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. 2026 Jan 28;26:423. doi: 10.1186/s12879-026-12565-7

The increased detection of recombinant norovirus GII.4 Sydney_2012[P16] strains in hospitalized pediatric patients with gastroenteritis in Shanghai, China

Fangyuan Yu 1,2,3, Xuhua Feng 4, Haiqin Ye 1,2,3, Qin Cai 1,2,3, Jie Jiang 1,2,3, Tiandong Zhang 1,2,3, Fen Pan 1,2,3,#, Wenhao Weng 1,2,3,✉,#
PMCID: PMC12924388  PMID: 41606719

Abstract

Background

To understand the genetic diversity and recombination of norovirus infection in children with hospital-acquired acute gastroenteritis in Shanghai, and to provide a scientific basis for the prevention of norovirus infection in hospitalized children.

Methods

12,485 stool specimens of children with hospital-acquired acute gastroenteritis were collected from October 2018 to June 2021. Gene amplification and sequencing of VP1, RdRp and RdRp-VP1 region were performed on norovirus-positive specimens using RT-PCR method. Genotyping and recombination analysis of sequenced sequences were performed using online analysis tools.

Results

The positive rate of norovirus infection in children with hospital-acquired diarrhea by real-time quantitative RT-PCR was 16.2% (2,017/12,485). Based on the gene sequencing analysis of norovirus across the RdRp-VP1 region, nine norovirus recombinant strains were detected. From October 2018 to September 2020, the proportion of norovirus GII.4 Sydney_2012[P31] was 56.5% (231/409), while the proportion of GII.4 Sydney_2012[P16] was only 1.2% (5/409) in the same period. However, from October 2020 to June 2021, the detection rate of the recombinant strain GII.4 Sydney_2012[P16] increased to 38.8% (57/147), which exceeded that of the recombinant strain GII.4 Sydney_2012[P31] (19.0%, 28/147).

Conclusions

Norovirus GII.4 Sydney_2012 remained the main prevalent genotype, but the recombinant strain of GII.4 Sydney_2012[P16] had an increased positivity rate since October 2020. It is imperative that surveillance and management of hospital-acquired norovirus acute gastroenteritis in hospitalized children be strengthened to prevent nosocomial norovirus outbreaks.

Keywords: Norovirus, Acute gastroenteritis, Recombinants, Children

Introduction

Norovirus is highly contagious and rapidly transmissible, and is the leading cause of acute non-bacterial gastroenteritis worldwide, with a severe disease burden [1]. Norovirus belongs to the genus Norovirus in the Caliciviridae family and is a non-enveloped, single-stranded, positive-stranded RNA virus with a genome length of 7.5–7.7 kb, which is divided into three open reading frames (ORFs) [2]. ORF1 encodes a polyprotein that is post-translationally cleaved into seven replication-relevant non-structural proteins, including RNA-dependent RNA polymerase (RdRp), while ORF2 and ORF3 encode major structural proteins (VP1) and minor structural proteins (VP2), respectively [3]. Based on amino acid diversity of the complete VP1 gene, norovirus can be divided into 10 genogroups (GI ~ GX) and 2 tentative genogroups (GNA1 and GNA2), classified into 48 genotypes and 5 tentative genotypes [4, 5]. Based on nucleotide diversity in the RdRp region, norovirus can be divided into 8 P-groups comprising 60 P-types (14 GI, 37 GII, 2 GIII, 1 GIV, 2 GV, 2 GVI, 1 GVII and 1 GX), 2 tentative P-groups and 14 tentative P-types [5]. Continuous genotyping of norovirus is critically important, as this virus frequently undergoes recombination at the junction of the ORF1 (RdRp) and ORF2 (VP1) genomic regions [6]. Thus, surveillance is essential for tracking the emergence of recombinant strains, analyzing transmission chains, and understanding viral evolution. The ongoing monitoring of its genetic characteristics and epidemiological trends provides key scientific evidence for formulating effective prevention and control strategies against norovirus infection.

Hospital-acquired infections (HAIs) are infections that occur after a patient has been in hospital for 48 h. In hospitals, pathogens that cause gastroenteritis can be transmitted through contact with contaminated surfaces, medical equipment or personnel [7]. Norovirus can easily cause outbreaks and epidemics in some closed places such as hospitals and schools. A study in the United Kingdom found that norovirus was the second most common virus causing nosocomial infections in terms of detection rate and severity, after rotavirus [7].

