Less (Transfusion) Is More—Enhancing Recovery through Implementation of Patient Blood Management in Cardiac Surgery: A Retrospective, Single-Centre Study of 1174 Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Population and Data Collection
2.2. Clinical Management
2.3. Statistical Analysis
3. Results
Demographic Characteristics and Outcomes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Gombotz, H.; Rehak, P.H.; Shander, A.; Hofmann, A. The second Austrian benchmark study for blood use in elective surgery: Results and practice change: The Second Austrian Benchmark Study. Transfusion 2014, 54, 2646–2657. [Google Scholar] [CrossRef]
- Bennett-Guerrero, E.; Zhao, Y.; O’Brien, S.M.; Jr, T.B.F.; Peterson, E.D.; Gammie, J.S.; Song, H.K. Variation in Use of Blood Transfusion in Coronary Artery Bypass Graft Surgery. JAMA 2010, 304, 1568–1575. [Google Scholar] [CrossRef] [Green Version]
- Mazzeffi, M.A.; Holmes, S.; Taylor, B.; Ghoreishi, M.; McNeil, J.; Kertai, M.; Bollen, B.; Tanaka, K.; Raphael, J.; Glance, L. Red Blood Cell Transfusion and Postoperative Infection in Patients Having Coronary Artery Bypass Grafting Surgery: An Analysis of the Society of Thoracic Surgeons Adult Cardiac Surgery Database. Anesth. Analg. 2022, 135, 558–566. [Google Scholar] [CrossRef] [PubMed]
- Tauriainen, T.; Kinnunen, E.-M.; Laitinen, I.; Anttila, V.; Kiviniemi, T.; Airaksinen, J.K.E.; Biancari, F. Transfusion and blood stream infections after coronary surgery. Interact. Cardiovasc. Thorac. Surg. 2018, 26, 325–327. [Google Scholar] [CrossRef]
- Cataife, G.; Pagano, M.B. How much does a blood transfusion cost?: EDITORIAL. Transfusion 2018, 58, 833–835. [Google Scholar] [CrossRef] [Green Version]
- Stokes, M.E.; Ye, X.; Shah, M.; Mercaldi, K.; Reynolds, M.W.; Rupnow, M.F.; Hammond, J. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv. Res. 2011, 11, 135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shander, A.; Hardy, J.-F.; Ozawa, S.; Farmer, S.L.; Hofmann, A.; Frank, S.M.; Kor, D.J.; Faraoni, D.; Freedman, J. Collaborators A Global Definition of Patient Blood Management. Anesth. Analg. 2022, 135, 476–488. [Google Scholar] [CrossRef] [PubMed]
- Tibi, P.; McClure, R.S.; Huang, J.; Baker, R.A.; Fitzgerald, D.; Mazer, C.D.; Stone, M.; Chu, D.; Stammers, A.H.; Dickinson, T.; et al. STS/SCA/AmSECT/SABM Update to the Clinical Practice Guidelines on Patient Blood Management. Ann. Thorac. Surg. 2021, 112, 981–1004. [Google Scholar] [CrossRef] [PubMed]
- Boer, C.; Meesters, M.I.; Milojevic, M.; Benedetto, U.; Bolliger, D.; Von Heymann, C.; Jeppsson, A.; Koster, A.; Osnabrugge, R.L.; Ranucci, M.; et al. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. J. Cardiothorac. Vasc. Anesth. 2018, 32, 88–120. [Google Scholar] [CrossRef] [Green Version]
- Dhir, A.; Tempe, D.K. Anemia and Patient Blood Management in Cardiac Surgery—Literature Review and Current Evidence. J. Cardiothorac. Vasc. Anesth. 2018, 32, 2726–2742. [Google Scholar] [CrossRef]
- Baron, D.M.; Metnitz, P.G.H.; Fellinger, T.; Metnitz, B.; Rhodes, A.; Kozek-Langenecker, S.A. Evaluation of clinical practice in perioperative patient blood management. Br. J. Anaesth. 2016, 117, 610–616. [Google Scholar] [CrossRef] [Green Version]
