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. 2025 Jun 26;27(126):274–281. doi: 10.4103/nah.nah_152_24

Effects of Noise Reduction on the Physical and Mental State of Patients with Lumbar Disc Herniation in an Orthopedic Outpatient Clinic

Bin Wang 1, Cheng Shu 2, Lirong Bai 3,
PMCID: PMC12282959  PMID: 40574298

Abstract

Objective:

This study aimed to explore the effects of noise reduction on the physical and mental state of patients with lumbar disc herniation (LDH) in an orthopedic clinic.

Methods:

A retrospective analysis was conducted on 120 patients with LDH who received conservative treatment in the orthopedic outpatient clinic of Tsinghua University Hospital from February 2022 to February 2023. The orthopedics department underwent noise reduction renovations in August 2022 and has implemented noise control management since then. Sixty patients admitted before the renovations were assigned to the conventional group, and 60 patients admitted after the renovations were assigned to the noise reduction group. The two groups were compared in terms of noise levels during treatment, subjective negative perceptions of noise, pain level (visual analog scale [VAS] scores), negative emotions (self-rating anxiety scale [SAS] and self-rating depression scale [SDS], sleep quality (Pittsburgh sleep quality index [PSQI] and quality of life (36-item short-form health survey [SF-36] before and after a 2-week treatment.

Results:

Noise level and negative perception of noise in the noise reduction group were significantly lower than those in the conventional group (P < 0.05). After treatment, the noise reduction group had lower VAS, SAS, SDS, and PSQI scores (P < 0.05) but higher a SF-36 score than the conventional group (P < 0.05).

Conclusion:

Noise reduction in an orthopedic clinic can reduce pain levels and negative emotions and improve the sleep quality and quality of life of patients with LDH.

Keywords: outpatient clinic, noise, lumbar disc herniation, pain, anxiety

KEY MESSAGES

  • (1)

    Noise reduction may alleviate pain levels in patients with lumbar disc herniation (LDH).

  • (2)

    Noise reduction can relieve the negative emotions of patients with LDH.

  • (3)

    Noise reduction can improve the sleep quality and quality of life of patients with LDH.

INTRODUCTION

Lumbar disc herniation (LDH) is a prevalent orthopedic disease characterized by degenerative changes in the components of the lumbar disc, especially the nucleus pulposus. These alterations can compress neighboring spinal nerve roots, potentially causing lumbar pain, radiating lower extremity discomfort, and neurological dysfunction. The global incidence of LDH is approximately 2%–3%; owing to the normalization of long-standing, sedentary behavior and other unhealthy lifestyle patterns, the incidence of LDH continues to rise; notably, a trend toward early onset in young people has emerged, which interferes with normal work, study and rest; long-term pain may also lead to psychological problems such as anxiety and depression.[1,2] The management of LDH primarily involves two approaches: surgery and conservative treatment. For elderly patients and patients presenting with mild symptoms, conservative treatment is preferred because it can alleviate symptoms while ensuring patient safety.[3,4] The common conservative treatments for LDH in outpatient clinics include pharmacological therapy (such as muscle relaxants and nonsteroidal anti-inflammatory drugs), traction therapy, acupuncture, massage, and heat application.[5]

Studies have shown that environmental noise in hospitals has many adverse effects on patients’ sleep, blood pressure, and immune function.[6] A study has shown that long-term exposure to noise over 66 dB activates the human stress system, making the heart rate speed up and the blood pressure rise, enhancing the sensitivity of the nervous system and increasing a patient’s sensitivity to pain.[7] Fumey et al.[8] demonstrated that during outpatient hemodialysis treatment, the level of noise exposure in the surrounding environment will greatly affect patients’ psychological state, thereby having a significant impact on their quality of life. Other studies have found that ward noise control considerably reduces patients’ fatigue and improves quality of life and sleep quality.[9,10]

The primary sources of noise within hospitals are the conversations between medical staff and patients, footsteps, wheelchairs, medical equipment, wall-mounted call systems, televisions, and vehicles, which are loud and can last for long periods. These noise sources are common in orthopedic clinics, waiting areas, and treatment rooms. The adverse effects of hospital noise on patients’ health have been emphasized, but a small number of studies have specifically examined the impact of noise on outpatients. This study will explore the impact of outpatient noise on pain levels in patients with LDH and analyze the effects of noise control.

