Abstract
Background
With aging, knee joint problems and total knee arthroplasty (TKA) to improve knee function have increased in older persons. Enhanced recovery after surgery (ERAS) protocols aim to aid recovery, but their impact on older TKA patients is uncertain.
Methods
This study employs a systematic review and meta-analysis to synthesize the effects of ERAS on older patients with TKA from randomized controlled trials. PubMed, Cochrane, Web of Science, and EMBASE databases were searched, and the Analysis was conducted using Review Manager 5.4 software.
Results
The ERAS group showed a significantly shorter length of hospital stay, fewer postoperative complications, and no significant difference in readmission rates compared to the control group. Regarding pain management, the ERAS group had significantly lower VAS scores on the first two postoperative days, reduced analgesic use, and lower hospitalization costs, demonstrating clear clinical advantages.
Conclusion
ERAS accelerates older patients' TKA recovery, reducing hospital stays and complications, and has important clinical implications.
Keywords: Aging, Enhanced recovery after surgery, Postoperative accelerated recovery, Total knee replacement
Highlights
Knee joint issues rise with aging, making TKA essential for older person recovery. Enhanced Recovery After Surgery protocols further improve outcomes and satisfaction.
Significance of TKA:
TKA boosts functionality, crucial for the older person's quality of life.
Potential of Enhanced Recovery:
Protocols accelerate recovery, shorten hospital stays, and enhance outcomes for older person TKA patients.
1. Introduction
Kehlet introduced Enhanced Recovery after Surgery (ERAS), which emerged in the 1990s under the leadership of a renowned Danish surgeon who pioneered the concept.1 The Kehlet recovery model encompasses a comprehensive set of optimized perioperative interventions to enhance the surgical experience. By utilizing evidence-based medical strategies, Kehlet's approach focuses on minimizing postoperative physical and psychological trauma and stress, thereby facilitating a faster recovery.1, 2, 3, 4 The fundamental principle of ERAS revolves around reducing surgical trauma and stress through the use of minimally invasive surgical techniques.20, 21, 22, 23 This approach has shown favorable outcomes, including decreased postoperative complications, cost reduction, shorter hospital stays (LOS), improved patient satisfaction, and accelerated recovery. Initially, ERAS exhibited promising results in gastrointestinal surgery. 20,21 However, recent advances in orthopedic surgical techniques and anesthesia have shown promising clinical outcomes to promote postoperative recovery, particularly in joint surgeries.
Despite these advances, there is still no unanimous recognition or acceptance among orthopedic surgeons regarding the effectiveness of ERAS in the context of joint replacement surgery. 13, 14, 15, 16 Studies such as systematic reviews and meta-analyses are needed to provide information for discussions between surgeons evaluating the utilization of ERAS.17, 18, 19
2. Methods
2.1. Document retrieval
According to registration number CRD42023441050, this review has been registered in the International Prospective Register of Systematic Reviews (PROSPERO). Two authors conducted a comprehensive literature review, focusing on studies published until December 31, 2024. The search was undertaken systematically across multiple databases, including PubMed, Cochrane, Web of Science, and EMBASE, using specific keywords and predefined inclusion criteria. The search terms employed were “total knee arthroplasty (TKA) or total knee replacement” and “ERAS, Enhanced Recovery after Surgery, enhanced recovery protocols, or rapid recovery surgery”. The selection process was constrained by inclusion criteria and limited to controlled clinical trials and randomized controlled trials that investigated the implementation of ERAS protocols after total knee arthroplasty. Additionally, the review was restricted to research articles written in English to ensure consistency in the interpretation and analysis of the results.
2.2. Inclusion criteria
The study included older patients who underwent enhanced recovery after surgery of total knee arthroplasty. On the other hand, the control group received traditional recovery protocol. All studies cited in this review met the inclusion criteria and provided relevant data on post-operative recovery protocol.
2.3. Exclusion criteria
To ensure the reliability and validity of the results, review articles, case reports, and single-arm or non-controlled studies were excluded from the analysis. Inclusion criteria focused on total knee arthroplasty, excluding studies without relevant postoperative indicators and those concentrating on enhanced recovery after joint surgeries other than the knee. Additionally, duplicate or previously published literature was excluded to avoid redundancy and ensure the inclusion of independent studies.