However, data on norovirus-associated acute gastroenteritis in hospitalized children in Shanghai are scarce, and active surveillance of norovirus infection in hospitalized patients is lacking. Therefore, we investigated pediatric patients who developed acute gastroenteritis during hospitalization at a children’s hospital in Shanghai from October 2018 to June 2021. This study aimed to help clinicians understand the role of norovirus and provide data to support the development of strategies to prevent and control norovirus infections.

Materials and methods

Study population

Between October 2018 and June 2021, 12,485 fecal samples were collected from children with acute gastroenteritis at Shanghai Children’s Hospital. Clinical data of enrolled children were collected, including age, admission diagnosis and time of onset of symptoms of acute gastroenteritis. Patients enrolled in the study were aged up to 16 years. The study population showed the following age distribution: 0~1 years (28.3%), 1~2 years (27.6%), 2~3 years (22.1%), 3~4 years (11.5%), 4~5 years (4.8%), and >5 years (5.7%), with a median age of 18.6 months. The acute gastroenteritis was considered hospital-acquired if symptoms developed ≥ 48 h after admission. Acute gastroenteritis was defined as 3 loose or looser-than-normal stools in 24 h and/or significant changes in stool appearance, with or without fever or vomiting. Specimens were collected consistently throughout the 33-month study period. We established a systematic specimen collection protocol requiring a minimum of 200 qualified samples per month throughout the study period. Duplicate samples from the same child were excluded.

Nucleic acid extraction, amplification and sequencing of norovirus

Viral nucleic acid was extracted with Trizol reagent (Invitrogen, USA) from supernatant. Norovirus nucleic acid detection kit (Hubei Lande Medical Technology Co., Ltd.) was used for norovirus nucleic acid detection. For specific operation steps, see the kit instruction manual. The instrument model used is ABI 7500.

Random primer (N6) was used for reverse transcription of viral nucleic acid, the Ct ≤ 28 detected by real-time quantitative RT-PCR, using M-MLV reverse transcriptase (Invitrogen, USA). Reverse transcription was performed in two sequential steps: 65 °C for 5 min (4 °C hold); then 25 °C for 10 min, 37 °C for 60 min, 70 °C for 15 min (4 °C hold). The partial capsid region of the VP1 gene was amplified by PCR using the primers G1SKF/G1SKR and COG2F/G2SKR [8], respectively for GⅠ and GⅡ strains. The partial capsid region of the RdRp and RdRp-VP1 gene were amplified by PCR using the primers P290/P289 [9] and P290/G2SKR, respectively. PCR was performed at 94 ℃ for 5 min followed by 35 cycles at 94 ℃ for 30 s, 50 ℃ for 30 s (RdRp region gene amplification 58℃ for 30 s) and 72 ℃ for 80 s, and then a final extension step of 72 ℃ for 7 min (Beijing TransGen Biotech Co., Ltd.). The PCR products from norovirus-positive samples were visualized by 2.0% agarose gel electrophoresis and sequenced with corresponding primers (Shanghai Sangon Biotech Co., Ltd.).

Phylogenetic analysis

Phylogenetic trees in VP1 (the best nucleotide substitution model K2 + G + I) and RdRp regions (the best nucleotide substitution model TN93 + G + I) were constructed using the Maximum Likelihood method in MEGA 12.0.11 software.

Statistical analysis

Statistical software SPSS 20.0 was used for data processing. The categorical data were expressed as proportion or rate (%), and the positive rate and proportion were compared by χ2 test. P < 0.05 was considered statistically significant.

Results

Positive rate of norovirus infection in children with acute gastroenteritis

From October 2018 to June 2021, a total of 12,485 compliant fecal specimens were collected. Following real-time quantitative RT-PCR, 2,017 of 12,485 specimens tested positive for norovirus (16.2%).