MATERIALS AND METHODS

Study design and sample size estimation

This study adopts a retrospective design. The clinical data of patients with LDH treated in the orthopedic outpatient clinic of Tsinghua University Hospital from February 2022 to February 2023 were collected.

The sample size was calculated using PASS 2021 software (NCSS, USA), and the visual analog scale (VAS) score was selected as the main outcome measure. Sample size estimation was performed using a bilateral alpha of 0.05, a power of 0.8, an expected difference of 0.5, and a standard deviation of 0.92. The minimum sample size needed for each group was determined to be 54 cases, yielding a total of 108 cases for the two groups. Considering an exclusion rate of 10%, we initially recruited 126 participants, which exceeded the expected sample size and, therefore, met the requirements of the study. In accordance with the exclusion criteria, six patients were excluded: three who did not receive conservative treatments, one who had a history of lumbar spine surgery, and two who had severe spinal deformities. Finally, 120 patients were included in this study.

Inclusion and exclusion criteria and grouping method

The inclusion criteria are listed as follows: (1) patients with typical symptoms of LDH, including low back pain, numbness, and swelling of the lower limbs, and diagnosed by lumbar CT or MRI;[11] (2) involvement of a single lumbar vertebral segment; (3) eligibility for conservative treatments; and (4) complete clinical data.

The exclusion criteria were as follows: (1) severe spinal deformities or structural lesions; (2) a history of lumbar surgery; and (3) absence of conservative treatments.

The orthopedics department underwent noise reduction renovations in August 2022 and has implemented noise control management since then. Sixty patients admitted before the renovations (from February to July 2022) were enrolled in the conventional group, and 60 patients admitted after the renovations (from August 2022 to February 2023) were enrolled in the noise reduction group.

Outpatient conservative treatment for LDH

All patients received conservative treatment consisting of massage therapy and acupuncture. Each treatment lasted approximately 150 min, and the frequency was every 2 days for 2 weeks, with a total of seven treatments.

(1) Massage: Activating collateral oil was applied to a patient’s waist, and then palm pressing and kneading techniques were performed on both hands. Additional techniques were used to promote waist muscle relaxation. Then, the acupoints of Weizhong, Huantiao, Chengshan, Kunlun, and Yanglingquan were pressed for 30 min. Lumbar vertebrae manipulation was performed. Each patient lied on his or her side, with a bent upper leg and straightened lower leg. The doctor pressed the patient’s intervertebral disc protrusion segment and used the protrusion segment as the center. The shoulders were rotated forward, and the buttocks backward. Then, the patient’s lower limbs were straightened, and the hips were flexed and extended. The same procedures were performed on the opposite side. After the massage therapy, the patients rested for 60 min until the muscles relaxed and then received acupuncture.

(2) Acupuncture: Six acupoints were selected: Dachangshu, Shenshu, Guanyuan, Yaoyangguan, Huantiao, and Zhibian. The skin around the acupoints was routinely sterilized, and sterilized acupuncture needles (0.30 mm × 75 mm) were inserted into the acupoints. Reinforcing techniques were performed until the patient felt localized soreness and numbness. Following the attainment of qi, the needles were retained for 30 min. During the needle retention period, two moxa sticks (Procured from Jiangsu Jiuaitang Pharmaceutical Technology Co., Ltd, Jiangsu, China; Specification: 18 mm × 20 mm) were inserted into the end of each needle, and heat-insulating paper was placed on the skin to prevent burns.

Noise reduction measures in outpatient clinics

The orthopedic outpatient department in the hospital can be found on the first floor of the clinic building, and it is neighboring the parking area. It is accessible by turning left upon entering the registration hall. The orthopedic waiting area is behind the waiting service desk. A corridor to the left of the desk leads to three consultation rooms, two treatment areas, and one nurses’ station, which is between the consultation rooms and treatment areas.

The conventional group did not undergo any noise reduction measures and was exposed to the original noise environment.

The noise reduction group received noise reduction management with two stages: (1) stage 1 (nurse training and equipment renovation in 7 days) and (2) stage 2 (formal execution of noise reduction management). The specific measures are provided in the subsequent sections.

