International Comparisons of ICU Performance: A Proposed Approach to Severity Scoring Systems
Amanda Quintairos 1 2, Rashan Haniffa 1 2 3 4 5 6 7 8 9, Dave Dongelmans 7 8, Jorge I F Salluh 1 9; LOGIC (Linking of Global Intensive Care)
Crit Care Med. 2022 Nov 1;50(11):e799-e800. doi: 10.1097/CCM.0000000000005619. Epub 2022 Oct 13.
PMID: 36227050
Abstract
No abstract available
Conflict Of Interest Statement
Dr. Salluh is a shareholder of Epimed Solutions. Dr. Haniffa was a founding collaborator of the Global Open Source Severity of Illness Score initiative. Dr. Haniffa disclosed that he is the founding collaborator of Linking of Global Intensive Care, director of Crit Care Asia Network Registry, trustee of Network for Improving Critical Care Systems and Training, and co-lead of Critical Care Asia and Africa; received support for article research from the Wellcome Trust/Charity Open Access Fund. The remaining authors have disclosed that they do not have any potential conflicts of interest.
Four decades of prognostic scores in intensive care
Amanda Quintairos,1,2 David Pilcher,3,4 and Jorge I. F. Salluh1,5
Intensive Care Med. 2022 Oct 31:1-3. doi: 10.1007/s00134-022-06914-8. Online ahead of print.
PMID: 36315260
Intensive care units (ICUs) are people- and technology-intensive environments where timely and wise use of advanced monitoring and life support is crucial to revert or avoid life-threatening conditions. From their inception, this highly complex environment has been confronted with a need to demonstrate its effectiveness to healthcare stakeholders [1]. In the 1970s and 80s, increasing costs of intensive care, associated with poor outcomes of patients with multi-organ failure, urged intensivists and healthcare managers to look for metrics could concisely express ‘severity of illness’ and, thus, allow measurement of risk-adjusted outcomes [2].
In the early 1980s, the Acute Physiology and Chronic Health Evaluation (APACHE) system was a milestone in the history of ICU outcome prediction. This scoring system translated domains of pre-morbid conditions (age and co-morbidities), diagnoses and early physiologic derangements (organ failures, laboratory and physiological abnormalities) into a numeric expression of illness severity. In addition to the absolute value of the score, the APACHE system provided an estimate of the risk of death for each individual patient. APACHE was soon followed by the development of the Mortality Prediction Model (MPM) in the United States and the Simplified Acute Physiology Score (SAPS) in Europe. As the technologies improved, new treatments and protocols of care were applied, and the case-mix of the ICU changed (more elderly, co-morbidities and immunocompromised), scores needed to be updated to remain valid predictors of outcomes. The pioneering early versions of APACHE, SAPS and MPM were updated, with SAPS3, APACHE IV, and MPM0-III published, respectively, in 2005, 2006, and 2007 [3]. One of the important differences among these scores relates to the time when they are calculated. SAPS3 and MPM0-III use data from the first hour of ICU admission; whereas, APACHE IV uses the “worst” measurements from the first 24 h. Therefore SAPS3/MPM0-III potentially reflects the early severity of the non-resuscitated patient. APACHE IV provides more time for data collection and less missing data.
Finally, dynamic scores may be applied in the ICU. The most commonly used is the Sequential Organ Failure Assessment (SOFA) which was developed to define the degree of organ failure, to stratify risk particularly in patients with sepsis, and to monitor response to treatment. Scoring systems, although useful for individual risk assessment, are not as applicable for mortality prediction and ICU performance monitoring. They are often used to complement more general mortality scores in ICU.
Obstetric admission to intensive care units in Japan: a cohort study using the Japanese Intensive care PAtient Database
Hitomi Asaba 1, Yoshitaka Aoki 2, Chieko Akinaga 1, Satoshi Naruse 1, Sakiko Uchizaki 1, Mikio Nakajima 3 4, Matsuyuki Doi 1, Hiroaki Itoh 5, Yoshiki Nakajima 1
J Anesth. 2023 May 24. doi: 10.1007/s00540-023-03200-9. Online ahead of print.PMID: 37222956
Abstract
Purpose: This study aimed to describe the epidemiology and annual trends of obstetric patients using a multicenter intensive care database.
