ABSTRACT
Background
Elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically changed the landscape of cystic fibrosis (CF) care, including in those who require lung transplantation. The objectives of the study were to describe the cohort demographics and outcomes of primary lung transplant recipients before and after the availability of ETI.
Methods
This is a descriptive study of lung transplants performed at the Toronto Lung Transplant Program for CF during two time periods: 2019 (pre‐ETI era) and 2021–2023 (post‐ETI era). All subjects were referred from the Adult CF program at St. Michael's Hospital, Toronto. Data were obtained from chart review and the Toronto Lung Transplant database. The Kaplan–Meier method was used to estimate survival probability at 1 year post‐transplant.
Results
There were 22 lung transplants performed in 2019 (19 [86.4%] primary and 3 [13.6%] re‐transplants) compared to 11 lung transplants (8 [72.7%] primary and 3 [27.3%] re‐transplants) in the post‐ETI era. In primary transplant recipients, median age was 29.4 years (Range 18.6–67.6 years) in 2019 compared to 30.0 years (Range 19.1–64.0 years) in 2021–2023. In the post‐ETI era, none of the individuals had a deltaF508 variant, compared to 84% in 2019. One‐year survival probability was lower in the post‐ETI era (62.5% vs. 84.2%, respectively).
Conclusion
Lung transplant recipients in the post‐ETI era were more complex with high‐risk characteristics and had worse post‐transplant outcomes. This study highlights the importance of further investigation to better understand the impact of ETI on transplant referral patterns, recipient characteristics, and post‐transplant outcomes in the CF population.
Keywords: cystic fibrosis, lung (allograft) function/dysfunction, lung disease, lung transplantation, patient survival
Abbreviations
- CF
cystic fibrosis
- CFTR
cystic fibrosis transmembrane conductance regulator
- CIT
cold ischemic time
- ECMO
extracorporeal membrane oxygenation
- ETI
elexacaftor/tezacaftor/ivacaftor
- ICU
intensive care unit
- TLTP
Toronto Lung Transplant Program
- WIT
warm ischemic time
1. Introduction
Survival in cystic fibrosis (CF) has been increasing over the past three decades, and individuals with CF are living longer with advanced lung disease [1, 2]. The availability of highly effective modulator therapy, such as ivacaftor and, more recently, elexacaftor/tezacaftor/ivacaftor (ETI), has dramatically changed the landscape of CF care, even in those with advanced lung disease, and reduced the number of individuals who require lung transplantation [3, 4, 5]. Although eligibility for ETI is a moving target, it is estimated that about 91% of individuals with CF globally have an ETI‐responsive variant [6]. Data from France have shown that 96% of individuals with advanced CF lung disease who were started on ETI no longer met the criteria for being listed for lung transplant at 12 months [7]. They also found a reduced need for oxygen and noninvasive ventilation and a significant improvement in lung function and nutritional status following ETI initiation in this cohort of people with severe lung impairment. Furthermore, real‐world studies using US CF Foundation Patient Registry data report a 72% reduction in deaths and an 85% reduction in lung transplantation in those started on ETI when compared to historical controls from 2019 [8].
Although there are fewer lung transplants done since the availability of ETI, lung transplantation is still required for some individuals who continue to deteriorate despite maximal medical therapy. Even prior to ETI, the CF lung transplant landscape was shifting. A study examining CF lung transplant recipients from 1999 to 2013 showed increasing recipient age, greater pre‐transplant ventilator use, and lower lung function at listing—likely due to improved diagnostics and management [9]. ETI represents an even more significant shift, though only a few studies have examined its impact on transplant practices, with very little demographic information [10, 11, 12, 13].
Given this major shift in the health of the CF population in the ETI era, it is unclear if previously published risk factors for mortality [14] and post‐transplant survival estimates [15] apply to the current population of individuals requiring lung transplantation. The indication for ETI is based on genotype, with initial approval by Health Canada and the Food and Drug Administration (FDA) stating that eligible individuals must have at least one copy of deltaF508 in combination with any other CF transmembrane conductance regulator (CFTR) variant for therapy initiation. This means that approximately 90% of the CF population in North America would be eligible for ETI. Therefore, individuals moving forward for transplant likely do not qualify for ETI and have a genotype that does not include deltaF508. There is literature to suggest a survival difference exists after lung transplantation based on genotype, which is further evidence that the previously published estimates may no longer apply [16].