Renovation of equipment and environment

Sound insulation boards or sound-absorbing cotton were installed on the walls and ceilings to reduce noise transmission. Shock-absorbing, easy-to-clean, and disinfected materials were installed on the floor. The windows facing the parking lot were installed with double-glazed glass that effectively isolated traffic noise. Nursing vehicles were replaced with silent wheels and lubricated regularly to reduce movement noise. Noisy equipment was moved away from the treatment areas and covered with soundproof materials. Shock-absorbing cushions were installed on equipment that generated vibrations. Noise management measures were implemented through noise control protocols, specified noise level limits, and scheduled equipment maintenance cycles. Preventive strategies were adopted to minimize noise generated by aging equipment. “Keep quiet” signs were prominently displayed at all entrances and exits of the corridors.

Noise reduction management

Medical staff received training on noise control. During patient consultations and treatments, the staff is encouraged to speak and move with care, open and close doors gently, and set mobile devices to vibrate mode while on duty. Whenever possible, phone calls should be avoided.

Nursing staff assisted patients with the registration process and facilitated orderly queuing by ensuring that patients waited for their designated numbers to be called to prevent queue jumping. Patients and their families were discouraged from gathering in the corridors and aisles and asked to speak in lower voices.

Observation indicators

General information

The general information of the subjects was collected from hospital medical records, including gender, age, disease duration, body mass index, education level, area of residence, comorbidities, location of affected discs, and the degree of intervertebral disc herniation (Pfirrmann classification[12].

Noise level measurement

The environmental noise level was measured for 24 h with a portable sound level meter (Taishi Electronics Industry Co. Ltd., Taiwan, Model: TES-1350A), and the average noise level during the patient’s treatment period was collected.

Negative perceptions of noise

After the 7th treatment, a questionnaire was given to each patient, and perception of noise was assessed. Five main noise sources are found in an orthopedic clinic: conversations between patients and their families, conversations between medical staff, medical equipment and nursing vehicles, footsteps, and office equipment (computers and printers). Responses were recorded in binary format as “yes/no” or “impact/no impact.” The scale was developed by our hospital’s respiratory department in 2021 for 100 patients and had a Cronbach’s α coefficient of 0.854 and good internal consistency reliability.

Pain severity scoring

Before treatment and after the 2nd, 5th, and 7th treatments, the patients’ pain levels were evaluated using the VAS scores.[13] A straight line was drawn on a white paper, with one end marked as 10 points to indicate the most severe pain and the opposite end marked as 0 points to indicate the absence of pain. Patients can subjectively select a score that represents their pain level. Cronbach’s α coefficient of the scale is 0.838.

Negative emotion scores

Before the 1st treatment and after 7th treatment, the self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were used in evaluating the anxiety and depression levels of the patients.[14,15] Cronbach’s α coefficients of the SAS and SDS were 0.852 and 0.830, respectively.

The scales both contain 20 four-point items. The combined raw score reaches 80 points, and by multiplying it by 1.25, one can obtain a criterion-referenced score of 100 points. Negative emotion levels of patients are positively correlated with the scores.

Sleep quality

Before the 1st treatment and after 7th treatment, the Pittsburgh sleep quality index (PSQI) was used in evaluating sleep quality.[16] This scale consists of seven items. The score of each item ranges from 0 to 3, and the total score range is 0–21. Sleep quality is negatively correlated with the score. Cronbach’s α coefficient was 0.816.

Quality of life

Before the 1st treatment and after the 7th treatment, the quality of life of the patients was evaluated using the 36-item short-form health survey (SF-36).[17] Cronbach’s α coefficient was 0.813. The SF-36 consists of eight dimensions, namely, vitality, physical functioning, bodily pain, general health perception, physical role functioning, emotional role functioning, social role functioning, and mental health. Each dimension is scored from 0 (worst quality of life) to 100 (best quality of life).

Statistical analysis

Data were statistically analyzed using SPSS 22.0 software (IBM, USA), and figures were plotted using Origin 2023 software (OriginLab, USA). Measurement data conforming to a normal distribution were expressed as mean ± standard deviation and analyzed using t-tests for statistical comparison. Categorical data were expressed as (n [%], and the chi-square tests were used. A P value of <0.05 was considered indicative of statistical significance.

RESULTS

General information

No significant differences in gender, age, disease duration, body mass index, education level, area of residence, diabetes, hypertension, location of affected discs, and Pfirrmann classification were found between the groups (P > 0.05; Table 1).