2.4. Data extraction
After thoroughly reviewing the abstracts and titles, two reviewers conducted a detailed examination of the full-text articles based on predefined inclusion criteria. Relevant clinical and study data were extracted, including author details, publication year, sample size, demographic data of participants (age and gender), and details of the recovery measures. ERAS vs. non-ERAS were compared for surgical site, complications, hospital stay, and readmission. The extracted data were organized in tabular format and recorded in an Excel spreadsheet. To ensure precision, two copies of the spreadsheet were created. In cases where there were discrepancies in the data extractions between the reviewers, any disputes were resolved by consensus or with the potential participation of a third-party investigator, if required.
2.5. Qualitative assessment of included studies
Multiple criteria were employed to assess the relevance of the included studies. These criteria included randomization, concealment of allocation, blinding of interventions and outcome evaluations, discontinuation or abandonment of postoperative treatment, and intention-to-treat analysis.
This classification system allowed for evaluating and classifying the included studies based on their adherence to important methodological standards and relevance to the research question.
2.6. Outcome measures
The evaluation of outcomes in this study encompassed several key measures, including the assessment of various factors such as the duration of hospitalization, readmission rate, and complication rate. LOS refers to the duration from the surgical procedure to the patient's discharge from the hospital. In addition, other important outcomes such as VAS (Visual Analog Scale) scores, satisfaction levels of patients, financial costs, and reported assessments were also taken into account.
These results provided valuable insights into various aspects of the surgical recovery process and the overall patient experience. The LOS reflected the efficiency of the recovery protocol, while the readmission rate and complication rate offered indicators of postoperative complications and the need for additional medical attention. Furthermore, measures such as VAS scores, patient satisfaction levels, financial costs, and reported assessments allowed a comprehensive evaluation of the overall impact and effectiveness of the interventions implemented.
2.7. Statistical analysis
The statistical examination of the studies included in the analysis encompassed computing and presenting the mean difference, calculated for continuous outcomes alongside a corresponding 95 % confidence interval. For binary outcomes, the odds ratio (OR) was reported in the analysis, accompanied by a 95 % confidence interval. An assessment was conducted to evaluate the heterogeneity among the studies. Chi-square and I2 are used to assess study heterogeneity. These statistical measures helped evaluate the consistency and variability of the study results, allowing for a comprehensive assessment of the overall effect size and the presence of heterogeneity across the included studies.
Depending on the I2 values, either a fixed-effect model or a random-effects model was utilized for the analysis. Random-effect models were utilized to conduct subgroup and sensitivity analyses. Review Manager 5.4 software was utilized for data analysis, enabling the computation and synthesis of the extracted data.
3. Results
3.1. Study characteristics and quality evaluation
Table 1 presents the key features and quality evaluation of the studies included in this analysis. The studies varied in terms of publication year, country, and sample characteristics. The total number of participants and their respective demographic details are provided for both the ERAS and non-ERAS groups. For example, Malviya et al. (2011) included 1,500 participants in the non-ERAS group and 3,000 in the ERAS group, with an average age of 68 years for both groups. Similarly, the studies by den Hertog et al. (2012), Macdonald et al. (2012), and others are listed, showing a range of surgeries, predominantly Total Hip and Knee Arthroplasties (THA/TKA), with varied sample sizes and age distributions. The studies are from diverse countries, including the UK, Germany, the USA, Australia, and New Zealand, demonstrating the international scope of the research.
Table 1.
Features and evaluation of included studies' quality.
| Study | Publication Year | Country | Non-ERAS N, male/female, age (years) mean (SD) | ERAS N, male/female, age (years) mean (SD) |
|---|---|---|---|---|
| Malviya A et al.9 | 2011 | UK | 1500, 711/789, 68 | 3000, 1482/1518, 69 |
| denHertog A et al.7 | 2012 | Germany | 74, 23/51, 66.58 (8.21) | 73, 20/53, 68.25 (7.91) |
| Macdonald DA et al.10 | 2012 | UK | 1081, 439/642, 69 (11) | 735, 307/428, 70 (13) |
| Scott NB et al.11 | 2013 | UK | 405,/, 68 (11) | 873,/, 68 (10) |
| Ouyang DB et al.5 | 2015 | USA | 126, 41/85, 68.44 (9.98) | 126, 44/82, 66.02 (10.02) |
| Christelis N et al.6 | 2015 | Australia | 297, 113/184, 67 (10) | 412, 164/248, 68 (11) |
| Maempel JF et al.8 | 2015 | UK | 84, 42/42, 69.8 (8.9) | 81, 40/44, 70.1 (10.5) |
| Storrs MD et al.12 | 2016 | New Zealand | 100, 47/53, 66.7 (9.2) | 100, 41/59, 65.4 (12.5) |
ERAS: Enhanced Recovery After Surgery.
