Glioblastoma (GBM) represents one of the deadliest tumors owing to a lack of effective treatments. The adverse outcomes are worsened by high rates of treatment discontinuation, caused by the severe side effects of temozolomide (TMZ), the reference treatment. Therefore, understanding TMZ’s effects on GBM and healthy brain tissue could reveal new approaches to address chemotherapy side effects. In this context, we have previously demonstrated the membrane lipidome is highly cell type-specific and very sensitive to pathophysiological states. However, little remains known as to how membrane lipids participate in GBM onset and progression. Hence, we employed an ex vivo model to assess the impact of TMZ treatment on healthy and GBM lipidome, which was established through imaging mass spectrometry techniques. This approach revealed that bioactive lipid metabolic hubs  were altered in healthy brain tissue treated with TMZ. To better understand these changes, we interrogated RNA expression and DNA methylation datasets of the Cancer Genome Atlas database. The results enabled GBM subtypes and patient survival to be linked with the expression of enzymes accounting for the observed lipidome, thus proving that exploring the lipid changes could reveal promising therapeutic approaches for GBM, and ways to ameliorate TMZ side effects. Glioblastomas (GBM), the most aggressive type of astrocytoma, are the most frequent malignant primary brain tumor, accounting for 15% of all brain tumors and presenting a worldwide incidence of 3–4 per 100,000 people . UnfortuAs in many other cancers, the lack of models accurately mimicking genetic heterogeneity and tumor microenvironment hinders the study of glioblastoma . HoweverSecond to adipose tissue, the brain is the most lipid enriched organ in the body, particularly in membrane lipids, phospholipids, and sphingolipids. Cell membrane lipid composition, or membrane lipidome, includes hundreds of molecular species, each of which have specific roles that remain mostly unknown. Consistently, the lipidome has proven to be highly sensitive to pathophysiological processes, and alterations in cell lipid profile are associated with multiple pathophysiological processes such as differentiation ,16,17,18In addition, the regulation of several genes involved in lipid metabolism, such as SCD and ELOVL6 which participate in mono- and polyunsaturated fatty acid  synthesis, is altered in GBM ,33. One Taking into account the close relationship already established between lipid metabolism and GBM development, we considered the study of its lipidome and the impact on lipid composition of TMZ established with spatial resolution which could help to reveal new targets to treat GBM or address TMZ side effects.An ex vivo approach was employed to assess the impact of TMZ on GBM lipidome. Thus, surgically healthy and GBM biopsies were obtained from the same patient, immediately placed into DMEM-F12 cell culture medium and incubated in the presence or absence of TMZ  or DMSO (vehicle). After the incubation period, biopsies were snap-frozen in the absence of cryoprotective substances, and healthy brain and GBM sections were analyzed using MALDI-IMS in negative- and positive-ion mode at 50 µm lateral resolution.First, the presence of the regions differing in their lipidome within the brain and GBM biopsies were investigated to establish the differences between healthy and GBM lipidome. We previously demonstrated the high correlation existing between IMS lipid clusters stablished by K-means and HD-RCA algorithms and histological tissue structures, cell types, or even cell pathophysiological states ,22,35,36Next, we compared the lipid profile of the highly proliferative areas of healthy and GBM samples. Lipidome analysis detected 124 different lipid species belonging to 11 lipid classes. Unsupervised PCA using all lipid species demonstrated that the lipidome of the highly proliferative regions (MKI67+ clusters) discriminates between healthy and GBM tissue a.Statistical comparison of lipid classes demonstrated that phosphatidylethanolamine (PE), PI, and sphingomyelin (SM) were significantly increased in GBM . Conversely, a statistical decrease was observed in sulfatide content in GBM tissue (2.9-fold decrease). It is worth mentioning that the values represented in Next, we analyzed the changes occurring at the molecular species level. Of special interest was the differential impact on diacyl PE and PE P- species. In the healthy brain, the most abundant PE diacyl species were 36:1, 40:6, and 38:4 . In GBM tissue, the most abundant species were 36:1, 38:4, and 36:2 . Total diacyl PE levels were greatly increased in GBM tissues , especiaRegarding sphingolipids, the main SM species in the healthy brain were d36:1, d42:2, and d34:1 , whereas in GBM they were d34:1, d36:1 and d36.2 . The most striking changes between study groups were the sharp increase in d34:1 and d40:1 molecular species and the decrease in d42:2 in GBM tissue d. FinallAlthough TMZ is the standard care treatment for GBM, the impact it might have on the lipidome remains unknown. Thus, to further understand this aspect, we compared the lipid profiles of the clusters overlapping with the most proliferative areas, i.e., the MKI76+ areas in the biopsies incubated with TMZ.PCA revealed that the two experimental groups, TMZ treated and non-treated GBM, could be successfully differentiated based on the lipid profile of the proliferative regions . HoweverOne of the most relevant clinical issues of GBM treatment is the discontinuity of chemotherapy due to side effects. In this study, we investigated the impact of TMZ on healthy brain lipid composition. The results showed that the treatment induced changes at the level of both lipid classes and molecular species composition. Thus, PCA clearly separated the study groups based on lipid class composition a. StatisRegarding diacyl PE species, the most abundant species in healthy TMZ treated brain were 36:1, 40:6, and 38:4 . In this class, the only significant changes were a slight increase in 34:0 (3.2 vs. 5.5%) and a decrease in 38:1 (6.1 vs. 4.0%) a. The moFinally, TMZ treatment did not drastically affect SM lipid composition in healthy brain. The main SM species in treated tissue were d36:1, d38:1, and d42:2 . TMZ decreased the level of d42:2, d42:1, and d44:2 compared to vehicle-treated tissue d. MeanwhIn summary, our results demonstrated changes in various lipid species such as phosphatidylinositols (PI), sulfatides, and phosphatidylethanolamine plasmalogens (PE P-) in GBM tissue. Thus, PE P- species were the most affected by the tumor transformation, showing a general increase in PUFA-containing species. On the other hand, TMZ treatment of healthy and tumor brain tissue revealed that, in short-term treatments, this compound barely affected the GBM lipidome. Conversely, this compound induced multiple changes in the healthy brain, with PE plasmalogen species the most affected.The brain represents one of the tissues showing the most singular lipid profile and, as expected, such a complex process as tumorigenesis bears a profound impact on it. In order to outline the mechanisms accounting for the altered lipid phenotypes observed in GBM and to delve into the regulatory mechanisms, we interrogated a publicly accessible transcriptome database, specifically, the TCGA-GBM transcriptome database. Co-expression modular analysis (CEMiTool)  was perfThe CEMiTool analysis returned seven modules wherein it was possible to distinguish several hub genes . Using tBased on the lipidomic differences observed between Healthy vs. GBM study groups , we deciThe Classical and Mesenchymal subtype modules contained several enzymes involved in fatty acid uptake and intracellular signaling (FABPs), fatty acid release from phospholipids by hydrolysis (PLA2s), PUFA synthesis (ELOVL2), and eicosanoid synthesis , which would be in line with the increase in PUFA-containing PE P- and PI species. On the other hand, the Neural subtype was enriched with INPP5F and DGKB, both involved in phospholipid metabolism homeostasis and intracellular signaling by hydrolyzing one phosphate from the phosphoinositides and adding one phosphate to DG, respectively. Finally, the module enriched in the Proneural subtype contained UGT8, a sphingolipid related enzyme necessary for the synthesis of the myelin sheath. Hence, we analyzed the patient survival data associated with the expression levels of the genes included in Importantly, we discovered that the expression of five of the genes, enriched in Classical and Mesenchymal subtypes, were significantly associated with poor overall patient survival  . These gPLA2G5, FABP7, and ALOX5AP  and 1,5-diaminonaphtalene (DAN), hematoxylin and eosin for histological staining, Ki67 primary antibody marked with FITC , DMEM-F12, FBS, penicillin–streptomycin, and TMZ were purchased from Sigma–Aldrich .®  surgical microscope with BLUE 400TM integrated fluorescence module was used for surgical resections. Between 3 and 4 h after administration of 5-aminolevulinic acid, positive tumor samples and healthy samples were obtained during surgical resection from the surgical margin and immediately incubated in DMEM-F12 in the presence or absence of TMZ ) for 4 h at 37 °C and 5% O2. These were then collected and stored at −80 °C until processing.Human sample collection: Sample collection for this study was specifically approved by the Ethics Research Committee of the Balearic Islands (nº IB 3626/18 PI). Informed consent in writing was obtained for each patient enrolled in the study. Four patients harboring brain tumors suggestive of GBM, newly diagnosed after neurological symptoms in which surgical resection or open biopsy were indicated, were included. Anatomopathological analysis confirmed the diagnosis of glioblastoma in the four patients recruited. Patients received the pharmacy-compounded solution of 5- aminolaevulinic acid 1 h before anesthetic induction. Total dose was according to patient weight (20 mg/kg). The PenteroHistological sections: Sections 10 μm thick were obtained with a cryostat  at −20 °C without using cryoprotective substances or embedding material. Sections were placed on plain glass microscope slides for MALDI-IMS analysis and consecutive sections for IF analysis were placed on positive charged adherent plain glass microscope slides. Samples were stored at −80 °C until subsequent MALDI-IMS or immunofluorescence analysis.v/v) and then incubated with 1:500 MKI67 primary antibody marked with FITC (10 mg/mL)  in 0.2% BSA-PBS, following the previously described protocol in Bestard-Escalas et al. [Immunofluorescence analysis: Histological sections were fixed with −20 °C prechilled 100 µL methanol–acetone  histological sections obtained from four different patients were prepared and analyzed by MALDI-IMS as described in Garate et al. . Brieflym/z and the species in the software’s database  and in the lipid maps database (www.lipidmaps.org (last accessed on 10 January 2022)). Mass accuracy always measured better than 9 ppm and was typically better than 3 ppm. In this type of analyzers, mass accuracy depends somehow on the intensity of the peaks, therefore, the m/z with higher intensity present better mass accuracy. For m/z channels with several lipid assignments, “On-tissue” MS/MS and MS3 was carried out in order to unequivocally assign them.Data were acquired with a mass resolution of 60,000 in the scanning range of 550–1000 for negative-ion mode and 480–100 Da for positive-ion mode. Two microscans of 10 laser shots were recorded for each pixel and the raster size used was 50 microns. Spectra were aligned and analyzed using in-house programs developed in Matlab . Lipid assignment was based on the comparison between the experimental For the sake of clarity, only species present in at least 80% of the analyzed samples were considered for further statistical analysis.Interrogation of GBM gene expression and methylation datasets: Human TCGA GBM Affymetrix U133a and Methylation27k datasets were interrogated using Xena Browser. The data relative to the selected genes shown in Co-Expression Modules identification Tool (CemiTool): CEMiTool was used to identify co-expression of lipid related genes associated with the GBM molecular subtypes, according to Verhaak et al. . To thisGene ontology (GO) analysis: This was carried out using the DAVID bioinformatic resources 6.8 server .t-test, ANOVA, and Post Hoc analysis were computed using SPSS Statistics 25.0 for Windows . PCA analysis and separation models were carried out by Orange Biolab 2.7.8  [Statistical analysis: To establish tissue clusters, an in-house programmed clustering algorithm was used, setting the number of segments from 2 to 8. To statistically evaluate the differences in the lipid fingerprints between the identified areas, lovenia) . For TCGAltogether, the present study provides solid evidence regarding the sensitivity of the membrane lipidome in the development of GBM and describes the multiple effects occurring at the level of lipid composition in brain tissue upon TMZ treatment. The results suggest a scenario where, over short time periods, the tumor tissue lipidome is initially impervious to treatment, while the healthy brain is more sensitive to it. The unexpected sensitivity of healthy tissue to this treatment could be related to the side effects of blurry vision or dizziness that eventually lead to high discontinuity rates. There is no doubt that knowledge of the side effects could help reduce discontinuity rates, which currently affect 20% of the patients, and increase the effectiveness of future therapies. However, this study contains some limitations; namely, the number of samples included was limited, due to the difficulty in obtaining these types of samples and the challenges associated with the ex vivo model, which can rapidly compromise tissue structure. It is in the light of these limitations, that the results of the in silico approach gain more relevance, as the transcriptomic and genomic results support the lipidomic results described herein. Thus, the interrogation of the TCGA-GBM transcriptome database highlighted the role of PUFAs in GBM progression, especially in the Classical and Mesenchymal subtypes. The description of how lipid enzymes are differently regulated according to molecular subtype was discovered to be in line with the changes in PUFA-containing phospholipids described in this work. This genomic analysis revealed a specific lipid gene signature depending on the molecular classification of GBM. Globally, the results showed newly coordinated lipid–genetic changes that could set the base for other approaches to GBM treatment.


