Homocysteine and C-reactive protein (CRP) may serve as biomarkers of postoperative delirium. We set out to compare the role of blood concentration of homocysteine versus CRP in predicting postoperative delirium in patients.In this prospective observational cohort study, the plasma concentration of preoperative homocysteine and postoperative CRP was measured. Delirium incidence and severity within 3 days postoperatively were determined using the Confusion Assessment Method and Confusion Assessment Method-Severity algorithm.P = 0.026], and severity  after adjusting age, sex, preoperative Mini-Mental State Examination score and the days when postoperative CRP was measured. A statistically significant interaction (adjusted P = 0.044) was also observed, in which the association between postoperative plasma concentration of CRP and postoperative delirium incidence was stronger in the participants with lower preoperative plasma concentrations of homocysteine compared to those with higher preoperative levels.Of 143 participants  who had knee or hip surgery under general anesthesia, 44 (31%) participants developed postoperative delirium. Postoperative plasma concentration of CRP was associated with postoperative delirium incidence [adjusted odds ratio (OR) per one standard deviation change in CRP: 1.51; 95% Confidence Interval (CI): 1.05, 2.16; Pending validation studies, these data suggest that preoperative plasma concentration of homocysteine modifies the established association between postoperative plasma concentration of CRP and postoperative delirium incidence. Postoperative delirium, an acute confusion status after anesthesia and surgery, is associated with adverse effects with annual care costs of $ 32.9 billion . Populatvia increased production of pro-inflammatory cytokines in the blood and brain  is a potential predisposing factor owing to its involvement in cardiovascular disease  and AD . PreoperA recent study demonstrated the interaction between gene Apolipoprotein E (a predisposing factor) and postoperative CRP (a protein and precipitating factor) on postoperative delirium . HoweverTherefore, we set out to determine the effects of preoperative plasma concentration of homocysteine, the postoperative plasma concentration of CRP, and their interactions on the incidence and severity of postoperative delirium in patients. It was hypothesized that preoperative plasma concentrations of homocysteine would modify the established association between postoperative plasma concentration of CRP and postoperative delirium in patients.Preoperative homocysteine and postoperative CRP were evaluated in this study because postoperative CRP is an established blood biomarker of postoperative delirium . HoweverWe performed a prospective observational cohort study from June 22, 2016 to May 5, 2017, at Shanghai Tenth People’s Hospital, a university-affiliated hospital in Shanghai, P. R. China. The study protocol was approved by the hospital’s Human Research Ethics Committee (SHSY-IEC-3.0/15-78/01) on May 12, 2016.All participants provided written informed consent for the study before initiating any study procedures. This study is being reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria.We screened patients scheduled for knee/hip replacement surgeries. Participants were included if they: (1) were 60 years old or older; (2) spoke Mandarin Chinese; (3) had general anesthesia, and (4) were able to provide informed consent. Patients were excluded if they had any of the following: (1) pre-existing delirium assessed according to the Confusion Assessment Method (CAM) algorithm ; (2) priPreoperative assessments were performed one day before the scheduled surgery by well-trained researchers following a standard protocol. Participant characteristics were collected, including age, sex, education, body mass index (BMI), and Charlson Comorbidity Index (CCI) . PreoperAll participants underwent a hip or knee replacement under general anesthesia. The preoperative fasting, anesthetics used, airway management, opioid and neuromuscular blocking agent  usage, intravenous fluid administration, and mechanical ventilation were performed per the hospital policy and at the anesthesiologist’s discretion. The participants generally received 1–2 mg midazolam preoperatively. Anesthesia was induced with propofol (2 mg/kg), sufentanil (0.5–1 μg/kg), and cisatracurium (0.5 mg/kg) and was maintained with anesthetic sevoflurane or propofol. We obtained information regarding the American Society of Anesthesiologists (ASA) Physical Status Classification System , surgeryWe collected 4 ml of venous blood during the insertion of intravenous catheters before the anesthesia and surgery in all participants to measure preoperative plasma concentrations of homocysteine. The blood sample was collected in anticoagulant tubes and was immediately centrifuged to collect the supernatant plasma. The plasma was stored in a −80°C freezer until measurement. Preoperative plasma concentration of homocysteine was determined by using the Roche Cobas 8000 system  with the enzyme cycling method.Postoperative measurement of blood CRP was part of the clinical care of the patients. Thus, we obtained the postoperative blood CRP concentrations by checking the participants’ medical records. If participants had several postoperative CRP measurements, the concentration of the first postoperative measurement of plasm CRP was used for the final data analysis in the present study. Since the postoperative CRP measurement was part of the routine postoperative clinical care, the time of the postoperative blood collection  was not fixed on a particular day. Notably, in the clinical laboratory, the postoperative plasma concentrations of CRP were measured using an immunonephelometric method on a Nephelometer BNII , measuring a range from 3–200 mg/L.The primary outcome was the presence of delirium at any postoperative assessments performed in the first three days postoperatively. Postoperative delirium was determined by daily interviews on postoperative days 1, 2, and 3 using the CAM . Each paThe severity of delirium was assessed as a secondary outcome. The severity of postoperative delirium was quantified using the CAM-Severity (CAM-S) long-form , comprisWe estimated that 140 participants would provide 90% power to detect the potential difference in postoperative plasma concentration of CRP between the participants with and without postoperative delirium at a 5% significance level. This estimation was based on a previous study of elderly patients aged 65 years old. The patients who developed postoperative delirium had higher postoperative CRP concentrations than those who did not: 10.26 ± 5.81 mg/dL versus 6.96 ± 4.89 mg/dL .According to our previous study, the estimated incidence of postoperative delirium was 25.6% , so we sThe study included the data analysis of plasma concentrations of preoperative homocysteine, postoperative CRP, and the incidence and severity of postoperative delirium. Notably, all postoperative CRP measurements were performed as part of routine clinical care, mostly occurring within 1–3 days after surgery. The statistical analysis plan was finalized before analyzing the data.t-test or Mann–Whitney U test. Categorical variables  are presented as frequencies and proportions and assessed with chi-square or Fisher’s exact test.Normally distributed continuous variables  and non-normally distributed continuous variables  are presented as the mean ± standard deviation (SD) and median , respectively. As appropriate, the differences between patients who did and did not develop delirium were assessed with an independent samples Preoperative homocysteine and postoperative CRP were scaled using z-scores in all models for analysis, which were calculated by subtracting the mean from an individual raw score and then dividing the difference by the standard deviation. The association between preoperative plasma concentration of homocysteine, the postoperative plasma concentration of CRP, and postoperative delirium incidence were assessed using logistic regression. Results are presented as odds ratio (OR) per one standard deviation change in the biomarker and their associated 95% confidence intervals (CI). The association between the biomarkers and the worst delirium severity was estimated using linear regression, with results reported as a mean difference [beta coefficient (β)] and it’s associated 95% CI. Model fit assuming a Gaussian distribution was evaluated by examining the residuals and model calibration.p-values less than 0.05 were considered statistically significant for all analyses.The association between preoperative homocysteine and postoperative plasma concentration of CRP was assessed for both the primary (delirium incidence) and secondary (delirium severity) outcomes. Both predictors were evaluated in separate univariate models with each of the main effects, one model including postoperative CRP and preoperative homocysteine, and the final model including the main effects and the inclusion of an interaction term between preoperative homocysteine and postoperative CRP together. In order to visualize the interaction between postoperative CRP and preoperative homocysteine, the relationship between postoperative CRP and the predicted probability of postoperative delirium was reported for different preoperative plasma concentrations of homocysteine, namely the 10th, 25th, 50th, 75th, and 90th percentiles. Multivariable models were then created to adjust the associations between the biomarkers and outcomes for age, sex, preoperative MMSE, and day of postoperative CRP measurement for both the primary and secondary outcomes. These variables were selected for the adjustment based on previous studies as deemed clinically relevant while still considering model parsimony. Pearson Correlation was used to determine the relationship between pre-operative homocysteine and postoperative CRP. SPSS version 22.0  and R  were used to analyze the data. Two-sided N = 65), had abnormal cognitive function (N = 6), did not plan to have general anesthesia or changed anesthesia (N = 12), had prior neurologic diseases (N = 3), had an infection/fever (N = 1), and had a significant past medical history (N = 3). Thus, 168 participants were enrolled in the study. After obtaining the consent, 25 participants were excluded because they were not interested in further participation in the study (N = 18), or canceled surgery (N = 7). Participants in the present study did not include patients who took psychoactive drugs to treat mental disorders or neurological diseases. No major complications occurred during the immediate postoperative period. There were no missing data for variables of interest in the current study. The final data analysis included 143 participants  who underwent knee (88.0%) or hip (12.0%) surgery  and without (N = 99) postoperative delirium, except for the length of surgery duration, the preoperative and postoperative day 2 VAS scores  patients received all six assessments, seven (4.9%) participants received five assessments, and one (0.7%) participant received four assessments. Forty-four of the 143 participants (31%) developed postoperative delirium. There were no statistically significant differences in demographic, clinical characteristics, type of surgery, anesthesia, and other perioperative factors between participants with  mg/L versus 46.50 , mg/L, P < 0.001] than the participants without postoperative delirium  mmol/L versus 12.51  mmol/L, delirium .P = 0.026; The postoperative plasma concentration of CRP was associated with the incidence of postoperative delirium before and after adjusting for age, sex, preoperative MMSE, and day of postoperative CRP measurement .Moreover, preoperative plasma homocysteine was not associated with postoperative plasma CRP before and after adjusting for age and sex  genotype  4 genotype  and the genotype . Specifigenotype , suggest12 and folic acid could reduce cognitive impairment in aged mice by lowering homocysteine concentrations  on May 12, 2016. The patients/participants provided their written informed consent to participate in this study.YS and ZX: study concept and design. XM, XCM, TT, MW, XW, HLZ, and JC: acquisition of data. HZ, KC, EM, ZX, and YS: analysis and interpretation of data. ZX, XM, and YS: drafting of the manuscript. KC, LX, and EM: critical manuscript revision for important intellectual content. XCM, LX, and YS: obtained funding. YS and XM: administrative, technical, and material support. YS: study supervision. All authors contributed to the article and approved the submitted version.


