Since disturbances of appetite and sleep are closely related and both affect metabolic disorders, it would be expected that a renal specific oral nutritional supplement (RS-ONS) that covers the energy the patient does not consume on the HD day, could contribute to improve the nutritional status and body composition, as well as sleep quality. There is still scarce information related to this topic.To evaluate the effect of the use of intra-dialytic RS-ONS vs. RS-ONS at home on sleep quality, nutritional status, and body composition in patients on HD.Adult patients < 65 years, with ≥3 months on HD were invited to participate in an open randomized pilot study (ISRCTN 33897). Patients were randomized to a dialysis-specific high-protein supplement provided during the HD session  or at home (control), during non-HD days  12 weeks. The primary outcome was sleep quality defined by the Pittsburgh Sleep Quality Index (PSQI) score. Nutritional assessment included Malnutrition Inflammation Score (MIS), bioelectrical impedance analysis, anthropometry, 3-day food records, and routine blood chemistries.P < 0.01). Patients in the ION group improved the overall PSQI score to median 3 (2–5), and assessment of sleep duration and sleep disturbances (pre- vs. post-intervention P < 0.05), with a trend toward an effect difference compared to patients consuming the supplement at home (P for treatment-effect across arms 0.07 for PSQI score and 0.05 for sleep latency).A total of 23 patients completed the study. Age was median 35 (range 24–48 years), 42% were women. At baseline, the PSQI score was median 4 (range 2–7), and MIS showed a median of 6 (range 5–8); there were no baseline differences between groups. After intervention, both groups improved their MIS scores and similarly when we analyzed the whole cohort (pre- vs. post-intervention Oral supplementation improved nutritional status in the whole cohort, but only ION improved the PSQI score. More studies are needed to explore the nutritional strategies that influence the relationship between sleep and nutritional status in HD patients. Patients with Chronic Kidney Disease (CKD) undergoing hemodialysis (HD) frequently experience loss of appetite and poor sleep quality, conditions that are closely interrelated. It has been reported that having a good nutritional status and good sleep quality are essential to maintaining quality of life. Previous studies have reported that around 30–80% of patients with advanced CKD had sleep disorders, with a higher prevalence and severity in HD patients –3. FurthA decreased nutrient and protein intake due to loss of appetite, a hypercatabolic state, metabolic acidosis, comorbidities, and dialysis itself may all contribute to malnutrition and inflammation also known as protein-energy wasting (PEW) , identifNutritional guidelines establish the need of nutritional supplementation in order to maintain a minimum energy intake of 25–35 kcal/kg/body weight/day, for those patients with chronically inadequate intake and whose protein and energy requirements cannot be attained by dietary counseling; they suggest a minimum of a 3-month of oral nutritional supplements . The usevia oral supplementation  vs. RS-ONS at home on sleep quality, nutritional status, and body composition in patients on HD.randomizer.org).We performed a single center, open randomized pilot study for prevalent patients undergoing HD in our unit. The study was approved by the institutional ethics committee (registration number 2229), in addition to having the registration of International Standard of Randomized Controlled Trials Number (ISRCTN 33897). Eligible participants were adults (>18 years), both sexes, under maintenance HD (at least 3 months on therapy), thrice weekly, and Kt/V >1.2 or URR >65%. Patients with (1) amputation of any extremity, (2) planned renal transplant within the next 3 months, (3) acute kidney injury, hospitalization 1 month prior to the initiation of the study, and (4) those who had ultrafiltration volumes of more than 3 liters per session or with sleep disorders (diagnosed by sleep clinic experts) were excluded. All patients were informed about the nature of the study and signed an informed consent. Simple randomization to one of two groups was performed by an external collaborator without contact with the research team in charge of enrollment and intervention using a website  with the following nutritional content in 237 ml: 434 kcal, 37.9 g of carbohydrates, 22.8 g of lipids, 19.2 g of protein, and 3 g of fiber in 237 ml . Cans were washed with 2.0% wide spectrum chlorhexidine, following appropriate guidelines. The intervention was provided over 36 consecutive HD sessions . If a patient missed a session, the respective supplement was labeled with a code and saved until the end of the study .The participants in this group received the same RS-ONS on a non-dialysis day at home (thrice weekly for 12 weeks). They were encouraged to consume their can in two portions, following the suggested schedule  and wash the canned product before consuming it. The patients were asked to return the empty can on the following HD day so they could receive the next can .The assessment of sleep pattern and quality was performed by a sleep specialist before a HD session with the Pittsburgh Sleep Quality Scale (PSQI), which is a self-report tool of 19 items regarding sleep quality and degree of difficulty sleeping during the last month. It is made up of 7 components: sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. The 7 components are added to produce an overall score with a range from 0 to 12; higher scores indicate poorer sleep quality. An overall score >5 has a diagnostic sensitivity of between 89.6 and 98.7%, and specificity of 84.4–86.5%, differentiating between bad and good sleepers , 26.The Malnutrition Inflammation Score (MIS) calculation method includes (A) medical history: Changes in dry weight after dialysis (3–6 months), dietary intake, gastrointestinal symptoms, functional capacity, and comorbidity according to time on HD. (B) Physical exam, loss of fat stores or subcutaneous fat below eyes, triceps, biceps, chest, and signs of loss of lean mass in temple, clavicle, scapula, ribs, quadriceps, knee, interosseous, (C) body mass index (BMI), and (D) biochemical parameters such as serum albumin and total iron binding capacity (TIBC) or transferrin, which are estimated from the results of the various evaluations. Each of them is classified into four degrees of severity. Starting from 0 to 3 on the scale, the sum of all 10 MIS components can range from 0  to 30 —a higher score reflects a more severe degree of malnutrition and inflammation .The participants were evaluated at the end of the HD session at the following time points: at baseline, and at the end of the follow-up—we included body weight and height to determine BMI. For the measurement of bioelectrical impedance analysis (BIE), two “emitting electrodes and two sensor electrodes” were carefully placed . Measurements were conducted by the same operator using an impedance device that emitted 800 μA and 50 kHz alternating sinusoidal current (Multifrequency Bodystat Quadscan 4000 BODYSTAT Ltd.), strictly following the methods reported elsewhere .via standardized methods and included demographics such as self-reported civil status, employment, comorbidities, medications, and laboratory measurements. History of comorbidities and ongoing medications were obtained from consultation of the patient's clinical files. Kt/V as a measurement of dialysis adequacy  was extracted from the medical records which was calculated by the machine  at the end of the sessions. All measurements were carried at baseline and 12 weeks after the completion of the nutritional intervention.Other study covariates were collected 19® . A statistical power calculation was made with the included sample size in which the effect size was 0.50, giving a total power of 0.608 with two tails considering the whole cohort.Since there are no previous studies that have evaluated the effect of ION supplementation on sleep quality, we analyzed the entire population of our HD unit, and subsequently performed a statistical power analysis. Power of the sample size was calculated using GPowert-test was employed, depending on their distribution. Wilcoxon or paired T-tests were used to determine the differences between the basal and final groups, according to the distribution of the data.Descriptive statistics were performed, and continuous variables were presented as arithmetic means and standard deviation for those that had a normal distribution, and those that did not were presented as medians or the inter-quartile range. We carried out analysis following protocol, and to determine whether there were statistical differences between the groups, the chi-square test was performed for the qualitative variables. For the quantitative, the Mann Whitney U tests or the Student's A subanalysis was performed by group and in all the patients as one group.p ≤ 0.05 was established for statistical significance.The analyses were performed using STATA  and A total of 26 participants were randomized, of which 23 finished the study; in general, 94% adherence to treatment was observed. The description of patient selection and monitoring are explained in detail in The basal median of the total sample on PSQI was 4 (range 2–7) points. Sleepiness was present in 8% of the sample at baseline and 14 patients (46%) were poor sleepers (PSQI > 5).p < 0.05 for both groups). The ION group showed improvement in the sleep duration and disturbances as well as a decreased prescription of sleep medications. The total score improved in the ION group , whereas no differences were found in the home group (pre- vs. post-intervention)  . When wevention) .When we evaluated the Pittsburgh score individually for each patient, we observed a trend to improve mainly in those of the ION group , while tp < 0.05), but no statistically significant differences were observed between the groups. In the ION group, BMI showed improvement; however, in the home group, the BMI decreased and nPNA improved after intervention, while no other differences were observed  were effective in improving nutritional status.When we analyzed sleep results, an effect was found only in the group that received ION. There is evidence linking the nutritional status assessed by the MIS score and sleep quality, where those patients who had the worst sleep quality were also those who had the worst nutritional status . TherefoThere are other studies that associate nutritional status with sleep quality in this population. Burrowes et al.  found a Recent research has shown an association between dietary intake and sleep health that can influence risk factors for chronic diseases. In a recent review, it was described that meal time and sleep hygiene are two of the most important aspects to investigate in the link between diet and sleep . And in The presence of sleep disturbances is highly prevalent