Methods: This multicenter, retrospective cohort study used the Japanese Intensive care PAtient Database (JIPAD). We included obstetric patients registered in the JIPAD between 2015 and 2020. We investigated the proportion of obstetric patients among all patients in the intensive care unit (ICU). We also described the characteristics, procedures, and outcomes of obstetric patients. In addition, the annual trends were examined by nonparametric tests for trends.
Results: Of the 184,705 patients enrolled in the JIPAD, 750 (0.41%) were obstetric patients from 61 facilities. The median age was 34 years, the number of post-emergency surgeries was 450 (60.0%), and the median APACHE III score was 36. Mechanical ventilation was the most common procedure performed in 247 (32.9%) patients. There were five (0.7%) in-hospital deaths. The proportion of obstetric patients in the ICU did not change between 2015 and 2020 (P for trend = 0.32). However, there was a trend for a significant decrease in the severity of illness and length of hospital stay on an annual basis between 2015 and 2020. Most patients were admitted to the ICU because of a pregnancy-related disorder postoperatively.
Conclusion: The proportion of obstetric patients was 0.41% of all ICU admissions. The proportion of obstetric patients admitted to the ICU did not change from 2015 to 2020, but the patients’ severity of illness and length of hospital stay significantly decreased over time.
Keywords: Critical care; Epidemiology; Intensive care unit; Maternal health; Obstetrics.
© 2023. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.
Determinants of Implementation of a Critical Care Registry in Asia: Lessons From a Qualitative Study
Timo Tolppa 1, Vrindha Pari 2, Christopher Pell 3 4, Diptesh Aryal 5, Madiha Hashmi 6, Maryam Shamal Ghalib 7, Issrah Jawad 1, Swagata Tripathy 8, Bharath Kumar Tirupakuzhi Vijayaraghavan 2 9 10, Abi Beane 11, Arjen M Dondorp 12, Rashan Haniffa 11; Collaboration of Research Implementation & Training in Critical Care in Asia Investigators 13
J Med Internet Res. 2023 Mar 6;25:e41028. doi: 10.2196/41028.
Abstract
Background: The Collaboration for Research, Implementation, and Training in Critical Care in Asia (CCA) is implementing a critical care registry to capture real-time data to facilitate service evaluation, quality improvement, and clinical studies.
Objective: The purpose of this study is to examine stakeholder perspectives on the determinants of implementation of the registry by examining the processes of diffusion, dissemination, and sustainability.
Methods: This study is a qualitative phenomenological inquiry using semistructured interviews with stakeholders involved in registry design, implementation, and use in 4 South Asian countries. The conceptual model of diffusion, dissemination, and sustainability of innovations in health service delivery guided interviews and analysis. Interviews were coded using the Rapid Identification of Themes from Audio recordings procedure and were analyzed based on the constant comparison approach.
Results: A total of 32 stakeholders were interviewed. Analysis of stakeholder accounts identified 3 key themes: innovation-system fit; influence of champions; and access to resources and expertise. Determinants of implementation included data sharing, research experience, system resilience, communication and networks, and relative advantage and adaptability.
Conclusions: The implementation of the registry has been possible due to efforts to increase the innovation-system fit, influence of motivated champions, and the support offered by access to resources and expertise. The reliance on individuals and the priorities of other health care actors pose a risk to sustainability.
Keywords: CCU; South Asia; critical care; health care; implementation; qualitative research; registry; stakeholders.
©Timo Tolppa, Vrindha Pari, Christopher Pell, Diptesh Aryal, Madiha Hashmi, Maryam Shamal Ghalib, Issrah Jawad, Swagata Tripathy, Bharath Kumar Tirupakuzhi Vijayaraghavan, Abi Beane, Arjen M Dondorp, Rashan Haniffa, Collaboration of Research Implementation & Training in Critical Care in Asia Investigators. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 06.03.2023.
Conflict Of Interest Statement
Conflicts of Interest: AB has received a salary from Wellcome. RH has received grants from Wellcome, Canadian Institutes of Health Research, UK Research and Innovation/Medical Research Council and International COVID-19 Data Alliance. CP has received a part-time salary from the Wellcome Trust.