3.2. Data sources and extraction for length of stay (LOS)
Table 2 summarizes the data sources and extraction methods for the length of hospital stay (LOS) across the included studies. The studies were conducted in various countries, primarily in English-speaking regions, and focused on THA and TKA surgeries. The sample sizes ranged from 74 to 3,000 participants, with the ERAS group ranging from 73 to 3,000 participants. The LOS data indicated variability, with Auyong et al. (2015) reporting the shortest LOS of 2.34 ± 0.97 days in the ERAS group, while Malviya et al. (2011) reported a longer LOS of 4.8 ± 3 days for the non-ERAS group. Other studies, such as Christelis et al. (2015) and Maempel et al. (2015), reported LOS values ranging from 3 to 6.75 days, showing a trend toward shorter stays in the ERAS group.
Table 2.
Incorporate research testing data sources and data extraction (Length of Stay - LOS).
| Study | Year | Country | Language | Surgery | Total | ERAS Group | Control Group |
|---|---|---|---|---|---|---|---|
| Malviya et al.9 | 2011 | UK | English | THA/TKA | 1500 | 3000 | 4.8 ± 3 |
| den Hertog et al.7 | 2012 | Germany | English | Total Knee Arthroplasty | 74 | 73 | 6.75 |
| Macdonald DA et al.10 | 2012 | UK | English | Total Knee Arthroplasty | 1081 | 735 | 4 ± 2 |
| Scott NB et al.11 | 2013 | UK | English | THA/TKA | 405 | 873 | 5 |
| Auyong DB et al.5 | 2015 | USA | English | Total Knee Arthroplasty | 126 | 126 | 2.34 ± 0.97 |
| Christelis N et al.6 | 2015 | Australia | English | THA/TKA | 297 | 412 | 4.9 ± 1.6 |
| Maempel et al.8 | 2015 | UK | English | Total Knee Arthroplasty | 84 | 81 | 3 ± 2.14 |
| Storrs MD et al.12 | 2016 | New Zealand | English | THA/TKA | 100 | 100 | 4 ± 2 |
ERAS: Enhanced Recovery After Surgery; TKA: Total Knee Arthroplasty.
3.3. Data sources and extraction for complications
Table 3 presents data on the incidence of complications, another critical outcome evaluated across the studies. Malviya et al. (2011) reported a complication rate of 2.6 % in the ERAS group compared to 3.43 % in the non-ERAS group, while Macdonald et al. (2012) showed similar rates of 2.5 % and 2.18 %, respectively. Some studies, such as den Hertog et al. (2012) and Christelis et al. (2015), reported higher complication rates, with ERAS group complications ranging from 3.57 % to 10.81 % and non-ERAS rates ranging from 6.17 % to 16.44 %. The study by Storrs et al. (2016) showed a significant difference in complication rates between the two groups, with 15 % in the ERAS group and 22 % in the non-ERAS group. This table provides a comprehensive view of the complication rates, highlighting the potential benefits of ERAS in reducing adverse outcomes.
Table 3.
Test data sources and data extraction (incidence of complications).
| Study | Year | Country | Language | Surgery | Total Cases | ERAS Group | Non-ERAS Group | ERAS Complication Rate (%) | Non-ERAS Complication Rate (%) |
|---|---|---|---|---|---|---|---|---|---|
| Malviya et al.9 | 2011 | UK | English | THA/TKA | 1500 | 3000 | 39 | 2.6 % | 3.43 % |
| Macdonald DA et al.10 | 2012 | UK | English | Total Knee Arthroplasty | 1081 | 735 | 27 | 2.5 % | 2.18 % |
| den Hertog et al.7 | 2012 | Germany | English | Total Knee Arthroplasty | 74 | 73 | 8 | 10.81 % | 16.44 % |
| Auyong DB et al.5 | 2015 | USA | English | Total Knee Arthroplasty | 126 | 126 | 3 | 2.38 % | 7 |
| Christelis N et al.6 | 2015 | Australia | English | THA/TKA | 297 | 412 | 30 | 10.1 % | 11.89 % |
| Maempel et al.8 | 2015 | UK | English | Total Knee Arthroplasty | 84 | 81 | 3 | 3.57 % | 6.17 % |
| Storrs MD et al.12 | 2016 | New Zealand | English | THA/TKA | 100 | 100 | 15 | 15 % | 22 % |
TKA: Total knee arthroplasty; ERAS: Enhanced recovery after surgery.