Accurately predicting survival post‐transplant in people with CF in this new era is critical to allow patients and caregivers to accurately outline the risks and benefits of transplantation, which can impact decision‐making. The objectives of this study were to describe the characteristics and clinical outcomes of lung transplant recipients for end‐stage CF lung disease after the availability of ETI in comparison to lung transplant recipients in the pre‐ETI era.
2. Methods
2.1. Study Design
This is a descriptive, retrospective study of lung transplants for CF performed in a large transplant center during two time periods: 2019 (pre‐ETI era) and 2021–2023 (post‐ETI era). The year 2020 was excluded because ETI was made available in Canada through a compassionate access program beginning in the early part of 2020 for those with advanced lung disease; therefore, 2020 does not truly reflect the post‐ETI era but may include individuals who were transplanted prior to accessing ETI. It is worth noting this study took place during the COVID‐19 pandemic when solid organ transplantation decreased globally in part due to lockdowns and hospital policies. This decrease was most evident in 2020, with the number of transplants generally stabilizing after 2020, providing further rationale for excluding this year from our analysis [17].
2.2. Study Population
Individuals with CF who were followed at the adult CF clinic at St. Michael's Hospital and who ultimately received a lung transplant at the Toronto Lung Transplant Program (TLTP) during the pre‐ and post‐ETI time period were eligible for inclusion to the study. The two hospitals are in close proximity to each other and have a long standing, collaborative relationship with shared care. Physicians from each site meet regularly to discuss transplant candidates, and both sites follow patients at regular intervals. The number of people who received a second transplant in the time periods was reported; however, the clinical characteristics and outcomes pertain only to those who received a first lung transplant. This study was approved by the research ethics board (REB # 24‐099) at St. Michael's Hospital as well as University Health Network‐Toronto General Hospital (REB# 24‐5513).
2.3. Data Sources
Pre‐transplant demographic and clinical data were obtained from chart reviews at St. Michael's Hospital and Toronto General Hospital. Detailed demographic and clinical information on all CF patients followed in Toronto was extracted from the medical record. Post‐transplant data and donor characteristics were obtained from the TLTP database, supplemented by chart review when required. The TLTP captures detailed information on the post‐transplant course for all individuals followed at the Toronto Transplant Program.
2.4. Variables
Baseline demographic and pre‐transplant characteristics included sex, genotype, age at CF diagnosis, pancreatic status, pre‐transplant microbiology, comorbidities (including asthma, diabetes, and liver disease), and medications. We recorded whether known complications related to CF such as pneumothorax, allergic bronchopulmonary aspergillosis, or hemoptysis occurred in the year prior to transplant. Further, we included whether individuals were using oral steroids 3 months prior to their transplant date. Donor information including sex, age, smoking history, and ischemic times were recorded. Variables of interest related to the course of the primary hospital admission for the lung transplant specifically were obtained. Extracorporeal membrane oxygenation (ECMO) use during transplant and the total estimated blood loss reported by the operating surgeon was recorded. With respect to hospitalization outcomes, the total days ventilated, the total days spent in ICU, and the total dialysis days following transplantation and prior to a patient's discharge were recorded. Transfusion of packed red blood cells during the first 24 h and during the first hospital admission was collected.
2.5. Statistical Analysis
Descriptive statistics were summarized using frequency and proportion for categorical variables and median and range for continuous variables. The Kaplan–Meier method was used to estimate the probability of survival at 1 year post‐transplant. All analyses were done using the open source software R version 4.3.1.
3. Results
3.1. Demographics
Within the TLTP, the number of individuals who underwent lung transplantation for CF in 2019 was 22 out of a total of 209 lung transplant recipients (11%) compared to 11 CF lung transplants out of a total of 538 lung transplant recipients (2%) in 2021–2023. In 2019, there were 19 primary CF lung transplants and three re‐transplants (13.6%). In 2021–2023, re‐transplants represented a higher proportion of individuals, with eight individuals who underwent primary lung transplantation and three people who had re‐transplants (27.3%). Demographic and clinical characteristics are shown in Table 1.
TABLE 1.
