This study aimed to investigate the association of the cardiovascular risk burden assessed by the Framingham General Cardiovascular Risk Score (FGCRS) with the trajectories of motor function over time and to assess the mediating effects of cardiovascular diseases (CVDs) accumulation and cognitive decline in such association.In Rush Memory and Aging Project, a total of 1,378 physical health participants (mean age: 79.3 ± 7.3 years) were followed up for up to 22 years. FGCRS at baseline was assessed and categorized into tertiles . Global motor function  was assessed annually with 10 motor tests. CVDs  were ascertained at baseline and follow-ups, and the number of CVDs accumulation over time was assessed. Global cognitive function was tested annually by 19 tests. Data were analyzed using the linear mixed-effects models and mediation analysis.At baseline, FGCRS ranged from 4 to 28 (mean score: 15.6 ± 3.7). Over the follow-up , in multi-adjusted mixed-effects models, the highest FGCRS was associated with faster decline in global motor function , dexterity , gait , and hand strength  compared with the lowest tertile. In mediation analysis, CVDs accumulation and cognitive decline mediated 8.4% and 42.9% of the association between FGCRS and global motor function over time, respectively.Higher cardiovascular risk burden is associated with a faster decline in motor function including dexterity, gait, and hand strength. CVDs accumulation and cognitive decline may partially mediate the association between cardiovascular risk burden and global motor function decline. Population aging is accelerating worldwide, while the size of the elderly population and its share of the total population are growing rapidly . MeanwhiA number of studies have demonstrated that single cardiovascular risk factors, such as smoking , hyperteMany studies have shown that people with higher FGCRS are at increased risk of CVDs , 13 and The Rush Memory and Aging Project (MAP) is an ongoing longitudinal prospective cohort study on the decline in cognition and motor function in the elderly. The MAP study's design and evaluation protocol were described in detail previously . In brieOf all participants, 814 participants including 573 participants with missing data on FGCRS, 260 participants with a disability in basic activities of daily living (ADL) at study entry, and 462 participants with missing data on global motor function at baseline or during follow-up were excluded. Finally, a total of 1,378 participants were admitted to this study .https://www.radc.rush.edu for more information on the data.Rush Memory and Aging Project received approval from the Rush University Medical Center's Institutional Review Board . In accoEach participant obtained a uniform comprehensive clinical evaluation including detailed medical histories, thorough physical examination, and systematic function tests by trained staff at the time of enrollment and follow-up . Data onEducation level was obtained based on the maximum years of regular schooling (range: 3–28 years) . AlcoholParticipants sat with their arms at heart level and had their blood pressure measured two times at 5-min intervals on their right arm by trained research assistants using a mercury sphygmomanometer, and the average of the two measurements was recorded as the blood pressure value. Hypertension was considered as systolic blood pressure (SBP) ≥140 mm Hg, diastolic blood pressure (DBP) ≥90 mm Hg, or the use of antihypertensive medications.Blood samples were taken from all the participants, and total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and blood glucose levels were measured by a professional diagnostic company . DiabeteActivities of daily living was a composite measure of disability using the Katz ADL Scale, which measured six basic physical abilities, namely, eating, dressing, bathing, toileting, getting from bed to chair, and walking across a small room .Following the Framingham General Cardiovascular Risk Prediction Model, we assessed and calculated the FGCRS at baseline for each participant based on the information on age, sex, current smoking status, SBP, antihypertensive medication use, diabetes mellitus, TC, and HDL cholesterol , 2 9). . 9). AllCardiovascular diseases encompassed congestive heart failure, stroke, and other heart diseases including heart attack or coronary, coronary thrombosis, coronary occlusion, and myocardial infarction. Stroke events were obtained based on a clinician review of self-reported questions, neurological examination (if available), cognitive testing, and interviews with participants. Information on congestive heart failure was obtained from self-reports by asking participants if they had been told that they had congestive heart failure since the date of the last interview by a doctor, nurse, or therapist. Information related to other heart diseases was obtained in the same manner as above except for the questions revolved. The three categories of stroke, congestive heart failure, and other heart diseases were dichotomized as present and absent at baseline and follow-ups, and CVD events accumulation was summed as the number of CVDs (range: 0–3).A battery of 21 cognitive performance tests was used to assess cognitive function at baseline and at each follow-up. Of the 21 tests, the Mini-Mental State Examination (MMSE) was used primarily to describe the cohort but not for analysis, while another test named Complex Ideational Material was only used for diagnostic classification. The remaining 19 tests, namely, Word List Memory, Word List Recall, Word List Recognition, immediate and delayed recall of the East Boston Story and Story A from Logical Memory, Boston Naming Test, Category Fluency, National Adult Reading Test, Digit Span Forward and Backward, Digit Ordering, Symbol Digit Modalities Test, Number Comparison, word reading and color naming from a modified version of the Stroop Neuropsychological Screening Test, Judgment of Line Orientation, and the Standard Progressive Matrices, were used to construct a summary measure of global cognitive function .z-scores, which were averaged to yield a global cognition score if more than half of the z-scores were not missing. The score describes the extent to which a point deviates from the mean or a specific point, while higher global cognition scores indicate better global cognitive function.The raw scores of each cognitive performance test were converted to A comprehensive measure of global motor function including subcomponents of dexterity, gait, and hand strength was evaluated by a 10-item motor function test at baseline and at each follow-up visit.Motor dexterity is a combined measure consisting of two motor tests, namely, the Purdue pegboard test and the finger-tapping test. Participants were asked to place pegs into the holes of a pegboard (Purdue Pegboard) within 30 s and to tap an electronic tapper with their index finger as fast as possible for 10 s. The above trials were performed two times for each hand separately. The average of the number of pegs placed into the pegboard and the number of taps by each participant in four trials yielded a Purdue Pegboard score and a tapping score, respectively.motor gait, we asked participants to walk a distance of 8 feet two times and turn 360° two times, recording the time and number of steps required for each test. The two measurements for each test were averaged to provide the following performance scores: walking time, walking steps, turning time, and turning steps.To evaluate Hand strength was composed of two tests, namely, grip strength and pinch strength. We measured participants' grip and pinch strength two times for each hand using the Jamar hydraulic hand and pinch dynamometers . The average of the four trials for each test represented the performance scores for grip and pinch strength in terms of pounds of pressure. Balance was assessed by asking participants to stand on each leg and their toes for 10 s each.raw scores for each of the above 10 tests were converted to z-scores, and the results of all motor tests were averaged together to construct a global motor function score.The To compare the differences of the baseline characteristics among three groups of participants by FGCRS tertiles, one-way ANOVA or Kruskal-Wallis rank-sum test was used for numerical variables, and the chi-square test was used for categorical variables.The β-coefficients and 95% confidence intervals (CIs) for the association between cardiovascular risk burden  and annual changes in global motor function and the three specific motor functions were estimated using linear mixed-effects models with follow-up time (years) as the time scale. The fixed effect included cardiovascular risk burden, follow-up time, and their interactions. The random effect included random slopes and intercepts, allowing for the individual differences at baseline and across follow-up.To test and quantify the mediating role of CVDs accumulation and cognitive decline in the association between FGCRS and changes in motor function, we performed a mediation analysis in two independent models using the bootstrapping methods. Linear mixed-effects models were used to test the three pathways of the mediation analysis: (1) the association between FGCRS and changes in motor function ; (2) the association between FGCRS and CVDs accumulation or cognitive decline; and (3) the association between CVDs accumulation or cognitive decline and changes in motor function, controlling for FGCRS. The mediating role was significant if the bias-corrected 95% CI of the indirect effects estimated by bootstrapping did not include zero .Education, BMI, alcohol consumption, physical activity, social activity, baseline number of CVDs, and baseline global cognitive function as potential confounders were adjusted in the linear mixed-effects models and mediation analysis.In the sensitivity analysis, we excluded 382 participants who had dementia at baseline and during the follow-up because some components of FGCRS and CVDs were based on self-report. Linear mixed-effects models and mediation analysis were repeated in the above populations severally.P-value < 0.05 was considered statistically significant for each test. All statistical analyses were performed using Stata SE 15.0 .A two-tailed n = 1,378; mean age: 79.3 ± 7.3 years; 73.5% female participants), FGCRS ranged from 4 to 28 (mean score: 15.6± 3.7) at