systolic blood pressure; 67.51 mmHg in Seg 1 and 61.64 mmHg in Seg 2 for diastolic blood pressure; 97.38 in Seg 1 and 100.55 in Seg 2 for heart rate; 15.32 in Seg 1 and 16.23 in Seg 2 for respiratory rate; 37.06 in Seg 1 and 37.19 in Seg 2 for body temperature; and 94.86 in Seg1 and 93.43 in Seg 2 for oxygen saturation. Systolic blood pressure (p<0.001), diastolic blood pressure (p<0.001), heart rate (p=0.002), respiratory rate (p=0.004), body temperature (p=0.001), and oxygen saturation (p<0.001) varied significantly between Segment 1 and Segment 2. The changes in vital signs to predict impending death were generally characterized by low sensitivity (4.8–51.8%) and high specificity (68.0–96.0%).
Conclusions
Vital signs significantly change near impending death in patients with cancer. The changes in vital signs to predict impending death were generally characterized by low sensitivity and high specificity.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1280P - Validation of HAprog, an app for advanced cancer outpatient prognostication in routine practice
- Daniel D. Preto (Barretos, Brazil)
Abstract
Background
HAprog is a freely and user-friendly app for prognostication of advanced cancer outpatients. It is a computational transcription of two prognostic models: a ‘full version' composed of 6 parameters: sex, locoregional disease, sites of metastasis, ECOG-PS, WBC and albumin; and a 'clinical version' adding 'antineoplastic treatment' and without laboratory variables. The prognostic predictions are expressed in probability of being alive (in 30, 90 and 180 days) and expected scenarios (days).
Methods
A sample of advanced cancer outpatients were randomly selected from a retrospective databank cohort (2015-2019). HAprog was assessed at the time patients were first referred to palliative care. The clinical version was evaluated in all cases and the complete version when laboratory variables were available. Calibration (Hosmer-Lemeshow test) and discrimination (C-index and area under the receiver operating characteristic curve [AUROC]) were measured. Agreement analyzes were performed comparing predicted survival scenarios with the actual overall survival. Correlation analysis were performed using Spearman's test.
Results
HAprog clinical and full versions were evaluated in a total of 255 and 133 patients, respectively. The median overall survival (mOS) was 82 (95% CI 72-105) days. The C-index was similar in HAprog full and clinical versions (0.698 and 0.684, respectively). The AUROC were >0.75 at 30, 90 and 180 days in both versions and there were good calibration results. The absolute agreement rate between the actual survival time and the interval between expected scenarios (lower-upper) was 65.9% (95% CI 60.1-71.9%). The agreement rate between the actual survival time and the interval between the worst and best scenarios was 92.2% (95% CI 88.5-95.4%). The mean times of the HAprog expected scenarios were significant correlated with the actual patient survival (Rho=0.663, 95% CI 0.578-0.725).
Conclusions
The HAprog is an app for prognostication with adequate calibration and discriminations properties. It is able to provide prognostic information with good accuracy and correlation in order to assist the clinicians in decision making process.
Legal entity responsible for the study
Barretos Cancer Hospital.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1281P - Attitude toward palliative care among Panamanian physicians: A national questionnaire-based study
- Omar Castillo Fernandez (Panama City, Panama)
Abstract
Background
In Panama cancer is one of the leading causes of death. The palliative care need is growing and there is limited training on palliative care for health professionals in our country. To address and understand this unmet situation a national survey of non-oncologist Panamanian physicians was done to evaluate their confidence to handle palliative situations and their disposition to take palliative care courses.
Methods
A survey was sent through mail and physicians’ group in which self-estimation of confidence about somatic, psychological, and spiritual aspects of care was evaluated and the disposition to take palliative care courses in the future. Variable comparisons were done using the chi-squared test.
Results
340 physicians answered the questionnaire. Median age 42years (23-77). 53% women and 42% males. 156 (46%) general practitioners and 183 (54%) non oncologist specialists. 226 (67%) did not have previous palliative care courses, 70 (23%) took courses less than 3 months, and 10 (3%) have a Master's degree in Palliative Care. Overall, only 8% to 20% of physicians declared a high level of confidence in dealing with palliative care issues. Pain management, basic principles of palliative care, and accompaniment of terminally ill and dying patients questions showed a lack of self-confidence greater than 50% among physicians. Variables associated with lack of self-confidence were age (p=0.001), type of practice (p=0.032) no previous palliative course (p< 0.001), and burden of chronic patients in usual practice (p=0.002). Female sex was associated with a lack of self-confidence only in explaining to a patient the inability to cure (p=0.043). 88% of physicians considered that in Panama palliative care access for patients is a problem and 91% of participants are interested in taking palliative care educational courses.