- Hofmann, A.; Spahn, D.R.; Holtorf, A.-P.; PBM Implementation Group; Isbister, J.; Hamdorf, J.; Campbell, L.; Benites, B.; Duarte, G.; Rabello, G.; et al. Making patient blood management the new norm(al) as experienced by implementors in diverse countries. BMC Health Serv. Res. 2021, 21, 634. [Google Scholar] [CrossRef]
- Rancati, V.; Scala, E.; Ltaief, Z.; Gunga, M.Z.; Kirsch, M.; Rosner, L.; Marcucci, C. Challenges in Patient Blood Management for Cardiac Surgery: A Narrative Review. J. Clin. Med. 2021, 10, 2454. [Google Scholar] [CrossRef] [PubMed]
- Klein, A.; Agarwal, S.; Cholley, B.; Fassl, J.; Griffin, M.; Kaakinen, T.; Mzallassi, Z.; Paulus, P.; Rex, S.; Siegemund, M.; et al. A survey of patient blood management for patients undergoing cardiac surgery in nine European countries. J. Clin. Anesth. 2021, 72, 110311. [Google Scholar] [CrossRef] [PubMed]
- Van Der Linden, P.; Hardy, J.-F. Implementation of patient blood management remains extremely variable in Europe and Canada: The NATA benchmark project An observational study. Eur. J. Anaesthesiol. 2016, 33, 913–921. [Google Scholar] [CrossRef]
- World Health Organization. The Urgent Need to Implement Patient Blood Management: Policy Brief; World Health Organization: Geneva, Switzerland, 2021; Available online: https://apps.who.int/iris/handle/10665/346655 (accessed on 27 April 2023).
- Blaudszun, G.; Butchart, A.; Klein, A.A. Blood conservation in cardiac surgery. Transfus. Med. 2017, 28, 168–180. [Google Scholar] [CrossRef] [PubMed]
- Order of the Romanian Ministry of Health, no 1251/2018 for the Approval of the Guideline for Patient Blood Management during the Peri-Operative Period; published in the Official Gazette of Romania no 877; Romanian Ministry of Health: Bucharest, Romania, 2018.
- Filipescu, D.; Banateanu, R.; Beuran, M.; Burcos, T.; Corneci, D.; Cristian, D.; Diculescu, M.; Dobrota, A.; Droc, G.; Isacoff, D.; et al. Perioperative Patient Blood Management Programme. Multidisciplinary recommendations from the Patient Blood Management Initiative Group. Rom. J. Anaesth. Intensive Care 2017, 24, 139–157. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stefan, M.; Lupu, A.R.; Andrei, Ș.; Văleanu, L.; Știru, O.; Robu, C.; Bute, T.; Moroșanu, B.; Dumitrescu, A.; Stegaru, A.; et al. Perioperative trajectory of haemoglobin, predictors of blood transfusion and tailoring targets for patient blood management interventions: A single-centre, retrospective study of non-emergent cardiac surgery patients. Rom. J. Anaesth. Intensive Care 2022, 28, 47–56. [Google Scholar] [CrossRef]
- Ristescu, I.; Pintilie, G.; Filip, D.; Jitca, M.; Fecheta, R.; Florescu, I.; Scripcariu, V.; Filipescu, D.; Grigoraş, I. Perioperative Anemia and Transfusion in Colorectal Cancer Patients. Chirurgia 2019, 114, 234. [Google Scholar] [CrossRef]
- Ranucci, M.; Conti, D.; Castelvecchio, S.; Menicanti, L.; Frigiola, A.; Ballotta, A.; Pelissero, G. Hematocrit on Cardiopulmonary Bypass and Outcome After Coronary Surgery in Nontransfused Patients. Ann. Thorac. Surg. 2010, 89, 11–17. [Google Scholar] [CrossRef]