In addition, a slightly positive correlation was found between indices and HbA1c in both sexes . None of the measures achieved acceptable levels of discrimination in ROC analysis . Assessing BMI, the prevalence of prediabetes among men increased from 20.4% to 36.2% around the cutoff of 28.2 kg/m2, with similar data among women (from 29.3 to 44.8% with a cutoff of 28.6 kg/m2). No lonely obesity index appears to be the perfect biomarker to use in clinical practice to detect individuals with prediabetes.Prediabetes is closely related to excess body weight and adipose distribution. For this reason, we aimed to assess and compare the diagnostic usefulness of ten anthropometric adiposity indices to predict prediabetes. Cross-sectional study with 8188 overweight subjects free of type 2 diabetes from the ILERVAS project (NCT03228459). Prediabetes was diagnosed by levels of glycated hemoglobin (HbA1c). Total body adiposity indices  and abdominal adiposity  were calculated. The area under the receiver-operating characteristic (ROC) curve, the best cutoff and the prevalence of prediabetes around this value were calculated for every anthropometric index. All anthropometric indices other than the A body adiposity were higher in men and women with prediabetes compared with controls ( The occurrence of prediabetes has expanded progressively in recent decades, reaching the 374 million people affected in 2017 according to the International Diabetes Federation ,6. TherePrediabetes is closely related to excess body weight and adipose distribution in several cross-sectional and longitudinal studies ,11,12,13On this basis, the main objective of this study was to determine and compare the diagnostic performance of adiposity estimated by different indices in the prediabetes stage in a large cohort of middle-aged overweight participants with low to moderate cardiovascular risk. For this purpose, we calculated ten anthropometric indices . The study was done stratified by sex, as its disproportion in body fatness and adiposity distribution has been well documented .ClinTrials.gov (accessed on 21 November 2020) Identifier: NCT03228459) comprises a complete cohort of 8330 participants enrolled between January 2015 and December 2018 from 32 primary health care centers from the Catalan Health Institute in the province of Lleida, Spain −1/2 1/2. After, the following formula measures the A body shape index: 364.2 − (365.5 × ε), in which values closer to 1 are related to rounder individuals, whereas lower values are associated with leaner individuals. Finally, the body roundness index was calculated as: WC (m)/[BMI2/3 × height (m)1/2] [The WHR was measured as WC (m) divided by height (m) . The equ (m)1/2] .As hip circumference was not included in the initial design of the ILERVAS study, anthropometric indices containing hip circumference such as abdominal volume index, body adiposity index, and waist to hip ratio were not reflected in our study. The short version of The International Physical Activity Questionnaire (IPAQ) was administered to all participants. The metabolic equivalent of task (METs)-min per week, a multiple of the resting metabolic rate, was assessed .Participants were classified based to the presence of prediabetes. The normal distribution of the variables was evaluated using the Shapiro-Wilk test. Known for its skewed distribution, quantitative data were showed as the median [interquartile range]. Baseline characteristics through the diagnosis of prediabetes were analyzed using the Mann-Whitney U test for quantitative variables, and the Pearson’s chi-squared for categorical variables. The risk ratio was shown. The bivariate interactions between obesity indices were evaluated by the Spearman correlation test. Because differences in the amount and distribution between men and women are recognized, we showed our results by sex .p-values were based on a two-sided test of statistical significance, set at p < 0.050.The areas under Receiver Operating Characteristic (ROC) curves with a whole sensitivity/specificity report and calculating Youden J statistic were designed to study the diagnostic performance of all anthropometric indices to discriminate prediabetes. In addition, a new variable obtained from the combination of anthropometric indices  significantly related with the presence of prediabetes in the logistic regression model (backward method) was calculated. An odds ratio with its 95% confidence interval was also calculated. The area under the ROC curve was interpreted following the next guidelines: 0.9 to 1.0, excellent; 0.8 to 0.9, good; 0.7 to 0.8, fair; 0.6 to 0.7, poor; and 0.5 to 0.6, not useful. All statistical analyses were made via the SSPS statistical package . All Informed written consent was obtained from all subjects, and the ILERVAS protocol was approved by the ethics committee of the Arnau de Vilanova University Hospital (CEIC-1410). The investigation was completed agreeing with the ethical guidelines of the Declaration of Helsinki and also followed Spanish legislation concerning the protection of personal data.p < 0.001).The ILERVAS cohort comprises 2731 (33.4%) individuals with prediabetes. The main clinical and metabolic data according to the presence of prediabetes are displayed in p = 0.984).In both sexes, as well as in the entire population, prediabetes was associated with significantly higher values of total and visceral adiposity indices, with the exception of the A body shape index . Similar2 , with similar data among women   . SimilarIn the middle-aged Caucasian ILERVAS cohort, participants with prediabetes showed a significant increase in estimated total body and abdominal fat. However, our study also reveals that this association between equations used to estimate body composition and prediabetes was weak. Furthermore, our research was not able to find any anthropometric index that deserves to replace BMI in clinical practice.Prediabetes is a metabolic condition with serious health consequences that needs to be screened . As blooChina National Diabetes and Metabolic Disorders Study, with 10,098 men and 17,454 women with a BMI < 25 kg/m2, for each increase in the standard deviation of BMI (2.1 kg/m2) and WC (8.3 cm), fasting glucose levels increased by 0.128 and 0.170 mmol/L in men, and by 0.112 and 0.167 mmol/L in women, respectively [When three of the most popular anthropometric indices have been used, including BMI, WC and WHR, instead of standard gold techniques in general practice, similar results have been achieved ,12,14,33ectively .In our study, total adiposity was examined using CUN-BAE and Deurenberg’s equations together with BMI. Although there was no prior information on these two indices and the presence of prediabetes, our results showed a similar predictive power between the three indices, in both men and women.2015 Health, Well-Being, and Aging Study, with a total of 3307 Colombian individuals over the age of 60, there were significant differences in the BMI, body roundness index and conicity index between healthy patients and subjects with prediabetes, but with limited prediction capacity [Regarding the estimation of abdominal obesity and the prevalence of prediabetes, excluding WC and WHR, absent or scarce information is available ,14,37,38capacity . Howevercapacity . In addicapacity . In the capacity . Thus, aThe neck circumference requires some additional comment. It is a simple and reliable anthropometric measure that has been proposed as a metabolic risk marker . In a poSome limitations of our research should be noted. First, the lack of an accurate measure of body composition determined with a DXA or magnetic resonance imaging. In fact, among 1603 Korean adults, the visceral fat mass measured with DXA had a higher OR for prediabetes than BMI, WC and WHR . Second,2 in males ≥ 28.6 kg/m2 in females). Additional studies are needed, using the combination of new indices and the addition of other capital factors related with glucose abnormalities such as patient’s physical activity or patient phenotype to improve the explanatory power of anthropometric indices for glucose abnormalities.In closing, the main finding of our work was the lack of differences between the indices related to total body or abdominal adiposity to better categorize the presence of prediabetes. Moreover, total area under ROC indicates that none of them were useful in making clinical decisions in the ILERVAS population owing to low statistical power. Consequently, no isolated obesity index appears to be the perfect biomarker to use in clinical practice to detect subjects at risk for prediabetes. Even so, we recommend narrowing prediabetes screening in subjects with some cardiovascular risk factor and moderate overweighed (in our cohort, a BMI ≥ 28.2 kg/m


PurposeIn this study, we investigated the association between the body mass index (BMI) and varicocele recurrence post-intervention in our local Saudi population. We also explored the association between recurrence and other predictors such as age, laterality, indication for surgery, type of intervention, clinical grade, testicular delivery, and method of ligation.MethodsWe conducted a retrospective cohort study, including all patients who had microscopic varicocelectomy surgery or radiographic embolization for varicoceles over a five-year period. The data included demographic information and intervention-related variables. Descriptive and analytical statistics were used to analyze the data.ResultsWe included 147 patients who had microscopic varicocelectomy surgery or radiographic embolization. We categorized the patients according to their BMI as underweight, normal, overweight, and obese. We found no statistical association between any BMI group and the recurrence of varicocele (P>0.05). However, there was a significant association between the clinical grade and recurrence (P<0.05).ConclusionThis study did not show any significant correlation between height, weight, BMI, and varicocele recurrence after an intervention. The only predictor of varicocele recurrence was the clinical grade. A varicocele is an abnormal dilation of the venous pampiniform plexus of the spermatic cord. It is found in 15% of adolescent males and more than 30% of infertile men . Though Multiple modalities are available for the treatment of varicocele. Retroperitoneal and laparoscopic operations aim to isolate the internal spermatic vein proximally near the internal inguinal ring . MicrosuAs more modalities are becoming available, practitioners are required to offer the patients evidence-based counseling regarding the risks related to the interventions. Recurrence is a complication frequently explored in the literature; however, few papers focus on the predisposing pre-intervention factors. The incidence of recurrence post-intervention is between 0.6% and 28%, depending on the chosen modality -7. AdditIn the current study, we aimed to assess the association between body mass index (BMI) and varicocele recurrence post-intervention. We also explored the association between varicocele recurrence and other predictors such as age, clinical grade, laterality, reason for surgery, and type of intervention.The study design was a retrospective cohort study. The patients' medical records were reviewed, and the data were collected using a data collection form. All patients who underwent microscopic varicocelectomy surgery or radiographic embolization of a unilateral or bilateral varicocele from January 1, 2016, to December 31, 2019, in our tertiary care center were included in the study. All the patients diagnosed with varicocele but not with microscopic varicocelectomy surgery or radiographic embolization were excluded. We also excluded patients who had previous interventions in other centers, and patients lost to follow-up post-intervention. The record of the first visit to the clinic was used to report the clinical