Conclusions
This study identifies physicians’ limited self-confidence in palliative care in Panama and underlines the importance of integrating a palliative care curriculum in continuing medical education and undergraduate programs.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1282P - An interim report on the piloting of care of the dying patient guidance in an acute hospital
- Orfhlaith Mc Carthy (Cork, Ireland)
Abstract
Background
Palliative care is delivered in specialist inpatient units, in the community and in the acute hospital. Optimizing treatment provision to a dying patient in the acute setting can be challenging. A form to provide guidance to teams in the acute hospital managing a patient at end of life has been developed. The aim of this guidance is to improve patient management at end of life and improve outcomes for the patient and their loved ones. This form was piloted on an oncology and geriatrics ward in a 600-bed acute hospital for a period of 6 weeks.
Methods
A retrospective audit was completed on the forms of patients who had died in the 6-week pilot period. Form users provided feedback on the usefulness of the form highlighting any areas for improvement they noted.
Results
There were 18 deaths in total in the 6-week period. Forms were completed for 50% of patients. The portion of the form to be completed before a patient died demonstrated significantly higher compliance (89%) compared to the portion to be completed post death (11%). 78% recorded whether death notification to the coroner was required, 67% noted that family had been advised that the patient was dying. The consideration of referral to the palliative care team was documented in 67% of forms. Only 22% noted that chaplaincy had been advised. Only 11% recorded considering bereavement support through either social work or chaplaincy referral. 11% noted that the GP had been advised of the patients’ death. User feedback was positive in relation to the use of the guidance with users finding it very helpful as a reference point in end-of-life situations.
Conclusions
Many medical teams in the acute hospital have little experience of managing a dying patient. This form provides useful guidance going forward and should improve patient and family outcomes. A 50% form completion rate indicates that more awareness of the form and its purpose is required. The lack of completion of the post death section is attributable to the removal of patient notes from wards shortly post death. This is an area which requires attention to ensure important post death support is provided to families and to ensure GPs are informed of the death of their patient in hospital. The aim is to implement this document across the hospital and potentially nationwide.
Legal entity responsible for the study
Orfhlaith Mc carthy.
Funding
Has not received any funding.
Disclosure
The author has declared no conflicts of interest.
1283P - Psychiatric disorders associated with immune checkpoint inhibitors
- Chaozheng Zhou (Guangzhou, China)
Abstract
Background
With the increasing application of immune checkpoint inhibitors (ICIs) in tumor immunotherapy, the side effects on the immune system, known as immune-related adverse reactions (irAEs), also pose a key challenge to the clinical use of ICIs. Prior to this study, there was yet to be a comprehensive and systematic analysis of the relationship between ICIs, psychiatric complications and their influencing factors.
Methods
A decade of ICI data (2012-2021) submitted to the FDA Adverse Events Reporting System (FAERS) database was retrieved to show the basic incidence of psychiatric adverse events of ICIs. The relationship between ICIs and psychiatric complications is evaluated using the reporting odds ratio (ROR) algorithm. Univariate Logistic regression was used to calculate the odds ratio (OR) of ICI-related pAEs under different ICI treatment strategies and clinical features.
Results
The overall incidence of psychiatric complications related to ICIs in the past ten years was 4.7%, and was relatively constant every year (3.8-4.9%). 14 psychiatric complications shown to have strong correlation to treatment with ICIs were defined as ICI-related psychiatric adverse events (ICI-related pAEs). A total of 2373 patients with ICI-related pAEs were identified. Among them, the elderly patients (60.13%, older than 65 years old) and male patients (58.67%) are the main part. The main cancer sites of indications are the lungs (27.6%) and skin (18.64%). Elderly patients with ICI-related pAEs have a higher mortality rate. The risk of ICI-related pAEs was the highest when combination therapy (OR = 0.71[0.61-0.81], p = 2.6e-06) were used, followed by anti-PD-1 antibodies. Older patients have a higher risk of ICI-related pAEs.