Fig. 1: The study selection process initially involved the selection of more than 3000 articles based on predefined inclusion criteria. After the abstract and full-text review, a comprehensive evaluation was conducted on 37 full-text articles to determine their eligibility. Ultimately, after meeting the criteria, eight studies were analyzed. ERAS group: 3,667 participants Control group: 5,400 participants All studies included in the analysis provided data on the length of hospital stay (LOS), with 7 studies reporting postoperative complication rates and 4 studies reporting readmission rates.
Fig. 1.
Search process flowchart.
The included studies exhibited similarities in gender, age, and type of surgery. Further information on the characteristics of each study can be found in Table 1. Table 2 summarizes the length of stay (LOS) data, while5, 6, 7, 8, 9, 10, 11, 12 Table 3, Table 4 present summaries of the complications and readmission data, respectively. Fig. 6: Risk of bias summary. These tables comprehensively overview the relevant information extracted from the included studies.
Table 4.
Test data sources and data extraction (30-day readmission rate).
| Study | Year | Country | Language | Surgery | Total Cases | ERAS Group | Non-ERAS Group | ERAS 30-Day Readmission Rate (%) | Non-ERAS 30-Day Readmission Rate (%) |
|---|---|---|---|---|---|---|---|---|---|
| Malviya et al.9 | 2011 | UK | English | THA/TKA | 1500 | 3000 | 70 | 4.67 % | 4.8 % |
| Auyong DB et al.5 | 2015 | USA | English | Total Knee Arthroplasty | 126 | 126 | 3 | 2.38 % | 5.56 % |
| Christelis N et al.6 | 2015 | Australia | English | THA/TKA | 297 | 412 | 10 | 3.37 % | 3.4 % |
| Storrs MD et al.12 | 2016 | New Zealand | English | THA/TKA | 100 | 100 | 8 | 8 % | 14 % |
TKA: Total knee arthroplasty; ERAS: Enhanced recovery after surgery.
Fig. 6.
Risk of bias summary& Risk of bias graph.
3.4. Meta-analysis results
The findings of the study demonstrated a significant reduction in the length of hospital stay (LOS) in the ERAS group, which included 3,104 patients from 8 studies. Contrasted with the 7,478 patients in the control group, p = 0.01, I2 = 99 %, standardized mean difference = −1.45, 95 % CI -2.60-0.31).5,6,9,10,12 Fig. 2A shows the subgroup analysis performed, and Fig. 2B5,6,9,10,12 provides a visual representation of the results of the subgroup analysis.
Fig. 2.
Hospital stay: ERAS vs. control.
3.5. Comparison of postoperative complication rates: two groups
The analysis comprised a total of 7 studies (Fig. 3), which encompassed 7,789 patients. Among them, the ERAS group consisted of 3,262 patients, while the control group consisted of 4,527 patients. Among the 7 studies that reported complication data, the initial review by Stowers et al. did not show a significant difference (p = 0.372). However, upon reanalysis that included Stowers et al.'s study, as shown in Figs. 3,5, 6, 7, 8, 9, 10,12 there was a statistically significant difference in the complication rates between the ERAS and control groups (odds ratio = 0.77, 95 % CI 0.61–0.98, p = 0.03). The 30-day readmission rates did not significantly differ between ERAS and control groups 5,6,9,12 (OR = 0.90, 95 % CI 0.69–1.16, p = 0.41; Fig. 4).
Fig. 3.
ERAS vs. control: Comparison of complications.
Fig. 4.
ERAS vs. control: Comparison of the publication bias of 30-day readmission.
Publication bias analysis of seven studies on postoperative complications (comparison of log odds ratios with standard error funnel plot) between ERAS and non-ERAS groups (Fig. 5).
Fig. 5.
Minimal publication bias is observed.