Table 1.

Comparison of general information between the two groups

General information Conventional group (n = 60) Noise reduction group (n = 60) t/χ 2 P
Gender (n [%] Male 32 (53.33) 35 (58.33) 0.304 0.581
Female 28 (46.67) 28 (46.67)
Age (years) 48.63 ± 7.21 51.31 ± 8.54 1.845 0.066
Disease duration (years) 5.39 ± 1.21 5.10 ± 1.14 1.351 0.179
Body mass index (kg/m2) 22.82 ± 1.36 23.01 ± 1.18 0.805 0.422
Education level (n [%] High school and below 25 (41.67) 24 (40.00) 0.506 0.776
College and junior college 28 (46.67) 31 (51.67)
Master’s degree 7 (11.67) 5 (8.33)
Area of residence (n [%] Rural 35 (58.33) 32 (53.33) 0.304 0.581
Urban 25 (41.67) 28 (46.67)
Diabetes (n [%] 13 (21.67) 17 (28.33) 0.711 0.399
Hypertension (n [%] 16 (26.67) 15 (25.00) 0.043 0.835
Location of the affected disc (n [%]) L 3–4 8 (13.33) 10 (16.66) 0.868 0.648
L 4–5 22 (36.67) 25 (41.67)
L5–S1 30 (50.00) 25 (41.67)
Pfirrmann classification (n [%]) Grade I 13 (21.67) 15 (25.00)
Grade II 30 (50.00) 26 (43.33) 0.540 0.764
Grade III 17(28.33) 19 (31.67)

Noise level during treatment

The average noise level in the orthopedic clinic during treatment in the noise reduction group was significantly lower than that of the conventional group (P < 0.05; [Figure 1].

Figure 1.

Figure 1

Noise levels in the orthopedic clinic during the treatment of the two groups. Note: *, P < 0.05.

The negative perception of noise

The noise reduction group had a significantly lower negative perception of the five types of noise in the noise reduction group than the conventional group (P < 0.05; Table 2).

Table 2.

Negative perception of the five types of noise in the orthopedic clinic (n [%]

Noise type Conventional group (n = 60) Noise reduction group (n = 60) χ 2 P
Conversation of patients and their families 39 (65.00) 27 (45.00) 4.848 0.028
Conversation of medical staff 32 (53.33) 20 (33.33) 4.887 0.027
Sound of footstep 35 (58.33) 20 (33.33) 7.552 0.006
Office equipment (computers and printers) 25 (41.67) 14 (23.33) 4.596 0.032
Medical equipment and nursing vehicles 26 (43.33) 15 (30.00) 4.483 0.034

Pain level

After the 2nd, 5th, and 7th treatments, the VAS scores of the noise reduction group exhibited a significant decrease compared to the conventional group (P < 0.05; Table 3).

Table 3.

Comparison of VAS scores between the two groups (points, Inline graphic ± s)

Group Before treatment After 2nd treatment After 5th treatment After 7th treatment
Conventional group (n = 60) 7.35 ± 0.97 5.70 ± 0.94* 3.40 ± 0.81* 2.52 ± 0.92*
Noise reduction group (n = 60) 7.60 ± 1.13 4.98 ± 0.98* 3.05 ± 0.70* 2.15 ± 0.70*
T 0.781 4.073 2.539 2.429
P 0.436 <0.001 0.012 0.017

Note: VAS, visual analogue scale; * indicates comparison with before treatment, P < 0.05.

Negative emotions

Before treatment, no significant differences in SAS and SDS scores were observed between the groups (P > 0.05). After treatment, the SAS and SDS scores of the noise reduction group were significantly lower than those of the conventional group (P < 0.05; Table 4).

Table 4.

Comparison of negative emotions between the two groups (points, Inline graphic ± s)

Group SAS SDS


Before treatment After treatment Before treatment After treatment
Conventional group (n = 60) 52.26 ± 5.26 40.15 ± 4.00* 55.68 ± 5.81 35.25 ± 3.44*
Noise reduction group (n = 60) 53.30 ± 5.20 38.16 ± 4.14* 54.46 ± 4.67 32.98 ± 2.48*
T 1.081 2.672 1.264 4.138
P 0.282 0.009 0.209 <0.001

Note: SAS, the self-rating anxiety scale; SDS, the self-rating depression scale;* indicates comparison with before treatment, P < 0.05.

