Peripheral neuropathy significantly increases the risk of persistent lower extremity ulcers in individuals with diabetes in the United States: a cross-sectional study based on National Health and Nutrition Examination Survey data

Peripheral neuropathy significantly increases the risk of persistent lower extremity ulcers in individuals with diabetes in the United States: a cross-sectional study based on National Health and Nutrition Examination Survey data | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Peripheral neuropathy significantly increases the risk of persistent lower extremity ulcers in individuals with diabetes in the United States: a cross-sectional study based on National Health and Nutrition Examination Survey data Zirui Li, Zairong Wei This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3974995/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Lower extremity ulcers are a major health concern in the diabetic population as they can result in chronic wounds, infection, and amputation. Previous studies have shown that one of the major consequences of peripheral neuropathy (PN) is an increased risk of lower extremity ulcers, which can lead to significant morbidity and mortality in individuals with diabetes. However, the specific role of PN in increasing the risk of persistent lower extremity ulcers (PLEU) in this population has not been well elucidated. We aimed to examine and establish a connection between PN and PLEU in individuals with diabetes in the United States. Methods A cross-sectional study was conducted using the National Health and Nutrition Examination Survey data from 1999 to 2004 for participants aged ≥40 years with a diagnosis of diabetes. PLEU was defined based on questionnaires assessing the presence of non-healing ulcers in the lower extremities for >4 weeks in patients with diabetes. PN was defined as numbness, loss of sensation, painful sensations, tingling in one’s feet in the last 3 months or ≥1 area of no sensation based on monofilament testing. Logistic regression analysis was performed to assess the relationship between PN and PLEU. Results In total, 1,671 participants were included (1,018 and 653 participants with and without PN, respectively). The overall prevalence of PLEU was 9% (151/1,671), whereas it was 12.5% (127/1,018) and 3.7% (24/653) in PN and non-PN participants, respectively. We found that PN was associated with a 274% greater incidence of PLEU (odds ratio [OR]=3.74, 95% confidence interval [CI]=2.39–5.85, p<0.001) compared with participants without PN. After adjusting for potential confounders, PN was associated with a 209% higher incidence of PLEU (OR=3.09, 95% CI=1.95–4.92, p<0.001) compared with participants without PN. The results remained stable based on our subgroup analyses and propensity score matching. Conclusion PN is significantly associated with PLEU in patients with diabetes in the United States. Peripheral neuropathy Lower extremity ulcer Diabetes mellitus National Health and Nutrition Examination Survey Cross-sectional study Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Diabetes is a chronic metabolic disorder affecting millions of people worldwide [1], and its prevalence is increasing in developed and developing countries [2]. Peripheral neuropathy (PN) is a common complication of diabetes [3], affecting a significant proportion of individuals with diabetes in the United States [4]. PN is characterized by damage to the peripheral nerves, resulting in impaired sensation, muscle weakness, and loss of reflexes [5]. Lower extremity ulcers are a major health concern in the diabetic population [6] because they can result in chronic wounds, infections, and even amputation [7]. One of the major consequences of PN is an increased risk of lower extremity ulcers, which can lead to significant morbidity and mortality in individuals with diabetes [8, 9]. However, the specific role of PN in increasing the risk of persistent lower extremity ulcers (PLEUs) in this population has not been well elucidated. This observational study aimed to investigate the association between PN and PLEU in patients with diabetes. The findings of this study may contribute to the development of evidence-based guidelines for the prevention and management of PN and PLEU, ultimately improving the quality of life in individuals with diabetes. Methods Study design and participants Health and nutritional data were gathered from American individuals as part of the National Health and Nutrition Examination Survey (NHANES). Participants completed questionnaires on their histories and habits and underwent physical and laboratory examinations. Researchers, decision-makers, and healthcare professionals utilize these data to better understand health issues, identify patterns and inequities, and promote nutrition and public health. For our analysis, we used open data from three NHANES cycles (1999–2000, 2001–2002, and 2003–2004). To participate in the survey, the participants were required to submit a blood test. In-person interviews conducted at participants’ homes were also used to gather data on basic demographics and medical histories. A stratified multistage probability survey was used in the NHANES research to assess the health and nutritional status of noninstitutionalized Americans [10]. A mobile examination center conducted home visits, screenings, and laboratory tests as part of the NHANES to gather detailed demographic and health data. The NHANES research was approved by the National Center for Health Statistics Ethics Review Committee, and all participants provided written informed consent. No additional Institutional Review Board permission was required for secondary analysis [11]. The NHANES website (http://www.cdc.gov/nchs/nhanes.htm) provides access to the NHANES data. Outcome and variables PLEUs were identified using questionnaires that evaluated the >4-week presence of non-healing ulcers in the lower limbs of individuals with diabetes. PN was assessed using self-reported symptoms and by testing foot sensation with a standard monofilament (5.07-gauge Semmes‒Weinstein nylon), according to a standard protocol [12]. Health technicians applied pressure via the monofilament at three sites (plantar, first metatarsal head; plantar, fifth metatarsal head; and plantar, hallux) at the bottom of each foot, resulting in a total of six sites. The monofilament was applied until it buckled and held for 1 s. A site was considered inflated if the participant incorrectly met the criteria for two of the three monofilament applications. Impaired sensation was quantified by the total number of insensate areas in both feet, which ranged from zero to six. PN was defined as the presence of at least one insensate area. During the interview, participants were asked whether they had experienced numbness, loss of feeling, painful sensations, or tingling of their feet in the last 3 months. PN cases were defined as those who reported “yes” to this question [13]. Questionnaires were used to assess a history of physician-diagnosed hypertension, sex, age, race/ethnicity, marital status, smoking status, and education level. Participants were classified as married, living with a partner, or living alone based on a marital questionnaire. Smoking status was classified as never smoked (100 cigarettes smoked in a lifetime, but no longer smoking), or current smoker (>100 cigarettes smoked in a lifetime and currently smoking). Educational level was classified into different groups (<9, 9–12, and ≥12 years). Participants were divided into normal, overweight, and obese groups based on body mass index (BMI) (<25.0, 25.0–29.9, and ≥30.0 kg/m 2 , respectively). The determination of previous disease (hypertension or chronic heart disease [CHD]) status was based on whether the doctor had been informed of the patient’s condition in the past. Other covariates included white blood cell (WBC) count (×10 9 /L), lymphocyte count (×10 9 /L), monocyte count (×10 9 /L), C-reactive protein (CRP), glucose (mmol/L), hemoglobin (HGB, g/dL), glycohemoglobin (HbA1C, %), high-density lipoprotein cholesterol (HDL, mmol/L) and total cholesterol (mmol/L). Statistical analysis The statistical software packages R 3.3.2 (http://www.R-project.org, The R Foundation) and Free Statistics Software version 1.8 were used for all analyses. Demographic and clinical characteristics are expressed as means, standard deviations, and frequencies (percentages). Differences between continuous and categorical data were examined using independent and chi-squared tests, respectively. Binary logistic regression analysis was used to examine the relationship between PN and PLEU. Single- and multiple-variable analyses were conducted. We constructed four models for multivariate logistic regression: (1) Model 1: unadjusted; (2) Model 2: adjusted for sociodemographic variables (sex, age, race/ethnicity, marital