Incidence of death or disability at 6 months after extracorporeal membrane oxygenation in Australia: a prospective, multicentre, registry-embedded cohort study
Carol L Hodgson 1, Alisa M Higgins 2, Michael J Bailey 2, Shannah Anderson 3, Stephen Bernard 4, Bentley J Fulcher 2, Denise Koe 5, Natalie J Linke 2, Jasmin V Board 6, Daniel Brodie 7, Heidi Buhr 8, Aidan J C Burrell 9, D James Cooper 9, Eddy Fan 10, John F Fraser 11, David J Gattas 8, Ingrid K Hopper 5, Sue Huckson 12, Edward Litton 13, Shay P McGuinness 14, Priya Nair 15, Neil Orford 16, Rachael L Parke 17, Vincent A Pellegrino 6, David V Pilcher 18, Jayne Sheldrake 6, Benjamin A J Reddi 19, Dion Stub 4, Tony V Trapani 2, Andrew A Udy 9, Ary Serpa Neto 20; EXCEL Study Investigators on behalf of the International ECMO Network and the Australian and New Zealand Intensive Care Society Clinical Trials Group
Lancet Respir Med. 2022 Nov;10(11):1038-1048. doi: 10.1016/S2213-2600(22)00248-X. Epub 2022 Sep 26.
Abstract
Background: Extracorporeal membrane oxygenation (ECMO) is an invasive procedure used to support critically ill patients with the most severe forms of cardiac or respiratory failure in the short term, but long-term effects on incidence of death and disability are unknown. We aimed to assess incidence of death or disability associated with ECMO up to 6 months (180 days) after treatment.
Methods: This prospective, multicentre, registry-embedded cohort study was done at 23 hospitals in Australia from Feb 15, 2019, to Dec 31, 2020. The EXCEL registry included all adults (≥18 years) in Australia who were admitted to an intensive care unit (ICU) in a participating centre at the time of the study and who underwent ECMO. All patients who received ECMO support for respiratory failure, cardiac failure, or cardiac arrest during their ICU stay were eligible for this study. The primary outcome was death or moderate-to-severe disability (defined using the WHO Disability Assessment Schedule 2.0, 12-item survey) at 6 months after ECMO initiation. We used Fisher’s exact test to compare categorical variables. This study is registered with ClinicalTrials.gov, NCT03793257.
Findings: Outcome data were available for 391 (88%) of 442 enrolled patients. The primary outcome of death or moderate-to-severe disability at 6 months was reported in 260 (66%) of 391 patients: 136 (67%) of 202 who received veno-arterial (VA)-ECMO, 60 (54%) of 111 who received veno-venous (VV)-ECMO, and 64 (82%) of 78 who received extracorporeal cardiopulmonary resuscitation (eCPR). After adjustment for age, comorbidities, Acute Physiology and Chronic Health Evaluation (APACHE) IV score, days between ICU admission and ECMO start, and use of vasopressors before ECMO, death or moderate-to-severe disability was higher in patients who received eCPR than in those who received VV-ECMO (VV-ECMO vs eCPR: risk difference [RD] -32% [95% CI -49 to -15]; p<0·001) but not VA-ECMO (VA-ECMO vs eCPR -8% [-22 to 6]; p=0·27).
Interpretation: In our study, only a third of patients were alive without moderate-to-severe disability at 6 months after initiation of ECMO. The finding that disability was common across all areas of functioning points to the need for long-term, multidisciplinary care and support for surviving patients who have had ECMO. Further studies are needed to understand the 180-day and longer-term prognosis of patients with different diagnoses receiving different modes of ECMO, which could have important implications for the selection of patients for ECMO and management strategies in the ICU.
Funding: The National Health and Medical Research Council of Australia.
Copyright © 2022 Elsevier Ltd. All rights reserved.