The highest detection rate was observed in November 2018, with a detection rate of 33.8% (123/364). The peak in 2019 was also in November, with the detection rate of 28.0% (137/489), and there was a subsequent minor peak in January of the same year, with a detection rate of 28.4% (141/496). The peak in 2020 was observed in November and December, with a detection rate of 25.7% (118/459) and 33.3% (205/616), respectively. The peak in the first half of 2021 was in January, with a detection rate of 23.3% (141/606). The period between February and August 2020 was characterized by a low norovirus detection rate, with a total positive rate of no more than 4.0% (Fig. 1). A chi-squared test was conducted to ascertain the statistical significance of the variation in the norovirus-positive detection rate across different months. The result of this test yielded a significant difference (χ2 = 938.125, P < 0.05).

Fig. 1.

Fig. 1

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Norovirus positive cases and detection rate among children with acute gastroenteritis in Shanghai.

The amplification results based on norovirus VP1 and RdRp genes

Based on norovirus VP1 and RdRp gene sequencing, genotyping was performed on 620 screening-positive samples with Ct values ≤ 28. Successful typing was achieved for 603 samples based on the VP1 region and 612 based on the RdRp region.

The phylogenetic analysis revealed that all specimens belonged to the norovirus GII genogroup. The GII.4 Sydney_2012 was predominant, comprising 55.6% (335/603) of the typed strains, followed by GII.3 (21.2%, 128/603) and GII.2 (14.1%, 85/603). Minor genotypes included GII.13 (7.6%, 46/603), GII.6 (0.8%, 5/603), and GII.17 (0.7%, 4/603). Temporal distribution analysis revealed that GII.4 Sydney_2012 was the dominant lineage throughout most of the study period. However, a shift in predominance was observed between October 2018 and February 2019, when GII.3 became the most prevalent strain. Genotypes GII.13, GII.6, and GII.17 were only sporadically detected during specific months (Figs. 2a and 3a).

Fig. 2.

Fig. 2

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Phylogenetic analysis of norovirus based on the partial sequences of the VP1 (a) and RdRp (b). Phylogenetic trees in VP1 (the best nucleotide substitution model K2+G+I) and RdRp regions (the best nucleotide substitution model TN93+G+I) were constructed using the Maximum Likelihood method with 1,000 bootstrap replications in MEGA 12.0.11 software. The norovirus GII.4 Sydney_2012[P16] strain is highlighted in red.

Fig. 3.

Fig. 3

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Distribution of norovirus genotypes detected in children with acute gastroenteritis in Shanghai. (a) The results based on norovirus VP1 genes. (b) The results based on RdRp genes. (c) The results based on norovirus RdRp-VP1 genes

Analysis of the RdRp region identified seven polymerase genotypes. The most prevalent genotype was GII.P31 (46.4%, 284/612), followed by GII.P16 (24.5%, 150/612), GII.P12 (20.6%, 126/612), and GII.P21 (7.2%, 44/612). The remaining genotypes—GII.P7, GII.P17, and GII.P25—were detected at low frequencies of 0.7% (4/612), 0.5% (3/612), and 0.2% (1/612), respectively (Figs. 2b and 3b).

The amplification results based on norovirus RdRp-VP1 genes

Based on the sequencing analysis of norovirus across the RdRp-VP1 region, recombinant analysis was completed for 556 samples. The results of recombinant analysis showed that a total of 9 recombinant strains were identified, and among these 9 recombinant strains, GII.4 Sydney_2012[P31] was the recombinant strain with the highest number of detections, accounting for 46.6% (259/556); followed by GII.3[P12], accounting for 20.1% (112/556); and then GII.2[P16] with 14.6% (81/556); then GII.4 Sydney_2012[P16] with 11.2% (62/556); GII.13[P21] with 6.3% (35/556); and the remaining four recombinant strains were detected in smaller numbers, GII.4 Sydney_2012[P21] 0.2% (1/556); GII.17[P17] 0.4% (2/556); GII.3[P25] 0.2% (1/556); GII.6[P7] 0.5% (3/556).

From October 2018 to September 2020, the proportion of recombinant strains of norovirus GII.4 Sydney_2012[P31] was 56.5% (231/409), while the proportion of recombinant strains of GII.4 Sydney_2012[P16] was only 1.2% (5/409) in the same period. However, from October 2020 to June 2021, the detection rate of the recombinant strain GII.4 Sydney_2012[P16] increased to 38.8% (57/147), which exceeded that of the recombinant strain GII.4 Sydney_2012[P31] (19.0%, 28/147) (Fig. 3c).