in this population and dialysis modality or age can be important factors , 32. Botp < 0.05 intra-group effect). Similarly, there was an effect on the total PSQI score in the ION group. No effects were found between supplementation at home and sleep quality nor when exploring the difference between the groups. But, when we analyzed the whole cohort the results shown an improvement in sleep duration, sleep hours, fewer poor sleepers, and lower PSQI total score.When we evaluated sleep quality characteristics, the group receiving ION presented improvement, mainly in terms of sleep duration and sleep disturbances as well as in a reduction of use of sleep medications , and this is consistent when we analyzed the whole cohort, were we found improvements in all the components an exception of BMI, which was already normal at the beginning of the study. One explanation for these positive results could be adherence to treatment, which was higher than 90% in all the population.There are multiple proven benefits regarding the use of ION in HD patients; it has been shown to have persistent anabolic benefits for muscle protein metabolism in the post-HD phase, while the anabolic benefits of parenteral nutrition during HD sessions dissipated during the same period. These data support both the anabolic and anti-catabolic functions of ION . HoweverThere is a large body of evidence that states that oral supplementation decreases hospital admission rates, serum IL-6 levels , improveOn the other hand, BMI has been reported to be a nutritional status factor that can be maintained regardless of the supplement used during dialysis, as recently reported in a 6-month follow-up clinical trial, comparing consumption of a normal meal vs. a hyper-protein meal intra-dialysis; both groups maintained BMI but not for albumin, where the results were better for the group that received the hyper-protein meal .Martin-Alemañy et al. demonstrated the combined effect of oral supplementation plus aerobic or resistance exercise on nutritional status, and physical functionality . Ocepek A major limitation of our study is our small sample size and its low mean age, which may not reflect the usual on dialysis in most countries; however, this is the first trial that associates sleep quality with the use of oral supplementation. The use of oral supplementation improves nutritional status but it is necessary to perform more RCTs with larger sample sizes to explore the mechanisms that influence the relationship between ION and sleep quality, and is necessary to implement strategies to help compliance for a long time.A clinical application of this paper is that oral supplementation has been studied in different outcomes, however, studies about sleep outcomes are missing.In Conclusion, the results of this pilot study support the implementation of oral supplementation, as a strategy to improve nutritional outcomes and that could have an effect on sleep quality.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 Comité de ética, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán #2229. The patients/participants provided their written informed consent to participate in this study.AG-O and SR-A participated in study conception, design the research generation, analysis of the data, and writing the paper. ÁE-C participated in study conception and design, revision, analysis of the data, writing the paper, and approval of the final version of the manuscript. VS-A, GG, RC-R, MV-F, HX, and JJC participated in interpretation of the data and/or critical revision of the manuscript to its final form. All authors read and approved the final manuscript.AG-O and SR-A were supported by The National Council of Science and Technology (CONACYT), CVU 373297 and 779601, respectively.JJC reports grant funding from AstraZeneca, ViforPharma and Astellas, consulting for Baxter and AstraZeneca, speaker fees for Abbott, Nutricia, AstraZeneca, and ViforPharma all outside the submitted work. ÁE-C acknowledges speaker honoraria from Abbott Laboratories and AbbVie. AG-O acknowledges being speaker for Abbott Laboratories. RC-R reports grant funding from AstraZeneca, Novonordisk, and Glaxo. Consulting fees for Boheringer Ingelheim, AstraZeneca, Chinook, and all unrelated to the submitted work. The remaining 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.


Their parents completed the CBCL twice—first during the summer medication-free period, that is, at least one month after drug interruption; and again after three months of treatment restart. Results demonstrate that MPH is associated with a statistically significant reduction in ED in ADHD and ASD, without substantial adverse events, supporting the use of psychostimulants for the treatment of ED in these neurodevelopmental disorders.Emotional dysregulation (ED) is common in attention-deficit/hyperactivity disorder (ADHD). Nonetheless, research on ADHD in children with autism spectrum disorder (ASD) and ADHD is still ongoing. Several studies suggest that methylphenidate (MPH) may be effective for ED in ADHD, while there is not enough evidence about its use in ASD with comorbid ADHD. This naturalistic study aims to investigate the effectiveness of immediate- and extended-release MPH in the treatment of ED in 70 children and adolescents (6–18 years), with a diagnosis of ADHD ( Emotional dysregulation (ED) is characterized by an inability to modulate emotional responses, resulting in extreme reactions of an internalizing or externalizing nature, inappropriate for developmental age . It has As for therapy, to date, no data are available regarding a specific pharmacological treatment for ED. To date, in most cases, treatment choice was guided by the main psychiatric condition behind ED. In ADHD individuals, preliminary evidence suggests that psychostimulants improve emotional recognition and reduce emotional lability and irritability . NeverthThe aim of this study was to evaluate the effectiveness and tolerability of immediate- and extended-release MPH treatment on ED in children and adolescents with ADHD, with or without ASD.This was a naturalistic study based on a clinical database of Caucasian young people, aged between 6 and 18 years, consecutively referred to the Child Neuropsychiatric Unit of the University of Bari during a two-year period (September 2019–September 2021). The inclusion criteria were a diagnosis of moderate to severe ADHD, according to DSM-5 , pharmacThe starting dose of MPH was 0.3–0.5 mg/kg/day. The dosage could be increased up to 1 mg/kg/day depending upon the subject’s clinical response and tolerability, up to a maximum of 60 mg/day. The total dose could be administered in two or three doses/day. After one month of titration, the IR-MPH was generally replaced with ER-MPH. The therapeutic management of ADHD children in our unit comprises short breaks in summer, in agreement with parents and patients about the best pattern of use, with the aim of investigating the ongoing benefit of medication, helping to verify need and the possibility of a reduction in side effects relating to sleep and appetite, albeit considering its reintroduction whenever needed. The median MPH dose and therapy duration are described in For the specific purpose of this study, ED was studied through the evaluation of CBCL scores.The CBCL is a self-reported scale developed by Achenbach and Edelbrock to evaluate existing competencies and behavioral, emotional, and social problems in children and adolescents aged between 6 and 18 years, through information derived from parents. The behavioral problems scales include 118 items, divided in internalizing and externalizing subscales. The internalizing subscale contains items concerning withdrawn behavior, somatic complaints, and anxious/depressed behavior. The externalizing subscale includes items concerning delinquent and aggressive behavior. Furthermore, there are subscales that contain social, thought, and attention problems. The higher score represents a higher level of problems. A computer program calculates the t scores  for each scale. Raw scores are converted to gender- and age-standardized scores.According to Biederman ,49,50,51Data obtained from the ADHD group and the ADHD and ASD group were compared to each other, henceforth analyzed.The Ethic Committee of the Azienda Ospedaliera-Universitaria Consorziale Policlinico di Bari approved the study. Informed consent from parents and assent from children and adolescents were obtained prior to enrollment. Among 75 patients who were prescribed MPH, 5 were excluded because their caregiver did not sign the informed consent. The enrolled sample consisted of 70 patients of which 41 had a diagnosis of ADHD (henceforth named the ADHD group) and 29 had a diagnosis of ASD with comorbid ADHD (henceforth named the ADHD and ASD group).es) and the pooled standard deviation: D = es × Sp.Comparisons between the two groups were analyzed by t-test or Wilcoxon test for independent samples, appropriately selected according to the evaluation of normality of quantitative variables. Comparisons of proportions between independent groups have been performed by the chi-square test or the Fisher exact test, according to appropriateness. Comparisons between proportions in paired samples were compared by the McNemar test. A general linear model was also applied to evaluate the difference between the two groups at the two timepoints. The main aim was to evaluate whether there was a difference between the two groups (ADHD vs. ADHD and ASD) in terms of effectiveness and tolerability of MPH on ED; therefore, a test of equivalence was performed: the Two One Side Test (TOST) was applied comparing the limits of the 90% confidence interval of the difference between the two means with the of equivalence (D). They were determined as the product between the effect size (ES) .All the analyses were performed using SAS 9.4 for personal computer. The significance level was set at Demographic and clinical characteristics of the two groups, comorbidities and pharmacological treatments in addition to MPH are described in p = 0.08 and p = 0.18, respectively). Conversely, comparing CBCL-AAA profiles in T0 and T1 in each group and in the total sample, the difference was statistically significant (p < 0.01)  at T0 and at T1 was not statistically significant ( < 0.01) .p = 0.32, attention: p = 0.42, aggressive: p = 0.27; T1 anxious: p = 0.31, attention: p = 0.04, aggressive: p = 0.29). Conversely, comparing the scores of CBCL-AAA subscales in T0 and T1 in each group and in the total sample, the difference was statistically significant (p < 0.01).Comparing the ADHD group with the ADHD and ASD group, the difference between each subscale of CBCL-AAA both at T0 and at T1 was not statistically significant . Conversely, comparing the CBCL-AAA total score in T0 and T1 in each group and in the total sample, the difference was statistically significant (p = 0.01)  .Evaluating the equivalence between the difference T0–T1 of the CBCL-AAA total scores, the