status, and education level; (3) Model 3: adjusted for sociodemographic variables and variables reflecting overall health status, including BMI, smoking status, hypertension, and CHD; and (4) Model 4: adjusted for age, sex, marital status, race/ethnicity, education level, BMI, smoking status, hypertension, CHD, WBC, lymphocyte count, CRP, glucose, HGB, HbA1C, HDL cholesterol, and total cholesterol. A subgroup analysis was also conducted to examine the association between PN and PLEU, considering factors such as sex, age (<60 years, ≥60 years), hypertension, and CHD. A multivariate logistic regression model was used for analysis. A logistic regression model interaction test was performed to examine the odds ratios (ORs) between the subgroups. In the sensitivity analysis, we used propensity score matching (PSM) to minimize the effects of confounding variables, which might have led to outcome bias [14]. The following variables were used to generate the propensity score with a caliper width of 0.01 and a one-to-one closest neighbor matching algorithm: age, sex, marital status, race/ethnicity, education level, BMI, smoking status, hypertension, CHD, WBC, lymphocyte, monocyte, CRP, glucose, HGB, HbA1c, HDL, and total cholesterol. The degree of PSM was measured using standardized mean difference. A value of <0.1 was considered acceptable. The inverse probability of treatment weighting (IPTW) model was utilized to produce a weighted cohort using the calculated propensity scores as weights. The propensity score was adjusted using univariate logistic regression. On average, <5% of the variable data were missing, and the missing data were removed. Results Selected participants and baseline characteristics This study collected data from three NHANES cycles: 1999–2000, 2001–2002, and 2003–2004. The initial pool of potential participants comprised 31,126 individuals. From this pool, 21,156 participants aged <40 years, 8,110 participants without diabetes, 187 participants with missing PLEU data, and two participants with missing PN data were excluded. A total of 1,671 participants were included in the analysis. Figure 1 presents the inclusion and exclusion criteria with a flowchart outlining the participant selection process. Table 1 summarizes the baseline characteristics of the patients with and without PLEU in terms of demographic and socioeconomic factors, comorbidities, and laboratory metrics. Of the 1,671 included participants, 151 (9.04%) were identified as having PLEU. Statistical analysis revealed significant differences in marital status, BMI, CHD incidence, WBC, glucose, HGB, and HbA1c levels between the PLEU and non-PLEU groups (p<0.05). Specifically, compared with the non-PLEU group, the PLEU group had a significantly greater proportion of individuals living alone (p=0.023), a greater proportion of individuals with obesity (p=0.002), a greater proportion of individuals with CHD (p<0.001), a higher WBC count (p=0.048), a greater glucose level (p<0.001), a higher HbA1c level (p=0.039), and a lower HGB level (p<0.001). Multivariate logistic regression between PN and the presence of PLEU In this study, we constructed four models to analyze the independent effects of PN on PLEU. The effect sizes (ORs) and 95% confidence intervals (CIs) are shown in Table 2 . According to the unadjusted model (Model 1), PN was significantly associated with the occurrence of PLEU (OR=3.74, 95% CI=2.39–5.85, p<0.001). The model-based effect size indicated that, for participants with PN, the risk of PLEU increased by 274%. In Model 2, after adjusting for sex, age, race/ethnicity, marital status, and education level, the presence of PLEU increased by 279% for the population with PN (OR=3.79, 95% CI=2.41–5.95, p<0.001). After adjusting for BMI, smoking status, hypertension, and CHD incidence, the OR was 3.59 (95% CI=2.27–5.68, p<0.001) in Model 3. According to the fully adjusted model (Model 4) (adjusted for all covariates presented in Table 1 ), for participants with PN, the risk of PLEU increased by 209% compared with that of participants without PN (OR=3.09, 95% CI=1.95–4.92, p<0.001). Subgroup analysis We also conducted subgroup analyses to examine variables that may affect the association between PN and the presence of PLEU. We used sex, age (<60, ≥60 years), hypertension, and CHD as stratification variables to observe the trend of effect sizes in these subgroups ( Figure 2 ). The effect size of PN on the occurrence of PLEU was consistent across all subgroups. No statistically significant interactions were observed between PN and sex (p for interaction=0.648), age (p for interaction=0.685), hypertension (p for interaction=0.888), or CHD (p for interaction=0.358) in the presence of PLEU. Sensitivity analysis In the sensitivity analysis, to minimize the bias of confounding factors, we generated a propensity score for the logistic regression. Eighteen variables were initially used to create the propensity score model. Figure 3 illustrates the contributions of individual factors to the final propensity score. CHD, hypertension, age, and HGB level were the top variables. IPTW was used to normalize the differences between the PN and non-PN cohorts based on the estimated propensity scores. A regression model was developed to adjust for unbalanced covariates in the weighted cohort. In the original cohort, 12.48% (127/1,018) and 3.68% (24/653) of the PLEUs were detected in the PN and non-PN groups, respectively (Table 2). IPTW was associated with a significantly greater risk of PLEU in the PN group (OR=3.15, 95% CI=2.04–4.88, p<0.001). After the patients were adjusted for propensity score and matched, the results were stable, and the ORs were 3.03 (95% CI=1.92–4.78, p<0.001) and 3.14 (95% CI=1.93–5.11, p<0.001), respectively ( Figure 4 ). Discussion The findings of this retrospective cross-sectional study based on the NHANES data provide valuable insights into the relationship between PN and the risk of PLEU in individuals with diabetes in the United States.This study highlights the significant impact of PN on PLEU risk, emphasizing the need for early detection and intervention in individuals with diabetes. Our findings demonstrated a significant relationship between these two variables, consistent with previous research. Previous studies have consistently reported an association between PN and the development of lower extremity ulcers. Neuropathic changes in the peripheral nerves, particularly in patients with diabetes, can lead to a loss of protective sensation and altered biomechanics, increasing the susceptibility to foot trauma and subsequent ulceration [15]. More than half of patients with diabetes and PN develop foot ulcers during their lifetime [16]. Furthermore, individuals with PN have a greater risk of developing persistent or chronic lower extremity ulcers than those without neuropathic changes. This could be attributed to the impaired healing process and increased vulnerability to infections as a result of sensory and autonomic nerve damage associated with PN [17, 18]. In addition, our findings align with those of other studies that demonstrated the effect of PN on the recurrence of lower extremity ulcers. Previous research has indicated that PN leads to an increased risk of ulcer recurrence due to ongoing sensory loss and mechanical abnormalities that predispose individuals to foot trauma and subsequent ulceration [19]. The findings of this observational study provide significant evidence supporting an association between PN and PLEU. The pathophysiological mechanisms underlying this relationship can be attributed to several factors. First, PN leads to loss of protective sensation, thereby increasing the risk of trauma and injury to the lower extremities [20]. The diminished ability to perceive pain and pressure results in prolonged, unnoticed injuries, which can develop into persistent ulcers. This finding is supported by previous research demonstrating that individuals with neuropathy are more susceptible to developing chronic wounds because of their inability to detect and respond to harmful stimuli [21]. Second, PN causes motor and autonomic dysfunction, leading to diminished muscle strength and impaired blood flow to the lower extremities [22]. This compromises the healing process and exacerbates persistent ulcer formation. Reduced muscle function impairs the body’s ability to offload pressure from vulnerable areas, thereby contributing to developing chronic wounds [23]. Additionally, PN is associated with impaired immune function, leading to increased susceptibility to infection and delayed wound healing [24]. The compromised immune response in individuals with neuropathy contributes to the chronicity of lower extremity ulcers, as infections further hinder the healing process and perpetuate the existence of wounds [25]. Furthermore, altered biomechanics and gait