Conclusions
Our research summarized the incidence of psychiatric complications of ICIs and found 14 ICI-related pAEs and their influencing factors. This is a good reference in clinical practice, which can help clinical workers to better identify the possible psychiatric complications related to ICIs. In the future, more clinical research and mechanism exploration are needed for psychiatric complications related to ICIs.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1284P - Detection and evaluation of immune-related adverse event signals: A nationwide, population-based study
- Eo Jin Kim (Seoul, Korea, Republic of)
Abstract
Background
Immune checkpoint inhibitors (ICIs) are one of the main pillars of cancer therapy. Since the adverse events (AEs) of ICIs differ from those of non-ICIs, it is important to investigate the safety profile of ICIs using real-world data. We aimed to identify incidence of ICI-related AEs in ICI users compared to AEs in non-ICI users and to detect and evaluate signals using real-world data.
Methods
Cancer patients treated with anticancer medications were analyzed using the nationwide health insurance claims database from 2015 to 2019, and a tertiary care hospital database from 2012 to 2019. ICI users were compared with non-ICI users. PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab) were evaluated. We analyzed immune-related AEs (irAEs) using all diagnostic codes after ICI prescription utilizing nationwide health insurance claims database. A signal was defined as an AE that met all 4 indices of data mining: hazard ratio (HR), proportional claims ratio (PCR), claims odds ratio (COR), and information component (IC). All detected signals were reviewed and classified into well-known or potential irAEs, which were severe or unknown. Second category signals were verified from hospital electronic medical record (EMR) using diagnostic codes and text mining.
Results
We identified 141 different signals of ICI users defined using diagnostic codes, and were compared with those of non-ICI users. We detected 37 well-known irAEs, most of which were endocrine diseases and skin diseases. We also detected 24 potential irAEs related to disorders in the nervous system, eye, circulatory system, digestive system, skin and subcutaneous tissues, and bones. Especially, portal vein thrombosis and bone disorders such as osteoporosis with pathological fracture and fracture of shoulder, upper arm, femur, and lower leg showed high HR in ICI users than in non-ICI users. The signals from hospital database were verified using diagnostic codes and text mining.
Conclusions
This real-world data analysis demonstrated an efficient approach for signal detection and evaluation of ICI use. An effective real-world pharmacovigilance system of the nationwide claims database and the EMR could complement each other in detecting significant AE signals.
Legal entity responsible for the study
The authors.
Funding
This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean government (NRF-2019M3E5D4064636).
Disclosure
All authors have declared no conflicts of interest.
1285P - Risk of immune-related adverse events associated with adjuvant antiPD-1/PDL-1 in solid tumors
- Cristina Serrano (Madrid, Spain)
Abstract
Background
Immune checkpoint inhibitors targeting PD-1/PD-L1 (IO) have deeply transformed the landscape of treatment of metastatic solid tumors and are likely to shape the adjuvant setting. Balance between safety and efficacy should be considered, especially potential serious adverse events. The aim of this systematic review was to determine the risk of developing serious immune related adverse events (irAEs) in patients treated with IO in the adjuvant setting.
Methods
We performed a systematic review of the evidence available in Pubmed of all randomized phase II-III clinical trials comparing IO versus placebo or observation in the adjuvant setting published up to March 2022. Protocol was registered in PROSPERO. Odds ratio (OR) of adverse events for all grade and high-grade were calculated.
Results
Seven studies involving 5425 patients were included (2876 patients in the IO arm and 2549 in the observation/placebo control group). 19% of patients receiving IO reported an irAE compared to 8,7% in the control arm, and 1 out of 7 patients had a high-grade irAE with IO compared to 1 out of 14 patients in the control arm. The OR in the IO group vs placebo/observation was 3,20 (95% CI, 2,41 – 4,26) in all-grade irAEs; 3,49 (95% CI, 1,82 – 6,69) in high-grade (grade 3-4) irAEs; and 4,17 (95% CI, 1,47 – 11,89) in serious AEs. There was not a statistically significant difference between the incidence of deaths due to irAEs, with an OR 3,66 (95% CI, 0,60 – 22,32).