baseline, and 530 (38.5%) participants had the lowest FGCRS, 412 (29.9%) participants had middle tertile, and 436 (31.6%) participants had the highest tertile.Among all participants  and motor dexterity  when FGCRS was used as a continuous variable. When FGCRS was used as tertiles, participants with the highest tertile had poorer motor dexterity  compared to those with the lowest tertile .Over the 22 years of follow-up , in multi-adjusted mixed-effects models, increased FGCRS as continues variable was dose-dependently related to global motor function , dexterity , gait , and hand strength  decline, respectively. β denoted the rate of accelerated decline in motor function per 1-score change in FGCRS per year.Compared with the lowest FGCRS, the highest FGCRS was associated with faster decline in global motor function , dexterity , gait , and hand strength  over the follow-up time .In the mediation analysis, the direct effect of FGCRS on changes in global motor function was diminished when the changes in the number of CVDs  and global cognition  were added to the model separately. In mediating effect models, 8.4% of the association between FGCRS and global motor function was mediated by CVDs accumulation, and 42.9% was mediated by changes in cognitive function during follow-up .Similar results to the initial analysis were obtained in the linear mixed-effects models and mediation analysis when we excluded 382 participants with dementia at baseline and during the follow-up period . FurtherIn this prospective community-based cohort study, we found that (1) higher FGCRS is associated with a faster decline in global motor function, dexterity, gait, and hand strength over time; and (2) CVD accumulation (about 8.4%) and cognitive decline (about 42.9%) partially mediated the association between FGCRS and motor function decline.The relationship between single cardiovascular risk factors  and motor function decline has been reported in many studies –33. As cFrom the perspective of life course epidemiology, one type of the chains of risk models is that each exposure not only has an independent impact on the risk of diseases but also increases the risk of subsequent exposures leading to changes in health outcomes . It has There are two pathways that may explain the link between cardiovascular risk burden and motor function decline. First, cardiovascular risk factors  are traditional risk factors for atherosclerosis, which is a major component of cardiovascular diseases . AtherosAs a community-based longitudinal cohort study, this study presents several strengths. We followed participants with a relatively large sample size for up to 22 years annually. Furthermore, we assessed cardiovascular risk burden by FGCRS as exposure and evaluated comprehensibly global motor function and its subcomponents by a battery of 10 tests over the yearly follow-up. However, some limitations need to be pointed out. First, participants were recruited from the community as volunteers with generally good education and performed well on cognitive tests; thus, the representativeness of the findings was limited, and the observed associations were likely to be underestimated. Moreover, the study participants were in good living conditions with regular medical supervision, and thus, caution is needed when generalizing our findings to other populations. Second, CVD events were assessed based on retrospective self-reports, which may have contributed to information bias leading to underestimation of the given association. Third, information on specific medications used for the treatment of CVD was not available, and thus, the role of CVD-related drug use in the association between FGCRS and motor functions could not be assessed. Finally, potential confounders such as occupational characteristics and medical histories of brain trauma could not be considered due to data.In conclusion, this study provides evidence of the association between cardiovascular risk burden assessed by the FGCRS and trajectories of mobility and hand strength in aging. The accumulation of CVDs and cognitive decline may partially mediate the relationship between cardiovascular risk burden and changes in motor function. Our findings emphasize the importance of monitoring and controlling cardiovascular risk to prevent both CVDs and cognitive decline in order to slow down the progression of motor impairments and disability among older adults.https://www.radc.rush.edu.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The Rush Alzheimer's Disease Center Resource Sharing Hub, The studies involving human participants were reviewed and approved by Rush University Medical Center's Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.ZW and KC: performed statistical analysis, drafting the article. RS and XL: analysis and interpretation of data. XQ and AB: revising the article critically for important intellectual content. DB and WX: conception and design, major role in the acquisition of data, final approval of the version to be published. All authors contributed to the article and approved the submitted version.WX received grants from the Swedish Research Council (Nos. 2017-00981 and 2021-01647), the Swedish Council for Health Working Life and Welfare (No. 2021-01826), the National Natural Science Foundation of China (No. 81771519), Alzheimerfonden (No. 2021-2022), Karolinska Institutet Research Foundation (No. 2020-01660), Lindhés Advokatbyrå AB (No. 2021-0134), Stiftelsen För Gamla Tjänarinnor (No. 2021-2022) and Demensfonden. Bennett received grants from the National Institutes of Health (R01AG17917 and UH2NS100599).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The purpose of this study was to assesses the effectiveness of proactive and reactive methods in the recruitment of Black and Latino adolescents into a vaping-prevention randomized controlled trial (RCT). This study also assessed the characteristics of study participants by recruitment method. Proactive recruitment strategies included study presentations at community-based events , school-based events , and recreational centers . Reactive recruitment strategies included study advertisements via social media , word of mouth, and an academic-based research hub. Using proactive and reactive methods, in a 4-month period, 362 Black and Latino adolescents were successfully enrolled into the RCT. Compared to the proactive method, adolescents screened reactively were equally likely to be eligible but significantly more likely to enroll in the study. However, both proactive and reactive strategies made notable contributions to the overall recruitment effort. Moreover, proactive and reactive methods attracted adolescents with different characteristics . These findings suggest that both proactive and reactive recruitment strategies should be implemented for studies interested in recruiting a diverse sample of Black and Latino adolescents. Adolescence (ages 10 to 19 years) ,3,4,5. ADespite the potential adverse effects and high prevalence of e-cigarette use among adolescents, there is limited research on effective strategies in the scope of prevention. Moreover, the limited research on vaping prevention is hampered by methodological limitations, such as the underrepresentation of Black and/or Latino individuals, a lack of multi-modal recruitment strategies, and scarce reporting of recruitment data. Examples from the available literature include one study assessing different message themes to prevent vaping among adolescents and young adults . RecruitLiterature on the recruitment of Black and Latino individuals into tobacco-control  studies have described the use of different recruitment methods ,24,25,26ClincialTrials.gov (NCT04899999).We conducted a randomized controlled trial (RCT) to assess the impact of theoretical-based graphic messages at preventing vaping among 362 Black and Latino adolescents. The graphic messages were developed using participatory research methods and incorporate four main theoretical constructs: health reward, financial reward, self-efficacy, and social norms . ParticiRecruitment was conducted by a team of diverse , bilingual (English and Spanish), trained recruiters. Recruitment started in August 2021 and ended in December 2021. Proactive recruitment strategies included study presentations supported by a display table at community-based events , school-based events , and recreational centers . At the end of each study presentation, recruiters asked individuals if they were interested in participating in the RCT. The proactive recruitment strategies mostly took place in Hackensack, New Jersey, and Rochester, New York. U.S. Census Bureau data for the city of Hackensack, New Jersey, indicate lower proportions of White (49.7% vs. 72.1%) and more African American/Black (24.1% vs. 15.0%) as well as Hispanic/Latino (36.3% vs. 20.4%) residents than statewide, more residents speaking languages other than English at home (48.6% vs. 31.0%), and those living in poverty (12.3% vs. 10.0%) . U.S. CeReactive recruitment strategies included study advertisements via social media , word of mouth, and an academic-based research hub . UR Health Research connects individuals to clinical trials, promotes research findings, and educates the community about health research. No paid online advertisements via social media  were used.Individuals who were interested in participating in the study received two informational letters, namely one addressed to the adolescent and the other to the parents/caregivers. The informational letters (available in Spanish and English) described the study, explained the benefits and risks, and included the study team contact information. Once the parents/caregivers received and reviewed the informational letter, they were instructed to contact the study team via electronic email or phone call. Research staff then scheduled a phone call with interested parents/caregivers to obtain permission for their adolescent to participate. During the phone call, the research team discussed all aspects of study participation and confidentiality and answered any questions. Parents/caregivers and adolescents were informed that they were free to decline study participation and end their involvement at any time without negative consequences. Once the parents/caregivers gave verbal permission for their adolescent to participate, study staff contacted the adolescent to conduct the