abnormalities associated with PN contribute to PLEU formation [26]. Unstable gait patterns and abnormal foot mechanics increase the likelihood of pressure points and friction, thereby predisposing individuals with neuropathy to chronic ulceration [27]. However, it is important to acknowledge the limitations of this study. First, PN and PLEU data were collected only from the NHANES between 1999 and 2004. This made it impossible to further validate the use of the NHANES data from different periods. Second, even with regression models, stratified analysis, and sensitivity analysis, the residual confounding effects of unmeasured or unknown factors could not be completely excluded. Third, these findings were derived from a survey of American adults, and further research is required to determine whether these findings can be generalized to other populations. Fourth, relying on self-reported data for diagnosing PN and PLEU might have introduced bias and underreporting. Finally, the cross-sectional design of this study prevented us from establishing a causal relationship between PN and PLEU. Longitudinal studies are required to examine the temporal relationships between these variables. Conclusion This observational study provides robust evidence supporting the significant association between PN and the risk of PLEU in individuals with diabetes in the United States. Further research is needed to establish a causal relationship between these variables and explore potential interventions to reduce the burden of lower extremity ulcers in this population. Abbreviations BMI, body mass index; CHD, chronic heart disease; CI, confidence interval; CRP, C-reactive protein; HbA1C, glycohemoglobin; HDL, high-density lipoprotein cholesterol; HGB, hemoglobin; IPTW, inverse probability of treatment weighting; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio; PN, peripheral neuropathy; PLEU, persistent lower extremity ulcer; PSM, propensity score matching; WBC, white blood cell. Declarations Ethics approval and consent to participate: The NHANES research was approved by the National Center for Health Statistics Ethics Review Committee, and all participants provided written informed consent. No additional Institutional Review Board permission was required for secondary analysis. The NHANES website (http://www.cdc.gov/nchs/nhanes.htm) provides access to the NHANES data. Consent for publication: Not applicable. Availability of data and materials: Publicly available datasets are available online for this study. The repository/repositories name and accession numbers are available online at http://www.cdc.gov/nchs/nhanes.htm Competing interests: The authors declare that they have no competing interests. Funding: This study was supported by the Collaborative Innovation Center of Chinese Ministry of Education (2020-39) ; and the Scientific and Technological Innovation Talent Team of Wound Surgery Integrated Treatment of Guizhou Province (Talents Science Cooperation Platform of Guizhou, No. 2020-5012) ; and the Constructive Project of Innovative Talent Platform Carrier for Precise Repair of Wounds (Talents Science Platform of Zunyi city, No. 2021-3) ; and the Scientific Research and Talent Training Funds of Kweichow Moutai Hospital (MTYK, No.2022-13); and the Shanghai Wang Zhengguo Trauma Medicine Development Foundation (SZYZ-TR-05). Author contributions: Li and Wei: contributed to the conception or design of the work; Li: conducted the study, analyzed data and wrote the manuscript. All authors read and approved the final manuscript. Acknowledgements: We thank Dr. Jie Liu (People’s Liberation Army of China General Hospital, Bei-jing, China) for helping with this revision. 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Baseline characteristics of the study participants Characteristics All patients Persistent lower extremity ulcer p (n=1 671) No (n=1 520) Yes (n=151) Age (years) 64.8 ± 11.8 64.8 ± 11.7 64.9 ± 11.9 0.912 Sex, n (%) 0.197 Male 857 (51.3) 772 (50.8) 85 (56.3) Female 814 (48.7) 748 (49.2) 66 (43.7) Race/ ethnicity, n (%) 0.461 Non-Hispanic white 687 (41.1) 628 (41.3) 59 (39.1) Non-Hispanic black 391 (23.4) 355 (23.4) 36 (23.8) Mexican American 462 (27.6) 414 (27.2) 48 (31.8) Others 131 ( 7.8) 123 (8.1) 8 (5.3) Marital status, n (%) 0.023 Married or living with a partner 997 (59.7) 920 (60.5) 77 (51) Living alone 674 (40.3) 600 (39.5) 74 (49) Education level (years), n (%) 0.941 12 515 (30.8) 467 (30.7) 48 (31.8) BMI, n (%) 0.002 Underweight/ normal 254 (15.2) 232 (15.3) 22 (14.6) Overweight 602 (36.0) 566 (37.2) 36 (23.8) Obese 815 (48.8) 722 (47.5) 93 (61.6) Smoking status, n (%) 0.803 Never 769 (46.0) 699 (46) 70 (46.4) Current 261 (15.6) 235 (15.5) 26 (17.2) Former 641 (38.4) 586 (38.6) 55 (36.4) Hypertension, n (%) 0.359 No 588 (35.2) 540 (35.5) 48 (31.8) Yes 1083 (64.8) 980 (64.5) 103 (68.2) CHD, n (%) < 0.001 No 1250 (74.8) 1156 (76.1) 94 (62.3) Yes 421 (25.2) 364 (23.9) 57 (37.7) WBC (×10 9 /L) 7.5 ± 2.2 7.5 ± 2.1 7.8 ± 2.6 0.048 Lymphocyte (×10 9 /L) 2.2 ± 0.9 2.2 ± 0.9 2.1 ± 0.9 0.078 Monocyte (×10 9 /L) 0.6 ± 0.2 0.6 ± 0.2 0.6 ± 0.2 0.132 CRP 0.3 (0.2, 0.8) 0.3 (0.2, 0.7) 0.4 (0.2, 0.9) 0.076 Glucose (mmol/L) 8.3 ± 4.0 8.2 ± 3.9 9.5 ± 5.0 < 0.001 HGB (g/dL) 14.1 ± 1.6 14.1 ± 1.6 13.6 ± 1.6 < 0.001 HbA1C (%) 7.4 ± 1.8 7.4 ± 1.8 7.7 ± 2.2 0.039 Total cholesterol (mmol/L) 5.3 ± 1.3 5.3 ± 1.3 5.1 ± 1.1 0.108 HDL (mmol/L) 1.2 ± 0.4 1.2 ± 0.4 1.3 ± 0.4 0.37 Abbreviations : OR, odds ratio; CI, confidence interval; BMI, body mass index; CHD, chronic heart disease; WBC, white blood cell count; CRP, C-reactive protein; HGB, hemoglobin; HbA1C, glycohemoglobin; HDL, high-density lipoprotein cholesterol. Table 2 . Multivariate analysis for the presence of PLEU number of PLEU OR 95%CI p -value with PN without PN Model 1 127/1 018 24/653 3.74 (2.39~5.85) <0.001 Model 2 127/1 018 24/653 3.79 (2.41~5.95) <0.001 Model 3 127/1 018 24/653 3.59 (2.27~5.68) <0.001 Model 4 127/1 018 24/653 3.09 (1.95~4.92) <0.001 Abbreviations : PN, peripheral neuropathy; PLEU, persistent lower extremity ulcer; OR, odds ratio; CI, confidence interval; BMI, body mass index; CHD, chronic heart disease; WBC, white blood cell count; CRP, C-reactive protein; HGB, hemoglobin; HbA1C, glycohemoglobin; HDL, high-density lipoprotein cholesterol. Model 1: unadjusted. Model 2: adjusted for sociodemographic variables (sex, age, race/ethnicity, marital status and educational level). Model 3: further adjusted for BMI, smoking status, hypertension and CHD. Model 4: further adjusted for WBC, lymphocyte, monocyte, CRP, glucose, HGB, HbA1C, HDL and total cholesterol Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3974995","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":274243129,"identity":"219a0632-6967-49fb-b9a3-df6128fc4fa6","order_by":0,"name":"Zirui Li","email":"","orcid":"","institution":"Affiliated Hospital of Zunyi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zirui","middleName":"","lastName":"Li","suffix":""},{"id":274243130,"identity":"d5f8f595-107c-4ea1-a167-761cec8541fe","order_by":1,"name":"Zairong Wei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYFACxgYIzcx84MCHH6RpYUs8OLOHNOt4jA9zsBGhTr79cNuHjztqE/vZeT4cZuBhkOcXO0DAWT2JzTNnnjmeOLOZd8PhAgsGw5mzE/BrYWZIbGbmbTuWu+EwUMsMHoYEg9sEtLDxP4Ro2X+Y58FhHjYitPBIgG2pyd3AzMNAnBYJiYfNjDPbDtTPOMxmAAxkCcJ+ke9Pf8zwsa3OmL//8OMPH37YyPNLE9ACBYfhthKlHATqiFY5CkbBKBgFIxAAAJWtRUVTgT0OAAAAAElFTkSuQmCC","orcid":"","institution":"Affiliated Hospital of Zunyi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Zairong","middleName":"","lastName":"Wei","suffix":""}],"badges":[],"createdAt":"2024-02-21 08:48:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3974995/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3974995/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51566194,"identity":"75fb4a77-7234-4c07-b810-ad9d3f152b1d","added_by":"auto","created_at":"2024-02-23 19:11:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":123794,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow diagram\u003c/p\u003e\n\u003cp\u003eNHANES, National Health and Nutrition Examination Survey\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3974995/v1/d45204d43873697034f2a6d3.png"},{"id":51566539,"identity":"74d4131a-7795-4e52-8bcb-b4f8634e9309","added_by":"auto","created_at":"2024-02-23 19:19:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":185076,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis.\u003c/p\u003e\n\u003cp\u003eAbbreviations : PN, peripheral neuropathy; OR, odds ratio; CI, confidence interval; CHD, chronic heart disease.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3974995/v1/2c4436a81e565609e746cf54.png"},{"id":51566193,"identity":"6bef71f2-1c81-45ec-8dc4-2c559d00a5e8","added_by":"auto","created_at":"2024-02-23 19:11:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":302041,"visible":true,"origin":"","legend":"\u003cp\u003eRelative influence factor of covariates.