examination. We used the measurements of height and weight recorded in the clinic preoperatively. The BMI score was calculated using the formula: weight in kilogram divided by the square of the height in meters. All the patients who received a surgical intervention had a sub-inguinal microscopic varicocelectomy and operated on as day surgery cases by two surgeons with fellowships in andrology. We reviewed the operative notes to obtain the data. Varicocele recurrence was defined by the clinical examination findings at least three months after the intervention. Follow-up ultrasound studies were requested for patients with a clinical recurrence. The radiologist reviewed all the ultrasound findings to standardize reporting between patients.Descriptive and analytical statistics were conducted. The Statistical Package for the Social Sciences (SPSS) software for Windows ver. 24  was used for data analysis. The mean and standard deviation (SD) were calculated for quantitative variables such as age, weight, height, BMI, veins ligated, first ultrasound study maximum diameter, and follow-up ultrasound study maximum diameter. Frequency and percentage were calculated for the qualitative variables. A one-way analysis of variance (ANOVA) test was used to compare the recurrence of varicocele and the quantitative data (BMI and age). A Chi-square test was used for both dependent and independent qualitative variables.The study was approved by the Institutional Review Board at King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (IRB#: RYD-20-419812-174023). The manuscript has been read and approved by all the authors, and each author indicated that this manuscript represents appropriate and honest research.In total, 147 patients who underwent surgery or embolization from January 1, 2016, to December 31, 2019, after applying our exclusion criteria, were included. Table 2), normal (18-25 kg/m2), overweight (25-30 kg/m2), and obese (>30 kg/m2).Age was categorized as less than 25 years, 25-45 years, and above 45 years. The BMI was categorized according to the National Institutes of Health Clinical guidelines as underweight , the indication for surgery was infertility, followed by symptomatic causes  and occupational causes . The majority  of the varicoceles were left-sided, two (1.4%) right-sided, and 37 (25.2%) bilateral. A small proportion  had grade I varicoceles, 80 (54.4%) grade II varicoceles, and 44 (29.9%) grade III varicoceles.Regarding the type of intervention, the majority n=122, 83%) had surgical intervention, while 25 (17%) had embolization. Additional details of the surgical intervention are shown in Table 2, 83% haOf the sample, 111 (75.5%) had reflux on ultrasound preoperatively. In terms of the ultrasound grading, 75 (51%) of the sample had grade I varicocele, 38 (25.9%) grade II, and only 8 (5.4%) grade III. Regarding the patients with a suspicion of clinical recurrence at their follow-up consultation, 21 (14.3%) had reflux on ultrasound, and 1 (0.7%) no reflux on ultrasound. In addition, 17 (11.6%) with a recurrence on the follow-up ultrasound had grade I varicocele, 3 (2%) grade II, and only 1 (0.7%) grade III.Analytical statistics were done to determine any statistical association between multiple factors and varicocele recurrence. There was no significant association between the BMI or age groups and varicocele recurrence (P>0.05). There was also no statistical association between the reason for surgery and the recurrence of varicocele (P>0.05), between laterality and recurrence of varicocele (P>0.05), or the type of intervention and varicocele recurrence (P>0.05). However, the association between the clinical grade and recurrence was statistically significant  of the sample had grade I varicocele, 38 25.9%) grade II varicocele, and only eight (5.4%) grade III varicocele. The results indicated a significant association between clinical grade and recurrence (P<0.05). In other words, an advanced grade of varicocele was associated with a higher recurrence rate, which is supported in the literature. We recommend that patients with higher grades of varicocele be counseled regarding the risk of recurrence, and the choice of intervention should be limited to the modalities with the lowest recurrence % grade I.A systematic review by Fazeli et al.  reportedThere are several limitations to our study. First, the sample included only the patients attending one tertiary care hospital, primarily treating persons with a military background and their immediate family, which may not be applicable to the general wider population. Second, there was a high rate of loss to follow-up. From our experience with our patients, this is due to a tendency to avoid going to the hospital unless there is an active problem. Third, the sample size of the group with a recurrence was relatively small. Studies with a larger sample size are required to explore these findings in-depth.The results of the current study indicated a significant association between an advanced grade of varicocele and recurrence; however, the small sample size and retrospective design limited this study. Though the study did not show a significant association between height, weight, BMI, and varicocele recurrence after an intervention, it highlighted the necessity for further studies in this area, to provide insight into the pathophysiology of varicocele and improve patient care.


Polymyxins are antibiotics developed in the 1950s. Polymyxin-induced neurotoxicity has been often described in medical literature. The same cannot be said of nephrotoxicity or tubulopathy in particular. This report describes the case of a patient prescribed polymyxin B to treat a surgical wound infection, which led to significant increases in fractional excretion of calcium, magnesium, and potassium and subsequent persistent decreases in the levels of these ions, with serious consequences for the patient. Severe hypocalcemia, hypomagnesemia, and hypokalemia may occur during treatment with polymyxin. Calcium, magnesium and potassium serum levels must be monitored during treatment to prevent life-threatening conditions. Bacillus polymyxa strains. They work by competitively displacing calcium and magnesium ions from the cell membrane, thereby causing the cell wall of Gram-negative bacteria to rupturePolymyxins are antibiotics developed in the 1950s from -Side effects - neurotoxicity and nephrotoxicity in particular - have limited the use of polymyxin³. Nephrotoxicity is a multifactorial event caused in part by high levels of the drug in proximal tubule cells, increased oxidative stress, and cell death/necrosisAcute Kidney Injury (AKI) is the most common clinical symptom of polymyxin-induced nephrotoxicity. A recently published review on drug-induced nephrotoxicity mentioned that hypokalemia and hypomagnesemia are often present in cases of polymyxin-induced AKIWe were unable to find reports of tubular alterations caused by polymyxin B that led to hypokalemia, hypomagnesemia, and hypocalcemia to a degree as severe as the one seen in the case described in this report. This paper reports the case of a patient prescribed polymyxin B who suffered significant tubular injury with exacerbated renal excretion of calcium, magnesium, and potassium.An infectious disease physician referred a 67-year-old woman to our hospital after she failed to improve from infection in a surgical wound on her left shoulder from an orthopedic procedure, despite outpatient therapy initiated 20 days prior to her arrival at the hospital. The patient has been treated for depression with escitalopram. Her medical history included a right nephrectomy performed 20 years ago for staghorn calculi. Her serum creatinine on admission was 0.6 mg/dL.Acinetobacter baumannii and Pseudomonas aeruginosa.Since the patient did not improve after initial therapy with teicoplanin for five days even with the addition of piperacillin and tazobactam, the surgical wound was debrided and specimens were sent for culturing, which came back positive for multidrug resistant Treatment with polymyxin B was started with 1.5 mg/kg/day. Four days into therapy the patient complained of increased anxiety, upper extremity paresthesia, and insomnia. On the following two days, tremor in the extremities and dyspnea set in. A psychiatrist called in for a consult concluded that she was probably worsening from depression as a result of hospitalization. The patient's serum creatinine level increased from 0.6 mg/dL while she was being treated with polymyxin and plateaued at 1 mg/dL. Fifteen days into therapy with polymyxin she had dyspnea, difficulty swallowing, and muscle stiffness in association with the changes in kidney function described above, at which time the nephrology team was invited to assess the situation. Treatment with polymyxin B was discontinued.2: 40.1 mmHg, HCO3-: 26.6 mEq/l; H+: 36.3 nmol/l, which was indicative of mild metabolic alkalosis. Urine sediment examination did not present signs of glucosuria or proteinuria; urine density: 1015; pH: 6.5; white cell count: 29,000; epithelial cells: 23,000; and red blood cells: 7,000/mL.In addition to the tests performed previously, the nephrology team ordered calcium, albumin, magnesium, venous blood gas, and urine sediment tests. The patient's total serum calcium level was 3.8 mg/dL (RR: 8.8 to 10.3 mg/dL) and her serum albumin was 2.6 mg/dL (RR: 3.5 to 5 mg/dL); her serum phosphorus level was normal ; her serum potassium was 2.5 mEq/l (RR: 3.5 to 5 mEq/l) and her serum magnesium was 0.52 mg/dL (RR: 1.7 to 2.5 mg/dL). The patient had severe hypocalcemia, hypokalemia, and hypomagnesemia. Her venous blood gas was as follows: pH: 7.44, pCOShe was started on intravenous electrolyte replacement and improved markedly from symptoms within 24 hours of therapy. Serum creatinine resumed to baseline levels and the patient was administered replacement therapy with 50% magnesium sulfate (5 g/day), 10% calcium gluconate , and 19.1% potassium chloride (50 mEq/day).Three days into replacement therapy the patient's serum electrolyte levels had not increased substantially. Tests were ordered to verify the fractional excretion of calcium, magnesium, and potassium.As recommended, the serum level of magnesium was multiplied by 0.7. The fractional excretion of calcium was presented solely for the purpose of observing its decrease with time and treatment, since total calcium - not ionized calcium  - was used.Data on the fractional excretion of calcium, magnesium, and potassium on Days 3, 5, and 7 of intravenous replacement therapy are shown in The patient was discharged two weeks later after discontinuation of therapy with polymyxin B. She was free from infection, her kidney function was restored to baseline levels, and she had normal serum calcium, magnesium, and potassium levels.Polymyxins have been prescribed more frequently on account of the growing number of cases of infection caused by multidrug resistant Gram-negative bacteria in hospital settings. Polymyxin B and polymyxin E (colistin) have been prescribed more commonly.Polymyxins are filtered and nearly entirely reabsorbed in the proximal convoluted tubule (PCT). A study of human tubule epithelial cells found that the intracellular concentration of polymyxin B was about 4,000 times higher than the luminal concentration of the drug.,In fact, the nephrotoxicity caused by polymyxins has been associated to cytotoxicity, more specifically in the proximal tubule cellsIn regard to the electrolyte level changes associated with the use of polymyxin in the case described in this report, a few comments about the management of calcium, magnesium, and potassium are warranted.Calcium: in regard to the urinary excretion of calcium, one should realize that 50% of serum calcium is in ionized form (filtered form). Once filtered, calcium is reabsorbed along the tubules by paracellular diffusion in the PCT and in the thick ascending limb of Henle's loop  and by transcellular diffusion in the distal convoluted tubules and connecting tubules (8%); in normal conditions, only about 2% of the filtered calcium is excreted in urine .Magnesium: most of the filtered magnesium is reabsorbed in the thick ascending limb of Henle's loop via permeability modulation of the tight junctions. The PCT reabsorbs 10%-20% and the distal convoluted tubule another 5% of the filtered magnesium.,Potassium: potassium is freely filtered and almost entirely reabsorbed in the PCT and in Henle's loop. Potassium excretion varies with intake, in a response affected by factors such as circulating levels of aldosterone, urinary output, and acid-base balance. A study with 312 healthy individuals  reported an average fractional excretion of K+ of 8% (range: 4-16%)The changes in electrolytes along with the symptoms presented by the patient and the neurotoxic effects associated with polymyxin culminated with her referral to the intensive care unit to manage severe dyspnea.In patients not prescribed other potentially nephrotoxic drugs, the summation of low serum calcium, magnesium, and potassium levels and elevated fractional excretion of these electrolytes might be interpreted as severe polymyxin-induced tubulopathy.Nephrotoxicity following the prescription of polymyxins is a well-known event. We were unable to find reports of significant hypocalcemia, hypomagnesemia, and hypokalemia in patients prescribed polymyxins in the literature. However, our patient presented with life-threatening electrolyte alterations that required the monitoring of serum electrolyte and creatinine levels during the course of therapy with polymyxins.