two groups were equivalent to each other.Conversely, evaluating the equivalence between the CBCL-AAA scores in the two group at T0 and at T1, the two groups were not equivalent to each other.No severe adverse events were reported; indeed, among these, no cardiovascular events neither suicidal ideation or behaviors were seen .The most frequent side effects in the ADHD group were loss of appetite, abdominal discomfort, and headache , each only temporary, in the first days or weeks of treatment; the same side effects were seen in the ADHD and ASD group . The difference between each side effect in the two groups was not statistically significant. Two ASD patients with comorbid ADHD, both with intellectual disability, of which one was affected by level 3 ASD and the other by level 2 ASD, presented worsening of behavior, with restlessness and increased stereotypes that caused the interruption of treatment and completely resolved after treatment discontinuation.This study analyzes MPH effectiveness and tolerability on emotional dysregulation (ED) in a naturalistic setting of 70 ADHD patients, of which 29 also had ASD. To the best of our knowledge, this is the first study focusing on the effect of MPH on ED in ASD children and adolescents.Several studies analyzed the prevalence of ED both in ADHD, finding percentages between 24 and 55% in children and adolescents and 34 to 70% in adults , and in ED is a challenging pharmacological target, and the scientific literature to date does not provide tailored guidelines for its management, probably because most of the available pharmacological trials did not focus on ED per se. Given the transnosographic quality of ED, pharmacological approaches aimed at it are largely guided by the presence of comorbid illnesses: risperidone and aripiprazole in the context of ASD and/or intellectual disability, serotonin reuptake inhibitors in the context of depression or generalized anxiety disorders, and mood stabilizers  in the context of bipolar spectrum disorders ,53,54,55Previous research and clinical experience clearly demonstrated that MPH has a beneficial effect on ADHD core symptoms ,57,58. RConcerning the use of MPH in ASD patients, efficacy and safety data are controversial: some early studies reported that stimulant medication resulted in increased stereotypical movements in children with ASD or in additional adverse events that may impact negatively on social interaction. However, these results are based on small samples of patients (frequently case report), often comorbid with intellectual disability ,60,61. Tp< 0.0001) reduction in CBCL-AAA score was found both in the ADHD group and in the ADHD and ASD group. Within these findings, it is remarkable to note that the median of intellectual quotient was 97.2 in the ADHD group and 96.3 in the ADHD and ASD group. As for tolerability, treatment with MPH was well tolerated; there were no serious adverse events, with the main adverse events being temporary loss of appetite, abdominal discomfort, and headache, without significant differences in the two groups.The present study suggests that MPH is associated with a significant improvement in ED in ADHD children and adolescents with or without ASD. Actually, after MPH use, a statistically significant , with a specific focus on ED, assessed through a standardized measure. Being a naturalistic study, medication titration and dose adjustment were possible as necessary, almost like in a real-life setting.Study limitations include the lack of randomization or blinding and control of other pharmacological/behavioral treatments and the small sample size. The suitability of our study design used to measure ED administering the CBCL during the summer medication-free period and after three months of treatment restart (employing each patient as his/her own control) could be discussed. Future research in this field should involve proper administration of the CBCL before the beginning of treatment and the extension of ED assessment through other measures, as objective as possible and preferably not only parent mediated.In conclusion, our study shows that MPH treatment is well tolerated and effective in reducing ED in children and adolescents with ADHD who may also have high-functioning ASD. Thus, the routine use of MPH in this group of children and adolescents is recommended.


Dyslipidemia and hypertension are both important risk factors for atherosclerotic cardiovascular diseases. However, the relationship between dyslipidemia and incident hypertension remains to be elucidated comprehensively. The main purpose of this study was to construct the lipid risk score to explore the risk prediction effect of integrated lipid indices on new-onset hypertension.This prospective cohort study with 2116 non-hypertensive subjects was conducted from 2009 to 2020. New hypertension events during the follow-up period were recorded and verified. The lipid risk score was calculated by summing coded total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol weighted with corresponding effect sizes. Cox regression analysis was used to estimate the association between the lipid risk score or lipid indices and incident hypertension in the subgroup of age (< 55 and≥ 55 years at baseline).After a median of 10.75-year follow-up, 637 incident hypertension cases were identified. The restricted cubic spline showed that the lipid risk score had a positive linear correlation with hypertension (P< 0.001). Among people< 55 years, with every increase of 0.94 in lipid risk score, the risk of hypertension increased by 37% (adjusted HR [95%CI]: 1.369 [1.164-1.610]). This association was not modified by overweight or obesity.The integrated lipid risk score, independent of traditional risk factors, has a significantly predictive effect on hypertension in people younger than 55 years. This finding may aid in identifying high-risk individuals for hypertension, as well as facilitating early intervention and management to reduce adverse cardiovascular events. Comprehensive lipid management should be attached importance in the prevention and control of hypertension. Hypertension is a serious public health issue that serves as a primary risk factor for cardiovascular disease and a major cause of premature death worldwide , 2. An eDyslipidemia, characterized by abnormalities of serum cholesterol or triglyceride levels, is also an established risk factor for atherosclerotic cardiovascular diseases . The coeDeveloping risk prediction models for hypertension is an important approach to identifying high-risk individuals and conducting targeted interventions. To date, plenty of prediction models have been constructed and validated for various populations. The variables included in these risk models mainly involve traditional risk factors or genetic factors, yet few models incorporate lipid indices . Thus, rTherefore, the primary objective of this study was to evaluate the association between abnormalities of multiple lipid indices and new-onset hypertension in a prospective cohort, and construct the lipid risk score to explore the combined risk-prediction effect of integrated lipid profiles on hypertension.This prospective cohort research commenced from May 2009 in China, which recruited a total of 4128 subjects by a cluster sampling approach from 6 villages in Yixing City, Jiangsu Province. Eligible participants included at baseline were community residents aged 24 to 96 years old. 2116 baseline subjects free of hypertension  were followed up until July 27, 2020 for hypertension status.The study has been approved by the Ethics Committee of Nanjing Medical University in Jiangsu Province of China, and all participants signed the written informed consent before entering the study cohort. Data and information of every subject in the current study were de-identified and kept confidential.2 as normal or underweight, 24-27.9 kg/m2 as overweight, and ≥ 28 kg/m2 as obese. Blood pressure measurements for all participants were conducted in the morning (7:00-10:00 am) after at least 8-hour self-administered fasting. Mercury sphygmomanometers were used on the right arm to read the blood pressure value at least three times after a 5-minute rest in the sitting position. The final blood pressure was the average value of three measurements. Individuals with fasting plasma glucose (FPG) ≥ 7.0 mmol/L, or self-reported diabetes diagnosis, or currently receiving antidiabetic medication were recorded as diabetes cases. After data collection, we used EpiData 3.0 software for double entry and consistency check to ensure the authenticity and accuracy of the entered information.The baseline investigation for all eligible participants was administered by well-trained and qualified researchers at the time of enrollment. Each subject completed a validated questionnaire with demographic information, smoking/drinking status, family history, and medical history of chronic diseases including hypertension. Smokers were defined as individuals having more than 20 cigarettes/week for at least 3 months per year. Drinkers in this study referred to individuals with current or past alcohol consumption more than two times per week lasting at least 6 months a year. All subjects received physical examinations conducted by professional doctors or nurses for basic physiological information. Height, weight, and blood pressure were measured by calibrated instruments. Body mass index (BMI) was calculated by the ratio of weight in kilograms to the square of height in meters, with< 24 kg/mOvernight fasting blood samples (10mL) were collected from all participants and transported to the hospital within 24 hours for laboratory tests. TC, TG, HDL-C, LDL-C, and FPG were measured by an automatic biochemical analyzer. Non-HDL-C was calculated as the difference value of TC and HDL-C.Blood lipid levels were categorized in the light of Chinese Guidelines for the Management of Dyslipidemia in Adults . We clasThe first field follow-up investigation for baseline participants began from May to October in 2014 with the same approach and content as the baseline survey. The follow-up proceeded until July 27, 2020, with annual regular monitoring for hypertension events. Individuals with an average systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg were diagnosed with hypertension during the follow-up. The incidence of hypertension was recorded strictly according to the local management system of disease and death of the Center for Disease Control and Prevention (CDC) or the regular registration in community health centers. All monitored hypertension events were further verified by the end-point committee.We constructed the lipid risk score in the population under 55 years at baseline by integrating four lipid indices  which were significantly associated with the risk of hypertension. Each individual aged< 55 years was assigned a score based on the levels of selected four lipid indices. Each of the four lipid indices was assigned corresponding code. Normal