Pre‐ and post‐lung transplant characteristics for primary lung transplants.
|
2019 (N = 19) |
2021–2023 (N = 8) |
|
|---|---|---|
| Pre‐transplant | ||
| Female sex | 12 (63.2) | 6 (75) |
| White race | 18 (95) | 6 (75) |
| No deltaF508 variant | 3 (15.8) | 8 (100) |
| Pancreatic insufficiency | 19 (100) | 6 (75) |
| Pre‐transplant CF‐related diabetes | 11 (57.9) | 6 (75) |
| FEV1 percent predicted, median (Range) | 25.1 (11.9–41.2) | 27.2 (19–50.1) |
| BMI (kg/m2), median (Range) | 19.2 (15.8–27.0) | 20.2 (16.8–26.96) |
| 6‐minute walk distance (meters; median Range) | 391 (114–576) | 400 (180–603) |
| Oral steroids within 3 months of transplant | 6 (31.6) | 7 (87.5) |
| Pneumothorax a | 3 (15.8) | 0 |
| Asthma/ABPA a | 7 (36.8) | 4 (50.0) |
| Hemoptysis a | 13 (68.4) | 6 (75) |
| Osteoporosis | 2 (10.5) | 2 (25) |
| B. cepacia complex | 2 (10.5) | 1 (12.5) |
| P. aeruginosa | 12 (63.2) | 2 (25) |
| At transplant | ||
| Any donor specific antibody | 2 (10.5) | 0 (0.0) |
| ECMO use | 14 (73.7) | 8 (100.0) |
| Age (years), median (Range) | 29.4 (18.6–67.6) | 30.0 (19.1–64.0) |
| Estimated blood loss (mL); median (Range) | 1100 (500–8000) | 2000 (650–8000) |
| Post‐transplant | ||
| Length of hospital stay (days), mean (SD) | 22 (16.8) | 42.6 (16.9) |
| Total days ventilated; mean (SD) | 4.6 (5.5) | 17.3 (5.5) |
| Tracheostomy in first 30 days, n (%) | 1 (5.3) | 3 (37.5) |
| ICU length of stay > 1week | 4 (21.1) | 3 (37.5) |
| ICU days, mean (SD) | 7.1 (7.3) | 29.3 (7.3) |
| Dialysis days, mean (SD) | 3 (7.4) | 19 (7.4) |
| Dialysis > 2 weeks | 2 (10.5) | 2 (25) |
| Return to the OR | 0 | 4 (50) |
| Total number of units of pRBC during hospital admission (units) b , median (Range) | 3 (1–17) | 6.5 (1–44) |
| Number of units of pRBC in first 24 h post‐transplant (units) b , median (Range) | 2 (0–16) | 4.5 (1–13) |
| CMV status | ||
| Matched recipient and donor | 8 (42.1) | 2 (25) |
| Mismatched recipient and donor | 11 (57.9) | 6 (75) |
Note: Data are presented as N (%) unless otherwise specified.
Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; B. cepacia complex, Burkholderia cepacia complex; BMI, body mass index; CF, cystic fibrosis; CMV, cytomegalovirus; ECMO, extracorporeal membrane oxygenation; FEV1, forced expiratory volume in 1 s; ICU, intensive care unit; OR, operating room; pRBCs, packed red blood cells.
Within 1 year prior to transplant date.
Includes pRBCs received during the OR.
The age at transplant was similar in the two time windows (29 years in 2019 vs. 30 years in 2021–2023). The proportion of individuals who were non‐White was higher in the post‐ETI period (25%) compared to 5.3% in the pre‐ETI period. None of the individuals in the post‐ETI era carried a deltaF508 variant compared to 84.2% in the pre‐ETI period, and none of those transplanted in the post‐ETI era were receiving ETI therapy. Baseline lung function and BMI were similar between the study time windows. A higher proportion of individuals was diagnosed with asthma/allergic bronchopulmonary aspergillosis (50.0% vs. 36.8%), was receiving oral corticosteroids prior to transplant (87.5% vs. 31.6%), and had CF‐related diabetes (75% vs. 57.9%) prior to transplant in the post‐ETI period.