\u003c/p\u003e\n\u003cp\u003eThe relative influence factor measures how discriminative the 18 covariates of the propensity score model are when predicting the likelihood of peripheral neuropathy performance. IPTW, Inverse Probability of Treatment Weighting.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3974995/v1/731357d4544b7f4a032e5e63.png"},{"id":51566192,"identity":"8dea547e-bfcd-4a85-954c-0b757810a365","added_by":"auto","created_at":"2024-02-23 19:11:20","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":147675,"visible":true,"origin":"","legend":"\u003cp\u003eAssociations between PN analysis and PLEU in the crude analysis, multivariable analysis, and propensity-score analyses.\u003c/p\u003e\n\u003cp\u003ePN, peripheral neuropathy; PLEU, persistent lower extremity ulcer; OR, odds ratio; CI, confidence interval; IPTW, inverse probability of treatment weighting.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3974995/v1/40c345b22578160a502e0efd.png"},{"id":51761269,"identity":"9a06e7e4-690b-4b65-a5f6-bbb7f8f0e73d","added_by":"auto","created_at":"2024-02-28 16:29:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1090237,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3974995/v1/813c1855-9dd3-4aeb-b6bd-a7e31bdc0669.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Peripheral neuropathy significantly increases the risk of persistent lower extremity ulcers in individuals with diabetes in the United States: a cross-sectional study based on National Health and Nutrition Examination Survey data","fulltext":[{"header":"Background","content":"\u003cp\u003eDiabetes is a chronic metabolic disorder affecting millions of people worldwide [1], and its prevalence is increasing in developed and developing countries [2]. Peripheral neuropathy (PN) is a common complication of diabetes [3], affecting a significant\u0026nbsp;proportion of individuals with diabetes in the\u0026nbsp;United States [4]. PN is characterized by damage to\u0026nbsp;the peripheral nerves, resulting in impaired sensation, muscle weakness, and loss of reflexes [5].\u003c/p\u003e\n\u003cp\u003eLower extremity ulcers are a major health concern in the diabetic population [6] because they can result in chronic wounds, infections, and even amputation\u0026nbsp;[7]. One of the major consequences of PN is an increased risk of lower extremity ulcers, which can lead to significant morbidity and mortality in individuals with diabetes [8, 9]. However, the specific role of PN in increasing the risk of persistent lower extremity ulcers (PLEUs) in this population has not been well elucidated.\u003c/p\u003e\n\u003cp\u003eThis observational study aimed to investigate the association between PN and PLEU in patients with diabetes. The findings of this study may contribute to the development of evidence-based guidelines for the prevention and management of PN and PLEU, ultimately improving the quality of life in individuals with diabetes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHealth and nutritional data were gathered from American individuals as part of the National Health and Nutrition Examination Survey (NHANES). Participants completed questionnaires on their histories and habits and underwent physical and laboratory examinations. Researchers, decision-makers, and healthcare professionals utilize these data to better understand health issues, identify patterns and inequities, and promote nutrition and public health.\u003c/p\u003e\n\u003cp\u003eFor our analysis, we used open data from three NHANES cycles (1999\u0026ndash;2000, 2001\u0026ndash;2002, and 2003\u0026ndash;2004). To participate in the survey, the participants were required to submit a blood test. In-person interviews conducted at participants\u0026rsquo; homes were also used to gather data on basic demographics and medical histories.\u003c/p\u003e\n\u003cp\u003eA stratified multistage probability survey was used in the NHANES research to assess the health and nutritional status of noninstitutionalized Americans [10]. A mobile examination center conducted home visits, screenings, and laboratory tests as part of the NHANES to gather detailed demographic and health data. The NHANES research was approved by the National Center for Health Statistics Ethics Review Committee, and all participants provided written informed consent. No additional Institutional Review Board permission was required for secondary analysis [11]. The NHANES website (http://www.cdc.gov/nchs/nhanes.htm) provides access to the NHANES data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome and variables\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePLEUs were identified using questionnaires that evaluated the\u0026nbsp;\u0026gt;4-week\u0026nbsp;presence of non-healing ulcers in the lower limbs of individuals with diabetes. PN was assessed using self-reported symptoms and by testing foot sensation\u0026nbsp;with a standard monofilament (5.07-gauge Semmes‒Weinstein nylon), according to a standard protocol [12]. Health technicians applied pressure via the monofilament at three sites (plantar, first metatarsal head; plantar, fifth metatarsal head; and plantar, hallux) at the bottom of each foot, resulting in a total of six sites. The monofilament was applied until it buckled and held for 1 s. A site was considered inflated if the participant incorrectly met the criteria for two of the three monofilament applications. Impaired sensation was quantified by the total number of insensate areas in both feet,\u0026nbsp;which ranged from zero to six. PN was defined as the presence of at least one insensate area. During the interview, participants were asked whether they had experienced numbness, loss of feeling, painful sensations, or tingling of their feet in the last 3 months. PN cases were defined as those\u0026nbsp;who reported \u0026ldquo;yes\u0026rdquo; to this question [13].\u003c/p\u003e\n\u003cp\u003eQuestionnaires were used to assess a history of physician-diagnosed hypertension, sex, age, race/ethnicity, marital status, smoking status, and education level. Participants were classified as married, living with a partner, or living alone based on\u0026nbsp;a marital questionnaire. Smoking status was classified as never smoked (\u0026lt;100 cigarettes smoked in a lifetime), former smoker (\u0026gt;100 cigarettes smoked in a lifetime, but no longer smoking),\u0026nbsp;or current smoker (\u0026gt;100 cigarettes smoked in a lifetime and currently smoking). Educational level was\u0026nbsp;classified into different groups (\u0026lt;9, 9\u0026ndash;12, and \u0026ge;12 years). Participants were divided into normal, overweight, and obese groups based on body mass index (BMI) (\u0026lt;25.0, 25.0\u0026ndash;29.9, and \u0026ge;30.0 kg/m\u003csup\u003e2\u003c/sup\u003e, respectively). The determination of previous disease (hypertension or chronic heart disease [CHD]) status was based on whether the doctor had been informed of the patient\u0026rsquo;s condition in the past. Other covariates included white blood cell (WBC) count (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L), lymphocyte count (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L), monocyte count (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L), C-reactive protein (CRP), glucose (mmol/L), hemoglobin (HGB, g/dL), glycohemoglobin (HbA1C, %), high-density lipoprotein cholesterol (HDL, mmol/L) and total cholesterol (mmol/L).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe statistical software packages R 3.3.2 (http://www.R-project.org, The R Foundation) and Free Statistics Software version 1.8 were used for all analyses. Demographic and clinical characteristics are expressed as means, standard deviations, and frequencies (percentages). Differences between continuous and categorical data were examined using independent and chi-squared tests, respectively. Binary logistic regression analysis was used to examine the relationship between PN and PLEU. Single- and multiple-variable analyses were conducted. We constructed four models for multivariate logistic regression: (1) Model 1: unadjusted; (2) Model 2: adjusted for sociodemographic variables (sex, age, race/ethnicity, marital status, and education level; (3) Model 3: adjusted for sociodemographic variables and variables reflecting overall health status, including BMI, smoking status, hypertension, and CHD; and (4) Model 4: adjusted for age, sex, marital status, race/ethnicity, education level, BMI, smoking status, hypertension, CHD, WBC, lymphocyte count, CRP, glucose, HGB, HbA1C, HDL cholesterol, and total cholesterol. A subgroup analysis was also conducted to examine the association between PN and PLEU, considering factors such as sex, age (\u0026lt;60 years, \u0026ge;60 years), hypertension, and CHD. A multivariate logistic regression model was used for analysis. A logistic regression model interaction test was performed to examine the odds ratios (ORs) between the subgroups. In the sensitivity analysis, we used propensity score matching (PSM) to minimize the effects of confounding variables, which might have led to outcome bias [14]. The following variables were used to generate the propensity score with a caliper width of 0.01 and a one-to-one closest neighbor matching algorithm: age, sex, marital status, race/ethnicity, education level, BMI, smoking status, hypertension, CHD, WBC, lymphocyte, monocyte, CRP, glucose, HGB, HbA1c, HDL, and total cholesterol. The degree of PSM was measured using standardized mean difference. A value of \u0026lt;0.1 was considered acceptable. The inverse probability of treatment weighting (IPTW) model was utilized to produce a weighted cohort using the calculated propensity scores as weights. The propensity score was adjusted using univariate logistic regression. On average, \u0026lt;5% of the variable data were missing, and the missing data were removed.