N = 86) is associated with prefrontal activation during the joint attention task. Results verified that low-SES children show lower right prefrontal activation during joint attention than Relatively High-SES children. In addition, our findings confirmed the mediating effect of HRE on the association between SES and brain activation during joint attention, as well as that between SES and language ability. These results suggest that SES contributes to functional development of the prefrontal regions, and the improvement of HRE could be a potential strategy to intervene SES-related disparities on child development.Low socioeconomic status (SES) may generally have a long-lasting negative effect on cognitive development, and show deficits in the development of executive functions. However, it is unclear whether there is an SES-dependent disparity in the functional brain development of the prefrontal cortex. By collecting task-related functional near-infrared spectroscopy (fNIRS) data and behavioral data , family income, and parental education level), the current study aimed to detect whether the SES of preschool children ( Socioeconomic status (SES) has long been recognized as an important determinant of cognitive and academic functioning throughout life. Children from low-SES backgrounds generally have a poor executive function and thereby, lead to low psychometric intelligence, working memory capacity, reading skills, literacy, and academic performance. By using brain imaging tools such as magnetic resonance imaging (MRI) and electroencephalography (EEG), some scientists have just investigated the effect of SES-dependent disparity on brain development recently . AvailabChildhood SES is the social standing or class of an individual or group. Measurement of childhood SES is complex, and the most common indicators are family income, parental education, and parental occupation . Some scInitiating joint attention (IJA) defines as the ability of an individual to spontaneously seek to direct the attention of a social partner, and to share their experience of an object or event. The IJA involves aspects of executive attention regulation, inhibitory control, and self-monitoring that are critical for the subsequent development of cognitive, social, and learning skills . The IJATaken together, this study aimed to detect the effect of SES disparities on prefrontal activation during IJA tasks for two kinds of preschool children , by the functional near-infrared spectroscopy (fNIRS). The reason for using fNIRS is due to its safety, portability, relatively high temporal resolution, insensitivity to head movement, and reliable clinical utility. As the main motivation, the current study intended to detect two hypotheses: (i) SES of preschool children is associated with prefrontal activation during the IJA task; and (ii) HRE mediates the influence of SES on brain activation and cognitive abilities . This study also discussed the group differences of behavioral measures .The participants were recruited from a kindergarten in a village (corresponding to the Low-SES group) and from a kindergarten in a suburban area (corresponding to the Relatively High SES group) in China, respectively. The interested families contacted the teachers to confirm their understanding of the research content and completed a brief screening to determine eligibility. Children were excluded from participants in this study if they had a history of a neurological disorder, loss of consciousness, sensory impairments, autism spectrum disorder, or an intellectual disability. All study procedures and research methods were carried out in accordance with the Declaration of Helsinki  by the WAlthough 104 preschool children were recruited in the study, 10 subjects were excluded due to loss of fNIRS data, unacceptable head movement, or refusal to attend the experiments. Eight children were further excluded because their parents did not complete all questionnaires as expected. Therefore, only 86 participants  aged 40–75 months (60.9 ± 7.61 months) were actually considered in this study.For each participated child’s parents, they were asked to complete two questionnaires, i.e., the Family Basic Information Questionnaire (FBIQ) and the Home Reading Environment Parental Questionnaire (HRE-PQ), to collect the basic information of participants, SES and HRE.Parental education level was assigned a value from 1 to 7 as follows: 1, less than primary school; 2, middle school; 3, high school; 4, technical secondary school; 5, college; 6, undergraduate degree; and 7, graduate level or above. In addition, the monthly family income (in Chinese RMB) was assigned a value from 1 to 7 by the following rule: 1, 2,000 or below; 2, 2,001–4,000; 3, 4,001–6,000; 4, 6,001–8,000; 5, 8,001–12,000; 6, 12,001–15,000; and 7, >15,000.The number of storybooks in the home, the frequency of parent-child reading, and days of reading per week were considered as factors of the HRE measure. The number of storybooks in home was assigned a value from 1 to 9 as follows: 1, ≤10; 2, 11–20; 3, 21–50; 4, 51–80; 5, 81–110; 6, 111–140; 7, 141–170; 8, 171–200; and 9, >200. While, the frequency of parent-child reading at home was coded from 1 to 5 .For participated children, they were asked to complete an intelligence test and a Chinese receptive language task by the Combined Raven’s Test (CRT)  and PeabThe experimental protocol (including 2 conditions) was clearly shown in As shown in The IJA task with a block design was programmed and conducted with the software E-prime . The whole experiment (lasting 7–8 min) was presented on a 14-inch computer screen  with a white background. Before a formal experiment, participants were instructed to do some practice for the understanding of the whole experimental procedure under the standard exceeding 80% accuracy.During IJA tasks, the oxy-hemoglobin (HbO) and deoxy-hemoglobin (HbR) concentration changes at the wavelengths of 630 and 850 mm were recorded using an fNIRS equipment, i.e., NIRSport 8*8  Optical Topography System, with sampling frequency 7.81 Hz. This fNIRS equipment had 8 light sources and 8 detectors, evenly distributed over the left and right prefrontal regions according to the 10-10 transcranial positioning system. Hence, this fNIRS equipment had 20 neural channels covering the bilateral inferior frontal gyrus (IFG) and middle frontal gyrus (MFG) . Therefore, HbO concentration changes at the range of 11–21 s were actually taken into account for time-series analysis.Participants were divided into two SES groups, i.e., Low-SES and Relatively High-SES groups, according to their monthly family income and place of residence. The Low-SES group was corresponding to children with monthly family income below 8,000 RMB and living in the rural area; while the Relatively High-SES group was corresponding to children with monthly family income above 8,000 RMB and living in the suburban area.The experiments in this study included two factors, i.e., partner-types (teacher and stranger) and SES-types (Low-SES and Relatively High-SES). By SPSS , a two-factor ANOVA (with 2 partner-types*2 SES-types) was conducted to examine the main effects for prefrontal activation, with the significance level 0.05. The false discovery rate (FDR) correction was conducted for results with multiple comparisons .Comprehensive evaluations of SES and HRE levels were conducted by the factor analysis. In particular, it was required to calculate the regressed function  of SES level on three factors , as well as the regressed function  of HRE level on three factors .The mediating effect of HRE on the association relation between SES and brain activation, as well as that between SES and cognitive abilities , were also detected. The correlations between behavioral measures  and prefrontal activation were analyzed as well.t = 1.993, p = 0.05). In addition, for each behavioral measure, Relatively High-SES children had a significantly higher score than Low-SES children (p < 0.05).By the factor analysis, we verified that: (i) the SES level may be predicted by the weighted sum of family income (with weight coefficient β = 0.87), mother’s education level (with weight coefficient β = 0.95), and father’s education level (with weight coefficient β = 0.93); and (ii) the HRE variable may be predicted by the weighted sum of the number of storybooks in the home (with weight coefficient β = 0.93), days of reading per week (with weight coefficient β = 0.93), and the frequency of parent-child reading at home (with weight coefficient β = 0.94).r = 0.843, p < 0.001). Additionally, the PPVT score was correlated with SES level  and HRE level ; while the Raven test score was correlated with SES level  and HRE level .We interestingly found see  that theF = 6.03, p = 0.045), CH10 , CH15 , CH17 , CH18 , CH19 , and CH20 , covering bilateral MFG and right IFG , CH19 , and CH20 , covering right IFG (We conducted a 2 × 2 ANOVA between two SES groups (Low-SES and Relatively High-SES children) under two conditions  to examine the main effects for prefrontal activation during the IJA tasks. Results showed that the main effect of two joint attention conditions is significant. In particular, compared with T-IJA condition, S-IJA condition evoked higher brain activation in CH5 , CH15 , CH18 , CH19 , and CH20  in the S-IJA condition, as well as that in CH12 , CH19 , and CH20  in the T-IJA condition. We also revealed that HRE level was significantly correlated with brain activation in CH14 , CH15 , CH18 , CH19 , and CH20  in the S-IJA condition, as well as that in CH12 , CH14 , and CH20  in the T-IJA condition.We conducted the correlation between behavioral measures and brain activation during IJA tasks. We found that SES level was significantly correlated with brain activation in CH14  in the S-IJA condition. In addition, the IQ score (Raven score) was significantly correlated with brain activation in CH15  in the S-IJA condition, and CH20  in the T-IJA condition.Interestingly, we found that the language ability (PPVT score) was significantly correlated with brain activation in CH20  in the S-IJA condition .We first evaluated the correlations among SES, HRE, brain activation, and language ability (PPVT score), and