- Roman, M.A.; Abbasciano, R.G.; Pathak, S.; Oo, S.; Yusoff, S.; Wozniak, M.; Qureshi, S.; Lai, F.Y.; Kumar, T.; Richards, T.; et al. Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: A network meta-analysis. Br. J. Anaesth. 2021, 126, 149–156. [Google Scholar] [CrossRef] [PubMed]
- Snyder-Ramos, S.A.; Mhnle, P.; Weng, Y.-S.; Bttiger, B.W.; Kulier, A.; Levin, J.; Mangano, D.T. Investigators of the Multicenter Study of Perioperative Ischemia; MCSPI Research Group The ongoing variability in blood transfusion practices in cardiac surgery. Transfusion 2008, 48, 1284–1299. [Google Scholar] [CrossRef] [PubMed]
- McQuilten, Z.K.; Andrianopoulos, N.; Wood, E.M.; Cole-Sinclair, M.F.; McNeil, J.J.; Cameron, P.A.; Reid, C.M.; Newcomb, A.E.; Smith, J.A.; Phillips, L.E. Transfusion practice varies widely in cardiac surgery: Results from a national registry. J. Thorac. Cardiovasc. Surg. 2014, 147, 1684–1690.e1. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shehata, N.; Mistry, N.; Da Costa, B.R.; Pereira, T.V.; Whitlock, R.; Curley, G.F.; Scott, D.A.; Hare, G.M.T.; Jüni, P.; Mazer, C.D. Restrictive compared with liberal red cell transfusion strategies in cardiac surgery: A meta-analysis. Eur. Heart J. 2019, 40, 1081–1088. [Google Scholar] [CrossRef]
- Mazer, C.D.; Whitlock, R.P.; Fergusson, D.A.; Hall, J.; Belley-Cote, E.; Connolly, K.; Khanykin, B.; Gregory, A.J.; De Médicis, É.; McGuinness, S.; et al. Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery. N. Engl. J. Med. 2017, 377, 2133–2144. [Google Scholar] [CrossRef]
- Mazer, C.D.; Whitlock, R.P.; Fergusson, D.A.; Belley-Cote, E.; Connolly, K.; Khanykin, B.; Gregory, A.J.; De Médicis, É.; Carrier, F.M.; McGuinness, S.; et al. Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery. N. Engl. J. Med. 2018, 379, 1224–1233. [Google Scholar] [CrossRef]
- Mueller, M.M.; Van Remoortel, H.; Meybohm, P.; Aranko, K.; Aubron, C.; Burger, R.; Carson, J.L.; Cichutek, K.; De Buck, E.; Devine, D.; et al. Patient Blood Management: Recommendations From the 2018 Frankfurt Consensus Conference. JAMA 2019, 321, 983. [Google Scholar] [CrossRef]
- Ad, N.; Massimiano, P.S.; Rongione, A.J.; Taylor, B.; Schena, S.; Alejo, D.; Fonner, C.E.; Salenger, R.; Whitman, G.; Metkus, T.S.; et al. Number and Type of Blood Products Are Negatively Associated With Outcomes After Cardiac Surgery. Ann. Thorac. Surg. 2022, 113, 748–756. [Google Scholar] [CrossRef]
- Ming, Y.; Liu, J.; Zhang, F.; Chen, C.; Zhou, L.; Du, L.; Yan, M. Transfusion of Red Blood Cells, Fresh Frozen Plasma, or Platelets Is Associated With Mortality and Infection After Cardiac Surgery in a Dose-Dependent Manner. Anesth. Analg. 2020, 130, 488–497. [Google Scholar] [CrossRef]
- Kaserer, A.; Rössler, J.; Braun, J.; Farokhzad, F.; Pape, H.-C.; Dutkowski, P.; Plass, A.; Horisberger, T.; Volbracht, J.; Manz, M.G.; et al. Impact of a Patient Blood Management monitoring and feedback programme on allogeneic blood transfusions and related costs. Anaesthesia 2019, 74, 1534–1541. [Google Scholar] [CrossRef] [Green Version]
- An EU-Wide Overview of the Market of Blood, Blood Components and Plasma Derivatives Focusing on Their Availability for Patients; Creative Ceutical Report, Revised by the Commission, to Include Stakeholders’ Comments; European Commission: Brussels, Belgium, 2015.