Donor characteristics can be found in Table 2. The median age of donors was older in the pre‐ETI era (40 years in 2019 vs. 32 years in 2021–2023). Rates of donation by circulatory death (DCD) and donation by brain death (DBD) were similar between time eras. Cold ischemic time (CIT) refers to the time from donor lung cross‐clamp to removal from cold storage prior to implantation [18]. Warm ischemic time (WIT) in this study refers to the time from removal from cold storage to reperfusion of the organ [18]. Median WITs were similar between the two cohorts, with the CITs being higher in the post‐ETI cohort. A higher percentage of lungs had ex‐vivo lung perfusion in the pre‐ETI era compared to post (36.8% vs. 12.5%).
TABLE 2.
Donor characteristics used for primary lung transplantation.
|
2019 (N = 19) |
2021–2023 (N = 8) |
|
|---|---|---|
| Female sex | 12 (63.2) | 3 (37.5) |
| Age (years) | 40.0 (32.0–51.0) | 32 (29.8–38.8) |
| White race | 11.0 (57.9) | 7 (87.5) |
| Mode of death | ||
| Circulatory (DCD) | 5 (26.3) | 2 (25.0) |
| Neurologic (DBD) | 14 (73.7) | 6 (75.0) |
| Warm ischemic time (minutes) | ||
| Right lung | 60.0 (55.0–66.0) | 53.5 (49.8–67.8) |
| Left lung | 59.0 (52.0–69.0) | 56.5 (46–84.8) |
| Cold ischemic time (minutes) | ||
| Right lung | 509.0 (432.0–723.0) | 695.5 (552.8–851.5) |
| Left lung | 623.0 (428.0–694.5) | 640.0 (504.5–861.3) |
| Ex Vivo lung perfusion | 7 (36.8) | 1 (12.5) |
Note: Data are presented as N (%), median (IQR).
Abbreviations: DBD, donation by brain death; DCD, donation by circulatory death; IQR, interquartile range.
3.2. Post‐Transplant Course
Post‐transplant characteristics are seen in Table 1. At the time of transplant listing in Canada and throughout the pre‐transplant follow‐up period, urgency of transplantation is assigned and is characterized from 1 to 3, with 3 being the most urgent. Fifty percent of individuals were considered status 3 at the time of admission for lung transplant in the post‐ETI period compared to 26% in the pre‐ETI period. The mean number of days in the ICU was longer in the post‐ETI period (29 vs. 7 days), as was the mean length of stay in hospital (43 vs. 22 days) and the mean number of days on dialysis (19 vs. 3 days).
Primary graft dysfunction was recorded for each individual if it was identified as a problem post‐operatively in the transplant respirologist's or transplant surgeon's note. The actual PaO2/FiO2 ratios were not available and therefore were not calculated in this study. Based on the above definition, there was primary graft dysfunction in 3/19 individuals (15.8%) from 2019 and in 3/8 (37.5%) from 2021 to 2023.
The probability of survival at 6 and 12 months is shown in Figure 1. All patients with primary lung transplants in the pre‐ETI window were discharged alive compared to 62.5% of the post‐ETI group. For those in the pre‐ETI era, 100% of individuals were alive at 90 days compared to 75% of individuals in the post‐ETI era. In the pre‐ETI era, 5.3% died within 6 months, compared to 38% in the post‐ETI era.
FIGURE 1.
Survival probabilities for primary transplants. CI, confidence interval.
There were three individuals who died within 1 year of transplant in the pre‐ETI era. The causes of death included pulmonary emboli with right‐sided heart failure in an individual 8 months post‐transplant. Additionally, respiratory failure due to severe aspiration occurred 9 months post‐transplant. Finally, another individual died due to Burkholderia cenocepacia complex sepsis 3 months post‐transplant in the setting of post‐operative abscesses.
In contrast, all three individuals who died within 1 year in the post‐ETI cohort died from sepsis. One patient died 5 days post‐transplant due to septic shock from multi‐drug resistant Pseudomonas aeruginosa, which had been identified as an inpatient pre‐transplant and again in blood cultures post‐operatively. Another patient died approximately 2 months after transplant following a complicated course with recurrent Achromobacter xylosoxidans/dentrificans bacteremia and pneumonia. The final patient died around 4 months post‐transplant with sternal osteomyelitis. Cultures from sternal tissue grew vancomycin‐resistant Enterococcus faecium and Saccharomyces cerevisiae.
COVID‐19, other respiratory viruses, and CMV were not implicated in any of the deaths. All individuals in the post‐ETI era were fully vaccinated for COVID‐19 prior to their transplant as an institutional requirement.