then conducted a multiple linear regression to analyze the mediating effect of HRE. Our results confirmed that there is a significant mediating effect of HRE on the association between SES level and brain activation in CH19 , the current study aimed to bring some new insights into the understanding of brain structural and functional differences underlying childhood SES disparities. In particular, it was expected to verify whether SES of preschool children is associated with prefrontal activation during joint attention tasks. In addition, this study discussed the mediating effect of HRE on the association between SES and brain activation, as well as the relation between SES and language. To cope with questions above, preschool children with two different SES levels  were recruited, and IJA tasks were chosen as stimuli to capture fNIRS imaging data associated with social cognition processing.Results verified that compared with Low-SES children, Relatively High-SES children evoked significantly higher brain activation during joint attention in right IFG. This finding is consistent with previous results that: (i) Low SES contributed to reduced prefrontal activation and affects the functional development of the prefrontal regions ; (ii) LoThe current study showed significant brain activation differences between social interactions with a familiar partner (teacher) and that with an unfamiliar partner (stranger) in the IJA tasks. In particular, compared with the familiar interaction case (corresponding to the T-IJA condition), the unfamiliar interaction case (corresponding to the S-IJA condition) evoked higher brain activation in bilateral MFG and right IFG. This result is consistent with previous research that unfamiliar faces evoked significantly higher activation in the right inferior parietal lobule encroaching on the TPJ . It willRelatively High-SES children may usually obtain better home facilities, more opportunities for social interaction with parents, more opportunities for enhancing cognitive abilities, and higher affordability for supporting diverse learning environments . Our behLongitudinal studies illustrated that better HRE provides more opportunities for teaching and learning activities, and thereby, contributes to better cognitive development  . We signOur results showed that: (i) mother’s education level plays the most important role in SES measure and thereby, in cognitive and brain development; and (ii) parental education level is more significant than family income in SES measure. In addition, the factors  almost have the same importance in the HRE measure.Socioeconomic status is a multifaceted structure and its measure is very complex. The most common indicators are family income, parental education, and parental occupation. The SES measure in this study considered only family income and parental education and did not contain the factor of parental occupation, because occupations of low-SES children’s parents are relatively single, basically due to extremely low education level in China. It will deserve in a future study to consider more factors in SES measure, such as food restriction, negative emotionality , and motivation .The current study aimed to investigate the effect of SES on brain activation, and revealed the brain activation difference between Low-SES and Relatively High-SES preschool children during joint attention. Our findings support that low SES contributes to decreased right prefrontal activation during joint attention. In addition, our results verified the significant mediating effect of HRE on the association between SES level and brain activation during joint attention, as well as that between SES level and language ability. Remarkably, a mother’s education level plays the most important role in SES measure.The current study provides behavioral and neural evidence that SES contributes to cognitive and brain development. The mediating effect of HRE and the role of a mother’s education level in SES measure may bring us some new insights into the understanding of the effect of SES on child development. To reduce SES-related disparities, some potential intervention strategies include the improvement of mothers’ education level, offering libraries, book sharing, e-storybooks, and online storytelling programs for low-SES children.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 Institutional Review Board of Southeast University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.KD, CL, and DY developed the idea for the study. KD and CL collected the data. KD, CL, YL, and HW did the analyses. KD and DY wrote the manuscript. All authors contributed to the article and approved the submitted version.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.


Age and several comorbidities, as well as the Deyo Comorbidity Index, were found to predict mortality in a multivariable analysis. Conclusion: A reverse J-shaped relationship between body mass index and in-hospital mortality was documented in patients admitted for a stroke in the U.S. during the study period. The above findings support the existence of an “obesity paradox” in patients hospitalized following a stroke, similar to that described in other cardiovascular conditions.Background: Obesity has been associated with increased incidence and severity of various cardiovascular risk factors and increased risk for stroke. However, the evidence of its effect on outcomes in stroke victims have been equivocal. We aimed to investigate the distribution of BMI in a nation-wide cohort of individuals, admitted for a stroke, and the relationship between BMI and in-hospital mortality. Methods: Data from the U.S. National Inpatient Sample (NIS) was collected, to identify hospitalizations for stroke, between October 2015 and December 2016. The patients were sub-divided into six groups based on their BMI: underweight, normal weight, overweight, obese I, obese II and extremely obese groups. Various sociodemographic and clinical parameters were gathered, and incidence of mortality and the length of hospital stay were analyzed. Multivariable analysis was performed to identify independent predictors of in-hospital mortality. Results: A weighted total of 84,185 hospitalizations for stroke were included in the analysis. The approximate mean patients aged was 65.5 ± 31 years, the majority being female (55.3%) and white (63.1%). The overall in-hospital mortality during the study period was 3.6%. A reverse J-shaped relationship between the body mass index and in-hospital mortality was documented, while patients with elevated BMI showed significantly lower in-hospital mortality compared to the underweight and normal weight study participants, 2.8% vs. 7.4%, respectively,  Constantly growing number of people are affected by obesity worldwide. According to a recent report by the World Health Organization, the rate of obesity has tripled since the 70s, and by 2016 over 1.9 billion adults 31%) were overweight, of them 650 million (13%) were obese 1% were o,5,6.Obesity and stroke, both reaching epidemic proportions, are clearly associated. Based on recent data, up to 25% of adults over the age of 25 are expected to experience a stroke during their lifetime . WorldwiNumerous studies linked obesity with higher incidence and increased severity of several cardiovascular risk factors, including increased risk for stroke. However, studies looking into the effect of obesity on outcomes in stroke victims have produced conflicting results. Several studies showed favorable outcomes, in terms of mortality, in overweight and obese stroke patients ,17,18,19A detailed description of the study methods and the used dataset has been provided previously by our group . The data were collected from the National Inpatient Sample (NIS), the Healthcare Cost and Utilization Project (HCUP), and Agency for Healthcare Research and Quality (AHRQ) ,27. The th Revision, Clinical Modification—ICD-10-CM) was used from October of 2015 and thereafter to report procedural and clinical diagnoses in the NIS database. The reason we included only the data coded with ICD-10 system is that the ICD-10 codes include individual codes for BMI values and ranges. For this study, we collected data for U.S. hospitalizations between October 2015 and December 2016. The ICD-10 coding system  was calculated for each patient, using the 17 comorbidity conditions  (Appendi2) test and to compare continuous and categorical variables, respectively. The NIS dataset includes discharge sample weights, calculated within each sampling stratum as the ratio of discharges in the universe to discharges in the sample [® software version 9.4 . A p-value < 0.05 was considered statistically significant. We used the Wilcoxon Rank Sum test and chi-square , and the approximate mean age was 65.5 ± 31 years.2).The majority of the study population (63.1%) was white, 56.9% had Medicare coverage . With rep < 0.001). Female predominance was noted in the underweight and in patients with BMI ≥ 40 (extremely obese). Younger age and increased prevalence of diabetes, hypertension and heart failure were observed in the obese patient subgroups (ubgroups .p < 0.001). Only 2.8% of the total study population underwent mechanical thrombectomy and 1.3% underwent in hospital carotid endarterectomy.Of the total population admitted for a stroke, 8.7% received thrombolytic therapy. Obese patients had higher chances to receive thrombolytic therapy during the hospitalization compared to underweight and normal weight patients, 9.3% vs. 6.2%, respectively . Higher BMI as well as diabetes were associated with reduced mortality in a univariate analysis.Several parameters were found to significantly increase the odds of in-hospital mortality in an unadjusted analysis . These ip < 0.001.After adjusting for potential confounders, most of the above  remained an independent predictor of in-hospital mortality in a multivariable analysis . Higher Using the NIS database, we analyzed a weighted total of 84,185 hospitalizations for a stroke, during the study period of Oct. 2015 to Dec. 2016. This nation-wide data analysis showed a reverse J-shaped association between the BMI and mortality in hospital, in the study population. Elevated BMI was found to be an independent predictor of lower in-hospital mortality and length of hospital stay in patients admitted for a stroke during the study period.In this study, we aimed to analyze the relationship between BMI and in-hospital outcomes in a nation-wide population of patients, admitted in the US following a cerebrovascular event, in order to overcome the potential biases of the prior, smaller studies. In addition, we wanted to improve the differentiation between the different obese patients BMI subgroups, dividing them into mild (30 < BMI ≤ 35), moderate (35 < BMI < 40) and extremely obese (BMI ≥ 40) groups. The different sociodemographic and clinical characteristics of our study population were comparable with prior publications on stroke patients as to their age and comorbidities such as hypertension, diabetes mellitus, atrial fibrillation and others ,19,24.A recent systematic review of 25 studies  showed that a vast majority of these studies reported a survival benefit for obese study participants, suffering from a stroke. However, due to methodological limitations, study design, lacking adjustment for comorbidities, selection bias and survival bias, it was difficult to draw firm conclusions as to the real-world relationship between BMI and outcomes in post stroke patients [p < 0.001.The effect of elevated BMI on the risk for stroke can be explained by elevated prevalence of risk factors such as diabetes, hyperlipidemia and hypertension in the obese patients. However, prospective studies did not show that these co-morbidities necessarily modify the relationship between BMI and stroke ,12. In o2  exhibited the lowest in-hospital mortality in