Based on the available literature, women living with HIV (WLWH) seem to show greater cognitive and emotional disadvantages than men living with HIV (MLWH). Our aim was to compare the cognitive performance of MLWH and WLWH in an Italian cohort of People Living With HIV (PLWH) and to analyse factors potentially contributing to sex differences in cognitive function. We ran a retrospective, cross-sectional analysis of a monocentric dataset of PLWH who were administered a standardized neuropsychological test battery (SNB) during routine clinical care. We enrolled 161 Italian PLWH who are on combined antiretroviral therapy (cART): 114 (70.8%) MLWH and 47 (29.2%) WLWH.z score) (GCP) was significantly higher in MLWH than WLWH . Moreover, WLWH obtained significantly higher scores on the Zung Depression Scale than MLWH . However, there was no statistically significant direct effect between male sex and better GCP (p = 0.692) in the context of a mediation model. On the contrary, the associations between male sex and better GCP were mediated by higher level of education  and a lower Zung depression score .Global cognitive performance (composite In conclusion, the global cognitive performance of WLWH is lower than that of MLWH. However, other demographic and clinical factors besides sex might help explain differences in their neurocognitive functions and make it possible for us to monitor them and identify those patients most in need. There are several issues relating to the HIV care that make it important to differentiate women living with HIV (WLWH) from men living with HIV (MLWH)   during routine clinical care between January 2011 and March 2019.Data concerning the following demographic, clinical, and laboratory variables were collected for each participant at the time of the neuropsychological testing: age, education, ethnicity, risk factors for HIV infection, time from HIV diagnosis, current and past antiretroviral regimen, current and nadir CD4 cell count, HIV-1 viral load, co-infection with hepatitis C virus (HCV), comorbidities, use of antidepressant and concomitant medications.learning memory: The Rey Auditory Verbal Learning Test – RAVLT;attention: WAIS Digit Span, WAIS Digit Symbol;verbal fluency: FAS Test (subtest of the Neurosensory Center Comprehensive Examination for Aphasia-NCCEA);executive functioning: Multiple features target cancellation- MFTC;fine motor skills: Grooved Pegboard Test.By means of SNB we investigated the following cognitive areas:Z scores using means and standard deviations of Italian normative data  by transforming raw scores obtained on each task into standardized Each patient was also administered the Zung Self-Rating Depression Scale Zung , 1986, aDescriptive statistics were calculated for quantitative variables  and qualitative variables (percent frequencies).T tests or the Chi-square test were performed to determine differences in cognitive performance and Zung scores among groups based on sex: WLWH = group 1 and MLWH = group 2.When appropriate, d in order to identify effect sizes and show the clinical significance of comparisons between groups 1 and 2.We also computed Cohen’s We performed a mediation analysis through a bootstrapping method using SPSS Process Macro to examine the effect of mediating variables on the relationship between sex and cognitive performance .A total of 161 Italian PLWH on cART were enrolled: 114 (70.8%) MLWH and 47 (29.2%) WLWH. Their demographic and clinical characteristics are summarized in Table p = 0.006], with a medium effect size (d = 0.59), time from HIV diagnosis , with a small effect size (d = 0.43), and from first cART , with a small effect size (d = 0.38).The subjects in the two groups (MLWH vs WLWH) significantly differed in mean education  with a small effect size (d = 0.35). Considering each cognitive domain separately, MLWH performed better than WLWH on attention , with a medium effect size (d = 0.59), and executive functions , with a small effect size (d = 0.35). Nevertheless, the percentage of patients affected by HAND did not significantly differ between MLWH and WLWH .GCP was significantly higher in MLWH than WLWH , with a medium effect size (d = 0.50), indicating more symptoms of depression in the former group and a significantly higher percentage of subjects with probable depression according to the Zung Depression normative cut-off . Results of the neuropsychological performances in each cognitive domain are shown in Table Moreover, WLWH obtained significantly higher scores on the Zung Depression Scale than MLWH  and for approximately 27% of the total effect on attention skills [PM = (0.12) / (0.43)]. Moreover, the mediator, Zung depression score, accounted for approximately 32% of the total effect on GCP [PM = (0.10) / (0.32)], for approximately 23% of the total effect on attention skills [PM = (0.10) / (0.43)] and for approximately 24% of the total effect on executive skills [PM = (0.07) / (0.29)].The mediator, education, accounted for approximately 46% of the total effect on GCP [c) between sex and GCP , attention skills , and executive skills  in the context of the mediation model.On the other hand, there was no statistically significant direct effect (The aim of this study was to analyse the cognitive profile of MLWH and WLWH in an Italian cohort of PLWH and to examine the effect of mediating variables on the relationship between sex and cognitive function. Indeed, based on the available literature, WLWH seem to have cognitive and emotional disadvantages (Rubin et al. Overall, the WLWH in our cohort of patients had a lower level of education and longer time from HIV diagnosis and from first cART compared to MWLH. In line with previous evidence (Sundermann et al. In this regard, discrepant data emerged from previous observations. For example, Sundermann et al.  found a However, we identified other demographic and clinical factors besides sex that could help explain the aforementioned difference between WLWH and MLWH. Indeed, our results showed that there was no statistically significant direct effect between sex and GCP, attention and executive skills. On the contrary, the associations between male sex and better GCP and attention skills were mediated by higher level of education and fewer depressive symptoms. Moreover, a lower Zung depression score mediated the association between male sex and better executive skills.Thus, as suggested in previous studies, we confirm that depressive symptoms seem to be more prevalent in WLWH than in MLWH (Aljassem et al. Indeed, we corroborate the finding that adjusting for critical factors such as education, clinical variables, and mental health reduces the dimension of the sex difference and elucidates factors contributing to NCI in women (Rubin et al. We acknowledge that our study has some limitations. First, our conclusions are limited by the small sample size of the study. Indeed, due to the small number of patients who were submitted to a completed SNB in the dataset used for the retrospective analysis, our study reached a low statistical power. Thus, in future studies, it will be important to extend the sample to confirm the generalizability of the results achieved.Second, this is a cross-sectional study and uncontrolled biases can occur in routine clinical practice. Thus, future longitudinal studies are needed to confirm our findings also given the fact that only one longitudinal study to date has examined the risk of neurocognitive decline in WLWH and MLWH (Heaton et al. Lastly, in future investigations, it would be useful to include a healthy control group to compare differences in cognitive functions between women and men and between PLWH and the general population. In addition, our WLWH and MLWH subgroups were not matched for education, years from HIV diagnosis and years from first ARV; future investigations that include matched groups are needed to check the probable influences of these disparities on cognitive performance.In conclusion, taken together, our findings suggest that in our sample, WLWH demonstrate lower global cognitive performance, attention, and executive skills compared to MLWH. However, other demographic and clinical factors might be able to explain these disadvantages in WLWH besides sex, in particular the lower level of education and more depressive symptoms. On these bases, in planning cognitive interventions, it seems appropriate to pay particular attention to WLWH, but it would also be helpful to monitor demographic, clinical, and mental health factors to identify the patients who are most in need and to detect cognitive impairments as soon as possible and intervene to improve the psychological wellbeing of PLWH.