- Saxena, S.; Krombach, J.W.; Nahrwold, D.A.; Pirracchio, R. Anaesthesia-specific checklists: A systematic review of impact. Anaesth. Crit. Care Pain Med. 2020, 39, 65–73. [Google Scholar] [CrossRef] [PubMed]
- Gunertem, E.; Urcun, S.; Pala, A.A.; Budak, A.B.; Ercisli, M.A.; Gunaydin, S. Predictiveness of different preoperative risk assessments for postoperative bleeding after coronary artery bypass grafting surgery. Perfusion 2021, 36, 277–284. [Google Scholar] [CrossRef] [PubMed]
- Hung, M.; Besser, M.; Sharples, L.D.; Nair, S.K.; Klein, A.A. The prevalence and association with transfusion, intensive care unit stay and mortality of pre-operative anaemia in a cohort of cardiac surgery patients*: Pre-operative anaemia in a cohort of cardiac surgery patients. Anaesthesia 2011, 66, 812–818. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Domenica Cappellini, M.; Motta, I. Anemia in Clinical Practice—Definition and Classification: Does Hemoglobin Change With Aging? Semin. Hematol. 2015, 52, 261–269. [Google Scholar] [CrossRef] [PubMed]
- Stammers, A.H.; Tesdahl, E.A.; Mongero, L.B.; Stasko, A. Gender and intraoperative blood transfusion: Analysis of 54,122 non-reoperative coronary revascularization procedures. Perfusion 2019, 34, 236–245. [Google Scholar] [CrossRef]
- Muñoz, M.; Acheson, A.G.; Auerbach, M.; Besser, M.; Habler, O.; Kehlet, H.; Liumbruno, G.M.; Lasocki, S.; Meybohm, P.; Rao Baikady, R.; et al. International consensus statement on the peri-operative management of anaemia and iron deficiency. Anaesthesia 2017, 72, 233–247. [Google Scholar] [CrossRef] [Green Version]
Type of Surgery | Before (Number and Percentage) | After (Number and Percentage) |
---|---|---|
CABG | 252 (35.5%) | 171 (36.9%) |
One valve replacement/repair | 256 (36.1%) | 144 (31%) |
Two or more valves replacement/repair | 59 (8.3%) | 42 (9.1%) |
Valve(s) and CABG | 69 (9.7%) | 52 (11.4%) |
Surgery on thoracic aorta | 44 (6.2%) | 32 (6.9%) |
Other | 29 (4.1%) | 23 (4.9%) |
Variable | Before | After | p = | Matched Before | Matched After | p = |
---|---|---|---|---|---|---|
Number | 710 | 464 | 157 | 169 | ||
Age | 64 (58–69) | 64 (56–69) | 0.643 | 66 (60–69) | 65 (59–69) | 0.504 |
Sex (M) | 469 (66.1%) | 306 (65.9%) | 0.970 | 111 (70.7%) | 117 (69.2%) | 0.772 |
Hospital LOS (days) | 13 (10–16) | 14 (11–18) | 0.037 | 12 (9–15) | 12 (10–15) | 0.412 |
ICU LOS (days) | 2 (2–4) | 3 (3–4) | <0.001 | 2 (2–3) | 3 (3–3) | <0.001 |
Surgical re-exploration n (%) | 45 (6.3%) | 53 (11.4%) | 0.002 | 0 | 0 | |
Surgery time (mins) | 270 (220–330) | 245 (210–290) | <0.001 | 240 (210–300) | 245 (210–280) | 0.987 |
Hb < 13 g/dl | 288 (40.5%) | 183 (39.4%) | 0.701 | 49 (31.1%) | 55 (32.5%) | 0.796 |
Hb1 (g/dl) | 13.4 (12.3–14.4) | 13.4 (12.3–14.3) | 0.863 | 13.6 (12.6–14.5) | 13.6 (12.7–14.5) | 0.844 |