eligibility assessment. Individuals were eligible if they (1) self-identified as African American/Black and/or Hispanic/Latino, (2) knew how to read and speak English and/or Spanish, (3) were at least 12 but no greater than 17 years old, (4) had never used e-cigarettes, and (5) had access to a device that would allow them to connect to the online survey . Exclusion criteria included (1) not identifying as African American/Black and/or Hispanic/Latino and (2) currently using e-cigarettes. Eligibility assessment was conducted by study staff in the adolescent’s language of preference: either English or Spanish.Adolescents who were eligible to participate in the study received a unique link to REDCap, a secure web application for building and managing online surveys and databases . ThroughAll assessments were completed in the participants’ language of preference, either English or Spanish. Assessments were adapted from surveys used in previous studies and pre-tested for survey administration among the study team . The basFor each recruitment method, characteristics of enrolled participants were summarized with percentages for categorical variables and with means and standard deviations (SD) for continuous variables. Rates of eligibility and enrollment across the two recruitment methods were compared using chi-square tests. Differences in categorical variables were exploratorily compared using Pearson’s chi-square tests or Fisher exact test, while differences in continuous variables were compared using one-way ANOVA tests or Nonparametric Wilcoxon test depending on data distributions. Logistic regressions were used to estimate relative risks and 95% confidence intervals to measure the (1) association between recruitment method and the likelihood of obtaining eligible individuals among screened individuals and the (2) association between recruitment method and the likelihood of enrolling the screened participants. Intention-to-treat (ITT) was applied for missing data, and all analyses were performed in SPSS 14.0.n = 204, 56.4%) compared to the proactive recruitment strategies . p = 0.29) but statistically significantly more likely to enroll in the study .Of the 408 individuals who completed screening, 401 (98.2%) met eligibility criteria, and 362 (88.7%) enrolled in the RCT. Most participants were enrolled via reactive recruitment strategies ; 50% of participants self-identified as African American/Black, and 50% self-identified as Hispanic/Latino . Almost p < 0.001). Latino participants were significantly more likely to be recruited proactively compared to their non-Latino counterparts (p < 0.001). Participants recruited reactively were older (p < 0.001), more likely to be male (p < 0.001), more likely to be heterosexual, more likely to select English as their language of preference (p < 0.001), more likely to be currently employed (p = 0.019), and more likely to be susceptible to future vaping (p = 0.027) compared to participants recruited proactively.In a 4-month period, 362 Black and Latino adolescents were successfully enrolled into an RCT testing the impact of theoretical-based graphic messages at preventing future vaping. To the best of our knowledge, this is the first study to describe the effectiveness of diverse strategies for identifying and recruiting Black and Latino adolescents into a vaping-prevention RCT. This study compared proactive and reactive recruitment strategies on eligibility and enrollment rates. Results of this study show that compared to the proactive method, adolescents screened reactively were equally likely to be eligible but significantly more likely to enroll in the study. However, both proactive and reactive strategies made notable contributions to the overall recruitment effort.The overall greater enrollment efficiency of reactive strategies compared to proactive strategies is consistent with other tobacco-control research among Black and Latino adults ,24,35,36personalismo (preference for warm relationships that convey care and acceptance of participants and their circumstances), simpatía , respeto (respect), confianza (trust), and familismo  [In this study, proactive and reactive methods attracted adolescents with different characteristics. Black adolescents were significantly more likely to be recruited reactively compared to proactively. This result is consistent with previous studies indicating that, among Black adults, reactive recruitment is the most successful recruitment method in tobacco-control  studies ,35,36. Iendence) ,43. In this study, female participants were significantly more likely to be recruited via proactive strategies compared to reactive strategies. This result is consistent with other studies that have found that proactive approaches are successful to recruiting female adolescents from minority backgrounds ,45. MoreThe study team included Black and Latino researchers and staff. Thus, factors that contributed to recruitment success may include race, ethnicity, and language matching of research staff to both parents/caregivers and adolescents. In addition, recruitment efforts involved close partnership with key leaders of the Black and Latino communities, and study materials were culturally relevant and language appropriate. As recommended by Rhodes et al., emphasizing the study uniqueness was a vital recruitment tactic . RecruitThis study adds valuable insights to the expanding literature on vaping prevention. Study results demonstrate that it is feasible to recruit Black and Latino adolescents—two traditionally hard-to-reach groups—into a vaping-prevention RCT. These findings provide evidence of Black and Latino adolescents being interested in participating in vaping-prevention research if recruited in a culturally and linguistically appropriate manner. Proactive and reactive methods attracted adolescents with different characteristics . An appreciation of these differences is important, as this information could be utilized to tailor recruitment strategies for Black and Latino adolescents. This study is timely given that Black and Latino adolescents are often underrepresented in tobacco-control studies, and this study suggests that 55% of them are susceptible to future vaping. Moreover, Black and Latino communities have a history of being targeted by the tobacco industry ,57. For To the best of our knowledge, this is the first study to purposely focus on African American/Black and Hispanic/Latino adolescents for a vaping-prevention RCT. It is important to acknowledge that in the U.S., African American/Black is typically assessed as a race and Hispanic/Latino as an ethnicity and that these groups are not mutually exclusive. In this study, we did not encounter participants who self-identified as both African American/Black and Hispanic/Latino.One of the strengths of this study and a possible facilitator of recruitment is that this research builds upon our established history of smoking-cessation treatment and research within the community ,62,63,64Another strength of the study is the use of proactive and reactive methods for recruitment. The design of the study allowed us to isolate and determine the unique contribution of each recruitment approach while tracking critical denominators to calculate both eligibility and enrollment efficiency. The inclusion of Spanish-speaking participants is another study strength: 18% of participants in this study selected Spanish as their language of preference. Despite these strengths, the current study has several methodological limitations. First, this study was not designed to test the efficiency of recruitment strategies. Given the broad reach of our channels, it is possible that participants were exposed to multiple strategies. It is also possible that individuals responding reactively may have been exposed to a prior or concomitant proactive strategy. Therefore, some cross-contamination effect cannot be ruled out. Lastly, we did not conduct a cost effectiveness analysis in this study because we did not track total costs and time spent. Moreover, the study relied on volunteers and the support of CBOs. We acknowledge that an essential component in determining the effectiveness of one recruitment method over another is to consider the costs and time spent. For example, the high eligibility and enrollment efficiency ratios of social media in this study are very promising given that no paid online advertisements  were used. Moreover, the study flyer that was shared on social mediums was designed by the research staff and not a professional graphic designer. In contrast, all proactive recruitment strategies demanded staff resources, and results were mixed. For example, one recruiter (R.H.O.) attended one event at the Boys and Girls Club of Rochester—a local recreational center—for one hour. At this event, the recruiter identified 12 individuals who were interested in participating in the RCT. All 12 individuals were eligible to participate in the RCT and enrolled in the study; the eligibility and enrollment efficiency ratios of this particular event were both 100%. Another example was a back-to-school event organized by the Eugenio María de Hostos Charter School. Two recruiters (R.H.-T. and A.P.C.) attended the 4-hour event and identified 22 individuals who were interested and eligible to participate in the RCT (eligibility efficiency ratio of 100%). Of the 22 individuals, 13 were enrolled in the study (enrollment efficiency ratio was 59%). A third example was a community-based event at the International Plaza of the City of Rochester to celebrate Hispanic Heritage Month. Two recruiters (R.H.O. and A.C.-I.) attended the 3-hour event and did not identify a single individual who was interested in participating in the study.Using proactive and reactive methods, a heterogeneous sample of Black and Latino adolescents was enrolled in a vaping-prevention RCT. Compared to the proactive method, adolescents screened reactively were equally likely to be eligible but significantly more likely to enroll in the study. However, both proactive and reactive strategies made notable contributions to the overall recruitment effort. Moreover, proactive and reactive methods attracted adolescents with different characteristics . These findings suggest that both proactive and reactive recruitment strategies should be implemented for studies interested in recruiting a diverse sample of Black and Latino adolescents.