4. Discussion
In the era of ETI, the demographic and clinical characteristics of individuals with advanced CF lung disease requiring lung transplantation are changing. Our study found that individuals with CF represent a lower proportion of lung transplants in the adult population in the post‐ETI era, which is similar to larger studies in France, Germany, and the United States [11, 12, 13, 19]. In our study, we found there was a higher proportion of transplant recipients with risk factors associated with worse health outcomes, such as non‐deltaF508 variants or non‐White racial background in the post‐ETI time period. Furthermore, individuals in the contemporary era were medically more complex prior to transplant and experienced a more complicated post‐transplant course, which had a negative impact on overall health outcomes, including survival, following transplant [15].
Our data raise the possibility that currently published survival metrics that are often quoted when providing information to potential transplant candidates may no longer be reflective of the transplant journey for those with CF and give unrealistic expectations. A prior study using Canadian and US CF registry data between 2005 and 2016 reported 1‐, 3‐, and 5‐year survival rates of 88.3%, 71.8%, and 60.3% in the United States and 90.5%, 79.9%, and 69.7% in Canada. This is in stark contrast to the 1‐year survival of 62.5% in our study for the post‐ETI era cohort. A much higher percentage of people died within 6 months of transplant in the recent era. Transplant referral guidelines for CF were published in 2019, before the widespread availability of ETI [20]. The guidelines anticipated that modulator therapy may have a significant impact on the health for the majority of individuals with CF and that this benefit may be sustained over time [21]. There is now published literature that confirms the dramatic and profound impact ETI can have to stabilize lung function even in the setting of advanced lung disease [7, 8]. This means that people will live longer with low lung function, and survival studies in those with advanced lung disease need to be revisited, as this may impact discussions about referral for lung transplant and decisions around listing for transplant. As such, there is a pressing need for further study to characterize the outcomes post‐transplant for people with CF. The drastic reduction in the number of lung transplants for end‐stage CF lung disease globally is a welcomed consequence of ETI therapy; however, this makes it more challenging to obtain stable and robust metrics with respect to post‐transplant outcomes in CF for a given country or region. Instead, an international effort will likely be required in order to gather robust post‐transplant survival estimates and a better understanding of the potentially modifiable risk factors for post‐transplant mortality in this changing cohort.
Fewer CF transplants internationally may have policy and resource implications for transplant programs requiring them to adapt in the ETI era. Transplant volume has been associated with health outcomes like survival [15, 22, 23]. A study by our group reported the median post‐transplant survival for high‐volume centers was 8.7 years (95% CI 7.9–N/A) compared to 6.2 years (95% CI 5.1–7.0) at low‐volume centers. Patients transplanted at a low‐volume center were 1.32 times (95% CI 1.16–1.49) more likely to die compared to patients transplanted at a high‐volume center [15]. Thus, in countries where transplantation centers are widely available, it may be important to consider fewer programs that do CF lung transplants in order to maintain expertise and technical skill and optimize outcomes. This may disproportionately affect pediatric centers where lung transplantations are of lower volume in general. Considering fewer programs, however, would understandably have to be balanced with the cost of travel and other inconveniences individuals may experience with relocation. Another important consideration is the fact that the proportion of re‐transplants is increasing, which is a more complicated procedure with worse survival outcomes [24]. Moving forward, transplant centers need to have expertise managing these more complex cases.
Health disparities are another critical consideration. The higher proportion of non‐White individuals transplanted in the post‐ETI era is a reflection of the fact that individuals with non‐deltaF508 variants are more likely to be non‐White. Several survival studies in the non‐transplanted CF population have shown worse survival for non‐White individuals with CF, with an increased risk of death without transplant in the non‐White CF population [25, 26]. There are many factors contributing to such disparities, including access to care, socioeconomic factors, or other determinants of health. Further research is needed to understand these trends and ensure equitable access to advanced CF care and optimal outcomes post‐transplant for all individuals with CF.