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSelected participants and baseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study collected data from three NHANES cycles: 1999\u0026ndash;2000, 2001\u0026ndash;2002, and 2003\u0026ndash;2004. The initial pool of potential participants comprised 31,126 individuals. From this pool, 21,156 participants aged \u0026lt;40 years, 8,110 participants without diabetes, 187 participants with missing PLEU data, and two participants with missing PN data were excluded. A total of 1,671 participants were included in the analysis. \u003cstrong\u003eFigure 1\u003c/strong\u003e presents the inclusion and exclusion criteria with a flowchart outlining the participant selection process. \u003cstrong\u003eTable 1\u003c/strong\u003e summarizes the baseline characteristics of the patients with and without PLEU in terms of demographic and socioeconomic factors, comorbidities, and laboratory metrics. Of the 1,671 included participants, 151 (9.04%) were identified as having PLEU. Statistical analysis revealed significant differences in marital status, BMI, CHD incidence, WBC, glucose, HGB, and HbA1c levels between the PLEU and non-PLEU groups (p\u0026lt;0.05). Specifically, compared with the non-PLEU group, the PLEU group had a significantly greater proportion of individuals living alone (p=0.023), a greater proportion of individuals with obesity (p=0.002), a greater proportion of individuals with CHD (p\u0026lt;0.001), a higher WBC count (p=0.048), a greater glucose level (p\u0026lt;0.001), a higher HbA1c level (p=0.039), and a lower HGB level (p\u0026lt;0.001).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMultivariate logistic regression between PN and the presence of PLEU\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, we constructed four models to analyze the independent effects of PN on PLEU. The effect sizes (ORs) and 95% confidence intervals (CIs) are shown in \u003cstrong\u003eTable 2\u003c/strong\u003e. According to the unadjusted model (Model 1), PN was significantly associated with the occurrence of PLEU (OR=3.74, 95% CI=2.39\u0026ndash;5.85, p\u0026lt;0.001). The model-based effect size indicated that, for participants with PN, the risk of PLEU increased by 274%. In Model 2, after adjusting for sex, age, race/ethnicity, marital status, and education level, the presence of PLEU increased by 279% for the population with PN (OR=3.79, 95% CI=2.41\u0026ndash;5.95, p\u0026lt;0.001). After adjusting for BMI, smoking status, hypertension, and CHD incidence, the OR was 3.59 (95% CI=2.27\u0026ndash;5.68, p\u0026lt;0.001) in Model 3. According to the fully adjusted model (Model 4) (adjusted for all covariates presented in \u003cstrong\u003eTable 1\u003c/strong\u003e), for participants with PN, the risk of PLEU increased by 209% compared with that of participants without PN (OR=3.09, 95% CI=1.95\u0026ndash;4.92, p\u0026lt;0.001).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe also conducted subgroup analyses to examine variables that may affect the association between PN and the presence of PLEU. We used sex, age (\u0026lt;60, \u0026ge;60 years), hypertension, and CHD as stratification variables to observe the trend of effect sizes in these subgroups (\u003cstrong\u003eFigure 2\u003c/strong\u003e). The effect size of PN on the occurrence of PLEU was consistent across all subgroups. No statistically significant interactions were observed between PN and sex (p for interaction=0.648), age (p for interaction=0.685), hypertension (p for interaction=0.888), or CHD (p for interaction=0.358) in the presence of PLEU.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the sensitivity analysis, to minimize the bias of confounding factors, we generated a propensity score for\u0026nbsp;the logistic regression.\u0026nbsp;Eighteen variables were initially used to create the propensity score model.\u0026nbsp;\u003cstrong\u003eFigure 3\u003c/strong\u003e illustrates the contributions of individual factors to the final propensity score. CHD, hypertension, age, and HGB level\u0026nbsp;were the top variables. IPTW was used to normalize the differences between the PN and non-PN cohorts based on the estimated propensity scores. A regression model was developed to adjust for unbalanced covariates in the weighted cohort. In the original cohort, 12.48% (127/1,018) and 3.68% (24/653) of the PLEUs were detected in the PN and non-PN groups, respectively\u0026nbsp;(Table 2). IPTW was associated with a significantly greater risk of PLEU in the PN group (OR=3.15, 95%\u0026nbsp;CI=2.04\u0026ndash;4.88, p\u0026lt;0.001). After the patients were adjusted for propensity score and matched, the results were stable, and the ORs were 3.03 (95% CI=1.92\u0026ndash;4.78, p\u0026lt;0.001) and 3.14 (95% CI=1.93\u0026ndash;5.11, p\u0026lt;0.001), respectively (\u003cstrong\u003eFigure 4\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings of this retrospective cross-sectional study based on the NHANES data provide valuable insights into the relationship between PN and the risk of PLEU in individuals with diabetes in the United States.This study highlights the significant impact of PN on PLEU risk, emphasizing the need for early detection and intervention in individuals with diabetes.\u003c/p\u003e\n\u003cp\u003eOur findings demonstrated a significant relationship between these two variables, consistent with previous research.\u0026nbsp;Previous studies have consistently reported an association between PN and the development of lower extremity ulcers. Neuropathic changes in\u0026nbsp;the peripheral nerves, particularly in\u0026nbsp;patients\u0026nbsp;with diabetes, can lead to a loss of protective sensation and altered biomechanics,\u0026nbsp;increasing\u0026nbsp;the susceptibility\u0026nbsp;to foot trauma and subsequent ulceration [15]. More than half of patients with diabetes and PN develop foot ulcers during their lifetime [16]. Furthermore, individuals with PN have a greater risk of developing persistent or chronic lower extremity ulcers than those without neuropathic changes. This could be attributed to the impaired healing process and increased vulnerability to infections as a result of sensory and autonomic nerve damage associated with PN [17, 18]. In addition, our findings align with those of other studies that demonstrated the effect of PN on the recurrence of lower extremity ulcers. Previous research has indicated that PN leads to an increased risk of ulcer recurrence due to ongoing sensory loss and mechanical abnormalities that predispose individuals to foot trauma and subsequent ulceration [19].\u003c/p\u003e\n\u003cp\u003eThe findings of this observational study provide significant evidence supporting an association between PN and PLEU. The pathophysiological mechanisms underlying this relationship can be attributed to several factors. First, PN leads to loss of protective sensation, thereby increasing the risk of trauma and injury to the lower extremities [20]. The diminished ability to perceive pain and pressure results in prolonged, unnoticed injuries, which can develop into persistent ulcers. This finding is supported by previous research\u0026nbsp;demonstrating that individuals\u0026nbsp;with neuropathy are more susceptible to developing chronic wounds\u0026nbsp;because of their inability to detect and respond to harmful stimuli [21]. Second, PN causes motor and autonomic dysfunction, leading to diminished muscle strength and impaired blood flow to the lower extremities [22]. This compromises the healing process and exacerbates persistent ulcer formation. Reduced muscle function impairs the body\u0026rsquo;s ability to offload pressure from vulnerable areas,\u0026nbsp;thereby contributing to developing chronic wounds [23]. Additionally,\u0026nbsp;PN is associated with impaired immune function, leading to increased susceptibility to infection and delayed wound healing [24]. The compromised immune response in individuals with neuropathy contributes to the chronicity of lower extremity ulcers, as infections further hinder the healing process and perpetuate the existence of wounds [25]. Furthermore, altered biomechanics and gait abnormalities associated with PN contribute to PLEU formation [26]. Unstable gait patterns and abnormal foot mechanics increase the likelihood of pressure points and friction,\u0026nbsp;thereby predisposing individuals\u0026nbsp;with neuropathy to chronic ulceration [27].