In ROC curve analysis, the AUC difference between Rater I and Rater II was 0.024 (0.726 vs. 0.702). In multivariate analysis, high-risk VFL was positively related to unilateral plaque localization (p = 0.003), the type III VLE classification (p = 0.013), absence of a mucosal wave (p = 0.034), and a positive history of alcohol consumption (p = 0.047). In ROC analysis, VLE had an AUC of 0.726, with a high sensitivity of 95.7% and low specificity of 40.8%. The NPV was high, at 93.9%; however, the PPV was low, at 50%. The proposed logistic regression model including features significant in multivariate analysis showed lower sensitivity (80.9% vs. 95.7%) and lower NPV (86.2% vs. 93.9%); however, the specificity and PPV were improved . Conclusions: The combination of clinical history with endoscopic (plaque morphology) and stroboscopic examination  can fairly estimate the degree of dysplasia in VFL and thus is recommended for use in clinical settings. The findings of this study can be used to guide the decision regarding immediate biopsy or watchful waiting.Background: Vocal fold leukoplakia (VFL), despite our knowledge of its etiopathogenetic factors, and the development of laryngeal visualization, remains a diagnostic and therapeutic challenge. Objective: This research aimed to explore the efficacy of clinical and morphological feature identification in videolaryngoendoscopy (VLE) using a three-tier classification, and videolaryngostroboscopy (VLS) in predicting the risk of VFL malignant transformation. Material and Methods: We examined 98 patients with VFL by flexible endoscopy under VLE and VLS. Morphological characteristics of 123 lesions including the surface, margin, and texture were assessed; then, VFL was subdivided into three types: I—flat and smooth, II—elevated and smooth, and III—rough. Based on the histopathological findings, 76 (61.79%) lesions were classified as low- and 47 (38.21%) lesions as high-grade dysplasia. Results: The inter-rater agreement between two raters evaluating the VFL in VLE was almost perfect (Cohen’s kappa = 0.826;  One of the most common precancerous lesions in otolaryngological practice is vocal fold leukoplakia (VFL). The term “vocal fold leukoplakia” refers to thick whitish or grey patches without regard to their histological features and without implying any histological or prognostic information ,2,3. TheThe lesions can be either exophytic or flat, depending on the thickness of the keratin layer of the epithelium . As the The average age of diagnosis of VFL is 50 years. The incidence reported in the USA is generally higher in males than in females, with 10.2 and 2.1 lesions per 100,000, respectively ,10. The The underlying etiologies for the development of leukoplakia patches or plaques are long-term smoking and alcohol abuse, inhaled irritant substances, and viral infections such as HPV . Other pVFL has a malignancy transformation rate of approximately 8% . Around Since survival significantly depends on the stage of detection of disease, it is important to focus early on the pathogenesis of laryngeal carcinoma at the precancerous or leukoplakic stage, to begin suitable therapy. Clinical diagnosis is made by imaging the larynx, and subsequently, by sampling the tissue, usually in the operating room. Histopathology has traditionally been used and is essential to determine the presence and degree of dysplasia in tissue samples .The last two decades have seen major technological advancement in endoscopic methods, which has resulted in improved resolutions of images, contrast enhancement, magnification, and special filters for better exposure of the vascular structure of the mucosa. These high-quality digital systems, distal chips, and a filtered spectrum of light have improved the clinical accuracy in distinguishing between benign and malignant lesions. Videolaryngoendoscopy (VLE) remains the most widely used method for laryngeal examination. It relies on an analysis of a lesion’s visible morphological features. Specific morphological characteristics can vary and can be subtle, particularly in the early stages of the disease. As a result, any suspicious lesion is often biopsied for a definitive histopathological diagnosis. It should be noted that many of the characteristics are nonspecific and can be mimicked by benign pathologies, resulting in a significant number of unnecessary biopsies. Hence, several visualization techniques and technologies have been put forward to improve the diagnostic accuracy of physical examination of suspicious lesions, including VFL . It is bAlong with new visualization techniques, in recent years, several studies have reported laryngeal leukoplakia classification using morphological characteristics ,21,22,23The presented research aimed to predict the degree of VFL and assess the risk of its malignant transformation using clinical features, videolaryngoendoscopy, and videolaryngostroboscopy. The efficacy of this newest classification method, based on the assessment of morphological features, supplemented with stroboscopy, had not previously been studied extensively.The study included 98 patients, comprising 19 women (19.39%) and 79 men (80.61%) aged from 38 to 85 (mean age 62.18), with clinically diagnosed vocal fold leukoplakia. Among the sample, 73 patients presented with unilateral VFL and 25 patients with bilateral VFL. In total, 123 cases of VFL were diagnosed. The patients were examined at the Otolaryngology, Head and Neck Oncology Department of the Medical University of Lodz from April 2015 to September 2020. The inclusion criteria were diagnosed VFL, no prior vocal fold-related medical intervention or procedure , and preoperative endoscopic assessment by VLE and VLS. The exclusion criterion was the disqualification of the patient from direct laryngoscopy with the collection of material for histopathological examination, e.g., when conservative treatment or work with a speech therapist could reduce pathological changes in the larynx. Furthermore, patients who had previously had surgical interventions with the vocal fold or were diagnosed with leukoplakia in a location other than the glottis were not included in the study. Patients who could not be operated on due to severe systemic diseases were excluded, as well. Approval for this study was granted by the Ethical Committee of the Medical University of Lodz  and informed consent was obtained from each patient before their inclusion.The medical history was gathered for each patient including their age, gender, lifestyle habits , and comorbidities. The endoscopic examination was performed using a transnasal flexible video endoscope with an LED light  by an experienced team of otorhinolaryngologists. After VLE examination, the endoscope mode was switched to VLS. The patients were examined while in the sitting position after the application of nasal cavity anesthesia. Topically applied lidocaine spray was administered in the throat if necessary (in the case of patients with strong gag reflex). The endoscope was inserted through the wider nasal cavity.Morphological classification of VFL was performed according to the protocol proposed by Chen et al. (2019). Two laryngologists  blinded to the patients’ identities and pathological results concurrently but independently assessed the lesions. Morphological characteristics including the surface, margin, and texture were recorded; then, vocal fold leukoplakia was subdivided into three types: I—flat and smooth, II—elevated and smooth, and III—rough . Types IThe patients underwent phonosurgical treatment of their leukoplastic lesions to remove the lesions, and we verified the findings of the endoscopic assessment using a histopathological examination. All patients underwent surgical removal of the lesions under general anesthesia by endotracheal intubation. The final diagnosis was established based on histopathological examinations of the specimens. The morphology of vocal fold leukoplakia was compared with the respective histopathological (HP) diagnosis. Leukoplakia was divided into two types: (1) low-grade dysplasia (squamous hyperplasia or mild dysplasia); (2) high-grade dysplasia  .p-value of 0.05 was considered statistically significant.Data were analyzed using the STATISTICA 13.1 software . Continuous variables were tested for normality using the Shapiro–Wilk test. To compare independent groups, a Kruskal–Wallis non-parametric ANOVA was conducted with Dunn’s post hoc test. In all statistical tests, a two-tailed The sensitivity, specificity, and positive and negative predictive values were calculated, and an optimal cut-off value was established based on the receiver operating curve (ROC) analysis .Cohen’s kappa index (κ) was used to assess the inter-rater agreement between two physicians evaluating the endoscopic images, along with the intra-rater agreement for both Rater I and Rater II. We used Landis and Koch’s commonly applied guidelines to interpret Cohen’s κ: (κ) 0.00–0.20 indicates slight agreement, (κ) 0.21–0.40 fair agreement, (κ) 0.41–0.60 moderate agreement, (κ) 0.61–0.80 substantial agreement, and (κ) 0.81–1.00 almost perfect agreement .p-value < 0.05.The univariate and multivariate analysis was performed using logistic regression, the results of which are presented in a format suggested by Peng et al. . To perfp = 0.025; therefore, the variable was non-linear. Age was then categorized into dichotomic categories and included in further analysis. A mixed-effects logistic regression model was constructed to model a binary outcome of 0: low-risk leukoplakia, 1: high-risk leukoplakia. The predictive ability of the model was validated using the V-fold cross-validation method with 10 subsets of data. The goodness-of-fit of the model was evaluated with the Hosmer–Lemeshow test.The variables were checked for interactions and linearity of predictors using the LR test. No interactions between variables were detected. The linearity test result for age was There were 123 cases of VF leukoplakia from 98 examined patients who met the inclusion and exclusion criteria. In terms of localization of the lesions, unilateral vocal fold leukoplakia was diagnosed in 73 patients (74.49%) and bilateral vocal fold leukoplakia in the remaining 25 patients (25.51%). Based on the histopathological findings 76 (61.79%) lesions were classified as low-grade dysplasia and 47 (38.21%) lesions as high-grade dysplasia. Demographic and clinical data are presented in p < 0.001), 95%CI . In ROC curve analysis for both observers, the AUC difference between Rater I and Rater II was 0.024 (0.726 vs. 0.702); therefore, in further results, we only report ROC curve parameters from Rater I.The inter-rater agreement between two raters evaluating the VFL in white light endoscopy according to Chen’s classification from 2019 was almost perfect, with Cohen’s kappa = 0.826 , but for the comparison of the morphological types elevated and smooth vs. rough, the results were statistically non-significant (p = 1.0).In the results from both raters , signifiThe VLE classification according to Chen (2019) and mucosal wave in the VLS were evaluated twice, once for an initial evaluation, then subsequently during anonymized video playback. The results are presented in p < 0.001), and a history of alcohol consumption  was associated with a three-fold increase in the odds of developing a malignancy  was associated with a 5.081 times greater increase in the probability of developing high-risk VFL.p < 0.001)-fold increase in the odds of malignant transformation.The absence of a mucosal wave in a VLS examination can be considered a risk factor, with an 8.75 ; however, these observations were not found to improve the overall predictive capabilities of the multivariate logistic regression model.An important predictor in VLE analysis could be the involvement of the inferior surface of the vocal fold (p < 0.001).The type III VLE classification was most strongly associated with an increased risk of cancer within leukoplakia plaque  were not associated with a statistically significant greater chance of malignant transformation within VFL.p = 0.003), the type III VLE classification (p = 0.013), absence of a mucosal wave (p = 0.034), and a positive history of alcohol consumption (p = 0.047). Moreover, the odds of malignant transformation developing within leukoplakia plaque in unilateral changes were 5.458 times greater than in bilateral VFL. This finding was confirmed by the positive coefficient (1.697) associated with the leukoplakia localization predictor.According to the model, the log of the odds of high-risk leukoplakia was positively related to unilateral plaque localization  compared to flat or elevated plaque but with a smooth surface (Type I and II). Confirmation of this observation may be derived from the positive regression coefficient of 2.231. Moreover, the absence of a mucosal wave is correlated with 4.479 times greater odds of developing high-risk VFL. Finally, considering the patient’s history, alcohol consumption is associated with a 3.357 times higher risk of developing a malignancy. The results of multivariate analysis are presented in To determine an individual’s predisposition to high-risk leukoplakia , a logistic regression equation was plotted taking into account characteristics with independent prognostic significance for the occurrence of high-grade leukoplakia .−logit(p)). For example, the IPHRL for a patient not consuming alcohol, with diagnosed unilateral Type III leukoplakia in VLE, without a preserved mucosal wave, is 50.42%. Alternatively, the presence of all features with a significant influence increases the risk of developing high-risk leukoplakia to 77.35%.The individual predisposition to high-risk leukoplakia (IPHRL) was determined by the formula: IPHRL = 1/, improves the clinical utility of VLE morphological classification and shows improved diagnostic performance. The AUC of this model is higher (0.861). This model shows a lower sensitivity (80.9% vs. 95.7%) and NPV (86.2% vs. 93.9%), but the specificity and PPV are improved .Vocal cord leukoplakia is a clinical diagnosis regarded as a precancerous condition . One of VLE plays the main role in the diagnosis of patients with laryngeal diseases and, to date, is the most widely used diagnostic tool in the assessment of premalignant lesions or cancer of the larynx . Beyond There are several reports on the clinical classification of vocal fold leukoplakia. Fang et al. 2016) aimed to establish a scoring system by combining clinical demographic and laryngoscopic characteristics, to improve the management of VFL. They classified lesions based on their morphology, including the color, texture, size, hyperemia, thickness, and symmetry . Li et a016 aimedYet, there are some limitations to the described classifications. While the classification by Fang et al., is very detailed, it may be difficult to incorporate this form of VFL assessment into daily clinical practice as it requires detailed analysis of six particular aspects of the VFL morphology. Thus, the assessment is time-consuming and should be performed by a specialist with substantial experience. The classification by Lee et al., in contrast, is short and easy to perform in daily clinical practice, but as the authors admit, it is based only on the texture of the lesions, and it mainly reflects the evolutional process of vocal cord leukoplakia from early- to late-stage .In 2019, a new classification was proposed by Chen et al., based on morphological characteristics of leukoplakia. At the time when we set out to conduct this study, there has been no research exploring its efficacy. The authors of the present study examined 98 patients with 123 vocal fold lesions to evaluate the diagnostic value of the Chen (2019) classification. We used the correlation between the results of the morphological assessment and histological diagnosis to assess the clinical applicability of the newly proposed classification for everyday clinical practice. We have demonstrated its usefulness in daily clinical practice and identified type III patients as significantly at risk of cancer with the VFL. VLE was used to assess the morphological structure of leukoplakia based on the proposed three-tier classification. The authors tried to determine to what extent each of the three morphological aspects, namely the surface, margin, and texture of the lesion, should be considered to accurately determine the presence of malignancy or lack thereof.p < 0.001). In the original study by Chen et al. [p < 0.001). Our improved agreement confirms that the examined classification is, as the authors intended, both simple and comprehensive.Although VLE plays an essential role in the diagnosis of vocal cord diseases, even for experienced doctors, it is difficult to distinguish benign lesions from malignant lesions . Nonethen et al. , that agRicci and Isenberg reported that approximately 50% of patients with a clinical diagnosis of vocal fold leukoplakia do not have dysplasia, making a point that these patients receive unnecessary surgical treatment . Our resIn the original study by Chen et al. , the autp < 0.001) with the histopathological results [In our study, several factors were taken into account  but the  results .Although cigarette smoking was entered into multivariable modeling, it was ultimately removed due to the lack of significance in this dataset. This obviously does not exclude smoking as a risk factor or undermine its importance. It was likely not significant because 87% of the studied group were smokers, making the non-smoking group too small to provide a suitably good reference with enough statistical power for smoking to reach significance.Even though a vast number of publications have confirmed noninvasive biological endoscopy, such as narrow-band imaging (NBI) and Storz SPIES ,35,36,37The above-mentioned methods are very useful tools, but they require additional, cost-incurring equipment and the learning curve is relatively long , while VIt should be underlined that in a great number of institutions, VLE is still the only method at clinicians’ disposal. Hence, the application of the proposed scoring system for VLE could help ensure timely detection of leukoplakia lesions with malignant transformation potential and thereby prevent unnecessary surgery. Given that a histological classification can only be made after excising lesions, and severe hoarseness may occur post-surgery, it is important to identify preoperative factors and classify lesions before excision, and in this way, decrease the incidence of such complications .The research presented here had some limitations. Our goal was to present a ready-to-use, effective tool in daily clinical practice. In the future, this could be extended with biological endoscopy methods; however, it should be kept in mind that they require a long learning curve and equipment availability.Vocal fold leukoplakia can be classified according to the plaque morphology, distinguishing three types: flat and smooth, elevated and smooth, and rough. This classification, despite being a subjective method of assessment, seems to be consistent between independent raters.Morphological types of VFL correlate with the degree of histopathological advancement—type III according to Chen (2019) is the predictor of malignant transformation. For institutions that do not have NBI at their disposal, the analyzed classification is a helpful diagnostic tool for assessing precancerous lesions as it allows for accurate detection of benign lesions. Localization of the lesions to one vocal fold, absence of a mucosal wave, an alcohol consumption history, and the morphological type of the lesion may increase the possibility of malignant transformation. Armed with this knowledge, clinicians can plan treatments accordingly.Videolaryngoendoscopy, complemented by videolaryngostroboscopy, which has previously been used mainly for the functional assessment of the vocal folds, is now becoming an indispensable tool in everyday clinical practice for a head and neck oncologist. Beyond the morphology of the plaque, the presence of a mucosal wave is also crucial for complex prognosing of high-risk vocal fold leukoplakia.


The aims were to examine the prevalence of comorbidities and role of oral analgesic use in people with knee pain (KP) compared with those without.The Knee Pain and related health In the Community (KPIC) cohort comprises community-derived adults aged ≥40 years, irrespective of knee pain. Thirty-six comorbidities across 10 systems were compared between people with KP and controls without KP or knee OA. Multivariable logistic regression analysis was used to determine the adjusted odds ratio (aOR) and 95% CI for multimorbidity (at least two chronic conditions) and each specific comorbidity. Both prescribed and over-the-counter analgesics were included in the model, and their interactions with KP for comorbidity outcomes were examined.Two thousand eight hundred and thirty-two cases with KP and 2518 controls were selected from 9506 baseline participants. The mean age of KP cases was 62.2 years, and 57% were women. Overall, 29% of the total study population had multimorbidity . After adjustment for age, sex, BMI and analgesic use, KP was significantly associated with multimorbidity  and with cardiovascular , gastrointestinal , chronic widespread pain  and neurological  comorbidities. For multimorbidity, the use of paracetamol and opioids interacted positively with KP, whereas the use of NSAIDs interacted negatively for seven comorbidities.People with KP are more likely to have other chronic conditions. The long-term benefits and harms of this change remain to be investigated.http://clinicaltrials.gov, NCT02098070.ClinicalTrials.gov,  Key messagesPeople with knee pain have increased association with multiple chronic conditions and other comorbidities.Use of paracetamol and opioids for knee pain is strongly associated with other chronic conditions.However, association of the use of NSAIDs with comorbidities was less evident.Knee pain (KP) is one of the major reported musculoskeletal problems worldwide , and in A recent systematic review reported that 67% of people with any OA have at least one other chronic condition . ComorbiAgeing, obesity, movement restriction, pathophysiological changes and analgesic drug intake might all contribute to development of comorbidities in KP. However, current evidence is often prone to selection bias . For exaWe used baseline data from the Nottingham Knee Pain and related health In the Community (KPIC) study, a prospective cohort study in the East Midlands region of the UK, which began in 2014 . The stuThis was a cross-sectional study using baseline questionnaire data of KPIC. At baseline, 40 505 questionnaires were mailed to all men and women aged ≥40 years, irrespective of knee pain status, who were registered with 12 participating general practices in the East Midlands area. Exclusion criteria were inability to give informed consent, terminal illness or severe mental illness . The queFor the present study, KP was defined as either chronic knee pain or physician-diagnosed knee OA (KOA). KP was defined using a self-reported question: ‘Have you experienced pain in or around a knee on most days of the last month and has your current knee pain lasted more than 3 months?’