The phylogenetic analysis of GII.4 Sydney_2012[P16]

The phylogenetic tree of the VP1 gene region shows that GII.4 Sydney_2012[P16] belongs to the same cluster as GII.4 Sydney_2012[P31] (Fig. 2a), while the phylogenetic tree of the RdRp gene region shows that GII.4 Sydney_2012[P16] belongs to the same cluster as GII.2[P16] (Fig. 2b).

Distribution of different norovirus genotypes in age

Norovirus GII.4 Sydney_2012[P31] and GII.4 Sydney_2012[P16] were both most common in the 1~2 year age group. Norovirus GII.13[P21] was most common in the 0~1 year age group with 88.6% (31/35), with a predominance of 96.8% (30/31) in children younger than 6 months. Norovirus GII.3[P12] was more prevalent in the 0~1 year and 1~2 year age groups and higher than in other age groups. Norovirus GII.2[P16] had the highest prevalence in the >5 year age group (Fig. 4).

Fig. 4.

Fig. 4

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Distribution of norovirus recombinant strains in children of different age groups in Shanghai

Discussion

Norovirus is a major cause of sporadic cases and outbreaks of acute gastroenteritis in all age groups, especially in children under five years of age [1]. One potential source of acute gastroenteritis is hospital-acquired infections, and norovirus is one of the most common causes of hospital-acquired infections [10]. Hospitalized children often have underlying medical conditions, and most are in an immunocompromised state following infection or surgery, as well as neonates with immature immune systems, who are at high risk of severe sequelae following norovirus infection [11]. At the same time, because the symptoms of norovirus infection are dominated by vomiting and diarrhea, and because norovirus is highly transmissible and contagious, it can easily cause outbreaks and epidemics in hospitals [12]. Therefore, it is necessary to investigate the study of hospital-acquired norovirus infection in children.

Norovirus has some seasonal prevalence [13]. In this study, the epidemiological peak of norovirus was mainly from October to January in the following year, which was similar to the epidemiological peak of community-acquired norovirus infection in Shanghai [14, 15]. In contrast, the positive detection rate of norovirus from February 2020 to August 2020 was significantly lower, both below 4.0%. It is speculated that the reason may be related to the outbreak of COVID-19. Since 20 January 2020, China has classified COVID-19 as a Category B infectious disease and managed it in accordance with Category A control measures [16]. These measures included maintaining social distancing, restricting mass gatherings, and the temporary closure of certain indoor public spaces. These prevention and control measures proved effective in suppressing viral transmission [17]. In the case of norovirus, the route of long-term virus shedding after infection makes it susceptible to outbreaks in closed and semi-closed environments [18], with the most common modes of transmission being ingestion of aerosolized vomitus via the faecal-oral route or contact with contaminated surfaces [19]. It is hypothesized that the significant reduction in crowd gatherings and the closure of indoor recreation venues have greatly impeded the spread of norovirus, resulting in a significant reduction in its detection rate, and that this phenomenon has also gradually disappeared with the relaxation of prevention and control measures for the COVID-19 outbreak, as evidenced by a gradual increase in the rate of positive norovirus detections from October 2020 onwards.

Despite the low norovirus positive rate (≤ 4.0%), over 200 stool samples were collected monthly between February and August 2020, indicating a sustained burden of pediatric gastroenteritis. The sharp decline in viral gastroenteritis, particularly norovirus, is widely attributed to several implemented interventions (e.g., social distancing, hand hygiene) that effectively disrupt person-to-person transmission. In contrast, foodborne bacterial pathogens were less impacted by these measures. Bacterial infections, such as those caused by Campylobacter and nontyphoidal Salmonella persisted during the pandemic [20]. Therefore, a larger proportion of the diarrhea cases in this period was likely caused by bacterial agents. Our retrospective review of patient medical records from this period revealed that a subset of children presented with conditions related to immune dysfunction. This could have been secondary to factors such as prolonged antibiotic use, stress, or underlying conditions requiring medication (e.g., chemotherapeutic agents), potentially leading to non-infectious or opportunistic gastroenteritis.