Studies have shown that a direct association exists between the diet and blood uric acid concentrations. However, works on the association of dietary patterns with blood uric acid concentrations and hyperuricemia remain limited. This study aims to evaluate the association of dietary patterns with blood uric acid concentrations and hyperuricemia.n = 4855). Three statistical methods, including principal component analysis, reduced rank regression (RRR), and partial least squares regression, were used to extract dietary patterns. General linear regression and logistic regression analyses were utilized to explore the relationship of dietary patterns with blood uric acid concentrations and hyperuricemia.The relationship between dietary patterns and hyperuricemia was explored through a nutritional epidemiological survey in China (P < 0.05), whereas those in the highest quartile of animal dietary pattern scores were at a high risk of hyperuricemia . The participants in the third quartile of scores for the RRR dietary pattern, which was characterized by the relatively high intake of poultry, sugary beverages, and animal organs and the low intake of desserts and snacks, had a significantly higher risk of hyperuricemia than those in the first quartile of scores for the RRR dietary pattern .After adjusting for potential confounding factors, the score for the plant-based dietary pattern was found to be negatively correlated with blood uric acid levels (β =  − 3.225) and that for the animal dietary pattern was discovered to be directly correlated with blood uric acid levels (β = 3.645). The participants in the highest quartile of plant-based dietary pattern scores were at a low risk of hyperuricemia (OR = 0.699; 95% CI: 0.561–0.870, Our research indicated that plant-based dietary pattern analyzed by PCA was negatively associated with blood uric acid concentrations, while animal-based dietary pattern was directly associated with blood uric acid concentrations. The RRR dietary pattern may have the potential to induce elevations in blood uric acid concentrations.The online version contains supplementary material available at 10.1186/s12937-022-00789-7. Hyperuricemia is a chronic metabolic disease caused by blood uric acid accumulation due to purine metabolism disorders. It is the leading cause of gout and is also related to diabetes, chronic kidney disease, cardiovascular disease, and other diseases –4. SeverThe data used in this work were from the baseline data of the Community Cohort Study on Specialized Nervous System Diseases (No.2017YFC0907701), which is a National Key R&D Program of China Precision Medicine Project. This study was reviewed and approved by the Institutional Review Board of the National Institute for Nutrition and Health . In this project, the study population was selected in 2018 from four Chinese provinces via the segmented cluster sampling method. Information on the general demographics, disease history, diet, and other lifestyle habits of the research population were collected via face-to-face interviews. Physical examination was performed, and blood samples were collected. In this study, a total of 6720 people, of whom 5466 were adults, from Hebei Province were recruited. A total of 611 people were excluded due to incomplete data. Finally, 4855 people were included  of each food item in the reference categories within the past 12 months. Food consumption was converted into daily food intake on a uniform basis and into g/day. In accordance with the Chinese food composition table, the 65 items were classified into 17 categories: cereals and potatoes, legumes and their products, fresh vegetables, mushrooms and algal food, preserved and processed vegetables, fruits, poultry, meat, fish and shrimp, animal organs, processed meats, eggs, snacks and desserts, dairy products, nuts, sugary beverages, and tea or coffee ; educational level . A questionnaire was used to collect the following lifestyle-related information: smoking status (yes or no) and drinking status (yes or no). Current smokers were defined as having smoked at least one cigarette per day. Recent drinking was defined as alcohol consumption at least once in the past 1 year.Hyperuricemia was defined as serum blood uric acid concentration ≥ 416.5 μmol/L in men and 357 μmol/L in women . BMI wasPROC PLS statement in SAS  was utilized to conduct RRR and PLS analyses with the definitions “METHOD = PLS” or “METHOD = RRR.” In the analysis, the values of blood uric acid were used as response variables, the 17 food groups were considered as predictors, and one factor was extracted from each of the two methods as the dietary pattern. Food groups with absolute factor loading value > 0.20 were considered to be the main contributors to a dietary pattern and included in this study. A pattern score was obtained for each participant by obtaining the total consumption of each food group weighted by factor loading. A high score indicated that the intake of food groups associated with a specific pattern was high.Data reduction techniques based on PCA, PLS, and RRR were used to identify dietary patterns involving the 17 food groups. The Kaiser–Meyer–Olkin measure of sampling adequacy and Bartlett’s test of sphericity were used to evaluate the adequacy of correlation matrixes with the data. PCA was used to derive the major dietary patterns on the basis of the frequency of the consumption of the 17 food groups in this FFQ. Varimax was applied to maintain factorial independence and increase interpretability. Factors with eigenvalue > 1 were extracted, and then scree plots were used to identify the major dietary patterns. The 2 test and ANOVA were used to compare categorical and continuous variables, respectively. We estimated the associations of dietary pattern factor scores with blood uric acid concentrations by using multivariate linear regression models. Hyperuricemia status was used as the dependent variable for binary logistic regression analysis, and confounders, such as age, gender, smoking, alcohol consumption, blood pressure, and blood lipids, were adjusted. RRR and PLS analyses were performed with SAS version 9.1 . All other analyses were conducted by using SPSS software package version 22.0 for Windows . A two-tailed P < 0.05 was considered significant.The basic characteristics of the participants were described in accordance with the quartile of the scores for each dietary pattern (ascending from Q1 to Q4). The data of continuous variables were expressed as mean ± SD and those of categorical variables were expressed as frequencies (percentage). χA total of 4855 participants were included in the present study. The overall prevalence of hyperuricemia was 19.3%. The prevalence of hyperuricemia among males was 22.0% and that among females was 17.3%. The demographic and clinical characteristics of the participants with and without hyperuricemia are shown in Table P < 0.01) showed that the correlation among variables was sufficiently strong for factor analysis. Three major dietary patterns were determined by using PCA. The first dietary pattern was characterized by the high intake of fresh vegetables, fruits, dairy products, eggs, and legumes and their products. This pattern was designated as the plant-based pattern. The second type featured the high intake of pickled and processed vegetables, processed meat, snacks, and mushrooms and algal food and was denoted as the processed food pattern. The third type was characterized by the high intake of poultry, livestock, fish and shrimp, processed meats and nuts and was considered as the animal dietary pattern. The dietary pattern obtained through RRR was distinguished by the high intake of poultry meat, sugar-sweetened beverages, animal organs, and tea or coffee, and the low intake of snacks and desserts. The dietary pattern obtained from PLS was similar to that obtained from RRR but had a higher intake of fruits and beans (Table The Kaiser–Meyer–Olkin index 0.753) and Bartlett’s test ( and BartWe identified the characteristics of the participants on the basis of the quartile of their score for each eating pattern Table . CompareP = 0.007). The score for the animal dietary pattern was directly correlated with blood uric acid levels . Values were adjusted for sex, age, residence, educational status, alcohol status, smoking status, BMI, hypertension, diabetes, and dyslipidemia.The linear regression relationship between the scores for different dietary patterns and blood uric acid concentrations is shown in Table  P < 0.05), whereas the highest quartile of animal diet pattern scores was associated with a high risk of hyperuricemia . For the RRR dietary pattern, the ratio of Q3 to Q1 was statistically significant  (Table In logistic regression analysis, the highest quartile of plant-based dietary pattern scores was associated with a low risk of hyperuricemia (OR = 0.699; 95% CI: 0.561–0.870,In the present study, the relationship between Chinese dietary patterns and serum uric acid was investigated by using three statistical methods, namely, PCA, RRR and PLS. The plant-based dietary pattern determined by PCA was negatively correlated with serum uric acid, whereas the animal-based dietary pattern was directly correlated with serum uric acid. Although no significant association was found between RRR and PLS dietary patterns and serum uric acid concentrations, the RRR dietary pattern may be a potential risk factor for hyperuricemia.6, and vitamin B12 may have important functions in reducing blood uric acid concentrations. Vitamin C may regulate blood uric acid concentration via its uricosuric effect. Increasing the concentration of vitamin C may competitively inhibit the reabsorption of uric acid given that vitamin C and uric acid are reabsorbed through anion exchange transport in proximal tubules [Similar to the Mediterranean and DASH diets, the plant food dietary pattern is characterized by the intake of large quantities of fresh vegetables, fruits, beans, dairy products, and eggs. Two studies have shown that the Mediterranean and DASH diets are associated with the low risk of hyperuricemia , 27. Veg tubules . Folate  tubules . Studies tubules . Soy bea tubules .Consistent with previous studies, this work found that the animal food dietary pattern is directly associated with uric acid concentration and hyperuricemia risk. This association can be ascribed to the following aspects: First, considering that animal foods are normally high in purine, the high intake and accumulation of purine increase uric acid . At sameThe processed food diet pattern is not mentioned in previous reports. With the development of the economy and the increase in social pressure, the number of people who may prefer the processed food dietary pattern is increasing because processed foods are convenient to eat and have long storage times. This situation may encourage the development of a new dietary pattern. In the present study, we found no significant association between the processed food diet pattern and hyperuricemia. However, previous studies have reported that the consumption of processed food is associated with the increased risk of cardiovascular disease , 34. TheThe potential interactions between different food ingredients remain worthy of in-depth study. Although our results did not reveal significant associations between serum uric acid levels and RRR dietary patterns, we speculated that the low intake of snacks and desserts in the RRR dietary pattern may offset the effect of meat on serum uric acid concentrations. After adjustment for confounding factors, we found that for the RRR dietary pattern, scores in the third quartile were directly correlated with hyperuricemia compared to scores in the first quartile. Therefore, we speculated that the RRR dietary pattern may have a potential positive correlation with blood uric acid concentration and hyperuricemia. Although the PLS and RRR dietary patterns have high intakes of animal foods, such as animal organs and poultry, vegetable and bean intake was higher in the PLS dietary pattern than in the RRR dietary pattern. The complex nature of this pattern may explain this finding to some extent. Although the high intake of animal food increases blood uric acid concentration, the intake of large quantities of vegetables and fruits accelerates the metabolism of blood uric acid. The potential interactions between different foods and nutrients have promoted these results.To summarize, we discussed the relationship between several dietary patterns and blood uric acid concentration. Although blood uric acid may induce oxidative stress, atherosclerosis, vascular inflammation, and other tissue damage, it also has protective roles by acting as an antioxidant that scavenges free radicals and reducing the permeability of the blood–brain barrier –39. We sThe present study has some limitations. First of all, it is a cross-sectional survey. Therefore, the judgment of causality is limited. Further prospective longitudinal studies are needed to prove causality. Second, we obtained the data on dietary intakes on the basis of the memory of the participants. Such data may have some deviation from the actual intake. Finally, this study did not include the intake of dietary supplements by the participants.The plant-based dietary pattern established by PCA was negatively correlated with serum uric acid concentrations, whereas the animal dietary pattern was directly correlated with serum uric acid concentrations. Although the RRR dietary pattern did not show a linear relationship with uric acid concentrations, it does have the potential for inducing increased serum uric acid concentrations. The PLS dietary pattern was more balanced than other patterns and had no relationship with uric acid concentrations. Further longitudinal studies are needed, and dietary uric acid must be maintained within a reasonable range.Additional file 1. Sensitivity analysis.