. Clinically, chronic KP in people >40 years old has shown congruity with KOA . KOA wasRheumatology Advances in Practice online.We selected all the eligible people with neither KP nor KOA from the KPIC database as controls. Of 9506 individuals who responded to the survey, 78 gave no information on age or sex, and 4078 people gave no information about KP/KOA, and these were excluded from the analyses. Thus, the total available eligible individuals for the study were 5350, of whom 2832 had either KP and/or KOA and the remaining 2518 were selected as controls. Controls were not matched for any variables. Details of the participant selection is provided in We used the available information from a previous study on comorbidities in OA for sample size calculation . The minRheumatology Advances in Practice online).KPIC also collected information on self-reported physician-diagnosed chronic conditions. The questionnaire provided a check list of 10 physician-diagnosed chronic conditions to choose from , together with an open-ended question ‘other’. From open responses to the ‘others’, 26 additional chronic conditions were added to the above list of 10, giving a total of 36 possible comorbidities. These were grouped into 10 systems according to similar physiological and pathological characteristics  recorded in primary care records [Self-reported use of prescribed and/or over-the-counter oral analgesics at baseline, specifically paracetamol, NSAIDs including Cyclooxygenase-2 (COX-2) selective inhibitors, and opioids (might or might not be for KP), were included in the analysis. Participants were asked to list the names of current medicines and the duration of their use in years and months. Use of drugs by the participants was coded as ‘yes’, otherwise ‘no’. Furthermore, the years of exposure were categorized as 0, 1–5, 6–10 or >10 years since the first date of reported use.s.d. or median with interquartile range (IQR) as appropriate across the KP and non-KP groups. Obesity was defined as a BMI of ≥30 kg/m2 [2 tests and unpaired Student’s t-tests. Participants with missing information on age and sex were excluded from the final analysis [Descriptive analysis was done for baseline characteristics such as age, sex,and BMI. Categorical variables were described with proportions, and continuous variables were described as the mean and 30 kg/m2 . Univarianalysis .The main objective was to examine the prevalence of any comorbidities in those with KP compared with those without. The number of comorbidities was calculated by adding all the chronic conditions reported (other than KP) and grouped into categories of none, one, two or three or more. The prevalence with individual comorbidities in the two groups was also calculated. Also, the pattern of combinations of two chronic conditions (dyads) was described and examined using simple exploratory methods. We did not explore patterns in more than two conditions owing to small numbers of people in each possible pattern. In this analysis, we created a network mapping of conditions in relationship to each other and their connection to obesity. The leading combination of two comorbidities within each of the two groups was plotted.Rheumatology Advances in Practice online). We also estimated the dose–response relationship between the years of exposure to analgesics and association with multimorbidity, and a trend test was performed for each type of analgesic. Adjustment for multiple testing was done using the false discovery rate method suggested by Benjamini & Yekutieli [Associations between individual comorbidities, multimorbidity (at least two comorbidities) (yes/no) and KP (yes/no) were estimated in a comparison of KP cases with the controls using univariate and multivariable logistic regression models . In the ekutieli  using thekutieli . All oths.d. 10.4 years), and 58% were women. In the 2518 non-KP controls, the mean age was 61 years (s.d. 11 years), and 55% were women. The distribution of BMI and other covariates across the groups are given in P < 0.05). The prevalence of a single morbidity was 31.7 and 33.8% in the KP and non-KP groups, respectively, whereas prevalence of multimorbidity was higher in the KP (34%) than the control (24%) group  reported KP only, 370 (3.9%) reported physician-diagnosed KOA only, and 909 (9.6%) reported both. In total, 2953 (31.1%) had KP as defined for this study, of whom 2832 had complete demographic data and were included. The mean age was 62 years (%) group .Of the 36 individual conditions that were considered, 13 were significantly more prevalent in the KP group than in controls . FM [adjRheumatology Advances in Practice online). However, the prevalence of the dyad patterns was always higher in the KP than the non-KP group (Rheumatology Advances in Practice online). KP had higher significant associations with each dyad pattern except for dyads that included cancer or stroke. The risk of having combined presence of IBS + FM and hypertension + FM was respectively 3.10  and 3.49  times higher in people with KP compared with non-KP (Rheumatology Advances in Practice online).We plotted the pairwise association of comorbidities in both KP and non-KP groups separately . The patP < 0.05) for opioids and paracetamol (Rheumatology Advances in Practice online).Examination of interactions of analgesic use with KP revealed no significant results in the multiplicative interaction model. However, in the additive interaction model, the interaction between paracetamol and KP contributes 30%  of risk for multimorbidity, 27%  of risk for musculoskeletal and 21%  of risk for respiratory conditions. For the remaining comorbidities, except genitourinary, the interaction of paracetamol with KP had negative contributions. Interaction between KP and opioids shared 18%  of the total association with the risk of multimorbidity, 34%  of association with psychological problems, and 8%  of association with endocrine disorders. Negative contributions were seen from opioids for the remaining comorbidities. The interaction between KP and NSAIDs contributed 22%  towards risk of cancer, 3%  towards cardiovascular, 50%  towards genitourinary and 43%  towards endocrine disorders . HoweverThe aims of this large, community-based study were to estimate the risk of comorbidities and the use of three types of oral analgesics in people with KP compared with those without. The key findings were that people with KP had greater risks of having multimorbidity, specifically chronic widespread pain, cardiovascular, gastrointestinal and neurological conditions than people without KP; and that although the use of paracetamol and opioids was increased, the use of NSAIDs was decreased in people with KP and comorbidities. The study has confirmed the current common use of oral analgesics (both prescribed and over-the-counter drugs) by people in the UK .The increased prevalence of multimorbidity in people with OA and joint pain is increasingly evident in recent studies . HoweverOf the individual comorbidities, KP was most strongly associated with cardiovascular disease and diabetes. Likewise, in a study based in UK primary care, the risks of angina and heart failure were 36 and 28% higher, respectively, among OA cases compared with non-OA controls , and conWe also found strong associations with FM, fatigue and IBS. The associations with other chronic pain-related conditions, such as FM, back pain and IBS, could result from shared non-restorative sleep and central pain sensitization, which causes a decreased threshold to painful stimuli and exacerbates other causes of pain . EstimatThe risks of developing gastrointestinal problems, especially upper gastrointestinal problems such as gastritis and stomach ulcer, were highly associated with KP. Gastrointestinal disorders are known comorbidities in OA resulting from analgesic use . We alsoA significant association of reported opioid use with KP and multimorbidity was seen in the study. Association of opioid prescription with multimorbidity is evident in both community and electronic health record research . OpioidsOur interaction analyses showed that the use of NSAIDs is associated with an increase in risk for cardiovascular and genitourinary disorders, consistent with previous evidence of high risk of cardiovascular and renal problems with long-term use of NSAIDs . Unlike Rheumatology Advances in Practice online, nearly half of the people in the KPIC survey did not have any information about KP status, which led to a reduced sample size and could have introduced selection bias.There are several limitations to this study. Firstly, this is a cross-sectional study, hence it cannot explain the direction of the association . Secondly, the inherent recall bias in self-reported questionnaires might have under- or over-estimated the prevalence of the conditions and the use of medications. Thirdly, because of unavailability of complete data, we did not measure or adjust in our analyses for smoking status, education level or alcohol consumption, and these are important risk factors for comorbidities. Fourthly, we used KP and self-reported physician diagnosis of KOA, which is open to misclassification and ascertainment bias. As shown in KP is associated with higher risks of multimorbidity and cardiovascular, chronic widespread pain, gastrointestinal and neurological comorbidities. There is a significant association of paracetamol and opioid use with comorbidities in people with KP compared with use of NSAIDs. Therefore, care must be taken, because the use of opioids and paracetamol instead of NSAIDs might still have severe consequences for older people with KP and other multiple chronic conditions. Further longitudinal large-scale studies are required to confirm the risk associations with opioids and paracetamol.rkac049_Supplementary_DataClick here for additional data file.