lipid levels were coded as 0, and marginal increase or increase of lipid indices was coded as 1. Due to the unequal effects of different lipid indices and different lipid levels on the risk of hypertension, we introduced the weight or effect size for each category of four lipid indices into the calculation of the lipid risk score. Adjusted Cox regression analyses between lipid indices and hypertension incidence were conducted to determine the effect of different lipid levels on hypertension risk by the estimate of β coefficient. β estimates for every category of lipid indices from multivariable Cox regression analyses are listed in χ2.)test. Incidence density was calculated by the ratio of the number of incident hypertension cases to person-years. Bivariate correlations between lipid indices and hypertension were also analyzed by χ2 test. Cox proportional hazard regression was applied to calculate the hazard ratio (HR) with 95% confidence interval (CI), so as to test whether significant associations exist between blood lipid levels and the risk of hypertension in two age groups (< 55 and ≥ 55 years at baseline) after adjusting for age, gender, smoking, drinking, hypertension family history, baseline diabetes.We first evaluated the distribution of baseline characteristics of the study population by whether the participant had dyslipidemia. Continuous variables were presented as medians and interquartile range for the non-normality of distribution, and the Mann-Whitney U test was performed to examine the differences between the two groups. Categorical variables were presented as frequencies and proportions, and differences between two groups were compared using the Chi-square  for Cox regression were computed to evaluate the improvement in discrimination after adding the lipid risk score to the traditional prediction model for hypertension. The likelihood ratio test was conducted to compare the goodness of fit of the two models.Statistical analyses were carried out using SAS 9.4 software  and R software 3.5.0 . Analysis results were considered statistically significant at the two-sided 5% level.2. 31.9% of the participants had dyslipidemia at the time of enrollment. Significant differences existed between people with and without dyslipidemia regarding BMI, TC, TG, HDL-C, and non-HDL-C levels (P< 0.001). A higher proportion of dyslipidemic subjects had diabetes compared to those without dyslipidemia (P< 0.001). Among all 676 participants with dyslipidemia at baseline, there were 23.8% who had high levels of TC, 50% who had increased TG, 46% who had low levels of HDL-C, and 17.3% who had increased non-HDL-C. During the follow-up, 216 subjects in the dyslipidemia group and 421 in the non-dyslipidemia group developed hypertension. The incidence rate of hypertension in the dyslipidemic population was 378.21 per 10000 person-years, while 336.89 per 10000 person-years in the non-dyslipidemic population . In contrast, among those older than 55 years, none of the lipid indices had a significant relationship with hypertension (P > 0.05). In P > 0.05).The bivariate correlation between lipid indices and hypertension stratified by baseline age is presented in P< 0.001), which indicated that the lipid risk score had a positive linear correlation with hypertension. The hazard of developing hypertension tended to increase as the lipid risk score was getting higher.In Based on the result of restricted cubic spline analysis, we divided the lipid risk score (range: 0-2.81) into four categories with equal intervals, generating four risk groups for hypertension , and the model with lipid risk score plus traditional factors was statistically fitted.We also evaluated the predictive effect of the lipid risk score for hypertension by comparing the Cox regression model with commonly included traditional risk factors  and the model with lipid risk score added. C-statistic for the traditional model was 0.624 and C-statistic for the combination model was 0.651. The likelihood ratio test for these two models manifested that the lipid risk score had a significantly independent effect when added to the traditional risk model , which indicated the rationality of using the averaged β estimate for the weight of TG in the calculation of lipid risk score. Another finding of our study worth mentioning was the correlation between LDL-C and hypertension. Though the P-value for the category of LDL-C >160 mg/dl was not significant, the HR and β estimate still showed a potentially stronger association of hypertension with the increased level than the marginally increased level (trendP = 0.005). This situation was probably due to the very few subjects in the group of LDL-C higher than 160 mg/dl with only 8 out of 23 individuals developing hypertension during follow-up.Hypertension and dyslipidemia are both independent and modifiable risk factors of great importance for atherosclerotic cardiovascular diseases –32. Abnovia the imbalance between vasodilatory and vasocontrictory substances  cascade , has alwbstances , 39, 40.bstances , 41. Insbstances , 43. Sombstances . In addibstances –47. Somebstances , 48.Based on the intricate mechanisms of the relationship between dyslipidemia and hypertension, many kinds of cholesterols and triglycerides participate in the pathogenesis. Though previous research indicated that TC, TG, LDL-C, HDL-C, or non-HDL-C, individually, has some relation to the risk of hypertension, it is necessary to investigate the comprehensive effects of lipid profiles and hypertension. Therefore, our research evaluated the combined effects of multiple lipid indices on the risk of incident hypertension. And we found that with every increase of 0.94 in lipid risk score, the risk of hypertension increased by 37% in the population younger than 55 years. The lipid risk score integrated several lipid indices weighted by effect sizes, which will help depict the lipid characteristic for each individual more accurately.For multi-factorial disorders like hypertension, scholars around the world never cease to pursue the optimal prediction model to precisely assess the risk of disease for individuals. All kinds of risk prediction models have been developed from equations to risk scores, from Western populations to Asian populations. However, based on the systematic review, only a few models included lipid indices . So, ourThough this study has notable strengths, some limitations are worth mentioning. First, the sample size of this study was still relatively small and all subjects were recruited from Jiangsu Province in China, which is a lack of representativeness and external validity. Thus, studies with larger sample sizes and different populations are warranted to validate these findings. Second, since the lipid data for analyses were collected at baseline, we were not able to evaluate the effect of lipid level changes on the development of hypertension. Third, a potential confounding bias is also noticeable. The possible use of lipid-lowering medications during the follow-up period might distort the relationship between dyslipidemia and new-onset hypertension. Fourth, the median LDL-C levels at baseline in groups with or without dyslipidemia were the same due to the low proportion of dyslipidemia subjects having LDL-C levels higher than normal. In this situation, the effect of elevated LDL-C could not have a clear manifestation in the correlation between dyslipidemia and incident hypertension. Moreover, the selected cut-off values and categorization of lipid index levels in this study have to some extent masked the effect of lipid levels above-median yet currently classified in the normal group on the risk of hypertension. Additionally, restricted by the sample size of our study, HDL-C was not found to have significant association with incident hypertension in any population. So, we did not include HDL-C in the calculation of lipid risk score in this study, which might potentially make our lipid risk score less effective and less comprehensive. Finally, lipid indices included in this study are still limited, so further analyses of the correlation between hypertension and nonconventional or derived lipid indices such as TC/HDL-C are necessary.In conclusion, the current results of this prospective study provide convincing evidence for the causal relationship between dyslipidemia and hypertension, as well as the combined effects of multiple lipid indices on hypertension. Our findings may also contribute to the proposition that the risk score with integrated lipid indices could serve as an independent risk factor of developing hypertension. Therefore, the lipid risk score combined with traditional risk factors could delineate a more comprehensive and more accurate risk profile for hypertension, which may aid in optimizing the risk prediction model and identifying the high-risk individuals of hypertension. In addition, the comprehensive risk assessment will help improve individuals’ prophylactic awareness and compliance, as well as facilitate personalized intervention strategies. This study also highlights the importance of integrated management of dyslipidemia and hypertension. Comprehensive lipid controls should be paid more attention in the prevention of hypertension. Nevertheless, future clinical applications of the finding still need corroboration and adjustment in more and larger studies. Moreover, the extent to which treatment of dyslipidemia reduces the risk of developing hypertension is also worth exploring.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 Nanjing Medical University (#200803307). The patients/participants provided their written informed consent to participate in this study. The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Nanjing Medical University (#200803307), Nanjing, China. Written informed consent has been obtained from all participants to publish this paper.Conceptualization, CS and SY; methodology, CS; software, HX; formal analysis, HX; investigation, QZ, JS, PW, XZ, YC, JD, CC, JM, LW, YY; resources, CS and SY; data curation, JD; writing—original draft preparation, HX; writing—review and editing, CS; visualization, HX; supervision, CS; project administration, CS and SY; funding acquisition, CS. All authors contributed to the article and approved the submitted version.This research was funded by the National Key Research and Development Program of China (Grant No. 2018YFC2000703), Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancers of Chinese Academy of Medical Sciences (2019RU038). National Natural Science Foundation of China , the Priority Academic Program for the Development of Jiangsu Higher Education Institutions , and the Flagship Major Development of Jiangsu Higher Education Institutions.The authors would like to express gratitude to all participants in this study for providing valuable data and information, and to the clinical staff at the People’s Hospital of Yixing City for their support.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.