3.5.1. Overall assessment
Based on the evaluation of postoperative pain from 5 studies1,3,5,12,14 the ERAS group demonstrated superior outcomes in pain management. Auyong et al. reported a significantly higher Visual Analog Scale (VAS) score of 5.7 on the day of surgery in the ERAS cohort compared to 4.5 (p < 0.01) in the non-ERAS cohort. However, both groups experienced lower VAS scores over the initial two postoperative days, with the ERAS group showing a faster rate of improvement. On the first day, the ERAS group had a lower VAS score (6.3 vs. 7.1, p < 0.01), and on the second day, the ERAS group had a lower VAS score (5.7 vs. 6.3, p = 0.03). From the third day onwards, no statistically significant differences were observed in the Visual Analog Scale scores between the groups. The ERAS group also exhibited a lower dependence on costly opioid analgesics during hospitalization, leading to decreased hospital expenses compared to the non-ERAS group.
There were no discernible variations in VAS scores, according to Den Hertog et al. However, significant differences were observed on the first day of recovery and from day 5 to day 7, with the ERAS group having better cumulative pain relief scores (p = 0.0003). Mapel's study indicated significant differences in VAS scores (p < 0.001), with the ERAS cohort outperforming the non-ERAS cohort, but no significant difference in variability (p = 0.55). Higher pain medication requirements were observed for all patients during the initial two days of recovery. Additionally, a higher percentage of ERAS patients stopped using pain medication earlier compared to the non-ERAS group. Christelis et al.'s study reported no VAS score difference at 6 weeks after surgery but higher satisfaction in the ERAS group. The study conducted by Stowers et al. encompassed a thorough analysis of hospitalization costs.
3.6. Visual Analog Scale (V A S)
In terms of pain management, the table presents the data extracted from various studies on VAS scores. VAS is used to measure postoperative pain, with scores ranging from 0 (no pain) to 10 (severe pain). Several studies indicated that the ERAS group had significantly lower VAS scores on the first and second days after surgery than the non-ERAS group.
For example, Auyong et al. (2015) reported that the ERAS group had a VAS score of 6.3 on the first postoperative day, while the non-ERAS group had a score of 7.1 (p < 0.01). On the second postoperative day, the ERAS group's VAS score was 5.7, compared to 6.3 in the non-ERAS group (p = 0.03). This suggests that the ERAS group had more effective pain management and experienced faster pain relief in the early postoperative period. However, from the third postoperative day onwards, no significant difference in VAS scores was observed between the two groups.
Den Hertog et al. (2012) noted that while there was no significant difference in VAS scores on the first day, the ERAS group showed better cumulative pain relief from days 5–7 after surgery (p = 0.0003). Additionally, Mapel et al. (2015) found that the ERAS group had significantly better VAS scores postoperatively (p < 0.001), but no significant difference in variability between the groups (p = 0.55).
Overall, these results demonstrate that the ERAS protocol has a positive impact on postoperative pain management, particularly in the early postoperative period. Additionally, patients in the ERAS group tend to stop using pain medication earlier than those in the non-ERAS group, contributing to reduced hospital costs.
3.7. Risk of bias
The quality assessment of the included studies is presented in Fig. 6. The quality assessment for the selected prospective studies and randomized clinical trials was rated as high. The patients in the studies are representative of the overall experience, and the confirmation of exposure and outcomes is quite comprehensive. Additionally, the duration of follow-up is considered adequate.
4. Discussion
Following the 1990s debut of the ERAS concept by Danish surgeon H. Kehlet, an increasing number of studies showed that ERAS is safer and more effective than traditional treatment for a variety of perioperative conditions.15
The more we learn about the ERAS idea, the more practical it becomes for improving the effectiveness and safety of orthopedic joint replacement patients' postoperative treatment and recovery. Studies show that the postoperative Length of Stay (LOS) for joint replacement can be shortened from 4–12 days to 1–3 days without appreciably increasing the risk of complications or readmissions.12,15, 16, 17 At the same time, studies show that ERAS can help most patients having knee replacement surgery, including older patients, those with cardiovascular or type II diabetes conditions, and those who have complications from alcoholism, drug abuse, smoking, or other substance misuse issues.18,19 The safety and effectiveness of ERAS in Total Hip Arthroplasty (THA) and Total Knee Arthroplasty (TKA) seem quite clear. However, what specific changes need to be implemented in our current practices? The changes required for the application of ERAS in the perioperative period of joint replacement can be summarized as follows20: The objectives are to improve patient education, provide perioperative nutritional support, optimize anesthesia management, minimize fasting time,21 preoperative oral carbohydrate intake,22 early postoperative feedings, and fluid restriction23; perform minimally invasive surgery, including the Direct Anterior Approach and Medial Parapatellar Approach; manage blood pressure, anemia, apply tranexamic acid, and prevent infection and venous thromboembolism; following methods of pain management: sleep management, functional recovery exercises, prevention of nausea and vomiting, peripheral nerve blockade, local infiltration anesthesia, postoperative multimodal analgesia, optimal use of tourniquet, drainage tube, and catheter.