Conflict Of Interest Statement
Declaration of interests CLH leads the bi-national EXCEL registry, with funding from the Australian National Health and Medical Research Council (NHMRC) and the Heart Foundation of Australia (HFA), holds an NHMRC investigator grant, and is on the executive committee of the International ECMO Network (ECMONet). AMH, AJCB, and DJC receive research support from NHMRC. AMH, MJB, SB, BJF, NJL, DJC, DJG, IKH, DVP, TVT, and AAU received funding for the EXCEL registry from NHMRC and HFA. DB is Chair of the Executive Committee of ECMONet and President-elect of ELSO, receives research support from ALung Technologies, and has been on medical advisory boards for Abiomed, Xenios, Medtronic, and Cellenkos. DJC holds an NHMRC practitioner fellowship. EF is on the executive committee of ECMONet and the steering committee of the Extracorporeal Life Support Organization (ELSO). JFF and VAP are on the Executive Committee of ECMONet. JFF is President of the Asia-Pacific Chapter of ELSO, Chair of the Queensland Cardiovascular Research Network, co-founder of BiVACOR, and receives research support from Xenios, Mallenkrodt Getinge, and MERA (all ECMO companies). DS received research support from a HFA fellowship. AAU is on the executive committee of the Australian and New Zealand Intensive Care Society Clinical Trials Group. All other authors declare no competing interests.
Impact of frailty on clinical outcomes in patients with and without COVID-19 pneumonitis admitted to intensive care units in Australia and New Zealand: a retrospective registry data analysis
Ashwin Subramaniam 1 2 3, Kiran Shekar 4 5 6, Christopher Anstey 7, Ravindranath Tiruvoipati 8 9, David Pilcher 10 11 12
Crit Care. 2022 Oct 3;26(1):301. doi: 10.1186/s13054-022-04177-9.
Abstract
Background: It is unclear if the impact of frailty on mortality differs between patients with viral pneumonitis due to COVID-19 or other causes. We aimed to determine if a difference exists between patients with and without COVID-19 pneumonitis.
Methods: This multicentre, retrospective, cohort study using the Australian and New Zealand Intensive Care Society Adult Patient Database included patients aged ≥ 16 years admitted to 153 ICUs between 01/012020 and 12/31/2021 with admission diagnostic codes for viral pneumonia or acute respiratory distress syndrome, and Clinical Frailty Scale (CFS). The primary outcome was hospital mortality.
Results: A total of 4620 patients were studied, and 3077 (66.6%) had COVID-19. The patients with COVID-19 were younger (median [IQR] 57.0 [44.7-68.3] vs. 66.1 [52.0-76.2]; p < 0.001) and less frail (median [IQR] CFS 3 [2-4] vs. 4 [3-5]; p < 0.001) than non-COVID-19 patients. The overall hospital mortality was similar between the patients with and without COVID-19 (14.7% vs. 14.9%; p = 0.82). Frailty alone as a predictor of mortality showed only moderate discrimination in differentiating survivors from those who died but was similar between patients with and without COVID-19 (AUROC 0.68 vs. 0.66; p = 0.42). Increasing frailty scores were associated with hospital mortality, after adjusting for Australian and New Zealand Risk of Death score and sex. However, the effect of frailty was similar in patients with and without COVID-19 (OR = 1.29; 95% CI: 1.19-1.41 vs. OR = 1.24; 95% CI: 1.11-1.37).
Conclusion: The presence of frailty was an independent risk factor for mortality. However, the impact of frailty on outcomes was similar in COVID-19 patients compared to other causes of viral pneumonitis.
Keywords: ANZICS-APD; CFS; COVID-19; Clinical Frailty Scale; Frailty; Pandemic.
© 2022. The Author(s).
Conflict Of Interest Statement
The other authors declare that they have no conflicts of interest.
Characteristics and Outcomes of Very Elderly Patients Admitted to Intensive Care: A Retrospective Multicenter Cohort Analysis.
Sumeet Rai 1 2, Charlotte Brace 3, Paul Ross 4 5, Jai Darvall 6 7, Kimberley Haines 6 8, Imogen Mitchell 1 2, Frank van Haren 1 9, David Pilcher 4 5 10
Crit Care Med. 2023 May 23. doi: 10.1097/CCM.0000000000005943. Online ahead of print.PMID: 37219961
Abstract
Objectives: To characterize and compare trends in ICU admission, hospital outcomes, and resource utilization for critically ill very elderly patients (≥ 80 yr old) compared with the younger cohort (16-79 yr old).
Design: A retrospective multicenter cohort study.