Inflammation is closely related to the pathogenesis of multiple system atrophy (MSA). As markers of inflammation, the monocyte to high-density lipoprotein ratio (MHR), neutrophil to lymphocyte ratio (NLR), and red cell distribution width to platelet ratio (RPR) have been proven to be associated with a large variety of diseases. The aim of this study was to explore the association between inflammatory markers  and MSA, and the difference between MSA and Parkinson’s disease (PD) was further compared by these inflammatory markers.This study was divided into three groups: 47 patients with MSA, 125 patients with PD, and 124 healthy controls. The corresponding laboratory indicators of subjects were collected and analyzed to obtain MHR, NLR, and RPR values.P < 0.05), and the MHR was higher in the MSA group than in the PD group (P < 0.001). Multivariate logistic regression analysis showed that MHR*10  and RPR*100  were positively correlated with the risk of MSA. The receiver operating characteristic (ROC) curve indicated that the areas under the curve (AUCs) of the MHR, NLR, and RPR for predicting MSA were 0.651 , 0.6 , and 0.612 , respectively. The AUC of MSA and PD predicted by the MHR was 0.727 (P < 0.001). When the cut-off value was 0.38, the sensitivity and specificity were 60 and 77%, respectively. Spearman correlation analysis showed that the MHR was significantly and positively correlated with the course of MSA cerebellar type (MSA-C) patients.Compared with healthy controls, the MHR, NLR, and RPR were higher in the MSA group (There may be peripheral inflammation in patients with MSA. Compared with NLR and RPR, MHR has higher predictive value for the diagnosis and differential diagnosis of MSA. Known as multiple system atrophy (MSA), this neurodegenerative condition affects multiple systems. MSA is a disease that causes Parkinsonian symptoms as well as cerebellar and autonomic dysfunction, with various clinical manifestations. MSA falls into two categories: multiple system atrophy-parkinsonism (MSA-P) and multiple system atrophy-cerebellar ataxia (MSA-C) . Some scThe pathogenesis of MSA is unclear, and neuroinflammation may be one of them. We collected the data of 172 patients hospitalized in the Department of Neurology of the Second Affiliated Hospital of Nanchang University from January 2016 to May 2022, including 47 patients with MSA and 125 patients with PD. Based on the Consensus of the American Academy of Neurology, the diagnosis was possible MSA . MDS cliThis study was a retrospective study and was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University.9/L. The reference ranges of red cell distribution width (RDW-CV) and HDL were 10.9–15.4% and 1.16–1.42 mmol/L, respectively. All detection indicators were measured by an automatic hematology analyzer  and automatic biochemical analyzer .General information of all patients was recorded, including age, gender, disease duration, past medical history, tobacco and alcohol use and medication history, and family history. NLR, MHR, and RPR values were calculated by recording neutrophils, lymphocytes, monocytes, red cell distribution width, platelets (PLTs), and high-density lipoprotein (HDL) values. The units of neutrophils, monocytes, lymphocytes, and PLTs were all ×10t-test was adopted. When the measurement data did not conform to normality, the Mann–Whitney U test was used and data were expressed as the median (quartile) [M ]. The counting data were compared between groups by Pearson’s chi-square test and expressed as n (%). Binary logistic regression was established by the backward LR method to analyze the relationship between novel inflammatory factors  and the risk of MSA. The variables in univariate analysis (P < 0.1) were incorporated into the multifactor logistic regression analysis. To evaluate the predictive value of NLR, MHR, and RPR for MSA and PD, receiver operating characteristic (ROC) curves were plotted. Finally, Spearman’s correlation test was conducted to analyze the correlation between NLR, MHR, RPR and course of disease in patients with different types of MSA. In all of the above analyses, P < 0.05 was recognized as statistically significant.SPSS software  was used for statistical analysis. The Kolmogorov–Smirnov test was used for normality testing. The measurement data conforming to the normality test were represented as the mean ± standard deviation (mean ± SD), and a P > 0.05). Compared with the HC group, the MHR, NLR, RPR, and monocytes of the MSA group were higher, the distribution width of erythrocytes and HDL were lower, and the differences were statistically significant. Compared with the HC group, the RPR and red blood cell distribution width (RDW) were higher in the PD group (P < 0.05), and the neutrophils, monocytes, lymphocytes, PLTs, and MHR were lower (P < 0.05). The MSA group had higher levels of MHR, neutrophils, and monocytes and lower levels of HDL than the PD group (P < 0.05). The results are presented in In the MSA group, there were 47 cases, including 30 males (63.8%), with an age of 61 years (55–66). Among 125 PD patients, 72 (57.6%) were males, with an age of 63 years (56–68). There were 124 healthy controls, including 60 males (48.4%), with an age of 58 years (52–67.75). There were no significant differences in age, sex, smoking, drinking or hypertension among the three groups  and RPR*100  were positively correlated with the risk of MSA, as shown in P < 0.05)  . The cutP < 0.001). When the cut-off value was 0.22, it predicted MSA with 77% sensitivity and 52% specificity (95% CI 0.604–0.771).The AUC of MHR combined with NLR and RPR was 0.688 (P < 0.001), when the cut-off value was 0.38 , suggesting a correlation between MSA and NLR. MSA may have peripheral inflammation.Neutrophils and lymphocytes are important indicators of inflammation and are linked to the occurrence, progression, and severity of inflammation. Some studies have shown that the secretion of IL-2 and IL-15, which are involved in T lymphocyte maturation, is significantly increased in the serum of patients with MSA. In addition, the numbers of CD3 + T lymphocytes and CD4 + T lymphocytes were increased in the peripheral blood of MSA patients . The NLRP < 0.05), while the platelet counts of the MSA group and PD group was lower. Previous studies have found that the activity of enzymes involved in the oxidative respiratory chain in PLTs of PD patients is reduced by half, resulting in decreased ATP production, which may affect platelet growth or proliferation.Red blood cell distribution width is an indicator of the variability of red cell volume in blood. Studies have shown that inflammatory factors inhibit erythrocyte maturation by reducing the sensitivity of hematopoietic stem cells to erythropoietin (EPO) . PreviouThis study explored the relationship between MSA and peripheral inflammatory markers . The results of this study confirmed the correlation between MSA and peripheral inflammation and further provided evidence that peripheral inflammation was involved in the pathogenesis of MSA. However, limitations exist in this study. First, our study was a retrospective study. The time points of blood samples collected in the included population were different. Additionally, our study was a single-center study. The incidence of MSA is relatively low, and the number of MSA patients included is small. Moreover, the diagnosis of MSA is exclusive. However, typical clinical manifestations and pontine “hot cross bun sign” contribute to the diagnosis of MSA. Nevertheless, a considerable number of early stage patients do not show significant clinical characteristics. Specialists with rich clinical experience in motion disorders are also often unable to accurately identify them. Thus, there may be selection bias. In view of the fact that the sensitivity and specificity of the indicators in this study are not very high, it may be necessary to combine with the common autonomic symptoms of multiple system atrophy such as postural hypotension and urinary symptoms in subsequent studies in order to improve the sensitivity and specificity of the testing index. In addition, in subsequent studies, it is also necessary to strictly and accurately control the diagnostic criteria and include adequate sample sizes in prospective and multicenter studies.In conclusion, peripheral inflammation is correlated with MSA and is connected with the onset of MSA. The study further confirmed that MSA may be higher than PD at the level of inflammation. In addition, the MHR may be used as an indicator of differential diagnosis between MSA and PD. It has certain clinical value and significance. However, despite the presence of peripheral inflammation in MSA, it is not clear whether inflammation is a trigger or a consequence of MSA. The specific related pathways remain unclear and need to be further explored by basic research.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the Second Affiliated Hospital of Nanchang University. The patients/participants provided their written informed consent to participate in this study.LJ wrote the manuscript. HB, ZZ, and JH reviewed and revised the manuscript. WH directed the study. All authors contributed to the article and approved the submitted version.