Regretfully, most surgeons tend to ignore perioperative patient management entirely in favor of concentrating only on surgical methods. Not all doctors have adopted ERAS to the fullest extent in their thinking. Procedures must follow optimal medical models, evidence-based best practices, and ERAS within the pathophysiology. More significant, though, is that every employee must actively participate in teamwork. Nurses, physiotherapists, anesthesiologists, and nutritionists. Win the patients' understanding and support. The only way we can overcome conventional wisdom and expedite our recovery.
The use of ERAS can shorten hospital stays, according to the systematic meta-analysis this study includes. (Fig. 2). However, it does not affect the 30-day readmission rate or problems. (Fig. 3, Fig. 4). In this article, the length of stay exhibits significant heterogeneity. Therefore, we further analyzed a subset of LOS, and the results indicate that one of the reasons for heterogeneity in sample size is between the ERAS group and the control group, and there are many clinical factors affecting LOS heterogeneity (including various optimization measures taken by ERAS). However, we believe that the results of LOS heterogeneity are significant: the perioperative goal of ERAS for joint replacement is to reduce LOS without increasing complications and readmissions. Compared to the non-ERAS group,5,6,9,10,12, 13, 14 One of the primary clinical causes of variability in ERAS groups is the various degrees of decrease in perioperative length of stay that these groups demonstrated following a succession of joint replacement optimization strategies. This has important guiding implications for applying ERAS during the clinical joint replacement perioperative phase. This article provides evidence-based medical evidence for best practice clinical work by further elucidating the safety and efficacy of ERAS for patients having joint replacement during the perioperative phase by integrated analysis. With the benefit of all patients, we seek to firmly establish the idea of ERAS in the minds of all doctors.
In joint replacement surgery, this is the first comprehensive analysis of ERAS. We ensured the scientific trustworthiness of the research by maximizing the sample size by extracting a large and robust database from pertinent studies that satisfied effective limits (including solely controlled clinical trials, or CCT, and randomized controlled trials, or RCT) investigations. There are certain restrictions, however. Because only English-language papers were retrieved for this investigation, there may be biases related to language or publication standards. Furthermore, there isn't nearly enough truly excellent research that fits these requirements, which could skew the results. Certain research that we disqualified used the word "random," but they did not specify the precise techniques employed, whether blinding was applied, or whether there were dropouts. These omissions could have introduced bias into the discussion to some extent. However, we think that this investigation has given us the most recent insight into how current surgical techniques affect recuperation. We have observed numerous improvements following surgery, a considerable decrease in length of stay , and a decrease in complications as a result of these evidence-based modifications.
Ethics approval
The registration number for PROSPERO CRD42023441050.
Consent for publication
For that section, it is not applicable.
Contributions
HW: Writing: first draft; and Writing: editing and review.
Consent for publication
That section is not applicable.
Funding
Not applicable for that section.
Declaration of competing interest
There are no competing interests disclosed by the writers.
Acknowledgments
Research Team Members: Thanks to all the team members who contributed to this study. Their hard work and expertise were crucial to the success of the research.
Footnotes
Abbreviations
- TKA
Total knee arthroplasty
- ERAS
Enhanced recovery after surgery
- RCTs
Randomized controlled trials
- CCTs
Controlled Clinical Trials
- LOS
Length of Stay
- MD
Mean Differences
- CI
Confidence Intervals
- OR
Odds Ratio
- VAS
Visual Analog Scale
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Data availability
Upon request, the authors can obtain the datasets created for this investigation.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Upon request, the authors can obtain the datasets created for this investigation.