A Pb-free PSC device (FTO/TiO2/NH3(CH2)2NH3MnCl4/spiro-OMeTAD/Au) was simulated via SCAPS-1D software. The simulated Pb-free PSCs (FTO/TiO2/NH3(CH2)2NH3MnCl4/spiro-OMeTAD/Au) showed decent power conversion efficiency (PCE) of 20.19%. Further, the impact of the thickness of absorber (NH3(CH2)2NH3MnCl4), electron transport (TiO2), and hole-transport (spiro-OMeTAD) layers were also investigated. Subsequently, various electron transport layers (ETLs) were also introduced to investigate the role of ETL. In further studies, an NH3(CH2)2NH3MnCl4-based PSC device (FTO/TiO2/NH3(CH2)2NH3MnCl4/spiro-OMeTAD/Au) was also developed (humidity = ~30–40%). The fabricated PSCs displayed an open circuit voltage (Voc) of 510 mV with a PCE of 0.12%.Recently, the design and fabrication of lead (Pb)-free perovskite or perovskite-like materials have received great interest for the development of perovskite solar cells (PSCs). Manganese (Mn) is a less toxic element, which may be an alternative to Pb. In this work, we explored the role of NH Mixed halide (NH4)3Sb2I3Br6 was used by Zuo et al. [3(CH2)2NH3MnCl4 as an absorber layer, which exhibited decent photovoltaic performance, as listed in 3(CH2)2NH3MnCl-based fabricated PSC device is poor (0.12%) but showed a decent Voc. The absorber layer should have a low band gap for better light absorption. Although NH3(CH2)2NH3MnCl4 has a good optical band gap, we believe that the poor PCE and Jsc of the NH3(CH2)2NH3MnCl4-based fabricated PSC device may be attributed to the poor morphological characteristics and fast crystallization process. The rapid crystallization of perovskite films has been a major concern in developing high-performance photovoltaic devices. The preparation of pin-hole-free and high-quality thin films with large grain boundaries is of great importance for the construction of highly efficient PSC devices. Previously, two-step deposition methods or anti-solvents such as chlorobenzene have been used for the preparation of high-quality thin films of perovskite materials. Some new preparation methods need to be developed to exert tight control on the crystallization process. It is also important to study the mechanism of thin film formation, charge-separation/recombination at interfaces/grain boundaries to further improve the performance of NH3(CH2)2NH3MnCl4-based PSCs. We believe that, if systematic investigations are implemented, significant improvements in the performance of the NH3(CH2)2NH3MnCl4-based PSCs can be seen in the near future. Previously, many research groups have developed Pb-free PSCs using different light absorbers. In 2015, Park et al.  developea et al.  used a cn et al. , and then et al.  reportedabsorber . Thind eabsorber  utilizedo et al. , and the2, ZnO, SnO2, TiO2, ZnSe, and WO3) were employed, and ZnSe-based PSCs showed the highest efficiency, which may be due to the high electron-hole mobility and suitable energy level values of ZnSe. Furthermore, NH3(CH2)2NH3MnCl4 was prepared, and its optical band gap was found to be 1.81 eV, which is suitable for a light absorber layer. Further, PSCs were fabricated, and the developed device exhibited a good Voc of 510 mV with a poor PCE of 0.12%. We believe this PCE may be further enhanced in the future by using/introducing some new device architectures or fabrication methods.Finally, it can be summarized that highly efficient Pb-free PSCs have been simulated via SCAPS-1D. Further, we optimized the thickness of electron, absorber, and hole transport material layers. The numerically simulated PSCs exhibited good efficiency of 20.30% via SCAPS-1D. Various electron transport layers (WS


FH cells control IgE synthesis by secreting IL-4 to allergen-specific B cells. IL-5 promotes eosinophil inflammation, while IL-13 and IL-4 are involved in goblet cell metaplasia and bronchial hyperresponsiveness. Currently, “Type-2 low” asthma is defined as asthma with low levels of T2 biomarkers due to the lack of reliable biomarkers, which is associated with other Th cells. Th1 and Th17 are capable of producing cytokines that recruit neutrophils, such as IFN-γ and IL-17, to participate in the development of “Type-2-low” asthma. Precision medicine targeting Th cells and related cytokines is essential in the management of asthma aiming at the more appropriate patient selection and better treatment response. In this review, we sort out the pathogenesis of Th cells in asthma and summarize the therapeutic approaches involved as well as potential research directions.Prosperous advances in understanding the cellular and molecular mechanisms of chronic inflammation and airway remodeling in asthma have been made over the past several decades. Asthma is a chronic inflammatory disease of the airways characterized by reversible airway obstruction that is self-resolving or remits with treatment. Around half of asthma patients are “Type-2-high” asthma with overexpression of type 2 inflammatory pathways and elevated type 2 cytokines. When stimulated by allergens, airway epithelial cells secrete IL-25, IL-33, and TSLP to derive a Th2 immune response. First ILC2 followed by Th2 cells produces a series of cytokines such as IL-4, IL-5, and IL-13. T With inFH), Th17, and Th1 cells. Activation of Th2-pathways is at the core of type 2 inflammation, producing excessive amounts of the cytokines IL-4, IL-5, and IL-13. IL-5 induce eosinophil activation, maturation, and recruitment, while IL-4 and IL-13 are involved in goblet cell metaplasia, airway smooth muscle(ASM) contractility, and airway hyperresponsiveness(AHR)  . TFH celructures , 9. Accuructures . Th1 celructures . Some otructures , 13. HowCurrently, conventional asthma medications include bronchodilators and glucocorticoids. They focus on symptom control, are not curative, and are often ineffective in severe cases. Th cells remain at the forefront of asthma pathogenesis due to chronic airway inflammation and airway remodeling Figure 222.1Epithelial cytokines play a role as “whistle-blowers” in developing allergic responses at barrier surfaces and are involved in the pathogenesis of type 2 inflammatory diseases, typically asthma. The release of these “alarmins”, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), occurs when the allergen stimulates bronchial epithelial cells . AlthougTSLP is considered to be a primary regulator of type 2 immune response to the respiratory barrier, which activates Th2 cells, innate lymphoid cells (ILCs)-2, mast cells, and other immune cells by inducing costimulatory molecules on DCs . AccumulIn addition, interactions between cytokines released by Th cells or other cells and AECs contribute to the progression of asthma. While higher levels of activin-A expressed by AECs may promote an increase in Th2 and Th9 cells , upregul2.2Th2-driven adaptive immune response and ILC2s-driven innate immune response are currently regarded as two independent but linked pathogenic mechanisms of asthma, both of which produce type 2 cytokines . ILC2s pin vitro for about 48 hours, however, IL-5 can prolong the survival time of eosinophils ) controls eosinophils’ maturation, differentiation, and release . In the 2+ mobilization that was accompanied by increased mRNA expression of histamine H1 and cysteinyl leukotriene CysLT1 receptors, inducing glucocorticoid-insensitive AHR in isolated human small airways  expression on human endothelial cells and are involved in collagen production in fibroblasts . In addi airways . Further airways , 52.2.3FH cells, rather than Th2 cells, drive IgE responses in asthma. Using house dust mites (HDM) and mice, León and her colleagues found that after the first sensitizing exposure, TFH cells reside in the draining mediastinal lymph nodes of the lungs and differentiate into Th2 and migrate to the lungs to exert their effects after a second attack by HDM allergens  was elevated in allergic asthma, with increased production of IL-4, and IL-21, and positively correlated with total IgE in the blood  or biomarker restrictions. In phase 2 and 3 clinical trials, including patients with severe asthma, Tezepelumab (subcutaneous injection) consistently and significantly reduced acute asthma exacerbations regardless of key biomarkers , 65. In Clinical trials with anti-IL-25 antibodies have not been conducted, but anti-IL-33 has obtained prospective results in a few trials. Itepekimab, a monoclonal antibody targeting IL-33, causes a reduction in blood eosinophils with a long-lasting effect in patients with moderate asthma . Results3.23.2.1Based on accumulating evidence implicating IL-4, IL-5, and IL-13 are responsible for the occurrence and development of asthma. Several clinical trials targeting type 2 cytokines are currently underway, and some of the relevant biologics have been approved for the treatment of severe asthma. Mepolizumab, Reslizumab (anti-IL-5 mAb), and Benralizumab (anti-IL-5R mAb) were FDA-approved to treat patients with severe eosinophilic asthma . Several3.2.21 and asthma symptom control, with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline , Lavolta I enrolled 2,000 patients with severe asthma and showed that lebrikizumab significantly reduced acute asthma exacerbations and also improved lung function in patients, yet similar results were not obtained in Lavolta II . A phasebaseline . In addibaseline . The lonbaseline .3.2.3s  was effective in reducing asthma exacerbations and hospitalizations . Evidencs .3.2.4IL-9-targeted therapy may offer a new approach to treating patients with asthma, but clinical studies are not well underway. In two randomized phase 2a studies in asthmatic subjects, patients who received MEDI-528, a humanized anti-IL-9 monoclonal antibody, showed a slight improvement in symptoms without a change in lung function . Another44.1Th1 inflammation is mainly characterized by an increase in Th1 cells and infiltration of signature cytokines including IFN-γ and TNF-α. Because of the inhibition Th2 inflammatory response, Th1 is considered to have an inhibitory effect on asthmatic airway inflammation in early investigations. Several studies have shown that IFN-γ inhibits Th2 cell function to attenuate the inflammatory response in asthma . Further+CD4+ T cells were concentrated in the BALF of adult patients with severe asthma and that Th1 airway inflammation was evident in children with allergic and non-allergic severe asthma  mAb, was used in two patients with recurrent acute exacerbations of asthma, both of whom showed a good clinical response and reduced hospital admissions . ClazakiIL-23 is a pro-inflammatory cytokine regulated in Th17 and targeting IL-23 may be particularly beneficial in neutrophilic