Clinicians estimate the risk of thyroid nodules and make subsequently decision on the basis of clinical and ultrasonographic findings. Currently, there is no comprehensive diagnostic tool for predicting the malignancy rates of thyroid nodules. Our aim was to develop and validate a novel integrate diagnostic tool for predicting the malignancy probability of thyroid nodules based on clinical, B-mode, Color Doppler and elastographic ultrasonographic characteristics.A total of 1016 nodules in 1016 patients who underwent thyroid ultrasonography and surgery from July 2021 to December 2021 were included in this retrospective study. All nodules were confirmed by pathology and randomly classified into the training and validation groups. Clinical, B-mode, Color Doppler and elastographic (CBCE) ultrasonographic characteristics of nodules were recorded. Univariate and multivariate analyses were performed to screen independent predictors associated with thyroid cancer. A multivariate model containing the extracted predictors was constructed and presented in the form of a nomogram. The validation and applicability of the CBCE nomogram was evaluated using the receiver operating characteristic (ROC) curve. Diagnostic performances were calculated to compare the CBCE nomogram with ACR-TIRADS (Thyroid Imaging Reporting Data System by American College of Radiology) and EU-TIRADS (Thyroid Imaging Reporting Data System by European Thyroid Association).The following factors were included in the CBCE nomogram: patient gender, age, shape, margin, composition and echogenicity, calcification, vascularization distribution, vascularization degree, suspicious lymph node metastases and elastography. The area under the curve (AUC) values were 0.978 and 0.983 for the training and validation groups, respectively. Compared with ACR-TIRADS and EU-TIRADS, the CBCE nomogram showed improved accuracy (0.944) and specificity (0.913) without sacrificing sensitivity (0.963) and showed the highest AUC with an optimal cutoff value of 0.55.The CBCE nomogram has good and high clinical practicability in predicting the malignancy probability of thyroid nodules. Thyroid nodules (TNs) are very common , 2. TherMoreover, clinicians estimate the risk of TNs and make subsequent decisions based on comprehensive information including clinical and US findings , 16, 17.This research aims to develop and validate a comprehensive and easy-to-use diagnostic tool for TNs based on clinical, B-mode, Color Doppler and elastographic US characteristics, providing more information for clinicians as well as avoiding overdiagnosis and overtreatment.This retrospective study was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and the requirement for written informed consent was waived. Between July 2021 and December 2021, a total of 1085 thyoid nodules from 1085 consecutive patients in our hospital were included. Diagnostic thyroid ultrasonography and surgery were performed on all nodules to obtain a definitive pathological diagnosis. Among them, 69 nodules were excluded. The exclusion criteria were as follows (1): patients with insufficient demographic and laboratory data including BMI (Body Mass Index) and preoperative TSH level (n=33) (2); patients with a history of thyroid surgery (n=11) (3); nodules with inadequate sonographic images including unsatisfied vascularity and elastographic images (n=17) (4); nodules with borderline types of pathological diagnoses including NIFTP (Noninvasive follicular thyroid neoplasm with papillary-like nuclear features) and diagnosis of undetermined malignant potential. (n=8). Ultimately, a total of 1016 nodules from 1016 patients were included. All nodules were randomly divided into the training group (n=712) and the validation group (n=304) at a ratio of 7:3. The training group was used to build the nomogram, while the validation group was used to evaluate the diagnostic performance of this tool. The study flow chart is shown in Clinical data were gathered by searching the medical records of patients gender, age, BMI, residence, family history of TC and preoperative TSH level. Residences were divided into inland areas and coastal areas. Family history of TC was defined as a first-degree relative with a history of TC. Preoperative TSH level was defined as the test results within one week before surgery. The normal range of TSH levels in our institution is 0.35–4.94 µIU/ml.Two radiologists (S.Y.X and X.F.N) with over ten years of experience in thyroid sonography used a 4-15 MHz linear probe  to perform all grayscale, color Doppler and elastography sonographic examinations. Images in the longitudinal and transverse directions of each target nodule were obtained. A picture archive and communication system recorded and uploaded all the images for later retrospective analysis. The grayscale, color Doppler and elastography sonographic features of the target nodules were assessed by two radiologists (S.Y.X and X.F.N) with professional training in thyroid ultrasound in consensus. In the case of disagreement between the two radiologists, the final decision was made by a third radiologist (W.Z) with 20 years of experience in thyroid ultrasound.The B-mode, color Doppler US features of TNs included shape , margin , composition and echogenicity , calcification , vascularization distribution , vascularization , diffuse lesion  and suspicious lymph node metastases (LNM)  in the cervical compartment. The vascularization distribution is divided into types 1-4 ; type 3: mild intranodular vascularity with or without perinodular vascularity (vascularity<50%); type 2: perinodular vascularity only; type 1: no vascularity) . In our Continuous variables are expressed as the mean ± SD. The variances were equal or unequal for continuous data using Student’s t test. The Mann–Whitney U test was used for continuous data with a non-normal distribution. Categorical variables were expressed as numbers (%), and categorical data were evaluated by Fisher’s exact test and Pearson’s χ2. Univariate and multivariate analyses were performed to screen independent predictors associated with TC. A multivariate logistic model containing the extracted predictors was constructed and presented in the form of a nomogram.P value < 0.05 was considered for significant differences.To measure the accuracy of the nomogram, the Hosmer–Lemeshow goodness-of-fit test was applied. To validate the nomogram, two ROC curves were produced for the training and validation groups. Diagnostic values were calculated to assess the applicability of the nomogram and to compare it with ACR-TIRADS  and EU-TAmong the 1016 thyroid nodules, 374 were benign and 642 were malignant. The average maximum diameters were 34.15 ± 17.16 mm for benign nodules and 10.23 ± 7.38 mm for malignant nodules. Follicular adenoma (n=22), Hashimoto thyroiditis (n=39), and nodular goiter (n=313) were benign lesions. Malignant lesions included follicular thyroid carcinoma (n=10), medullary thyroid carcinoma (n=15), and papillary thyroid carcinoma (n=617).P < 0.05). P < 0.05). These ten features were included into the development of the nomogram associated with TC.The univariate and multivariate analyses results were showed in In this study, a novel integrated diagnostic tool called the CBCE nomogram was developed and validated for predicting the malignancy probability of TNs based on clinical, B-mode, Color Doppler and elastographic US characteristics. The CBCE nomogram is not only based on B-mode US features, but also includes clinical, vascularity and elastographic US characteristics, which can provide more information on TNs. Compared with ACR-TIRADS and EU-TIRADS, the CBCE nomogram showed improved accuracy (0.944) and specificity (0.913) without sacrificing sensitivity (0.963) for predicting malignancy. With the optimum cutoff value of 0.55, the CBCE nomogram showed the highest AUC of 0.983 in the validation group. This means that when the malignancy probability of a nodule is higher than 0.55, it is regarded as a high-risk nodule and FNA (fine needle aspiration) is recommended; when the malignant probability of a nodule is lower than 0.55, it is regarded as a low-risk nodule and follow-up ultrasonography is recommended. The significance of this study is to provide a new strategy for clinicians as well as to avoid overdiagnosis and overtreatment.The clinical characteristics plays an important role in the diagnosis and treatment of patients with TNs. Some studies suggested that thyroid cancer has been more common in women than men, which may related to sexual hormones, although this has been controversial , 26. In Thyroid ultrasonography is the preferred tool for thyroid imaging because it can clarify the location, size, shape, echogenicity, composition, margin, calcification and vascularity of nodules, as well as the features of cervical lymph nodes. Results , 35–41 cThe US-based RSSs of TNs provides clinicians with an estimated malignancy rate based on the category. Currently, B-mode US-based RSSs include ACR-TIRADS , ATA 1919, KTA-Tour study has several highlights. First, to our knowledge, this is the first study to develop and validate an integrated diagnostic tool for predicting the malignancy probability of TNs based on clinical, B-mode, Color Doppler and elastographic US characteristics. Second, the CBCE nomogram has been demonstrated to have better diagnostic performances in predicting malignancy than ACR-TIRADS and EU-TIRADS. Third, the CBCE nomogram is an easy-to-use diagnostic tool for predicting malignancy. The corresponding malignancy probability of each nodule will be obtained by adding up the specific points of each predictor. Fourth, our study obtained an optimal cut-off value of 0.55 for distinguishing low-risk from high-risk nodules. The cut-off value separates the thyroid nodules into two groups, one of which is high risk with a malignancy probability above 0.55 and the other of which is low risk with a malignancy probability below 0.55. FNA and US follow-up are recommended for the two groups, separately. The significance of this study is to provide a new strategy for clinicians.There are some limitations in this study. First, as findings from a single center, our results have limited generalizability. Although our study has been internally validated and showed good diagnostic performance, it needs to further external validation. Second, as this is a retrospective study, data bias is inevitable. Further prospective studies will be needed to improve the model. Third, our study does not address FNA thresholds for thyroid nodules, which requires further research in the future. Despite these limitations, In conclusion, this study developed and validated a novel, comprehensive and reliable diagnostic tool based on clinical, B-mode, Color Doppler and elastographic ultrasonographic characteristics for thyroid nodules. Our research has two potential benefits, one of which is to identify patients with high-risk nodules who are the candidates for FNA, and the other is to provide a new strategy for clinical practice.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 the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by SX and XN. The first draft of the manuscript was written by SX and all authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.The authors are grateful to all participants of this study.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.