Conclusions
Our study showed that the risk of developing irAEs is a more than three times higher risk of developing an immune-related adverse event in the group of adjuvant antiPD-1/PDL-1 compared to observation/placebo, with no differences in the incidence of deaths. This analysis provides a comprehensive overview of ICI-associated AEs in the adjuvant setting, and these findings may help and guide clinicians in management and decision-making of patients with indication of adjuvant treatment.
Legal entity responsible for the study
Hospital 12 de Octubre.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1287P - A clinical controlled study of fecal microbiota transplantation in the treatment of advanced cancer with cachexia
- Yuying Hu (Dalian, China)
Abstract
Background
Cachexia is one of the most common complications of advanced tumors. About 20 % of patients with malignant tumors die from cachexia.It has been proved that the intestinal microecological environment can be improved by fecal microbiota transplatation to improve the nutritional status of patients.Therefore, we suggest that for patients with cachexia, the use of fecal microbiota transplatation on the basis of standardized nutrition therapy can improve the nutritional status of patients, improve the quality of life of patients.
Methods
A total of 20 patients with terminal tumor complicated with cachexia were included in the study.According to the propensity score principle, all the selected subjects were divided into the experimental group (10 cases) and the control group (10 cases ).The control group was only given standardized nutrition therapy, and the experimental group was given fecal microbiota transplatation on the basis of standardized nutrition therapy. The paired T test was used to analyze and compare the differences in skeletal muscle, protein, body mass index, hemoglobin, albumin, prealbumin, and triglyceride between the two groups before and after treatment, and the changes in cytokines in the experimental group before and after treatment.
Results
There was no statistically significant difference in hemoglobin and other indicators between the two groups before intervention(
Conclusions
For patients with advanced cancer complicated with cachexia, fecal microbiota transplatation of healthy people can significantly improve the nutritional status of patients, increase nutritional intake, improve the quality of life, which has clinical significance and application value.
Clinical trial identification
CHiCTR2000035014.
Legal entity responsible for the study
Changzhou Second People's Hospital.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1288P - Efficacy and safety of palliative procedures for malignant gastric outlet obstruction: A systematic review and network meta-analysis
- Khoi V. Tran (Hue City, Viet Nam)
Abstract
Background
Only head-to-head trials evaluated between gastrojejunostomy (G), endoscopic stenting (S), stomach partitioning gastrojejunostomy (P), and endoscopic ultrasound-guided gastroenterostomy (E) for malignant gastric outlet obstruction (GOO). We conducted a network meta-analysis (NMA) to compare the efficacy and safety among these treatments.
Methods
We searched for randomized controlled trials (RCTs) and non-RCTs that compared palliative surgical strategies for malignant GOO from Pubmed, Medline, Embase, ClinicalTrial.gov, and Cochrane databases. We included studies that reported at least one outcome of interest (clinical success, mortality, and reintervention rate). Evidence from RCTs and non-RCTs were combined through the frequentist framework, inverse variance model, and naïve combination. We estimated the effective results using relative risks (RR). The probability of best treatment was ranked by P-score (0-1), a higher score indicating better treatment.
Results
This NMA included 4 RCTs and 37 non-RCTs (4 prospectives and 33 retrospectives) with 3462 patients. The overall rates of clinical success, mortality, and reintervention were 85.3%, 7.95%, and 17.07%, respectively. P was ranked the best approach for clinical success rate and reintervention rate (P-score: 0.92, 0.80, respectively). E had the highest probability of being the best for mortality rate (P-score: 0.8). Cluster rank combined the probability of the best treatment for safety regarding mortality and efficacy regarding reintervention prevention showed the benefit of P and E (cophenetic correlation coefficient: 0.90, P and E were in the same cluster).
Conclusions
Stomach partitioning gastrojejunostomy and endoscopic ultrasound-guided gastroenterostomy should be recommended for malignant GOO. Stomach partitioning gastrojejunostomy could be an alternative approach when endoscopic ultrasound-guided gastroenterostomy is unsuccess or not feasible.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1289P - Quality of death in cancer patients managed by gastroenterologists
- Catarina N. Nascimento (Loures, Portugal)
Abstract
Background
Care in hospitals is generally focused on prolonging life and may not adequately address the needs of dying patients. The incidence of oncologic diseases is rising, and efforts should be made to guarantee a better quality of death and dying. Aim: to evaluate the end-of-life care in patients with cancer under gastroenterologist care.