Although the vast majority of patients with a myocardial bridge (MB) are asymptomatic, the anomaly was found to be associated with stable or unstable angina, vasospastic angina, acute coronary syndrome, and even malignant arrhythmias and sudden cardiac death in some cases.By retrieving the relevant literature on MB from 1 January 1980 to 31 July 2022 from the Web of Science Core Collection (WoSCC) database, we used the bibliometric tools, including CiteSpace, VOS viewer, and alluvial generator, to visualize the scientific achievements on MB.A total of 630 articles were included. The number of published articles was in a fluctuating growth trend. These publications came from 37 contries, led by the USA and China. The leading country on MB was the United States, the leading position among institutions was Stanford University, and the most productive researcher on MB was Jennifer A. Tremmel. After analysis, the most common keywords were myocardial bridge, mortality, coronary angiography, descending coronary artery, and sudden death.Our findings can aid researchers in understanding the current state of MB research and in choosing fresh lines of inquiry for forthcoming investigations. Prevalence and prognosis, mechanism atherosclerosis, hemodynamic significance, and molecular autops will likely become the focus of future research. In addition, more studies and cooperations are still needed worldwide. Anatomically speaking, a myocardial bridge (MB) is a congenital anomaly that includes systolic arterial compression and a length of tunneled artery beneath a portion of the myocardium. Although case studies suggest that MB may clinically show as angina, acute coronary syndrome, or malignant arrhythmias potentially leading to sudden cardiac death, the majority of MBs are asymptomatic –3. UnlikTo our knowledge, there are no bibliometric analyses of MB currently. Our goal was to use this approach to assess the state of the art and new directions in MB-related study and to offer an in-depth analysis of the field's state of development for researchers to refer to for future work.*”); time span: 1 January 1980 to 31 July 2022; with language type: English, literature type: article; and index: sci-expanded, SSCI. As shown in Web of Science Core Collection (WoSCC) was used to collect research on MB in the study. The search parameters were as follows: TS =  were utilized to mine the intellectual foundation and boundaries of MB research. To guarantee the correctness and dependability of the data, Liang C and Wen-Yuan Y did data extraction and analysis management, respectively.Then, using 630 articles, we created a clustered network. By performing co-citation analysis and burst identification during the last 43 years, three types of bibliometric analysis tools VOS viewer 1.6.18, CiteSpace 6.1.R3 Advanced and alluvial generator , with 7 years per slice and top 50% criteria.The VOS viewer was used to display the co-citation analysis of references, journals, and authors, as well as the co-occurrence of keywords. Different points in the co-citation maps stand in for various components , and the size of the points is proportional to the number of citations the articles have received . Co-citaTo comprehend the structural changes in co-cited references and investigate the consistently significant research throughout the previous 6 years, we employed an alluvial diagram. Our study's alluvial flow map was constructed using information obtained from CiteSpace. An alluvial generator was used to directly import the networks of co-cited references that were first created in CiteSpace by g-index with a scale factor of 25 in the most recent 6 years (2017–2022). The articles presented more than 3 years over the previous 6 years were emphasized by coloring their flows.Journal Citation Reports (JCRs) for 2021 were used to obtain the journal impact factors. No informed permission or ethical approval was needed for this research because the data and information were all secondary data that were accessed from the open database (WOSCC).In MB research, only 37 nations made significant contributions . The topReferences cited simultaneously by two different publications were called co-cited references. The co-cited references yielded 10 co-cited authors and periodicals . Tables Finding the references with the strongest citation bursts might help researchers identify hot subjects that are suddenly becoming more popular in a certain field and changes in the direction of their study. The references with the strongest citation bursts were examined. We especially concentrated on the references that started to burst after 2015 among the top 25 references with the strongest citation bursts . Two artIn the last 40 years, there have been 14 major study subjects that have been concentrated in the area of MB, as illustrated in There are only roughly 630 articles discussing MB in the previous 43 years, owing to the low rate and wide range of clinical manifestations. An erratic growth tendency in articles indicates rising interest in MB .The top 10 active countries consist of six European countries, three Asian countries, and the United States, accounting for 81.9% of the total literature . Among t2021 = 39.918), Journal of the American College of Cardiology (IF2021 = 27.203), European Heart Journal (IF2021 = 35.855), and Chest (IF2021 = 10.262).According to the top 10 most popular journals, 40% (4/10) of the journals had an impact factor of more than 10, ranked in the JCR Q1 zone . These jThe second most frequent co-cited reference was published by Noble et al. in 1976. They found that during tachycardia, patients with a systolic grade 3 milking effect in the left anterior descending (LAD) coronary artery may result in angina and anterior wall ischemia due to the severe obstruction of LAD by analyzing the hemodynamic data during a 60-watt supine ergocycle exercise test .The reviews published in 2002 by Stefan Moehlenkamp et al. and in 2015 by Alegria et al. were the most and third most often mentioned references . The artIn As technology advances, a variety of invasive and noninvasive procedures for assessing MB can be utilized. MB was originally noticed in 1951 when an in-depth examination of postmortem samples was reported, but clinical interest and systematic research were sparked in the 1970s by an observed link of MB with myocardial ischemia , 21, 22.201Tl Myocardial SPECT can be used to assess the myocardial ischemia of a patient with MB, and it has played an important role in clinical decision-making  after a median of 4.5 (2.2–7.1) years of follow-up in patients with implanted cardioverter defibrillator (ICD). They revealed that patients with MB had significantly higher rates of LTVA and a higher prevalence of vasospastic angina than patients without MB. It may account for some potential mechanisms for bad prognosis in patients with myocardial infarction/ischemia with non-obstructive coronary arteries (MINOCAs) . MB may There are still no guideline recommendations for MB due to the lack of randomized clinical trials. Although its medical management and surgical treatment did not change much during these four decades, the studies evaluating their prognosis never stopped. In general, medical therapy should be regarded as the initial therapeutic strategy, with the beta-blockers and/or non-dihydropyridine calcium channel blockers serving as first-line treatment and ivabradine as the second-line choice for those who do not tolerate beta-blockers or calcium channel blockers –46. As sBinet et al. were the first to describe surgical unroofing (or myotomy) for persons who were unresponsive to treatment in 1975 . AccordiThis research has certain limitations. To begin, we collected scientific articles from WoSCC but excluded other databases such as Google Scholar and PubMed, and the language was limited to English, which may have resulted in bias. Second, because the material we downloaded initially was not the whole text, some relevant facts or perspectives may have been excluded. Nonetheless, our research is based on all objectively gathered data, with no supervisor bias. Third, we have tried our best to replace the authors' full names in analyzing co-authorship, but in analyzing co-reference, the bibliometrics software was unable to identify the authors with the same name owing to the similar abbreviations of certain authors' names in references. Loss of accuracy may still be inevitable in co-reference analysis. Finally, there may still be some literature not being read and analyzed by authors, losing some more meaningful research directions.In our study, we found that MB research has shown a variable growth tendency over the previous four decades. Our goal was to review previous studies in the field of MB, understand the context of MB research, and recommend new directions for future study. Standard guidelines for the optimum diagnosis and therapy of MB require more collaboration and exchange between countries and organizations. The current focus of MB research in cardiovascular science is on the prevalence and prognosis, mechanism of atherosclerosis, hemodynamics, and molecular autopsy, all of which will be the focus of future studies.webofscience.com.Publicly available datasets were analyzed in this study. This data can be found here: LC and W-YY: conceptualization, formal analysis, and software. B-LW and M-XG: data curation. YY: investigation, project administration, and resources. LC, W-YY, RL, and X-HD: methodology. LC: writing—original draft. YY, M-XG, and B-LW: writing—review and editing. All authors contributed to the article and approved the submitted version.