Setting: One-hundred ninety-four ICUs contributing data to the Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation Adult Patient Database between January 2006 and December 2018.
Patients: Adult (≥ 16 yr) patients admitted to Australian and New Zealand ICUs.
Interventions: None.
Measurements and main results: Very elderly patients with a mean ± sd age of 84.8 ± 3.7 years accounted for 14.8% (232,582/1,568,959) of all adult ICU admissions. They had higher comorbid disease burden and illness severity scores compared with the younger cohort. Hospital (15.4% vs 7.8%, p < 0.001) and ICU mortality (8.5% vs 5.2%, p < 0.001) were higher in the very elderly. They stayed fewer days in ICU, but longer in hospital and had more ICU readmissions. Among survivors, a lower proportion of very elderly was discharged home (65.2% vs 82.4%, p < 0.001), and a higher proportion was discharged to chronic care/nursing home facilities (20.1% vs 7.8%, p < 0.001). Although there was no change in the proportion of very elderly ICU admissions over the study period, they showed a greater decline in risk-adjusted mortality (6.3% [95% CI, 5.9%-6.7%] vs 4.0% [95% CI, 3.7%-4.2%] relative reduction per year, p < 0.001) compared with the younger cohort. The mortality of very elderly unplanned ICU admissions improved faster than the younger cohort (p < 0.001), whereas improvements in mortality among elective surgical ICU admissions were similar in both groups (p = 0.45).
Conclusions: The proportion of ICU admissions greater than or equal to 80 years old did not change over the 13-year study period. Although their mortality was higher, they showed improved survivorship over time, especially in the unplanned ICU admission subgroup. A higher proportion of survivors were discharged to chronic care facilities.
Copyright © 2023 The Author(s).
Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.
Conflict Of Interest Statement
Dr. Haines’ institution received funding from the Society of Critical Care Medicine. Dr. van Haren’s institution received funding from the Australian National University; he received funding from Phico Therapeutics and Fresenius Kabi. The remaining authors have disclosed that they do not have any potential conflicts of interest.
ICU scoring systems
Amanda Quintairos 1 2, David Pilcher 3 4, Jorge I F Salluh 5 6
Intensive Care Med. 2023 Feb;49(2):223-225. doi: 10.1007/s00134-022-06914-8. Epub 2022 Oct 31.PMID: 36315260
Abstract
No abstract available
Conflict Of Interest Statement
The other authors declare that they have no conflicts of interest.
Trends in Intensive Care Admissions and Outcomes of Stroke Patients Over 10 Years in Brazil: Impact of the COVID-19 Pandemic
Pedro Kurtz 1, Leonardo S L Bastos 2, Fernando G Zampieri 3, Gabriel R de Freitas 4, Fernando A Bozza 5, Marcio Soares 6, Jorge I F Salluh 7
Chest. 2023 Mar;163(3):543-553. doi: 10.1016/j.chest.2022.10.033. Epub 2022 Nov 5.PMID: 36347322 Free PMC article.
Abstract
Background: The coronavirus 2019 (COVID-19) pandemic affected stroke care worldwide. Data from low- and middle-income countries are limited.
Research question: What was the impact of the pandemic in ICU admissions and outcomes of patients with stroke, in comparison with trends over the last 10 years?
Study design and methods: Retrospective cohort study including prospectively collected data from 165 ICUs in Brazil between 2011 and 2020. We analyzed clinical characteristics and mortality over a period of 10 years and evaluated the impact of the pandemic on stroke outcomes, using the following approach: analyses of admissions for ischemic and hemorrhagic strokes and trends in in-hospital mortality over 10 years; analysis of variable life-adjusted display (VLAD) during 2020; and a mixed-effects multivariable logistic regression model.
Results: A total of 17,115 stroke admissions were analyzed, from which 13,634 were ischemic and 3,481 were hemorrhagic. In-hospital mortality was lower after ischemic stroke as compared with hemorrhagic (9% vs 24%, respectively). Changes in VLAD across epidemiological weeks of 2020 showed that the rise in COVID-19 cases was accompanied by increased mortality, mainly after ischemic stroke. In logistic regression mixed models, mortality was higher in 2020 compared with 2019, 2018, and 2017 in patients with ischemic stroke, namely, in those without altered mental status. In hemorrhagic stroke, the increased mortality in 2020 was observed in patients 50 years of age or younger, as compared with 2019.