Sleep quality

Before treatment, no significant difference in PSQI score was found between the groups (P > 0.05). After treatment, the PSQI score of the noise reduction group was lower than that of the conventional group (P < 0.05; Table 5).

Table 5.

Comparison of the PSQI scores of the groups (points, Inline graphic ± s)

Group Before treatment After treatment T P
Conventional group (n = 60) 8.21 ± 1.35 3.82 ± 0.87* 21.153 <0.001
Noise reduction group (n = 60) 8.46 ± 1.52 3.26 ± 0.84* 23.146 <0.001
T 0.950 3.514
P 0.344 <0.001

Note: PSQI, the Pittsburgh sleep quality index.

Quality of life

Before treatment, no significant difference in SF-36 score was found between the groups (P > 0.05). After treatment, the SF-36 scores in all dimensions of the noise reduction group were significantly higher than those of the control group (P < 0.05; Table 6).

Table 6.

Comparison of quality of life between the groups (points, Inline graphic ± s)

SF-36 dimension Conventional group (n = 60) Reduction group (n = 60) t P
Vitality Before treatment 56.26 ± 2.89 56.15 ± 2.96 0.218 0.828
After treatment 76.33 ± 3.23* 86.68 ± 3.83* 15.954 <0.001
Physical functioning Before treatment 53.13 ± 2.43 54.00 ± 3.51 1.571 0.119
After treatment 75.46 ± 3.64* 88.41 ± 4.09* 18.306 <0.001
Bodily pain Before treatment 51.38 ± 2.56 52.08 ± 3.12 1.341 0.183
After treatment 75.13 ± 2.89* 87.63 ± 3.42* 21.606 <0.001
General health perception Before treatment 54.55 ± 2.78 53.96 ± 2.42 1.223 0.224
After treatment 77.98 ± 3.93* 85.18 ± 3.82* 10.171 <0.001
Role Physical Before treatment 55.91 ± 2.52 55.71 ± 2.39 0.445 0.657
After treatment 78.68 ± 3.70* 86.88 ± 3.86* 11.878 <0.001
Role emotional Before treatment 59.78 ± 2.11 58.93 ± 3.03 1.781 0.077
After treatment 79.36 ± 3.85* 84.23 ± 3.41* 7.330 <0.001
Social role functioning Before treatment 60.15 ± 2.44 59.95 ± 2.62 0.432 0.667
After treatment 80.21 ± 3.82* 88.48 ± 4.15* 11.346 <0.001
Mental health Before treatment 56.38 ± 2.88 55.35 ± 3.87 1.655 0.101
After treatment 77.41 ± 3.53* 87.45 ± 3.55* 15.510 <0.001

Notes: SF-36, 36-item short-form health survey; * indicates comparison with before treatment, P < 0.05.

DISCUSSION

Noise is a common environmental pollutant in today’s society, not only disrupting human’s normal hearing but also affecting the endocrine and cardiovascular systems.[18,19] The outpatient clinic is an important place for patients receiving consultations and treatments, providing basic environmental hygiene requirements. However, the acoustic environment cannot be ignored. Various sources of noise can be found in orthopedic clinics, such as wheelchairs and crutches, patient’s groaning, shouting, and conversations between patients and their families, and the noise level is considerably higher than that in other departments.[20] Patients with LDH need a relatively long time to receive outpatient physical therapy. Long-term noise exposure can interfere with their physiological and psychological state, contributing to the increased secretion of adrenal hormones and blood pressure. The patients’ weak constitutions are at risk of developing symptoms such as dizziness, insomnia, dreaminess, headache, and generalized fatigue.[21]

In this study, after comprehensive noise reduction, the average noise level in the orthopedic clinic during treatment and negative perception of the five types of noise in the noise reduction group were significantly lower than those of the conventional group. The possible explanation is that noise control training for medical staff enhanced their awareness of the adverse effects of noise, promoted discipline, and reduced noise due to staff activities. Encouraging patients and their families to keep quiet and wait for their numbers to be called can reduce noise from patients. Installing shock-absorbing and sound-insulating materials and regularly maintaining and repairing medical equipment can reduce noise generated by the equipment. Moreover, displaying ‘keep quiet’ signs remind patients and medical staff to minimize noise.