this study. Prior studies have suggested that the “obesity paradox”, described in various cardiovascular conditions including in myocardial infarction, heart failure and sudden death, may apply to patients admitted with a stroke, resulting in lower mortality in obese patients ,17,18,192 .Interestingly, patients suffering from overweight and obesity were shown to be younger, a fact that could have theoretically contributed to better survival in these patients. Niedziela et al, has described this observation in the past, showing that in 20 out of 26 reports included in his meta-analysis of the “obesity paradox” in myocardial infarction studies, patients suffering from overweight and obesity were younger compared to patients in other subgroups .Several protective pathophysiological mechanisms have been suggested to play a role in improving the survival of critically ill patients, including the potential benefit of nutritional reserves in obese patients ,35,36 anThis implication of obesity and improved survival after a stroke should be by no means interpreted as supporting weight gain. Elevated body weight index has been documented to be an independent risk factor for several cardiovascular conditions such as ischemic heart disease, myocardial infarction, heart failure, cardiac arrhythmia , sudden cardiac arrest and stroke ,40. The Our study has several limitations. The National Inpatient Sample database is an administrative retrospective database, containing discharge-level records, hence, it is susceptible to potential coding errors. The lack of patient identifiers in the NIS database does not allow us to analyze other outcomes such as 30-day mortality. We could only document events occurring during the hospitalization, with no longer term follow up. We also cannot rule out that some of the hospitalizations were “readmissions” of the same patients with another cerebrovascular event. Several important parameters are not collected into the NIS database such as additional patient characteristics, chronic medical therapy, laboratory tests etc. Therefore, we cannot completely rule out residual confounding of the correlation we observed in this study. These limitations are counterbalanced by the nation-wide, real-world nature of the data, lack of selection bias and the absence of reporting bias introduced by selective publication from specialized centers.In conclusion, a reverse J-shaped correlation between the body mass index and in-hospital mortality was documented in patients hospitalized for a stroke in the U.S. during this study period. The presented findings support the existence of an “obesity paradox” in patients hospitalized following a stroke, similar to that described in other cardiovascular conditions.


MAFLD was also identified as the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses . Among the three subtypes of MAFLD, non-obese MAFLD was the sole independent factor associated with the presence of colorectal adenoma . Non-obese MAFLD was also the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses . MAFLD, particularly non-obese MAFLD, is the most important factor associated with the presence of colorectal adenoma rather than NAFLD. Colonoscopy examination should be considered in patients with MAFLD, especially those who are non-obese.Colorectal adenoma is linked to metabolic dysfunction. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a precise definition and three subtypes, including non-obese MAFLD. We aimed to investigate the impact of MAFLD on the prevalence of colorectal adenoma by comparing it to non-alcoholic fatty liver disease (NAFLD) in health check-up examinees. This is a multicenter retrospective study. We enrolled 124 consecutive health check-up examinees who underwent colonoscopy. NAFLD and MAFLD were present in 58 and 63 examinees, respectively. Colorectal adenoma was diagnosed by biopsy. The impact of the MAFLD definition on the prevalence of colorectal adenoma was investigated by logistic regression, decision-tree, and random forest analyses. In logistic regression analysis, MAFLD was identified as the only independent factor associated with the presence of colorectal adenoma (OR 3.191; 95% CI 1.494–7.070;  The prevalence of colorectal cancer is increasing, with over 1.8 million new colorectal cancer cases being reported each year . A multiAging, gender, and family history increase the risk of colorectal cancer; however, these factors are unchangeable . Many liRecently, a panel of experts from 22 countries proposed a new definition for the diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD) . The diaThe aim of this study is to investigate the impact of MAFLD on colorectal adenoma by comparing it to NAFLD in health check-up examinees.In all subjects, the median age was 59 years and the male ratio was 80.6% . The medn = 72), respectively. Patients overlapping NAFLD and MAFLD comprised 69.4% (50/72) of the subjects with fatty liver  3.191; 95% confidence intervals (CI) 1.494–7.070; In a decision-tree algorithm, MAFLD was identified as the most important classifier for the presence of colorectal adenoma. Colorectal adenoma was observed in 51% of subjects with MAFLD, while colorectal adenoma was observed in 25% of subjects in the absence of MAFLD B. The seIn a random forest analysis for the presence of colorectal adenoma, MAFLD was identified as the distinguishing factor with the highest variable importance. NAFLD, age, and sex were the second, third, and fourth distinguishing factors, respectively C.Patients’ characteristics for subtypes of MALFD are summarized in p ≤ 0.001; We analyzed 7 factors, namely, obese-MAFLD, non-obese MAFLD, T2DM-MAFLD, age, sex, alcoholic intake, and smoking in the stepwise procedure. In the stepwise procedure, non-obese MAFLD was only selected as an explanatory variable for the logistic regression analysis. Non-obese MAFLD was identified as the only independent factor associated with colorectal adenoma . The prevalence of NAFLD has been reported to be between 40 and 52% in subjects who undergo colonoscopy ,14,15. MMAFLD was an independent factor for colorectal adenoma in this study. Decision-tree and random forest analyses also revealed that MAFLD, but not NAFLD, was the most important factor for the presence of colorectal adenoma. Recently, several studies have shown the superiority of MAFLD over NAFLD for the identification of patients with significant hepatic fibrosis, cardiovascular event, and chronic kidney disease ,12,19,20MAFLD consists of three subtypes, namely, obese-MAFLD, non-obese MAFLD, and T2DM-MAFLD ,22. We fThere are several limitations to this study. First, this study is retrospective, with a small sample size. Second, all participants were of Asian ancestry. Third, we did not evaluate factors associated with colorectal cancer, including dietary habits and physical activity. Fourth, since all subjects were health check-up examinees, the prevalence of severe steatosis and advanced fibrosis was low in this cohort. Therefore, we could not evaluate the impact of severity of hepatic steatosis and fibrosis on the prevalence of colorectal adenomas. Fifth, we also could not evaluate the impact of MAFLD on colorectal cancer, because of the small number of patients with colorectal cancer in this cohort (2/126). Accordingly, further studies should be designed in an international prospective study with a large sample size to more comprehensively evaluate the effects of MAFLD on the development of colorectal adenomas/adenocarcinomas using various factors including lifestyle habits and hepatic steatosis/fibrosis using FibroMax indexes ,34,35.In conclusion, we found that MAFLD was the only independent factor associated with the presence of colorectal adenoma. In both decision-tree and random forest analyses, these results were confirmed, while NAFLD was not an independent factor. In addition, we identified that non-obese MAFLD was associated with the presence of colorectal adenoma among the three subtypes of MAFLD. Since the identification of colorectal adenoma is an effective strategy to reduce the death rate from colorectal cancer, we suggest that colonoscopy examination is better considered in patients with MAFLD, particularly those who are non-obese.This study was designed as a multicenter cross-sectional retrospective study in Japan. The protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected by prior approval from the institutional review board of Kurume University School of Medicine (ID 20114). This research was performed in accordance with relevant guidelines and regulations. An opt-out approach was used to obtain informed consent from patients, and personal information was protected during data collection.n = 130): (1) subjects who were 20 years old or greater, and (2) subjects who underwent colonoscopy examination from 2018 to 2020. Of these, we have excluded subjects with (1) incomplete colonoscopy examination (n = 1), (2) positive results of hepatitis B virus surface antigen (n = 1) or hepatitis C virus antibody (n = 2), and (3) colorectal cancer (n = 2). Thus, a total of 124 subjects were analyzed in this study (n = 2) or with an incomplete examination, defined as an endoscope not reaching the cecum as documented by a picture of the ileocecal valve (n = 1). Finally, 124 health check-up examinees were analyzed in this study.We enrolled health check-up examinees who met the following inclusion criteria at the Kurume University Hospital, Kumamoto Central Hospital, and Kurate Hospital in Japan from April 2018 to March 2020  2 in this Asian cohort and T2DM was defined as HbA1c ≥6.5% or specific drug treatment. Metabolic dysregulation was defined as the presence of at least two metabolic risk abnormalities: (1) Central obesity (waist circumstance ≥90/80 cm in men and women), (2) blood pressure ≥130 mmHg or specific drug treatment, (3) plasma triglycerides ≥150 mg/dL or specific drug treatment, (4) plasma HDL-cholesterol <40 mg/dL for men and <50 mg/dL for women or specific drug treatment, and (5) prediabetes (fasting glucose levels 100 to 125 mg/dL or HbA1c 5.7–6.4%) [MAFLD was diagnosed according to the criteria proposed in 2020 by an international expert panel . The criColonoscopy examination  was performed by endoscopists with experience of performing more than 1000 procedures. Subjects were given polyethylene glycol for bowel preparation according to the manufacturer’s instructions. A complete examination was defined as an endoscope reaching the cecum as documented by a picture of the ileocecal valve. All identified colorectal polyps were removed and were tubular adenomas, which were diagnosed by pathological findings. This is a retrospective study and diagnosis of colorectal adenoma had already been made at the entry of this study.In all colonoscopy examinations, the quality of bowel preparation was graded as good . The withdrawal time of the colonoscopy procedure was at least 6 min to minimize the chance of missing lesions . IncomplContinuous variables are expressed as median and range or number. Categorical variables are expressed as frequencies and percentages. The differences between groups were analyzed using the Wilcoxon rank-sum test for continuous variables and the Fisher’s exact test for categorical variables. A logistic regression model was used to identify independent factors associated with the presence of colorectal adenoma. Data are expressed as OR and 95% CI.p < 0.05 was considered to indicate statistical significance. Data were analyzed using the JMP Pro15 .A decision-tree algorithm was constructed to reveal profiles associated with the presence of colorectal adenoma as previously described ,40. A raMAFLD, particularly non-obese MAFLD, is the most important factor associated with the presence of colorectal adenoma rather than NAFLD. Colonoscopy examination should be considered in patients with MAFLD, especially those who are non-obese.