Interpretation: Hospital outcomes of stroke admissions worsened during the COVID-19 pandemic, interrupting a trend of improvements in survival rates over 10 years. This effect was more pronounced during the surge of COVID-19 ICU admissions affecting predominantly patients with ischemic stroke without coma, and young patients with hemorrhagic stroke.
Keywords: COVID-19 pandemic; coronavirus 2019; hemorrhagic; ischemic; outcomes; stroke.
Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
Non-COVID-19 intensive care admissions during the pandemic: a multinational registry-based study
Joshua McLarty 1 2, Edward Litton 3 4, Abigail Beane 5 6, Diptesh Aryal 7, Michael Bailey 2, Stepani Bendel 8 9, Gaston Burghi 10, Steffen Christensen 11, Christian Fynbo Christiansen 12, Dave A Dongelmans 13 14, Ariel L Fernandez 15, Aniruddha Ghose 16, Ros Hall 17, Rashan Haniffa 5 6, Madiha Hashmi 18, Satoru Hashimoto 19 20, Nao Ichihara 21, Bharath Kumar Tirupakuzhi Vijayaraghavan 22 23, Nazir I Lone 24, Maria Del Pilar Arias López 25 26, Mohamed Basri Mat Nor 27, Hiroshi Okamoto 28, Dilanthi Priyadarshani 29, Matti Reinikainen 8 9, Marcio Soares 30, David Pilcher 31 2, Jorge Salluh 30 32; Linking of Global Intensive Care (LOGIC) Collaboration
Abstract
Background: The COVID-19 pandemic resulted in a large number of critical care admissions. While national reports have described the outcomes of patients with COVID-19, there is limited international data of the pandemic impact on non-COVID-19 patients requiring intensive care treatment.
Methods: We conducted an international, retrospective cohort study using 2019 and 2020 data from 11 national clinical quality registries covering 15 countries. Non-COVID-19 admissions in 2020 were compared with all admissions in 2019, prepandemic. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included in-hospital mortality and standardised mortality ratio (SMR). Analyses were stratified by the country income level(s) of each registry.
Findings: Among 1 642 632 non-COVID-19 admissions, there was an increase in ICU mortality between 2019 (9.3%) and 2020 (10.4%), OR=1.15 (95% CI 1.14 to 1.17, p<0.001). Increased mortality was observed in middle-income countries (OR 1.25 95% CI 1.23 to 1.26), while mortality decreased in high-income countries (OR=0.96 95% CI 0.94 to 0.98). Hospital mortality and SMR trends for each registry were consistent with the observed ICU mortality findings. The burden of COVID-19 was highly variable, with COVID-19 ICU patient-days per bed ranging from 0.4 to 81.6 between registries. This alone did not explain the observed non-COVID-19 mortality changes.
Interpretation: Increased ICU mortality occurred among non-COVID-19 patients during the pandemic, driven by increased mortality in middle-income countries, while mortality decreased in high-income countries. The causes for this inequity are likely multi-factorial, but healthcare spending, policy pandemic responses, and ICU strain may play significant roles.
Keywords: COVID-19; Clinical Epidemiology; Critical Care.
© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.
Conflict Of Interest Statement
Competing interests: DP and Dr EL are members of the Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcome and Resources Evaluation management committee. AB is funded by Wellcome. JS and MS are cofounders and shareholders of Epimed Solutions, a healthcare cloud-based analytics company. They are also supported in part by individual research grants from CNPq and FAPERJ. SB is the current chair, and MR is the past chair of the Finnish Intensive Care Consortium (both unpaid). DAD is unpaid chair of NICE foundation. NI’s primary affiliation is the Department of Healthcare Quality Assessment, which is a social collaboration department at the University of Tokyo supported by National Clinical Database, Johnson & Johnson K.K., and Nipro corporation. BKTV is the National Coordinator for the Indian Registry of IntenSive care (IRIS) and is supported for 0.5 FTE by funding from the Wellcome Trust, UK. The remaining authors have no conflicts of interest to declare.