asthma. In a randomized, double-blind, placebo-controlled phase 2a study, IL-23 p19 inhibitor, Risankizumab was used in adult patients with severe asthma. However, disappointingly the study did not meet the primary endpoint. time to first asthma worsening was shorter in the risankizumab group than in the placebo group, and the annualized rate of asthma worsening was higher in the risankizumab group than in the placebo group. Lung function, ACQ-5 scores, and the incidence of severe asthma exacerbations were similar in both groups .5.31, or short-acting β2-agonist (SABA) use  for the duration of the study, and inhaled glucocorticoids were available. At week 12, Brodalumab did not produce any statistically significant benefit in terms of ACQ scores, FEVABA) use . BITS720ABA) use . SecukinABA) use . Althoug5.4The current focus of asthma treatment remains on pharmacotherapy, and the main drugs can be divided into bronchodilators such as SABA which provide rapid symptomatic relief by relaxing ASM and control drugs that inhibit inflammation represented by inhaled corticosteroids (ICS) . In the AIT is the only disease-modifying and potentially preventive asthma treatment based on repeated injections or sublingual administration of specific allergens to allergic individuals to induce immune tolerance . The mec6FH cells control IgE synthesis by secreting IL-4 to allergen-specific B cells. Epithelial-derived TLPS, IL-25, and IL-33 can awaken ILC2 and Th2, while IL-4, IL-5, and IL-13 play a central role in the subsequent series of transformations. In the past few years, significant advances in Th17 and Th1 cell research have revealed new aspects of the “Type-2 low” asthma cellular machinery. Th1 and Th17-related cytokines act as central effector mediators and continuity factors in airway inflammatory storms and airway injury.Complex interactions between cellular participants and the innate and adaptive immune systems in response to multiple allergenic stimuli coordinate the immune response in the lung. In Type-2 high asthma, TAt present, the efficacy and safety of various biologics for Th2 responses have been well evaluated. Several biologics have been approved by the FDA for the treatment of “Type 2 high” asthma, such as benralizumab, dupilumab, and mepolizumab. They have demonstrated favorable results in clinical trials and real-world studies on reducing exacerbations, improving quality of life and lung function in patients with severe asthma, and even reducing OCS doses. However, various biologics for Th1 and Th17 are still struggling to move forward. Two biological agents (Tezepelumab and Astegolimab) have shown partial effects on “Type-2 low” asthma by blocking epithelial cell cytokines. More in-depth study of the pathological mechanism and the selection of the appropriate patient population based on the corresponding clinical indicators may bring about a turnaround. There is no silver bullet in asthma treatment. Asthma treatment may be individualized in the future. Perhaps more in-depth research on Th cells and big data analysis to match different clinical manifestations of asthma with specific Th cells for targeted and individualized treatment will be the new direction in the future.TJ, access to literatures and writing of the manuscript. HL, revising the manuscript. Both authors contributed to the article and approved the submitted version.


Asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) or without (CRSsNP) are chronic respiratory diseases. These two disorders often co-exist based on common anatomical, immunological, histopathological, and pathophysiological basis. Usually, asthma with comorbid CRSwNP is driven by type 2 (T2) inflammation which predisposes to more severe, often intractable, disease.In the past two decades, innovative technologies and detection techniques in combination with newly introduced targeted therapies helped shape our understanding of the immunological pathways underlying inflammatory airway diseases and to further identify several distinct clinical and inflammatory subsets to enhance the development of more effective personalized treatments. Presently, a number of targeted biologics has shown clinical efficacy in patients with refractory T2 airway inflammation, including anti-IgE , anti-IL-5 /anti-IL5R , anti-IL-4R-α , and anti-TSLP (tezepelumab). In non-type-2 endotypes, no targeted biologics have consistently shown clinical efficacy so far. Presently, multiple therapeutical targets are being explored including cytokines, membrane molecules and intracellular signalling pathways to further expand current treatment options for severe asthma with and without comorbid CRSwNP. In this review, we discuss existing biologics, those under development and share some views on new horizons. Asthma is a chronic respiratory disease, that is often associated with allergy and/or upper airway involvement and/or other conditions outside of the respiratory tract, such as food allergy and atopic dermatitis ,2. The hIn the past two decades, our knowledge of the multifaceted nature of asthma and the link to chronic rhinosinusitis has vastly increased ,9. So faType 2 (T2) asthma is presently the best defined endotype, which makes up approximately 50–60% of the asthma population ,12. WhilThe definition of non-T2 asthma seems more complex than the one of T2-asthma given the vast heterogeneity of its underlying mechanisms, varying from predominant inflammatory pathways (e.g. airway neutrophilia in the absence of respiratory infections) to the lack of eosinophilic or other inflammation (as in paucigranulocytic asthma), or predominant airway smooth muscle (ASM) dysfunction (characterised by fixed airway narrowing and severe AHR) ,25. PathIn this review, we provide an overview of existing and emerging treatment options for asthma and comorbid CRSwNP, targeting the underlying inflammatory pathways, and discuss our current knowledge and future perspectives.Asthma and chronic rhinosinusitis (CRS) represent frequently occurring, often coexisting diseases, located at the ultimate ends of the respiratory tract and interrelated through joint underlying mechanisms which respond to targeted biologics . Both coIn the late 1940s, asthma was already identified as a heterogeneous condition and since then a plethora of studies has added accumulating evidence on the stratification of asthmatic patients into different clinical phenotypes and later on, based on the predominant inflammatory sputum cell profile, into inflammatory phenotypes .In the 2000s, asthma was further subcategorised into two major endotypes: Th2 and non-Th2 asthma, based on the presence or absence of (i) CD4+ T-helper cell type 2 (Th2)-driven inflammatory responses , or Th17-driven responses , (ii) IgE, and (iii) increased levels of eosinophils, neutrophils, basophils, and mast cells in the airways . More reIn T2 asthma, the presence of copious amounts of type 2 cytokines at mucosal sites, as well as intrinsic down-regulation of the expression of claudin-18 and E-cadherins, are linked to the reduced structural integrity of the airway epithelium and the enhanced permeability and responsiveness of the epithelial barrier to exogenous triggers . ConsequIn contrast with T2 eosinophilic non-atopic asthma which usually manifests at a later age (late-onset), the allergic subset of T2 asthma usually presents at a young age (early-onset). This subtype is characterized by positive allergy skin tests, increased serum total and specific IgE and clinical symptoms upon allergen exposure. Notwithstanding, little is known about the precise roles of cells from the innate and adaptive immune compartments specifically in early-onset allergic asthma as compared with other subsets of T2 non-atopic asthma . In alleEosinophils, due to their pleiotropic effect on various cell types, are perhaps the most recognized cells in the pathophysiology of T2 asthma. Eosinophils are found at inflamed mucosal sites and upon activation they are capable of producing and releasing numerous pro-inflammatory mediators, including IL-5, IL-13, eotaxins, cysteinyl leukotrienes , major basic protein (MBP), eosinophil peroxidase (EPX), eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN) . EosinopIn children, the eosinophilic phenotype is commonly present which is associated with early-onset disease with atopy, impaired lung function and increased airway hyperresponsiveness .Non-T2 asthma  is a heterogeneous condition which may comprise several underlying mechanisms including the influx of CD4+ type 1 T helper (Th1) and type 17 T helper (Th17) cells, type 1 and type 3 innate lymphoid cells (ILC1 and ILC3 respectively), neutrophils as well as increased levels of pro-inflammatory mediators in the lung tissues, among others including IL-1ß, IL-6, IL-8, IL-17A/F, IL-22, IFN-γ, and TNF-α. Studies point out that an imbalance in Th17/Treg cells may play a role in corticosteroid-resistant neutrophilic asthma ,65. In aCRS is a common chronic inflammatory disorder of the upper airways with an estimated prevalence of approximately 10–15% in the general adult population ,67. CRS Based on endoscopic or imaging findings, CRS comprises two major clinical phenotypes, i.e., with (CRSwNP) or without (CRSsNP) nasal polyps (NP); the latter being approximately twice as prevalent. Although less prevalent, CRSwNP is the most cumbersome phenotype which often coexists in patients with more severe asthma ,72,73. IAn additional clinical subset of CRSwNP and late-onset T2 asthma includes aspirin-exacerbated respiratory disease (AERD) or nonsteroidal anti-inflammatory drugs (NSAIDs) exacerbated respiratory disease (NSAID-ERD). As part of the previously termed ‘Samter's triad’, patients with AERD/NSAID-ERD present with asthma and concomitant CRSwNP with often intractable disease ,74,75. TApart from the aforementioned ‘traditional’ classification, CRS phenotypes are highly heterogeneous and show a substantial geographical with racial variability across inflammatory profiles. For example, in Caucasian populations, CRSwNP most frequently presents with a type 2 inflammatory (eosinophilic) profile, while in Asian populations mixed inflammatory profiles in both CRS clinical phenotypes have been found ,77. ThisBased on increased levels of inflammatory proteins and cytokine profiles, CRS (with and without NP) comprises three different endotypes, i.e., T1 characterised by type1 cytokines IFN-γ and TGF-β, T2 by type2 proteins and cytokines IgE and IL-4, IL-5, and IL-13, and T3 by Th17 cytokine IL-17A ,80,81.In T2 CRSwNP, eosinophils usually make up the predominant inflammatory cells , while IWhile NP are commonly found