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ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 4  |  Page : 205-212

Retrospective cohort study of preimplantation genetic testing for aneuploidy with comprehensive chromosome screening versus nonpreimplantation genetic testing in normal karyotype, secondary infertility patients with recurrent pregnancy loss


1 Department of Genetics, Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
2 Department of Clinical Epidemiology Research, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
3 Department of Genetics, Shanghai Ji Ai Genetics and IVF Institute; Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China

Date of Submission06-May-2019
Date of Web Publication2-Jan-2020

Correspondence Address:
Xiao-Xi Sun
Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, No. 588 Fangxie Road, Shanghai 200011
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.274544

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  Abstract 


Objective: To evaluate whether preimplantation genetic testing for aneuploidy (PGT-A) with comprehensive chromosome screening increases live birth rate (LBR) in normal karyotype couples with recurrent pregnancy loss (RPL).
Methods: A retrospective cohort follow-up study of 506 couples with RPL was conducted between April 2014 and March 2017. Couples were allocated to two groups according to their decision to choose PGT-A or not. The primary outcome was LBR per start/transfer cycle; secondary outcomes were ongoing pregnancy rate and miscarriage rate. Statistical analyses were conducted using univariate and multivariate logistic regression models adjusted for maternal age.
Results: LBR per start (26.6% vs. 15.4%, relative risk [RR]: 2.66, 95% confidence interval [CI] [1.69–4.20], P < 0.0001; adjusted RR [aRR]: 2.40, 95% CI [1.49–3.86], P = 0.0004) and per transfer (44.9% vs. 25.1%, RR: 3.00, 95% CI [1.96–4.60], P < 0.0001; aRR: 2.64, 95% CI [1.68–4.14], P < 0.0001) was significantly higher in the PGT-A group than in the non-PGT-A group. The miscarriage rate was significantly lower in the PGT-A group compared to the non-PGT-A group (15.7% vs. 34.6%, RR: 0.27, 95% CI [0.13–0.57], P = 0.00005; aRR: 0.26, 95% CI [0.12–0.57], P = 0.0007).
Conclusions: LBR per start cycle following PGT-A is significantly higher, and risk of miscarriage is significantly lower among infertile couples with RPL, irrespective of maternal age. PGT-A should be recommended to infertile couples with RPL.

Keywords: Comprehensive Chromosome Screening; Preimplantation Genetic Testing for Aneuploidy; Recurrent Pregnancy Loss


How to cite this article:
Lei CX, Ye JF, Sui YL, Zhang YP, Sun XX. Retrospective cohort study of preimplantation genetic testing for aneuploidy with comprehensive chromosome screening versus nonpreimplantation genetic testing in normal karyotype, secondary infertility patients with recurrent pregnancy loss. Reprod Dev Med 2019;3:205-12

How to cite this URL:
Lei CX, Ye JF, Sui YL, Zhang YP, Sun XX. Retrospective cohort study of preimplantation genetic testing for aneuploidy with comprehensive chromosome screening versus nonpreimplantation genetic testing in normal karyotype, secondary infertility patients with recurrent pregnancy loss. Reprod Dev Med [serial online] 2019 [cited 2020 Apr 1];3:205-12. Available from: http://www.repdevmed.org/text.asp?2019/3/4/205/274544




  Introduction Top


The Practice Committee of the American Society for Reproductive Medicine (ASRM) defines recurrent pregnancy loss (RPL) as two or more failed clinical pregnancies as documented by ultrasound or histopathologic examination.[1],[2] Approximately 1%–5% of couples trying to conceive will suffer from RPL.[3] The miscarriage specimen examination has discovered that 50%–70% of early pregnancy losses are due to chromosomal abnormalities,[4],[5],[6] which can either be of parental origin or arise de novo in the embryo from parents with a normal karyotype.[7] Among these, aneuploidy is considered the most common chromosome abnormality and is the main abnormality found in normally developing monospermic embryos during in vitro fertilization (IVF) treatment.[8] Recently, a large genetic survey of embryos supports that aneuploidy is the leading chromosome abnormality in IVF and is primarily due to maternal meiosis and mitotic errors.[9] The association between aneuploidy and increasing maternal age has been recognized for decades.[10] However, aneuploidy in normal karyotype couples with a history of RPL at a relatively younger maternal reproductive age cannot be attributed to advanced age only. It is not known why RPL occurs frequently in these patients, and the mechanism remains to be elucidated.