\u003c/p\u003e\n\u003cp\u003eHowever, it is important to acknowledge the limitations of this study. First, PN and PLEU data were collected only from the NHANES between 1999 and 2004. This made it impossible to further validate the use of the NHANES data from different periods. Second, even with regression models, stratified analysis, and sensitivity analysis, the residual confounding effects of unmeasured or unknown factors could not be completely excluded. Third, these findings were derived from a survey of American adults, and further research is required to determine whether these findings can be generalized to other populations. Fourth, relying on self-reported data for diagnosing PN and PLEU might have introduced bias and underreporting. Finally, the cross-sectional design of this study prevented us from establishing a causal relationship between PN and PLEU. Longitudinal studies are required to examine the temporal relationships between these variables.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis observational study provides robust evidence supporting the significant association between PN and the risk of PLEU in individuals with diabetes in the United States. Further research is needed to establish a causal relationship between these variables and explore potential interventions to reduce the burden of lower extremity ulcers in this population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eBMI,\u0026nbsp;\u003c/strong\u003ebody mass index;\u003cstrong\u003e\u0026nbsp;CHD,\u0026nbsp;\u003c/strong\u003echronic heart disease;\u003cstrong\u003e\u0026nbsp;CI,\u0026nbsp;\u003c/strong\u003econfidence interval;\u003cstrong\u003e\u0026nbsp;CRP,\u0026nbsp;\u003c/strong\u003eC-reactive protein;\u003cstrong\u003e\u0026nbsp;HbA1C,\u0026nbsp;\u003c/strong\u003eglycohemoglobin;\u003cstrong\u003e\u0026nbsp;HDL,\u0026nbsp;\u003c/strong\u003ehigh-density lipoprotein cholesterol; \u003cstrong\u003eHGB,\u003c/strong\u003e hemoglobin; \u003cstrong\u003eIPTW,\u0026nbsp;\u003c/strong\u003einverse probability of\u0026nbsp;treatment weighting;\u003cstrong\u003e\u0026nbsp;NHANES,\u0026nbsp;\u003c/strong\u003eNational Health and Nutrition Examination Survey;\u003cstrong\u003e\u0026nbsp;OR,\u0026nbsp;\u003c/strong\u003eodds ratio;\u003cstrong\u003e\u0026nbsp;PN,\u0026nbsp;\u003c/strong\u003eperipheral neuropathy;\u003cstrong\u003e\u0026nbsp;PLEU,\u0026nbsp;\u003c/strong\u003epersistent lower extremity ulcer; \u003cstrong\u003ePSM,\u003c/strong\u003e propensity score matching; \u003cstrong\u003eWBC,\u003c/strong\u003e white blood cell.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThe\u0026nbsp;NHANES research was approved by the National Center for Health Statistics Ethics Review Committee, and all participants provided written informed consent. No additional Institutional Review Board permission was required for secondary analysis. The NHANES website (http://www.cdc.gov/nchs/nhanes.htm) provides access to the NHANES data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003ePublicly available datasets are available online for this study. The repository/repositories name and accession numbers are available online at http://www.cdc.gov/nchs/nhanes.htm\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study was supported by the Collaborative Innovation Center of Chinese Ministry of Education (2020-39) ; and the Scientific and Technological Innovation Talent Team of Wound Surgery Integrated Treatment of Guizhou Province (Talents Science Cooperation Platform of Guizhou, No. 2020-5012) ; and the Constructive Project of Innovative Talent Platform Carrier for Precise Repair of Wounds (Talents Science Platform of Zunyi city, No. 2021-3) ; and the Scientific Research and Talent Training Funds of Kweichow Moutai Hospital (MTYK, No.2022-13); and the Shanghai Wang Zhengguo Trauma Medicine Development Foundation (SZYZ-TR-05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eLi and Wei: contributed to the conception or design of the work; Li: conducted the study, analyzed data and wrote the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eWe thank Dr. Jie Liu (People\u0026rsquo;s Liberation Army of China General Hospital, Bei-jing, China) for helping with this revision.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRedondo MJ, Hagopian WA, Oram R, Steck AK, Vehik K, Weedon M, et al. The clinical consequences of heterogeneity within and between different diabetes types. Diabetologia. 2020 Oct;63(10):2040\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eChavda VP, Ajabiya J, Teli D, Bojarska J, Apostolopoulos V. Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review. Molecules. 2022 Jul 5;27(13):4315. \u003c/li\u003e\n\u003cli\u003eGandhi M, Fargo E, Prasad-Reddy L, Mahoney KM, Isaacs D. Diabetes: how to manage diabetic peripheral neuropathy. Drugs Context. 2022;11:2021-10\u0026ndash;2. \u003c/li\u003e\n\u003cli\u003eHicks CW, Wang D, Windham BG, Matsushita K, Selvin E. Prevalence of peripheral neuropathy defined by monofilament insensitivity in middle-aged and older adults in two US cohorts. Sci Rep. 2021 Sep 27;11(1):19159. \u003c/li\u003e\n\u003cli\u003eMarchettini P, Lacerenza M, Mauri E, Marangoni C. Painful Peripheral Neuropathies. CN. 2006 Jul 1;4(3):175\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eDepartment of Surgery, Faculty of Medicine- Omar Almukhtar University, Alshallwi AM. Evaluation of Risk factors in diabetic foot ulcers patient as predictors of lower extremity amputation: a hospital-based case control study. jmscr [Internet]. 2019 Sep 4 [cited 2023 Nov 19];7(9). Available from: http://jmscr.igmpublication.org/v7-i9/21%20jmscr.pdf\u003c/li\u003e\n\u003cli\u003eGao H, Yi Y. Association of Monocyte to Lymphocyte, Neutrophil to Lymphocyte, and Platelet to Lymphocyte Ratios With Non-Healing Lower Extremity Ulcers in Patients With Type 2 Diabetes. The International Journal of Lower Extremity Wounds. 2023 Sep 13;15347346231197884. \u003c/li\u003e\n\u003cli\u003eAdler AI, Boyko EJ, Ahroni JH, Smith DG. Lower-extremity amputation in diabetes. The independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers. Diabetes Care. 1999 Jul 1;22(7):1029\u0026ndash;35. \u003c/li\u003e\n\u003cli\u003eLehmann HC, Wunderlich G, Fink GR, Sommer C. Diagnosis of peripheral neuropathy. Neurol Res Pract. 2020 Dec;2(1):20. \u003c/li\u003e\n\u003cli\u003eZipf G, Chiappa M, Porter KS, Ostchega Y, Lewis BG, Dostal J. National health and nutrition examination survey: plan and operations, 1999-2010. Vital Health Stat 1. 2013 Aug;(56):1\u0026ndash;37. \u003c/li\u003e\n\u003cli\u003eUS Department of Health \u0026amp; Human Services. Office of Extramural Research. Available online: http://grants.nih.gov/grants/policy/hs/hs_policies.htm (accessed on 1 September 2023). \u003c/li\u003e\n\u003cli\u003eNational Center for Health Statistics: NHANES 1999\u0026ndash;2000 data release (June 2002): lower extremity disease exami- nation (LEX), MEC examination [article online], 2003. Available from http://www.cdc.gov/nchs/data/nhanes/ie.pdf. Accessed 1 September 2023. \u003c/li\u003e\n\u003cli\u003eGregg EW, Sorlie P, Paulose-Ram R, Gu Q, Eberhardt MS, Wolz M, et al. Prevalence of lower-extremity disease in the US adult population \u0026gt;=40 years of age with and without diabetes: 1999-2000 national health and nutrition examination survey. Diabetes Care. 2004 Jul;27(7):1591\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eZhang Z. Propensity score method: a non-parametric technique to reduce model dependence. Ann Transl Med. 2017 Jan;5(1):7\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eBoulton AJM, Armstrong DG, Albert SF, Frykberg RG, Hellman R, Kirkman MS, et al. Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care. 2008 Aug;31(8):1679\u0026ndash;85. \u003c/li\u003e\n\u003cli\u003eBoulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. The Lancet. 2005 Nov;366(9498):1719\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eBoulton AJM, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, et al. Diabetic Neuropathies. Diabetes Care. 2005 Apr 1;28(4):956\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eToth C, Hebert V, Gougeon C, Virtanen H, Mah JK, Pacaud D. Motor unit number estimations are smaller in children with type 1 diabetes mellitus: A case\u0026ndash;cohort study. Muscle and Nerve. 