in adults, they are rare in children under the age of 10 years. Furthermore, the presence of NP in children usually indicates underlying systemic diseases, such as cystic fibrosis, primary ciliary dyskinesia or immunodeficiencies. The association with asthma and other allergic/eosinophilic comorbidities is not as clearly expressed in children .Structural changes including epithelial abnormalities, subepithelial matrix deposition, ASM cell alterations and mucus hyperproduction contribute to airway remodelling in asthma resulting in small airways disease, non-specific AHR and accelerated lung function decline leading to fixed airflow obstruction . Recent Airway epithelial cells are capable of producing large amounts of cytokines, antimicrobial peptides and multiple proteases, and thus, contribute to the creation of a physical barrier restraining both pathogens and allergens ,93. AirwUnder specific conditions, such as allergen-mediated epithelial damage, airway epithelial cells lose their protective function, become highly pro-inflammatory and, by promoting airway remodelling, they become crucial players in asthma pathophysiology . EpithelFurthermore, IL-4 and IL-13 released from ILC2s and Th2 cells directly stimulate airway epithelial cells and induce mucus overproduction ,102. DynDCs act as antigen presenting cells (APCs) but their actions can vary according to their phenotype . MyeloidAnother crucial component of airway remodelling represents ASM abnormalities (hypertrophy and hyperplasia) . StructuLung function is also regulated by a network of afferent and efferent nerves . Airway Dysregulation of the DC-epithelium interactions also represents a crucial aspect in CRSwNP pathophysiology . In CRSwUntil recently, no truly disease-modifying therapies existed for asthma and/or CRSwNP. However, in terms of airway remodelling, a study including mild asthmatics receiving only SABA showed that three infusions with anti- IL-5 monoclonal antibody mepolizumab reduced the expression of extracellular matrix proteins  in the bronchial basement membrane. It also reduced TGF-β1 level in BAL fluid and TGF-β1 mRNA expression in eosinophils . Early iSeveral triggers and external factors  can directly or indirectly interfere with our immune system. In this complex interplay, it has become evident that the microbiome plays an important regulatory or even ‘disease driving or modulating’ role . For insn = 7115 adults; follow-up over 15 years) using metagenomic sequencing of stool samples [Escherichia, Enterococcus, Clostridium, Veillonella, and Bacteroides fragilis was found to be associated with a higher incidence of asthma over time [Staphylococcus aureus colonization may contribute to its pathogenesis [An increasing number of studies support the existence of the gut-lung axis and the role of gut microbiome alteration in the pathogenesis of chronic inflammatory diseases including asthma and COPD. Only recently, this association has been underscored by data from a large prospective population-based study  may be beneficial components of asthma management and several studies with tailored approaches are currently ongoing in different patient populations . In thisThe role of the microbiome in health and disease as well as the effects of new and existing therapeutic modalities, including the long-term application of corticosteroids and biologics, on the composition of the microbiome in the context of disease control and remission is a new area of exploration with the potential to further shape personalized medicine.Clinically applicable biomarkers help clinicians to define inflammatory asthma phenotypes and to identify responders to (biologic) treatments ,137. SimIn a cohort of patients with severe asthma, the sinonasal mucosal thickness was correlated with levels of systemic (blood eosinophils) and lower airways  type 2 biomarkers, indicative of more severe disease . There iPresently, several T2-biologic treatment options exist, blocking the following targets: IgE, IL-5 and IL-5R, IL-4R, and TSLP. A short outline per biologic is provided underneath including the mechanism of action and clinical effectiveness , Figure2Omalizumab, a recombinant humanized anti-IgE monoclonal antibody, was the first biologic drug aimed at uncontrolled severe allergic asthma, which effectively reduced severe asthma exacerbations, improved asthma symptoms and lung function, and decreased the use of inhaled glucocorticosteroids with a long established , favourable safety profile. It is approved for patients with allergic asthma older than 6 years . In addiex vivo [NCT03758716) and allergic asthma (NCT05008965) without any published data, yet.Based on the success of this approach, new monoclonal antibodies targeting different epitopes on the IgE molecule emerged. Ligelizumab, a high-affinity IgG1kappa humanized anti-IgE monoclonal antibody was shown to be very potent in IgE binding to the FcεRI, but failed to significantly improve asthma control and exacerbation rates in severe asthma, possibly because of its faster clearance as compared to omalizumab . Quilizuex vivo . This anex vivo . A new hThe relevance of IL-4 and IL-13 in the pathophysiology of asthma has been extensively addressed throughout various studies and reports ,189. BotFollowing a positive phase IIb study , a phaseAnother therapeutic agent targeting both IL-4 and IL-13, pitrakinra, a dual IL-4/IL-13 antagonist, reduced asthma exacerbations only in a subgroup of patients with specific gene polymorphisms of IL-4 receptor .Targeted drugs aiming for selective inhibition of IL-13 include lebrikizumab, tralokinumab, anrukinzumab, decrecumab, GSK679586, and ASLAN 004. Out of these agents, only lebrikizumab and tralokinumab have reached phase 3 clinical trials so far. Lebrikizumab, a humanized monoclonal antibody targeting IL-13, was previously shown to improve asthma symptoms particularly in patients with a high serum IgE level, high blood eosinophil counts, and an increased expression of interleukin-13–related genes in the lung . HoweverAmong selective IL-4 inhibitors, pascolizumab, AMG-317 and VAK694, were those to reach phase 2 of clinical development. Pascolizumab and VAK694 are monoclonal antibodies neutralizing IL-4 while AMG 317 is an IL-4 receptor antagonist . AlthougTargeting IL-5 has become a well-established therapy for patients with uncontrolled severe asthma caused predominantly by T2 inflammation with eosinophilia . MepolizNCT04719832).Similar to mepolizumab, reslizumab targets IL-5 and blocks the subsequent recruitment and activation of eosinophils. In clinical trials, reslizumab was associated with reduction in exacerbations, improvements in lung function, and quality of life ,224. TheBronchial epithelium derived cytokines, also called alarmins, include thymic stromal lymphopoietin (TSLP), IL-33, and IL-25, regulate the differentiation of ILC2 and Th2 lymphocytes  and reprNCT04410523). An alternative approach to block TSLP is targeting its receptor. A fully human monoclonal antibody against TSLP receptor (TLPR), ASP7266, is currently being evaluated in pre-clinical studies and in a monkey experimental model completely inhibited induced allergic skin reactions [Another anti-TSLP drug, CSJ117, a neutralizing antibody fragment, is currently being tested in an inhaled formulation in patients with severe uncontrolled asthma (eactions .NCT05166889). Similarly for IL-25, no data regarding blocking monoclonal antibody, ABM125, have been published, yet. No significant improvement in asthma exacerbations or in lung function were observed with humanized anti-IL-9 monoclonal antibody enokizumab [IL-33 is a member of IL-1 cytokine family potentiating both Th1 and Th2 responses . IL-33 dokizumab .Although initial studies with fevipiprant, an oral antagonist of chemoattractant receptor-homologous molecule on T-helper type-2 cells (CRTH2) serving as a receptor of prostaglandin D2, showed promising efficacy in patients with allergic asthma , the phaInhibition of CCR3 receptor for eotaxin, a chemokine attracting eosinophils, by specific inhibitor GW766994 failed to reduce blood or sputum eosinophilia and to improve lung function in patients with asthma .Nemolizumab, a humanized monoclonal antibody against IL-31 receptor markedly reduced pruritus in patients with atopic dermatitis  and down1 monoclonal antibody targeting an anti–sialic acid–binding immunoglobulin-like lectin 8 (Siglec-8) expressed by eosinophils and mast cells has been tested in a Phase 2 study in antihistamine-refractory patients with chronic urticaria leading to improved disease control [NCT04322708) and duodenitis (NCT04856891).Lirentelimab (AK002), a humanized, nonfucosylated IgG control . There aCompared to T2-biologic therapies, with anti-IgE and anti-IL-5 therapies globally used to treat severe allergic and eosinophilic asthma (+/- CRS), respectively, and with IL-4/13R inhibition being highly effective in atopic dermatitis, CRSwNP +/- severe asthma, targeting non-T2 mechanisms with monoclonal antibodies or inhibitors has been much less explored as well as less successful, so far.Different approaches have been tested to either down-regulate recruitment of neutrophils to the airways, or inhibit cytokines associated with Th1/Th17 inflammation. CXCR1 and CXCR2 receptors for chemokines attracting preferentially neutrophils, particularly CXCL8/IL-8, CXCL3/Groα or CXCL5/ENA-78, seemed to be natural targets to reduce recruitment of these cells. Treatment with AZD5069, a CXCR2 antagonist, failed to reduce exacerbation rates in patients with uncontrolled persistent asthma  despite NCT01478360) was terminated requiring changes in study design and human anti-IL-17RA antibody brodalumab failed to show clinical efficacy in severe asthma [A study with humanized anti-IL-17 monoclonal antibody, secukinumab, in asthmatics  was recently stopped by COVID-19 pandemic . Regarding other options for IL-1 blocking, a clinical study with bermekimab, an anti-IL-1α monoclonal antibody in patients with atopic dermatitis (NCT04990440) has been terminated due to low efficacy.IL-1 is another important pro-inflammatory cytokine with a potential role in bronchial asthma . AnakinrPro-inflammatory effects of IL-6 may be inhibited by a humanized monoclonal antibody against IL-6 receptor, tocilizumab, which failed to show protection against allergen-induced bronchoconstriction in asthmatic subjects .More recently, blocking of IL-22 by the human monoclonal antibody fezakinumab affected transcription of multiple genes associated with severe neutrophilic asthma and atopic dermatitis . In a raNCT04728711). Furthermore, MTPS9579A, a monoclonal antibody