Hb2 (g/dl) | 13.3 (12.2–14.4) | 13 (11.7–14.1) | <0.001 | 13.6 (12.6–14.5) | 13.2 (12.1–14.2) | 0.004 |
ROTEM use n (%) | 123 (17.3%) | 98 (21.5%) | 0.822 | 6 (3.8%) | 7 (4.1%) | 0.883 |
Cell saver n (%) | 7 (1.2%) | 7 (1.5%) | 0.657 | 0 | 0 |
Variable | Before | After | p = | Matched Before | Matched After | p = |
---|---|---|---|---|---|---|
PRBC transfusion, n patients (%) | 369 (52%) | 266 (57.3%) | 0.072 | 79 (50.3%) | 78 (44.9%) | 0.334 |
Perioperative PRBC transfusion (units, medians, and IQR) | 1 (0–2) | 1 (0–3) | 0.009 | 1 (0–2) | 0 (0–1) | 0.424 |
Perioperative PRBC transfusion (units, means, and SD) | 1.39 (2.26) | 2.04 (3.88) | <0.001 | 0.94 (1.32 | 0.89 (1.32) | 0.705 |
Intraoperative PRBC transfusion (units, medians, and IQR) | 0 (0–1) | 0 (0–1) | 0.802 | 0 (0–1) | 0 (0–1) | 0.283 |
Intraoperative PRBC transfusion (units, means, and SD) | 0.84 (1.46) | 0.82 (1.46) | 0.797 | 0.6 (1.01) | 0.47 (0.85) | 0.190 |
Postoperative PRBC transfusion (units, medians, and IQR) | 0 (0–1) | 0 (0–1) | 0.021 | 0 (0–1) | 0 (0–1) | 0.960 |
Postoperative PRBC transfusion (units, means, and SD) | 0.67 (1.56) | 1.2 (3.4) | <0.001 | 0.36 (0.64) | 0.41 (0.8) | 0.529 |
Hb3 (g/dl) | 9.9 (8.9–10.8) | 9.3 (8.6–10.2) | <0.001 | 10.1 (9.1–11.1) | 9.4 (8.7–10.1) | <0.001 |
Hb4 (g/dl) | 9.7 (9–10.6) | 9.2 (8.5–9.9) | <0.001 | 9.8 (9.2–10.7) | 9.3 (8.5–9.9) | <0.001 |
Perioperative FFP transfusion (units, medians, and IQR) | 0 (0–2) | 0 (0–2) | 0.348 | 0 (0–0) | 0 (0–0) | 0.04 |
Perioperative FFP transfusion (units, means, and SD) | 1.02 (2.34) | 1.83 (5.27) | <0.001 | 0.7 (1.73) | 0.38 (1.05) | 0.04 |
Intraoperative FFP transfusion (units, medians, and IQR) | 0 (0–0) | 0 (0–0) | 0.387 | 0 (0–0) | 0 (0–0) | 0.004 |
Intraoperative FFP transfusion (units, means, and SD) | 0.76 (1.7) | 0.77 (1.92) | 0.933 | 0.59 (1.31) | 0.23 (0.79) | 0.003 |
Postoperative FFP transfusion (units, medians, and IQR) | 0 (0–0) | 0 (0–0) | 0.002 | 0 (0–0) | 0 (0–0) | 0.481 |
Postoperative FFP transfusion (units, means, and SD) | 0.29 (1.23) | 1.05 (4.38) | <0.001 | 0.11 (0.73) | 0.15 (0.74) | 0.591 |
PLT transfusion, n patients (%) | 65 (9.3%) | 40 (8,6%) | 0.748 | 10 (6.3%) | 6 (3.5%) | 0.239 |
Preoperative anaesthetic consultation (days before surgery, median with IQR) | 1 (1–1) | 1 (0–1) | <0.001 | 1 (1–1) | 1 (1–1) | 0.005 |
Preoperative anaesthetic consultation (days before surgery, mean, SD) | 1.32 | 0.96 | <0.001 | 1.3 (1.4) | 0.9 (0.7) | 0.002 |
Standardised haemostasis questionnaire, n patients (%) | 72 (10.14%) | 332 (71.8%) | <0.001 | 19 (12.1%) | 128 (75.7%) | <0.001 |
Standardized pretransfusion checklist, n patients (%) | 0 | 301 (65.1%) | 0 | 93 (55%) |
Variables | Univariate | Multivariate | ||
---|---|---|---|---|