2014 Oct;50(4):593\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eNajafi B, Mishra R. Harnessing Digital Health Technologies to Remotely Manage Diabetic Foot Syndrome: A Narrative Review. Medicina (Kaunas). 2021 Apr 14;57(4):377. \u003c/li\u003e\n\u003cli\u003eReeves ND, Orlando G, Brown SJ. Sensory-Motor Mechanisms Increasing Falls Risk in Diabetic Peripheral Neuropathy. Medicina (Kaunas). 2021 May 8;57(5):457. \u003c/li\u003e\n\u003cli\u003ePatel S, Mittal R, Felix ER, Sarantopoulos KD, Levitt RC, Galor A. Differential Effects of Treatment Strategies in Individuals With Chronic Ocular Surface Pain With a Neuropathic Component. Front Pharmacol. 2021;12:788524. \u003c/li\u003e\n\u003cli\u003eAndersen H, Nielsen S, Mogensen CE, Jakobsen J. Muscle strength in type 2 diabetes. Diabetes. 2004 Jun;53(6):1543\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eB\u0026aacute;nv\u0026ouml;lgyi A, G\u0026ouml;r\u0026ouml;g A, Gad\u0026oacute; K, Holl\u0026oacute; P. Chronic wounds in the elderly: Decubitus, leg ulcers, and ulcers of rare aetiology. DHS. 2022 Jul 5;4(4):81\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eChandra D. Effect of Hyperglycemia on Immune Function. AIBM [Internet]. 2018 Aug 31 [cited 2024 Jan 5];10(4). Available from: https://juniperpublishers.com/aibm/AIBM.MS.ID.555792.php\u003c/li\u003e\n\u003cli\u003eGangwar R, Sahu PK, Rao KT, Supraja P, Tripathy S, Subrahmanyam C, et al. Electrochemical Investigation of TLR4/MD-2-Immobilized Polyaniline and Hollow Polyaniline Nanofibers: Toward Real-Time Triaging of Gram-Negative Bacteria Responsible for Delayed Wound Healing. IEEE Sens Lett. 2023 Dec;7(12):1\u0026ndash;4. \u003c/li\u003e\n\u003cli\u003eHazari A, Maiya AG, Shivashankara KN, Agouris I, Monteiro A, Jadhav R, et al. Kinetics and kinematics of diabetic foot in type 2 diabetes mellitus with and without peripheral neuropathy: a systematic review and meta-analysis. Springerplus. 2016;5(1):1819. \u003c/li\u003e\n\u003cli\u003eKorkusuz S, Se\u0026ccedil;kinoğulları B, Y\u0026uuml;r\u0026uuml;k Z\u0026Ouml;, Uluğ N, Kibar S. Balance and gait in individuals with diabetic peripheral neuropathy. Neurological Research. 2023 Sep 15;46(1):14\u0026ndash;22. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003eBaseline characteristics of the study participants\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.144329896907216%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.02061855670103%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePersistent lower extremity ulcer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003e\u003cstrong\u003e(n=1 671)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo (n=1 520)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003e\u003cstrong\u003eYes (n=151)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e64.8 \u0026plusmn; 11.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e64.8 \u0026plusmn; 11.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e64.9 \u0026plusmn; 11.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.912\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.197\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e857 (51.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e772 (50.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e85 (56.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e814 (48.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e748 (49.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e66 (43.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRace/ ethnicity, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.461\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eNon-Hispanic white\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e687 (41.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e628 (41.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e59 (39.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eNon-Hispanic black\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e391 (23.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e355 (23.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e36 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eMexican American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e462 (27.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e414 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e48 (31.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e131 ( 7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e123 (8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e8 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMarital status, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eMarried or living with a partner\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e997 (59.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e920 (60.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e77 (51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eLiving alone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e674 (40.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e600 (39.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e74 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eEducation level (years), n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.941\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u0026lt;9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e472 (28.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e431 (28.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e41 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e9\u0026ndash;12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e684 (40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e622 (40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e62 (41.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u0026gt;12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e515 (30.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e467 (30.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e48 (31.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eUnderweight/ normal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e254 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e232 (15.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e22 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eOverweight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e602 (36.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e566 (37.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e36 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eObese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e815 (48.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e722 (47.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e93 (61.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking status, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.803\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eNever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e769 (46.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e699 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e70 (46.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eCurrent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e261 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e235 (15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e26 (17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eFormer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e641 (38.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e586 (38.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e55 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypertension, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.359\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e588 (35.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e540 (35.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e48 (31.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e1083 (64.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e980 (64.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e103 (68.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCHD, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e1250 (74.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e1156 (76.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e94 (62.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e421 (25.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e364 (23.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e57 (37.