In hospital environments, the impacts of noise control on patients’ sensation of pain have emerged as an important research topic.[22,23] This study showed that after the 2nd, 5th, and 7th treatments, the VAS scores of the noise reduction group were lower than those of the conventional group. Continuous exposure to noise may set off the activation of the sympathetic nervous system, leading to a stress response in the endocrine system, and can considerably increase the patient’s perception of pain.[24,25] Noise reduction strategies, including minimizing the noise emitted by medical devices and enhancing the acoustic architecture of buildings, can significantly alleviate patients’ pain perception. Moreover, utilizing noise-canceling headphones, in the outpatient treatment process of kidney stones can play a role in lessening pain and reducing patients’ anxiety.[26]

In addition, reasonable outpatient noise control strategies cannot only improve patients’ psychosocial status but also improve overall healthcare quality. The results of this study showed that the SAS and SDS scores of the noise reduction group were lower than those of the conventional group after treatment. The reason is that high noise exposure can activate the hypothalamic–pituitary–adrenal axis, prompting the excessive secretion of cortisol and catecholamines, which in turn enhance the sensitivity of pain perception through the β-adrenergic receptor pathway, stimulate neurons to release acetylcholine and cause anxiety and tension.[27] Extended exposure to a clamorous environment may lead to a decrease in the levels of dopamine and 5-hydroxytryptamine and trigger anxiety and depression, forming a vicious cycle of “noise–stress–pain–emotional disorders.”[28,29] A cohort study confirmed that hospital noise intensity is considerably and positively correlated with patients’ anxiety and depression scale scores, suggesting a dose–effect relationship between the level of noise exposure and deterioration of psychosomatic state.[30]This study found that after treatment, the noise reduction group had a lower PSQI score and higher SF-36 scores than the conventional group. The results showed that noise reduction measures had a positive effect on patients’ sleep quality and quality of life. Jemielita et al.[31] demonstrated that noise reduction measures restore sympathetic and parasympathetic balance, promote physical relaxation, and promote deep sleep. Outpatient noise reduction initiative further improves patients’ quality of life more effectively via psychological pathways, including the alleviation of anxiety and depression, improving emotional regulation, enhancing subjective well-being, and promoting psychological relaxation.

The study is subject to some limitations, including that the sample is from a single origin and the study design is retrospective. In addition, potential confounding factors were found, such as different geographic locations of different clinics with different predominant noise types. These factors resulted in different levels of outpatient noise. The compliance of different outpatient medical staff with noise reduction methods varies, which undermines the effectiveness of noise reduction measures. Moreover, these confounding factors may reduce the generalizability of the results of this study. Therefore, multicenter and multisample studies should be considered to reduce sample bias. Prospective study protocols can be designed to further analyze the relationship between outpatient noise and patient outcomes.

CONCLUSION

Outpatient noise reduction management has a certain control effect on pain levels in patients with LDH and can alleviate their anxiety and depression, improve their sleep quality, and enhance their overall quality of life. Noise reduction in outpatient areas holds paramount significance for the rehabilitation treatment of patients.

Author Contributions

Bin Wang: conception and design; Cheng Shu: administrative support; Lirong Bai: provide research materials and subjects; Bin Wang, Cheng Shu: data collection and summary; Lirong Bai, Bin Wang: data analysis and interpretation; All authors: manuscript writing and final approval of the manuscript.

Availability of Data and Materials

The data used and/or analyzed in this study are available from the corresponding author upon reasonable request.

Ethics Approval and Consent to Participate

This research was approved by the ethics committee of Beijing Ditan Hospital affiliated to Capital Medical University (approval number: QH-LL-ZD00109). It was carried out in compliance with the ethical guidelines set forth in the Declaration of Helsinki, safeguarding the rights, safety, and privacy of the participants. The individuals involved were made aware of the study’s objectives and methods, as well as the possible risks and advantages. Their involvement was entirely optional. Before the commencement of the study, all participants provided written informed consent.

Conflicts of Interest

All authors declare no conflicts of interest.

Acknowledgment

Not applicable.

Funding Statement

Not applicable.

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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 data used and/or analyzed in this study are available from the corresponding author upon reasonable request.


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