Owing to the high frequency of aneuploidy in patients with RPL with normal karyotypes, preimplantation genetic testing for aneuploidy (PGT-A, also known in the literature as PGD for aneuploidy screening/PGD-AS/PGS) is recommended to detect aneuploidy before transfer to decrease miscarriage rate and increase ongoing pregnancy rate (OPR) and live birth rate (LBR).[11] Fluorescence in-situ hybridization technology (FISH), with limited probes analyzing the 5–10 most common aneuploidies in one or two blastomeres biopsied from day 3 cleaving embryos, has been applied in the last two decades. However, a few randomized clinical trials have failed to show an increase in OPR and LBR after FISH-PGT.[12],[13] This disappointing result could be because of three reasons: first, the cleavage stage biopsy may harm the embryo's development potential; second, FISH may only be able to detect a limited number of aneuploidies; third, the mosaicism of the cleaving embryo may lead to false results. A new generation of PGT-A has been introduced, which prefers trophectoderm biopsy and comprehensive chromosome aneuploidy screening (CCS),[14],[15] and many reports with PGT-A show increased OPR and LBR.[16],[17],[18] However, the benefits of PGT-A have not yet been proved in randomized controlled trials (RCTs),[19] and there are no RCTs on RPL couples to analyze the benefits of the new generation of PGT-A. A retrospective cohort study of 300 RPL couples undergoing PGT-A compared with expectant management showed similar clinical outcomes between groups, but a longer time to become pregnant in the couples undergoing PGT-A.[20] This makes LBR per start cycle for RPL couples a critical question. Furthermore, the invasive procedure requires 3–10 trophectoderm cells biopsied at the blastocyst stage, which might harm the implantation potential and cause epigenetic changes leading to long-term implications on the offspring. However, some available data have shown that trophectoderm biopsy and vitrification do not compromise the developmental competence of blastocysts or change clinical outcomes.[21],[22],[23] PGT-A is considered a good treatment for patients with RPL, but whether it is beneficial and should be applied to all couples with RPL remains controversial. Two controlled studies support the use of PGT-A for couples with RPL to reduce pregnancy loss,[24],[25] whereas others have conflicting results. No concrete evidence now supports PGT-A application for RPL patients, even for infertile RPL patients who need IVF. The Practice Committees of the ASRM and the Society for Assisted Reproductive Technology has not recommended PGT-A for couples with RPL;[26] however, the value of the new-generation PGT-A has yet to be determined as previous studies generate conclusions on applying the first generation of PGT-A.

In this study, we retrospectively collected data, at one IVF institute, of infertile normal karyotype couples with a history of RPL who chose to undergo either PGT-A or non-PGT. We focused on the clinical outcomes of LBR per start/transfer cycle, OPR, and miscarriage rate. We used an adjusted model that included variables that may influence the clinical prognosis. On the basis that the new-generation PGT-A results are considered clinically accurate,[27] we assume euploid embryo transfer should increase LBR and decrease miscarriage rate in infertile RPL patients. The results are very important for clinicians treating RPL and for patients who experience RPL.