At the genus level, 14 enriched and 10 decreased microbes in the G group and 13 enriched and 18 decreased microbes in the GY group were identified. Among them, four microbes were enriched in both the G and GY groups, including Turicibacter, Romboutsia, Atopobium, and Coprobacillus. Although two microbes (Lachnospiraceae_ND3007_group and Eggerthella) exhibited similar tendencies in the G and GY groups, changes in these microbes were more significant in the GY group (p < 0.05). Interaction analysis showed that Intestinibacter, Romboutsia, and Turicibacter, which were enriched in both the G and GY groups, correlated positively with each other. In addition, nine microbes were decreased in the GY group, which demonstrates a potential protective role for these microbes in the pathogenesis of scleritis via interactions with each other.We compared intestinal microbes in anterior noninfectious scleritis patients with and without rheumatoid arthritis. Active noninfectious anterior scleritis patients without other immune diseases  or with active rheumatoid arthritis  were included in this study. Eight age- and sex-matched healthy subjects served as controls (N group). DNA was extracted from fecal samples. The V3-V4 16S rDNA region was amplified and sequenced by high-throughput 16S rDNA analysis, and microbial contents were determined. A significant decrease in species richness in the GY group was revealed by α- and β-diversity analyses ( Scleritis is an immune-mediated disease with initial symptoms of red eyes and pain. Scleritis can be divided into anterior scleritis and posterior scleritis according to anatomical location. Furthermore, anterior scleritis can be divided based on clinical manifestations into nodular anterior scleritis, diffuse anterior scleritis and necrotizing anterior scleritis. Overall, the pathogenesis of scleritis has not been completely elucidated. Although the immune response and infection are considered the main two causes of anterior scleritis, scleritis caused by direct infection of the sclera by pathogenic microorganisms such as bacteria is relatively rare. More than 50% of scleritis cases are associated with immune-mediated diseases, including rheumatoid arthritis and antineutrophil cytoplasmic antibody (ANCA)-associated granulomatosis GPA; . Among tCoprobacillus, Romboutsia, Atopobium, and Turicibacter. In addition, the abundances of three microbes  were altered in noninfectious anterior scleritis patients without other immune-mediated diseases, and the abundances of nine microbes  were changed in noninfectious anterior scleritis patients with RA. All these results suggest that intestinal microbes have coexisting identical and distinct roles in the development of scleritis in patients with and without RA.Intestinal microbes are closely related to the occurrence of RA. However, the role of intestinal microbiota in the pathogenesis of scleritis has not been reported, and whether the intestinal microbiota involved in RA is also related to scleritis is still unknown. Therefore, we investigated the relationship between intestinal microbes and scleritis by comparing intestinal microbes between noninfectious scleritis patients with and without RA. Our results showed four bacterial genera to be enriched in noninfectious anterior scleritis patients both with and without RA, including Thirty-one individuals were enrolled in the study, including 16 patients with active noninfectious anterior scleritis , seven patients with active noninfectious anterior scleritis combined with active RA , and eight healthy controls without immune-mediated diseases . Healthy controls consisted of family members from scleritis patients and age-related cataract patients without immune-mediated diseases. There was no significant difference in age or sex among the three groups in this study. The inclusion criteria for individuals enrolled in the study were as follows: (1) without other immune system diseases, such as ulcerative colitis, systemic lupus erythematosus, or Crohn’s disease; (2) without infectious disease; and (3) patients in the active stage of disease and not taking any medications. The diagnosis of noninfectious anterior scleritis was based on characteristic clinical manifestations, including ocular tenderness to touch, painful inflammation radiating to the forehead, edema affecting episcleral and scleral tissues, and injections of both the superficial and deep episcleral vessels . The diaFeces were collected from patients with anterior scleritis and healthy controls admitted to the Ophthalmologic Center of the Second Hospital between July 2018 and December 2019 and stored at ~80°C for analysis. DNA extraction from feces was performed according to E.Z.N.A. Stool DNA Kit  following the manufacturer’s instructions. The quality of the extracted DNA was assessed by 1% agarose gel electrophoresis and spectrophotometry . The target sequence that needed to be amplified was introduced in the sequencing of the 16S ribosomal RNA (rRNA) gene amplicon.The extracted DNA was sent to Beijing Aoweisen Gene Technology Co., Ltd. . We referred to previously reported experimental methods to amplify the target gene , as follWe used previously reported experimental methods to analyze the sequence  as follop < 0.05 indicated significance. Linear discriminant analysis (LDA) coupled with effect size (LEfSe) was performed using Glaxy . Only data with a p < 0.05 and a log LDA score > 2 are reported. Spearman correlation analysis was used as the mapping parameter of the correlation diagram. We visualized and analyzed the network using the personalbio platform , and the correlation was | R | > 0.6, p < 0.05.To explore differences between groups, Mothur software (version 1.31.2) was used to perform Metastats analysis, and a p = 0.02) groups. Differences in species richness between the N and GY (p = 0.004) groups were detected by β-diversity analysis, and differences between the G and GY (p = 0.04) groups were significant.The α-diversity  and β-diversity [analysis of molecular variance (AMOVA)] of the intestinal microbes in each group were analyzed ,B. AccorWe examined the number of reads sampled and found that the number of OTUs did not further increase with an increase in the number of samples sequenced. Thus, the sequencing depth and coverage were sufficient to cover the total diversity of the microbiomes examined .To investigate microbes involved in the pathogenesis of noninfectious anterior scleritis, we screened microorganisms with significantly different abundances between healthy people (Group N) and patients with noninfectious anterior scleritis without RA Group G; .Rikenellaceae_RC9_gut_group, Candidatus_Stoquefichus, Anaeroplasma, Enterorhabdus, Howardella, and Coprobacillus. Eight microbes were detected in both Group G and Group N, but the contents in the former were higher, including Prevotella, Megasphaera, Romboutsia, Intestinibacter, Lactobacillus, Atopobium, Turicibacter, and Eggerthella. Among the 10 microbes with decreased abundance, 4 were only detected in Group N: Senegalimassilia, Dielma, Gelria, and Prevotellaceae_Ga6A1_group. Six microbes were detected in both Group G and Group N, but the content in Group G was lower, including Ruminococcaceae_UCG-007, Lactococcus, Holdemanella, Cellulosilyticum, Lachnospiraceae_ND3007_group, and Lactonifactor.At the genus level, 14 enriched and 10 decreased microbes were detected in the G group. Among these enriched microbes, six were only detected in Group G, including Romboutsia, Turicibacter, and Eggerthella and a decrease in Lachnospiraceae_ND3007_group, Holdemanella, and Dielma in the G group , Romboutsia (both p < 0.01), Atopobium (both p < 0.05), and Turicibacter (both p < 0.01). The abundances of these microbes were significantly different between Groups N and G or GY, but there was no significant difference between Groups G and GY. We consider these microbes to be related to the pathogenesis of scleritis.Four microbes were enriched in both Groups G and GY, including Candidatus_Stoquefichus, Anaeroplasma, and Lactococcus. We consider that these microbes may be specifically related to scleritis pathogenesis.Microbes were enriched or decreased only in the G group, and not in the GY group, including Eubacterium_eligens_group, Odoribacter, Family_XIII_UCG-001, Ruminiclostridium_9, Ruminococcaceae_UCG-003, Ruminococcaceae_UCG-009, Eubacterium_rectale_group, Roseburia, and Catabacter. We consider these microbes to be related to the pathogenesis of RA or the shared pathogenesis pathway of scleritis and RA.Microbes were enriched or decreased only in the GY group, and not in Group G, including Lachnospiraceae_ND3007_group, Eggerthella) that exhibited similar abundances in both the G and GY groups. The abundance of Lachnospiraceae_ND3007_group was decreased and that of Eggerthella enriched. The changes in both the G and GY groups were significant compared with those in the N group, but the Eggerthella content was higher and the Lachnospiraceae_ND3007_group content lower in the GY group than in the G group. Interestingly, these two microbes also exhibited similar changes between patients with active VKH and patients with scleritis , which only exhibited significantly decreased contents in the GY group and were negatively related to each other. The final consequence of the mutual negative regulation between the two microbes appears to be related to the pathogenesis of RA or the shared pathogenesis pathway of scleritis and RA , is related to SCFAs. Previous studies have shown that a decrease in SCFA levels is closely related to the pathogenesis of RA . Odoribaribacter , Roseburoseburia , and Rumridium_9  are butyoccaceae  and Eubaacterium  are shorEggerthella and a decrease in Lachnospiraceae were found in both the G and GY groups, with the changes in the latter being more severe. Lachnospiraceae is an SCFA producer, and the decreased abundance of Lachnospiraceae_ND3007_group may have decreased SCFA production (Eggerthella enrichment might induce inflammatory cytokines, including TNF-α, IL-1β, and IL-6 (Eggerthella and a decrease in Lachnospiraceae have also been found in other immune-mediated diseases, including Vogt–Koyanagi–Harada (VKH; Eggerthella and Lachnospiraceae are not specific. The content of Lachnospiraceae_ND3007_group was lower and that of Eggerthella higher in the GY group. Whether the levels of these two microbes are related to the severity of eye disease needs to be further studied.An increase in oduction . Eggerthand IL-6 . An incrada VKH;  Crohn’s ada VKH; . This reOur study suggests the existence of a gut-eye axis. Intestinal dysbiosis may be a crucial factor influencing ocular diseases. Dysbiosis of the intestinal microbiota causes upregulated expression of inflammatory cytokines in peripheral blood, which in turn causes ocular inflammation. In addition, the gut microbiota may cause extraintestinal diseases, including RA, through antigenic mimicry . These aIn conclusion, our study indicates that intestinal microbes are involved in the pathogenesis of noninfectious anterior scleritis in patients with and without rheumatoid arthritis. The roles of these microbes are both pathogenic and protective. They may participate in the pathogenesis of anterior scleritis by interacting with each other and altering immunity.In vitro studies of the effects of these intestinal microbes on patient’s immune cells might provide some clues. Additionally, whether the extent of these changed microbes correlates with the severity of scleritis requires further investigation.This is a descriptive study about changes in intestinal microbes in noninfectious anterior scleritis patients with and without RA, and there is a lack of research on the mechanisms by which these altered intestinal microbes cause scleritis. As there is currently no accepted animal model of anterior scleritis, it is not feasible to validate the mechanisms of these intestinal microbes. The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.This study was approved by the Ethics Committee of the Second Hospital of Jilin University. The number is 2021120. The patients/participants provided their written informed consent to participate in this study.ML: data collection and analysis and writing the manuscript. LY, FB, and LZ: collection of samples, data analysis, and editing the manuscript. XL: acquisition of funding, supervision and planning of experiments, data analysis, and writing the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China, grant no. 81300752, the Jilin Province Science and Technology Development Plan Project, grant no. 20200201333JC, and the Jilin Province Health Special Project, grant no. 2020SCZT058.