Methods
Cross-sectional study including all in-patients with cancer who deceased in a Gastroenterology department in Portugal between 2012-2021. Demographic characteristics, clinical attitudes, therapeutic interventions and symptom control up to 6 months prior to the patient’s death were assessed.
Results
We included 120 patients, 73% male, mean age 71±12.5 years. The most common cancers were hepatocellular carcinoma (35%), gastric cancer (16%), pancreatic cancer (15%) and cholangiocarcinoma (14%). One third of the patients had ECOG of 0-1 at admission and 77% (n=92) had advanced disease (stage IV or Barcelona Clinic Liver Cancer C/D). The median number of emergency consultations and hospitalizations in the 6 months before death was 2 (IQR 1-4). In their last month of life, the median time of hospitalization was 21.5 (IQR 12-25) days. It was documented the presence of an available caregiver in 56%(n=68) and spiritual support in only 2% (n=2) of the cases. One quarter of the patients experienced not adequately controlled pain and 72% received opioids. Palliative care consultation occurred in 60% (n=72) with a median time between that and death of 12 (IQR 3-18) days. Invasive procedures (diagnostic and therapeutic endoscopy, ERCP and EUS) were performed in half of the patients, achieving technical and clinical success in 62% (n=38) and 32% (n=19) of the cases, respectively. The mean time between those interventions and death was 12±10 days. The prognosis was discussed with the patient and family in 35% and 68% of the cases, respectively. At least 73% of the patients had visits at the end of life, which was negatively affected by the COVID-19 pandemic (p=0.022).
Conclusions
In our cohort, we found a high hospitalization length of stay in the last month of life and high percentage of invasive treatments until shortly before dying. Thus, it is urgent to define and implement metrics of quality of death to prevent futile/potentially inappropriate treatment.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1290P - The effect of electric massage chair on chemotherapy-induced nausea and vomiting in cancer patients
- Ju Won Kim (Seoul, Korea, Republic of)
Abstract
Background
Chemotherapy-induced nausea and vomiting (CINV) are the most common and serious side effects of chemotherapy. Multiple antiemetic agents are widely used to reduce CINV, but they are not completely control the symptom and often cause undesirable side effects. There has been evidence that massage therapy helps cancer patients physically and emotionally, improving quality-of-life (QoL). This study was conducted to evaluate clinical role of electric massage chair to relieve CINV as an alternative therapy.
Methods
We conducted a phase 2 randomized crossover trial on solid cancer patients who were scheduled to receive chemotherapy with moderate to high emetic risk(HEC/MEC). The participants were randomly assigned to two groups. Group A received standard care only while group B received additive massage therapy with electric massage chair in their 1st cycle of chemotherapy. The patients in each group were then crossed over in the next cycle. Electric massage chair was applied on the 1st day of chemotherapy, for at least 20 minutes. Rhodes Index of Nausea, Vomiting and Retching (INVR) scale and EORTC-QLQ-C30 questionnaire were self-reported by the participants.
Results
A total of 59 patients completed the protocol and included for analysis. Forty-three (72.88%) patients received MEC, and 16 (27.12%) patients received HEC. The INVR score at 1st cycle of chemotherapy was 2.76 in group A and 3.63 in group B (p-value = 0.5367). The functional scale of EORTC-QLQ-C30 was improved after applying electric massage chair in both groups, regardless of the cycles (+2.1 in 1st cycle and +3.8 in 2nd cycle). In the subgroup analysis conducted in high-risk patients, patients who received massage chair therapy showed lower CINV score than control group in both cycle (1st cycle 4.78 vs. 4.083 and 2nd cycle 2.78 vs. 3.58, p-value 0.09). High-risk patients who received HEC (1st cycle 6.25 vs. 5.17 and 2nd cycle 3.25 vs. 5.0, p-value 0.0495) presented statistically significant differences of CINV score according to additive massage chair therapy.
Conclusions
Short-course electric massage chair to standard care can help preserving quality-of-life and reducing the CINV in high-emetic risk patients.
Legal entity responsible for the study
The authors.
Funding
Bodyfriend.
Disclosure
All authors have declared no conflicts of interest.