  Methods Top


Study design

We searched the database of Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, for infertile women with a medical history of RPL who underwent IVF between April 2014 and March 2017. The inclusion criteria were as follows: (1) the couple had experienced two or more failed clinical pregnancies occurring between 6 and 24 weeks of gestation (mostly between 6 and 12 weeks); ectopic, molar, or biochemical pregnancies were excluded (according to the ASRM definition) and (2) the karyotypes of both partners were normal (polymorphic chromosomes were considered normal also). According to their written informed consent, we identified 215 PGT-A group couples and 364 non-PGT-A group couples. We all knew that hypothyroidism, anatomic, thrombophilia/antiphospholipid antibody syndrome would cause RPL; thus, these patients were excluded from the study. Women with anatomic reasons (uterine malformations [unicornuate uterus and duplex uterus], untreated septate uterus, adenomyoma, submucous uterine fibroids, or endometrial polyps), hypothyroidism, and thrombophilia/antiphospholipid antibody syndrome were excluded. Finally, we conducted a retrospective cohort follow-up study of 506 RPL couples (212 PGT-A couples + 294 non-PGT-A couples) who met the above criteria. All of the included patients had outcome data even if they had delivered at a different hospital. All cycles assigned to the patient were identified by a consistent patient identification. Each patient's cycles were ordered by the date of oocyte retrieval and transfer. This retrospective data analysis study was approved by the Faculty of Ethics Committee of Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University (JI AI E2017-23).

Ovarian stimulation, embryo culture, trophectoderm biopsy, and preimplantation genetic testing for aneuploidy

Conventional antagonist stimulation protocols were used, and IVF or intracytoplasmic sperm injection (ICSI) was performed according to the presence or absence of male factor infertility in the non-PGT group. For the PGT-A group, fertilized oocytes were produced using ICSI. Zygotes were cultured postfertilization for 3 days in an IVF laboratory to reach the cleaving stage or 5–6 days to reach the blastocyst stage. Blastocysts were evaluated according to a grading system widely recommended by Gardner et al.[28] Three to ten trophectoderm cells were biopsied and immediately transported to the PGD laboratory of the same institute for whole-genome amplification (WGA) and single nucleotide polymorphism microarray analysis. The day of the biopsy was dependent on embryo development and when trophectoderm cells were expanded from the breaching hole. Blastocysts were cryopreserved immediately after the biopsy was finished. For the PGT-A group, one euploid blastocyst could be frozen-thawed and transferred in the following menstrual cycle for up to 1 year. For the non-PGT group, one to two embryos could be freshly transferred on day 3 of the cleaving stage, on day 5/6 of the blastocyst stage, or could be frozen-thawed and transferred in the next transfer cycle.

SNP microarray analysis

WGA was performed using REPLI-g Single Cell Kit (Qiagen, Hilden, Germany), following the manufacturer's recommendations. SNP microarray analysis was performed according to the Infinium Chip procedure (Illumina, Inc., San Diego, CA, USA) as described previously.[29] The Beadchips were read on an iScan reader and genotype calls were made automatically by Illumina BlueFuse ® software.

Analysis of euploidy or aneuploidy of the embryo

Embryos without any perceived unbalance were designated as euploidy. Embryos with segmental aneuploidy, whole-chromosome aneuploidy, or segmental plus whole-chromosome aneuploidy were designated as aneuploidies. Embryos with mosaic aneuploidy were designated as mosaics. Embryos without results were designated as failures.

Clinical outcome recording after fresh transfer or frozen-thawed embryo transfer and follow-up

The serum level of human chorionic gonadotropin (hCG) was measured 14 days after transfer, and a serial ultrasound was performed 5, 7, and 9 weeks after transfer (about 8, 10, and 12 weeks of gestation). The clinical pregnancy was confirmed if an intrauterine gestational sac with fetal heart beat was visualized. Monochorionic diamniotic (MCDA) twins or dichorionic diamniotic (DCDA) twins were considered one pregnancy cycle. Biochemical pregnancy was recorded if the hCG level was positive, but no gestational sac was seen. Miscarriage was recorded if the fetal heart beat was observed in one of the serial ultrasounds, but was no longer observed by 28 weeks of gestation. The pregnancy status was followed up once in the second trimester, and prenatal diagnosis (if necessary) was done during this period. Live or stillbirth was recorded when the baby was born after 28 weeks of gestation.