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. 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Tegumentary leishmaniasis (TL) includes cutaneous (CL) and mucosal (ML) leishmaniasis; despite being endemic in southern Europe, it is often underdiagnosed and underreported. This study aimed to retrospectively examine data collected from patients with TL in a selected area of northeastern Italy . A network of 10 diagnostic units within RER was established, and TL cases diagnosed in RER from 2017 to 2020 were evaluated. A total of 135 TL cases were collected ; patients ranged from 1 to 84 years, with a median age of 57. Among these cases, 113 (84%) were notified to the public health authorities. The average annual incidence of TL was 0.76 cases per 100,000 inhabitants. Infections were acquired within the RER in 84% of cases; the 113 autochthonous cases were distributed in the foothills areas of the region. We provide evidence of a defined spatial distribution of TL cases in a selected area of northeastern Italy, as well as a relevant number of ML cases. Our observations suggest the need to raise awareness about TL among clinicians and pathologists, promote the molecular confirmation of cases by reference laboratories, and encourage the establishment of surveillance networks for this neglected disease. Leishmania and transmitted by phlebotomine sand flies (Diptera: Psychodidae) [Leishmaniases are a group of vector-borne diseases caused by protozoan parasites of the genus hodidae) . The clihodidae) .CL is the most common form of the disease, with a global incidence of around 1 million cases/year . It has TL is a neglected disease in Europe; it is often misdiagnosed or diagnosed with delay, and its surveillance is not mandatory in Austria, Belgium, France, and Germany . The CL Leishmania infantum is the causative agent of canine leishmaniasis (CanL) in the Mediterranean basin as well as human VL and TL [L. infantum are not clearly reported to be associated with previous CL [L and TL ,10. ML lvious CL ; the chrvious CL ,11.In Italy, case notification for human leishmaniasis is mandatory, but a high rate of undernotification is estimated as TL is often a benign disease that does not require hospitalization . In 2018Nevertheless, the epidemiological pattern of leishmaniasis in Italy is changing, leading to an increase in human cases in the northern part of the country. An upsurge of CL cases was recently observed in the Emilia-Romagna region (RER) in northeastern Italy, with clusters in areas between the provinces of Modena and Bologna and in the provinces of Forlì-Cesena and Rimini . A studyIn 2014, the upsurge of human leishmaniasis cases in RER ,16,17,18Despite the strengthening of the surveillance system, underdiagnosis and undernotification of TL cases are still a problem in RER. This study aimed to retrospectively examine the cases of TL identified in RER from 2017 to 2020. To ameliorate the evaluation of TL cases within RER, a network of 10 diagnostic units was established. Each unit was composed of a multidisciplinary team of dermatologists, infectious disease specialists, pathologists, parasitologists, and epidemiologists. 2 [2 [2; 25%), hills , and an alluvial plain .This study area is the RER, which is located in northeastern Italy and covers 22,445 km2 . The regLeishmania parasites were detected by histology and/or by molecular methods. Different TL types were defined following definitions that were established by the European LeishMan consortium [The definition of a case of TL was based on the WHO directives ,23: a paTL cases were classified as: (i) autochthonous, when the place of infection was within RER; (ii) Italian extra-RER, when the place of infection was in Italy but outside RER; and (iii) imported, when the place of infection was outside Italy.Human leishmaniasis is a notifiable disease in Italy through an infectious disease reporting system, which is centralised at the national Ministry of Health ,8. PhysiThe Skin_Leish_RER network was established to improve the surveillance of TL cases in RER. Epidemiological data, clinical features, and data on anti-leishmanial therapy and outcome were collected. The network included ten diagnostic units: Piacenza, Parma, Reggio-Emilia, Modena, Bologna, Ferrara, Ravenna, Forlì, Cesena, and Rimini; these units include specialists in Parasitology, Dermatology, Infectious Diseases, and Pathology . The SkiHistological and molecular diagnosis were performed on skin or mucosal biopsies. For histological examination, biopsies were routinely formalin-fixed and paraffin-embedded (FFPE). Five- to six-µm sections were obtained from the block and stained with haematoxylin and eosin (HE) to detect leishmanial amastigotes. Slides were observed at 100×, 400×, and 600× magnification. If necessary, a Giemsa stain was evaluated in addition to HE. Molecular confirmation was performed on FFPE at RRL. DNA extraction was performed by the NucleoSpin DNA FFPE XS kit . Real-time PCR was carried out with two in-house assays, one targeting a segment of the small-subunit ribosomal RNA (rRNA) gene  and the We collect all confirmed cases of TL  that were diagnosed in RER, for which biopsy samples were obtained between 1 January 2017 and 31 December 2020. Data were collected from the national notification system (SMI) and from the recovery activities of the Skin_Leish_RER network and organized in an electronic database that was shared with network members by using a password-protected platform. The sensible data of patients involved in this study were anonymized by an alphanumerical code. This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the Area Vasta Emilia Centro (study number: EM1008-2021_97/2017/O/Tess/AOUBo). We performed a descriptive analysis of TL cases by year of diagnosis, notification to LHU, origin of the case (autochthonous or imported), type of leishmaniasis, sex, age, molecular confirmation performed by RRL, clinical form, anatomical area of lesion/s, number of lesions, and presence of immunosuppressive conditions. The yearly incidence was evaluated for autochthonous cases. The seasonality of symptoms’ onset and delay in diagnosis were also assessed. All analyses were performed with Ms Excel 2017 and R 4.0.2 . The spaBetween January 2017 and December 2020, 135 cases of TL were identified in the RER, of which 113 (84%) were notified to the LHU . The estConcerning the place of infection, 113 TL cases (84%) were classified as autochthonous . Among tp = 0.39). Among the clinical forms of TL, the most represented was CL , while ML was present in 11 cases (8%) . Males wCL lesions were more often single (n = 88) than multiple (n = 19); for 17 CL cases, we had no information about the number of lesions. Concerning ML, five out of eleven cases (46%) presented multiple lesions, and five cases (46%) exhibited a single lesion, while no information was available for one case. As shown in As shown in Information about potential immunosuppressive conditions was recorded for 102 patients; 16 individuals showed underlying conditions that could cause immune impairment, including HIV (4 patients), autoimmune diseases (5 cases), cancer (5 patients), and diabetes (1 case), while in one patient the immunosuppressive condition was undefined. As shown in Data on time to diagnosis were available for 92 patients; 36 cases of TL (39%) were diagnosed more than 6 months after the lesions’ onset . The diagnosis of TL was carried out by histology and/or molecular tools. Histological examination was carried out in 118 out of 135 cases ; among tData on treatment were recorded in 90 out of 135 (66%) cases . TherapyData on treatment outcome were available for 84 out of 135 cases 62%, . Among tLeishmaniases are considered endemic and emerging infections in southern and continental Europe, respectively, yet these infections are underrecognized and underreported in most EU countries . DespiteOur study examined TL cases that were identified in an endemic area of 4.4 million inhabitants in northeastern Italy. The retrospective collection of cases between 2017 and 2020 was implemented by the establishment of a multidisciplinary network of medical specialists (Skin_Leish_RER network). The network recovered 22 cases beyond the 113 notified cases, for a total of 135 confirmed cases of TL in a 4-year period, with a yearly incidence ranging from 0.54 to 0.98 cases per 100,000 inhabitants. The drop in TL cases in 2020  was likely due to the disruption of the health system due to the COVID pandemic .Phlebotomus (Ph). perfiliewi, a sand fly species able to maintain the circulation of L. infantum [Most of the TL cases in the selected region were autochthonous  and distributed in foothills areas, which are characterized by climatic and environmental conditions more suitable for the occurrence of phlebotomine sand flies as compared to the plain areas of the RER . Indeed,infantum ,31,32. Tinfantum ,17,18,33L. infantum were male and older than 43 years; the predominant clinical feature was a single cutaneous nodule in the head, neck or in the upper extremities. Further, we observed that 8% of TL cases were ML; in line with recent findings [L. infantum can disseminate to the mucous membranes with a higher frequency than previously reported [L. infantum could be linked to the intrinsic virulence of the parasite [In line with published evidence , most pafindings  L. infanreported . Besidesparasite  and/or sparasite . MoleculAmong the 16 immunocompromised patients, 10 (63%) exhibited a severe disease, i.e., ML and/or more than 4 CL lesions and/or a lesion’s diameter > 4 cm and/or plaques, while only 26 (31%) out of 84 individuals with no underlying immunosuppressive conditions exhibited a severe TL. Despite data being available only for 84 individuals, the treatment failure rate was also higher in immunocompromised patients than in immunocompetent individuals . These findings are not surprising, as immunocompromised patients are predisposed to develop multiple lesions with a higher frequency of ML and exhibit higher rates of treatment failure . Case confirmation of TL relies on the direct demonstration of the parasite or its genome in clinical specimens from the skin or mucous membranes, using microscopic examination or molecular analysis, respectively . It is wDifferently from other European countries, including France , there aThis study has several limitations. By collecting data from a limited geographic area, the results cannot be generalized to the entire country. Further, because of the retrospective nature of this study, information regarding significant variables, including follow-up data, were often lacking. In addition, HIV testing was not systematically performed, and the condition of immunosuppression was not always recorded; therefore, the actual prevalence of TL in immunocompromised patients in northeastern Italy cannot be defined. We provided evidence of a high incidence of TL with a specific geographic pattern in RER, a region of northeastern Italy, as well as a relevant number of ML cases. Our observations suggest the need to raise awareness about TL among clinicians and pathologists, promote the molecular confirmation of cases by reference laboratories, and encourage the establishment of surveillance networks for this neglected disease.