Internet Addiction is positively associated with a range of psychological risk factors such as childhood trauma and sleep disorders. However, it remains unclear if sleep duration mediates the association between childhood trauma and Internet addiction.We enrolled 14,263 students from Shenzhen Polytechnic College, China. Sleep duration, Internet addiction and childhood maltreatment were assessed in these students by self-report measures, Internet Addiction Test (IAT) and Childhood Trauma Questionnaire (CTQ), respectively. With bootstrap approach and path analysis, the mediating role of sleep duration in the association between childhood trauma and Internet addiction was analysed.p < 0.001). The CTQ total score and subscores showed a positive correlation with IAT scores both for males  and females . The CTQ subcores were negatively related to sleep duration both for males  and females  and sleep duration was negatively correlated with IAT scores both in males  and females . Further, the path analysis suggested that EA and SA mediated significantly to the Internet addiction when all types of childhood trauma were examined in one model (both p < 0.001).The Internet-addicted group exhibited a higher level of the emotional abuse (EA) score, physical abuse (PA) score, sexual abuse (SA) score, a lower level of emotional neglect (EN) score and sleep duration compared with the control group (all In the current study, a great proportion of students met criteria for Internet addiction. Sleep duration mediated a significant proportion of the indirect effect between EA/SA and Internet addiction. The findings may help with prevention and intervention of Internet addiction in the future. The limitation of this study was that it was a cross-sectional study and not controlling for other mental disorders. Future large-scale longitudinal studies will be needed to further clarify the relationship between childhood abuse and Internet addiction and the mediation role of sleep duration. Internet addiction is defined as the inability to control Internet using, leading to physical, psychological and social difficulties . The preAlong with Internet addiction, childhood abuse is one of the world’s major public health problems . ChildhoSleep is an unavoidable activity in the daily living and one of the most important factors to promote health . As manyIn this study, the outcome variable we intended to focus more on was Internet addiction. On the one hand, with the global epidemic of COVID-19, the incidence of Internet addiction is gradually increasing . On the This study was a cross-sectional study, which recruited the students in Shenzhen Polytechnic College from May to August in 2019. A total of 14,263 subjects aged 15∼29 years old were enrolled and finished the questionnaire. The students who were on leave or sick were excluded. Subjects scanned a QR code to fill out an electronic questionnaire. All participants were asked to answer the questionnaires independently and not discuss with others. After the questionnaires were collected, the questionnaires with obvious logic errors were excluded. Finally, 13,454 valid questionnaires were obtained. The effective response rate of the questionnaire was 94.91%. This study was approved by the Ethics Committee of Shenzhen Maternity & Child Healthcare Hospital (SFYLS [2020]031).The questionnaire consists of two scales and a number of questions, including general information, sleep duration, Childhood Trauma Questionnaire Short Form (CTQ-SF) and Internet Addiction Test (IAT).p < 0.001).Childhood trauma was measured by the Chinese version of the CTQ-SF . The 28-p < 0.001, and Cronbach’s α was 0.922, indicating a high reliability and validity.The IAT is a 20-item scale that measures addictive Internet use developed by Young , who repSleep duration were obtained by self-report in the questionnaire . The que2 test to analyze the grade and household variables and a Student’s t-test for other variables. A Spearman’s correction was performed to analyze the relationships between CTQ scores, sleep duration and IAT scores. Two-sided p-values less than 0.05 were considered to be statistically significant in this study.Epidata 3.1 was used to input the questionnaire information. SPSS 26.0 software was used to analyze the data. The data cleaning method in statistics was used to filter out invalid values and missing values, and we check the consistency of data to ensure the validity and accuracy. We conducted an χMediation analysis was applied to further explore whether sleep duration played a mediation role in the association of childhood trauma and Internet addiction by using the Bootstrap method and the SPSS PROCESS 4.0 package, and Bootstrap was set to 10,000 times. The test level was α = 0.05. In the mediation analysis, the relation between the independent variable CTQ score and the dependent variable IAT score was tested to see if it was significantly mediated by sleep duration. Path a. the association between CTQ score and sleep duration (the mediator). Path b. the association between sleep duration and IAT score (the outcome). Path c and Path c’, the total and direct effects of CTQ score on IAT score, respectively. Full mediation effect exists when the indirect effect was significant.Using AMOS 26.0, we performed path analysis to identify the relationships between childhood trauma, sleep duration and Internet addiction by structural equation modeling (SEM). The advantage of SEM is that it can simultaneously estimate multiple interdependent relationships, identify the potential relationships of these variables, and obtain the direct and indirect effects. Importantly, SEM can deal with multiple dependent variables simultaneously. Since each CTQ subfraction was highly correlated, sleep duration, IAT and all CTQ subfractions were incorporated into one model by SEM to illustrate the correlation between each CTQ subfraction. SEM has been widely used in the research of Internet addiction.p < 0.001), and there was no statistical difference in BMI between the Internet addiction group and the non-Internet addiction group. The frequency of weekly physical exercise of male students was higher than that of female students (p < 0.001), and the frequency of weekly physical exercise of Internet addiction group was lower than that of non-Internet addiction group (p < 0.001). The Internet-addicted vs. the control group exhibited a higher level of the IAT score, EA score, PA score, SA score  and a lower level of EN score and sleep duration  but not CTQ total score (p = 0.063) and PN (p = 0.077) score. In the sex main effect, the females showed a higher level of IAT score, CTQ total score, EN score, PN score, sleep duration  and a lower level of PA and SA score  but not EA score (p = 0.537) compared with males.The prevalence of Internet addiction in this sample was 41.29%  based on Young’s criteria of an IAT score = 40. Of the 5,089 individuals in the Internet-addicted group, 43.09%  were males and 56.85%  were females. The mean ± standard deviation values of the clinical variables, the statistics of the group main effect, and sex main effect were shown in r = 0.199, p < 0.001 for the total score, r = 0.356, p < 0.001 for EA, r = 0.270, p < 0.001 for PA, r = 0.249, p < 0.001 for SA, and r = 0.132, p < 0.001 for PN) and females . The CTQ subscores were negatively related to sleep duration both for males  and females . Further, the sleep duration was negatively correlated with IAT score both in males  and females .Spearman’s rank correlation coefficient was used to analyze the association between the IAT score, sleep duration, CTQ total score and all subscores for the Internet-addicted group . The CTQb = 1.579, 1.327, 1.635, p < 0.01). When sleep duration was included in the regression equation, the indirect effects of EA, PA, and SA on Internet addiction mediated by sleep duration were 0.045, 0.075, and 0.100, and the corresponding contribution rates of sleep duration were 2.8, 5.7, and 6.1%, respectively. b = −0.074, −0.094, −0.125, p < 0.01), and sleep duration negatively predicted Internet addiction . The result showed that all models were significant with the sleep duration mediating the correlation between the CTQ subscore  and IAT score.As the CTQ subscore  and sleep duration were pair-wise correlated with Internet addiction, a mediation analysis was conducted to examine whether the sleep duration mediated the relationship between the CTQ EA, PA and SA subscore and the IAT score. Findings from the mediational analysis with sleep duration as the mediator is presented in p < 0.001) and SA  had significant positive effects on the IAT. The EA , PA  and SA  score were negatively related to sleep duration, and the sleep duration was negatively correlated to IAT score . These results suggested that sleep duration contributed a significant partial mediating role between childhood abuse (EA and SA score) and Internet addiction.A path analysis was applied to include the sleep duration, IAT score and three CTQ subscores  in one model for Internet-addicted group . The modIn this study, we assessed the relationships between childhood trauma, sleep duration and Internet addiction in Internet-addicted college students in urban areas of south China, and we found childhood trauma total score was positively associated with Internet addiction and the sleep duration, while the sleep duration showed a negative relationship with Internet addiction. Differently, three CTQ subscores  were positive related to Internet addiction, and had a negative relationship with sleep duration. Another important finding is that sleep duration mediated the relationships between childhood trauma  and Internet addiction. A path analysis further suggested that emotional abuse and sexual abuse contributed more significantly to Internet addiction when three childhood trauma subtypes  were examined together in one model.per se (In the past decade, Internet addiction of young people has gradually become a worldwide psychological behavior problem . Accordiper se . The resper se that increased risk of Internet addiction but a battery of predictors including childhood trauma and sleep duration that affected Internet addiction. A recent study suggested that a wide range of abnormal connections in the hippocampus might mediate sleep disorders and Internet addiction, and sleep disorders may further aggravate the degree of IAT and be mediated by this connectivity (A number of studies found that the incidence of sleep problems was 8.7–59.5% in people who had suffered childhood maltreatment , and chiectivity . On the ectivity , individectivity . It is wectivity  revealedectivity . As a reThe findings from this study indicate that the experience of childhood maltreatment predicts shorter sleep duration in adolescents and young adults. Therefore, our findings were useful for identifying adolescents and young adults who might be at risk of shorter sleep duration and at high risk of Internet addiction. In addition, these findings highlighted the importance of accessing childhood maltreatment history, especially in adolescents and young adults with shorter sleep duration. Furthermore, understanding the mediating role of sleep duration between childhood maltreatment and Internet addiction might also help the prevention and treatment interventions of shorter sleep duration for adolescents and young adults who suffered from childhood maltreatment. Finally, we suggested that childhood maltreatment should be prevented from happening in the first place . AdditioThe strengths of our study are as follows. First, we performed a comprehensive analysis of the association between sleep duration, childhood trauma, and Internet addiction in a multi-factor model. Besides, we conducted path analysis which is a new approach to assess the potential role of sleep duration in the associations between childhood trauma and Internet addiction.However, several limitations of our study should be noted. First, the current results were based on a cross-sectional study. We are unable to determine the causal relationships between childhood trauma and Internet addiction. Therefore, this pathway should be validated in larger cohort studies. Secondly, the sleep duration of participants in this study was obtained by means of self-report rather than validated questionnaires. There may be some recall bias and misclassification. Furthermore, the associations between childhood trauma and Internet addiction were also affected by other mental disorders, which were not assessed in our analysis. Future large-scale longitudinal studies may be able to include screening for relevant psychiatric symptoms to further clarify the relationship between childhood abuse and Internet addiction.In conclusion, this study provided important evidence that childhood trauma was negatively associated with sleep duration, and sleep duration was negatively related to Internet addiction in young Chinese adults. Sleep duration played an important role in the association between childhood trauma and Internet addiction. It is important to understand the mediating role of sleep duration between child abuse and Internet addiction, which will provide new ideas and strategy for solving the problem of Internet addiction from public health prospective. It is equally important that these findings need to be confirmed in future multi-center, large-scale studies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Shenzhen Maternity and Child Healthcare Hospital. Written informed consent from the participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.YW: conception and design of study. HW, CC, YZ, and SH: acquisition of data. HW, HX, SC, and WLi: analysis of data. HW, PL, WLu, and WH: revising the manuscript critically for important intellectual content. HW: drafting the manuscript. All authors contributed to the article and approved the submitted version.