Statistical analysis

Normally distributed continuous variables were presented as means and standard deviation, and a two-tailed unpaired t-test was used to evaluate the difference between the PGT-A and non-PGT groups. The Chi-square test (or Fisher's exact test as appropriate) was conducted for categorical variables. The generalized linear mixed models were used to fit the relationship between PGT-A and various cycle outcomes including clinical pregnancy, biochemical pregnancy or miscarriage, pregnancy persistence for more than 12 weeks of gestation, and live birth. Each woman represented one unit at level two, whereas transfer cycles nested within women were units at level one.

According to previous literature, potential covariates included maternal and paternal age (<20, 20–29, and 30–39 years), times of miscarriage, body mass index (BMI, <18.50, 18.50–24.99, 25.00–29.99, and ≥30.0), basal follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH) level, and number of embryos transferred.[30] Variables that were significantly different between the PGT-A and non-PGT groups, significantly associated with the outcome in multiple variable analyses (P < 0.05), or improved point precision, were retained. Finally, maternal age was included in the adjusted models. All analyses were carried out using the statistical package SAS version 9.2 (SAS Institute Inc., Cary, NC, USA).


  Results Top


Baseline characteristics of infertile patients in all oocyte retrieval cycles

A total of 506 women met the criterion described in the materials and methods and were retrospectively collected for this study [Table 1]. No significant differences were found in maternal age, paternal age, paternal BMI, and maternal BMI between the PGT-A and control groups. The rate of previous miscarriage was higher in the PGT-A group. AMH was higher, and basal FSH was lower in the PGT-A group. No significant difference was found in other basal reproductive endocrine hormones.
Table 1: Baseline characteristics of infertile patients in all oocyte retrieval cycles

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The characteristics of two groups in controlled ovarian stimulation cycles and embryo development

The PGT-A group underwent 282 controlled ovarian stimulation (COH) cycles (among these 8 cycles were canceled before fertilization, and 31 cycles were canceled before vitrification/biopsy); eight cycles had no euploid embryos for transfer. The control group underwent 564 COH cycles [among these, 64 cycles were canceled before fertilization, and 177 cycles were canceled before vitrification, [Figure 1]. The average number of COH cycles per couple was 1.33 in the PGT group versus 1.92 in the control group (P = 0.0016). The cancellation rate was significantly less in the PGT group (11.0% vs. 31.4%, P < 0.0001).
Figure 1: Flowchart of the study.

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The gonadotropin delivering days and total gonadotropin delivering dosage were similar [Table 2]. The rates of MII oocytes and fertilization were comparable across the two groups [Table 2]. However, the rates of cleaving zygotes and cleaving embryos were significantly higher, and canceled cycles before vitrification were significantly lower in the PGT group [Table 2]. The number of embryos transferred per cycle was significantly lower in the PGT group [Table 2].
Table 2: Data of the COH, IVF/ICSI, and embryo development of RPL groups

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The euploid rate in the preimplantation genetic testing for aneuploidy group

A total of 798 blastocysts were biopsied in 251 biopsy cycles in the PGT-A group, the mean number of blastocysts biopsied per cycle was 2.8 ± 2.3, and blastocyst formation rate in the PGT-A group was 52%. The euploid, aneuploid, mosaic, and failure rates were 52.1%, 41.2%, 5.4%, and 1.3%, respectively [Figure 2]a. Increasing maternal age [Figure 2]b and FSH levels and decreasing AMH levels [Figure 2]c reduced euploid embryo amount.
Figure 2: Frequency of PGT results and relationship of maternal age and FSH and AMH level with euploid embryo amount. (a) The euploidy and aneuploidy rate of the embryos. (b) The relationship of maternal age and euploid embryo amount. (c) The relationship of FSH and AMH level and euploid embryo amount. PGT: Preimplantation genetic testing; FSH: Follicle-stimulating hormone; AMH: Anti-Mullerian hormone.