OR (95% CI) | p | OR (95% CI) | p | |
Age > 64 years | 2.31 (1.825–2.922) | <0.001 | 1.652 (1.17–2.331) | 0.004 |
Female sex | 2.645 (2.048–3.415) | <0.001 | 2.404 (1.655–3.492) | <0.001 |
Hospital LOS (days) | 1.037 (1.021–1.054) | <0.001 | 1.02 (0.994–1.047) | 0.138 |
ICU LOS (days) | 1.168 (1.097–1.243) | <0.001 | 1.065 (0.995–1.14) | 0.067 |
Surgery time (hours) | 1.348 (1.219–1.489) | <0.001 | 1.295 (1.126–1.488) | <0.001 |
Hb < 13 g/dl | 4.315 (3.34–5.576) | <0.001 | 3.611 (2.528–5.158) | <0.001 |
Re-exploration for bleeding | 6.879 (3.717–12.733) | <0.001 | 3.988 (1.248–12.738) | 0.020 |
ROTEM use | 4.401 (3.053–6.344) | <0.001 | 2.18 (1.34–3.544) | <0.001 |
FFP transfusion | 7.898 (5.601–11.135) | <0.001 | 4.023 (2.426–6.671) | <0.001 |
PLT transfusion | 3.32 (2.059–5.354) | <0.001 | 0.951 (0.478–1.892) | 0.887 |
Standardised haemostasis questionnaire use | 0.766 (0.6–0.976) | 0.031 | 0.565 (0.371–0.861) | 0.008 |
Standardized pretransfusion checklist use | 8.151 (5.73–11.596) | <0.001 | 8.875 (5.496–14.332) | <0.001 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Ștefan, M.; Tomescu, D.; Predoi, C.; Goicea, R.; Perescu, M.; Popescu, M.; Dorobanțu, D.; Droc, G.; Andrei, Ș.; Știru, O.; et al. Less (Transfusion) Is More—Enhancing Recovery through Implementation of Patient Blood Management in Cardiac Surgery: A Retrospective, Single-Centre Study of 1174 Patients. J. Cardiovasc. Dev. Dis. 2023, 10, 266. https://doi.org/10.3390/jcdd10070266
Ștefan M, Tomescu D, Predoi C, Goicea R, Perescu M, Popescu M, Dorobanțu D, Droc G, Andrei Ș, Știru O, et al. Less (Transfusion) Is More—Enhancing Recovery through Implementation of Patient Blood Management in Cardiac Surgery: A Retrospective, Single-Centre Study of 1174 Patients. Journal of Cardiovascular Development and Disease. 2023; 10(7):266. https://doi.org/10.3390/jcdd10070266
Chicago/Turabian StyleȘtefan, Mihai, Dana Tomescu, Cornelia Predoi, Raluca Goicea, Mihai Perescu, Mihai Popescu, Dan Dorobanțu, Gabriela Droc, Ștefan Andrei, Ovidiu Știru, and et al. 2023. "Less (Transfusion) Is More—Enhancing Recovery through Implementation of Patient Blood Management in Cardiac Surgery: A Retrospective, Single-Centre Study of 1174 Patients" Journal of Cardiovascular Development and Disease 10, no. 7: 266. https://doi.org/10.3390/jcdd10070266
APA StyleȘtefan, M., Tomescu, D., Predoi, C., Goicea, R., Perescu, M., Popescu, M., Dorobanțu, D., Droc, G., Andrei, Ș., Știru, O., Bubenek Turconi, Ș. -I., & Filipescu, D. (2023). Less (Transfusion) Is More—Enhancing Recovery through Implementation of Patient Blood Management in Cardiac Surgery: A Retrospective, Single-Centre Study of 1174 Patients. Journal of Cardiovascular Development and Disease, 10(7), 266. https://doi.org/10.3390/jcdd10070266