The increased complexity of the transplant recipients in the post‐ETI era may be due to several factors. This cohort included individuals with less common genotypes with a higher urgency at transplant listing that may portend a more severe phenotype. In addition, this group was more likely to be non‐White, which has previously been associated with worse outcomes, and they experienced more complex medical issues with asthma and corticosteroid use prior to transplant. Their course post‐transplant was also more complex with increased use of dialysis and ECMO. They had prolonged intubation times, which were multi‐factorial, due to both respiratory failure and underlying medical issues, such as sepsis. There were no meaningful differences in donor characteristics to explain the difference in outcomes. In addition, deterioration and delayed referrals were not a factor, as the same guidelines for transplant referral were utilized in both timeframes and there were no expedited referrals. With respect to donor characteristics, there was decreased use of EVLP in the post‐ETI cohort despite there being no major changes in EVLP protocols. This is likely due to the small sample size of the cohort and would not explain observed outcomes. Although longer ischemic times have been associated with worse outcomes, both WITs and CITs were within acceptable ranges [18].
It may be that as therapeutics allow patients to live longer and be more stable with low lung function, the future generations of transplant recipients may enter transplant with a much more complex disease profile and be at higher risk for complications in the post‐transplant period. This is an area that should be prioritized for study in order to best understand how to optimize care and reduce morbidity and mortality in this group.
The strengths of this study include the comprehensive and detailed data obtained on included subjects. The TLTP is the largest and oldest CF lung transplant program globally, performing the first double lung transplant for CF in 1987, revolutionizing CF care [27]. Therefore, re‐evaluating the CF experience at this center nearly 40 years later provides critical information to the CF community. However, the limitations need to be acknowledged. The number of transplants done in the latter time window was small and limited our power to show statistical significance. This is a single‐center experience, which raises the question of generalizability; however, the experience of reduced lung transplants for end‐stage CF lung disease has been noted globally, and similar clinical and demographic changes have been noted in national CF registry annual data reports. Further study is needed to obtain up‐to‐date and robust survival metrics in this new era. None of the patients transplanted in the contemporary cohort were on ETI; however, it is possible that even those on modulator therapy may ultimately progress to severe lung disease requiring a transplant. Our data do not include information on outcomes in that population.
In conclusion, fewer primary transplants and more re‐transplants are being done in the post‐ETI era. An international effort will likely be required to obtain updated metrics on health outcomes, as well as transplant‐specific outcomes like primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction, in this new generation of transplant candidates. This will inform new lung transplant referral guidelines and provide potential transplant candidates with accurate and up‐to‐date information about the risks and benefits of lung transplant in this evolving population.
Author Contributions
Study concept and design: Anne L. Stephenson and Stephanie Y. Cheng. Acquisition and merging of data: Anne L. Stephenson, Julie Semenchuk, Xiayi Ma, Eliza Tuff‐Gordon, and Jenna Sykes. Analysis and interpretation of data: Jenna Sykes, Xiayi Ma, and Anne L. Stephenson. Drafting of the manuscript: Julie Semenchuk. Critical revision of the manuscript for important intellectual content: Anne L. Stephenson, Elizabeth Tullis, Cecilia Chaparro, and Meghan Aversa. Statistical analysis: Jenna Sykes and Xiayi Ma. Study supervision: Anne L. Stephenson. Dr. Stephenson had full access to all the data in the study and takes responsibility for the integrity of the data, the accuracy of the data analysis, and had final responsibility for the decision to submit for publication.
Conflicts of Interest
ALS has received grants from the Cystic Fibrosis Foundation and Cystic Fibrosis Canada outside of the submitted work. ALS has received honoraria from Vertex Pharmaceuticals and GSK for speaking at educational events and funding for travel from Vertex Pharmaceuticals and Viatris outside of the submitted work. ET has received honoraria from Vertex pharmaceuticals for presentations and travel funds from Viatris outside of the submitted work. There are no disclosures for any other listed authors.
Acknowledgments
We would like to acknowledge the involvement and continued participation of those living with cystic fibrosis who consent to having their data submitted to the Toronto Lung Transplant Program database and collected for research purposes, as well as the efforts and contribution from team members who collect and enter the data.
Semenchuk J., Tuff‐Gordon E., Ma X., et al. “The Changing Transplant Landscape in the Era of Elexacaftor/Tezacaftor/Ivacaftor: A Word of Caution.” Clinical Transplantation 39, no. 10 (2025): e70317. 10.1111/ctr.70317
Funding: The authors received no specific funding for this work.
Data Availability Statement
There is no shared data file publicly available related to this manuscript.
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