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Live birth rate per start, per transfer, and per pregnancy was higher in the preimplantation genetic testing for aneuploidy group

The PGT-A group had 167 transfer cycles and 89 pregnancy cycles. There were 77 ongoing pregnancy cycles at 12 weeks of gestation, among which 2 were MCDAs and 4 DCDAs; unfortunately, two babies were stillborn after 28 weeks of gestation, so the sum of live birth cycles was 75 [Figure 1]. The control group had 346 transfer cycles (among these 32 fresh transfer cycles and 314 frozen-thawed transfer cycles) and 133 pregnancy cycles (among these 9 fresh transfer cycles and 124 frozen pregnancy cycles). By 12 weeks of gestation, there were only 87 ongoing pregnancy cycles including 25 DCDAs (fresh 2, frozen 23) in the control group, all of which were live births [Figure 1]. The average number of embryos transferred per transfer cycle was significantly lower in the PGT-A group (1.05 ± 0.23 vs. 1.92 ± 0.34, P < 0.0001).

Mixed models fitted for the relationship between PGT-A and cycle outcomes are shown in [Table 3]. Each woman represented one unit at level two, whereas ovarian stimulation or transfer cycles nested within women were units at level one. The LBR per start and per transfer cycle, the OPR per start and per transfer cycle, and the OPR per pregnancy cycle were significantly higher in the PGT-A group [Table 3]. Moreover, the miscarriage rate was lower and the LBR per pregnancy was significantly higher in the PGT-A group [Table 3].
Table 3: Relationship of PGT with perinatal outcomes*

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  Discussion Top


This retrospective study has demonstrated that the LBR per start (26.6%) and per transfer (44.9%) cycle was significantly higher in the PGT-A group than in the non-PGT group in couples with RPL. In addition, the OPR per start (27.3%) and per transfer (46.1%) cycle was significantly higher, and the miscarriage rate (15.7%) was significantly lower in the PGT-A group compared with the non-PGT group. Studies of LBR among normal karyotype couples with RPL using PGT-A are rare. Although PGT-A enables a detailed investigation of the chromosome content of human embryos and should be effective in reducing pregnancy loss and increasing LBR in RPL patients by selecting euploid embryos for transfer,[31] previous studies failed to give concrete evidence. Munné et al. showed that PGT had a beneficial effect on pregnancy outcome in couples with RPL, especially women over 35 years of age; however, they included only a limited number of couples (58 cases couples), COH cycles (69 cycles), and pregnancy events (30 pregnancies) using FISH techniques.[24] Murugappan et al. found that age-stratified analysis showed significantly improved LBR in the PGT group of RPL patients who reached transfer of a euploid embryo,[20] which was similar to our results that PGT-A could improve LBR per transfer cycle; however, they only followed 112 RPL patients, 198 COH cycles (PGT-A 158 cycles and non-PGT 40 cycles), and 88 pregnancy events (PGT 72 pregnancies and non-PGT 16 pregnancies). Our study is currently the largest cohort study (506 RPL couples, 846 COH cycles, and 222 pregnancies) comparing the LBR per start cycle in RPL patients with normal karyotypes.

The ASRM recommends expectant management rather than PGT-A because the literature has not suggested an improved LBR using PGT-A in RPL patients; however, they also note “important limitations” in previous studies and state that the “value of PGT-A has yet to be determined.”[26] For infertile couples with RPL who need assisted reproductive technologies, could PGT-A be a superior choice? RCTs on PGT-A using FISH and cleavage stage biopsy strategy failed to improve LBR in the treatment group.[32] Trophectoderm biopsy plus CCS was introduced in 2010, and the impact of comprehensive techniques for embryo testing is sparse. Furthermore, the clinical effect of the techniques is unknown. Although there have been studies comparing PGT versus non-PGT tested ETs,[33] there has not been a study comparing LBR per start cycle in PGT versus non-PGT RPL patients since the introduction of the new generation of PGT-A. Counseling RPL patients on PGT-A can be challenging when the data of LBR per start cycle are missing. Our results gave strong evidence for PGT-A in the treatment of couples with RPL. Furthermore, the number of embryos transferred per transfer cycle was significantly lower in the PGT-A group (average one blastocyst per transfer); however, the clinical outcome of LBR and OPR was significantly higher in the PGT-A group, showing that the increasing transfer embryo number failed to give any benefit to the control group. On the contrary, the increasing multiple pregnancies in the control group, underling high risks of transferring two or more embryos, and the PGT-A plus one euploid embryo transfer strategy have not only reduced the miscarriage rate but also decreased the multiple pregnancy events.