Backround and Objectives: Alternative, non-invasive, and non-pharmaceutical options are gaining place in the battle of Alzheimer’s Disease treatment control. Lately, the magnetic stimulation of the brain is the most prevalent technique with encouraging results. The aim of this study is to establish any possible change on the Primary Dominant Frequencies (PDF) (range 2–7 Hz) of the affected brain regions in Alzheimer Disease (AD) patients after applying extremely weak Transcranial Magnetic Stimulation. Materials and Methods: For this purpose, all AD patients were scanned with the use of MagnetoEncephaloGraphy (MEG) recordings through a whole-head 122–channel MEG system. Results: Our results exerted statistically significant PDF changes due to weak TMS accompanied by rabid attenuation of clinical symptoms. Conclusion: Thus, this is the first time that a positive therapeutic effect is being demonstrated even at pico-Tesla range magnetic fields in a small clinical group of studies for AD. Alzheimer Disease (AD), one of the most prevailing types of dementia, is a neurodegenerative disorder with a worldwide occurrence, which is strongly related to the aging process . The ageNumerous histopathalogical modifications take place in the AD patients’ brain that eventually lead to general brain atrophy mainly in the temporal and frontal lobes ,6,7,8. TSeveral studies have already been conducted in order to provide a full-spectrum theory of AD’s pathogenesis . ComplexDespite the progress in research, providing insight into the pathophysiology of AD, the therapeutic options of dementia syndrome still remain a challenge. Transcranial Magnetic Stimulation, as many studies imply, can positively modify brain activity in AD and thus, mitigate clinical symptoms . The bra−12 T, and can easily be detected and scored by using MEG recordings [In our clinical trial, in order to estimate the atypical magnetic fields, due to abnormal neuronal activity of the AD patients’ brain, we used the sensitive technique of the Transcranial MagnetoEncephaloGraphy (T-MEG) ,12. Thiscordings .Our goal is to detect possible alterations in the front temporal lobes of the patient’s AD brain through the use of pT-TMS electronic device after applying FFT analysis . This deThe study sample included 10 volunteer patients, 7 male, and 3 female. All the patients that were referred to our laboratory of Medical Physics by neurologists, were diagnosed with AD and had normal complete serum biochemical profile. The patients’ age scale in the present study was from 55 to 72 years.All AD patients prior the procedure, were informed and gave their consent for the methodology and the aim of the study.The Research Committee of Democritus University of Thrace gave its approval for the protocol of our study.The General Secretariat of Research and Technology, GR, and the ERGO AEBE INC, GR (Grant Number: 80623) funded the research.The study was planned for 3 days duration. The first day (day 1) every AD patient underwent, ensuring alertness, a 2 min brain scannin2g session, through the use of the whole head 122-channel 2nd order gradiometer device NEUROMAG-122 SQUID , and thus, MEG signals were recorded for each subject before pT-TMS. The whole-head 122 channel MEG system, embodied in a specially designed room in order to diminish the magnetic noise and provide accurate results, has already been described in our previous publications ,18,19,20The second day (day 2) pT-TMS was applied for 60 s on each participant with a whole head device, especially designed to adjust in the Alpha Brain Frequency of every subject (customized brain stimulation). ,18,19,20In order to score the Primary Dominant Frequencies (PDF) changes, we developed a software program ,18,19,20Two-dimensional color maps for the spatial distribution of the primary dominant frequencies were constructed based on these frequencies estimation for each affected brain region and channel. Each color in the maps depicts different primary dominant frequencies. Finally, each number in the map squares indicates groups of MEG channels, in line with the whole-head device for each brain area according to t-test. Statistical analysis was employed by SPSS 16.0 . Values with p < 0.05 were considered statistically significant.Data were displayed as mean ± standard error of the mean. Single comparisons were performed with unpaired Student’s In In t-test. The results were statistically significant at 7 out of 10 patients (70%).In In Finally, in AD is a common degenerative brain disorder with multi-complex clinical symptomatology, which debilitates the patient from daily routine and reduces the quality of life ,22. DespAs far as we know, the therapeutic strategies for AD preserve two ways, the pharmaceutical and the non-pharmaceutical trail . Drugs aIn our study, 3 out of 10 participants with extremely serious symptoms did not have any improvement, through weak TMS, in their clinical profile. Our results are in line with previous studies applying a range stimulation protocol from 1 Hz up to 20 Hz on patients with mainly severe symptomatology and prolonged disease progression .−12 Tesla, is applied on AD patients, through a whole head personalized brain stimulation apparatus, for a very short period of time  and accompanied by MEG neurosensitive scanning, pre- and post-stimulus.On the other hand, the pT-TMS on AD patients with mild symptomatology exhibited a positively statistically significant effect since 7 out of 10 patients declared substantial clinical improvement. To our knowledge, this is the first time that TMS, as weak as 10However, the encouraging outcome with the up to now AD knowledge cannot be totally explicated. Still, one rational explanation might be the fact that weak magnetic fields hold a strong positive impact on the pineal gland’s ability, through melatonin, to control endogenous opioid signal pathways ,27,28 anTo summarize, the use of pT-TMS preserves a promising positive outcome of the clinical image of AD patients, as it lightens’ their daily symptoms, in no time, with the use of a totally safe model. Nevertheless, in order to prove pT-TMS effectiveness on AD treatment, further studies with larger groups of AD patients are needed to be conducted.Anninos, P.A, and Tsagas, N. Electronic apparatus for treating Epileptic individuals. USA patent 5453072, 1995.


Exposure to polluted outdoor air has been proven to be harmful to human eyes. On the other hand, indoor air pollution from environmental tobacco smoking, heating, cooking, or poor indoor ventilation is also related to several eye diseases, including conjunctivitis, glaucoma, cataracts, and age-related macular degeneration (AMD). In the past 30 years, no updated review has provided an overview of the impact of air pollution on the eye. We reviewed reports on air pollution and eye diseases in the last three decades in the PubMed database, Medline databases, and Google Scholar and discussed the effect of various outdoor and indoor pollutants on human eyes.Air pollution is inevitably the result of human civilization, industrialization, and globalization. It is composed of a mixture of gases and particles at harmful levels. Particulate matter (PM), nitrogen oxides (NOx), and carbon dioxides (CO Air is essential for the survival and development of all lives on Earth. Its quality directly influences human health and is closely affected by the extent of civilization. Air pollution is a major contributor to the global burden of disease. There was increased mortality related to air pollution in both developing countries and developed countries such as the United States, despite more rigorous air quality standards ,2,3. Alt2), nitrogen dioxide (NO2), carbon dioxide (CO2), nitrogen monoxide (NO), carbon monoxide (CO), nitrogen oxides (NOx), particulate matter 2.5 (PM2.5), and particulate matter 10 (PM10), mostly generated from burning fuels or industrial production. In addition to traffic and industry activities, daily life activities, including tobacco smoking, household decorating and cooking, also produce COx, NOx, and volatile organic compounds (VOCs). For example, formaldehyde can cause DNA damage in animal cells, and its carcinogenicity has been assessed by many studies in the past three decades [Air pollution comprises a complex mixture of gas-phase pollutants and particles at harmful levels that are disbursed into the atmosphere due to either natural or human activities . There aIndoor activities with poor ventilation of buildings in modern life are another cause of health problems. There is an increasing prevalence of asthma, autism, and childhood cancer with everyday exposure to these indoor chemical pollutants .Air pollution influences daily living in societies and even jeopardizes the survival of humans. It is widely known that outdoor air pollution influences health. Air pollution induces many health problems and diseases, such as cardiovascular disorders, respiratory tract problems, ocular disease, neurologic disease, cancer, and death ,8,9,10.The cornea is the most sensitive structure in the human body due to numerous innervations in the ocular surface and thus is extremely sensitive to environmental agents ,12. The 3 on human eyes consist of mostly irritation and inflammation, with conjunctivitis being a frequent problem [3 suffered from extensive subclinical ocular surface changes [2.5 are associated with allergic conjunctivitis [The adverse effects of air pollutants such as CO, NOx, PM, and O problem . Numerou changes . Versura changes . An incrctivitis ,17 and gctivitis ,19, and ctivitis . Moreovectivitis .Many research investigations have surveyed the association between air quality and outpatient or emergency room visits with respect to respiratory or cardiovascular symptoms. However, only a limited number of studies have investigated the relationship between air pollution and ocular diseases. In the past three decades, no updated review has provided an overview of the impact of air pollution on the eye. This article aimed to determine the significance of the influence of air pollution on the eye and will discuss the effects of various outdoor and indoor pollutants on human eyes by reviewing papers in the last three decades.The authors performed a review of the literature using PubMed databases, Medline databases and Google Scholar from 1 January 1990, to 31 July 2021. The main inclusion criterion for this review was data on ocular diseases associated with air pollution. The following keywords were used to search the databases: environmental pollution, air pollution, eye disease, ocular disease, acute effect, chronic or long-term effect, ocular surface, inflammation, conjunctivitis, cornea, dry eye, cataract, glaucoma, retinal disease, and retinal vascular disease. Health issues about moisture damage and microbiology-related topics were excluded from this overview. To provide the most up-to-date evidence, we preferred to choose more recent articles that were published in the last five years. The results were restricted to publications in English. Totally, 28 review papers and 83 research papers were cited in the review paper.There are multitudes of studies elucidating that environmental pollution is harmful to the health of human organ systems, including the skin, oropharyngeal, and respiratory systems ,7,8,9,10Our analysis of the relevant studies included in this narrative review see  demonstr3), nitrogen dioxide (NO2), sulfur dioxide (SO2), lead (Pb), carbon monoxide (CO), and particulate matter (PM). The components vary seasonally and are affected by human activity and climatic events [10, PM with an aerodynamic diameter ≤ 10 μm), fine PM , and ultrafine PM  [Outdoor air pollution is a significant public health problem in population centers worldwide. For decades, studies have demonstrated a strong association between air pollution and a spectrum of ill health effects. Outdoor air pollution is a major environmental health hazard that was associated with 3.7 million deaths worldwide in 2012  and 4.2 c events . PM is f 1.0 μm) .2 and ground-level O3 (which derives from the effect of ultraviolet light on nitrogen dioxide) are primarily emitted from vehicle exhaust systems, while SO2 originates from the burning of sulfur-containing fuels . Coarse PM primarily results from scattered ground or airborne dust; fine and ultrafine PM derive primarily from vehicular exhaust [10 primarily consists of geological materials, in comparison to PM2.5 and PM1.0, which have larger fragments of elemental and organic carbon [Pollutants originate from different sources. For example, NO exhaust . Coarse c carbon . These vc carbon . Outdoorc carbon .3 set by the World Health Organization (WHO). One study showed that people in New Delhi who commuted daily to the workplace using open vehicles  for more than 10 years had more ocular surface symptoms, such as redness, irritation, lacrimation, burning, and dryness, than people living near their workplace [2, the primary products of diesel oil consumption by trucks and large vehicles, can travel long distances. A study indicated that higher nitric oxide (NO) and NO2 concentrations were related to more severe conjunctivitis in people in Paris [10 and PM2.5, NO2, SO2, and O3 [Traffic- and industry-related airborne byproducts account for most outdoor air pollution. For example, in New Delhi, India, the transportation component of air pollution was 72%, and the industry component was 20% in 2003. The level of suspended particulate matter (SPM) in New Delhi was five times higher than the annual average control limit of 60 mg/min Paris . Another, and O3 . Conjunc, and O3  that fre, and O3 . Discomf2.5 eyedrops, and apoptosis of corneal superficial and basal epithelial cells was observed [In addition, air pollution may exacerbate dry eye disease . Dysfuncobserved .2.5 is one of the strongest and most consistent predictors of mortality. It is associated with pulmonary and cardiovascular disease and central nervous system conditions such as Alzheimer’s disease, Parkinson’s disease, and stroke [2.5 [2.5 has been shown to be toxic to intraocular tissues and contribute to the development of ocular hypertension and glaucoma. Mechanistically, PM2.5 and PM10 induce the production of NO and interleukin 8, causing increased oxidative stress [2.5 also increased oxidative stress and induced NLRP3 inflammasome-mediated pyroptosis, a form of nonapoptotic cell death in trabecular meshwork cells, in an in vitro study [2.5 exposure inhibited the proliferation of and increased apoptosis in neural retina cells, resulting in the abnormal development of the neural retina [Among air pollutants, PMd stroke . Wang anoke [2.5 . PM2.5 he stress . Furtherro study . Anotherl retina .2.5 concentrations were more likely to report a diagnosis of glaucoma and to have a thinner macular ganglion cell–inner plexiform layer (GCIPL), as measured by spectral-domain optical coherence tomography (SD-OCT), than their counterparts [2.5 exposure, suggesting that the relationship may occur through a pressure-independent mechanism, possibly neurotoxic and/or vascular effects [2.5 was related to the diagnosis of primary open-angle glaucoma (POAG) in Taiwanese adults [2.5 was associated with the incidence of POAG. In a retrospective cohort study, Min and colleagues evaluated whether exposure to PM10 was related to the occurrence of childhood glaucoma [10 increased the probability of developing childhood glaucoma. This finding implies that PM10 exposure may be a risk factor for childhood glaucoma.According to the results of a UK Biobank study, participants in areas with higher PMterparts . There w effects . Sun ande adults . They foglaucoma . Their r2.5-induced dysfunction in retinal cells [2.5 and NOx was reported to increase ocular surface inflammation and retinal inflammation, increasing the risk of developing myopic macular diseases [2.5 and PM10 concentrations and more PM2.5 absorbance were associated with inner and outer retinal layer thinning [2 or CO significantly increased the risk of AMD [2.5 was related to an increased risk of diabetic retinopathy (DR) among diabetic patients in rural China. They postulated that PM could raise glucose levels and induce oxidative stress, inflammation, specific cytokine activity, and endothelial dysfunction, contributing to diabetic retinopathy.Air pollution can induce oxidative stress, activate inflammatory pathways, and increase coagulation ,65,66. Tal cells . As a real cells ,27,29,69diseases . A UK Bik of AMD . One stuIndoor air pollution is associated with indoor tobacco smoking, dissipation of compounds used in building materials and decorations in buildings, cooking with oil and high heat, burning coal or biomass for cooking or heating, using pesticides, etc. ,71. MoreSeveral VOCs, especially aldehydes, have low odor thresholds . This in3 µg/m3 for 30 min or 100 × 103 µg/m3 for 15 min, could lead to health effects [Exposure to high concentrations of indoor air pollutants, for example, concentrations of carbon monoxide at 60 × 10 effects . Example effects . Example effects , respira effects , elevate effects . Some po effects , whereas effects .These indoor air pollutants are reported to be harmful to the human eye, as discussed below.Tobacco smoking affects the ocular surface, resulting in symptoms such as itchiness, redness, and irritation of the eyes. The changes on the ocular surface include alteration of the lipid layer of the tear film, reduced tear secretion, and decreased corneal and conjunctival sensitivity and can cause disorders such as atopic kerato-conjunctivitis and allergic conjunctivitis. Tanisha et al. reported that aldehydes and free radicals released from electronic cigarettes may disturb the stability of the tear film, and vape flavoring may damage the lipid layer through peroxidation. Furthermore, nicotine and acrolein in cigarette vapors cause an inflammatory response in corneal epithelial cells ,23.2.5 that is 10 times higher than that in nonsmoking homes. Long-term exposure to fine PM induced oxidative stress in human corneal epithelial-transformed (HCE) cells and altered the cytokine content of tears; moreover, inflammation of the ocular surface and dry eye syndrome subsequently developed in a mouse model [Indoor smoking can cause an increased level of PMse model . Accordise model . In addise model .Indoor smoke can be produced by other sources, such as cookstoves. For example, a study in Guatemala showed that more than 60% of women who used cookstoves for cooking reported that their eyes were always irritated. However, when these participants were divided into those with exposure to miniature chimney stoves and those with exposure to open stoves, the chimney stove group had less eye irritation than the open stove group .Many in vivo and in vitro studies have focused on outdoor air pollution-induced eye disease; however, other studies have revealed correlations between eye diseases and indoor air pollutants. For example, Vitoux’s in vitro study investigated the cytotoxic and inflammatory responses of the conjunctival cell line WKD exposed to combinations of environmental pollutants, such as air–liquid interface conditions combining low humidity, airflow, and formaldehyde gas, to mimic the inflammatory responses observed in dry eye patients . FurtherCigarette smoking is associated with many chronic disorders that have been considered serious global public health problems. However, investigations on the correlation between smoking and ocular disorders are scarce. Mechanistically, cigarette smoke extract (CSE) caused injury in primary rat retinal ganglion cells (RGCs) via apoptosis and autophagy by upregulating the mRNA levels of proapoptotic Bad and Bax and the protein level of the autophagy marker LC3B II . This meBlue Mountains Eye Study data implied a moderate positive association between smoking and elevated IOP (a significant risk factor for glaucoma) . A systeCataracts have long been linked to cigarette smoking . The mecOne-third of the world’s population burns organic material, including wood, feces, or charcoal (BMF), for cooking, heating, and lighting. This form of energy usage is related to high levels of indoor air pollution and an increase in the incidence of respiratory diseases, cardiovascular disorders, and cataracts . EpidemiAs uveitis develops due to immune dysregulation, data on the association between smoking and uveitis are rare. An epidemiological study in the American adult population using data from the National Health and Nutrition Examination Survey (NHANES) for 2009 and 2010 demonstrated that smoking was positively associated with uveitis . The PacChronic exposure to ROS in cigarette smoke upregulates the expression of TLR4 by human macrophages, promoting NF-κB activation and the production of interleukin (IL)-8 ,97. NicoSeveral carcinogenic compounds cause Th17 cell expansion by binding aryl hydrocarbon receptors on memory T cells ,99. The Previous studies have shown that cigarette smoking is related to an increased risk of AMD . RegardiA systematic review of the impact of direct tobacco smoking on the pathogenesis of many disorders of the posterior segment of the eye in adults and children revealed that tobacco smoking had a positive association with AMD, polypoidal choroidal vasculopathy, and inflamed cystoid macular edema in adults. Tobacco smoking decreases retinal and choroidal thickness. In addition, maternal smoking is a significant risk factor for stage 3 and 4 retinopathy of prematurity and a thinner retinal nerve fiber layer in children . GovindaHousehold fuel consumption is related to an increased indoor concentration of fine particles. Exposure to fine particles associated with solid fuel use causes systemic inflammatory responses and cytokine production. To our knowledge, AMD is due to genetic polymorphisms, and innate immune reactions and inflammation are recognized as etiologies. Although there is a lack of evidence, chronic inflammation induced by indoor air pollution is a possible cause of AMD .Outdoor and indoor air pollution is derived from different sources and can cause different eye diseases. Ocular surface irrigation, conjunctivitis and dry eye disease are the most direct results of air pollution. However, chronic inflammation, oxidative stress, and toxicity resulting from air pollution can further cause cataracts, glaucoma, uveitis, retinal layer thinning, macular degeneration, and diabetic retinopathy. Further research on the effects of air pollution on retinal ganglion cells and the chorioretinal vasculature may help identify the underlying pathological mechanisms. In addition, further research on the association between air pollutants and ophthalmological disorders is needed to improve the understanding of exposure patterns and ocular effects. Such studies will help determine the long-term impacts of air pollutants on the eye, which are currently unknown.