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eWBC (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e7.5 \u0026plusmn; 2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e7.5 \u0026plusmn; 2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e7.8 \u0026plusmn; 2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.048\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymphocyte (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e2.2 \u0026plusmn; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e2.2 \u0026plusmn; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e2.1 \u0026plusmn; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.078\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMonocyte (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e0.6 \u0026plusmn; 0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e0.6 \u0026plusmn; 0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e0.6 \u0026plusmn; 0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.132\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCRP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e0.3 (0.2, 0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e0.3 (0.2, 0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e0.4 (0.2, 0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.076\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlucose (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e8.3 \u0026plusmn; 4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e8.2 \u0026plusmn; 3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e9.5 \u0026plusmn; 5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHGB (g/dL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e14.1 \u0026plusmn; 1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e14.1 \u0026plusmn; 1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e13.6 \u0026plusmn; 1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHbA1C (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e7.4 \u0026plusmn; 1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e7.4 \u0026plusmn; 1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e7.7 \u0026plusmn; 2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal cholesterol (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e5.3 \u0026plusmn; 1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e5.3 \u0026plusmn; 1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e5.1 \u0026plusmn; 1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.108\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.541666666666664%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHDL (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e1.2 \u0026plusmn; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e1.2 \u0026plusmn; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e1.3 \u0026plusmn; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations : OR, odds ratio; CI, confidence interval; BMI, body mass index; CHD, chronic heart disease; WBC, white blood cell count; CRP, C-reactive protein; HGB, hemoglobin; HbA1C, glycohemoglobin; HDL, high-density lipoprotein cholesterol.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e Multivariate analysis for the presence of PLEU\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.36082474226804%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003enumber of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePLEU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e95%CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.36363636363637%\"\u003e\n \u003cp\u003e\u003cstrong\u003ewith PN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.63636363636363%\"\u003e\n \u003cp\u003e\u003cstrong\u003ewithout PN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\"\u003e\n \u003cp\u003e127/1 018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.742268041237114%\"\u003e\n \u003cp\u003e24/653\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\"\u003e\n \u003cp\u003e3.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\"\u003e\n \u003cp\u003e(2.39~5.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\"\u003e\n \u003cp\u003e127/1 018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.742268041237114%\"\u003e\n \u003cp\u003e24/653\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\"\u003e\n \u003cp\u003e3.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\"\u003e\n \u003cp\u003e(2.41~5.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\"\u003e\n \u003cp\u003e127/1 018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.742268041237114%\"\u003e\n \u003cp\u003e24/653\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\"\u003e\n \u003cp\u003e3.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\"\u003e\n \u003cp\u003e(2.27~5.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\"\u003e\n \u003cp\u003e127/1 018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.742268041237114%\"\u003e\n \u003cp\u003e24/653\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\"\u003e\n \u003cp\u003e3.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\"\u003e\n \u003cp\u003e(1.95~4.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations : PN, peripheral neuropathy; PLEU, persistent lower extremity ulcer; OR, odds ratio; CI, confidence interval; BMI, body mass index; CHD, chronic heart disease; WBC, white blood cell count; CRP, C-reactive protein; HGB, hemoglobin; HbA1C, glycohemoglobin; HDL, high-density lipoprotein cholesterol.\u003c/p\u003e\n\u003cp\u003eModel 1: unadjusted.\u003c/p\u003e\n\u003cp\u003eModel 2: adjusted for sociodemographic variables (sex, age, race/ethnicity, marital status and educational level).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eModel 3: further adjusted for BMI, smoking status, hypertension and CHD.\u003c/p\u003e\n\u003cp\u003eModel 4: further adjusted for WBC, lymphocyte, monocyte, CRP, glucose, HGB, HbA1C, HDL and total cholesterol\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Peripheral neuropathy, Lower extremity ulcer, Diabetes mellitus, National Health and Nutrition Examination Survey, Cross-sectional study","lastPublishedDoi":"10.21203/rs.3.rs-3974995/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3974995/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLower extremity ulcers are a major health concern in the diabetic population as they can result in chronic wounds, infection, and amputation. Previous studies have shown that one of the major consequences of peripheral neuropathy (PN) is an increased risk of lower extremity ulcers, which can lead to significant morbidity and mortality in individuals with diabetes. However, the specific role of PN in increasing the risk of persistent lower extremity ulcers (PLEU) in this population has not been well elucidated. We aimed to examine and establish a connection between PN and PLEU in individuals with diabetes in the United States.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA cross-sectional study was conducted using the National Health and Nutrition Examination Survey data from 1999 to 2004 for participants aged ≥40 years with a diagnosis of diabetes. PLEU was defined based on questionnaires assessing the presence of non-healing ulcers in the lower extremities for \u0026gt;4 weeks in patients with diabetes. PN was defined as numbness, loss of sensation, painful sensations, tingling in one’s feet in the last 3 months or ≥1 area of no sensation based on monofilament testing. Logistic regression analysis was performed to assess the relationship between PN and PLEU.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 1,671 participants were included (1,018 and 653 participants with and without PN, respectively). The overall prevalence of PLEU was 9% (151/1,671), whereas it was 12.5% (127/1,018) and 3.7% (24/653) in PN and non-PN participants, respectively. We found that PN was associated with a 274% greater incidence of PLEU (odds ratio [OR]=3.74, 95% confidence interval [CI]=2.39–5.85, p\u0026lt;0.001) compared with participants without PN. After adjusting for potential confounders, PN was associated with a 209% higher incidence of PLEU (OR=3.09, 95% CI=1.95–4.92, p\u0026lt;0.001) compared with participants without PN. The results remained stable based on our subgroup analyses and propensity score matching.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePN is significantly associated with PLEU in patients with diabetes in the United States.\u003c/p\u003e","manuscriptTitle":"Peripheral neuropathy significantly increases the risk of persistent lower extremity ulcers in individuals with diabetes in the United States: a cross-sectional study based on National Health and Nutrition Examination Survey data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-23 19:11:12","doi":"10.21203/rs.3.rs-3974995/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"385d9c4c-2a19-4bd6-b232-4aa96a25aa91","owner":[],"postedDate":"February 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-02-28T16:21:00+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-23 19:11:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3974995","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3974995","identity":"rs-3974995","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}