inhibiting tryptase activity by its dissociation from active tetramers into inactive monomers showed a favourable safety profile [Among new drugs targeting inflammatory mediators, a clinical study with the inhibitor of reactive aldehyde species, ADX-629, is currently recruiting patients with mild asthma  which regulates their proliferation and migration, with induction of multiple asthma-associated proteins and driving of the airway hyperreactivity in a murine model of asthma .Selective inhibitor of NLRP3, OLT1177® (dapansutrile), down-regulated T2 and pro-inflammatory cytokines, caspase-1 activity, reduced lung inflammatory cells and airway hyperreactivity in a model of ovalbumin-induced asthma .Poly (ADP-ribose) polymerase (PARP) is involved in the regulation of multiple genes involved in the pathogenesis of bronchial asthma including lung expression of VCAM-1  and in aAnother approach to targeting immune cell communication is to either block or engage with their membrane molecules. CD200R engagement with CD200-Fc reduced activation, proliferation and production of type 2 cytokines in isolated lung ILC2s and downregulated airway hyperreactivity in a humanized mouse model .Dual inhibition of OX40L and CD30L reduced eosinophilic inflammation and inhibited effector memory Th2 lymphocytes expansion in house dust mite challenged mice .In addition to the already mentioned receptor for PGD2, CRTH2, there are multiple other eicosanoid receptors studied as potential targets of asthma therapy as reviewed recently ,279.Inhibition of purinergic receptors regulating the release of alarmins HMGB and IL-33 can attenuate experimental asthma onset and reduce the severity of a rhinovirus-induced asthma exacerbation .Intranasal administration of standardized bacterial lysate OM-85 protected against experimental allergic asthma by multiple mechanisms including effects on airway epithelial cells, regulation of IL-33 and type 2 responses, and by DC tolerogenic reprogramming .In experimental models, inhibitors of phosphoinositide-3-kinase (PI3K) and specifically PI3K-Δ were found to decrease total IgE, and T2 cytokines IL-4, IL-5, and IL-13 together with down-regulation of proinflammatory cytokines TNF-α and IL-1β while having no effect on IL-6 . A dual To target anaphylaxis, the fast acting IgE inhibitors based on designed ankyrin repeat protein (DARPin) scaffolds were engineered to neutralize free IgE, dissociate preformed IgE/FcεRI complexes and actively remove prebound IgE from FcεRI on blood basophils .In the future, using of microRNAs (miRNAs) inhibiting translation and upregulating mRNA degradation may be an alternative approach to target specific cells or cytokines involved in allergic inflammation . IntraceAsthma affects over 350 million people globally, and a substantial proportion of this population has concomitant CRS. While many patients can reach a satisfactory disease control with standard therapies , many others remain uncontrolled with an increased risk for severe exacerbations and accelerated lung function decline  or requiAn expanding number of biologics targeting T2 asthma (+/- comorbid CRSwNP) has already entered clinical practice showing clinical effectiveness in distinct (partly overlapping) inflammatory phenotypes/endotypes: anti-IgE , anti-IL5 /anti-IL5R , anti-IL4Rα , and only recently anti-alarmin TSLP (tezepelumab) . HoweverApart from offering targeted treatment options and preventing toxic effects associated with corticosteroid-overuse, these new molecules further helped to unravel underlying mechanisms and to define disease subsets. Based on their respective mechanisms of action, some biologics may achieve disease remission  and evenSo far, no biologic therapies have shown consistent clinical benefits in non-T2 asthma, although the lack of a (sputum) inflammatory signature may present a significant bias in patients well-controlled by ICS with or without targeted treatments . Hence,


The role of type 2 inflammation has been progressively associated with many diseases, including severe asthma, atopic dermatitis, nasal polyposis, eosinophilic granulomatosis with polyangiitis, and, recently, eosinophilic esophagitis. Despite this, the association between asthma and esophagitis is still poorly known, and this is probably because of the low prevalence of each disease and the even lower association between them. Nonetheless, observations in clinical trials and, subsequently, in real life, have allowed researchers to observe how drugs acting on type 2 inflammation, initially developed and marketed for severe asthma, could be effective also in treating eosinophilic esophagitis. For this reason, clinical trials specifically designed for the use of drugs targeted to type 2 inflammation were also developed for eosinophilic esophagitis. The results of clinical trials are presently promising and envisage the use of biologicals that are also likely to be employed in the field of gastroenterology in the near future. This review focuses on the use of biologicals for type 2 inflammation in cases of combined severe asthma and eosinophilic esophagitis. Type 2 (T2) inflammation was identified as a pathogenic phenomenon underlying various diseases, such as asthma, nasal polyposis, and atopic dermatitis. The eosinophilic inflammatory infiltrate, which is typical of T2 inflammation, has been demonstrated to be present in other diseases, including eosinophilic esophagitis (EoE). Asthma is a well-known disease, characterized by chronic airway inflammation and bronchial hyperresponsiveness, resulting in airflow limitation and respiratory symptoms. In the pathogenesis of asthma, interactions between genetic predisposition, environmental factors, and immune dysregulation play a role in the genesis of disease. The hallmark of asthma is chronic airway inflammation, primarily driven by type 2 (T2) immune responses. This immune activation results in the recruitment of eosinophils, mast cells, IgE, and other inflammatory cells to the airways, leading to structural changes and remodeling, increased mucus production, and bronchospasm. Several cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-25, and IL-33, thymic stromal lymphopoietin (TSLP), and cells such as innate lymphoid cells type 2 (ILC2s), play crucial roles in orchestrating the inflammatory response in asthma. Among the cells responsible for inflammation that are regulated by the inflammatory pathway related to the cytokines earlier mentioned, are eosinophils. These cells are increased in both the blood and airway tissues of asthma patients and have become direct or indirect targets of many drugs developed to be controllers of asthma. With the development of knowledge regarding the pathophysiological mechanisms of T2-defined inflammation, it has been possible to associate some diseases with asthma, not only epidemiologically, but also using the inflammation pathway. These certainly include chronic rhinosinusitis with nasal polyposis (CRSwNP) and atopic dermatitis, which have a rather high incidence of coexistence with asthma. In contrast, diseases that are less frequently associated with asthma include eosinophilic esophagitis (EoE), despite it being proven that the presence of type 2 inflammatory diseases significantly increases the risk of EoE [EoE is an emerging chronic immune-mediated disorder that primarily affects the esophagus, leading to esophageal dysfunction and associated symptoms. EoE is characterized by eosinophilic infiltration and inflammation of the esophagus. Patients with EoE often present with symptoms such as dysphagia, food impaction, chest pain, and heartburn, mimicking gastroesophageal reflux disease (GERD). However, unlike GERD, EoE usually does not respond to acid-suppressive therapy. As previously described in asthma, the pathogenesis of EoE also involves a combination of genetic predisposition, environmental triggers, and dysregulated immune responses. Similar to asthma, the T2 immune response is also a key driver of the inflammatory process in EoE. Eosinophils and other inflammatory cells infiltrate the esophageal tissue, leading to mucosal damage, fibrosis, and impaired esophageal motility. Cytokines such as IL-4, IL-5, and IL-13, as well as eotaxins—chemokines involved in eosinophil recruitment—contribute to the pathogenesis of EoE. Although both conditions involve inflammation and share some similarities, they affect different anatomical sites and exhibit distinct clinical manifestations.asthma of the esophagus” due to the similarities between diseases to emphasize the similarities of two diseases too often regarded as two entities that are distinctly separate from each other [Despite the evident common inflammatory pathway, there are not many studies linking these two diseases. About 10 years ago, Virchow defined EoE as “ch other . Understanding the shared and distinct mechanisms of inflammation in asthma and EoE is essential for developing targeted therapies. Current treatments for both conditions focus on controlling symptoms and reducing inflammation. In asthma, inhaled corticosteroids, long-acting beta-agonists, leukotriene modifiers, and monoclonal antibodies targeting specific cytokines have revolutionized management. Similarly, in EoE, dietary management, proton pump inhibitors, and topical corticosteroids are the mainstay of current treatments. However, there is still an unmet need for more effective and personalized therapies that can address the underlying inflammatory processes and provide long-term remission.The development of biological drugs  and several sub-analyses of clinical trials have made it possible to evaluate the effect of biologicals initially developed for asthma on eosinophilic esophagitis. The results obtained so far are encouraging and contribute to the knowledge of this type of inflammation; moreover, they provide useful suggestions when both diseases are present to orient a clinician’s therapeutic choices. The research of both pathologies is crucial, both to know the real prevalence of asthma in EoE patients and vice versa and to confirm that the same drug can affect both pathologies, allowing the clinician to choose one molecule, rather than another, in the case of comorbid patients.This manuscript provides an overview of the inflammatory mechanisms underlying asthma and eosinophilic esophagitis, highlighting their etiology, pathogenesis, and potential therapeutic strategies.The type 2 immune response encompasses both the innate and adaptive arms of the immune system and represents the common inflammatory pathway within a broad range of inflammatory and infectious diseases . HistoriThe