In the present study, all the successfully typed positive specimens of norovirus were of GII genotype, with the highest percentage of 55.6% (335/603) being of GII.4 Sydney_2012. Norovirus GII.4 is the predominant strain of acute gastroenteritis globally and frequently undergoes new recombinant mutations to evade the body’s immune attack, resulting in outbreaks. According to the molecular epidemiological survey of norovirus in Shanghai from 2012 to 2017, the norovirus strains prevalent in the Shanghai area were characterized by GII.4_2006b[P31] in 2012, while GII.4 Sydney_2012[P31]completely replaced GII.4_2006b[P31] became the predominant epidemic strain in from 2013 to 2017 [21]. The first report of GII.4 Sydney_2012[P31] was from Australia in March 2012 [22]. GⅡ4 Sydney_2012[P31] recombinant strains rapidly proliferated and became the predominant cause of acute gastroenteritis outbreaks in several countries [23, 24]. From October 2018 to September 2019, the predominant norovirus strains in Shanghai were characterized by the GII.4 Sydney_2012[P31] recombinant strain, and no previously reported GII.4_2006b[P31] or GII.4 New_Orleans[P31] was identified [14]. In the present study, the GII.4 Sydney_2012 strain was recombined with the RdRp region, yielding three distinct recombination strains: GII.4 Sydney_2012[P31], GII.4 Sydney_2012[P16], and GII.4 Sydney_2012[P21]. GII.4 Sydney_2012[P31] was the recombinant strain with the highest number of detections, accounting for 46.6% (259/556); followed by GII.4 Sydney_2012[P16] with 11.2% (62/556); GII.4 Sydney_2012[P21] with 0.2% (1/556). In 2015, GII.4 Sydney_2012[P16] recombinant strains of the norovirus emerged as a cause of an outbreak epidemic in the United States [25]. Subsequent reports have emerged from Japan and France, documenting outbreaks attributable to the GII.4 Sydney_2012[P16] norovirus recombinant strain [26, 27]. Notably, from October 2018 to September 2020, the proportion of recombinant strains of norovirus GII.4 Sydney_2012[P31] was 56.5% (231/409), while the proportion of recombinant strains of GII.4 Sydney_2012[P16] was only 1.2% (5/409) in the same period. However, from October 2020 to June 2021, the detection rate of the recombinant strain GII.4 Sydney_2012[P16] increased to 38.8% (57/147), which exceeded that of the recombinant strain GII.4 Sydney_2012[P31] (19.0%, 28/147). An increase in the detection rate of community-acquired norovirus acute gastroenteritis in children in Shanghai, China, has been reported since 2020. The strain of virus responsible for this increase is GII.4 Sydney_2012[P16] [15]. In 2020, the predominant prevalent strain of acute gastroenteritis-associated norovirus among children in Beijing was the GII.4 Sydney_2012[P16] recombinant strain, accounting for 36.4% (56/154), while the GII.4 Sydney_2012[P31] strain accounted for 19.5% (30/154) [28]. It was hypothesized that GII.4 Sydney_2012[P16] prevalent in New Zealand in 2017 was derived from a combination of GII.4 Sydney_2012[P31] and GII.2[P16] [29]. The VP1 and RdRp of norovirus GII.2[P16] and GII.4 Sydney_2012[P16] exhibit distinct evolutionary trajectories. GII.4 Sydney_2012[P16] may generate potential novel epidemic variants by accumulating mutations in its P2 domain, similar to previously prevalent GII.4 variants, whereas GII.2[P16] maintains conserved predicted antigenicity, and its evolution may be achieved through alterations in the properties of non-structural proteins, such as polymerase replicational fidelity and efficiency [30]. Although no unique amino acid substitutions were found in the capsid protein of this GII.4 Sydney_2012[P16] strain, significant mutations occurred in the RdRp region, and these mutation sites are proximal to key regions known to influence polymerase function and viral transmission. It is noteworthy that these polymerase mutations are consistent with those carried by the GII.2[P16] virus strain that dominated outbreak events in Germany in the winter of 2016 [31]. We will continue to monitor the prevalence of GII.4 Sydney_2012[P16] and conduct more in-depth studies to understand the evolutionary and mutational characteristics of the prevalent GII.4 Sydney_2012[P16] strains in the Shanghai area.