To confirm that the improvement in LBR and OPR in the PGT group was related to the genetic testing alone irrespective of maternal age, number of miscarriages, and basal endocrine hormone levels, we adjusted these variables in the mixed model. Potential covariates in these patients such as maternal and paternal age, times of miscarriage, BMI, FSH and AMH level, and number of embryos transferred were considered to be included in the multiple variable analyses. However, only variables that were significantly associated with the outcome in multiple variable analyses (P < 0.05) or improved point precision were retained. Finally, maternal age was included in the adjusted models. Our results gave strong evidence that PGT-A was beneficial for infertile RPL couples because of the significant increase in LBR per start and per transfer cycle in the adjusted mixed model. In addition, the OPR per pregnancy cycle was significantly higher in the PGT-A group, showing the benefit of transferring a euploid embryo. Selection bias might exist for couples and clinicians that consider PGT-A, and only couples with a good prognosis might reach the blastocyst stage and have a euploid embryo to transfer. The number of previous miscarriages was significantly higher, AMH was higher, and FSH was lower in the PGT-A group. The greater the number of miscarriages, the more likely a woman was to use PGT. The lower AMH and higher FSH measures indicated that women in the control group may have impaired ovarian reserve, which meant that women tended to decline PGT-A when they thought they might have no embryo for PGT-A. The number of COH cycles per couple was higher in the control group, indicating that women went through cancelation of transfer or vitrification more often in the control group, and this was confirmed by statistics of cancelation rate between the two groups. Some studies provided data that the higher the number of previous miscarriages, the higher the probability that the miscarriages were euploid, and thus, PGT should be less effective in these patients,[34],[35] which made genetic counseling to couples with RPL more confusing. However, the number of miscarriages did not statistically significantly influence the clinical outcomes in our model, so we did not include this variable. We could argue that RPL patients could benefit from PGT-A for any number of previous miscarriages. The gonadotropin delivering days and dosage were not different between the two groups; however, the maximum estrogen levels were higher in the PGT-A group, highlighting the better ovarian response in this group. However, different age groups might have bias when choosing PGT and some advance maternal aged couples may be less likely to have blastocysts and pursue genetic testing.

Although the present study did reveal a significant improvement in LBR either per transfer or per start cycle using frozen-thawed euploid embryos in the PGT-A group compared with the control group, it was unable to adjust all the confounders in the process. The PGT-A plus frozen-thawed transfer strategy in the PGT-A group can be a source of great bias when assessing clinical outcomes, whereas women in the control group underwent both fresh and frozen-thawed transfers of embryos in the cleavage and blastocyst stage. The nonstimulated uterine environment in a frozen-thawed transfer cycle might result in pregnancies with fewer obstetric complications, as shown by previous studies.[36],[37] The development of the embryo stage might have a great effect on implantation rates and OPR, as was shown in previous studies that implantation rates and OPR were higher in the blastocyst transfer cycle.[38] Therefore, the blastocyst transfer strategy might have had a great effect on the pregnancy rates between the two cohorts. Further randomized control trials using the same transfer strategy should be executed.

In conclusion, our findings suggest that PGT-A plus the frozen-thawed euploid blastocyst transfer strategy increases LBR per start cycle and decreases miscarriage rate in infertile RPL patients. PGT-A could be recommended to all infertile RPL patients who need IVF to conceive.

Acknowledgments

We appreciate Zi-Wen Lin from the Information Department at Shanghai Ji Ai Genetics and IVF Institute for his generous help in database searching.

Financial support and sponsorship

This study was supported by Shanghai Municipal Commission of Health and Family Planning Project (No. 201640365) and Shanghai Shen Kang Hospital Development Center Municipal Hospital New Frontier Technology Joint Project (SHDC12017105). There are no competing interests to declare.

Conflicts of interest

There are no conflicts of interest.



 
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