identification of the phenotype first , and theIn cases of severe asthma, the use of several biological drugs has achieved a significant reduction in exacerbations, the need for systemic corticosteroid use, and, in some cases, an improvement in respiratory function ,52,53. TSubsequently, other biological drugs targeting IL-5 were developed, namely, mepolizumab and reslizumab. Regarding the former, data from clinical and real-life trials showed its efficacy in reducing disease exacerbations in patients with an eosinophil count above 150 cells/mcl, allowing, in addition, a significant reduction in daily dosing and, in most cases, the discontinuation of systemic steroid therapy ,56. OtheReal-life data has also suggested that mepolizumab is equally effective in patients with and without certain comorbidities such as nasal polyposis ,63,64,65Again, observations in real life have shown the efficacy of the drug in other diseases such as eosinophilic esophagitis ,68,69. MAs with mepolizumab, although there is no primary indication for this condition, in real life, it has been shown to be effective on nasal polyposis, and this comorbidity has again been associated with improved therapeutic response in patients treated for asthma ,79,80,81Similarly, against IL-5, reslizumab was able to reduce asthma exacerbations and OCS intake in treated patients; unlike other drugs, it was administered intravenously, which is a method that is yet to be approved in several countries ,34,35,82Dupilumab, another drug directed on T2 inflammation mechanisms, was precisely directed to the IL-4 receptor, which is a molecule that can interact both with IL-4 and IL-13 . The administration of dupilumab has been demonstrated to be able to reduce exacerbations and systemic corticosteroid use, and, regarding nasal polyposis, it showed efficacy in reducing the polyp volume ,84,85,86Lastly, tezepelumab, an anti-TSLP antibody, is the first drug to interfere with the alarmin chain. One of the most interesting aspects of the molecule is precisely its action on a chain of inflammation beyond that of specifically type 2 cytokines , acting on what is produced as a result of epithelial damage.Current available data demonstrate a significant efficacy in patients with T2 inflammation, as well as partial efficacy in those with T2-low characteristics ,90,91,92The results about hyperactivity include differentiators from other drugs available for asthma at this time; in fact, omalizumab was able to reduce AHR only in several studies using methacholine, acetylcholine, or adenosine monophosphate; mepolizumab did not achieve this result as no results were obtained with benralizumab, lebrikizumab, tocilizumab, efalizumab, and tralokinumab. The only other drug, which is currently not marketed for asthma, that achieved the result of reducing AHR was etanercept in one study. In the end, the only two drugs that are currently available for asthma and able to reduce AHR are tezepelumab and omalizumab . Regarding efficacy on OCS-dependent patients, however, in clinical trials, tezepelumab did not meet the endpoint of the reduction in exacerbations in this category of patients. Sub-analyses of the dedicated study, however, showed that the administration of the biologic drug was able reduce exacerbations and OCS use in dependent patients, with results being proportionally related to the eosinophilic count at baseline. A new clinical trial with this aim is ongoing . The lonCurrently, a new anti IL-5 biological, depemokimab, is under investigation. Its distinguishing characteristic is its long-life capability, which allows for administration every 6 months . Two molecules targeting IL-13 have been under study for several years, with controversial results. Certainly, the addition of the effect on IL-4r and not only IL-13 demonstrates a more effective result. Lebrikizumab (anti IL-13) was demonstrated to be effective on adolescents (12–17 years) in reducing the exacerbation rate after 52 weeks, despite the fact that the study was prematurely terminated (sponsor’s decision), potentially limiting our interpretation of the results . LebrikiOther therapeutic targets under study, at this time, are being directed toward mediators of type 2 inflammation, as well as TSLP, with CSJ117 , and IL-Eosinophilic esophagitis (EoE) is an emerging disease that is defined by symptoms of esophageal dysfunction and abnormal eosinophilic inflammation within the esophagus. The diagnosis is histological and depends on the number of eosinophils detected  ,104,105.The mechanism of inflammation is Th2-mediated, and aeroallergens/food antigens are the most important triggers. The migration to the esophageal wall and the activation of eosinophils and mast cells promote the release of proinflammatory cytokines, such as interleukin (IL)-4, IL-5, IL-13, and transforming growth factor (TGF) β, causing epithelial barrier disruption, smooth muscle impairment, and tissue remodeling ,108,109.Nowadays, several new targeted therapies that can arrest the inflammation cascade are being investigated for EoE. Some drugs are imported from bronchial asthma and atopic dermatitis since these diseases have the same mechanism of inflammation  Table 2Table 2.Dupilumab, a monoclonal antibody that inhibits the action of IL-4 and IL-13 by blocking the shared IL-4 receptor α subunit has been approved by the FDA for moderate–severe atopic dermatitis, asthma, and rhinosinusitis with nasal polyposis treatment. It suppresses most Th2 inflammatory biomarkers, representing an optimal target drug for Th2-mediated diseases; moreover, for this reason, it was also studied in the context of EoE . In May Another monoclonal antibody that acts on IL-13 is cendakimab (previously RPC4046). It inhibits binding at the IL-513 receptor and is administered weekly via subcutaneous injections. It demonstrated a histological and endoscopic improvement in a 16-week phase 2 study in adults with active EoE but not a clinical remission, although an improving trend was shown . An endoIL-5, which is produced by T helper 2 cells, is involved in the differentiation, maturation, and migration process from the bone marrow of eosinophils favoring their adhesion to the esophageal wall. Eosinophils are directly involved in tissue remodeling as shown in an experimental model . TherefoLymphocyte-trafficking modulation is currently being explored as a possible target for therapy in refractory eosinophilic gastro-intestinal disorders including EoE. Vedolizumab, a monoclonal integrin α4β7 antibody, mainly blocks CD4+T lymphocytes from binding to MAd CAM1 on intestinal endothelial cells, ensuring gut-selective, anti-inflammatory activity; for this reason, it has been approved to treat inflammatory bowel disease. In addition, it also blocks αE/β7 integrin, which has been found in Th2 lymphocyte cells in EoE patients, and this effect could lead to hypotheses regarding its role in the context of EoE patients ,120. VedLirentelimab (or antolimab) is a monoclonal antibody to sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8), a CD33 receptor located on the surface of eosinophils and mast cells. It induces eosinophilic apoptosis and inhibits mast cell activation. In a small clinical trial, histologic remission (≤6 eos/hpf) was achieved, but there was no statistical significance for the patient-reported symptomatic coprimary endpoints; however, the results of these trials have not yet been published . The ENIGMA trial, a randomized, phase 2, placebo-controlled study aiming to assess the efficacy of the anti Siglec-8 antibody (AK002) in adult patients with eosinophilic gastritis and gastroenteritis, has recently demonstrated histologic remission in patients with concomitant EoE . For thiTezepelumab, a TSLP antagonist used for asthma and atopic dermatitis, has a mechanism of action that targets the top of the inflammatory cascade, and a recent clinical trial has started to evaluate its role in improving outcomes for EoE patients ,129. Moreover, chronic inflammation leads to progressive esophageal remodeling, and TGF-β plays a relevant role in this process. Losartan, an antigotensin-1 receptor antagonist approved to treat high blood pressure, has been proposed due to its ability to reduce the signaling of TGF-β as a therapy in EoE patients. An ongoing phase 2 trial with increasing doses of losartan is ongoing .Finally, the JAK–STAT pathway has been identified as a potential target in the treatment of EoE. There are no studies on the JAK inhibitor tofacitinib in EoE patients, but it has been reported that it was able to reduce esophageal eosinophilic infiltration in a patient with EoE . The long-term efficacy of these drugs will be determined by further studies, but they seem to be promising in modifying the course of the disease.Although the effect of biologicals both in asthma and eosinophilic esophagitis was demonstrated, some points remain unclear and require further investigation . In the In conclusion, the effect of eosinophils and T2 inflammation has been proven to be present both in asthma and eosinophilic esophagitis. In the field of asthma, the role of monoclonal antibodies is pivotal in the treatment of the severe form of this disease, which is currently not responding adequately to traditional therapy, to reduce OCS use; the real-life analysis and sub-analysis of randomized trials of patients treated for asthma and their pathology have demonstrated the effect of antibodies also in esophagitis. The development of trials dedicated to esophagitis provides interesting results and different targets which are also directed to T2 cytokines and mediators. Further studies will be needed to evaluate the relationship between asthma and eosinophilic esophagitis, with a search for common inflammatory pathways and interactions between the diseases, as has already been evaluated in rhinosinusitis with nasal polyposis, to better understand the role of type 2 inflammation and the possible causes of the imbalance of inflammatory mechanisms.The evidence of a common inflammatory pathway in these two diseases dictates increased attention to the management of these patients. As the search for polyposis comorbidity has become more routinary over time in asthmatic patients, any pathology related to a similar mechanism, but located in a different district than the airway, must be considered. This review aimed to focus on raising awareness of one of the diseases related to T2 inflammation, that is generally seldom considered as a possible comorbidity of asthma, aiming to inform gastroenterologists and pulmonary-allergologists of the importance of the search for these two diseases.