In the winter of 2014, norovirus GII.17 became the main genotype of norovirus-associated acute gastroenteritis in several regions of China. However, reports were still dominated by adults infected with norovirus GII.17 [32, 33]. This study identified two strains of norovirus GII.17[P17]. Further analysis is necessary to determine whether children are susceptible to GII.17[P17] and to understand the susceptibility of different age groups. In this study, we found that norovirus GII.13[P21] recombinant strains were most prevalent in the 0~1 year age group, especially in children younger than 6 months of age. However, given the limited number of recombinant strains of norovirus GII.13[P21] detected in this study, further investigation is necessary to substantiate the hypothesis that these strains are more likely to infect younger children.

Based on our results, we observed GII.4 Sydney_2012 was the predominant strain during multiple periods, suggesting it may have caused typical clusters of nosocomial transmission. More importantly, in most months, we detected the simultaneous presence of multiple genotypes (such as GII.2[P16], GII.3[P12], etc.). This indicates that norovirus epidemiology within the hospital setting is not always characterized by a single transmission chain, but rather represents a complex pattern involving multiple sources and concurrent transmission chains. This research did not involve extensive viral sampling of the ward environment, air, or healthcare workers. Therefore, we are unable to reconstruct precise, ward-specific transmission networks or completely rule out the possibility of healthcare workers acting as vectors transmitting different strains. Despite these limitations, we found that children infected with different genotypes had overlapping admission times and hospitalization areas. This observation rules out a simple model where a single strain exclusively occupied a specific ward, thereby further supporting the hypothesis of concurrent circulation of multiple strains within the hospital.

The main limitation of this study is that genotyping was only performed on a subset of screening-positive samples with a Ct value ≤ 28. This is because the conventional RT-PCR used for genotyping has higher requirements for template quantity and quality compared to the highly sensitive real-time RT-PCR used for initial screening. We employed this pre-established cut-off to maximize the success rate and reliability of genotyping. However, this may lead to an underrepresentation of genotype diversity in samples with low viral loads. Nonetheless, we are confident that this strategy ensured the accuracy of the acquired genotypic data and provides a solid foundation for subsequent in-depth studies on more representative sample sets.

Conclusions

In conclusion, the present study found that norovirus infections in children with hospital-acquired acute gastroenteritis were predominantly concentrated in November, December, and January each year from October 2018 to June 2021. During the study period, the prevalence of norovirus was observed to be prevalent in multiple recombinant forms, with the GII.4 Sydney_2012 genotype maintaining its predominance. However, a notable increase in the positivity of the GII.4 Sydney_2012[P16] recombinant strain has been documented since October 2020, which is a matter of concern. In light of these findings, it is imperative that surveillance and management of hospital-acquired norovirus acute gastroenteritis in hospitalized children be strengthened to prevent nosocomial norovirus outbreaks. RdRp-VP1 gene sequence analysis is instrumental in comprehending the prevalence of recombinant norovirus strains, thereby providing a scientific foundation for the prevention and control of norovirus outbreaks and epidemics.

Acknowledgements

No.

Author contributions

Fangyuan Yu: conceptualization, project administration, methodology, data curation, statistic analysis, writing-original draft, writing-review and editing. Xuhua Feng: data curation, methodology, investigation. Haiqin Ye: data curation, methodology. Qin Cai: data curation, methodology. Jie Jiang: data curation, investigation. Tiandong Zhang: data curation, investigation. Fen Pan: resources, supervision, writing-review and editing. Wenhao Weng: conceptualization, funding acquisition, resources, supervision, writing-review and editing. All authors reviewed and approved the final draft.

Funding

This work was supported by The Youth Talent Development Program of Shanghai Children’s Hospital(2021YQ10).

Data availability

The datasets presented in this article are not readily available because the data are part of on ongoing study. Requests to access the datasets should be directed to the corresponding authors.

Declarations

Ethics approval and consent to participate

The protocol of this study complied with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Shanghai Children’s Hospital(2023R075-E01). The fecal samples used in this study were leftover samples from clinical testing. The subjects could no longer be contacted either because they had been discharged from hospital or because their contact information was unavailable. This research project does not involve personal privacy or commercial interests. In addition, as this was a retrospective study and the clinical data were anonymized, the Ethics Committee of Shanghai Children’s Hospital approved the waiver of informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Fen Pan and Wenhao Weng contributed equally to this work.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets presented in this article are not readily available because the data are part of on ongoing study. Requests to access the datasets should be directed to the corresponding authors.

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